Logo Medical Science Monitor

Call: +1.631.470.9640
Mon - Fri 10:00 am - 02:00 pm EST

Contact Us

Logo Medical Science Monitor Logo Medical Science Monitor Logo Medical Science Monitor

10 September 2020: Review Articles  

The Role of Epigallocatechin-3-Gallate in Autophagy and Endoplasmic Reticulum Stress (ERS)-Induced Apoptosis of Human Diseases

Shuangshuang Zhang1ABCDE, Mengke Cao2BCDE, Fang Fang3AEFG*

DOI: 10.12659/MSM.924558

Med Sci Monit 2020; 26:e924558



ABSTRACT: Tea containing abundant catechins is a popular non-alcoholic beverage worldwide. Epigallocatechin-3-gallate (EGCG) is the predominately active substance in catechins, exhibiting a wide range of functional properties including cancer suppression, neuroprotective, metabolic regulation, cardiovascular protection, stress adjustment, and antioxidant in various diseases. Autophagy, a basic cell function, participates in various physiological processes which include clearing away abnormally folded proteins and damaged organelles, and regulating growth. EGCG not only regulates autophagy via increasing Beclin-1 expression and reactive oxygen species generation, but also causing LC3 transition and decreasing p62 expression. EGCG-induced autophagy is involved in the occurrence and development of many human diseases, including cancer, neurological diseases, diabetes, cardiovascular diseases, and injury. Apoptosis is a common cell function in biology and is induced by endoplasmic reticulum stress (ERS) as a cellular stress response which is caused by various internal and external factors. ERS-induced apoptosis of EGCG influences cell survival and death in various diseases via regulating IRE1, ATF6, and PERK signaling pathways, and activating GRP78 and caspase proteins. The present manuscript reviews that the effect of EGCG in autophagy and ERS-induced apoptosis of human diseases.

Keywords: Endoplasmic reticulum stress, Cardiovascular Diseases, Catechin, Diabetes Mellitus, Endoplasmic Reticulum Chaperone BiP, Neoplasms, Nervous System Diseases


Tea is a popular non-alcoholic beverage and the second most consumed drink after water worldwide [1–3]. Depending on the antioxidant levels and fermentation degree, tea is divided into oolong, black, and green teas [2,4]. Currently, people drink tea in their daily life and the average consumption of tea is about 120 mL per day per person worldwide [5–7]. Green tea as one of the most popular and favorite teas, contains a large amount of catechins. Catechins are the main biologically active components in green tea leaves [8,9]. The catechin group includes major phenolic flavonoids, which are epicatechin, epicatechin-3-gallate, epigallocatechin, and epigallocatechin-3-gallate (EGCG). EGCG has the highest biological activity and is the most common component in total catechins [10,11]. Thus, EGCG is a common and important catechin that has been widely studied in the research of green tea [12,13].

EGCG has the highest concentration in green tea. There are 2 aromatic structures, including 3 carbon bridge structures and a hydroxyl group, in the molecule of EGCG [1,14]. EGCG has health benefits including anti-tumor [15], anti-inflammatory [16], anti-diabetes [17], anti-myocardial infarction [18], anti-cardiac hypertrophy [19], anti-atherosclerosis [20], and antioxidant [21] owing to its abundant phenolic hydroxyl groups. These effects are mainly related to low-density lipoprotein (LDL) cholesterol inhibition, NF-κB inhibition, MPO activity inhibition, decreased levels of glucose and glycated hemoglobin in plasma, decreased inflammatory markers, and reduced reactive oxygen species (ROS) generation [22].

The present manuscript reviews the effect of EGCG in autophagy and endoplasmic reticulum stress (ERS)-induced apoptosis of human diseases narratively. The references are searched for EGCG, autophagy, ERS, apoptosis in PubMed database, and those are selected from 2000–2020.

The Role of EGCG in Autophagy


Autophagy is an important cellular mechanism including cell degradation and recovery, and is highly conserved in all eukaryotes [23]. Autophagy participates in normal physiological processes, which includes clearing away abnormally folded proteins and damaged organelles, and regulating growth [24]. Autophagy includes microautophagy, chaperone-mediated autophagy (CMA), and macroautophagy which function to transport components to lysosomes for degradation and recycling [25]. Microautophagy is directly involved in the phagocytosing and digesting tiny components by lysosomes [26,27], while CMA is regulated and controlled by physiological pressure [28,29]. CMA transfers the cargo into lysosome via the lysosomal membranes [30]. In contrast to microautophagy and CMA, macroautophagy captures cellular components with autophagosomes fusing with lysosome to transport them into the cavity for degradation [31,32]. Macroautophagy is the primary and universal process that cells use to clear away damaged components. Thus, the term macroautophagy is used to represent autophagy in this manuscript.

The Role of EGCG in Autophagy and Human Diseases


In the process of tumor progression, autophagy has been found to be downregulated. Autophagy plays a role as a barrier in which a normal cell transforms into a cancerous cell since tumor cells can promote high expression of anti-autophagy genes. EGCG-induced autophagy participates in the development process of various human diseases, including cancer, neurological diseases, diabetes, cardiovascular diseases, injury, and infection. During cancer treatment, EGCG-induced autophagy not only directly affects tumor cells, but also enhances the effect of inhibiting tumor development of targeted drugs, chemotherapy, and combination therapies [33].

EGCG directly kills tumor cells via regulating autophagy with reactive oxygen species (ROS) and light chain 3 (LC3) transition [34,35] in many cancers, including primary effusion lymphoma, breast cancer, oral cancer, mesothelioma, and glioblastoma. In primary effusion lymphoma, EGCG significantly inhibited the growth of BABL-1 and BC-1. EGCG induced autophagy to improve cell death through LC3 transition with increasing Beclin-1 expression and formation of acidic vesicular organelles, and through enhancing ROS generation in primary effusion lymphoma cells [34]. EGCG inhibited cell proliferation since EGCG induced autophagy by enhancing Beclin-1, ATG5, and LC3B and promoted mitochondrial depolarization in breast cancer cells. In vivo, 5, 10, and 20 mg kg−1 EGCG reduced the weight of breast cancer by 20%, 31%, and 34% and only 20 mg kg−1 EGCG significantly decreased glucose, lactic acid, and vascular endothelial growth factor (VEGF) levels [36]. The accumulations of a series of epigenetic and genetic alterations resulted in uncontrolled proliferation division in oral squamous cells. The time-dependent maximal inhibitory concentration of EGCG is 52.3 uM in the SSC-4 cells. EGCG treatment (20 uM) inhibited the proliferation through activating autophagy via upregulating ZEB1, WNT11, IGF1R, FAS, BAK, and BAD genes and inhibiting TP53, MYC, and CASP8 genes in SSC-4 human oral squamous cells [37,38]. The main ROS coming from mitochondria played a crucial role in apoptosis and autophagy. EGCG induced autophagy by increasing the LC3-II expression levels and induced apoptosis via inducing ROS in mesothelioma cell lines, but low concentrations failed to induce cell death [35,39]. However, different concentrations of EGCG have different effects on tumor cells. In primary glioblastoma cell cultures, strong autophagy induction and apoptosis induction was observed after 500 μM EGCG, but the signs of cell death of glioblastoma cells during the observation period of 6 days were not detected under 100 nM EGCG. The data showed that EGCG with a low dose might have chemopreventive effects, but without direct cytotoxicity [40].

