Skeletal muscle health and regeneration are highly orchestrated processes governed by a complex interplay of muscle stem cells, fibro-adipogenic progenitors, immune cells, and endothelial cells. Among these cell types, endothelial cells play a central role not only by regulating blood and nutrient flow to support metabolic and regenerative needs, but also by directly interacting with muscle stem cells and fibro-adipogenic progenitors to regulate stem cell quiescence or activation, and muscle tissue remodeling during its regeneration and growth. The current review article provides a broad overview of the crucial role of the endothelial cells during muscle health and growth, their expansion and interaction with key muscle cell types, governing signaling pathways, and their role in metabolism. Furthermore, we discuss the role of endothelial dysfunction as a pathogenic mechanism in muscular dystrophies, diabetes, peripheral artery disease, and sarcopenia. We also overview current therapeutic approaches targeting endothelial cells in the muscle and highlight biological and research barriers causing underdeveloped therapeutics in this field.
The finTRIM (FTR) subfamily, a group of fish-specific tripartite motif proteins, has arisen through gene duplication events specific to particular genera or species. However, the regulatory mechanisms of FTR in antiviral immune response remains largely unknown. In the present study, we identified a fish novel tripartite motif member (finTRIM, FTR) in common carp (Cyprinus carpio L.) and named it CcFTR85, which contains a RING (really interesting new gene) domain, a coiled-coil region, and a PRY/SPRY domain. Its expression can be induced following spring viremia of carp virus (SVCV) infection and poly(I:C) stimulation. Overexpression of CcFTR85 significantly inhibits the expression of IFNφ1 and IFN-stimulated genes, thereby facilitating SVCV replication. Mechanistically, CcFTR85 binds to interferon regulatory factor 3 (IRF3) and promotes its K48-linked polyubiquitination at K329, causing a proteasomal degradation of IRF3 and consequent suppression of IRF3-mediated antiviral immune responses. In addition, ftr85-deficient zebrafish are more resistant to SVCV infection. Our study reveals a role for FTR85 in the regulation of antiviral responses, suggesting that it may serve as a potential target for controlling fish viral infections.
Elsinoë species are slow-growing, hemibiotrophic to necrotrophic fungi that cause scab diseases on economically important fruit crops. Genome resources for many host-specific species remain limited. We report high-quality draft genome assemblies for the ex-type strains of Elsinoë mangiferae (CBS 226.50) and E. perseae (CBS 406.34), causal agents of mango and avocado scab, respectively. Among five approaches tested, a Nanopore-only NextDenovo assembly produced the most contiguous genomes, yielding 24.5 Mb (E. mangiferae) and 25.1 Mb (E. perseae) assemblies with 13 and 18 contigs, respectively, BUSCO completeness scores of ∼94%, and multiple putative telomere-to-telomere chromosomes. Gene prediction identified 9,134 and 9,243 genes, respectively. Functional annotation revealed enrichment of metabolic and regulatory pathways, including those involved in posttranslational modification, protein transport, and secondary metabolism. Carbohydrate-active enzyme repertoires were small but conserved, consistent with stealth pathogenicity strategies and low plant cell wall degradation. Both genomes encoded large secretomes (>850 proteins), diverse protease repertoires (>300 proteins), Ecp2-like effector proteins, and multiple biosynthetic gene clusters, including clusters with similarity to those associated with elsinochrome and ACT-toxin II biosynthesis, some of which may contribute to host-pathogen interactions and disease development. A large fraction of genes lacked functional characterization, suggesting incomplete databases and/or the presence of lineage-specific genes potentially involved in virulence or host adaptation. These genome resources fill critical gaps for underrepresented Elsinoë species and provide taxonomically anchored references essential for diagnostics, comparative genomics, and research into the molecular basis of host specificity and pathogenicity in scab-causing fungi.
