Current molecular pharmacology最新文献

Background: Status Epilepticus (SE) leads to the development of epilepsy with the contribution of Endoplasmic Reticulum (ER) stress. Uridine, a pyrimidine nucleoside, has been shown to have neuroprotective and antiepileptogenic effects in animal models. This study aimed to determine whether uridine ameliorates ER stress and apoptosis following epileptogenic insult. Secondly, this study aimed to establish the effect of uridine on inflammatory and oxidative stress parameters that contribute to ER stress.

Methods: Status epilepticus was induced using lithium-pilocarpine in adult male Sprague-Dawley rats. Following SE termination, rats were treated with uridine, 4-phenylbutyric acid (4-PBA), or saline twice daily for 48 h. Expressions of hippocampal glucose-regulated protein 78 (GRP78), Inositol- Requiring Protein 1 (IRE1α), Protein kinase RNA-like Endoplasmic Reticulum Kinase (PERK), and C/EBP Homologous Protein (CHOP) were determined by western blotting 48 h after SE. Uridine's effects on apoptosis, inflammation or oxidation were evaluated by analyses of cleaved caspase-3 and poly(ADP-ribose) polymerase 1 (PARP1) protein expressions or pro-inflammatory cytokine levels or levels of oxidative stress markers, respectively.

Results: Expressions of all ER stress-related proteins significantly increased 48 h after SE. Uridine treatment markedly decreased GRP78, IRE1α, and CHOP levels. A decrease in the PERK level was observed following the administration of 4-PBA; however, uridine had no effect. Cleaved caspase-3 and PARP1 levels were increased in the SHAM group, while uridine and 4-PBA treatment effectively decreased their expressions. Treatment with uridine significantly reduced Myeloperoxidase (MPO) and Malondialdehyde (MDA) levels while tending to increase Catalase (CAT) and Glutathione Peroxidase (GPx) levels. Uridine treatment also significantly attenuated levels of TNF-α and IL-1β, the pro-inflammatory cytokines, which increased 48 h post-SE.

Conclusion: Our data indicate that uridine alleviates ER stress after SE. This effect may be attributed to the regulation of inflammation and oxidative stress. Uridine shows promise as a potential preventive agent for epilepsy.

Background and objectives: Artemisinin and its derivatives, the well-known anti-malarial drugs extracted from traditional Chinese medicine, Artemisia annua, have been implicated in treating fibrotic diseases. However, whether artemisinin affects cardiac fibrosis in the pathogenesis of heart failure is still unknown. This study aimed to evaluate the possible effects of artemisinin on cardiac function and myocardial fibrosis in the heart failure model and to explore the underlying mechanisms.

Methods: Isoproterenol was injected subcutaneously for induction of the cardiac fibrosis model. Proteomic analysis was performed after 4 four weeks of artemisinin treatment. Echocardiography was used to evaluate cardiac function and structure. Hematoxylin and eosin (H&E) staining, as well as Masson trichrome staining, were performed for histopathology. The α-SMA, collagen I, and III expression in the myocardium was detected by immunohistochemical staining. The ratio of heart weight to body weight (HW/BW, mg/kg) and the ratio of heart weight to tibia length (HW/TL, mg/mm) were calculated as indicators for cardiac remodeling. Brain natriuretic peptide (BNP) levels were quantified in rat plasma using enzymelinked immunosorbent assay (ELISA). In contrast, the protein levels of TGF-β1, p-Smad2/3, and Smad2/3 were assessed in the myocardium andfibroblasts via western blot analysis. RT-qPCR was performed to analysis the expression of Col-I, Col-III, α-SMA, NLRP3, Caspase-1, IL-1β, andIL-18.