Autophagy is utilized by cancer cells to protect themselves from risk factors in order to improve their survival in targeted therapy, chemotherapy and combination therapies [41]. In targeted therapy, EGCG-induced autophagy enhanced the sensitivity of tumor cells to target drugs. Recent studies found that drug resistance is triggered by ROS and reduced by antioxidants in lung cancer cells with gefitinib treatment [42,43]. Drug resistance of gefitinib is related to high LC3 expression and the autophagosomes markers in autophagy [44]. EGCG overcame gefitinib resistance by inhibiting gefitinib-induced autophagy with the decreased expressions of ATG5 and LC3-II/I and the increased p62 expression in A549 cells, and EGCG suppressed tumor growth and increased the survival time in A549 xenograft mouse model [45]. P53 is an important gene which participates in autophagy and apoptosis to promote cell survival. Dual therapy with EGCG and P53 siRNA led to activating pro-apoptotic genes and inhibiting pro-autophagy genes in the Hs578T cell model of TNBC, which suggested that this dual therapy could promote treatment effect [46,47]. The study showed that tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induced apoptosis in a variety of tumor cells by activating apoptosis markers [48]. TRAIL-induced apoptosis was inhibited by EGCG via manipulating autophagy flux and subsequently reducing the number of death receptors in TRAIL-sensitive HCT116 cells [49].

In chemotherapy, cisplatin as one of the most commonly used chemotherapy drugs for oral squamous cell carcinoma and colorectal cancer, and has drug resistance and serious side effects after treatment. EGCG enhances autophagy and apoptosis with activating AGTs, Beclin-1 and LC3B related pathway, and inhibiting AKT/STAT3 pathway in CAR cells [50–52]. EGCG enhances autophagy effect, which is induced by cisplatin and oxaliplatin with increasing autophagosomes, acidic vesicular organelles, and LC3-II protein in colorectal cancer cells [53]. Clinical effect of doxorubicin (DOX), a significant chemotherapeutic drug for several tumors, is seriously limited because increasing the dose can cause severe cardiotoxicity and lowering the dose impairs treatment effect with drug resistance [54]. In osteosarcoma, EGCG not only could reduce autophagy by decreasing SOX2OT variant 7 to enhance the growth inhibition of DOX, but also could reduce partially Notch3/DLL3 to reduce drug-resistance and the stemness of tumor cells [55]. These results indicate that EGCG may be beneficial in cancer treatment via downregulating death markers and activating autophagy markers. However, autophagy inhibition also contributes to killing tumor cells. In the treatment of hepatocellular carcinoma, EGCG and DOX treatment produce a synergistic effect with increasing cell death by 40 to 60%, increasing apoptosis by 45%, downregulating DOX-induced autophagy and inhibiting the expression of autophagic hallmark microtubule-associated protein LC3 compared with DOX alone [54]. In addition, photothermal-chemotherapy also ablates tumor size and improves the anticancer effect through autophagy flux and inducing the formation of autophagosomes, which is induced by the duo of DOX and EGCG in HeLa tumor models [56].

In combination therapies, low-intensity pulsed electric field (PEF) can improve EGCG to affect tumor cells; ultrasound (US) with tumor cells is the application of physical stimulation in cancer therapy. EGCG combined with low-energy US and low-intensity PEF treatment might cause 20% change in the survival of human pancreatic tumor cells after 72 hours. In addition, 20 μM EGCG increased intracellular ROS levels and LC3-II, and inhibited p-Akt in PANC-1 cells. And 100 μM EGCG increased LC3-II, activated caspase-3 and PARP, and reduced p-Akt in HepG2 cells to result in tumor cell death [57–59].


Neurological diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), produce a huge social problem in the world. Both AD and PD are very popular neurodegenerative diseases worldwide [60,61]. Neurodegenerative diseases are caused by various factors, such as the accumulation of α-synuclein in PD and β-amyloid protein in AD with increased pro-apoptotic proteins, inflammation, and oxidative stress. EGCG has been utilized as the drug for neurodegenerative diseases with extensive biological and pharmacological activities [62,63].

In neurons, autophagy can protect neuronal cells from stress to improve cell survival [64]. EGCG protected neuronal cells against human viruses by inhibiting cytochrome c and Bax translocations, and reducing autophagy with increased LC3-II expression and decreased p62 expression [65]. In addition, EGCG restored autophagy in the mTOR/p70S6K pathway to weaken memory and learning disorders induced by CUMS [66]. EGCG provided the neuroprotective effect in subarachnoid hemorrhage (SAH). EGCG induced normal autophagic flux, regulated Beclin-1 and Atg5 and promptly eliminated damaged mitochondria after SAH. Finally, EGCG increased the neurological scores through inhibiting cell death [67]. Another study found that under EGCG treatment, [Ca2+]m and [Ca2+]i expressions were reduced and oxyhemoglobin-induced mitochondrial dysfunction lessened. Finally, EGCG could rescue autophagy via regulating mRNA expressions of Becn-1, LC3B, and Atg5 after SAH. Therefore, EGCG can protect neuronal cells from or attenuate external damage through the autophagy pathway [68].


Diabetes is a common metabolic disease characterized by hyperglycemia caused by insulin damage. Clinically, the main and common symptoms are polyuria, blurred vision, and weight loss. Persistent hyperglycemia leads to autonomic dysfunction, foot ulcers, renal failure, and blindness. Flavonoids are beneficial through improving the secretion of insulin, regulating glucose metabolism of hepatocytes, inhibiting the apoptosis of pancreatic β-cells, attenuating oxidative stress, inflammation and insulin resistance, and improving glucose uptake in muscle cells. And EGCG is a member of flavonoids family [69,70].

In GK (Goto-Kakizaki) rats, EGCG enhanced glucose metabolism, inhibited mitochondrial loss and dysfunction, decreased oxidative stress, and reduced autophagy by downregulating the JNK-p53 and ROS-ERK pathways in muscle cells [71]. EGCG-induced autophagy also reduced retinal damage and relieved myocardial mitochondrial dysfunction in chronic complications of diabetes. EGCG protected Müller cells under high glucose from apoptosis through activating autophagy and restoring degradation. EGCG decreased retinal damage and inhibited the reactive gliosis of Müller cells in diabetic retinopathy models [72]. FoxO1 plays as an important transcription factor in insulin signaling. In H9c2 cardiomyoblasts, FoxO1 induced autophagy through the ROS pathway to regulate glucose metabolism, which is inhibited by EGCG [73]. EGCG improved mitochondrial function by increasing autophagy and upstream FoxO factors in the myocardium of diabetic models [74]. These results showed that EGCG would be a potential drug for regulating glucose metabolism and myocardial damage involving diabetes.


