- Research Article
- 10.1002/cmdc.202501029
An Internal Sulfur-Lone Pair Interaction Enabled the Discovery of Potent and Sub-Family Selective PKMYT1 Inhibitors.
- Mar 27, 2026
- ChemMedChem
- Yazhou Wang + 9 more +9
Publications from 2021 to 2026
Showing 10 of 185 papers
An Internal Sulfur-Lone Pair Interaction Enabled the Discovery of Potent and Sub-Family Selective PKMYT1 Inhibitors.
Clinical study on improving lung function in children after Mycoplasma pneumoniae pneumonia (MMP) via traditional Chinese medicine meridian massage.
Pneumonia impairs lung development, structure, and function during children’s critical growth stages. Traditional Chinese Medicine (TCM) boosts constitution, yet the efficacy of TCM meridian massage for post-pneumonia lung function improvement remains unclear. This study investigates its role as an adjuvant therapy for lung function recovery in post-discharge children with Mycoplasma pneumoniae pneumonia (MMP). Sixty-four MMP children with abnormal lung function at discharge (Jan 2023–Dec 2024) were randomized to treatment (n = 32) or control (n = 32) groups. The treatment group received meridian massage (3 sessions/week for 1 month) with three acupoint categories: lung-ventilating/cough-relieving (Feishu BL13, Danzhong CV17), phlegm-resolving (Tiantu CV22, Fenglong ST40), and spleen-lung-nourishing (Zusanli ST36, Pishu BL20). The control group only underwent lung function re-evaluation 1 month post-discharge. Data were analyzed via Prism® 10.0. Twenty-five treatment and 31 control patients completed follow-up finally. Baseline mixed-type lung function abnormalities and key parameters (e.g., FVC, FEV1) were comparable (p ≥ 0.05). At 1month post-discharge, recovery rates were 88.8% (22/25) vs. 41.9% (13/31) in the two groups, respectively. The treatment group showed superior improvements in large (FVC, FEV1, PEF) and small (MEF25, MEF50, MEF75, MMEF) airway parameters (p < 0.05), with no difference in FEV1/FVC (p > 0.05). Meridian massage safely and effectively promotes lung function recovery in post-MMP children through anti-inflammatory immune modulation and meridian-zang-fu regulation. It provides a novel therapeutic option for post-pneumonia lung dysfunction and evidence-based support for preventing long-term pulmonary sequelae.
Read moreBifidobacterium Infantis Promotes FOSL1-Mediated Transcriptional Repression of VDR to Accelerate Autoimmune Pancreatitis Progression Through Activation of Oxidative Stress.
Long-term regulatory effects of high-fiber low-fat diet on gut microbiota diversity and inflammatory marker expression in DSS-induced recurrent colitis in mice.
To evaluate the long-term regulatory effects of high-fiber low-fat (HFLF) diet on gut microbiota diversity and inflammation/barrier-related markers in DSS-induced recurrent colitismice. A recurrent DSS model was established through multiple cycles of DSS administration. Mice were randomly assigned to HFLF diet vs. control/standard chow±positive control groups. Multi-timepoint sampling was conducted throughout the study. 16S rRNA sequencing, SCFA quantification, and qPCR/ELISA/immunohistochemistry/Western blot analyses were performed. HFLF diet significantly improved clinical phenotype, increased gut microbiota diversity, promoted beneficial bacterial genera, enhanced SCFA production, and modulated inflammation/barrier indicators throughout the recurrence-remission cycles. HFLF diet provides sustained protection during recurrence-remission processes through microbiota-SCFA-inflammation axis modulation, offering potential translational applications for IBD management.
Read moreLactylation Plays a Novel Role in the Tumor Microenvironment and its Prognostic Implications for Breast Cancer.
This study aims to develop a predictive signature based on lactylation to complement existing staging systems and improve prognostic accuracy in clinical settings. A database of lactylation-associated genes was obtained from The Cancer Genome Atlas (TCGA). Cox and LASSO regression analyses were used to identify a risk signature. Differential expression and enrichment analyses were performed to explore functional differences between these groups, and the influence of lactylation-associated genes on the tumor immune microenvironment and chemotherapy sensitivity was evaluated. After screening for lactylationassociated genes highly expressed and prognostically relevant in BC, in vitro assays were conducted to examine the role of these genes in tumor proliferation and metastasis. We identified six lactylation-associated genes, including SH3GL1, XRCC4, PCMT1, DECR1, ALDH1A1, and RPL14. XRCC4 was highly expressed and identified as a significant factor affecting patients' overall survival in BC. Patients in the high-risk groups exhibited poorer prognoses compared to those in the low-risk groups. Tumor mutation burden, chemotherapeutic sensitivity, and immune infiltration differed significantly between the two groups. Our results propose XRCC4 as a potential therapeutic target in BC. Although the current evidence is constrained, we are actively expanding the sample size and will develop dedicated validation cohorts to corroborate the lactylation-related findings. Our findings highlight the potential of lactylation-associated genes, particularly XRCC4, in BC progression and clinical treatment strategies. The development of an XRCC4 inhibitor may be eligible for patent protection and could potentially serve as a novel therapeutic option for BC.
