BackgroundLung cancer (LC) patients account for 20% of all cancer-related venous thromboembolism (VTE) events, which is the second leading cause of mortality in these patients. However, there are no LC-specific risk scores for VTE prediction. Therefore, we considered that an LC-specific nomogram would more accurately predict VTE probability for these patients than the current widely used VTE risk scores.MethodsA total of 676 patients from the Guizhou Provincial People’s Hospital (January 2016 to September 2021) were included in this study, of which 169 LC patients who developed VTE were time-matched with 507 (1:3 ratio) LC patients without VTE. These patients were randomly divided at a 2:1 ratio to form primary (451) and validation (225) cohorts. The accuracy of six VTE risk scores was assessed by producing area under the receiver operating characteristic (ROC) curves (AUC). A multivariate analysis was employed to select predictive features, which were then used to construct a nomogram for VTE prediction.ResultsAmong the scoring methods, COMPASS-CAT had the highest AUC (0.799). The multivariate analyses revealed that acute infection, bed rest (>3 days), D-dimer level >1.47 μg/mL, adenocarcinoma, and carcinoembryonic antigen (CEA) >10.935 ng/mL were independent predictors of VTE risk for LC patients. The nomogram constructed using these factors enabled VTE prediction with a concordance index of 0.882 and an AUC of 0.894.ConclusionThis article describes the construction and validation of a new nomogram for VTE prediction in LC patients, which has a predictive performance that is higher than any of the widely used conventional risk assessment tools.
Acute kidney injury superimposed on chronic kidney disease (acute-on-chronic kidney injury, hereinafter referred to as AoCKI) is a common clinical syndrome with a generally poor prognosis compared to isolated acute kidney injury (AKI). Patients with AoCKI often face significantly heightened mortality, increased dependence on renal replacement therapy (RRT), and reduced likelihood of renal function recovery. Crucially, the pathophysiological mechanism of AoCKI is not merely an additive effect of two separate conditions, but a distinct synergistic insult driven by pre-existing microvascular and metabolic vulnerabilities. While recent clinical epidemiological studies have enhanced understanding of AoCKI, the mechanisms underlying its poor prognosis remain insufficiently elucidated, and research on population-specific biomarkers is limited. Most currently available biomarkers were identified in patients with isolated AKI and have not been specifically studied in the context of CKD. This review synthesizes previous findings and relevant research to examine the risk factors for AoCKI, as well as the potential pathophysiological mechanisms and biomarkers associated with impaired renal adaptive repair. The objective is to inform the development of more effective preventive measures, diagnostic criteria, and treatment strategies to improve outcomes for this patient population.
Ischemic stroke profoundly disrupts the homeostatic dialogue between microglia and neurons, converting a physiological surveillance network into a dynamic, injury-responsive, and spatially heterogeneous communication system. Under physiological conditions, neurons regulate microglia through diverse signaling pathways, while microglia support neuronal health via synaptic remodeling, inflammatory regulation, metabolic balance, and debris clearance. Following cerebral ischemia, cascades involving excitotoxicity, energy failure, ionic imbalance, damage-associated molecular patterns (DAMPs), complement activation, and cell death signals rapidly reprogram this bidirectional communication. In this Review, we propose the Microglia-Neuron Communication Continuum (MNCC) model as a conceptual framework for understanding post-stroke microglia-neuron crosstalk. The MNCC model conceptualizes these interactions as a multidimensional continuum defined by three core axes: time, communication mode, and functional outcome. Along the temporal axis, crosstalk evolves from the hyperacute and acute phases to the subacute and chronic stages. Along the communication-mode axis, interactions span direct contact-dependent mechanisms and indirect soluble signaling pathways. Along the functional-output axis, the biological consequences range from damage amplification to tissue repair and chronic maladaptation. Using this framework, we first summarize the physiological basis of bidirectional microglia-neuron signaling under homeostatic conditions. We then examine how ischemic stroke reprograms this network across distinct temporal stages and spatial niches, emphasizing that post-stroke crosstalk is a continuous, context-dependent, spatially heterogeneous, and functionally plastic process. Finally, we discuss current and emerging therapeutic strategies through the lens of the MNCC model, focusing on temporal matching, dominant communication modes, regional heterogeneity, and translational barriers. A deeper understanding of this communication continuum may facilitate the development of targeted interventions that restrain harmful signaling, preserve beneficial interactions, and ultimately improve long-term neurological recovery after ischemic stroke.