Ischemic heart disease is a common cardiovascular disease with a high mortality rate. Reperfusion after myocardial ischemia can easily cause injury. EGCG pretreatment reduced autophagy induced by ischemia/reperfusion (I/R), increased cell number, and decreased myocardial infarction area. EGCG protected I/R via inhibiting autophagy through activating PI3K/Akt signals, decreasing Beclin-1, and improving MiR-384 in H9c2 cell lines [75]. Another study found that EGCG post-treatment significantly reduced CK-MB levels and LDH release, decreased myocardial infarct area, reduced apoptosis number, and retained partial heart function in I/R injury models. In addition, EGCG post-treatment decreased I/R injury by rescuing autophagy and reducing apoptosis with reduced cleaved caspase-3, p62, Atg5, Beclin-1, and the ratio of LC3-II/LC3-I, upregulation of PI3K, cathepsin D, endothelial nitric oxide synthase, and Akt [76]. Recent studies have shown autophagy is related to lipid metabolism, which is induced by cholesterol efflux and lipolysis in foam cells. Thence, activating autophagy promoted cholesterol outflow to hinder the formation of advanced atherosclerotic plaques in foam cells. Combined EGCG and oligomeric proanthocyanidins treatment not only activated autophagy, but also stimulated cholesterol efflux via regulating class III PI3K/Beclin-1, implying that is a potential therapeutic method for atherosclerosis [77].


The liver, an important metabolic organ, is closely related to autophagy. EGCG increased autophagy through promoting lysosomal acidification and improving the formation of autophagosomes in the liver. EGCG alleviated liver injury via regulating apoptosis and autophagy by inhibiting IL-6/JAKs/STAT3/BNIP3 in ConA-induced hepatitis models [78,79]. EGCG promoted cell survival via upregulating autophagy and shifting the balance of mTOR-AMPK pathways [80]. EGCG treatment inhibited UVB-induced autophagy through reducing autophagosomes and LC3-II, and activating mTOR signals in the age-related macular degeneration. Furthermore, EGCG reduced the toxic effects of UVB on retinal pigment epithelial cells in an autophagic pathway [81].

In bacterial infections, EGCG limited Burkholderia cenocepacia metabolism by enhancing autophagy and inhibiting spread in cystic fibrosis, and promoted cystic fibrosis transmembrane conductance regulator (CFTR) expression [82]. Combined EGCG and 5-AZA treatment could inhibit Legionella infection by rescuing the gene expression of autophagy in infected macrophages [83].


Endoplasmic reticulum (ER) is a crucial organelle which can synthesize, fold, and secret various proteins in eukaryotic cells. About 30% of cellular proteins are synthesized, folded, processed, and modified to form active functional proteins, including most secreted proteins, membrane-bound proteins, and integrated membrane proteins. The new synthesized proteins encapsulated in vesicles leaves the ER and is transported to Golgi apparatus, then is directed to the inner membrane system or secreted outside the cell. Also, ER participates in some cellular functions, including calcium ion storage, gluconeogenesis, lipid and cholesterol synthesis, and formation of autophagic vesicles. When receiving endogenous or exogenous stimuli including lack of molecular chaperone or cellular energy or Ca2+, disulfide reduction, protein mutations and redox homeostasis, the function of folding protein in ER is disordered. A large number of misfolded or unfolded proteins accumulate in the cavity and cause a series of subsequent reactions called endoplasmic reticulum stress (ERS) [84–86].


ERS is one of common stress responses, which induced apoptosis and interferes with cellular homeostasis. Upon ERS, cells will activate many adaptive functions to respond to changes in protein-folding, called unfolded protein response (UPR). UPR protects cells from stress by improving the ability of synthesizing new proteins and improving protein degradation through autophagy. When ERS is continuous and robust, the amount of the protein in the ER exceeds greatly its fold ability. This pathway clears away damaged cells through apoptosis, suggesting the mechanism controlling cell survival might depend on the intensity and duration of stress stimulation. UPR is mainly activated by 3 signaling pathways: protein kinase RNA like ER kinase (PERK), activating transcription factor-6 (ATF6), and inositol requiring protein 1 (IRE1) [84,86].

The accumulation of unfolded proteins stimulates autophosphorylation and oligomerization of IRE1α in the ER. IRE1α, TRAF2, and ASK1 form a complex to activate JNK which promotes apoptosis or autophagy [87]. After being transferred from ER to the Golgi apparatus, ATF6 is cleaved by Site-1 and Site-2 proteases. The N-terminal cytosolic domain of cleaved ATF6 combined with ERS and cAMP response elements, and is transferred into the nucleus to activate target genes such as X-box binding protein 1 (XBP1), C/EBP homologous protein (CHOP), immunoglobulin heavy chain binding protein (BIP), and 78 kDa glucose regulated protein (GRP78). ATF6 directly regulates apoptosis and autophagy through CHOP and XBP-1 [88]. The function of PERK is that attenuates the translation of mRNA under ERS and prevented synthesized proteins from flowing into the already stressed ER region. The activation of PERK inhibits protein translation through eIF2α phosphorylation and allows the specialized translation of transcripts including the vital sensor ATF4. ATF4 could promote apoptosis by degrading apoptosis protein inhibitors and autophagy by regulating ATG genes under prolonged ERS [84,89]. In addition, ER molecular chaperones including GRP78, BIP, GRP94, and PDI, participate in folding, assembling, and transporting of secreted and membrane proteins. See Table 1.

The Role of EGCG in ERS-Induced Apoptosis and Human Diseases


Apoptosis is a common cell function in biology and is induced by ERS as a cellular stress response which is caused by various internal and external factors. EGCG directly inhibits tumor cell growth via ERS-induced apoptosis in different cancers. In colorectal cancer cells, EGCG induced ERS in HT-29 cells by upregulating BiP, PERK, phosphorylation eIF2α, ATF4, and IRE1α. And apoptosis was induced by increased the activity of caspase-3/7 after EGCG treatment [90,91]. EGCG efficiently inhibited glucosidase II, which participates in quality control and glycoprotein processing in the ER of rat liver microsomes. EGCG interfered with protein processing owing to inhibiting glucosidase II in liver microsomes of hepatoma cells, and ERS induced incomplete UPR with main pro-apoptotic components, including increased eIF2α phosphorylation, cleavage of procaspase-12, induction of CHOP/GADD153, and depletion of ER calcium [92,93]. GRP78 can trigger UPR via activating XBP1 and CHOP in the endoplasmic reticulum to restore cell homeostasis. MMe cells with EGCG treatment improved GRP78 expression in the endoplasmic reticulum, and induced EDEM, CHOP, XBP1, and ATF4 expressions, and increased the activity of caspase-3 and caspase-8. GRP78 accumulation converted UPR of MMe cells into pro-apoptotic ERS [94,95]. Furthermore EGCG only induced ERS related apoptosis in tumor cells and was not effective for normal cells. EGCG promoted ROS production and induced apoptosis via p38 MAPK phosphorylation, caspase-8 activation, and proteolytic cleavage of Bid and JNK pathway activation in glioblastoma cells. However, EGCG did not promote apoptosis in astrocytes [96].

