Search Results (6,085)

Microcin C7 (McC7) is a ribosomally synthesized antimicrobial peptide that has emerged as a promising candidate due to its dual antibacterial and immunomodulatory activities. This study evaluated the preventive effect of McC7 against cyclophosphamide (CTX)-induced immunosuppression and intestinal injury. An immunosuppression model was established by intraperitoneal CTX injection in mice, which were randomly allocated into five groups (n = 15): a negative control, a CTX model group, and three McC7 treatment groups receiving dietary McC7 at 100, 200, or 400 mg/kg both before and during CTX exposure. Body weight and feed intake were monitored throughout the study. Organ indices, serum biochemical parameters, immune and antioxidant markers, and intestinal morphology were assessed. Splenic T-cell subsets were analyzed by flow cytometry, and gut microbiota composition was evaluated by 16S rRNA sequencing. McC7 supplementation significantly attenuated the CTX-induced reduction in body weight, feed intake, and organ indices, ameliorated markers of hepatic and renal injury, and restored the splenic CD4⁺/CD8⁺ T-cell ratio. McC7 enhanced intestinal mucosal barrier integrity, increased the abundance of beneficial bacteria such as Candidatus Arthromitus and ASF356, and reduced the abundance of the potentially pathogenic genus Bilophila. In conclusion, our results demonstrate that McC7 alleviates CTX-induced immunosuppression by regulating T-cell differentiation, maintaining cytokine homeostasis, and modulating gut microbial composition to support intestinal health. Full article

Background/Objectives: Although tissue inhibitors of metalloproteinases (TIMPs) are key regulators in breast cancer, their differential expression, clinical relevance, and molecular roles remain unclear. This study aimed to compare the expression patterns of the four TIMPs in breast cancer and evaluate their molecular interactions and associated pathways through an integrated bioinformatic analysis. Methods: The expression of TIMPs and their correlations with MMPs were analyzed using the TCGA PanCancer, cBioPortal, and GEO datasets. Associations between TIMP expression and overall survival were assessed in the TCGA Breast Invasive Carcinoma PanCancer cohort. Pathway enrichment analysis was performed using GO, KEGG, and DAVID. The relationships between immune cell infiltration, stromal cells, and TIMP expression were assessed using the EPIC algorithm. Statistical analyses were performed using R. Results: TIMP1 was the only inhibitor overexpressed in breast tumors and showed significant associations with the Luminal B, HER2, TNBC, and normal-like subtypes, along with a modest increase across stages. TIMP2, TIMP3, and TIMP4 were downregulated in tumors. High expression of TIMP1 and TIMP4 correlated with better overall survival. TIMP1-associated genes were enriched in NF-kappa and PI3K–Akt signaling and actin cytoskeleton components. TIMP2 was linked to Hedgehog and MAPK pathways and actin-related elements. TIMP3 correlated with Hedgehog and PI3K–Akt signaling, DNA damage response, and membrane components. TIMP4 was associated with VEGF, MAPK, PI3K–Akt, DNA damage pathways, and actin organization. TIMP2 showed strong positive correlations with MMP2 and MMP14, while TIMP4 showed negative correlations with MMP1 and MMP9. Interestingly, we found a strong positive correlation between TIMP2 and TIMP3 with ADAM12, as well as between TIMP2 and TIMP3 with ADAM10, and negative correlations with ADAM15. The differential expression of TIMPs favors greater infiltration of immune cells related to tumor progression and poor prognosis in breast cancer patients. Conclusions: TIMPs display contrasting expression profiles and distinct pathway associations in breast cancer. TIMP1 emerges as the only consistently overexpressed inhibitor, while TIMP4 appears as a promising prognostic marker with unique MMP correlations that may influence tumor behaviors. Full article

