A document by Mohammad Yassin Zamanian. Click on the document to view its contents.

A document by Mohammad Yassin Zamanian. Click on the document to view its contents.

Metformin (MET) is a preferred drug for the treatment of type 2 diabetes mellitus. Recent studies show that apart from its blood glucose-lowering effects, it also inhibits the development of various tumours, by inducing autophagy. Various studies have confirmed the inhibitory effects of MET on cancer cell lines’ propagation, migration, and invasion. The objective of the study was to comprehensively review the potential of MET as an anticancer agent, particularly focusing on its ability to induce autophagy and inhibit the development and progression of various tumors. The study aimed to explore the inhibitory effects of MET on cancer cell proliferation, migration, and invasion, and its impact on key signaling pathways such as AMPK, mTOR, and PI3K. This review noted that MET exerts its anticancer effects by regulating key signalling pathways such as phosphoinositide 3-kinase (PI3K), LC3-I and LC3-II, Beclin-1, p53, and the autophagy-related gene (ATG), inhibiting the mTOR protein, downregulating the expression of p62/SQSTM1, and blockage of the cell cycle at the G0/G1. Moreover, MET can stimulate autophagy through pathways associated with the 5′ adenosine monophosphate-activated protein kinase (AMPK), thereby inhibiting he development and progression of various human cancers, including hepatocellular carcinoma, prostate cancer, pancreatic cancer, osteosarcoma, myeloma, and non-small cell lung cancer. In summary, this detailed review provides a framework for further investigations that may appraise the autophagy-induced anticancer potential of MET and its repurposing for cancer treatment.

Flavonoids, including fisetin, have been linked to a reduced risk of colorectal cancer (CRC) and have potential therapeutic applications for the condition. Fisetin, a natural flavonoid found in various fruits and vegetables, has shown promise in managing CRC due to its diverse biological activities. It has been found to influence key cell signaling pathways related to inflammation, angiogenesis, apoptosis, growth factors, and transcription factors. The results of this study demonstrate that fisetin induces colon cancer cell apoptosis through multiple mechanisms. It impacts the p53 pathway, leading to increased levels of p53 and decreased levels of MDM2, contributing to apoptosis induction. Fisetin also triggers the release of important components in the apoptotic process, such as Smac/DIABLO and cytochrome c. Furthermore, fisetin inhibits the COX2 and Wnt/EGFR/NF-ĸB signaling pathways, reducing Wnt target gene expression and hindering colony formation. It achieves this by regulating the activities of CDK2 and CDK4, reducing Rb phosphorylation, decreasing cyclin E levels, and increasing p21 levels, ultimately influencing E2F-1 and CDC2 protein levels. Additionally, fisetin has various effects on CRC cells, including inhibiting the phosphorylation of YB-1 and RSK, promoting the phosphorylation of ERK1/2, and disrupting the repair process of DSBs. Moreover, fisetin serves as an adjunct therapy for the prevention and treatment of PIK3CA-mutant CRC, resulting in a reduction of PI3K expression, AKT phosphorylation, mTOR activity, and downstream target proteins in CRC cells with a PIK3CA mutation. These findings highlight the multifaceted potential of fisetin in managing CRC and position it as a promising candidate for future therapy development.

Dry eye disease (DED) represents a prevalent visual ailment, defined by insufficient wetting and lubrication of the ocular surface. The principal management strategy for dry eye involves the application of artificial tear solutions to mitigate eye discomfort. Moreover, immune-modulating agents such as cyclosporine A and tacrolimus (FK506) are employed in the therapeutic regimen for this condition. These drugs regulate the immune response and reduce ocular inflammation. Tacrolimus (TAC) is 10-100 times more effective than cyclosporine and has a better safety profile. Nevertheless, the modest aqueous solubility and substantial molecular size of TAC present obstacles to its efficient administration to the eye. Consequently, a range of TAC formulations including ointments, micelles, liposomes, and nanocarriers are under exploration to enhance ocular delivery. Findings from this investigation indicated that TAC impedes the secretion of pro-inflammatory cytokines and dampens immune activity by restraining the activation of T and B lymphocytes. Furthermore, TAC elevates goblet cell populations in the conjunctiva, pivotal for mucin production and the preservation of ocular surface integrity. Additionally, using TAC-loaded liposomes can further enhance its therapeutic efficacy by improving ocular bioavailability. Furthermore, 0.03% TAC eye drops applied directly to the eye successfully improve tear film stability and the health of the eye’s surface in patients with DED. Overall, TAC has shown promising effects in treating DED by reducing inflammation and improving tear secretion in experimental and clinical studies. However, more studies are needed to fully understand the mechanism of action and long-term effects of TAC on DED.