Results: Proteomic analysis identified 227 differentially expressed proteins (DEPs), including 119 upregulated and 108 downregulated proteins. These proteins were identified as the core proteins targeted by artemisinin for improving myocardial remodeling. GO annotation of the DEPs indicated that the DEPs were mainly associated with biological processes such as inflammation regulation. In the in vivo study of an isoproterenol-inducedrat cardiac remodeling model, we found that artemisinin administration significantly ameliorated cardiac dysfunction and reduced collagen production by suppressing TGFβ-1/Smads signaling and inhibiting NLRP3 inflammasome activation. As manifested by downregulating the expression of α-SMA, Col-I, and Col-III, NLRP3, IL-1β, IL-18, Caspase-1 mRNA, and TGF-β1, p-SMAD 2/3 protein in the myocardium. Similar beneficial effects of artemisinin were consistently observed in TGF-β1 treated primary cardiac fibroblasts.

Conclusions: Extracts from Artemisia annua relieves myocardial remodeling through TGF-β1/Smad2/3 pathway and NLRP3 inflammasome

Alnustone (4(E)-,6(E)-1,7-Diphenyl-hepta-4,6-dien-3-one) is a non-phenolic natural diarylheptanoid, which was first isolated and identified from the male flower of Alnus pendula (Betulaceae). It can also be isolated from Curcuma xanthorrhiza Roxb (Zingiberaceae) rhizomes and Alpinia katsumadai Hayata (Zingiberaceae) seeds. It was first synthesized through a five-step process from β-phenyl propionyl chloride. In later years, new methods for synthesizing Alnustone were designed and performed with different yields. Due to the various therapeutic effects exhibited by alnustone like other diarylheptanoids, its biological activities such as antioxidant, antibacterial, and anti-inflammatory properties have been the subject of many studies.This article has reviewed different aspects of this valuable natural compound, including its natural and synthetic sources, therapeutic effects, and pharmacokinetics as a potential future therapeutic agent.

Background: Arsenic is present in above permissible safe limits in groundwater, soil, and food, in various areas of the world. This is increasing exposure to humankind and affecting health in various ways. Alternation in cognition is one among them. Epidemiological research has reflected the impact of arsenic exposure on children in the form of diminished cognition.

Aims: Considering this fact, the present study reviewed the impact of arsenic on amyloid precursor protein, which is known to cause one of the commonest cognitive disorders such as Alzheimer's disease.

Methods: The present study reviews the arsenic role in the generation of amyloid-beta from its precursor that leads to Alzheimer's disease through the published article from Pubmed and Scopus.

Description: According to the findings, regular, long-term exposure to arsenic beginning in infancy changes numerous arsenic level-regulating regions in the rat brain, which are related to cognitive impairments. Arsenic also affects the BBB clearance route by increasing RAGE expression. Arsenic triggers the proamyloidogenic pathway by increasing APP expression and subsequently, its processing by β-secretase and presenilin. Arsenic also affects mitochondrial dynamics, DNA repair pathway and epigenetic changes. The mechanism behind all these changes is explained in the present review article.

Conclusion: A raised level of arsenic exposure affects the amyloid precursor protein, a factor for the early precipitation of Alzheimer's disease.

Background: Activation of microglia and astrocytes has been observed in Alzheimer's disease (AD). Transglutaminase 2 (TG2) is reported to be activated in AD and involved in cell proliferation, differentiation, and inflammation. Moreover, amyloid β (Aβ) aggregation is detected as a characteristic pathology in the AD brain, and is known to be a substrate of TG2. All-trans retinoic acid (ATRA) can modify cell proliferation and differentiation, and is reported to have therapeutic effects on AD pathology.

Objective: We aimed to assess the effects of ATRA in microglia and astrocytes on TG2 expression and glial functions.

Methods: After treatment with ATRA, TG2 expression and TG activity were assayed in both murine microglia BV-2 cells and cultured rat brain astrocytes. Endocytosis activity in BV-2 cells and Aβ aggregation by astrocytes conditioned medium were also assessed.

Results: In both BV-2 cells and cultured astrocytes, ATRA increased TG2 expression and TG activity. The increase was blocked by AGN194310, an RA receptor antagonist. ATRA enhanced the endocytosis activity in BV-2 cells, and the addition of AGN194310 reversed it. The addition of cystamine, a competitive TG inhibitor, also reduced ATRA-enhanced endocytosis activity. On the other hand, Aβ aggregation was potentiated by ATRA-treated astrocytes conditioned medium compared to control astrocytes conditioned medium.

