Solute carrier family 35 member F2 (SLC35F2) is a transporter located predominantly at the plasma membrane and Golgi apparatus and is predicted to contain ten transmembrane helices. Recent studies have identified SLC35F2 as the only currently known queuosine (Q)-specific transporter in human cells and as the principal high-affinity transporter of queuine (q), although it is not the absolutely exclusive route for q uptake. SLC35F2 is also aberrantly expressed in multiple cancers and has been associated with cell proliferation, migration, invasion, chemoresistance, and ferroptosis regulation. However, the available evidence derives mainly from database analyses, individual cell-based studies, and limited animal experiments and does not yet demonstrate that its tumor-promoting effects directly depend on q/Q uptake or tRNA queuosine modification. SLC35F2 is also an important uptake transporter for the anticancer agent YM155, and its expression can influence intracellular drug exposure and DNA-damage toxicity. YM155 was initially classified as a survivin transcriptional inhibitor, but subsequent studies indicate that its actions also involve DNA intercalation and oxidative DNA damage. Previous clinical trials did not prospectively stratify patients by SLC35F2 expression and showed limited overall efficacy; consequently, its clinical value remains translationally uncertain and biomarker-dependent. Using a structured narrative-review approach, this article critically evaluates the structure and localization of SLC35F2, q/Q transport, regulation of its expression and protein stability, tumor-associated functions, and YM155 delivery. It distinguishes replicated mechanisms from findings supported by single studies and from testable hypotheses, thereby providing a framework for future mechanistic research and precision drug delivery.

Lipid oversupply induces insulin resistance in skeletal muscle (SkM), partly by altering mitochondrial function and dynamics. Although electrical pulse stimulation (EPS) improves insulin signaling in myotubes, the mechanisms contributing to this effect under lipotoxic conditions remain unclear. Thus, we investigated whether EPS restores lipid-induced insulin resistance in association with changes in mitochondrial respiration and dynamics, lipotoxic intermediates and evaluated the contribution of contraction-induced secreted factors, including small extracellular vesicles (sEV). Murine C2C12 myotubes were treated with palmitate (PA, 0.3 mmol/l) and subjected to EPS (1 Hz, 11.5 V) for 24 h. Insulin signaling, mitochondrial dynamics, respiratory capacity and lipotoxic intermediates were assessed by Western blotting, high-resolution respirometry and liquid chromatography-tandem mass spectrometry in control (CON) and PA-treated cells before and after EPS. Additionally, CON and PA-treated cells were incubated for 24 h with conditioned media and sEV from unstimulated or EPS-stimulated CON and PA-treated cells to evaluate the effect of the myocellular secretome on AKT signaling. PA reduced insulin-stimulated AKT(Ser473) and (Thr308) phosphorylation, which was partially rescued by EPS. In PA cells, EPS decreased the fusion proteins mitofusin 1 and 2 (MFN1, MFN2) and increased the fission marker dynamin-related protein 1 (DRP1). However, mitochondrial respiration and lipid accumulation were unaffected by EPS. Furthermore, conditioned media and sEV from EPS-stimulated cells enhanced AKT phosphorylation in PA-treated cells. These findings demonstrate that attenuation of lipid-induced insulin resistance is independent of mitochondrial respiratory capacity and lipid accumulation, but it is associated with alterations in proteins involved in mitochondrial dynamics and is likely mediated by exercise-derived sEV.

Hypertension is a highly prevalent clinical condition and a major contributor to global cardiovascular morbidity and mortality. Despite extensive research, its complex and multifaceted pathogenesis is yet to be fully elucidated. This paper explores the updated understanding of primary hypertension as a systemic disorder rather than an isolated vascular or renal abnormality. At the center of this multifactorial disease lie three primary and interrelated pathophysiological mechanisms: dysregulation of the renin-angiotensin-aldosterone system, dysfunction of the central nervous system, and activation of inflammatory and oxidative stress pathways. These core drivers not only interact with each other in a self-reinforcing cycle but also serve as convergence points for a range of additional contributors. Specifically, suboptimal dietary patterns, salt sensitivity, gut microbiota dysbiosis, circadian rhythm disruption, and insulin resistance act by modulating these central processes, thereby perpetuating blood pressure elevation. This review further elaborates on how these mechanisms span across multiple organ systems, driving vascular, renal, neurohumoral, and immune dysfunction. Taken together, this perspective underscores the need for integrated, upstream-targeted therapeutic strategies. By highlighting the interconnected nature of these drivers and contributors, this paper provides a comprehensive framework to inform future research and guide more effective preventive and management approaches for hypertension.

