Frontiers in bioscience (Landmark edition)最新文献

Objective: Small ubiquitin-related modifier protein (SUMO)ylation is a reversible post-translational modification of proteins. SENP5, a SUMO-specific protease, plays key roles in a wide range of cellular processes. This study aims to investigate the potential involvement of SENP5 in lipopolysaccharide (LPS)-induced acute lung injury (ALI).

Methods: First, we established LPS-treated human normal lung epithelial cells (BEAS-2B) and a lung injury mouse model. SENP5 expression was then analyzed in vivo and in vitro using quantitative real-time PCR (qRT-PCR), Western blot, hematoxylin-eosin (H&E) staining, and immunohistochemistry. Then, CCK-8 assay and flow cytometry were employed to assess inflammatory response and apoptosis following SENP5 knockdown in LPS-induced BEAS-2B cells. Next, H&E, immunohistochemistry, and survival analysis were conducted to investigate apoptosis and proliferation in SENP5 conditional knockout (cKO) mice. Finally, RNA sequencing was used to screen for differentially expressed genes in SENP5 knockdown BEAS-2B cells. Downstream molecules and signaling pathways were analyzed using Western blot and qRT-PCR.

Results: SENP5 was notably upregulated in both LPS-induced BEAS-2B cells and the lung injury mouse model. In vitro, SENP5 knockdown markedly exacerbated the LPS-induced suppression of BEAS-2B cell viability and promoted inflammatory response and apoptosis. Besides, the conditional knockout of SENP5 significantly increased apoptosis and inhibited proliferation in the lungs of mice. RNA sequencing indicated SENP5 deficiency inhibited solute carrier family 7 member 5/mechanistic target of rapamycin (SLC7A5/mTOR) signaling in LPS-induced BEAS-2B cells. Therefore, we confirmed that SENP5 might exert a protective effect against LPS-induced lung injury by inhibiting apoptosis of lung epithelial cells through the SLC7A5/mTOR signaling pathway.

Conclusion: SENP5 might play a protective role in LPS-induced lung injury by inhibiting apoptosis of lung epithelial cells through the SLC7A5/mTOR signaling pathway.

Background: Myocardial fibrosis is a key pathological driver of Hypertrophic Cardiomyopathy (HCM), contributing to adverse remodeling and poor prognosis. The transforming growth factor-β₁/Smad3 (TGF-β₁/Smad3) signaling cascade plays a central role in fibrogenesis; however, effective antifibrotic therapies remain limited. Astragalus polysaccharide (APS), a bioactive constituent of Astragalus membranaceus, has demonstrated cardioprotective potential. Nevertheless, the mechanisms underlying its effects in HCM-associated fibrosis remain unknown.

Methods: Pressure overload induced HCM was established in C57BL/6J mice using transverse aortic constriction (TAC), and animals were randomized to control, TAC, low-dose APS (50 mg/kg/day), or high-dose APS (100 mg/kg/day) groups. Cardiac function was evaluated by echocardiography, while myocardial hypertrophy and fibrosis were assessed by morphometry, Masson's staining, and collagen I (Col-I) expression analysis. Parallel in vitro studies employed angiotensin II stimulated (Ang II-stimulated) H9C2 cardiomyocytes, with or without the TGF-β₁/Smad3 agonist SRI-011381, to explore mechanistic pathways.

Results: TAC induced marked cardiac dysfunction, ventricular dilation, and extensive fibrosis, accompanied by upregulation of TGF-β₁, phosphorylated Smad3, and Col-I expression (all p < 0.05). APS treatment dose-dependently preserved systolic function, attenuated collagen deposition, and suppressed activation of the TGF-β₁/Smad3 axis, with the strongest effects observed in the high-dose group. In vitro, APS significantly inhibited Ang II induced hypertrophy and fibrotic protein expression; these effects were abrogated by SRI-011381, confirming pathway specificity.

Conclusions: APS exerts cardioprotective and antifibrotic effects in HCM by inhibiting the TGF-β₁/Smad3 signaling pathway. These findings highlight APS as a promising therapeutic candidate for targeting myocardial fibrosis and improving outcomes in HCM.

