Similarly, another study examined the effect of green tea catechins on adults ages 50—69 in Japan. The authors suggest daily green tea supplementation may benefit working memory. According to a review , certain amino acids in green tea have an anti-stress element that helps to slow brain aging.

This may be due to the neuroprotective effects, including anti-inflammation and anti-oxidative stress, of certain catechins in green tea. Green tea may also benefit other conditions.

For example, the United States Food and Drug Administration FDA has approved a green tea extract ointment as a prescription treatment option for genital warts. A review suggests green tea phytochemicals may reduce skin aging.

Other research suggests green tea may have the following effects:. Unsweetened brewed green tea contains fewer than 3 calories per cup. Green tea contains a relatively small amount of caffeine, approximately 29 milligrams mg per 8-ounce cup, compared with black tea, which has around 47 mg per cup, and coffee, which has about 95 mg per cup.

The caffeine in a cup of tea can vary according to the duration of infusing time and the amount of tea infused. Green tea contains one of the highest amounts of antioxidants of any tea. In adults, there are few known side effects associated with drinking green tea. However, the following risks and complications are important to note:.

Most research suggests that the rare cases of liver injury from green tea extract consumption are idiosyncratic reactions. Reviews of these instances have yet to conclude direct causality. The Food and Drug Administration FDA does not regulate green tea supplements.

As a result, these supplements may contain other substances that are unsafe for health or have unproven health benefits. Further research is necessary to determine the best time to drink green tea. However, since green tea contains caffeine, some people may prefer to drink it in the morning.

Research suggests it is safe for most adults to drink up to 8 cups of unsweetened green tea daily. However, people should be aware of the amount of caffeine in the brand they choose. Some research suggests that regular tea consumption, including green tea, may help to reduce body weight and waist-to-hip ratios.

However, several factors can influence fat loss, including total calorie intake and exercise levels. Green tea may have several health benefits. For example, it may help with weight management, skin inflammation, and type 2 diabetes. Some research also links green tea consumption to improved cardiovascular health.

Green tea has one of the highest concentrations of antioxidants of any tea. It is naturally low in calories and contains less caffeine than black tea and coffee. Most people can drink green tea daily with no side effects. However, some people may experience sleep disturbances due to the caffeine in green tea if they drink large amounts or consume it late in the day.

Do you enjoy tea for its flavor or the soothing feeling brought by holding a steaming cup? In this Spotlight, we tell you which brews are best for…. Matcha is a green tea powder that people tend to use in traditional tea ceremonies.

Modern uses include flavoring smoothies, cakes, and lattes. It may…. Some studies have shown that caffeine can benefit overall health. However, others suggest that it may be harmful in excess. Read more to find out…. What are micronutrients? Read on to learn more about these essential vitamins and minerals, the role they play in supporting health, as well as….

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Medical News Today. Health Conditions Health Products Discover Tools Connect. What are the health benefits of green tea? Medically reviewed by Jared Meacham, Ph. Cancer prevention Weight loss Skin conditions Heart health Lower cholesterol Stroke risk Type 2 diabetes Memory Alzheimer's disease Other benefits Nutrition Types Side effects FAQ Summary People have hailed the health benefits of green tea for centuries.

Cancer prevention. Weight loss. Inflammatory skin conditions. Heart health. Lower cholesterol. Stroke risk. Type 2 diabetes. Working memory. Other benefits. Nutritional breakdown. Side effects and risks. However, more work is still needed to identify the most active molecule and the mechanism of action of coffee oil.

On the other hand, coffee has an anti-angiogenesis effect due to cafestol and kahweol. Therefore, anti-angiogenic compounds in coffee are promising for treating cancer. Cafestol provides benefits through various biological activities, including antitumorigenic, antioxidant, and anti-inflammatory effects.

Cafestol inhibits human umbilical vascular endothelial cell angiogenesis by influencing proliferation, migration, and tube formation. Caffeine is an alkaloid found in coffee that serves as an antioxidant and anti-inflammatory agent in wound healing mechanisms. Furthermore, the study confirmed that caffeine could limit keratinocyte cell proliferation depending on the dose.

Moreover, differentiation and cell adhesion remained unaffected in single layer cultures treated with different caffeine doses. Caffeine has also been shown to inhibit epithelialization in human ex vivo studies. Several studies in animal models showed the biocompatibility of the active ingredients of coffee in providing wound-healing effects.

Setyawan et al. aureus infected wounds using macroscopic indicators dry wounds, non-hyperemic wound edges, and average leukocyte count in male Wistar rats. There was a significant difference in healing infected wounds using coffee grounds compared to honey.

The healing time of infected wounds using coffee grounds is faster than using honey 3. Coffee plus honey was the most effective treatment modality for persistent post-infectious cough PPC. Histopathological studies on thirty-six New Zealand white rabbits supported the wound healing activity of green coffee bean extracts.

Shahriari et al. The effectiveness of coffee in healing acute and chronic wounds has been proven by Yuwono et al. A total of wound patients suffering from type-2 diabetes mellitus 90 cases , autoimmune disorder 1 case juvenile rheumatoid arthritis , burns 6 cases , post amputation wounds in Buerger's disease 15 cases , cellulitis 6 cases , venous malformations 10 cases , and deep femoral soft tissue injuries 2 cases were studied.

They have identified that the healing of diabetic wounds by coffee grounds depends on the size and depth of the wound. Wound drying occurs at week 8, and skin epithelial closure occurs at week 12—16, depending on the size of the wound.

In juvenile rheumatoid arthritis patients, soft tissue and skin covered the wound with a typical scar by the eighth week. In the case of venous malformations Klippel—Trenaunay syndrome , ground coffee could stop bleeding from the subcutaneous layer at week 8, which was difficult to stop with tight sutures only.

A low pH environment can suppress bacterial growth, control infection, release oxygen, alter protease activity, reduce the bacterial end product toxicity, and promote epithelialization and angiogenesis. Acids for topical application, including citric acid, acetic acid, ascorbic acid, boric acid, and alginic acid, have been reported to control infection and promote wound healing.

Coffee has a pH ranging from 4. Although a wound pH of 4—6 creates an unfavorable environment for bacterial growth, this will reduce the chances of inflammatory complications. Arimbi and Yuwono 96 have reported the clinical effect of coffee acidity on wound healing mechanisms.

Besides that, the pH profiles of healthy skin and acute and chronic wounds differ significantly. Chronic wounds have an alkaline pH, whereas healthy skin has a slightly acidic pH. Although pH affects protease production and bacterial proliferation in wounds, there is little evidence to suggest an effect on ECM synthesis and degradation.

The function of topical antioxidants in coffee grounds is critical in diabetic or autoimmune ulcers e. The methanol extract from coffee was proven to scavenge the increase in free radicals by the DPPH test, thereby contributing to anti-inflammatory activity.

The antioxidant and radical scavenging activities of coffee ground biomass and chlorogenic acid can accelerate wound healing by controlling overexposure to wound oxidative bed stress.

Chlorogenic acid also reduced the level of lipid peroxidation. Therefore, chlorogenic acid, one of the most extensive constituents of coffee, is a good candidate for diabetic wound management both for topical application and dietary intake.

