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Electrodeposited Co-W-P Ternary Switch regarding Hydrogen Evolution Effect.
The results have been evaluated by herbal medicine experts' domain knowledge.Background Cardio-renal profiles are available from cardiovascular outcome trials of glucagon-like peptide-1 receptor agonists (GLP-1 RAs). Methods A comprehensive systematic review of Embase, Medline, Web of Knowledge, and CENTRAL databases was conducted. Randomized controlled cardiovascular outcome trials of type 2 diabetes mellitus (T2DM) patients administered GLP-1 RAs were included. The following primary outcomes were examined cardiovascular death, major adverse cardiovascular events (MACE), myocardial infarction, stroke, mortality, heart failure, hypoglycemia, pancreatitis, and thyroid carcinoma. Secondary outcomes included composite kidney outcome, worsening kidney function, macroalbuminuria, and retinopathy. Results Seven trials involving 56,004 patients and eight interventions were identified. Albiglutide was associated with fewer MACE and myocardial infarction events compared with lixisenatide. Lixisenatide was related to a greater number of stroke events and cardiovascular deaths compared to once-weekly semaglutide and oral semaglutide, respectively. Improved mortality was associated with oral semaglutide compared with once-weekly semaglutide, albiglutide, dulaglutide, exenatide, or lixisenatide. Risks of heart failure, thyroid carcinoma, and pancreatitis were similar among all the treatments. Weighting of the nine primary outcomes identified oral semaglutide as first among the eight treatments examined. Among three of the secondary outcomes, once-weekly semaglutide ranked first. Better composite kidney outcome was observed with once-weekly semaglutide than with dulaglutide or exenatide; once-weekly semaglutide improved macroalbuminuria compared with exenatide or lixisenatide; and albiglutide, exenatide, and placebo was associated with fewer cases of retinopathy compared with once-weekly semaglutide. Meanwhile, kidney function was less likely to worsen with dulaglutide than with lixisenatide or placebo. Conclusion Semaglutide should be considered when GLP-1 RAs are indicated for T2DM patients.Cyclin-dependent kinases (CDKs) are key players in cell cycle regulation. So far, more than ten CDKs have been described. Their direct interaction with cyclins allow progression through G1 phase, transitions to S and G2 phase and finally through mitosis (M). While CDK activation is important in cell renewal, its aberrant expression can lead to the development of malignant tumor cells. Dysregulations in CDK pathways are often encountered in various types of cancer, including all gastrointestinal (GI) tract tumors. This prompted the development of CDK inhibitors as novel therapies for cancer. Currently, CDK inhibitors such as CDK4/6 inhibitors are used in pre-clinical studies for cancer treatment. In this review, we will focus on the therapeutic role of various CDK inhibitors in colorectal cancer, with a special focus on the CDK4/6 inhibitors.Serine proteases are elevated in arthritic joints where they can cleave protease activated receptors (PARs) to modulate pain and inflammation. Activation of protease-activated receptor 4 (PAR4) has been implicated in inflammatory joint pain. SAR405 price Whether PAR4 is involved in osteoarthritis (OA) pain has not yet been explored. The aim of this study was to compare the role of PAR4 in modulating early versus late stage OA pain using two models of OA viz. monoiodoacetate (MIA) and medial meniscal transection (MMT). G-ratio calculation and electron microscopy analysis revealed saphenous nerve demyelination and structural damage during late stage but not early OA in both models. Using immunohistochemistry, neuronal expression of PAR4 was higher in early versus late OA. Systemic administration of the PAR4 antagonist pepducin P4pal10 reduced both secondary allodynia (von Frey hair algesiometry) and joint nociceptor firing (single unit recordings) in MMT and MIA animals compared to vehicle-treated animals in early OA. The PAR4 antagonist was ineffective at altering pain or joint afferent firing in post-inflammatory OA. During the acute phase of the models, joint inflammation as determined by laser speckle contrast analysis and intravital microscopy could be partially blocked by pepducin P4pal10. Compared to late-stage disease, inflammatory cytokines were elevated in early MIA and MMT rats. These findings suggest that PAR4 may be a viable target to treat the pain of early onset OA or during episodic inflammatory flares.Traditional Chinese medicine (TCM) has been practiced in the treatment of bone diseases and alcoholism. Chronic excessive alcohol use results in alcohol-induced bone diseases, including osteopenia and osteoporosis, which increases fracture risk, deficient bone repair, and osteonecrosis. This preclinical study investigated the therapeutic effects of TCM herbal extracts in animal models of chronic excessive alcohol consumption-induced osteopenia. TCM herbal extracts (Jing extracts) were prepared from nine Chinese herbal medicines, a combinative herbal formula for antifatigue and immune regulation, including Astragalus, Cistanche deserticola, Dioscorea polystachya, Lycium barbarum, Epimedium, Cinnamomum cassia, Syzygium aromaticum, Angelica sinensis, and Curculigo orchioides. In this study, Balb/c male mice were orally administrated alcohol (3.2 g/kg/day) with/without TCM herbal extracts (0.125 g/kg, 0.25 g/kg, or 0.5 g/kg) by gavage. Our results showed that after 50 days of oral administration, TCM herbal extracts prevented alcohol-induced osteopenia demonstrated by μ-CT bone morphological analysis in young adults and middle-aged/old Balb/c male mice. Biochemical analysis demonstrated that