a H 2 O 2 - and 2-ME-induced apoptosis formation of sub-G1 peaks was determined in HEK and U87 cells over a h time course. c Silencing of Beclin-1, ATG-5 and ATG-7 expression by siRNAs was performed on HEK cells as described in Materials and Methods section.

H 2 O 2 and 2-ME have been reported to induce ROS generation and cell death. Tiron also significantly blocked H 2 O 2 -or 2-ME-induced autophagosome accumulation. The formation of AVOs and GFP-LC3 vacuoles induced by H 2 O 2 and 2-ME was decreased following addition of tiron Figure 4bi.

Expression of beclin-1 and conversion of LC3-I to LC3-II induced by H 2 O 2 or 2-ME were also suppressed by the addition of tiron Figure 4bii. The addition of tiron also reduced the levels of cell death induced by H 2 O 2 and 2-ME in HEK cells Figure 4c.

Interestingly, H 2 O 2 - or 2-ME-induced apoptosis formation of sub-G1 peaks was not affected by the addition of tiron Figure 4d. This suggests that ROS are involved in the induction of autophagosomes and autophagic cell death induced by H 2 O 2 or 2-ME.

Tiron decreases autophagic cell death induced by H 2 O 2 and 2-ME. HEK cells were treated with H 2 O 2 1. a Reactive oxygen species ROS was determined as described in Materials and Method section. b i Formation of AVOs and GFP-LC3 vacuoles dots were determined as described above. ii Expression of beclin-1 and conversion of LC3-I to LC3-II were determined by western blotting.

c Cell death was determined by membrane permeablization. d Apoptosis was determined by formation of sub G: peak as described in Materials and Methods section. Another way to reduce ROS damage is to enhance the ability of the antioxidant system in cells.

In cells, antioxidant enzymes such as SOD, catalase and glutathione peroxidase can eliminate ROS. Formation of AVOs and GFP-LC3 vacuole following H 2 O 2 and 2-ME treatment were decreased by overexpression of SOD2, to the levels similar to control Figure 5bi.

Expression of beclin-1 and conversion of LC3-I to LC3-II induced by H 2 O 2 and 2-ME were also greatly suppressed by overexpression of SOD2 Figure 5bii. Lastly, overexpression of SOD2 decreased the levels of H 2 O 2 - and 2-ME-induced cell death Figure 5c. When 3-MA was added, the levels of H 2 O 2 - and 2-ME-induced cell death were decreased in the wild-type cells, but in the SOD2-overexpressing cells, the levels of cell death were not affected Figure 5c.

Taken together, overexpression of SOD2 in HeLa cells decreased ROS generation, autophagosomes and autophagic cell death. Overexpression of SOD2 decreases autophagic cell death induced by H 2 O 2 and 2-ME.

Wild-type wt and SOD2-overexpressed SOD2 HeLa cells were treated with H 2 O 2 1. a i Confirmation of SOD2 overexpression was determined by western blotting using β -actin as a loading control. ii ROS generation was determined as described in Materials and Methods section.

b i The amount of autophagy formation of AVOs and GFP-LC3 vacuoles dots was determined following treatment with H 2 O 2 and 2-ME. c Cell death was determined as described above. In contrast to overexpressing SOD2, suppressing expression of SOD2 would theoretically increase ROS generation, autophagosomes and autophagic cell death.

In HeLa cells, expression of SOD2 was successfully reduced by SOD2 siRNA Figure 6a. As expected, the levels of H 2 O 2 - and 2-ME-induced ROS generation, autophagosomes formation of AVOs and GFP-LC3 vacuoles and cell death were significantly increased by SOD2 siRNA Figure 6b—d.

Addition of 3-MA reduced H 2 O 2 -induced cell death in cells with knock down SOD2 expression Figure 6d. In contrast, the level of H 2 O 2 -induced apoptosis formation of sub-G1 peaks was not significantly affected by SOD2 siRNA Figure 6e.

Silencing SOD2 expression by siRNA increases autophagic cell death induced by H 2 O 2. a SOD2 expression was reduced by SOD2 siRNA in HeLa cells wt as determined by western blotting. Since it was reported that the caspase inhibitor zVAD induced autophagy which then led to catalase degradation and ROS generation, 15 we have investigated whether ROS generation was also a downstream effect of autophagy induced by oxidative stress H 2 O 2 or 2-ME.

When H 2 O 2 -induced autophagosome accumulation was inhibited by beclin-1, atg-5 and atg-7 siRNAs in HEK cells Figure 2c , H 2 O 2 -induced ROS generation was not affected Figure 7.

Similar results were found in U87 cells transfected with atg-7 siRNA Supplementary Figure S4F and in HeLa cells transfected with beclin-1 and atg-5 siRNA data not shown. This indicates that H 2 O 2 - and 2-ME-induced ROS generation occurs upstream of autophagy.

Inhibition of autophagy has no effect on ROS production induced by H 2 O 2 and 2-ME. ROS generation was determined as described in Materials and Methods section after autophagy genes beclin-1 , atg-5 and atg-7 were silenced by siRNAs and cells treated with H 2 O 2 1.

Since H 2 O 2 and 2-ME can induce ROS generation that triggers autophagy and autophagic cell death in astrocyte-derived glioma cells U87 cells , we investigated whether H 2 O 2 and 2-ME can increase autophagosomes and autophagic cell death in primary mouse astrocytes.

Primary mouse astrocytes were treated with increasing concentrations of H 2 O 2 0. This induced ROS generation Figure 8a but at lower levels compared to HEK or U87 cells Figure 4a and Supplementary Figure S6. Increasing concentration of H 2 O 2 also failed to further increase ROS generation Figure 8a.

After H 2 O 2 and 2-ME treatment, mouse primary astrocytes failed to significantly increase AVOs formation, GFP-LC3 vacuoles formation, beclin-1 expression and conversion of LC3-I to LC3-II even in the presence of lysosomal inhibitor NH 4 Cl that prevents degradation of LC3-II 24 in these cells Figure 8b.

Even at 3. This indicates that oxidative stress fails to induce autophagy in mouse primary astroyctes. However, H 2 O 2 and 2-ME treatment induced apoptosis Figure 8c and cell death Figure 8d in these astrocytes.

Under starvation conditions, primary mouse astroyctes were capable of inducing autophagy as determined by increased AVO formation and GFP-LC3 vacuole formation Supplementary Figure S7 and by increased expression of LC3-II Figure 8biv. To determine whether this difference between human transformed cell lines and mouse primary cells was not due to differences between human and mouse cells, the transformed mouse NIH 3T3 fibroblast cell line was treated with H 2 O 2 and 2-ME.

The amount of ROS generation, AVO formation and GFP-LC3 vacuoles formation increased and the amount of H 2 O 2 - and 2-ME induced cell death was blocked by 3-MA Supplementary Figure S8. Therefore, unlike in transformed cells, H 2 O 2 and 2-ME preferentially induced apoptotic cell death in nontransformed primary mouse astrocytes.

H 2 O 2 and 2-ME fail to induce autophagy in primary mouse astrocytes. Primary mouse astrocytes were treated with H 2 O 2 or 2-ME as indicated.

b Autophagy was determined as described above. ii Formation of GFP-LC3 vacuoles dots over a h time course in the absence and presence of NH 4 Cl. iii Beclin-1 expression was determined by western blotting after cells were treated with H 2 O 2 1. d Cell death was determined as previously indicated.

Oxidative stress has been shown to induce autophagy under certain conditions such as ischemia and reperfusion. Herein we demonstrated for the first time that using H 2 O 2 and 2-ME to induce oxidative stress caused autophagy-induced cell death in transformed cell line HEK and cancer cell lines U87 and HeLa cells.

Blocking autophagosome accumulation through chemical inhibitors or knocking down autophagy genes effectively blocked oxidative stress-induced cell death. Furthermore, blocking ROS generation also effectively blocked autophagy and cell death.

In contrast, mouse primary astrocytes following oxidative stress failed to undergo autophagy. This indicates that oxidative stress induces autophagy-mediated cell death in transformed and cancer cells.

Autophagic cell death remains controversial since autophagy contributes to cell survival under stress such as starvation. The metabolic toxin arsenic trioxide induced autophagic cell death mediated by upregulation of pro-cell death Bcl-2 family member BNIP3.

We have determined that under oxidative stress, autophagy contributes to cell death. Taken together, autophagy could contribute to both cell survival and cell death. Besides autophagy, oxidative stress has been shown to induce apoptotic signaling pathways leading to cell death. This is similar to the effect of arsenic trioxide As 2 O 3 on cell death in human T-lymphocytic leukemia and myelodysplastic syndrome MDS cell lines.

This indicates that when H 2 O 2 -or 2-ME-induced apoptotic cell death pathway is blocked, cells preferentially die by the autophagic pathway. Conversely, blockage of autophagosome accumulation failed to significantly alter apoptosis.

This suggest that apoptosis occurs independent of autophagy. The amount of oxidative stress-induced cell death was not completely blocked by inhibiting either apoptosis or autophagy. This indicates that there is a third cell death pathway. This third type of cell death could be the necrotic cell death pathway.

This form of cell death is passive and causes cellular contents to be released to the extracellular space and often causes inflammation. Reports have shown that when apoptotic or autophagic cell death was blocked, necrotic cell death was observed. Nevertheless, our results indicate that autophagic cell death pathway plays an important role in oxidative stress-induced cell death.