Energy-conserving mechanisms are essential in supporting cellular life. Yet in synthetic biology, it remains a challenge to reconstruct such processes from the bottom-up and integrate them with other biological functions to create complex systems with life-like properties. Recent efforts to build higher-order cell-free metabolic networks have suffered from the fact that their central oxidation reactions are not coupled to energy conservation, causing kinetic and thermodynamic limitations. Here, we developed an artificial respiratory chain that we tailored to sustain rapid electron transfer in a CO2-fixing 16-enzyme catalytic cycle (crotonyl-CoA/ethylmalonyl-CoA/hydroxybutyryl-CoA), while also exploiting the concurrent electron flow for adenosine triphosphate synthesis. We demonstrate how such artificial respiratory chains can be further diversified to accept multiple electron entries and coupled to other biological functionalities, such as cell-free transcription-translation networks. Altogether, our work highlights the opportunities and challenges of directly integrating energy conservation mechanisms when building toward self-sustaining/self-energizing artificial life-like systems.
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) represent two neurodegenerative diseases on opposite sides of a movement disorder continuum. However, like many other neurodegenerative diseases, the molecular pathogenesis of FTD and ALS is not fully understood. Our group has previously reported evidence for a pervasive elevation of brain urea levels in five other dementia-causing diseases. However, brain urea levels have yet to be measured in ALS and FTD. Here, we employed ultra-high-performance liquid chromatography-tandem mass spectrometry to characterise brain urea differences between control (n = 14/12) and ALS/FTD (FTD: n = 8/9; ALS: n = 13/14) cases in post-mortem tissue from two brain regions with different levels of neuropathological burden (high versus low). Elevated urea levels were observed in both the frontal cortex (high neuropathological burden) and primary visual cortex (low neuropathological burden) in cases with FTD. Contrastingly, in cases with ALS, elevated urea was observed in the primary motor cortex (high neuropathological burden), but not the dentate nucleus (low neuropathological burden). These results not only suggest that elevated urea levels are also present in ALS and FTD but imply that elevated brain urea is linked to a multi-dementia pathogenic mechanism. In contrast to ALS, the observation of elevated urea in regions of both high and low neuropathological burden in FTD implies that this phenotype is likely widespread and, therefore, may play a larger role in the pathogenesis of disease. Such a mechanism could offer new directions for developing treatments targeting this underlying pathology.
The deep ocean hosts autochthonous pressure-adapted microorganisms that are unique to this environment, as well as allochthonous pressure-sensitive members transported from shallow depths by vertical advection and particle-sinking. However, conventional sampling instruments decompress and warm deep-sea samples during retrieval, potentially altering microbial properties when studied ex situ. Here, we assess this potential sampling bias by comparing seawater microbial communities collected with or without measures aimed at minimising pressure and temperature effects. When compared to samples collected under pressurised conditions, conventional sampling (using Niskin bottles) was found to affect prokaryotic cells retrieved by reducing their total numbers, diminishing protein synthesis activity (>10%), and also causing overall shifts in the community composition. The most significant compositional change was a > 20% decrease in metagenomic archaeal representation (TACK-group/Thaumarchaeota/Nitrososphaerota). Deep-sea bacterial groups had mixed responses to preserving pressure during retrieval, with some groups exhibiting higher representation when samples were maintained pressurised (e.g., members of the family Pelagibacteraceae, unclassified Thiotricales, Thioglobaceae, and Chitinophagaceae), whereas others increased their representation when decompressed (e.g., Burkholderiaceae, Comamonadaceae, and Oxalobacteraceae). This study reveals the existence of bias introduced by the complete decompression of samples retrieved with traditional instrumentation, as well as a decrease in overall bacterial activity when samples are completely decompressed during retrieval. Additionally, incubations lasting for >24 h were shown to transform the original prokaryotic community composition. Precautions addressing these effects are necessary to enhance the reliability of ex situ measurements and improve our understanding of deep-sea microbial ecology and biogeochemistry.
