MicroRNA-124a/Sirtuin 1 pathway inhibits autophagy to promote hepatocyte apoptosis in acute-on-chronic liver failure.

Background: The roles of microRNAs in the regulation of autophagy and apoptosis in hepatic cells suggest that they may serve as novel biomarkers or therapeutic targets for various liver injuries. In this study, we aim to analyze whether miR-124a regulates autophagy and apoptosis in hepatic cells, particularly in acute-on-chronic liver failure (ACLF).

Materials And Methods: The plasma and liver tissues from the healthy control (HC) and ACLF patients were included.

Analysis of genotypic distribution and rare variants of patients with α/β-thalassemia screened in one hospital in Beijing, China.

Objective: Thalassemia is among the most common inherited diseases worldwide. We aimed to analyze the genotype and frequency distribution of thalassemia in a general hospital in Beijing and provide a reference for genetic counseling and prenatal diagnosis.

Methods: A total of 3196 cases of thalassemia screened at Peking Union Medical College Hospital (PUMCH) between January 2018 and January 2022 were collected.

Development of rapid evaluation scale for pericardiectomy of tuberculous constrictive pericarditis by 12-lead electrocardiogram.

Aim: We developed a rapid evaluation scale for pericardiectomy through a 12-lead electrocardiogram (ECG), in order to improve the diagnostic accuracy of pericardiectomy of tuberculous constrictive pericarditis.

Method: In this study, 262 patients with tuberculous constrictive pericarditis (102 patients) and non-tuberculous constrictive pericarditis (160 patients) were selected by convenience sampling method as participants in Hangzhou Red Corss Hospital from January 2018 to April 2023. The expert validity analysis was carried out by cross-sectional investigation combined with the results of the previous expert questionnaire to establish 12-lead ECG-based the rapid evaluate scale for pericardiectomy of tuberculous constrictive pericarditis.

Discovery of a Potent and Selective GSPT1 Molecular Glue Degrader for the Treatment of Castration-Resistant Prostate Cancer.

The treatment of castration-resistant prostate cancer (CRPC) remains a significant challenge, necessitating the development of new and promising therapeutic strategies. Utilizing molecular glue to degrade previously intractable cancer drivers represents an emerging and promising therapeutic approach to cancer treatment. In this study, we developed a novel CRBN-interacting molecular glue, (XYD049), which exhibits potent and selective degradation of G1 to S phase transition 1 (GSPT1), a well-known untargetable cancer driver in diverse cancer cells.

Progressive Evolution of Flow and Heat Transfer Channels in Hot Dry Rock Stimulated by Liquid Nitrogen Cold Shock.

Hot dry rock (HDR) is a novel green, low-carbon energy. Its development requires the creation of fracture channels in deep thermal reservoirs. Traditional methods such as hydraulic fracturing have limited effectiveness in reservoir stimulation, so a method of liquid nitrogen cold shock was proposed.

Efficient Chemical Synthesis of Multi-Monoubiquitylated and Diubiquitylated Histones by the α-Halogen Ketone-Mediated Strategy.

The chemical synthesis of homogeneously ubiquitylated histones is a powerful approach to decipher histone ubiquitylation-dependent epigenetic regulation. Among the various methods, α-halogen ketone-mediated conjugation chemistry has recently been an attractive strategy to generate single-monoubiquitylated histones for biochemical and structural studies. Herein, we report the use of this strategy to prepare not only dual- and even triple-monoubiquitylated histones but also diubiquitin-modified histones.

Discovery of a Promising CBP/p300 Degrader XYD129 for the Treatment of Acute Myeloid Leukemia.

The epigenetic target CREB (cyclic-AMP responsive element binding protein) binding protein (CBP) and its homologue p300 were promising therapeutic targets for the treatment of acute myeloid leukemia (AML). Herein, we report the design, synthesis, and evaluation of a class of CBP/p300 PROTAC degraders based on our previously reported highly potent and selective CBP/p300 inhibitor . Among the compounds synthesized, (XYD129) demonstrated high potency and formed a ternary complex between CBP/p300 and CRBN (AlphaScreen).

Discovery of Highly Potent and Efficient CBP/p300 Degraders with Strong Antitumor Activity.

The transcriptional coactivator cAMP response element binding protein (CREB)-binding protein (CBP) and its homologue p300 have emerged as attractive therapeutic targets for human cancers such as acute myeloid leukemia (AML). Herein, we report the design, synthesis, and biological evaluation of a series of cereblon (CRBN)-recruiting CBP/p300 proteolysis targeting chimeras (PROTACs) based on the inhibitor CCS1477. The representative compounds (XYD190) and (XYD198) potently inhibited the growth of AML cells with low nanomolar IC values and effectively degraded CBP and p300 proteins in a concentration- and time-dependent manner.