Fetal growth restriction (FGR) is a major obstetric complication characterized by the inability of the fetus to reach its genetic growth potential, most commonly due to placental insufficiency. It contributes substantially to perinatal morbidity, stillbirth, and long-term cardiometabolic disease. Emerging evidence indicates that FGR arises not from a single defect but from a convergent, self-reinforcing network of placental dysfunction involving impaired trophoblast invasion, defective spiral artery remodeling, oxidative stress, angiogenic imbalance, immune dysregulation, nutrient transport failure, and epigenetic reprogramming. In early-onset FGR, hypoxia-driven HIF-1α signaling serves as an important integrating node linking angiogenic, inflammatory, and metabolic dysfunction, whereas additional HIF-1α-independent pathways appear to contribute more prominently in late-onset disease. Advances in single-cell and multi-omics technologies have refined the cellular and molecular landscape of the placenta, revealing complex intercellular interactions and regulatory circuits underlying disease heterogeneity. Clinically, diagnosis relies on integrated assessment of fetal biometry, Doppler velocimetry, and biomarkers such as the sFlt-1/PlGF ratio, while management remains largely surveillance-based with limited effective therapeutic options once placental dysfunction is established. Translational research is increasingly focused on precision approaches, including multi-omics biomarker panels, machine learning-based risk prediction, and pathway-targeted interventions. However, clinical implementation remains constrained by biological heterogeneity and lack of standardized validation. This review synthesizes current mechanistic insights and highlights emerging diagnostic and therapeutic strategies, emphasizing the need to shift from single-pathway models toward network-based and mechanism-stratified approaches. Advancing toward precision obstetrics will require integration of molecular profiling with clinical decision-making to improve outcomes for pregnancies affected by FGR.
BackgroundThalassemia is the most common single-gene inherited blood disorder worldwide, being relatively rare in northern China but more prevalent in southern China. To facilitate effective prevention and control of thalassemia, we analyze the genotype and frequency distribution of rare thalassemia variants in the general population of the Ganzhou area, offering valuable insights for genetic counseling and prenatal diagnosis.MethodsBetween January 2022 and January 2025, a cohort of 84,067 individuals was screened in Ganzhou. Following the exclusion criteria, 1,081 participants with rare thalassemia variants were included in the final analysis. Genotypes associated with thalassemia were determined using next-generation sequencing (NGS). Variant classification adhered to ACMG/AMP guidelines.ResultsAmong the participants with rare thalassemia variants, 495 individuals presented with rare α-thalassemia variants and 560 with rare β-thalassemia variants, including 26 newly identified variants. Rare thalassemia variants accounted for 1.29% of the total screened population. The distribution of rare thalassemia variants exhibited regional variation across Ganzhou, with the highest rates in Nan Kang (12.69%), followed by Xingguo (10.49%) and Zhanggong (8.80%). Chongyi had the lowest rate at 1.78%, with all these locations located to the northwest of Ganzhou. Additionally, 26 individuals carried novel thalassemia variants. Six of these variants were classified as “Likely Pathogenic,” and the HBB:c.50G>T (Gly > Val) genotype was associated with hypochromic anemia.ConclusionThis study offers a comprehensive analysis of rare and newly identified thalassemia variants in the Ganzhou area, highlighting the complexity and heterogeneity of the condition. These findings underscore the necessity for effective screening methods in regions with a high incidence of thalassemia and provide essential insights for the targeted prevention and management of this disorder in the future.
BackgroundOsteosarcoma remains the most prevalent primary malignant bone tumor in adolescents and young adults. For patients with localized disease, 5-year overall survival reaches 60%–70%; however, for those with metastatic or recurrent disease, 5-year survival remains stagnant at approximately 20%, and chemoresistance represents the primary obstacle to improved outcomes.ObjectiveThis review systematically elucidates the crosstalk among glycolytic, lipid, and glutamine pathways and their synergistic interactions with the immune microenvironment in driving osteosarcoma drug resistance, while evaluating the translational potential of metabolic targeted therapies.ResultsWe highlight that aerobic glycolysis-derived histone lactylation, which has been shown to activate multidrug resistance gene transcription in other cancers and represents a candidate epigenetic mechanism warranting investigation in osteosarcoma; SCD1-mediated monounsaturated fatty acid synthesis confers ferroptosis resistance; glutamine-derived α-KG supports epigenetic programming and redox homeostasis; and metabolic competition creates an immunosuppressive tumor microenvironment. We further discuss metabolic heterogeneity, plasticity, and metabolomic methodologies as applied to osteosarcoma.ConclusionSingle-agent metabolic inhibitors show limited clinical efficacy due to metabolic plasticity and compensatory activation. Almost all metabolic targeting evidence remains preclinical; no metabolic therapy has yet entered standard osteosarcoma care. Triple combination strategies (metabolic inhibitors + immunotherapy + chemotherapy) represent a mechanistically attractive but clinically untested hypothesis. Telaglenastat (CB-839), a glutaminase inhibitor, has been prioritized for osteosarcoma clinical trials but efficacy data in osteosarcoma patients remain pending.