Autophagy pathways have been extensively studied. A recent report suggests that ROS could be involved in caspase-independent cell death in macrophage cells. Tiron treatment however failed to completely eliminate oxidative stress-induced ROS generation suggesting that higher levels of ROS or the types of ROS generated might be important in regulating autophagy independent of apoptosis.

Indeed, ROS have many effects on cells including DNA damage, mitochondrial dysfunction, activation of signaling pathways and activation of transcription factors leading to upregulation of genes.

This agrees with the report by Thorpe et al. The mechanism for ROS-mediated upregulation of beclin-1 and the differences between ROS-induced apoptosis and autophagy will be the focus for further investigation.

Cancer cells produce higher levels of ROS than normal cells, and this contributes to cancer progression. Hagen et al. Indeed, overexpression of mitochondrial SOD2 blocks ROS generation and autophagosome accumulation induced by 2-ME.

A strategy to sensitize cancer cells to drug-induced apoptosis is to combine an ROS-generating drug with the inhibition of mitochondrial respiration enhancing ROS production and cell death such as combining As 2 O 3 with rotenone an inhibitor of mETC complex I.

In addition, autophagy failed to be significantly induced in primary astrocytes under oxidative stress. Thus, targeting ROS generation could selectively induce autophagic cell death in cancer cells. In conclusion, oxidative stress induces autophagy and provides a novel mechanism for oxidative stress-induced cell death that is selective toward transformed and cancer cells.

This may lead to new strategies to develop therapeutic drugs that will selectively target cancer cells to undergo autophagy-induced cell death independent of apoptosis. Benzyloxycarbonyl-Val-Ala-Asp zVAD fmk, zVAD was purchased from Calbiochem Mississaga, Ontario and dihydroethidium HE from Invitrogen Burlington, Ontario.

HE, 2-ME, zVAD and DAPI were dissolved in dimethyl sulfoxide DMSO. AO, EB and trypan blue were dissolved in 1 × PBS. The final concentration of DMSO in media was less than 0. The concentrations of some reagents used in this study were: H 2 O 2 , 1.

Beclin-1 and ATG-5 primary antibodies and their secondary antibody donkey anti-goat HRP were purchased from Santa Cruz Biotechnology, Inc.

CA, USA. ATG-7 antibodies were purchased from PromoKine Inc. SOD2 antibodies were purchased from StressGen Biotechnologies Victoria, Canada. Rabbit anti-actin antibody was purchased from Sigma, rabbit anti-LC3 antibody from Abgent Inc. The siRNA specific for human beclin-1 was purchased from Dharmacon Lafayette, CO, USA and the sequences used were same as those by Degenhardt et al.

TX, USA targeting exons 1 and 2 and sod-2 siRNA was purchased from Ambion Inc. Medium for the stabilized HeLa cells with overexpression of SOD2 was also supplemented with 0. In this study, except otherwise stated, HeLa cells refer to the wild-type cell line.

Cell death was analyzed by measuring the permeability of the plasma membrane to AO-EB or trypan blue. Cell suspension was centrifuged in an eppendorf tube. Live cells are permeable to AO but not to EB and stained green, and dead cells permeable to both AO and EB, and EB stains the DNA red. This red staining is distinctive from AO staining of autolysosomes red in the cytoplasm.

At least cells were counted for each treatment. Cell death can also be analyzed by staining cells with trypan blue and counting cells under a microscope.

Briefly, cells were collected and suspended in 0. Then, cells were stained with trypan blue with a final concentration of 0. Stained cells were analyzed on a flow cytometer using CellQuest software Becton Dickinson, San Jose, CA. Two peaks in the histograph were observed.

The first peak represents viable cells, which were dimly fluorescent and not permeable to trypan blue. The second peak represents dead cells, which were brightly fluorescent and permeable to trypan blue.

On the fourth day, cells from each big plate were split into six-well plates with same amount of cells in each well. On the fifth day, old media were removed, and fresh media and H 2 O 2 were added. On the sixth or seventh day, cells were collected and analyzed, and partial cells were lysed to make protein lysates for western blot.

Transfection of siRNA into cells follows the Invitrogen protocols with some modifications. The cells were washed once with plain DMEM medium. Then, 2. Autophagy is characterized by the formation of AVOs autophagosomes and autolysosomes.

The intensity of the red fluorescence is proportional to the degree of acidity. Thus, the formation of AVOs can be quantified. Cells were washed twice with PBS, resuspended in 0. The DNA was stained with antifade DAPI solution after cells were fixed with 3.

Apoptosis was analyzed by measuring sub-G1 peaks indication of DNA fragmentation on a flow cytometer after cells were fixed with ethanol and stained with propidium iodide as stated previously.

TUNEL assay Roche Inc. that detects DNA breaks was detected on flow cytometer as per the manufacturer's instructions. ROS generation was determined by flow cytometry after cells were stained with HE. First, HE was dissolved in DMSO to make aliquots of stock solution of 1. When used HE is taken out, covered with aluminum foil, and kept on ice until it is melt.

For staining of cells, cells were centrifuged down and the pellet was resuspended in 0. glutaraldehyde in 0. The samples were then washed again, dehydrated with graded alcohol, and embedded in Epon-Araldite resin Canemco Inc.

Ultrathin sections were cut on a Reichert ultramicrotome, counterstained with 0. Western blot analysis was performed as stated previously. All experiments were repeated at least three times and each experiment was carried out at least by triplicates.

The data were expressed as means±S. Statistical analysis was performed by using Student's t test using at least three independent data points. The software used is excel or sigma blot. Levine B, Yuan J.

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The ischemia—reperfusion injury IRI may be characterized as a problematical pathologic condition encompassing numerous factors such as oxidative stress. Extensive damages attributed to mitochondria have been considered in IRI containing unbalanced swelling and crista fragmenting of mitochondria, in ischemic cerebrovascular disease, particularly throughout the acute phase.

This impairment motivates mPTP to open unremittingly, leading to the occurrence of an alteration in ROS formation, energy shortage, and membrane potential, thus prompting autophagy. It has been witnessed that autophagy is caused in the mouse striatum and cortex subsequent cerebral hypoxic-ischemia and augmented by a consequent ROS overproduction.

Oxidative damage in mouse striatum and cortex subsequent cerebral hypoxia—ischemia causes autophagy. Autophagy during this circumstance can noticeably save neurons in the ischemic condition by inhibiting necrosis and apoptosis via abolishing damaged mitochondria [ ].

It has been conveyed that insufficiency of fatty acids FAs intensely alters ischemia-induced autophagy activation. This is revealed by the raised levels of LC3 and Beclin1 expression, along with significant growth in 8-OHdG, signifying that FAs deficiency can ameliorate the levels of autophagy via induction of oxidative damage.

A study has presented that together ROS and autophagy are involved in reperfusion injury afterward cerebral ischemia which antioxidants frequently stimulate autophagy [ ]. The use of antioxidants well-identified as revulsive of autophagy has the ability to attenuate neuronal damage and expressively alleviate the infarcted area.

Therefore, we will wonder that antioxidants might play a defensive character in ischemic injury by prompting autophagy. There could also be some more complex crosstalk mechanisms concerning autophagy and oxidative stress in the necessity of additional research [ ]. Furthermore, SIRT3 may be a well-maintained deacetylase connected to biological roles like stress resistance, mitochondrial redox homeostasis, and energy metabolism.

Pharmacological or genetic impeding of autophagy can amend SIRT6-mediated neuronal damage, feasibly via mitigating Akt signaling allied with oxidative damage in the OGD model of SH-SY5Y neurons. Besides, moderate activation of ROS can encourage Parkin translocation into the injured mitochondria, afterward suffer Parkin-mediated mitophagy and certify the mitochondria integrity in ischemic brain injury [ ].

So, as a blood flow reduction situation, chronic cerebral hypoperfusion is a problem for treating many debilitating cerebral disorders, leading to apoptotic neuronal cell death and cognitive disorders.

Hence, for decreasing apoptotic neuronal cell death, a treatment for chronic cerebral hypoperfusion could be a good idea [ 76 ]. Su and colleagues explored cannabinoid receptor agonist WIN55,—2 WIN and fatty acid amide hydrolase inhibitor URB URB in a rat model to be considered for treating chronic cerebral hypoperfusion induced apoptosis.

They found that WIN and URB treated rats showing better action in memory tests and neural cells counting, proteomics, genomics, and brain sections analysis showed a reduction of neurotoxicity, phosphorylation of c-Jun N-terminal kinases JNK , caspase-3 initiation, and Bcl-2 to Bax ratio [ , , ].

In another study by this team, they investigated the URB effect on up-regulated autophagy in chronic cerebral hypoperfusion status in the brains of a rat model of chronic cerebral hypoperfusion; they reported that inhibition of autophagy by URB reduced autophagosomes accumulation and decreased synaptic degradation caused by excessive autophagy, and diminished mitochondrial dysfunction and mitophagy.

Based on increasing phosphorylated Akt and mTOR levels and unchanged AMPK, they suggested Akt-mTOR signaling as a possible pathway to inhibit autophagy by URB [ ]. A meta-analysis about the effect of autophagy regulation on spinal cord injury improvement showed it altered neurological recovery, whether it is increased or decreased, but no apparent discrepancy was seen among increment and decrement of autophagy in spinal damage treatment in a rat model [ ].

