Pharmacology最新文献

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.

Introduction: Previously, we reported that interleukin-8 (IL-8) was associated with poor prognosis of basal-like breast cancer patients and has been identified as a pro-tumorigenic factor, facilitating cell invasion and migration. Here, we investigated the pharmacological impact of inhibitors targeting the chemokine receptors, C-X-C chemokine receptor 1 (CXCR1) and C-X-C chemokine receptor 2 (CXCR2), which are activated by IL-8.

Methods: The survival rates of triple-negative breast cancer (TNBC) patients by IL-8 were analyzed by the Kaplan-Meier plotter. The levels of mRNA and protein expression were analyzed by real-time PCR and Western blotting. The alteration of apoptotic cell death-related proteins by SB225002 was analyzed by the Proteome Profiler Human Apoptosis Array. Cell growth was analyzed by MTT and colony-forming assay. Apoptosis and cell cycle were analyzed by fluorescence-activated cell sorting.

Results: Aberrant IL-8 expression is involved with the prognosis of TNBC patients. Basal IL-8 levels are markedly elevated in TNBC cells compared to those in HER2+ and/or ER+ breast cancer cells. Furthermore, recombinant human IL-8 treatment enhanced cell invasiveness in TNBC cells. To counteract the tumor-promoting effects of IL-8, we assessed the therapeutic potential of CXCR1 and CXCR2 inhibitors. Notably, while reparixin, a CXCR1-specific inhibitor, exhibited no impact on cell viability, SB225002, a CXCR2-specific inhibitor, significantly reduced cell viability in a dose-dependent manner. There was a noticeable reduction in the levels of anti-apoptotic biomarkers, including Bcl-2, cIAP-1, cIAP-2, Survivin, XIAP, HIF-1α, and HO-1, following SB225002 treatment. Our findings indicate an increase in the apoptotic cell population with SB225002 treatment in TNBC cells. In xenograft models, SB225002 effectively diminished the metastatic potential of 4T1 cells, which are known to metastasize to the lung and liver.

Conclusion: Our results underscore the significant role of the IL-8/CXCR2 signaling axis in the metastasis of TNBC and suggest that CXCR2 inhibitors such as SB225002 may be promising therapeutic agents for TNBC patients.

Introduction: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) has a protective effect on acute coronary syndrome (ACS). However, most studies have shown that this protective effect is based on a decrease in low-density lipoprotein cholesterol, while other mechanisms remain limited. This study aimed to determine whether PCSK9i can improve the prognosis of ACS patients by protecting endothelial function.

Methods: A total of 113 ACS patients were enrolled and randomly assigned to PCSK9i group (PCSK9i combined with statins) and control group (statins only). Blood lipids and endothelial function indicators were measured and analyzed 6 weeks before and after treatment. The effect of PCSK9i on the expression and secretion of endothelial function indicators in vascular endothelial cells were studied by cell experiments.

Results: After 6 weeks of treatment, endothelial function indicators such as nitric oxide (NO), thrombomodulin, intercellular cell adhesion molecule-1, endothelin-1, and flow-mediated vasodilation were significantly improved in PCSK9i group compared with control group. Only the changes of NO and von Willebrand factor were associated with blood lipid levels, whereas the changes of other endothelial function indicators were not significantly associated with blood lipid levels. PCSK9i reduced the incidence of major adverse cardiovascular events in patients with ACS compared to those in the control group. In cell experiments, PCSK9i treatment significantly ameliorated LPS induced endothelial injury in HUVECs.

Conclusion: PCSK9i can protect vascular endothelial function partly independently of its lipid-lowering effect and ameliorate the prognosis of patients with ACS within 6 weeks. This mechanism may involve heat shock transcription factor 1/heat shock proteins -related signaling pathways. Early use of PCSK9i in patients with ACS should be strongly considered in clinical practice.

Introduction: Batryticatus bombyx (BB) (Beauveria bassiana Vuill.) is used as a herbal medicine and food additive. Although BB has neuroprotective and antiapoptotic effects, its impacts on atopic dermatitis (AD) are unknown. We evaluated the effects of BB in an NC/Nga mouse model of house dust mite (HDM)-induced AD, in TNF-α- and IFN-γ (TI)-stimulated HaCaT keratinocytes, and in a 3D human skin model.

Methods: NC/Nga mice were induced with HDM and treated with BB for 6 weeks. We assessed skin symptoms, serum levels of IgE, histamine, and IL-6, immune cell counts and performed histological analysis of dorsal skin tissue. Additionally, we induced inflammation in HaCaT cells and a 3D human skin model using TNF-α/IFN-γ. We measured inflammatory cytokine levels and skin hydration factors and delved into underlying mechanisms via ELISA, real-time PCR, and Western blot.

Results: BB improved skin lesions, reduced thickness, and inflammatory cell infiltration in HDM-induced mice. It alleviated scratching, improved moisture retention, and reduced IgE, histamine, and IL-6 levels. In HaCaT cells, BB inhibited thymic stromal lymphopoietin and increased hyaluronan content. It also upregulated aquaporin-3, hyaluronan synthase-1/3, filaggrin, involucrin, and occludin, enhancing skin hydration and tight junction stability. BB decreased STAT1, p38 MAPK, and NF-κB p65 levels in HaCaT cells and exhibited antioxidant effects by increasing HO-1/Nrf2 expression.

Conclusion: BB may serve as a therapeutic alternative for AD treatment by inhibiting skin inflammation.

Background: Doxorubicin is a first-line drug used in cancer chemotherapy, but its severe myocardial toxicity limits its widespread use. Indole derivatives, a large class of substances widely found in natural plants and metabolic products, exhibit a variety of biological effects.

Summary: Previous studies have shown that indole compounds can protect against doxorubicin-induced myocardial damage through multiple mechanisms, including antioxidant activity, mitochondrial protection, anti-inflammatory effects, ferroptosis inhibition, apoptosis suppression, and endoplasmic reticulum stress attenuation. Understanding the pathogenesis of doxorubicin-induced cardiomyopathy and the molecular mechanisms by which indole compounds protect the myocardium is crucial for the development of novel drug molecules based on indole compounds in the future.

Key messages: Focusing on the molecular characteristics of indole derivatives, investigating their pharmacodynamics and safety, and developing safe and effective antagonistic molecules to counteract doxorubicin toxicity, holds great potential, and significance.

Background: Cancer is a major cause of death worldwide. Although modern medicine has made strides in treatment, a complete cure for cancer remains elusive.

Summary: Utilization of medicinal plants in traditional medicine for the treatment of multiple diseases, including cancer, is a well-established practice. Sinomenine is an alkaloid extracted from a medicinal plant and has a diverse range of biological properties, including anti-oxidative, anti-inflammatory, and antibacterial effects. Sinomenine exhibits inhibitory effects on various types of tumor cells, including breast, lung, and liver cancers. The anticancer properties of sinomenine are believed to involve stimulation of apoptosis and autophagy as well as suppression of cell proliferation, invasion, and metastasis.

Key message: This review summarizes the current research on sinomenine's potential as an anticancer agent, which may contribute to the discovery of more effective cancer treatments.