IntroductionTemporal lobe epilepsy is associated with systemic metabolic alterations that may evolve during disease progression and in response to pharmacological treatment. This study employed a longitudinal 1H NMR-based metabolomics approach to characterize the serum metabolic profile of a chronic pilocarpine-induced rat model of temporal lobe epilepsy.MethodsSerum samples were collected longitudinally to identify phase-specific metabolic signatures. Following phenobarbital administration, animals were classified as drug-sensitive or drug-resistant according to their treatment response. The resulting metabolic profiles were investigated using multivariate and univariate statistical analyses.ResultsThe analysis revealed progressive systemic metabolic remodeling characterized by extensive alterations in lipid-related signals and significant increases in the ketone bodies 3-hydroxybutyrate and acetoacetate, as well as in glutamine. Following phenobarbital treatment, OPLS-DA showed a strong metabolic similarity between the drug-sensitive and drug-resistant groups, which occupied nearly identical metabolic spaces. Nevertheless, after stratification, creatine emerged as the only significantly different metabolite between responders and non-responders (p = 0.001).DiscussionThe convergence of the metabolic profiles of drug-sensitive and drug-resistant animals suggests that the systemic effects of chronic epilepsy and phenobarbital treatment dominate the serum metabolome, potentially masking subtle molecular signatures associated with drug resistance. Creatine represents a notable exception and warrants further investigation as a potential marker distinguishing responders from non-responders.
Nonsense-mediated mRNA decay (NMD) is a basic post-transcriptional mechanism ensuring the fidelity of many biological processes including brain development. Together with alternative splicing, it regulates the inclusion of poison exons. NMD is involved in the control of multiple processes during brain development such as neural progenitor proliferation and differentiation, neuronal migration, axonal guidance, and synaptic plasticity. Under physiological conditions, this mechanism safeguards neuronal identity and the functional maturation of the brain. When disrupted, the consequences range from structural cerebral anomalies to cognitive impairment and epilepsy. This review examines NMD-mediated regulatory mechanisms across different stages of brain development. Special emphasis is placed on how dysfunction in NMD pathway components—specifically core degradation factors, the exon junction complex, and neuron-specific splicing regulators—underpins an extensive array of neurodevelopmental disorders (NDDs). Furthermore, we delineate the relationship between the position of a premature termination codon (PTC) within a transcript and the resulting molecular outcome. While the degradation of aberrant mRNAs often leads to haploinsufficiency, their escape from NMD might result in the accumulation of truncated proteins with dominant-negative effects, thereby causing specific clinical phenotypes in affected patients. Elucidating these mechanisms is essential for both the interpretation of variant pathogenicity and the development of targeted therapeutic strategies.
ObjectiveThis study aims to evaluate the oxidative stress alleviating potential of glucan exopolysaccharide (EPS) using in vitro (biochemical and cell culture) and in vivo Caenorhabditis elegans model systems.MethodsThe in vitro antioxidant potential of EPS from Enterococcus hirae OL616073 of food origin was evaluated using reducing power, ferric-reducing antioxidant power (FRAP) assay, and 2,2-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical-scavenging activity assays. The antioxidant effect of EPS was also evaluated in C. elegans (wild type Bristol N2), a simple multi-cellular eukaryotic model via survival assay, gene expression, DCF-DA staining, reproduction, and pharyngeal pumping assay. Finally, the ROS scavenging activity of EPS was investigated in human colon cancer cells (Caco-2 cell line) by DCF-DA staining and flow cytometry.Results and discussionThe in vitro assays showed the significant antioxidant activity of EPS as evidenced by reducing power, FRAP, and ABTS radical-scavenging activity. In C. elegans, EPS treatment (150 and 300 μg/mL) significantly extended the lifespan of wild-type (Bristol N2) C. elegans (∼1.21% and ∼0.83%) compared to control. EPS treatment (150 μg/mL) resulted in increased egg-laying capacity and little change in the pharyngeal pumping rate of C. elegans over five consecutive days. In addition, pre-, post-, and co-treatment of EPS (150 μg/mL) in the presence or absence of H2O2 (1 mM) showed a reduction in ROS generation. Similarly, in the colorectal cancer cell line (Caco-2), high basal intracellular ROS levels were reduced with increasing concentration of EPS via an increase in intracellular antioxidant enzymes.ConclusionEPS from E. hirae OL616073 of food origin exhibited significant antioxidant potential across diverse model systems. These findings highlight its potential as a natural antioxidant ingredient for applications in functional foods, nutraceuticals, and pharmaceutical formulations.