Caffeine or caffeic acid provides an antibacterial effect against S. coli OH7. pneumonia , A. baumannii , P. aeruginosa , and E. cloacae and S. Trigonelline, caffeine, and protocatechuic acid were natural antimicrobial agents against S.

coli , P. mirabilis , P. aeruginosa , K. pneumoniae , A. baumannii , E. faecalis , S. aureus , and B. In addition, the coffee extract is known to inhibit the growth of C.

albicans , , possibly due to the effect of caffeine. Most of the compounds showed significant potency against C. neoformans and Candida species. The 4,5-dihydroxyl group in the quinic acid group is required for activity, and introducing a free amino group increases activity against A.

da Silva tested the antifungal activity of chlorogenic acid against fluconazole-resistant strains of Candida spp. Chlorogenic acid can decrease cell viability, increase mitochondrial depolarization potential and reactive oxygen species production, DNA fragmentation, and phosphatidylserine externalization, which indicate apoptotic processes.

In addition, chlorogenic acid showed a significant interaction with the ALS3 active site residue of C. albicans , which is vital in the process of adhesion and resistance to fluconazole.

In addition, it was also reported that the lower concentration of coffee ground extracts 0. krusei and C. Tea polyphenols can support the mechanism of wound healing.

Green tea contains catechins, polyphenolic or flavonoid compounds, polysaccharide conjugates, amino acids, caffeine, and vitamins. Theaflavins and thearubigins are commonly found in black tea.

Epigallocatechingallate is the most common green tea catechin. Collagen sponges containing epigallocatechingallate at low concentrations improved diabetic rats' wound healing by accelerating angiogenesis and re-epithelialization and increased cellular reorganization of granulation tissue by triggering cellular reorganization by triggering myofibroblast activity.

Epigallocatechingallate affects transforming growth factor -β1 in the collagen gel contraction inhabited by fibroblast cells through myofibroblast differentiation and expression of connective tissue growth factor genes; and reduces the expression of collagen type I gene regulation.

Several composite products from tea constituents have been investigated for wound healing. Shahrahmani et al. An electrospinning technique by Sadri et al.

When tested in a mouse model, a composite based on polyethylene oxide, green tea, and chitosan showed the best healing effect compared to other wound dressings. In this composite, GTE helped reduce inflammation, keep the wound surface moist, and increase the rate of wound healing.

Qin et al. The combination of epigallocatechin gallate with gold nanoparticles and lipoic acid was shown to significantly accelerate wound healing in rat skin through its anti-inflammatory and antioxidant effects.

Kim et al. Several studies utilizing tea in wound healing mechanisms are summarized in Table 3. The total antioxidant capacity of tea is not related to the specific type of polyphenol but rather to the combined activity of various antioxidants. Green tea has higher antioxidants than black tea.

Green and black teas in animal models of atherosclerosis improved lipoprotein resistance to oxidation ex vivo. Epigallocatechingallate has been reported to inhibit S. maltophilia , MRSA, and multidrug-resistant P. aureus inhibition zone of 19 mm and V. parahaemolyticus inhibition zone of GTE in methanol showed the same inhibition zone against Pseudomonas spp.

clear zone of 18 mm. aureus ATCC , P. aeruginosa ATCC , E. coli ATCC , K. pneumoniae ATCC , and S. enterica ATCC Generally, complex active compounds in coffee and tea can be polar and non-polar. The selection of the correct type of solvent and extraction method will impact the effectiveness of the wound healing mechanism.

For example, when selecting a target compound, chlorogenic acid, the researcher must identify the solubility properties and characteristics of the compound.

If the chlorogenic acid is polar, it can be extracted using a solvent of suitable polarities, such as methanol. Both polar and non-polar fractions need to be investigated in vivo and in vitro. It should be noted that some solvents may be toxic to skin cells, so the extraction process must ensure that the final isolate is solvent-free.

Knowledge of the characteristics of the extracted active ingredients will also determine the appropriate extraction method.

Some compounds may be sensitive to high temperatures. Therefore, controlling the temperature during the extraction process is very important to avoid damage to the active compounds. There are exciting things about the active compounds that have been reported to have performance as antibiofilms.

In the future, this knowledge will be advantageous in reducing the use of antibiotics that cause microbial resistance. Cellulose is a hydrophilic biopolymer that does not readily bind to hydrophobic active constituents. Therefore, it is necessary to add an emulsifier or modify the cellulose to be more hydrophobic, and an understanding of the hydrophilicity of other biopolymers that need to be considered as cellulose composites to be explored.

The nature of the active ingredients will also impact the drug release rate. One of the conditions for an ideal wound dressing is to absorb excess exudate.

This aspect should be considered in selecting and studying the active ingredients and biopolymers and their release profile. This is where the importance of modifying the properties of cellulose to be highly hydrophilic is.

The dosage of active ingredients and their level of toxicity also need to be studied in formulating wound dressing biomaterials. View PDF Version Previous Article Next Article. DOI: Received 5th June , Accepted 6th August Abstract Cellulose-based wound dressings are increasingly in demand due to their biocompatibility and extracellular matrix ECM mimicking properties.

Table 1 Study of cellulose as a wound dressing. Type of cellulose Active compound Cell culture model Microbial target Methods Results Ref. Hydroxyethylcellulose Tungsten oxide Human dermal fibroblast cell Salmonella sp.

aeruginosa Crosslink with citric acid The hydrogel membrane was anti-inflammatory and antibacterial, and tungsten was safe against normal human cells white blood cells and dermal fibroblasts. aureus Self-assembly of silver nanoparticles on the BC surface BC-containing silver nanoparticles reduce inflammation, inhibit bacterial growth and low cytotoxicity, and accelerate the healing of blisters.

coli , S. aureus , P. aeruginosa Synthesize and impregnate silver nanoparticles onto the BC The composite had significant antibacterial properties and allowed epidermal cell attachment and growth without cytotoxicity, reduced inflammation, and accelerated wound healing.

aureus Immersion of BC in silver nitrate solution and reducing it using sodium borohydride The membrane had a potent effect against Gram-negative E. coli and Gram-positive S. aureus bacteria 45 Cellulose Lysostaphin Keratinocytes S.

aureus Immobilization of lysostaphin enzymes and cellulose-chitosan and polymethylmethacrylate cellulose Bandage preparations showed activity against S. aureus based on in vitro skin models, low keratinocyte toxicity, and good biocompatibility in wound healing applications. Wounds treated with BC and vaccarin resulted in faster epithelialization and regeneration than those treated with BC.

coli Silver nanoparticle synthesis in BC by UV irradiation. Composites killed bacteria and supported wound healing. aeruginosa , E. aureus Immersing BC into silver sulfadiazine suspension using ultrasonication The BC and silver sulfadiazine membrane composites showed potential as antimicrobial and biocompatible wound dressings.

coli , C. albicans , S. aureus Synthesized using glutaraldehyde The BC and gelatin composite sponge showed excellent antibacterial activity and potential as a wound dressing.

Table 2 Cellulose application as a medium of DDSs. Type of cellulose Drug model Characteristics of drug delivery vehicles Ref. Cellulose nanofiber Bendamustine hydrochloride The porous and woven matrix had good mechanical properties with the release of approximately Cellulose nanofiber gels are helpful for a gastroretentive DDS.

aureus growth, which was maintained for up to 72 hours, making it potentially efficient antibacterial dressing material for a long time without frequent replacement. This composite proved to be an effective DDS with good cytocompatibility and antibacterial properties.

Therefore, the process can be an effective alternative delivery approach for hydrochlorothiazide. The aspect that distinguishes coffee from other wound remedies is the coffee aroma. Coffee contains distinctive aromatic compounds.

Therefore, the use of coffee as a wound medicine can disguise the smell of wounds or other unpleasant drugs and increase enthusiasm for the wound healing process. Acidity aspects. During the wound healing process, the increase in proteases and the release of oxygen will affect the pH level on the wound surface to become acidic.