Colorectal cancer (CRC) is a common and highly metastatic cancer affecting people worldwide. Drug resistance and unwanted side effects are some of the limitations of current treatments for CRC. Naringenin (NAR) is a naturally occurring compound found in abundance in various citrus fruits such as oranges, grapefruits, and tomatoes. It possesses a diverse range of pharmacological and biological properties that are beneficial for human health. Numerous studies have highlighted its antioxidant, anti-cancer, and anti-inflammatory activities, making it a subject of interest in scientific research. This review provides a comprehensive overview of the effects of NAR on CRC. The study’s findings indicated that NAR: 1) interacts with estrogen receptors, 2) regulates the expression of genes related to the p53 signaling pathway, 3) promotes apoptosis by increasing the expression of proapoptotic genes (Bax, caspase9, and p53) and downregulation of the antiapoptotic gene Bcl2, 4) inhibits the activity of enzymes involved in cell survival and proliferation, 5) decreases cyclin D1 levels, 6) reduces the expression of cyclin-dependent kinases (Cdk4, Cdk6, Cdk7) and anti-apoptotic genes (Bcl2, x-IAP, c-IAP-2) in CRC cells. In vitro CDK2 binding assay was also performed, showing that the NAR derivatives had better inhibitory activities on CDK2 than NAR. Based on the findings of this study, NAR is a potential therapeutic agent for CRC. Additional pharmacology and pharmacokinetics studies are required to fully elucidate the mechanisms of action of NAR and establish the most suitable dose for subsequent clinical investigations.

Breast cancer (BC) has emerged as the fifth most prevalent cause of cancer-related morbidity, prompting considerable interest from researchers due to its increased malignancy and resistance to drugs. Traditional chemotherapy methods have demonstrated limited effectiveness in treating all BC subtypes, underscoring the pressing demand for innovative therapeutic strategies or medications. Curcumin, a bioactive substance extracted from Curcuma longa, has been widely examined for its potential as an oncology drug. Research indicates that turmeric extract and its derivatives effectively inhibit STAT3, resulting in downstream effects like reducing cancer cell growth, triggering cell death, and preventing metastasis. The research on curcumin’s impact on the STAT3 pathway in BC demonstrated that curcumin effectively inhibits STAT3, leading to downstream effects such as the downregulation of Bcl-xL, Bcl-2, and Survivin, and the induction of apoptosis in H-Ras MCF10A cells. Additionally, it showed curcumin’s ability to hinder proliferation and anchorage-independent cell growth. The research also examined the effects of curcumin derivatives, like FLLL11, FLLL12, hydrazinocurcumin (HC), and GO-Y030, on STAT3 inhibition and their potential as therapeutic agents for BC. Observed results indicated the promise of curcumin and its derivatives in targeting the STAT3 signaling pathway for BC therapy.