Oxidative stress, driven by an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, plays a pivotal role in cancer biology. While persistent, moderately elevated ROS levels can promote genomic instability, tumor progression, and immune evasion, excessive ROS accumulation can overwhelm antioxidant defenses and trigger cancer cell death. Despite promising preclinical findings, clinical translation remains a challenge because of the context-dependent effects of ROS. A deeper understanding of oxidative stress regulation may lead to the development of novel precision medicine strategies, optimizing cancer therapies while minimizing adverse effects. This review highlights the concentration-dependent effects of oxidative stress in tumorigenesis, focusing on its impact on DNA damage, metabolic reprogramming, and immune modulation. We discuss recent advancements in ROS-targeting strategies, including pro-oxidant therapies that exploit redox vulnerabilities in cancer cells and antioxidant-based approaches aimed at mitigating oxidative stress-driven resistance to treatment. Moreover, we examine the interplay between oxidative stress and the tumor microen-vironment, emphasizing its influence on immune surveillance and therapeutic responses. This re-view provides insights into ROS-targeting interventions and their potential in oncologic treatment paradigms.
The present study aims to identify the key metabolic compounds of supragingival plaque and potential metabolic pathways associated with severe early childhood caries (S-ECC) in preschool children, and to provide a basis for screening candidate biomarkers that could be beneficial to clinical practice guidelines. A cohort of 93 children, including 32 healthy controls (HC group), 31 children with S-ECC (SECC group) and 30 children with S-ECC and black stain (SECCBS group), were recruited. Supragingival plaques were collected for UHPLC-MS analyses followed by bioinformatics analysis. Differential metabolites (DMs) were screened through Partial Least Squares Discriminatory Analysis (PLS-DA) and enriched in KEGG pathways. Ecological network analysis and WGCNA were performed to construct co-expression networks. Ten machine learning (ML) models were optimized by feature selection and hyperparameter tuning, and evaluated using the area under the ROC curve (AUC), sensitivity, specificity, precision, and predictability comparison. A total of 1,069 metabolites were detected, with 497 annotated into 40 KEGG pathways, primarily amino acid and lipid metabolism. We identified 134 DMs between the HC and SECC groups, and 49 DMs between the SECC and SECCBS groups. WGCNA identified 32 co-expression modules in each paired comparison. In the HC-SECC comparison, the top correlated module pathways (neuroactive ligand-receptor interaction and pyrimidine metabolism) aligned precisely with the KEGG enrichment results of the DMs. In the SECC-SECCBS comparison, biosynthesis of unsaturated fatty acids and fatty acid degradation were uniquely enriched. For clinical prediction, the random forest (RF) model achieved the highest AUC (98.38) in the HC-SECC group, while the SVM-Poly model was superior in the SECC-SECCBS group (AUC = 95.10). The supragingival plaque metabolome is discernibly different among healthy children, those with severe caries, and those with black stain. Key metabolites including uracil, uridine 5’-diphosphate, cytosine, epinephrine, uridine, and deoxycytidylic acid are closely associated with dental caries occurrence and represent promising targets for early diagnosis. Additionally, Glycerophospho-N-palmitoyl ethanolamine (GP-NPEA) and lipid metabolic adaptations (such as unsaturated fatty acid pathways) in the SECCBS group provide a novel mechanistic explanation for the lower caries susceptibility and the pigment formation associated with black stain. These biomarkers offer valuable insights for precision risk stratification and personalized therapeutic strategies in pediatric dentistry.
