Discovering Uncharted Binding Pockets on E3 Ligases Leads to the Identification of FBW7 Allosteric Modulators.

E3 ligases are key regulators of the ubiquitin-proteasome system (UPS) and have emerged as attractive drug target candidates for precise therapeutic intervention. Additionally, their ligands are extremely valuable as handles for Targeted Protein Degradation (TPD). However, only a limited number of E3 ligases have been targeted with small molecules.

Exploring the interactions of gut microbiome and metabolites in polycystic ovary syndrome: a review.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine metabolic disorder significantly impacting female health. While its etiology remains incompletely understood, emerging evidence highlights the gut microbiome as a key modulator, affecting not only the gut but also physiology beyond it. Many studies have been committed to exploring the role played by the gut microbiome and have discovered that gut microbiome is commonly dysregulated in PCOS patients.

Identification and catalytic mechanisms of key enzymes in the biosynthesis of asperosaponin VI from Dipsacusasperoides.

Asperosaponin Ⅵ is the major active compound in the traditional Chinese medcinal herb Dipsacus asperoides (Xu-Duan), exhibits diverse pharmacological activities, including treating osteoporosis, anti-inflammatory effects, and neuroprotective properties. However, due to limited natural sources and challenges in chemical extraction, heterologous biosynthesis offers a strategy for efficient production of asperosaponin Ⅵ and its intermediates and derivatives. Despite its potential, the biosynthetic pathway of asperosaponin Ⅵ remains poorly understood, primarily due to its complex multi-step reaction network.

Localized Amorphization Engineering in Ultrathin MnRuO Nanosheets for Robust Hydrogen Evolution Reaction.

Although ultrathin noble-metal nanosheets have arisen as promising high-efficient electrocatalysts, their catalytic behaviors are still far to be satisfied due to lacking of additional active sites on the basal plane of 2D structure. Herein, partially amorphization strategy is adopted to construct localized amorphous area in ultrathin RuO nanosheets by doping Mn. This strategy endows the MnRuO catalyst enriched basal plane active sites, channels for mass transfer, amorphous/crystalline interfaces, and thus a superior HER activity.

Push Forward Clinical Management of Hematological Toxicity due to Lenalidomide Overexposure: Model-Informed Precision Dosing for Chinese Population With Renal Insufficiency.

Dose-dependent hematological toxicity of lenalidomide has been reported previously, and thus, there is a clinical need for dose individualization to manage toxicities. The objectives of this study were to explore optimal individualized dosing regimens for Chinese B-cell malignancies patients with varying degrees of renal function, and to push forward clinical management of hematological toxicity due to lenalidomide overexposure. A total of 164 plasma concentrations of lenalidomide were obtained from 97 Chinese patients with multiple myeloma (MM) and B-cell non-Hodgkin lymphoma (NHL) from a multicenter prospective study.

Telomere-to-telomere genome assembly and 3D chromatin architecture of insight into evolution and genetic basis of triterpenoid saponin biosynthesis.

is renowned for its medicinal properties, particularly due to its triterpenoid saponins, such as asiaticoside and madecassoside, which are in excess demand for the cosmetic industry. However, comprehensive genomic resources for this species are lacking, which impedes the understanding of its biosynthetic pathways. Here, we report a telomere-to-telomere (T2T) genome.

O-methylation modifications in the biosynthetic pathway of dibenzocyclooctadiene lignans.

Schisandra chinensis, a well-known traditional Chinese herb used for hepatitis treatment, contains dibenzocyclooctadiene lignans as its primary active compounds, which undergo extensive multi-site O-methylation. However, O-methyltransferases (OMT) involved in this process have not been previously reported. This study employed transcriptomic analysis of S.

Pt(OH) Coordination Engineering of Bifunctional Pt/NiFe LDH-O Catalyst for Robust Water Splitting.

Modulating the coordination environment of metal active sites and adjacent atoms significantly enhances the catalytic activity of heterogeneous catalysts owing to the local synergistic effect between metal sites and supports. While layered double hydroxide (LDH)-supported Pt catalysts exhibit complementary advantages and exceptional performance in overall water splitting (OWS), the absence of a robust coordination structure between Pt and LDH constrains their activity and stability. Herein, we report a coordination engineering strategy to alter the coordination structure of Pt on the surface of NiFe LDH using atomic layer deposition (ALD) for OWS.

Endothelial TDP-43 depletion disrupts core blood-brain barrier pathways in neurodegeneration.

Endothelial cells (ECs) help maintain the blood-brain barrier but deteriorate in many neurodegenerative disorders. Here we show, using a specialized method to isolate EC and microglial nuclei from postmortem human cortex (92 donors, 50 male and 42 female, aged 20-98 years), that intranuclear cellular indexing of transcriptomes and epitopes enables simultaneous profiling of nuclear proteins and RNA transcripts at a single-nucleus resolution. We identify a disease-associated subset of capillary ECs in Alzheimer's disease, amyotrophic lateral sclerosis and frontotemporal degeneration.

Quantitative Comparison of Glucagon-Like Peptide-1 Receptor Agonists on Weight Loss in Adults: A Systematic Review and Model-Based Meta-Analysis.

The objective of this study is to quantitatively compare the weight loss effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in adult patients with no diabetes and type 2 diabetes (T2D). PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Embase have been used as data sources from database inception to January 6, 2024. A total of 137 trials, encompassing 310 treatment arms, 17 GLP-1RAs, and 56,683 patients, were included in the analysis.

Nimodipine ameliorates subarachnoid hemorrhage-induced neuroinflammation and injury by protecting mitochondrial function and regulating autophagy.

Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke, and the neuroprotective effects of nimodipine following SAH have been well-documented. Sirtuin 3 (SIRT3), a mitochondrial nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, plays a significant role in mitigating oxidative stress in various neurodegenerative conditions. However, the role of SIRT3 in the neuroprotective mechanisms of nimodipine after SAH remains unclear.

Backbone assignment of the N-terminal domain of the A subunit of the Bacillus cereus GerI germinant receptor.

The nutrient germinant receptors (GRs) in spores of Bacillus species consist of a cluster of three proteins- designated A, B, and C subunits- that play a critical role in initiating the germination of dormant spores in response to specific nutrient molecules. The Bacillus cereus GerI GR is essential for inosine-induced germination; however, the roles of the individual subunits and the mechanism by which germinant binding activates GR function remain unclear. In this study, we report the backbone chemical shift assignments of the N-terminal domain (NTD) of the A subunit of GerI (GerIA).

Impact of Methotrexate and 7-Hydroxymethotrexate Exposure on Renal Toxicity in Pediatric Non-Hodgkin Lymphoma.

Background: 7-Hydroxymethotrexate (7-OHMTX) is the main metabolite in plasma following high-dose MTX (HD-MTX), which may result in activity and toxicity of the MTX. Moreover, 7-OHMTX could produce crystalline-like deposits within the renal tubules under acidic conditions or induce renal inflammation, oxidative stress, and cell apoptosis through various signaling pathways, ultimately leading to kidney damage. The objectives of this study were thus to explore the exposure-safety relationship of two compounds and search the most reliable marker for predicting HDMTX nephrotoxicity.

A improved group quantum key distribution protocol with multi-party collaboration.

The rapid advancement of quantum key distribution technology in recent years has spurred significant innovation within the field. Nevertheless, a crucial yet frequently underexplored challenge involves the comprehensive evaluation of security quantum state modulation. To address this issue, we propose a novel framework for quantum group key distribution.

Research progress on gene mutations and drug resistance in leukemia.

Leukemia is a type of blood cancer characterized by the uncontrolled growth of abnormal cells in the bone marrow, which replace normal blood cells and disrupt normal blood cell function. Timely and personalized interventions are crucial for disease management and improving survival rates. However, many patients experience relapse following conventional chemotherapy, and increasing treatment intensity often fails to improve outcomes due to mutated gene-induced drug resistance in leukemia cells.

Development, validation, and clinical application of LC-MS/MS method for simultaneous determination of ibrutinib, zanubrutinib, orelabrutinib, acalabrutinib, and their active metabolites in patients with B-cell lymphoma.

Bruton's tyrosine kinase inhibitors (BTKis) exhibit significant interindividual pharmacokinetics, making therapeutic drug monitoring (TDM) a promising approach for personalized therapy. However, simultaneous quantification of multiple BTKis poses technical challenges. A unified protocol for BTKis detection would be clinically desirable.

Genome-wide profiling of WRKY genes involved in flavonoid biosynthesis in .

The transcription factors of WRKY genes play essential roles in plant growth, stress responses, and metabolite biosynthesis. , a traditional Chinese herb, is abundant in flavonoids and has been used for centuries to treat cardiovascular and cerebrovascular diseases. However, the WRKY transcription factors that regulate flavonoid biosynthesis in remain unknown.

Integrated metabolome and transcriptome analyses reveal the molecular mechanism underlying dynamic metabolic processes during taproot development of Panax notoginseng.

Background: Panax notoginseng (Burk) F. H. Chen is one of the most famous Chinese traditional medicinal plants.

Biosynthetic pathway of prescription cucurbitacin IIa and high-level production of key triterpenoid intermediates in engineered yeast and tobacco.

Cucurbitacin IIa is a triterpenoid isolated exclusively from Hemsleya plants and a non-steroidal anti-inflammatory drug that functions as the main ingredient of prescription Hemslecin capsules and tablets in China. Synthetic biology provides new strategies for production of such valuable cucurbitacins at a large scale; however, the biosynthetic pathway of cucurbitacin IIa has been unknown, and the heterologous production of cucurbitacins in galactose medium has been expensive and low yielding. In this study, we characterized the functions of genes encoding two squalene epoxidases (HcSE1-2), six oxidosqualene cyclases (HcOSC1-6), two CYP450s (HcCYP87D20 and HcCYP81Q59), and an acyltransferase (HcAT1) in cucurbitacin IIa biosynthesis by heterologous expression in Saccharomyces cerevisiae and Nicotiana benthamiana.

Biosynthetic pathway of prescription bergenin from and .

Bergenin is a typical carbon glycoside and the primary active ingredient in antitussive drugs widely prescribed for central cough inhibition in China. The bergenin extraction industry relies on the medicinal plant species and as their resources. However, the bergenin biosynthetic pathway in plants remains elusive.

Integrated metabolome and transcriptome analysis reveals the regulatory mechanism of low nitrogen-driven biosynthesis of saponins and flavonoids in Panax notoginseng.

Background: Nitrogen (N) is an important macronutrient involved in the biosynthesis of primary and secondary metabolites in plants. However, the metabolic regulatory mechanism of low-N-induced triterpenoid saponin and flavonoid accumulation in rhizomatous medicinal Panax notoginseng (Burk.) F.

Controlled attenuation parameters to assess liver steatosis in obese patients with polycystic ovary syndrome.

Objectives: This study was performed to investigate the changes and influencing factors of liver controlled attenuation parameter (CAP) in obese patients with polycystic ovary syndrome (PCOS), and to determine the prevalence and risk factors of nonalcoholic fatty liver disease (NAFLD) in PCOS patients with obesity.

Methods: Forty-one PCOS patients with obesity and twenty age- and body mass index (BMI)-matched control women without PCOS were enrolled in this study. General data, body composition, biochemical parameters, sex hormones, and liver CAP in the two groups were collected and compared.