Search Results (644)

Short-chain fatty acids (SCFAs) and medium-chain fatty acids (MCFAs) include small organic anions derived from the gut microbiome that interact with organic anion transporters of the SLC22 family, many of which are expressed in the kidney proximal tubule. According to the Remote Sensing and Signaling Theory (RSST), crosstalk between organs (e.g., gut–liver–kidney axis, gut–brain axis) and the gut microbiome is mediated by metabolites and signaling molecules transported by multi-specific “drug” transporters. The renal drug transporter OAT1 (SLC22A6) is also a major transporter of gut-microbiome products and uremic toxins (e.g., indoxyl sulfate); it has been shown to act as part of a regulatory feedback loop involving the gut microbiome. SCFAs, especially propionate and butyrate, have been shown to play a central role in the transcriptional regulation of OAT1 through HDAC inhibition. By fecal metagenomics analyses of Oat1 knockout mice, we now find that propionate synthesis is among the most altered pathways in the gut microbiome. In contrast, these pathways were only minimally altered in the Oat3 (Slc22a8) knockout. Metabolomics analyses indicate that serum propionate derivatives (e.g., propionyl glycine) and 3-hydroxybutyrate are dependent on OAT1 in the knockout mice and in humans treated with probenecid, an OAT1 inhibitor. The gut microbiome of the Oat1 knockout mice also exhibited greater fatty acid synthesis, which generates odd-chain-length fatty acids (e.g. heptanoate) when propionate is available. Overall, the data, especially when considered in light of in vitro experiments of others, indicates the in vivo existence of a feedback loop connecting gut-microbiome-derived SCFAs and MCFAs to kidney proximal tubule uptake via OAT1. This bidirectional feedback loop in turn regulates OAT1 expression through HDAC inhibition. The feedback loop is clearly consistent with the Remote Sensing and Signaling Theory—in particular, the centrality of multi-specific “drug” transporters in organ crosstalk and host–microbiome interactions via small molecules with “high information content.” The key role of OAT1 function in maintaining tubular secretion in CKD supports the importance of this RSST loop in renal pathophysiology. Modulating this RSST loop could have therapeutic value in chronic kidney disease and other contexts. Full article

Background. Neuroinflammation, driven by chronic microglial activation and blood–brain barrier dysfunction, is increasingly recognised as a key pathogenic mechanism in neurodegenerative disorders. Achillea erba-rotta subsp. moschata, an alpine medicinal plant traditionally employed for inflammatory conditions, has demonstrated antioxidant and anti-inflammatory properties; however, its effects on brain-related cell types and the underlying neuropharmacological mechanisms remain largely unexplored. This study investigated the molecular pathways by which A. erba-rotta subsp. moschata modulates neuroinflammation in key cellular components of the neurovascular unit. Methods. We evaluated the pharmacological activity of A. erba-rotta subsp. moschata aqueous extract (20–200 µg/mL) in LPS-stimulated BV2 microglial cells and human brain microvascular endothelial cells (hBMECs). Molecular mechanisms were characterised using qRT-PCR and Western blot analysis, focusing on inflammatory, antioxidant (Nrf2/HO-1), and AhR signalling pathways. Results. A. erba-rotta subsp. moschata extract significantly attenuates inflammatory responses in both cell types. In BV2 microglia, the extract reduced pro-inflammatory mediators and promoted anti-inflammatory signalling, including dose-dependent upregulation of TGF-β. In parallel, in hBMECs, the extract preserved endothelial integrity and mitigated inflammation-induced alterations without affecting cell viability. At the molecular level, the extract modulated key transcriptional pathways involved in inflammation and redox homeostasis, including NF-κB and the Nrf2/HO-1 axis. Importantly, robust CYP1A1 induction indicated aryl hydrocarbon receptor (AhR) activation, revealing coordinated crosstalk between inflammatory and antioxidant pathways. Conclusions. A. erba-rotta subsp. moschata exerts balanced, tissue-dependent immunomodulatory activity through multi-target neuropharmacological mechanisms. The anti-inflammatory effects in microglia combined with barrier-preserving actions in brain endothelium, support its therapeutic potential as a neuropharmacological agent for neuroinflammatory disorders. Full article

