Search Results (3,480)

Objectives: Saccharomyces boulardii CNCM I-745, a probiotic yeast, is effectively used for the treatment of acute diarrhea as well as for the prevention and treatment of traveller‘s diarrhea and diarrhea under tube feeding. The underlying mechanisms are not fully elucidated. Both antitoxic and regulatory effects on the intestinal barrier, mediated either by the yeast or yeast-derived substrates, have been discussed. Methods: To examine the effects of Saccharomyces boulardii released substrates (S.b.S) on gastrointestinal (GI) barrier function, a murine small intestinal organoid cell model under stress was used. Stress was induced by lipopolysaccharide (LPS) exposure or withdrawal of growth factors from cell culture medium (GF_Red). Stressed organoids were treated with S.b.S (200 µg/mL), and markers of GI barrier and inflammatory response were assessed. Results: GF_Red-induced stress was characterized by disturbances in selected tight junction (TJ) (p < 0.05), adherent junction (AJ) (p < 0.001), and mucin (Muc) formation (p < 0.01), measured by gene expressions, whereby additional S.b.S treatment was found to reverse these effects by increasing Muc2 (from 0.22 to 0.97-fold change, p < 0.05), Occludin (Ocln) (from 0.37 to 3.5-fold change, p < 0.0001), and Claudin (Cldn)7 expression (from 0.13 ± 0.066-fold change, p < 0.05) and by decreasing Muc1, Cldn2, Cldn5, and junctional adhesion molecule A (JAM-A) expression (all p < 0.01). Further, S.b.S normalized expression of nucleotide binding oligomerization domain (Nod)2- (from 44.5 to 0.51, p < 0.0001) and matrix metalloproteinase (Mmp)7-dependent activation (from 28.3 to 0.02875 ± 0.0044 ** p < 0.01) of antimicrobial peptide defense and reduced the expression of several inflammatory markers, such as myeloid differentiation primary response 88 (Myd88) (p < 0.01), tumor necrosis factor α (Tnfα) (p < 0.01), interleukin (IL)-6 (p < 0.01), and IL-1β (p < 0.001). Conclusions: Our data provide new insights into the molecular mechanisms by which Saccharomyces boulardii CNCM I-745-derived secretome attenuates inflammatory responses and restores GI barrier function in small intestinal organoids. Full article

Ischemic stroke is a primary cause of cerebrovascular diseases and continues to be one of the leading causes of death and disability among patients worldwide. Pathological processes caused by vascular damage due to stroke occur in a time-dependent manner and are classified into three categories: acute, subacute, and chronic. Current treatments for ischemic stroke are limited to effectiveness in the early stages. In this study, we investigated the therapeutic effect of an oriental medicine, Gosha-jinki-gan (TJ107), on improving chronic ischemic stroke using the mouse model with middle cerebral artery occlusion (MCAO). The changes in the intracerebral inflammatory response (macrophages (F4/80), TLR2•4, IL-23, IL-17, TNF-α, and IL-1β) were examined using real-time RT-PCR. The MCAO mice showed the increased expression of glial fibrillary acidic protein (GFAP) and of F4/80, TLR2, TLR4, IL-1β, TNF-α, and IL-17 in the brain tissue from the MCAO region. This suggests that they contribute to the expansion of the ischemic stroke infarct area and to the worsening of the neurological symptoms of the MCAO mice in the chronic phase. On the other hand, the administration of TJ107 was proven to reduce the infarct area, with decreased GFAP expression, suppressed macrophage infiltration in the brain, and reduced TNF-α, IL-1β, and IL-17 production compared with the MCAO mice. This study first demonstrated Gosha-jinki-gan’s therapeutic effects on the chronic ischemic stroke. Full article