This condition will reduce the toxicity of bacteria as ammonia products increase collagen breakdown in wounds, trigger angiogenesis, and increase macrophage, fibroblast, and enzyme activity. If the pH of the wound exudate is around 7.

Antioxidant activity. ROS radical formation plays a vital role in delayed wound healing. Coffee contains many polyphenol constituents as antioxidants in controlling ROS radicals. A good balance between the endogenous antioxidant defense system and oxidative stress is beneficial for wound healing under redox control.

The therapeutic potential of coffee is derived from its bioactive compounds, especially chlorogenic acid, caffeine, caffeic acid, cafestol, and kahweol. Together, the compounds have been shown to reduce inflammation, accelerate wound healing, and modulate inflammatory and neuropathic pain in animal models.

Antimicrobial activity. Daglia et al. For example, robusta coffee grounds inhibited methicillin-resistant S.

aureus MRSA 81 due to phenolic acidity and hyperosmolarity when mixed with wound fluid. Plain caffeine, trigonelline, chlorogenic acid, caffeic acid, and protocatechuic acid at 2. Table 3 Wound healing activity by utilizing the active constituents of tea.

Preparation Test model Results Ref. The material reduces the growth of bacteria at the site of the infected wound on the skin and enhances the wound healing process. Tea contains high antioxidants due to various polyphenols that can modulate oxidative stress in vivo , especially epigallocatechingallate, epicatechingallate, theaflavins, and thearubigins.

Theaflavin is one of the constituents that play a role in the antimicrobial mechanism of tea. typhimurium , E. coli , and P.

Topical application of ex vivo expanded endothelial progenitor cells promotes vascularisation and wound healing in diabetic mice. International Wound Journal. Barrientos S, Brem H, Stojadinovic O, Tomic-Canic M. Clinical application of growth factors and cytokines in wound healing.

Wound Repair and Regeneration. Gil ES, Panilaitis B, Bellas E, Kaplan DL. Functionalized silk biomaterials for wound healing.

Advanced Healthcare Materials. Kumar S, Pandey AK. Chemistry and Biological Activities of Flavonoids: An Overview. The Scientific World Journal. Houghton PJ, Hylands PJ, Mensah AY, Hensel A, Deters AM.

In vitro tests and ethnopharmacological investigations: Wound healing as an example. Journal of Ethnopharmacology. Surjushe A, Vasani R, Saple DG.

Aloe vera: A short review. Indian Journal of Dermatology. Evaluation of antioxidant potential of Aloe vera Aloe barbadensis Miller extracts.

Journal of Agricultural and Food Chemistry. Hutter JA et al. Antiinflammatory C-glucosyl chromone from Aloe barbadensis. Journal of Natural Products. Irshad S, Butt M, Younus H. In-vitro antibacterial activity of Aloe barbadensis Miller Aloe vera. International Research Journal.

Hashmat I, Azad H, Ahmed A. Neem Azadirachta indica A. International Research Journal of Biological Sciences. Koul O, Isman MB, Ketkar CM. Properties and uses of neem, Azadirachta indica. Canadian Journal of Botany.

Krup V, Prakash LH, Harini A. Pharmacological activities of turmeric Curcuma longa Linn : A review. DOI: Rafieian-Kopaei M, Nasri H, Sahinfard N, Rafieian M, Rafieian S, Shirzad M. Turmeric: A spice with multifunctional medicinal properties.

Journal of Herbmed Pharmacology. Aslam MS, Ahmad MS, Mamat AS. A review on phytochemical constituents and pharmacological activities of Clinacanthus nutans. International Journal of Pharmacy and Pharmaceutical Sciences.

Ayyanar M, Ignacimuthu S. Herbal medicines for wound healing among tribal people in southern India: Ethnobotanical and scientific evidences. International Journal of Applied Research in Natural Products. Owoyele BV, Oguntoye SO, Dare K, Ogunbiyi BA, Aruboula EA, Soladoye AO. Analgesic, anti-inflammatory and antipyretic activities from flavonoid fractions of Chromolaena odorata.

Journal of Medicinal Plants Research. Orhan IE. Centella asiatica L. Urban: From traditional medicine to modern medicine with neuroprotective potential. Evidence-based Complementary and Alternative Medicine.

Dipankar CR, Barman SK, Shaik MM. Current updates on Centella asiatica : Phytochemistry, pharmacology and traditional uses. Hiradeve SM, Rangari VD.

Elephantopus scaber Linn. Journal of Applied Biomedicine. Papiya B, Rana C. A comprehensive phyto-pharmacological review of Euphorbia neriifolia Linn. Pharmacognosy Reviews. Ahmed SA, Nazim S, Siraj S, Siddik PM, Wahid CA.

Euphorbia neriifolia Linn: A phytopharmacological review. International Research Journal of Pharmacy. Saxena J, Khare S. A brief review on: Therapeutical values of Lantana camara plant. International Journal of Pharmacy and Life Sciences. Kalita S, Kumar G, Karthik L, Rao KVB.

A review on medicinal properties of Lantana camara Linn. Research Journal of Pharmacy and Technology. Mundada S, Shivhare R. Pharmacology of Tridax procumbens a weed: Review. International Journal of PharmTech Research. Pietta PG. Flavonoids as antioxidants. Cushnie TPT, Lamb AJ. Antimicrobial activity of flavonoids.

International Journal of Antimicrobial Agents. Procházková D, Boušová I, Wilhelmová N. Antioxidant and prooxidant properties of flavonoids. Ren W, Qiao Z, Wang H, Zhu L, Zhang L. Flavonoids: Promising anticancer agents.

Medicinal Research Reviews. Kim HP, Son KH, Chang HW, Kang SS. Anti-inflammatory plant flavonoids and cellular action mechanisms. Journal of Pharmacological Sciences.

Chirumbolo S. Flavonoids in propolis acting on mast cell-mediated wound healing. Daglia M. Polyphenols as antimicrobial agents.

Current Opinion in Biotechnology. Williams RJ, Spencer JP, Rice-Evans C. Flavonoids: Antioxidants or signalling molecules?

Sharma N, Dobhal M, Joshi Y, Chahar M. Flavonoids: A versatile source of anticancer drugs. Schmidt CA et al. Catechin derivatives from Parapiptadenia rigida with in vitro wound-healing properties. Ozay Y et al. Evaluation of the wound healing properties of luteolin ointments on excision and incision wound models in diabetic and non-diabetic rats.

Records of Natural Products. Tran NQ, Joung YK, Lih E, Park KD. In situ forming and rutin-releasing chitosan hydrogels as injectable dressings for dermal wound healing.

Mensah AY et al. Effects of Buddleja globosa leaf and its constituents relevant to wound healing. Muhammad AA, Pauzi NAS, Arulselvan P, Abas F, Fakurazi S.

In vitro wound healing potential and identification of bioactive compounds from Moringa oleifera Lam. BioMed Research International. Muralidhar A, Sudhakar Babu K, Sankar TR, Reddanna P, Latha J. Wound healing activity of flavonoid fraction isolated from the stem bark of Butea monosperma Lam in albino wistar rats.

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Toh JY, Tan VMH, Lim PCY, Lim ST, Chong MFF. Flavonoids from fruit and vegetables: A focus on cardiovascular risk factors. Current Atherosclerosis Reports. Ambiga S, Narayanan R, Gowri D, Sukumar D, Madhavan S. Evaluation of wound healing activity of flavonoids from Ipomoea carnea Jacq. Ancient Science of Life.

Written By Muhammad Shahzad Aslam, Muhammad Syarhabil Ahmad, Humayun Riaz, Syed Atif Raza, Shahzad Hussain, Omer Salman Qureshi, Povydysh Maria, Zainab Hamzah and Osama Javed. Continue reading from the same book View All. However, more evidence is necessary for researchers to definitively prove these health benefits.

