查看更多>>摘要：The mechanism by which acetaminophen produces its analgesic effects is not fully understood. One possible mechanism is the activation of the spinal 5-hydroxytryptamine (5-HT) receptor, although direct evidence of spinal 5-HT release has not yet been reported. N-arachidonoylphenolamine (AM404), a metabolite of acetaminophen, is believed to be the key substance that contributes to the analgesic effects of acetaminophen. In this study, we examined whether acetaminophen and AM404 induce spinal 5-HT release and the mechanism through which spinal 5-HT receptor activation exerts analgesic effects in a rat formalin test in an inflammatory pain model. Spinal 5-HT release was examined by intrathecal microdialysis in conscious and freely moving rats. Acetaminophen was administered orally, and AM404 was administered intracerebroventricularly. In rat formalin tests, oral acetaminophen and intracerebroventricular AM404 induced significant spinal 5-HT release and produced analgesic effects. The analgesic effect of oral acetaminophen was partially antagonized by intrathecal administration of WAY100135 (a 5-HT_1A receptor antagonist) and SB269970 (a 5-HT_7 receptor antagonist). In contrast, the analgesic effect of intracerebroventricular AM404 was completely antagonized by WAY100135, while SB 269970 had no effect. Our data suggest that while oral acetaminophen and intracerebroventricular AM404 activate the spinal 5-HT system, the role of the spinal 5-HT system activated by oral acetaminophen differs from that activated by intracerebroventricular AM404.
Siphamla R. NgcoboBongani B. NkambuleTawa M. NyambuyaKabelo Mokgalaboni...
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查看更多>>摘要：Low grade inflammation is associated with the progression of atherosclerosis. Patients with type 2 diabetes (T2D) have altered cholesterol levels, which are targeted by free radicals to promote lipid peroxidation. Elevated levels of monocyte-associated cytokines such as interleukin (IL)-6, monocyte chemoattractant protein 1 (MCP-1), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and tumor necrosis factor-alpha (TNF-α), subsequently drive endothelial tissue injury. In fact, the levels of circulating platelet-monocyte aggregates in patients with T2D is a robust marker for atherosclerosis and a cardiovascular disease (CVD)-risk factor. To identify eligible studies, we searched the major online databases using PubMed and Google Scholar. The cumulative evidence synthesized in the current review suggests that, traditional therapies which include thiazo-lidinediones, statins and some calcium channel blockers can be useful in the primary prevention of atherosclerosis by inhibiting the formation of monocyte-derived microparticles, and pro-inflammatory cytokines such as IL-6, TNF-α, MCP-1, and NF-κB in patients with T2D. Future studies are needed to ascertain whether the combination of dietary interventions and glucose or lipid lowering agents can provide an enhanced car-dioprotection in patients with T2D.
Tony Eight LinMin-Wu ChaoWei-Chun HuangFuHuang-Ju Tu...
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查看更多>>摘要：The dysregulation of DYRK1A is implicated in many diseases such as cancer, diabetes, and neuro degenerative diseases. Alzheimer's disease is one of the most common neuro degenerative disease and has elevated interest in DYRK1A research. Overexpression of DYRK1A has been linked to the formation of tau aggregates. Currently, an effective therapeutic treatment that targets DYRK1A is lacking. A specific small-molecule inhibitor would further our understanding of the physiological role of DYRK1A in neurodegenerative diseases and could be presented as a possible therapeutic option. In this study, we identified pharmacological interactions within the DYRK1A active site and performed a structure-based virtual screening approach to identify a selective small-molecule inhibitor. Several compounds were selected in silico for enzymatic and cellular assays, yielding a novel inhibitor. A structure-activity relationship analysis was performed to identify areas of interactions for the compounds selected in this study. When tested in vitro, reduction of DYRK1A dependent phosphorylation of tau was observed for active compounds. The active compounds also improved tau turbidity, suggesting that these compounds could alleviate aberrant tau aggregation. Testing the active compound against a panel of kinases across the kinome revealed greater selectivity towards DYRK1A. Our study demonstrates a serviceable protocol that identified a novel and selective DYRK1A inhibitor with potential for further study in tau-related pathologies.