The two-spotted spider mite, Tetranychus urticae, is one of the polyphagous pests of several crops and forestry, resistant to numerous conventional chemicals. Due to the negative side effects of harmful chemical pesticides, such as environmental pollution, and risks to human health, the introduction of effective and low-risk alternatives is essential. The promising pesticidal effects of essential oils (EOs) isolated from Artemisia annua have been documented in recent studies. In the present study, the acaricidal effects of an A. annua EO, along with its two dominant monoterpenoids, 1,8-cineole and camphor, were investigated against adults of T. urticae. Artemisia annua EO, 1,8-cineole, and camphor, with 24 h-LC₅₀ values of 0.289, 0.533, and 0.64 µL/L air, respectively, had significant toxicity by fumigation against T. urticae adults. Along with lethality, A. annua EO and monoterpenoids had significant inhibitory effects on the activity of detoxifying enzymes, including α- and β-esterases, glutathione S-transferases, and cytochrome P-450 monooxygenase. According to the findings of the present study, A. annua EO and its two dominant monoterpenoids, 1,8-cineole and camphor, with significant toxicity and inhibitory effects on detoxifying enzymes, can be introduced as available, effective, and eco-friendly acaricides in the management of T. urticae. Full article

Background/Objectives: Breast cancer was the leading cause of malignant tumors among women in 2022. About two-thirds of breast cancer cases are hormone-receptor-positive. In these patients, aromatase inhibitors are a mainstay of treatment, but associated musculoskeletal symptoms can negatively affect patient compliance. Aromatase-inhibitor-induced carpal tunnel syndrome represents one of the main causes of aromatase inhibitor discontinuation, with a non-compliance rate of up to 67%, potentially leading to increased cancer mortality. This study investigates estrogen receptor expression in aromatase-inhibitor-induced carpal tunnel syndrome tissues, in order to better define its etiopathogenesis and derive preventive or therapeutic measures that can improve aromatase inhibitor patient compliance. To our knowledge, there is no study on this subject in the literature. Methods: Between 2023 and 2024, we recruited 14 patients at the Jewish Hospital of Rome, including seven patients with aromatase-inhibitor-induced carpal tunnel syndrome (study group) and seven with postmenopausal idiopathic carpal tunnel syndrome (control group). Each patient was evaluated based on a clinical visit, a questionnaire, instrumental exams, and serum hormone dosages and were treated with open carpal tunnel release surgery, during which transverse carpal ligament and flexor tenosynovium samples were collected. For immunohistochemical experiments, sections were treated with anti-estrogen receptor α and anti-estrogen receptor β antibodies. Results: The immunohistochemical features in the study and control groups were similar, demonstrating that tissues affected by aromatase-inhibitor-induced carpal tunnel syndrome are targets of direct estrogen action and that estrogen deprivation is correlated with disease etiogenesis. Surgery was effective in patient treatment. Conclusions: Aromatase-inhibitor-induced carpal tunnel syndrome represents a newly defined form of the disease. This syndrome represents one of the main causes of aromatase inhibitor discontinuation, due to its negative impact on the patient’s quality of life. The identification by clinicians of aromatase inhibitor use as a possible risk factor for carpal tunnel syndrome development is of essential importance, as early diagnosis and prompt management can improve patient compliance and overall breast cancer treatment outcomes. Full article

The green renovation of existing residential buildings is a key way for the construction industry to achieve sustainable development and the dual carbon goals of China, which makes it urgent to make collaborative decisions among multiple stakeholders. However, because of divergent interests and risk perceptions among governments, energy service companies (ESCOs), and owners, the implementation of green renovation is hindered by numerous obstacles. In this study, we integrated prospect theory and evolutionary game theory by incorporating core prospect-theory parameters such as loss aversion and perceived value sensitivity, and developed a psychologically informed tripartite evolutionary game model. The objective was to provide a theoretical foundation and analytical framework for collaborative governance among stakeholders. Numerical simulations were conducted to validate the model’s effectiveness and explore how government regulation intensity, subsidy policies, market competition, and individual psychological factors influence the system’s evolutionary dynamics. The findings indicate that (1) government regulation and subsidy policies play central guiding roles in the early stages of green renovation, but the effectiveness has clear limitations; (2) ESCOs are most sensitive to policy incentives and market competition, and moderately increasing their risk costs can effectively deter opportunistic behavior associated with low-quality renovation; (3) owners’ willingness to participate is primarily influenced by expected returns and perceived renovation risks, while economic incentives alone have limited impact; and (4) the evolutionary outcomes are highly sensitive to parameters from prospect theory, The system’s evolutionary outcomes are highly sensitive to prospect theory parameters. High levels of loss aversion (λ) and loss sensitivity (β) tend to drive the system into a suboptimal equilibrium characterized by insufficient demand, while high gain sensitivity (α) serves as a key driving force for the system’s evolution toward the ideal equilibrium. This study offers theoretical support for optimizing green renovation policies for existing residential buildings in China and provides practical recommendations for improving market competition mechanisms, thereby promoting the healthy development of the green renovation market. Full article

