Surface-Functionalized Nanoceria: Dual Action in Diabetes Management via Glucose-Responsive Insulin Delivery and Oxidative Stress Mitigation.

Nanoceria (NC) is gaining scientific attention due to its widespread drug delivery efficacy and modulation of oxidative stress. Herein, we developed dextran (Dex) capped insulin (INS)-loaded phenylboronic acid (PBA)-functionalized nanoceria (NC-PBA-INS-Dex) for glucose-responsive insulin delivery and mitigating excessive ROS production to regulate both hyperglycemia and oxidative stress in diabetes mellitus (DM). The prepared nanoparticle showed favorable loading capacity and excellent encapsulation efficiency of insulin. Glucose-responsive insulin release from NC-PBA-INS-Dex was observed initially in the cell-free mode when subjected to varying glucose concentrations (5.5, 11, and 25 mM). Interestingly, under in vitro setting, promising insulin release from NC-PBA-INS-Dex was found in muscle cells (major glucose storage cells) compared to lung cells against exposure to different glucose concentration suggesting a glucose-sensitive intracellular insulin delivery. NC-PBA-INS-Dex treatment further upregulated GLUT4 translocation and glucose uptake/utilization in sodium palmitate-exposed muscle cells, and results were significantly higher compared to NC or INS alone treated cells. Studies in diabetic animals demonstrated the maintenance of normoglycemia for up to 12 h upon gavaging a single dose of NC-PBA-INS-Dex compared to INS alone treatment (subcutaneous/oral). Oral administration of NC-PBA-INS-Dex also increased insulin bioavailability (in both serum and muscle tissue) compared with either subcutaneous or oral insulin administration. NC-PBA-INS-Dex further exhibited ROS scavenging (superoxide radical) potential in cell-free, in vitro, and in vivo systems, and results were comparable to treatment with NC alone. NC-PBA-INS-Dex could effectively regulate the expression of occludin and induce the reversible opening of a tight junction in intestinal epithelial cells, allowing the particle transport through the intestinal mucosa. Treatment with NC-PBA-INS-Dex did not exhibit any toxicity to in vitro and in vivo models. The NC-based drug delivery system will mimic the physiological regulation of insulin secretion in a noninvasive manner, offering improved patient compliance, reduced risk of hyperglycemia, and enhanced overall management of DM.

Anti-inflammatory potential of Piper betleoides C. DC., a promising Piper species of Northeast India: in vitro and in vivo evidence and mechanistic insight.

The present study aims to investigate the anti-inflammatory potential of the leaf hydroalcoholic extract of Piper betleoides C. DC., also known as "Jangli Paan" in Northeast India, using lipopolysaccharide (LPS)-treated both cell culture (RAW264.7, macrophage cells) and animal (albino rat) model of inflammation. Treatment with leaf hydroalcoholic extract of Piper betleoides (PBtE) dose-dependently (5, 10, and 20 µg/mL) decreased the secretion of pro-inflammatory (TNF-α, IL-6, and MCP-1) and increased anti-inflammatory (IL-4 and IL-10) cytokines in LPS-treated macrophages. Similarly, treatment with PBtE also prevented the alternation in mRNA expression of inflammatory markers (TNF-α, CCL-2, IL-6, and IL-10) in LPS-treated macrophages. Dose-dependent supplementation with PBtE further reduced the production of intracellular ROS and increased the phagocytosis efficacies in LPS-treated cells. Further in vivo studies demonstrated that treatment with PBtE dose-dependently (50, 100, and 200 mg/kg body weight) prevented the dysregulation of the secretion of inflammatory cytokines (TNF-α, IL-4, IL-6, and IL-10) and reduced the circulatory levels of prostaglandin (PGE2) and nitric oxide products (nitrite) in LPS-treated animals. In addition, alternation of blood cell profiling and the liver as well as kidney dysfunctions were also prevented by the treatment with PBtE in LPS-treated rats. The anti-inflammatory potential of PBtE was comparable to those seen in sodium diclofenac (positive control) treated group. LC-MS analyses showed piperine, piperlongumine, piperolactam-A, and dehydropipernonaline and GC-MS analyses demonstrated phytol, caryophyllene, and falcarinol as the phytochemicals present in Piper betleoides, which might play an important role in preventing inflammation and associated pathophysiology. Different treatments didn't cause any toxicity in cell culture and animal models. This study for the first time demonstrated the promising anti-inflammatory potential of the leaf hydroalcoholic extract of Piper betleoides.

Access to Isoxazoles via Photo-oxygenation of Furan Tethered α-Azidoketones.

Photocatalyst-free visible light-enabled direct oxygenation of furan-tethered α-azidoketones was studied. The reaction yielded various products depending on the substituents, with isoxazoles forming as the major products. The findings suggest that singlet oxygen was generated during the reaction and reacted with α-azidoketones in a [4 + 2] fashion to yield endoperoxides, which rearranged in multiple ways to generate isoxazoles. Some of the synthesized isoxazoles were evaluated as α-glucosidase inhibitors, and three of them 5bi, 5bj, and 5bl exhibited good activity with IC50 values of 454.57 ± 29.34, 147.84 ± 2.28, and 272.58 ± 42.06 µM, respectively, when compared with the standard drug acarbose (IC50 = 1224.33 ± 126.72 µM).