Tissue & cell最新文献

The kynurenine pathway is the principal route of tryptophan metabolism in the brain, generating several neuroactive metabolites, including kynurenic acid (KYNA). KYNA functions as both a neuromodulator and a neuroprotective compound, and its dysregulation has been associated with numerous neurological and psychiatric disorders. Kynurenine aminotransferase-2 (KAT-2) is the key enzyme responsible for KYNA synthesis, yet its precise cellular localization in the mouse brain remains insufficiently characterized. In this study, we systematically compared KAT-2 expression in primary astrocytic, microglial, and neuronal cultures derived from mouse brain, complemented by in situ immunolabeling of brain sections. Immunocytochemistry combined with quantitative colocalization analysis revealed that KAT-2 is expressed in all three major brain cell types, with significant overlap with cell type-specific markers. Furthermore, KAT-2 immunoreactivity was largely restricted to the soma, showing a perinuclear distribution in glial cells and partial extension into dendritic compartments in neurons. These findings provide the first parallel characterization of KAT-2 distribution across astrocytes, microglia, and neurons in the mouse brain. Overall, our results indicate that KAT-2 is widely expressed in neural cells, a finding that supports the hypothesis that KAT-2 contributes broadly to kynurenine metabolism. Taken together, our findings provide a foundation for future studies aimed at defining the cell type-specific functional roles of KAT-2.

Background: Anaplastic thyroid carcinoma (ATC) is an exceptionally aggressive thyroid cancer subtype. Protein arginine methyltransferases (PRMTs), particularly PRMT1, have emerged as key regulators in cancer biology. This study investigates the therapeutic potential of targeting PRMT1 as a novel strategy for ATC intervention.

Methods: ATC samples were stratified into high and low PRMT1 expression groups based on PRMT1 levels. Dot blot assay was utilized to assess m6A methylation levels, while RT-PCR quantified the level of m6A-related proteins. Pearson correlation analysis evaluated the relationship between PRMT1 and Wilms'tumor 1-associating protein (WTAP) expression. Mitochondrial membrane potential was measured using the TMRE probe, and Western blotting was used to analyze cuproptosis markers. The m6A modification level of PRMT1 was determined via meRIP-qPCR. Additionally, a xenograft tumor model was established to validate the role of the PRMT1/WTAP pathway in vivo.

Results: The mRNA and protein expressions of PRMT1 were significantly upregulated in ATC clinical samples and cell lines compared to normal controls. ATC samples were stratified into high and low PRMT1 expression groups using the median PRMT1 protein expression level (determined by immunohistochemistry) as the cutoff. Elevated m6A modification levels were observed in the high PRMT1 expression group. A positive correlation was identified between PRMT1 and WTAP mRNA expression in ATC clinical samples. In vitro studies demonstrated that PRMT1 regulates cuproptosis as the primary mode of cell death in ATC. PRMT1 silencing led to a reduction in mitochondrial membrane potential and increased expression of cuproptosis markers. WTAP knockdown reduced the m6A modification of PRMT1 and decreased its mRNA stability.

Conclusion: WTAP regulated the m6A modification and mRNA stability of PRMT1. The WTAP/PRMT1 signaling axis modulated cuproptosis, thereby influencing ATC progression. These findings highlighted the potential of targeting the WTAP/PRMT1 pathway as a therapeutic strategy for ATC.

Background: Chronic intermittent hypoxia (CIH) is a typical feature of obstructive sleep apnea (OSA), and CIH exposure can lead to the development of lung injury (LI). While tempol can be used to treat CIH-induced LI, its regulatory mechanism remains unclear. Therefore, the present study aimed to investigate the potential mechanism through which tempol improves the progression of CIH-induced LI.

Methods: In vitro and in vivo CIH-associated LI models were constructed using intermittent hypoxia (IH)-induced BEAS-2B cells and C57BL/6 mice. Cell viability was determined via the CCK-8 assay, and changes in related proteins were detected via Western blot analysis. The levels of Fe^2 + , malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH) were detected via kits, and the level of reactive oxygen species (ROS) was detected via fluorescence microscopy and flow cytometry. Lung tissue injury was evaluated by hematoxylin and eosin (HE) staining and Masson's trichrome staining.

Results: After IH induction, the levels of ferroptosis-related indicators (GPX4, FTH1, and SLC7A11), SOD and GSH were decreased in BEAS-2B cells and mouse lung tissues, whereas the levels of Fe²⁺, ROS and MDA were increased in BEAS-2B cells and mouse lung tissues. In addition, IH decreased BEAS-2B cell viability and aggravated lung tissue damage and fibrosis in mice. The addition of the Fer-1 ferroptosis inhibitor or tempol weakened the effects of IH, indicating that tempol treatment improved the progression of CIH-induced LI through the inhibition of ferroptosis. Mechanistically, tempol activated the Nrf2/GSH signaling axis through suppressing TLR4 expression, thereby inhibiting ferroptosis and improving CIH-induced LI.