chronic alcohol consumption inhibits bone formation and has a neutral impact on bone resorption, suggesting that TCM herbal extracts (Jing extracts) mitigate the alcohol-induced abnormal bone metabolism in middle-aged/old male mice. Protocatechuic acid, a natural phenolic acid in Jing extracts, mitigates in vivo alcohol-induced decline of alkaline phosphatase (ALP) gene expression in the bone marrow of Balb/c male mice and in vitro ALP activity in pre-osteoblast MC3T3-E1 cells. Our study suggests that TCM herbal extracts prevent chronic excessive alcohol consumption-induced osteopenia in male mice, implying that traditional medicinal plants have the therapeutic potential of preventing alcohol-induced bone diseases.Purpose This study aimed to investigate the potential mechanisms and related bioactive components of ZSS for the treatment of insomnia. Method The insomnia model of rat induced by PCPA was established. After oral administration of ZSS extract, the general morphological observation, pentobarbital sodium-induced sleep test and histopathological evaluation were carried out. Network pharmacology, assisted by UHPLC-Q-Exactive-MS/MS analysis, was developed to identify the targets of ZSS in the treatment of insomnia, as well as the corresponding signaling pathways. In addition, we validated the identified targets and pathways by RT-qPCR and immunohistochemical analysis. Results The pentobarbital sodium-induced sleep test, determination of 5-HT and GABA levles in hypothalamic tissues and HE staining showed that ZSS extract was an effective treatment for insomnia. Network pharmacology analysis identified a total of 19 candidate bioactive ingredients in ZSS extract, along with 433 potentially related targets. Next, we comprehensive network pharmacology and in vivo experiments, we successfully identified the potential pharmacological mechanisms underlying the action of ZSS in the treatment of insomnia. The results provide a theoretical basis for further development and utilization of ZSS, and also provide support for the development of innovative drugs for the treatment of insomnia.Background Although kidney injury has been reported as a serious adverse effect in patients treated with ibuprofen or acetaminophen (APAP), there are still few real-world studies to compare the specific differences in the adverse effects of nephrotoxicity. Methods Disproportionality analysis and Bayesian analysis were devoted to data-mining of the suspected kidney injury after using ibuprofen and APAP based on the FDA's Adverse Event Reporting System (FAERS) from January 2004 to March 2021. The times to onset, fatality, and hospitalization rates of ibuprofen-associated kidney injury and APAP-associated kidney injury were also investigated. Results 2,453 reports of ibuprofen-associated kidney injury and 1,288 reports of APAP-associated kidney injury were identified. Ibuprofen appeared to affected more middle-aged patients than elderly ones (27.76 vs 16.53%) while APAP appeared to affected more young patients than middle-aged patients (45.24 vs 29.10%) and elderly patients were fewer (13.99%). Compared to ibuprofen, APAP had the higher association with renal injury based on the higher reporting odds ratio (ROR = 2.45, 95% two-sided CI = 2.36-2.56), proportional reporting ratio (PRR = 2.39, χ 2 = 2002.94) and empirical Bayes geometric mean (EBGM = 2.38, 95% one-sided CI = 2.3). In addition, APAP-associated kidney injury had earlier onset (32.74 vs 115.82 days, p less then 0.0001) and a higher fatality rate (44.43 vs 7.36%, p less then 0.001) than those of ibuprofen-associated kidney injury. Conclusion The analysis of FAERS data provides a more accurate profile on the incidence and prognosis of kidney injury after ibuprofen and acetaminophen treatment, enabling continued surveillance and timely intervention in patients at risk of kidney injury using these drugs.GTP cyclohydrolase I (GTPCH I) is the rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis; the latter is an essential factor for iNOS activation that contributes neuronal loss in Huntington's disease (HD). The aim of the study was to investigate the neuroprotective effect of 2,4-diamino-6-hydroxypyrimidine (DAHP), GTPCH I enzyme inhibitor, against neuronal loss in 3-nitropropinic acid (3-NP)-induced HD in rats and to reveal the possible involved mechanisms mediated through PI3K/Akt axis and its correlation to Mas receptor (MasR). Rats received 3-NP (10 mg/kg/day; i.p.) with or without administration of DAHP (0.5 g/kg/day; i.p.) or wortmannin (WM), a PI3K inhibitor, (15 μg/kg/day; i.v.) for 14 days. DAHP improved cognitive, memory, and motor abnormalities induced by 3-NP, as confirmed by striatal histopathological specimens and immunohistochemical examination of GFAP. Moreover, DAHP treatment inhibited GTPCH I activity, resulting in decreased BH4 levels and iNOS activation. Also, DAHP upregulated the protein expression of survival protein; p85/p55 (pY458/199)-PI3K and pS473-Akt that, in turn, boosted the activation of striatal neurotrophic factors and receptor, pS133-CREB, BDNF and pY515-TrKB, which positively affect MasR protein expression and improve mitochondrial dysfunction, as indicated by enhancing both SDH and PGC-1α levels. Indeed, DAHP attenuates oxidative stress by increasing SOD activity and Nrf2 expression in addition to reducing neuro-inflammatory status by inhibiting NF-κB p65 and TNF-α expression. Interestingly, all the previous effects were blocked by co-administration of WM with DAHP. In conclusion, DAHP exerts neuroprotective effect against neuronal loss induced by 3-NP administration via inhibition of GTPCH I and iNOS activity and activation of MasR/PI3K/Akt/CREB/BDNF/TrKB axis besides its antioxidant and anti-inflammatory effect.
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