Search Results (18,868)

Acute inflammatory challenge can impair intestinal barrier function and bile acid homeostasis in weaned piglets. Glutamate serves as an important energy substrate and functional amino acid for intestinal epithelial cells, yet the epitranscriptomic mechanisms underlying its potential protective effects remain poorly defined. This study investigated whether dietary glutamate supplementation is associated with m⁶A-dependent regulation of SLC10A2 and bile acid signaling in weaned piglets subjected to an acute LPS challenge, with supporting validation in IPEC-J2 cells. LPS challenge (100 μg/kg body weight) impaired ileal morphological structure, activated the TLR4/NF-κB signaling pathway, and aggravated intestinal inflammatory responses in piglets. In contrast, glutamate supplementation was associated with restored ileal mucosal morphology, up-regulated expression of intestinal tight junction proteins, and suppressed TLR4/NF-κB pathway activation. Further metabolomic analysis indicated that LPS stimulation and glutamate intervention altered ileal bile acid metabolism: LPS decreased total bile acid (TBA) content in ileal tissue while increasing TBA accumulation in ileal chyme, whereas glutamate treatment partially reversed this pattern, by elevating ileal tissue TBA and reducing chyme TBA, suggesting a facilitatory effect of glutamate on intestinal bile acid reabsorption. Glutamate supplementation was also associated with increased ileal ASBT (SLC10A2) and FXR (NR1H4) expression. The SLC10A2 transcript exhibited detectable m⁶A modification; glutamate supplementation rescued the LPS-induced downregulation of m⁶A demethylases FTO and ALKBH5, which was associated with reduced global and SLC10A2-specific m⁶A modification. In vitro experiments in IPEC-J2 cells suggested that inhibition of FTO or glutamate dehydrogenase attenuated the effects of glutamate on m⁶A modification and SLC10A2 expression, and that YTHDF2 may contribute to the degradation of hyper-m⁶A-modified SLC10A2 mRNA. Glutamate-derived α-KG may serve as a cofactor supporting demethylase expression and activity after LPS stimulation. Collectively, these findings suggest that glutamate may alleviate LPS-induced intestinal inflammation in weaned piglets through a pathway involving α-KG-dependent maintenance of m⁶A demethylase expression, reduced m⁶A modification of SLC10A2, and preserved ASBT/FXR signaling. This study provides evidence for a nutritional–epitranscriptomic axis that may contribute to intestinal protection under acute inflammatory stress. Full article

Recent years have seen growing medical interest in the influence of crosstalk between the gut microbiota and the endocannabinoidome (eCBome) on inflammation and pain modulation. Growing evidence indicates that gut microbiota can modify the effects of several marketed drugs, including analgesics. Cannabigerol (CBG) is an overlooked phytocannabinoid with a broad pharmacological spectrum and no psychotropic effects, which has anti-inflammatory and antinociceptive properties. This review aims to provide a comprehensive exploration of CBG and its role at the intersection of gut microbiota and eCBome, detailing the pharmacological mechanisms by which it acts as a promising therapeutic agent to modulate chronic inflammation and pain. Our data review suggests that CBG could act on the eCBome by activating CB2, PPARs, TRPV1, TRPA1, and α2-adrenergic receptors, while suppressing cellular and molecular mechanisms of inflammation, such as TNFα, COX-2, iNOS, IL-1β, and IL-6, and increasing antioxidant factors. These receptors and enzymes are distributed across neurons, glial, immune, and epithelial cells, which can also positively modulate gut microbiota and its metabolites, producing neurotransmitters, cytokines, and enzymes that regulate eCBome tone, and generating cannabinoid-mimetic compounds as part of pleiotropic functions. Nevertheless, CBG may exert direct effects on gut microbiota, promoting eubiosis and symbiotic bacteria. Moreover, there are no specific preclinical assays that demonstrate how CBG modulates the bidirectional communication between the gut microbiota and eCBome, addressing the specific mechanism involved in eCBome activation, and determining whether its anti-inflammatory and analgesic effects are dependent on gut microbiota type. Therefore, studies are required to evaluate this hypothesis to achieve translational medicine impact. Full article

