Acute kidney injury (AKI), triggered by ischemia, sepsis, toxicity, or obstruction, is marked by a rapid impairment of renal function and could lead to the initiation and advancement of chronic kidney disease (CKD). The concept of AKI to CKD transition has gained much interest. Despite a series of studies highlighting the diverse roles of renal macrophages in the immune response following AKI, the intricate mechanisms of macrophage-driven cell-cell communication in AKI to CKD transition remains incompletely understood. In this review, we introduce the dynamic phenotype change of macrophages under the different stages of kidney injury. Importantly, we present novel perspectives on the extensive interaction of renal macrophages with adjacent cells, including tubular epithelial cells, vascular endothelial cells, fibroblasts, and other immune cells via soluble factors, extracellular vesicles, and direct contact, to facilitate the transition from AKI to CKD. Additionally, we summarize the potential therapeutic strategies based on the adverse macrophage-neighboring cell crosstalk.

Lupus nephritis (LN) emerges as a severe complication of systemic lupus erythematosus (SLE), significantly affecting patient survival. Despite improvements in treatment reducing LN's morbidity and mortality, existing therapies remain suboptimal, emphasizing the necessity for early detection to improve patient outcomes.

This study employs bioinformatics and machine learning to identify and validate potential LN biomarkers using immunohistochemistry (IHC). It explores the relationship between these biomarkers and the clinical and pathological characteristics of LN, assessing their prognostic significance. The research provides deeper mechanistic insights by employing Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Additionally, the study characterizes the immune profiles of LN patients through the CIBERSORT algorithm, focusing on the role of interferon-inducible protein 44 (IFI44) as a key biomarker.

IFI44 shows elevated expression in LN-affected kidneys, compared to healthy controls. The levels of IFI44 positively correlate with serum creatinine and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and inversely with serum complement C3 and initial estimated glomerular filtration rate (eGFR).

IFI44 is identified as a promising biomarker for LN, offering potential to refine the assessment of disease progression and predict clinical outcomes. This facilitates the development of more personalized treatment strategies for LN patients.

Acute kidney injury (AKI) substantially increases the risk of developing and worsening chronic kidney disease (CKD). The shift from AKI to CKD is a complex process that involves various cell types, with macrophages playing a key role in responding to renal injury. M1 and M2 macrophages-the two main types of macrophages-have distinct functions at various stages. M1 macrophages induce kidney damage by secreting pro-inflammatory cytokines immediately after injury, whereas M2 macrophages subsequently facilitate kidney tissue repair. The conversion of macrophages from the M1 to M2 subtype is vital for effective repair after renal injury. However, when M2 macrophages infiltrate persistently, they can paradoxically cause fibrosis, thereby complicating recovery. As a key epigenetic regulatory factor, the deacetylase SIRT6 exerts various biological effects through its enzymatic reactions, including the regulation of cellular metabolism, antioxidant stress response, and inhibition of fibrosis. SIRT6 is expressed in all major types of renal resident cells and is demonstrated to protect the kidneys. SIRT6 promotes the transition from the M1 to M2 subtype; nevertheless, this process poses the risk of fibrosis if macrophages remain in the M2 subtype because of the influence of SIRT6. This review aimed (i) to delve into the intricate role of SIRT6 in macrophage polarization toward the M2 subtype in the context of the progression from AKI to CKD and (ii) to explore potential strategies that may effectively target and mitigate the progression from AKI to CKD.

Inflammatory injury promotes the chronic kidney disease (CKD) progression，with renal macrophage accumulation and proliferation of as typical manifestations of inflammatory injury. We aimed to verify fibroblast to macrophage-like cell transition as a new source of macrophages that participate in renal inflammatory injury.

Wistar rats were divided into Sham, ALD (aldosterone infusion for 12 weeks), and ESA (aldosterone infusion and esaxerenone by diet for 12 weeks) groups. Rat kidney interstitial fibroblast (RKF) were cultured, induced with aldosterone or CSF1, and treated with antagonists in vitro. The proportions of FSP-1+ F4/80+ cells in the rat kidney and RKF, including M1 marker iNOS/CD86 and M2 marker CD206/CD163 were assessed by flow cytometry and immunofluorescence staining. Single-cell RNA sequencing was used to assess the origin of macrophages in the rat kidneys and related gene expression. Additionally, immunofluorescence was used to detect FSP-1+ F4/80+ cells in kidney biopsy samples from CKD patients.

Fibroblast to macrophage-like cell transition was observed in both the kidneys of aldosterone-infused rats and in vitro aldosterone-treated RKF, with a predominant differentiation into the M1 phenotype. This transformation was mediated through the MR/CSF1 signalling pathway, revealing a novel source of macrophages and providing significant insights into the mechanisms underlying organ fibrosis.

Aldosterone induces fibroblast to macrophage-like cell transition through the MR/ CSF1 pathway.

Damage to myocardial tissues, leading to myocardial fibrosis, is a significant pathological hallmark across various heart diseases. SMAD3, a central transcriptional regulator within the transforming growth factor-beta (TGF-β) signaling pathway, plays a pivotal role in the pathological progression of myocardial fibrosis and cardiac remodeling. It intricately regulates physiological and pathological processes encompassing cell proliferation, differentiation, tissue repair, and fibrosis. Notably, SMAD3 exerts crucial influences in myocardial fibrosis subsequent to myocardial infarction, pressure overload-induced myocardial fibrosis, diabetic cardiomyopathy (DCM), aging-associated cardiac fibrosis and myocarditis-related myocardial fibrosis. The targeted modulation of genes or the utilization of compounds, including traditional Chinese medicine (paeoniflorin, baicalin, and genistein et al.) and other pharmaceutical agents that modulate SMAD3, may offer avenues for restraining the pathological cascade of myocardial fibrosis. Consequently, targeted regulation of SMAD3 associated with myocardial fibrosis may herald novel therapeutic paradigms for ameliorating myocardial diseases.