Ultrafine bubbles (UFBs) represent an emerging technology with unique physicochemical properties. This study investigated the effects of air-filled UFBs infused in drinking water on gut microbiota composition and the associated health markers in Sprague Dawley rats over a 12-week period. Using a two-phase design, UFB concentration was increased from 1.7 × 10⁶ to 6.5 × 10⁹ UFBs/mL at week 7 to assess dose-dependent effects. Administration of UFBs in drinking water induced significant shifts in gut microbiome populations, characterized by increased Bacteroidetes (+122% weeks 8–12) and decreased Firmicutes (−43% weeks 8–12) compared to controls. These microbial shifts coincided with enhanced short-chain fatty acid production (butyrate +56.0%, p ≤ 0.001; valerate +63.1%, p ≤ 0.01) and reduced inflammatory markers (TNF-α −84.0%, p ≤ 0.05; IL-1β −41.0%, p ≤ 0.05; IL-10 −69.8%, p ≤ 0.05). UFB effects demonstrated systematic concentration-dependent threshold responses, with 85.7% of parameters exhibiting directional reversals between low (1.7 × 10⁶ UFBs/mL) and high (6.5 × 10⁹ UFBs/mL) concentration phases rather than linear dose–response relationships. The systematic nature of these threshold effects, with 71.4% of parameters achieving statistical significance (p ≤ 0.05), indicates concentration-dependent biological mechanisms rather than random effects on gut biology. Despite current metagenomic techniques identifying only 25% of the total gut microbiome, the observed changes in characterized species and metabolites demonstrate UFB technology’s therapeutic potential for conditions requiring microbiome modulation, providing new insights into UFB influence on complex biological systems. Full article

Skeletal muscle development is a critical economic trait in livestock, governed by myogenic satellite cell regulation. Integrins mediate mechanical anchorage to the ECM and enable ECM–intracellular signaling. CIB2, as an EF-hand-domain protein involved in mechanotransduction, shows significant developmental regulation in goat muscle. Although the role of CIB2 in skeletal muscle growth is poorly characterized, we observed pronounced developmental upregulation of IB2 in postnatal goat muscle. CIB2 expression increased >20-fold by postnatal day 90 (P90) compared to P1, sustaining elevation through P180 (p < 0.05). Functional investigations indicated that siRNA-mediated knockdown of CIB2 could inhibit myoblast proliferation by inducing S-phase arrest (p < 0.05) and downregulating the expression of CDK4/Cyclin D/E. Simultaneously, CIB2 interference treatment was found to decrease the proliferative activity of goat myogenic satellite cells, yet it significantly promoted differentiation by upregulating the expression of MyoD/MyoG/MyHC (p < 0.01). Mechanistically, CTCF was identified as a transcriptional repressor binding to an intragenic region of the CIB2 gene locus (ChIP enrichment: 2.3-fold, p < 0.05). Knockdown of CTCF induced upregulation of CIB2 (p < 0.05). RNA-seq analysis established CIB2 as a calcium signaling hub: its interference activated IL-17/TNF and complement cascades, while overexpression suppressed focal adhesion/ECM–receptor interactions and enriched neuroendocrine pathways. Collectively, this study identifies the CTCF-CIB2–integrin α7β1–PI3K/AKT axis as a novel molecular mechanism that regulates the balance of myogenic fate in goats. These findings offer promising targets for genomic selection and precision breeding strategies aimed at enhancing muscle productivity in ruminants. Full article

