Accumulating evidence shows that excess cholesterol and glucose uptake stimulates the expansion of hematopoietic stem/progenitor cells and myeloid progenitors, resulting in increased production of inflammatory cells and atherosclerotic progression. However, the role of other metabolites in plaque progression remains unclear. Hereby, we observed elevated α-ketoglutarate levels in granulocyte-monocyte progenitors (GMPs) of Ldlr-/- mice on a high-fat diet (HFD), determined by targeted metabolomics. On top of HFD, α-ketoglutarate administration further increased GMP proportion, myeloid cell production, and plaque progression in Ldlr-/- mice. The regulation of α-ketoglutarate in atherosclerosis required the expression of its receptor, oxoglutarate receptor 1 (OXGR1), in bone marrow cells (BMCs), as transplantation of OXGR1-/- BMCs attenuated plaque progression compared to transplantation of OXGR1+/+ BMCs in HFD-fed Ldlr-/- recipients. Using targeted metabolomics, single-cell RNA sequencing and validation experiments, we demonstrated that the α-ketoglutarate/OXGR1 axis upregulated the expression of purine nucleoside phosphorylase (PNP) in GMPs, which promoted de novo purine biosynthesis and reduced the levels of nicotinamide mononucleotide and nicotinamide adenine dinucleotide (NAD), thereby disturbing mitochondrial homeostasis and increasing the production of myeloid cells. Furthermore, proteomics data revealed that PNP treatment regulated the redox status by increasing the expression of NAD kinase (NADK), thereby accelerating NAD consumption. Additionally, PNP promoted the transcriptional activation of NF-κB via ubiquitin, enhancing ROS production and inflammation in lineage-/low cells. Spearman's correlation analysis revealed a positive association between isocitrate and low-density lipoprotein cholesterol levels in human plasma. Overall, HFD potentiated α-ketoglutarate, contributing to atherosclerosis.

Matrine (MAT), a commonly employed Chinese botanical, has a long-standing history of application in the treatment of inflammation and cancer. Nevertheless, the precise molecular mechanism underlying MAT's impact on thymoma remains unresolved. Consequently, the objective of this investigation was to assess the influence of MAT on thymomas and ascertain the potential mechanisms through which it modulates the Wnt3a/β-catenin pathway. Thy0517 cells were treated with different doses of MAT to construct a thymoma cell therapy model in vitro, and given Wnt3a/β-catenin pathway agonist Laduviglusib for follow-up experiments. The effect of different doses of MAT on the proliferation, colony formation ability, apoptosis, migration, invasion, and stemness of Thy0517 cells was determined by MTT, colony formation assay, flow cytometry, wound healing assay, Transwell assay, and spheroid formation assay, respectively. Genes and proteins were evaluated by RT-qPCR and/or Western blot. High-dose MAT significantly inhibited the proliferation, migration, invasion, and stemness of Thy0517 cells, which also proved the anti-tumor effect of MAT. The suppressive impact of MAT on cellular function could potentially be augmented through the blockade of the Wnt3a/β-catenin pathway, thereby providing additional evidence for the pivotal role of MAT as a signaling pathway in governing the migratory and invasive capabilities of thymoma cells. We found that MAT has anti-tumor effects, inhibiting the proliferation, migration, invasion, and stemness of thymoma cells by regulating the Wnt3a/β-catenin pathway.