Diabetes mellitus (DM), a chronic metabolic disorder associated with hyperglycemia and other complications, is one of the five priority non communicable diseases of global interest with unprecedented rise in developing countries. Whereas, the current treatment with insulin and oral hypoglycemic agents is aimed at managing the hyperglycemia and associated complications, there is need to explore other critical pathways in the pathogenesis of DM that can act as potential drug targets with better treatment outcomes. This study comprehensively explains the role of cellular and molecular elements, like hyperglycemia-induced oxidative stress, endothelial dysfunction, and Nuclear Factor Kappa B (NF-κB)’s involvement in inflammation and immune regulation, in the onset of DM. With bioactive compounds from natural products gaining popularity as novel drug molecules due to their diverse pharmacological actions, the study also extensively explores the prospective therapeutic benefits of curcumin (CUR), a bioactive compound known for its antioxidant, anti-inflammatory, and hypoglycemic properties, in addressing diabetic complications, predominantly via the modulation of the NF-κB pathway. The findings reveal that CUR administration effectively lowered blood glucose elevation, reinstated diminished serum insulin levels, and enhanced body weight in Streptozotocin -induced diabetic rats. CUR exerts its beneficial effects in management of diabetic complications through regulation of signaling pathways, such as CaMKII, PPAR-γ, NF-κB, and TGF-β1. Moreover, CUR reversed the heightened expression of inflammatory cytokines (TNF-α, IL-1β, IL-6) and chemokines like MCP-1 in diabetic specimens, vindicating its anti-inflammatory potency in counteracting hyperglycemia-induced alterations. CUR diminishes oxidative stress, avert structural kidney damage linked to diabetic nephropathy, and suppress NF-κB activity. Furthermore, CUR exhibited a protective effect against diabetic cardiomyopathy, lung injury, and diabetic gastroparesis. Conclusively, the study posits that CUR could potentially offer therapeutic benefits in relieving diabetic complications through its influence on the NF-κB pathway.

Retinal ganglion cells (RGCs) are the major cells that are damaged in glaucoma leading to vision loss and blindness. The damage to RGCs in glaucoma is caused by various mechanisms such as elevated intraocular pressure, oxidative stress, inflammation, and other neurodegenerative processes. As the disease progresses, more and more RGCs are lost, leading to a gradual loss of vision. Therefore, protecting RGCs from damage and promoting their survival is an important goal in the treatment of glaucoma. Resveratrol (RES) exerts anti-oxidant effects and slows down the evolution and progression of glaucoma. This review was prepared using databases such as Google Scholar, PubMed, Scopus, and ScienceDirect. Based on the findings of this review, RES has a protective role on RGCs in cases of ischemic injury and hypoxia as well as ErbB2 protein expression in the retina. Additionally, RES has protective effects on RGCs by promoting cell growth, reducing apoptosis, and decreasing oxidative stress in H2O2-exposed RGCs. RES was also found to inhibit oxidative stress damage in RGCs and suppress the activation of MAPK signaling pathways. Moreover, RES could alleviate retinal function impairment by suppressing the HIF-1a/VEGF and p38/p53 axis while stimulating the PI3K/Akt pathway. Hence, RES might exert potential therapeutic effects in the treatment of glaucoma by protecting RGCs from damage and promoting their survival.

This study conducted an investigation into the impact of different dosages of vitamin E supplementation on histopathological alterations, cognitive behaviors, and the expression of age-associated genes in the heart and hippocampus of aged mice. Mice at 12 months of age received varying doses of vitamin E (100 mg/kg, 200 mg/kg, and 400 mg/kg) orally through gavage for 28 days. The results indicated that vitamin E supplementation improved working memory and spatial learning, reduced oxidative stress in the heart and brain tissues, and positively influenced the expression of SIRT1, Nrf2, and Calstabin2 genes. Interestingly, the efficacy of vitamin E was dose-dependent, with higher doses demonstrating more beneficial effects. The study also examined the influence of vitamin E on the activities of antioxidant enzymes, such as SOD and GPX, as well as the levels of MDA, a marker of oxidative stress, and found that vitamin E supplementation resulted in dose-related changes in these parameters. The findings also indicate that higher doses of vitamin E, particularly at 400 mg/kg, demonstrated more beneficial effects. However, the study emphasizes the need for further research to confirm these findings and to explore the potential clinical applications of vitamin E supplementation in addressing age-related conditions.