Background: Autism spectrum disorder (ASD) represents a neurobiological disorder with a high prevalence in the children’s population. The aim of the present review was to assess the current evidence on the use of salivary biomarkers for the early diagnosis of ASD. Materials and methods: A search was conducted on the electronic databases PUBMED/Medline, Google Scholar and Scopus for the retrieval of articles concerning the study topic. Results: A total of 22 studies have been included in the present review considering 21 articles identified from databases and 1 article included using a manual search. A wide range of biomarkers have been proposed for early detection of ASD diseases including nonspecific inflammation markers like interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor α (TNFα), oxidative stress markers like superoxide dismutase and glutathione peroxidase, hormones such as cortisol and oxytocin, various microRNAs including miR-21, miR-132 and miR-137, and exosomes. The techniques used for biomarke detection may vary according to molecule type and concentration. Conclusions: salivary biomarkers could represent a potential useful tool for the primary detection of several systemic diseases including ASD, taking advantage of non-invasiveness and cost-effective capability compared to other biofluid-based diagnostic techniques. Full article

Treatment-resistant depression (TRD) is associated with immune dysregulation. Ketamine, a rapid-acting antidepressant, may exert effects via immunomodulation. The aim was to examine ketamine’s impact on immune markers in TRD, including T-cell subsets, cytokines, and in vitro T-cell responses. Eighteen TRD inpatients received 0.5 mg/kg iv ketamine. Blood was sampled at baseline, 4 h, and 24 h to analyze T-cell phenotypes (CD28, CD69, CD25, CD95, HLA-DR) and serum cytokines (IL-6, IL-8, IL-10, TNF-α, IL-1β, IL-12p70). In vitro, PBMCs from TRD patients and controls were exposed to low (185 ng/mL) and high (300 ng/mL) ketamine doses. Ketamine induced a transient increase in total T cells and CD4⁺CD25⁺ and CD4⁺CD28⁺ subsets at 4 h, followed by a reduction in CD4⁺ and an increase in CD8⁺ T cells at 24 h, decreasing the CD4⁺/CD8⁺ ratio. Activation markers (CD4⁺CD69⁺, CD4⁺HLA-DR⁺, CD8⁺CD25⁺, CD8⁺HLA-DR⁺) declined at 24 h. Serum IL-10 increased, IL-6 decreased, and IL-8 levels—initially elevated—showed a sustained reduction. In vitro, high-dose ketamine enhanced the proliferation of TRD CD4⁺ T cells and dose-dependent IL-8 and IL-6 secretion from activated cells. Ketamine induces rapid, transient immune changes in TRD, including reduced T-cell activation and cytokine modulation. A sustained IL-8 decrease suggests anti-inflammatory effects and potential as a treatment-response biomarker. Full article

The matrix metalloproteinase (MMP) family includes several membrane-bound enzymes. Membrane-type 5 matrix metalloproteinase (MT5-MMP) is unique amongst the MMP family in being primarily expressed in the brain and during development. It is proposed to contribute to synaptic plasticity and is implicated in several pathologies, including multiple cancers and Alzheimer’s disease. In cancer, MT5-MMP expression has been correlated to cancer progression, but a distinct mechanistic role has yet to be uncovered. In Alzheimer’s disease, MT5-MMP exhibits pro-amyloidogenic activity, functioning as an η-secretase that cleaves amyloid precursor protein (APP), ultimately generating two synaptotoxic fragments, Aη-α and Aη-β. Several intracellular binding partners for MT5-MMP have been identified, and of these, N4BP2L1, EIG121, BIN1, or TMX3 binding to MT5-MMP results in a significant increase in MT5-MMP η-secretase activity. Beyond direct effects on APP, MT5-MMP may also facilitate APP trafficking to endosomal/lysosomal compartments and enhance proinflammatory responses. Overall, the substrate profile of MT5-MMP has not been well defined, and selective inhibitors of MT5-MMP have not been described. These advances will be needed for further consideration of MT5-MMP as a therapeutic target in Alzheimer’s disease and other pathologies. Full article

