Advanced biology最新文献

HK1 and HK2 are increasingly recognized not only as glycolytic enzymes but also as key modulators of mitochondrial function and cell fate through dynamic interactions with VDAC. This review explores how HK-VDAC complexes support metabolic flexibility, regulate apoptosis, and coordinate glycolytic and mitochondrial activity across diverse physiological and pathological conditions. We incorporate recent reinterpretations of the Warburg effect, emphasizing how spatial and functional reorganization of HK supports proliferative metabolism beyond classical models of mitochondrial dysfunction. Importantly, the HK-VDAC interaction is dynamically regulated by post-translational modifications and signaling pathways that control its stability and mitochondrial anchoring. Disruption of these regulatory mechanisms can impair the balance between glycolytic and mitochondrial metabolism, contributing to disease progression. Emerging evidence links altered HK-VDAC interactions to the metabolic and apoptotic imbalances observed in cancer, neurodegeneration, and aging. By integrating insights from structural biology, bioenergetics, and disease models, we highlight mitochondrial HK anchoring as a central hub for metabolic adaptation and stress response.

Gender-affirming hormone therapy (GAHT) relies on exogenous hormones to produce hormonal milieus that achieve and/or maintain embodiment goals. Another potential route to these endpoints is transplantation of novel steroidogenic tissue. To develop a pre-clinical model, we asked whether different-sex gonad transplants can be functionally integrated into the adult mouse hypothalamic-pituitary-gonadal (HPG) axis. Adult male and female mice are gonadectomized and implanted with gonads from genetically matched but different-sex pups. Controls received gonads from same-sex pups. Temporal changes to gonadotropin and steroid hormone levels reveal the decoupling of the HPG following gonadectomy and gonad-dependent levels after transplanting donor gonads. After six weeks, histological structures in transplanted gonads are consistent with expected steroidogenesis and gametogenesis. Interestingly, pituitary, ARC, and AVPV mRNA showed gonad- and sex-dependent expression patterns. Future work with this technique could lead to translation to gender affirming care and explorations of gonad-dependent sex differences in biomedical and basic research.

Heme is an iron-containing porphyrin that plays an indispensable role in biological system, involved in oxygen transport, electron transfer, gas sensing, enzyme catalysis, etc. Beyond its physiological functions, heme also has wide-ranging applications in pharmaceuticals, food additives, and biotechnology. However, conventional production methods-such as chemical synthesis and extraction from animal blood are hindered by high costs, ethical concerns, environmental burdens, and safety risks. Recent progresses in metabolic engineering and synthetic biology have made it possible to produce free heme using microorganisms, offering a scalable, cost-effective, and sustainable alternative. This review provides a comprehensive overview of bio-based heme production, focusing on: 1) Structure, functions, and synonyms of different heme types; 2) Conserved and divergent heme biosynthetic pathways; 3) Heme biosynthesis regulation involving transcription factors, protein interactions, and small molecules; 4) Recent advances in microbial production of heme and porphyrin intermediates using metabolic engineering strategies; 5) Methods for heme detection, including spectroscopy, chromatography, enzyme-linked immunosorbent assays (ELISA) and whole-cell biosensors. Finally, current challenges and future opportunities, highlighting microbial heme production as a transformative and sustainable strategy to meet growing global demand are discussed.

Non-small cell lung cancer (NSCLC) relapse after therapy is linked to the high aggressiveness, chemoresistance and metastatic potential of tumor cells due, in part, to the presence of cancer stem cells (CSCs). Pro-differentiation approaches have shown promising results for leukemia and in some solid cancer models, offering a possibility to enhance current anti-cancer therapies. Here, the human NSCLC line A549 is exposed to a serum-containing medium supplemented with pro-differentiation factors (DM), and effects on the cells' proliferation, migration and adhesion properties are assessed in vitro, alongside CSC marker expression analyzed after treatment in 2D or 3D culture conditions. A549 cells exposed to DM exhibited notable morphological changes, with significant increase in cellular footprint and vesicle accumulation. These phenotypic alterations coincided with significant inhibition of proliferation and migration, whereas adhesion properties increased, similar to alkaline phosphatase activity. DM treatment of A549 cells also caused a significant reduction in clonogenic ability by two thirds, as well as halving anchorage-independent colony formation and spheroid growth, alongside a reduced expression of stemness markers SOX2, NANOG, CD44 and ABCG2, and of ALDH activity and aquaporin function. These results indicate decreased pathogenic features of NSCLC cells after DM exposure, suggesting that pro-differentiation treatment may represent a valuable option for further preclinical testing.

