PANoptosis in atherosclerotic plaques: Molecular mechanisms, clinical significance, and therapeutic potential.

Impact of poly(rC)-binding protein 2 (PCBP2) on the malignant phenotype of cholangiocarcinoma.

Human Staufen1 (hStau1, UniProt O95793.2) is a double-strand RNA (dsRNA) binding protein that modulates gene expression via mRNA-dependent mechanisms such as Staufen-mediated mRNA decay (SMD). This modular protein is dynamic and binds to both messanger RNA (mRNA) targets and proteins. The Staufen-swapping motif (SSM) domain is reported to play a key role in hStau1 dimerization. Our data confirm that SSM deletion decreases hStau1 dimerization. This protein shows higher protein disorder in the absence of SSM. Thus, SSM plays not only a key role in hStau1 dimerization but also modulates its tertiary structure. Surprisingly, increased disorder upon SSM deletion does not affect affinity for mRNA targets or protein/RNA stoichiometry but SMD efficiency since SMD targets are upregulated upon SSM deletion. In conclusion, hStau1 dimerization via SSM affects the overall structure and dynamics of the protein required for efficient regulation of gene expression via SMD.

Icariin, the principal active compound of Epimedium species used in traditional East Asian medicine, exhibits anti-inflammatory and lipid-regulating effects. However, its effects on human sebocytes and dermal fibroblasts, which could be implicated in the management of acne and atrophic scarring, remain unexplored. This study aimed to evaluate the effects of icariin on human sebocytes, keratinocytes and dermal fibroblasts. Icariin's effects on cell viability, lipid synthesis, inflammation, abnormal keratinization and extracellular matrix (ECM) synthesis were assessed using human SEB-1 sebocytes, HaCaT keratinocytes and Detroit 551 fibroblasts. Icariin modestly promoted the proliferation of SEB-1 sebocytes, HaCaT keratinocytes and Detroit 551 fibroblasts. It reduced mRNA levels of lipogenic and proinflammatory markers in SEB-1 sebocytes and HaCaT keratinocytes. Icariin counteracted arachidonic acid-induced lipogenesis in SEB-1 sebocytes in parallel with modulation of the insulin-like growth factor 1 receptor/Akt signalling pathway. In Detroit 551 fibroblasts, it enhanced ECM protein expression and reduced the expression of ECM-degrading enzymes, accompanied by upregulation of platelet-derived growth factor receptor and latent transforming growth factor β binding protein 4. In conclusion, this study demonstrates that icariin modulates key pathophysiological processes of acne and promotes ECM synthesis, suggesting its potential as a novel therapeutic agent for managing both acne and atrophic acne scars.

Factors affecting perfluorooctanesulfonic acid (PFOS) serum concentration following fish consumption: implications for fish consumption advisories.

Gastrointestinal cancer (GIC) frequently causes cancer cachexia, the major feature of which is the loss of skeletal muscle mass. The degradation of muscular proteins by cancer‑derived factors in the major pathogenesis of cancer‑induced muscle wasting is a known phenomenon. However, this mechanism has mainly been demonstrated using rodent cancer cells, and it may not always be applicable to human cancer types. Impaired skeletal muscle differentiation and regeneration have attracted attention as alternative inducers of cancer cachexia. The present study revealed that conditioned medium from four human GIC cell lines inhibited C2C12 myoblast differentiation by inducing the expression of the inhibitor of DNA binding (Id) proteins Id1 and Id3, which mediated via bone morphogenetic protein (BMP)‑Smad signaling. The results suggested that BMP‑Smad1/5/8‑Id signaling inhibited the expression of a MRF member, myogenin and its downstream myogenic genes, thus leading to unsuccessful differentiation into myotubes. Furthermore, the present study identified high levels of BMP4 secretion from these four human GIC cell lines and demonstrated that an inhibitor of BMP receptor, dorsomorphin or abrogation of BMP4 by siRNA in the GIC cells restored myogenic differentiation in C2C12 cells. The present study uncovered, for the first time, that BMP4 derived from human GIC cells exogenously inhibited myoblast differentiation by activating the Smad1/5/8‑Id signaling axis. In the future, this in vitro study may help to elucidate the complicated mechanisms underlying cancer‑induced cachexia in humans.