Sepsis remains a leading cause of global mortality and is characterized by a dysregulated host immune response to infection. Early deaths often result from hyperinflammation and organ dysfunction, whereas late-stage mortality is increasingly attributed to sepsis-induced immunosuppression, leading to secondary infections and viral reactivation. Challenges persist in the identification and management of sepsis-induced immunosuppression, including the lack of standardized immune monitoring methods, the absence of reliable immune biomarkers to guide therapy, and the limited success of immunomodulatory therapies in clinical trials. This review comprehensively summarizes the pathophysiology of sepsis-induced immunosuppression, encompassing immune cell apoptosis and exhaustion, the expansion and activation of immunomodulatory cells, metabolic reprogramming, epigenetic alterations, and iatrogenic factors. We also discuss current diagnostic challenges and explore emerging immunomodulatory strategies, such as cytokine therapies, immune checkpoint inhibitors, and metabolic modulators, as potential approaches to restore immune function. Finally, we highlight the importance of immune phenotyping and individualized precision medicine in the future management of sepsis, and integrating multidisciplinary approaches from mechanistic research to targeted therapies holds promise for improving patient outcomes. Full article

Deoxynivalenol (DON) is a common mycotoxin in cereal crops such as corn, wheat, and their processed products. It can cause feed refusal and growth retardation in piglets. This study systematically evaluated the effects of dietary exposure to purified DON at low doses of 0.25, 0.5, 1.0, and 2.0 mg/kg on growth performance, blood biochemistry, antioxidant capacity, immune function, intestinal health, and reproductive development in female weaned piglets over a 42-day period. Although dietary exposure to 0.25–2.0 mg/kg of DON did not significantly affect growth performance, it induced subclinical multi-organ toxicity. Notably, decreased platelet count (PLT) at 0.25–2.0 mg/kg and increased serum alanine aminotransferase (ALT) activity at 2.0 mg/kg were observed. DON exposure also impaired antioxidant function with reduced serum total antioxidant capacity (T-AOC) at 0.25–2.0 mg/kg, and elevated malondialdehyde (MDA) content in the jejunum and ileum at 0.5–2.0 mg/kg. Furthermore, at all doses tested (0.25–2.0 mg/kg), DON suppressed anti-inflammatory cytokine interleukin-10 (IL-10) levels in both serum and intestine, reduced duodenal villus height (VH), and decreased serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels. Additionally, histopathological injuries of liver, kidney, duodenum, jejunum, ileum, uterus and ovaries were also observed at doses of 1.0–2.0 mg/kg. In summary, this study confirms the multi-organ toxicity of low-dose DON in piglets. Our findings suggest that DON concentrations in pig feed should be more strictly controlled and highlight the importance of considering subclinical health endpoints, such as oxidative stress markers and immune parameters, in future risk assessments of mycotoxin exposure. Full article

Liver fibrosis is a significant consequence of severe liver injury resulting from viral hepatitis, alcohol, and metabolic dysfunction. Progressive fibrosis and ultimate cirrhosis are leading causes of morbidity and mortality worldwide, generally irreversible and poorly targeted by current therapies. Traditional in vitro models and animal models mostly fail to fully recapitulate human multicellular crosstalk, extracellular matrix (ECM) remodeling, and the chronic, immune modulated nature of the disease. Recent advances in three-dimensional (3D) cell culture models including organoids, spheroids, bioprinted constructs, and organ-on-a-chip systems are advantageous for reconstructing cellular diversity and mechanical microenvironments to understand pathophysiology and aid in drug discovery. Emerging multi-organ models are capable of incorporating microbiome derived cues and using multi-omics readouts and imaging-enabled mechanistic dissection for more predictive anti-fibrotic screening. These technologies align well with the recent Modernization 3.0 regulation and New Approach Methodologies by the Food and Drug Administration (FDA) and recent EU Pharmaceutical Reform. This review summarizes the pathophysiology of liver fibrosis, the current landscape of 3D human liver models, and examines how microbiome interfaces modulate fibrogenesis. Full article