This review provides a comprehensive analysis of recent advancements in elucidating the molecular mechanisms underlying human immunodeficiency virus (HIV)-1 entry, focusing on the intricate interplay between the viral envelope glycoproteins (Env) and host cell receptors. We detail how structural insights into glycoprotein (gp)120-Cluster of Differentiation 4 (CD4)/coreceptor interactions and gp41-mediated membrane fusion inform therapeutic interventions, including fusion inhibitors and broadly neutralizing antibodies (bnAbs). The HIV-1 Env trimer undergoes a series of highly coordinated conformational transitions from a metastable prefusion state to a stable postfusion structure. CD4 engagement induces allosteric remodeling of gp120, unveiling coreceptor (C-C chemokine receptor type 5 (CCR5)/C-X-C chemokine receptor type 4 (CXCR4)) binding sites and priming gp41 activation. Fusion peptide insertion, six-helix bundle formation, and membrane merger are critical targets for inhibitors like T20 (enfuvirtide). Comparative analyses with other viruses reveal conserved fusion mechanisms despite distinct activation triggers, offering broader insights for antiviral development. By integrating structural biology, virology, and translational research, this review highlights how the mechanistic dissection of viral entry informs the design of next-generation therapeutics. We highlight strategies to disrupt Env-receptor interactions, block fusion intermediates, and harness cross-viral principles to counteract drug resistance and refine vaccine approaches. These insights not only deepen our understanding of HIV-1 pathogenesis but also drive the innovation of novel antiviral strategies.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder characterized by immune system dysfunction, the production of autoantibodies, and multi-organ inflammation. Lupus nephritis (LN) is one of the most severe complications of this condition. Approximately 60% of patients with SLE develop LN, which leads to both increased morbidity and mortality. Furthermore, LN has the potential to progress to end-stage renal disease. Macrophages, key components of the innate immune system, are involved in the pathophysiology of LN through immune complex clearance, antigen presentation, regulation of inflammation, and tissue repair. Macrophage polarization into pro-inflammatory (M1) versus anti-inflammatory (M2) functional phenotypes is a component of LN disease progression. M1 macrophages are responsible for supporting pro-inflammatory immunity and promoting tissue damage, whereas M2 macrophages are necessary for tissue repair and resolution of inflammation. However, dysregulated M2 function may exacerbate the pathogenesis of LN, indicating the complex role of macrophages in LN. Novel therapeutic approaches associated with the mechanisms of macrophage polarization and/or macrophage signaling pathways have emerged as therapeutic targets to modify the progression of LN. Furthermore, proinflammatory cytokines enhance renal inflammation and autoimmunity; alternatively, anti-inflammatory cytokines play a dual role in LN, contributing positively and negatively to the disease process. The purpose of this review is to investigate the role of macrophages in the pathogenesis of LN and highlight macrophage-targeted therapies or biomarkers as diagnostic tools and new therapeutic avenues to improve long-term outcomes for patients.

Background: Resistance to anoikis is a critical mechanism that enables metastatic dissemination. Abrogation of this cellular safeguard is therefore a hallmark of aggressive cancer progression. Despite the importance of anoikis, there are still few biomarkers among anoikis-related genes (ARGs) that could aid in the prognostication of bladder cancer (BC) patients and potentially serve as drug targets.

Methods: This study leveraged bioinformatics analyses of publicly available BC datasets to evaluate the association between differentially expressed ARGs and patient prognosis. Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis was employed to build a novel prognostic signature model for BC based on ARGs. This model was also used to predict the response of BC to anticancer drugs. Additionally, immunohistochemistry was used to assess expression of the key gene, MYC, in BC samples obtained from patients undergoing surgery and from those receiving immune checkpoint inhibitor (ICI) therapy.

