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9 recordsLinked to original sources
PubMed2026

α-Ketoglutarate Promotes Ciprofloxacin Tolerance in Methicillin-Resistant Staphylococcus aureus via Glutamate-Mediated Metabolic Remodeling.

Methicillin-resistant Staphylococcus aureus (MRSA) is a globally significant pathogen causing severe infections. The chronicity and recurrence of its infection pose serious challenges to public health. In this study, we reported that intracellular accumulation of α-ketoglutarate (α-KG) significantly increased ciprofloxacin (CIP) tolerance in MRSA. Using integrated metabolomic and functional genomic approaches, we demonstrated that both exogenous α-KG and genetic knockout of α-KG dehydrogenase (ΔsucA, ΔsucB) induced CIP tolerance in MRSA. Mechanistically, elevated α-KG levels drive the accumulation of glutamate (Glu), which in turn reduced bacterial membrane potential and cellular ATP content. Furthermore, Glu accumulation raised intracellular osmotic pressure, leading to decreased CIP uptake. These metabolic alterations enable MRSA to sustain high tolerance toward ciprofloxacin. Our findings reveal a key role of the α-KG-Glu metabolic axis in driving antibiotic tolerance and provide novel insights into the metabolic adaptations underlying drug persistence in MRSA.

Ciprofloxacin↗
PubMed2024

FANCJ DNA helicase is recruited to the replisome by AND-1 to ensure genome stability.

FANCJ, a DNA helicase linked to Fanconi anemia and frequently mutated in cancers, counteracts replication stress by dismantling unconventional DNA secondary structures (such as G-quadruplexes) that occur at the DNA replication fork in certain sequence contexts. However, how FANCJ is recruited to the replisome is unknown. Here, we report that FANCJ directly binds to AND-1 (the vertebrate ortholog of budding yeast Ctf4), a homo-trimeric protein adaptor that connects the CDC45/MCM2-7/GINS replicative DNA helicase with DNA polymerase α and several other factors at DNA replication forks. The interaction between FANCJ and AND-1 requires the integrity of an evolutionarily conserved Ctf4-interacting protein (CIP) box located between the FANCJ helicase motifs IV and V. Disruption of the CIP box significantly reduces FANCJ association with the replisome, causing enhanced DNA damage, decreased replication fork recovery and fork asymmetry in cells unchallenged or treated with Pyridostatin, a G-quadruplex-binder, or Mitomycin C, a DNA inter-strand cross-linking agent. Cancer-relevant FANCJ CIP box variants display reduced AND-1-binding and enhanced DNA damage, a finding that suggests their potential role in cancer predisposition.

Humans↗
PubMed2025

Circulating inflammatory proteins and osteomyelitis: A bidirectional Mendelian randomization and colocalization analysis.

Circulating inflammatory proteins (CIPs) have been implicated in the progression of osteomyelitis (OM); however, whether these proteins play a causal role or are merely a consequence remains unclear. This study aimed to assess the causal relationships between CIPs and OM using a bidirectional 2-sample Mendelian randomization (MR) approach. MR analyses were performed using genome-wide association study summary statistics for 91 inflammation-related proteins (n&#x2005;=&#x2005;14,824) and OM (1881 cases and 3,91,037 controls). The inverse variance weighted method was used as the primary analytical approach, supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Sensitivity analyses were conducted to evaluate heterogeneity, horizontal pleiotropy, and robustness. Colocalization analysis was applied to identify shared causal variants, and pathway enrichment analysis was used to explore underlying biological mechanisms. Forward MR analysis revealed that elevated levels of tumor necrosis factor-beta (TNF-&#x3b2;) were significantly associated with increased OM risk (odds ratio [OR]&#x2005;=&#x2005;1.132; 95% confidence interval [CI]: 1.052-1.217; false discovery rate [FDR]&#x2005;=&#x2005;0.027). Conversely, decreased levels of osteoprotegerin (OR&#x2005;=&#x2005;0.772; 95% CI: 0.671-0.889; FDR&#x2005;=&#x2005;0.015) and adenosine deaminase (OR&#x2005;=&#x2005;0.811; 95% CI: 0.736-0.894; FDR&#x2005;<&#x2005;0.001) were associated with increased OM risk. Reverse MR analysis identified increased levels of interleukin-15 receptor alpha, C-X-C motif chemokine ligand 1, fms-related tyrosine kinase 3 ligand, interleukin-20, interleukin-10 (IL10), C-C motif chemokine ligand 19, and CXCL6 as being significantly associated with OM susceptibility (all FDR&#x2005;<&#x2005;0.05). Colocalization analysis provided strong evidence for a shared causal variant between TNF-&#x3b2; and OM (posterior probability for hypothesis 4&#x2005;=&#x2005;0.999). Enrichment analyses indicated involvement of implicated proteins in Toll-like receptor signaling and T-helper 17 cell differentiation pathways. This study identified several CIPs - including TNF-&#x3b2;, osteoprotegerin, and adenosine deaminase - as potentially causal in OM development. These findings highlight promising targets for future immunomodulatory therapies aimed at preventing or mitigating osteomyelitis.