Sepsis is a life-threatening condition caused by a dysregulated host immune response to infection, leading to systemic inflammation, organ dysfunction, and potentially death. Despite significant advances in understanding the pathophysiology of sepsis, effective therapeutic options remain limited, and mortality rates remain unacceptably high. Therefore, a deeper understanding of sepsis pathogenesis and the identification of novel therapeutic targets are urgently needed to improve patient outcomes. Recent studies have revealed that RNAs can undergo glycosylation, generating a previously unrecognized class of molecules known as glycosylated RNAs (glycoRNAs), which are localized on the outer surface of cells. GlycoRNAs are highly expressed in immune cells, and accumulating evidence indicates that they play important roles in regulating immune responses, including immune cell adhesion and infiltration, immune cell activation, and immune evasion. In addition, glycoRNAs are abundantly expressed on the epithelial cell surfaces of the respiratory, digestive, urinary, and reproductive systems, suggesting that glycoRNAs may function as a component of epithelial barriers that protect against pathogenic invasion. Collectively, these findings suggest that glycoRNAs may play a critical role in the pathogenesis of sepsis. This review summarizes the expression and functions of glycoRNAs in immune and barrier systems and highlights their potential roles during distinct immunological phases of sepsis. Full article

Implant science has traditionally treated “biocompatibility” as the master criterion of success, focusing on cytotoxicity, corrosion, immune response, infection control, and the chemical stability of materials in vivo. However, many clinically “biocompatible” devices still fail at the point where the body actually meets the device: the mechanical interface. The interface is not a passive boundary. It is a living, adapting, mechanosensitive microenvironment in which cells integrate stiffness, micromotion, surface roughness, fluid shear, and wear debris with biochemical signals to decide whether to incorporate an implant, wall it off, resorb adjacent tissue, or trigger chronic inflammation. In load-bearing orthopaedics, stiffness mismatch produces stress shielding and maladaptive remodelling; excessive micromotion drives fibrous encapsulation rather than osseointegration; abrasive wear creates particulates that sustain macrophage activation and osteolysis; and design choices that are mechanically adequate in bench tests can still fail in vivo when the implant–tissue system evolves. In soft-tissue implantation, substrate stiffness can be a primary driver of the foreign body response and fibrotic capsule formation through mechanosensitive pathways, such as TRPV4-mediated macrophage–fibroblast signalling. Mechanical compatibility is not a replacement for classical biocompatibility; rather, it should be treated as a co-equal, first-class design requirement in mechanosensitive organisms. Chemically biocompatible materials can still fail through stiffness mismatch, micromotion, fretting and wear debris generation, and mechanobiology-driven fibrosis or osteolysis. We therefore propose a process view of implant success: tissue mechanics should be measured in clinically relevant states, transformed into constitutive models and interface performance envelopes, translated into explicit mechanical-compatibility specifications, and then realised through manufacturing process windows that can reliably reproduce targeted architectures and surface states. Additive manufacturing and microstructural engineering enable the tuning of modulus, the formation of porosity gradients, and the generation of patient-specific compliance fields, but these advances only improve outcomes when coupled to metrology, statistical process control, and validation loops that close the gap between intended and realised interface mechanics through clinical surveillance. Full article

