Current molecular pharmacology最新文献

Background: Due to their plasticity, macrophages exert critical effects on both promoting and suppressing inflammatory processes. Pathologic inflammatory conditions are frequently correlated with dynamic alterations in macrophage activation, with classically activated M1 cells associated with the promotion and maintenance of inflammation and M2 cells being linked to the resolution or smouldering of chronic inflammation. Inflammation deputes a common feature of various chronic diseases and the direct involvement in the insurgence and development of these conditions. Macrophages participate in an autoregulatory loop characterizing the inflammatory process, as they produce a wide range of biologically active mediators that exert either deleterious or beneficial effects during the inflammation. Therefore, balancing the favorable ratios of M1/M2 macrophages can help ameliorate the inflammatory landscape of pathologic conditions. Curcumin is a component of turmeric with many pharmacological properties.

Objective: Recent results from both in-vivo and in-vitro studies have indicated that curcumin can affect polarization and/or functions of macrophage subsets in the context of inflammation-related diseases. There is no comprehensive review of the impact of curcumin on cytokines involved in macrophage polarization in the context of inflammatory diseases. The present review will cover some efforts to explore the underlying molecular mechanisms by which curcumin modulates the macrophage polarization in distant pathological inflammatory conditions, such as cancer, autoimmunity, renal inflammation, stroke, atherosclerosis, and macrophage-driven pathogenesis.

Results: The accumulation of the findings from in vitro and in vivo experimental studies suggests that curcumin beneficially influences M1 and M2 macrophages in a variety of inflammatory diseases with unfavorable macrophage activation.

Conclusion: Curcumin not only enhances anti-tumor immunity (via shifting M polarization towards M1 phenotype and/or up-regulation of M1 markers expression) but ameliorates inflammatory diseases, including autoimmune diseases (experimental autoimmune myocarditis and Behcet's disease), nephropathy, chronic serum sickness, stroke, and atherosclerosis.

Background: The mechanisms underlying synaptic injury and anxiety-like behavioral changes caused by diabetes and the strategies to reverse these changes are not well understood.

Objectives: This study examined the neuroprotective effects of hesperidin on anxiety-like behaviors in diabetic rats and investigated the underlying mechanisms from the perspective of the PKA/CREB pathway.

Methods: Rats with streptozotocin-induced diabetes were treated orally with hesperidin (50 and 150 mg/kg) for 10 weeks. The elevated plus maze (EPM), hole board test (HBT), and marbleburying test (MBT) were used to assess anxiety-like behaviors. We further examined the effects of hesperidin on the PKA/CREB pathway in vivo and in vitro.

Results: The results show that supplementation with hesperidin exerted anxiolytic effects on the diabetic rats, as evidenced by increased percentages of open arm entries and time spent in the open arms in the EPM; decreased numbers of hole visits in the HBT; decreased numbers of marbles buried; and increased expression of PKA, CREB, BDNF, and synaptic proteins in the amygdala and hippocampus of diabetic rats. Hesperidin was found to reverse the imbalance in the PKA/CREB/BDNF pathway. In vitro, we found that the PKA inhibitor H89 reversed the protective effects of hesperidin against cell injury and reversed the HG-induced expression of PKA, pCREB/CREB, and BDNF.

Conclusion: Our results demonstrated that hesperidin could ameliorate the anxiety-like behaviors of diabetic rats and that activating the PKA/CREB/BDNF pathway contributed to the beneficial effects. This study may provide important insights into the mechanisms underlying anxiety-like behaviors in diabetes and identify new therapeutic targets for clinical treatment.

Mechanistic/Mammalian target of rapamycin (mTOR) orchestrates cellular homeostasis by controlling cell growth, proliferation, metabolism, and survival by integrating various growth factors, nutrients and amino acids. Eccentric synchronization of mTOR has been incriminated in various diseases/disorders like cancer, neurodegenerative disorders, and diabetes mellitus and its complications. Recent reports also highlight the role of mTOR in diabetes and its associated complications. This review tries to fathom the role of mTOR signaling in diabetes mellitus and its complications- diabetic cardiomyopathy, diabetic nephropathy, and diabetic retinopathy and highlights mTOR as a putative target for the development of novel anti-diabetic drug candidates.