Aims: The effects of two Lactiplantibacillus plantarum strains and their probiotics on loperamide-induced constipation in mice were compared, and the possible mechanisms of the two strains in alleviating constipation were explored. Methods: KM mice were divided into the normal group, model group, positive control group, LTJ53 group, LP11824 group, HK-LTJ53 group and HK-LP11824 group. Loperamide was used to induce constipation in the mice. The study examined changes in defecation time, intestinal propulsion rate, gastric emptying rate, gastrointestinal peptides, colon histology, expression of intestinal barrier function genes, gut microbiota, and short-chain fatty acids (SCFAs). Results: Both live and postbiotic forms of L. plantarum significantly shortened defecation time, improved gastric emptying and intestinal motility, increased the levels of 5-hydroxytryptamine (5-HT), gastrin (GAS) and motilin (MTL), decreased the level of vasoactive intestinal peptide (VIP), restored colon morphology, upregulated the expression of Zonula Occludens-1 (ZO-1), mucin 2 (MUC2) and aryl hydrocarbon receptor (AhR), and downregulated the expression of aquaporin 4 (AQP4). They can also regulate the composition of the gut microbiota and alter the levels of SCFAs. Strain-specific effects were observed: LTJ53 was more effective in improving weight loss and gastric emptying, while LP11824 showed stronger efficacy in promoting small intestinal motility. Conclusions: L. plantarum and its postbiotics can relieve constipation through regulating the intestinal flora, enhancing gastrointestinal motility, adjusting the levels of neurotransmitters, and improving the intestinal barrier function. The specific effects of the two strains can support the selection of function-oriented precise intervention. Full article

Dioxins are highly persistent organic pollutants that exist in soil. Their hydrophobic and lipophilic characteristics facilitate long-term stability, posing high risks to the ecosystem and human health. They can be released by different sources, such as the incineration of waste materials, industrial activities, the production of pesticides, and natural or accidental events like forest fires. Dioxins accumulate in food chains and persist in the environment because dioxins are less volatile as well as chemically stable and can strongly bind to organic matter. The accumulation and persistence of dioxins in aquatic and terrestrial systems make them a significant threat to the environment, even at very low concentrations. This review explains the key sources of dioxin-contaminated soil, including industrial emissions and atmospheric deposition, and assesses the associated risks. The transport, places of contamination, and overall status of dioxins are also highlighted in this study. The review also examines the mechanisms of dioxin toxicity, focusing on their interference with hormonal functions and gene expression, as mediated through the aryl hydrocarbon receptor (AhR). This AhR activation leads to gene responses and causes immunotoxicity, endocrine disruption, and oxidative stress. Furthermore, various remediation strategies like biological, physical, and chemical remediation are discussed here as effective approaches for reducing ecological and health risks and promoting soil sustainability. Full article

Zika virus (ZIKV) is an emerging flavivirus associated with congenital malformations and ocular complications, representing a significant public health concern. Retinal pigment epithelium (RPE) cells play a key role in maintaining retinal integrity and represent a primary target of ZIKV infection, making them a relevant model for studying host–virus interactions. In this study, we evaluated the antiviral activity of fat- and water-soluble vitamins against ZIKV in hTERT RPE-1 (hRPE1) cells. Particularly, vitamin A was identified as the compound that most effectively inhibited viral replication. Molecular dynamics simulations focusing on the PAS-B domain of the aryl hydrocarbon receptor (AHR) revealed a high affinity of vitamin A for the receptor. In hRPE1 cells, vitamin A treatment reduced viral RNA levels and decreased CYP1A1, TDO, and AHR mRNA expression. In parallel, IFNB1 expression increased, consistent with the involvement of type I interferon (IFN-I), as no antiviral effect was observed in IFN-I-deficient Vero cells. These findings suggest that vitamin A restricts ZIKV replication through host antiviral responses, potentially involving modulation of AHR-associated signaling. The combination of vitamin A and the well-known polyphenol resveratrol further enhanced antiviral activity, showing predominantly additive effects. Together, these results support the potential use of both bioactive compounds as a combined therapeutic strategy. Full article

