Biomedical Journal最新文献

Myocardial infarction (MI) is one of the leading causes of death worldwide, with its high incidence and mortality posing a significant threat to human health. Despite some progress in the treatment of myocardial infarction, mortality rates remain alarmingly high. Adult mammals have limited myocardial regenerative capacity, and extensive cell death caused by myocardial ischemia severely impairs cardiac function, leading to heart failure or death. In contrast, neonatal myocardium possesses a robust regenerative ability, which gradually diminishes after birth. The loss of cardiomyocyte regenerative capacity is often accompanied by a shift in energy metabolism-from reliance on glucose (glycolysis) to fatty acid oxidation. This metabolic reprogramming significantly impacts CM proliferation. Long non-coding RNAs (lncRNAs) orchestrate cardiac regeneration through epigenetic control (e.g., Bvht/PRC2-mediated silencing), metabolic reprogramming (e.g., GATA6-AS1 suppression of FAO), and miRNA sponging (e.g., CAREL sequestration of miR-296). However, our understanding of the metabolic determinants and pathways that promote myocardial regeneration after myocardial infarction is still insufficient. This review investigates the interplay between lncRNAs and metabolic reprogramming in cardiovascular function, aiming to identify novel therapeutic targets and strategies to enhance myocardial regeneration post-MI.

Background: Obesity is a major contributor to metabolic dysfunction and is driven by complex genetic, behavioral, and physiological factors. Neuropeptide FF receptor 2 (NPFFR2) has been implicated in regulating feeding behavior, as well as energy and glucose homeostasis. However, its precise role in obesity and metabolic disorders remains unclear. This study aimed to investigate the systemic role of NPFFR2 in obesity-induced metabolic dysfunction.

Material and methods: The role of NPFFR2 was examined using wild-type and Npffr2-overexpressing transgenic mice subjected to 15 weeks of high-fat high-sucrose diet to induce obesity. Systemic, tissue-specific, and serum metabolic profiles were analyzed, with a particular focus on lipid abnormalities in the liver and adipose tissues.

Results: Npffr2 overexpression exacerbated obesity-induced metabolic dysfunction, including accelerated body weight gain, impaired glucose homeostasis, altered fat composition, adipose tissue inflammation, and dysregulated lipid metabolism. In addition, hypertrophy of both hepatocytes and adipocytes was aggravated in Npffr2-overexpressing mice, collectively contributing to excessive energy storage and reduced metabolic efficiency.

Conclusions: These findings suggest that NPFFR2 may contribute to the regulation of energy balance and lipid metabolism, potentially via central regulatory pathways. These findings highlight the need for mechanistic studies to clarify its region-specific roles and therapeutic potential in metabolic disorders.

Background: Pelvic floor disorders (PFDs) severely and negatively impact on quality of life, affecting physical, psychological, and social well-being. Historically, PFDs have been managed within single-specialty frameworks, yet the complexity of these conditions often necessitates a comprehensive, multidisciplinary team (MDT) approach. This systematic review assesses the effectiveness of MDT strategies in improving outcomes for individuals with PFDs, aiming to identify the benefits and potential advantages of integrated, multi-specialty care for these complex conditions.

Methods: Following PRISMA guidelines, a systematic search of PubMed, EMBASE, and Cochrane CENTRAL was conducted through September 25, 2024. Inclusion criteria were studies of adult patients with PFDs in which MDT protocols were integrated for diagnosis, treatment, or rehabilitation. Eligible studies included comparisons between MDT and non-MDT care, as well as studies without a comparison group. Outcomes of interest were patient-reported outcomes, therapy adherence, complication rates, and recurrence rates. Three independent reviewers screened titles and abstracts for eligibility, with discrepancies resolved through discussion to reach a consensus. Data extraction was independently performed by two reviewers, and any discrepancies were adjudicated by a third reviewer.

Results: In total, 24 studies conducted across various countries were included, comprising 21 retrospective cohort studies, 2 prospective cohort studies, and 1 randomized controlled trial (RCT), with sample sizes ranging from 36 to 3,600 patients. The findings generally indicate favorable outcomes with an MDT approach, including enhanced surgical results, greater symptom relief, reduced recurrence and complication rates following surgical interventions, improved treatment adherence, and high patient satisfaction.

Conclusions: An MDT approach offers benefits for PFD management, improving patient-reported outcomes, treatment adherence, and quality of life. This review supports the broader adoption of MDT approaches for comprehensive PFD management. Further research is warranted to confirm long-term effectiveness and standardize MDT protocols.

Background: Lung cancer is the leading cause of cancer-related mortality worldwide. Although immune checkpoint inhibitors (ICIs), chemotherapy, and molecular targeted therapies have improved survival rates, therapeutic resistance remains a major barrier to curative outcomes. Recently, plasminogen activator inhibitor-1 (PAI-1) has been implicated in lung cancer progression and treatment resistance.