Gastric gland cells originate from two proliferative niches: the main rapid one in the isthmus, and the slow secondary one in the base. However, while nutrition is dependent on breastfeeding, the proliferative niches are not established, and proliferation occurs along the gland. Currently, we investigated the influence of early weaning (EW) on shaping gastric proliferative niches and their signaling. Wistar rats were separated into suckling (S) and EW groups on postnatal day (PND) 15 for gastric mucosa collection. BrdU was administered (PND 14 and 15) and as it diluted between daughter-cells we evaluated migration and differentiation. In parallel EdU incorporation was used to identify cells during S phase. Through these tools, we studied the different profiles of BrdU/EdU dual labeling at 18, 21 and 30 PND. At 18 PND, EW decreased BrdU+ population (p < 0.0001 vs. S group) in the upper and bottom gland areas (p < 0.05). The BrdU + /EdU+ cells were concentrated in the upper gland, where we recorded a larger EdU+ population after EW (p < 0.05). On PND 30, EW decreased BrdU+ cells in the gland (p < 0.05), whereas EdU+ cells were more numerous in the isthmus. At 18 PND, EW reduced Wnt3, Notch1, and Notch2 expressions (p < 0.05), while increasing Bmp2. In contrast, at 60 PND, Axin2, Notch1, and Notch2 transcripts were elevated after EW (p < 0.05). Notch1 and Notch2 distribution indicated that EW might shift Notch2 to the upper gland, potentially affecting the fate of progenitor cells in pups. In silico analyses showed that zymogenic cells are in a renewal-promoting environment, while parietal cells contribute to differentiation and signaling. Therefore, EW restricted the proliferative activity to the isthmus, altering the spatiotemporal expression of genes involved in stemness and differentiation, and reshaped the distribution of Notch receptors, without affecting the distribution of its downstream effector Hes1. These spatially organized molecular landscapes are crucial for proper epithelial renewal and function, and our data suggest that early nutritional disruption reprograms these niches with long-term consequences.

Lysosomes are important organelles for the degradation of unwanted biomolecules via autophagy. Lysosomal dysfunction is apparent in ageing tissues, and can cause various neurodegenerative diseases. It is imperative to understand the mechanisms and implications of lysosomal malfunction and to find strategies to ameliorate diseases. To investigate this, we induced lysosomal dysfunction with Bafilomycin A1 (BAF), a drug that hinders lysosomal acidification by blocking vATPase-mediated proton pumping, in myoblasts and myotubes. Myotubes were subjected to chronic contractile activity (CCA) to mimic "exercise" to evaluate any therapeutic potential and reversal of pathophysiology. Induced lysosomal dysfunction was evident from impaired processing of the protease cathepsin B, enhanced lysosomal accumulation and increased autophagic markers Lamp1, p62, and the LC3II/I ratio. BAF attenuated lysosomal protease degradation measured using the substrate DQ-BSA in both myoblasts and myotubes. Many of the adverse effects generated by BAF in myotubes were reversed by CCA, manifested by a decrease in immature cathepsin B, a down-regulation of Lamp1, p62, LC3II/I and partial restoration of lysosomal protein degradation enzymatic capacity. To investigate further improvements in lysosomal function in a healthy cellular model, we treated myotubes with C1, a curcumin analogue. C1 decreased Lamp1, p62 and the LC3II/I ratio, all of which indicate improved lysosomal function and autophagosome clearance with a greater lysosomal ability to degrade substrates. Additionally, C1 was able to mimic the improved mitochondrial content induced by CCA. Thus, contractile activity and curcumin analogues may provide useful therapeutic potential to resuscitate lysosomal function, improve muscle health and ameliorate lysosome-mediated diseases. NEW AND NOTEWORTHY: This study explores the potential of chronic contractile activity (CCA) in reversing the compromised lysosomes caused by the disruption of lysosomal acidification in myotubes. Remarkably, CCA mitigated the effects of Bafilomycin A1-induced lysosomal dysfunction, enhancing protease activity and increased mitochondrial content. Treatment of myotubes with the curcumin analogue C1 reduced lysosomal accumulation and enhanced mitochondrial content suggesting that contractile activity-based interventions and small-molecule modulators of lysosomal pathways may represent promising complementary strategies for treating lysosome-related diseases and enhancing muscle health.

