Latest ArticlesThis research investigated the mechanism by which bupivacaine inhibits glutamate-induced intracellular free Ca2+ increases in primary cultured hippocampal astrocytes. Immunofluorescence was used to demonstrate the expression of metabotropic glutamate receptor (mGluR5 receptor) on neurons and astrocytes. Calcium imaging was used to measure the alteration of intracellular free Ca2+ ([Ca2+]i) in primary cultured rat hippocampal neurons and astrocytes. The animal experiments were approved by the Animal Experiments Ethical Committee of Hebei Medical University. The results showed that mGluR5 receptor was abundantly expressed in the primary cultured rat neurons and astrocytes. Bupivacaine (300 μmol·L-1) significantly inhibited 1 mmol·L-1 glutamate-induced[Ca2+]i increase in astrocytes (P < 0.01). 2-Methyl-6-(2-phenylethynyl)-pyridine (MPEP) (10 μmol·L-1) completely abolished the increase of[Ca2+]i induced by 1 mmol·L-1 glutamate in the astrocytes (P < 0.01), while the inhibitory effect on neurons was only 10%-20%. Bupivacaine (300 μmol·L-1) completely inhibited the[Ca2+]i increase induced by mGluR5 receptor agonists (RS)-3, 5-dihydroxyphenylglycine (DHPG) (50 μmol·L-1) and (RS)-2-chloro-5-hydroxyphenylglycine sodium salt (CHPG) (1 mmol·L-1) in astrocytes (P < 0.01). In addition, bupivacaine inhibited the CHPG-induced[Ca2+]i increase in a dose-dependent manner in astrocytes with an IC50 of 100 μmol·L-1. The results from this study indicate that bupivacaine inhibits glutamate-induced[Ca2+]i elevation by acting on the mGluR5 receptor in primary cultured hippocampal astrocytes.
The chemical constituents of gorgonian Junceella fragilis Ridley, collected from Ximao Island, the South China Sea, were investigated. A new briarane-type diterpenoid, named fragilide Y (1), together with five known compounds (2-6), namely fragilide D (2), cholesterol (3), ergosterol peroxide (4), 2'-deoxythymidine (5) and cis-thyminenol (6), were isolated from the acetone extract of J. fragilis. The structure of the new compound 1 was elucidated by extensive spectroscopic analysis, while the known compounds were identified by comparison with the reported data. In bioassay, none of these compounds displayed obvious anti-inflammatory and cytotoxic effects.
Obesity is an important cause of a panel of metabolic diseases, such as hypertension, hyperlipidemia, arteriosclerosis, type 2 diabetes and various cancers. Discovery of anti-obesity agents has always been a hot spot in the field of new drug research and development. Pancreatic lipase (PL, also named triacylglycerol acyl hydrolase), a key enzyme responsible for the hydrolysis of 50%-70% dietary fats in the gastrointestinal system, which has been recognized as a crucial target for the prevention and treatment of obesity. PL inhibitors can reduce the decomposition and absorption of dietary fat in the digestive organs by decreasing the hydrolytic activity of this key enzyme, which can alleviate the symptoms of metabolic diseases such as obesity and hyperlipidemia. Although a potent PL inhibitor (orlistat) has been marketed, it may trigger gastrointestinal side effects after long-term use. Therefore, it is necessary to develop more new PL inhibitors with strong inhibition potency and safety. In recent years, a large number of studies have found that some Chinese herbal extracts and their constituents can regulate lipid metabolism and treat obesity via inhibiting PL. In this paper, the research progress in the field pancreatic lipase inhibitors, as well as the extracts of Chinese herbs and their constituents with pancreatic lipase inhibitory effects were summarized. Meanwhile, the PL inhibition activities and inhibitory mechanisms of herbal constitutes were also summarized systematically. In addition, the authors also highlight the challenges in this field and the future research directions. All information and knowledge presented in this review will be very helpful for the medicinal chemists to find more potent PL inhibitors from herbs or to develop next generation anti-obesity drugs, as well as helpful for the prevention and treatment of obesity and other related metabolic diseases using herba medicines or related products.
Bile acids (BAs) are increasingly being appreciated as signaling molecules. Studies have shown that BAs regulate glucose and lipid metabolism mainly through the intracellular nuclear receptor farnesoid X receptor (FXR) and the transmembrane G protein-coupled receptor 5 (TGR5). FXR and TGR5 are highly expressed in the intestine. This article summarizes the synthesis, circulation, and regulation of BAs, as well as the effects of BAs on glycolipid metabolism through activation of liver FXR and inhibition or activation of intestinal FXR and TGR5. Furthermore, we illustrate the molecular mechanism of BAs on glycolipid metabolism by the relevant signaling pathways, including small heterodimer partner (SHP), fibroblast growth factor 15/19 (FGF15/19), ceramide and glucagon like peptide-1 (GLP-1). This review may serve as a reference for basic and clinical studies.