(1) Background/Objective: Routine blood tests may provide useful information at different stages of epithelial ovarian cancer (EOC) management. This study evaluated continuous lactate dehydrogenase (LDH), carbohydrate antigen 125 (CA125), and neutrophil-to-lymphocyte ratio (NLR) values for diagnostic discrimination in epithelial ovarian cancer (EOC) and, separately, triple-positive status in relation to platinum resistance and survival. (2) Methods: This retrospective study included 238 patients with EOC and 238 individually matched patients with benign ovarian lesions. Continuous biomarkers were entered into logistic regression models for diagnosis. Triple-positive status was defined as LDH > 195.5 U/L, CA125 > 35.37 U/mL, and NLR > 2.63. Logistic regression was used for platinum resistance and Cox regression for progression-free survival (PFS) and overall survival (OS). Bootstrap internal validation was performed for the diagnostic models and PFS nomogram. (3) Results: The continuous LDH + CA125 + NLR model yielded an AUC of 0.873, with 75.97% sensitivity and 88.66% specificity; AUCs were 0.751 in early-stage and 0.958 in advanced-stage EOC. Adding NLR to LDH + CA125 did not significantly improve the AUC overall or within stage groups. Triple-positive status was associated with platinum resistance (adjusted OR = 3.488, 95% CI 1.504–8.087; p = 0.004), shorter PFS (adjusted HR = 3.109, 95% CI 1.772–5.456; p < 0.001), and shorter OS in advanced-stage EOC (adjusted HR = 3.538, 95% CI 1.385–9.038; p = 0.008). The PFS nomogram had a bootstrap-corrected C-index of 0.7521. (4) Conclusions: The continuous three-marker model showed diagnostic discrimination in this selected surgical cohort, while triple-positive status was associated with platinum resistance and adverse survival outcomes. External validation is needed. Full article

Short bowel syndrome is a rare and clinically heterogeneous condition resulting from extensive intestinal resections or functional impairment, leading to malabsorption, fluid and electrolyte losses, and potential progression to intestinal failure requiring long-term parenteral nutrition. The long-term outcome of SBS is largely determined by intestinal adaptation, a progressive physiological response involving epithelial remodeling, intestinal stem cell expansion, lineage-specific proliferation, vascular remodeling, and the activity of trophic mediators—most notably glucagon-like peptide-2 (GLP-2)—whose clinical relevance is exemplified by teduglutide. Despite significant therapeutic advances, the mechanisms underlying adaptation remain incompletely understood, and preclinical models are essential tools for addressing this gap. In vitro systems—including Caco-2 epithelial cultures, intestinal organoids and enteroids, and tissue-engineered intestinal constructs—enable pathway-specific mechanistic investigation and hold promise as regenerative platforms. Murine surgical models of small bowel resection and ileocecal resection provide an integrated in vivo context for dissecting cellular and molecular mechanisms of adaptation. Large animal models, particularly minipig platforms, offer anatomical and physiological proximity to humans required for translational and therapeutic evaluation. In this narrative review, we provide an updated overview of these preclinical systems, critically examining their respective strengths, limitations, and translational relevance to advance the understanding of intestinal adaptation and inform the development of more effective therapeutic strategies for SBS (graphical abstract). Full article

Background/Objectives: Prostate cancer remains a major cause of cancer-related mortality in men. Arctigenin (ATG) and curcumin (CUR) exhibit anticancer activity; however, their combined effects on redox and metabolic stress remain incompletely understood. This study investigated the anticancer effects of combined ATG and CUR treatment in prostate cancer cells. Methods: PC-3 prostate cancer cells and normal human prostate epithelial (HPrEC) cells were treated with ATG and CUR alone or in combination. Cell viability, combination index, reactive oxygen species (ROS), GSH/GSSG ratio, ATP levels, AMPK phosphorylation, and apoptosis-related responses were evaluated. The contribution of oxidative stress was examined using N-acetyl-L-cysteine (NAC), and treatment effects were further assessed in three-dimensional (3D) spheroids. Results: Combined ATG and CUR treatment produced greater growth-inhibitory and apoptotic responses in PC-3 cells than in HPrEC cells and was synergistic under the tested condition in PC-3 cells. The combination increased ROS, reduced the GSH/GSSG ratio and ATP levels, increased AMPK phosphorylation, and enhanced apoptosis-related responses. NAC attenuated ROS accumulation, partially restored cell viability and ATP levels, and reduced caspase-3/7 activity in PC-3 cells. In 3D PC-3 spheroids, NAC also partially restored viability and ATP levels and attenuated increases in cleaved caspase-3 and cleaved PARP. Conclusions: Combined ATG and CUR treatment induces redox and metabolic stress and enhanced apoptotic responses in PC-3 cells, with weaker effects in HPrEC cells. NAC rescue supports a functional contribution of oxidative stress. These findings support an association between ROS-related metabolic stress, AMPK phosphorylation, and apoptotic signaling, while precise causal relationships require further investigation. Full article