Fetal growth restriction (FGR) is a major contributor to perinatal morbidity and mortality, most commonly arising from placental dysfunction, with increasing evidence implicating aberrant DNA methylation in its pathogenesis. To identify robust epigenetic alterations associated with FGR, we analyzed placental chorionic villi from an in-house early-onset FGR cohort and compared them with a publicly available dataset (GSE100197). DNA methylation profiling was performed using Illumina EPIC (in-house) and 450K (public) arrays, processed with identical normalization and quality-control pipelines, including adjustment for gestational age and estimation of placental cell-type composition. Differentially methylated positions (DMPs) were identified using linear regression models, revealing 10,427 DMPs in the in-house cohort and 7467 in the public dataset, with 108 shared DMPs showing consistent direction of change across both cohorts. Promoter-associated DMPs were mapped to genes involved in angiogenesis, morphogenesis, immune regulation, and transcriptional control, including EPHA1, ANGPTL6, ITGAX, BCL11B, and CYP19A1, while additional novel candidates such as SLC39A12, YEATS4, and MIR515 family members were also identified. Functional annotation suggests that these methylation changes may influence pathways essential for placental vascular development and structural organization. Overall, this cross-cohort comparison highlights reproducible epigenetic signatures of FGR and underscores the need for standardized approaches to clarify the molecular mechanisms underlying placental insufficiency. Full article

The development of next-generation HIV-1 therapeutics, including ultralong-acting antivirals, novel mechanistic classes, and curative immunotherapies, promises to overcome the limitations of lifelong, daily antiretroviral therapy (ART). However, the real-world efficacy of these treatments depends on the complex epidemiological landscapes in which they are used. In South America, HIV-1 epidemics intersect hyperendemic arboviruses, including dengue, Zika, chikungunya, and yellow fever, and regionally isolated pathogens, such as mammarenaviruses. These co-infections cause profound episodic immune activation and organ dysfunction that alter drug pharmacokinetics, disrupting healthcare access and adherence. These factors can compromise ART efficacy, promote resistance, and influence latent reservoir dynamics. This review synthesizes clinical and translational evidence of this intersection. We evaluate how emergent agents, such as capsid inhibitors (lenacapavir), long-acting injectables (cabotegravir/rilpivirine), maturation inhibitors (GSK3640254), and broadly neutralizing antibodies (bNAbs), perform in the context of co-endemic viral challenges. Specifically, we argue that therapeutic development must become “co-infection-aware” to progress toward a cure and achieve durable HIV-1 control. We provide a translational roadmap that explicitly incorporates co-infection endpoints into clinical trials, develops preclinical models that better reflect real-world viral exposures, and prioritizes implementation strategies that remain effective in the case of recurrent outbreaks. Integrating regional viral ecology into HIV-1 therapeutic research is therefore a necessary step toward developing interventions that are durable and effective on a global scale. Full article

Antimicrobial resistance (AMR) remains a major clinical challenge, with Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species (ESKAPE) accounting for a substantial share of multidrug-resistant (MDR) infections worldwide. These organisms undermine antibiotic efficacy through reduced permeability, surface shielding, biofilm formation, and rapid genetic adaptation, mechanisms that primarily restrict effective exposure at infection sites. Bacteriophages, phage-derived enzymes, and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based antimicrobials provide selective and mechanistically distinct alternatives to conventional antibiotics, but their performance in vivo is often limited by instability in physiological environments, immune neutralization, uneven tissue distribution, and insufficient access to bacteria protected by biofilms or surface-associated barriers. This narrative review examines how nanotechnology-based delivery systems can address these constraints. We first outline the delivery-relevant biological barrier characteristic of ESKAPE pathogens, then summarize the therapeutic potential and inherent limitations of whole phages, phage-derived enzymes, and CRISPR-based antimicrobials when used without formulation. Major nanotechnology platforms for antibacterial delivery are reviewed, followed by analysis of how nano-enabled systems can improve stability, localization, and persistence of these biological agents. A pathogen-aware integration framework is presented that links dominant barriers in each ESKAPE pathogen to the biological modality and nano-enabled delivery strategy most likely to enhance exposure at infection sites. Translational challenges, regulatory considerations, and emerging directions, including responsive delivery systems and personalized approaches, are also discussed. Overall, nano-enabled phage-based therapeutics represent a realistic and adaptable strategy for managing MDR ESKAPE infections. Therapeutic success depends on both continued discovery and engineering of antibacterial agents and effective delivery design. Full article

