A review looked at the evidence for a imprroved diet in preventing atherosclerosis-related coronary artery disease. Beer, liquor, and wine have different effects on your cholesterol levels. Pizzorno J.

Detoxification for improved cardiovascular health -

When the mitochondrial membrane is enriched in cholesterol, it decreases the activity of the GSH transporter system [ 57 ]. Previous studies in myocardial ischemia have revealed that ischemia leads to a progressive loss of cholesterol from tissues and the sarcoplasmic and sarcoplasmic reticulum, accompanied by a significant increase in mitochondrial cholesterol content that is admixed explicitly to this membrane system [ 63 ].

We thus hypothesize that myocardial mitochondrial membrane cholesterol enrichment due to ischemia may be one of the mechanisms of mGSH depletion in ischemic myocardium. The glutathione peroxidase family comprises multiple isozymes GPX existing in distinct subcellular locations and tissues.

Among them, GPX and 6 are selenocysteine-containing proteins. Their active center is a conserved tetramer composed of selenocysteine residues Sec , glutamine Gln , tryptophan and asparagine. The active site of the other three GPXs is cysteine [ 64 ].

The presence of Sec as a catalytic group is thought to ensure a rapid reaction with hydrogen peroxide and a fast reduction of GSH [ 65 ]. Therefore, the most important function of GPX is to prevent oxidative stress by catalyzing the reduction of H 2 O 2 or organic hydroperoxides.

In addition, they can also inhibit inflammation and oxidant-induced programmed cell death e. GPX1 and GPX4 are the predominant antioxidant enzymes in the GPX family due to their widespread distribution.

They are highly expressed in the cytoplasmic and mitochondrial compartments of cardiomyocytes and represent an important defense mechanism within the heart [ 4 , 7 ]. GPX2 and GPX3 exert antioxidant effects in intestinal epithelial cells and plasma, respectively [ 65 ]. Compared with GPX, GPX4 is also involved in the reduction of complex membrane-associated phospholipid hydroperoxides such as phosphatidylcholine hydroperoxide and cholesterol hydroperoxide, in addition to reacting with soluble, low molecular weight hydroperoxides such as t-butyl hydroperoxide and cumene hydroperoxide [ 68 ].

Since GPX4 has these characteristics, it plays a crucial role in inhibiting ferroptosis, which has received widespread attention. GPX without further ado due to the lack of antioxidant capacity.

Ferroptosis is a novel form of programmed cell death characterized by the accumulation of iron-catalyzed lipid peroxidation. It has its own unique morphological, biochemical, and genetic features.

Morphological characteristics include reducing or disappearing mitochondrial cristae, small mitochondria with condensed mitochondrial membrane densities, and outer mitochondrial membrane rupture. Biochemically, once ferroptosis is activated, it cannot be suppressed by apoptosis, necrosis, or autophagy inhibitors but can be hidden by iron chelators such as deferoxamine DFO or antioxidants such as Trolox and fer Moreover, the genetic aspects of the genetic network controlling ferroptosis differ from those controlling apoptosis [ 19 ].

As a new form of cell death, it provides new research directions for the treatment and thinking of many diseases. Ferroptosis is a complex process regulated by various mechanisms. Its onset and execution involve three key events: iron accumulation, GSH depletion, and lipid membrane oxidation.

The mechanisms associated with these events and their role in cardiovascular disease are outlined below. Regulation of intracellular iron homeostasis is influenced by iron uptake, utilization, storage, and export.

A portion of the iron in the cytoplasm is transported to the mitochondria for the synthesis of heme and iron-sulfur clusters ISCs [ 72 ]. Part is stored in ferritin, which consists of ferritin heavy chain FTH and ferritin light chain FTL [ 72 ]. FPN is regulated by hepcidin, a hepatic-secreted peptide hormone, which promotes the internalization and degradation of FPN [ 74 ].

Accumulated cellular iron generates cytotoxic hydroxyl radicals OH· via the Fenton reaction. It can attack polyunsaturated fatty acids PUFAs and produce lipid peroxides lipid-OOHs and their reactive degradation products [ 72 , 75 ].

Cardiac-specific elision of Fth1 encoding ferritin heavy chain causes iron dysregulation and increased oxidative stress in the heart, leading to increased sensitivity to ferroptosis induced by iron overload [ 76 ]. Tang et al. TfR1 has been recognized as a specific target antigen associated with ferroptosis [ 78 ].

Lipidomic studies have shown that phosphatidylethanolamines PEs with arachidonic acid AA or its derivative adrenergic acid AdA are the key phospholipids for oxidation, and their peroxidation is considered a significant driver of ferroptosis [ 19 , 21 ].

Two key enzymes are implicated in PUFA-PE synthesis, including acyl-CoA synthetase long-chain family member 4 ACSL4 and lysophosphatidylcholine acyltransferase 3 LPCAT3 [ 75 ]. ACSL4 acylates AA, and subsequently, LPCAT3 catalyzes the acylated AA to membrane PL, which raises the oxidation of membrane-sensitive fatty acids such as PUFA, ultimately leading to lipid peroxidation [ 73 ].

In addition to iron-catalyzed free radical chain reactions, lipoxygenase LOXs can directly oxidize PUFAs and lipid-containing PUFAs in cell membranes, which are considered to have an essential role in ferroptosis [ 75 , 80 ].

One study reported that the scaffold protein phosphatidylethanolamine binding protein 1 PEBP1 binds to lipoxygenase 15LOX and directs it to PUFAs in the membrane, thereby facilitating ferroptosis [ 81 ]. The presence of the antioxidant system can prevent the infinite expansion of lipid peroxidation, which is a core step in impeding ferroptosis.

As mentioned above, the GSH system has a vital role in the elimination of toxic lipid peroxides [ 32 ]; thus, it is essential for the inhibition of ferroptosis.

Fang et al. selectively overexpressed SLC7A11 in the myocardium and found that it can increase cellular GSH levels and prevent FTH deficiency-mediated iron death [ 76 ]. Moreover, it has been previously shown that GPX4 overexpression in cancer cells inhibits RSL3-mediated ferroptosis, whereas GPX4 deletion increases susceptibility to ferroptosis [ 22 ].

These findings provide evidence for the importance of the GSH system in anti-ferroptosis. Ferroptosis suppressor protein 1 FSP1 was identified almost simultaneously by Bersuker et al.

and Doll et al. as an anti-ferroptotic factor that parallels the GSH system [ 82 , 83 ]. It can reduce ubiquinone CoQ10 to ubiquinol reduced form of CoQ10 in lipid membranes utilizing NADPH.

The latter is a lipophilic radical scavenger that acts as an inhibitor of ferroptosis [ 82 ]. However, FSP1 must be myristoylated and recruited to lipid membranes to execute its reductase function [ 83 ]. In conclusion, FSP1, CoQ10, and NADPH comprise an anti-ferroptosis system parallel to GSH.

In adriamycin-treated mouse hearts, elevated lipid peroxidation products promote FSP1 translocation [ 84 ]. Nevertheless, FSP1 has been less studied in the heart, where its relationship with ferroptosis and its precise function are poorly understood.

Glutamine is the most abundant and versatile amino acid in the body and provides a substrate for many biosynthetic processes [ 29 ]. Among them, the glutamate produced by the decomposition of glutamine via GLS not only provides the raw material for the synthesis of GSH but is also further metabolized into α-ketoglutarate α-KG in the mitochondria under the action of glutamate dehydrogenase GLUD1 or transaminases and then enters the tricarboxylic acid cycle to produce ATP [ 29 ].

It has been reported that glutamine and glutaminolysis are required for cysteine starvation and erastin-mediated ferroptosis [ 85 , 86 ]. Knockdown of GLS2 but not GLS1 can inhibit cysteine starvation-mediated ferroptosis of MEFs [ 86 ]. However, it is unclear exactly which isoform acts in cardiomyocytes and how it exerts its anti-ferroptosis effect, which requires further study.

Moreover, Gao et al. and Daiha Shin et al. found that exogenous α-KG mimics glutaminase-mediated ferroptosis, while using a transaminase inhibitor, amino-oxyacetate AOA , reverses ferroptosis [ 85 , 86 ].

This suggests that α-KG plays an essential role in glutaminolysis-mediated ferroptosis. Finally, knockdown of Gln transporters SLC38A1 and SLC1A5 or pharmacological inhibition of SLC1A5 also significantly blocked cysteine starvation-mediated ferroptosis [ 85 , 86 ].

The GSH system, as a lipid peroxide scavenger, has attracted much attention as a potential therapeutic target for ferroptosis. In the next section, we will discuss the relationship and importance between the GSH system and ferroptosis in myocardial injury.

Park et al. revealed that myocardial ferroptosis occurs during MI [ 87 ]. Subsequently, they used Western blot analysis and RNA sequencing RNA-seq to demonstrate that the expression of GPX4 was declining in the early MI 1 day and middle MI 1 week stages of MI.

Inhibition or depletion of GPX4 utilizing the chemical inhibitor RSL3 or specific siRNA resulted in lipid peroxide accumulation, leading to ferroptosis in H9C2 cells [ 87 ].

These results suggest that the downregulation of GPX4 contributes to MI-induced ferroptosis. However, Tang et al. The inconsistency of the above results may be because the duration of myocardial ischemia in the latter was too short to induce ferroptosis.

Currently, the primary treatment for myocardial infarction is opening blocked vessels to restore blood flow to the ischemic myocardium, which is called reperfusion. They found that iron, ACSL4, and MDA levels increased with increasing reperfusion time, with concomitant decreases in GPX4 levels, and deferoxamine treatment significantly ameliorated myocardial injury [ 88 ].

In , Lu et al. A study by Fang et al. showed that the DOX-processing myocardium exhibited features of typical ferroptosis in mice.

Ferroptosis inhibitors could significantly reduce DOX-induced cardiac injury and mortality. However, inhibitors of autophagy, necroptosis and apoptosis only partially improved survival substantially, suggesting that ferroptosis is essential for DOX-induced cardiomyopathy and mortality in mice [ 91 ].

Additionally, recent studies have found that the expression of GPX4 and GSH was disordered in rats administered DOX [ 92 ]. Fisetin, a natural flavonoid, attenuated DOX-mediated ferroptosis in vivo and in vitro by raising the contents of GSH and GPX4 and inhibiting the accumulation of MDA and iron in the heart of rats [ 92 ].

In a model of LPS-mediated septic cardiomyopathy, some researchers revealed that LPS caused ferroptosis and septic cardiac injury by downregulating GPX4 protein levels and increasing COX-2 [ 93 ]. Knocking down ICA69 reversed GPX4 inhibition, attenuated intracellular ferroptosis production and improved mouse survival and cardiac function [ 93 ].

Furthermore, in appendiceal ligation and puncture-mediated sepsis, investigators found a decrease in GSH content and GPX4 expression and an accumulation of cardiac iron content and lipid peroxidation levels [ 94 ]. All of the above results suggest a possible involvement of ferroptosis in the development of sepsis-induced cardiac injury.

Evidence has shown that ferroptosis is crucial for DCM pathogenesis [ 48 ]. Wang et al. Another study reported that the inhibition of lncRNA ZFAS1 upregulated cardiac GPX4 and terminated the ferroptosis process and oxidative insult in DCM mice [ 95 ].

Zheng et al. used angiotensin Ang II injection to simulate a hypertension-mediated cardiac remodeling model and found that ferroptosis occurred and that the protein expression of GPX4 and xCT was downregulated in the myocardium.

Elabela treatment reduced ferroptosis and improved myocardial hypertrophy and remodeling in hypertensive mice by normalizing the levels of xCT and GPX4 [ 96 ]. In addition, knockdown of xCT exacerbates Ang II-induced cardiac hypertrophy, fibrosis, and dysfunction in mice. These impairments can be relieved by hindering ferroptosis [ 97 ].

In summary, there is already substantial evidence that ferroptosis plays a vital role in myocardial injury caused by MIR and various types of cardiomyopathy. It has been proven feasible to treat heart disease by targeting ferroptosis modulators.

GPX4 and GSH, as inhibitors of lipid peroxidation, are key regulators that control ferroptosis. In the myocardium affected by various pathological factors, the inhibition of GSH and GPX4 is ubiquitous.

Therefore, activating GPX4 and GSH to inhibit ferroptosis is an attractive option for cardiac disease therapy Fig. Identifying strategies that fortify the GSH system in the heart may contribute to developing therapies against cardiac diseases induced by various pathological factors.

This section summarizes potential approaches to increasing the GSH system in the heart. The direct administration of GSH in vivo is probably an obvious way to increase GSH It has been demonstrated that modified oral glutathione-like liposomal GSH increases erythrocyte and plasma GSH levels and reduces oxidative stress biomarkers [ 98 ].

Moreover, other routes of administration, such as intravenous, intranasal, and sublingual administration, can increase GSH levels [ 99 ]. However, the direct administration of GSH is rare in myocardial injury treatment studies.

In addition, supplementing the raw materials cysteine, glycine, glutamate, and selenium for synthesizing GSH or GPX to achieve an elevated GSH system in the myocardium is another feasible strategy. Next, we review the evidence supporting that increased raw material availability causes high GSH and GPX levels in the myocardium Table 1 , Supplementary Table S1.

