Search Results (407)

Sepsis induces profound alterations in liver function that contribute to disease progression. We previously demonstrated that peritoneal sepsis is associated with marked disruption of hepatic transcriptional programs, including loss-of-function of Hepatocyte Nuclear Factor 4 alpha (HNF4α), a master regulator of hepatic identity and metabolism. Using hepatocyte-specific HNF4α knockout mice, we further showed that loss of HNF4α is detrimental during peritoneal sepsis. Here, we investigated whether this response is conserved in pneumonia-induced sepsis and assessed its functional significance. Bulk liver RNA sequencing revealed that suppression of hepatic metabolic pathways and HNF4α target genes are conserved features of both peritoneal and Streptococcus pneumoniae-induced sepsis. Unexpectedly, hepatocyte-specific HNF4α deficiency was associated with lower bacterial burden and increased survival during pneumococcal sepsis. Mechanistically, this protective effect was dependent on neutrophils and not macrophages. These findings demonstrate that sepsis-induced hepatic HNF4α dysregulation is conserved across distinct infectious etiologies but exerts context-dependent effects on disease outcome. Full article

The agri-food industry generates substantial amounts of waste, which are increasingly regarded as valuable resources within the framework of the circular economy. Among the recoverable bioactive molecules, phenolic compounds are of particular interest for nutraceutical and biomedical applications. Olive oil production by-products, such as olive oil dregs (OOD), represent a rich source of polyphenols, especially hydroxytyrosol (3,4-DHPEA). In this study, we investigated the in vitro biological properties of OOD extracts obtained through methanolic or eco-friendly aqueous extraction methods, both characterized by a high 3,4-DHPEA content. The antioxidant potential of the extracts was evaluated together with their activity in murine peritoneal macrophages, while their ability to counteract osteoclastogenesis was assessed using RAW 264.7 cells stimulated with receptor activator of nuclear factor kappa-B ligand (RANKL). Our results demonstrated that both extracts showed a total antioxidant effect and significantly reduced intracellular reactive oxygen species (ROS) levels. Notably, this antioxidant activity was accompanied by a marked inhibition of RANKL-induced osteoclast formation, as evidenced by a reduction in tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells together with fewer mature osteoclasts displaying well-structured F-actin rings and bone-resorbing activity as demonstrated by the pit formation assay. Taken together, these findings suggest that OOD extract, through its dual antioxidant and anti-osteoclastogenic properties, may represent a promising strategy for the prevention of inflammation-driven pathological bone loss. Full article

Background: Postoperative peritoneal adhesions arise from a dysregulated wound-healing response in which macrophages may have context-dependent effects. We investigated the contribution of macrophage-rich peritoneal and mesenteric compartments, the origin of macrophage-like cells in ischemic lesions, and the association between CCR2-dependent recruitment and postoperative inflammatory and reparative gene expression. Methods: Using a murine ischemic-button model, we assessed the effects of clodronate liposome treatment, bone marrow chimerism, and global CCR2 deficiency. Adhesion formation, F4/80+ cell accumulation, donor-marker expression, and selected inflammatory and wound-healing-associated transcripts were analyzed at predefined postoperative time points. Results: Clodronate liposome treatment was associated with reduced adhesion formation and substantial depletion of F4/80+ cells in peritoneal lavage and mesenteric tissue. However, F4/80+ cell numbers within ischemic buttons at postoperative day 3 were not significantly reduced, indicating that the depletion experiment does not establish selective depletion of all lesional macrophages. Bone marrow chimera experiments identified donor-marker-positive, F4/80+ cells within ischemic buttons, supporting recruitment of hematopoietic cells with a macrophage-like phenotype. CCR2 deficiency reduced F4/80+ cell accumulation in ischemic buttons and was associated with increased adhesion scores and altered expression of inflammatory and wound-healing-associated genes. These findings identify differential associations of clodronate-sensitive macrophage-rich compartments and CCR2-dependent hematopoietic recruitment with postoperative adhesion formation. Conclusions: Depletion of macrophage-rich peritoneal and mesenteric compartments was associated with reduced adhesion formation, whereas global CCR2 deficiency was associated with fewer lesional F4/80+ cells and greater adhesion severity. Because clodronate depletion, F4/80 staining, bone marrow chimerism, and global CCR2 deficiency do not provide cell-specific or fate-mapped resolution, these data do not establish distinct resident versus infiltrating macrophage functions or a reparative phenotype of CCR2-dependent cells. Cell-specific and temporally resolved validation is required to define the contributions and temporal relationships of individual macrophage subsets. Full article

