Atherosclerosis develops through oxidative stress and inflammatory responses induced by oxidized low-density lipoprotein (oxLDL), and excessive lipid accumulation in macrophages accelerates disease progression by facilitating foam cell formation. In this study, we investigated the protective effects of the α-melanocyte-stimulating hormone-derived endogenous tripeptide Lysine-Proline-Valine (KPV) against oxLDL-induced cellular injury in RAW264.7 macrophages. Exposure to oxLDL markedly increased lipid accumulation in RAW264.7 macrophages, concomitantly enhancing inflammatory signaling and promoting foam cell formation. Treatment with KPV significantly attenuated oxLDL-induced lipid accumulation, thereby suppressing foam cell formation, while also suppressing inflammatory responses without inducing cytotoxicity. Mechanistic analyses revealed that KPV reduced intracellular reactive oxygen species (ROS) levels, thereby suppressing the activation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB), which serve as key regulators of Interleukin-1β (IL-1β) expression. In addition, KPV suppressed the assembly of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, leading to a reduction in apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, caspase-1 cleavage, and IL-1β maturation. These findings suggest that KPV functions as an effective modulator of oxidative stress and inflammatory signaling and may hold substantial therapeutic potential for suppressing foam cell formation and attenuating disease progression in atherosclerosis.

Tropomyosin 1 (TPM1) encodes tropomyosin alpha-1 chain, a key cardiac sarcomere component, while TPM1 mutations cause hypertrophic cardiomyopathy (HCM), a major cause of sudden cardiac death in the young. We generated the human iPSC line ZZUNEUi040-A from peripheral blood mononuclear cells of a 10-year-old male with non-obstructive asymmetric HCM carrying a heterozygous TPM1 c.644C > T (p.Ser215Leu) mutation via Sendai virus non-integrating reprogramming technology. The line showed normal karyotype (46,XY), undifferentiated hPSC-State markers, and trilineage differentiation potential, serving as a valuable model for HCM pathogenesis studies and drug screening.

Gut microbiota plays a crucial role in animal health and immunity, and the broiler gut community is particularly sensitive during the early growing and finisher phases, when it is still maturing and immune development is active. In this study, we investigated the association between changes in the intestinal flora and splenic immune parameters in Qingyuan partridge chickens. A total of 40 twenty-week-old roosters were used. The results showed that antibiotic treatment (ABX) reduced the proportion (percentage) of splenic CD3+ T cells and increased the levels of inflammatory cytokines (IL-6, IL-1β, and TNF-α). Antibiotic treatment also reduced α- and β-diversity of the gut microbiota. Transcriptomic analysis identified 145 differentially expressed genes (DEGs, |log2FoldChange| > 1, Benjamini-Hochberg-adjusted P < 0.05) in the spleen, including CCR9, OPCML, and HEBP1, enriched in neuroactive ligand-receptor interaction, phagosome, and lysosome pathways. Antibiotic treatment reduced the relative abundance of Verrucomicrobiota and Actinobacteriota at the phylum level. At the genus level, Wilcoxon analysis showed Ligilactobacillus was reduced in ABX (P = 0.031), although LEfSe flagged it as ABX-enriched owing to a single high-abundance outlier. Microbacterium was consistently enriched in ABX. Correlation analysis revealed that Actinobacteriota and the genera Ligilactobacillus and Aeriscardovia were positively associated with CD3+ T-cell proportions. In summary, changes in gut microbiota were associated with altered splenic immune parameters in chickens.

Soilborne fungal pathogens must locate host roots, stably attach to their surface and assemble a persistent mycelial network before invading the plant, yet how host perception is coupled to these cellular outputs remains poorly understood. Here, we characterize HAM-7, a GPI-anchored cell wall protein of Fusarium oxysporum and orthologue of the Neurospora crassa cell wall integrity sensor, and show that it is required for two mechanistically distinct processes essential for root colonization. Targeted deletion of ham-7 strongly impaired stable mycelial retention on tomato roots while leaving germling adhesion to abiotic surfaces and biofilm formation unaffected, indicating a defect in fusion-dependent cohesion rather than in surface adhesion. This defect is coupled with a complete loss of vegetative hyphal fusion (23% WT vs. 0% ham-7Δ), preventing the formation of interconnected mycelial networks that promote stable retention of fungal biomass on the root surface. In parallel, ham-7Δ mutants are severely defective in chemotropism toward plant peroxidases but retain intact responses to synthetic α-pheromone, revealing a specific requirement for HAM-7 upstream of the redox-dependent branch of host cue perception. Consistent with this, ham-7Δ mutants constitutively downregulate nox genes under basal conditions and fail to upregulate noxB and noxR upon exposure to tomato root exudates. Accordingly, exogenous H2O2 fully rescues the chemotropism defect but leaves the fusion deficiency intact, demonstrating that HAM-7 acts upstream of two separable downstream pathways. Combined, these defects significantly attenuate virulence on tomato plants, identifying HAM-7 as an upstream actor of Nox-dependent signalling.