Tryptophan (Trp) metabolism sits at the intersection of nutrition, the microbiome, mucosal immunity, and tumor adaptation. The broad observation that microbial indoles can support barrier function, whereas tumors exploit kynurenine-pathway metabolism to suppress immunity, is already established in publications. The specific contribution of this review is to organize that literature into a context- and network-based translational framework. Rather than treating indoleamine 2,3-dioxygenase 1 (IDO1) as a single bottleneck, we frame tumor Trp metabolism as a compensatory system linking IDO1, tryptophan 2,3-dioxygenase (TDO2), interleukin-4-induced gene 1 (IL4I1), amino-acid transport, amino-acid stress sensing, and downstream aryl hydrocarbon receptor (AHR) signaling. In healthy tissue, especially the gut, dietary Trp and microbiota-derived indoles can promote epithelial integrity, interleukin-22 (IL-22)-associated programs, and mucosal restraint. In tumors, the same substrate pool is redirected toward Kynurenine, kynurenic acid, indole-3-pyruvate, and related catabolites that impair cytotoxic lymphocytes, expand regulatory T-cell (Treg) and suppressive myeloid compartments, and reinforce invasion and treatment resistance. We also argue that the potential metabolite biomarker interpretation should be context-dependent. Finally, we propose a clinical-context–specific framework for intervention. Dietary and microbiome-based strategies may be most effective in prevention, premalignant states, or supportive care, whereas established cancers are more likely to require biomarker-guided targeting of tumor-associated catabolic pathways and convergent signaling mechanisms. The “paradox” is therefore not that Trp changes chemistry across settings, but that the same nutrient is routed through different cellular contexts, enzymes, ligands, and cell states. Full article

Now, half a century after the Vietnam War, Agent Orange exposure during the war is increasingly discussed as a risk factor for neurological diseases, particularly dementia and Alzheimer’s disease, among Korean and U.S. Vietnam War veterans. Emerging evidence supports associations between dioxin exposure originating from Agent Orange and alterations in brain morphology and function among Vietnamese residents, including children living in areas around former U.S. airbases exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) after the Vietnam War. This paper summarizes what is known about the effects of Agent Orange exposure in the context of neurological disorders, including Alzheimer’s disease, Parkinson’s disease, autism spectrum disorder, attention-deficit/hyperactivity disorder, and psychiatric disorders. Molecular biological studies have reported that TCDD may increase the risks of these neurological diseases by accelerating brain aging and inducing atypical neurodevelopment, partly mediated by the aryl hydrocarbon receptor. However, the effects of TCDD, which is a highly toxic contaminant of Agent Orange, as well as dioxin congeners other than TCDD, exhibit some inconsistencies. This review aims to provide new insights for mitigating the adverse neurological effects of dioxin exposure from Agent Orange, contributing to a healthier life for residents in Vietnam. Full article

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous combustion-derived contaminants that represent a significant cross-cutting threat to human, animal, and environmental health. Viewed through an explicit One Health lens, this review shows how the shared combustion sources, evolutionarily conserved toxicological mechanisms, and food-web linkages connecting environmental contamination to wildlife and human exposure justify an integrated, cross-domain approach to PAH risk assessment and management. PAHs are generated predominantly through incomplete combustion of organic materials and are globally distributed through atmospheric transport, aquatic runoff, and food-web transfer, persisting in soils and sediments for decades. The present review synthesizes current knowledge on PAHs through an explicit One Health lens, examining shared sources, environmental fate, and convergent health effects across species and health domains, while also highlighting the need to move beyond the classical US EPA priority PAHs to include high-molecular-weight PAHs (>302 Da), alkylated homologues, and transformation products such as oxy- and nitro-PAHs. Common pathways such as dietary intake of grilled and smoked foods, inhalation of contaminated air, and occupational exposure create parallel toxicological burdens in both human and wildlife populations, particularly through genotoxic mechanisms mediated by aryl hydrocarbon receptor (AhR) activation and CYP1A1/CYP1B1-catalyzed bioactivation to reactive diol epoxides. The resulting DNA adduct formation links environmental PAH exposure to carcinogenicity, reproductive toxicity, immunosuppression, and developmental impairment across vertebrate species with remarkable mechanistic consistency. Wildlife, especially fish, marine mammals, and seabirds, serve as critical sentinels for environmental PAH contamination, while simultaneously facing direct health impacts on immune function, reproduction, and population viability. Vulnerable human populations, including children, subsistence communities, occupational workers, and residents near combustion-intensive industries, bear disproportionate burdens reflecting underlying environmental justice concerns. Integrated intervention strategies encompassing source control, dietary exposure reduction, site remediation, and coordinated biomonitoring are urgently needed. By incorporating emerging PAH classes with distinct persistence, trophic behavior, and toxicological potency, the One Health paradigm provides a more comprehensive conceptual framework for modern environmental surveillance, food safety, and integrated risk assessment, recognizing that the health of terrestrial and aquatic ecosystems is inseparable from that of the animals and humans within them. Full article