Read moreHepatic GPR110 contributes to sex disparity in the development of MASH through oestrogen receptor α-dependent signalling.
Metabolic dysfunction-associated steatohepatitis (MASH) is an important phase in the progression of metabolic dysfunction-associated steatotic liver disease to end-stage liver diseases, posing an increasing threat to public health worldwide with limited treatment options. Here we show that GPR110 is a liver-selective G-protein-coupled receptor closely associated with MASH in a sex-specific manner. Hepatocyte-specific Gpr110 knockout protects against MASH in female, but not male mice. The GPR110 variant rs937057 T > C is associated with a higher prevalence of metabolic dysfunction-associated steatotic liver disease in women. The improved liver phenotypes in female mice are abrogated by knocking down the expression of hepatic oestrogen receptor alpha (Esr1). Mechanistically, GPR110 couples to Gαs and activates protein kinase A, thereby inducing phosphorylation of NFAT2, which inhibits its nuclear translocation and transcriptional activity, leading to suppressed Esr1 transcription in hepatocytes. Taken together, these results demonstrate a sex-specific role of GPR110 in MASH by regulating hepatic oestrogen sensitivity, suggesting inhibition of GPR110 as a potential sex-specific therapy for MASH.
Read moreIn vitro characterisation of the SETD8-MCM7 axis in driving gastric cancer progression and epithelial-mesenchymal transition.
SETD8, a histone methyltransferase catalyzing H4K20 monomethylation (H4K20me1), is crucial for epigenetic regulation, yet its role in gastric cancer (GC) progression remains unclear. This study investigated whether SETD8 promotes epithelial-mesenchymal transition (EMT) and GC progression by regulating MCM7. expression and clinical relevance of SETD8 and MCM7 were analyzed using TCGA and GEO databases, and validated in GC cell lines and normal gastric epithelial cells. SETD8 knockdown and inhibitor UNC0379 were used to assess its functions. Proliferation, apoptosis, invasion, migration, EMT and stemness were evaluated by CCK-8, flow cytometry, Transwell, wound healing, immunofluorescence and sphere formation assays. ChIP-qPCR measured H4K20me1 enrichment and SETD8 binding at the MCM7 promoter. Rescue experiments were performed by overexpressing MCM7 in SETD8-knockdown cells. Supplementary single-cell and immunotherapy cohort analyses were also conducted. SETD8 and MCM7 were overexpressed in GC tissues and cell lines, correlating with advanced stage and poor prognosis. SETD8 knockdown suppressed proliferation, migration, invasion and stemness, induced apoptosis, and reversed EMT (downregulating Snail, N-cadherin, Vimentin; upregulating E-cadherin). Mechanistically, SETD8 knockdown reduced global H4K20me1 and MCM7 expression. H4K20me1 was enriched at the MCM7 promoter, while direct SETD8 binding was not detected, suggesting a non-canonical regulatory mode. MCM7 overexpression rescued the malignant phenotypes inhibited by SETD8 knockdown. SETD8 promotes EMT and GC progression primarily by upregulating MCM7 expression, likely via an H4K20me1-dependent epigenetic mechanism. MCM7 acts as a key downstream effector. The SETD8/MCM7 axis represents a novel driver and potential therapeutic target in GC.
Read moreICBCCR: A new path for harmonization and clinical verification on a multi-center real-world cohort of 278703.
Comparative Genomic and Resistance Analysis of ST859-KL19 and ST11 Carbapenem-Resistant Klebsiella pneumoniae with Diverse Capsular Serotypes.
