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Ageing-associated functional decline of organs and increased risk for age-related chronic pathologies is driven in part by the accumulation of senescent cells, which develop the senescence-associated secretory phenotype (SASP). Here we show that procyanidin C1 (PCC1), a polyphenolic component of grape seed extract (GSE), increases the healthspan and lifespan of mice through its action on senescent cells. By screening a library of natural products, we find that GSE, and PCC1 as one of its active components, have specific effects on senescent cells. At low concentrations, PCC1 appears to inhibit SASP formation, whereas it selectively kills senescent cells at higher concentrations, possibly by promoting production of reactive oxygen species and mitochondrial dysfunction. In rodent models, PCC1 depletes senescent cells in a treatment-damaged tumour microenvironment and enhances therapeutic efficacy when co-administered with chemotherapy. Intermittent administration of PCC1 to either irradiated, senescent cell-implanted or naturally aged old mice alleviates physical dysfunction and prolongs survival. We identify PCC1 as a natural senotherapeutic agent with in vivo activity and high potential for further development as a clinical intervention to delay, alleviate or prevent age-related pathologies. The polyphenol procyanidin C1, a compound found in grape seeds, possesses senomorphic or senolytic activity and is shown to extend the healthspan and survival of old mice and in various models of senescence-associated disability.

Background Mucormycosis is a significant cause of morbidity and mortality in patients with hematological malignancies, but its characteristics are not fully understood. This study aimed to gain a better understanding of the clinical features of mucormycosis in patients with hematological malignancies in eastern China. Methods A single-center retrospective analysis was conducted on the demographic profile, microbiology, management, and 90-day mortality of mucormycosis patients with hematological malignancies between 2018 and 2023. Results A total of 50 cases were included in the study, consisting of 11 proven and 39 probable cases of mucormycosis. The median age of the patients was 39.98 ± 18.52 years, with 52% being male. Among the cases, 46% had acute myeloid leukemia (AML), 16% had acute lymphoblastic leukemia (ALL), and 16% had myelodysplastic syndrome. The most common manifestations of mucormycosis were pulmonary (80%), disseminated (16%), and rhinocerebral (4%). The diagnosis was confirmed through histology, culture, microscopy, and molecular diagnostic techniques. The most commonly identified fungal species were Cunninghamella (40%), Rhizopus (26%), and Rhizomucor (22%). Treatment involved antifungals in 84% of cases and surgery in 10% of cases. The 90-day mortality rate was 76%. Logistic regression analysis revealed that treatment with amphotericin B and surgery was associated with improved survival, while neutropenia and administration of voriconazole prior to diagnosis was associated with higher mortality. Conclusions Mucormycosis continues to have a high mortality rate in patients with hematological malignancies. Early diagnosis using various techniques, including molecular biology, along with the appropriate use of amphotericin B and surgery when possible, is vital for the successful treatment of mucormycosis.

The senescence-associated secretory phenotype (SASP) can be provoked by side effects of therapeutic agents, fueling advanced complications including cancer resistance. However, the intracellular signal network supporting initiation and development of the SASP driven by treatment-induced damage remains unclear. Here we report that the transcription factor Zscan4 is elevated for expression by an ATM-TRAF6-TAK1 axis during the acute DNA damage response and enables a long term SASP in human stromal cells. Further, TAK1 activates p38 and PI3K/Akt/mTOR to support the persistent SASP signaling. As TAK1 is implicated in dual feedforward mechanisms to orchestrate the SASP development, pharmacologically targeting TAK1 deprives cancer cells of resistance acquired from treatment-damaged stromal cells in vitro and substantially promotes tumour regression in vivo. Together, our study reveals a novel network that links functionally critical molecules associated with the SASP development in therapeutic settings, thus opening new avenues to improve clinical outcomes and advance precision medicine. In cancer the side effects of therapeutic agents can provoke senescence-associated secretory phenotype (SASP), which can drive cancer resistance. During the DNA damage response, transcription factor Zscan4 expression is elevated by an ATM-TRAF6-TAK1 axis leading to long term SASP in human stromal cells.