Renal fibrosis is a critical pathological characteristic of chronic kidney disease, and current antifibrotic therapies has limited efficacy. Sodium butyrate (NaB) has been shown to be highly effective in mitigating bleomycin-induced pulmonary fibrosis; however, its specific impact on renal fibrosis and the underlying mechanisms remain unclear. This study aims to elucidate the role and mechanism of NaB in renal fibrosis by using a mouse model of renal fibrosis induced through Unilateral Ureteral Obstruction (UUO) and folic acid (FA) administration.

NaB significantly decreased the distribution of collagen fibers in renal tissues and mitigated fibrosis in a dose-dependent manner. Further analysis indicated that NaB inhibited M2 macrophage polarization in the renal tissues of UUO model mice by blocking the phosphorylation of STAT6, hence reducing renal fibrosis. Additionally, in vitro experiments demonstrated that NaB inhibited fibroblast activation induced by M2 macrophages. Mechanistic studies revealed that NaB attenuates fibroblast activation and M2 macrophage polarization by upregulating LKB1 and inhibiting the activation of the STAT6 signaling pathway.

NaB may exert its effects by inhibiting the activation of the IL-4/STAT6 signaling pathway through the upregulation of LKB1, which suppress the polarization of M2 macrophages and consequently reduce renal fibrosis. These findings establish a theoretical foundation for NaB as a novel drug candidate for renal fibrosis and indicate its potential applicability in clinical treatments for this condition.

Inflammation plays a crucial role in the occurrence and development of renal fibrosis. Lymphatic vessels have emerged as new hotspots in the domain of inflammation. Recent studies have revealed that macrophages are involved in lymphangiogenesis through direct and indirect mechanisms. However, the underlying mechanisms of macrophage transdifferentiation into lymphatic endothelial cells (LECs) are still poorly understood.

In vivo, thirty male Wistar rats were randomly divided into a sham group, an aldosterone group and an aldosterone + esaxerenone group. In vitro, Raw 264.7 cells and bone marrow-derived macrophages (BMDMs) were used. H&E, Masson, western blotting, immunohistochemistry, immunofluorescence, flow cytometry, and BMDM tube formation assays were used to assess renal fibrosis and lymphangiogenesis in a rat model of aldosterone-induced renal injury.

In this study, we observed pathological renal fibrosis and lymphangiogenesis in 12-week-old rats after aldosterone infusion. In addition, the treatment of rats with esaxerenone, a mineralocorticoid receptor blocker (MRB), significantly reduced renal lymphangiogenesis and fibrosis. Interestingly, we found that aldosterone can activate MR to stimulate macrophages to secrete vascular endothelial growth factor C (VEGF-C) and promote lymphatic angiogenesis.

Our data suggest that renal fibrosis occurs in aldosterone-treated rats and that inflammation-induced macrophage transdifferentiation into LECs occurs during this process and that MRB attenuates renal fibrosis and lymphangiogenesis due to inflammatory injury.

The inflammatory phenotype of vascular smooth muscle cells (VSMCs) is an important factor in triggering vascular disease, and interleukin-6 (IL-6) is one of the earliest inflammatory cytokines upregulated in many inflammatory contexts. Angiotensin II-1 receptor autoantibody (AT1-AA) can promote the phenotypic transformation of VSMCs into macrophage-like cells, then synthesize abundant IL-6 to induce vascular inflammation. Previous studies suggested that abnormal BK channel function on the surface of VSMCs played an important role in the synthesis of IL-6, but the mechanism of abnormal BK channel involvement in AT1-AA-induced IL-6 synthesis in VSMCs was unclear. In this study, the agonist NS1619 of the BK channel and the inhibitor Paxilline were used to reverse or exacerbate IL-6 synthesis in AT1-AA-induced VSMCs. It is known that NF-κB can enter the nucleus due to increased calcium ion concentration caused by BK channel dysfunction, thereby increasing IL-6 transcription. This study observed that Paxilline pretreatment significantly increased the residence time of AT1-AA-induced NF-κB in the nucleus, while NS1619 pretreatment showed the opposite trend. JSH-23 inhibiting NF-κB nuclear entry reversed the increase in IL-6 expression in VSMCs induced by AT1-AA. This study found that AT1-AA enhanced NF-κB nuclear translocation by inhibiting BK channel function, which in turn promoted IL-6 transcription in VSMCs, increased IL-6 synthesis, and induced vascular inflammation. This study revealed the importance of BK channel dysfunction in the process of AT1-AA increasing IL-6 synthesis and promoting vascular inflammation, and provided a new idea for alleviating vascular inflammatory diseases from the perspective of improving potassium channel function.