Antimicrobial resistance and biofilm-associated oral infections require multi-target therapeutic strategies beyond single-extract herbal testing. Using the L-optimal mixture design approach, we optimized a ternary combination of Thymus vulgaris, Moringa oleifera, and Echinacea purpurea ethanolic extracts against Candida albicans and Streptococcus mutans, then characterized the optimized blend’s phytochemistry, antimicrobial and antibiofilm efficacy, time–kill pharmacodynamics, antioxidant capacity, and cytotoxic safety. Through HPLC, apigenin, chlorogenic acid, resorcinol, and ferulic acid were identified as dominant constituents. The optimal blend (Run 14: T. vulgaris 0.331, M. oleifera 0.318, E. purpurea 0.352) achieved a fractional inhibitory concentration index of 0.50 against both organisms, maximum inhibition zones of 3.10 cm (C. albicans) and 4.10 cm (S. mutans), biofilm inhibition of up to 93.2 ± 2.1% for C. albicans and 78.4 ± 2.8% for S. mutans, and confirmed fungicidal and bactericidal activity within 48 and 24 h, respectively. DPPH scavenging ranged from 55.19 to 68.73%, and oral epithelial cells (OEC) viability exceeded 83% at 300 µg/mL. All assays included three independent biological replicates; statistical significance was defined as p < 0.05. These findings identify the T. vulgaris–M. oleifera–E. purpurea blend as a synergistic, multi-target antimicrobial candidate with a favorable preliminary safety profile, supporting further development and evaluation against clinical isolates for oral fungal and bacterial infections. Full article

Although the relevance of thymic epithelial cell–thymocyte interactions for thymus function has long been emphasised, the mechanisms that govern the biology of thymic epithelial cells (TECs) are not fully understood. In other epithelial tissues, erythropoietin-producing hepatocellular carcinoma (Eph) receptors and their ligands, the Eph receptor-interacting proteins (ephrins), have been demonstrated to be important regulators of epithelial homeostasis. Accordingly, we have studied the function of Eph/ephrin signalling in the organisation, phenotypes and function of mouse thymic epithelial cells, as well as its effects on T-cell differentiation, for over 20 years. This review provides a detailed description of these results, concluding that the absence of certain EphA/B receptors or ephrins B generates specific phenotypes that affect T-cell differentiation and immunological function in different ways. This suggests that the proper histological organisation of the epithelial thymic stroma is not essential for normal T-cell maturation, or that at least some aspects of the process are preserved. Full article

Sodium glucose cotransporter-2 inhibitors (SGLT2is) have rapidly evolved from glucose-lowering agents to multifaceted therapies with significant renoprotective and cardioprotective potential. Although originally developed to inhibit glucose reabsorption within the renal proximal tubule for the treatment of Type 2 diabetes mellitus (T2DM), growing evidence indicates that SGLT2is exert broad systemic actions extending beyond glycemic control. Among this drug class, dapagliflozin has emerged as a clinically important agent with pleiotropic effects involving renal hemodynamics, inflammatory signaling, mitochondrial function, fibrosis regulation, and cellular stress adaptation. This review outlines the historical progression from the discovery of phlorizin to the development of highly selective modern SGLT2 inhibitors while emphasizing mechanistic insights gained from experimental and clinical studies of dapagliflozin. In addition to the established effects on sodium–glucose transport, dapagliflozin modulates multiple epithelial transport proteins including NHE3, NaPi-2a, NCC, and NCX1, highlighting complex regulatory effects on sodium handling and tubular electrolyte transport. Emerging evidence further demonstrates that dapagliflozin suppresses inflammatory and profibrotic pathways involving YAP/TAZ, STAT1, TGF-β, NLRP3, and NF-KB signaling. Restoration of tubuloglomerular feedback, attenuation of oxidative stress, and preservation of mitochondrial function also appear to contribute substantially to the renoprotective actions of SGLT2 inhibition. Beyond the kidney, dapagliflozin and related SGLT2is exert cardioprotective effects through coordinated improvements in cardiac energetics, inflammatory regulation, and hemodynamic function. Emerging studies additionally suggest potential pulmonary benefits, including reductions in inflammatory signaling, pulmonary edema, and respiratory complications. Collectively, these findings support a shift in understanding SGLT2is from targeted metabolic therapies to broader regulators of cellular and organ function. Continued investigation into the glucose-independent mechanisms of dapagliflozin may reveal additional therapeutic applications across chronic metabolic, cardiovascular, and inflammatory diseases. Full article

