Rashmi Santosh Tupe

D-galactose (D-Gal) is used to induce aging-associated pathological complications; however, its dose-dependent effects on RAGE-NF-κB and Nrf2 pathways remain unexplored. We examine the effects of D-Gal (400, 500, and 600 mg/kg body weight) on glycation, inflammation, and detoxification parameters in the liver and kidney tissues of Wistar rats. Rats received subcutaneous D-Gal injections for 56 days, while the control rats received 0.9% saline. Blood samples were collected at 15-day intervals, and renal function was assessed using 24-h urine samples. After treatment, rats were sacrificed, liver and kidney tissues were harvested. D-Gal administration altered liver and kidney function by a dose-dependent increase in creatinine excretion upto 1.3-fold. Histological analysis revealed glomerular hypertrophy and hepatocellular injury. Additionally, an increase in GFR by 1.8-fold was observed (p < 0.05). D-Gal treatment showed a time-dependent increase in fructosamine (day 15), protein carbonyl content (day 30), and advanced glycation end products (AGEs) by day 56, accompanied by reduced free amino and thiol groups. Similar trends were observed in tissues, with D-Gal 500 showing the most pronounced effects (p < 0.001). Antioxidant and detoxification parameters exhibited time-dependent alterations, with changes in GSH levels and catalase activity in tissues (p < 0.001). D-Gal treatment significantly modulated RAGE and NF-κB expression at the gene and protein levels. D-Gal 600 induced a 7.5-fold increase in RAGE expression (p < 0.0001). NF-κB and Nrf2 expression were concentration-dependent, with changes at the protein level. Overall, D-Gal 500 exerted maximal effects via the RAGE-NF-κB-Nrf2 axis without significant cellular damage.

Glycation due to increased blood sugar levels aggravates diabetic complications. Glycation hampers the structural and functional integrity of human serum albumin (HSA). Acetylsalicylic acid (ASA)/aspirin exhibits anti-glycation properties. Although the precise molecular mechanism of ASA in glycation has not yet been conclusively demonstrated, acetylation has been considered the central mechanism underlying its biological action. The present study aims to unveil the specific mechanism of action of ASA on glycated HSA through meticulously designed approaches. Fluorescence and UV-visible spectroscopy were used to analyse glycation adducts in the presence of ASA. ANS-based fluorescence spectroscopy, sodium dodecyl sulfate polyacrylamide gel electrophoresis, Fourier transform infrared spectroscopy, field-emission scanning electron microscopy, and high-performance liquid chromatography were used to study the structural modifications of glycated HSA in the presence of ASA. Furthermore, we investigated functional modifications in glycated HSA using nuclear magnetic resonance spectroscopy. The analyzed data showed a direct association between glycation and the impaired structural and functional integrity of HSA, which was partially restored by ASA. Our data corroborate that ASA’s prominent anti-glycation activity may be attributable to mechanisms other than acetylation.

Objective: This study investigates how hydroalcoholic and ethanolic extracts from Angelica sinensis (Oliv.) Diels, Nelumbo nucifera Gaertner, Coccinia indica Wight & Arn, Syzygium jambolanum (Lam.) DC, Cardiospermum helicacabum L, and Solanum trilobatum L impact the glycation, Amyloid β (Aβ) aggregation, inflammation, and oxidative stress—processes central to age-related disorders. Methodology: Using spectrofluorimetric and Thioflavin T fluorescence tests, the activity of plant extracts (ethanolic and hydroalcoholic) on albumin glycation and Aβ _25-35 self-aggregation was examined. To comprehend the effects of plant extracts on inflammation, macrophages were subjected to plant extract treatment and, subsequently assessed for, cell viability, cytokine production (TNF-α, IL-6, and IL-10), and nitric oxide generation using XTT assay, ELISA, and nitric oxide estimation kit, respectively. Additionally, the DPPH and ABTS assays were used to evaluate the plant extracts capacity to scavenge radicals, and the total phenolic content was determined. Results: Among the 12 plant extracts examined, S. trilobatum hydroalcoholic (Sth) extracts significantly reduced the three AGEs content (Malondialdehyde, pentosidine, and crossline) as compared to glycated BSA (p < 0.0001). Moreover, A. sinensis hydroalcoholic (Ash) extracts inhibited the self-aggregation of Aβ _25-35 fargments by 87%, exhibiting significant anti-amyloid activity and a possible function in preventing protein aggregation linked to neurodegenerative conditions like Alzheimer's disease (AD). Meanwhile, C. indica hydroalcoholic (Cih) extracts displayed substantial anti-inflammatory activity by maintaining the cell viability and reducing the pro-inflammatory cytokine and nitric oxide production, highlighting their potential to control inflammation, a significant factor in age-related diseases. Conclusion: The results demonstrated that S. triolobatum , A. sinensis , and C. indica hydroalcoholic extracts contain significant anti-glycation, anti-aggregation, and anti-inflammatory activities. These findings are highly relevant, as they address key contributors such as AGEs, aggregation, and inflammation, which drive age-related disorders. The study underscores the potential of these extracts as natural interventions targeting the molecular hallmarks of ageing, supporting their role in preventive healthcare.

Diabetes mellitus is a chronic metabolic disorder characterized by persistent hyperglycemia, insulin dysfunction, and a substantial global health burden. Current pharmacological therapies often bring undesired side effects and limited long-term efficiency. These factors drive interest in the direction of preventive and complementary strategies. Plant-derived secondary metabolites – phenolics, alkaloids, terpenes, organosulfur compounds and polyacetylenes, demonstrate promising anti-diabetic activities. These compounds can modulate key molecular targets involved in glucose metabolism, insulin signaling, and development of oxidative stress, thereby improving glycemic control and reducing the risk of complications. Also, natural products can inhibit carbohydrate-digesting enzymes, enhance insulin secretion and sensitivity, regulate glucose transporters, and suppress pathways associated with inflammatory responses and the formation of advanced glycation end products (AGEs). Many of them also demonstrate pronounced antioxidant and antiglycative properties with all accompanying features - metal-chelating effects, α-dicarbonyl trapping properties, and interference with the AGE-RAGE axis, collectively mitigating vascular damage and attenuating diabetic complications such as nephropathy, neuropathy, and retinopathy. Recent studies highlight that certain plant metabolites can stabilize Nrf2, inhibit NF-κB activation, improve pancreatic β-cell function, and reduce protein tyrosine phosphatase activity. In this review we comprehensively address all this aspects with a special emphasis on the antiglycative properties as one of the central component of the overall anti-diabetic activity. Further, we discuss the further prospective in the biochemistry of plant-derived natural products in terms of antidiabetic, antiglycative and antioxidant agents. Although further research is needed to clarify their pharmacokinetics, safety, and efficacy in humans, the emerging evidence underscores the potential of plant secondary metabolites as natural, multifaceted agents for the prevention and management of diabetes and its associated complications.