查看更多>>摘要：Epimedium koreanum Nakai (EKN) is a popular plant in Korean and Chinese medicine for treating a variety of ailments. The aqueous extract of EKN has a significant inhibitory impact on influenza A virus (IAV) infection by directly blocking viral attachment and having a virucidal effect, according to this study. Using fluorescent microscopy and fluorescence-activated cell sorting (FACS) with a green fluorescent protein (GFP)-tagged Influenza A/PR/8/34 virus, we examined the effect of EKN on viral infection. By viral infection, EKN strongly suppresses GFP expression, and at a dosage of 100 |ag/mL, EKN decreased GFP expression by up to 90% of the untreated infected control. Immunofluorescence and Western blot analyses against influenza viral proteins revealed that EKN decreased influenza viral protein expression in a dose-dependent manner. EKN inhibited the H1N1 influenza virus's hemagglutinin (HA) and neuraminidase (NA), preventing viral attachment to cells. Furthermore, EKN had a virucidal impact and inhibited the cytopathic effects of H1N1, H3N2 and influenza B virus infection. Finally, our findings show that EKN has the potential to be developed as a natural viral inhibitor against influenza virus infection.
查看更多>>摘要：Growth and differentiation factor 15 (GDF-15) was discovered as a member of the transforming growth factor β (TGF-β) superfamily and the serum level of GDF-15 was significantly correlated with glucolipid metabolic disorders (GLMD) and cardiovascular diseases. In 2017, a novel identified receptor of GDF-15—glial-derived neurotrophic factor receptor alpha-like (GFRAL) was found to regulate energy homeostasis (such as obesity, diabetes and non-alcoholic fatty liver disease (NAFLD)). The function of GDF-15/GFRAL in suppressing appetite, enhancing glucose/lipid metabolism and vascular remodeling has been gradually revealed. These effects make it a potential therapeutic target for GLMD and vascular diseases. In this narrative review, we included and reviewed 121 articles by screening 524 articles from literature database. We primarily focused on the function of GDF-15 and its role in GLMD/cardiovascular diseases and discuss its potential clinical application.
查看更多>>摘要：Andrographis paniculata (A. paniculata) is a traditional herbal medicine that has been widely used in Asian countries for hundreds of years. Andrographolide (AG) is a diterpene lactone extracted from A. paniculata. Owing to the in-depth study of pharmacological mechanisms, the therapeutic potential of AG, including its anti-inflammatory, anti-tumor, and immunoregulatory attributes, has attracted the attention of many researchers. Studies testing the therapeutic effects of AG have demonstrated desirable results in the treatment of a variety of clinical diseases. With high safety and various biological functions, AG might be a promising candidate for the treatment of musculoskeletal disorders. Here, we review all available literatures to summarize the pharmacological effects of AG and facilitate further researches on musculoskeletal diseases.
查看更多>>摘要：Heart muscle injury and an elevated troponin level signify myocardial infarction (MI), which may result in defective and uncoordinated segments, reduced cardiac output, and ultimately, death. Physicians apply thrombolytic therapy, coronary artery bypass graft (CABG) surgery, or percutaneous coronary intervention (PCI) to recanalize and restore blood flow to the coronary arteries, albeit they were not convincingly able to solve the heart problems. Thus, researchers aim to introduce novel substitutional therapies for regenerating and func-tionalizing damaged cardiac tissue based on engineering concepts. Cell-based engineering approaches, utilizing biomaterials, gene, drug, growth factor delivery systems, and tissue engineering are the most leading studies in the field of heart regeneration. Also, understanding the primary cause of MI and thus selecting the most efficient treatment method can be enhanced by preparing microdevices so-called heart-on-a-chip. In this regard, micro-fluidic approaches can be used as diagnostic platforms or drug screening in cardiac disease treatment. Additionally, bioprinting technique with whole organ 3D printing of human heart with major vessels, cardiomyocytes and endothelial cells can be an ideal goal for cardiac tissue engineering and remarkable achievement in near future. Consequently, this review discusses the different aspects, advancements, and challenges of the mentioned methods with presenting the advantages and disadvantages, chronological indications, and application prospects of various novel therapeutic approaches.