Developing therapies and vaccines against integral membrane proteins is hindered by their extensive hydrophobic surfaces, which complicate production and structural analysis. Here, we describe a general deep learning-based design approach for solubilizing native membrane proteins while preserving their sequence, fold, active-site, and ligand-binding properties. Genetically encoded de novo protein WRAPs [water-soluble RFdiffused amphipathic proteins] surround the lipid-interacting hydrophobic surfaces, rendering them thermostable and water-soluble without the need for detergents. We design WRAPs for both monomeric and oligomeric beta-barrel outer membrane proteins and helical multipass transmembrane proteins. A 2.95-angstrom-resolution cryo-electron microscopy structure of WRAPed mycobacterial porin demonstrates that WRAPs can be used for the structural determination of membrane proteins in solution. As a step toward syphilis vaccine development, we generated soluble versions of Treponema pallidum antigens.
HIV-1 cure requires preventing viral rebound after treatment interruption, but quantitative criteria defining the rebound-competent reservoir are lacking. We studied individuals undergoing observational treatment interruption without confounding interventions to identify virologic and immunologic determinants of rebound. In 9 of 13 participants, rebound viruses were genetically identical or similar to proviruses in circulating resting CD4+ T-cells. We found no evidence of recombination among rebound sequences. Instead, resistance to autologous neutralizing antibodies (aNAbs) was a critical determinant of viral rebound. Increased suppression of viral outgrowth by contemporaneous IgG isolated from plasma was correlated with longer time to rebound. Using inhibitory potential (IP), the log reduction in single-round infection at physiologic IgG concentrations, we defined quantitative limits governing rebound-competency with respect to contemporaneous aNAbs. Contemporaneous IgG antibodies inhibited different reservoir variants with a wide range of IP values (0.4 to 8.2 logs), whereas rebound viruses were minimally inhibited (0.5 to 2.8 logs), indicating that inhibition by even up to 2.8 logs (631-fold) cannot prevent rebound. Longitudinal analyses revealed that waning aNAb potency over time on antiretroviral therapy (ART) allows previously neutralized variants to gain rebound potential, consistent with the finding that rebound can come from variants deposited in the reservoir at different pre-ART time points. Thus, rebound competency is a dynamic, immune-governed property defined by quantitative immunologic constraints, including those exerted by aNAbs.
MR1 is a non-polymorphic, ubiquitously expressed, MHC class I-like antigen-presenting molecule that presents small-molecule metabolites to T cells. Studies have shown that MR1 plays a role in microbial infection, inflammation, and tumor immunity. The antigens it presents include metabolites of microbial and self-origin as well as small-molecule drugs and form stable complexes with MR1 that are displayed on the cell surface to activate T cells. However, unlike classical MHC I and II molecules, the fundamental biology of MR1 remains poorly understood, particularly the mechanisms governing antigen loading and intracellular trafficking. This knowledge gap is largely due to the lack of molecular tools available to precisely manipulate MR1 function. In this study, we describe a high-affinity (1.6 nM KD) anti-MR1 nanobody, MR1Nb1. We characterize the binding of this nanobody including affinity by ELISA and kinetics by BLI. Crucially, we map the binding epitope of MR1Nb1 on MR1 by HDX-MS, providing key insights into the mechanism through which it blocks MR1T cell activation. In functional assays MR1Nb1 effectively and specifically blocks MR1T cell activation by cells infected with M. tuberculosis or treated with M. smegmatis supernatant or the synthetic ligand deazalumazine. MR1Nb1 further stains MR1-ligand complexes on the cell surface in a flow cytometry assay. This nanobody represents a unique and versatile tool for the field, as it can be produced inexpensively and expressed intracellularly within antigen presenting cells. Hence, our study provides a powerful new molecular probe for dissecting the mechanistic underpinnings of MR1 biology and uncover its broader roles in immunity.
