Molecular mechanisms and therapeutic potential of natural flavonoids in diabetic nephropathy: Modulation of intracellular developmental signaling pathways.

Recognized as a common microvascular complication of diabetes mellitus (DM), diabetic nephropathy (DN) is the principal cause of chronic end-stage renal disease (ESRD). Patients with diabetes have an approximately 25% risk of developing progressive renal disease. The underlying principles of DN control targets the dual outcomes of blood glucose regulation through sodium glucose cotransporter 2 (SGLT 2) blockade and hypertension management through renin-angiotensin-aldosterone inhibition. However, these treatments are ineffective in halting disease progression to kidney failure and cardiovascular comorbidities. Recently, the dysregulation of subcellular signaling pathways has been increasingly implicated in DN pathogenesis. Natural compounds are emerging as effective and side-effect-free therapeutic agents that target intracellular pathways. This narrative review synthesizes recent insights into the dysregulation of maintenance pathways in DN, drawing from animal and human studies. To compile this review, articles reporting DN signaling pathways and their treatment with natural flavonoids were collected from PubMed, Cochrane Library Web of Science, Google Scholar and EMBASE databases since 2000. As therapeutic interventions are frequently based on the results of clinical trials, a brief analysis of data from current phase II and III clinical trials on DN is discussed.

Caffeic acid phenethyl ester mediates apoptosis in serum-starved HT29 colon cancer cells through modulation of heat shock proteins and MAPK pathways.

Colorectal cancer (CRC) is among the most prevalent gastrointestinal cancers of epithelial origin worldwide, with over 2 million cases detected every year. Emerging evidence suggests a significant increase in the levels of inflammatory and stress-related markers in patients with CRC, indicating that oxidative stress and lipid peroxidation may influence signalling cascades involved in the progression of the disease. However, the precise molecular and cellular basis underlying CRC and their modulations during bioactive compound exposure have not yet been deciphered. This study examines the effect of caffeic acid phenethyl ester (CAPE), a natural bioactive compound, in HT29 CRC cells grown under serum-supplemented and serum-deprived conditions. We found that CAPE inhibited cell cycle progression in the G2/M phase and induced apoptosis. Migration assay confirmed that CAPE repressed cancer invasiveness. Protein localisation by immunofluorescence microscopy and protein expression by western blot analysis reveal increased expressions of key inflammatory signalling mediators such as p38α, Jun N-terminal kinase and extracellular signal-regulated kinase (ERK) proteins. Molecular docking data demonstrates that CAPE shows a higher docking score of -5.35 versus -4.59 to known p38 inhibitor SB203580 as well as a docking score of -4.17 versus -3.86 to known ERK1/2 inhibitor AZD0364. Co-immunoprecipitation data reveals that CAPE treatment effectively downregulates heat shock protein (HSP) expression in both sera-supplemented and limited conditions through its interaction with mitogen-activated protein kinase 14 (MAPK14). These results suggest that stress induction via serum starvation in HT29 CRC cells leads to the induction of apoptosis and co-ordinated activation of MAPK-HSP pathways. Molecular docking studies support that CAPE could serve as an effective inhibitor to target p38 and MAPK compared to their currently known inhibitors.

Systemic and Anticancer Potential of Adaptogenic Constituents Isolated from Traditional Herbs - A Mini-Review.

Adaptogens were initially recognized as stress-resistance inducing compounds. Recent studies reveal that adaptogens are pleiotropically-acting chemical constituents that can be isolated from traditional herbs. They are gaining increasing attention in cancer chemotherapy. This review summarizes the physiological action of adaptogens isolated from the 9 most widely used traditional herbs implicated in cancer therapy viz., Withania somnifera, Tinospora cordifolia, Rhodiola rosea, Emblica officinalis, Glycyrrhiza glabra, Bacopa monnieri, Asparagus racemosus, Ocimum sanctum, and Panax notoginseng. The studies were identified through a systematic search of major computerized databases such as Pubmed, Embase, Medline, Inflibnet, Google Scholar, and Cochrane Library. Individual names of each herb and biological action were the search terms employed. In this review, we have enlisted the chemical constituents and their mechanism of action in a few organ systems as well as in cancer cells. Studies indicate that the adaptogens isolated from these herbs can be broadly arranged into 2 classes based on their chemical structure. These molecules exert a positive influence on several organ systems such as respiratory, nervous, cardiovascular, immune, and gastrointestinal tracts. It is also clear that adaptogens act as effective chemopreventive agents alone or in combination with chemo drugs in multiple cancers by targeting multiple intracellular target proteins. Therefore, we conclude that adaptogens are versatile ligands capable of eliciting many systemic effects. Their biological functions are complex, varied, and context-dependent in various cancers. This offers great scope for personalized treatment and cancer chemoprevention in the future.

Diabetic nephropathy: recent advances in pathophysiology and challenges in dietary management.

BACKGROUND: Diabetic nephropathy (DN) or diabetic kidney disease refers to the deterioration of kidney function seen in chronic type 1 and type 2 diabetes mellitus patients. The progression of the disease is known to occur in a series of stages and is linked to glycemic and blood pressure control. However, despite aggressive blood sugar control the prevalence of chronic kidney disease (CKD) in diabetic patients has not witnessed any decrease in the last two decades; which has lead to identification of additional factors in its progression. The nutritional status of patients is an important and modifiable factor that may influence CKD processes and outcome. It directly stems from the traditional dietary choices that patients make due to poor nutritional awareness. Dietary management of DN patients is challenging, as the twin factors of diet overload on kidney function needs to be balanced with malnutrition. Patient education seems to be the key in avoiding overindulgence of carbohydrate and protein-rich foods while favoring inclusion of essential fats in their diet. CONCLUSION: This review will summarize current advances in staging and molecular pathogenesis of DN. It will highlight recent studies focusing on patient-customized dietary interventions that offer new hope as an effective tool in improving quality of life and delaying disease progression in DN patients.