Obesity is associated with the gut microbiome. Here, we report that gut commensal Clostridia bacteria regulate host energy balance through the tryptophan-derived metabolite indole-3-propionic acid (IPA). IPA acts as an endogenous leptin sensitiser to counteract obesity. Mechanistically, IPA is secreted from the gut into the circulation, and then targets to the STAT3 in the hypothalamic appetite regulation centre, promoting its phosphorylation and nuclear translocation, which enhances the body’s response to leptin, and regulates the balance between appetite and energy metabolism. The in vitro pull-down assays involving site-directed mutagenesis demonstrate that Trp623 in the SH2 domain is the key binding site for STAT3-IPA interaction. High-fat diet (HFD), rather than genetic factors, induces excessive secretion of antimicrobial peptides by Paneth cells, inhibiting the growth of Clostridia in the gut and resulting in decreased production of the beneficial metabolite IPA. IPA or Clostridium sporogenes supplement effectively controls weight gain, improves glucose metabolism, and reduces inflammation in DIO mice. IPA fails to achieve such effects in ob/ob mice, while exogenous leptin administration restores the therapeutic effect of IPA. Our study suggests that the IPA-based gut-brain axis regulates host metabolism, and supplementation with microbiome-derived IPA could be a promising intervention strategy for treating obesity.
•Extracellular vesicles (EVs) of creeping fat (CrF) derived adipose stem cells effectively attenuate chronic mesenteritis and colitis in Crohn’s disease (CD). | |
•The lymphatic vessels play an important role in disease development of CD and their functions are improved by CrF-EV-miR-132-3p through RASA1/ERK1/2 signaling. | |
•MiR-132-3p expression is upregulated in CrF and serum of CD patients, and tightly linked with inflammation and disease activity. |
Dengue virus (DENV) and Zika virus (ZIKV) have emerged as major global public health challenges, causing numerous infections and fatalities each year. However, current measures, including vaccines and treatments, are often limited or ineffective. This highlights the urgent need for novel preventive strategies to control the spread of key mosquito-borne viruses like DENV and ZIKV. In a recent study published in Science, Zhang et al. isolated a bacterium named Rosenbergiella_YN46 from the gut of field-caught Aedes albopictus mosquitoes in Yunnan Province, China. This commentary reviews their findings, published on April 19, 2024, which describe the symbiotic bacterium Rosenbergiella_YN46 and its ability to block flavivirus transmission, including both DENV and ZIKV. The bacterium shows promising potential for future dengue fever prevention and provides valuable insights into a novel biological approach for controlling mosquito-borne viral diseases.
•Comparative scRNA-seq analysis reveals significant similarities in genetic, transcriptomicand immune profiles between MPLCs and SPLCs. | |
•Identification of a unique immunosuppressive F13A1+ macrophage subtype, preferentially enriched in MPLCs, linked to immune evasion and tumourprogression. | |
•SPP1-CD44/CCL13-ACKR1 interactions are crucial in MPLC tumour microenvironment, indicating potential targets for therapeutic intervention. |
•UPCs from porcine urine can be used to generate a cell therapy product based on extracellular vesicles (pUPC-EVs). | |
•pUPC-EVs injection during HMP and NMP decreases cell damage markers and has an immunomodulatory effect. | |
•pUPC-EVs-treated kidneys have distinct biochemical, metabolic, and transcriptomic profiles highlighting targets of interest. | |
•Our results pave the way for combining machine perfusion with EV-based cell therapy for kidney conditioning. |
•NLRP3 inflammasome activation is pivotal in mediating the excessive inflammatory response in ALI/ARDS. | |
•Glycolytic reprogramming regulates NLRP3 inflammasome activation. | |
•Therapeutic potential of targeting glycolytic reprogramming to inhibit NLRP3 inflammasome activation in ALI/ARDS. |
| •Activation of the NLRP3-GSDMD pathway in the ileum of Alcoholic liver disease (ALD) mice. | |
•NLRP3 activation maintains homeostasis of gut microbiota and intestinal epithelial barrier in ALD mice. | |
•ALD mice infected with V. vulnificus infection exhibited no further activation of NLRP3 in the ileum, leading to increased intestinal permeability and bloodstream infections. |
•CircHipk3 is significantly upregulated in abdominal aortic aneurysms (AAA) compared to normal arteries, contributing to macrophage pyroptosis. | |
•CircHipk3 promotes the synergistic effect of inflammation and matrix metalloproteinase (MMP) activity, accelerating Angiotensin II- and porcine pancreatic elastase-induced AAA formation in mice. Mechanistically, CircHipk3 interacts with Stat3 to elevate NLRP3 levels and binds Snd1 to promote Ptbp1 mRNA degradation, inhibiting autophagy. | |
•CircHipk3’s dual role in enhancing NLRP3 inflammasome activation and inhibiting autophagy makes it a critical regulator in AAA development and rupture. | |
| •Targeting CircHipk3 may offer a novel therapeutic strategy to prevent pyroptosis and AAA development, positioning it as a potential treatment target. |
As a chromatin remodelling factor, high mobility group A1 (HMGA1) plays various roles in both physiological and pathological conditions. However, its role in DNA damage response and DNA damage-based chemotherapy remains largely unexplored. In this study, we report the poly ADP-ribosylation (PARylation) of HMGA1 during DNA damage, leading to desensitization of esophageal squamous cell carcinoma (ESCC) cells to the poly(ADP-ribose) polymerase 1 (PARP1) inhibitor, olaparib. We found that HMGA1 accumulates at sites of DNA damage, where it interacts with PARP1 and undergoes PARylation at residues E47 and E50 in its conserved AT-hook domain. This modification enhances the accumulation of Ku70/Ku80 at the site of DNA damage and activates the DNA-dependent protein kinase catalytic subunit, facilitating nonhomologous end-joining repair. In both subcutaneous tumour models and genetically engineered mouse models of in situ esophageal cancer, HMGA1 interference increased tumour sensitivity to olaparib. Moreover, HMGA1 was highly expressed in ESCC tissues and positively correlated with PARP1 levels as well as poor prognosis in ESCC patients. Taken together, these findings reveal a mechanistic link between HMGA1 and PARP1 in regulating cell responses to DNA damage and suggest that targeting HMGA1 could be a promising strategy to increase cancer cell sensitivity to olaparib.