Results: The ARG-based signature, developed and validated through the analysis of public databases, was an independent predictor of patient outcomes. Furthermore, it effectively stratified patients into two cohorts (high- and low-risk), allowing investigation of differential drug sensitivities. The risk stratification model identified 10 ARGs (IGF1, CALR, E2F1, MYC, PLK1, SATB1, FASN, ID2, RAC3, and GKN1) as potential therapeutic vulnerabilities. Notably, MYC was identified as a central hub gene within the ARG signature. Elevated MYC expression was strongly associated with worse prognosis in muscle-invasive bladder cancer (MIBC), and with a diminished response to immunotherapy.

Conclusion: This work demonstrated significant prognostic value for the ARG-based model. Specific ARGs could function as crucial biomarkers for patient outcome, while simultaneously offering new avenues for therapeutic intervention.

Despite extensive research, the systemic biological mechanisms underlying exercise-induced physiological adaptations remain incompletely understood. While animal models (e.g., rodents, non-human primates) have been instrumental in elucidating exercise-mediated benefits in aging and disease, interspecies differences in genomics, epigenetics, and metabolic regulation limit their translational relevance. The advent of induced pluripotent stem cell (iPSC)-derived 3D organoids revolutionizes exercise biology research by enabling human-specific modeling of tissue architecture and donor genomic/epigenetic profiles. This review highlights three transformative strategies: (1) Athlete-derived organoids preserving exercise-induced epigenetic memory to study muscle/neural adaptations; (2) Engineered systems integrating optogenetics and microfluidics to simulate mechanical forces (e.g., muscle contraction) and systemic signals (e.g., cytokines); (3) multi-omics mapping revealing exercise-responsive pathways like mitochondrial biogenesis. Collectively, these patient-specific models bridge pathophysiology with high-throughput screening, advancing precision medicine-from personalized training regimens to therapies counteracting sedentary-related diseases.

Background: Acute lung injury (ALI) triggered by sepsis continues to pose a significant difficulty in clinical practice. Due to its anti-inflammatory and antioxidant activities, calcitonin is considered a potential therapeutic option in sepsis.

Methods: Bioinformatics analysis was performed using the GSE89376 and GSE67652 datasets. Serum levels of CD3D and NLR family pyrin domain containing 3 (NLRP3) inflammasome, as well as high-mobility group box 1 (HMGB1)/myeloid differentiation primary response gene 88 (MyD88)/nuclear factor-κB (NF-κB) pathway components, were evaluated in sepsis/ALI patients. The effects of calcitonin and CD3D knockdown on human pulmonary microvascular endothelial cells (hPMECs) activated by lipopolysaccharide (LPS) were investigated in vitro. Experimental assays, including quantitative real-time polymerase chain reaction (qRT-PCR), Cell Counting Kit-8 (CCK-8) assay, western blotting (WB), enzyme-linked immunosorbent assay (ELISA), and flow cytometry, were used to assess cell viability, apoptosis, cell cycle, and oxidative stress markers.

Results: CD3D was identified as a key sepsis/ALI-associated hub gene and correlated with NF-κB pathway activation in patients. CD3D silencing in hPMECs effectively suppressed LPS-induced inflammation, oxidative stress, apoptosis, and G1 phase arrest by downregulating the expression of NLRP3, phosphorylation (p)-NF-κB, MyD88, and HMGB1. Calcitonin alone mitigated LPS-induced injury in a dose-dependent way and further enhanced the protective impacts of CD3D knockdown. Co-treatment resulted in synergistic inhibition of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, a reduction in oxidative markers, restoration of antioxidant capacity (superoxide dismutase (SOD) and glutathione (GSH)), improved endothelial cell viability, and attenuation of apoptosis. Notably, combined treatment more robustly suppressed the HMGB1/MyD88/NF-κB pathway than either intervention alone.

Conclusion: CD3D exacerbates sepsis-induced ALI by potentiating the HMGB1/MyD88/NF-κB pathway and NLRP3 inflammasome, driving inflammation and oxidative stress. Combined CD3D knockdown and calcitonin treatment offers a novel synergistic therapeutic strategy for mitigating pulmonary endothelial injury in sepsis.