Chlamydia psittaci (C. psittaci) is a major intracellular pathogen of pigeons that often requires prolonged antimicrobial therapy; however, high-dose oxytetracycline (OTC) may increase toxicity. Glycyrrhizic acid (GA), a bioactive licorice constituent, has anti-inflammatory, antioxidant, and antimicrobial-enhancing properties. This study evaluated whether GA improves the pharmacokinetics, therapeutic efficacy, and safety of OTC against experimental C. psittaci infection in pigeons. C. psittaci was isolated and confirmed via embryonated egg inoculation and real-time PCR. Eighty-four pigeons were allocated to seven groups: negative control (G1), infected control (G2), oral OTC (G3), intravenous OTC (G4), oral GA (G5), oral OTC plus GA (G6), and intravenous OTC plus GA (G7). Pharmacokinetics were assessed using a validated green HPLC-UV method, while antimicrobial efficacy, inflammatory and oxidative stress markers, and hepatic and renal biomarkers were evaluated. GA showed borderline synergism with OTC (fractional inhibitory concentration index, 0.499) against the tested isolate. The HPLC method showed excellent analytical performance, with an AGREE greenness score of 0.82. Compared with OTC alone, GA significantly (P < 0.05) increased Cmax and AUC₀-₂₄, improved absolute oral bioavailability from 29% to 38%, increased relative bioavailability 1.5-fold, and reduced apparent oral and systemic clearance. Combination therapy markedly reduced chlamydial burden and inclusion body formation, attenuated IL-6, TNF-α, and malondialdehyde levels, and restored glutathione and hepatic and renal biomarkers compared with monotherapies. These findings support GA as a promising adjunct to OTC therapy for avian chlamydiosis, enhancing OTC exposure and therapeutic efficacy while reducing infection-associated tissue injury, potentially mitigating adverse effects associated with prolonged OTC therapy.

Loss-of-function mutations in the human OTULIN gene, encoding a deubiquitinase with exclusive specificity for linear ubiquitin chains, cause a severe multiorgan autoinflammatory condition involving the skin. Mice lacking OTULIN selectively in keratinocytes develop inflamed skin lesions that progress into squamous tumors, a phenotype driven by excessive tumor necrosis factor (TNF)-induced cell death. Previous studies suggest a role for OTULIN in mediating Wnt signaling during development, but the physiological relevance of this association is unknown. Here, we show that OTULIN promotes Wnt signaling in keratinocytes by regulating the linear ubiquitination status of β-catenin. Stabilization of β-catenin in OTULIN-deficient keratinocytes prevents progressive skin inflammation in prophylactic and therapeutic settings by blocking keratinocyte death. We demonstrate that OTULIN prevents proteasomal degradation of β-catenin in cultured keratinocytes. Reduced Wnt signaling in OTULIN-deficient keratinocytes leads to degradation of TCF3/4, an essential survival factor for keratinocytes. Collectively, our data identify OTULIN's linear deubiquitination activity as a key regulator of epithelial cell viability, not only by preventing cell death downstream of TNF, but also by promoting canonical Wnt signaling.

Cells throughout the body release small extracellular vesicles (sEVs), including exosomes, that function as modulators of both local and systemic metabolism. Using mice in which ALIX, a key regulator of sEV biogenesis, was selectively deleted in PDGFRα+ mesenchymal progenitors (Pα-ALIXKO mice), we demonstrate a critical role for mesenchymal sEV production in metabolic regulation. In high-fat diet-induced obesity, Pα-ALIXKO mice exhibited reduced weight gain and smaller subcutaneous adipocytes compared with control mice. Despite similar insulin sensitivity, these mice showed impaired glucose tolerance, which was associated with reduced pancreatic β cell area and smaller islets. sEVs isolated from conditioned media of knockout (KO)-derived mesenchymal stem cells (MSCs) exhibited a reduced capacity to promote β cell proliferation. Furthermore, MSCs isolated from subcutaneous adipose tissue of KO mice showed elevated mRNA expression of inflammatory genes. Together, these findings indicate that ALIX in tissue-resident mesenchymal progenitors is required for pancreatic β cell proliferation and glucose homeostasis in obesity.

Rapid development of host immunity is critical during the emergence of viral outbreaks when vaccines are not yet available. Here, we demonstrate that CpG oligodeoxynucleotide-schizophyllan complex (K3-SPG) induces antigen-independent, long-term protection against lethal respiratory virus infection. A single intranasal administration successfully enhanced host resistance to infection for as long as 100 days posttreatment. Mechanistically, we observed a lung-restricted biphasic innate activation of macrophages and innate lymphoid cells. Early protection was mediated by CD11b+CD11c+ macrophages (DP MΦ) and monocyte-derived interstitial macrophages (IMΦ). Late protection was mediated by innate lymphoid cells that were epigenetically reprogrammed, suggesting that two distinct innate immune subsets contribute to the maintenance of disease tolerance in the lung microenvironment. Deficiency of TLR9 or TNF-α abrogated innate activation and protective immunity. Collectively, these findings demonstrate that adjuvant-induced prophylaxis is a promising approach to enhancing host resistance against respiratory virus infection, involving the biphasic cooperation between innate immune cells in the local tissue.

Influenza A virus (IAV) infection during pregnancy is associated with stillbirth and preterm birth. We hypothesized that maternal IAV infection disrupts placental and fetal immune networks in ways that correlate with disease severity. Pregnant pigtail macaques were inoculated with IAV [A/California/07/2009 (H1N1)] and underwent delivery and fetal necropsy 5 days postinfection (N = 11), with comparison to uninfected controls (N = 16). Stillbirth occurred in 18% of infected pregnancies and in no controls. Although vertical transmission was not observed, low levels of viral RNA were detected in two placentas. Maternal infection was associated with induction of a type I interferon response in the placenta and altered innate and adaptive immune cell populations in the fetus. Maternal disease metrics (e.g., lung viral load and interferon-α) were rarely associated with placental immune perturbations but frequently linked to fetal immune cell populations (CD4+ and CD8+ T cells and monocyte subsets). Collectively, these data indicate that maternal IAV disease severity is associated with dysregulated fetal immunity.