•Insights into the heterogeneity and transcriptional patterns of sarcoma cells may explain the challenges in treating primary cardiac angiosarcoma (PCAS) using the current therapeutic modalities. | |
•Characterization of the immune microenvironment revealed significant immunosuppression mediated by specific myeloid cell populations (SPP1+ and OLR1+ macrophages). | |
•Identification of mitochondrial dysfunction in immune cells within the PCAS microenvironment, particularly the notable downregulation of the MTRNR2L12 protein, suggests a new avenue for therapeutic targeting. |
•A largest longitudinal follow-up study of gastric precursor lesions in Chinese patients. | |
| •Revealing novel 5hmC molecular landscape linked to gastric premalignant lesions. | |
•The feasibility of an innovative 5hmC-based predictive model for assessing gastric cancer progression risk. |
| •This study firstly used spatial transcriptomics technique to analyse the neointima and generated a specific neointimal transcriptomic atlas. | |
•Fhl1 exhibits specific and stable expression in the spatial region of the neointima. It has thus far the highest enrichment of expression in the neointima in NIH phases, suggesting that it is a prominent molecular biomarker of neointima. | |
•We generated rats with a Fhl1 deletion and found that insufficient Fhl1 expression caused an increase in the severity of vascular inflammation and proliferation during neointimal hyperplasia. Adenovirus-mediated FHL1 overexpression in human saphenous vein have beneficial effects in preventing neointimal hyperplasia. These highlight its potential as a therapeutic target for mitigating vein graft failure associated with cardiovascular procedures. | |
•Spatial transcriptomics profiles and morphological observations demonstrated that a newly generated cell population outside the grafted vein with hybrid phenotype between SMCs and fibroblasts contributes to neointimal formation. |
•EA commonly protects dopaminergic neuronsby reducing neuroinflammation, oxidative stress, and apoptosis. | |
•New findings reveal that EA alleviates motor symptoms in a parkinsonian rat model without restoring striatal dopamine levels. | |
•EA effectively suppresses excessiveglutamate transmission and high-beta synchronization, contributing to motorsymptom relief. | |
| •Activation of corticostriatalglutamatergic projections may hinder the efficacy of EA. |
•This study highlights the considerable regulatory role of LINC01419 in the metabolism of HCC. | |
•The newly identified LINC01419/YBX1-PDK1 axis constitutes a valuable target. | |
| •Hepatic-specific delivery of GalNAc-siLINC01419 presents a promising therapeutic strategy for HCC. |
•In this study, we investigated the role of the histone methyltransferase NSD2 in preventing intestinal barrier disruption by sustaining taurine biosynthesis. NSD2 levels were reduced in both human specimens and mouse models of IBD. We demonstrate that NSD2 loss hinders the process of taurine synthesis in intestinal cells, leading to increased intestinal inflammation. | |
•Supplementation with taurine significantly relieved the symptoms caused by NSD2 deficiency. These data suggest that maintenance of NSD2-mediated taurine biosynthesis is vital for preserving the intestinal barrier and attenuating inflammation. |
1. Estrogen-activated GPER in CAFs enhances GLUL and LDHB expression via the cAMP/PKA/CREB signalling, facilitating glutamine production and utilization. | |
2. Microenvironmental GPER-induced glutamine serves as a crucial mediator of metabolic coupling between CAFs and TNBC cells, boosting tumour progression by enhancing mitochondrial function. | |
3. Targeting the glutamine metabolic coupling triggered by estrogen/GPER/GLUL signalling in CAFs is a promising therapeutic strategy for TNBC treatment. |
| •LRH-1/NR5A2 activation in inflammatory cells of individuals with type 1 diabetes (T1D) reduces pro-inflammatory cell surface markers and cytokine release. | |
•LRH-1/NR5A2 promotes a mitohormesis-induced immuno-resistant phenotype to pro-inflammatory macrophages. | |
•Mature dendritic cells acquire a tolerogenic phenotype via LRH-1/NR5A2-stimulated mitochondria turnover. | |
•LRH-1/NR5A2 agonistic activation expands a CD4+/CD25+/FoxP3+ T-cell subpopulation. | |
•Pharmacological activation of LRH-1/NR5A2 improves the survival iPSC-islets-like organoids co-cultured with PBMCs from individuals with T1D. |