The effect of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) on intervertebral disc degeneration (IVDD) repair and healing and its possible mechanism were investigated. Tail IVDD puncture was performed on mice, and BMSC-Exos were injected into the joint cavity. The disc morphology was observed by HE staining, apoptosis rate of nucleus pulposus (NP) tissues was determined by TUNEL, and polarization of macrophages and NP cell damage were detected by Western Blot. An in vitro experimental model was established by co-culture of nucleus pulposus (NP) cells and M1 macrophages in a conditioned medium, and the improvement effect of BMSC-Exos on the proliferation of damaged NP cells was detected by CCK-8 assay. NP cell apoptosis was determined by flow cytometry. Inflammatory factors in NP cell supernatant was measured by ELISA. In results: BMSC-Exos reversed the degenerative changes of IVDD in mice. BMSC-Exos promoted the transformation of THP-1 cells from M1 to M2 and inhibited the release of inflammatory cytokines. BMSC-Exos inhibited matrix metallopeptidase 13 (MMP-13), matrix metallopeptidase 3 (MMP-3), and Cleaved caspase-3 expression in damaged NP tissues. BMSC-Exos significantly increased NP cell proliferation and blocked apoptosis. The concentration of inflammatory factors in the supernatant of NP cells treated with BMSC-Exos was significantly down-regulated. Conclusion: BMSC-Exos have a regenerative effect on IVDD, encourage macrophages to transform from M1 to M2, suppress NP cell apoptosis and inflammatory responses, and improve degenerative alterations in the intervertebral disc.

Dermatoporosis (DP) or chronic cutaneous fragility syndrome has traditionally been linked to extracellular matrix (ECM) dehydration, reduced cellular turnover, epidermal thinning, and vascular fragility. However, recent imaging methods and clinical evidence indicate that the dermoepidermal junction (DEJ) might be the earliest change reflecting DP reversal.

Periodontitis is a common inflammatory disease of the oral cavity that often leads to alveolar bone loss and eventually causes tooth detachment, seriously damaging the physical and mental health of patients. This study developed an osteogenic scaffold (G-nHA/SIS) derived from porcine small-intestinal submucosa (SIS), functionalized with Gly-Arg-Gly-Asp-Ser (GRGDS) peptide and nanohydroxyapatite (nHA) to promote alveolar bone regeneration. The scaffold has a three-dimensional (3D) porous structure, similar to that of the natural extracellular matrix (ECM), providing physical support for cell infiltration and nutrient exchange. The GRGDS peptide and nHA work synergistically to promote the proliferation and adhesion of bone marrow mesenchymal stem cells (BMSCs), enhance alkaline phosphatase (ALP) activity, upregulate the expression of osteogenesis-related genes and proteins, and facilitate osteogenic differentiation of cells. In a periodontitis rat model with an alveolar bone defect, the G-nHA/SIS scaffold exhibited excellent biocompatibility and mechanical properties. Its osteogenic effect was comparable to that of commercially available products but with lower cost and easier availability. Therefore, this scaffold has broad clinical application potential in the field of bone repairs.

NOTCH3 variants cause CADASIL (cerebral autosomal dominant arteriopathy and subcortical infarcts and leukoencephalopathy), the most common monogenetic form of small vessel disease (SVD) and vascular dementia (VaD). The molecular mechanisms driving CADASIL pathogenesis remain poorly understood, and no specific treatments are currently available. NOTCH3 is mainly expressed in vascular smooth muscle cells (VSMCs) that arise from different embryonic origins. Using human induced pluripotent stem cell (iPSC) models, we generated origin-specific VSMCs and found that cerebral, but not peripheral, VSMC mimics are selectively vulnerable to NOTCH3 variants. CADASIL iPSC-derived brain-specific VSMCs acquired a synthetic phenotype, accompanied with extensive extracellular matrix accumulation and impaired cell adhesion leading to anoikis. Furthermore, an endothelial-independent nitric oxide signaling was substantially impaired in CADASIL iPSC-derived VSMCs. Phosphodiesterase-5 inhibition successfully reversed the functional abnormality and survival of mutant VSMCs. Our findings uncovered mechanistic insights and suggest a viable therapeutic strategy for NOTCH3-associated SVD/VaD, reinforcing the value of patient-specific iPSCs for disease modeling and potential drug discovery.

It has been demonstrated that both hUCMSC-exo and Cyasterone exhibit protective effects against steroid-induced osteonecrosis of the femoral head (SIONFH). Additionally, studies have shown that CTSD N-glycosylation influences BMSC apoptosis. Based on these findings, we aim to investigate the mechanism of hUCMSCs-exo@Cyasterone in the Dex-induced BMSCs model of SIONFH, focusing on its regulatory role in CTSD N-glycosylation during apoptosis.