Endometriosis is a chronic estrogen-dependent systemic inflammatory disorder characterized by ectopic implantation of endometrial-like tissue, primarily on the ovaries, pelvic peritoneum, and bowel. According to the World Health Organization (WHO) estimate updated in 2025, endometriosis affects approximately 10% (about 190 million) of reproductive-age women worldwide and is a major contributor to chronic pelvic pain, dysmenorrhea, dyspareunia, and infertility. Standard medical therapies focus on ovarian suppression, which alleviates symptoms but precludes conception and carries significant metabolic and skeletal adverse effects. Recent multi-omics research has raised interest in the gut microbiome and the estrobolome, defined as the microbial gene repertoire involved in estrogen metabolism, as potential modulators of systemic estrogen exposure and immune homeostasis. Altered microbiota composition and microbial β-glucuronidase activity may influence enterohepatic estrogen recirculation; however, endometriosis-specific evidence is predominantly associative or preclinical and does not establish a causal pathway. Dysbiosis and increased bacterial β-glucuronidase activity promote enterohepatic recirculation of estrogens, contributing to hyperestrogenism and ectopic lesion proliferation. Concurrently, oxidative stress, peritoneal inflammation, aberrant macrophage polarization, and neoangiogenesis sustain lesion survival and contribute to chronic pelvic pain. This comprehensive review synthesizes mechanistic, preclinical, and clinical evidence regarding microbiome-targeted interventions and nutritional compounds, including probiotics, prebiotics, N-acetyl cysteine (NAC), curcumin, resveratrol, epigallocatechin gallate (EGCG), omega-3 polyunsaturated fatty acids (PUFAs), and vitamin D, in modulating the estrobolome, immune responses, and oxidative microenvironment in endometriosis. We further discuss dietary patterns, bioavailability challenges, and the potential of precision nutrition to optimize reproductive outcomes. These approaches may be considered complementary or investigational adjuncts; current evidence is insufficient to demonstrate disease modification or improvements in spontaneous pregnancy, assisted reproductive technology (ART) outcomes, or live birth. Here, “fertility-sparing” denotes the absence of intentional ovulation suppression rather than proven fertility enhancement. Full article

The host cellular mechanisms determining whether Dirofilaria immitis (canine heartworm) larvae establish infection remain poorly understood. The Mongolian gerbil (Meriones unguiculatus), a naturally nonpermissive host, mounts a rapid macrophage-dominated peritoneal cellular response to intraperitoneal (IP) larval challenge. To test whether macrophages mediate larval clearance, peritoneal macrophages were selectively depleted with IP clodronate liposomes (100 µL/10 g body weight; days −4 and −1 relative to infection) before challenge with approximately 40 D. immitis third-stage larvae (L3). A rat anti-mouse anti-F4/80 antibody was validated as a cross-reactive macrophage marker in jird peritoneal exudate cells (PECs) by standard and imaging flow cytometry, and depletion efficacy was confirmed prior to infection. Significantly more L3 were recovered from macrophage-depleted jirds (mean = 17.7%; SEM = 6.0%) than from PBS liposome controls (mean = 3.8%; SEM = 1.9%) at 1-day post-infection (p < 0.03). Cytology and flow cytometry confirmed near-complete macrophage depletion, and a significant compensatory neutrophilia was observed in depleted animals (64.5% ± 5.7% vs. 19.6% ± 5.1% in controls; p < 0.0001). These findings establish peritoneal macrophages as the primary innate cellular mediators of D. immitis L3 clearance in a nonpermissive host, providing a validated in vivo framework for mechanistic dissection of filarial host specificity. Full article