Conclusion: Tempol promotes Nrf2/GSH signaling through suppressing TLR4 expression, thereby inhibiting ferroptosis and alleviating CIH-induced LI.

The therapeutic potential of Wnt/β-catenin signaling to enhance proliferation in differentiated cardiomyocytes remains underexplored, particularly in genetically diverse disease models. Here, we systematically evaluated whether pharmacological Wnt activation overrides genetic constraints to drive expansion of induced pluripotent stem cell-derived cardiomyocytes (iCMs) from healthy donors and inherited cardiomyopathy models (GAA-Pompe disease, RYR2-catecholaminergic polymorphic ventricular tachycardia, and KCNQ1-long QT syndrome type 1). Using a component-defined GiWi protocol, functionally mature iCMs were generated from a high-quality iPSC line with validated trilineage differentiation capacity. Longitudinal analysis of CHIR-induced Wnt/β-catenin activation demonstrated dose-dependent proliferative amplification, with CHIR-treated iCMs achieving > 400-fold monolayer expansion by passage 4 versus ∼8-fold in controls. Immunofluorescence quantification revealed significantly elevated Ki67⁺ /cTnT⁺ double-positive cardiomyocytes under CHIR treatment (∼20 % vs. ∼9 % in controls at passage 3). Strikingly, proliferative responses showed genetic neutrality: healthy iCMs exhibited ∼432-fold expansion compared to ∼406-fold in disease models (p = 0.72), with comparable Ki67⁺/cTnT⁺ ratios by passage 4 (healthy: ∼8.9 %; disease: ∼8.3 %). These findings demonstrate that timed Wnt activation overrides genetic lesions to enable disease-agnostic proliferation in differentiated iCMs. This genetic neutrality supports standardized regenerative strategies for genetically heterogeneous cardiomyopathies and arrhythmias, addressing a critical challenge in developing personalized cardiac therapies.

The repair of cartilage and bone defects, both structurally and functionally, remains a significant challenge. Traditional treatment methods, such as autogenous and allogeneic bone grafts, face limitations, including issues of availability, cost, immune rejection, and other concerns, making them insufficient to fully address clinical needs. As a result, the integration of biomaterials with tissue engineering strategies has emerged as a promising research direction. Among various materials, hydrogels have attracted considerable attention due to their biological activity, degradability, absorbability, plasticity, and ease of preparation. Hyaluronic acid (HA), a key natural polysaccharide and a major constituent of the extracellular matrix (ECM), has been extensively applied in tissue healing and regeneration because of its excellent biocompatibility, biodegradability, bioactivity, and the availability of reactive functional groups for modification. In particular, HA-composed hydrogels, compared to typical hydrogels, provide a highly adaptable structure and a tissue-mimetic microenvironment that closely resembles the ECM, thereby supporting and enhancing tissue repair and regeneration. In this review, we have discussed the mechanisms through which HA-based hydrogels promote ECM formation in cartilage and bone, their combination with other natural polymers, hyaluronic acid composited injectable hydrogel and the application of 3D bio-printed HA hydrogels for effective cartilage and bone regeneration.

This study presents the first ultrastructural analysis of the Eurasian stone-curlew's oropharyngeal cavity through scanning electron microscopy (SEM) and gross anatomical observations, focusing on the tongue, laryngeal mound, and palate to understand structural adaptations related to feeding habits. The short tongue was divided into apex, body, and root, each exhibiting distinct anatomical and morphometric features. SEM showed the apex had a pointed nail, scales, and is bordered laterally by 2-3 membranes. The body is divided into a rostral papillary area and a caudal non-papillary area. The papillary system is restricted to the dorsal surface, especially on the apex and the rostral part of the body. Within this papillary area, there are three distinct filiform papillae types: thick papillae at the apex, elongated, pointed papillae along the lateral margins of the body, and broad, scale-like papillae at the median body region, along with the conical papillae on the papillary crest. Meanwhile, the caudal body part and root were devoid of papillae, yet featured numerous rounded salivary gland openings. The papillary crest had 14 small, pointed papillae arranged symmetrically on each side, with two large papillae at their lateral edges, each dividing into three papillae. The laryngeal mound had a notable glottis and a W-shaped papillary arrangement. The palatine region consists of rostral, middle, and caudal parts, with 2, 8, and 1 ridge(s), respectively. The choana is divided into a papillary rostral part and a non-papillary caudal part. The infundibulum had a median opening with no papillae and multiple sphenopterygoid gland openings.