Fibrosis, characterized by abnormal deposition of structural proteins, is a major cause of tissue dysfunction in chronic diseases. The disease burden associated with progressive fibrosis is substantial, and currently approved drugs are unable to effectively reverse it. Immune cells are increasingly recognized as crucial regulators in the pathological process of fibrosis by releasing effector molecules, such as cytokines, chemokines, extracellular vesicles, metabolites, proteases, or intercellular contact. Therefore, targeting the immune microenvironment can be a potential strategy for fibrosis reduction and reversion. This review summarizes the recent advances in the understanding of the immune microenvironment in fibrosis including phenotypic and functional transformations of immune cells and the interaction of immune cells with other cells. The novel opportunities for the discovery and development of drugs for immune microenvironment remodeling and their associated challenges are also discussed.

Cellular senescence participates in the pathophysiology of post-stenotic kidney damage, but how it regulates tissue remodeling is incompletely understood. Macrophage-myofibroblast transition (MMT) contributes to the development of tissue fibrosis. We hypothesized that cellular senescence contributes to MMT and renal fibrosis in mice with renal artery stenosis (RAS). INK-ATTAC mice expressing p16INK-4a and green fluorescent protein in senescent cells were assigned to control or unilateral RAS, untreated or treated with AP20187 (an apoptosis inducer in p16INK-4a-expressing cells) for 4 weeks. Renal perfusion was studied in vivo using micro-MRI, and kidney morphology, senescence, and MMT ex vivo. Cellular senescence was induced in human renal proximal tubular epithelial cells (HRPTEpiC) in vitro, and interferon-induced transmembrane protein-3 (IFITM3), a cellular senescence vector, was silenced (siRNA) or over-expressed (plasmid). HRPTEpiC were then co-incubated with macrophages with silenced integrin-3 (ITGB3), a regulator of mesenchymal transitions. CD68/p16INK-4a/α-SMA co-expression and senescence markers were studied. Murine RAS kidneys showed increased expression of p16INK-4a and MMT markers (F4/80, α-SMA) vs. controls, which decreased after AP20187, as did renal fibrosis and plasma creatinine, whereas renal perfusion increased. IFITM3 and ITGB3 expression were upregulated in senescent HRPTEpiC or co-cultured macrophages, respectively. MMT markers and TGF-β/Smad3 expression also rose in these macrophages and decreased after IFITM3 or ITGB3 silencing. p16INK-4a-expressing macrophages may regulate interstitial fibrosis in RAS via MMT. This process is associated with elevated expression of ITGB3 and TGF-β/Smad3 pathway activation through neighboring senescent cell-derived IFITM3. These findings may implicate MMT as a therapeutic target in ischemic kidneys.

Renal fibrosis is a pathological consequence of end-stage chronic kidney disease, driven by factors such as oxidative stress, dysregulated fatty acid metabolism, extracellular matrix (ECM) imbalance, and epithelial-to-mesenchymal transition. Peroxisomes play a critical role in fatty acid β-oxidation and the scavenging of reactive oxygen species, interacting closely with mitochondrial functions. Nonetheless, current research often prioritizes the mitochondrial influence on renal fibrosis, often overlooking the contribution of peroxisomes. This comprehensive review systematically elucidates the fundamental biological functions of peroxisomes and delineates the molecular mechanisms underlying peroxisomal dysfunction in renal fibrosis pathogenesis. Here, we discuss the impact of peroxisome dysfunction and pexophagy on oxidative stress, ECM deposition, and renal fibrosis in various cell types including mesangial cells, endothelial cells, podocytes, epithelial cells, and macrophages. Furthermore, this review highlights the recent advancements in peroxisome-targeted therapeutic strategies to alleviate renal fibrosis.

Massive of macrophages are recruited to the injured nerve to remove the axonal and myelin debris for creating a conducive micro-environment for nerve regeneration. However, the fate of macrophages after the debris clearing remains unclear. In this study, we demonstrated that the number of macrophages in the crush injured sciatic nerve of mice peaked at 7 days post injury (dpi) and then decreased significantly in the late stage of nerve injury. Mechanismly, the macrophage elimination was primarily attributed to TGF-β/Smad3 signaling dependent macrophage-myofibroblast transition (MMT), rather than apoptosis or out-migration. Furthermore, MMT caused collagen deposition is conducive to nerve regeneration. Both macrophage depletion via clodronate liposomes and MMT blockade using TGF-β/Smad3 inhibitor significantly reduced collagen deposition and impaired functional nerve regeneration. In summary, the present study indicates that TGF-β/Smad3 regulated MMT contributes to macrophage elimination and functional recovery in the injury nerve.

Atherosclerosis (AS) is a chronic progressive arterial disease that is associated with macrophage autophagy and AMP-activated protein kinase (AMPK)/mechanistic target of the rapamycin (mTOR) pathway. Tetrahydropalmatine (THP) can activate AMPK-dependent autophagy. We aim to study the mechanism of macrophage autophagy mediated by THP in the treatment of AS via the AMPK/mTOR pathway.

High-fat diet apolipoprotein E-deficient mice and ox-LDL-induced RAW264.7 cells were used to mimic the AS model, then THP was administered. Cell viability was detected by MTT. Pathological aorta lesions were detected using Hematoxylin and Eosin, Masson, and oil red staining. Lipid metabolism indices and inflammatory factors were measured using ELISA. A transmission electron microscope was used to observe autophagosomes. Autophagy and AMPK/mTOR pathway protein expression was detected by immunofluorescence and Western blot. The AMPK inhibitor 9-β-d-Arabinofuranosyl Adenine (Ara-A) was used to validate the effect of THP. The mRNA expression of Beclin-1 and MCP-1 was detected by q-PCR.