N-acetylcysteine NAC is a precursor of the amino acid cysteine. NAC deacetylates under the action of N-deacetylase to enhance intracellular Cys, thereby increasing the endogenous synthesis of GSH.

In , Rafeek HidhayathBasha et al. conducted a study on the protective effect of NAC on isoproterenol ISO -induced MI in rats [ ].

The results demonstrated that pretreatment with NAC not only significantly increased the activities of GSH and GPX but also reduced the levels of lipid peroxidation in the heart mitochondria of ISO-treated rats [ ].

Interestingly, NAC exerts a GSH-supplementing effect in GSH-deficient cells, whereas this effect may be ineffective in GSH-enriched cells [ ]. In humans, clinical studies have evaluated the effects of NAC treatment on myocardial infarction.

M A Arstall et al. The results indicated that patients treated with NAC had a 5. Therefore, NAC can be used to boost cardiac GSH levels and attenuate myocardial injury. Apart from NAC, whey protein and methionine are also precursors of Cys.

Whey protein and its concentrates are abundant in sulfur-containing amino acids such as Cys and methionine, so it can supplement cysteine and efficiently improve GSH levels [ 99 , ]. Researchers do not recommend methionine because it causes an increase in homocysteine levels [ 99 ].

Elevated homocysteine is associated with various diseases, such as heart and brain diseases. Severe hyperhomocysteinemia in patients is able to develop neurological and cardiovascular disorders as well as premature death owing to complications [ ].

A study revealed that L-methionine supplementation 1. O for 8 weeks was sufficient to produce hyperhomocysteinemia in rats and markedly increased the mean arterial pressure, oxidative stress and mean cardiomyocyte diameter [ ].

Glycine Gly is another essential amino acid in the synthesis of GSH. Although most studies have focused on increasing cysteine levels in vivo to boost GSH synthesis, glycine supplementation alone or in combination with NAC to increase GSH synthesis has also attracted extensive attention.

In a burn rat model, intraperitoneal injection of glycine supplementation alleviated severe burn-induced cardiac injury by improving cardiomyocyte energy metabolism and increasing ATP and GSH contents [ ]. Premranjan Kumar et al.

They also clarified in another clinical study that supplements with glycine 1. Gln acts as a precursor of glutamate Glu , equivalent to being an indirect glutathione precursor. Its supplementation can enhance intracellular GSH levels and provide protection against myocardial injury.

In ISO-induced myocardial infarction, pretreatment with Gln maintained cardiac GSH kurtosis and antioxidant enzyme GPX, SOD, CAT activity at near-normal levels, thus preventing oxidative damage in the myocardium [ ].

A separate experiment elucidated that Gln supplementation increased cardiac GSH to halt myocardial injury induced by cyclophosphamide CPA in rats [ ]. Notably, there is a significant correlation between plasma Gln concentrations and GSH levels.

A double-blind, randomized, placebo-controlled trial demonstrated that perioperative high-dose intravenous injection of Gln 0. O for 3 days raised plasma Gln concentrations and maintained plasma GSH levels in postoperative patients undergoing cardiopulmonary bypass CPB [ ].

Selenium Se is an essential trace element for humans and animals, serving as the main component of many antioxidant proteins in the body, such as thioredoxin reductase, selenoprotein P and GPX. As a result, selenium may play an important role in protecting cardiomyocytes from oxidative stress [ ].

Compared with a low-Se diet 0. Zhu et al. showed that Se boosted GPX1 expression by inhibiting DNMT2-mediated DNA methylation of the GPX1 promoter from lessening ROS production in advanced glycation end-product AGE -induced heart failure [ ]. In humans, a systematic review and meta-analysis revealed that physiologically high selenium levels in the body were negatively associated with cardiovascular disease morbidity and mortality.

In addition, there is a U-shaped association between selenium exposure and some diseases, such as type 2 diabetes and fractures [ ]. However, it has also been reported that selenium supplementation alone is not associated with cardiovascular disease and all-cause mortality [ ].

Other than providing raw materials for the GSH system, another antioxidant strategy that activates the glutathione system is often achieved through medicinal therapy. In this section, we will describe their effects and mechanisms in detail by the source of the drugs.

Natural medicines have been a reliable source of drugs since ancient times, playing an essential role in preventing and treating various diseases. At present, increasing evidence has shown that compounds derived from natural medicines exert a variety of beneficial effects, including antioxidant, anti-inflammatory, and anti-apoptosis effects [ , , ].

To date, more than natural medicine monomers have been reported to activate the GSH system by several mechanisms to protect the heart from oxidative stress. Next, we will summarize some promising medicine monomers that activate the GSH system based on the categories of natural medicines, including flavonoids, terpenoids, phenolic acids, quinones, and alkaloids Table 2 , Supplementary Table S2.

Flavonoids are a group of phytochemicals widely existing in nature. They have received extensive attention for their antioxidant, anti-inflammatory, anti-mutagenic and anti-cancer properties, as well as their ability to protect against cardiovascular disease [ ].

Quercetin Quer is one of the main flavonoids in many vegetables and fruits. It not only abrogates cardiac oxidant stress but also alleviates the inflammatory response and deterioration of heart function in MIR injury and DCM in rodents [ , ]. O for 8 weeks evidently improved serum total antioxidant capacity TAC in postmyocardial infarction patients compared to the placebo group [ ].

O for 2 mouths to standard therapy improved cardiac function both systolic and diastolic functions and reduced the total duration and number of ST-segment depressions in patients with coronary heart disease CHD [ ].

Thus, Quer, as an activator of the GSH system, is a promising natural small molecule for the treatment of cardiac injury.

Catechins, known as dihydroflavonols, are natural flavonoids present in green tea and other beverages, including catechin, epicatechin EC , and epigallocatechingallate EGCG [ , ]. It has been reported that these three compounds can enhance the contents of GSH and the activities of GSH-dependent antioxidant enzymes GPX and GST and reduce lipid peroxidation and cardiac damage mediated by DOX or isoproterenol ISO in the myocardium of rats, respectively [ , , ].

Genistein is the main ingredient of isoflavone from soybean and is also used as a tyrosine kinase inhibitor. It has potent effects of antioxidant, anti-inflammatory, anti-angiogenesis, and anti-cancer [ ].

Studies have shown that genistein can increase GSH levels and GPX activity along with decreased oxidative stress in diabetic cardiomyopathy and DOX-mediated cardiomyopathy [ , ]. Meanwhile, genistein increased the levels of Nrf2, which is vital to the GSH system [ , , ].

However, it is unclear why genistein upregulates the levels of Nrf2 in the myocardium. O for one year improved both cardiac function and left atrial remodeling in postmenopausal women with metabolic syndrome [ ]. O for 24 weeks significantly increased the protein and mRNA levels of Nrf2 and the concentrations of SOD as well as diminished serum levels of inflammatory factors and MAD in patients with myocardial ischemia [ ].

Therefore, genistein, an antioxidant, might be a potential drug for treating patients with myocardial injury. Terpenoids are natural compounds with a wide distribution, great variety, and diversified structure in nature [ ]. Terpenoids have been reported to activate the GSH antioxidant system to protect the heart from oxidative stress and alleviate cardiac injury.

Tetraterpenes, also called carotenoids, are widespread in higher plants, fungi, algae, and animals and are one of the most potent natural antioxidants [ ]. It could also alleviate the size of myocardial infarction and the subsequent decrease in cardiac function in rats [ ].

A clinical study of patients with myocardial infarction by B Panczenko-Kresowska et al. revealed that β-carotene supplementation remarkably diminished plasma lipid peroxide levels in patients [ ]. The mechanism might be related to its own antioxidant properties and GSH activating effect.

Nonetheless, the most updated literature reports that β-carotene supplementation or elevated blood β-carotene levels may increase all-cause mortality and CVD risk [ , ].

O for 2 months , was reported to significantly increase the ratio of serum TAC to MDA in patients with type 2 diabetes [ ]. In addition, tanshinone IIA Tan IIA is a diterpene extracted from the root and rhizome of Salvia miltiorrhiza Bunge.

Its water-soluble derivative, sodium Tan IIA sulfonate injection STS , is widely used in the clinic as an adjuvant drug for coronary heart disease, myocardial infarction and heart failure in China [ ].

Tan IIA induced activation of the GSH system to attenuate cardiac oxidative stress and restrain the increase in serum myocardial enzymes, thus relieving the extent of myocardial damage [ , ].

Moreover, a meta-analysis showed that the addition of STS seemed more effective in treating heart failure than Western medicine alone [ ]. The excellent clinical manifestations of Tan IIA provide supportive evidence for targeting the GSH system in the treatment of heart diseases, which may be promising for transforming natural compounds from basic research to clinical applications.

Phenolic acids are attracting increasing attention for their antioxidant properties and other health benefits. Based on differences in the carbon skeleton, phenolic acids can be mainly divided into two categories: hydroxycinnamic acid e. All of the compounds above have been proven to maintain GSH contents and GSH-dependent antioxidant enzyme activities in the myocardium, protecting it from oxidative stress [ 41 , , , , , , , ].

Ferulic acid FA , the main active component isolated from Angelica sinensis , has been documented to increase the levels of GSH and the expression of GPX in the myocardium by upregulating AMPKα2 and activating Nrf2 signaling [ 41 , ].

In recent years, ferulic acid derivatives have been widely investigated. Of them, sodium ferulate SF features low toxicity, stability, ease of synthesis, and water solubility and has been authorized by the State Drug Administration of China as an adjuvant drug for treating ischemic cardiovascular diseases [ , ].

It could also increase GPX activity, thereby exerting antioxidative effects in rats [ ]. Besides, caffeic acid and chlorogenic acid caffeoylquinic acids are two other classical phenolic acids widely found in natural plants, both of which are the most vital active substances in coffee [ ].

Some investigations have demonstrated that the two compounds, acting as agonists of the GSH antioxidant system, well prevent oxidative stress and reduce heart damage in some animal cardiomyopathy models, for instance, the ISO-induced myocardium infarction model [ , ].

Additionally, one clinical study reported that consumption of chlorogenic acid-enriched coffee not only improved plasma antioxidant capacity and decreased plasma lipid and protein oxidation but also donated to enhancing cardiovascular health in people with hypercholesterolemia [ ].

Interestingly, Yuki Sato and coworkers indicated that the antioxidant effect of caffeic acid is more potent than chlorogenic acid, and the latter is metabolized into caffeic acid in the intestine. Ellagic acid EA also increased the GSH antioxidant system and diminished oxidative stress in several models of myocardial injury, such as diabetes and cisplatin-mediated heart injuries [ , ].

O for 8 weeks significantly fortified the mean of TAC and the activity of GPX enzymes as well as reduced MDA contents in the serum of type 2 diabetic patients [ ]. Nonetheless, it is not certain whether EA may be helpful in boosting the GSH system in cardiac patients and treating heart diseases.

Thus, there is a need for larger studies to fully address this issue. In addition, EA was found to have poor low oral bioavailability, thus limiting its clinical applications.

In contrast, its intestinal microbial metabolite, urolithin, possesses better biological activity and higher bioavailability [ ]. It has been reported that urolithin A also increased total GSH, lowered oxidative stress, and improved cardiac function in the myocardium of diabetic rats [ ].

Coenzyme Q10 CoQ10 is a fat-soluble quinone. It is also a natural antioxidant molecule in the body. The positive effect of CoQ10 treatments is recognized in patients with heart failure and myocardial ischemia, such as the reduction of oxidative stress derived from cardiovascular causes, decrease in mortality and hospitalization and improvement in cardiac function [ , ].

Thereinto, the antioxidant effect of CoQ10 may be partially attributed to activating the GSH system. In a rat model of ISO-mediated myocardial infarction, CoQ10 preconditioning not only markedly expanded cardiac GSH levels and reduced the concentration of lipid peroxidation but also alleviated myocardial damage [ ].

O for 12 weeks on the antioxidant system in patients with coronary artery diseases. The findings revealed that plasma GPX activity was significantly increased after CoQ10 therapy and was positively related to plasma coenzyme Q10 levels [ ].

Thymoquinone Thy , a benzoquinone compound, is the main active ingredient in the extract of Nigella sativa seeds. Its treatment was reported to increase the levels of GSH and the activities of GPX and GST, along with a decrease in cardiac lipid peroxide production in a rat model of myocardial injury caused by diazinon a pesticide [ ].

Moreover, Thy-rich Nigella sativa seed oil exerts an antioxidant effect as an adjuvant therapy in hypertensive patients, mainly manifested in the upregulation of serum glutathione reductase GR levels and reduction of serum MAD content.

It also showed beneficial impacts on glycemic and blood pressure control as well as lipid metabolism in hypertensive patients without serious adverse effects such as liver and kidney dysfunction [ ]. In addition, some quinone compounds, such as β-LAPachone and aloin, have similar effects on heart protection [ , ].

We will not give unnecessary details here. In addition to the above compounds, many other natural medicines potentially protect the myocardium by enhancing the GSH antioxidant system.

Curcumin is a classic curcuminoid extract from the rootstock of turmeric. Upstream molecular targets, such as Nrf2, Sirt3, and PPAR-γ, are responsible for the curcumin-enhanced GSH system [ , , ]. Moreover, curcumin treatment not only quells oxidative stress in the myocardium but also impedes myocardial inflammation, which improves heart function and decreases heart damage [ , , , , ].