Developmental potency-the ability of cells to differentiate into specialized identities-is progressively lost during development. This phenomenon, known as lineage restriction, is poorly understood. Here, we show that a cell's developmental potency is associated with which genes retain transcriptional potency, and that a molecular relay progressively strips the genome of transcriptional potency during differentiation. Mechanistically, genes chromatinized into nucleosomes can intrinsically lack transcriptional potency, remaining silent even when their transcriptional activators are present. Naive pluripotent stem cells uniquely possess the capacity to restore genome-wide transcriptional potency, but such capacity is decommissioned when cells transition into the primed pluripotent state. Thereafter, placeholder factors (PFs) in stem cells counteract chromatinization to preserve transcriptional potency of specific silent genes, thereby maintaining developmental potency for downstream lineages requiring these genes. As differentiation proceeds, PFs disappear. The genes they protect can then permanently lose transcriptional potency via chromatinization, leading to irreversible lineage restriction.

Sickle cell disease is characterized by chronic hemolytic anemia and recurrent severe vaso-occlusive crises. Ristoglogene autogetemcel (risto-cel) includes autologous CD34+ hematopoietic stem and progenitor cells that have been base-edited to target the HBG1 and HBG2 promoters and inhibit BCL11A binding without altering BCL11A expression, yielding a switch in hemoglobin production from sickle hemoglobin (HbS) to antisickling fetal hemoglobin (HbF).

Toxoplasma gondii is a widespread parasite that impacts both human and animal health. Increasing use of organoid model systems has made previously challenging aspects of the T. gondii lifecycle more accessible. The media for these organoid systems are highly complex with many growth factors and pathway inhibitors that promote stem cell retention or differentiation of the cells. We noticed changes in T. gondii growth and development in our intestinal organoid system and wanted to determine if this was driven by cell type or media components. We found that low concentrations of SB202190 (a p38 MAPK inhibitor) and A83-01 (an ALK 4/5/7 receptor inhibitor) are each sufficient to alter T. gondii growth even in fibroblast cells. Further investigation with our qPCR panel of T. gondii stage markers revealed that these compounds promote bradyzoite cyst development and prime parasites for pre-sexual and sexual stage gene expression. As these complex organoid systems become more common in microbiology research, this study highlights the role of organoid media components in controlling pathogen growth and development.

Tendons are specialized connective tissues that transmit mechanical forces from muscle to bone, ensuring joint stability and efficient locomotion. Their homeostasis and regenerative capacity depend on the interplay between extracellular matrix (ECM), resident and recruited cell populations, and immune-mediated signaling. This review provides an overview of tendon structure and composition, emphasizing the collagen-based organization and the functional role of non-collagenous matrix components in mechanotransduction and cell signaling. The heterogeneity of tendon-resident cells, including tenocytes, tendon stem/progenitor cells, and vascular- and immune-associated cells, is discussed, highlighting their roles in tissue maintenance, adaptation, and repair. Tendon aging is characterized by altered cellular responsiveness, ECM disorganization, and reduced capacity to resolve inflammation, predisposing tissues to degeneration and chronic tendinopathies. Emerging evidence underscores the central role of the immune response in both inflammatory and healing processes. Key bioactive compounds used in tendinopathy management, such as collagen, vitamin C, vitamin D, methylsulfonylmethane, hyaluronic acid, and manganese, are discussed regarding their mechanistic effects on collagen synthesis, matrix remodeling, oxidative stress, immune modulation, and cell-matrix interactions. Overall, tendon health emerges from a dynamic balance between structural integrity, cellular activity, and immune regulation, supporting the rationale for targeted nutritional strategies to promote tendon homeostasis and regeneration.