This article lists some potential health benefits and types of green tea, its nutrition content, and the potential side effects.

In countries with high green tea consumption, some cancer rates tend to be lower. However, human studies have not shown consistent evidence that drinking green tea reduces the overall risk of cancer.

The topical application of green tea polyphenol extracts may have a role in protecting the skin from UVB radiation. A review of in vitro, in vivo, and human studies demonstrated the potential benefits of tea polyphenols in the chemoprevention of UVB-induced skin cancer.

A review suggests green tea catechins have some positive impacts on the following types of cancer:. Overall, more research on humans is necessary to prove the benefit of green tea on the overall risk of cancer.

A review suggests green tea and the catechin epigallocatechin gallate EGCG it contains may help people with obesity to reduce their body weight. A further meta-analysis of several different tea polyphenols-induced weight loss mechanisms suggested that catechins and caffeine synergistically produced weight loss effects, as opposed to them being the result of caffeine alone.

However, the impact of drinking green tea on weight loss is unlikely to be of clinical importance. Most studies that have shown small changes in metabolism used green tea extracts with extremely high concentrations of catechins.

Learn more about green tea and weight loss. Green tea has anti-inflammatory properties. Research highlights the anti-inflammatory effects of green tea.

A analysis of tea extract use in cosmetics determined that solutions including tea extracts promoted anti-inflammatory responses when applied topically. The authors also found that skin microcirculation improved in the affected areas.

A review suggests green tea catechins have anti-inflammatory properties that target free radicals and protect heart health. A study of 18, Japanese participants found no correlation between green tea consumption and death from heart disease , regardless of blood pressure levels.

Another study associated green tea consumption with a lower risk of the following conditions:. Separate reviews from and also found that the polyphenols in green tea may lower blood pressure, decrease inflammation , and improve epithelial function, which can help reduce heart disease risk in people with excess weight or obesity.

A review concluded that green tea consumption can significantly lower total cholesterol and low-density lipoprotein cholesterol in people with moderate weight, overweight, or obesity.

However, the authors highlight the need for more research, particularly longer studies with more diverse populations.

According to the American Heart Association AHA , drinking large amounts of green tea without sugar may reduce the risk of stroke. A review and meta-analysis supports this, associating moderate green tea consumption with a lower risk of stroke after evaluating five studies with , participants and 11, incidents of stroke.

Studies concerning the relationship between green tea and diabetes have been inconsistent. Some have suggested a lower risk of type 2 diabetes in people who drink green tea than in those who consume no tea.

One study of people with and without diabetes in China associates daily green tea consumption with a lower risk of type 2 diabetes. It also associated daily green tea consumption with a lower risk of all-cause mortality in people with diabetes. A further review of dietary polyphenol studies also associated green tea, as part of the Mediterranean diet , with a reduced risk of type 2 diabetes.

However, further research is necessary to fully determine the relationship between diabetes risk and green tea. A study of adults in China associates regular green tea consumption with better cognitive function, particularly executive function and memory.

Several smaller studies support this. A study suggests acute green tea extract supplementation improved working memory capacity in 10 women ages 50—63, although there was no significant effect for younger adults. Similarly, another study examined the effect of green tea catechins on adults ages 50—69 in Japan.

The authors suggest daily green tea supplementation may benefit working memory. According to a review , certain amino acids in green tea have an anti-stress element that helps to slow brain aging.

This may be due to the neuroprotective effects, including anti-inflammation and anti-oxidative stress, of certain catechins in green tea. Green tea may also benefit other conditions.

For example, the United States Food and Drug Administration FDA has approved a green tea extract ointment as a prescription treatment option for genital warts.

A review suggests green tea phytochemicals may reduce skin aging. Other research suggests green tea may have the following effects:.

Unsweetened brewed green tea contains fewer than 3 calories per cup. Green tea contains a relatively small amount of caffeine, approximately 29 milligrams mg per 8-ounce cup, compared with black tea, which has around 47 mg per cup, and coffee, which has about 95 mg per cup. The caffeine in a cup of tea can vary according to the duration of infusing time and the amount of tea infused.

Green tea contains one of the highest amounts of antioxidants of any tea. In adults, there are few known side effects associated with drinking green tea. However, the following risks and complications are important to note:. Most research suggests that the rare cases of liver injury from green tea extract consumption are idiosyncratic reactions.

Reviews of these instances have yet to conclude direct causality. The Food and Drug Administration FDA does not regulate green tea supplements. As a result, these supplements may contain other substances that are unsafe for health or have unproven health benefits. Further research is necessary to determine the best time to drink green tea.

However, since green tea contains caffeine, some people may prefer to drink it in the morning. Research suggests it is safe for most adults to drink up to 8 cups of unsweetened green tea daily. However, people should be aware of the amount of caffeine in the brand they choose.

Some research suggests that regular tea consumption, including green tea, may help to reduce body weight and waist-to-hip ratios. However, several factors can influence fat loss, including total calorie intake and exercise levels. Green tea may have several health benefits.

Shahrahmani et al. An electrospinning technique by Sadri et al. When tested in a mouse model, a composite based on polyethylene oxide, green tea, and chitosan showed the best healing effect compared to other wound dressings.

In this composite, GTE helped reduce inflammation, keep the wound surface moist, and increase the rate of wound healing. Qin et al. The combination of epigallocatechin gallate with gold nanoparticles and lipoic acid was shown to significantly accelerate wound healing in rat skin through its anti-inflammatory and antioxidant effects.

Kim et al. Several studies utilizing tea in wound healing mechanisms are summarized in Table 3. The total antioxidant capacity of tea is not related to the specific type of polyphenol but rather to the combined activity of various antioxidants.

Green tea has higher antioxidants than black tea. Green and black teas in animal models of atherosclerosis improved lipoprotein resistance to oxidation ex vivo. Epigallocatechingallate has been reported to inhibit S.

maltophilia , MRSA, and multidrug-resistant P. aureus inhibition zone of 19 mm and V. parahaemolyticus inhibition zone of GTE in methanol showed the same inhibition zone against Pseudomonas spp.

clear zone of 18 mm. aureus ATCC , P. aeruginosa ATCC , E. coli ATCC , K. pneumoniae ATCC , and S. enterica ATCC Generally, complex active compounds in coffee and tea can be polar and non-polar. The selection of the correct type of solvent and extraction method will impact the effectiveness of the wound healing mechanism.

For example, when selecting a target compound, chlorogenic acid, the researcher must identify the solubility properties and characteristics of the compound.

If the chlorogenic acid is polar, it can be extracted using a solvent of suitable polarities, such as methanol. Both polar and non-polar fractions need to be investigated in vivo and in vitro.

It should be noted that some solvents may be toxic to skin cells, so the extraction process must ensure that the final isolate is solvent-free. Knowledge of the characteristics of the extracted active ingredients will also determine the appropriate extraction method.

Some compounds may be sensitive to high temperatures. Therefore, controlling the temperature during the extraction process is very important to avoid damage to the active compounds.

There are exciting things about the active compounds that have been reported to have performance as antibiofilms. In the future, this knowledge will be advantageous in reducing the use of antibiotics that cause microbial resistance.

Cellulose is a hydrophilic biopolymer that does not readily bind to hydrophobic active constituents. Therefore, it is necessary to add an emulsifier or modify the cellulose to be more hydrophobic, and an understanding of the hydrophilicity of other biopolymers that need to be considered as cellulose composites to be explored.

