Clinical Pharmacokinetics of Semaglutide: A Systematic Review.

Purpose: The aim of this review was to provide all the pharmacokinetic data for semaglutide in humans concerning its pharmacokinetics after subcutaneously and oral applications in healthy and diseased populations, to provide recommendations for clinical use. Methodology: The PubMed and Embase databases were searched to screen studies associated with the pharmacokinetics of semaglutide. The pharmacokinetic parameters included area under the curve plasma concentrations (AUC), maximal plasma concentration (Cmax), time to Cmax, half-life (t1/2), and clearance. The systematic literature search retrieved 17 articles including data on pharmacokinetic profiles after subcutaneously and oral applications of semaglutide, and at least one of the above pharmacokinetic parameter was reported in all included studies. Results: Semaglutide has a predictable pharmacokinetic profile with a long t1/2 that allows for once-weekly subcutaneous administration. The AUC and Cmax of both oral and subcutaneous semaglutide increased with dose. Food and various dosing conditions including water volume and dosing schedules can affect the oral semaglutide exposure. There are limited drug-drug interactions and no dosing adjustments in patients with upper gastrointestinal disease, renal impairment or hepatic impairment. Body weight may affect semaglutide exposure, but further studies are needed to confirm this. Conclusion: This review encompasses all the pharmacokinetic data for subcutaneous and oral semaglutide in both healthy and diseased participants. The existing pharmacokinetic data can assist in developing and evaluating pharmacokinetic models of semaglutide and will help clinicians predict semaglutide dosages. In addition, it can also help optimize future clinical trials.

Potential lipolytic regulators derived from natural products as effective approaches to treat obesity.

Epidemic obesity is contributing to increases in the prevalence of obesity-related metabolic diseases and has, therefore, become an important public health problem. Adipose tissue is a vital energy storage organ that regulates whole-body energy metabolism. Triglyceride degradation in adipocytes is called lipolysis. It is closely tied to obesity and the metabolic disorders associated with it. Various natural products such as flavonoids, alkaloids, and terpenoids regulate lipolysis and can promote weight loss or improve obesity-related metabolic conditions. It is important to identify the specific secondary metabolites that are most effective at reducing weight and the health risks associated with obesity and lipolysis regulation. The aims of this review were to identify, categorize, and clarify the modes of action of a wide diversity of plant secondary metabolites that have demonstrated prophylactic and therapeutic efficacy against obesity by regulating lipolysis. The present review explores the regulatory mechanisms of lipolysis and summarizes the effects and modes of action of various natural products on this process. We propose that the discovery and development of natural product-based lipolysis regulators could diminish the risks associated with obesity and certain metabolic conditions.

Ferroptosis as a Novel Therapeutic Target for Diabetes and Its Complications.

The global diabetes epidemic and its complications are increasing, thereby posing a major threat to public health. A comprehensive understanding of diabetes mellitus (DM) and its complications is necessary for the development of effective treatments. Ferroptosis is a newly identified form of programmed cell death caused by the production of reactive oxygen species and an imbalance in iron homeostasis. Increasing evidence suggests that ferroptosis plays a pivotal role in the pathogenesis of diabetes and diabetes-related complications. In this review, we summarize the potential impact and regulatory mechanisms of ferroptosis on diabetes and its complications, as well as inhibitors of ferroptosis in diabetes and diabetic complications. Therefore, understanding the regulatory mechanisms of ferroptosis and developing drugs or agents that target ferroptosis may provide new treatment strategies for patients with diabetes.

Piperazine ferulate prevents high-glucose-induced filtration barrier injury of glomerular endothelial cells.