Lactic acid bacteria (LAB) are regarded as promising probiotics with multiple beneficial properties for humans’ and animals’ health. In this study, ten LAB isolates were screened and Lactiplantibacillus plantarum (L. plantarum) CLPX21 was selected as a candidate strain with its probiotic potential based on in vitro screening of antimicrobial activity and environmental stress tolerance, including its resistance to acidic environments and bile salts. This strain displayed adhesion capacity with an auto-aggregation rate of 47.15% at 24 h, co-aggregation rates above 67% with pathogenic bacteria, and an ability to adhere to IPEC-J2 cells (6.37%). CLPX21 showed broad-spectrum antimicrobial activity against common foodborne pathogens including Escherichia coli (E. coli), Salmonella, and Staphylococcus aureus. In addition, CLPX21 inhibited E. coli biofilm formation. Furthermore, CLPX21 significantly suppressed E. coli-induced inflammatory cytokine production in mouse peritoneal macrophages. Importantly, CLPX21 did not exhibit hemolytic activity. Genomic analysis further revealed that the CLPX21 genome encoded multiple functional genes and gene clusters, including biosynthesis of bacteriocins and secondary metabolites associated with antimicrobial and antioxidant functions, which provide a genetic basis for its beneficial phenotypic characteristics. In conclusion, L. plantarum CLPX21 displays probiotic properties with potent antimicrobial and anti-inflammatory activities, representing a promising candidate strain for applications in the food and health industries. Full article

Endometriosis affects approximately 10% of women of reproductive age and is associated with infertility in up to half of those diagnosed. Despite decades of research, the molecular basis of its reproductive consequences remains poorly defined. Among the pathophysiological features most consistently documented in affected women, chronic oxidative stress within the peritoneal cavity has attracted sustained attention, yet its relationship to the extracellular vesicle biology that has emerged as central to endometriosis pathogenesis has never been systematically examined. Iron-catalyzed radical chemistry, macrophage-derived superoxide, and mitochondrial electron leak in ectopic stromal cells collectively sustain a peritoneal redox burden that modifies exosomal biogenesis, alters microRNA sorting, and reprograms vesicle lipid and protein cargo. Oxidatively conditioned exosomes skew peritoneal macrophages toward an immunosuppressive M2 phenotype through miR-301a-3p, miR-146a-5p, and miR-196a-5p, suppress natural killer cell cytotoxicity through NKG2D ligand decoy delivery, facilitate peritoneal dissemination and neuroangiogenesis, and compromise oocyte developmental competence through ferroptosis-derived vesicles carrying aberrant miR-122-5p, oxidized phosphatidylethanolamines, and damaged mitochondria. These mechanisms map directly onto the clinical deficits observed in women with endometriosis undergoing assisted reproduction, including reduced oocyte yield, lower fertilization rates, elevated embryo aneuploidy, and impaired implantation. Follicular and peritoneal fluid exosomal microRNA profiles represent promising non-invasive biomarkers, while combinatorial strategies targeting the iron-ROS-exosome axis offer a more coherent therapeutic framework than the single-antioxidant approaches that have so far shown limited benefit. Full article