High Mobility Group ^{Box 1} (HMGB1) and S100 proteins are major ligands of Receptor for Advanced Glycation End-products (RAGE) and have causal roles in endometriosis lesions. Yet the AGE–RAGE pathway that unifies Advanced Glycation End-products (AGEs) with these ligands has not been assessed in endometriosis. In diabetes, atherosclerosis, and chronic kidney disease, AGE–RAGE links insulin resistance and oxidative stress to inflammation, fibrosis, and organ harm. Endometriosis shares key drivers of AGE accumulation, including insulin resistance, oxidative stress, and chronic inflammation. Endometriosis is also linked to higher vascular risk and arterial stiffness. We asked whether AGE–RAGE could bridge metabolic stress to pelvic lesions and systemic risk. We did a focused review of mechanisms and an evidence map of studies on AGEs, RAGE, or known RAGE ligands in endometriosis. We grouped findings as most consistent with a driver, amplifier, consequence, or parallel role. We included 29 studies across human samples, cell systems, and animal models. Few studies measured AGE adducts directly. Most work tracked RAGE ligands (mainly HMGB1 and S100 proteins) and downstream immune and angiogenic programs. Across models, this pattern fits best with a self-reinforcing loop after lesions form. RAGE expression often aligned with lesion remodeling, especially fibrosis. Blood and skin readouts of AGE burden were mixed and varied by cohort and sample type. A central gap is receptor proof. Many models point to shared Toll-like receptor 4 (TLR4)/ nuclear factor kappa B (NF-κB) signaling, but few test RAGE dependence. Overall, current evidence supports AGE–RAGE as a disease-amplifying loop involved in chronic inflammation and fibrosis rather than an initiating trigger. Its effects likely vary by stage and site. Priorities now include direct lesion AGE measurement, paired systemic–pelvic sampling over time, receptor-level studies, and trials testing diet or drug interventions against clear endpoints. Outcomes could include fibrosis, angiogenesis, immune state, pain, and oocyte and follicle function. Full article

Background/Objectives: Systemic sclerosis (SSc) is a rare autoimmune disease characterized by chronic inflammation, microvascular injury, and fibrosis of the skin and internal organs. Although there are therapies, there is a need for treatments targeting early pathogenic mechanisms. Type I interferons (IFN-I) are key mediators linking immune dysregulation to vascular and fibrotic damage in SSc. This review summarizes the current evidence supporting IFN-I blockade with anifrolumab as a novel therapeutic strategy. Methods: A narrative review of preclinical, translational, and emerging clinical studies was conducted to evaluate the role of IFN-I signaling in SSc and the therapeutic potential of anifrolumab. Particular focus was placed on the IFN signature, upregulation of interferon-stimulated genes (ISGs), and the association with disease activity and organ involvement. Results: Anifrolumab, a fully human monoclonal antibody targeting the IFN-I receptor subunit 1 (IFNAR1), inhibits the signaling of all IFN-I isoforms, suppressing downstream JAK–STAT activation and ISG expression. Mechanistic data suggest that IFNAR blockade modulates vascular injury, immune activation, and fibrosis. Early findings and ongoing trials indicate potential benefits, particularly in patients with a high IFN signature or rapidly progressive cutaneous and cardiac disease. Conclusions: The current evidence supports IFN-I pathway inhibition as a promising approach in SSc. Ongoing trials will help to determine the clinical efficacy, safety, and optimal patient selection for anifrolumab in this rare but severe disease. Full article