EGCG not only has a direct effect on tumors through ERS-induced apoptosis, but also promotes the sensitivity of tumor cells to therapeutic drugs or methods. siRNA downregulation of GRP78 and EGCG treatment improved apoptosis induced by celecoxib, thereby activating CHOP, caspase-4, GRP78, and IRE-1α in urothelial carcinoma cells [97]. During chemotherapy, EGCG enhanced chrysin-induced apoptosis by overcoming GRP78 expression and enhancing caspase-7 and poly polymerase cleavage in human hepatoma cells [98]. EGCG alone wasn’t beneficial for survival, but significantly promoted the current treatment effect of temozolomide by reducing GRP78 expression and increasing CHOP expression. And life span extension was significantly higher under combination therapy compared with temozolomide alone [99]. EGCG enhanced the activation of ERS-induced apoptosis markers including PARP cleavage, caspase-7 and JNK phosphorylation in breast cancer with vinblastine and Taxol treatment. Inhibition of caspase-7 and JNK eliminated the sensitivity to vinblastine and Taxol in breast cancer with EGCG treatment [100].

However, another research reported that EGCG can antagonize chemotherapy drugs to prevent tumor cell apoptosis. EGCG effectively prevented tumor cell death mediated by BZM in glioblastoma and multiple myeloma. EGCG could only significantly antagonize the function of boronic acid proteasome inhibitors, but not the function of non-boronic acid proteasome inhibitors. Since EGCG directly reacted with BZM to block the effect of BZM, BZM could not trigger tumor cell death through activation of ERS and caspase-7. These results indicated that drinking tea would be banned during BZM therapy owing to antagonistic effect of EGCG on BZM [101,102].


Previous studies have found that EGCG protects central nervous system from diseases with its anti-inflammatory and antioxidant properties. Recent studies showed that EGCG reduced ERS-induced apoptosis by downregulating cleaved caspase-3 and caspase-12, CHOP, and GRP78 in a dose-dependent manner in SH-SY5Y Cells. Simultaneously EGCG inhibited neuronal apoptosis with reducing ER abnormal ultrastructural swelling and downregulating ERS-associated proteins in APP/PS1 transgenic mice. In conclusion, EGCG decreased the neurotoxicity via decreasing ERS related apoptosis in the AD [103,104]. In transient focal cerebral ischemia rat models, EGCG treatment after ischemia inhibited ERS with decreasing the expression of glucose-regulated caspase-12, CHOP, and GRP78, and improved the neurological status via inhibiting TRPC6 proteolysis and activating CREB in the MEK/ERK pathway [105]. In familial amyloidotic polyneuropathy mice models, EGCG inhibited 50% deposition of transthyretin toxic that aggregates along peripheral nervous system and gastrointestinal tract system. In addition, EGCG significantly reduced the expression of the markers related non-fibrillar transthyretin deposition, including BiP, the phosphorylated eIF2a, protein oxidation marker-3-nitrotyrosine and death receptor Fas [106].


The β cells of Langerhans islets absorb glucose by GLUT2, which results in the secretion of insulin to maintain glucose homeostasis. EGCG promoted the secretion of insulin and glucose tolerance, reduced the number of Langerhans pathological islets and ERS markers of the islet, increased area and number of islets, and increased the pancreatic endocrine area of db/db mice [107,108]. A-type-EGCG-dimer is beneficial for the body and affect glucose metabolism in the liver. A-type EGCG dimer prevented insulin resistance and hyperglycemia by inhibiting ERS-induced apoptosis, decreasing the levels of G6Pase and PEPCK, and the activations of ATF4, p-JNK, p-IRE1, and p-PERK in rat liver [109]. Podocytes participate in maintaining the integrity of the glomerular filtration barrier and preventing the production of proteinuria. Podocyte injury can affect the development and prognosis of diabetic nephropathy. EGCG attenuated apoptosis of glucose-induced podocyte through inhibiting ERS with attenuating the expressions of caspase-12, p-PERK, and GRP78 in mouse podocytes [110]. It has been found that activating nuclear factor erythroid 2 related factor 2 (NRF2) can attenuate diabetic testicular damage in rodents. EGCG reduced apoptosis of testicular cell by ERS, oxidative damage, and inflammation, and activated the expression of NRF2 in diabetic mice [111].


Endothelial dysfunction is a common cause of cardiovascular diseases, which is affected by many factors including oxidative stress, renin-angiotensin system, oxidized low density lipoprotein, and homocysteine. ERS related NOD-like receptor pyrin domain containing-3 (NLRP3) and thioredoxin-interacting protein (TXNIP) signals are important factors in the endothelial dysfunction and induce inflammation and cell death by producing IL-1β. EGCG is a member of flavonoids groups and has beneficial effects on cardiovascular diseases. One study showed that EGCG inhibited ROS levels and the activation of NLRP3 and TXNIP inflammasome, resulting in decreased IL-1β expression. Simultaneously EGCG reduced cell apoptosis by inhibiting the activity of caspase-3 and restoring mitochondrial membrane potential. EGCG inhibited the activation of NLRP3 and TXNIP inflammasome by regulating the activity of AMPK to protecting endothelial cells from inflammatory and apoptosis [112,113].


Cisplatin (CP) is widely used in the chemotherapy for various cancers and is limited high-dose treatment due to its serious adverse reactions, especially nephrotoxicity. CP causes acute renal injury via renal tubular dysfunction in many patients. In CP-induced nephrotoxicity mice, EGCG reduced immunohistochemical damage and biochemical factors, and decreased the expression of phosphorylated ERK, GRP78, and caspase-12. EGCG reduced renal apoptosis by inhibiting ERS [114–116]. Partial bladder outlet obstruction (pBOO) caused by many etiologies, including benign prostatic hyperplasia, cystocele, posterior urethral valves, bladder stones, and urethral stricture, is a common disease of the urinary tract. After the female Sprague-Dawley rats received EGCG treatment, bladder injury and dysfunction was significantly promoted by inhibiting inflammation and ERS-related apoptosis with increased the expression of caspase-12, CHOP, and cyclooxygenase-2 at 48 hours and 30 days [117,118]. ERS-induced apoptosis closely correlated with the progression of age-related macular degeneration. ERS caused the accumulation of misfolded proteins and activated UPR to promote cell survival. EGCG inhibited ERS-mediated apoptosis via downregulating cleaved caspase-12, cleaved caspase-3, cleaved PARP, IRE1α, ERO1α, PERK, CHOP, GRP78, and phosphorylation at ser9 of GSK3β, and upregulating the expression of phosphorylation ser380 of PTEN and ser473 of AKT in retinal pigment epithelial cells [119,120]. See Table 2.


