Harbomccarty6939

Pulmonary fibrosis is a kind of interstitial lung disease with progressive pulmonary scar formation, leading to irreversible loss of lung functions. The TGF-β1/Smad signaling pathway plays a key role in fibrogenic processes. It is associated with the increased synthesis of extracellular matrix, enhanced proliferation of fibroblasts, and transformation of alveolar epithelial cells into interstitial cells. We investigated P-Rex1, a PIP3-Gβγ-dependent guanine nucleotide exchange factor (GEF) for Rac, for its potential role in TGF-β1-induced pulmonary fibrosis. A high expression level of P-Rex1 was identified in the lung tissue of patients with pulmonary fibrosis than that from healthy donors. Using the P-Rex1 knockdown and overexpression system, we established a novel player of P-Rex1 in mouse lung fibroblast migration. P-Rex1 contributed to fibrogenic processes in lung fibroblasts by targeting the TGF-β type Ⅱ receptor (TGFβR2). The RNA-seq analysis for expression profiling confirmed the modulation of P-Rex1 in cell migration and the involvement of P-Rex1 in TGF-β1 signaling. These results identified P-Rex1 as a signaling molecule involved in TGF-β1-induced pulmonary fibrosis, suggesting that P-Rex1 may be a potential target for pulmonary fibrosis treatment.Bone remodeling, a dynamic process in which bone formation by osteoblast is preceded by bone resorption by osteoclast, is a vital physiological process for maintaining bone mass and strength, imbalances in which could precipitate osteoporosis. Due to the unilateral mechanism of the existing bone remodeling drugs, identifying compounds that could regulate the balance between osteoclast and osteoblast could improve the treatment of osteoporosis. Here, we show that compounds isolated from Wikstroemia taiwanensis modulate osteoclast and osteoblast activities. Specifically, astragalin (1) and kaempferol 3-O-β-D-apiofuranosyl-(1→6)-β-D-glucopyranoside (2), besides increasing mineral deposition, increased alkaline phosphatase activity (137.2% for 1 and 115.8% for 2) and ESR-α expression (112.8% for 1 and 122.5% for 2) in primary human osteoblasts. In contrast, compounds 1, 2, 3, and 5 inhibited tartrate-resistant acid phosphatase (TRAP) activity in receptor activator of nuclear factor-κB ligand-induced osteoclasts by 40.8, 17.1, 25.9, and 14.5% and also decreased the number of TRAP-positive cells by 51.6, 26.8, 20.5, and 18.6%, respectively. Our findings, therefore, showed that compounds isolated from W. taiwanensis could increase osteoblast activity while simultaneously decreasing osteoclast activity, and hence, warrant further evaluation for development as anti-osteoporosis agents.The aim of this study was to investigate the effects of the GSK-3β/NF-κB pathway on integrin-associated protein (CD47) expression after myocardial infarction (MI) in rats. An MI Sprague Dawley rat model was established by ligating the left anterior descending coronary artery. The rats were divided into three groups Sham, MI, and SB + MI (SB216763) groups. Immunohistochemistry was used to observe the changes in cardiac morphology. A significant reduction in the sizes of fibrotic scars was observed in the SB + MI group compared to that in the MI group. SB216763 decreased the mRNA and protein expression of CD47 and NF-κB during MI. Primary rat cardiomyocytes (RCMs) and the H9c2 cell line were used to establish in vitro hypoxia models. Quantitative real-time PCR and western blotting analyses were conducted to detect mRNA and protein expression levels of CD47 and NF-κB and apoptosis-related proteins, respectively. Apoptosis of hypoxic cells was assessed using flow cytometry. SB216763 reduced the protein expression of CD47 and NF-κB in RCMs and H9c2 cells under hypoxic conditions for 12 h, and alleviated hypoxia-induced apoptosis. SN50 (an NF-κB inhibitor) also decreased CD47 protein expression in RCMs and H9c2 cells under hypoxic conditions for 12 h and protected cells from apoptosis. GSK-3β upregulates CD47 expression in cardiac tissues after MI by activating NF-κB, which in turn leads to myocardial cell damage and apoptosis.Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related death in western countries. The successful treatment of PDAC remains limited. We investigated the effect of Fraction B, which is a fraction purified from catfish (Arius bilineatus, Val.) skin secretions containing proteins and lipids, on PDAC biology both in-vivo and in-vitro. We report here that Fraction B potently suppressed the proliferation of both human and mouse pancreatic cancer cells in vitro and significantly reduced the growth of their relevant xenograft (Panc02) and orthotopic tumors (human Panc-1 cells) (p less then 0.05). The Reverse Phase Protein Array (RPPA) data obtained from the tumor tissues derived from orthotopic tumor bearing mice treated with Fraction B showed that Fraction B altered the cancer stem cells related pathways and regulated glucose and glutamine metabolism. The down-regulation of the cancer stem cell marker CD44 expression was further confirmed in Panc-1 cells. CBC and blood chemistry analyses showed no systemic toxicity in Fraction B treated Panc-1 tumor bearing mice compared to that of control group. Our data support that Fraction B is a potential candidate for PDAC treatment.Myocardial ischemia-reperfusion (I/R) injury, characterized by myocardial cell death (e.g., apoptosis) and generation of reactive oxygen species (ROS) such as superoxide (O2 ·-) and hydrogen peroxide (H2O2), is a serious threat to human health and property. Saponin astragaloside IV (ASIV), extracted from Chinese herbal medicine astragalus, is effective in resolving multiple pathological issues including myocardial I/R injury. Recent studies have shown that autophagy is regulated by ROS and plays an important role in myocardial I/R injury. However, regulation of autophagy by ASIV