Background/Objectives: Malignant ascites is characterized by extensive tumor dissemination within the peritoneal cavity, abnormal fluid accumulation, and progressive multiorgan dysfunction, including hepatic and renal impairment. Methods: The present study was conducted to evaluate the protective effects of resveratrol (RSV) and its nanocrystal formulation (NANO-RSV) at doses of 25 and 50 mg/kg against Ehrlich ascites tumor (EAT)-induced hepatic and renal injury by assessing proliferating cell nuclear antigen (PCNA) expression and apoptosis/necrosis rates, which are key indicators of tissue injury, repair, and regeneration. In addition, microvessel density (MVD) was evaluated in peritoneal tumor tissue, liver, and kidneys to assess angiogenesis and tissue remodeling, while macrophage polarization in the spleen was examined to determine the immunomodulatory effects of RSV and NANO-RSV. Results: Resveratrol and its nano formulations acted as potent inhibitors of EAT cells growth through downregulation of PCNA expression, leading to increased tumor cell death via apoptosis and secondary necrosis. In EAT-bearing mice, the hypoxic microenvironment was associated with increased PCNA expression, enhanced angiogenesis, and reduced apoptosis in hepatic tissue. In contrast, treatment with resveratrol and nano-resveratrol reduced PCNA expression, increased apoptotic activity, suppressed angiogenesis, and induced hepatic steatosis. Progression of steatosis, particularly in resveratrol-treated animals, was associated with impaired hepatic regenerative capacity. In the kidneys, elevated PCNA expression and increased cell death indicated active tissue injury accompanied by compensatory proliferative responses. Furthermore, increased splenic arginase-1 activity correlated with enhanced tissue damage and activation of M2 macrophage-mediated repair mechanisms. Conclusions: In conclusion, resveratrol exhibits significant antitumor activity but may induce organ toxicity, whereas its nanocrystals formulation demonstrates improved safety while maintaining efficacy. Enhanced stability, bioavailability, and sustained-release properties of nano-resveratrol contribute to reduced hepatic and renal injury compared with native resveratrol. Full article

Background: Endotoxemia is a severe inflammatory condition that is characterized by acute immune responses and oxidative stress; endotoxemia can further develop into a cytokine storm and sepsis leading to severe organ damage. Our recent studies revealed that the growth hormone secretagogue receptor (GHSR) regulates macrophage polarization in obesity- and aging-associated chronic inflammation. However, its role in acute inflammation during endotoxemia remains unclear. Methods: We subjected myeloid-specific Ghsr knockout mice (LysM-Cre;Ghsr^f/f) to lipopolysaccharide (LPS)-induced endotoxemia in vivo and treated bone marrow-derived macrophages (BMDMs) with LPS in vitro. Subsequently, mouse survival rate and inflammatory signatures in the blood, peritoneal cavity, liver, and BMDM were assessed. In the ex vivo study, conditioned medium (CM) from BMDMs was applied to primary hepatocytes to assess how BMDM-derived CM influences hepatocyte inflammatory responses. Results: Myeloid-specific Ghsr knockout mice exhibited a significantly improved survival rate following LPS-induced endotoxemia, accompanied by reduced systemic inflammation, evident in the blood, peritoneal macrophages, and liver. In addition, Ghsr deficiency suppressed LPS-induced caspase-1 activation and pro-inflammatory cytokine secretion in macrophages. Consistent with these results, conditioned media from Ghsr-deficient BMDMs attenuated the inflammatory responses of primary hepatocytes. Mechanistically, LPS increased GHSR expression in BMDMs, and Ghsr-deficient BMDMs activated mitochondrial respiration and suppressed production of mitochondrial reactive oxygen species (ROS), resulting in downregulation of inflammatory activation of macrophages following LPS exposure. Conclusions: These data demonstrate that macrophage GHSR promotes systemic and tissue inflammation during endotoxemia by regulating mitochondria-associated macrophage polarization. The findings suggest that macrophage GHSR may represent a promising immunomodulatory target for acute inflammatory states, including endotoxemia and sepsis. Full article

