The phenotypic heterogeneity and functional diversity of macrophages confer on them complexed roles in the development and progression of kidney diseases. After kidney injury, bone marrow-derived monocytes are rapidly recruited to the glomerulus and tubulointerstitium. They are activated and differentiated on site into pro-inflammatory M1 macrophages, which initiate Th1-type adaptive immune responses and damage normal tissues. In contrast, anti-inflammatory M2 macrophages induce Th2-type immune responses, secrete large amounts of TGF-β and anti-inflammatory cytokines, transform into αSMA+ myofibroblasts in injured kidney, inhibit immune responses, and promote wound healing and tissue fibrosis. Previous studies on the role of macrophages in kidney fibrosis were mainly focused on inflammation-associated injury and injury repair. Apart from macrophage-secreted profibrotic cytokines, such as TGF-β, evidence for a direct contribution of macrophages to kidney fibrosis is lacking. However, under inflammatory conditions, Wnt ligands are derived mainly from macrophages and Wnt signaling is central in the network of multiple profibrotic pathways. Largely underinvestigated are the direct contribution of macrophages to profibrotic signaling pathways, macrophage phenotypic heterogeneity and functional diversity in relation to kidney fibrosis, and on their cross-talk with other cells in profibrotic signaling networks that cause fibrosis. Here we aim to provide an overview on the roles of macrophage phenotypic and functional diversity in their contribution to pro-fibrotic signaling pathways, and on the therapeutic potential of targeting macrophages for the treatment of kidney fibrosis.

Lactate, once considered a mere byproduct of anaerobic metabolism, is now recognized as a critical signaling molecule with diverse roles in physiology and pathology. There are two stereoisomers of lactate: L- and D-lactate. Recent studies have shown that disruptions in these two lactate stereoisomers have distinct effects on health and disease. L-lactate is central to glycolysis and energy transfer through the Cori cycle but also acts as the dominant lactylation isomer induced by glycolysis, influencing metabolism and cell survival. Although less studied, D-lactate is linked to metabolic disorders and plays a role in mitochondrial dysfunction and oxidative stress. This review focuses on both L- and D-lactate and examines their biosynthesis, transport, and expanding roles in physiological and pathological processes, particularly their functions in cancer, immune regulation, inflammation, neurodegeneration and other diseases. Finally, we assess the therapeutic prospects of targeting lactate metabolism, highlighting emerging strategies for intervention in clinical settings. Our review synthesizes the current understanding of L- and D-lactate, offering insights into their potential as targets for therapeutic innovation.

Myocardial infarction (MI) results in cardiomyocyte necrosis and conductive system damage, leading to sudden cardiac death and heart failure. Studies have shown that conductive biomaterials can restore cardiac conduction, but cannot facilitate tissue regeneration. This study aims to add regenerative capabilities to the conductive biomaterial by incorporating human endometrial mesenchymal stem cell (hEMSC)‐derived exosomes (hEMSC‐Exo) into poly‐pyrrole‐chitosan (PPY‐CHI), to yield an injectable hydrogel that can effectively treat MI. In vitro, PPY‐CHI/hEMSC‐Exo, compared to untreated controls, PPY‐CHI, or hEMSC‐Exo alone, alleviates H₂O₂‐induced apoptosis and promotes tubule formation, while in vivo, PPY‐CHI/hEMSC‐Exo improves post‐MI cardiac functioning, along with counteracting against ventricular remodeling and fibrosis. All these activities are facilitated via increased epidermal growth factor (EGF)/phosphoinositide 3‐kinase (PI3K)/AKT signaling. Furthermore, the conductive properties of PPY‐CHI/hEMSC‐Exo are able to resynchronize cardiac electrical transmission to alleviate arrythmia. Overall, PPY‐CHI/hEMSC‐Exo synergistically combines the cardiac regenerative capabilities of hEMSC‐Exo with the conductive properties of PPY‐CHI to improve cardiac functioning, via promoting angiogenesis and inhibiting apoptosis, as well as resynchronizing electrical conduction, to ultimately enable more effective MI treatment. Therefore, incorporating exosomes into a conductive hydrogel provides dual benefits in terms of maintaining conductivity, along with facilitating long‐term exosome release and sustained application of their beneficial effects.

ObjectiveTumor microenvironment, especially the host immune system, plays a pivotal role in tumor initiation and progression. Profiling of immune signature within tumor might uncover biomarkers for targeted therapies and clinical outcomes. However, systematic analysis of immune-related genes in gastric cancer (GC) has not been reported. MethodsExpressions of a total of 718 immune-related genes were generated in 372 stomach adenocarcinoma (STAD) patients from The Cancer Genome Atlas (TCGA) database using RNA-sequencing data. Integrated bioinformatics analyses were performed to identify prognostic factors as well. ResultsSurvival analyses revealed 73 genes, which were significantly associated with patient’s overall survival (OS). Taken together with clinicopathological parameters, we established a predictive model, containing 10 immune-related genes, which were NRP1, C6, CXCR4, LBP, PNMA1, TLR5, ITGA6, MICB, PBK and TNFRSF18, with powerful efficiency in distinguishing satisfactory or poor survival of STAD patients. Moreover, the top 3 ranked prognostic genes, NRP1, TGFβ2 and MFGE8, were also significantly associated with patient’s OS by an independent validation achieved from Kaplan-Meier plotter database. ConclusionsWe profiled prognostic immune signature and established prognostic predictive model for GC, which could reflect immune disorders within tumor microenvironment, and also may provide novel predictive and therapeutic targets for GC patients in the near future.

Background: Neural tube defects (NTDs) are severe, common birth defects that result from failure of normal neural tube closure during early embryogenesis. Accumulating strong evidence indicates that genetic factors contribute to NTDs etiology, among them, HOX genes play a key role in neural tube closure. Although abnormal HOX gene expression can lead to NTDs, the underlying pathological mechanisms have not fully been understood. Method: We detected that H3K27me3 and expression of the Hox genes in a retinoic acid (RA) induced mouse NTDs model on E8.5, E9.5 and E10.5 using RNA-sequencing and chromatin immunoprecipitation sequencing assays. Furthermore, we quantified 10 Hox genes using NanoString nCounter in brain tissue of fetuses with 39 NTDs patients including anencephaly, spina bifida, hydrocephaly and encephalocele. Results: Here, our results showed differential expression in 26 genes with a > 20-fold change in the level of expression, including 10 upregulated Hox genes. RT-qPCR revealed that these 10 Hox genes were all upregulated in RA-induced mouse NTDs as well as RA-treated embryonic stem cells (ESCs). Using ChIP-seq assays, we demonstrate that a decrease in H3K27me3 level upregulates the expression of Hox cluster A–D in RA-induced mouse NTDs model on E10.5. Interestingly, RA treatment led to attenuation of H3K27me3 due to cooperate between UTX and Suz12, affecting Hox gene regulation. Further analysis, in human anencephaly cases, upregulation of 10 HOX genes was observed, along with aberrant levels of H3K27me3. Notably, HOXB4, HOXC4 and HOXD1 expression was negatively correlated with H3K27me3 levels. Conclusion: Our results indicate that abnormal HOX gene expression induced by aberrant H3K27me3 levels may be a risk factor for NTDs and highlight the need for further analysis of genome-wide epigenetic modification in NTDs.