Posttraumatic bone repair is not a simple osteogenic process but a spatiotemporal dynamic reconstruction involving the coordinated participation of neural, immune, vascular, and bone-lineage cells. Clinically, structural healing does not always align with pain relief, weight-bearing recovery, and improvement in motor function, suggesting that beyond mechanical stability and bone formation, neuro-immune regulation may govern overall repair quality. This article adopts a structured narrative review framework to discuss the stage-specific roles of the neuro-immune axis in post-traumatic bone repair, focusing on inflammatory initiation and resolution, reinnervation, neurovascular coupling, and functional outcomes. Existing studies on fractures and bone defects indicate that neuropeptides, neurotransmitters, and neurotrophic signals derived from sensory and autonomic nerves can modulate immune cell recruitment and functional status, and contribute to vascularization, osteogenesis, and bone remodeling. The effects of neural signals are highly context-dependent. Appropriate and temporally coordinated neural activation may support inflammatory resolution and tissue reconstruction, whereas nerve injury, sustained excitation, or signaling dysregulation may be associated with abnormal reinnervation, pain sensitization, and impaired repair. The relationship between neural and immune responses is not a fixed unidirectional upstream-downstream cascade but is better characterized as stage-dependent parallel activation and bidirectional regulation. Some mechanisms are still primarily derived from models of peripheral nerve injury, chronic pain, or other tissues, and their applicability to traumatic bone repair requires direct validation. This article further evaluates the evidence base, safety, potential application scenarios, and translational pathways of pharmacological modulation of neural signals, modulation of local immune function, extracellular vesicles, neuroaffinity biomaterials, and neuromodulation techniques. Overall, localized, stage-specific, and adjunctive interventions hold the most immediate translational potential, offering a bridge between structural healing, pain control, and functional recovery. However, their intervention windows, safety boundaries, and beneficiary populations still need to be clarified through clinically relevant models, dynamic biomarkers, and patient stratification.

Hemoglobin (Hb) is traditionally recognized as an erythroid-specific protein with the core function of mediating transmembrane transport of oxygen and carbon dioxide. In recent years, emerging studies have confirmed that hemoglobin is also expressed in the cytoplasm of various normal somatic cells and tumor cells. In normal somatic cells such as alveolar epithelial cells, vascular endothelial cells and chondrocytes, hemoglobin exerts multiple biological functions including oxygen storage, protection of smooth muscle soluble guanylate cyclase from excessive desensitization to nitric oxide, as well as hypoxia resistance, blood pressure regulation and antioxidant effects. In most tumor cells, hemoglobin expression is abnormally upregulated, while a small number of cases show a downregulated trend. Its expression level is closely associated with malignant biological behaviors of tumor cells such as survival, radioresistance and distant metastasis, making it a potential biomarker for tumor diagnosis and prognostic evaluation. This paper systematically reviews the discovery process and functional research progress of hemoglobin in normal non-erythroid somatic cells and tumor cells, explores the feasibility of hemoglobin as a therapeutic target for related diseases, and provides new ideas and directions for the diagnosis and treatment of these diseases.

Psoriasis is a chronic and recurrent inflammatory dermatosis characterized by dysregulated keratinocyte proliferation. Calcium-binding protein 39 (CAB39), a critical regulatory scaffold for Sterile 20 kinase, has been implicated in multiple diseases, but its role and regulatory mechanisms in psoriasis remain unclear. Here, we found that CAB39 was significantly upregulated in psoriatic lesions, and CAB39 knockdown inhibited keratinocyte proliferation and attenuated psoriasis progression. Further investigations revealed that CAB39 crotonylation at lysine 196 was reduced in psoriatic lesions. Functional analyses in normal human epidermal keratinocytes (NHEKs) showed that the crotonylation-deficient CAB39 K196A mutant significantly promoted keratinocyte hyperproliferation and glycolytic remodeling. Dysregulation of modifying enzymes, including downregulated CBP and upregulated HDAC2/3, drives CAB39 K196 decrotonylation in psoriasis. Mechanistically, CAB39 K196 decrotonylation weakens its binding affinity to STRAD (STE20-related adaptor), disrupts the stability of the CAB39-STRAD-LKB1 (liver kinase B1) complex, and inhibits the LKB1/AMPK signaling pathway. Concurrently, decrotonylated CAB39 promotes phosphatidic acid (PA, a lipid second messenger) synthesis, activating the pro-proliferative PA/MAPK/mTOR signaling cascade. Our findings uncover a novel pathogenic mechanism in psoriasis, wherein CAB39 K196 decrotonylation drives keratinocyte dysfunction, and expand our understanding of non-histone crotonylation in inflammatory skin diseases. Importantly, targeting the CBP/HDAC2/3-CAB39 crotonylation axis may represent a potential therapeutic strategy for psoriasis.