The nature of the active ingredients will also impact the drug release rate. One of the conditions for an ideal wound dressing is to absorb excess exudate.

This aspect should be considered in selecting and studying the active ingredients and biopolymers and their release profile. This is where the importance of modifying the properties of cellulose to be highly hydrophilic is. The dosage of active ingredients and their level of toxicity also need to be studied in formulating wound dressing biomaterials.

View PDF Version Previous Article Next Article. DOI: Received 5th June , Accepted 6th August Abstract Cellulose-based wound dressings are increasingly in demand due to their biocompatibility and extracellular matrix ECM mimicking properties.

Table 1 Study of cellulose as a wound dressing. Type of cellulose Active compound Cell culture model Microbial target Methods Results Ref.

Hydroxyethylcellulose Tungsten oxide Human dermal fibroblast cell Salmonella sp. aeruginosa Crosslink with citric acid The hydrogel membrane was anti-inflammatory and antibacterial, and tungsten was safe against normal human cells white blood cells and dermal fibroblasts.

aureus Self-assembly of silver nanoparticles on the BC surface BC-containing silver nanoparticles reduce inflammation, inhibit bacterial growth and low cytotoxicity, and accelerate the healing of blisters. coli , S. aureus , P. aeruginosa Synthesize and impregnate silver nanoparticles onto the BC The composite had significant antibacterial properties and allowed epidermal cell attachment and growth without cytotoxicity, reduced inflammation, and accelerated wound healing.

aureus Immersion of BC in silver nitrate solution and reducing it using sodium borohydride The membrane had a potent effect against Gram-negative E.

coli and Gram-positive S. aureus bacteria 45 Cellulose Lysostaphin Keratinocytes S. aureus Immobilization of lysostaphin enzymes and cellulose-chitosan and polymethylmethacrylate cellulose Bandage preparations showed activity against S.

aureus based on in vitro skin models, low keratinocyte toxicity, and good biocompatibility in wound healing applications. Wounds treated with BC and vaccarin resulted in faster epithelialization and regeneration than those treated with BC.

coli Silver nanoparticle synthesis in BC by UV irradiation. Composites killed bacteria and supported wound healing. aeruginosa , E. aureus Immersing BC into silver sulfadiazine suspension using ultrasonication The BC and silver sulfadiazine membrane composites showed potential as antimicrobial and biocompatible wound dressings.

coli , C. albicans , S. aureus Synthesized using glutaraldehyde The BC and gelatin composite sponge showed excellent antibacterial activity and potential as a wound dressing. Table 2 Cellulose application as a medium of DDSs. Type of cellulose Drug model Characteristics of drug delivery vehicles Ref.

Cellulose nanofiber Bendamustine hydrochloride The porous and woven matrix had good mechanical properties with the release of approximately Cellulose nanofiber gels are helpful for a gastroretentive DDS. aureus growth, which was maintained for up to 72 hours, making it potentially efficient antibacterial dressing material for a long time without frequent replacement.

This composite proved to be an effective DDS with good cytocompatibility and antibacterial properties. Therefore, the process can be an effective alternative delivery approach for hydrochlorothiazide.

The aspect that distinguishes coffee from other wound remedies is the coffee aroma. Coffee contains distinctive aromatic compounds. Therefore, the use of coffee as a wound medicine can disguise the smell of wounds or other unpleasant drugs and increase enthusiasm for the wound healing process.

Acidity aspects. During the wound healing process, the increase in proteases and the release of oxygen will affect the pH level on the wound surface to become acidic. This condition will reduce the toxicity of bacteria as ammonia products increase collagen breakdown in wounds, trigger angiogenesis, and increase macrophage, fibroblast, and enzyme activity.

If the pH of the wound exudate is around 7. Antioxidant activity. ROS radical formation plays a vital role in delayed wound healing. Coffee contains many polyphenol constituents as antioxidants in controlling ROS radicals. A good balance between the endogenous antioxidant defense system and oxidative stress is beneficial for wound healing under redox control.

The therapeutic potential of coffee is derived from its bioactive compounds, especially chlorogenic acid, caffeine, caffeic acid, cafestol, and kahweol. Together, the compounds have been shown to reduce inflammation, accelerate wound healing, and modulate inflammatory and neuropathic pain in animal models.

Antimicrobial activity. Daglia et al. For example, robusta coffee grounds inhibited methicillin-resistant S. aureus MRSA 81 due to phenolic acidity and hyperosmolarity when mixed with wound fluid.

Plain caffeine, trigonelline, chlorogenic acid, caffeic acid, and protocatechuic acid at 2. Table 3 Wound healing activity by utilizing the active constituents of tea. Preparation Test model Results Ref. The material reduces the growth of bacteria at the site of the infected wound on the skin and enhances the wound healing process.

Tea contains high antioxidants due to various polyphenols that can modulate oxidative stress in vivo , especially epigallocatechingallate, epicatechingallate, theaflavins, and thearubigins.

Theaflavin is one of the constituents that play a role in the antimicrobial mechanism of tea. typhimurium , E. coli , and P. putida and Gram-positive B. subtilis and S. aureus bacteria. Tea polyphenols also inhibited the growth of violin production in C.

aeruginosa by reducing total proteolytic activity and swarming motility, elastase, and biofilm formation, depending on concentration. The authors explained that they could develop new non-antibiotic quorum sensing inhibitors from tea polyphenols, which would act as antivirulence compounds to control bacterial infections without killing the bacteria.

Table 4 Antimicrobial properties of compounds contained in tea. Constituents Effect of antimicrobials Ref. intermedia and P. gingivalis Catechin, chlorogenic acid, dan phloridzin All phenolics inhibited E. coli OH7, L. innocua , and P. chrysogenum at 25 mM. Owing to the structural characteristics of an electrospun network of nanofibers, these fibers are capable of absorbing exudates and providing wettability microenvironment suitable for cell respiration and proliferation.

For example, very small size pores seem to reduce the possibility of bacterial infection and allow high permeability, preventing the injured area from dehydration.

Another significant privilege of this technique is its capability and plasticity in loading drugs and some other crucial biomolecules such as growth factors, nanoparticles, antimicrobials, and anti-inflammatory reagents into the nanofibers Infection in wounds leads to increased amount of exudates, preventing formation of granulation tissue and delaying the wound healing process.

It is necessary to use healthy substances to treat wounds. Some biopolymers are routinely used to create healthy materials with wound healing capabilities Due to the formation of biofilm, wounds and burns are likely to be accompanied with chronic infections caused by bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa.

Thus, the presence of an effective antibacterial in wound dressings seems necessary. Silversulfadiazine has been used as an external antimicrobial agent since , and it is used in wounds and burns with partial and full thickness of the skin to prevent infection. Silversulfadiazine, however, has a series of side effects such as allergic reactions and reduced white blood cells.

Moreover, whether silversulfadiazine will actually lead to wound healing or whether it has genuine antibacterial properties has been a matter of dispute. Therefore, to alleviate these limitations, nanotechnology has placed silver sulfadiazine in nanofibrous scaffolds There are many different approaches to wound healing, all of which need a careful balance of oxidative stress and antioxidants, which can help to reduce oxidative stress at the wound and increasingly accelerate the healing process Grape seed extract GSE , which contains most of the active substances and a mixture of polyphenols, has shown the potential to scavenge free radicals, being 20—50 times more efficient than vitamin E or C in wound healing.

Epicatechin and Catechin are two of the most essential biochemical components of GSE. Therefore, it appears that GSE affects the wound healing process through two routes, namely the repairing of injured blood vessels and promoting the process of defensive cell aggregation at the wound site, significantly evacuating the site from bacterial infections 16 , Previous investigations have shown that electrospun COLL-based nanofibrous mats can improve wound healing in vitro and in vivo.