Senescent cells remain metabolically active, but their metabolic landscape and resulting implications remain underexplored. Here, we report upregulation of pyruvate dehydrogenase kinase 4 (PDK4) upon senescence, particularly in some stromal cell lines. Senescent cells display a PDK4-dependent increase in aerobic glycolysis and enhanced lactate production but maintain mitochondrial respiration and redox activity, thus adopting a special form of metabolic reprogramming. Medium from PDK4 + stromal cells promotes the malignancy of recipient cancer cells in vitro, whereas inhibition of PDK4 causes tumor regression in vivo. We find that lactate promotes reactive oxygen species production via NOX1 to drive the senescence-associated secretory phenotype, whereas PDK4 suppression reduces DNA damage severity and restrains the senescence-associated secretory phenotype. In preclinical trials, PDK4 inhibition alleviates physical dysfunction and prevents age-associated frailty. Together, our study confirms the hypercatabolic nature of senescent cells and reveals a metabolic link between cellular senescence, lactate production, and possibly, age-related pathologies, including but not limited to cancer. PDK4-dependent lactate production by senescent stromal cells is shown to promote cancer growth and drug resistance and might have a broader role in the emergence of age-associated diseases.

Chemotherapy and radiation not only trigger cancer cell apoptosis but also damage stromal cells in the tumour microenvironment (TME), inducing a senescence-associated secretory phenotype (SASP) characterized by chronic secretion of diverse soluble factors. Here we report serine protease inhibitor Kazal type I (SPINK1), a SASP factor produced in human stromal cells after genotoxic treatment. DNA damage causes SPINK1 expression by engaging NF-κB and C/EBP, while paracrine SPINK1 promotes cancer cell aggressiveness particularly chemoresistance. Strikingly, SPINK1 reprograms the expression profile of cancer cells, causing prominent epithelial-endothelial transition (EET), a phenotypic switch mediated by EGFR signaling but hitherto rarely reported for a SASP factor. In vivo, SPINK1 is expressed in the stroma of solid tumours and is routinely detectable in peripheral blood of cancer patients after chemotherapy. Our study substantiates SPINK1 as both a targetable SASP factor and a novel noninvasive biomarker of therapeutically damaged TME for disease control and clinical surveillance. Tumour microenvironment actively contributes to drug resistance in clinical oncology. Here, the authors show that genotoxic stress induces senescence in human stromal cells, which in turn secrete serine protease inhibitor Kazal type 1 (SPINK1) and promote acquired resistance of cancer cells via EGFR-mediated paracrine signaling.

Background A large proportion of pulmonary embolism (PE) heritability remains unexplained, particularly among the East Asian (EAS) population. Our study aims to expand the genetic architecture of PE and reveal more genetic determinants in Han Chinese. Methods We conducted the first genome-wide association study (GWAS) of PE in Han Chinese, then performed the GWAS meta-analysis based on the discovery and replication stages. To validate the effect of the risk allele, qPCR and Western blotting experiments were used to investigate possible changes in gene expression. Mendelian randomization (MR) analysis was employed to implicate pathogenic mechanisms, and a polygenic risk score (PRS) for PE risk prediction was generated. Results After meta-analysis of the discovery dataset (622 cases, 8853 controls) and replication dataset (646 cases, 8810 controls), GWAS identified 3 independent loci associated with PE, including the reported loci FGG rs2066865 ( p -value = 3.81 × 10 −14 ), ABO rs582094 ( p -value = 1.16 × 10 −10 ) and newly reported locus FABP2 rs1799883 ( p -value = 7.59 × 10 −17 ). Previously reported 10 variants were successfully replicated in our cohort. Functional experiments confirmed that FABP2-A163G (rs1799883) promoted the transcription and protein expression of FABP2 . Meanwhile, MR analysis revealed that high LDL-C and TC levels were associated with an increased risk of PE. Individuals with the top 10% of PRS had over a fivefold increased risk for PE compared to the general population. Conclusions We identified FABP2 , related to the transport of long-chain fatty acids, contributing to the risk of PE and provided more evidence for the essential role of metabolic pathways in PE development.

Cellular senescence is a cell fate triggered by stressful stimuli and displays a hypersecretory feature, the senescence‐associated secretory phenotype (SASP). Senescent cell burden increases with aging and contributes to age‐related organ dysfunction and multiple chronic disorders. In this study, a large scale screening of a natural product library for senotherapeutic candidates is performed. Apigenin, a dietary flavonoid previously reported with antioxidant and anti‐inflammatory activities, exhibits capacity for targeting senescent cells as a senomorphic agent. This compound blocks the interactions between ATM/p38MAPK and HSPA8, preventing the transition of an acute stress‐associated phenotype (ASAP) toward the SASP. Mechanistically, apigenin targets peroxiredoxin 6 (PRDX6), an intracellular redox‐active molecule, suppressing the iPLA2 activity of PRDX6 and disrupting downstream reactions underlying SASP development. Apigenin reduces the severity of cancer cell malignancy promoted by senescent stromal cells in culture, while restraining chemoresistance when combined with chemotherapy in anticancer regimens. In preclinical trials, apigenin improves the physical function of animals with a premature aging‐like state, alleviating physical frailty and cognitive impairment. Together, the study demonstrates the feasibility of exploiting a natural compound with senomorphic capacity to achieve geroprotective effects by modulating the SASP, thus providing a baseline for future exploration of natural agents for alleviating age‐related conditions. As a plant‐derived flavonoid, apigenin directly targets PRDX6 to inhibit its PLA2 activity, blocking HSPA8 activation and disturbing its interactions with ATM and p38MAPK in senescent cells. By dampening wide spectrum expression of the SASP, apigenin prevents loss of tissue homeostasis, improves organ function, and alleviates multiple age‐related pathologies as an emerging senomorphic agent.