BackgroundMicronutrients such as zinc, selenium, and vitamin D play a crucial role in prostate physiology. Deficiencies in these nutrients may be associated with prostate-specific antigen (PSA) levels and with impaired urinary tract parameters, including the International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax), and post-void residual (PVR) volume. This retrospective study evaluated the association between serum micronutrient status and prostate health indicators in adult men.MethodsMedical records of 400 men aged ≥45 years who underwent prostate evaluation between 2019 and 2022 were retrospectively analyzed. Serum zinc, selenium, and 25-hydroxyvitamin D levels were recorded alongside PSA values and urinary tract parameters, including IPSS, Qmax, and PVR volume. Based on reference ranges, participants were categorized into low- or normal-micronutrient groups. Correlation analyses and multivariable logistic regression were performed to identify independent predictors of elevated PSA (>4 ng/mL) and severe urinary symptoms (IPSS ≥20).Results120 participants exhibited low micronutrient levels. Compared with men with normal levels, this group showed significantly higher PSA (5.2 ± 2.8 vs. 2.9 ± 1.5 ng/mL), higher IPSS scores (16.5 ± 5.8 vs. 10.2 ± 5.2), lower Qmax (11.2 ± 4.1 vs. 16.1 ± 4.7 mL/s), and higher PVR (61.7 ± 20.3 vs. 42.2 ± 18.5 mL) (all p < 0.001). Serum zinc, selenium, and vitamin D levels were inversely correlated with PSA and IPSS and positively correlated with Qmax (all p < 0.001). In multivariable regression analysis, low zinc (OR 2.48; 95% CI: 1.45–4.23), low selenium (OR 2.12; 95% CI: 1.27–3.52), and low vitamin D (OR 1.87; 95% CI: 1.11–3.16) were independent predictors of elevated PSA.ConclusionMicronutrient deficiencies were associated with altered PSA levels and impaired urinary tract function. Monitoring and correcting micronutrient deficiencies may represent a valuable component of prostate health management, though prospective studies are needed to confirm causality.
Plant Homeodomain Finger Protein 14 (PHF14) is a known epigenetic regulator involved in chromatin-mediated gene regulation. PHF14 belongs to the plant homeodomain (PHD) family, and possesses four PHD zinc-finger domains. The N-terminal PHD1 and PHD2 domain of PHF14 mediate histone recognition through specific PHD1–ZnK–PHD2 (PZP) cassettes and thereby contribute to the regulation of transcriptional activation and gene silencing. PHF14 plays a role in regulating essential cellular processes such as the cell cycle, mesenchymal proliferation, DNA damage response, and B-cell proliferation. Genetic variants of PHF14 have been identified across multiple clinical conditions, underscoring its physiological and pathologic relevance. Over the past 5 years, PHF14 has garnered substantial attention for its dysregulation or sequence variation associated with various cancers. PHF14-mediated interactions are implicated in neurodevelopmental disorders and also contribute to lung and renal fibrosis, as well as Dandy–Walker syndrome, underscoring its role in diverse pathological conditions. This review summarizes current knowledge on PHF14 structure, interaction partners, molecular functions, associated signaling pathways, and roles in diseases.
BackgroundFabry disease (Anderson–Fabry disease,FD) is an X-linked lysosomal storage disorder caused by variants in GLA, resulting in α-galactosidase A (α-Gal A) deficiency and accumulation of globotriaosylsphingosine (lyso-Gb3), with frequent cardiac involvement.Case SummaryA 53-year-old man presented with exertional chest tightness and dyspnea. Electrocardiography and echocardiography demonstrated marked left ventricular hypertrophy. Cardiac magnetic resonance revealed diffuse hypertrophy with extensive subendocardial late gadolinium enhancement. ^99mTc-pyrophosphate scintigraphy showed minimal myocardial uptake, arguing against transthyretin cardiac amyloidosis. Biochemical testing showed markedly reduced α-Gal A activity and elevated lyso-Gb3 levels. Whole-exome sequencing identified a previously unreported GLA variant (NM_000169.3:c.752A>C; p.Glu251Ala), which was confirmed by Sanger sequencing and detected in multiple family members. The variant is currently classified as a variant of uncertain significance (VUS). Familial analysis demonstrated a segregation pattern consistent with X-linked inheritance.ConclusionWe report a novel GLA variant associated with biochemical abnormalities and familial segregation consistent with FD. These findings support a potential role of this variant in Fabry cardiomyopathy and expand the mutational spectrum of GLA, although its pathogenicity requires further validation.