Zhu et al. discussed that acupuncture could increase mTORC1expression in the peri-infarct cortex and decrease ULK1 , ATG13 , and Beclin1 amounts. However, above and beyond, acupuncture attenuated LC3-II and Beclin 1 expression and the number of autophagosomes [ ].

Transcription factor E3 TFE3 has excellent potential for use in ROS-mediated autophagy dysfunction following spinal cord injury. TFE3 has been regulated partially afterward the spinal cord injury via regulation of AMPK-mTOR and AMPK-SKP2-CARM1 signaling pathways [ 61 ].

The induction of therapeutic autophagy acts as a survival mechanism. However, progressive autophagy, also known as autophagic cell death, can lead to non-apoptotic cell death.

Many human diseases such as autoimmune diseases, cancers, cardiovascular disorders, microbial infections, metabolic diseases, inflammatory responses, bone diseases, renal ailments, liver disorders, NDDs, etc. Autophagy can be utilized both in maladaptive and adaptive functions in the pathogenesis of various diseases Fig.

A variety of autophagy implications are exhibited in this figure. Khandia and coworkers explained the roles of autophagy in infectious diseases in their recent review article very carefully.

Autophagy has a critical role in viral infections, for instance, bird flu, swine fever, Ebola virus disease, Zika virus infection, SARS, Chikungunya infection, Dengue virus infection, viral encephalitis, Crimean-Congo hemorrhagic fever CCHF virus, Hendra virus infection, Nipah virus infection, and the West Nile virus infection [ ].

Autophagosome formation is induced in the early stages of the influenza A virus. However, later stages result in the inhibition of autophagosomal maturation. MTORC1 downregulates classical swine fever virus replication through autophagy and IRES-dependent translation.

Transcription of ATGs is promoted in severe acute respiratory syndrome SARS -coronavirus. Moreover, it has been reported that endoplasmic reticulum ER stress in Dengue virus DENV infections led to autophagy activation, viral replication, and pathogenesis. Autophagy has also been shown to have a crucial role in microbial infections, including those caused by Listeria , Salmonella , Shigella , Streptococcus , Mycobacterium tuberculosis , and Salmonella enterica serovar Typhimurium [ ].

The role of autophagy in Toxoplasmacidal mechanisms has been observed [ ]. Autophagy is more involved in cancers than other diseases; the effects of autophagy on cancer are highly dependent on the situation.

It can eliminate the tumor or be ineffective or even strengthen the spread of the tumor. In recent years many studies have been conducted to investigate the use of autophagy to treat diseases. However, the critical question of whether autophagy could be regulated for cancer treatment or not remained unanswered, although there are now pieces of evidence that autophagy in cancer acts as a lifeline to chemotherapy.

Although, studies have shown that autophagy is a vital cell rescue mechanism for clearing defective proteins and damaged organelles that conserve cell energy and function [ 21 , , ].

Plumbagin, a quinonoid component isolated from Plumbago zeylanica L. The roles of miRNAs in osteosarcoma in recent investigations showed miRNAs like MiR involved in determinant sectors of autophagy gene regulation. Beclin1 , LC3 , Metadherin MTDH , ATG5 genes, and the proteins of LC3 , ATG5 that are closely related to autophagy regulation and anticancer drug resistance, when an encounter with miR downregulate obviously [ , , ].

Lovastatin inhibition of autophagy in glioblastoma cells which were resistant to temozolomide, enhanced efficacy of temozolomide through cessation of autophagy cascade by inhibition of LAMP2 and dynein proteins.

Impermanent formation of autolysosomes increased glioblastoma cell death [ , ]. Proof of bufalin-induced autophagy comprised the formation of the acidic vesicular organelles, augmentation of autophagolysosomes, and accumulation of LC3-II.

More reports presented that the mechanism of bufalin-induced autophagy connected with ATP depletion involved an increased AMPK activation, diminished phosphorylation of mTOR, and its downstream targets 4EBP1 and p70S6K1 [ ].

Autophagy inhibition in lung cancer can overcome drug resistance, like the effect of candesartan and gingerol on TRAIL-resistant lung cancers via autophagy inhibition caused a reduction of drug resistance [ , ].

A study on the effect of cigarette smoke extract CSE on fibroblast cells of the lung seen CSE induction of autophagy and related proteins, such as optineurin.

Inhibition optineurin reversed the pathway and reduced p62 protein and IL-8 expression in these treated fibroblasts. Zhang and colleagues explored the linkage of autophagy to the effectiveness of chemotherapy with a regimen of 5-FU and 3-MA in the treatment of Squamous cell carcinoma SCC.

SCC is a type of malignant skin cancer, and its prevalence is one-fifth of non-melanoma skin cancers. Yi Zhang and colleagues explored the effect of sodium selenite on leukemia. They found p53 was a primary up regulator of phospholipid scramblase 1 PLSCR1 , acting as a confluence shifting autophagy to apoptosis in leukemia.

PLSCR1 Tuning of apoptosis and autophagy possibly is the primary mechanism in the efficacy of chemotherapy [ 76 , ]. Ectopic expression of Beclin1 in breast cancer cells MCF-7 activated autophagy. Moreover, the monoallelic deletion of Beclin1 was witnessed in numerous specimens of human breast, ovarian, and prostate cancer cells [ ].

UVRAG, an upregulating agent of the Beclin1-class III PI3K complex, suppressed the proliferation and tumorigenicity of colon cancer cells. In addition, knockout of Bif-1which interacted with Beclin1 and activated the Beclin1-class III PI3K complex, ameliorating spontaneous tumors' progression in vivo [ , , ].

A systemic mosaic deletion of ATG5 or a liver-specific ATG7 deficiency in mice led to the development of benign liver tumors, proposing the critical role of autophagy in the abrogation of spontaneous tumor genesis [ ]. Autophagy decreases during the aging process.

It seems that maintaining autophagy is an effective anti-aging treatment. During the aging process, the innate immune system response to external antigen decreases, ROS production and IL-1B concentration, and IL Increase by macrophages.

Other innate immune cells that are affected by aging are neutrophils. Although there is no reduction in the total number of these cells during aging, studies have shown that their capacity for phagocytosis and xenophagy have an inverse relationship with age.

They find similar conditions diminish antigens presentation and chemotaxis. In addition to the weakening of immunity against pathogens, chronic inflammation develops, and immune cells do not return to the basal level of homeostasis after inflammation. Peripheral cells such as adipose increase inflammatory status by increasing the release of cytokines.

Cell-mediated immunity because of DNA damages and shortening of telomeres have obstacles to replicating and reproducing. Their ability to create a memory is reduced [ , ]. T cells secrete proinflammatory cytokines without antigen stimulation, do not respond to apoptotic signals, diminished the production of the central cytokines like TNF-α, IL-2, INF-γ, and granzyme B, and consequently, their response to infections decreases.

Although B lymphocytes are less studied in aging research, in some studies on human vaccination, due to reduced humoral immune response, it appears to be related to B cells malfunction [ 76 , ]. Furthermore, macrophages, B, and T cells for phagocytosis, antigen presentation, and hemostasis require autophagy.

Therefore, it is conceivable to reduce the immunological effects of aging by targeting autophagy [ ]. Recent studies indicated that AMPK activation inhibited cell-induced aging by boosting activation of autophagy, detention of mTORC1 process, and reducing oxidative stress.

Hence, it seems to be an excellent strategy to enable AMPK to stop cell aging [ , ]. Moreover, the ATG5 gene has participated in the incidence and development of systemic lupus erythematosus as an autoimmune disease [ ]. Additionally, autophagy and chronic inflammation involved cystic fibrosis, an incurable genetic condition initiated by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator.

Meng and colleagues claimed autophagy could mitigate pulmonary fibrosis by mediating the activation of the NOD-like receptor family pyrin domain containing 3 NLRP3 inflammasome induced by angiotensin II-mediated ROS via modulation of redox balance [ ].

Moreover, asthma and COPD can be related to the role of autophagy [ ]. Evidence indicated that autophagy plays a central role in tissue remodeling.

The changed autophagy pathway in response to cellular stress in asthma and COPD resulted in activation and crosstalk between structural airway and immune cells. This further leads to autophagy impairment causing intracellular constituents degradation and secreting inflammation mediators, which cause lung airway remodeling [ ].

Corneal oxidative stress upregulated LC3 , Beclin 1 , and ATG12 levels; however, P62 were downregulated. Hence, various signaling pathways, such as the mTOR, showed the interplay of ROS and autophagy in corneas [ ]. Regulation of the expression of LC3II and P62 regarding suppression of the senescence of lens epithelial cells by restoring autophagy flux after metformin administration was observed.

More studies about the role of autophagy in glaucoma have been reported [ ]. Autophagy can act as a cyto-protector or a cyto-killer in glaucoma. The dual role of autophagy in glaucoma progression is related to the glaucoma stage, autophagy stage, autophagy detection time, and even genomic changes [ ].

Cardiometabolic disease comprises a wide range of cardiovascular diseases, diabetes, and obesity [ ]. In vitro and in vivo results elucidated that hindering the expression of ATG7 had a defective role regarding insulin signaling and augmented ER stress.