In the present study, we used a natural polymer COLL , a biodegradable synthetic polymer PCL along with SSD as an effective antiinfection substance in synergistic effect with GSE as an antimicrobial agent against different bacterial, viral, and fungal pathogens.

The main purpose of this study was to develop antimicrobial wound dressing capable of cell seeding. After physicochemical characterization, antibacterial and antioxidant activity along with MTT assay were evaluated. Finally, in vivo evaluation of the healing ability in normal and diabetic rat models was carried out.

Streptozotocin STZ , poly ε-caprolactone, Mw of 80 kDa , MTT M , dialysis bag 12 and KDa , and collagen type I C were obtained from Sigma Aldrich St. Louis, MO, USA , and acetic acid purity Tolou Gostar Bokhara Co.

donated the grape seed extract powder GSE Ahvaz, Iran. The COLL solution was mixed with the PCL solution in a weight ratio and stirred for 24 h.

The solution was transferred into a 10 ml syringe, and electrospinning process was carried out at ambient temperature under the following conditions: rpm, 16 cm distance, 17kv voltage and 0. The collected nanofibers on aluminum foil were dried overnight, then the nanofibrous mat was detached and utilized for the other tests and experiments.

Designing this layer of the nanofibrous mat was done according to a previous study, with some modification 19 , The solutions were mixed with a magnetic stirrer overnight. The electrospinning condition was as follows: rpm, 20 kv, 18 cm distance, and 0. Surface morphology of the electrospun nanofibers was examined under a Field-Emission Electron Microscope Mira3Tescan, Czech.

Qualitative elemental analysis such as the presence of SSD and GSE loaded into nanofibers was also performed with EDX. Tensile tests were carried out to evaluate the mechanical properties of the monolayered and double-layered nanofibrous mats.

At predetermined time points 0. After that, the data were statistically analyzed, and the results were expressed in mean and standard deviation.

The findings were obtained using distilled water as a blank. The calibration curve was plotted using the x-axis for drug concentration and the y-axis for absorbance.

The antioxidant activities of the GSE extract were evaluated using DPPH radical scavenging activity The extracts were prepared by five-time dilution method in well microtitre plates , , 50, 25, An aliquot of extract 10 μL was mixed to μL of methanolic DPPH in well microtitre plates.

The reaction mixtures were incubated at room temperature for 30 min in the dark. The lower absorbance of the reaction mixture indicated higher DPPH radical scavenging activity. The inhibition zone test was used to evaluate the antibacterial properties of the double-layered nanofibrous mat containing SSD against Staphylococcus aureus ST ATCC and Pseudomonas aeruginosa PS ATCC 20 , FE-SEM was used to examine cell attachment and morphology of HDF stem cells on a double-layered nanofibrous mat with and without GSE.

Both nanofibers were cut out with a punch and sterilized via UV radiation for 1 h before being placed in well cell culture plates. The HDFs were acquired according to the serial culture plate method similar to previous procedures After complete drying, nanofibers with cells were sent to BuAli Research Institute at Mashhad University of Medical Sciences and observed using FE-SEM.

In brief, the medium was removed 24, 48, and 72 h after cell seeding, and MTT reagent was added. After the crystals were dissolved in DMSO, each homogenate sample was transferred in triplicate to a well plate.

The final measurement was taken at nm with a microplate reader Bio-Rad , USA. The data were analyzed using GraphPad Prism software's paired t-test analysis. An in vitro wound-healing assay was used to evaluate the wound healing potential of the realized formulations Then, a scratch was made across the middle of each well using a sterile μL pipet tip, and the plates were washed twice with PBS to remove the detached cells.

Scratches were observed and imaged under the microscope Olympus IX71 immediately after the wounding procedure and after 24 and 48 h of incubation.

Animal experiments were performed according to ethical guidelines and approved by the Ethics Committee of Ahvaz Jundishapur University of Medical Sciences IR.

The effect of designed nanofibrous mat was evaluated on 27 male Sprague—Dawley rats. Three groups of rats were used in this study: 1. The animals were euthanized on days 3, 7, and 14, and the wound closure process were documented using a digital camera.

After implantation of scaffolds with a thickness of µm, 5—0 nylon sutures were used to stabilize the scaffolds. A rotating microtome was used to cut samples into 5-µm thick sections for histological studies and to assess the wound area and repair process.

Each experiment was repeated at least three times. A schematic illustration of the double-layered nanofibrous mat is shown in Fig. Manufacturing process of the scaffold via electrospining. Schematic illustration of fabrication of the double-layered nanofibrous mat.

The morphology, size of nanofibers, and elemental analysis were investigated through the SEM—EDX micrographs in the range of nanoscale Fig. The diameters were calculated at Morphological characteristics of the double-layered nanofibrous mat with FE-SEM.

The placement of the double-layered nanofibrous mat is shown in the bottom-most panel. The presence of nanofiber filaments in the cross-section between the two layers indicates that the two layers are connected to each other.

Elemental analysis was done on the double-layered nanofibrous mat without GSE B and the double-layered nanofibrous mat with GSE C. These results were in the range of elastic modulus in normal human skin i.

Thermal and mechanical properties of the electrospun nanofibers. A TGA, B DTG, and C DTA graphs of the samples. D Tensile test of the electrospun nanofibers. The release study of the double-layered nanofibrous mat containing GSE is shown in Fig.

The antioxidant property of GSE was investigated through the DPPH assay Fig. As can be seen, the GSE showed antioxidant activity in a dose-dependent manner. GSE possesses a high content of flavonoids e. With increasing the concentration of the extract, the antioxidant properties of the extract also increased, and this shows that this extract has antioxidant properties.

Release profile and antioxidant activity. A Release profile of the GSE from the nanofibrous mat. B Antioxidant activity of GSE. C Some available compounds responsible for antioxidant activity of the GSE. Antibacterial systems can enhance the tissue regeneration process by inhibiting pathogenic microorganisms 28 , The antibacterial activity of the double-layered nanofibrous mat with and without SSD against S.

aurous and P. aeruginosa is shown in Fig. The inhibition zone around the nanofiber sample shows the antibacterial effect of the SSD loaded in the nanofibrous mat. The nanofibrous mat exhibited higher activity against P.

aeruginosa , compared to S. The antibacterial effect of the prepared nanofibrous mats against S. aureus and P. aeruginosa is shown in a bar graph A. The inhibition zone against the nanofibrous mat with and without SSD in S.

aureus B and P. aeruginosa is presented C. The FE-SEM showed cell proliferation on the double-layered nanofibrous mat with and without GSE, and found that scaffolds provided a favorable environment Fig.

Statistical analysis of the data revealed that the double-layered nanofibrous mat had no effect on the viability of HDF stem cells after 48 h of culture Fig. The bright-field images of the cell migration assay and the scratch area immediately, 24, and 48 h after incubation with the nanofibrous mat.

are shown in Fig. As can be seen, the gap wound area shrinks over time, indicating the nanofibrous mat's ability to facilitate cell migration. A FE-SEM image of HDF stem cells proliferation on the nanofibrous mat with and without GSE. The cells were artificially colored to be more distinguishable in the image.

B Bar graph and heatmap related to the results of the MTT assay. C In vitro cell migration assay at different times. The images were colored to show the different areas.

Macroscopic images of the nanofibrous mats transplanted in rats in the diabetic, normal, and control groups during days 0, 3, 7, and 14 of the repair periods showed that the repair processes in the three groups were progressive Fig. During the healing process, no infection was seen at or around the transplant site in the transplanted groups according to macroscopic examination.