Conclusion: These results suggest that ATRA increased TG2 expression and TG activity via RA receptor in microglia and astrocytes. ATRA-enhanced TGs might be involved in phagocytosis and Aβ aggregation. Adequate control of TGs expression and function in microglia and astrocytes can be an important factor in AD pathology.

Almost 20-40% of all patients suffering from diabetes mellitus experience chronic kidney disease, which is related to higher mortality (cardiovascular and all-cause). The implication of several pathophysiological mechanisms (hemodynamic, tubular, metabolic and inflammatory) in the pathogenesis of diabetic kidney disease generates an urgent need to develop multitarget therapeutic strategies to face its development and progression. SGLT2 inhibitors are undoubtedly a practice-changing drug class for individuals who experience type 2 diabetes and diabetic kidney disease. In vitro studies, exploratory research, sub-analyses of large randomized controlled trials, and investigation of several biomarkers have demonstrated that SGLT2 inhibitors achieved multiple beneficial activities, targeting several renal cellular and molecular pathways independent of their antihyperglycemic activity. These mainly include the reduction in intraglomerular pressure through the restoration of TGF, impacts on the renin-angiotensin-aldosterone system, improvement of renal hypoxia, adaptive metabolic alterations in substrate use/energy expenditure, improvement of mitochondrial dysfunction, and reduction of inflammation, oxidative stress and fibrosis. This manuscript thoroughly investigates the possible mechanisms that underlie their salutary renal effects in patients with diabetes, focusing on several pathways involved and the interplay between them. It also explores their upcoming role in ameliorating the evolution of chronic kidney disease in patients with diabetes.

Resveratrol, a polyphenolic phytoalexin found in a wide range of plants, including grapes, berries, and peanuts, is an extensively researched phytochemical with unique pharmacological capabilities and amazing potential to affect many targets in various cancers. Resveratrol's anti-cancer activities are due to its targeting of a variety of cellular and molecular mechanisms and crucial processes involved in cancer pathogenesis, such as the promotion of growth arrest, stimulation of apoptosis, suppression of cell proliferation, induction of autophagy, regulating oxidative stress and inflammation, and improving the influence of some of the other chemotherapeutic agents. MicroRNAs (miRNAs) are non-coding RNAs that modulate gene expression by degrading mRNA or inhibiting translation. MiRNAs serve critical roles in a wide range of biological activities, and disruption of miRNA expression is strongly linked to cancer progression. Recent research has shown that resveratrol has anti-proliferative and/or pro-apoptotic properties via modulating the miRNA network, which leads to the inhibition of tumor cell proliferation, the activation of apoptosis, or the increase of traditional cancer therapy effectiveness. As a result, employing resveratrol to target miRNAs will be a unique and potential anticancer approach. Here, we discuss the main advances in the modulation of miRNA expression by resveratrol, as well as the several miRNAs that may be influenced by resveratrol in different types of cancer and the significance of this natural drug as a promising strategy in cancer treatment.

Background: Cholangiopathies comprise a spectrum of diseases without curative treatments. Pharmacological treatments based on bile acid (BA) metabolism regulation represent promising therapeutic strategies for the treatment of cholangiopathies. Gentiopicroside (GPS), derived from the Chinese medicinal herb Gentianae Radix, exerts pharmacological effects on bile acid metabolism regulation and oxidative stress.

Objective: The present study aims to investigate the effect of GPS on 3,5-diethoxycarbonyl-1,4dihydrocollidine (DDC)-induced cholangiopathy.

Methods: Two independent animal experiments were designed to evaluate the comprehensive effect of GPS on chronic DDC diet-induced cholangiopathy, including bile duct obliteration, ductular reaction, BA metabolism reprogramming, liver fibrosis, oxidative stress and inflammatory responses.