Differences between partner gametes, which evolved repeatedly in eukaryotes, can contribute to the evolution of the sexes, sexual selection, and non-Mendelian inheritance. Yet, the empirical evidence for how functional asymmetries arise between initially equivalent gametes is limited. Here, we combine theoretical and experimental approaches in the fission yeast Schizosaccharomyces pombe to show how selective pressures acting concurrently on gametes and zygotes drive the evolution of gamete differences. We find that despite being morphologically identical, P- and M-type partner gametes invest asymmetrically in zygotic development by contributing different amounts of conserved meiotic cohesins. P-gametes preferentially produce the Rec8 cohesin that increases zygotic fitness but reduces gamete viability, revealing a trade-off between reproductive success and gamete survival. We demonstrate that this asymmetry is mediated by partner-specific communication and model its evolutionary dynamics using empirically determined parameters. Our results support classical theoretical predictions for the evolution of gamete differences and provide a mechanistic understanding of how molecular asymmetries between partners can originate from opposing selection pressures acting in species that lack morphologically distinct gametes.
Scabies, caused by the ectoparasitic mite Sarcoptes scabiei, is a contagious zoonotic disease that poses a significant global health burden. The emergence of drug resistance and the lack of effective vaccines underscore the urgent need for novel molecular targets. In this study, we characterized a novel Kazal-type serine protease inhibitor from S. scabiei (SsKaSPI). Immunofluorescence assays localized native SsKaSPI within the mite body and throughout the infested host skin, suggesting that SsKaSPI may be released into host tissues and act at the host-parasite interface. In an in vitro PMA-induced NETosis model using murine bone marrow neutrophils, recombinant SsKaSPI (rSsKaSPI) significantly reduced NET formation without inducing detectable cytotoxicity. Mechanistically, molecular docking predicted a potential interaction between SsKaSPI and elastase, while an in vitro enzymatic assay showed that rSsKaSPI moderately inhibited porcine pancreatic elastase activity. These findings suggest a possible elastase-associated mechanism underlying the suppression of NETosis, although direct inhibition of host neutrophil elastase remains to be further validated. Furthermore, transcriptomic profiling showed that rSsKaSPI altered inflammatory gene expression in neutrophils, with enrichment of IL-17 and TNF signaling pathways. This transcriptional response was accompanied by decreased IL-1β mRNA expression and increased IL-10 mRNA expression. Together, these findings suggest that SsKaSPI may contribute to S. scabiei immune evasion by modulating NET formation and host inflammatory gene expression, although its role under natural infestation conditions remains to be fully investigated. Our results highlight SsKaSPI as a potential molecular target for future anti-scabies studies.
Lung cancer remains the primary cause of cancer-related mortality globally, despite significant advancements in therapeutic strategies. Overall survival rates remain unsatisfactory. Chronic inflammation and microRNAs both play pivotal roles in cancer development. This study aimed to elucidate the roles of key microRNAs in inflammation-associated non-small cell lung cancer (NSCLC) development. Our findings reveal a significant reduction in miR-125b expression within NSCLC cell lines when stimulated by IL-10. Furthermore, when stimulated by IFN-γ, the expression levels of miR-125b markedly increase. Enforced expression of miR-125b markedly bolstered cell proliferation, migration, and invasion, while diminishing cell apoptosis. Conversely, inhibition of miR-125b produced opposing effects. Mechanistically, DAZAP2 was identified as a direct regulatory target of miR-125b However, because both miR-125b inhibition and DAZAP2 knockdown suppressed malignant phenotypes, DAZAP2 may represent one component of a broader miR-125b-associated regulatory network rather than the sole mediator of miR-125b function. Combined inhibition of miR-125b and DAZAP2 produced more pronounced tumor-suppressive effects both in vitro and in vivo. Our data suggest that miR-125b and DAZAP2 are involved in the cytokine-responsive regulatory network of inflammation-related NSCLC progression.