Asthma is a heterogeneous chronic airway disease in which eosinophilic inflammation represents a major type 2 endotype. The airway epithelium plays a central role in disease pathobiology by regulating barrier integrity, immune signaling, and tissue repair. In eosinophilic asthma, interactions between eosinophils and epithelial cells are associated with epithelial barrier disruption, altered differentiation, mucus hypersecretion, and airway remodeling. This review summarizes current evidence on the role of eosinophils in epithelial dysfunction and discusses biomarkers of epithelial injury, including epithelial-derived alarmins, chemokines, secretory proteins, and structural junctional markers. These biomarkers reflect different aspects of epithelial activation, injury, and repair and may contribute to improved characterization of disease mechanisms and inflammatory endotypes. The effects of biologic therapies targeting eosinophilic inflammation are also reviewed. While these treatments are associated with improved clinical outcomes and reduced eosinophil levels, available evidence indicates that epithelial alterations and remodeling processes may persist despite treatment. Overall, integrating epithelial biomarkers with clinical and inflammatory parameters may provide additional insight into disease activity and support more comprehensive assessment of asthma beyond conventional measures. Full article

Malignant tumors are the second major disease threatening human health, and their early diagnosis can significantly improve patients’ prognosis. [¹⁸F]FDG PET/CT is currently the most important method in nuclear medicine for tumor diagnosis and staging. However, due to variations in the glucose uptake characteristics of tumors, some tumors with low FDG uptake (e.g., gastric mucinous adenocarcinoma and indolent lymphoma) are prone to false-negative results. Therefore, new tumor-specific imaging tracers are urgently needed. Due to the significant differences in target expression among various tumor cells, the method of focusing on a single target is unlikely to work for all tumors. Therefore, researchers are exploring the possibility of targeting tumor-associated macrophages (TAMs) in the tumor microenvironment for imaging because this offers several advantages. First, unlike most tumors, which originate from epithelial cells, TAMs arise from monocyte–macrophage polarization, leading to greater target specificity on their surfaces. Second, TAMs are the most abundant non-tumor cells in the tumor microenvironment, ensuring a certain level of expression abundance. Furthermore, numerous preclinical studies and clinical trials targeting TAMs with immunotherapy are currently underway, making the non-invasive assessment of certain TAM targets’ expression levels a critical issue that needs to be addressed. This article summarizes the potential targets and nuclear medicine tracers for targeting TAMs. Full article

Background: The relationship between acute fibrinous and organizing pneumonia (AFOP) and organizing pneumonia (OP) remains debated, and direct comparative evidence is limited. We aimed to delineate their differences across clinical, radiological, histological, and immunophenotypic dimensions. Methods: We conducted a retrospective study of 85 consecutive patients with pathologically confirmed AFOP (n = 49) or OP (n = 36). Clinical data, radiological patterns, laboratory findings, and immunohistochemical profiles of alveolar epithelial, macrophage, lymphocyte, vascular, and mesenchymal markers were comprehensively compared. Results: The two groups were comparable in demographics, clinical symptoms, and dominant radiological patterns. However, median C-reactive protein (CRP; 80.45 vs. 12.65 mg/L, p < 0.001) and neutrophil-to-lymphocyte ratio (NLR; 4.56 vs. 2.42, p = 0.013) were higher in AFOP, with CRP demonstrating an apparent area under the curve (AUC) of 0.798 for discriminating AFOP from OP in this derivation cohort. After Benjamini–Hochberg correction for multiple comparisons, CD68 was significantly higher, and CD38 was significantly lower in AFOP than in OP. Trends were also observed for CD163, surfactant protein A (SP-A), and CD34, but these did not remain statistically significant after correction. All three deaths and all cases requiring mechanical ventilation occurred in the AFOP group, though these differences were not statistically significant. Conclusions: Despite clinical and radiological overlap, AFOP and OP exhibit distinct systemic inflammatory responses and pulmonary immunophenotypes, with AFOP characterized by macrophage-predominant inflammation and qualitatively fewer CD34+ microvessels within fibrin balls. These immunophenotypic findings are descriptive and require further validation. Full article