O for 12 weeks in patients with CHD [ , ]. Considering that curcumin is nontoxic, readily available and inexpensive, it is a prospective candidate for treating heart diseases. Resveratrol RSV is a stilbene found in grapes, wine and blueberries that possesses potent antioxidant activity to protect the myocardium from oxidative damage.

In particular, the enhanced GSH system plays an essential role in the antioxidant capacity of RSV [ ]. In , Elif Tatlidede et al. demonstrated that RSV treatment notably raised cardiac GSH contents and suppressed oxidant responses in DOX-processed rats; Simultaneously, it ameliorated DOX-induced deterioration of cardiac function and myocardial injury [ ].

In the following decade, many researchers verified in various models of myocardial injury that RSV can exert an antioxidant effect and protect the myocardium by increasing the level of GSH and upregulating the activity of GSH-dependent antioxidant enzymes [ , , , , ].

Moreover, they revealed that the mechanism by which RSV enhances the GSH system involves the AMPK signaling pathway, the Nrf2 signaling pathway, the Sirt1 pathway, noncoding RNA miR and the KAT5 gene [ , , , , ].

O for 2 months better improved left ventricular ejection fraction and left ventricular diastolic function in patients with CHD compared with standard treatment alone [ ]. Synthetic drugs have been researched and developed in recent modern times, a proportion of which have already been in clinical use for the treatment of various diseases, such as myocardial infarction, heart failure, diabetes, hypertension, oncology, and sepsis.

Similar to natural drugs, many synthetic drugs have properties that enhance the GSH system and thus protect cells from oxidative damage. The following section describes and summarizes these drugs in terms of the mechanisms by which they activate the GSH system Table 3 , Supplementary Table S3.

The key upstream target for GSH system modulation is generally considered to be Nrf2, a redox-sensitive regulator. Nrf2 is involved in not only the regulation of GSH synthesis and reduction via upgrading some enzymes and proteins SLC7A11, GCLM, GCLC, GR but also the activation of GSH-dependent antioxidant enzymes GPX, GST [ , ].

Furthermore, Gobinath Shanmugam et al. revealed that in an ISO-mediated model of myocardial infarction, direct overexpression of the Nrf2 gene enhanced GSH levels in cardiomyocytes and guarded cardiomyocytes against oxidative damage and lessened the occurrence of ferroptosis [ ].

This further confirms that the enhancement of Nrf2 is a viable strategy for activating the GSH system. Melatonin prevents Nrf2 degradation and augments its nuclear accumulation by inhibiting proteasomal [ ].

In in vivo and in vitro studies, melatonin was proven to increase the level of Nrf2 in cardiomyocytes exposed to oxidative stress. Among them, Cai et al. revealed the grievous connection between oxidative stress, pyroptosis, inflammation response, and xenobiotic metabolism in the myocardium of TMT-treated rats by String database analyzing the proteome interaction protein [ ].

In addition, Shaghayegh Haghjooy Javanmard et al. O for 30 days notably raised Nrf2 levels in peripheral blood mononuclear cells of patients undergoing coronary artery bypass grafting CABG [ ]. O for 12 weeks increased serum GSH levels while reducing serum MDA and protein carbonyl PCO in CHD patients with type 2 diabetes.

Additionally, it was reported that trimetazidine TMZ , a piperazine derivative, mediated activation of the GSH system and had antioxidant and cytoprotective effects in several myocardial injury models [ , , , ].

For instance, in the myocardium of exhaustive-exercised rats, TMZ produced specific cardioprotective outcomes by increasing GSH and GPX activity to clear oxidative stress.

Further mechanistic studies have found that treatment with TMZ promoted cardiac Nrf2 expression, indicating that TMZ enhanced the clearance of oxidative stress by activating the GSH system through the Nrf2 signaling pathway [ ].

Moreover, TMZ also has other benefits to the myocardium, including increased coronary blood flow reserve, maintenance of cardiac energy metabolism, anti-apoptosis, and anti-inflammation.

It has been approved for clinical use in the therapy of angina pectoris [ , ]. In addition to Nrf2, activation of PPAR-γ and the AMPK pathway can also facilitate the GSH system. Rosiglitazone and pioglitazone belong to the thiazolidinedione class of hypoglycemic agents and are recognized as PPAR-γ agonists.

O for 4 weeks exhibits antioxidant properties in diabetic patients, as reflected by a decrease in MDA [ , ]. In addition, there is evidence that pioglitazone reduces the risk of MI and acute coronary syndrome in patients with cardiovascular diseases CVD and patients with type 2 diabetes who had previous myocardial infarction [ , , ].

Notably, it increases the risk for the development of heart failure [ , ]. Compared to pioglitazone treatment, rosiglitazone increases the risk of AMI and heart failure in type 2 diabetic patients and elderly patients [ , , ].

Metformin is a traditional drug for the treatment of type 2 diabetes. In addition to its antidiabetic results, it was also found to achieve cardiac protection by activating the AMPK pathway [ ].

Some researchers have shown that metformin activates AMPK and triggers the downstream GSH system to slow DOX-mediated oxidative impairment in the myocardium [ , ].

O for 12 months not only decreased oxidative stress but also lowered left ventricular mass LVM and improved blood pressure [ ]. SLC7A11 is an essential molecule that limits the Cys transport rate, thus restricting the synthesis of GSH. Direct SlC7A11 overexpression in cardiac myocytes boosted GSH levels and reduced cardiac ferroptosis and injury, suggesting that it is feasible to fortify GSH levels by increasing SLC7A11 [ 76 ].

Atorvastatin, a statin that reduces cholesterol, is a first-line drug for treating cardiovascular disease. It was reported that it could raise intracellular GSH by increasing SLC7A11 expression, efficiently leading to GPX4 enhancement and ferroptosis suppression in the ISO-induced injury model of H9C2 cells and rat myocardium [ 49 ].

Additionally, one clinical trial by Douglas Greig et al. O for 4 weeks reduced plasma MDA while improving the functional capacity assessed via a 6-minute walk test in patients with chronic heart failure CHD [ ]. However, it is not clear whether they regulate the expression of SLC7A Dexmedetomidine DEX , an α2-adrenergic receptor, also augments the expression of SLC7A In the same year, Wang et al.

Moreover, DEX treatment 0. A previous clinical study also showed that perioperative DEX 0. These results suggest that DEX has antioxidant and cardioprotective potential. However, clinical studies of the drug have focused on surgical patients.

It is unclear whether it exhibits cardioprotective effects in patients with post-PCI, AMI, or other cardiomyopathies. Many studies have concentrated on the direct effects of synthetic drugs on GSH and GSH-dependent antioxidant enzymes in damaged myocardium without further mechanistic investigations.

Herein, we discuss some critical examples of representative synthetic compounds. Captopril, an angiotensin-converting enzyme inhibitor, is widely used in clinical practice to treat hypertension, MI, and congestive heart failure and is effective in attenuating left ventricular LV dilatation, ameliorating LV ejection fraction and improving cardiovascular morbidity and mortality [ , ].

Captopril has been revealed to facilitate the GSH system in several rodent models of myocardial injuries, such as clozapine and DOX-induced damage models, thereby protecting cardiomyocytes from oxidative stress [ , ]. A recent clinical trial in type 2 diabetes patients with CVDs following captopril treatment O for 3 months found a significant improvement in plasma GSH levels and a concomitant decline in lipid peroxidation [ ].

Consequently, these results partially explain the pharmacological mechanism of captopril as a cardioprotective agent.

Similar to the statin lipid-lowering drugs mentioned earlier, other lipid-lowering drugs, such as probucol, also exhibit the capability to restore the inhibited GSH system and defend the myocardium from oxidative damage after exposure to pathological factors, for example, ISO and cyclophosphamide [ , ].

Exosomes EXOS of mesenchymal stem cells MSCs from human umbilical cord blood increased GSH and attenuated lipid peroxidation and ferroptosis in cardiomyocytes in a rat infarction model.

However, it has no effect on the level of GPX4 [ ]. A recent study reported that exosomes derived from mouse bone marrow MSCs exerted similar cardio-protective effects [ ].

However, not all exosomes positively impact the myocardium and GSH. For instance, exosomes secreted by adipose tissue macrophages caused ferroptosis by targeting SLC7A11 to inhibit GSH synthesis in the heart [ ].

Current gene therapy research aims to target, for example, upstream targets of the GSH system or molecules associated with it such as Nrf2, GPX, SLC7A11 , genes aberrantly expressed in myocardial injury, and noncoding RNAs regulating mRNA transcription [ 76 , , , , , ].

Recombinant human GPX4 alleviated ISO-induced myocardial ischemia injury [ ]. In addition, some investigators found that USP22 and lncRNA PART1 expression was decreased in a MIR injury model. In addition, Zhang et al. overexpressed miRp in the myocardium by direct myocardial injection of AVV-9 containing miRp precursor, which targeted inhibition of MyD88 and thus restored declining GSH levels, alleviated insult of cardiac function and oxidative injury induced by sepsis in the hearts of mice [ ].

The GSH system is one of the most significant members of the cellular antioxidant defensive system, which is essential for eliminating excess ROS and protecting the myocardium in the presence of pathological cardiovascular factors. Notably, glutathione balance and GPX4 levels are deeply involved in the susceptibility of cardiomyocytes to ferroptosis, a novel form of cell death.

Furthermore, many researchers have found that reduced GSH levels and GSH-dependent antioxidant enzyme activity in damaged myocardium due to excess ROS and disruption of the GSH synthesis process, along with increased oxidative damage and ferroptosis.

Based on this, therapeutic strategies to restore the activity of the GSH system in the heart are beneficial in the treatment of myocardial injury. Precursors of GSH or GPX biosynthesis, various small molecule activators related to the GSH system and some novel therapeutic approaches, such as exosomes and gene therapy, can boost the activity of the GSH system and reduce cardiac damage and ferroptosis.

Notably, despite constant progress in diverse aspects of natural drug monomers that protect against myocardial injury by activating the GSH system, great challenges remain in translating these compounds into future clinical pharmaceuticals.

First, most natural small molecules present low bioavailability problems [ ], so further research on delivery systems and formulations for these drugs is needed. Second, the development of new drugs requires additional and more detailed preclinical and clinical studies to determine whether long-term use is biotoxic, whether the drug has adverse effects on other peripheral organs or whether the drug candidate has a real therapeutic effect on the patients.

In addition, a portion of synthetic agents have been used clinically to treat various diseases, such as myocardial infarction, heart failure, diabetes, hypertension, tumors, and sepsis.

These studies on myocardial injury and the GSH system reveal new roles of these clinical drugs in the treatment and further elaborate their mechanisms, which provide new ideas for their clinical application.

However, more clinical studies must be encouraged to evaluate whether these drugs can act as GSH system enhancers and cardioprotective agents in patients.

Moreover, some emerging therapeutic approaches to enhance the GSH system have attracted much attention. These results show that although the expected therapeutic effect has not been achieved, AVV-based therapy has acceptable safety. This opens up the possibility of our gene therapy targeting the GSH system.

Overall, we can see the value of targeting the GSH system in myocardial injury. Despite being faced with many problems, it provides new directions and ideas for the treatment of myocardial injury.

The continuous exploration of new treatment modalities will be critical to successfully combat myocardial damage in the future. All data generated or analyzed during this study are included in this published article and its supplementary information files. Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, et al.

Global burden of cardiovascular diseases and risk factors, update from the GBD study. J Am Coll Cardiol. Article PubMed PubMed Central Google Scholar. Kong X, Liu H, He X, Sun Y, Ge W. Unraveling the mystery of cold stress-induced myocardial injury. Front Physiol. Ansley DM, Wang B. Oxidative stress and myocardial injury in the diabetic heart.

J Pathol. Article CAS PubMed PubMed Central Google Scholar. The role of oxidative stress in cardiac disease: from physiological response to injury factor.

Oxid Med Cell Longev. Raedschelders K, Ansley DM, Chen DDY. The cellular and molecular origin of reactive oxygen species generation during myocardial ischemia and reperfusion.

Pharmacol Therapeutics. Article CAS Google Scholar. Zhang J, Pan W, Zhang Y, Tan M, Yin Y, Li Y, et al. Comprehensive overview of Nrf2-related epigenetic regulations involved in ischemia-reperfusion injury. Dubois-Deruy E, Peugnet V, Turkieh A, Pinet F.

Oxidative stress in cardiovascular diseases. van der Pol A, van Gilst WH, Voors AA, van der Meer P. Treating oxidative stress in heart failure: past, present and future. Eur J Heart Fail. Article PubMed Google Scholar. Sawyer DB, Colucci WS.

Circ Res. Article CAS PubMed Google Scholar. Perrelli M-G, Pagliaro P, Penna C. Introduction About Our Approach Applications How it works Resource Centre First Visit Practitioners Introduction About Our Approach Applications How it works Resource Centre First Visit Practitioners.

Learn More. Overview A complete heavy metal detoxification plan supports your detox organs, chelates binds heavy metals, ensures healthy nutrient status, and eliminates sources of exposure.

Benefits Clearing heavy metals from the body can improve neurological health, support regulation of the immune system, and aid in the restoration of hormonal balance. About About Heavy Metal Chelation and Detoxification Ideally, our bodies can dispose of them; however, if we absorb them faster than our body can excrete them, they can accumulate.