Humans↗
PubMed2026

Effectiveness of Topical Huzhang Sanhuang with Standard Nursing for Chemotherapy-Induced Phlebitis: Randomized Controlled Study.

Chemotherapy-induced phlebitis (CIP) is a common complication of peripheral intravenous chemotherapy that can cause pain, local inflammation, treatment interruption, and diminished quality of life. This randomized controlled trial evaluated the efficacy and safety of the topical Huzhang Sanhuang (HZSH) formula, combined with standard nursing care, in managing CIP. Ninety-four hospitalized patients with CIP (grade I or higher) were randomly assigned in a 1:1 ratio to receive either topical HZSH formula plus standard nursing care (experimental group, n = 47) or 50% magnesium sulfate wet dressing plus standard nursing care (control group, n = 47) for 14 days. Prespecified outcomes included phlebitis grade, visual analog scale (VAS) pain score, high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), symptom resolution time, and safety indicators. By Day 14, patients in the experimental group demonstrated significantly greater improvement in phlebitis severity than those in the control group (risk ratio for grade &#x2265; II, 0.42; 95% confidence interval, 0.20-0.87; P = 0.012). The experimental group also showed significantly larger reductions in VAS pain scores, hs-CRP levels, and IL-6 concentrations (all P < 0.01). Kaplan-Meier analysis further demonstrated faster resolution of multiple local symptoms in the experimental group. Treatment adherence was high in both groups, and no serious adverse events or major safety concerns were observed. These findings indicate that the topical HZSH formula, combined with standard nursing care, is a safe and effective integrative nursing intervention that accelerates clinical recovery, alleviates local symptoms, and reduces the inflammatory burden in patients with chemotherapy-induced phlebitis.

Humans↗
PubMed2026

A bivalent molecular glue linking lysine acetyltransferases to oncogene-induced cell death.

Developing cancer therapies that induce specific death of malignant cells is critical for preventing relapse. Highly effective strategies, such as immunotherapy, exemplify this principle. Here, we provide the mechanistic basis for a small-molecule approach that leverages chemically induced proximity (CIP) to kill diffuse large B cell lymphoma, the most common non-Hodgkin lymphoma. We developed lysine acetyltransferase (KAT)-based TCIPs (transcriptional/epigenetic chemical inducers of proximity), or KAT-TCIPs, which redirect p300/CREB-binding protein (CBP) to activate cell-death networks repressed by the oncogenic driver BCL6. Our lead KAT-TCIP reprograms the epigenome to initiate apoptosis. The crystal structure of the chemically induced p300-BCL6 complex reveals how chance protein-protein interactions may be exploited to confer the potency and selectivity of KAT-TCIPs. Thus, oncogenic drivers can be co-opted to activate robust cell death. Consistent with their gain-of-function mechanism, TCIPs recruiting different transcriptional activators-p300, BRD4, or CDK9-produce distinct genomic responses, suggesting specialized therapeutic uses.

Humans↗
PubMed2026

A novel biocontrol Pseudomonas species with broad-spectrum antagonistic activity against phytopathogens.