Sickle cell disease (SCD) affects about 100 000 Americans with higher prevalence in minorities such as African and Hispanic Americans. Despite current standards of care, patients with SCD have a lower quality of life and 20 years shorter life expectancy compared to the general population. Curative approaches like allogeneic hematopoietic stem cell transplant (HSCT) have limited applications due to lack of compatible donors, risk for graft versus host disease, graft rejection, and the high fitness requirements for the patients. The Townes SCD mice are useful for evaluation of gene therapies in the preclinical setting; they recapitulate human SCD, displaying severe anemia, end-organ damage, and early mortality.

Chimeric antigen receptor (CAR) T-cell therapy has significantly improved the prognosis of relapsed B-cell acute lymphoblastic leukemia (B-ALL) patients with recurrent disease after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, whether to use donor- or patient-derived CAR T cells has not yet been clarified.

High mobility group box 3 (HMGB3) acts as an essential participator in fundamental biological processes, including transcriptional regulation, chromatin remodeling and DNA repair. HMGB3 is highly expressed and functionally essential during embryonic development, particularly in the hematopoietic and nervous systems, but it is significantly downregulated or silenced in most normal adult tissues. Its aberrant upregulation has been revealed in numerous human malignancies, such as leukemia, as well as breast, bladder, colorectal and gastric cancer, and its expression levels have been established to be closely associated with poor prognosis of specific patients. Accordingly, the present review systematically explores the central roles of HMGB3 in mediating resistance to cancer therapy. This review focuses on its multifaceted mechanisms of maintaining cancer stemness, enhancing DNA damage repair, modulating cell death pathways and remodeling the tumor microenvironment, thereby contributing to the resistance to chemotherapy, radiotherapy, targeted therapy and immunotherapy collectively. HMGB3 can be accepted as a key target in the development of highly promising therapeutic strategies, given its pivotal involvement in multidrug resistance, which may offer novel avenues for overcoming clinical treatment resistance and improving patient outcomes.

Spinal cord injury (SCI) poses a significant therapeutic challenge, largely due to the formation of an inhibitory microenvironment. In this study, cell-free DNA (cfDNA) was found to induce neuroinflammation and accelerate neuronal apoptosis. Leveraging the neuroprotective properties of extracellular vesicles from induced pluripotent stem cell-derived neural stem cells (Nev), a spatiotemporally controlled cfDNA scavenger (Nev-RA) was established by functionalizing the Nev with oligoarginines and reactive oxygen species (ROS)-cleavable poly(ethylene glycol)-angiopeps. Following angiopep-mediated penetration of the blood-spinal cord barrier and ROS-sensitive cleavage at the lesion site, the exposed oligoarginines scavenge pathogenic cfDNA, thereby attenuating toll-like receptor 9-mediated inflammation, while the Nev facilitates the survival of impaired neurons. This biomimetic strategy concurrently addresses the dual barriers of a hostile inflammatory microenvironment and an insufficient intrinsic repair capacity. Collectively, this work reveals an important therapeutic target for SCI and proposes a promising and translatable treatment paradigm.

Mesenchymal stem cell‑derived extracellular vesicles (MSC‑EVs) have garnered research attention due to their unique biological functionalities and therapeutic potential. Compared with the parent MSCs from which they originate, MSC‑EVs are typically free from systemic allergic reactions, hemolysis, pyrogenic reactions, abnormal hematological changes, and vascular and muscle irritation problems, and thus, exhibit therapeutic potential. The present review provides a comprehensive analysis of numerous isolation methodologies for MSC‑EVs, with each method being evaluated based on key parameters, including principles, advantages, limitations and applications. Notably, the therapeutic potential of MSC‑EVs in the treatment of tuberculosis (TB) has been emphasized. MSC‑EVs have demonstrated unique capacities to modulate the T helper cell (Th)1/Th2/T regulatory cell balance, promote M2 macrophage polarization, alleviate inflammation through microRNA‑mediated mechanisms and enhance host defense through antimicrobial peptide responses. The integration of MSC‑EVs with anti‑TB therapy can improve lung, kidney and bladder health by reducing TNF‑α levels and increasing IL‑10/TGF‑β ratios. Notably, functional discrepancies between EVs derived from distinct MSC sources, such as umbilical cord vs. bone marrow cells, underscore the need for targeted optimization strategies. Adequate risk assessment is important before clinical trials, particularly concerning immunogenicity, potential pro‑inflammatory effects and promotion of TB latency. The present review explores the potential clinical applications of MSC‑EVs in TB and other infectious diseases, offering key insights into their therapeutic potential, with the aim of guiding future research.

