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Objective(s): Nephropathy is the most common comorbidity linked to T2D. The present study aimed to examine the potential of saroglitazar in the context of a high-fat diet and low-dose streptozotocin-induced diabetic nephropathy in Wistar rats. Materials and Methods: Molecular docking simulation investigations were conducted on the ligand- binding region of type IV collagen and Kidney injury molecule-1 (KIM-1), using saroglitazar and fenofibrate as the subjects. The rats were fed either a conventional rodent diet or a high-fat diet ad libitum for two weeks. Following a two-week period, the rats given an HFD were administered with a low-dose of STZ (35 mg/kg, IP). Rats with experimentally induced diabetes were categorized into five groups: normal control; diabetic control; HFD+STZ+saroglitazar (2 mg/kg); HFD+STZ+saroglitazar (4 mg/kg); HFD+STZ+fenofibrate (100 mg/kg) treated orally for 21 days with continuation on HFD. After 21 days, rats were kept on fasting overnight, blood and urine was acquired for various biochemical analysis. Animals were sacrificed, and kidney tissues were removed for histopathological studies. Results: In-silico investigation showed a substantial affinity between saroglitazar and fenofibrate with KIM-1 and type IV collagen. Saroglitazar produced a significant (P<0.01) reduction in weight of the body, serum blood sugar, albumin, creatinine, and BUN levels. Further, saroglitazar significantly (P<0.01) reduced the KIM-1 and type IV collagen levels in the urine of diabetic rats. Histopathological results showed improvement in tubular degeneration, necrosis, and dilatation of Bowman's space in kidney tissue. Conclusion: Saroglitazar attenuated renal injury by improving renal function in HFD+STZ-induced DN in Wistar rats. [ABSTRACT FROM AUTHOR]

Inflammation triggers immune system-mediated actions that contribute to the development of multiple diseases. Zymosan, a polysaccharide derived from the Saccharomyces cerevisiae cell wall, is mainly made up of glucan and mannan residues and is used as an inflammatory agent. Zymosan is a fungal product that activates the immune system through the activation of inflammatory signaling pathways, and releases a variety of harmful chemicals including pattern recognition receptors, reactive oxygen species (ROS), and the excitatory amino acid glutamate, cytokines, adhesion molecules, etc. Furthermore, we will dive into the molecular mechanistic insights through which this fungal agent induces and influences various inflammatory diseases such as cardiovascular, neuroinflammation, diabetes, arthritis, and sepsis. Based on the evidence, zymosan appears to be a promising inflammatory-inducing agent. Nonetheless, more animal data is the need of the hour to catch a glimpse and unravel the capacity of zymosan. [ABSTRACT FROM AUTHOR]

Objective(s): Inflammation is the major progenitor of obesity and associated metabolic disorders. The current study investigated the modulatory role of saroglitazar on adipocyte dysfunction and associated inflammation in monosodium glutamate (MSG) obese Wistar rats. Materials and Methods: The molecular docking simulation studies of saroglitazar and fenofibrate were performed on the ligand-binding domain of NLRP3 and NF-κB. Under in vivo study, neonatal pups received normal saline or MSG (4 g/kg, SC) for 7 alternate days after birth. After keeping for 42 days as such, animals were divided into seven groups: Normal control; MSG control; MSG + saroglitazar (2 mg/kg); MSG + saroglitazar (4 mg/kg); saroglitazar (4 mg/kg) per se; MSG + fenofibrate (100 mg/kg); fenofibrate (100 mg/kg) per se. Drug treatments were given orally, from the 42nd to 70th day. On day 71, blood was collected and animals were sacrificed for isolation of liver and fat pads. Results: In silico study showed significant binding of saroglitazar and fenofibrate against NLRP3 and NF-κB. Saroglitazar significantly reduced body weight, body mass index, Lee's index, fat pad weights, adiposity index, decreased serum lipids, interleukin-1β (IL-1β), tumor necrosis factor-α(TNF-α), interleukin-6 (IL-6), leptin, insulin, blood glucose, HOMA-IR values, oxidative stress in the liver and increased hepatic low-density lipoprotein receptor levels. Histopathological analysis of the liver showed decreased inflammation and vacuolization, and reduced adipocyte cell size. Immunohistochemical analysis showed suppression of NLRP3 in epididymal adipocytes and NF-κB expression in the liver. Conclusion: Saroglitazar ameliorated obesity and associated inflammation via modulation of NLRP3 inflammasome and NF-κB in MSG obese Wistar rats. [ABSTRACT FROM AUTHOR]

