Genetic variation in human populations can result in the misfolding and aggregation of proteins, giving rise to systemic and neurodegenerative diseases that require management by proteostasis. Here, we define the role of GRP94, the endoplasmic reticulum Hsp90 chaperone paralog, in managing alpha-1-antitrypsin deficiency on a residue-by-residue basis using Gaussian process regression-based machine learning to profile the spatial covariance relationships that dictate protein folding arising from sequence variants in the population. Covariance analysis suggests a role for the ATPase activity of GRP94 in controlling the N- to C-terminal cooperative folding of alpha-1-antitrypsin responsible for the correction of liver aggregation and lung-disease phenotypes of alpha-1-antitrypsin deficiency. Gaussian process-based spatial covariance profiling provides a standard model built on covariant principles to evaluate the role of proteostasis components in guiding information flow from genome to proteome in response to genetic variation, potentially allowing us to intervene in the onset and progression of complex multi-system human diseases.
Severe burns may cause intense stress and persistent inflammation, resulting in intestinal mucosal barrier damage. In this study, we evaluated the effects of glutamine (Gln) on intestinal mucus barrier after burn injury. The results showed that glutamine could improve intestinal mucosal blood flow (IMBF), decrease diamine oxidase (DAO) activity, and reduce intestine damage, thereby alleviate intestinal mucous permeability. Severe burn was associated with subsequent decrease in mucus thickness, levels of hexose, sialic acid, and protein. Glutamine administration might partially reverse these changes. Additional experiments showed that supplementation with glutamine could markedly raise the content of glutamine, glutathione (GSH), and ATP in intestinal tissue. Moreover, the levels of mRNA and protein expression of MUC2, intestinal trefoil factor (ITF) were increased remarkably, but contrary to the trend of GRP-78, CHOP. These results suggest that glutamine can improve tissue perfusion and increase energy synthesis in enterocytes, decrease endoplasmic reticulum stress (ERS) and improve mucin and ITF synthesis. Finally, lessen intestinal mucus barrier damage after burn injury.
Pan-bromodomain and extra terminal (Pan-BET) inhibitors show profound efficacy but exhibit pharmacology-driven toxicities in clinical trials. The development of domain-selective BET inhibitors to separate efficacy and toxicity is urgently needed. Herein, we report a series of furo[3,2-c]pyridin-4(5H)-one derivatives as novel BD2-selective BET inhibitors. The representative compound 8l (XY153) potently bound to BRD4 BD2 with an half-maximum inhibitory concentration (IC50) value of 0.79 nM and displayed 354-fold selectivity over BRD4 BD1. Besides, 8l exhibited 6-fold BRD4 BD2 domain selectivity over other BET BD2 domains. Compound 8l displayed potent antiproliferative activity against multiple tumor cell lines, especially MV4-11 (IC50 = 0.55 nM), while showing weak cytotoxicity against the normal lung fibroblast cell line. It highlights the safety profile of this series of BD2 inhibitors. 8l also demonstrated good metabolic stability in vitro. These data indicate that 8l may serve as a new and valuable lead compound for the development of potential therapeutics against acute myeloid leukemia (AML).
Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. Although fish oil has been used as an immunonutritional preparations for the treatment of sepsis patients, there is still controversy as to whether it is beneficial to them. We systematically reviewed published clinical trial data to evaluate the effectiveness of fish oil-containing nutrition supplementation in sepsis patients.A systematic search was undertaken in PubMed, Embase, Chinese Biomedicine Database, the Cochrane Library and the China Knowledge Resource Integrated Database to obtain clinical controlled trails. RCTs on nutrition therapy containing fish oil among adult sepsis patients were selected for analysis in comparison with routine therapy.Twenty-five published trials were included in the meta-analysis. Fish oil-containing nutrition supplementation reduced the mortality compared with the control group (relative risk (RR) 0.74, I2 = 0%). Fish oil also shortened the ICU stay (MD -3.57 days; 95% CI -4.54, -2.59; p<0.00001; I2 = 76%), hospital stay (MD -9.92 days; 95% CI -15.37, -4.46; p = 0.0004; I2 = 91%) and the duration of mechanical ventilation support (MD -2.26; 95% CI -4.27, -0.26; p = 0.03; I2 = 83%). A subgroup analysis based on the route of administration revealed that parenteral administration of fish oil could reduce mortality in septic patients (RR =0.68, I2 = 0%), but no significant difference in mortality was observed in the fish oil group administered by enteral route (RR = 0.80, I2 = 0%). No statistically significant publication biases were detected for the above clinical endpoints (p>0.05).Parenteral nutrition containing fish oil could significantly decrease mortality in sepsis patients while enteral administration could not. Fish oil-containing nutrition supplementation.
The number of edge villages in the mountain areas in south of Hunan province is large,and the amount of the population is huge,the work is great and urgent.But it is short of norm policy to guide the moving.The present situation of moving makes us feel concerned.It is quite urgent to establish the moving policy.The future policy should express fair,voluntary,compulsive,systematic,appropriate and prospective.The main system is a series of measures of national territory,forestry,domestic affairs,education,and medical treatments.It's quite necessary for officials to make out power and obligations,and so on.
Glutamine is an important amino acid that plays a crucial role in nutritional therapy for patients with burns, but its effects on post-burn metabolism and the underlying mechanisms are unclear. In this study,
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