Analysis of the process of wound closure in the normal and diabetic groups with and without GSE shows that in the normal group, transplantion of the nanofibrous mat with GSE in the right region of the rats looked more suitable than the left region, and the wound healing process is significantly faster compared with the control group with gauze.

Wound closure in the two groups normal and diabetic with a double-layered nanofibrous mat with GSE was faster and better compared with the double-layered nanofibrous mat without GSE and the control group with gauze.

However, the difference in wound closure between two sides of rats with and without GSE is not significant in the normal group macroscopically.

Macroscopic evaluation of wound healing in normal and diabetic rats. A Models on days 0, 3, 7, and 14 following surgery, demonstrating the wound's gradual healing over time. Scale bar represents 10 mm. B Wound closure percentage and heatmap graph in diabetic and normal groups with and without extract during days 3, 7 and 14 of the repair processes.

Therefore, dressing with the desired scaffolds accelerated the wound healing process. Histological observations of hematoxylin—eosin staining by light microscopy on days 3, 7, and 14 were examined for collagen production, the epithelialization process, and skin appendage formations Fig.

The wound area for mats containing GSE in the normal group in 3,7, and 14 days was reduced compared to wounds sealed with mats alone in normal and diabetic rats. Microscopic evaluation of wound healing. Hematoxylin—eosin staining A and trichromassonʼs staining B. Scale bar represents µm.

The proliferation process in groups receiving GSE in normal and diabetic rats happened faster than groups without GSE at day 3. In groups with GSE, the presence of fibroblast cells and collagen fibers increased, compared to groups without GSE. After 14 days in the groups undergoing transplantion with double-layered nanofibrous mat containing GSE, the edges of the wound showed a good healing process towards the center of the wound.

Clear granulation was seen immediately in the wound area after 3 days. Inflammatory cells such as lymphocytes and neutrophils were particularly reduced in the group receiving double-layered nanofibrous mat containing GSE. A uniform epithelium was seen in the entire wound area in all groups with double-layered nanofibrous mat on all days.

After 14 days, new fibroblasts and collagen fibers were formed with special regulation and orientation under the new epithelium. On the other hand, the presence of a large number of matured hair follicles at the double —layered dressing treated wounds on day 14 demonstrated the effective healing ability Fig.

Masson's trichrome staining, which was used to evaluate collagen formation and remodeling, revealed a very clear difference between the nanofibrous mat with and without GSE Fig. In normal and diabetic groups without GSE, collagen formation and maturation of fibers was in the early steps, so bundle formation did not occur properly.

The development of collagen bundles was promoted in the double-layered nanofibrous mat without GSE when compared to the normal group, but the process of collagen formation was in earlier stages in the double-layered nanofibrous mat with GSE. Compared with other groups, the double-layered nanofibrous mat with GSE revealed final and formed collagen bundles with acceptable morphology, similar to normal skin.

The collagen bundle shape and organization in the double-layered nanofibrous mat with GSE clearly demonstrated the formation of a high-quality skin that could serve as a flawless skin. Figure 9 shows the schematic illustration of the application of a double-layered nanofibrous mat with antibacterial and antioxidant properties to promote wound healing.

Schematic illustration of the application of a double-layered nanofibrous mat with antibacterial and antioxidant properties to promote wound healing. Electrospun wound dressings offer comfort and flexibility during and after application.

Because there is no need for frequent changing of the dressing, the patient may be more adaptable. Due to their high compatibility with blood and tissues, biodegradable electrospun wound dressings promote the healing process and accelerate cell growth.

The rate of tissue regeneration can be used to control the rate of scaffold degradation 30 , 31 , 32 , 33 , Reduction of the wound healing period in diabetic patients is a major challenge for physicians due to the pathophysiology of these patients. Diabetic ulcer as a medical and economic problem has been observed around the world for many years, and the number of patients and the risk of amputation are constantly on the rise.

One of the major concerns of diabetic wound care physicians is development of infection at the wound site, which leads to poor wound healing Due to these challenging conditions, the present study was conducted to develop methods in the field of reconstructive medicine with the aim of improving wound healing in normal and diabetic patients.

Strong antioxidant compounds such as proanthocyanidins and polyphenols that can facilitate wound healing are found abundantly in grape seed extract Proanthocyanidins are a group of biologically active polyphenolic bioflavonoids that are synthesized by many plants such as cranberry, blueberry, and grape seeds.

The effect of proanthocyanidins in the body is 20 and 50 times higher compared with vitamins C and E, respectively. These antioxidant compounds prevent cell damage caused by the production of free radicals during wound healing and neutralize the effects of free radicals Several studies either on animal models or humans have shown the ability of GSE to promote wound healing 38 , However, GSE loading in nanofiber scaffolds has not been used to evaluate the wound healing process.

The bottom layer contains silver sulfadiazine, which has antibacterial properties The double-layered nanofibrous mat was initially evaluated for mechanical properties.

In terms of appearance, the formed scaffold resembled nanofibers, and the two layers were placed well on top of each other with interaction, as evidenced by SEM results. FE-EDX results also showed the presence of silver ions as an indicator of the presence of silver sulfadiazine in the nanofibrous mat PLoS ONE 15 12 : e Received: July 23, ; Accepted: November 24, ; Published: December 11, Copyright: © Chaniad et al.

This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: This work was supported by a grant from the Research Institute for Health Sciences, Walailak University, Nakhon Si Thammarat, Thailand Grant No. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist. During acute inflammatory responses, cellular and molecular events and interactions efficiently minimize impending injury or infection. This mitigation is a coordinated and active process to restore tissue integrity and function [ 1 ].

Dysregulation of the inflammatory response may lead to prolonged inflammation, possibly resulting in host tissue damage and pathological chronic inflammation [ 2 ]. Wound healing is a complex and dynamic physiological process that results in the recovery of structural and functional tissue integrity [ 3 ].

Many cell types and mediators are involved in the normal process of wound healing to restore barrier function and prevent further damage or infection [ 4 ].

Unhealable wounds have a significant impact on the health and quality of life of patients and cause pain, function loss, mobility loss, depression, and anxiety, prolong hospitalization and increase morbidity and mortality [ 5 ]. The wound healing process can be characterized by three overlapping inflammatory, proliferative and remodeling phases that repair and organize structures to increase the tensile strength of the damaged tissue partially or completely depending on the severity of the wound [ 6 ].

It is well known that when wounding occurs, the short-term process of inflammation caused by the release of inflammatory mediators and radical oxygen species via macrophages mainly impairs and delays the process of wound repair.

Thus, the inhibition of reactive radical production is an important consideration in the recruitment of fibroblasts, which are attracted to the site to initiate the proliferative phase of repair or the wound healing process [ 7 ].

family, Dioscoreaceae is commonly known as air potato. Its bulbils have been traditionally used in Thai folk medicine as a diuretic and anthelmintic, in longevity preparations, and for wound and inflammation treatment [ 8 ].

In traditional Indian and Chinese medicine, this plant is commonly also used to treat sore throat, gastric cancer, rectal carcinoma and goiters [ 9 ].

Moreover, in Cameroon and Madagascar, pounded bulbs are applied to abscesses, boils, and wound infections [ 10 ]. Crude extracts of this plant have been found to possess antihyperglycemic, antidyslipidemic, antimicrobial, antidiabetic, analgesic and anti-HIV-1 integrase activities [ 9 — 13 ].

Moreover, D. bulbifera extract has reported to present a potential anti-inflammatory effect that reduces paw edema [ 10 ] and produce a high rate of wound contraction [ 14 ].