Driving under the influence of drugs is a major cause of road traffic accidents, and alcohol markedly increases crash risk. A clinical test of impairment (CTI) is in some countries performed alongside blood sampling in apprehended drivers, yielding a conclusion of either "impaired" or "not impaired". While the relationship between CTI results and blood drug concentrations has been examined, no previous studies have evaluated CTI outcomes in relation to traffic accidents. This study assesses whether ethanol-positive drivers judged as "impaired" have a higher risk of traffic accident involvement than those assessed as "not impaired", and whether accident involvement increases with impairment severity and ethanol concentration. Drivers positive for ethanol alone were included if a valid CTI conclusion was available and blood sampling occurred 0.25-3 h after the incident. Cases were categorized as either traffic accident group or non-accident controls, the latter including police stops unrelated to accidents (e.g., routine checks, license issues, erratic driving). Age, sex, blood ethanol concentration and CTI results were compared between groups. Associations between impairment level and accident risk were analyzed using multivariable logistic regression. The accident included group 5,290 cases and the non-accident group included 17,596 cases. Accident-involved drivers were younger (median 30 vs. 34 years, p < 0.001), had higher ethanol concentrations (median [IQR] 1.60 g/kg [1.06, 2.05] vs. 1.29 g/kg [0.63, 1.89], p < 0.001) and were more often assessed as "impaired" (94.8% vs. 90.3%, p < 0.001) compared to non-accident drivers. After adjusting for age, sex, ethanol concentration and driving time, CTI-assessed impairment remained significantly associated with accident involvement (OR 1.47; 95% CI 1.28, 1.69). Accident odds increased progressively with both impairment severity and ethanol concentration (ptrend < 0.001). Ethanol-positive drivers assessed as "impaired" by the CTI had 47% higher odds of being involved in traffic accidents compared with drivers apprehended for other reasons, independent of ethanol concentration and demographic factors. Being assessed as "impaired" by the CTI therefore appear to be independently associated with accident risk among alcohol-positive drivers.
Emphysematous cholecystitis (EC) is a rare and severe variant of acute cholecystitis in dogs. Published data regarding EC are limited. To retrospectively describe the clinical presentation, relevant laboratory values, ultrasonographic findings, bile cytology, bacterial culture and susceptibility results, gallbladder histopathology, treatment, and outcomes in a group of dogs diagnosed with EC. Thirty-five client-owned dogs diagnosed with EC. A retrospective review of medical records from 4 referral veterinary teaching hospitals between January 2000 and December 2024 was conducted to describe dogs diagnosed with EC via ultrasonography or computed tomography. Common clinical signs reported included vomiting (23/35, 66%), lethargy (23/35, 66%), or inappetence (15/35, 43%) in dogs. Common clinicopathologic abnormalities were an inflammatory leukogram (21/31, 68%) and elevated serum liver enzyme activity with or without hyperbilirubinemia (28/33, 85%). The most frequent bacteria isolated were Escherichia coli (13/36 isolates) and Clostridium spp. (12/36 isolates). Postoperative death among dogs that underwent cholecystectomy was 29% (4/14). Eleven of 35 (31%) dogs were treated medically and survived to discharge and 5 of 6 dogs with long-term follow-up survived > 6 months. Dogs with EC often present as clinically ill with an inflammatory leukogram, elevated serum liver enzyme activity, and mild hyperbilirubinemia. Cholecystectomy permits source control and collection of gallbladder culture to guide antimicrobial therapy, but empirical medical management can be successful.
Human stem cell-derived miniature organs, including kidney organoids, reproduce aspects of tissue development but lack reliable spatial patterning. In embryos, spatial organization is often established by developmental organizers that generate morphogenetic fields. However, how such organizing geometry operates in kidney nephrogenesis-and whether it can be reconstructed in vitro-has remained unclear. Using spatial transcriptomics of human kidney development, we found that nascent nephrons establish a collecting duct adjacent-to-distant polarity bordering a WNT11-WNT9B signaling boundary. Engineered WNT-secreting cellular organizers introduced into kidney organoids restored this organizing geometry, biasing distal nephron differentiation and orienting nephron morphogenesis toward the signal source, which demonstrates that developmental signaling geometry can be reconstructed synthetically to control tissue patterning.