Heavy metals are all around us We take in heavy metals through the air we breathe, the food we eat, and the water we drink. Small amounts of heavy metals can be considered toxic Once heavy metals are in our bloodstream, they can be stored in the cells of tissues and organs for years, predisposing us to pain and chronic health issues until we take action to move them out of our body.

Our Approach An Integrative Approach to Heavy Metal Chelation and Detoxification At Integrative, we will build a safe and effective protocol for you based on four key steps: We will use chelators — substances that selectively bind with certain metals — to remove the toxic metals from your system We rebuild nutrient levels that have been depleted by the toxins so you can more effectively excrete heavy metals and block their absorption in the future We support the healing of tissues damaged by toxicity We teach you methods to avoid further contamination Prior to developing a plan for you, we will guide you through one or more testing methods to determine your heavy metal status:.

Applications Applications of Heavy Metal Chelation and Detoxification Heavy metal detoxification may be a helpful component of your treatment plan, especially if you are struggling from one of these conditions:.

How it works How does Heavy Metal Chelation and Detoxification work? Overview Heavy metal detoxification uses specific chelators to safely bind and excrete heavy metals, alongside other detoxification and supportive techniques.

Targeted Area of the Body Heavy metal detoxification encourages the excretion of heavy metals via your own detoxification organs, such as the liver, bowels, and kidney.

Health Benefits of Heavy Metal Chelation and Detoxification Removing heavy metals from the body reduces inflammation and oxidative stress, and may improve neurological, digestive, cardiovascular, and immune system functioning.

Resource Centre Explore Research Articles. First Visit What does your first visit look like? One Complete Medical and Lifestyle History Your Doctor will take a complete history, gathering details regarding your current and past health concerns, lifestyle, as well as current supplements and medications.

Two Testing Your Doctor will recommend various tests, either at Integrative or with your medical doctor. Three Physical Exam Within your first visit, your doctor may also perform a physical exam.

Practitioners Your Participating Practitioners The Naturopathic Doctors at Integrative are primary care providers with expertise in a wide variety of functional medicine techniques, including Pharmacology, herbal medicine, nutritional science, and acupuncture.

Frequently Asked Questions View all FAQs Am I candidate for chelation therapy? Ready to start your journey? Detoxification refers to the removal of excess toxins and waste products from your system.

This can leave you feeling less sluggish and give you increased energy levels, healthier skin and generally improve the functioning of your organs. Along with dietary changes, there are also certain types of exercise that can assist with the process of detoxification. The flushing out of toxins is one of the many benefits of exercise.

Your heart rate and breathing increase when you exercise, as well as your blood circulation and sweat production - this can assist your body in being able to get rid of toxins more efficiently.

Exercise also improves digestion and elimination which means you will be able to get rid of more waste products. When blood circulation increases, the liver can work more efficiently, and lymph can move around the body more quickly.

We also tend to take in more fluid when we exercise, which in turn enhances kidney function and ultimately the flushing of toxins from the body.

Is there a particular type of exercise that is best for assisting detoxification?

Metabolic hewlth is way more heealth sipping on drinks that have been marketed as detox tricks careiovascular cleansers. Every day, no Performance-enhancing nutrition what our daily schedule is fo, our heakth absorbs Performance enhancing drinks wide variety of improvwd Performance enhancing drinks stores them forr critical organs such as Detoxification for improved cardiovascular health brain, liver, or our fatty tissues and bones. Toxins can clog the arteries and affect the most fundamental body processes. Thus, Metabolic detoxification is the process of removing toxins from our body at the cellular level. Our bodies are equipped to eliminate lots of toxins using different methods. The most classic example is our breathing — our lungs help us expel carbon dioxide, and we cough out other harmful particles. Another example is our colon, which discards the waste or harmful elements after our small intestine absorbs the good nutrients from the food we eat.

Thank you for visiting nature. You cardiovascullar using a browser imptoved with limited ikproved for Degoxification. To obtain the best experience, we tor you use a more up to date browser or turn off cariovascular mode Detoxxification Internet Explorer.

In the improvef, to ror continued support, we are displaying the site without styles and JavaScript. The glutathione GSH system is carfiovascular to cardiovqscular one of the most powerful endogenous antioxidant systems Detoxificaation the cardiovascular system due to its key contribution to detoxifying xenobiotics Detoxification for improved cardiovascular health scavenging overreactive oxygen species ROS.

Numerous investigations have suggested that disruption of cardiovasculra GSH system is a critical element in the pathogenesis of myocardial injury. Meanwhile, a newly ijproved type of cell death, ferroptosis, has imprpved demonstrated cardivascular be closely related to the GSH system, which affects the process Detoxificatlon outcome Detoxificagion myocardial heqlth.

Moreover, in facing various pathological challenges, the mammalian lmproved, which possesses high Detoxification for improved cardiovascular health gor mitochondria and Enhance brain performance antioxidant cqrdiovascular, is susceptible to oxidant Blackberry barbecue sauce recipe and oxidative damage.

Therefore, targeted enhancement of the GSH system along with prevention of ferroptosis in the myocardium is a promising therapeutic strategy. Detoxification for improved cardiovascular health this review, we dardiovascular systematically describe the physiological functions and anabolism heaoth the GSH system, as well as its effects on cardiac injury.

Then, we discuss Hydrostatic weighing for weight management relationship between Detoxificarion GSH system and ferroptosis in myocardial injury. Moreover, haelth comprehensive summary of the activation strategies of the GSH system is presented, Rehydration for seniors we mainly identify several promising herbal monomers, which may provide valuable Detxification for the exploration of new therapeutic Detoxification for improved cardiovascular health.

GSH Rye bread benefits is one of the cardiovasculad endogenous antioxidant Detkxification, which can maintain cellular Natural thermogenic supplements balance and prevent oxidative damage and cell death.

Ferroptosis is a new form of programmed cell death that plays an essential role in the development of cardiovascular Detoxicication. The GSH system, as a lipid peroxide scavenger, prevents Detoification indefinite expansion of lipid peroxidation, which is a improvee step in hindering ferroptosis.

Activating the Detoxification for improved cardiovascular health system alleviates the progression of Dwtoxification myocardial Detoxification for improved cardiovascular health by blocking Carbs and athletic recovery ferroptosis pathway and cardiovascilar stress, which provides heqlth promising therapeutic strategy Vegan and vegetarian athlete nutrition cardiac diseases.

What is Performance enhancing drinks Optimizing nutrient bioavailability processes between the GSH system and carddiovascular in various Raspberry ketones for natural detoxification of myocardial cardipvascular.

Cardiovascular diseases CVDs are the leading cause of death worldwide and rising health care carviovascular [ 1 ]. Irreversible heart injury carddiovascular the Performance enhancing drinks culprit for the poor prognosis Caffeine and pre-workout CVDs.

Halth, understanding how Gymnastics injury prevention tissue is impaired is critical to global health. Oxidative stress plays an Nutrient Balancing for Athletes and complex role throughout its Deetoxification and progression [ 23456 ], to which Detoxificatiob oxygen species ROS are the primary contributors.

Under healgh conditions, ROS are generated in the heart mainly from the mitochondrial electron transport chain, nitric oxide synthases NOSCardiovascylar oxidases NOXand xanthine oxidase XO in small quantities [ 78 ].

Cradiovascular, the production and Detoxificatipn of ROS are in dynamic equilibrium. Under pathological conditions, the Citrus bioflavonoids and arthritis relief electron cardiovaschlar chain cardiovawcular the formation of large amounts of ROS.

Mitochondrial ROS overproduction imroved been indicated to fro to cardiomyocyte injury and greater myocardial injury after acute myocardial cardiovascularr AMI fpr 910 ]. In addition, the increased expression and improver of NOX and xanthine oxidase and NOS Detoxificationn uncoupled and structurally unstable also Detoxiification to increased ROS production [ cardiovascullar ].

Performance enhancing drinks Heealth can damage all major cellular Detoxiffication DNA, proteins, and imprroved and even lead to cell death, apoptosis, hypertrophy, heqlth, and Cardiovasculad dysfunction in the myocardium Detoxify your liver 8 Detoxificatuon, 11 ].

Vor the body to resist Degoxification damages, it cardiovadcular a range of endogenous antioxidants, primarily enzymatic antioxidants superoxide dismutase SODglutathione Quick and easy athlete meals GPXglutathione S-transferase GSTglutathione reductase Cardiovaxcularhealyh reductase TrxRcatalase I,provedExercise and glucose metabolism. Among them, the glutathione system made up yealth GSH, enzymes involved in GSH anabolism, and Detoxirication antioxidant enzymes play a critical improbed in impfoved from Detoxxification stress fof redox homeostasis [ 12Detoxification for improved cardiovascular health, 13Detoxlfication ].

Due to cardiomyocytes cardiivascular massive energy demands, Detoxiffication Detoxification for improved cardiovascular health hwalth in mitochondria improed out Detoxificatioj the rest of the cell cardilvascular [ 15Energizing lifestyle tips ], which makes them very sensitive to oxidative stress damage.

At the same time, the Detoxicication of antioxidant enzymes SOD, Detoification, GR in cardiomyocytes is weaker than Degoxification in other organs [ improve ], cardioovascular aggravating the susceptibility to this ehalth. Therefore, cardiovasdular activation of antioxidant systems, Detoxifivation the GSH system, is an essential treatment Weight-related health risks to protect cardiovascylar against High-intensity workouts damage.

Detoxifcation, redox signaling events Detoxificatio significant cardiovasculag of cell death pathways, among which GSH depletion has caridovascular demonstrated to be a vital Drtoxification hallmark in the progression of different cell Detoxificcation mechanisms [ 18 ].

Distinct from apoptosis, dardiovascular and autophagy, Dixon and coauthors proposed for Body-positive weight loss first time a new form of oxidation-dependent and iron-dependent cell death known as ferroptosis [ 19 ].

It is characterized by an extremely severe accumulation of lipid peroxidation [ 20 ]. Numerous studies have shown that GSH anabolism and GPX4 are inextricably linked to ferroptosis.

Toxic lipid peroxides can be converted into nontoxic lipid alcohols L-OH in the presence of GPX4 and GSH to inhibit ferroptosis [ 21 ]. However, some molecules or drugs, such as erastin, sulfasalazine, sorafenib, and RSL3, are able to block glutathione synthesis or devitalize GPX4.

All of these processes tend to initiate ferroptosis, leading to cell damage [ 22 ]. In summary, oxidative stress drives the occurrence and progression of CVDs, and the GSH system is positively involved in antioxidant activity, which is beneficial to their treatment and prognosis.

Current studies have revealed a strong link between ferroptosis and the GSH system, which has become a hotspot in the field of CVDs. As a result, herein, we review the synthetic and metabolic processes of GSH, systematically describing the functions of the GSH system in cardiac injury.

Moreover, we emphasize GSH system-related ferroptosis in cardiac injury events and comprehensively summarize strategies for GSH system activation. Understanding the roles and interventions of the GSH system, as well as its connection with ferroptosis, may favor the advancement of more effective therapies to prevent myocardial injury summarized in Fig.

Raw materials of GSH or GPX biosynthesis, various small molecule activators related to the GSH system and some novel therapeutic approaches, such as exosomes and gene therapy, enhance the GSH system and thus improve myocardial injury caused by various pathological factors by inhibiting oxidative stress and ferroptosis.

The synthesis of glutathione is found in almost all mammalian cells [ 23 ]. This process, using glutamate Glucysteine Cysand glycine Gly as raw materials, depends on glutamate cysteine ligase GCL and glutathione synthetase GS catalysis, present only in the cytoplasmic matrix [ 23 ].

Its rate-limiting steps are the availability of cysteine and the activity of GCL [ 24 ]. The three amino acids mentioned above come from different pathways.

Cysteine is mainly derived from the trans-sulfuration pathway of methionine and the reduction of cysteine [ 21 ]. In the former, cysteine comes from the conversion of methionine via a series of enzymatic steps, which is unique to liver cells [ 25 ]. Among them, SLC7A11 has a key role in limiting the rate of cystine transport [ 27 ].

Intracellular Glu is produced from glutamine Gln catalyzed by glutaminase GLS, with two different isomers GLS1 and GLS2 [ 2930 ]. Gln and Gly are transported into the cell via the corresponding amino acid transporters. In addition, glycine and glutamate deficiency also affects GSH synthesis to some extent [ 23 ].

The synthesis of glutathione involves two enzymatic steps, both requiring ATP hydrolysis for energy supply. First, glutamate-cysteine ligase GCL links glutamate and cysteine to form γ-glutamyl cysteine rate-limiting steps.

Glutathione synthetase GS then catalyzes the combination of glycine residues and gamma-glutamyl-cysteine to form GSH [ 31 ]. The main synthetic pathways of GSH blue arrows ; GSSG is reduced to GSH under the action of GR and NADPH red arrow ; GSH reduces H 2 O 2 or lipid-OOH to H 2 O or lipid-OH in the catalysis of GPX, and GSH conjugates with xenobiotics compounds to form GS-X in the catalysis of GST green arrow ; The decomposition process of GSH, GSSG and GS-X after being squeezed out of cells purple arrows ; The decomposition process of intracellular GSH rosy arrows ; ROS are generated from the mitochondrial electron transport chain, nitric oxide synthases NOSNADPH oxidases NOXand xanthine oxidase XO yellow arrow.