On the contrary, reinstatement of ATG7 expression in the liver limited ER stress and improved insulin activity and systemic glucose tolerance in mice with obesity.

Furthermore, autophagy has a crucial role in normal adipogenesis, and abridge of autophagy has anti-obesity and insulin-sensitizing properties [ , ].

According to the shreds of evidence, impaired autophagy might contribute to insulin deficiency and hyperglycemia. Autophagy was considered a significant regulator in pancreatic β-cells, and ATG7 mutation exhibited damaged glucose tolerance.

In an investigation on the effect of liraglutide on cardiac fibrosis caused by aortic banding in rats, results indicated that inhibition of p70S6K , a ribosomal protein S6 kinase, and mTOR signaling by liraglutide, showing a positive effect on reduction of heart dysfunction emanating from fibrosis and cardiomyocyte hypertrophy by increase autophagy [ ].

ATG5 deficiency was reported to contribute to various cardiovascular diseases [ ]. Dysregulation of autophagy is one of the reasons responsible for the pathogenesis of acute kidney injury, or incomplete kidney repair after acute kidney injury and chronic kidney disease of diverse aetiologies, comprising diabetic kidney disease, focal segmental glomerulosclerosis, and polycystic kidney disease.

Autophagy also plays a critical role in kidney aging. CMA, AMPK, sirtuins, and the mTOR pathway are considered the most feasible gates for regulating autophagy-related to renal disease [ 11 , , ].

Autophagy has an emerging primary function in maintaining the balance of liver metabolism and the modulation of its physiology. On the contrary, numerous documents have shown that autophagy may disease-dependently play a part in the pathogenesis of liver disorders, like Wilson's disease, α-1 antitrypsin deficiency, hepatocellular carcinoma, cirrhosis, acute liver injury, chronic alcohol-associated liver disease, liver hepatitis, fibrosis, steatosis, and non-alcoholic fatty liver disease NAFLD [ ].

Carbamazepine, rapamycin, and ursodeoxycholic acid are drugs with autophagy induction and assistive in combating various liver diseases [ ]. There are a number of transcription factors that can assist in regulating hepatic functions related to autophagy.

These transcription factors are encompassing CREB, Nrf2, PPARα, and TFEB. Ueno et al. demonstrated that the mTORC1 complex acts as a fundamental portion of the liver's amendment to metabolic disorders, containing nutrient starvation.

Inactivation of mTORC1 causes TFEB activation and NCOR1 inactivation. Moreover, the integral functioning of Nrf2 and Parkin-mediated mitophagy have participated in the modulation of autophagy in liver disorders [ , , , ]. Autophagic catabolism is involved in controlling and managing the survival and working of osteoclasts, osteocytes, and osteoblasts.

Hence it is essential for the conservation of skeletal homeostasis. Unusual autophagic action causes obviation of the balance of the bone-remodeling manifesting as pathological conditions, comprising osteopetrosis and osteoporosis.

Regulation of autophagy has eliminated therapeutic potential in the treatment and prevention of bone-related diseases. According to the pivotal character of skeletal muscles in metabolism control, maintaining the muscle homeostasis through making balance among catabolic and anabolic processes is of high emphasis.

Hence, autophagy is a principle catabolic mechanism in the skeletal muscles which helps in the achievement of the mentioned aim. The significance of autophagy as a helpful target and recommend explaining associations between protein unfurling and mTOR-dependent or mTOR-independent hypertrophic reactions is likely to uncover particular helpful windows for treating muscle squandering clutters muscle function loss or paralysis [ 19 , ].

While the appropriate function of autophagy is vital for the exact function and CNS development, any single gene disorder related to autophagy signaling can be harmful. In summary, regarding the emerging emphasis on cellular autophagy, a comprehensive literature overview was conducted to discuss the pharmacological aspects of autophagy, focusing on its interplay with oxidative stress in neurological disorders.

Various human diseases have been contributed to alterations in autophagy entailing cancers, cardiometabolic diseases, renal and liver diseases, bone diseases, neurological disease, aging, and immune dysfunctions.

This interplay assists in the foundation of variable targets for drug discovery. Wang M-M, Feng Y-S, Yang S-D, Xing Y, Zhang J, Dong F, et al.

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Download references. Department of Physiology, Kalpana Chawla GMC, Karnal, Haryana, India. Intern, Faculty of Medicine and Health Sciences, SGT University, Gurugram, Haryana, India. You can also search for this author in PubMed Google Scholar. Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, India.

Chair and Department of Toxicology, Jagiellonian University Collegium Medicum, Kraków, Poland. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.

University of Burdwan, Bardhaman, West Bengal, India. Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland. Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA.

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mTOR signaling in stem and progenitor cells. Download references. The authors would like to acknowledge the published work that were cited for this review and those that were not cited because of space and our own limitations.

The work was supported by the NIH CORE Grant P30 EY to the Department of Ophthalmology University of Pittsburgh, the Eye and Ear Foundation of Pittsburgh, and from an unrestricted grant from Research to Prevent Blindness, New York, NY, Ministry of Science and Technology MOST BMY3 and BMY3 and the National Sun Yat-sen University-KCGMH Joint Research Project and Department of Ophthalmology and Neurobiology, Louis J.

Fox Center for Vision Restoration, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Department of Biomedical Science and Environmental Biology, PhD Program in Life Science, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan. Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.

Institute of BioPharmaceutical Sciences, National Sun Yat-Sen University, No. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.

Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan. Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan. Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.

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Skip to main content. Search all BMC articles Search. Download PDF. Review Open access Published: 03 January The interplay of autophagy and oxidative stress in the pathogenesis and therapy of retinal degenerative diseases Kun-Che Chang ORCID: orcid. Abstract Oxidative stress is mainly caused by intracellular reactive oxygen species ROS production, which is highly associated with normal physiological homeostasis and the pathogenesis of diseases, particularly ocular diseases.

Background Christian de Duve, a Nobel Prize winner in , observed cellular autophagic structures by electron microscopy sixty years ago due to the discovery of peroxisomes and lysosomes [ 1 , 2 ].

Macroautophagy Since macroautophagy is the most common form of autophagy, autophagy usually means macroautophagy. CMA CMA is a chaperone HSC70 -dependent degradation pathway. Microautophagy Microautophagy was defined as micro portion of lysosomal membrane to engulf autophagic cargos, including proteins and organelles, in cells [ 17 ].

Autophagy-related proteins There are more than 40 Atg proteins involved in macroautophagy signaling in yeast cells.

In conclusion, oxidative stress and autophagy regulate each other, with autophagy regulating redox homeostasis through the Nrf2 and SESNs antioxidant pathways. COPD is a respiratory disease caused by direct and long-term exposure to toxic particulates or gases. It triggers airway or alveolar abnormalities, leading to symptoms of chronic bronchitis and emphysema, which usually manifest as persistent respiratory symptoms and airflow restriction Rodriguez-Roisin et al.

CS is a major risk factor for COPD, and thus the mortality rate of COPD among smokers is higher than that of non-smokers Vestbo et al. Notably, CS is a complex mixture containing 4, chemical components, including carbon monoxide, heavy metals, aldehydes, aromatic hydrocarbons, free radicals, and other oxidizing compounds Church and Pryor, Studies have shown that although e-cigarettes produce fewer toxic substances than traditional cigarettes, they also contain nicotine, also making them potentially harmful to the lungs Zhang et al.

Our previous studies found that exposure to CS significantly reduced the expression levels of protein tyrosine phosphatase-like Adomain containing 2 PTPLAD2 and ubiquitin specific peptidase 49 USP49 in BEAS-2B cells, suggesting that these genes might play a key role in CSE-induced COPD Zhang et al.

The primary targets of inhaled CS are airway and alveolar epithelial cells Racanelli et al. Exposure to CS, uncontrolled chronic inflammation and oxidative stress are the main drivers of the pathogenesis of COPD in airway epithelial cells, and are involved in many forms of regulated cell death i.

Smoking is a major cause of systemic oxidative stress, excessive inflammation, and emphysema. Patients with COPD are continuously exposed to high levels of oxidative stress and lung inflammation, which can lead to airway obstruction and destruction of the lung parenchyma Tan et al.

The large oxidative burden, caused by mitochondrial dysfunction, has been confirmed to be the principal cause of abnormal response and refractory inflammation due to exposure to CS Jiang et al.

In addition, the free radical theory states that oxidative stress is the primary driving factor leading to cellular aging Radak et al. Autophagy is a process of homeostatic degradation of organelles or proteins involved in oxidative stress damage, and also plays a role in regulating inflammation by regulating the development and survival of inflammatory cells Qian et al.

A number of studies have confirmed the importance of oxidative stress for inducing lung disorders. These studies have determined the existence of free radical biomarkers that induce lung inflammation and autoimmune responses and damage in patients with COPD.

The principal sources of ROS and RNS in the lungs are the environment and cells Yao and Rahman, Injury and exposure to triggers stimulates the production of endogenous oxidation products by epithelial cells, endothelial cells, airway cells, and alveolar macrophages, and also recruits inflammatory cells to the lungs, generating additional oxidative stress Rogers and Cismowski, ROS and RNS are also known to be produced by various inflammatory and structural cells in the airway.