Objectives. To evaluate the risks of mortality, cardiovascular events, and pulmonary complications among cancer patients who quit, continued smoking, or switched to e-cigarettes after diagnosis. Methods. Using the Korean National Health Insurance Service database (2015-2022), we identified 46 834 cancer patients who were smoking at diagnosis. Patients were categorized as continued smokers (n = 17 418), quitters (n = 25 909), or e-cigarette users (n = 3507) after diagnosis. We used multivariable Cox proportional hazards models to assess associations. Results. During a median 4.2 years of follow-up, all-cause mortality was significantly lower in quitters (hazard ratio [HR] = 0.92; 95% confidence interval [CI] = 0.86, 0.98) and e-cigarette users (HR = 0.84; 95% CI = 0.72, 0.99) than continued smokers. Both groups also showed lower cardiovascular event risks (HR = 0.64; 95% CI = 0.57, 0.72 and HR = 0.72; 95% CI = 0.53, 0.97, respectively). Compared with quitters, e-cigarette users had increased pulmonary complication risk (HR = 1.26; 95% CI = 1.00, 1.58). Conclusions. E-cigarette use was associated with lower mortality and cardiovascular risks than continued smoking, though complete cessation conferred greater benefits. Elevated pulmonary complications in e-cigarette users warrant caution. (Am J Public Health. Published online ahead of print July 2, 2026:e1-e12. https://doi.org/10.2105/AJPH.2026.308512).
Helicobacter pylori infects nearly half of the global population and has traditionally been viewed as a pathogen restricted to the gastric mucosa. Growing evidence, however, suggests that chronic infection may exert systemic effects extending to the central nervous system. This review critically examines the potential neurological implications of H. pylori infection within the emerging framework of the gut-brain axis. We performed a narrative, hypothesis-generating review of human observational and interventional studies complemented by mechanistic experimental research. The literature was evaluated with particular attention to study design, heterogeneity, and potential confounding in reported associations between H. pylori infection and neurological disorders. Across multiple studies, H. pylori infection has been linked to a modestly increased prevalence of Parkinson's disease and dementia, although findings remain heterogeneous. In Parkinson's disease, infection may exacerbate motor fluctuations and reduce levodopa bioavailability, with partial clinical improvement reported following eradication in selected patients. Experimental studies further demonstrate that bacterial outer membrane vesicles can access the brain and promote neuroinflammatory and amyloidogenic processes, supporting biological plausibility. By contrast, several epidemiological studies report an inverse association with multiple sclerosis, suggesting potential immunomodulatory effects. Evidence relating H. pylori to migraine and mood disorders remains inconsistent. Current data do not support H. pylori as a primary cause of neurological disease. Instead, the infection may act as a context-dependent modifier within the complex inflammatory and immunometabolic networks of the gut-brain axis. Clarifying this relationship will require prospective studies integrating microbial strain profiling, biomarker-defined neurological phenotypes, and adequately powered interventional trials.
Chemsex, defined as the use of psychoactive substances to sustain sexual activity or intensify the experiences associated with it, occurs primarily among men who have sex with men. This article presents the case of a 30-year-old HIV-positive man who engaged in chemsex primarily with mephedrone and, occasionally, GHB, and who subsequently developed mephedrone dependence. He sought psychiatric care because of severe drug craving, recurrent depressive and anxiety symptoms accompanying withdrawal syndromes, and fears of losing control over his addiction. A comprehensive evaluation revealed no co-occurring psychiatric disorders or other clinically significant medical abnormalities apart from known HIV infection, which was effectively controlled with antiretroviral therapy. After initiation of bupropion at a dose of 150 mg per day, improvement in mood, reduction in mephedrone craving, and a marked decrease in the frequency of chemsex were observed. This supports the hypothesis that bupropion-induced stabilization of dopaminergic and noradrenergic neurotransmission may indirectly attenuate craving for stimulants such as mephedrone. Psychotherapy introduced during the course of treatment further supported the patient in pursuing long-term abstinence. To our knowledge, this is the first case report describing successful reduction of drug craving with bupropion in an HIV-positive patient engaging in chemsex without co-occurring psychiatric disorders. This case suggests the potential utility of bupropion in reducing mephedrone craving in individuals engaging in chemsex; however, conclusions drawn from a single clinical observation should be interpreted with caution.