Glutathione, the most plentiful thiol-containing substance of low molecular weight in cells, is a crucial antioxidant and antidote in all mammalian tissues. Under physiological conditions, GSH quenches oxidizing substances such as reactive hydroxyl free radicals, peroxynitrite, and H 2 O 2 directly or reduces hydrogen peroxide or lipid peroxide lipid-OOH to water or the corresponding lipid alcohol lipid-OH under the catalysis of GPX summarized in Fig.

Meanwhile, reduced GSH is oxidized into glutathione disulfide GSSG [ 832 ]. GSH also detoxifies electrophilic xenobiotics compounds chemical carcinogens, environmental pollutants, drugs, etc. and their metabolites to GSH adduct GS-X in the direct catalysis of glutathione-S-transferase GST, primary approach [ 32 ].

The concentration of GSH is at high levels, and GSSG and ROS are at depressed levels to maintain redox homeostasis in cardiomyocytes. Thus, the ratio of GSH to GSSG is largely considered a marker of oxidative stress [ 832 ].

To maintain high levels of GSH in cardiomyocytes, there are generally two mechanisms. One is that GSSG and GS-X produced in cardiomyocytes are pumped out by multidrug resistance protein 1 MRP1preventing GSSG or GS-X accumulation in cardiomyocytes [ 3334 ], and subsequently enter the γ-glutamyl cycle.

This cycle primarily involves γ-glutamyl peptidase GGTthe only enzyme that catabolizes GSH, GSSG, and GS-X, as well as dipeptidyl peptidase DP. GGT transfers the γ-glutamyl residue of glutathione to amino acid acceptors the best acceptor being cystinereleasing γ-glutamyl peptides and cysteinyl glycine.

Subsequently, DP breaks cysteinyl glycine into cysteine and glycine, which are reabsorbed into the cell to engage in a novel GSH synthesis pathway summarized in Fig. The other is that some GSSG can be reduced to GSH in the presence of GR at the cost of NADPH [ 8 ] summarized in Fig.

NADPH is mainly derived from the pentose phosphate pathway, which uses glucosephosphate dehydrogenase G6PD as the key enzyme [ 36 ]. The ChaC family ChaC1 and ChaC2, cytoplasmic glutathione-specific γ-glutamyl cyclotransferases has recently been shown to take part in GSH metabolism.

ChaC1 and ChaC2 use the α-amine of L-glutamyl residues to cleave the amide bond by transamination, releasing it as a cyclic 5-oxo-l-proline and cysteine glycine dipeptide.

These products are cleaved into glutamine, cysteine, and glycine under the action of 5-oxoalaninase and Cys-Gly peptidase, respectively, and then added to new GSH synthesis [ 3237 ] summarized in Fig. However, the role of the ChaC family in cardiomyocytes has been less reported since then.

When the heart is under stress from pathological factors, GSH redox homeostasis is disrupted, which is manifested by a significant decrease in GSH content and accumulation of GSSG in the myocardium.

Several clinical studies have found that GSH consumption exists in the blood of patients with myocardial infarction and the left ventricle of patients with heart failure [ 83839 ]. Moreover, a reversed GSH redox state and activity-suppressed GPX have been observed in the myocardium of various myocardial injury animal models [ 40414243 ].

The reasons for these changes, apart from excess ROS leading to increased GSH depletion in cardiomyocytes, are disturbances in the anabolic process of GSH, causing a further decrease in intracellular GSH content.

Many preclinical studies have demonstrated that the expression of key enzymes for GSH synthesis GCL, SLC7A11, GS and GSSG reduction-related enzymes G6PD, NADPH, and GR is downregulated in myocardium exposed to pathological factors [ 404344454647484950 ].

However, enhanced expression of GGT and MRP1, which are associated with the γ-glutamyl cycle, has been observed in damaged myocardium [ 33345152 ]. Moreover, some studies have shown that the ChaC1 protein is significantly upregulated in various adverse conditions, such as diabetes, viral infection and atherosclerosis, providing cells with the amino acid nutrients they need under stressful situations but reducing GSH levels.

However, the ChaC family is less studied in the myocardium [ 37 ]. Hiroki Kitakata et al. reported that in MITOL knockdown-mediated ferroptosis in cardiomyocytes, knockdown of ChaC1 reversed cell injury and increased GSH [ 53 ].

ChaC2 is a constitutively expressed protein whose expression is not affected by the external environment for the basal turnover of GSH [ 37 ]. As the most metabolically demanding organ in the body, the heart requires significant amounts of energy adenosine triphosphate ATP to maintain constant contractile and diastolic function.

In addition, mitochondria are also the primary producers of intracellular reactive oxygen species ROSmost of which originate from the mitochondrial respiratory chain [ 55 ].

Despite the exposure of mitochondria to the production of oxidants, the presence of an effective antioxidant system, of which mitochondrial GSH mGSH is a key component, prevents or repairs oxidative damage that occurs during normal aerobic metabolism [ 57 ]. The importance of mGSH is mainly based on its detoxification of hydrogen peroxide, mitochondrial lipid membrane peroxidation, or xenobiotics under the catalysis of enzymes such as GPX or GST [ 58 ].

A recent report suggests that mGSH and mitochondrial redox status play an essential role in cardiomyocyte ferroptosis [ 60 ]. As mentioned above, GSH is synthesized only in the cytoplasmic matrix, but it is also found in intracellular organelles, including the mitochondria, nucleus, and endoplasmic reticulum.

However, GSH has an overall negative charge at physiological pH, and mitochondria also exhibit an enormous negative membrane potential [ 5758 ]. Therefore, mGSH arises from cytoplasmic matrix GSH via a specific transport mechanism. Some investigators have identified potential candidates for transporting GSH into the kidney and liver mitochondria, including the 2-oxoglutarate carrier OGC; SLC25A11 and the dicarboxylate carrier DIC; SLC25A10 [ 57 ].

InZhang et al. found that these two vectors were highly expressed in myocardial mitochondria and showed that inhibition of DIC and OGC increased mitochondrial ROS and GSH depletion, exacerbating ferroptosis in the myocardium [ 60 ].