One of the characteristics of COPD is its inflammatory immune response, which is characterized by the recruitment and activation of epithelial cells and macrophages, neutrophils, monocytes, and lymphocytes.

In particular, once inflammatory cells are recruited into the airway, they are activated, producing ROS Yao and Rahman, Some researchers have found that CS participates in the progression of COPD by inducing the M1 and M2 polarization of macrophages Feng et al.

Oxidases, including nicotinamide adenine dinucleotide phosphate NADPH oxidase NOXs , are the primary source of oxidative stress in the lungs. Studies have found that NOXs produce a large amount of oxidative agents that protect the lungs Al Ghouleh et al.

Lung hypoxia, ischemic injury, and airway inflammation irreversibly convert peroxisomal xanthine dehydrogenase into xanthine oxidase, which is the principal source of the production of superoxide and is also involved in COPD process Rogers and Cismowski In addition, the pulmonary endothelium also upregulates the production of NO by increasing the NOS activity.

The balance of autophagy plays an important role in maintaining the dynamics of the intracellular environment. Nonetheless, COPD can cause cellular damage severe enough to trigger autophagy in lung cells Dan Dunn et al.

As CS inhalation inactivates proteases necessary for protecting the lungs, the development and progression of COPD have been closely related to the oxidation of essential proteins and lipids in the airway epithelium and sputum and the decrease in the levels of antioxidants, such as glutathione and superoxide dismutase Drost et al.

The pathogenesis of COPD has been associated with an excessive increase in autophagy and mitophagy, which lead to programmed cell death of epithelial cells and emphysema Chen et al. Mutations in the ATG16L1 autophagic gene constitute a major risk factor for susceptibility to COPD.

Autophagy is also increased in the lung epithelium of patients with mutations in emphysema genes, such as 1-antitrypsin deficiency 1-AT ; however, its etiology is independent of smoke or particulate inhalation Chen et al. CS has been shown to cause abnormal autophagy and mitophagy through apoptosis, leading to programmed cell death in bronchial cells Chen et al.

Studies have shown a significant increase in the levels of autophagic proteins in the lung tissues of patients with COPD at different stages of disease Chen et al.

In contrast, inhibiting autophagy by silencing LC3B protected epithelial cells from CSE-induced apoptosis Chen et al. Moreover, the activity of histone deacetylase HDAC was reduced in the lungs of patients with COPD, whereas the expression of the LC3-II autophagosome formation marker and that of other autophagy-related proteins, including ATG4b, ATG5, ATG12, and ATG7, was significantly increased and associated with the increased activation of caspase-3 Chen et al.

Electron microscopy analysis of lung tissues of patients with COPD showed that the production of autophagosomes was increased in their lungs compared with to that in the lungs of the control group.

The same phenomenon was also observed in animal experiments. The lungs of CS-exposed mice exhibited increased formation of autophagosomes under electron microscopy observations, as well as increased expression of LC3B-II Chen et al. The initial suggestion of the importance of autophagy in the progression of COPD came from studies on upstream regulators of autophagy, such as toll-like receptor 4 TLR4 and early growth response-1 EGR In these studies, inhibition of autophagy limited in vivo inflammation, cell dysfunction, and apoptosis observed with chronic exposure to CS Chen et al.

Overexpression of exogenous superoxide dismutase SOD reduced the levels of expression of early growth response 1 Egr-1 gene and protein, a transcription factor essential for hypoxia-related autophagy in the lungs Nozik-Grayck et al. Studies have shown that CSE reduces the activity of HDAC in lung epithelial cells, thereby increasing the binding of Egr-1 and the E2F transcription factor to the LC3B promoter, thus increasing the expression of LC3B Chen et al.

Consequently, the CS-mediated reduction in the activity of HDAC leads to the transcriptional activation of Egr-1 and E2F-4, thereby inducing autophagic death Chen et al. These results suggested that regulating the autophagic pathway might be beneficial in COPD interventions Yao and Rahman, Knockdown of LC3b was reported to inhibit the activation and apoptosis of caspase-3 and improve cell viability in bronchial epithelial cells exposed to CSE, which was consistent with the view that autophagy is harmful Chen et al.

Furthermore, the increased expression of the early growth response protein 1 EGR-1 transcription factor was shown to be necessary for increasing the levels of LC3B and ATG4B Egrdeficient mice exhibited a decrease in the levels of LC3B-II and ATG4B after exposure to CS, thereby mitigating the development of emphysema Chen et al.

Studies in mice exposed to CS for 16 weeks showed that CS induced autophagy in neutrophils through the activation of platelet-activating factor receptor PAFR.

Conversely, blockade of PAFR with rupatadine reduced the autophagic death of neutrophils, thereby reducing emphysema Lv et al. The activity of LC3B is regulated by a variety of membrane-associated and cytoplasmic factors.

Studies have found that LC3B is bound to the Fas complex, a component of the DISC, in a manner dependent on the caveolin-1 caveolae-scaffolding protein. Exposure to CS has been shown to result in the rapid dissociation of LC3B from the Fas complex, consistent with the activation of the extrinsic apoptotic pathway Nakahira et al.

Accordingly, mutations in the caveolin-1 binding motif of LC3B have been reported to attenuate the proapoptotic effect resulting from the expression of LC3 Chen et al. Deletion of the LC3B autophagic protein inhibited CS-induced airspace enlargement in vivo Chen et al. Our previous studies showed the protective effects of IP 3 R against damage in extracted smoke solution ESS -treated HBE cells, which was achieved by reducing oxidative stress.

Some researchers have observed that CS can induce the deposition of proteases, thereby driving the accumulation of ubiquitinated proteins aggregates in epithelial cells and exacerbating chronic inflammation van Rijt et al.

Oxidative stress-induced increases in histone deacetylase-6 have been associated with autophagic degradation and shortening of bronchial cilia, suggesting mucociliary dysfunction Harris and Rubinsztein. Fujii et al. found that CS activated autophagy in human bronchial epithelial cells isolated from patients with COPD, leading to increased cell senescence and accumulation of the p62 autophagic adaptor protein and several ubiquitinated proteins Fujii et al.

Inhibition of autophagy was shown to further increase the levels of p62 and ubiquitinated proteins Fujii et al. Researchers have speculated that the accumulation of p62 and ubiquitinated proteins observed in the lung tissues of patients with severe COPD-emphysema suggests an insufficient autophagic clearance is involved in the pathogenesis of COPD Tran et al.

Racanelli et al. found that the CS-induced excessive autophagy and mitophagy led to bronchial cell apoptosis and necroptosis, respectively, thereby providing a possible mechanism for the development of emphysema Racanelli et al. The activation of mitochondrial selective autophagy, namely the connection between mitophagy and other regulated forms of cell death, such as apoptosis and necroptosis, is a driving factor of the COPD phenotype and underscores its importance in normal lung homeostasis and pathogenesis Hou et al.

CS-induced mitochondrial dysfunction and loss of mitochondrial phagocytosis have also been reported to induce cellular senescence and progression of COPD.

Recent studies have shown that oxidative stress can accelerate aging by depleting stem cells, thereby causing accumulation of dysfunctional mitochondria, and decreasing autophagy, all of which generate additional oxidative stress Mercado et al.

Numerous studies have shown that CSE causes accumulation of damaged mitochondria with severe mitochondrial damage through mitophagy Mizumura et al. Likewise, CS-induced endogenous ROS are known to stimulate the production of mitochondrial fragments in primary human bronchial epithelial cells.

These mitochondrial fragments produce additional ROS, accelerating cellular aging Hoffmann et al. Induction of mitochondrial autophagy reduces the production of ROS by removing damaged mitochondria, conferring a significant protective effect on human bronchial epithelial cells Ito et al.

As such, mitochondrial phagocytosis might downregulate excessive inflammation and serve as a protective mechanism in patients with COPD Yao et al. Inhibiting the activation of mitochondrial phagocytosis by inhibiting either the PINK or PRKN signaling pathways led to the increased production of ROS and activation of inflammasome in small airway epithelial cells of patients with COPD Ito et al.

In general, CSE has been confirmed to induce mitochondrial dysfunction, damage mitochondrial phagocytosis, and cause accumulation of damaged mitochondrial DNA Ahmad et al. Parkin is a key regulator of mitochondrial phagocytosis and has been shown to be downregulated in tissues of patients with COPD Ito et al.

Therefore, reversing dysfunctional mitochondrial phagocytosis should be the first choice for the treatment of COPD. In vitro experiments, overexpression of Parkin in epithelial cells resulted in inhibition of mitochondrial production of ROS, whereas CS extracts caused cell senescence Araya et al.

In vivo and in vitro studies showed that the increased levels of Parkin enhance mitochondrial phagocytosis and disrupt the progression of COPD Araya et al. Autophagy is one of the most important biological responses for regulating the levels of ROS and oxidative stress in cells Mizushima, through the clearance and degradation of damaged mitotic and oxidized proteins Yao and Rahman, For example, sirtuin 1 SIRT1 , a type III histone deacetylase, was reported to positively regulate mitochondrial phagocytosis by upregulating the expression of the peroxisome proliferator-activated receptor-γ coactivator 1α PGC-1α ; the expression of PGC-1α decreased in the lungs of patients with moderate and severe COPD El-Khamisy et al.