Uveal melanoma (UM) is one of most common ocular cancers and is extremely malignant; so far there is no effective treatment. Moreover, the survival period is only 2-7 months after metastasis. It has been proven that more than 83% of uveal melanomas harbor mutations in G protein subunit α q (GNAQ) or G protein subunit α 11 (GNA11), among which 95% are a Q209P/L single-site mutation. Q209P/L mutations lead to dysfunction of guanine triphosphatase (GTPase) in the G protein and result in constitutive activation of downstream pathways including mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), Ras homologue (Rho)/Rho-associated kinase (Rock)/Yes-associated protein (YAP) and others. Therefore, targeting GNAQ/GNA11 mutations are potential strategies for UM treatment. This review will focus on roles of G protein mutations in UM progression, and the potential therapeutic effects of GNAQ/GNA11 inhibitors, and will provide insights into basic and clinical research on UM treatment.
Autophagy is a widespread and unique degradation process in eukaryotic cells. When cells are under various stress conditions such as nutritional deficiencies, growth factor deficiencies or hypoxia, autophagy will be initiated to maintain the stability of the internal environment and ensure normal proliferation and differentiation. At present, research on autophagy-related targets is mostly focused on tumor cells. In contrast, research on fungal autophagy targets is still limited. Autophagy plays an important role in growth, development and morphological changes of fungal cells, suggesting that research on fungal autophagy as a drug target should be useful. This article reviews the signal regulation and detection strategies for autophagy in fungal cells, and provides a research basis for the screening of antifungal drugs targeting autophagy-related proteins.
Psoriasis, bringing great trouble to patients' life, is a common chronic immune skin disease which is relapsed and difficult to cure. Further understanding of the pathogenesis of psoriasis will be benefit for potential drug targets and the development of therapeutic drugs. In recent years, "interleukin-23/T helper17 (IL-23/Th17) cell axis" has attracted more and more attention in the pathogenesis of psoriasis. Some drugs targeting the cell axis have also been successfully listed in the market to improve psoriasis and achieved good results. This review focuses on the "IL-23/Th17 cell axis" system to elaborate the role of a variety of immune cells involved in the pathogenesis of psoriasis, such as dendritic cells, macrophages, neutrophils and T cells, and summarizes multiple therapeutic antibodies targeting this cell axis in the treatment of psoriasis. In addition, this review also summarizes the current small molecule drugs for the treatment of psoriasis.
Galectin-3 is an endogenous β-galactoside-binding lectin widely distributed in the human body, and it plays an important role in various functions such as cell proliferation, differentiation, apoptosis, cell adhesion, immune response and signal transduction. Accumulating evidence has shown that galectin-3 is involved in the occurrence and development of respiratory diseases, including idiopathic pulmonary fibrosis, lung cancer, pulmonary hypertension and bronchial asthma. This review summarizes and analyzes the research progress on galectin-3 in the above respiratory diseases in order to clarify its role and mechanism, and to provide new ideas for clinical treatment.
Vascular endothelial cells play a major role in maintaining the oxygen and nutrient supply to all tissues in the body. Endothelial cells, together with vascular endothelial growth factor, are also the driving forces of tumor angiogenesis, a process describing the growth of blood vessels from the existing vasculature in tumor tissues. Reprogramming of endothelial cell metabolism satisfied the needs for biomass and energy in the process of tumor angiogenesis, which are known to involve the aspects of glucose metabolism, amino acid metabolism, and fatty acid metabolism. Recently, with the increasing interest to understand the metabolic regulation in cancer, the investigation into the metabolism of endothelial cells has made progress. We herein review the role of endothelial cell metabolism in angiogenesis, with a particular focus on the metabolic regulation of endothelial cells in tumor angiogenesis, which hopes to provide insights for the intervention of tumor angiogenesis in cancer therapy.
Two-pore domain potassium channels (K2P) make up a subfamily of potassium channels discovered in the 1990s, and TREK-1 is the most widely studied subtype of K2P. TREK-1 is widely expressed in the body and especially in the central nervous system, where its main role is to control cell excitability and maintain the membrane potential below the depolarization threshold. It thereby participates in regulating various physiological and pathological processes. TREK-1 is also a potential drug target in many diseases. It is known that many marketed drugs can affect the function of TREK-1, but currently there are no specific TREK-1 modulators or drugs. We review the structure, distribution and regulation of TREK-1 and focus on recent progress in understanding the pharmacology of TREK-1 and its role in neuroprotection, depression, anesthesia and epilepsy. The research status of TREK-1 modulators is discussed.
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