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Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease. Despite advances in current therapies, safer, more effective drugs are urgently needed. Traditional Chinese herbal formula Gegen Qinlian Decoction (GQD) has been used for gastrointestinal disorders, including UC, though its exact mechanisms require further clarification. This study aimed to systematically evaluate the therapeutic effects of GQD in UC mice, focusing on serum metabolomics, gut microbiota, and immunomodulatory mechanisms. A dextran sulfate sodium (DSS)-induced mouse model of UC was established. Serum metabolomics and 16S rRNA sequencing analysis of GQD's effects on metabolites and gut microbiota. Correlation analysis and network pharmacology identified potential targets and pathways of GQD. Immunofluorescence detected the expression of γδT cells, TNF-α, IFN-γ, and IL-17 proteins in the colonic tissue. Using UPLC-QE-Orbitrap-MS, 71 compounds were identified in the GQD quality control analysis. GQD markedly attenuated colonic histopathological damage and suppressed serum pro-inflammatory cytokines IFN-γ, IL-17, and TNF-α. It also modulated key serum metabolites, including succinic acid, glyoxylate, and xanthine, which are primarily involved in amino acid and purine metabolic pathways. GQD further influenced intestinal microbial diversity and composition. Joint analysis revealed GQD modulates gut microbiota, serum amino acid and purine metabolism, and inflammation pathways. Immunohistochemical results demonstrated enhanced infiltration of γδT cells following GQD treatment, accompanied by reduced protein expression levels of TNF-α, IFN-γ, and IL-17. GQD exerts therapeutic effects on UC by reshaping gut microbiota composition and metabolic activities, thereby ameliorating intestinal mucosal injury, regulating γδT cell-mediated immune responses, and influencing amino acid and purine metabolic pathways.

Background The rheological properties of wheat dough exert a profound influence on the baking process and the quality of the final food products. Previous studies have partially elucidated the genetic basis of wheat flour rheological characteristics; however, multi-locus genome-wide association studies (ML-GWAS) investigating these traits under multi-year single-location field trials remain scarce and have yielded highly variable results. Therefore, the identification of stable genetic loci associated with dough rheological properties has become particularly critical. Results This study conducted a comprehensive analysis of a diverse natural population comprising 273 wheat varieties (lines) using a 55 K SNP array and an ML-GWAS model. This approach identified with high precision 239 quantitative trait nucleotides (QTNs) significantly associated with wheat flour dough rheological properties. Among these QTNs, 13 mono-effect QTNs were consistently detected across at least two environments and two distinct models, with only 3 classified as major-effect QTNs. Additionally, 7 pleiotropic QTNs were identified. Eleven of the mono-effect QTNs exhibited significant differences in phenotypic traits, while 3 pleiotropic QTNs demonstrated highly significant differences across all associated traits. Within a 4 Mb flanking region surrounding these major-effect and pleiotropic QTNs, a total of 606 genes were co-annotated. Gene annotation indicated these genes primarily participate in critical biological functions, including protein modification and degradation, and the regulation of seed development and maturation. Subsequent Gene Ontology (GO) enrichment analysis rigorously screened 18 promising candidate genes, and their expression profiles were analyzed throughout wheat tissue development and endosperm maturation. Ultimately, 6 SNP loci and 9 key candidate genes strongly linked to wheat flour dough rheological properties were identified. Conclusions This study employed ML-GWAS combined with the 55 K SNP array to analyze six dough rheological traits in 273 wheat germplasm accessions. SNP loci and candidate genes associated with dough rheological properties were identified, advancing molecular breeding technology in wheat and thereby establishing a theoretical foundation for genetic improvement and the cultivation of high-quality varieties.

Background The complement system constitutes a critical component of innate immunity against fungal pathogens. Complement component 9 (C9), an essential constituent of the membrane attack complex (MAC), plays a pivotal role in pathogen elimination. However, isolated C9 deficiency has not been previously reported in association with fungal esophagitis. Case presentation We present the case of a nearly 7-year-old girl who suffered from progressive dysphagia, nausea, and vomiting for more than two months. Esophagogastroduodenoscopy revealed esophageal stricture, and histopathological examination of mucosal biopsies confirmed Candida albicans infection. Despite multiple endoscopic dilations, symptomatic recurrence occurred monthly. Whole-exome sequencing identified a pathogenic variant confirming isolated C9 deficiency. Combined systemic antifungal therapy with fluconazole and repeated endoscopic dilatation achieved sustained symptomatic resolution. Conclusion Isolated C9 deficiency may represent a susceptibility factor for recurrent fungal esophagitis with stricture formation in children. Complement screening should be considered in unexplained recurrent cases. Combined antifungal therapy and endoscopic intervention achieved sustained remission in this patient.

