Pharmacology最新文献

Introduction: Autoimmune thyroiditis seems to be associated with increased cardiometabolic risk. Statins, the mainstay of cardiovascular risk reduction and prevention, were found to reduce thyroid antibody titers. The aim of this study was to investigate plasma markers of cardiometabolic risk in statin-treated women with thyroid autoimmunity.

Methods: We compared two matched groups of euthyroid women with hypercholesterolemia receiving atorvastatin treatment: subjects with autoimmune (Hashimoto's) thyroiditis (group A, n = 29) and subjects without thyroid pathology (group B, n = 29). Plasma lipids, glucose homeostasis markers, as well as circulating levels of uric acid, high-sensitivity C-reactive protein (hsCRP), fibrinogen, homocysteine, and 25-hydroxyvitamin D were measured before atorvastatin treatment and 6 months later.

Results: At entry, both groups differed in antibody titers, insulin sensitivity, and plasma levels of uric acid, hsCRP, fibrinogen, homocysteine, and 25-hydroxyvitamin D. Atorvastatin-induced reduction in hsCRP and homocysteine, but not in total cholesterol and LDL-cholesterol, was more pronounced in group B than in group A. Only in group B, the drug decreased uric acid and fibrinogen and increased 25-hydroxyvitamin D. In group A, atorvastatin reduced insulin responsiveness.

Conclusion: The obtained results indicate that euthyroid women with Hashimoto's thyroiditis may benefit to a lesser degree from atorvastatin treatment than other populations of women with hypercholesterolemia.

Introduction: Voltage-gated Kv7/M potassium channels play an essential role in the control of membrane potential and neuronal excitability. Fangchinoline, a bisbenzylisoquinoline alkaloid, displays extensive biological activities including antitumor, anti-inflammatory, and antihypertension effects. In this study, we investigated the effects of fangchinoline on Kv7/M channels.

Methods: A perforated whole-cell patch technique was used to record Kv7 currents from HEK293 cells and M-type currents from mouse dorsal root ganglion (DRG) neurons.

Results: Fangchinoline inhibited Kv7.2/Kv7.3 currents in a concentration-dependent manner, with an IC50 of 9.5 ± 1.2 μM. Fangchinoline significantly inhibited Kv7.1, Kv7.2, Kv7.3, Kv7.4, and Kv7.3/Kv7.5 channels without selective effects. Furthermore, fangchinoline significantly slowed the activation of Kv7.1-Kv7.5 channels and inhibited native M-channel currents of DRG neurons.

Conclusion: Taken together, our findings indicate that fangchinoline concentration-dependently inhibited Kv7/M channel currents.

Background: Acute kidney injury (AKI) is a common and potentially fatal complication encountered during a variety of kidney surgeries. Renal ischemia/reperfusion (I/R) injury is the predominant mechanism of AKI in this setting. Hence, controlling I/R injury is a key research imperative as it is directly related to the prognosis of patients.

Summary: In the last decade, studies in vitro and in animal models have demonstrated that flavonoids can significantly alleviate I/R-induced AKI through a variety of pathways, including anti-oxidative stress, anti-inflammation, anti-cell death, inhibition of endoplasmic reticulum stress, and alleviation of mitochondrial dysfunction. Based on the extensive role of flavonoids in ischemia-reperfusion injury, the lack of drugs entering the clinic so far is a question worthy of consideration.

Key messages: This review summarizes the available evidence pertaining to the protective effect of flavonoids against renal I/R injury and discusses their potential clinical application in renal I/R injury.

Introduction: Cisplatin is extensively used in the treatment of head and neck carcinomas. Cetuximab combination therapy is employed in recurrent and metastatic settings. Sunitinib showed positive results in the treatment of head and neck carcinomas, both as monotherapy or in combination with cetuximab. Nonetheless, the mechanism governing these pharmacological interactions is largely unresolved. This study investigates the impact of cetuximab on the cytotoxicity of cisplatin and sunitinib using cells representative of head and neck carcinoma and the oral epithelium.

Methods: The uptake and efflux activities of cells were determined using the prototypical fluorescent substrates 4-[4-[dimethylamino]styryl)-1-methyl pyridinium iodide, Hoechst 33342, and calcein-AM in the presence or absence of specific inhibitors in cells pretreated with cetuximab. The expression of key uptake and efflux drug transporters was analyzed using qPCR and immunofluorescence. Cisplatin and sunitinib cytotoxicities after cetuximab pretreatment were evaluated using the PrestoBlue viability assay.

Results: Both tumor and nontumor cells showed significant active drug transport activity. Cetuximab substantially deregulated the expression of key transporters involved in drug resistance in head and neck cancer cells. Transporter expression in the nontumor cell was unaffected. Upon cetuximab pretreatment, the half maximal effective toxic concentration of cisplatin was reduced by 0.75-fold and sunitinib by 0.82-fold in cancer cells. Nontumor cells were not sensitive to cisplatin or sunitinib under the conditions tested.

Conclusion: Cetuximab regulates the expression and activity of key membrane drug transporters in head and neck cancer cells, involved in drug resistance. The deregulation of the transport mechanism behind cisplatin and sunitinib uptake reverses drug resistance and enhances the cytotoxicity of both drugs.

Introduction: Our study aimed to investigate the effect of zonisamide (ZNS) on bone metabolism in the rat model.