Some compounds isolated from this plant, such as quercetin and kaempferol, have also been found in various medicinal plants that have previously been reported to possess wound healing effects [ 15 , 16 ].

However, limited information is available on the wound healing effect of D. Therefore, this study was conducted to identify compounds responsible for the wound healing activity of D.

bulbifera and to determine their potential anti-inflammatory and antioxidant activities. Roswell Park Memorial Institute medium RPMI , Dulbecco's modified Eagle medium DMEM , and 3- 4,5-dimethylthiazolyl -2,5-diphenyltetrazolium bromide MTT were purchased from Gibco Life Technologies, Paisley, Scotland.

L-Nitroarginine L-NA , caffeic acid phenethyl ester CAPE , indomethacin, lipopolysaccharide LPS , fetal bovine serum FBS , aspirin, ibuprofen, phosphate-buffered saline PBS , 2,2-diphenylpicrylhydrazyl DPPH , ethylenediaminetetraacetic acid EDTA , and L-ascorbic acid were purchased from Sigma-Aldrich USA.

All other chemicals were purchased from Merck Darmstadt, Germany. Bulbils of D. bulbifera were collected from Uttaradit Province, Thailand, in A voucher specimen SKP was identified by a botanist of the Forest Herbarium, Department of National Parks, Wildlife and Plant Conservation, Thailand, and has been deposited in the Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla, Thailand.

According to previous reports by our research group, D. bulbifera bulbils were extracted, the extracts were fractionated, and compounds were isolated.

Briefly, the powder of bulbils was separately extracted with ethanol by maceration at room temperature and extracted with water by the reflux method to produce crude ethanol and water extracts. Ethanol extract was subsequently partitioned with hexane, chloroform, ethyl acetate and water to obtain chloroform, ethyl acetate and water fractions without residue from the hexane fraction.

These fractions were further separated by chromatography methods to give purified compounds [ 13 , 17 ]. In the current study, the biological activities of the crude extracts EtOH and water extracts , their derived fractions CHCl 3 , EtOAc and water fractions and eleven compounds 1 — 11 were investigated.

To evaluate the anti-inflammatory activity, the inhibition of nitric oxide NO production was evaluated according to a previous report [ 18 ]. Briefly, RAW After 24 h of incubation, the nitrite NO 2 — concentration in the culture medium was determined as an indicator of NO production using Griess reagent to assay the accumulation of NO 2 — , a stable metabolite of NO.

The absorbance was measured using a microplate reader at nm. In this study, a NO synthase inhibitor L-nitroarginine, L-NA , an inhibitor of the nuclear translocation of NF-κB CAPE and a nonsteroidal anti-inflammatory drug NSAID; indomethacin and aspirin were used as positive controls.

The cytotoxicity of the test compounds after 24 h of incubation was determined according to a previously reported method [ 18 ].

The formazan products generated by MTT reduction were dissolved in dimethyl sulfoxide DMSO. Finally, the medium was removed, and μl of DMSO was added to each well and thoroughly mixed by gentle tapping on the test plate.

The absorbance of the formazan solution was measured at a wavelength of nm using a microplate reader. All medium was then aspirated and replaced with DMSO, and the optical density at nm was recorded.

The percentage of cell proliferation was calculated and compared to that of the negative control [ 18 ]. The migration of HDFs was examined using a wound healing method.

After the confluent monolayer of HDFs had formed, a sterile pipette tip was used to generate two horizontal scratches left and right in each well.

Any cellular debris was removed by washing with PBS and replacement with 1 ml of fresh medium in the absence or presence of the test sample. To determine the migration of HDFs, the images were analyzed using ImageJ.

The percentage of the closed area was measured and compared with the value obtained before treatment day 0. An increase in the percentage of closed area indicates cell migration [ 18 ]. The antioxidant activity of the samples against DPPH radicals was evaluated according to the method previously described [ 19 ] with slight modifications.

A total of 75 μl of sample solution at various concentrations 1— μM was mixed with μl of DPPH 0. The reaction mixture was incubated in the dark at room temperature for 30 min.

Then, the absorbance at nm of the mixture was determined using a microplate reader. A control solution was prepared by mixing absolute ethanol and DPPH solution. The antioxidant efficacy of all samples was compared with that of ascorbic acid, a positive control.

The experiment was carried out in triplicate independently. This assay was carried out according to a previous method [ 20 ] with slight modifications. Briefly, the reaction mixtures contained the following reagents in a final volume of 1.

After cooling at room temperature for 10 min, the absorbance was measured at nm. Butylated hydroxytoluene BHT was used as a positive control. For the statistical analyses, all data were expressed as the mean ± S.

of three determinations. The inflammatory phase is the first and essential stage in the wound healing process [ 21 ]. In this process, NO is an important biomolecule that causes vasodilation and cellular migration [ 22 ].

Therefore, suppression of NO may be a good therapeutic target to promote wound healing. Accordingly, in the present study, the anti-inflammatory activity of crude extracts, their fractions and isolated compounds from D. bulbifera bulbils was assessed in RAW The results revealed that the extracts and its fractions of D.

bulbifera possessed mild anti-inflammatory activity. The isolated compounds 1 — 11 were also evaluated for their anti-NO activity, and the results are shown in Table 1.

Among them, myricetin 11 exhibited the highest inhibitory activity, with an IC 50 value of A cytotoxic effect was observed for only sitosterol-β-D-glucoside 3 at concentrations of 10, 30 and μM. Regarding the other Dioscorea species, D. alata tuber extract has been reported to possess a potent anti-inflammatory effect by inhibition of the NO and TNF-α expression [ 23 ].

batatas peel extract decreased NO production and proinflammatory protein expression and decreased the level of ROS [ 24 ]. In addition, aerial bulblet extract of D. japonica was reported to exhibit anti-inflammatory activity, which may be attributed to its effect by the inhibition of nuclear factor kappa-B NF-κB and mitogen-activated protein kinase MAPK activation [ 25 ].

Regarding myricetin 11 , our study is in accordance with a previous report that it inhibited the LPS-stimulated production of NO and the production of prostaglandin E 2 PGE 2 and to decrease inducible nitric oxide synthase iNOS and cyclooxygenase-2 COX-2 expression [ 26 ].

Regarding the NO inhibitory activity of active flavonoid compounds 6 , 7 and 11 , the structure-activity relationship suggested that the C2-C3 double-bond and 4-oxo functional group of the C-ring are important factors responsible for the strong inhibition of COX-2 expression [ 27 ], and methoxylation at position 3, e.

As the cell proliferative phase progresses, fibroblasts become the predominant cells at the wound site that play an important role in wound contraction to restore the integrity of injured tissue [ 28 ]. Fibroblasts secrete the collagens and glycosaminoglycans for the new granulation tissue and subsequently affect the remodeling of the granulation tissue into mature dermis [ 29 ].

In the current study, HDFs, skin fibroblasts were used to investigate the ability of extracts, their derived fractions and purified compounds from D. bulbifera bulbils to promote cell proliferation. Regarding the cell proliferation in the presence of extracts of D.

Cell proliferation in the presence of compounds isolated from D. Therefore, these four compounds were tested in a HDF cell migration assay. Cell migration plays a key role in wound healing.

In an attempt to investigate the wound healing efficacy of the active fractions and compounds from D. bulbifera , an artificial wounded monolayer was created using the scratch assay to assess the fibroblast cell migration.

Consequently, fractions F1-F3, which resulted in good cell proliferation, were also tested in the cell migration assay. The wound closure in the control was According to the literature, D.