THP administration regulated lipid metabolism by lowering total cholesterol, triacylglycerol, low-density lipoprotein, and high-density lipoprotein levels, and suppressed aortic damage. THP suppressed aortic damage and regulated lipid metabolism by altering serum lipid levels. THP reduced inflammation and macrophage CD68 expression. Twenty μg/mL THP reduced cell viability. THP decreased cholesterol uptake and increased efflux, promoting autophagy. THP increased autophagosome number, LC3B expression, and autophagy markers p-AMPK/AMPK and LC3-II/LC3-I. THP also decreased p-mTOR/mTOR and P62. THP increased Beclin-1 mRNA expression and decreased MCP-1 mRNA expression. Ara-A reversed THP's effects.

THP promotes macrophage autophagy by inhibiting the AMPK/mTOR pathway to attenuate AS.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are inter-related clinical and pathophysiological disorders. Cells of the innate immune system, such as granulocytes and macrophages, can induce AKI through the secretion of pro-inflammatory mediators such as cytokines, chemokines and enzymes, and the release of extracellular traps. In addition, macrophages and dendritic cells can drive the progression of CKD through a wide range of pro-inflammatory and pro-fibrotic mechanisms, and by regulation of the adaptive immune response. However, innate immune cells can also promote kidney repair after acute injury. These actions highlight the multifaceted nature of the way by which innate immune cells respond to signals within the kidney microenvironment, including interaction with the complement and coagulation cascades, cells of the adaptive immune system, intrinsic renal cells and infiltrating mesenchymal cells. The factors and mechanisms that underpin the ability of innate immune cells to contribute to renal injury or repair and to drive the progression of CKD are of great interest for understanding disease processes and for developing new therapeutic approaches to limit AKI and the AKI-to-CKD transition.

Tendon degeneration and injury often result in significant pain and functional impairment. Typically, tendon healing occurs through a scar-mediated response and may progress to chronic tendinopathy without timely intervention. However, the molecular mechanisms underlying early tendon repair remain poorly understood. Further investigation is also impeded by the limited availability of early tendon injury samples in clinical settings. In this study, we established a puncture-induced tendon injury model to investigate the molecular patterns and cellular subpopulations involved in early tendon injury across multiple time points. RNA sequencing identified seven gene sets with distinct expression profiles during the early stages of tendon injury. Single-cell RNA sequencing further revealed eight myeloid cell types and seven mesenchymal cell types participating in the tendon repair process. Together, these findings illuminate the molecular and cellular dynamics coordinating early tendon repair, providing insights that could inform future clinical treatments for tendinopathy and tendon injury.

Cellular senescence disrupts tissue homeostasis and diminishes physiological integrity, leading to the accumulation of senescent cells (SCs) in multiple senescence-associated diseases such as chronic kidney disease (CKD). Treatment of SCs has been approved to be a feasible approach to these diseases. However, curing SCs in different cell types remains challenging. In this study, we leveraged the high expression of glutaminase (GLS) in SCs to develop a drug delivery system utilizing γ-poly glutamic acid (γ-PGA) conjugated with octadecylamine (ODA) to encapsulate rapamycin (RP), resulting in a GLS-responsive drug delivery system, designated as RPPO. In a model of drug induced senescence, the γ-PGA component of RPPO was degraded by cellular GLS, facilitating the release of encapsulated RP and rejuvenating SCs by restoring the autophagic capacity. Additionally, in a model of CKD in mice, RPPO enhanced recovery by rejuvenating SCs, reducing fibrosis, and alleviating inflammation. Thus, this senescent cell-responsive drug delivery system presents a novel approach for the treatment of CKD.

Despite standard-of-care immunosuppression, acute rejection remains commonly observed in kidney transplants and leads to chronic graft injury and failure in many transplanted patients. Mechanisms underlying acute and chronic kidney graft injury are incompletely understood, undermining the development and implementation of therapeutic strategies to improve outcomes. This compels the use of preclinical kidney transplant models to identify components and mechanisms mediating acute and chronic graft injury. Mouse models have been instrumental in establishing basic principles of alloimmune responses and the rejection of heart allografts. There is increasing use of mouse models to extend these studies to kidney transplantation, but the relevance of the findings to clinical kidney transplants remains under scrutiny. Here, we discuss the strengths and weaknesses of mouse models of kidney allograft responses and injury. Although obvious weaknesses arise when considering the relevance to clinical kidney transplants, there are new models that recapitulate many features of kidney graft injury in the clinical scenario and have much to contribute to understanding innate and donor alloantigen-specific mechanisms underlying kidney allograft injury. As in most preclinical studies, the pertinent use of kidney allogeneic transplants in mice comes down to the judicious choice of test questions and the choice of appropriate donors and recipients for the chosen model.

Radiotherapy is an effective treatment for head and neck cancer; however, irradiated normal tissues are inevitably damaged, resulting in skin radioactive fibrosis. Dicliptera chinensis polysaccharide (DCP), the primary active compound extracted from the natural medicinal Dicliptera chinensis, exhibits antioxidant, anti-inflammatory, and anti-radiation properties. In this study, we investigated the protective effects of DCP against radioactive fibrosis in rat dermal fibroblasts (RDF) and explored the underlying mechanisms involved.

RDFs were treated with DCP, and the CCK8 assay was used to determine cellular activity. The rates of apoptosis and cell cycle progression were detected using flow cytometry. mRNA expression levels were quantified using real-time polymerase chain reaction. Protein levels were analysed through Western blotting and immunofluorescence staining RESULTS: DCP reduced radiation-induced apoptosis, and the cell cycle G2/M arrest was alleviated. Furthermore, DCP decreased the expression of key fibrosis-related markers, including α-SMA, TGF-β1, Smad3, and CTGF.

