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Aim: Diabetic nephropathy (DN) is a type of microvascular complication that arises from diabetes mellitus and leads to further health issues. Most importantly, the prevalence of DN is steadily rising in developed countries. This research explored the therapeutic benefits of alogliptin, a dipeptidyl peptidase IV (DPP-4) inhibitor, on streptozotocin (STZ)-induced DN and its underlying mechanisms in rats., Main Methods: Ten rats were allocated to group 1, served as the normal group; and received saline. To develop diabetes, thirty rats were administered a single intraperitoneal dose of STZ (45 mg/kg). STZ-induced diabetic rats were randomly assigned to three groups: group 2 diabetic control; was given saline, groups 3 and 4 received alogliptin (10 mg/kg) and (20 mg/kg), respectively. The treatment began 8 weeks after diabetes onset and continued for four weeks. Histopathological alterations in the kidney were detected. Serum was collected to measure blood glucose levels (BGL), renal function, and lactate dehydrogenase (LDH). Tissue samples were collected to detect changes in oxidative stress (OS), inflammation, 5' adenosine monophosphate-activated protein kinase (AMPK), and the mammalian target of Rapamycin (mTOR) signaling pathways in addition to apoptotic and autophagy changes., Key Findings: Alogliptin reduced STZ-induced histological changes in the kidney as well as OS, and inflammation. Alogliptin also ameliorated the AMPK/mTOR signaling pathways, enhanced autophagy, and reduced apoptosis., Significance: These results demonstrate that alogliptin ameliorates inflammation and OS and consequently modulates the AMPK/mTOR axis along with targeting autophagy and apoptosis, leading to the alleviation of DN., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Exploring new inhibitors with good bioavailability and high selectivity for managing type 2 diabetes mellitus (T2DM) and its associated complications is a major challenge for research, academia, and the pharmaceutical industry. Protein tyrosine phosphatase-1B (PTP1B) arose as an important negative regulator in insulin signaling pathways associated with metabolic disorders, including T2DM and obesity. Novel neutral compounds with a benzene-sulfonamide scaffold were designed and synthesized based on structural- and ligand-based drug design strategies for fragment growth. Promising hits against PTP1B were identified through in vitro enzymology inhibition assay. Mechanistic aspects of the compound's different inhibition activities were rigorously investigated through molecular docking coupled with explicit dynamics simulations. Four identified hits, 3c, 8, 10a, and 11, with sub-micromolar PTP-1B IC 50 and significant predicted pharmacokinetic and pharmacodynamic parameters, were further biologically evaluated for their anti-diabetic, anti-obesity, anti-inflammatory, and anti-oxidant effects in a high-fat diet (HFD) + streptozotocin (STZ)-induced T2DM rat model. All these hit compounds exhibited a significant anti-diabetic and anti-obesity effect and a significant efficacy in reducing oxidative stress and increasing anti-oxidant enzymes while reducing inflammatory markers. Improving compound potency was further highlighted by improving the pharmacokinetic profile of the most active compound, 10a, through nano formulation. Compound 10a nano formulation showed the most promising anti-diabetic and anti-obesity effects and a remarkable histopathological improvement in all organs studied., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Different classes of phytochemicals were previously isolated from the Red Sea algae Hypnea   musciformis as sterols, ketosteroids, fatty acids, and terpenoids. Herein, we report the isolation of three fatty acids-docosanoic acid 4 , hexadecenoic acid 5 , and alpha hydroxy octadecanoic acid 6 -as well as three ceramides- A ( 1 ), B ( 2 ), and C ( 3 )-with 9-methyl-sphinga-4,8-dienes and phytosphingosine bases. Additionally, different phytochemicals were determined using the liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (LC-ESI-HRMS) technique. Ceramides A ( 1 ) and B ( 2 ) exhibited promising in vitro cytotoxic activity against the human breast adenocarcinoma (MCF-7) cell line when compared with doxorubicin as a positive control. Further in vivo study and biochemical estimation in a mouse model of Ehrlich ascites carcinoma (EAC) revealed that both ceramides A ( 1 ) and B ( 2 ) at doses of 1 and 2 mg/kg, respectively, significantly decreased the tumor size in mice inoculated with EAC cells. The higher dose (2 mg/kg) of ceramide B ( 2 ) particularly expressed the most pronounced decrease in serum levels of vascular endothelial growth factor -B (VEGF-B) and tumor necrosis factor-α (TNF-α) markers, as well as the expression levels of the growth factor midkine in tumor tissue relative to the EAC control group. The highest expression of apoptotic factors, p53, Bax, and caspase 3 was observed in the same group that received 2 mg/kg of ceramide B ( 2 ). Molecular docking simulations suggested that ceramides A ( 1 ) and B ( 2 ) could bind in the deep grove between the H2 helix and the Ser240-P250 loop of p53, preventing its interaction with MDM2 and leading to its accumulation. In conclusion, this study reports the cytotoxic, apoptotic, and antiangiogenic effects of ceramides isolated from the Red Sea algae Hypnea   musciformis in an experimental model of EAC.