Excessive use of immunosuppressive agents compromises host immune defenses and broad-spectrum antimicrobial drugs disrupts the normal microbiota, thereby promoting the overgrowth and dissemination of Candida albicans. As an opportunistic pathogen that commonly resides in the intestinal microbiota, C. albicans can subsequently translocate across the intestinal barrier and cause intra-abdominal infections. To investigate this process, a murine model of peritoneal C. albicans infection was established, in which sodium new houttuyfonate was administered for therapeutic evaluation. The therapeutic potential of sodium new houttuyfonate against abdominal C. albicans infection was evaluated through assessment of immune cell composition, peritoneal macrophage polarization, tissue fungal burden, and histopathological features. The molecular mechanisms of sodium new houttuyfonate therapy were also investigated with cellular experiments, including colony counting, real-time quantitative PCR, Western blotting, and the detection of reactive oxygen species (ROS) in RAW264.7 macrophages. Our results revealed that sodium new houttuyfonate exerts a dual anti-infective effect through its fungicidal activity and via the immunomodulation of immunoinflammatory states. Sodium new houttuyfonate also stimulates cytokine production (e.g., IL-1β, IL-6, IL-10, TNF-α, and MCP-1) via the TLR2/p38/NF-κB pathway and promotes the release of ROS and nitric oxide. Overall, these findings highlight the potential of exogenous sodium new houttuyfonate as a therapeutic option for abdominal C. albicans infection. Full article

Background/Objectives: Peritoneal metastases (PMs) arise from gastrointestinal, gynecologic, hepatobiliary, and colorectal origins and are associated with poor outcomes. Cytoreductive surgery (CRS) with intraperitoneal (IP) chemotherapy offers benefit for select patients, but survival remains limited. This review aims to summarize recent insights into the molecular and tumor microenvironmental (TME) changes characteristic of PMs and the impact of IP chemotherapy. Methods: A literature review was performed using recent clinical, translational, and preclinical studies examining alterations in molecular signaling, DNA repair alterations, metabolic pathways, and angiogenic factors in PMs before and after IP therapy. Results: Peritoneal metastases exhibit distinct biology after being treated with IP chemotherapy. Treatment induces alterations in gene expression, mutational patterns, and immune infiltrates. Heated intraperitoneal chemotherapy (HIPEC) has been associated with increased CD8+ T-cell activity, macrophage and NK cell shifts, and modulation of PD-1/PD-L1 signaling, which correlate with treatment response and survival. Emerging data on PIPAC similarly suggests induction of favorable gene expression changes with repeated treatment, though supporting evidence remains more limited than for HIPEC. Angiogenic pathways—particularly VEGF and HIF1α—remain key drivers of PM progression and predictors of post-operative outcomes. Early findings suggest potential synergy between IP chemotherapy and immunotherapy though clinical trials are ongoing. Conclusions: IP chemotherapy induces tumor microenvironmental changes that have potential to shape therapeutic response. Characterizing these measurable biologic changes may allow clinicians to improve patient selection and support the development of combination therapies to enhance outcomes. Full article

For decades, peritoneal metastases (PM) have been regarded as a terminal manifestation of advanced malignancies and managed primarily with palliative intent because of limited sensitivity to systemic therapies. Accumulating clinical, molecular, and immunological evidence now supports the view that PM is not merely an anatomic pattern of spread but a distinct metastatic niche with characteristic biological, microenvironmental, and therapeutic features. This review summarizes the major routes of PM development—transcoelomic, lymphatic, and hematologic dissemination—and emphasizes how these pathways converge through shared biological programs. Core mechanisms include epithelial–mesenchymal transition (EMT), adhesion signaling, extracellular matrix remodeling, and tumor–immune cell interactions. A central focus is the peritoneal tumor microenvironment: mesothelial-to-mesenchymal transition, cancer-associated fibroblast activity, adipocyte-derived metabolic support, macrophage polarization, and regulatory T-cell enrichment collectively shape an immunotolerant and treatment-resistant niche on the peritoneal surface. In addition, evidence from pre-metastatic niche biology suggests that primary tumor-derived exosomes and epitranscriptomic regulation can prime the peritoneal environment before overt implantation. These features provide a biological rationale for locoregional strategies such as cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, as well as emerging intraperitoneal modalities and microenvironment-targeted approaches. Finally, organoid platforms, liquid biopsy-based minimal residual disease monitoring, and theranostic technologies may enable more personalized, biology-driven management of PM. Full article