Exosomes have emerged as important resources in skin regenerative medicine. However, only a limited number of studies have demonstrated the anti-aging effects of progenitor cell-derived exosomes. In addition, the development of novel effective progenitor cell-based therapies is crucial for the treatment of skin aging. In this study, the viability and proliferation of human adipose-derived progenitor cells (APCs) from young (18-25 years) and old (60-67 years) donors were compared. Exosomes derived from young (yAPC-Exos) and old (oAPC-Exos) APCs were collected and characterized, and their effects on senescent human dermal fibroblasts (HDFs), as well as the underlying molecular mechanisms, were investigated. The proliferation capacity of aged APCs was significantly reduced. Both yAPC-Exos and oAPC-Exos promoted HUVEC migration and tube formation, as well as HDF migration. Exosome treatment decreased intracellular reactive oxygen species levels and alleviated aging-associated phenotypes in senescent HDFs. These effects occurred primarily through p21 and p53 downregulation and SIRT1 upregulation. Notably, yAPC-Exos exerted more pronounced anti-senescent effects than oAPC-Exos. Taken together, yAPC-Exos may represent an effective therapeutic strategy for aging-related skin pathologies and cosmetic applications.

Diabetes and its associated complications have been linked to high glucose environments. Diabetic wound repair is complex, which significantly affects endothelial cell function, and remains a major therapeutic challenge. Currently, few targeted interventions exist to promote effective healing. Here, the function of TICAM1 in diabetic angiogenesis was investigated, aiming to identify potential therapeutic targets to accelerate wound repair. Human umbilical vein endothelial cells (HUVECs) were grown with high glucose or corresponding control conditions and treated with a lentivirus expressing TICAM1-targeting shRNA, Licochalcone D, or a p65 overexpression plasmid. RNA sequencing, Western blotting, tube formation, and quantitative reverse transcription PCR were employed to assess angiogenic capacity and associated signaling pathways. Cell proliferation was evaluated using EdU and CCK-8 assays, and flow cytometry was utilized to measure apoptosis. Cell permeability was assessed using fluorescein isothiocyanate (FITC)-dextran and transendothelial electrical resistance (TEER) assays. Inflammatory mediator levels, including IL-1β, IL-6, and TNF-α, were measured with ELISAs. TICAM1 expression was upregulated in endothelial cells exposed to HG, resulting in reduced angiogenic activity and increased inflammatory cytokine release. Similar endothelial alterations were observed under hyperglycemic conditions across different experimental settings. Knockdown of TICAM1 or treatment with Licochalcone D restored angiogenesis and inhibited inflammation. On the other hand, p65 overexpression reversed the effects of TICAM1 knockdown under HG conditions. In conclusion, TICAM1 impairs angiogenesis and promotes inflammation under HG conditions through the p65-mediated NF-κB axis. These results suggest the potential of TICAM1 in promoting the repair of diabetic wounds.

Tapentadol (TAP) is a centrally acting analgesic which is broadly used in the management of moderate to severe pain. The current study was conducted to examine the dose-dependent hepatotoxic effects of TAP via evaluating molecular, biochemical, and histopathological parameters. Thirty-two Sprague Dawley rats were divided into four groups i.e., control, TAP (10 mg/kg), TAP (25 mg/kg), and TAP (50 mg/kg) treated group. Our results showed that TAP intoxication upregulated the gene expression of Yes-associated protein 1 (YAP1) while downregulating the gene expression of tumor suppressor kinase 1 (LATS1), mammalian sterile 20-like kinase 1 (MST1), farnesoid X receptor (FXR), small heterodimer partner (SHP) and bile salt export pump (BSEP), thereby suggesting a compromise Hippo-YAP signaling and bile acid homeostasis. TAP exposure suppressed the activities of glutathione reductase (GSR), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), hemeoxygenase-1 (HO-1), as well as glutathione S-transferase (GST) coupled with glutathione (GSH) contents while significantly augmented the levels of malondialdehyde (MDA) and reactive oxygen species (ROS). Furthermore, TAP intoxication elevated the levels of cholic acid, chenodeoxycholic acid, deoxycholic acid, taurocholic acid, glycocholic acid, alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate aminotransferase (AST), and Gamma-glutamyltransferase (GGT) while downregulating total protein and albumin. Moreover, TAP induced strong inflammatory and apoptotic responses, which were characterized by an increase in nuclear factor-κB (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-1-beta (IL-1β), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), Bcl-2 associated X protein (Bax), cysteine-aspartic acid protease-3 (caspase-3), and cysteine-aspartic acid protease-9 (caspase-9) while inhibition of B cell lymphoma-2 (Bcl-2). Similarly, TAP administration induced severe histopathological alterations including hepatic degeneration, sinusoidal dilation, inflammation, and necrosis. Our findings are further supported by in-silico analysis that showed strong binding affinity of TAP with key regulatory genes. Collectively, these findings suggest that TAP is a hepatotoxic agent and warrant further clinical trials to evaluate its effects in humans.