Results: In the first pharmacological experiment, three doses of GPS (5, 25 and 125 mg/kg) were injected intraperitoneally into mice fed a DDC diet for 14 days. DDC induced a typical ductular reaction, increased periductal fibrosis and mixed inflammatory cell infiltration in the portal areas. GPS treatment showed dose-dependent improvements in the ductular reaction, BA metabolism, fibrosis, oxidative stress and inflammatory response. In the second experiment, a high dose of GPS was injected intraperitoneally into control mice for 28 days, resulting in no obvious histologic changes and significant serologic abnormalities in liver function. However, GPS inhibited DDC-induced oxidative stress, serum and hepatic BA accumulation, proinflammatory cytokine production, and immunocyte infiltration. Specifically, the GPS-treated groups showed decreased infiltration of monocyte-derived macrophages and CD4+ and CD8+ T lymphocytes, as well as preserved Kupffer cells.

Conclusion: GPS alleviated chronic DDC diet-induced cholangiopathy disorder by improving the ductular reaction, periductal fibrosis, oxidative stress and inflammatory response. Its dosage-dependent pharmacological effects indicated that GPS warrants its further evaluation in clinical trials for cholangiopathy.

The incidence of nonalcoholic fatty liver disease (NAFLD) has been rising worldwide in parallel with diabetes and metabolic syndrome. NAFLD refers to a spectrum of liver abnormalities with a variable course, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), eventually leading to cirrhosis and hepatocellular carcinoma. Pregnane X receptor (PXR), a member of the nuclear receptor superfamily, plays a prominent part in the regulation of endogenous metabolic genes in NAFLD. Recent studies have suggested that PXR has therapeutic potential for NAFLD, yet the relationship between PXR and NAFLD remains controversial. In this review, PXR is proposed to play a dual role in the development and progression of NAFLD. Its activation will aggravate steatosis of the liver, reduce inflammatory response, and prevent liver fibrosis. In addition, the interactions between PXR, substance metabolism, inflammation, fibrosis, and gut microbiota in non-alcoholic fatty liver were elucidated. Due to limited therapeutic options, a better understanding of the contribution of PXR to the pathogenesis of NAFLD should facilitate the design of innovative drugs targeting NAFLD.

Background: Psoriasis is an acute to chronic multifunctional inflammatory skin disorder mediated through T-cell activation, dendritic cell intervention, local vascular variations, atypical keratinocyte proliferation, and neutrophil activation, leading to a skin disorder with no permanent cure.

Objective: This review aims to find a potent, secure, and dependable medication, with a more scientific examination of herbal resources and recent targeted immunobiological therapies.

Method: Reports evaluating the effectiveness of biologics & herbal remedies for the topical therapy of psoriasis against control therapies were taken into consideration (placebo or active therapy). The work examined cellular circuits involved in inflammation with its immunogenetic mechanism behind various options available for treating psoriasis in addition to the role of agents inducing psoriasis.

Results: The extent of psoriasis can range from small, localized spots to total body coverage, and it can happen at any stage of life. Several theories exist for clarification however, the exact cause of psoriasis is not entirely understood. Researchers have discovered genetic loci linkages, environmental changes, drug induction, lifestyle conditions, some infections, etc. resulting in this disorder. There are numerous known conventional medical treatments for psoriasis, ranging from topical and systemic medicines to phototherapy or combinations of both with recent immunobiological treatment. However, the majority of these treatments are ineffective and have a variety of side effects that limit their long-term usage, such as cutaneous atrophy, tissue toxicity, mutagenicity, and immunosuppression.

Conclusion: Herbal extracts or isolated compounds can be considered as a substitute for conventional psoriasis treatment. Unfortunately, many investigations often provide a small amount of facts about the safety and effectiveness of topically applied herbal remedies for the treatment of psoriasis. Thus, further factual evidences and validations are needed to promote herbal options, which must be supported by rigorous animal studies or clinical trials using standardised materials and compositions.