Background/Objectives: Celiac disease (CD) is an autoimmune disorder characterized by small intestinal enteropathy triggered by gluten ingestion, often associated with gut dysbiosis. The most effective treatment is strict adherence to a gluten-free diet (GFD), which alleviates symptoms. This study uniquely integrates taxonomic, functional, and resistance profiling to evaluate the gut microbiota of women with CD on a GFD. Methods: To evaluate the long-term impact of a GFD, this study analyzed the gut microbiota of 10 women with CD on a GFD for over a year compared to 10 healthy controls with unrestricted diets. Taxonomic diversity (16S rRNA gene sequencing and the analysis of α and β-diversity), metabolic functionality (Biolog EcoPlates^®), and antibiotic resistance profiles (Cenoantibiogram) were assessed. Results: Metagenomic analysis revealed no significant differences in taxonomic diversity but highlighted variations in the abundance of specific bacterial genera. Women with CD showed increased proportions of Bacteroides, Streptococcus, and Clostridium, associated with inflammation, but also elevated levels of beneficial genera such as Roseburia, Oxalobacter, and Paraprevotella. Despite no significant differences in metabolic diversity, higher minimum inhibitory concentrations (MICs) in women in the healthy control group suggest that dietary substrates in unrestricted diets may promote the proliferation of fast-growing bacteria capable of rapidly developing and disseminating antibiotic resistance mechanisms. Conclusions: These findings indicate that prolonged adherence to a GFD in CD supports remission of gut dysbiosis, enhances microbiota functionality, and may reduce the risk of antibiotic resistance, emphasizing the importance of dietary management in CD. Full article

Class D β-lactamases (DBLs) represent a major threat to antibiotic efficacy by hydrolyzing β-lactam drugs, including last-resort carbapenems, thereby driving antimicrobial resistance in Gram-negative bacteria. The enzymes share a structurally conserved two-domain α/β architecture with seven active-site motifs and three flexible extended loops (the P-loop, Ω-loop, and newly designated B-loop) that surround the active site. While each of these loops is known to influence enzyme function, their coordinated roles have not been fully elucidated. To investigate the significance of their interplay, we compared the sequences and crystal structures of 40 DBLs from clinically relevant Gram-negative pathogens and performed molecular dynamics simulations on selected representatives. Combined structural and dynamical analyses revealed a strong correlation between B-loop architecture and carbapenemase activity in the pathogens Klebsiella and Acinetobacter, particularly regarding loop length and spatial organization. These findings emphasize the B-loop’s critical contribution, in concert with the P- and Ω-loops, in tuning active site versatility, substrate recognition, catalytic activity, and structural stability. A deeper understanding of how these motifs and loops govern DBL function may inform the development of novel antibiotics and inhibitors targeting this class of enzymes. Full article

Mycoplasma bovis is an important pathogen that is associated with respiratory diseases, mastitis, and arthritis in cattle, leading to significant economic losses in the global cattle industry. Most notably in this study, we pioneer the discovery that its secreted effector ENO1 (α-enolase) directly targets host cytoskeletal proteins for metabolic–immune regulation. Using an innovative GST pull-down/mass spectrometry approach, we made the seminal discovery of β-actin (ACTB) as the primary host target of ENO1—the first reported bacterial effector–cytoskeleton interaction mediating metabolic reprogramming. ENO1–ACTB binding depends on a hydrogen bond network involving ACTB’s 117Glu and 372Arg residues. This interaction triggers (1) glycolytic activation via Glut1 upregulation, establishing Warburg effect characteristics (lactic acid accumulation/ATP inhibition), and (2) ROS-mediated activation of dual inflammatory axes (HIF-1α/IL-1β and IL-6/TNF-α). This work establishes three groundbreaking concepts: (1) the first evidence of a pathogen effector hijacking host ACTB for metabolic manipulation, (2) a novel ‘glycolysis–ACTB–ROS-inflammation’ axis, and (3) the first demonstration of bacterial proteins coordinating a Warburg effect with cytokine storms. These findings provide new targets for anti-infection therapies against Mycoplasma bovis. Full article

