Pharmacology最新文献

Introduction: The purpose of our study was to evaluate the safety, tolerability, and pharmacokinetics of furaprevir, a new highly selective hepatitis C virus NS3/4A protease inhibitor.

Methods: The study was divided into 2 parts: part A (single ascending dose study [SAD]) and part B (multiple ascending dose study [MAD]). A total of 62 healthy subjects were enrolled in the studies. DNA samples were extracted from all subjects, and genotypes of CYP3A5*3, CYP3A4*1 G, and POR*28 were analyzed by ligase detection reaction.

Results: We used nonlinear mixed-effects model (NONMEM) to construct furaprevir population pharmacokinetics model. (1) In SAD, C_max and area under the curve (AUC) were greater than dose increased ratio in the dose rang of 100-400 mg; (2) In MAD, C_max and AUC increased in an approximately dose-proportional manner in the dose range of 200-600 mg; (3) A one-compartment model with transit absorption described the plasma concentrations of furaprevir. The apparent clearance was estimated at 33.4 L/h. The distribution volume of compartment (V2) was 219.0 L. No serious adverse event occurred in the studies. But other screening gene mutations had no statistically significant effects on the pharmacokinetics of furaprevir.

Conclusion: Food significantly impacts the bioavailability of furaprevir. Furaprevir does not accumulate in vivo after multiple rising doses and has demonstrated safety and tolerability in healthy subjects, supporting its further investigation in patients with hepatitis C.

Introduction: Non-alcoholic fatty liver disease (NAFLD) is currently the most common type of chronic liver disease. Semaglutide is a glucose-lowering drug administered for the treatment of type 2 diabetes mellitus (T2DM) and is clinically effective in the treatment of NAFLD. X-box binding protein 1 (XBP1) is related to the pathogenesis of both NAFLD and T2DM. The aim of the present study was to demonstrate whether the underlying mechanism of semaglutide treatment for NAFLD is via downregulation of the inositol-requiring transmembrane kinase/endonuclease-1α (IRE1α)-XBP1-CCAAT/enhancer binding protein α (C/EBPα) signaling pathway in macrophages.

Methods: In the present study, NAFLD cell modeling was induced by oleic acid (0.4 mm) and palmitic acid (0.2 mm). Hepatocytes (AML12) and macrophages (RAW264.7) were co-cultured in 6-well Transwell plates. Semaglutide (60 or 140 nm) was administrated for 24 h, while pioglitazone (2 μm) and toyocamycin (200 nm) were used as a positive control drug and a XBP1 inhibitor, respectively. Autophagy and apoptosis of AML12 cells were detected by transmission electron microscopy and Western blotting (WB). Hepatocyte steatosis was evaluated by adopting total intracellular triglyceride determination, analysis of the relative expression of proteins and genes associated with lipid metabolism and hepatocyte Oil red O staining. Detection of inflammation factors was conducted by ELISA and WB. To explore the underlying mechanism of NAFLD treatment with semaglutide, the relative expression of related proteins and genes were tested.

Results: Our study demonstrated that semaglutide treatment improved autophagy and inhibited apoptosis of hepatocytes, while notably ameliorating steatosis of hepatocytes. In addition, inflammation was attenuated in the NAFLD cell co-culture model after semaglutide administration. Semaglutide also significantly reduced the protein and gene expression levels of the IRE1α-XBP1-C/EBPα signaling pathway in macrophages.

Conclusion: Semaglutide partially ameliorated NAFLD by downregulating the IRE1α-XBP1-C/EBPα signaling pathway in macrophages. These findings may provide a potential theoretical basis for semaglutide therapy for NAFLD.

Introduction: This study aimed to reveal the potential mechanism of Ginkgo biloba extract (GBE) in alleviating pulmonary fibrosis.

Methods: We examined cell viability, PTEN-induced putative kinase 1 (PINK1), Parkin, and microtubule-associated protein 1 light chain 3 (LC3) II/I ratio in paraquat (PQ)-stimulated rat alveolar epithelial type II cells (RLE-6TN) receiving GBE treatment. LC3 enrichment in mitochondria was detecting the immunofluorescence co-staining of LC3 and TOMM20. Then, epithelial-mesenchymal transition (EMT) was evaluated by α smooth muscle actin (α-SMA) and E-cadherin using immunofluorescence. Also, p-p38 and p38 were measured to evaluate p38 mitogen-activated protein kinase (MAPK) pathway using Western blot. SB203580 was used to inhibiting p38 in RLE-6TN cells. The changes in histopathological alteration, α-SMA, E-cadherin, PINK1, Parkin, LC3 II/I ratio, and collagen deposition were also investigated in rats with PQ stimulation and GBE treatment.

