Gradyhanley5562

y provide strong evidence for the clinical use of JTTF in the treatment of T2DM and NAFLD, leading to the possibility of further mechanistic exploration. Clinical Trial Registration This clinical trial has been registered in China Clinical Trial Registry (ChiCTR 2100051174).Background Ectopic activation of renin-angiotensin-system contributes to cardiovascular and renal diseases. (Pro)renin receptor (PRR) binds to renin and prorenin, participating in the progression of nephrology. However, whether PRR could be considered as a therapeutic target for cardiac remodeling and heart failure remains unknown. Materials and methods Transverse aortic constriction (TAC) surgery was performed to establish a mouse model of chronic pressure overload-induced cardiac remodeling. Neonatal rat cardiomyocytes (CMs) and cardiac fibroblasts (CFs) were isolated and stimulated by Angiotensin II (Ang II). PRR decoy inhibitor PRO20 was synthesized and used to evaluate its effect on cardiac remodeling. Results Soluble PRR and PRR were significantly upregulated in TAC-induced cardiac remodeling and Ang II-treated CMs and CFs. Results of In vivo experiments showed that suppression of PRR by PRO20 significantly retarded cardiac remodeling and heart failure indicated by morphological and echocardiographic analyses. In vitro experiments, PRO20 inhibited CM hypertrophy, and also alleviated CF activation, proliferation and extracellular matrix synthesis. Mechanically, PRO20 enhanced intracellular cAMP levels, but not affected cGMP levels in CMs and CFs. Moreover, treatment of PRO20 in CFs markedly attenuated the production of reactive oxygen species and phosphorylation of IRE1 and PERK, two well-identified markers of endoplasmic reticulum (ER) stress. Accordingly, administration of PRO20 reversed ER stressor thapsigargin-induced CM hypertrophy and CF activation/migration. Conclusion Taken together, these findings suggest that inhibition of PRR by PRO20 attenuates cardiac remodeling through increasing cAMP levels and reducing ER stress in both CMs and CFs.Acute pulmonary embolism (APE) is a debilitating condition with high incidence and mortality rates. APE is widely treated with the serine protease urokinase or urokinase-type plasminogen activator (uPA) that functions by resolving blood clots via catalyzing the conversion of plasminogen to plasmin. Treatment with recombinant uPA has been shown to increase endogenous expression of uPA and its cognate receptor, uPAR; however, the mechanisms for this induction are not known. Using an in vitro hypoxia/reoxygenation model in bronchial epithelial BEAS-2B cells, we show that induction of hypoxia/reoxygenation induces apoptosis and increases secretion of tumor necrosis factor-alpha, brain natriuretic peptide, and fractalkine, which are attenuated when treated with exogenous uPA. Induction of hypoxia/reoxygenation resulted in decreased expression of uPAR on cell surface without any significant changes in its messenger RNA expression, highlighting post-transcriptional regulatory mechanisms. Determination of uPAR protein half-life using cycloheximide showed treatment with uPA significantly increased its half-life (209.6 ± 0.2 min from 48.2 ± 2.3 min). Hypoxia/reoxygenation promoted the degradation of uPAR. Inhibition of proteasome-mediated degradation using MG-132 and lactacystin revealed that uPAR was actively degraded when hypoxia/reoxygenation was induced and that it was reversed when treated with exogenous uPA. Determination of the proteolytic activity of 20S proteasome showed a global increase in ubiquitin-proteasome activation without an increase in proteasome content in cells subjected to hypoxia/reoxygenation. Our results cumulatively reveal that uPAR is actively degraded following hypoxia/reoxygenation, and the degradation was significantly weakened by exogenous uPA treatment. Given the importance of the uPA/uPAR axis in a multitude of pathophysiological contexts, these findings provide important yet undefined mechanistic insights.Forsythiae Fructus (FF), the fruit of Forsythia suspensa (Thunb.) Vahl. (Lianqiao), is one of the most fundamental herbs in Traditional Chinese Medicines (TCM), mainly due to its heat-clearing and detoxifying effects. There are two types of FF, the greenish fruits that start to ripen (GF) and the yellow fruits that are fully ripe (RF), called "Qingqiao" and "Laoqiao" referred to the Chinese Pharmacopoeia, respectively. It undergoes a complex series of changes during the maturation of FF. However, the clinical uses and preparation of phytopharmaceuticals of FF have not been distinguished to date. Moreover, there is limited information on the study of the difference in pharmacological activity between RF and GF. Apocynin In this study, a rat model of bile duct ligation (BDL)-induced cholestasis was used to compare the differences in their effects. RF was found to have better results than GF in addressing toxic bile acids (BAs) accumulation and related pathological conditions caused by BDL. The underlying mechanism may be related to the interventions of gut microbiota. The results of the present study suggest that the better detoxifying effect of RF than GF may be indirectly exerted through the regulation of gut microbiota and thus the improvement of BAs metabolism.Daidzein (D1) has been proved to be of great benefit to human health. More and more attention was paid to the metabolic process of D1. Most studies focused on the metabolites of D1 and analogs were determined through the excretion of animals and humans by traditional HPLC-MS, while their in situ distribution and metabolism in organs in vivo has not been reported. In our group, novel daidzein sulfonate derivatives