Pharmacology最新文献

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.

Introduction: Atorvastatin (ATO) is often used to reduce blood lipids and prevent atherosclerosis, but excessive use of ATO will lead to hepatotoxicity. This paper investigated the effects of astragaloside IV (AS IV), which has multiple biological functions, on ATO-induced hepatotoxicity and the underlying mechanism.

Methods: ATO treatment induced a rat model of hepatotoxicity, followed by AS IV treatment. Colorimetric kits were used to detect rat liver function indexes including aspartate aminotransferase (AST), alanine transaminase (ALT), malondialdehyde (MDA), and reduced glutathione (GSH). Reactive oxygen species (ROS) level was determined by 2', 7'-Dichlorodihydrofluorescein diacetate kit. The liver fibrosis and F4/80 expression were detected by Sirius red staining and immunochemistry. Mitochondrial electron transport chain complex I and complex IV activities were examined. The level of mitochondrial membrane potential (MMP) was detected by JC-1 staining. The inflammatory factor levels were detected by quantitative real-time polymerase chain reaction. Western blot detected apoptosis-related proteins and AMPK/SIRT1-related proteins.

Results: ATO increased ALT, AST, MDA, and ROS levels and decreased GSH content but was subsequently reversed by AS IV. AS IV alleviated liver tissue damage caused by ATO. AS IV elevated complex I and complex IV activity and promoted MMP levels in ATO rats. ATO promoted inflammatory factor release in SD rats but was then suppressed by AS IV. AS IV inhibited Bax, cleaved caspase-3 but up-regulated Bcl-2 in ATO-induced rats. ATO inhibited SIRT1 expression and AMPK phosphorylation, which was subsequently promoted by AS IV.

Conclusion: AS IV inhibits ATO-induced hepatotoxicity by activating the AMPK/SIRT1 pathway.

Introduction: Ionizing radiation (IR) causes oxidative stress in kidneys and subsequently disrupts renal function. The use of green synthesized zinc nanoparticles (Zn NPs) with antioxidant properties may reduce the damage caused by IR.

Methods: Thirty-six mice were kept in a standard situation and divided into 6 groups: 1: Control; 2-4: receiving 5 mg/kg, 10 mg/kg, and 25 mg/kg of Zn NPs with IR; 5: receiving 5 mg/kg of ZnSO4 with IR; and 6: IR. After 15 days, half of the animals in each group were sacrificed and their blood samples isolated to evaluate the plasma urea and creatinine levels. The kidneys were kept for evaluating the glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) levels; on 21st day, the rest of the animals were sacrificed and their kidneys removed for histological assessments.

Results: IR decreased GSH content, increased MDA level, and reduced SOD and CAT activity. On the other hand, Zn NPs at 10 and 25 mg/kg doses increased GSH, decreased MDA, and enhanced SOD and CAT activities. Zn NPs treatment at 10 and 25 mg/kg doses decreased the plasma urea and creatinine levels induced by IR. Moreover, Zn NPs significantly decreased the level of urea and creatinine in irradiated mice in comparison with IR alone (p < 0.05). The main histopathological results were tubular and glomerular atrophy and interstitial fibrosis in irradiated mice, while tubular degeneration and atrophy were less frequent in Zn NPs + IR group than in IR group alone.

Conclusion: Zn NPs treatment, especially at 25 mg/kg dose, attenuates the side effect of IR on kidneys through reducing oxidative stress factors, biochemical, and histopathological changes.

Introduction: Luteolin is a flavonoid polyphenolic compound exerting broad pharmacological and medicinal properties. Diabetes-related obesity increases the total blood volume and cardiac output and may increase the myocardial hypertrophy progression. However, the mechanism of luteolin in diabetic myocardial hypertrophy remains uncertain. Therefore, this study aimed to evaluate whether luteolin improved diabetic cardiomyopathy (DCM) by inhibiting the proteasome activity.

