A novel indazole derivative, compound Cyy-272, attenuates LPS-induced acute lung injury by inhibiting JNK phosphorylation.

Acute lung injury (ALI) is a diffuse lung dysfunction disease characterized by high prevalence and high mortality. Thus far, no effective pharmacological treatment has been made for ALI in clinics. Inflammation is critical to the development of ALI. Therefore, anti-inflammation may be a potential therapy strategy for ALI. Indazole-containing derivatives, representing one of the most important heterocycles in drug molecules, are endowed with a broad range of biological properties, such as anti-cancer and anti-inflammation. In the current study, we investigated the biological effects of Cyy-272, a newly synthesized indazole compound, on LPS-induced ALI both in vivo and in vitro. Results show that Cyy-272 can inhibit the release of inflammatory cytokines in LPS-stimulated macrophage and alleviate LPS induced ALI. Further experiment revealed that Cyy-272 exhibit anti-inflammation activity by inhibiting JNK phosphorylation. Overall, our studies show that an indazole derivative, Cyy-272, is effective in suppressing LPS-induced JNK activation and inflammatory signaling.

Silybin enhances the blood concentration of brexpiprazole in rats by downregulating expression of CYP3A4 and CYP2D6.

In this study, we investigated the effect of silybin on the pharmacokinetics of brexpiprazole and the underlying mechanism in rats. Two groups of animals received silybin at different doses (50 mg/kg, 25 mg/kg) for 2 weeks, while another group was given vehicle alone. After that, rats were intragastrically administrated with 2 mg/kg brexpiprazole. Then, the tail blood and liver tissues were collected from each rat at different time points. Brexpiprazole in serum was determined by an established UPLC-MS/MS assay. Finally, pharmacokinetic parameters of animals in each group were figured out. The results show that silybin remarkably changed the pharmacokinetic properties of brexpiprazole, especially at the highest dose. AUC and Cmax in the combination group with 50 mg/kg silybin were enhanced approximately 4 times as much as after a single dose of brexpiprazole, p < 0.05. Meanwhile, total liver protein of each sample was extracted, and was subjected to immunoblotting assay for probing CYP3A4 and CYP2D6. Therein CYP3A4 was significantly downregulated compared to the control group. Overall, silybin can increase blood concentration of brexpiprazole in rat by downregulating its main metabolic enzyme CYP3A4. Therefore, the maintenance dose of brexpiprazole should be decreased while co-treating with silybin.

Compound LM9, a novel MyD88 inhibitor, efficiently mitigates inflammatory responses and fibrosis in obesity-induced cardiomyopathy.

Mechanisms of cardiomyopathy caused by obesity/hyperlipidemia are complicated. Obesity is usually associated with chronic low-grade inflammation and may lead to the onset and progression of myocardial fibrosis and remodeling. TLR4/MyD88 signaling pathway, as a key regulator of inflammation, plays an important role in the pathogenesis of obesity-induced cardiomyopathy. We previously demonstrated that LM9, a novel MyD88 inhibitor, attenuated inflammatory responses and fibrosis in obesity-induced cardiomyopathy by inhibiting the formation of TLR4/MyD88 complex. In this study, we investigated the protective effects of LM9 on obesity-induced cardiomyopathy in vitro and in vivo. We showed that LM9 (5, 10 µM) significantly attenuates palmitic acid (PA)-induced inflammation in mouse peritoneal macrophages, evidenced by decreased expression of proinflammatory genes including TNF-α, IL-6, IL-1ß, and ICAM-1. In cardiac-derived H9C2 cells, LM9 treatment suppressed PA-induced inflammation, lipid accumulation, and fibrotic responses. In addition, LM9 treatment also inhibited PA-activated TLR4/MyD88/NF-κB signaling pathway. We further revealed in HEK293 cells that LM9 treatment blocked the TLR4/MyD88 binding and MyD88 homodimer formation. In HFD-fed mice, administration of LM9 (5, 10 mg/kg, ig, every other days for 8 weeks) dose-dependently alleviated inflammation and fibrosis in heart tissues and decreased serum lipid concentration. In conclusion, this study demonstrates that MyD88 inhibitor LM9 exerts protective effects against obesity-induced cardiomyopathy, suggesting LM9 to be a promising therapeutic candidate drug for the obesity-related cardiac complications.

Pharmacokinetics, Bioequivalence, and Safety Studies of Prucalopride in Healthy Chinese Subjects.

The objectives of the present study were to evaluate the bioequivalence of 2 tablet formulations of prucalopride, generic and branded, and to investigate relevant pharmacokinetic and safety profiles. This study was designed as a randomized, open-label, fasting, single-dose, crossover, and dual-period trial. After overnight fasting, 12 subjects were given prucalopride tablets via oral administration, and blood specimens were obtained up to 96 hours after dosing. Prucalopride concentrations in plasma were measured using ultraprecision liquid chromatography-tandem mass spectrometry followed by calculation of pharmacokinetic parameters. The safety of prucalopride was assessed throughout the study. The pharmacokinetics of prucalopride can be defined as a 2-compartment model with a long elimination phase. No significant differences were observed between the pharmacokinetic profiles of the generic and branded prucalopride tablets. Bioequivalence was evaluated using 90%CIs for the ratio test/reference of log area under the concentration-time curve over 96 hours, log area under the concentration-time curve to infinity, and log peak concentration from generic and branded tablets, which were 100.06-109.94%, 100.63-110.32%, and 95.84-113.08%, respectively. During administration of the medication, there were 18 adverse events in 6 subjects in the test formulation group and 19 cases of adverse events in 6 subjects in the reference formulation group (P > .05). No severe adverse effects were detected. These results suggest that generic and branded prucalopride tablets are bioequivalent and show similar safety profiles.

Schisandrin B alleviates diabetic nephropathy through suppressing excessive inflammation and oxidative stress.

Diabetic nephropathy (DN) is a progressive kidney disease due to glomerular capillary damage in diabetic patients, with inflammation and oxidative stress implicated as crucial pathogenic factors. There is an urgent need to develop effective therapeutic drug. Natural medicines are rich resources for active lead compounds. They would provide new opportunities for the treatment of DN. The present study was designed to investigate the protective effects of Schisandrin B (SchB) on DN and to delineate the underlying mechanism. Oral administration of SchB in the diabetic mouse model significantly alleviated hyperglycemia-induced renal injury, which was accompanied by maintenance of urine creatinine and albumin levels at similar to those of control non-diabetic mice. Histological examination of renal tissue indicated that both development of fibrosis and renal cell apoptosis were dramatically inhibited by SchB. The protective effect of SchB on DN associated with suppression of inflammatory response and oxidative stress. These results strongly suggested that SchB could be a potential therapeutic agent for treatment of DN. Moreover, our findings provided a fuller understanding of the regulatory role of NF-κB and Nrf2 in DN, indicating that they could be important therapeutic targets.