Autophagy and apoptosis closely correlated with the progression of human diseases. As EGCG is associated with apoptosis and autophagy, EGCG exhibits a wide range of functional properties, including cancer prevention, neuroprotection, anti-cardiovascular effect, and anti-diabetic effect (Figure 1). EGCG not only regulates autophagy via increasing Beclin-1 expression and ROS generation, but also causing LC3 transition and decreasing p62 expression. ERS-induced apoptosis of EGCG influences cell survival and death in various diseases via regulating IRE1, ATF6, and PERK signaling pathways, and activating GRP78 and caspase proteins. EGCG-induced autophagy and ERS-induced apoptosis of EGCG is involved in human diseases, including cancer, neurological diseases, diabetes, cardiovascular diseases, and injury.

As natural compounds can interact with the complex network of interlinked physiological processes, these findings of EGCG obtained from a number of experimental models and cell lines cannot be directly inferred into humans. Humans and other organisms have conservative mechanisms, and these mechanisms were inherited in the course of biological evolution. But the models and cell lines of EGCG are not perfectly matched owing to human complex physiology [3,121]. In addition, EGCG metabolism in the intestine and the circulatory systems of these models were unique in different studies [122]. For example, there are different effects of different concentration EGCG in different model organisms for cancer therapy in the manuscript. Future studies should focus on humans to determine whether the same benefits in the models can be replicated. Clinical trials will be conducted to determine the optimal dosage of EGCG to achieve the maximum health benefits of humans, which will be the novel and potential leap in basic and clinical research. Researchers need to make more efforts to convert large amounts of preclinical data into effective human treatment methods.


1. Sharifi-Rad M, Pezzani R, Redaelli M, Preclinical pharmacological activities of epigallocatechin-3-gallate in signaling pathways: An update on cancer: Molecules, 2020; 25; E467

2. Graham HN, Green tea composition, consumption, and polyphenol chemistry: Prev Med, 1992; 21; 334-50

3. Prasanth MI, Sivamaruthi BS, Chaiyasut C, Tencomnao T, A review of the role of green tea (camellia sinensis) in antiphotoaging, stress resistance, neuroprotection, and autophagy: Nutrients, 2019; 11; E474

4. Chan EW, Soh EY, Tie PP, Law YP: Pharmacognosy Res, 2011; 3; 266-72

5. Vuong QV, Epidemiological evidence linking tea consumption to human health: A review: Crit Rev Food Sci Nutr, 2014; 54; 523-36

6. Wierzejska R, Tea and health – a review of the current state of knowledge: Przegl Epidemiol, 2014; 68; 501-6

7. Hayat K, Iqbal H, Malik U, Tea and its consumption: benefits and risks: Crit Rev Food Sci Nutr, 2015; 5; 939-54

8. Zink A, Traidl-Hoffmann C, Green tea in dermatology – myths and facts: J Dtsch Dermatol Ges, 2015; 13; 768-75

9. Pae M, Wu D, Immunomodulating effects of epigallocatechin-3-gallate from green tea: Mechanisms and applications: Food Funct, 2013; 4; 1287-303

10. Sang S, Lambert JD, Ho CT, Yang CS, The chemistry and biotransformation of tea constituents: Pharmacol Res, 2011; 64; 87-99

11. Min KJ, Kwon TK, Anticancer effects and molecular mechanisms of epigallocatechin-3-gallate: Integr Med Res, 2014; 3; 16-24

12. Nagle DG, Ferreira D, Zhou YD, Epigallocatechin-3-gallate (EGCG): Chemical and biomedical perspectives: Phytochemistry, 2006; 67; 1849-55

13. Mereles D, Hunstein W, Epigallocatechin-3-gallate (EGCG) for clinical trials: More pitfalls than promises?: Int J Mol Sci, 2011; 12; 5592-603

14. Botten D, Fugallo G, Fraternali F, Molteni C, Structural properties of green tea catechins: J Phys Chem B, 2015; 119; 12860-67

15. Fujiki H, Watanabe T, Sueoka E, Cancer prevention with green tea and its principal constituent, EGCG: from early investigations to current focus on human cancer stem cells: Mol Cells, 2018; 41; 73-82

16. Kumazoe M, Nakamura Y, Yamashita M, Green tea polyphenol epigallocatechin-3-gallate suppresses toll-like receptor 4 expression via up-regulation of E3 ubiquitin-protein ligase RNF216: J Biol Chem, 2017; 292; 4077-88

17. Li T, Liu J, Zhang X, Ji G, Antidiabetic activity of lipophilic (−)-epigallocatechin-3-gallate derivative under its role of α-glucosidase inhibition: Biomed Pharmacother, 2007; 61; 91-96

18. Othman AI, Elkomy MM, El-Missiry MA, Dardor M, Epigallocatechin-3-gallate prevents cardiac apoptosis by modulating the intrinsic apoptotic pathway in isoproterenol-induced myocardial infarction: Eur J Pharmacol, 2017; 794; 27-36

19. Sheng R, Gu ZL, Xie ML, EGCG inhibits proliferation of cardiac fibroblasts in rats with cardiac hypertrophy: Planta Med, 2009; 75; 113-20

20. Xu X, Pan J, Zhou X, Amelioration of lipid profile and level of antioxidant activities by epigallocatechin-gallate in a rat model of atherogenesis: Heart Lung Circ, 2014; 23; 1194-201

21. Campanella L, Bonanni A, Tomassetti M, Determination of the antioxidant capacity of samples of different types of tea, or of beverages based on tea or other herbal products, using a superoxide dismutase biosensor: J Pharm Biomed Anal, 2003; 32; 725-36

22. Eng QY, Thanikachalam PV, Ramamurthy S, Molecular understanding of Epigallocatechin gallate (EGCG) in cardiovascular and metabolic diseases: J Ethnopharmacol, 2018; 210; 296-310

23. Marshall RS, Vierstra RD, Autophagy: The master of bulk and selective recycling: Annu Rev Plant Biol, 2018; 69; 173-208

24. Ravanan P, Srikumar IF, Talwar P, Autophagy: The spotlight for cellular stress responses: Life Sci, 2017; 188; 53-67

25. Yang Z, Klionsky DJ, Mammalian autophagy: Core molecular machinery and signaling regulation: Curr Opin Cell Biol, 2010; 22; 124-31

26. Nagar R, Autophagy: A brief overview in perspective of dermatology: Indian J Dermatol Venereol Leprol, 2017; 83; 290-97

27. Paolini A, Omairi S, Mitchell R, Attenuation of autophagy impacts on muscle fibre development, starvation induced stress and fibre regeneration following acute injury: Sci Rep, 2018; 8; 9062

28. Campbell P, Morris H, Schapira A, Chaperone-mediated autophagy as a therapeutic target for Parkinson disease: Expert Opin Ther Targets, 2018; 22; 823-32

29. Orenstein SJ, Cuervo AM, Chaperone-mediated autophagy: Molecular mechanisms and physiological relevance: Semin Cell Dev Biol, 2010; 21; 719-26

30. Kunz JB, Schwarz H, Mayer A: J Biol Chem, 2004; 279; 9987-96

31. Yorimitsu T, Klionsky DJ, Autophagy: molecular machinery for self-eating: Cell Death Differ, 2005; 1542-52

32. Parzych KR, Klionsky DJ, An overview of autophagy: Morphology, mechanism, and regulation: Antioxid Redox Signal, 2014; 20; 460-73