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airway inflammation and metabolic dysregulation in immune cells, particularly macrophages. This study aimed to determine whether resveratrol (RES) delays COPD progression by modulating macrophage inflammatory activation and glycolytic reprogramming through the Toll-like receptor 4/hexokinase 2 (TLR4/HK2) signaling pathway. A COPD mouse model was established by lipopolysaccharide (LPS) instillation combined with cigarette smoke exposure, followed by treatment with RES at 50 mg/kg. Lung histopathology, mean linear intercept (MLI), destructive index (DI), bronchoalveolar lavage fluid (BALF) inflammatory cell counts, cytokine levels, macrophage polarization, and TLR4/HK2 pathway protein expression were assessed. In vitro, LPS-stimulated RAW264.7 macrophages were treated with RES, with or without TLR4 overexpression and HK2 silencing, to evaluate inflammatory responses, M1 polarization, glycolytic activity, and mitochondrial respiration. RES significantly alleviated lung tissue injury, decreased inflammatory scores, MLI, and DI, and reduced BALF inflammatory cell counts in COPD mice. RES also decreased inflammatory cytokine levels, suppressed macrophage M1 polarization, and downregulated TLR4, p-p65, and HK2 expression. In LPS-stimulated macrophages, RES reduced NO, IL-6, TNF-α, glucose uptake, lactate production, and ECAR, while improving OCR. TLR4 overexpression reversed the inhibitory effects of RES on inflammatory activation, M1 polarization, glycolytic reprogramming, and HK2 expression, whereas HK2 silencing partially restored the protective effects of RES under TLR4 overexpression. RES alleviates macrophage inflammatory activation, M1 polarization, and glycolytic reprogramming, in part through inhibition of the TLR4/HK2 pathway, suggesting its therapeutic potential for delaying COPD progression.

Small-diameter vascular grafts (≤ 6 mm) remain a critical unmet need in cardiovascular surgery, as autologous vessels are unavailable in up to 30% of patients requiring coronary or peripheral bypass. Induced pluripotent stem cells (iPSCs) have emerged as a transformative cell source for tissue-engineered vascular grafts (TEVGs), offering unlimited self-renewal, patient-specific or universal donor potential, and the capacity to generate all vascular cell lineages. Recent breakthroughs-including iPSC-derived grafts achieving 100% patency in allogeneic primate models and the first United States Food and Drug Administration (FDA) approval of an acellular tissue-engineered vessel (SYMVESS, December 2024)-signal that clinical translation is accelerating. This review provides a comprehensive synthesis of the iPSC-to-graft pipeline, encompassing vascular cell differentiation protocols, biomaterial scaffold design, immune engineering strategies for universal grafts, bioreactor maturation, preclinical evaluation, and the evolving clinical-regulatory landscape. We critically evaluate how the convergence of clustered regularly interspaced short palindromic repeats (CRISPR)-based immune editing, advanced biomaterials, and scalable manufacturing is reshaping the field toward off-the-shelf vascular grafts. Finally, we identify remaining challenges in long-term patency, thrombogenicity, and manufacturing scalability, and propose a translational roadmap for the next decade.

Intervertebral disc degeneration (IDD) serves as a critical structural basis for chronic low back pain, severely impairing patients' quality of life and imposing a significant socioeconomic burden. Current interventions remain largely limited to symptomatic treatments including pharmacological analgesia and surgical intervention. The recently proposed "gut-disc axis" suggests that the gut microbiome can reshape the endplate-disc microenvironment by influencing intestinal barrier integrity, microbial metabolite profiles, and host immune-metabolic status. Existing evidence indicates that dysbiosis-related increases in endotoxin load, dysregulated metabolism of short-chain fatty acids, tryptophan, and bile acids, systemic low-grade inflammation, and shifts in immune cell lineages may collectively promote nucleus pulposus cell senescence and apoptosis, matrix degradation, and endplate pathology. Mendelian randomization studies have also suggested potential causal links between certain gut microbiota and disc diseases. However, the determination of whether "microbial signals" detected within the intervertebral disc represent true colonization is currently hindered by methodological limitations, particularly low-biomass contamination. This review focuses on mechanisms through which gut microbiota influence the endplate-disc microenvironment via immune-metabolic pathways, including the LPS/TLR4/NF-κB axis, SCFAs-AhR axis, and lipid/iron metabolism, while only briefly addressing studies related to mechanical injury and surgery. Building on these insights, we integrate advances from clinical cohorts, animal models, and multiomics studies, summarize key actionable intervention nodes, and propose a preliminary patient stratification framework and validation pathway based on gut-immune-metabolic typing, providing a theoretical foundation for developing microbiome-guided disease-modifying interventions.