This relationship between mitochondrial phagocytosis and necroptosis is essential in the progression and outcomes of patients with COPD. The molecular mechanism and molecular entities involved in autophagy during oxidative stress in COPD are summarized in Figure 3 and Figure 4 , respectively.

FIGURE 3. Molecular mechanisms of autophagy during oxidative stress in COPD. CS induces activation of oxidative stress and production of reactive oxygen species ROS. The generation of ROS then triggers the formation of apoptosis and senescence, and degradation of autophagy and mitophagy, leading to emphysema and shortening of bronchial cilia, and ultimately induces COPD.

FIGURE 4. List of molecular entities involved in autophagy during oxidative stress in COPD. ROS induced by CS involve different molecular entities in apoptosis, senescence, autophagy and mitophagy in the pathogenesis of chronic obstructive pulmonary disease COPD.

An increasing body of evidence has indicated that autophagy in a variety of cell types plays a major role in the pathogenesis of COPD. Both excessive and insufficient autophagy drives the inflammation, cell death, and cell dysfunction that are observed in COPD.

Treatment options for COPD remain rather limited, and hence the potential of targeted autophagy as a treatment for COPD warrants further investigation Racanelli et al. Currently, only a few modulators of autophagy have been evaluated for clinical use, including rapamycin an activator of autophagy and chloroquine or hydroxychloroquine inhibitors of autophagy.

Likewise, strategies for the treatment of COPD might involve drugs that target autophagic proteins or modulate the selective clearance and turnover of autophagy Nakahira et al.

The use of the rapamycin mTOR inhibitor showed that although increasing autophagy to reducealveolar inflammation after exposure to CS might be beneficial, rapamycin increased autophagy and the number of apoptotic and inflammatory cells in control mice after indoor air exposure.

These findings underscored the complexity of targeted autophagy as a treatment modality for COPD Yoshida et al. To date, the number of clinical trials evaluating autophagy modulation therapy in patients with COPD remains insufficient.

This might be due to the consideration that increased autophagy is always beneficial for patients, and to the lack of a reliable method to study the effects of autophagy in patients.

Another reason might be that autophagy is a controversial process, as insufficient autophagy results in aging, whereas excessive autophagy results in cell death. The discovery of therapeutic drugs that modulate autophagy in COPD is still in the early stages, and many clinically effective drugs are being repositioned to promote autophagy in COPD in vivo and in vitro models Tan et al.

However, further research is needed to critically evaluate the role of these drugs in the treatment of abnormal autophagy in COPD. A number of natural and synthetic compounds have been shown to counteract CS-induced oxidative stress. These compounds have antioxidant activity and can be used to ameliorate chronic inflammatory and injurious responses in COPD.

For example, 3, 4, 5-trihydroxyhexanostyrene resveratrol , a plant polyphenol, has been shown to have both anti-inflammatory and antioxidant functions, inhibit CS-induced autophagy and improve the prognosis of COPD Hwang et al. Spermidine is a natural polyamine that restores autophagy activity and reduces oxidative stress de Cabo et al.

Rapamycin can reverse defective antioxidant responses or inhibit the mTOR pathway to reduce oxidative stress damage, which can prevent aging and chronic inflammation Mercado et al. N-acetylcysteine has anti-inflammatory and antioxidant effects Vanella et al.

These antioxidants bring new directions for the treatment of chronic inflammatory lung diseases such as COPD. Autophagy is a generalized response to oxidative stress, intended to remove damaged subcellular substrates and maintain mitochondrial homeostasis.

Autophagy serves a protective or adaptive function in the pathogenesis of disease, including metabolic or mitochondrial dysfunction, protein aggregation, inflammation, and oxidative stress. Consistently, it plays an essential role in maintaining the metabolic homeostasis of lung tissues in chronic respiratory diseases.

Therefore, regulation of autophagy under oxidative stress is critical to cell homeostasis and survival. Recent studies have also shown that autophagy profoundly affects inflammation and the immune system, impacting pathogen clearance, cytokine regulation, and antigen presentation.

Hence, autophagy plays a key role in human diseases associated with pro-oxidative or pro-inflammatory states. Oxidative stress is a complex phenomenon involved in the physiology and pathophysiology of many lung diseases, and a number of studies have shown that the interaction between ROS and autophagy is closely associated with the development of many lung diseases, including COPD.

In this review, we presented an overview of the interplay between autophagy and oxidative stress and focused on the regulation of autophagy under oxidative stress in patients with COPD. Oxidative stress due to CS and environmental pollution plays an essential role in lung inflammation by upregulating redox-sensitive transcription factors, the induction of autophagy as well as unfolded protein response.

Interestingly, ROS-induced autophagy can be both a cytoprotective mechanism alleviating oxidative stress and a destructive process.

The regulation of autophagy under oxidative stress plays an essential and complex role in the pathogenesis of COPD, but the signaling pathways involved and their molecular effects remain to be defined.

Studies have shown that oxidizing agents, hypoxia, and proinflammatory drugs that cause lung damage can activate autophagy, but there have been few studies on lung cells or human lung diseases to date. Appropriate modulation of autophagy is crucial for the development of new treatment strategies for COPD involving oxidative stress.

Future studies might include drug screening for molecules that inhibit or induce autophagy, as well as developing autophagy inhibitors or activators and antioxidants e. The paper was conceptualized, reviewed and edited by QZ and RZ, and XZ collected the literature and prepared the original draft.

All the authors have read and agreed to publish the manuscript. This study was supported by the grants from Key Laboratory of Intelligent Computing in Medical Image, Northeastern University, Ministry of Education No. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.

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Download references. Department of Pharmacognosy, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Department of Pharmaceutical Biotechnology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Department of Chemistry and Biochemistry, University of Texas at Arlington, Arlington, TX, , USA. Viatris Pharmaceuticals Inc, Research Plaza, San Antonio, TX, , USA. Medical Toxicology and Drug Abuse Research Center MTDRC , Birjand University of Medical Sciences, Birjand, Iran. Faculty of Pharmacy, Birjand University of Medical Sciences, Birjand, Iran.

Noncommunicable Diseases Research Center, Neyshabur University of Medical Sciences, Neyshabur, Iran.

You can also search for this author in PubMed Google Scholar. All authors contributed to the manuscript. Conceptualization, MT and SS; validation investigation, resources, data extraction, and writing, all authors; review and editing, MT and SS, All authors read and approved the final manuscript.

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Reprints and permissions. Talebi, M. et al. The interplay between oxidative stress and autophagy: focus on the development of neurological diseases.

Behav Brain Funct 18 , 3 Download citation. Received : 11 May Accepted : 17 January Published : 29 January Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative. Skip to main content. Search all BMC articles Search. Download PDF. Abstract Regarding the epidemiological studies, neurological dysfunctions caused by cerebral ischemia or neurodegenerative diseases NDDs have been considered a pointed matter.

Molecular regulation of autophagy The molecular mechanisms attributed to the occurrence of autophagy are widely researched. The relationship between reactive oxygen species and autophagy ROS are a large group of highly reactive-oxygen-containing species that comprise free radicals, oxygen anions, and hydrogen peroxide and are known for their short lives and high reaction desire [ 26 , 27 ].

Full size image. Autophagy and ROS in neurological diseases There are many relations observed between neurodegenerative disorders and autophagy. Table 1 Summary of compounds involved in regulation activation or inactivation of autophagy process of neurological diseases Full size table.

Therapeutic implications of autophagy dysregulation The induction of therapeutic autophagy acts as a survival mechanism. Conclusion In summary, regarding the emerging emphasis on cellular autophagy, a comprehensive literature overview was conducted to discuss the pharmacological aspects of autophagy, focusing on its interplay with oxidative stress in neurological disorders.

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To determine whether this difference between human transformed cell lines and mouse primary cells was not due to differences between human and mouse cells, the transformed mouse NIH 3T3 fibroblast cell line was treated with H 2 O 2 and 2-ME.

The amount of ROS generation, AVO formation and GFP-LC3 vacuoles formation increased and the amount of H 2 O 2 - and 2-ME induced cell death was blocked by 3-MA Supplementary Figure S8. Therefore, unlike in transformed cells, H 2 O 2 and 2-ME preferentially induced apoptotic cell death in nontransformed primary mouse astrocytes.

H 2 O 2 and 2-ME fail to induce autophagy in primary mouse astrocytes. Primary mouse astrocytes were treated with H 2 O 2 or 2-ME as indicated. b Autophagy was determined as described above.

ii Formation of GFP-LC3 vacuoles dots over a h time course in the absence and presence of NH 4 Cl. iii Beclin-1 expression was determined by western blotting after cells were treated with H 2 O 2 1. d Cell death was determined as previously indicated. Oxidative stress has been shown to induce autophagy under certain conditions such as ischemia and reperfusion.

Herein we demonstrated for the first time that using H 2 O 2 and 2-ME to induce oxidative stress caused autophagy-induced cell death in transformed cell line HEK and cancer cell lines U87 and HeLa cells.

Blocking autophagosome accumulation through chemical inhibitors or knocking down autophagy genes effectively blocked oxidative stress-induced cell death. Furthermore, blocking ROS generation also effectively blocked autophagy and cell death.