33. Khandia R, Dadar M, Munjal A, A comprehensive review of autophagy and its various roles in infectious, non-infectious, and lifestyle diseases: Current knowledge and prospects for disease prevention, novel drug design, and therapy: Cells, 2019; 8; E674

34. Tsai CY, Chen CY, Chiou YH, Epigallocatechin-3-gallate suppresses human herpesvirus 8 replication and induces ROS leading to apoptosis and autophagy in primary effusion lymphoma cells: Int J Mol Sci, 2017; 19; E16

35. Min NY, Kim JH, Choi JH, Selective death of cancer cells by preferential induction of reactive oxygen species in response to (−)-epigallocatechin-3-gallate: Biochem Biophys Res Commun, 2012; 421; 91-97

36. Wei R, Mao L, Xu P, Suppressing glucose metabolism with epigallocatechin-3-gallate (EGCG) reduces breast cancer cell growth in preclinical models: Food Funct, 2018; 9; 5682-96

37. Gualtero DF, Suarez Castillo A, Biomarkers in saliva for the detection of oral squamous cell carcinoma and their potential use for early diagnosis: A systematic review: Acta Odontol Scand, 2016; 74; 170-77

38. Irimie AI, Braicu C, Zanoaga O, Epigallocatechin-3-gallate suppresses cell proliferation and promotes apoptosis and autophagy in oral cancer SSC-4 cells: Onco Targets Ther, 2015; 8; 461-70

39. Satoh M, Takemura Y, Hamada H, EGCG induces human mesothelioma cell death by inducing reactive oxygen species and autophagy: Cancer Cell Int, 2013; 13; 19

40. Grube S, Ewald C, Kögler C: Nutr Cancer, 2018; 70; 1145-58

41. Kardideh B, Samimi Z, Norooznezhad F, Autophagy, cancer and angiogenesis: Where is the link?: Cell Biosci, 2019; 9; 65

42. Aljohani H, Koncar RF, Zarzour A, ROS1 amplification mediates resistance to gefitinib in glioblastoma cells: Oncotarget, 2015; 6; 20388-95

43. Okon IS, Coughlan KA, Zhang M, Gefitinib-mediated reactive oxygen species (ROS) instigates mitochondrial dysfunction and drug resistance in lung cancer cells: J Biol Chem, 2015; 290; 9101-10

44. Zhao L, Yang G, Shi Y, Co-delivery of Gefitinib and chloroquine by chitosan nanoparticles for overcoming the drug acquired resistance: J Nanobiotechnology, 2015; 13; 57

45. Meng J, Chang C, Chen Y, EGCG overcomes gefitinib resistance by inhibiting autophagy and augmenting cell death through targeting ERK phosphorylation in NSCLC: Onco Targets Ther, 2019; 12; 6033-43

46. Braicu C, Pileczki V, Pop L, Dual targeted therapy with p53 siRNA and epigallocatechin gallate in a triple negative breast cancer cell model: PLoS One, 2015; 10; e0120936

47. Crighton D, Wilkinson S, O’Prey J, DRAM, a p53-induced modulator of autophagy, is critical for apoptosis: Cell, 2006; 126; 121-34

48. Abdulghani J, El-Deiry WS, TRAIL receptor signaling and therapeutics: Expert Opin Ther Targets, 2010; 14; 1091-108

49. Kim SW, Moon JH, Park SY, Activation of autophagic flux by epigallocatechin gallate mitigates TRAIL-induced tumor cell apoptosis via down-regulation of death receptors: Oncotarget, 2016; 7; 65660-68

50. Pendleton KP, Grandis JR, Cisplatin-based chemotherapy options for recurrent and/or metastatic squamous cell cancer of the head and neck: Clin Med Insights Ther, 2013; 2013, doi: 10.4137/CMT.S10409

51. Lu CC, Yang JS, Chiang JH, Cell death caused by quinazolinone HMJ-38 challenge in oral carcinoma CAL 27 cells: Dissections of endoplasmic reticulum stress, mitochondrial dysfunction and tumor xenografts: Biochim Biophys Acta, 2014; 1840; 2310-20

52. Yuan CH, Horng CT, Lee CF, Epigallocatechin gallate sensitizes cisplatin-resistant oral cancer CAR cell apoptosis and autophagy through stimulating AKT/STAT3 pathway and suppressing multidrug resistance 1 signaling: Environ Toxicol, 2017; 32; 845-55

53. Hu F, Wei F, Wang Y, EGCG synergizes the therapeutic effect of cisplatin and oxaliplatin through autophagic pathway in human colorectal cancer cells: J Pharmacol Sci, 2015; 128; 27-34

54. Chen L, Ye HL, Zhang G, Autophagy inhibition contributes to the synergistic interaction between EGCG and doxorubicin to kill the hepatoma Hep3B cells: PLoS One, 2014; 9; e85771

55. Wang W, Chen D, Zhu K, SOX2OT variant 7 contributes to the synergistic interaction between EGCG and Doxorubicin to kill osteosarcoma via autophagy and stemness inhibition: J Exp Clin Cancer Res, 2018; 37; 37

56. Chen X, Tong R, Liu B, Duo of (−)-epigallocatechin-3-gallate and doxorubicin loaded by polydopamine coating ZIF-8 in the regulation of autophagy for chemo-photothermal synergistic therapy: Biomater Sci, 2020; 8(5); 1380-93

57. Hsieh CH, Lu CH, Chen WT, Application of non-invasive low strength pulsed electric field to EGCG treatment synergistically enhanced the inhibition effect on PANC-1 cells: PLoS One, 2017; 12; e0188885

58. Zhou YF, High intensity focused ultrasound in clinical tumor ablation: World J Clin Oncol, 2011; 2; 8-27

59. Hsieh CH, Lu CH, Kuo YY, Studies on the non-invasive anticancer remedy of the triple combination of epigallocatechin gallate, pulsed electric field, and ultrasound: PLoS One, 2018; 13; e0201920

60. Huang Y, Mucke L, Alzheimer mechanisms and therapeutic strategies: Cell, 2012; 148; 1204-22

61. Rocha EM, De Miranda B, Sanders LH, Alpha-synuclein: pathology, mitochondrial dysfunction and neuroinflammation in Parkinson’s disease: Neurobiol Dis, 2018; 109; 249-57

62. Lane DJR, Ayton S, Bush AI, Iron and Alzheimer’s diseases: an update on emerging mechanisms: J Alzheimers Dis, 2018; 64; S379-S395

63. Singh NA, Mandal AK, Khan ZA, Potential neuroprotective properties of epigallocatechin-3-gallate (EGCG): Nutr J, 2016; 15; 60

64. Cherra SJ, Chu CT, Autophagy in neuroprotection and neurodegeneration: a question of balance: Future Neurol, 2008; 3; 309-323

65. Lee JH, Moon JH, Kim SW, EGCG-mediated autophagy flux has a neuroprotection effect via a class III histone deacetylase in primary neuron cells: Oncotarget, 2015; 6; 9701-17