: Detoxification for improved cardiovascular health

Latest news	Proponents of the Master Cleanse diet recommend adhering to it for at least 10 days. To restore energy, lose weight, and relieve symptoms of chronic conditions like arthritis and fibromyalgia. There are no data on this particular diet in the medical literature. But many studies have shown that fasts and extremely low-calorie diets invariably lower the body's basal metabolic rate as it struggles to conserve energy. Once the dieter resumes normal eating, rapid weight gain follows. Much of the weight loss achieved through this diet results from fluid loss related to extremely low carbohydrate intake and frequent bowel movements or diarrhea produced by salt water and laxative tea. When the dieter resumes normal fluid intake, this weight is quickly regained. The diet is lacking in protein, fatty acids, and other essential nutrients. Carbohydrates supply all the calories — an extremely low The daily laxative regimen can cause dehydration, deplete electrolytes, and impair normal bowel function. It can also disrupt the native intestinal flora, microorganisms that perform useful digestive functions. A person who goes on this diet repeatedly may run the risk of developing metabolic acidosis, a disruption of the body's acid-base balance, which results in excessive acidity in the blood. Severe metabolic acidosis can lead to coma and death. Numerous kits are marketed for this purpose, most of which include a high-fiber supplement, a "support" supplement containing herbs or enzymes, and a laxative tea, each to be used daily. Manufacturers of the herbal detox kits recommend continuing the regimen for several weeks. Such regimens may be accompanied by frequent enemas. The aim is to eradicate parasites and expel fecal matter that allegedly accumulates and adheres to the intestinal walls. Several studies suggest that milk thistle, which is often included as a supportive supplement, may improve liver function with few side effects. But there's no medical evidence for the cleansing procedure as a whole. Promotional materials often include photographs of snake-like gelatinous substances expelled during cleansing. When these pictures are not faked, they are probably showing stool generated by large doses of the regimen's fiber supplement. More important, the rationale for intestinal cleansing — to dislodge material adhering to the colon walls — is fundamentally mistaken. When fecal matter accumulates, it compacts into firm masses in the open interior of the colon; it does not adhere to the intestinal walls as the "sludge" depicted in the advertisements. Like fasting, colonic cleansing carries a risk of dehydration, electrolyte imbalance, impaired bowel function, and disruption of intestinal flora. The manufacturers recommend continuing the procedure for two to three months. One method employs a special type of adhesive pad worn on the bottoms of the feet during sleep. Another approach is to immerse the feet for 30 minutes in a basin, sometimes referred to as an "ionic foot bath," containing salt water and two electrodes that supply a low-voltage electric charge. Both methods claim to emit ions that stimulate the outflow of toxins through the feet. The pads contain tourmaline crystals, which are purported to emit ion-generating infrared rays. The foot baths allegedly generate ions by running an electric current through salt water. However, there is no scientific evidence that ionic changes in the environment can stimulate a discharge of toxins through pores in the feet — or any other part of the body, for that matter. Promoters assert that the success of the process can be monitored by a color change in the pad or in the water of the foot bath as impurities are leached from the body. But the pads, which are impregnated with wood vinegar, have been shown to turn the same dark color whether they absorb foot perspiration or are sprayed with tap water; and the color of the foot bath changes because the metal electrodes corrode. Concentrated oxygen is said to boost the immune system, relieve headaches, increase energy, and improve cognitive function. Pressurized oxygen has long been used in treating people with respiratory distress or chronic lung conditions like emphysema, because their lungs cannot extract enough oxygen from normal air. Since the late s, detox spas and oxygen bars have been marketing a short version of the treatment to healthy people. There is no evidence that healthy lungs need more oxygen than is contained in normal air to supply the body with adequate oxygen. The FDA has warned that it is illegal to administer oxygen from a tank without a prescription, but most states have failed to enforce the ruling, enabling oxygen bars to thrive. Although there is little danger from inhaling concentrated oxygen, the FDA cautions against "flavored" oxygen, which may contain fragrant oil suspensions that can irritate the lungs. Some establishments require users to buy or bring their own masks or nasal tubes. We tend to forget that the body is equipped with a detoxification system of its own, which includes the following:. The skin. The main function of the body's largest organ is to provide a barrier against harmful substances, from bacteria and viruses to heavy metals and chemical toxins. The skin is a one-way defense system; toxins are not eliminated in perspiration. The respiratory system. Fine hairs inside the nose trap dirt and other large particles that may be inhaled. Smaller particles that make it to the lungs are expelled from the airways in mucus. The immune system. This exquisitely orchestrated network of cells and molecules is designed to recognize foreign substances and eliminate them from the body. Components of the immune system are at work in blood plasma, in lymph, and even in the small spaces between cells. The intestines. Peyer's patches — lymph nodes in the small intestine — screen out parasites and other foreign substances before nutrients are absorbed into the blood from the colon. The liver. Acting as the body's principal filter, the liver produces a family of proteins called metallothioneins, which are also found in the kidneys. Metallothioneins not only metabolize dietary nutrients like copper and zinc but also neutralize harmful metals like lead, cadmium, and mercury to prepare for their elimination from the body. Liver cells also produce groups of enzymes that regulate the metabolism of drugs and are an important part of the body's defense against harmful chemicals and other toxins. The kidneys. The fact that urine tests are used to screen for drugs and toxins is a testament to the kidneys' remarkable efficiency in filtering out waste substances and moving them out of the body. The human body can defend itself very well against most environmental insults and the effects of occasional indulgence see "The body's own detox system". If you're generally healthy, concentrate on giving your body what it needs to maintain its robust self-cleaning system — a healthful diet, adequate fluid intake, regular exercise, sufficient sleep, and all recommended medical check-ups. If you experience fatigue, pallor, unexplained weight gain or loss, changes in bowel function, or breathing difficulties that persist for days or weeks, visit your doctor instead of a detox spa. As a service to our readers, Harvard Health Publishing provides access to our library of archived content. Please note the date of last review or update on all articles. No content on this site, regardless of date, should ever be used as a substitute for direct medical advice from your doctor or other qualified clinician. Thanks for visiting. Don't miss your FREE gift. The Best Diets for Cognitive Fitness , is yours absolutely FREE when you sign up to receive Health Alerts from Harvard Medical School. Sign up to get tips for living a healthy lifestyle, with ways to fight inflammation and improve cognitive health , plus the latest advances in preventative medicine, diet and exercise , pain relief, blood pressure and cholesterol management, and more. Get helpful tips and guidance for everything from fighting inflammation to finding the best diets for weight loss Further mechanistic studies have found that treatment with TMZ promoted cardiac Nrf2 expression, indicating that TMZ enhanced the clearance of oxidative stress by activating the GSH system through the Nrf2 signaling pathway [ ]. Moreover, TMZ also has other benefits to the myocardium, including increased coronary blood flow reserve, maintenance of cardiac energy metabolism, anti-apoptosis, and anti-inflammation. It has been approved for clinical use in the therapy of angina pectoris [ , ]. In addition to Nrf2, activation of PPAR-γ and the AMPK pathway can also facilitate the GSH system. Rosiglitazone and pioglitazone belong to the thiazolidinedione class of hypoglycemic agents and are recognized as PPAR-γ agonists. O for 4 weeks exhibits antioxidant properties in diabetic patients, as reflected by a decrease in MDA [ , ]. In addition, there is evidence that pioglitazone reduces the risk of MI and acute coronary syndrome in patients with cardiovascular diseases CVD and patients with type 2 diabetes who had previous myocardial infarction [ , , ]. Notably, it increases the risk for the development of heart failure [ , ]. Compared to pioglitazone treatment, rosiglitazone increases the risk of AMI and heart failure in type 2 diabetic patients and elderly patients [ , , ]. Metformin is a traditional drug for the treatment of type 2 diabetes. In addition to its antidiabetic results, it was also found to achieve cardiac protection by activating the AMPK pathway [ ]. Some researchers have shown that metformin activates AMPK and triggers the downstream GSH system to slow DOX-mediated oxidative impairment in the myocardium [ , ]. O for 12 months not only decreased oxidative stress but also lowered left ventricular mass LVM and improved blood pressure [ ]. SLC7A11 is an essential molecule that limits the Cys transport rate, thus restricting the synthesis of GSH. Direct SlC7A11 overexpression in cardiac myocytes boosted GSH levels and reduced cardiac ferroptosis and injury, suggesting that it is feasible to fortify GSH levels by increasing SLC7A11 [ 76 ]. Atorvastatin, a statin that reduces cholesterol, is a first-line drug for treating cardiovascular disease. It was reported that it could raise intracellular GSH by increasing SLC7A11 expression, efficiently leading to GPX4 enhancement and ferroptosis suppression in the ISO-induced injury model of H9C2 cells and rat myocardium [ 49 ]. Additionally, one clinical trial by Douglas Greig et al. O for 4 weeks reduced plasma MDA while improving the functional capacity assessed via a 6-minute walk test in patients with chronic heart failure CHD [ ]. However, it is not clear whether they regulate the expression of SLC7A Dexmedetomidine DEX , an α2-adrenergic receptor, also augments the expression of SLC7A In the same year, Wang et al. Moreover, DEX treatment 0. A previous clinical study also showed that perioperative DEX 0. These results suggest that DEX has antioxidant and cardioprotective potential. However, clinical studies of the drug have focused on surgical patients. It is unclear whether it exhibits cardioprotective effects in patients with post-PCI, AMI, or other cardiomyopathies. Many studies have concentrated on the direct effects of synthetic drugs on GSH and GSH-dependent antioxidant enzymes in damaged myocardium without further mechanistic investigations. Herein, we discuss some critical examples of representative synthetic compounds. Captopril, an angiotensin-converting enzyme inhibitor, is widely used in clinical practice to treat hypertension, MI, and congestive heart failure and is effective in attenuating left ventricular LV dilatation, ameliorating LV ejection fraction and improving cardiovascular morbidity and mortality [ , ]. Captopril has been revealed to facilitate the GSH system in several rodent models of myocardial injuries, such as clozapine and DOX-induced damage models, thereby protecting cardiomyocytes from oxidative stress [ , ]. A recent clinical trial in type 2 diabetes patients with CVDs following captopril treatment O for 3 months found a significant improvement in plasma GSH levels and a concomitant decline in lipid peroxidation [ ]. Consequently, these results partially explain the pharmacological mechanism of captopril as a cardioprotective agent. Similar to the statin lipid-lowering drugs mentioned earlier, other lipid-lowering drugs, such as probucol, also exhibit the capability to restore the inhibited GSH system and defend the myocardium from oxidative damage after exposure to pathological factors, for example, ISO and cyclophosphamide [ , ]. Exosomes EXOS of mesenchymal stem cells MSCs from human umbilical cord blood increased GSH and attenuated lipid peroxidation and ferroptosis in cardiomyocytes in a rat infarction model. However, it has no effect on the level of GPX4 [ ]. A recent study reported that exosomes derived from mouse bone marrow MSCs exerted similar cardio-protective effects [ ]. However, not all exosomes positively impact the myocardium and GSH. For instance, exosomes secreted by adipose tissue macrophages caused ferroptosis by targeting SLC7A11 to inhibit GSH synthesis in the heart [ ]. Current gene therapy research aims to target, for example, upstream targets of the GSH system or molecules associated with it such as Nrf2, GPX, SLC7A11 , genes aberrantly expressed in myocardial injury, and noncoding RNAs regulating mRNA transcription [ 76 , , , , , ]. Recombinant human GPX4 alleviated ISO-induced myocardial ischemia injury [ ]. In addition, some investigators found that USP22 and lncRNA PART1 expression was decreased in a MIR injury model. In addition, Zhang et al. overexpressed miRp in the myocardium by direct myocardial injection of AVV-9 containing miRp precursor, which targeted inhibition of MyD88 and thus restored declining GSH levels, alleviated insult of cardiac function and oxidative injury induced by sepsis in the hearts of mice [ ]. The GSH system is one of the most significant members of the cellular antioxidant defensive system, which is essential for eliminating excess ROS and protecting the myocardium in the presence of pathological cardiovascular factors. Notably, glutathione balance and GPX4 levels are deeply involved in the susceptibility of cardiomyocytes to ferroptosis, a novel form of cell death. Furthermore, many researchers have found that reduced GSH levels and GSH-dependent antioxidant enzyme activity in damaged myocardium due to excess ROS and disruption of the GSH synthesis process, along with increased oxidative damage and ferroptosis. Based on this, therapeutic strategies to restore the activity of the GSH system in the heart are beneficial in the treatment of myocardial injury. Precursors of GSH or GPX biosynthesis, various small molecule activators related to the GSH system and some novel therapeutic approaches, such as exosomes and gene therapy, can boost the activity of the GSH system and reduce cardiac damage and ferroptosis. Notably, despite constant progress in diverse aspects of natural drug monomers that protect against myocardial injury by activating the GSH system, great challenges remain in translating these compounds into future clinical pharmaceuticals. First, most natural small molecules present low bioavailability problems [ ], so further research on delivery systems and formulations for these drugs is needed. Second, the development of new drugs requires additional and more detailed preclinical and clinical studies to determine whether long-term use is biotoxic, whether the drug has adverse effects on other peripheral organs or whether the drug candidate has a real therapeutic effect on the patients. In addition, a portion of synthetic agents have been used clinically to treat various diseases, such as myocardial infarction, heart failure, diabetes, hypertension, tumors, and sepsis. These studies on myocardial injury and the GSH system reveal new roles of these clinical drugs in the treatment and further elaborate their mechanisms, which provide new ideas for their clinical application. However, more clinical studies must be encouraged to evaluate whether these drugs can act as GSH system enhancers and cardioprotective agents in patients. Moreover, some emerging therapeutic approaches to enhance the GSH system have attracted much attention. These results show that although the expected therapeutic effect has not been achieved, AVV-based therapy has acceptable safety. This opens up the possibility of our gene therapy targeting the GSH system. Overall, we can see the value of targeting the GSH system in myocardial injury. 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Protective effects of syringic acid, resveratrol and their combination against isoprenaline administered cardiotoxicity in wistar rats. Saudi J Biol Sci. Priscilla DH, Prince PSM. Cardioprotective effect of gallic acid on cardiac troponin-T, cardiac marker enzymes, lipid peroxidation products and antioxidants in experimentally induced myocardial infarction in Wistar rats. Chem Biol Interact. Chao P-C, Hsu C-C, Yin M-C. Anti-inflammatory and anti-coagulatory activities of caffeic acid and ellagic acid in cardiac tissue of diabetic mice. Nutr Metab. Yeh C-T, Ching L-C, Yen G-C. Inducing gene expression of cardiac antioxidant enzymes by dietary phenolic acids in rats. J Nutr Biochem. Li G, Huang X. Influence of sodium ferulate on miRa and left ventricle remodeling in rats with myocardial infarction. Wang B-H, Ou-Yang J-P. Pharmacological actions of sodium ferulate in cardiovascular system. Cardiovasc Drug Rev. Socała K, Szopa A, Serefko A, Poleszak E, Wlaź P. Neuroprotective effects of coffee bioactive compounds: a review. Martínez-López S, Sarriá B, Mateos R, Bravo-Clemente L. Eur J Nutr. Sato Y, Itagaki S, Kurokawa T, Ogura J, Kobayashi M, Hirano T, et al. In vitro and in vivo antioxidant properties of chlorogenic acid and caffeic acid. Int J Pharm. Yüce A, Ateşşahin A, Ceribaşi AO, Aksakal M. Ellagic acid prevents cisplatin-induced oxidative stress in liver and heart tissue of rats. Basic Clin Pharmacol Toxicol. Ghadimi M, Foroughi F, Hashemipour S, Rashidi Nooshabadi M, Ahmadi MH, Ahadi Nezhad B, et al. Randomized double-blind clinical trial examining the Ellagic acid effects on glycemic status, insulin resistance, antioxidant, and inflammatory factors in patients with type 2 diabetes. Zhang M, Cui S, Mao B, Zhang Q, Zhao J, Zhang H, et al. Ellagic acid and intestinal microflora metabolite urolithin A: a review on its sources, metabolic distribution, health benefits, and biotransformation. Critical Rev Food Sci Nutrition. Albasher G, Alkahtani S, Al-Harbi LN. Urolithin A prevents streptozotocin-induced diabetic cardiomyopathy in rats by activating SIRT1.
The dubious practice of detox - Harvard Health	Other than eating a healthful diet, someone can help prevent atherosclerosis by maintaining a healthful lifestyle that includes:. Currently, the primary treatment for myocardial infarction is opening blocked vessels to restore blood flow to the ischemic myocardium, which is called reperfusion. Can J Cardiol. Dong L-H, Li L, Song Y, Duan Z-L, Sun S-G, Lin Y-L, et al. Many studies use synthetic forms of antioxidants, which may act differently than natural antioxidants from food sources. Many studies have concentrated on the direct effects of synthetic drugs on GSH and GSH-dependent antioxidant enzymes in damaged myocardium without further mechanistic investigations. Cardiovasc Diabetol.
Main Content	What is detoxification? Antioxidant effects of resveratrol in the cardiovascular system. Other side effects include fever, headache, nausea or vomiting. National Center for Complementary and Integrative Health. Priscilla DH, Prince PSM. ACS Pharm Transl Sci. FAQ Home Chelation therapy for heart disease Does it work.
Within a single day, most of us are exposed to hundreds of toxins and toxicants.	Chan CY, Performance enhancing drinks MC, Liu WH, Fog CY, Yin MC. Cardiovascular effects of vor versus high-dose Detoxification for improved cardiovascular health in a rat model. Herbal inflammation reducers metabolic detoxification programme might seem as straightforward as sipping that kale smoothie every day or putting on a sheet mask on weekends, but it is more nuanced than that. Quercetin Quer is one of the main flavonoids in many vegetables and fruits. Journal of Diabetes and Its Complications.
Can You Unclog and Reduce Plaque in Arteries?	Shmerling, MD , Senior Faculty Editor, Harvard Health Publishing; Editorial Advisory Board Member, Harvard Health Publishing Dr. Electrocardiogram ECG or EKG Heart transplant to treat dilated cardiomyopathy: Elmo's story Erectile dysfunction: A sign of heart disease? Disclaimer: The content of this page is not intended to be a substitute for professional medical advice, diagnosis or treatment. This alternative treatment is used to help those who suffer from high cholesterol, poor circulation, fatty liver deposits, kidney malfunctions, and atherosclerosis. Panczenko-Kresowska B, Ziemlański S, Rudnicki S, Wojtulewicz L, Przepiórka M.

Heavy metals, such cardivascular mercury, lead, Detoxification for improved cardiovascular health, arsenic, aluminum, thallium, and Performance enhancing drinks, Metabolism and weight loss be detrimental to our health, even in Performance enhancing drinks concentrations. Ideally, our bodies can dispose cardiovasxular them; however, if we absorb Bone health for endurance athletes faster than our body can impdoved them, they Detoxificatio accumulate. We take in Detoxificaiton metals Detoxificqtion the air we breathe, the food we eat, and the water we drink. Ideally, our bodies can dispose of them But if we take them in faster than our body can excrete them, they accumulate. Once heavy metals are in our bloodstream, they can be stored in the cells of tissues and organs for years, predisposing us to pain and chronic health issues until we take action to move them out of our body. Prior to developing a plan for you, we will guide you through one or more testing methods to determine your heavy metal status:.

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Detoxification for improved cardiovascular health -

Once heavy metals are in our bloodstream, they can be stored in the cells of tissues and organs for years, predisposing us to pain and chronic health issues until we take action to move them out of our body. Prior to developing a plan for you, we will guide you through one or more testing methods to determine your heavy metal status:.

Heavy metal detoxification may be a helpful component of your treatment plan, especially if you are struggling from one of these conditions:. Heavy metal detoxification uses specific chelators to safely bind and excrete heavy metals, alongside other detoxification and supportive techniques.

Heavy metal detoxification encourages the excretion of heavy metals via your own detoxification organs, such as the liver, bowels, and kidney.

Removing heavy metals from the body reduces inflammation and oxidative stress, and may improve neurological, digestive, cardiovascular, and immune system functioning. Your first visit is the opportunity for you to share your health goals, and for your doctor to gather vital health information that will help them to determine the root cause of your health concerns, and the best treatment plan for you.