The pivotal clinical trials, CARTITUDE-1 and KarMMa-3, showed promising response rates in relapsed and refractory multiple myeloma (RRMM) with use of BCMA-directed CAR T-cell therapy; however, a major challenge is determining suitability in patients who do not meet trial inclusion criteria due to suboptimal organ function. In this multicenter retrospective study, we evaluated the safety and efficacy of BCMA CAR-T therapy in patients with RRMM and renal impairment (RI), defined as creatinine clearance (CrCL) of less than 45 mL/min. We evaluated 223 patients treated with idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel) between May 2021 and April 2024. Outcomes were compared between baseline RI (11.2%) and normal renal function (nRF) cohorts. Response rates were similar at 1 month (p = 0.09), 3 months (p > 0.9), and 6 months (p = 0.8). Progression-free survival (PFS) was 21.9 months in the RI group compared to 15 months in the nRF group (p = 0.32), while overall survival (OS) was 27.9 months for patients with RI versus not reached for patients with nRF (p = 0.87). Patients with RI had higher rates of immune effector cell-associated neurotoxicity syndrome (ICANS) (60% vs. 19%, p = 0.04) and infections (44% vs. 20%, p = 0.008). We found that BCMA CAR-T demonstrated comparable efficacy in RRMM patients with baseline RI, although these patients exhibited increased rates of neurotoxicity and infections. Full article

Renal ischemia–reperfusion injury (IRI) is a leading trigger of acute kidney injury (AKI), a syndrome with high incidence and mortality worldwide. The kidney is among the most energy-demanding organs; its mitochondrial content is second only to the heart, rendering renal function highly contingent on mitochondrial integrity. Accumulating evidence places mitochondria at the center of IRI pathogenesis. During ischemia, ATP depletion, ionic disequilibrium, and Ca²⁺ overload set the stage for injury; upon reperfusion, a burst of mitochondrial reactive oxygen species (mtROS), collapse of the mitochondrial membrane potential (ΔΨm), aberrant opening of the mitochondrial permeability transition pore (mPTP), mitochondrial DNA (mtDNA) damage, and release of mitochondrial damage-associated molecular patterns (mtDAMPs) further amplify inflammation and drive regulated cell-death programs. In recent years, the centrality of mitochondrial bioenergetics, quality control, and immune signaling in IRI-AKI has been increasingly recognized. Building on advances from the past five years, this review synthesizes mechanistic insights into mitochondrial dysfunction in renal IRI and surveys mitochondria-targeted therapeutic strategies—including antioxidant defenses, reinforcement of mitochondrial quality control (biogenesis, dynamics, mitophagy), and modulation of mtDAMP sensing—with the aim of informing future translational efforts in AKI. Full article

The escalating challenge of antimicrobial resistance has spurred interest in probiotics as alternatives for combating bacterial infections. This study aimed to isolate and characterize probiotic Lactobacillus johnsonii (L. johnsonii) from yak feces with protective efficacy against acute Escherichia coli (E. coli) infection. In vitro, DY2 supernatant inhibited the growth of E. coli. In vivo, mice pretreated orally with DY2 (1 × 10⁹ CFU/mL) for 21 days before E. coli challenge exhibited significantly reduced weight loss (p < 0.001), lower bacterial translocation in the intestines (p < 0.001), and normalized organ indices (p < 0.05) compared to untreated infected controls. DY2 modulated host immune and oxidative responses by significantly lowering serum levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6; p < 0.001 to p < 0.05) and malondialdehyde (MDA; p < 0.001), while elevating levels of the anti-inflammatory IL-10 (p < 0.05) and antioxidant enzymes (SOD, GSH-Px, T-AOC; p < 0.001 to p < 0.01). Histologically, DY2 preserved intestinal mucosal integrity, with reduced villus shortening and inflammatory infiltration (p < 0.001 for villus length in key segments). 16S rRNA sequencing of intestinal microbiota revealed enhanced α-diversity (p < 0.05 to p < 0.001), community stability, and enrichment of beneficial genera such as Butyricimonas in DY2-treated mice. Conclusively, Lactobacillus johnsonii DY2 protects against acute E. coli infection via anti-inflammatory, antioxidant, gut barrier strengthening, and microbiota-modulating activities. Yak-derived lactobacilli are promising probiotics with excellent antibacterial properties. Full article