66. Gu HF, Nie YX, Tong QZ, Epigallocatechin-3-gallate attenuates impairment of learning and memory in chronic unpredictable mild stress-treated rats by restoring hippocampal autophagic flux: PLoS One, 2014; 9; e112683

67. Chen Y, Chen J, Sun X, Evaluation of the neuroprotective effect of EGCG: a potential mechanism of mitochondrial dysfunction and mitochondrial dynamics after subarachnoid hemorrhage: Food Funct, 2018; 9; 6349-59

68. Chen Y, Huang L, Zhang H, Reduction in autophagy by (−)-epigallocatechin-3-gallate (EGCG): A potential mechanism of prevention of mitochondrial dysfunction after subarachnoid hemorrhage: Mol Neurobiol, 2017; 54; 392-405

69. Babu PV, Liu D, Gilbert ER, Recent advances in understanding the anti-diabetic actions of dietary flavonoids: J Nutr Biochem, 2013; 24; 1777-89

70. Karaa A, Goldstein A, The spectrum of clinical presentation, diagnosis, and management of mitochondrial forms of diabetes: Pediatr Diabetes, 2015; 16; 1-9

71. Yan J, Feng Z, Liu J, Enhanced autophagy plays a cardinal role in mitochondrial dysfunction in type 2 diabetic Goto-Kakizaki (GK) rats: Ameliorating effects of (−)-epigallocatechin-3-gallate: J Nutr Biochem, 2012; 23; 716-24

72. Wang L, Sun X, Zhu M, Epigallocatechin-3-gallate stimulates autophagy and reduces apoptosis levels in retinal Müller cells under high-glucose conditions: Exp Cell Res, 2019; 380; 149-58

73. Liu J, Tang Y, Feng Z, Acetylated FoxO1 mediates high-glucose induced autophagy in H9c2 cardiomyoblasts: Regulation by a polyphenol -(−)-epigallocatechin-3-gallate: Metabolism, 2014; 63(10); 1314-23

74. Liu J, Tang Y, Feng Z, (−)-Epigallocatechin-3-gallate attenuated myocardial mitochondrial dysfunction and autophagy in diabetic Goto-Kakizaki rats: Free Radic Res, 2014; 48(8); 898-906

75. Zhang C, Liang R, Gan X, MicroRNA-384-5p/Beclin-1 As potential indicators for epigallocatechin gallate against cardiomyocytes ischemia reperfusion injury by inhibiting autophagy via PI3K/Akt pathway: Drug Des Devel Ther, 2019; 13; 3607-23

76. Xuan F, Jian J, Epigallocatechin gallate exerts protective effects against myocardial ischemia/reperfusion injury through the PI3K/Akt pathway-mediated inhibition of apoptosis and the restoration of the autophagic flux: Int J Mol Med, 2016; 38; 328-36

77. Jamuna S, Ashokkumar R, Sakeena Sadullah MS, Devaraj SN, Oligomeric proanthocyanidins and epigallocatechin gallate aggravate autophagy of foam cells through the activation of Class III PI3K/Beclin1-complex mediated cholesterol efflux: Biofactors, 2019; 45; 763-73

78. Li S, Xia Y, Chen K, Epigallocatechin-3-gallate attenuates apoptosis and autophagy in concanavalin A – induced hepatitis by inhibiting BNIP3: Drug Des Devel Ther, 2016; 10; 631-47

79. Zhou J, Farah BL, Sinha RA, Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, stimulates hepatic autophagy and lipid clearance: PLoS One, 2014; 9; e87161

80. Holczer M, Besze B, Zámbó V, Epigallocatechin-3-gallate (EGCG) promotes autophagy-dependent survival via influencing the balance of mTOR-AMPK pathways upon endoplasmic reticulum stress: Oxid Med Cell Longev, 2018; 2018 6721530

81. Li CP, Yao J, Tao ZF, Epigallocatechin-gallate (EGCG) regulates autophagy in human retinal pigment epithelial cells: A potential role for reducing UVB light-induced retinal damage: Biochem Biophys Res Commun, 2013; 438; 739-45

82. Caution K, Pan A, Krause K, Methylomic correlates of autophagy activity in cystic fibrosis: J Cyst Fibros, 2019; 18; 491-500

83. Abd E, Maksoud AI, Elebeedy D, Abass NH, Methylomic changes of autophagy-related genes by legionella effector Lpg2936 in infected macrophages: Front Cell Dev Biol, 2020; 7; 390

84. Song S, Tan J, Miao Y, Crosstalk of autophagy and apoptosis: Involvement of the dual role of autophagy under ER stress: J Cell Physiol, 2017; 232; 2977-84

85. Fernández A, Ordóñez R, Reiter RJ, Melatonin and endoplasmic reticulum stress: relation to autophagy and apoptosis: J Pineal Res, 2015; 59; 292-307

86. Bettigole SE, Glimcher LH, Endoplasmic reticulum stress in immunity: Annu Rev Immunol, 2015; 33; 107-38

87. Park S, Lim Y, Lee D, Modulation of protein synthesis by eIF2α phosphorylation protects cell from heat stress-mediated apoptosis: Cells, 2018; 7; E254

88. Oakes SA, Papa FR, The role of endoplasmic reticulum stress in human pathology: Annu Rev Pathol, 2015; 10; 173-94

89. Sano R, Reed JC, ER stress-induced cell death mechanisms: Biochim Biophys Acta, 2013; 1833; 3460-70

90. Md Nesran ZN, Shafie NH, Ishak AH, Induction of endoplasmic reticulum stress pathway by green tea epigallocatechin-3-gallate (EGCG) in colorectal cancer cells: Activation of PERK/p-eIF2α/ATF4 and IRE1α: Biomed Res Int, 2019; 2019 3480569

91. Wong RS, Apoptosis in cancer: From pathogenesis to treatment: J Exp Clin Cancer Res, 2011; 30; 87

92. Magyar JE, Gamberucci A, Konta L, Endoplasmic reticulum stress underlying the pro-apoptotic effect of epigallocatechin gallate in mouse hepatoma cells: Int J Biochem Cell Biol, 2009; 41; 694-700

93. Gamberucci A, Konta L, Colucci A, Green tea flavonols inhibit glucosidase II: Biochem Pharmacol, 2006; 72; 640-46

94. Martinotti S, Ranzato E, Burlando B, (−)- Epigallocatechin-3-gallate induces GRP78 accumulation in the ER and shifts mesothelioma constitutive UPR into proapoptotic ER stress: J Cell Physiol, 2018; 233; 7082-90

95. Korennykh A, Walter P, Structural basis of the unfolded protein response: Annu Rev Cell Dev Biol, 2012; 28; 251-77

96. Das A, Banik NL, Ray SK, Flavonoids activated caspases for apoptosis in human glioblastoma T98G and U87MG cells but not in human normal astrocytes: Cancer, 2010; 116; 164-76

97. Huang KH, Kuo KL, Chen SC, Down-regulation of glucose-regulated protein (GRP) 78 potentiates cytotoxic effect of celecoxib in human urothelial carcinoma cells: PLoS One, 2012; 7; e33615