DCP exhibits a protective effect against radiation-induced fibrosis.

Sepsis-associated pulmonary fibrosis (SAPF) is a critical pathological stage in the progression of sepsis-induced acute respiratory distress syndrome. While the aggregation and activation of lung fibroblasts are central to the initiation of pulmonary fibrosis, the macrophage-myofibroblast transition (MMT) has recently been identified as a novel source of fibroblasts in this context. However, the mechanisms driving MMT remain inadequately understood. Given the emerging role of migrasomes (novel extracellular vesicles mediating intercellular communication), we investigated their involvement in pulmonary fibrosis. Here we utilized a lipopolysaccharide-induced SAPF mouse model and an in vitro co-culture system of fibroblasts and macrophages to observe the MMT process during SAPF. We found that lipopolysaccharide exposure suppresses PGC-1α expression in lung fibroblasts, resulting in mitochondrial dysfunction and the accumulation of cytosolic mitochondrial DNA (mtDNA). This dysfunction promotes the secretion of mtDNA-containing migrasomes, which, in turn, initiate the MMT process and contribute to fibrosis progression. Notably, the activation of PGC-1α mitigates mitochondrial dysfunction, reduces mtDNA-migrasome release, inhibits MMT and alleviates SAPF. In conclusion, our study identifies the suppression of PGC-1α in lung fibroblasts and the subsequent release of mtDNA migrasomes as a novel mechanism driving MMT in SAPF. These findings suggest that targeting the crosstalk between fibroblasts and immune cells mediated by migrasomes could represent a promising therapeutic strategy for SAPF.

Acute kidney injury (AKI) is increasingly being recognized as a systemic disorder associated with significant morbidity and mortality. AKI manifests with extensive cellular damage, necrosis, and an intense inflammatory response, often leading to late-stage interstitial fibrosis. Although the mechanisms underlying renal injury and repair remain poorly understood, macrophages (pivotal inflammatory cells) play central roles in AKI. They undergo polarization into pro-inflammatory and anti-inflammatory phenotypes, contributing dynamically to both the injury and repair processes while maintaining homeostasis. Macrophages modulate microenvironmental inflammation by releasing extracellular vesicles (EVs) containing pro- or anti-inflammatory signaling molecules, thereby influencing the regulation of tissue injury. The injured tissue cells release EVs and activate local macrophages to initiate these responses. Our bibliometric analysis indicated that a shift has occurred in AKI macrophage research towards therapeutic strategies and clinical translation, focusing on macrophage-targeted therapies, including exosomes and nanoparticles. This review highlights the roles and mechanisms of macrophage activation, phenotypic polarization, and trans-differentiation in AKI and discusses macrophage-based approaches for AKI prevention and treatment. Understanding the involvement of macrophages in AKI contributes to the comprehension of related immune mechanisms and lays the groundwork for novel diagnostic and therapeutic avenues.

Natural products have emerged as crucial sources of biologically active compounds, holding promise for applications in drug development. Among the extensively researched pentacyclic triterpenes, hederagenin (HG) stands out for its diverse biological activities and serves as a valuable scaffold for synthesizing novel derivatives. These derivatives hold significant promise for the development of novel therapeutic agents aimed at treating a wide range of diseases. Over the past years, a multitude of HG derivatives with varied bioactivities have been synthesized through chemical modifications. This review article consolidates the most recent findings (since 2017) on HG derivatives, emphasizing their biological effects and mechanisms of action in both in vitro and in vivo models. The objective of this compilation is to offer insights and direct future research endeavors in the realm of HG.

METTL3, a key enzyme in N6-methyladenosine (m6A) modification, plays a crucial role in the progression of renal fibrosis, particularly in chronic active renal allograft rejection (CAR). This study explored the mechanisms by which METTL3 promotes renal allograft fibrosis, focusing on its role in the macrophage-to-myofibroblast transition (MMT). Using a comprehensive experimental approach, including TGF-β1-induced MMT cell models, METTL3 conditional knockout (METTL3 KO) mice, and renal biopsy samples from patients with CAR, the study investigates the involvement of METTL3/Smad3 axis in driving MMT and renal fibrosis during the episodes of CAR. We found that elevated m6A modification and METTL3 levels strongly correlated with enhanced MMT and increased fibrotic severity. METTL3 knockout (METTL3 KO) significantly increased the m6A modification of Smad3, decreased Smad3 expression, and inhibited M2-driven MMT. Smad3 knockdown with siRNA (siSmad3) further inhibited M2-driven MMT, while Smad3 overexpression rescued the inhibitory effects of METTL3 silencing, restoring M2-driven MMT and fibrotic tissue damage. Additionally, the METTL3 inhibitor STM2457 effectively reversed M2-driven MMT and alleviated fibrotic tissue damage in CAR. These findings highlight that METTL3 enhances M2-driven MMT in renal fibrosis during CAR by promoting the TGF-β1/Smad3 axis, suggesting that METTL3 is a promising therapeutic target for mitigating renal fibrosis in CAR.