The study investigates the influence of microstructures on fatigue behavior and failure mechanisms of the α-β titanium alloy Ti6246, fabricated via Powder Bed Fusion-Laser Beam (PBF-LB). In particular, the investigation assesses the effect of two post-processing heat treatments, namely α-β annealing at 875 °C (AN875) and solution treatment at 825 °C followed by aging at 500 °C (STA825), on the alloy’s rotating and bending fatigue behavior. The results indicate that the STA825 condition provides superior fatigue resistance (+25%) compared to AN875, due to the presence of a finer bilamellar microstructure, characterized by thinner primary α lamellae (α_p) and a more homogeneous distribution of secondary α lamellae (α_s) within the β matrix. Additionally, an investigation conducted using the Kitagawa–Takahashi (KT) approach and the El-Haddad model, based on the relationship between the fatigue limit and defect sensitivity, revealed improved crack propagation resistance from pre-existing defects (ΔK_th) for the STA825 condition compared to AN875. Notably, the presence of fine α_s after aging for STA825 is effective in delaying crack nucleation and propagation at early stages, while refined α_p contributes to hindering macrocrack growth. The fatigue behavior of the STA825-treated Ti6246 alloy was even superior to that of the PBF-LB-processed Ti64, representing a viable alternative for the production of high-performance components in the automotive and aerospace sectors. Full article

Inherited epidermolysis bullosa (EB) is a heterogeneous clinical entity that includes over 30 phenotypically and/or genotypically distinct inherited disorders, characterized by mechanical skin fragility and bullae formation. Junctional EB (JEB) is an autosomal recessive disease characterized by an intermediated cleavage level within the skin layers, commonly at the “lamina lucida”. Laryngo-onycho-cutaneous syndrome (LOC) is an extremely rare variant of JEB, characterized by granulation tissue formation in specific body sites (skin, larynx, and nails). Although most cases of JEB are caused by pathogenic variants occurring in the genes encoding for classical components of the lamina lucida, such as laminin 332 (LAMA3, LAMB3, LAMC2), integrin α6β4 (ITGA6, ITGB4), and collagen XVII (COL17A1), other variants have also been described. We report the case of a 4-month-old male infant who presented with recurrent bullous and erosive lesions from the first month of life. At the first dermatological evaluation, the patient was agitated and exhibited hoarse breathing, a clinical sign suggestive of laryngeal involvement. Multiple polygonal skin erosions were observed on the cheeks, along with similar isolated, roundish lesions on the scalp and legs. Notably, nail dystrophy and near-complete anonychia were evident on the left first and fifth toes. Due to the coexistence of skin erosions and nail dystrophy in such a young infant, a congenital bullous disorder was suspected, prompting molecular analysis of all potentially involved genes. In the patient’s DNA, clinical exome sequencing (CES) identified a pathogenic variant, apparently in homozygosity, in the exon 1 of the LAMA3 gene (18q11.2; NM_000227.6): c.47G > A;p.Trp16*. The presence of this variant was confirmed, in heterozygosity, in the genomic DNA of the patient’s mother, while it was absent in the father’s DNA. Subsequently, trio-based SNP array analysis was performed, revealing a paternally derived pathogenic microdeletion encompassing the LAMA3 locus (18q11.2). To our knowledge, this is the first reported case of JEB with a LOC-like phenotype caused by a maternally inherited monoallelic nonsense mutation in LAMA3, unmasked by an almost complete deletion of the paternal allele. The combined use of exome sequencing and SNP array is proving essential for elucidating autosomal recessive diseases with a discordant segregation. This is pivotal for providing accurate genetic counseling to parents regarding future pregnancies. Full article