To investigate the effects of Shenling Baizhu Powder (SLBZP) on non-tuberculous mycobacteria (NTM)-induced lung disease in mice. An NTM lung disease mouse model was established by Mycobacterium kansasii infection. C57BL/6J female mice were randomly divided into 5 groups by a random number table (n=6): negative control, NTM, SLBZP-L (2.34 g/kg), SLBZP-H (4.68 g/kg), and rifampicin (20 mg/kg). M. kansasii load in the lungs, liver, and spleen was quantified. Lung histology was performed using hematoxylin and eosin staining. Gene and cytokine expressions related to CD4+ T and natural killer (NK) cells were detected by enzyme linked immunosorbent assay, flow cytometry, real-time quantitative reverse transcription PCR, and Western blot, respectively. SLBZP-L and SLBZP-H treatments inhibited M. kansasii growth and reduced the histological damage and granuloma lesion areas in lungs of mice (P<0.01). SLBZP-H increased interleukin (IL)-17A and interferon-gamma (IFN-γ) levels, along with the proportion of CD4+ T cells, NK cells, and IFN-γ+ NK cells, while decreased IL-10 (P<0.01). Furthermore, SLBZP-H inhibited mRNA levels of tumor necrosis factor, IL-6, IL-1β, C-C motif chemokine ligand 2, C-X-C motif chemokine ligand (CXCL) 2, GATA binding protein 3 and T-bet, and increased mRNA level of retinoic acid receptor-related orphan receptor γ (P<0.05 or P<0.01). SLBZP-L and SLBZP-H also reduced the protein expressions of CXCL13 and C-X-C chemokine receptor type 5 (P<0.05 or P<0.01). SLBZP alleviated NTM-induced lung damage and enhanced NK cell immune response, which might be linked to CD4+ T cell immunity.

Loss of erythrocyte arginase-1 impairs vasorelaxation due to endothelial GSNOR overexpression and denitrosylation of G protein subunits.

Alcohol consumption is a common risk factor for esophageal squamous cell carcinoma (ESCC) and hepatic fibrosis. Mac-2 binding protein glycosylated isomer (M2BPGi), a sensitive marker of fibrosis, may predict postoperative skeletal muscle loss by reflecting the metabolic link between liver function and muscle maintenance. Eighty-nine patients with ESCC undergoing esophagectomy (June 2021-July 2024) with alcohol use and pretherapeutic M2BPGi levels were included; the cutoff was 0.66. Muscle mass was assessed by bioelectrical impedance analysis. The study population was stratified by M2BPGi levels into low (n = 59) and high (n = 30) groups. No significant differences were observed in sex, clinical stage, preoperative skeletal muscle mass, surgical approach, or intraoperative fluid balance. The high M2BPGi group showed lower preoperative albumin levels (4.2 vs. 4.0g/dL, p = 0.01) and higher CRP (0.1 vs. 0.4mg/dL, p < 0.01) and ICG R15 values (9.2% vs. 12.8%, p = 0.04). Although there was no difference in the incidence of complications, the decrease in skeletal muscle mass at 3months was significantly greater in the high M2BPGi group (- 7.6% vs. - 12.0%, p = 0.02). In the propensity score-matched cohort (low n = 40; high n = 20), the high M2BPGi group showed significantly greater muscle loss at 3months (- 7.5% vs. - 12.6%, p = 0.04) and a trend toward longer hospital stays (22 vs. 25.5days, p = 0.06). High pretherapeutic M2BPGi levels are independently associated with postoperative skeletal muscle loss at 3months.