Preclinical evaluation of the SARS-CoV-2 M inhibitor RAY1216 shows improved pharmacokinetics compared with nirmatrelvir.

Although vaccines are available for SARS-CoV-2, antiviral drugs such as nirmatrelvir are still needed, particularly for individuals in whom vaccines are less effective, such as the immunocompromised, to prevent severe COVID-19. Here we report an α-ketoamide-based peptidomimetic inhibitor of the SARS-CoV-2 main protease (M), designated RAY1216. Enzyme inhibition kinetic analysis shows that RAY1216 has an inhibition constant of 8.

Discovery of Novel Phenoxyaryl Pyridones as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with High Selectivity for the Second Bromodomain (BD2) to Potentially Treat Acute Myeloid Leukemia.

Bromodomain-selective BET inhibition has emerged as a promising strategy to improve the safety profiles of -BET inhibitors. Herein, we report the discovery of potent phenoxyaryl pyridones as highly BD2-selective BET inhibitors. Compound (IC = 2.

CTGF regulates mineralization in human mature chondrocyte by controlling Pit-1 and modulating ANK via the BMP/Smad signalling.

Objective: Connective tissue growth factor (CTGF) exhibits potent proliferative, differentiated, and mineralizing effects, and is believed to be contribute to cartilage mineralization in Osteoarthritis (OA). However, the underlying mechanism of chondrocyte mineralization induced by CTGF remains obscure. As a key regulator of mineral responses, type III phosphate transporter 1 (Pit-1) has been associated with the pathogenesis of articular mineralization.

Discovery of (R)-4-(8-methoxy-2-methyl-1-(1-phenylethy)-1H-imidazo[4,5-c]quinnolin-7-yl)-3,5-dimethylisoxazole as a potent and selective BET inhibitor for treatment of acute myeloid leukemia (AML) guided by FEP calculation.

The functions of the bromodomain and extra terminal (BET) family of proteins have been proved to be involved in various diseases, particularly the acute myeloid leukemia (AML). In this work, guided by free energy perturbation (FEP) calculation, a methyl group was selected to be attached to the 1H-imidazo[4,5-c]quinoline skeleton, and a series of congeneric compounds were synthesized. Among them, compound 10 demonstrated outstanding activity against BRD4 BD1 with an IC value of 1.

Discovery of a potent and selective CBP bromodomain inhibitor (Y08262) for treating acute myeloid leukemia.

The bromodomain of CREB (cyclic-AMP response element binding protein) binding protein (CBP) is an epigenetic "reader" and plays a key role in transcriptional regulation. CBP bromodomain is considered to be a promising therapeutic target for acute myeloid leukemia (AML). Herein, we report the discovery of a series of 1-(indolizin-3-yl)ethan-1-one derivatives as potent, and selective CBP bromodomain inhibitors focused on improving cellular potency.

Preparation of UFM1-Derived Probes through Highly Optimized Total Chemical Synthesis.

Ufmylation is involved in various cellular processes and associated with many human diseases. The understanding of this modification relies on the use of customized UFM1-derived probes for activity-based profiling of its related enzymes. This study presents a highly optimized total chemical synthesis for the generation of diverse UFM1-derived probes including UFM1-PA, Biotin-UFM1-PA and UFM1-AMC, in which a UFM1 C-terminal valine hydrazide was readily prepared by hydrazide-based ligation and used as a versatile handle for the installation of enzyme-sensitive warheads and fluorescent reporters.

An evaluation of the protective effects of chlorogenic acid on broiler chickens in a dextran sodium sulfate model: a preliminary investigation.

This study was conducted to investigate the protective effects of chlorogenic acid (CGA) on broilers subjected to dextran sodium sulfate (DSS)-induced intestinal damage. One hundred and forty-four 1-day-old male Arbor Acres broiler chicks were allocated into one of 3 groups with 6 replicates of eight birds each for a 21-d trial. The treatments included: 1) Control group: normal birds fed a basal diet; 2) DSS group: DSS-treated birds fed a basal diet; and 3) CGA group: DSS-treated birds fed a CGA-supplemented control diet.

Structural insights revealed by the cocrystal structure of CCS1477 in complex with CBP bromodomain.

Inhibition of the bromodomain of the CREB (cyclic-AMP response element-binding protein) binding protein (CBP) is a particularly promising new therapeutic approach for cancer. Benzimidazole derivatives CCS1477 and its analogues (8 and 9) are highly potent and selective CBP bromodomain inhibitors, with K values of 26.4, 37.