Fungal infections have been increasing continuously worldwide, especially in immunocompromised individuals. Fungi, regarded as eukaryotic pathogens, have many similarities to the host cells, which inhibit anti-fungal drug development progress. Various fungal model systems have been studied, and it was concluded that Candida spp. is the most common disease-causing fungus. Candida species are well known to cause infections not only in our mouth, skin, and vagina, but they are also a frequent cause of life-threatening hospital bloodstream infections. The morphological and developmental pathways of Candida have been studied extensively, providing insight into the fungus development. Candida albicans is known to be the most pathogenic species responsible for a variety of infections in humans. Conventional anti-fungal drugs, mainly azoles drugs available in the market, have been used for years developing resistance in C. albicans. Hence, the production of new anti-fungal drugs, which require detailed molecular knowledge of fungal pathogenesis, needs to be encouraged. Therefore, this review targets the new approach of "Green Medicines" or the phytochemicals and their secondary metabolites as a source of novel anti-fungal agents to overcome the drug resistance of C. albicans, their mechanism of action, and their combined effects with the available anti-fungal drugs.

Background and aims: Increasing research evidence indicates that temporal lobe epilepsy (TLE) induced by kainic acid (KA) has high pathological similarities with human TLE. KA induces excitotoxicity (especially in the acute phase of the disease), which leads to neurodegeneration and epileptogenesis through oxidative stress and inflammation. Ferulic acid (FA) is one of the well-known phytochemical compounds that have shown potential antioxidant and anti-inflammatory properties and promise in treating several diseases. The current study set out to investigate the neuroprotective effects of FA in a rat model of TLE.

Methods: Thirty-six male Wistar rats were divided into four groups. Pretreatment with FA (100 mg/kg/day p.o.) started one week before the intrahippocampal injection of KA (0.8 μg/μl, 5μl). Seizures were recorded and evaluated according to Racine's scale. Oxidative stress was assessed by measuring its indicators, including malondialdehyde (MDA), nitrite, and catalase. Histopathological evaluations including Nissl staining and immunohistochemical staining of cyclooxygenase-2 (COX-2), and neural nitric oxide synthases (nNOS) were performed for the CA3 region of the hippocampus.

Results: Pretreatment with FA significantly attenuates the severity of the seizure and prevents neuronal loss in the CA3 region of the hippocampus in rats with KA-induced post-status epilepticus. Also, nitrite concentration and nNOS levels were markedly diminished in FA-pretreated animals compared to non-pretreated epileptic rats.

Conclusion: Our findings indicated that neuroprotective properties of FA, therefore, could be considered a valuable therapeutic supplement in treating TLE.

Dysbiosis has been linked to various diseases ranging from cardiovascular, neurologic, gastrointestinal, respiratory, and metabolic illnesses to cancer. Restoring of gut microbiota balance represents an outstanding clinical target for the management of various multidrug-resistant diseases. Preservation of gut microbial diversity and composition could also improve stem cell therapy which now has diverse clinical applications in the field of regenerative medicine. Gut microbiota modulation and stem cell therapy may be considered a highly promising field that could add up towards the improvement of different diseases, increasing the outcome and efficacy of each other through mutual interplay or interaction between both therapies. Importantly, more investigations are required to reveal the cross-talk between microbiota modulation and stem cell therapy to pave the way for the development of new therapies with enhanced therapeutic outcomes. This review provides an overview of dysbiosis in various diseases and their management. It also discusses microbiota modulation via antibiotics, probiotics, prebiotics, and fecal microbiota transplant to introduce the concept of dysbiosis correction for the management of various diseases. Furthermore, we demonstrate the beneficial interactions between microbiota modulation and stem cell therapy as a way for the development of new therapies in addition to limitations and future challenges regarding the applications of these therapies.

Background: Acute liver injury (ALI) is a critical and fatal disorder associated with excessive oxidative stress and inflammation, ultimately leading to the death of hepatocytes. Myricetin is a bioflavonoid in some berries, including blueberries and strawberries, with anti-inflammatory, antioxidant and anti-apoptotic properties.

Objective: In the current research, the hepatoprotective potential of myricetin was studied in the LPS/D-GalN model of ALI in C57BL/6 mice.

Methods: For inducing liver injury, D-GalN (400 mg/kg) and LPS (50 µg/kg) were injected via intraperitoneal route and myricetin was orally administered (25 or 100 mg/kg/day) for two days before inducing injury. Functional indices of liver dysfunction along with hepatic apoptotic, autophagic, oxidative stress and inflammatory factors were measured.

Results: Myricetin (100 mg/kg) reduced the fatality rate of animals and pathological liver changes and suitably lowered serum levels of total bilirubin, 8-OH-dG, ALT, AST and ALP in addition to decreasing apoptotic, oxidative and inflammatory factors, NOX, NLRP3, caspase 3, MPO and enhancing some antioxidants. Besides, myricetin improved the hepatic level and activity of sirtuin 1 and reversed inappropriate alterations of autophagic parameters, including LC3 II, Beclin 1, and P62. The beneficial effects of myricetin were attenuated after co-treatment with the autophagy inhibitor 3- methyladenine.