Ischemic heart disease, a leading global cause of mortality, highlights the need for novel therapies. Electroacupuncture (EA) shows cardioprotective potential, yet the central neural mechanisms, particularly the role of the midbrain periaqueductal gray (PAG), remain unclear. This study investigated how EA at Shen men (HT7) improves cardiac function post-myocardial infarction (MI) via Ventrolateral Periaqueductal Gray Matter (vlPAG) glutamatergic(Glu) neurons. Neuronal activity monitored via c-Fos immunofluorescence and fiber photometry is detected. Chemogenetic tools selectively inhibited or activated vlPAG glutamatergic neurons. Cardiac function is assessed by echocardiography and histopathology, while inflammation is analyzed via Western blot and Reverse Transcription Quantitative Real-Time Polymerase Chain Reaction. Improvement of cardiac function: electroacupuncture significantly elevated cardiac function in MI mice to improve the prognostic level of mice; verification of neural mechanism: electroacupuncture selectively activated vlPAG glutamatergic neurons, and the cardioprotective effect of electroacupuncture is suppressed by inhibition of the vlPAG^Glu, whereas specific activation of this neuron can mimic the effect of electroacupuncture(EA). This study unveils a central "acupoint-brain-heart" axis, where EA at HT7 engages vlPAG to restore cardiac homeostasis. These findings bridge traditional acupuncture and modern neuroscience, proposing vlPAG glutamatergic pathways as novel targets for cardiovascular therapy.

Our lab recently discovered uniquely large (multiple micrometres) ring-shaped cellular structures composed of endosomal sorting complexes required for transport (ESCRT) proteins. These structures are formed by tissue infiltrating fibroblasts, dendritic cells (DCs) and macrophages but only in specific culturing conditions, notably in dense three-dimensional collagen matrices or without serum on glass supports. We also found that the structures are devoid of F-actin and form at membrane damage sites, suggesting a role of these structures in membrane repair. Another possibility is that these structures have a role in the immunological synapses (IS) with T cells, because they surround clusters of tetraspanins and integrins that have known roles at the IS. Therefore, we tested the hypothesis that giant ESCRT structures are present at the IS between DCs and T cells and contribute to its stability or signaling. Although we occasionally observed enrichment of ESCRT proteins at the interface between DCs, we do not observe this at the IS between human monocyte-derived DCs (moDCs) and allogenic T cells. Thus, our data do not support a role for the giant worm-shaped ESCRT structures at the IS, and suggest that they solely are involved in plasma membrane stability and integrity.

This study explores the interaction between immune and cancer cells in the tumor microenvironment (TME) of cervical carcinoma (CC), with emphasis on tumor-associated macrophages (M2-TAMs) and the STAT3-NF-κB signaling pathway. It investigates how Treg cell polymorphisms and TAM infiltration through these pathways influence overall survival (OS) in CC patients. This prospective study follows 100 CC patients from 2018 to 2023 using qRT-PCR and immunohistochemistry on tumor samples, and flow cytometry on blood samples to evaluate immunosuppressive cytokines and Treg cell polymorphisms. High stromal CD163+204+ TAM density, mediated by STAT3/NF-κB, correlates with biomarkers such as Ki-67, VEGFα, and FOXP3 (p < 0.001). XPO5 expression is associated with increased STAT3, SNAIL, and HPV 16/18 levels. FOXP3 T allele deletion and HLA-G polymorphism in the blood of patients correlate with higher STAT3 tumor expression and elevated IL-4 and IL-17 blood cytokines. The CXCL12-CXCR4 axis shows a strong association with STAT3, SNAIL in TME and blood cytokines, including IL-6 and IL-12. Elevated CXCL12, CXCR4, and SNAIL expression in TME significantly increases mortality risk. These findings underscore the role of M2TAM infiltration and immune modulation in tumor progression and clinical outcomes in CC.