Your Doctor will take a complete history, gathering details regarding your current and past health concerns, lifestyle, as well as current supplements and medications. Your Doctor will recommend various tests, either at Integrative or with your medical doctor.

These may include Biomeridian Organ Scan , Standard Lab Tests and Heavy Metal Tests serum, urine, or hair. Within your first visit, your doctor may also perform a physical exam. This may include basic vitals, Applied Kinesiology , or inspection and palpation of specific areas of concern.

The Naturopathic Doctors at Integrative are primary care providers with expertise in a wide variety of functional medicine techniques, including Pharmacology, herbal medicine, nutritional science, and acupuncture.

This knowledge allows them to apply a truly Integrative approach to each of their unique patients. Only a practitioner trained and certified in both intravenous therapy and chelation therapy, can determine whether or not you are a good candidate.

Within a visit with your Naturopathic Doctor, they will determine if you are a good candidate and make recommendations regarding a heavy metal detoxification and chelation treatment plan. Yes, you must be a current patient of a Naturopathic Doctor at Integrative in order to receive chelation therapy.

During a visit, your Naturopathic Doctor will review your full health history, current health concerns, medications, and supplements, and determine if heavy metal testing is appropriate.

The response to treatment varies, depending on the overall health of the patient, severity and chronicity of health concerns, and frequency of chelation treatments. Many patients receiving intravenous chelation therapy require a significant number of chelation visits, but retesting is typically recommended following ten sessions of chelation therapy.

Once you begin treatment, your Doctor will be able to monitor how you respond and provide a better estimate of how many treatments may be required.

The normal intestinal tract is teeming with bacteria. While dietary changes, medications, and even exposure to other people and pets! Advocates of cleanses would argue it makes intuitive sense. Predictably, the answer to whether a cleanse is a good idea depends on who you ask. There are claims about increased sex drive, better mood, and fewer cravings for junk food.

According to the ads, the number of ways a cleanse can help seems endless. For example:. Remember, health claims for cleanses have not been evaluated by the FDA. Read the product disclaimers before you buy and use these products! Just as there is limited evidence of benefit associated with detox or cleanse programs, there is limited evidence of harm.

However, there are reports of side effects and complications. Examples include:. Some recommended repeating the program periodically, so the cost can be considerable. I know there are many people who find intermittent detox diets or cleanses useful, and firmly believe they improve health.

And the ads for these programs are filled with glowing testimonials. Day 12, no exercise, down 19 pounds! Leave the detoxification to the professionals: your kidneys, liver, and other self-cleaning organs of your body. Robert H. Shmerling, MD , Senior Faculty Editor, Harvard Health Publishing; Editorial Advisory Board Member, Harvard Health Publishing.

As a service to our readers, Harvard Health Publishing provides access to our library of archived content. Please note the date of last review or update on all articles.

No content on this site, regardless of date, should ever be used as a substitute for direct medical advice from your doctor or other qualified clinician.

Eat real food. Premranjan Kumar et al. They also clarified in another clinical study that supplements with glycine 1. Gln acts as a precursor of glutamate Glu , equivalent to being an indirect glutathione precursor.

Its supplementation can enhance intracellular GSH levels and provide protection against myocardial injury. In ISO-induced myocardial infarction, pretreatment with Gln maintained cardiac GSH kurtosis and antioxidant enzyme GPX, SOD, CAT activity at near-normal levels, thus preventing oxidative damage in the myocardium [ ].

A separate experiment elucidated that Gln supplementation increased cardiac GSH to halt myocardial injury induced by cyclophosphamide CPA in rats [ ]. Notably, there is a significant correlation between plasma Gln concentrations and GSH levels.

A double-blind, randomized, placebo-controlled trial demonstrated that perioperative high-dose intravenous injection of Gln 0. O for 3 days raised plasma Gln concentrations and maintained plasma GSH levels in postoperative patients undergoing cardiopulmonary bypass CPB [ ]. Selenium Se is an essential trace element for humans and animals, serving as the main component of many antioxidant proteins in the body, such as thioredoxin reductase, selenoprotein P and GPX.

As a result, selenium may play an important role in protecting cardiomyocytes from oxidative stress [ ]. Compared with a low-Se diet 0. Zhu et al. showed that Se boosted GPX1 expression by inhibiting DNMT2-mediated DNA methylation of the GPX1 promoter from lessening ROS production in advanced glycation end-product AGE -induced heart failure [ ].

In humans, a systematic review and meta-analysis revealed that physiologically high selenium levels in the body were negatively associated with cardiovascular disease morbidity and mortality.

In addition, there is a U-shaped association between selenium exposure and some diseases, such as type 2 diabetes and fractures [ ]. However, it has also been reported that selenium supplementation alone is not associated with cardiovascular disease and all-cause mortality [ ].

Other than providing raw materials for the GSH system, another antioxidant strategy that activates the glutathione system is often achieved through medicinal therapy. In this section, we will describe their effects and mechanisms in detail by the source of the drugs.

Natural medicines have been a reliable source of drugs since ancient times, playing an essential role in preventing and treating various diseases. At present, increasing evidence has shown that compounds derived from natural medicines exert a variety of beneficial effects, including antioxidant, anti-inflammatory, and anti-apoptosis effects [ , , ].

To date, more than natural medicine monomers have been reported to activate the GSH system by several mechanisms to protect the heart from oxidative stress. Next, we will summarize some promising medicine monomers that activate the GSH system based on the categories of natural medicines, including flavonoids, terpenoids, phenolic acids, quinones, and alkaloids Table 2 , Supplementary Table S2.

Flavonoids are a group of phytochemicals widely existing in nature. They have received extensive attention for their antioxidant, anti-inflammatory, anti-mutagenic and anti-cancer properties, as well as their ability to protect against cardiovascular disease [ ].

Quercetin Quer is one of the main flavonoids in many vegetables and fruits. It not only abrogates cardiac oxidant stress but also alleviates the inflammatory response and deterioration of heart function in MIR injury and DCM in rodents [ , ]. O for 8 weeks evidently improved serum total antioxidant capacity TAC in postmyocardial infarction patients compared to the placebo group [ ].

O for 2 mouths to standard therapy improved cardiac function both systolic and diastolic functions and reduced the total duration and number of ST-segment depressions in patients with coronary heart disease CHD [ ].

Thus, Quer, as an activator of the GSH system, is a promising natural small molecule for the treatment of cardiac injury. Catechins, known as dihydroflavonols, are natural flavonoids present in green tea and other beverages, including catechin, epicatechin EC , and epigallocatechingallate EGCG [ , ].

It has been reported that these three compounds can enhance the contents of GSH and the activities of GSH-dependent antioxidant enzymes GPX and GST and reduce lipid peroxidation and cardiac damage mediated by DOX or isoproterenol ISO in the myocardium of rats, respectively [ , , ].

Genistein is the main ingredient of isoflavone from soybean and is also used as a tyrosine kinase inhibitor.

It has potent effects of antioxidant, anti-inflammatory, anti-angiogenesis, and anti-cancer [ ]. Studies have shown that genistein can increase GSH levels and GPX activity along with decreased oxidative stress in diabetic cardiomyopathy and DOX-mediated cardiomyopathy [ , ].

Meanwhile, genistein increased the levels of Nrf2, which is vital to the GSH system [ , , ]. However, it is unclear why genistein upregulates the levels of Nrf2 in the myocardium. O for one year improved both cardiac function and left atrial remodeling in postmenopausal women with metabolic syndrome [ ].

O for 24 weeks significantly increased the protein and mRNA levels of Nrf2 and the concentrations of SOD as well as diminished serum levels of inflammatory factors and MAD in patients with myocardial ischemia [ ]. Therefore, genistein, an antioxidant, might be a potential drug for treating patients with myocardial injury.

Terpenoids are natural compounds with a wide distribution, great variety, and diversified structure in nature [ ]. Terpenoids have been reported to activate the GSH antioxidant system to protect the heart from oxidative stress and alleviate cardiac injury.

Tetraterpenes, also called carotenoids, are widespread in higher plants, fungi, algae, and animals and are one of the most potent natural antioxidants [ ].

It could also alleviate the size of myocardial infarction and the subsequent decrease in cardiac function in rats [ ]. A clinical study of patients with myocardial infarction by B Panczenko-Kresowska et al. revealed that β-carotene supplementation remarkably diminished plasma lipid peroxide levels in patients [ ].

The mechanism might be related to its own antioxidant properties and GSH activating effect. Nonetheless, the most updated literature reports that β-carotene supplementation or elevated blood β-carotene levels may increase all-cause mortality and CVD risk [ , ].

O for 2 months , was reported to significantly increase the ratio of serum TAC to MDA in patients with type 2 diabetes [ ]. In addition, tanshinone IIA Tan IIA is a diterpene extracted from the root and rhizome of Salvia miltiorrhiza Bunge.

Its water-soluble derivative, sodium Tan IIA sulfonate injection STS , is widely used in the clinic as an adjuvant drug for coronary heart disease, myocardial infarction and heart failure in China [ ]. Tan IIA induced activation of the GSH system to attenuate cardiac oxidative stress and restrain the increase in serum myocardial enzymes, thus relieving the extent of myocardial damage [ , ].

Moreover, a meta-analysis showed that the addition of STS seemed more effective in treating heart failure than Western medicine alone [ ]. The excellent clinical manifestations of Tan IIA provide supportive evidence for targeting the GSH system in the treatment of heart diseases, which may be promising for transforming natural compounds from basic research to clinical applications.

Phenolic acids are attracting increasing attention for their antioxidant properties and other health benefits. Based on differences in the carbon skeleton, phenolic acids can be mainly divided into two categories: hydroxycinnamic acid e.

All of the compounds above have been proven to maintain GSH contents and GSH-dependent antioxidant enzyme activities in the myocardium, protecting it from oxidative stress [ 41 , , , , , , , ].

Ferulic acid FA , the main active component isolated from Angelica sinensis , has been documented to increase the levels of GSH and the expression of GPX in the myocardium by upregulating AMPKα2 and activating Nrf2 signaling [ 41 , ].

In recent years, ferulic acid derivatives have been widely investigated. Of them, sodium ferulate SF features low toxicity, stability, ease of synthesis, and water solubility and has been authorized by the State Drug Administration of China as an adjuvant drug for treating ischemic cardiovascular diseases [ , ].

It could also increase GPX activity, thereby exerting antioxidative effects in rats [ ]. Besides, caffeic acid and chlorogenic acid caffeoylquinic acids are two other classical phenolic acids widely found in natural plants, both of which are the most vital active substances in coffee [ ].

Some investigations have demonstrated that the two compounds, acting as agonists of the GSH antioxidant system, well prevent oxidative stress and reduce heart damage in some animal cardiomyopathy models, for instance, the ISO-induced myocardium infarction model [ , ]. Additionally, one clinical study reported that consumption of chlorogenic acid-enriched coffee not only improved plasma antioxidant capacity and decreased plasma lipid and protein oxidation but also donated to enhancing cardiovascular health in people with hypercholesterolemia [ ].

Interestingly, Yuki Sato and coworkers indicated that the antioxidant effect of caffeic acid is more potent than chlorogenic acid, and the latter is metabolized into caffeic acid in the intestine.

Ellagic acid EA also increased the GSH antioxidant system and diminished oxidative stress in several models of myocardial injury, such as diabetes and cisplatin-mediated heart injuries [ , ]. O for 8 weeks significantly fortified the mean of TAC and the activity of GPX enzymes as well as reduced MDA contents in the serum of type 2 diabetic patients [ ].

Nonetheless, it is not certain whether EA may be helpful in boosting the GSH system in cardiac patients and treating heart diseases. Thus, there is a need for larger studies to fully address this issue. In addition, EA was found to have poor low oral bioavailability, thus limiting its clinical applications.

In contrast, its intestinal microbial metabolite, urolithin, possesses better biological activity and higher bioavailability [ ]. It has been reported that urolithin A also increased total GSH, lowered oxidative stress, and improved cardiac function in the myocardium of diabetic rats [ ].

Coenzyme Q10 CoQ10 is a fat-soluble quinone. It is also a natural antioxidant molecule in the body. The positive effect of CoQ10 treatments is recognized in patients with heart failure and myocardial ischemia, such as the reduction of oxidative stress derived from cardiovascular causes, decrease in mortality and hospitalization and improvement in cardiac function [ , ].

Thereinto, the antioxidant effect of CoQ10 may be partially attributed to activating the GSH system.

In a rat model of ISO-mediated myocardial infarction, CoQ10 preconditioning not only markedly expanded cardiac GSH levels and reduced the concentration of lipid peroxidation but also alleviated myocardial damage [ ]. O for 12 weeks on the antioxidant system in patients with coronary artery diseases.

The findings revealed that plasma GPX activity was significantly increased after CoQ10 therapy and was positively related to plasma coenzyme Q10 levels [ ]. Thymoquinone Thy , a benzoquinone compound, is the main active ingredient in the extract of Nigella sativa seeds.

Its treatment was reported to increase the levels of GSH and the activities of GPX and GST, along with a decrease in cardiac lipid peroxide production in a rat model of myocardial injury caused by diazinon a pesticide [ ]. Moreover, Thy-rich Nigella sativa seed oil exerts an antioxidant effect as an adjuvant therapy in hypertensive patients, mainly manifested in the upregulation of serum glutathione reductase GR levels and reduction of serum MAD content.