Objective(s): Excess intake of a high-fatty diet (HFD) together with zymosan administration mediates vasculitis response which leads to impaired serum lipid levels and causes arterial stiffness. In the development of new cholesterol-lowering medications, PCSK9 inhibitor (proprotein convertase subtilisin/kexin type 9) is an emerging therapeutic. The goal of the present study was to see whether anti-PCSK9 mAb1 might prevent vasculitis in C57BL/6 mice by blocking TLR2/NF-B activation in HFD and Zymosan-induced vasculitis. Materials and Methods: Protein-protein molecular docking was performed to validate the binding affinity of anti-PCSK9 mAb1 against TLR2. Under the experimental study, mice were randomly allocated to the following groups: Group I: standard mice diet (30 days) + Zymosan vehicle (sterile PBS solution of 5mg/ml on 8th day); Group II: HFD (30 days) + Zymosan (single IP dose 80 mg/kg on day 8th); Group III: HFD+Zymosan + anti-PCSK9 mAb1 (6 mg/kg, s.c. on 10th and 20th days); Group IV: HFD+Zymosan+anti-PCSK9 mAb1 (10 mg/kg, s.c. on 10th and 20th days). Results: In comparison with the low dose of anti-PCSK9 mAb1 (6 mg/kg), the high dose of anti-PCSK9 mAb1 (10 mg/kg) together with HFD and Zymosan inhibited vasculitis more effectively by decreasing aortic TLR2 and NF-B levels, reducing serum TNF- and IL-6, and up-regulating liver LDLR levels, which down-regulated serum LDL-C and improved serum lipids levels. Histopathological studies showed that anti-PCSK9 mAb1 treatment reduced plaque accumulation in the aorta of mice. Conclusion: These findings indicate that anti-PCSK9 mAb1 has therapeutic potential in reducing HFD and Zymosan-induced vascular inflammation. [ABSTRACT FROM AUTHOR]

Objective(s): Accumulated evidence provides a strong connection between the immune system and vascular inflammation. The innate immune system's main sensors are toll-like receptors (TLRs). Zymosan (Zym), a fungal product, induces an inflammatory response via activating TLR2 of the immune system. Atorvastatin, a potent statin, possesses pleiotropic effects including immunomodulatory, lipid-lowering, and anti-inflammatory. Therefore, the current study aimed to evaluate the protective role of atorvastatin against a high-fat diet (HFD) and Zym-induced vascular inflammation in C57BL/6 mice via modulation of TLR2/NF-κB signaling pathway. Materials and Methods: In silico study was conducted to confirm the binding affinity of atorvastatin against TLR2. Under in vivo study, mice were divided into four groups: Normal control: normal standard chow-diet fed for 30 days + Zym vehicle (sterile PBS, 5 mg/ml on 8th day); HFD (30 days) + Zym (80 mg/kg, IP, on 8th day); HFD/Zym + atorvastatin vehicle (0.5% CMC, p.o., from 10th to 30th day); HFD/Zym + atorvastatin (3.6 mg/kg, p.o., from 10th to 30th day). Results: Atorvastatin treatment along with HFD and Zym inhibited vascular inflammation by suppressing the levels of aortic TLR2, cardiac NF-κB and decrease in serum TNF-α and IL-6. Further, there was an increase in hepatic LDLR levels, resulting in a decrease in serum LDL-C and an increase in HDL-C levels. Histopathological examination of the aorta showed a reduction in plaque accumulation with the atorvastatin-treated group as compared with HFD and Zym-treated group. Conclusion: Atorvastatin attenuates vascular inflammation mediated by HFD and Zym through suppression of TLR2, NF-κB, TNF-α, IL-6, and upregulation of LDLR levels. [ABSTRACT FROM AUTHOR]