Objective This study aimed to investigate the protective effect of a metformin (Met)-adipose-derived mesenchymal stem cell exosome (ADSC-Exo) complex (Met-Exo) against hepatic ischemia-reperfusion injury (IRI) and to determine whether this protection is mediated through the silent information regulator 1(SIRT1)-tissue inhibitor of metalloproteinase 3(TIMP3) axis. Methods Met-Exo was constructed and characterized by nanoparticle tracking analysis, Western blotting, and transmission electron microscopy (TEM). An in vitro model of hepatic IRI was established in mouse hepatocyte AML12 cells subjected to oxygen-glucose deprivation/re-oxygenation (OGD/R). Cell viability, apoptosis, and hepatocyte function markers (AST and ALT) were measured to compare the protective effects of Met-Exo, ADSC-Exo, and Met alone. A TranswellTM co-culture system was used to evaluate how macrophage polarization influences OGD/R-induced AML12 injury. AML12 cells were assigned to the following groups: Ctrl, OGD/R, Met, ADSC-Exo, Met-Exo, and macrophage-polarization groups (M0, M1, M1+Met-Exo, M1+pcDNA3.1, M1+pcDNA3.1-SIRT1, M1+pcDNA3.1-TIMP3). SIRT1 and TIMP3 protein levels in AML12 cells were determined by Western blot. Macrophage-polarization markers-inducible nitric-oxide synthase (iNOS) and arginase 1 (Arg1) were also quantified. In parallel, AML12 cells' viability, apoptosis, and hepatocellular function indices (AST& ALT) were assessed. A murine hepatic IRI model was constructed, and Met-Exo was administered to assess therapeutic efficacy in vivo. Results Met-Exo was successfully prepared. In vitro, Met-Exo attenuated OGD/R-induced hepatocyte injury, increased viability, reduced apoptosis, and lowered AST and ALT release. Met-Exo pre-treatment suppressed expression of the M1 marker iNOS and enhanced expression the M2 marker Arg1, thereby alleviating OGD/R damage in AML12 cells. OGD/R markedly decreased SIRT1 and TIMP3 expression in AML12 cells, whereas Met-Exo pre-treatment significantly up-regulated SIRT1 and consequently TIMP3 expression. In macrophage polarization experiments, M1 macrophages exacerbated AML12 injury, shown as decreased protein expression of SIRT1 and TIMP3, increased iNOS levels, reduced Arg1 levels, along with diminished AML12 cell viability, increased apoptosis, and elevated AST/ALT. Over-expression of either SIRT1 or TIMP3 reversed these detrimental effects, skewing macrophages toward the M2 phenotype and mitigating AML12 injury. In vivo, Met-Exo markedly ameliorated hepatic IRI in mice. Conclusion Met-Exo protects against hepatic IRI by activating the SIRT1-TIMP3 axis, thereby driving macrophage polarization toward the anti-inflammatory M2 phenotype, attenuating inflammation and apoptosis in hepatocytes subjected to OGD/R.

Glioblastoma or grade IV glioma is characterized by extremely poor prognosis. Resistance to radio- / chemotherapy and recurrences are associated with tumor stem cells. Transmembrane protein CD133 is considered a potential marker of tumor stem cells. To overcome the limitations of detecting cellular CD133 by antibodies, potential of aptamers (nucleic acid-based molecular recognition elements) is being explored. To obtain reproducible results, it is necessary to study the interaction of fluorescent aptamers to CD133 with standard cell lines and cell cultures derived from patient tumors using various methods.