Bacterial and fungal diseases cause significant losses in horticultural crops, and biocontrol using beneficial microorganisms offers a sustainable alternative to chemical pesticides. In this study, a novel Pseudomonas strain D3 was isolated from Actinidiae rhizosphere. D3 exhibited strong antibacterial activity in LB medium but showed no activity against fungi or oomycetes. However, when cultured in KIDO medium, it demonstrated potent antifungal activity. Phylogenetic analysis based on 16S rRNA gene showed that D3 was most closely related to Pseudomonas mosselii CIP_105259T, while whole-genome sequencing revealed ANI values below 95% with eight known P. mosselii strains. Digital DNA-DNA hybridization (dDDH) further confirmed its genomic distinctiveness, with the highest dDDH value (58.2%) against the type strain P. mosselii DSM 17497T, well below the 70% species delineation threshold, supporting D3 as a novel Pseudomonas species. Functional validation via targeted gene knockout revealed a dichotomy in the antagonistic mechanisms of D3. Knockout of individual biosynthetic gene clusters (BGCs) only partially reduced antibacterial activity against Pseudomonas syringae pv. actinidiae, indicating that multiple BGCs contribute to this activity in a partially redundant manner. In contrast, disruption of a specific lipopeptide synthase cluster completely abolished antifungal activity against Valsa mali. LC-MS/MS analysis confirmed that this lipopeptide was produced exclusively in KIDO medium, consistent with the observed medium-dependent antifungal activity. Detached leaf and twig assays showed that D3 provides strong preventive biocontrol against both pathogens. Collectively, strain D3 employs a dual biocontrol mechanism, combining antibacterial activity mediated by multiple BGCs with lipopeptide-dependent antifungal activity, positioning it as a promising agent for sustainable disease management in horticultural crops.

Pseudomonas↗
PubMed1979

Rapid isolation of carcinogen-bound DNA and RNA by hydroxyapatite chromatography.

Carcinogen-bound DNA and RNA are conveniently isolated by solvent extraction and hydroxyapatite (HAP) chromatography. Tissue is suspended in 8 M urea-0.24 M sodium phosphate-1% sodium dodecyl sulfate-10 mM EDTA, pH 6.8 (MUP-SDS-EDTA) and extracted with chloroform-isoamyl alcohol-phenol (24:1:25; CIP) to remove protein. RNA and DNA are separated by passing the aqueous solution through an HAP column; RNA is eluted with MUP, DNA with 0.48 M sodium phosphate, pH 6.8. Examples presented are: (1) calf thymus DNA that has been reacted with N-acetoxy-2-acetylaminofluorene (N-OAc-AAF), (2) isolated intact rat hepatocytes incubated with N-hydroxy-AAF and (3) livers from Sprague-Dawley rats treated with N-hydroxy-AAF.

Animals↗
PubMed2024

Acquired resistance of Stenotrophomonas maltophilia to antimicrobials induced by herbicide paraquat dichloride.

Stenotrophomonas maltophilia, a ubiquitous environmental bacterium, is an important cause of nosocomial infections. Although banned in some countries, paraquat (PQ) is commonly used to control weeds. In this study, we investigated the effects of increasing concentrations of PQ on S. maltophilia and its antimicrobial resistance. The sequential exposure of S. maltophilia K279a to increasing concentrations of PQ induces the formation of strains with increased resistance to PQ. Among the 400 PQ-resistant isolates tested, 70 clones were resistant to 16 &#x3bc;g/ml ciprofloxacin (CIP), and around 18% of the PQ/CIP-resistant isolates showed increased resistance to all the tested antimicrobials including, the aminoglycosides, quinolones, cephalosporin, chloramphenicol, and co-trimoxazole. The results of the expression analysis of the antimicrobial resistance genes in the five selected PQ/CIP-resistant isolates demonstrated the high expression of genes encoding efflux pumps (smeYZ, smaAB, smaCDEF, smeDEF, smeVWX, and smtcrA) and the enzymes aph(3')-IIc, blaL1, and blaL2. However, expression of the genes known for PQ resistance (i.e., mfsA and sod) were not altered relative to the wild-type levels. Whole genome sequence analysis identified gene mutations that could account for the antimicrobial resistance, namely, smeT (TetR family regulatory protein), rplA (ribosomal protein L1), and acnA (aconitase A). Ectopic expression of wild-type AcnA partially complemented the fluoroquinolone-resistant phenotype of the mutant with mutated acnA, which suggests the role of aconitase A in antimicrobial susceptibility. Exposure of S. maltophilia to PQ thus induces the development of strains that increase resistance to multiple antimicrobials.

Stenotrophomonas maltophilia↗