In contrast, mouse primary astrocytes following oxidative stress failed to undergo autophagy. This indicates that oxidative stress induces autophagy-mediated cell death in transformed and cancer cells. Autophagic cell death remains controversial since autophagy contributes to cell survival under stress such as starvation.

The metabolic toxin arsenic trioxide induced autophagic cell death mediated by upregulation of pro-cell death Bcl-2 family member BNIP3. We have determined that under oxidative stress, autophagy contributes to cell death. Taken together, autophagy could contribute to both cell survival and cell death.

Besides autophagy, oxidative stress has been shown to induce apoptotic signaling pathways leading to cell death. This is similar to the effect of arsenic trioxide As 2 O 3 on cell death in human T-lymphocytic leukemia and myelodysplastic syndrome MDS cell lines.

This indicates that when H 2 O 2 -or 2-ME-induced apoptotic cell death pathway is blocked, cells preferentially die by the autophagic pathway. Conversely, blockage of autophagosome accumulation failed to significantly alter apoptosis. This suggest that apoptosis occurs independent of autophagy.

The amount of oxidative stress-induced cell death was not completely blocked by inhibiting either apoptosis or autophagy. This indicates that there is a third cell death pathway. This third type of cell death could be the necrotic cell death pathway. This form of cell death is passive and causes cellular contents to be released to the extracellular space and often causes inflammation.

Reports have shown that when apoptotic or autophagic cell death was blocked, necrotic cell death was observed. Nevertheless, our results indicate that autophagic cell death pathway plays an important role in oxidative stress-induced cell death.

Autophagy pathways have been extensively studied. A recent report suggests that ROS could be involved in caspase-independent cell death in macrophage cells. Tiron treatment however failed to completely eliminate oxidative stress-induced ROS generation suggesting that higher levels of ROS or the types of ROS generated might be important in regulating autophagy independent of apoptosis.

Indeed, ROS have many effects on cells including DNA damage, mitochondrial dysfunction, activation of signaling pathways and activation of transcription factors leading to upregulation of genes. This agrees with the report by Thorpe et al.

The mechanism for ROS-mediated upregulation of beclin-1 and the differences between ROS-induced apoptosis and autophagy will be the focus for further investigation. Cancer cells produce higher levels of ROS than normal cells, and this contributes to cancer progression.

Hagen et al. Indeed, overexpression of mitochondrial SOD2 blocks ROS generation and autophagosome accumulation induced by 2-ME. A strategy to sensitize cancer cells to drug-induced apoptosis is to combine an ROS-generating drug with the inhibition of mitochondrial respiration enhancing ROS production and cell death such as combining As 2 O 3 with rotenone an inhibitor of mETC complex I.

In addition, autophagy failed to be significantly induced in primary astrocytes under oxidative stress. Thus, targeting ROS generation could selectively induce autophagic cell death in cancer cells. In conclusion, oxidative stress induces autophagy and provides a novel mechanism for oxidative stress-induced cell death that is selective toward transformed and cancer cells.

This may lead to new strategies to develop therapeutic drugs that will selectively target cancer cells to undergo autophagy-induced cell death independent of apoptosis. Benzyloxycarbonyl-Val-Ala-Asp zVAD fmk, zVAD was purchased from Calbiochem Mississaga, Ontario and dihydroethidium HE from Invitrogen Burlington, Ontario.

HE, 2-ME, zVAD and DAPI were dissolved in dimethyl sulfoxide DMSO. AO, EB and trypan blue were dissolved in 1 × PBS. The final concentration of DMSO in media was less than 0. The concentrations of some reagents used in this study were: H 2 O 2 , 1. Beclin-1 and ATG-5 primary antibodies and their secondary antibody donkey anti-goat HRP were purchased from Santa Cruz Biotechnology, Inc.

CA, USA. ATG-7 antibodies were purchased from PromoKine Inc. SOD2 antibodies were purchased from StressGen Biotechnologies Victoria, Canada.

Rabbit anti-actin antibody was purchased from Sigma, rabbit anti-LC3 antibody from Abgent Inc. The siRNA specific for human beclin-1 was purchased from Dharmacon Lafayette, CO, USA and the sequences used were same as those by Degenhardt et al.

TX, USA targeting exons 1 and 2 and sod-2 siRNA was purchased from Ambion Inc. Medium for the stabilized HeLa cells with overexpression of SOD2 was also supplemented with 0.

In this study, except otherwise stated, HeLa cells refer to the wild-type cell line. Cell death was analyzed by measuring the permeability of the plasma membrane to AO-EB or trypan blue. Cell suspension was centrifuged in an eppendorf tube.

Live cells are permeable to AO but not to EB and stained green, and dead cells permeable to both AO and EB, and EB stains the DNA red.

This red staining is distinctive from AO staining of autolysosomes red in the cytoplasm. At least cells were counted for each treatment. Cell death can also be analyzed by staining cells with trypan blue and counting cells under a microscope. Briefly, cells were collected and suspended in 0.

Then, cells were stained with trypan blue with a final concentration of 0. Stained cells were analyzed on a flow cytometer using CellQuest software Becton Dickinson, San Jose, CA.

Two peaks in the histograph were observed. The first peak represents viable cells, which were dimly fluorescent and not permeable to trypan blue. The second peak represents dead cells, which were brightly fluorescent and permeable to trypan blue.

On the fourth day, cells from each big plate were split into six-well plates with same amount of cells in each well. On the fifth day, old media were removed, and fresh media and H 2 O 2 were added. On the sixth or seventh day, cells were collected and analyzed, and partial cells were lysed to make protein lysates for western blot.

Transfection of siRNA into cells follows the Invitrogen protocols with some modifications. The cells were washed once with plain DMEM medium. Then, 2. Autophagy is characterized by the formation of AVOs autophagosomes and autolysosomes.

The intensity of the red fluorescence is proportional to the degree of acidity. Thus, the formation of AVOs can be quantified.

Cells were washed twice with PBS, resuspended in 0. The DNA was stained with antifade DAPI solution after cells were fixed with 3. Apoptosis was analyzed by measuring sub-G1 peaks indication of DNA fragmentation on a flow cytometer after cells were fixed with ethanol and stained with propidium iodide as stated previously.

TUNEL assay Roche Inc. that detects DNA breaks was detected on flow cytometer as per the manufacturer's instructions.

ROS generation was determined by flow cytometry after cells were stained with HE. First, HE was dissolved in DMSO to make aliquots of stock solution of 1. When used HE is taken out, covered with aluminum foil, and kept on ice until it is melt.

For staining of cells, cells were centrifuged down and the pellet was resuspended in 0. glutaraldehyde in 0. The samples were then washed again, dehydrated with graded alcohol, and embedded in Epon-Araldite resin Canemco Inc. Ultrathin sections were cut on a Reichert ultramicrotome, counterstained with 0.

Western blot analysis was performed as stated previously. All experiments were repeated at least three times and each experiment was carried out at least by triplicates. The data were expressed as means±S. Statistical analysis was performed by using Student's t test using at least three independent data points.

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The TRAIL apoptotic pathway mediates proteasome inhibitor induced apoptosis in primary chronic lymphocytic leukemia cells. Apoptosis ; 11 : — Download references. This work was supported from a grant from the Canadian Institutes for Health Research.

YC is supported by a post-doctoral fellowship from CancerCare Manitoba Foundation. SBG is supported by a New Investigator Award from the Canadian Institutes for Health Research.

We thank Dr. Ludger Klewes for technical support in using the flow cytometer. In addition, special thanks to Elizabeth Henson, Meghan Azad, Xiaojie Hu and WenYan Liu for technical assistance.

Manitoba Institute of Cell Biology, McDermot Ave, Winnipeg, Manitoba, Canada. Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada. CancerCare Manitoba, McDermot Ave, Winnipeg, Manitoba, Canada. Biochemistry and Medical Genetics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.

You can also search for this author in PubMed Google Scholar. Correspondence to S B Gibson. Reprints and permissions. Chen, Y. The immunomodulatory effects of MSCs have been extensively studied in the peripheral regions. A variety of cytokines secreted by MSCs have been linked to their immunoregulatory function.

These molecules include NO in mice , IDO in human , PGE2, TGF-β, HLA-G5, TSG-6, IL-1Ra, IL, and antagonistic variants of CCL2 Wang et al.

The production of these factors inhibits the differentiation, proliferation, and activation of various immune cell subgroups such as macrophages, neutrophils, T cells, B cells, natural killer NK cells, DCs, and mast cells, while it increases the generation of regulatory T cells Treg Li and Hua, Moreover, coculture with MSCs promotes macrophages, DCs, T cells, and NK cells toward anti-inflammatory phenotypes in vitro Cunningham et al.

Interestingly, the immunomodulatory properties of MSCs depends on the type and intensities of inflammatory mediators present in the microenvironment.

Diverse inflammatory states contribute to dramatically different responses to MSC therapy, suggesting a plasticity of MSCs in immunoregulation Li et al.

For instance, MSCs are activated by proinflammatory signals through TLR3 and exert immunosuppressive effects, denoted as MSC2 phenotype, while TLR4 priming results in a proinflammatory phenotype MSC1 accompanied by enhanced T cell responses in the absence of an inflammatory environment Li et al.

It is worth mentioning that NO or IDO are key participants and might be the target of manipulating the plasticity of MSC-mediated immunomodulation. In general, the anti-inflammatory molecules generated by MSCs also exhibit immunomodulatory properties in the central nervous system.