Results: PQ caused the decrease in cell viability and E-cadherin, and the increase in LC3 enrichment, α-SMA, PINK1, Parkin, and LC3 II/I ratio (p < 0.05). p-p38 was increased after PQ stimulation (p < 0.05). In PQ-stimulated RLE-6TN cells, GBE elevated cell viability and E-cadherin and reduced LC3 enrichment, α-SMA, PINK1, Parkin, LC3 II/I ratio, and p-p38 (p < 0.05). Both of GBE and SB203580 significantly reversed PQ-induced changes abovementioned in cells. Rats with PQ stimulation developed the increase in hydroxyproline activity, α-SMA, p-p38, PINK1, Parkin LC3 II/I ratio, and the decrease in E-cadherin (p < 0.05). GBE significantly reversed PQ-induced changes abovementioned in rats. GBE mitigated inflammatory infiltrates, alveolar wall thickening, and collagen deposition in rats undergoing PQ stimulation.

Conclusion: GBE significantly inhibited EMT and mitophagy in alveolar epithelial type II cells exposed to PQ via suppressing p38 MAPK pathway.

Introduction: Galectin-1 (Gal-1) is a lectin that has been shown to be involved in a number of pro-tumorigenic mechanisms and has also been shown to be immune-suppressive. Therefore, pharmacological blockade of Gal-1 has the potential to be therapeutically beneficial in cancers that overexpress this lectin where it is hypothesized to be driving cancer progression.

Methods: GB1908 is a novel, selective and high affinity inhibitor of the Gal-1 carbohydrate recognition domain and in this study, we have pharmacologically characterized this small molecule in a range of in vitro and in vivo systems in the context of cancer therapy. In addition, we used a data-driven approach to identify the cancer types which may benefit from Gal-1 inhibitor therapy.

Results: The selectivity of GB1908 for Gal-1 compared with galectin-3 (Gal-3) was confirmed in biophysical and cellular assays. GB1908 attenuated Gal-1-induced T cell (Jurkat) apoptosis and reduced the production of immunosuppressive cytokines in a stromal non-small cell lung cancer tumor microenvironment model. Breast carcinoma and metastatic skin cutaneous melanoma were identified as cancers in which high Gal-1 expression correlated with poorer survival outcomes in patients. Treatment with GB1908 slowed tumor growth in syngeneic mouse models of these cancers.

Conclusion: The inhibition of both tumor growth and immune-suppressive cytokines, in cancers in which high Gal-1 is associated with poorer survival outcomes, suggests a potential therapeutic benefit for Gal-1 inhibitors such as GB1908.

Introduction: The exosomes from adipose-derived mesenchymal stem cells (AMSCs) had therapeutic effects. However, whether the exosomes derived from hypoxia-treated AMSCs could improve renal functions in unilateral ureteral obstruction (UUO) mice remains unclear.

Methods: The exosomes were characterized using a transmission electron microscope and Western blot. Its size distribution was determined using the Zetasizer Nano ZS analysis system. The differentiation ability was assessed by alkaline phosphatase and oil red staining. Consequently, the function of exosomes in inhibiting inflammatory factors was evaluated using an enzyme-linked immunosorbent assay, and apoptosis inhibition was evaluated by Western blot. Finally, the function of exosomes to ameliorate kidney fibrosis was evaluated using quantitative reverse transcription polymerase chain reaction, Western blot, hematoxylin-eosin staining, and Masson staining.

Results: The cultured AMSCs could differentiate into osteoblast and adipocyte. Meanwhile, the cultured AMSCs could effectively secrete the exosomes, which were characterized by around 110 nm diameter and surface marker expression. Exosomes derived from hypoxia-treated AMSCs improved renal functions in UUO mice. The mechanism exploration revealed that exosomes could decrease the TNF-α and IL-6 and inhibit cell apoptosis. Finally, the fibrosis-associated protein was reversed, and the renal dysfunctions were ameliorated in UUO mice.

Conclusion: The exosomes derived from the hypoxia-treated AMSCs have a better effect than those from normal AMSCs in ameliorating renal dysfunctions in UUO mice.

Introduction: This meta-analysis aimed to assess the effectiveness and safety of combining anlotinib with chemotherapy in treating patients with small cell lung cancer (SCLC).

Methods: We systematically searched a range of databases, including PubMed, Embase, Cochrane Library, and Web of Science, up to July 28, 2023, complemented by searches in Chinese databases such as CNKI, Wanfang, and VIP, through July 4, 2023. The outcomes analyzed were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), median PFS (mPFS), overall survival (OS), vascular endothelial growth factor (VEGF) levels, and the adverse events.