Allergic asthma is characterized by goblet cell metaplasia and subsequent mucus hypersecretion that contribute to the morbidity and mortality of this disease. Here, we explore the potential role and underlying mechanism of protein SUMOylation-mediated goblet cell metaplasia. The components of SUMOylaion machinery are specifically expressed in healthy human bronchial epithelia and robustly upregulated in bronchial epithelia of patients or mouse models with allergic asthma. Intratracheal suppression of SUMOylation by 2-D08 robustly attenuates not only allergen-induced airway inflammation, goblet cell metaplasia, and hyperreactivity, but IL-13-induced goblet cell metaplasia. Phosphoproteomics and biochemical analyses reveal SUMOylation on K1007 activates ROCK2, a master regulator of goblet cell metaplasia, by facilitating its binding to and activation by RhoA, and an E3 ligase PIAS1 is responsible for SUMOylation on K1007. As a result, knockdown of PIAS1 in bronchial epithelia inactivates ROCK2 to attenuate IL-13-induced goblet cell metaplasia, and bronchial epithelial knock-in of ROCK2(K1007R) consistently inactivates ROCK2 to alleviate not only allergen-induced airway inflammation, goblet cell metaplasia, and hyperreactivity, but IL-13-induced goblet cell metaplasia. Together, SUMOylation-mediated ROCK2 activation is an integral component of Rho/ROCK signaling in regulating the pathological conditions of asthma and thus SUMOylation is an additional target for the therapeutic intervention of this disease. Allergic asthma is characterized by goblet cell metaplasia. Here, the authors show protein SUMOylation contributes to goblet cell metaplasia and SUMOylation-mediated ROCK2 activation is an integral component of Rho/ROCK signalling pathway in controlling the airway goblet cell metaplasia.

Background Current checkpoint immunotherapy has shown potential to control cancer by restoring or activating the immune system. Nevertheless, multiple mechanisms are involved in immunotherapy resistance which limits the clinical benefit of checkpoint inhibitors. An immunosuppressive microenvironment is an important factor mediating the original resistance of tumors to immunotherapy. A previous report by our group has demonstrated that local angiotensin II (AngII) predominantly exists in a tumor hypoxic microenvironment where hypoxic tumour cells produced AngII by a hypoxia-lactate-chymase-dependent mechanism. Results Here, using 4T1 and CT26 syngeneic mouse tumor models, we found that local AngII in the tumor microenvironment was involved in immune escape of tumour cells and an AngII signaling blockage sensitized tumours to checkpoint immunotherapy. Furthermore, an AngII signaling blockage reversed the tumor immunosuppressive microenvironment, and inhibition of angiotensinogen (AGT, a precursor of AngII) expression strongly triggered an immune-activating cytokine profile in hypoxic mouse cancer cells. More importantly, AGT silencing combined with a checkpoint blockage generated an abscopal effect in resistant tumors. Conclusion Our study demonstrated an important role of local AngII in the formation of a tumor immunosuppressive microenvironment and its blockage may enhance tumor sensitivity to checkpoint immunotherapy. The combination of an AngII signaling blocker and an immune-checkpoint blockage could be a promising strategy to improve tumors responses to current checkpoint immunotherapy.

During homeostasis and after injury, adult muscle stem cells (MuSCs) activate to mediate muscle regeneration. However, much remains unclear regarding the heterogeneous capacity of MuSCs for self-renewal and regeneration. Here, we show that Lin28a is expressed in embryonic limb bud muscle progenitors, and that a rare reserve subset of Lin28a + Pax7 – skeletal MuSCs can respond to injury at adult stage by replenishing the Pax7 + MuSC pool to drive muscle regeneration. Compared with adult Pax7 + MuSCs, Lin28a + MuSCs displayed enhanced myogenic potency in vitro and in vivo upon transplantation. The epigenome of adult Lin28a + MuSCs showed resemblance to embryonic muscle progenitors. In addition, RNA-sequencing revealed that Lin28a + MuSCs co-expressed higher levels of certain embryonic limb bud transcription factors, telomerase components and the p53 inhibitor Mdm4, and lower levels of myogenic differentiation markers compared to adult Pax7 + MuSCs, resulting in enhanced self-renewal and stress-response signatures. Functionally, conditional ablation and induction of Lin28a + MuSCs in adult mice revealed that these cells are necessary and sufficient for efficient muscle regeneration. Together, our findings connect the embryonic factor Lin28a to adult stem cell self-renewal and juvenile regeneration.