Cell sheet engineering has emerged as a scaffold-free biofabrication strategy that preserves intrinsic cell–cell and cell–extracellular matrix interactions, demonstrating significant translational potential in regenerative medicine, including cardiac patches, cartilage and skin reconstruction, and corneal transplantation. Despite these advances, thick or multilayered cell sheets remain constrained by diffusion related hypoxia, accumulation of reactive oxygen species, ECM destabilization, and insufficient mechanical reinforcement, all of which interact to compromise long term structural integrity. Rather than providing a conventional survey of recent developments, this conceptual integration review reframes these limitations as a coupled reaction–diffusion–mechanics problem. We examine how redox imbalance and structural insufficiency form a self-reinforcing failure network in thick scaffold-free constructs and propose a reciprocal dual-axis catalytic framework to address this instability. Nanozymes, through catalase-, peroxidase-, and superoxide dismutase-like catalytic activities, regulate oxidative stress, alleviate hypoxic amplification, and establish a permissive redox microenvironment that sustains cell viability and ECM synthesis. In parallel, immobilized enzyme systems facilitate collagen crosslinking and protease modulation, thereby reinforcing ECM architecture and enhancing tensile and shear resilience at the network level. Although nanozyme-based redox regulation and enzyme-mediated structural reinforcement have been extensively explored in oncology, antioxidant therapeutics, and industrial catalysis, their coordinated implications for scaffold-free cell sheet engineering have not been systematically integrated. By articulating a reciprocal dual-axis framework linking redox stabilization with biomechanical maturation, this review provides a systems-level design logic for improving thick cell sheet stability. Finally, we extend this catalytic paradigm beyond regenerative medicine to high-density sheet-like biofabrication systems, including cultured meat and cultured leather, positioning the framework as a transferable engineering principle across emerging biofabrication industries.
IntroductionSepsis-associated acute kidney injury (SA-AKI) is a prevalent, life-threatening sepsis complication with high mortality, prolonged organ support dependence, and scarce targeted therapies. Beyond being an anaerobic glycolysis byproduct, lactate serves as a critical circulating carbon source, mitochondrial fuel, redox regulator, signaling molecule, and lysine lactylation (Kla) substrate. Its multifaceted functions are vital to SA-AKI pathogenesis, which involves systemic lactate overload, impaired lactate clearance, renal metabolic reprogramming, and abnormal immune activation.MethodsThis review synthesizes up-to-date evidence to systematically elucidate lactate and Kla mechanisms in SA-AKI. We hierarchically integrate findings from systemic sepsis metabolism and renal tubular lactate handling to cell-specific Kla modifications, aiming to clarify their distinct roles in SA-AKI progression.ResultsSpecific Kla sites (H3K18la, Fis1 K20la, LDHB K156la, Ezrin K263la, HMGB1 lactylation, ALDH2 K68la) mediate SA-AKI pathologies including mitochondrial dysfunction, tubular death, endothelial injury, and cGAS-STING/NLRP3-neutrophil extracellular trap activation. Lactate accumulation, acidosis, transport, oxidation, metabolic routing, and Kla are mechanistically distinct rather than uniformly harmful. Lactate/pyruvate metabolism exerts context-dependent injurious or adaptive effects across kidney disease models, modulated by cell type, injury phase, and metabolic reserve.DiscussionLactate- and Kla-targeted strategies are promising for SA-AKI treatment yet require rigorous clinical validation. Blood lactate level and clearance are reliable clinical prognostic biomarkers, whereas Kla signatures remain investigational. Balanced understanding of lactate-Kla biology will refine precision diagnostic and therapeutic strategies for SA-AKI, advancing translational clinical application.