Conclusion: This study indicates the hepatoprotective potential of myricetin that can be ascribed to its down-regulation of oxidative, apoptotic, and inflammatory factors and upregulation of antioxidants besides its partial regulation of sirtuin 1 and autophagic pathway.

Background: The efficacy of Alzheimer's disease (AD) treatment can be enhanced by developing neurogenesis regulation approaches by synchronizing regenerative-competent cell (RCCs) activity. As part of the implementation of this direction, the search for drug targets among intracellular signaling molecules is promising.

Objective: This study aims to test the hypothesis that NF-кB inhibitors are able to synchronize the activities of different types RCCs in AD.

Methods: The effects of NF-κB inhibitor JSH-23 on the functioning of neural stem cells (NSCs), neuronal-committed progenitors (NCPs), and neuroglial cells were studied. Individual populations of C57B1/6 mice brain cells were obtained by immunomagnetic separation. Studies were carried out under conditions of modeling β-amyloid-induced neurodegeneration (βAIN) in vitro.

Results: We showed that β-amyloid (Aβ) causes divergent changes in the functioning of NSCs and NCPs. Also demonstrated that different populations of neuroglia respond differently to exposure to Aβ. These phenomena indicate a significant discoordination of the activities of various RCCs. We revealed an important role of NF-κB in the regulation of progenitor proliferation and differentiation and glial cell secretory function. It was found that the NF-κB inhibitor causes synchronization of the pro-regenerative activities of NSCs, NCPs, as well as oligodendrocytes and microglial cells in βAIN.

Conclusion: The results show the promise of developing a novel approach to Alzheimer's disease treatment with NF-κВ inhibitors.

Background: Valproic acid/sodium valproate (VPA), a well-known anti-epileptic agent, inhibits histone deacetylases, induces histone hyperacetylation, promotes DNA demethylation, and affects the histone methylation status in some cell models. Histone methylation profiles have been described as potential markers for cervical cancer prognosis. However, histone methylation markers that can be studied in a cervical cancer cell line, like HeLa cells, have not been investigated following treatment with VPA.

Methods: In this study, the effect of 0.5 mM and 2.0 mM VPA for 24 h on H3K4me2/me3, H3K9me/me2 and H3K27me/me3 signals as well as on KMT2D, EZH2, and KDM3A gene expression was investigated using confocal microscopy, Western blotting, and RT-PCR. Histone methylation changes were also investigated by Fourier-transform infrared spectroscopy (FTIR).

Results: We found that VPA induces increased levels of H3K4me2/me3 and H3K9me, which are indicative of chromatin activation. Particularly, H3K4me2 markers appeared intensified close to the nuclear periphery, which may suggest their implication in increased transcriptional memory. The abundance of H3K4me2/me3 in the presence of VPA was associated with increased methyltransferase KMT2D gene expression. VPA induced hypomethylation of H3K9me2, which is associated with gene silencing, and concomitant with the demethylase KDM3A, it increased gene expression. Although VPA induces increased H3K27me/me3 levels, it is suggested that the role of the methyltransferase EZH2 in this context could be affected by interactions with this drug.

Conclusion: Histone FTIR spectra were not affected by VPA under present experimental conditions. Whether our epigenetic results are consistent with VPA affecting the aggressive tumorous state of HeLa cells, further investigation is required.

Background: The activity of the amiloride-sensitive epithelial sodium channel (ENaC) in the tight epithelia of the lung is regulated by proteolytic activation and ubiquitination. Pathophysiology of lung diseases is directly related to changes in one or both of these mechanisms.

Methods: In this study, we investigated the impact of ubiquitination and cathepsin-mediated proteolytic activation mechanisms on the functional regulation of ENaC in lung cancer A549 cells using the patch-clamp technique.

Results: Our findings suggest that inhibiting the proteasome (polyubiquitination) with MG132 improves ENaC activity, whereas altering the pH of the lysosome (monoubiquitination inhibition) with NH4Cl has no effect on ENaC activity. In A549 cells, inhibition of cathepsin B (CSTB) decreased the ENaC current, open probabilities (NPo and Po), and the number of active channels.

Conclusion: These findings delineate novel modes of ENaC degradation and proteolytic activation of functional channels in A549 cells. Our findings indicate that both proteolytic activation and ubiquitination of ENaC significantly affect channel function and add new insights into the endogenous ENaC processing which might help to further understand the pathophysiology of the lung disease.