Oral cancer remains a deadly disease worldwide. Lymph node metastasis and invasion is one of the causes of death from oral cancer. Elucidating the mechanism of oral cancer lymph node metastasis and identifying critical regulatory genes are important for the treatment of this disease. This study aimed to identify differentially expressed genes (gene signature) and pathways that contribute to oral cancer metastasis to lymph nodes. The GSE70604-associated study compared gene profiles in lymph nodes with metastasis of oral cancer to those of normal lymph nodes. The GSE2280-associated study compared gene profiles in primary tumor of oral cancer with lymph node metastasis to those in tumors without lymph node metastasis. There are 28 common differentially expressed genes (DEGs) showing consistent changes in both datasets in overlapping analysis. GO biological process and KEGG pathway analysis of these 28 DEGs identified the gene signature CCND1, JUN and SPP1, which are categorized as key regulatory genes involved in the focal adhesion pathway. Silencing expression of CCND1, JUN and SPP1 in the human oral cancer cell line OECM-1 confirmed that those genes play essential roles in oral cancer cell invasion. Analysis of clinical samples of oral cancer found a strong correlation of these genes with short survival, especially JUN expression associated with metastasis. Our study identified a unique gene signature – CCND1, JUN and SPP1 – which may be involved in oral cancer lymph node metastasis.

During ageing, adult stem cells' regenerative properties decline, as they undergo replicative senescence and lose both their proliferative and differentiation capacities. In contrast, embryonic and foetal progenitors typically possess heightened proliferative capacities and manifest a more robust regenerative response upon injury and transplantation, despite undergoing many rounds of mitosis. How embryonic and foetal progenitors delay senescence and maintain their proliferative and differentiation capacities after numerous rounds of mitosis, remains unknown. It is also unclear if defined embryonic factors can rejuvenate adult progenitors to confer extended proliferative and differentiation capacities, without reprogramming their lineage‐specific fates or inducing oncogenic transformation. Here, we report that a minimal combination of LIN28A, TERT, and sh‐p53 (LTS), all of which are tightly regulated and play important roles during embryonic development, can delay senescence in adult muscle progenitors. LTS muscle progenitors showed an extended proliferative capacity, maintained a normal karyotype, underwent myogenesis normally, and did not manifest tumorigenesis nor aberrations in lineage differentiation, even in late passages. LTS treatment promoted self‐renewal and rescued the pro‐senescence phenotype of aged cachexia patients' muscle progenitors, and promoted their engraftment for skeletal muscle regeneration in vivo. When we examined the mechanistic basis for LIN28A's role in the LTS minimum combo, let‐7 microRNA suppression could not fully explain how LIN28A promoted muscle progenitor self‐renewal. Instead, LIN28A was promoting the translation of oxidative phosphorylation mRNAs in adult muscle progenitors to optimize mitochondrial reactive oxygen species (mtROS) and mitohormetic signalling. Optimized mtROS induced a variety of mitohormetic stress responses, including the hypoxic response for metabolic damage, the unfolded protein response for protein damage, and the p53 response for DNA damage. Perturbation of mtROS levels specifically abrogated the LIN28A‐driven hypoxic response in Hypoxia Inducible Factor‐1α (HIF1α) and glycolysis, and thus LTS progenitor self‐renewal, without affecting normal or TS progenitors. Our findings connect embryonically regulated factors to mitohormesis and progenitor rejuvenation, with implications for ageing‐related muscle degeneration. Model of how LIN28A, mitochondrial reactive oxygen species, and the HIF1α‐associated metabolic stress response network promotes stem cell self‐renewal.

Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are the causative agents of hand, foot, and mouth disease (HFMD). During recent epidemics of HFMD in China, medicinal herbals and preparations containing herbal extracts have demonstrated therapeutic efficacy with relative safety profiles. There have been no microbiological studies to validate their usefulness for HFMD. We selected 12 commonly used herbs for HFMD from government recommended guidelines as well as published reports and tested for their antiviral activity and anti-inflammatory activity. A water extract of Houttuynia cordata Thunb. (HCT) inhibited EV71 infection significantly and was marginally active against CVA16 infection. The IC50 (concentration to have 50% inhibitory effect) values of HCT against a Fuyang strain and a BrCr strain of EV71 were determined at 8.9 μg/mL and 20.6 μg/mL, respectively. Mentha haplocalyx Briq. (MHB) water extract was active against CVA16, with an IC50 value of 70.3 μg/mL. The extract did not exhibit activity against EV71 infection. Although the majority of the extracts showed no activity against viral infection, several extracts demonstrated activity in blocking proinflammatory response by viral infection. This study therefore validates the effectiveness of Chinese herbs for HFMD since some formulations containing the correct combination of the herbs can block viral replication as well as proinflammatory response of HFMD.