Endometriosis is increasingly recognized as a chronic systemic disorder extending beyond the classical estrogen-dependent paradigm, integrating metabolic, immune, fibrotic, and nociceptive pathways that sustain lesion persistence and refractory pelvic pain. We propose a mechanistic, translational hypothesis in which tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, may modulate four interconnected pathological axes of refractory endometriosis—Warburg-type metabolic reprogramming with lactate accumulation, peritoneal immune dysfunction, NF-κB/NLRP3/TGF-β1-driven inflammatory–fibrotic remodeling, and persistent nociceptive sensitization—through three convergent molecular nodes: AMPK-associated signaling, GLP-1 receptor activity in peritoneal macrophages and spinal microglia, and the NF-κB/NLRP3/TGF-β1 axis. Particular emphasis is placed on the concept of “peritoneal incretin deficiency”, characterized by reduced peritoneal GLP-1 concentrations and increased expression of incretin-degrading proteases. This concept currently rests on a single, non-replicated case–control study, and the broader mechanistic chain is supported largely by indirect evidence extrapolated from adjacent inflammatory, metabolic, and neuroimmune disease models rather than by endometriosis-specific data. Direct experimental or clinical validation in endometriosis-specific models is currently absent. Accordingly, this article represents a hypothesis-generating framework rather than evidence of established efficacy, or a clinical treatment recommendation, intended to guide future mechanistic and prospective clinical investigation of incretin-based modulation as a potential adjunctive strategy in refractory endometriosis. Full article

Leishmaniasis is a neglected tropical disease caused by parasites of the genus Leishmania. Curcumin (CUR) is a polyphenol with several biological properties, including antimicrobial effects. However, its low bioavailability remains a challenge, and nanoencapsulation may represent a useful strategy to overcome this limitation. This study aimed to evaluate, in vitro, the antipromastigote activity of free CUR and the antiamastigote effect of CUR nanoparticles and their association with antimoniate, as well as to elucidate possible mechanisms of action. Free CUR directly inhibited promastigote proliferation, with an IC₅₀ of 25 µM at 24 h. CUR induced mitochondrial hyperpolarization, increased the production of reactive oxygen species (ROS) and nitric oxide (NO), and enhanced lipid peroxidation and the accumulation of lipid droplets in promastigotes. These alterations were associated with autophagic and apoptotic processes, morphological and ultrastructural changes, DNA fragmentation, and cell cycle arrest. Free CUR also reduced the viability of BALB/c peritoneal macrophages, and this effect was attenuated after nanoencapsulation. Free CUR, CUR nanoparticles, and their association with antimoniate (AM) reduced both the percentage of infected macrophages and the number of intracellular amastigotes at all tested concentrations, with increased NO production observed at the highest concentrations of free CUR. Altogether, our findings suggest that CUR exerts leishmanicidal activity against promastigotes by disrupting oxidative metabolism and triggering autophagic and apoptotic pathways, while amastigote elimination appears to occur through mechanisms independent of oxidative stress. Full article

It has recently been shown that by sequential vibrational processing (named ‘crossing’) of two closely located vials with the initial substance in one of them and water or lactose in the other, it is possible to obtain novel products, or vibrational iterations. Vibrational iterations are, in certain cases, capable of exerting a modifying effect on the initial substance or its target, thereby altering its physicochemical and biological properties. Since water is the environment in which metabolic processes occur in cells, organs, and tissues, vibrational iterations obtained using water as initial substance can potentially affect their course. In this work, we assessed the effect of vibrational iterations of water on the metabolic activity of primary peritoneal macrophages of C57BL/6 mice and macrophage-like tumor cells of the RAW 264.7 line. It was shown that one vibrational iteration of water increased the metabolic activity of peritoneal macrophages and suppressed the metabolic activity of tumor cells. At the same time, another vibrational iteration of water did not influence the metabolic activity of peritoneal macrophages but decreased the metabolic activity of tumor cells. Probably, taking into account the modifying activity of vibrational iterations, their action is aimed at changing the properties (possibly, structuring) of intracellular water. The results obtained by us show the possibility of a fundamentally new differential effect on the metabolic activity of healthy and tumor cells, which opens up new prospects for antitumor therapy. Full article