The immunomodulatory and neuroprotective effects of MSCs in experimental ischemic stroke have also been gradually revealed. These beneficial effects are associated with the modulation of a number of processes, including elevated secretion of anti-inflammatory molecules accompanied by a decline in proinflammatory cytokines, inactivation of inflammatory cells, and inhibition of BBB leakage.

Early MSCs administration after stroke notably upregulated the expression level of IL, with decreased TNF-α level in the brain tissue Liu et al.

Cheng et al. found that bone marrow mesenchymal stem cells BMSCs attenuated neutrophil infiltration, MMP-9 function, and BBB destruction by inhibiting the expression of intracellular adhesion molecule 1 ICAM-1 in endothelial cells Cheng et al.

Another study suggested that MSCs therapy reduced astrocyte apoptosis and inhibited ischemia-induced aquaporin-4 AQP4 upregulation, and this was related to the activation of p38 signaling pathway Tang et al.

Meanwhile, that BMSCs inactivated the microglia and induced M2 polarization was further observed by other researchers Li et al. Oh et al. It has been recently shown that employed approaches in vitro were able to enhance the therapeutic potential of MSCs, like molecular priming and tissue engineering Cunningham et al.

Many researchers endowed MSCs with more potent anti-inflammatory properties using anti-inflammatory molecules. Other investigators found that CCL2-overexpressing hUMSCs or activation of MSCs with interferon-γ both induced a more forceful anti-inflammatory phenotype of MSCs relative to naive MSCs in ischemic stroke Lee et al.

Another significative study showed that the presence of minority population of regulatory T cells in BMSCs conferred them with immunomodulatory and neuroprotection effects against stroke Neal et al.

Furthermore, biomaterials have been reported to be able to modulate the behavior of stem cells. Zhai et al. demonstrated that nitrogen-doped carbon nanocages enhanced the therapeutic effects of hUMSCs on cerebral infarction and inhibited the microglia reactivation and neuroinflammation Zhai et al.

Besides, Huang and his group coated palmitic acid peptide onto the cell membrane of MSCs and thus increased the number of transplanted cells in the ischemic lesion Huang et al. Generally, these approaches used to modify MSCs might generate a potential therapeutic strategy for stroke management.

That MSC-derived EVs can be advantageous over MSCs in the field of stroke therapy is partly dependent on the EV-mediated molecular transfer. EVs always serve as molecular cargoes, such as membrane receptors, proteins, lipids, and various forms of RNA molecules Otero-Ortega et al.

Among the contents of EVs, miRNAs, endogenously expressed RNA molecules that function to inhibit messenger RNA mRNA translation, have been shown to govern important processes that are responsible for ischemic stroke injuries Khoshnam et al. Therefore, EV-mediated miRNA transfer provides an attractive candidate for the treatment of cerebral ischemic injury.

Recently, a number of studies have confirmed the therapeutic effectiveness of EV-mediated miRNA delivery in ischemic stroke. Plenty of miRNAs were involved in these processes, such as miRNAb-3p and miRNAb-5p Hou et al. However, more researchers used miRNAs to modify MSCs for producing more robust EVs.

In their investigations, EVs from MSCs primed with miRNA, miRNAp, miRNAp, miRNAb, and miRNAp showed stronger neuroprotection effects than EVs lacking additional miRNA. Those miRNAs mainly participated in the reduction in neuroinflammation, ROS production, as well as BBB dysfunction, and promotion of angiogenesis Xin et al.

Intriguingly, Xin et al. Moreover, other teams designed to modify MSCs in other ways to enhance the therapeutic potential of their EVs. A recent study showed that pretreatment of MSCs with lithium significantly upregulated the expression level of miRNA in MSC-derived EVs, thereby enhancing the resistance of cultured astrocytes, microglia, and neurons against hypoxic injury and reducing the levels of poststroke cerebral inflammation, and this process was connected with miRNA inhibition of TLR4 abundance Haupt et al.

Kim et al. There was also a report on the effective inhibition of ROS and inflammatory activity following cerebral ischemia by combined nanoformulation of curcumin and embryonic stem-cell-derived exosomes Kalani et al.

Despite that studies on MSC-based therapies that target pyroptosis are relatively few in ischemic stroke, eminent outcome has also been observed.

In vitro , the inhibitory effect of BMSC-derived exosomes on pyroptosis in PC12 cells was comparable to the NLRP3 inhibitor and was reversed by NLRP3 overexpression Zeng et al. Meanwhile, that human umbilical cord blood mononuclear cells cbMNCs inhibited the activation of NLRP3 inflammasome in vivo has also been documented Liu et al.

Another in vivo investigation demonstrated that lymphocytes cocultured with human cord blood-derived multipotent stem cells HCB-SCs attenuated inflammasome activity in middle cerebral artery occlusion MCAO rats by suppressing NLRP3 inflammasome activation and promoting Tregs differentiation Zhao et al.

In addition, a study on microglia revealed that hypoxia-preconditioned OM-MSCs suppressed pyroptotic death of microglia caused by cerebral ischemia—reperfusion insult by activating HIF-1α Huang et al.

The mechanism by which MSCs and secretome inhibit pyroptosis has been more deeply studied in other disease models. Several new findings showed that MSCs exosomes inhibited NLRP3 expression and pyroptosis of cardiomyocytes and myocardial infarction by delivering miRNAb or long non-coding RNA lncRNA KLF3-AS1 Mao et al.

Liu et al. Besides, Kong and his group transplanted IL gene-modified MSCs into rats model of intestinal ischemia—reperfusion injury and found that the expression of NLRP3 and downstream targets cleaved caspase-1, IL-1β, and IL were observably lessened Kong et al.

Overall, the underlying mechanism regarding multiple molecular pathways involved in the role of MSCs and secretome in other diseases are expected to further elucidate in ischemic stroke.

Different from the direct inhibition of oxidative stress level and inflammatory activity, MSCs have two-sided effects on autophagy in ischemic stroke. Accumulating evidence have implied that MSCs were able to suppress autophagy through numerous molecular pathways and then promoted functional recovery after ischemic injury.

Among these researches, Li et al. Second, exosome-mediated miRNAs delivery also took part in the regulatory process. miRNAa in exosomes from hUMSCs directly binds to beclin-1 and inhibits its expression, thereby inhibiting autophagic flux in ischemia—reperfusion-induced injury Zhang et al.

Third, a recent study suggested that the protective role of transplanted MSCs in a murine model of ischemic stroke was associated with their promotion of the molecular switch from autophagy to ubiquitin—proteasome system UPS Tadokoro et al. By contrast, some other investigations declared that MSCs combated ischemic injury by enhancing autophagy Huang et al.

Likewise, in most studies, MSCs play a role by targeting mTOR-mediated autophagy pathway. In PC12 cells treated with OGD insult, BMSC exosomes attenuated the pyroptosis mediated by NLRP3 inflammasome by promoting AMPK-dependent autophagy flux Zeng et al.

Besides, heme oxygenase-1 HO-1 -mediated autophagy could also be modulated by MSCs in ischemic injury models Wang et al. Collectively, the regulatory role of MSCs in autophagy following ischemic stroke is still under dispute. Even in the same cell or animal models of cerebral ischemic injury, MSCs can exhibit diametrically opposite effects on the modulation of autophagy, which is believed to be related to multiple factors, such as the length of modeling time and the time nodes of MSCs intervention.

From another point of view, the beneficial or detrimental impacts on ischemic brain tissue depend on the intensity of autophagy, and the transplanted MSCs exert neuroprotection effects through modulating their functions adaptively according to the state of autophagy.

The applicable therapeutic strategy to reduce or prevent the cerebral ischemic injury is still largely lacking. Abundant data implicated intricate rather than a single signaling pathway to frequently work together to undermine the cells in the setting of cerebral ischemia—reperfusion.

The crosstalk among oxidative stress, inflammatory activity, and autophagy dysfunction may raise the need of deeply taking into consideration these pathways in ischemic stroke. Nowadays, the pleiotropic ability of MSCs to exhibit antioxidative stress, reduce neuroinflammation, and regulate autophagy in experimental ischemic stroke has been recognized, most of which benefit from its robust paracrine activities Figure 2.

More importantly, the low immunogenicity, ability to cross the BBB, capacity of targeted delivering gene drugs, and similar properties as MSCs seem to make MSC-derived EVs a better clinical application candidate relative to MSCs. In summary, MSCs and secretome hold great promise in the clinical treatment of ischemic stroke.

Figure 2. MSCs rescue ischemic brain tissue and promote recovery by inhibiting oxidative stress as well as inflammatory activity and modulation autophagy. MSCs, mesenchymal stem cells; TNTs, tunneling nanotubes; EVs, extracellular vesicles; ROS, reactive oxygen species; RNS, reactive nitrogen species; BBB, blood—brain barrier; UPS, ubiquitin-proteasome system; HO-1, heme oxygenase ZH and HX acquired the funding.

JH attended in literature review and drafting the manuscript. JL and YH participated in literature review. XT and ZH supervised the project. All authors read and approved the final manuscript. This work was supported by the National Natural Science Foundation of China grant numbers and and the Natural Science Foundation of Hunan Province, China grant number JJ The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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