Filtration barrier injury induced by high glucose (HG) levels leads to the development of diabetic nephropathy. The endothelial glycocalyx plays a critical role in glomerular barrier function. In the present study, the effects of piperazine ferulate (PF) on HG-induced filtration barrier injury of glomerular endothelial cells (GEnCs) were investigated and the underlying mechanism was assessed. Immunofluorescence was used to observe the distribution of the glycocalyx as well as the expression levels of syndecan-1 and Zonula occludens-1 (ZO-1). Endothelial permeability assays were performed to assess the effects of PF on the integrity of the filtration barrier. Protein and mRNA expression levels were measured by western blotting and reverse transcription-quantitative PCR analyses, respectively. In vitro experiments revealed that adenosine monophosphate-activated protein kinase (AMPK) mediated HG-induced glycocalyx degradation and endothelial barrier injury. PF inhibited the HG-induced endothelial barrier injury and restored the expression levels of heparanase-1 (Hpa-1), ZO-1 and occludin-1 by AMPK. In vivo assays demonstrated that PF reduced the expression levels of Hpa-1, increased the expression levels of ZO-1 and attenuated glycocalyx degradation in the glomerulus. These data suggested that PF attenuated HG-induced filtration barrier injury of GEnC by regulating AMPK expression.

Esculin protects against methionine choline-deficient diet-induced non-alcoholic steatohepatitis by regulating the Sirt1/NF-κB p65 pathway.

CONTEXT: Esculin, an active coumarin compound, has been demonstrated to exert anti-inflammatory effects. However, its potential role in non-alcoholic steatohepatitis (NASH) remains unclear. OBJECTIVE: This study explored the hepatoprotective effect and the molecular mechanism of esculin in methionine choline-deficient (MCD) diet-induced NASH. MATERIALS AND METHODS: Fifty C57BL/6J mice were divided into five groups: control, model, low dosage esculin (oral, 20 mg/kg), high dosage esculin (oral, 40 mg/kg), and silybin (oral, 105 mg/kg). All animals were fed a MCD diet, except those in the control group (control diet), for 6 weeks. RESULTS: Esculin (20 and 40 mg/kg) inhibited MCD diet-induced hepatic lipid content (triglyceride: 16.95 ± 0.67 and 14.85 ± 0.78 vs. 21.21 ± 1.13 mg/g; total cholesterol: 5.10 ± 0.34 and 4.08 ± 0.47 vs. 7.31 ± 0.58 mg/g), fibrosis, and inflammation (ALT: 379.61 ± 40.30 and 312.72 ± 21.45 vs. 559.51 ± 37.01 U/L; AST: 428.22 ± 34.29 and 328.23 ± 23.21 vs. 579.36 ± 31.93 U/L). In vitro, esculin reduced tumour necrosis factor-α, interleukin-6, fibronectin, and collagen 4A1 levels, but had no effect on lipid levels in HepG2 cells induced by free fatty acid. Esculin increased Sirt1 expression levels and decreased NF-κB acetylation levels in vivo and in vitro. Interfering with Sirt1 expression attenuated the beneficial effect of esculin on inflammatory and fibrotic factor production in HepG2 cells. CONCLUSIONS: These findings demonstrate that esculin ameliorates MCD diet-induced NASH by regulating the Sirt1/ac-NF-κB signalling pathway. Esculin could thus be employed as a therapy for NASH.

Piperazine ferulate attenuates high glucose­induced mesangial cell injury via the regulation of p66Shc.

Diabetic nephropathy (DN) is a severe microvascular complication of diabetes. Hyperglycemia­induced glomerular mesangial cells injury is associated with microvascular damage, which is an important step in the development of DN. Piperazine ferulate (PF) has been reported to exert protective effects against the progression of DN. However, whether PF prevents high glucose (HG)­induced mesangial cell injury remains unknown. The aim of the present study was to investigate the effects of PF on HG­induced mesangial cell injury and to elucidate the underlying mechanisms. Protein and mRNA expression levels were determined via western blot analysis and reverse transcription­quantitative PCR, respectively. IL­6 and TNF­α levels were measured using ELISA. Reactive oxygen species levels and NF­κB p65 nuclear translation were determined via immunofluorescence analysis. Apoptosis was assessed by measuring lactate dehydrogenase (LDH) release, as well as using MTT and flow cytometric assays. The mitochondrial membrane potential of mesangial cells was determined using the JC­1 kit. The results revealed that LDH release were increased; however, cell viability and mitochondrial membrane potential were decreased in the HG group compared with the control group. These changes were inhibited after the mesangial cells were treated with PF. Moreover, PF significantly inhibited the HG­induced production of inflammatory cytokines and the activation of NF­κB in mesangial cells. PF also attenuated the HG­induced upregulation of the expression levels of fibronectin and collagen 4A1. Furthermore, the overexpression of p66Src homology/collagen (Shc) abolished the protective effect of PF on HG­induced mesangial cell injury. In vivo experiments revealed that PF inhibited the activation of inflammatory signaling pathways, glomerular cell apoptosis and mesangial matrix expansion in diabetic mice. Collectively, the present findings demonstrated that PF attenuated HG­induced mesangial cells injury by inhibiting p66Shc.