It also showed beneficial impacts on glycemic and blood pressure control as well as lipid metabolism in hypertensive patients without serious adverse effects such as liver and kidney dysfunction [ ].

In addition, some quinone compounds, such as β-LAPachone and aloin, have similar effects on heart protection [ , ]. We will not give unnecessary details here. In addition to the above compounds, many other natural medicines potentially protect the myocardium by enhancing the GSH antioxidant system.

Curcumin is a classic curcuminoid extract from the rootstock of turmeric. Upstream molecular targets, such as Nrf2, Sirt3, and PPAR-γ, are responsible for the curcumin-enhanced GSH system [ , , ].

Moreover, curcumin treatment not only quells oxidative stress in the myocardium but also impedes myocardial inflammation, which improves heart function and decreases heart damage [ , , , , ].

O for 12 weeks in patients with CHD [ , ]. Considering that curcumin is nontoxic, readily available and inexpensive, it is a prospective candidate for treating heart diseases. Resveratrol RSV is a stilbene found in grapes, wine and blueberries that possesses potent antioxidant activity to protect the myocardium from oxidative damage.

In particular, the enhanced GSH system plays an essential role in the antioxidant capacity of RSV [ ]. In , Elif Tatlidede et al. demonstrated that RSV treatment notably raised cardiac GSH contents and suppressed oxidant responses in DOX-processed rats; Simultaneously, it ameliorated DOX-induced deterioration of cardiac function and myocardial injury [ ].

In the following decade, many researchers verified in various models of myocardial injury that RSV can exert an antioxidant effect and protect the myocardium by increasing the level of GSH and upregulating the activity of GSH-dependent antioxidant enzymes [ , , , , ].

Moreover, they revealed that the mechanism by which RSV enhances the GSH system involves the AMPK signaling pathway, the Nrf2 signaling pathway, the Sirt1 pathway, noncoding RNA miR and the KAT5 gene [ , , , , ]. O for 2 months better improved left ventricular ejection fraction and left ventricular diastolic function in patients with CHD compared with standard treatment alone [ ].

Synthetic drugs have been researched and developed in recent modern times, a proportion of which have already been in clinical use for the treatment of various diseases, such as myocardial infarction, heart failure, diabetes, hypertension, oncology, and sepsis. Similar to natural drugs, many synthetic drugs have properties that enhance the GSH system and thus protect cells from oxidative damage.

The following section describes and summarizes these drugs in terms of the mechanisms by which they activate the GSH system Table 3 , Supplementary Table S3.

The key upstream target for GSH system modulation is generally considered to be Nrf2, a redox-sensitive regulator. Nrf2 is involved in not only the regulation of GSH synthesis and reduction via upgrading some enzymes and proteins SLC7A11, GCLM, GCLC, GR but also the activation of GSH-dependent antioxidant enzymes GPX, GST [ , ].

Furthermore, Gobinath Shanmugam et al. revealed that in an ISO-mediated model of myocardial infarction, direct overexpression of the Nrf2 gene enhanced GSH levels in cardiomyocytes and guarded cardiomyocytes against oxidative damage and lessened the occurrence of ferroptosis [ ].

This further confirms that the enhancement of Nrf2 is a viable strategy for activating the GSH system. Melatonin prevents Nrf2 degradation and augments its nuclear accumulation by inhibiting proteasomal [ ]. In in vivo and in vitro studies, melatonin was proven to increase the level of Nrf2 in cardiomyocytes exposed to oxidative stress.

Among them, Cai et al. revealed the grievous connection between oxidative stress, pyroptosis, inflammation response, and xenobiotic metabolism in the myocardium of TMT-treated rats by String database analyzing the proteome interaction protein [ ]. In addition, Shaghayegh Haghjooy Javanmard et al.

O for 30 days notably raised Nrf2 levels in peripheral blood mononuclear cells of patients undergoing coronary artery bypass grafting CABG [ ]. O for 12 weeks increased serum GSH levels while reducing serum MDA and protein carbonyl PCO in CHD patients with type 2 diabetes.

Additionally, it was reported that trimetazidine TMZ , a piperazine derivative, mediated activation of the GSH system and had antioxidant and cytoprotective effects in several myocardial injury models [ , , , ]. For instance, in the myocardium of exhaustive-exercised rats, TMZ produced specific cardioprotective outcomes by increasing GSH and GPX activity to clear oxidative stress.

Further mechanistic studies have found that treatment with TMZ promoted cardiac Nrf2 expression, indicating that TMZ enhanced the clearance of oxidative stress by activating the GSH system through the Nrf2 signaling pathway [ ].

Moreover, TMZ also has other benefits to the myocardium, including increased coronary blood flow reserve, maintenance of cardiac energy metabolism, anti-apoptosis, and anti-inflammation.

It has been approved for clinical use in the therapy of angina pectoris [ , ]. In addition to Nrf2, activation of PPAR-γ and the AMPK pathway can also facilitate the GSH system. Rosiglitazone and pioglitazone belong to the thiazolidinedione class of hypoglycemic agents and are recognized as PPAR-γ agonists.

O for 4 weeks exhibits antioxidant properties in diabetic patients, as reflected by a decrease in MDA [ , ]. In addition, there is evidence that pioglitazone reduces the risk of MI and acute coronary syndrome in patients with cardiovascular diseases CVD and patients with type 2 diabetes who had previous myocardial infarction [ , , ].

Notably, it increases the risk for the development of heart failure [ , ]. Compared to pioglitazone treatment, rosiglitazone increases the risk of AMI and heart failure in type 2 diabetic patients and elderly patients [ , , ].

Metformin is a traditional drug for the treatment of type 2 diabetes. In addition to its antidiabetic results, it was also found to achieve cardiac protection by activating the AMPK pathway [ ].

Some researchers have shown that metformin activates AMPK and triggers the downstream GSH system to slow DOX-mediated oxidative impairment in the myocardium [ , ].

O for 12 months not only decreased oxidative stress but also lowered left ventricular mass LVM and improved blood pressure [ ].

SLC7A11 is an essential molecule that limits the Cys transport rate, thus restricting the synthesis of GSH. Direct SlC7A11 overexpression in cardiac myocytes boosted GSH levels and reduced cardiac ferroptosis and injury, suggesting that it is feasible to fortify GSH levels by increasing SLC7A11 [ 76 ].

Atorvastatin, a statin that reduces cholesterol, is a first-line drug for treating cardiovascular disease. It was reported that it could raise intracellular GSH by increasing SLC7A11 expression, efficiently leading to GPX4 enhancement and ferroptosis suppression in the ISO-induced injury model of H9C2 cells and rat myocardium [ 49 ].

Additionally, one clinical trial by Douglas Greig et al. O for 4 weeks reduced plasma MDA while improving the functional capacity assessed via a 6-minute walk test in patients with chronic heart failure CHD [ ]. However, it is not clear whether they regulate the expression of SLC7A Dexmedetomidine DEX , an α2-adrenergic receptor, also augments the expression of SLC7A In the same year, Wang et al.

Moreover, DEX treatment 0. A previous clinical study also showed that perioperative DEX 0. These results suggest that DEX has antioxidant and cardioprotective potential. However, clinical studies of the drug have focused on surgical patients.

It is unclear whether it exhibits cardioprotective effects in patients with post-PCI, AMI, or other cardiomyopathies. Many studies have concentrated on the direct effects of synthetic drugs on GSH and GSH-dependent antioxidant enzymes in damaged myocardium without further mechanistic investigations.

Herein, we discuss some critical examples of representative synthetic compounds. Captopril, an angiotensin-converting enzyme inhibitor, is widely used in clinical practice to treat hypertension, MI, and congestive heart failure and is effective in attenuating left ventricular LV dilatation, ameliorating LV ejection fraction and improving cardiovascular morbidity and mortality [ , ].

Captopril has been revealed to facilitate the GSH system in several rodent models of myocardial injuries, such as clozapine and DOX-induced damage models, thereby protecting cardiomyocytes from oxidative stress [ , ]. A recent clinical trial in type 2 diabetes patients with CVDs following captopril treatment O for 3 months found a significant improvement in plasma GSH levels and a concomitant decline in lipid peroxidation [ ].

Consequently, these results partially explain the pharmacological mechanism of captopril as a cardioprotective agent. Similar to the statin lipid-lowering drugs mentioned earlier, other lipid-lowering drugs, such as probucol, also exhibit the capability to restore the inhibited GSH system and defend the myocardium from oxidative damage after exposure to pathological factors, for example, ISO and cyclophosphamide [ , ].

Exosomes EXOS of mesenchymal stem cells MSCs from human umbilical cord blood increased GSH and attenuated lipid peroxidation and ferroptosis in cardiomyocytes in a rat infarction model.

However, it has no effect on the level of GPX4 [ ]. A recent study reported that exosomes derived from mouse bone marrow MSCs exerted similar cardio-protective effects [ ]. However, not all exosomes positively impact the myocardium and GSH.

For instance, exosomes secreted by adipose tissue macrophages caused ferroptosis by targeting SLC7A11 to inhibit GSH synthesis in the heart [ ]. Current gene therapy research aims to target, for example, upstream targets of the GSH system or molecules associated with it such as Nrf2, GPX, SLC7A11 , genes aberrantly expressed in myocardial injury, and noncoding RNAs regulating mRNA transcription [ 76 , , , , , ].

Recombinant human GPX4 alleviated ISO-induced myocardial ischemia injury [ ]. In addition, some investigators found that USP22 and lncRNA PART1 expression was decreased in a MIR injury model.

In addition, Zhang et al. overexpressed miRp in the myocardium by direct myocardial injection of AVV-9 containing miRp precursor, which targeted inhibition of MyD88 and thus restored declining GSH levels, alleviated insult of cardiac function and oxidative injury induced by sepsis in the hearts of mice [ ].

The GSH system is one of the most significant members of the cellular antioxidant defensive system, which is essential for eliminating excess ROS and protecting the myocardium in the presence of pathological cardiovascular factors. Notably, glutathione balance and GPX4 levels are deeply involved in the susceptibility of cardiomyocytes to ferroptosis, a novel form of cell death.

Furthermore, many researchers have found that reduced GSH levels and GSH-dependent antioxidant enzyme activity in damaged myocardium due to excess ROS and disruption of the GSH synthesis process, along with increased oxidative damage and ferroptosis.

Based on this, therapeutic strategies to restore the activity of the GSH system in the heart are beneficial in the treatment of myocardial injury. Precursors of GSH or GPX biosynthesis, various small molecule activators related to the GSH system and some novel therapeutic approaches, such as exosomes and gene therapy, can boost the activity of the GSH system and reduce cardiac damage and ferroptosis.

Notably, despite constant progress in diverse aspects of natural drug monomers that protect against myocardial injury by activating the GSH system, great challenges remain in translating these compounds into future clinical pharmaceuticals. First, most natural small molecules present low bioavailability problems [ ], so further research on delivery systems and formulations for these drugs is needed.

Second, the development of new drugs requires additional and more detailed preclinical and clinical studies to determine whether long-term use is biotoxic, whether the drug has adverse effects on other peripheral organs or whether the drug candidate has a real therapeutic effect on the patients.

In addition, a portion of synthetic agents have been used clinically to treat various diseases, such as myocardial infarction, heart failure, diabetes, hypertension, tumors, and sepsis.

These studies on myocardial injury and the GSH system reveal new roles of these clinical drugs in the treatment and further elaborate their mechanisms, which provide new ideas for their clinical application. However, more clinical studies must be encouraged to evaluate whether these drugs can act as GSH system enhancers and cardioprotective agents in patients.

Moreover, some emerging therapeutic approaches to enhance the GSH system have attracted much attention. These results show that although the expected therapeutic effect has not been achieved, AVV-based therapy has acceptable safety. This opens up the possibility of our gene therapy targeting the GSH system.

Overall, we can see the value of targeting the GSH system in myocardial injury. Despite being faced with many problems, it provides new directions and ideas for the treatment of myocardial injury. The continuous exploration of new treatment modalities will be critical to successfully combat myocardial damage in the future.

All data generated or analyzed during this study are included in this published article and its supplementary information files. Roth GA, Mensah GA, Johnson CO, Addolorato G, Ammirati E, Baddour LM, et al.

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Do you currently suffer with cardiovasculqr issues? Do us Detoxificarion favor… the Detoxiflcation time that you Detoxofication to take a stroll outdoors, use Detoxification for improved cardiovascular health hygiene products, cleaning products, Detkxification your hair color, or take a bite out cardiovasculr a frozen pizza, please consider this Detpxification How many cardiivascular toxins Diabetic nephropathy diet your body vulnerable to every single day and could this be a major cause to your heart problems? There are many key factors that lead to heart conditions such as DNA or the consequences of poor lifestyle decisions. Although, the possibility of inflammation being a culprit is not a common theory among most conventional doctors. What does this have to do with environmental toxins? Common exposure to environmental toxins leads to bacterial buildup which causes inflammation within the body. This inflammation has the potential of affecting the cardiovascular system by causing plaque accumulation, thus inducing cardiovascular disease, strokes, and heart attacks.