Lung microbiome ecosystem homeostasis in idiopathic pulmonary fibrosis (IPF) remains uncharacterized. The aims of this study were to identify unique microbial signatures of the lung microbiome and analyze microbial gene function in IPF patients. DNA isolated from BALF samples was obtained for high-throughput gene sequencing. Microbial metagenomic data were used for principal component analysis (PCA) and analyzed at different taxonomic levels. Shotgun metagenomic data were annotated using the KEGG database and were analyzed for functional and metabolic pathways. In this study, 17 IPF patients and 38 healthy subjects (smokers and non-smokers) were recruited. For the PCA, the first and the second principal component explained 16.3 and 13.4% of the overall variability, respectively. The β diversity of microbiome was reduced in the IPF group. Signature of IPF's microbes was enriched of . The translocation of lung microbiome was shown that 32.84% of them were from oral. After analysis of gene function, ABC transporter systems, biofilm formation, and two-component regulatory system were enriched in IPF patients' microbiome. Here we shown the microbiology characteristics in IPF patients. The microbiome may participate in altering internal conditions and involving in generating antibiotic resistance in IPF patients.

Development of ovarian cancer involves the co-evolution of neoplastic cells together with the adjacent microenvironment. Steps of malignant progression including primary tumor outgrowth, therapeutic resistance, and distant metastasis are not determined solely by genetic alterations in ovarian cancer cells, but considerably shaped by the fitness advantage conferred by benign components in the ovarian stroma. As the dynamic cancer topography varies drastically during disease progression, heterologous cell types within the tumor microenvironment (TME) can actively determine the pathological track of ovarian cancer. Resembling many other solid tumor types, ovarian malignancy is nurtured by a TME whose dark side may have been overlooked, rather than overestimated. Further, harnessing breakthrough and targeting cures in human ovarian cancer requires insightful understanding of the merits and drawbacks of current treatment modalities, which mainly target transformed cells. Thus, designing novel and precise strategies that both eliminate cancer cells and manipulate the TME is increasingly recognized as a rational avenue to improve therapeutic outcome and prevent disease deterioration of ovarian cancer patients.

Key Clinical Message Early and timely closure of secondary tracheoesophageal fistula (TEF) is crucial for critically ill patients. For those requiring invasive mechanical ventilation, the Amplatzer Duct Occluder II (ADO II) can be used as an emergency therapeutic option to rapidly close secondary TEF, providing opportunities for subsequent treatments. Secondary tracheoesophageal fistula (TEF) is a life‐threatening condition characterized by high mortality, high recurrence rates, and multiple complications. Reports on the management of secondary TEF in critically ill patients are limited due to the challenges in treatment and the lack of suitable therapeutic options. We report a case of secondary TEF in a 69‐year‐old male diagnosed with severe pneumonia, whose condition deteriorated rapidly following the onset of TEF. Despite invasive mechanical ventilation, maintaining blood oxygen saturation above 80% was unachievable due to the TEF. Bedside bronchoscopy revealed expansion TEF expansion caused by gastrointestinal fluid reflux and respiratory machine pressure. The TEF was urgently closed using an ADO II device during invasive mechanical ventilation to prevent further deterioration. After the patient's condition stabilized, the ADO II was replaced with a Y‐shaped tracheal membrane‐covered stent for further TEF management. The patient's condition improved, meeting the criteria for liberation from invasive mechanical ventilation, and bedside chest X‐rays revealed a gradual resolution of pulmonary inflammation. Selecting appropriate treatment modalities for early and timely closure of secondary TEF is crucial for critically ill patients. ADO II can serve as a rescue therapy to achieve rapid closure of secondary TEF in critically ill patients requiring invasive mechanical ventilation support, providing opportunities and time for subsequent treatment.