Background: In China, Carbapenem-resistant Klebsiella pneumoniae (CRKP) is dominated by sequence type 11 (ST11) harbouring KPC-2, with KL64 displacing KL47 and KL25 emerging. ST859 (ST11 variant) has caused outbreaks, but its epidemiology is unclear. Materials and Methods: A total of 99 non-duplicate CRKP isolates were collected from June to December 2024. Antimicrobial susceptibility was determined by broth microdilution. The genomic sequences of the strains were obtained using next-generation sequencing technology. Resistance genes, virulence loci, and plasmid replicons were identified with Kleborate, Abricate, and MOB-suite, respectively. Results: ST11 accounted for 63.64% and ST859 for 15.15%. All ST859 were KL19, while ST11 were mainly KL25 (60.32%) and KL64 (26.98%). 76.8% co-harbored carbapenemase and extended-spectrum beta-lactamase (ESBL) genes, with KPC-2 and CTX-M-65 being the predominant types. Susceptibility rates were 100% to tigecycline, and 78.79% to ceftazidime/avibactam. ST859 CRKP isolates exhibited higher phenotypic resistance to tetracycline and colistin than ST11 CRKP isolates (p < 0.05), and carrying LAP-2, QnrS1, QnrS10, and tet(A) more frequently. ST11-KL25 showed higher resistance to amikacin, gentamicin, and chloramphenicol, with increased prevalence of CTX-M-65, TEM-1, rmtB, catA2, and dfrA14 compared to ST11-KL64 (p < 0.05). IncF was the most prevalent replicon and both ST859 and ST11 CRKP carry conjugative resistance plasmids, and the host range is predominantly Enterobacterales. Conclusions: ST859-KL19 ranks second to ST11 with higher resistance to tetracyclines and colistin. ST11-KL25 may have already displaced ST11-KL64 as the predominant capsular type in Shanghai, with distinct resistance profiles between KL variants. Long-term, multicenter surveillance is urgently needed to delineate the evolutionary trajectory and clinical impact of these emerging clones.
Read moreVaginal microecological characterization of women of childbearing age at different altitudes: a multi-omics exploration.
Reproductive tract diseases have become a serious public health problem threatening women's health. Vaginal microecological balance in women of childbearing age is essential for the maintenance of reproductive health, and different environmental conditions may have an impact on the composition of the vaginal microbial community and its metabolites. This is particularly true at different altitudes. Changes in environmental factors with increasing altitude may lead to vaginal microecological imbalances that increase the risk of reproductive tract infections and other gynecological diseases. Therefore, it is important to study vaginal microbial communities and metabolites in women of reproductive age at different altitudes. In this study, 16S rDNA sequencing and non-targeted metabolomics of vaginal secretions from healthy women of childbearing age at different altitudes were performed to analyze the composition of vaginal flora and metabolites of normal women of childbearing age at different altitudes, with the aim of providing new ideas for the prevention, diagnosis and treatment of diseases caused by vaginal microecological imbalance in women of childbearing age. General clinical data and vaginal secretions of a total of 60 healthy women of childbearing age were collected from four regions, namely, the low altitude group (8m above sea level), the middle altitude group (2,000m above sea level), the middle-high altitude group (2,800m above sea level), and the same as the high altitude group (4,000m above sea level), and were analyzed by sequencing of the V3-V4 region of the 16S rDNA and untargeted metabolomics sequencing. 16S rDNA sequencing can be used to comprehensively analyze the reproductive tract flora of women of childbearing age at different altitudes; the vaginal flora of normal women of childbearing age is dominated by the phylum Thick-walled Bacteria and Lactobacillus spp. The α-diversity of the vaginal flora increases with the elevation of altitude but there is no statistically significant difference; with the elevation of altitude, the percentage of the specialized anaerobic flora in the vagina is higher among the genera of Porphyromonas, Anaerobic Coccidia, and Peptostreptococcus. anaerobic increased in the vagina. Non-targeted metabolomics analysis revealed that there were differences in vaginal metabolites among women of childbearing age at different altitudes, with energy metabolism and nutrient metabolism being the main ones. Analysis of the four groups of differential metabolites showed that Ectoine, Thiamine, Taurine, D-glucono-1,5-lactone, 2-oxoadipic acid and N-Acetylserotonin differed significantly in the distribution of the four groups and were significantly elevated in the vaginas of women at high altitude. With the increase of altitude, the diversity of vaginal flora of women of childbearing age increased, and at the same time, there were differences in vaginal metabolites at different altitudes, which were hypothesized to be related to factors such as hypoxia, high altitude, and differences in hygiene habits in the plateau. The relationship between this and high altitude and reproductive tract diseases will be further explored in the future to provide theoretical guidance for improving the reproductive health of women of childbearing age in highland areas.
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