were synthesized and confirmed to have excellent pharmaceutical properties. They exhibited good anti-inflammatory, inhibitory activities on human vascular smooth muscle cell proliferation and other bioactivities. Compared with traditional analytical methods, matrix-assisted laser desorption ionization time-of-flight mass spectrometry imaging (MALDI-TOF MSI) can directly analyze the distribution of compounds in tissues and organs. In this study, we investigate the in situ distribution and metabolism of D1 and its derivatives (DD2, DD3) in the organs of mice based on MALDI-TOF MSI for the first time. Tcological studies and the clinical-use research of these compounds.Macleaya cordata extract (MCE) is widely used for its diverse pharmacological actions and beneficial effects on farm animals. Modern pharmacological studies have shown that it has anti-inflammatory, anti-cancer, and anti-bacterial activities, and is gradually becoming a long-term additive veterinary drug used to improve animal intestinal health and growth performance. Although some evidence points to the DNA mutagenic potential of sanguinarine (SAN), a major component of MCE, there is a lack of sufficient basic toxicological information on the oral route, posing a potential safety risk for human consumption of food of animal origin. In this study, we assessed the acute oral toxicity, repeated 90-day oral toxicity and 180-day chronic toxicity of MCE in rats and mice and re-evaluated the genotoxicity of MCE using a standard combined in vivo and ex vivo assay. In the oral acute toxicity test, the LD50 for MCE in rats and mice was 1,564.55 mg/kg (95% confidence interval 1,386.97-1,764.95 mg/kg) and 1,024.33 mg/kg (95% confidence interval 964.27-1,087.30 mg/kg), respectively. The dose range tested had no significant effect on hematology, clinical chemistry, and histopathological findings in rodents in the long-term toxicity assessment. The results of the bacterial reverse mutation, sperm abnormality and micronucleus test showed negative results and lack of mutagenicity and teratogenicity; the results of the rat teratogenicity test showed no significant reproductive or embryotoxicity. The results indicate that MCE was safe in the dose range tested in this preclinical safety assessment. This study provides data to support the further development of maximum residue limits (MRLs) for MCE.The prevalence of asthma is gradually increasing, and endangers human health. Many therapeutic agents have been developed to address this concern. Cinnamomum cassia (L.) J.Presl is a traditional herbal remedy in China, Japan, and Korea and used mainly to control common cold, cough, pneumonitis and fever in Donguibogam, a medical encyclopedia of Korea. Therefore, we investigated whether C. cassia (L.) J.Presl extract (CCE) confers protective effects on asthma model induced by ovalbumin (OVA). The animals were received intraperitoneal administration of OVA on day 1 and 14, and then subjected to OVA inhalation from day 21-23. They were orally treated CCE (30 and 100 mg/kg) from day 18-23. CCE administration decreased allergic responses, including airway hyperresponsiveness, eosinophilia, inflammatory cytokine production, and immunoglobulin E in OVA-exposed mice, along with the decline in inflammatory cell count and mucus secretion in respiratory tract. Additionally, CCE suppressed MAPK phosphorylation and MMP-9 expression in OVA-exposed mice. Overall, CCE treatment attenuated allergic responses induced by OVA exposure, which may be connected to the suppression of MAPK phosphorylation.Paeonia suffruticosa (Moutan) is a traditional medicinal plant in China. Its seed coat is rich in resveratrol oligomer, especially suffruticosol B (SB). Previous studies had shown that the seed coat extracts of Paeonia suffruticosa (PSCE) had good cholinesterase inhibitory activity and neuroprotective effect, but the effective dose range was unknown, and the pharmacodynamic components and molecular mechanism of PSCE had not been discussed. The current study aimed to screen the pharmacodynamic components in PSCE and investigate the improvement effect of PSCE and the selected SB on scopolamine-induced cognitive dysfunction in mice and its mechanism. The results of high-throughput sequencing and bioinformatics analysis showed that suffruticosol B (SB) and trans-gnetin H (GH) might be the main active components of PSCE; PSCE might improve cognitive dysfunction through p53, HIF-1, MAPK, and PI3K-Akt signaling pathways, while SB and GH might improve cognitive dysfunction through HIF-1 signaling pathway. SB and GH hn of Moutan bark.Objective Polyethylene glycol recombinant human growth hormone (PEG-rhGH, Jintrolong®) is the first long-acting rhGH preparation that is approved to treat children with growth hormone deficiency (GHD) in China. Clinical experience with dose selections of PEG-rhGH is scarce. The present study compared the efficacy and safety of a lower dose to increase dosing regimens of PEG-rhGH treatment. Methods A multicenter, randomized, open-label, dose-comparison clinical study was conducted to compare the improvements in the height standard deviation score (Ht SDS), height velocity (HV), insulin-like growth factor-1 (IGF-1) SDS, and safety profiles of children with GHD who are treated with 0.2 mg/kg/week of PEG-rhGH dose or 0.14 mg/kg/week for 26 weeks. Results Ht SDS, HV, and IGF-1 SDS increased significantly after PEG-rhGH treatment in the two dose groups (p less then 0.05). The improvements of Ht SDS, HV, and IGF-1 SDS were more significant in the high-dose group than in the low-dose group (p less then 0.05). Ht SDS improvement in low-dose group was not non-inferiority to that in the high-dose group (p = 0.