Lactate gives a sour taste
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Origin and de novo domestication of sweet orange
Sweet orange is cultivated worldwide but suffers from various devastating diseases because of its monogenetic background. The elucidation of the origin of a crop facilitates the domestication of new crops that may better cope with new challenges. Here we collected and sequenced 226 citrus accessions and assembled telomere-to-telomere phased diploid genomes of sweet orange and sour orange. On the basis of a high-resolution haplotype-resolved genome analysis, we inferred that sweet orange originated from a sour orange × mandarin cross and confirmed this model using artificial hybridization experiments. We identified defense-related metabolites that potently inhibited the growth of multiple industrially important pathogenic bacteria. We introduced diversity to sweet orange, which showed wide segregation in fruit flavor and disease resistance and produced canker-resistant sweet orange by selecting defense-related metabolites. Our findings elucidate the origin of sweet orange and de novo domesticated disease-resistant sweet oranges, illuminating a strategy for the rapid domestication of perennial crops.
PRMT3 drives PD-L1-mediated immune escape through activating PDHK1-regulated glycolysis in hepatocellular carcinoma
Aberrant expression of programmed death ligand-1 (PD-L1) facilitates tumor immune evasion. Protein arginine methyltransferase 3 (PRMT3), a member of type I PRMT family, mediates asymmetric dimethylarginine (ADMA) modification of various substrate proteins. This study investigates the role of PRMT3 in PD-L1-associated tumor immunosuppression in hepatocellular carcinoma (HCC). Hepatocyte-specific knockout of Prmt3 significantly suppressed HCC progression in DEN-CCL4-treated mice. Knockout of Prmt3 in HCC cells markedly increased CD8+ T cell infiltration, and reduced lactate production in tumors. PRMT3 interacted with pyruvate dehydrogenase kinase 1 (PDHK1), asymmetric dimethylation of PDHK1 at arginine 363 and 368 residues and increased its kinase activity. The R363/368 K mutant or inhibition of PDHK1 by JX06 blocked the effect of PRMT3 on lactate production. JX06 treatment also attenuated the tumor-promoting role of PRMT3 in HCC in vitro and in vivo. Furthermore, RNA-seq analysis revealed that knockout of PRMT3 downregulates the tumor-associated immune checkpoint, PD-L1, in tumor tissues. Chromatin immunoprecipitation (ChIP) assay demonstrated that PRMT3 promotes lactate-induced PD-L1 expression by enhancing the direct binding of histone H3 lysine 18 lactylation (H3K18la) to the PD-L1 promoter. Tissue microarray analysis showed a positive correlation between PRMT3 and PD-L1 expression in HCC patients. Anti-PD-L1 treatment reversed PRMT3-induced tumor growth and restored CD8+ T cell infiltration. Our research links PRMT3-mediated metabolic reprogramming and immune evasion, revealing that the PRMT3-PDHK1-lactate-PD-L1 axis may be a potential target for improving the efficacy of immunotherapy in HCC.
Sodium oligomannate disrupts the adherence of Ribhigh bacteria to gut epithelia to block SAA-triggered Th1 inflammation in 5XFAD transgenic mice
Sodium oligomannate (GV-971), an oligosaccharide drug approved in China for treating mild-to-moderate Alzheimer’s disease (AD), was previously found to recondition the gut microbiota and limit altered peripheral Th1 immunity in AD transgenic mice. As a follow-up study, we here made advances by pinpointing a Lactobacillus murinus (L.m.) strain that highly expressed a gene encoding a putative adhesin containing Rib repeats (Ribhigh–L.m.) particularly enriched in 5XFAD transgenic mice. Mechanistically, Ribhigh–L.m. adherence to the gut epithelia upregulated fecal metabolites, among which lactate ranked as the top candidate. Excess lactate stimulated the epithelial production of serum amyloid A (SAA) in the gut via the GPR81-NFκB axis, contributing to peripheral Th1 activation. Moreover, GV-971 disrupted the adherence of Ribhigh–L.m. to gut epithelia via direct binding to Rib, which corrected the excess lactate, reduced SAA, and alleviated Th1-skewed inflammation. Together, we gained further insights into the molecular link between gut bacteria and AD progression and the mechanism of GV-971 in treating AD.
Lactylation in cancer: metabolic mechanism and therapeutic strategies
Recent progress in cancer metabolism research has identified lactylation as a critical post-translational modification influencing tumor development and progression. The process relies on lactate accumulation and the activation of lactate-sensitive acyltransferases. Beyond its role in epigenetic regulation, lactylation has emerged as a significant factor in tumor metabolism and evolution, offering fresh opportunities for developing targeted therapies that transcend traditional approaches. This review explores the growing importance of lactylation in cancer biology and highlights its potential for advancing diagnostic tools and therapeutic strategies.
Organoids in the oral and maxillofacial region: present and future
The oral and maxillofacial region comprises a variety of organs made up of multiple soft and hard tissue, which are anatomically vulnerable to the pathogenic factors of trauma, inflammation, and cancer. The studies of this intricate entity have been long-termly challenged by a lack of versatile preclinical models. Recently, the advancements in the organoid industry have provided novel strategies to break through this dilemma. Here, we summarize the existing biological and engineering approaches that were employed to generate oral and maxillofacial organoids. Then, we detail the use of modified co-culture methods, such as cell cluster co-inoculation and air-liquid interface culture technology to reconstitute the vascular network and immune microenvironment in assembled organoids. We further retrospect the existing oral and maxillofacial assembled organoids and their potential to recapitulate the homeostasis in parental tissues such as tooth, salivary gland, and mucosa. Finally, we discuss how the next-generation organoids may benefit to regenerative and precision medicine for treatment of oral-maxillofacial illness.
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