Myofibroblasts combine features of fibroblasts and smooth muscle cells, and they are reactive cells present under injury conditions. This study was performed to explore the mechanism that methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2) mediated m6A modification in sepsis-induced AKI (SAKI) through regulating the collagen accumulation in myofibroblasts. Gene expression microarrays related to SAKI were obtained from the GEO database, and the hub protein involved was screened using PPI. The SAKI mice were induced by cecal ligation and puncture (CLP). MTHFD2 expression was significantly elevated in the kidneys of CLP-induced mice, and SAKI was ameliorated by knocking down MTHFD2 in kidney tissues. MTHFD2 promoted N6-methyladenosine (m6A) modification in kidney tissues of CLP-induced mice by increasing the content of methylated donor s-adenosylmethionine (SAM). MTHFD2 enhanced LOX mRNA stability in an m6A modification-dependent manner, thereby promoting its expression. Knockdown of MTHFD2 inhibited collagen accumulation in myofibroblasts, whereas overexpression of LOX accelerated fibrosis and SAKI in mice in the presence of sh-MTHFD2. In conclusion, our results show that MTHFD2 promotes LOX expression in an m6A-dependent manner, thereby mediating SAKI progression.

Long-term nephrocalcinosis leads to kidney injury, fibrosis, and even chronic kidney disease (CKD). Macrophage-to-myofibroblast transition (MMT) has been identified as a new mechanism in CKD, however, the effect of MMT in calcium oxalate (CaOx)-induced kidney fibrosis remains unclear. In this study, abundant MMT cells are identified by immunofluorescence (IF) and flow cytometry in kidney tissues of patients with CaOx-related CKD, a male mouse model, and CaOx-treated macrophages. Clodronate liposome (CLO)-mediated macrophage depletion attenuates fibrosis in male nephrocalcinosis mice. Transcriptomic sequencing reveals that histone methyltransferase (HMTs), EZH2, is highly expressed in nephrocalcinosis. Ezh2 inducible knock-out or inhibition by GSK-126 attenuates MMT and renal fibrosis. Mechanistically, ChIP and transcriptomic sequencing show that EZH2 inhibition reduces the enrichment of H3K27me3 on the Dusp23 gene promoter and elevates Dusp23 expression. The Co-IP and molecular docking analysis shows that DUSP23 mediates the dephosphorylation of pSMAD3 (Ser423/425). Thus, our study found that EZH2 promotes kidney fibrosis by meditating MMT via the DUSP23/SMAD3 pathway in nephrocalcinosis.

Hepatoblastoma (HB) is the predominant hepatic malignancy among children. Despite therapeutic options for HB were gradually refined in recent years, patients with metastasis suffer from an unsatisfactory prognosis. Pyroptosis is a type of programmed and inflammatory necrosis. Neutrophils are crucial in innate immunity, which were shown to be associated with tumor progression. Our study strived to unravel the relationship between neutrophil-induced pyroptosis (NIP) and HB.

The clinical and bulk RNA sequencing data of 38 patients with HB were obtained from Shanghai Children's Medical Center. We established NIP score based on the LASSO regression. The single-cell RNA sequencing data (GSE186975) were used for for key genes identification, cellular communication, and differentiation trajectories of neutrophils. KEGG, GO, GSVA, and ssGSEA enrichment were used to analyze biological functions, including neutrophil extracellular traps (NETs), NOD-like receptors pathway, neutrophil activation, neutrophil-mediated cytotoxicity, and others.

We constructed a NIP score based on the expression of three genes related to neutrophil and pyroptosis, namely ELANE, CASP1, and NOD2, which was positively correlated with a favorable prognosis of HB. Moreover, we clarified the function of ELANE in HB microenvironmwnt. Immunohistochemistry and transcriptome analysis unraveled a significant correlation between NETs and pyroptosis in HB, suggesting the key role of NETs-related neutrophils in inducing pyroptosis and prolonging survival. We also found upregulated tumor-promoting and immunosuppression-related pathways in the HB microenvironment. In addition, we clarified the growth trajectories and phenotypic changes of neutrophils in the immune microenvironment of HB, which can serve as potential targets for immunotherapy.

The novel NIP score for patients with HB shows high predictive value for survival. Moreover, we identified biological function, cellular communication, and growth trajectories of neutrophils in HB. Our findings broaden insights into the treatment of HB.

Chronic kidney disease (CKD) involves ongoing impairment of kidney function and structural changes. Previous studies indicated that males have a substantially higher prevalence of CKD than those observed in females. Here, we compared the gender differences in CKD development by comparing age-matched male and female mice subjected to a 0.25% adenine diet (AD) for two weeks. Male mice showed a significantly greater decrease in kidney function than female mice, as evidenced by the elevated blood urea nitrogen levels (M-AD: 160 ± 5 mg/dL, F-AD: 90 ± 4 mg/dL; p < 0.001). Furthermore, male mice kidneys exhibited pronounced tubule dilation and kidney damage, as detected by histological and biochemical methods. The extent of fibrosis was quantified using multiple biological methods, revealing a greater degree of fibrosis in male kidneys. We next indicated the inflammatory responses in the kidneys. Similar to the extent of fibrosis, AD-fed male mice showed significantly increased levels of pro-inflammatory markers, including cytokine expression and infiltration of immune cell, compared to female mice. Based on in vivo observations, the anti-inflammatory and anti-fibrotic effects of 17β-estradiol (E2) were further evaluated in vitro conditions. E2 pre-treatment significantly reduced lipopolysaccharide-induced inflammatory response through inhibition of the nuclear factor-kappa B (NF-κB) pathway in NRK52E renal epithelial cells. In NRK49F renal fibroblasts, E2 pre-treatment also reduced TGFβ-induced fibrotic responses. We further demonstrated that E2 markedly decreased fibrosis and inflammation in AD-fed mouse kidneys. Our observations revealed that male mice kidneys exhibited a heightened inflammatory and fibrotic response compared to female mice kidneys. Additionally, our findings suggest that the observed sex differences may be partially attributed to the potential anti-inflammatory and anti-fibrotic effects of E2.