Topical treatments for diabetic neuropathic pain.

Diabetic neuropathic pain (DNP) has a huge impact on quality of life and can be difficult to treat. Oral treatment is the most frequently used method for DNP, but its use is often limited by systemic side effects. Topical use of drugs as an alternative option for DNP treatment is currently gaining interest. In the present review, a summary is provided of the available agents for topical use in patients with DNP, including lidocaine plasters or patches, capsaicin cream, gel or patches, amitriptyline cream, clonidine gel, ketamine cream, extracts from medicinal plants including nutmeg extracts and Citrullus colocynthis extract oil, and certain compounded topical analgesics. Furthermore, the potential efficacy of these treatments is addressed according to the available clinical research literature. It has been indicated that these topical drugs have the potential to be valuable additional options for the management of DNP, with adequate safety and continuous long-term treatment efficacy. Compounded topical agents are also effective and safe for patients with DNP and could be another area worthy of further investigation based on the strategy of using low-dose, complementary therapies for DNP. The findings indicate that developing topical drugs acting on different targets in the process of DNP is a valuable area of future research.

Simple and rapid UPLC-MS/MS method for quantification of entecavir in human plasma: Application to a bioequivalence study
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A simple and fast ultra-performance liquid chromatography-tandem mass spectrometry method was developed and validated to determine entecavir in human plasma with the stable isotopically labeled internal standard entecavir-13C215N. Samples (100 µL each) were pretreated by protein precipitation with methanol, and then separated on an ACQUITY UPLC BEH C18 analytical column (2.1 × 50 mm, 1.7 µm) with a simple isocratic elution. The detection was operated by a positive ionization electrospray mass spectrometry in multiple reaction monitoring mode. The method had a short chromatographic run time of 2 minutes, and obtained sharp peaks of entecavir and the internal standard. Good linearity was found within 0.1 - 20 ng/mL. The intra- and inter-day precision and accuracy met the acceptance criteria, and no matrix effect was observed. This method was successfully applied in a bioequivalence study of two kinds of entecavir tablets in healthy Chinese volunteers. And the results showed that no significant differences were found between the test and reference preparations in pharmacokinetic parameters (p > 0.05) by ANOVA. The 90% confidence intervals for the geometric mean ratios (test/reference) of Cmax, AUC0-tlast, and AUC0-∞ fell within the bioequivalence acceptance criteria (80 - 125%). No significant difference was found in tmax between the two preparations. The two one-sided t-tests showed that these two products were bioequivalent.
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A review of biotransformation and pharmacology of ginsenoside compound K.

As an intestinal bacterial metabolite of ginseng protopanaxadiol saponins, ginsenoside compound K (20-O-beta-d-glucopyranosyl-20(S)-protopanaxadiol, CK) is a major deglycosylated metabolite form of ginsenosides which is absorbed into the systemic circulation. And it has demonstrated such diverse intriguing biological properties as anticarcinogenic, anti-inflammation, antiallergic, anti-diabetic, anti-angiogenesis, anti-aging, neuroprotective and hepatoprotective effects. The present review shall summarize recent studies on various biotransformation and pharmacological activities of CK.