Methods: Cardiomyopathy was induced in streptozotocin-treated diabetes mellitus (DM) and db/db mice. Luteolin (20 mg kg-1·day-1) was administrated via gavage for 12 weeks. In vitro, high glucose and high insulin (HGI, glucose at 25.5 mM and insulin at 0.1 µM) inducing primary neonatal rat cardiomyocytes (NRCMs) were treated with or without luteolin for 48 h. Echocardiography, reverse transcription quantitative polymerase chain reaction, histology, immunofluorescence, and Western blotting were conducted. Proteasome activities were also detected using a fluorescent peptide substrate.

Results: Luteolin administration significantly prevented the onset of cardiac hypertrophy, fibrosis, and dysfunction in type 1 DM (T1DM) and type 2 DM (T2DM). Compared with DCM mice, luteolin groups showed lower serum triglyceride and total cholesterol levels. Furthermore, luteolin attenuated HGI-induced myocardial hypertrophy and reduced atrial natriuretic factor mRNA level in NRCMs. Proteasome activities were inhibited by luteolin in vitro. Luteolin also reduces the proteasome subunit levels (PSMB) 1, PSMB2, and PSMB5 of the 20S proteasome, as well as proteasome-regulated particles (Rpt) 1 and Rpt4 levels of 19S proteasome. Furthermore, luteolin treatment increased protein kinase B (AKT) and GSK-3α/β (inactivation of GSK-3) phosphorylation. The phosphorylation level of AMPK activity was also reversed after the treatment with luteolin in comparison with the HGI-treated group.

Conclusion: This study indicates that luteolin protected against DCM in mice, including T1DM and T2DM, by upregulating phosphorylated protein AMPK and AKT/GSK-3 pathways while decreasing the proteasome activity. These findings suggest that luteolin may be a potential therapeutic agent for DCM.

Introduction: Worldwide, breast cancer is the most common cancer in women and is the main cause of death among all neoplasia in this group. Luminal A breast cancer represents approximately 70% of all breast cancers and is treated with hormone therapies targeting estrogen receptor alpha (ERα). Unfortunately, patients develop drug resistance leading to recurrence of neoplasia due to estrogen-independent ERα reactivation. Therefore, it is crucial to identify new molecular targets downstream ERα signaling pathway that allows the implementation of better treatments to improve the outcome of breast cancer patients. Overexpression of c-Fos, an ERα gene target, has been associated with increased cell motility, malignancy, metastasis, and invasion while its neutralization results in decreased breast cancer tumorigenesis. The aryl hydrocarbon receptor (AHR) ligands halogenated and polycyclic aromatic hydrocarbons, highly toxic compounds, down regulate c-Fos and ERα levels. The present study aimed to evaluate whether 6-formylindolo(3,2-b)carbazole (FICZ), a no toxic AHR agonist, modifies c-Fos levels in MCF-7 mammary carcinoma cells as well as to determine its effects on cell proliferation and migration. In addition, the possible mechanism through which FICZ mediates c-Fos levels in MCF-7 cells was investigated.

Methods: Initially, the effect of FICZ on c-Fos mRNA and protein levels in MCF-7 cells, untreated or treated with estradiol, was evaluated by qPCR and Western blot. 2,3,7,8-Tetrachloro-dibenzo-p-dioxin, an AHR prototype agonist, was used as a positive control. Next, we examined the effect of FICZ on MCF-7 cell proliferation and migration by cell counting, MTT, 3H-thymidine incorporation, and scratch-wound assays. Finally, the involvement of proteasome 26S on ERα and c-Fos protein degradation was investigated by the use of MG132 and Western blot.

Results: The data show that FICZ treatment downregulates c-Fos mRNA and protein levels, most likely by promoting ERα proteasome degradation, blocking MCF-7 cell proliferation and migration. The results also demonstrate that liganded ERα was required for FICZ-mediated ERα degradation.

Conclusions: Activation of AHR results in a decreased MCF-7 cell proliferation and migration by ERα and c-Fos down regulation. Targeting AHR might be a promising therapy for breast cancer treatment, particularly when estrogen-independent ERα reactivation presents.