As deoxyribonucleic acis (DNA) nanotechnology advances, DNA, a fundamental biological macromolecule, has been employed to treat various clinical diseases. Among the advancements in this field, tetrahedral frameworks nucleic acids (tFNAs) have gained significant attention due to their straightforward design, structural simplicity, low cost, and high yield since their introduction by Turberfield in the early 2000s. Due to its stable spatial structure, tFNAs can resist the impact of innate immune responses on DNA and nuclease activity. Meanwhile, structural programmability of tFNAs allows for the development of static tFNA-based nanomaterials through the engineering of functional oligonucleotides or therapeutic molecules and dynamic tFNAs through the attachment of stimuli-responsive DNA apparatuses. This review first summarizes the key merits of tFNAs, including natural biocompatibility, biodegradability, structural stability, unparalleled programmability, functional diversity, and efficient cellular internalization. Based on these strengths, this review comprehensively analyzes applications of tFNAs in different clinical settings, including orthopedics, stomatology, urinary system diseases, liver-related diseases, tumors, infection, neural system diseases, ophthalmic diseases, and immunoprophylaxis. We also discuss the limitations of tFNAs and the challenges encountered in preclinical studies. This review provides new perspectives for future research and valuable guidance for researchers working in this field.

Acute rejection (AR) is one of the significant factors contributing to poor prognosis in patients following kidney transplantation. Neutrophils are the main cause of early host-induced tissue injury. This paper intends to investigate the possible mechanisms of neutrophil involvement in acute rejection in renal transplantation.

Samples were analyzed for their relationship with immune cells using CIBERSORT. WGCNA was used to identify modules with high relevance to neutrophils and hub genes in the modules were extracted. The effect on neutrophil function after blocking formyl peptide receptor 1 (FPR1) was tested in vitro experiments. The effects of blocking FPR1 on neutrophil function as well as acute rejection were tested in vivo after constructing a mouse kidney transplant model.

The proportion of neutrophils was higher in the AR group than in the non-rejection group, and FPR1 was identified as an important gene in the regulation of acute rejection in kidney transplantation by neutrophils. At the cellular level, blocking FPR1 inhibited the activation of the ERK1/2 pathway, decreased ferrous ion content, affected the expression of iron metabolism-related proteins, and suppressed the formation of NETs. In the acute rejection model of renal transplantation, blockade of FPR1 decreased graft neutrophil infiltration and NETs content. Meanwhile, blocking FPR1 attenuated graft injury during acute rejection.

This study found that FPR1 might be an important molecule involved in neutrophils during acute rejection of kidney transplantation, explored the relationship between kidney transplantation and neutrophils, and provided potential treatment methods for clinical practice.

In our investigation, we aimed to shed light on the role of senescent cells in renal fibrosis, considering the observed correlation between renal tubular epithelial cell senescence and the presence of renal fibrosis. Our findings confirm the manifestation of senescence characteristics in renal tubular epithelial cells during renal fibrosis and establish their capacity to trigger a transition from macrophages to myofibroblasts, known as macrophage-myofibroblast transition (MMT). Additionally, our study uncovered that extracellular vesicles released by senescent HK-2 cells (sHK-2) play a pivotal role in facilitating MMT. Subsequently, we investigated the miRNA profile in sHK-2-derived extracellular vesicles (sHK-2-EVs) and confirmed the elevated abundance of specific miRNAs, including miR-20a-5p and miR-21-5p, compared to normal HK-2-EVs. Notably, these miRNAs possess the capability to induce M2-like polarization in macrophages and enhance the expression of TGF-β. Moreover, TGF-β can stimulate macrophages to produce miR-20a-5p and miR-21-5p, establishing a positive feedback loop that amplifies the TGF-β/Smad pathway and facilitates the process of macrophage-myofibroblast transition.

The risk of kidney fibrosis is significantly elevated in individuals with diabetes, chronic nephritis, trauma, and other underlying conditions. Concurrently, human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) and their extracellular vesicles (MSC-Exos) have gained prominence in regenerative medicine. In light of these observations, we are undertaking a meta-analysis to elucidate the influence of hUCB-MSCs and MSC-Exos on kidney fibrosis.

To identify eligible trials, we conducted a comprehensive search of the CNKI, PubMed, Web of Science and Wanfang databases from inception to 24 October 2022. Furthermore, the methodological quality of the included studies was evaluated using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) risk-of-bias tool. Besides, the weighted standard mean difference (SMD) with a 95% confidence interval (CI) was calculated using the Review Manager 5.4 software. The Stata (12.0) software was employed to assess the impact of factors on outcome heterogeneity and publication bias in the study. A total of 645 related research studies were retrieved, of which 14 that involved 219 experimental animals were included in the study.