Results: The analysis, which integrated data from 16 studies encompassing 1,083 patients, demonstrated that the combined treatment of anlotinib and chemotherapy significantly outperformed either anlotinib or chemotherapy alone in enhancing the ORR, DCR, and mPFS. Furthermore, this combination therapy also resulted in improved PFS, 1-year and 2-year overall OS, and reduced levels of VEGF) compared to chemotherapy alone, with all comparisons reaching statistical significance (p < 0.05). The combination of anlotinib with chemotherapy exhibited a considerably elevated risk of developing leukopenia (RR: 1.41, 95% CI: 1.09-1.82, p = 0.008). The subgroup analyses indicated the anlotinib plus etoposide group and anlotinib plus irinotecan were superior to the etoposide and the irinotecan groups, respectively, in terms of ORR outcome and DCR outcome. The subgroup analysis revealed that the combination of anlotinib and etoposide significantly increased the risk of thrombocytopenia and myelosuppression compared to etoposide alone. In patients with a history of one or an unspecified number of chemotherapy cycles, the integration of anlotinib into the chemotherapy regimen improved DCR. Conversely, in those who had undergone more than two prior treatment cycles, the risk of myelosuppression was heightened with the addition of anlotinib. Lastly, the risk of gastrointestinal adverse events was increased in patients receiving more than two treatment cycles of anlotinib plus chemotherapy compared to anlotinib monotherapy.

Conclusion: The findings of this investigation imply that the integration of anlotinib into chemotherapy regimens may enhance PFS, ORR, DCR, and OS in SCLC patients. This meta-analysis presents novel therapeutic prospects for SCLC, suggesting that the synergistic approach of anlotinib and chemotherapy could markedly enhance treatment outcomes for this patient population.

Introduction: Depression therapy has been linked to negative effects on energy metabolism, which can be attributed to various factors, including an ongoing inflammatory process commonly seen in metabolic disorders. Unhealthy lifestyle choices of patients and the impact of antidepressants on body weight and lipid and glucose metabolism also contribute to these metabolic side effects. Although not as pronounced as other psychopharmaceuticals, the increasing use of antidepressants raises concerns about their potential impact on public health. The study aimed to evaluate the short- and long-term effects of the antidepressant citalopram and its long-term combination with a special diet on metabolic parameters in mice.

Methods: Animals were randomly divided into 5 groups - control, control + special diet, citalopram (10 mg/kg for 35 days), citalopram + special diet (10 mg/kg for 35 days), and citalopram (10 mg/kg for 7 days). After a described time of administration, animals were anesthetized, blood and fat and liver tissues were collected. Biochemical parameters of lipid metabolism (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides) and glucose were analyzed using spectrophotometry and relevant adipokines and cytokines were evaluated by ELISA.

Results: After a week of application of citalopram, we observed dyslipidemia that persisted even at the end of the 5-week experiment. Furthermore, after 5 weeks of citalopram administration, we observed a significant decrease in body weight gain and decreased leptin levels. Changes in lipid metabolism, higher levels of adipokines leptin and PAI-1 were observed due to the special diet after 5 weeks.

Conclusions: Our research suggests that the effects of citalopram and a diet on the metabolism of mice can be significant, both in the short term (1 week) and in the long term (5 weeks).

Introduction: Melanocyte ferroptosis has been proven to contribute to the development of vitiligo. Tanshinone IIA (TSA), a Chinese herbal extract, has been shown to inhibit vitiligo progression. Whether TSA regulates ferroptosis in melanocytes remains unclear.

Methods: Hydrogen peroxide (H2O2) was used to induce melanocytes to stimulate vitiligo cell model in vitro. Cell proliferation was examined by 5-ethynyl-2'-deoxyuridine assay. The levels of malondialdehyde, reactive oxygen species, glutathione peroxidase, and iron were detected by corresponding commercial kit. The protein levels of ferroptosis-related markers and Nrf2 pathway-related markers were examined using western blot and immunofluorescence staining. Cell viability and cytotoxicity were analyzed using Cell Counting Kit-8 assay and lactate dehydrogenase detection. Mitochondrial morphology was examined using a transmission electron microscope.

Results: After H2O2 treatment, melanocyte proliferation was reduced, while oxidative stress and ferroptosis were enhanced. TSA treatment could inhibit ferroptosis in H2O2-induced melanocytes. Besides, TSA could activate Nrf2 pathway and promote Nrf2 nuclear translocation, and Nrf2-specific inhibitor (ML385) also reversed the inhibitory effect of TSA on H2O2-induced melanocyte ferroptosis.

Conclusion: Our data showed that TSA alleviated H2O2-induced melanocyte ferroptosis via activating Nrf2 pathway.