Material and methods: This review summarizes the recent evidence from preclinical and clinical studies on the Role of PAI-1 in the progression and treatment resistance in lung cancer, focusing on its contribution to tumor aggressiveness and resistance to therapy. As limited evidence is available regarding its role in small cell lung cancer, this review focuses on the findings reported to date for non-small cell lung cancer (NSCLC).

Results: PAI-1 promoted tumor invasion, angiogenesis, and epithelial-mesenchymal transition (EMT), thereby facilitating cancer progression. Elevated PAI-1 expression in tumor tissues and plasma is correlated with advanced disease stages and poor prognosis. Genetic polymorphisms such as A15T, which affect PAI-1 stability, are also associated with unfavorable outcomes. PAI-1 contributes to radiotherapy resistance through the hypoxia-induced upregulation of AKT/ERK signaling, chemotherapy by activating cancer-associated fibroblasts, and targeted therapies via integrin-mediated EMT. Moreover, it enhances immune evasion by promoting programmed cell death-ligand 1 expression and creating an immunosuppressive tumor microenvironment.

Conclusions: PAI-1 is a key regulator of tumor progression and therapeutic resistance in NSCLC. Targeting PAI-1 may offer a novel strategy to overcome resistance to multiple treatment modalities, and future research should focus on developing PAI-1-based biomarkers and therapeutic combinations for both NSCLC.

Macrophages play essential roles in maintaining immune defence and tissue homeostasis within the male genital tract, which is essential for reproductive health. Since their initial discovery in the testes, macrophages have been established as highly adaptable immune cells that perform diverse functions ranging from immune surveillance to tissue repair. In the testes, macrophages play a crucial role in maintaining immune privilege and tissue homeostasis by regulating inflammatory responses and supporting steroidogenesis and spermatogenesis via intricate crosstalk with Leydig and Sertoli cells. In the epididymis, macrophages maintain a balance between immune tolerance and pathogen defence, ensuring the integrity of maturing sperm. Moreover, recent evidence has begun to reveal the complex and unique characteristics of prostate tissue-resident macrophages and their roles in homeostasis and disease. Notably, these cells exhibit dual functions in pathological conditions, contributing both to chronic inflammation in prostatitis and to the modulation of tumour dynamics in prostate cancer. Remarkably, dysregulation of macrophage function has been implicated in several prevalent male urological diseases and male infertility. This review integrates historical perspectives with recent advances in the immunobiology of macrophages in the male genital tract, highlighting their role as pivotal regulators of reproductive tract homeostasis.

Current complex models of human nerve injury hinder the identification of cellular responses and the screening of therapies. As a solution, simpler in vitro axotomy models utilizing embryonic rat dorsal root ganglion (DRG) and spinal motor neuron aggregates (SMNAs) have been introduced. To ensure model consistency, DRG or SMNA was placed in a cross-shaped channel for axotomy, performed microscopically with a razor. Afterward, the expression of four regeneration-associated genes (RAGs) and regulatory genes was assessed, along with quantifying axon outgrowth and growth cone changes in response to ROCK inhibitor Y27632. Additionally, a mouse perforator flap model was created to evaluate Y27632's effect on DRG axon reinnervation. It turned out that complete and consistent severance of the axons from the DRGs and SMNAs could be easily achieved, with significantly increased expressions of the four RAGs, Rho A and ROCK2. Y27632 could significantly augment axon regeneration in DRGs with axotomy in vitro and in the flap model but showed no impact on DRG axon outgrowth without axotomy. In comparison, Y27632 could slightly increase axon outgrowth from SMNAs without axotomy but drastically boost the axon regeneration from SMNAs with axotomy. The growth cones of DRGs and SMNAs drastically shrunk after axotomy, which could be significantly expanded by Y27632. In contrast, no impact on the growth cones of DRG and SMNAs without axotomy by Y27632 could be observed. The novel in vitro axotomy models regulated by ROCK inhibitors can be used to optimize studies on peripheral nerve injury-related drug screening by observing neuroregeneration and growth cone changes.

Background: It has been well-validated that Occlusal Disharmony (OD) induces negative emotions, especially anxiety. While it leads to considerable frustration for both doctors and patients, its underlying mechanisms remain unclear, and effective treatment has been lacking. The present study aims to explore the pathological mechanisms of OD induced anxiety and to find a straightforward yet effective treatment strategy for this ostensibly intricate clinical phenomenon.

Material and methods: OD mice were established through binding a metal tube to their right mandibular incisor. Then, the mental state of the mice was assessed by various behavioral experiments. Additionally, the mood of OD mice was also evaluated similarly before and after the injection of mifepristone. Furthermore, neuronal excitability in the mPFC was examined by immunofluorescence and electrophysiology, with the potential mechanisms investigated through Western blotting.