In comparison to the control treatment, treatment with Human UCB MSC and MSC-Exos was observed to significantly enhance renal function in animal models of kidney fibrosis. This was evidenced by a reduction in serum creatinine (Scr) levels (p < 0.00001) and blood urea nitrogen (BUN) levels (p < 0.00001), as well as reduction of CD68+ macrophages (p < 0.00001), TdT-mediated dUTP Nick-End labeling (TUNEL)+ tubular cells(p < 0.00001), α-SMA levels (p = 0.0009) and TGF-β1 (p < 0.00001). P < 0.05 is deemed to indicate a statistically significant difference. Alpha-smooth muscle actin (α-SMA) is a specific protein that is normally expressed in myofibroblasts. The term "CD68+ macrophages" refers to macrophages that express the CD68 protein on their cell surface. Both macrophages and myofibroblasts have been linked to the development of kidney fibrosis. In this study, the quantity of CD68+ macrophages and α-SMA was employed as a means of gauging the extent of renal fibrosis. Additionally, transforming growth factor beta 1 (TGF-β1) is a significant cytokine implicated in the pathogenesis of kidney fibrosis. TUNEL-positive tubular cells represent tubular cells undergoing apoptosis. It is hypothesized that this may result in a reduction of tubular apoptosis and a delay in kidney fibrosis, due to the inhibition of the transformation of macrophages into myofibroblasts (MMT) and the disruption of the kidney fibrogenic niche.

The principal findings of this preclinical systematic review indicate that hUCB MSC and MSC-Exos have a substantial protective impact against kidney fibrosis. Kidney transfer remains the final option for traditional renal fibrosis treatment. The lack of donors and high cost make it challenging for many patients to access appropriate treatment. Although this study still suffers from three shortcomings: sample size, methodological consistency and translational challenges, the hUCB MSC and MSC-Exos have been demonstrated to reduce tubular apoptosis and inhibit fibrotic progression. The hUCB MSC and MSC-Exos offer a promising alternative due to their lower price and accessibility. Nevertheless, further high-quality studies are required in the future to address the methodological limitations identified in this review.

Identifier INPLASY2022100104.

Many studies have shown that specific lactic acid bacteria (LAB) strains can delay obesity, offering a viable alternative to medications and surgeries. However, the mining and development of highly effective LAB strains for obesity control is still limited. In this study, the naturally highly acid-tolerant and gamma-aminobutyric acid-producing Levilactobacillus brevis D17 and its glnR deletion strain were used to investigate their anti-obesity effects. In an 8-week mouse experiment, L. brevis D17 and its glnR-deletion strain D17ΔglnR significantly reduced weight gain by 28.4% and 29.1%, respectively, improving abnormal serum indicators and glucose metabolism caused by a high-fat diet. Furthermore, L. brevis D17 and its glnR-deletion strain D17ΔglnR successfully colonized in the gut. Both D17 and D17ΔglnR interventions significantly restored the relative abundance of Muribaculaceae, Ileibacterium valens, Lactobacillus, Faecalibaculum, Bifidobacterium globosum, Akkermansia muciniphila, and Romboutsia ilealis, whereas they significantly reduced potentially harmful bacteria like Leptogranulimonas, Flintibacter, and Alistipes. Additionally, L. brevis intervention effectively decreased the levels of primary bile acids and increased secondary bile acids in the gut, thus balancing bile acid metabolism. The transcriptional analysis suggested that D17 and D17ΔglnR interventions may activate the AMPK signaling pathway in the liver to inhibit lipogenesis, activate the cAMP pathway to promote lipolysis, and inhibit pro-inflammatory macrophage infiltration to block inflammatory responses. These results indicate that L. brevis D17 and its glnR-deletion mutant strain D17ΔglnR show great potential in combating obesity. Moreover, these results also provide insights into the underlying mechanism behind their anti-obesity properties.

Low back pain after spine surgery is a major complication due to excessive epidural fibrosis, which compresses the lumbar nerve. Macrophage-myofibroblast transition (MMT) promoted epidural fibrosis in a mouse laminectomy model. Previously, we demonstrated that LincR-PPP2R5C regulated CD4 + T-cell differentiation. Here, we aimed to explore the roles and mechanisms of LincR-PPP2R5C in macrophages in epidural fibrosis. In M2 macrophages, the level of LincR-PPP2R5C was significantly decreased. Upon overexpression, LincR-PPP2R5C induced M1-macrophage polarization and reduced MMT. In contrast, LincR-PPP2R5C deficiency promoted M2-macrophage polarization and increased MMT. Mechanistically, LincR-PPP2R5C modulated the expression of α-SMA in macrophages via the PP2A signaling pathway. In vivo, LincR-PPP2R5C deficiency aggravated epidural fibrosis by enhancing MMT in a mouse model of laminectomy, and this effect was abolished in mice with macrophage depletion. Our study shed light on the effects of LincR-PPP2R5C on macrophage differentiation and MMT in epidural fibrosis.

Single-cell RNA sequencing (scRNA-seq) has led to major advances in our understanding of proximal tubule subtypes in health and disease. The proximal tubule serves essential functions in overall homeostasis, but pathologic or physiological perturbations can affect its transcriptomic signature and corresponding tasks. These alterations in proximal tubular cells are often described within a scRNA-seq atlas as cell states, which are pathophysiological subclassifications based on molecular and morphologic changes in a cell's response to that injury compared with its native state. This review describes the major cell states defined in the Kidney Precision Medicine Project's scRNA-seq atlas. It then identifies the overlap between the Kidney Precision Medicine Project and other seminal works that may use different nomenclature or cluster proximal tubule cells at different resolutions to define cell state subtypes. The goal is for the reader to understand the key transcriptomic markers of important cellular injury and regeneration processes across this highly dynamic and evolving field.