查看更多>>摘要：The balance between ubiquitination and deubiquitination is crucial for protein stability, function and location under physiological conditions. Dysregulation of E1/E2/E3 ligases or deubiquitinases (DUBs) results in malfunction of the ubiquitin system and is involved in many diseases. Increasing reports have indicated that ubiquitin-specific peptidases (USPs) play a part in the progression of many kinds of cancers and could be good targets for anticancer treatment. Glioma is the most common malignant tumor in the central nervous system. Clinical treatment for high-grade glioma is unsatisfactory thus far. Multiple USPs are dysregulated in glioma and have the potential to be therapeutic targets. In this review, we collected studies on the roles of USPs in glioma progression and summarized the mechanisms of USPs in glioma tumorigenesis, malignancy and chemo-radiotherapy resistance.
查看更多>>摘要：Chronic alcohol consumption, which is observed worldwide, can damage pancreatic tissue and promote pancreatitis. Rhubarb is a widely used traditional Chinese herbal medicine for treating pancreatitis in China. However, few pharmacological studies have investigated its epigenetic regulation. In this study, we investigated whether chronic exposure to alcohol can alter inflammatory gene expression and the epigenetic regulation effect of cooked rhubarb in the pancreatic tissue of rats. First, changes in inflammatory cytokine DNA methylation (IL-10, IL-1α, TNF-α, NF-κB and TGF-β) were detected in pancreatic tissue of Sprague-Dawley rats with varying alcohol exposure times (4, 6, 8, or 12 weeks), and then with varying doses of cooked rhubarb treatment (3, 6, or 12 g/day). DNA methylation levels, related RNA concentrations and protein expression of specific inflammatory cytokines, and histopathological score were analysed in pancreatic tissue of Sprague-Dawley rats. The results showed that chronic alcohol exposure (8 weeks) reduced the level of IL-1α DNA methylation and increased its protein expression in acinar cells (P < 0.05). In the acinar cells, the level of IL-10 DNA methylation increased, resulting in a reduction of protein expression (P < 0.05). Simultaneously, chronic alcohol exposure increased the pathological damage to the pancreas (P < 0.05). Finally, cooked rhubarb treatment (3 g/kg/day) effectively alleviated these changes in pancreatic tissue from chronic alcohol exposure (P < 0.05). These results indicate that chronic exposure to alcohol leads to changes in DNA methylation and protein expression of inflammatory genes, and cooked rhubarb may have a protective effect on the pancreatic tissue of rats.
Ali BaradaranZahra AsadzadehbNima HemmatAmir Baghbanzadeh...
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查看更多>>摘要：Tumor-associated macrophages (TAMs) are among the abundant cell populations of the tumor microenvironment (TME), which have pivotal roles in tumor development, chemoresistance, immune evasion, and metastasis. Growing evidence indicates that TAMs and the cross-talk between TAMs and tumoral endothelial cells can substantially contribute to tumor angiogenesis, which is considered a vital process for cancer development. Besides, tumoral endothelial cells can regulate the leukocyte infiltration to the TME in solid cancers and contribute to immune evasion. Therefore, targeting the immunosuppressive TAMs and the cross-talk between them can be a promising strategy for improving anti-tumoral immune responses. This review aims to summarize the biology of TAMs, their recently identified roles in tumor development/angiogenesis, and recent advances in macrophage-based cancer immunotherapy approaches for treating cancers.
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