Results: OD mice exhibited anxiety-like behavior, and the administration of mifepristone, an anxiolytic drug, could alleviate it. Subsequently, an increase in n[1]euronal excitability was observed, accompanied by a reduction in the frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs) in the medial prefrontal cortex (mPFC). In addition, the expression of erb-b2 receptor tyrosine kinase 4 (ERBB4) and neuregulin 1 (NRG1), proteins associated with inhibitory neurotransmitter release, were found to be significantly downregulated in the mPFC.

Conclusion: OD attenuates GABAergic synaptic transmission in the mPFC, which may be the neural mechanism of anxiety caused by OD. But this phenomenon could be effectively alleviated by anti-anxiety treatment.

m⁶A, or N⁶-methyladenosine, is a the most abundant modification of mRNA transcripts. These modifications are known to influence mRNA transcript stability, transcription, translation, alternative splicing and decay, with undoubtedly more functions to be discovered. In this review, we explored the roles of m⁶A modifications in two groups of protozoan parasites: the apicomplexans, which include Plasmodium and Toxoplasma species, and kinetoplastids, which include Trypanosoma and Leishmania species. We also compared the key players of m⁶A epitranscriptomic machinery in creating, interpreting, and removing m⁶A modifications between these parasitic protists as well as a discussion of how m⁶A modifications facilitate parasite survival through features specific to apicomplexans and kinetoplastids. Beyond parasite epitranscriptomes, this review compares m⁶A dynamics in host and vector species (humans, flies and mosquitoes), highlighting coevolutionary adaptations. Strikingly, both the parasites and their vectors lack canonical m⁶A demethylases, implying a largely irreversible, streamlined m⁶A landscape fine-tuned for synchronized gene regulation. Overall, a mechanistic understanding is emerging of how m⁶A-modified RNAs and their binding proteins orchestrate RNA processing, translation, and turnover in parasitic protists, revealing an evolutionarily tuned epitranscriptomic system.

Introduction: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a major cause of nosocomial infections with high mortality rates. Persistent bacteremia, indicative of treatment failure, poses significant clinical challenges. This study aimed to identify clinical parameters for persistent CRKP bacteremia while exploring microbial and genetic characteristics.

Materials and methods: A case-control study was conducted on patients with CRKP bacteremia from January 2016 to July 2019 at a tertiary hospital in Taiwan. Clinical, demographic, and microbiological data were collected for 61 cases of persistent bacteremia and 122 matched controls without persistent infections. Conditional logistic regression was used to evaluate risk factors for persistent bacteremia. Whole-genome sequencing (WGS) was used to identify genotypes and factors mediating resistance and virulence in the strains.

Results: Persistent CRKP bacteremia was independently associated with mechanical ventilation (adjusted odds ratio [aOR] 11.007, 95% confidence interval [CI] 2.137-56.693), a lower Pitt bacteremia score (aOR 0.642, 95% CI 0.494-0.835), and the use of colistin (aOR 11.18, 95% CI 2.988-41.787) and tigecycline (aOR 16.42, 95% 4.495-60.0) in definitive therapy. Strains from either group shared similar capsular types. WGS identified three dominant multidrug-resistant clones, ST11, ST307, and ST15, harboring carbapenemase and virulence factors encoding yersiniabactin. A strain of hypervirulent clone ST23 exhibited high virulence but lacked carbapenemase genes, suggesting alternative resistance mechanisms of CR phenotype.

Conclusions: Antimicrobial regimens with tigecycline and colistin were insufficient for effectively managing CRKP bacteremia. The convergence of resistance and virulence in prevalent clones demands the urgent introduction of novel therapeutics. Aggressive and tailored strategies are critical for improving outcomes in high-risk patients.

Plasminogen activator inhibitor-1 (PAI-1), a key regulator of the fibrinolytic system, has emerged as a multifaceted contributor to the pathogenesis of systemic sclerosis (SSc). Beyond its classical role in inhibiting plasminogen activation, PAI-1 is implicated in the dysregulation of vascular remodeling, promotion of fibrosis, modulation of immune responses, and the maintenance of cellular senescence-all of which are hallmarks of SSc. Notably, elevated PAI-1 expression has been observed in both patient-derived tissues and experimental models of the disease. Mice deficient in the urokinase-type plasminogen activator receptor (uPAR), which functions with its ligand urokinase-type plasminogen activator (uPA) in the plasminogen activation system, exhibit impaired fibrinolysis and spontaneously develop vasculopathy and fibrosis, closely mirroring human SSc. These findings underscore the pathogenic relevance of the uPA-uPAR-PAI-1 axis in disease progression. Moreover, recent studies suggest that pharmacological inhibition of PAI-1 may not only ameliorate fibrosis and vascular abnormalities but also promote the clearance of senescent cells, thereby interrupting the vicious cycle of chronic inflammation and maladaptive tissue remodeling in SSc. This review highlights the emerging roles of PAI-1 in SSc pathophysiology and explores its potential as a novel therapeutic target for disease modification.