Osteogenesis imperfecta (OI) is a rare genetic bone disorder. Children with OI have a higher risk of intraoperative pain. The fascia iliaca compartment block (FICB) can reduce pain, improve intraoperative hemodynamic stability, and facilitate postoperative recovery. This study explores the feasibility and potential role of FICB in multimodal analgesia by describing its application experience in children with OI. This study involved children with OI who underwent surgery for femoral shaft fractures. The FICB group received ultrasound-guided FICB combined with general anesthesia, whereas the control group received general anesthesia alone. Hemodynamic parameters, serum inflammatory markers, intraoperative opioid consumption, recovery time, postoperative pain scores, and the incidence of postoperative nausea and vomiting (PONV) were recorded. A total of 126 children were enrolled. A significant time × group interaction was observed for changes in MAP and HR during surgery (F3,372 = 21.86 and F3,372 = 16.34, both P < 0.001). At all intraoperative time points, MAP and HR were lower in the FICB group than in the Control group (all P < 0.001). A significant time × group interaction was found for postoperative VAS scores (F2,248 = 3.18, P = 0.04); and they were lower in the FICB group at 2, 4, and 12 hours postoperatively (all P < 0.001). CRP levels also showed a significant time × group interaction (F1,124 = 290.3, P < 0.001); both groups exhibited elevated postoperative CRP versus baseline (P < 0.001), but the FICB group had lower levels. The FICB group had a shorter recovery time (P < 0.001), lower intraoperative fentanyl and remifentanil use (both P < 0.001), and a lower incidence of PONV (P = 0.026) compared to the Control group. In pediatric patients with OI undergoing femoral shaft fracture surgery, ultrasound-guided FICB has the potential to enhance intraoperative hemodynamic stability, alleviate postoperative pain, and decrease the incidence of adverse reactions, thereby facilitating the implementation of optimized multimodal analgesia.
The complement system and natural killer (NK) cells play crucial roles in tumor growth and metastasis. The role of the complement system in affecting the phenotype and anti-tumor function of NK cells remains poorly understood. Using the B16F10 mouse melanoma model, we demonstrated that NK cells from C3-/- mice exhibit increased expression of activation receptors (NKG2D, NKp46, and Ly49H) and reduced inhibitory receptors (NKG2A, Ly49A, and KLRG1) and high cytotoxic activity compared to C3+/+ mice NK cells. C3-/- mice show reduced melanoma tumor growth and metastasis in an NK cell-dependent manner compared to C3+/+ mice. Intratumoral NK cells in C3-/- mice formed a unique phenotypic cluster characterized by higher expression of T-bet, CD69, GITR, CD62L, CCR7, and increased secretion of effector cytokines (IFN-γ, TNF-α, and GM-CSF) and granzyme B expression compared to C3+/+ mice. In C3-/- mice, NK cells from both the spleen and tumors exhibit markedly higher expression levels of C3aR and C5aR1 compared to those from wild-type mice. Activation of C3aR by C3a, leads to phosphorylation of AKT and STAT3 molecules, resulting in phenotypic changes to NK cells. Furthermore, antagonising complement anaphylatoxin receptors C3aR or C5aR1 in wild-type mice resulted in reduced tumor growth, accompanied by an increase in intratumoral effector NK cells. Together, we demonstrated that complement C3 regulates the effector and cytotoxic functions of NK cells, suggesting that targeting complement C3 and the anaphylatoxin receptor may be beneficial in controlling tumor growth in the clinic.