Charles Darwin hypothesized that evolution is based on adaptations to a changing environment, and that organisms that developed even slightly favorable variations would ultimately be most likely to survive. This concept is clearly reflected in the life cycles of pathogenic species. While modern antibiotics, antiviral agents, and vaccines can successfully eliminate many pathogens and prevent infections, only susceptible strains are affected. Bacteria and viruses that can adapt and develop resistance mechanisms will survive and thrive in the absence of ongoing competition. We build on this framework by considering the evolutionary impact of microbial-mediated adaptations experienced by the host. For example, intracellular mitochondria, largely believed to be descendants of symbiotic ancestral bacteria, can be specifically targeted by viral pathogens. Taken one step further, we hypothesize that Darwinian theory may also apply to atoms and molecules, which are not "alive" by any conventional definition, but interact with one another and self-assemble according to the principles of thermodynamics that promote stability in defined environments. Building on these foundations, our hypotheses and conceptual framework will facilitate further exploration into the evolution of microbial mechanisms that modulate behavior, shape the development of the immune system, and promote host evolution.

The tumor microenvironment, especially the extracellular matrix (ECM), plays a critical role in cancer initiation and progression, although its underlying mechanisms remain incompletely understood. Conventional therapies (such as chemotherapy, surgery, and radiotherapy) often produce unsatisfactory outcomes. Immunotherapy, while showing limited clinical success to date, holds considerable promise. Growing evidence indicates that the biophysical properties of the ECM interact with immune cells, contributing to mechanisms of immunotherapy resistance in cancer. Alterations in these ECM properties can impair immune cell infiltration and function, thereby diminishing the effectiveness of immunotherapeutic approaches. This review explores how the biophysical features of the ECM and their crosstalk with tumor immune evasion pathways highlight the potential of ECM-targeted immunotherapy as an innovative strategy for cancer treatment.

Background: Congenital heart disease (CHD) is characterized by structural and functional anomalies of the heart and major blood vessels present at birth. It is recognized as the most common congenital defect. Epidemiological studies highlight the substantial contribution of genetic factors to CHD pathogenesis. In our previous study, RNA polymerase II subunit I (POLR2I protein) was identified as a candidate genetic contributor to CHD. However, its functional role remains largely unexplored.

Methods: First, we performed bioinformatics analyses to evaluate the evolutionary conservation of the POLR2I protein across vertebrate species. The amino acid sequence similarity of the POLR2I protein exceeds 90% in different vertebrates, suggesting a correlation between their species. Quantitative real-time PCR (qRT-PCR) revealed significantly elevated polr2i gene expression during early embryonic stages and in adult zebrafish organs, including the heart, eyes, and brain. Morpholino oligonucleotide (MO)-mediated gene editing was used to downregulate the polr2i gene in zebrafish, and rescue experiments were performed by co-injecting capped polr2i gene mRNA. Transgenic zebrafish labeled with specific fluorescent protein facilitated detailed studies of cardiac and vascular development, myocardial mitochondrial quality, and embryonic asymmetry, respectively. Hemoglobin staining with o-Dianisidine assessed red blood cell accumulation.

Results: Knocking down the polr2i gene through MO significantly disrupted developmental trajectories, as evidenced by reduced body size, axial curvature, enlarged yolk sacs, and elevated malformation and mortality rates. Rescue experiments confirmed the specificity of these phenotypes to polr2i gene loss. Affected embryos displayed elongated heart tubes with reduced overlap between chambers and significant pericardial edema, indicating severe cardiac malformations or functional impairments. Measured volume per beat, ejection fraction, and cardiac output decreased substantially. Furthermore, expression levels of critical cardiovascular markers were markedly reduced. Angiogenic processes were also disrupted, as evidenced by the reduced formation of intersegmental vessels and the caudal vein plexus. Impaired mitochondrial quality in myocardial cells was observed post-knockdown, along with notable defects in the left-right asymmetry of the heart, liver, and pancreas.

Conclusion: Knockdown of the polr2i gene not only impairs cardiac structure and function but also disrupts the normal developmental asymmetry of multiple organs. These findings enhance our understanding of polr2i gene's role in CHD and underscore its potential as a therapeutic target.