Olfactory dysfunction is an early non-cognitive feature of Alzheimer’s disease (AD), but smell impairment has traditionally been used mainly as a behavioral marker. This review examines the emerging use of the olfactory cleft as an accessible source of living neuronal, epithelial, progenitor, and immune cells for studying AD pathobiology. Histopathological and patient-derived culture studies have reported amyloid-β, tau, oxidative-stress, mitochondrial, biometal, and transcriptional abnormalities in olfactory tissue. More recent endoscopically guided brush sampling with single-cell profiling has identified activated memory CD8 T-cell states, inflammatory myeloid programs, and neuronal metabolic changes, including in cognitively unimpaired individuals with abnormal cerebrospinal-fluid amyloid biomarkers. These findings support olfactory-cleft sampling as a research platform for investigating early neural–immune changes, but current evidence is based on small, largely cross-sectional cohorts and does not establish disease specificity, causality, or prognostic utility. Longitudinal multicenter studies integrating olfactory-tissue profiling with established fluid, imaging, genetic, cognitive, and olfactory biomarkers are required before clinical translation. Full article

Alcohol consumption is associated with increased breast cancer risk, partly due to the accumulation of toxic aldehydes like acetaldehyde, a carcinogenic byproduct of ethanol metabolism. Acetaldehyde Dehydrogenase 2 (ALDH2), a key mitochondrial enzyme, detoxifies acetaldehyde and other reactive aldehydes that drive oxidative stress, DNA damage, and hormonal dysregulation—processes central to carcinogenesis. Although alcohol consumption has been implicated in breast cancer, the role of ALDH2 deficiency itself, in the absence of exogenous alcohol exposure, in mammary gland biology and cancer susceptibility remains unclear. Genetic variants that impair ALDH2 activity are highly prevalent in East Asian populations, where carriers of inactive ALDH2 alleles exhibit impaired aldehyde detoxification. While such individuals are more susceptible to alcohol-related cancers, the effects of ALDH2 deficiency on mammary gland development and homeostasis without alcohol exposure remain unexplored. To investigate the effects of ALDH2 deficiency on mammary proliferation and development, we utilized a C57BL/6-based ALDH2 knockout (Aldh2−/−) mouse model. Our findings revealed that Aldh2−/− mice displayed hyperproliferative mammary glands with increased epithelial cell density, ductal expansion, and increased numbers of Ki67+ cells. Flow cytometry analysis revealed expansion of luminal and basal epithelial subpopulations, accompanied by enhanced mammary epithelial stemness, as indicated by increased mammosphere formation and colony-forming efficiency. At the molecular level, ALDH2 deficiency activated oxidative stress pathways, reflected by elevated 8-OHdG, p38 MAPK, NF-κB, and Nrf2 signaling, along with DNA damage responses involving p53 and H2A.X. We also identified a novel upregulation of RANK and RANKL in Aldh2−/− mammary glands, identifying the RANK/RANKL upregulation associated with NF-κB/p38 MAPK activation and enhanced mammary stemness. Furthermore, hormonal dysregulation was observed, with a significant increase in ERα and PR expression and phosphorylation. Dysregulated ER signaling correlated with enhanced erbB3 activation and downstream signaling, including the cyclin D1–pRb-E2F1 axis. These findings suggest that ALDH2 deficiency, possibly through accumulated endogenous aldehydes, profoundly alters mammary morphogenesis, epithelial repopulation, and stemness. These effects are associated with activation of oxidative stress and DNA damage pathways, together with upregulation of RANKL, estrogen receptor and receptor tyrosine kinase signaling. This study is the first to identify ALDH2 deficiency as a novel factor associated with mammary epithelial alterations that may create a tissue state that could predispose to oncogenic transformation. Full article

Docosahexaenoic acid (DHA), an omega-3 fatty acid, has emerged as a promising adjuvant treatment for castration-resistant prostate cancer (CRPC), but its interactions with current therapies remain unclear. This study investigated the antitumor effects of DHA alone or in combination with enzalutamide (ENZ) or the PARP inhibitor AZD2461 (iP) in CRPC cell lines 22Rv1 and PC3. DHA enhanced the cytotoxic effect of iP in both cell lines and of ENZ in 22Rv1 cells. In PC3 cells, DHA-mediated potentiation of iP cytotoxicity was associated with downregulation of the AKT pathway, reduced expression of ERα and the lipid sensors PPARγ and LXRβ, and a shift in programmed cell death toward necroptosis. In 22Rv1 cells, the additive effects of DHA with ENZ or iP were independent of PI3K/pAKT and AR-FL/AR-V7 modulation but were associated with regulation of LXRβ, PPARγ, and TNFR1, along with activation of apoptosis. Wound-healing assays showed that DHA blocked the anti-migratory effects of ENZ and iP in 22Rv1 cells and did not alter iP effects in PC3 cells, indicating epithelial–mesenchymal transition heterogeneity. Overall, DHA potentiates the cytotoxic effects of iP in both models and of ENZ in 22Rv1 cells via differential modulation of cell death in a molecular context-dependent manner. Full article