Over the past decade, metabolic dysfunction-associated steatotic liver disease (MASLD) has become a leading cause of chronic liver disease in Japan, with estimated prevalence rising from 33.7% (2020) to 44.8% (2040), owing to an aging population and lean individuals. In this narrative review, we summarize the epidemiology, pathogenesis, diagnostic strategies, and emerging treatments for MASLD and metabolic dysfunction-associated steatohepatitis (MASH) in Japan, culminating in a proposed ideal patient care pathway tailored to local needs. MASLD pathogenesis involves complex interactions between metabolic dysfunction, inflammation, insulin resistance, and genetic susceptibility. In Japan, a stepwise diagnostic algorithm is endorsed, starting with non-invasive liver disease assessments (NILDA) such as fibrosis-4, followed by imaging-based fibrosis evaluation and selective biopsy. We propose a two-tiered diagnosis combining first-line NILDA (fibrosis-4) with second-line NILDA (e.g., enhanced liver fibrosis, Mac-2 binding protein glycosylation isomer, cytokeratin-18 fragment, andserum type IV collagen 7S) to refine risk stratification, reduce unnecessary referrals, and optimize healthcare resources, with qualifying patients referred to a hepatologist and treatment plans based on imaging-based NILDA or liver biopsy. The management of MASLD/MASH relies on lifestyle modification and pharmacological agents targeting metabolic comorbidities. However, novel anti-fibrotic, anti-inflammatory, and metabolism-targeted therapies are advancing, with future treatment decisions expected to integrate genomic and metabolomic profiling alongside NILDA. The proposed care model is multidisciplinary, engaging physicians, hepatologists, dietitians, psychologists, pharmacists, and hepatitis medical care coordinators to address both hepatic and systemic metabolic care. This evolving paradigm emphasizes proactive, personalized care informed by real-world data and long-term monitoring to improve outcomes and quality of life for patients with MASLD/MASH in Japan.

ENO1 lactylation drives bevacizumab resistance through metabolic reprogramming and angiogenesis in ovarian cancer.

Hypoxic pulmonary hypertension (HPH) is a representative vascular remodeling disease with a poor prognosis. Previous findings from our study have implicated the NICD4 (Notch4 intracellular domain) in pulmonary artery smooth muscle cells (PASMCs) in the pathogenesis of HPH. However, the underlying regulatory mechanisms remain unclear. In this study, we aimed to elucidate the potential regulatory mechanism of NICD4 in HPH. Using coimmunoprecipitation combined with mass spectrometry, we identified USP8 (ubiquitin-specific peptidase 8) as a novel binding protein of NICD4 in PASMCs. The functional role of USP8 was investigated in vivo using smooth muscle cell-specific Usp8 knockout (Usp8Acta2-/-) mice and in vitro using primarily cultured PASMCs, alongside pharmacological inhibition with DUB-IN-2 (deubiquitinase-inhibitor-2). USP8 was significantly upregulated in lung tissues from patients with HPH due to interstitial lung disease or chronic obstructive pulmonary disease, HPH rodent models, as well as in hypoxic PASMCs. Usp8 deficiency in Acta2-positive mice (Usp8Acta2-/-) or pharmacological inhibition of USP8 by DUB-IN-2 markedly attenuated HPH development. In vitro, USP8 knockdown suppressed hypoxia-induced PASMC proliferation, migration, and apoptosis resistance by modulating the NICD4-MAPK pathway. Mechanistically, USP8 was bound directly to NICD4 to maintain its stability by removing the K48-linked ubiquitin chain on NICD4 at lysine 1760, thus preventing proteasomal degradation. Furthermore, USP8 can be transcriptionally upregulated by CSL/NICD4 under hypoxia, forming a NICD4/USP8-positive feedback loop. Our study unveils a critical NICD4/USP8-positive feedback loop that drives HPH pathogenesis, highlighting the importance of ubiquitination in pulmonary vascular remodeling. Targeted disruption of this loop represents a promising therapeutic strategy for HPH.