98. Sun X, Huo X, Luo T, The anticancer flavonoid chrysin induces the unfolded protein response in hepatoma cells: J Cell Mol Med, 2011; 15; 2389-98

99. Chen TC, Wang W, Golden EB, Green tea epigallocatechin gallate enhances therapeutic efficacy of temozolomide in orthotopic mouse glioblastoma models: Cancer Lett, 2011; 302; 100-8

100. Wang J, Yin Y, Hua H, Blockade of GRP78 sensitizes breast cancer cells to microtubules-interfering agents that induce the unfolded protein response: J Cell Mol Med, 2009; 3; 3888-97

101. Golden EB, Lam PY, Kardosh A, Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors: Blood, 2009; 113; 5927-37

102. Ludwig H, Khayat D, Giaccone G, Facon T, Proteasome inhibition and its clinical prospects in the treatment of hematologic and solid malignancies: Cancer, 2005; 104; 1794-807

103. Du K, Liu M, Zhong X, Epigallocatechin gallate reduces amyloid β-induced neurotoxicity via inhibiting endoplasmic reticulum stress-mediated apoptosis: Mol Nutr Food Res, 2018; 62; e1700890

104. He Q, Bao L, Zimering J, The protective role of (−)-epigallocatechin-3-gallate in thrombin-induced neuronal cell apoptosis and JNK-MAPK activation: Neuroreport, 2015; 26; 416-23

105. Yao C, Zhang J, Liu G, Neuroprotection by (−)-epigallocatechin-3-gallate in a rat model of stroke is mediated through inhibition of endoplasmic reticulum stress: Mol Med Rep, 2014; 9; 69-76

106. Ferreira N, Saraiva MJ, Almeida MR: PLoS One, 2012; 7; e29933

107. Hanhineva K, Törrönen R, Bondia-Pons I, Impact of dietary polyphenols on carbohydrate metabolism: Int J Mol Sci, 2010; 11; 1365-402

108. Ortsäter H, Grankvist N, Wolfram S, Diet supplementation with green tea extract epigallocatechin gallate prevents progression to glucose intolerance in db/db mice: Nutr Metab (Lond), 2012; 9; 11

109. Liu CM, Ma JQ, Sun JM, Association of changes in ER stress-mediated signaling pathway with lead-induced insulin resistance and apoptosis in rats and their prevention by A-type dimeric epigallocatechin-3-gallate: Food Chem Toxicol, 2017; 110; 325-32

110. Xiang C, Xiao X, Jiang B, Epigallocatechin-3-gallate protects from high glucose induced podocyte apoptosis via suppressing endoplasmic reticulum stress: Mol Med Rep, 2017; 16; 6142-47

111. Pan C, Zhou S, Wu J, NRF2 Plays a critical role in both self and EGCG protection against diabetic testicular damage: Oxid Med Cell Longev, 2017; 2017 3172692

112. Wu J, Xu X, Li Y, Quercetin, luteolin and epigallocatechin gallate alleviate TXNIP and NLRP3-mediated inflammation and apoptosis with regulation of AMPK in endothelial cells: Eur J Pharmacol, 2014; 745; 59-68

113. Calles-Escandon J, Cipolla M, Diabetes and endothelial dysfunction: A clinical perspective: Endocr Rev, 2001; 22; 36-52

114. Chen B, Liu G, Zou P, Epigallocatechin-3-gallate protects against cisplatin-induced nephrotoxicity by inhibiting endoplasmic reticulum stress-induced apoptosis: Exp Biol Med (Maywood), 2015; 240; 1513-19

115. Luke DR, Vadiei K, Lopez-Berestein G, Role of vascular congestion in cisplatin-induced acute renal failure in the rat: Nephrol Dial Transplant, 1992; 7; 1-7

116. Bottone MG, Soldani C, Veneroni P, Cell proliferation, apoptosis and mitochondrial damage in rat B50 neuronal cells after cisplatin treatment: Cell Prolif, 2008; 41; 506-20

117. Hsieh JT, Kuo KL, Liu SH: Urology, 2016; 91; e1-9

118. Steers WD, De Groat WC, Effect of bladder outlet obstruction on micturition reflex pathways in the rat: J Urol, 1988; 140; 864-71

119. Karthikeyan B, Harini L, Krishnakumar V, Insights on the involvement of (−)-epigallocatechin gallate in ER stress-mediated apoptosis in age-related macular degeneration: Apoptosis, 2017; 22; 72-85

120. Fritsche LG, Fariss RN, Stambolian D, Age-related macular degeneration: Genetics and biology coming together: Annu Rev Genomics Hum Genet, 2014; 15; 151-71

121. Neuhaus CP, Humans as model organisms: Ethics Hum Res, 2019; 4; 35-37

122. Peluso I, Serafini M, Antioxidants from black and green tea: From dietary modulation of oxidative stress to pharmacological mechanisms: Br J Pharmacol, 2017; 174; 1195-208

In Press

Clinical Research  

The Influence of Gestational Diabetes Mellitus on Maternal and Neonatal Outcomes: A Retrospective Study in ...

Med Sci Monit In Press; DOI: 10.12659/MSM.943644  


Clinical Research  

Exploring the Educational Social and Physical Activities Among Health Care Undergraduates – a Cross-Section...

Med Sci Monit In Press; DOI: 10.12659/MSM.943399  


Clinical Research  

Percutaneous Coronary Intervention as a Non-Surgical Treatment for Ischemic Mitral Regurgitation in Patient...

Med Sci Monit In Press; DOI: 10.12659/MSM.943122  

Clinical Research  

Maxillary Canine Impaction: Assessing the Influence of Maxillary Anatomy Using Cone Beam Computed Tomography

Med Sci Monit In Press; DOI: 10.12659/MSM.944306  

Most Viewed Current Articles

17 Jan 2024 : Review article  

Vaccination Guidelines for Pregnant Women: Addressing COVID-19 and the Omicron Variant

DOI :10.12659/MSM.942799

Med Sci Monit 2024; 30:e942799


14 Dec 2022 : Clinical Research  

Prevalence and Variability of Allergen-Specific Immunoglobulin E in Patients with Elevated Tryptase Levels

DOI :10.12659/MSM.937990

Med Sci Monit 2022; 28:e937990


16 May 2023 : Clinical Research  

Electrophysiological Testing for an Auditory Processing Disorder and Reading Performance in 54 School Stude...

DOI :10.12659/MSM.940387

Med Sci Monit 2023; 29:e940387


01 Jan 2022 : Editorial  

Editorial: Current Status of Oral Antiviral Drug Treatments for SARS-CoV-2 Infection in Non-Hospitalized Pa...

DOI :10.12659/MSM.935952

Med Sci Monit 2022; 28:e935952


Your Privacy

We use cookies to ensure the functionality of our website, to personalize content and advertising, to provide social media features, and to analyze our traffic. If you allow us to do so, we also inform our social media, advertising and analysis partners about your use of our website, You can decise for yourself which categories you you want to deny or allow. Please note that based on your settings not all functionalities of the site are available. View our privacy policy.

Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750