Acute Respiratory Distress Syndrome (ARDS) is a life-threatening condition characterized by severe inflammation and lung damage, leading to critical hypoxemia. Despite its high mortality rate, the only currently available treatment, Dexamethasone, is associated with significant side effects. This study aims to evaluate the efficacy of primed human umbilical cord blood-derived mesenchymal stem cells (hUCB-pMSCs) as a potential alternative treatment for ARDS. A novel lung microphysiological system (MPS) modeling the lung environment is developed and treated with lipopolysaccharide (LPS) to simulate ARDS. The effects of hUCB-pMSCs and dexamethasone are compared using state-of-the-art methods, including fluorescence-based imaging and single-cell RNA sequencing. The hUCB-pMSCs significantly activated angiogenesis-related pathways in endothelial cells and enhanced the formation of tip-like endothelial cells involved in new blood vessel formation. These findings are corroborated by fluorescence microscopy, demonstrating the robust potential of hUCB-pMSCs as a therapeutic approach. Overall, the results support the potential of hUCB-pMSCs as a promising alternative treatment for ARDS.

This study investigates the role and mechanisms of Ras-related nuclear protein (RAN) in lung adenocarcinoma (LUAD). The expression of RAN in LUAD is studied using the The Cancer Genome Atlas (TCGA) database. Clinical samples are collected, and immunohistochemical (IHC) staining is performed to analyze the positive cell rate of RAN in normal and LUAD tissues. The study analyzes the effects of RAN overexpression in A549 and H1299 LUAD cell lines. Various methodologies are employed, including RT-PCR, Western blot, Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU) staining, wound healing, Transwell assays, immunofluorescence, and 3,3'-ctetraethylbenzimidazolylcarbocyanine iodide (JC-1) staining, to evaluate RAN's influence on cell proliferation, migration, and autophagy with mitochondrial homeostasis dysregulation. The findings reveal that RAN is significantly overexpressed in LUAD and associated with poorer prognosis. IHC analysis shows that the positive cell rate of RAN is significantly higher in LUAD tissues than in normal tissues. RAN overexpression facilitates proliferation and migration while enhancing autophagic activity, mitochondrial dysregulation, and increasing ATG101 expression. Suppression of ATG101 effectively counteracts the enhanced proliferation induced by RAN overexpression, highlighting ATG101 as a key mediator of RAN's effects. This study underscores the critical molecular dynamics of LUAD driven by RAN, suggesting that the RAN-ATG101 axis can serve as a novel therapeutic target.

Biologic medicines (or biologics) have revolutionized the treatment of cancer, autoimmune disorders, and genetic conditions. Their therapeutic success stems from complex structural properties that confer high target specificity and biological compatibility. However, their high cost and complex manufacturing limit patient access, with annual treatment expenses often reaching tens of thousands of dollars per patient. Biosimilars, developed to match reference biologics in quality, safety, and efficacy, provide a pathway to curb escalating costs. Having generated more than 36 billion USD in healthcare savings over the past decade, their wider adoption remains challenged by stringent regulatory pathways and the market exclusivity of reference products. These limitations have spurred the development of biobetters, which are engineered biologics with enhanced stability, potency, half-life, or reduced immunogenicity that maximize patient benefit. This review explores the distinctions, development strategies, and regulatory challenges of biologics, biosimilars, and biobetters. Biosimilarity establishment and biobetter design strategies are examined with emphasis on enzyme-based examples such as L-asparaginase and glucarpidase. Advanced delivery technologies have also been demonstrated to improve drug stability, bioavailability, and patient adherence. Finally, emerging innovations and future directions underscore the transformative potential of these biopharmaceuticals in addressing unmet medical needs and expanding global access.