Liver transplantation is the definitive treatment for advanced liver failure, yet ischemia-reperfusion injury (IRI) remains a major challenge—particularly for marginal, steatotic, or donation-after-circulatory-death (DCD) grafts. While oxidative stress and inflammation are long-recognized contributors to IRI, this review focuses on two tightly linked, mechanistically specific pathways: ferroptosis and mitochondrial reactive oxygen species (ROS). Together, these pathways convert reperfusion-associated metabolic stress into injury of hepatocytes, endothelium, and bile ducts. Anesthetic preconditioning has gained interest as a modulator of this injury cascade. Volatile anesthetics, alongside propofol and dexmedetomidine, show experimental efficacy in reducing IRI by stabilizing mitochondria, regulating redox status, preserving GPX4(Glutathione Peroxidase 4)/SLC7A11(Solute Carrier Family 7 Member 11)-mediated antioxidant capacity, limiting lipid peroxidation, and dampening innate immune responses. However, clinical translation is limited by heterogeneity in experimental models, variability in anesthetic regimens, overreliance on non-specific oxidative stress markers, and a lack of validated ferroptosis-related endpoints in human studies. In summary, ferroptosis and mitochondrial ROS provide a cohesive mechanistic framework for graft vulnerability at reperfusion. To advance this field, future clinical studies should move beyond general oxidative stress assessments toward biomarker-driven approaches—integrating ferroptosis-specific markers and mitochondrial function tests. Coupling these with risk stratification of donor livers based on biochemical profiles, and tracking clinically meaningful outcomes, will enable precision strategies to mitigate IRI. This review underscores the need for targeted mechanistic validation to translate anesthetic conditioning into effective clinical organ protection.
IntroductionMitochondrial phospholipids are crucial for maintaining structure and function; however, their roles and transport pathways are not fully understood in a multicellular model organism. In this study, we examined two putative Caenorhabditis elegans proteins, B0334.4 (PREL-1) and F15D3.6 (PREL-3), thought to be involved in intramitochondrial phospholipid transport.MethodsIn-silico molecular docking analysis was performed to predict phospholipid binding specificity of PREL-1 and PREL-3. RNA interference (RNAi) was used to knockdown the expression of these proteins in C. elegans. Upon knockdown, development, lifespan, reproduction, locomotion, stress response, and mitochondrial phospholipid composition were analysed.ResultsDocking studies predicted that phosphatidic acid (PA) preferentially binds to PREL-1 compared to PREL-3. Mitochondrial profiling revealed loss of mitochondrial phospholipid homeostasis upon RNAi knockdown. This resulted in mitochondrial dysfunction leading to impaired reproduction, respiration, locomotion, and elevated ROS levels in worms lacking these phospholipid transporters.ConclusionOur findings support the role of PREL-1 and PREL-3 proteins in mitochondrial phospholipid homeostasis and suggest their function as PRELI- family phospholipid transporters. This study demonstrates the importance of these phospholipid transporters in mitochondrial function, growth, lifespan, and organism physiology.
Inflammatory immune responses in the dental pulp are shaped by interacting cellular and molecular processes, and microRNAs (miRNAs) are important post-transcriptional regulators. However, an integrated understanding of how miRNA networks orchestrate the balance between pulpitis progression and tissue repair remains incomplete. This review examines the differential expression profiles of miRNAs in inflamed dental pulp, and evaluates their potential as adjunctive biomarkers of pulpitis status. We also summarize how miRNAs regulate key inflammatory signaling cascades, including the TLR/NF-κB, mitogen-activated protein kinase, and cGAS-STING pathways, and discuss their integration within broader epigenetic crosstalk networks involving lncRNAs and circRNAs. We further analyze how the inflammatory microenvironment and physicochemical stresses alter the osteogenic/odontogenic differentiation potential of dental pulp stem cells through miRNA-dependent regulation. We then assess the translational prospects of exosome-delivered miRNAs as cell-free therapeutics and highlight unresolved challenges in sampling feasibility, donor heterogeneity, delivery specificity, and clinical validation. By synthesizing evidence on miRNA regulatory networks in pulpal inflammation and regeneration, this review provides a framework for evaluating miRNA-based diagnostic tools and targeted therapies for pulpitis.
Phosphoglycerate mutase 1 (PGAM1) is a pivotal metabolic enzyme during the process of glycolysis, catalyzing the interconversion between 3-phosphoglycerate and 2-phosphoglycerate. PGAM1 is mainly involved in cellular energy metabolism and biosynthesis, it is generally upregulated in numerous human cancers and promotes cell proliferation, invasion, and drug resistance. It serves as a significant biomarker for tumor diagnosis and a potential therapeutic target. In this paper, the basic structure and functions of PGAM1 and its family members, metabolic, non-metabolic activity and the regulatory mechanisms of PGAM1 and its correlation with diseases, as well as the latest progress of PGAM1 inhibitors in tumor diagnosis and treatment are introduced, aiming to provide new ideas for the targeted therapy of related diseases.