Introduction:GATA binding protein 2 (GATA2) deficiency is an autosomal dominant disorder characterized by immunodeficiency, progressive cytopenias, and an increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Novel variants continue to broaden the clinical and genetic spectrum of this condition.Case Presentation:An 11-year-old girl presented with recalcitrant cutaneous warts, recurrent infections, and multilineage cytopenias. Her father had longstanding leukopenia and MDS that progressed to AML. Laboratory evaluation revealed monocytopenia, B- and Natural killer-cell lymphopenia, and dysplastic bone marrow findings. Genetic analysis identified a previously unreported heterozygous splice-site variant in GATA2 (c.1017 + 1 G > A), confirmed in stored DNA from her deceased father. Despite supportive care and allogeneic hematopoietic stem cell transplantation from a matched unrelated donor, she developed severe graft-versus-host disease and died from transplant-related complications.Conclusion:This report identifies a previously unreported GATA2 splice-site variant with clinical and familial evidence supporting pathogenicity, contributing to the expanding mutational spectrum and enhancing understanding of genotype-phenotype correlations in GATA2 deficiency.

Baicalein protects human keratinocytes against PM2.5-induced apoptosis by suppressing oxidative stress, endoplasmic reticulum stress, and ERK/JNK signaling.

Mutations in the MECP2 gene, encoding the epigenetic reader Methyl-CpG binding protein 2, are the main cause of Rett syndrome, a rare neurodevelopmental disorder. Besides severe symptoms such as profound intellectual disability, loss of speech and motor skills, and epilepsy, loss of function of MECP2 has been associated with pubertal dysregulation, but the biological mechanisms leading to this remain unclear. Using a mouse model of Rett, in which males are hemizygous and females heterozygous for Mecp2 loss of function mutation, we assessed the onset and progression of puberty, together with increase in body weight and onset of neurological symptoms in post-weaning mice until puberty. In brain samples of young adult mice, we analysed hypothalamic Gonadotropin releasing hormone (GnRH) neurons by immunofluorescent labelling, and in plasma samples we measured circulating GnRH, LH, and testosterone concentrations. Finally, we analysed testosterone-dependent arginine-vasopressin circuits. In our mouse model we found delayed puberty in Mecp2 CD1-null males, associated with a reduced rate of weight gain, but with puberty onset occurring at a lower body weight than in wildtype controls. Despite later puberty onset, Mecp2CD1-null male mice were found to have an increased number of GnRH neurons, but displayed lower levels of circulating reproductive hormones. Consequently, Mecp2CD1-null males have deficient testosterone-dependent arginine-vasopressin innervation. In female Mecp2CD1-heterozygous mice, we found no overall significant differences in pubertal development or GnRH neurons. The lack of significant alterations in females might be related to a later onset of neurological symptoms due to heterozygosity. Our data supports that MECP2 is essential for typical pubertal development, with complete loss of Mecp2 in a male murine model resulting in abnormalities of pubertal timing related to lower body weight, with an observed increase in hypothalamic GnRH neurons.

RNA binding proteins: Post-transcriptional regulation in craniofacial bone, tooth, and periodontium.

Strictosidinic acid is a key intermediate in the biosynthetic pathway of camptothecin, a plant alkaloid that serves as a precursor for semisynthetic anticancer drugs. At the moment, camptothecin is mainly sourced from trees, causing limited supply and high costs. Improving access to strictosidinic acid would help to elucidate yet unknown biosynthetic steps downstream of this intermediate and in the long term enable sustainable production of camptothecin in heterologous hosts. While structurally similar to the common monoterpene indole alkaloid precursor strictosidine, strictosidinic acid has not been the target of metabolic engineering efforts before. Here, we present a strategy to produce strictosidinic acid from glucose and tryptophan in engineered yeast. First, we create a basic strain that generates 75 mg/L strictosidine. We further optimise this strain by introducing a membrane steroid binding protein and a second copy of the farnesyl pyrophosphate synthase mutant gene ERG20WW, boosting strictosidine levels by 5.5-fold to 398 mg/L. At these higher titres, a previously overlooked shunt product, (2E,6E)-2,6-dimethylocta-2,6-dienedioic acid (DOA), was identified that diverts flux from the pathway. Lastly, we reprogrammed our strictosidine strain to strictosidinic acid production by four genomic modifications. Final fed-batch cultivation in shake flasks resulted in 843 mg/L strictosidine or 548 mg/L strictosidinic acid, respectively, after 168 h. Taken together, our work now grants access to strictosidinic acid by metabolic engineering, while revealing strategies to further enhance the production of strictosidine and related monoterpene indole alkaloids. These findings will help to produce plant alkaloids in microbial cell factories in the future at scale.