Methods: Eight-week-old rats were divided into four groups. The sham-operated control group (SHAM) and the control group after orchidectomy (ORX) received the standard laboratory diet (SLD). The experimental group after orchidectomy (ORX+ZNS) and the sham-operated control group (SHAM+ZNS) received SLD enriched with ZNS for 12 weeks. Bone marker concentrations in serum of receptor activator of nuclear factor kappa B ligand, PINP, and osteoprotegerin, and the levels of sclerostin and bone alkaline phosphatase in bone homogenate, were measured using an enzyme-linked immunosorbent assay. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. The femurs were used for biomechanical testing.

Results: We found a statistically significant reduction in BMD and biomechanical strength 12 weeks after orchidectomy of the rats (ORX). After ZNS administration to orchidectomized rats (ORX+ZNS) and the sham-operated control rats (SHAM+ZNS), there were no statistically significant changes in BMD, bone turnover markers, or biomechanical properties as compared with the ORX group and SHAM group.

Conclusions: The results suggest that administration of ZNS to rats exerts no negative effect on BMD, bone metabolism markers, or biomechanical properties.

Avians differ from mammals, especially in brain architecture and metabolism. Taurine, an amino acid basic to metabolism and bioenergetics, has been shown to have remarkable effects on metabolic syndrome and ameliorating oxidative stress reactions across species. However, less is known regarding these metabolic relationships in the avian model. The present study serves as a preliminary report that examined how taurine might affect avian metabolism in an aged model system. Two groups of pigeons (Columba livia) of mixed sex, a control group and a group that received 48 months of taurine supplementation (0.05% w/v) in their drinking water, were compared by using blood panels drawn from their basilic vein by a licensed veterinarian. From the blood panel data, taurine treatment generated higher levels of three ATP-related enzymes: glutamate dehydrogenase (GLDH), lactate dehydrogenase (LDH), and creatine kinase (CK). In this preliminary study, the role that taurine treatment might play in the adult aged pigeon's metabolism on conserved traits such as augmenting insulin production as well as non-conserved traits maintaining high levels of ATP-related enzymes was examined. It was found that taurine treatment influenced the avian glucose metabolism similar to mammals but differentially effected avian ATP-related enzymes in a unique way (i.e., ∼×2 increase in CK and LDH with a nearly ×4 increase in GLDH). Notably, long-term supplementation with taurine had no negative effect on parameters of lipid and protein metabolism nor liver enzymes. The preliminary study suggests that avians may serve as a unique model system for investigating taurine metabolism across aging with long-term health implications (e.g., hyperinsulinemia). However, the suitability of using the model would require researchers to tightly control for age, sex, dietary intake, and exercise conditions as laboratory-housed avian present with very different metabolic panels than free-flight avians, and their metabolic profile may not correlate one-to-one with mammalian data.

Background: Metastatic esophageal carcinoma (EC) has a poor prognosis and only limited treatment options. While immune checkpoint inhibitors (ICIs) have improved the treatment of a broad spectrum of cancers, patients with EC mostly fail to respond to this treatment. For that reason, it is crucial to understand the immune phenotype of each cancer patient and moreover, to understand how different therapies modulate the cancer microenvironment and sensitize the tumors to the treatment with ICIs.

Summary: We have conducted a systematic review of the literature to evaluate the potential of ICI therapy in combination with chemotherapy, radiotherapy, and/or biologic therapy in EC patients. In our review, we have discussed the effects of diverse treatment approaches on the tumor microenvironment of EC. In addition, we have reviewed the current phase II and III clinical trials in EC patients to provide a rationale for immunotherapy application in combination settings with chemotherapy, radiotherapy, and/or biologic therapy.

Key messages: A great effort is already underway in clinical trials evaluating the combinatorial administration of ICIs and other treatment modalities in metastatic EC patients. PD-L1 expression status was shown to be higher in the squamous cell carcinoma (SCC) as compared to adenocarcinoma. Thus, ICIs plus chemotherapy are being discussed as a particularly feasible option for patients with SCC. Radiation was shown to induce the expression of immune checkpoint molecules and to promote the priming and activation of cytotoxic T cells which provides a rationale for ICI administration in a combination with radiotherapy. The combination of ICIs with biologic therapy was shown to be safe; however, the impact on the clinical outcomes of EC patients varied among studies.

Introduction: Tumor exosome-derived miRNAs play important roles in the human laryngocarcinoma. However, it is still unknown if exosome miR-552 is involved in the laryngocarcinoma. The aim of the current study was to explore exosome miR-552's role in laryngocarcinoma and its underlying mechanisms.

Methods: Hep-2 exosome was characterized by transmission electron microscopy and nanoparticle tracking technology. CCK-8 was used to determine cell viability, and a xenograft animal model was used to determine the tumorigenicity. qPCR and Western blotting were used to measure the changes in target biomarkers. Luciferase reporter assay was used to evaluate the interactions between miR-552 and PTEN. miRNA sequencing was used to check the changes in miRNA profiles.

Results: miR-552 was upregulated in the laryngocarcinoma patients and was positively correlated to the cell proliferation and tumor growth. PTEN was identified as a direct target of miR-552. Hep-2 exosome is featured by high expression of miR-552 and treatment of Hep-2 exosome enhanced cell proliferation and tumorigenicity. The underlying mechanisms revealed that treatment of exosomes enhanced the malignant transformation of recipient cells in part by regulating epithelial-mesenchymal transition.

Conclusion: Exosome miR-552 promotes laryngocarcinoma cells' malignant progression in part by the regulation of the PTEN/TOB1 axis.