during myocardial I/R injury and the role of specific ROS involved in the process have been rarely reported. In the present study, we found that SOD2 was downregulated and O2 ·- was upregulated in H2O2-induced H9C2 cardiac myocyte injury in vitro and myocardial I/R injury in vivo, while such alterations were reversed by ASIV. ASIV possessed the ability to alleviate myocardial I/R injury via attenuating I/R-caused autophagosome accumulation. Upregulate of O2 ·- by 2-methoxyestradiol (2-ME) reversed the effect of ASIV-mediated autophagy regulation, which suggested that O2 ·- was vital in this process. In conclusion, our results contribute to understanding the mechanism of ASIV-induced cardioprotective effect.Alzheimer's disease (AD) is tightly related to endoplasmic reticulum stress (ER stress), which aggravates two dominant pathological manifestations of AD senile plaques and neurofibrillary tangles. Berberine is widely applied in the clinical treatment of many diseases and is reported to have anti-AD effects. In the present study, berberine was shown to ameliorate ER stress and cognitive impairment in APP/PS1 mice. Harmine We found ER stress plays a role as a central hub for signal transduction, which was evidenced by the hyperactivation of glycogen synthase kinase 3β (GSK3β) to phosphorylate tau and the activation of PRKR-like endoplasmic reticulum kinase (PERK) subsequently to phosphorylate eukaryotic translation initiation factor-2 α (eIF2α). Also, eIF2α has regulated the expression of beta-site APP cleaving enzyme-1 (BACE1), which cleaves APP into pro-oligomerized amyloid beta 42 (Aβ42), the main component of senile plaques, proven by using siRNA targeting at eIF2α. Mechanically, berberine can reduce GSK3β activity, contributing to the downregulation of tau phosphorylation. Berberine also suppressed Aβ42 production via inhibiting the PERK/eIF2α/BACE1 signaling pathway. Taken together, these findings indicated that berberine had the potential to ameliorate two major pathological manifestations of AD mainly by suppressing ER stress. Our work provided knowledge on the pharmacological intervention of AD and the possible targets for future drug development.Objective This systematic review and meta-analysis is aimed at assessing the risks of cardiovascular adverse events in patients with rheumatoid arthritis (RA) who have been treated with fostamatinib. Methods The electronic databases of OVID Medline, OVID EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science were searched to identify studies that reported cardiovascular events or hypertension in RA patients treated with fostamatinib. Two reviewers separately and simultaneously screened the retrieved studies based on study selection criteria, collected data and performed methodological quality assessments. The effect size of meta-analysis was estimated by the Peto odds ratio (OR) or relative risk (RR) with 95% confidence intervals (95%CI). Funnel plot was used to estimate publication bias and sensitivity analysis was performed to test the robustness of the results. Results A total of 12 trials composed of 5,618 participants with low to moderate risk of bias were included. In comparison to the placebo, the use of fostamatinib was found to elevate the risk of hypertension (RR=3.82, 95%CI 2.88-5.05) but was not associated with the risks of all-cause death (Peto OR=0.16, 95%CI 0.02-1.24), major adverse cardiovascular events (Peto OR=1.24, 95%CI 0.26-5.97), pulmonary heart disease and disease of pulmonary circulation (Peto OR=1.23, 95%CI 0.13-11.87), in addition to other forms of heart disease (Peto OR=1.96, 95%CI 0.72-5.38). Furthermore, sensitivity analysis showed no significant change in effective trends and no publication bias was found. Conclusion Fostamatinib is associated with increased risk of hypertension; however, no increased risks of cardiovascular events were observed. Further well-planned cohort studies with large study populations and longer follow-up times are needed to elucidate the outcomes. Systematic Review Registration [PROSPERO], identifier [CRD42020198217].Tetrastigma hemsleyanum Diels & Gilg (T. hemsleyanum) has attracted much attention due to its ability on pneumonia, bronchitis, and immune-related diseases, while its functional components and underlying mechanism of action on pneumonia have not been fully elucidated. Herein, we used a systematic network pharmacology approach to explore the action mechanism of T. hemsleyanum leaf in the treatment of pneumonia. In this study, the results of network pharmacology demonstrated that there were 34 active components and 80 drug-disease targets in T. hemsleyanum leaf, which were strongly in connection with signal transduction, inflammatory response, and the oxidation-reduction process. Subsequently, a mouse model of pneumonia induced by Pseudomonas aeruginosa (P. aeruginosa) was established to validate the predicted results of network pharmacology. In the animal experiments, aqueous extract of T. hemsleyanum leaf (EFT) significantly attenuated the histopathological changes of lung tissue in P. aeruginosa-induced mice and reduced the number of bacterial colonies in BALFs by 96.84% (p less then 0.01). Moreover, EFT treatment suppressed the increase of pro-inflammatory cytokines IL-17, IL-6, and TNF-α in lung tissues triggered by P. aeruginosa, which led to the increase of Th17 cells (p less then 0.05). High concentration of EFT treatment (2.0 g/kg) obviously increased the anti-inflammatory cytokine levels, accompanied by the enhancement of Treg proportion in a dose-dependent manner and a notable reversal of transcription factor RORγt expression. These findings demonstrated that network pharmacology was a useful tool for TCM research, and the anti-inflammatory effect of EFT was achieved by maintaining Th17/Treg immune homeostasis and thereby suppressing the inflammatory immune response.