Integrated Bioinformatics Analysis Identifies a New Stemness Index-Related Survival Model for Prognostic Prediction in Lung Adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is one of the most lethal malignancies and is currently lacking in effective biomarkers to assist in diagnosis and therapy. The aim of this study is to investigate hub genes and develop a risk signature for predicting prognosis of LUAD patients.

Methods: RNA-sequencing data and relevant clinical data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database.

SERP1 reduces inchoate acute hepatic injury through regulation of endoplasmic reticulum stress via the GSK3β/β‑catenin/TCF/LEF signaling pathway.

The liver is a crucial digestive organ of humans and in charge of detoxification. Acute hepatic injury is an aggressive type of hepatic disease and its harmful effect cannot be ignored. The present study examined the role and mechanism of stress‑associated endoplasmic reticulum protein 1 (SERP1) in acute hepatic injury.

Discovery, optimization and evaluation of 1-(indolin-1-yl)ethan-1-ones as novel selective TRIM24/BRPF1 bromodomain inhibitors.

TRIM24 (tripartite motif-containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are epigenetics "readers" and potential therapeutic targets for cancer and other diseases. Here we describe the structure-guided design of 1-(indolin-1-yl)ethan-1-ones as novel TRIM24/BRPF1 bromodomain inhibitors. The representative compound 20l (Y08624) is a new TRIM24/BRPF1 dual inhibitor, with IC values of 0.

Structure-Based Discovery and Optimization of Furo[3,2-]pyridin-4(5)-one Derivatives as Potent and Second Bromodomain (BD2)-Selective Bromo and Extra Terminal Domain (BET) Inhibitors.

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-]pyridin-4(5)-one derivatives as novel BD2-selective BET inhibitors.

High Expression Levels of SLC38A1 Are Correlated with Poor Prognosis and Defective Immune Infiltration in Hepatocellular Carcinoma.

Solute Carrier Family 38 Member 1 (SLC38A1) is a principal transporter of glutamine and plays a crucial role in the transformation of neoplastic cells. However, the correlation between SLC38A1 expression, prognosis, and immune infiltration in hepatocellular carcinoma (HCC) has yet to be elucidated. We used two independent patient cohorts, namely, a Genome Atlas (TCGA) cohort and a Clinical Proteomic Tumor Analysis Consortium (CPTAC) cohort, to analyze the role of SLC38A1 in HCC at the mRNA and protein levels, respectively.

Osthole inhibits proliferation of kainic acid‑activated BV‑2 cells by modulating the Notch signaling pathway.

Epilepsy is a syndrome involving chronic recurrent transient brain dysfunction. Activation and proliferation of microglia serve important roles in epilepsy pathogenesis and may be targets for treatment. Although osthole, an active constituent isolated from Cnidium monnieri (L.

NLRP3 inflammasome and related cytokines reflect the immune status of patients with HBV-ACLF.

Background: The NLRP3 inflammasome has been suggested to play a crucial role in host antiviral defense, including against hepatitis B virus (HBV) infection. In the present study, we measured expression of NLRP3 and its related cytokines in patients with different stages of HBV-related acute-on-chronic liver failure (HBV-ACLF), a pattern of end-stage liver disease that occurs frequently in patients with chronic HBV (CHB) infection or HBV-related cirrhosis.

Methods: A total of 75 subjects including 30 HBV-ACLF patients, 30 CHB patients, and 15 healthy controls (HCs) were enrolled.

MicroRNA-124a contributes to glucocorticoid resistance in acute-on-chronic liver failure by negatively regulating glucocorticoid receptor alpha.

Introduction And Objectives: Glucocorticoid resistance frequently associating with inflammation, may severely compromise the therapeutic effect of glucocorticoids. In this study, we aimed to investigate the regulation of glucocorticoid resistance by microRNA-124a (miR-124a) in patients with acute-on-chronic liver failure (ACLF).

Materials And Methods: The miR-124a levels and glucocorticoid receptor alpha (GRα) expressions in peripheral blood monocytes and liver tissues were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), flow cytometry, and western blot analyses in the following four groups: healthy controls (HC), moderate chronic hepatitis B (CHB) patients, hepatitis B virus-related ACLF (HBV-ACLF) patients, and alcohol-induced ACLF (A-ACLF) patients.

Osthole inhibits proliferation and induces apoptosis in BV-2 microglia cells in kainic acid-induced epilepsy via modulating PI3K/AKt/mTOR signalling way.

Context: Osthole is a natural coumarin compound most frequently extracted from plants of the Apiaceae family such as Cnidium monnieri (L.) Cusson, Angelica pubescens Maxin.f.