Functional characterization of odorant binding proteins involved in detection of host plant volatiles from the moringa pest Noorda blitealis.

Cell elongation and cytokinesis are mediated by two large multi-protein complexes in rod-shaped bacteria: the elongasome and divisome. These membrane-associated complexes ultimately recruit peptidoglycan cell wall remodeling and synthesis machineries, thus sculpting and extending growing cells or driving septation of two daughter cells. The elongasome and divisome have been well studied in model bacterial species, including Bacillus subtilis, Caulobacter crescentus, and Escherichia coli. Here, we present an analysis of these complexes in an obligate intracellular bacterium with a highly reduced genome. Orientia tsutsugamushi, a cytoplasm-dwelling Gram-negative alphaproteobacterium, only retains a subset of proteins normally found in the elongasome and divisome. It also lacks all copies of the major peptidoglycan polymerase, Class A Penicillin Binding Protein, and has been shown to build an intermediate peptidoglycan cell wall-like structure that is low in abundance and insufficient to consistently confer a rod shape to the bacterium. We have carried out a first analysis of the elongasome and divisome in Orientia tsutsugamushi, quantifying the expression and subcellular localization of five key proteins through early stages of the intracellular infection cycle. We show how these are affected by antibiotic treatment and present a model for minimal elongation and division in an obligate intracellular bacterium.

High-intensity interval exercise (HIIE) induces transient increases in reactive oxygen species (ROS) and inflammatory mediators that drive skeletal muscle adaptations. Sex influences oxidative stress and inflammation, yet the interplay between sex and exercise-induced signaling remains incompletely understood. The purpose of this study was to investigate sex differences in markers of inflammation, oxidative stress, and antioxidant status at rest and following acute HIIE in young, healthy males and females matched for aerobic fitness. Twenty-four participants (12/sex) underwent muscle biopsies and blood sampling at rest and immediately postexercise (10 × 1 min at 90% HRmax). Skeletal muscle was analyzed for oxidative stress [NADPH oxidase 2 (NOX2), 4-hydroxynonenal (4HNE), total protein carbonylation via oxyblot, p38 MAPK], antioxidant enzymes [thioredoxin 1 (TRX1), glutathione reductase (GR), and glutathione peroxidase 1 (GPX1)], and cytokine content (array), and plasma was analyzed for inflammatory markers (IL-6 and TNFα) and antioxidant status. Acute HIIE increased plasma IL-6 and TNFα and decreased total antioxidant status with no differences between sexes. Basally, females had higher phosphorylation of p38 MAPK and elevated growth- and repair-associated cytokines [insulin-like growth factor binding protein 1 and 3 (IGFBP-1/3), tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1/2), transforming growth factor- β2/3 (TGF-β2/3), FGF-7/9, macrophage colony-stimulating factor (M-CSF), and stromal cell derived factor (SDF)-1], whereas males had higher basal proinflammatory cytokines (IL-1α, IL-13, IP-10, and oncostatin M). Following exercise, males showed a greater upregulation of growth and repair mediators, whereas females had broader suppression of inflammatory and chemotactic factors. No sex differences were observed in muscle oxidative stress markers or antioxidant content. These findings indicate that although acute HIIE elicits comparable plasma inflammatory responses in males and females, underlying skeletal muscle cytokine signaling and adaptive potential are sex-specific, emphasizing the need to consider sex in exercise physiology studies. NEW & NOTEWORTHY We investigated whether sex influenced the inflammatory or oxidative stress response to acute exercise. Although no differences were observed in plasma markers, in skeletal muscle, females had elevated growth- and repair-associated cytokines, whereas males had higher proinflammatory cytokines at rest. Following exercise, males had greater upregulation of growth and repair mediators, whereas inflammatory and chemotactic factors were suppressed in females. The sex divergence in skeletal muscle cytokines may have implications postexercise signaling and chronic adaptations.