Astragaloside IV (AS-IV), a principal bioactive constituent of the medicinal and edible herb Radix astragali, exerts protective effects against ulcerative colitis (UC). This study investigated its underlying mechanisms in dextran sulfate sodium (DSS)-induced colitis using 16S rRNA sequencing, untargeted fecal metabolomics, and label-free proteomics. AS-IV intervention remodeled intestinal microbiota composition by markedly increasing Akkermansia abundance. Fecal metabolomic analysis revealed enhanced tryptophan (Trp) metabolism and elevated levels of kynurenic acid, 5-hydroxyindoleacetic acid and indole-3-acetic acid, which were significantly positively correlated with Akkermansia abundance. Proteomic analysis further identified Trp metabolism as a key pathway. Indoleamine 2,3-dioxygenase 1 (IDO1) and dopa decarboxylase (DDC) were recognized as differentially expressed proteins in colonic tissues. AS-IV ameliorated colitis by downregulating IDO1 expression, while upregulating the expression of tryptophan hydroxylase 1 (TPH1), DDC, monoamine oxidase A (MAO-A), and the aryl hydrocarbon receptor (AhR), as well as inhibiting NF-κB p65 phosphorylation. Collectively, these findings indicate that AS-IV enhances intestinal barrier function and mitigates colonic inflammation in DSS-induced UC. These beneficial effects are associated with the regulation of host–gut Trp metabolism, altered AhR expression, and suppressed NF-κB p65 activation. This study underscores the potential of AS-IV as a candidate functional food ingredient for the management of UC. Full article

Amino acids are essential nutrients for both tumor growth and immune cell function. Cancer cells actively deplete intracellular and extracellular amino acid pools, and limited amino acid availability in the tumor microenvironment (TME) reinforces immunosuppression. Mitochondria are not merely adenosine triphosphate-producing organelles. Amino acid metabolism within mitochondria contributes to tumor progression and influences immune cell fate and effector function. These effects are mediated through biosynthetic precursor generation for lipid, nucleotide, and polyamine synthesis, maintenance redox homeostasis through glutathione and NAD⁺ metabolism, and regulation of gene expression through aryl hydrocarbon receptor signaling. In this review, we discuss four major mitochondrial amino acid metabolic pathways: glutamine-driven anaplerosis, serine/glycine-dependent one-carbon metabolism, arginine–ornithine metabolism, and tryptophan–kynurenine metabolism. We examine how these pathways are rewired in cancer cells, how they influence immune cell function through direct or mitochondria-associated mechanisms, and how such metabolic reprogramming promotes tumor progression while impairing antitumor immunity. Finally, we consider therapeutic strategies to improve cancer immunotherapy by targeting amino acid metabolism, including mitochondrial metabolic enzymes. This review may help guide the development of more effective metabolic biomarkers and mitochondria-based therapeutic strategies for cancer immunotherapy. Full article

Toxic environmental contaminants, such as polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs), and polychlorinated biphenyls (PCBs) occur differentially in animal tissues. This study examined paired liver and muscle tissues from the same animals, reducing the uncertainty inherent in other studies that source tissues from different animals. Investigations were carried out on cattle and sheep from two separate herds in Southern Italy. As all animals experienced the same environmental impacts, husbandry, and feed regimes, contaminant distribution between tissues would result from physiological considerations, which would also allow for better examination of the effects of age. In both investigations, PCDD/F and PCB concentrations were significantly higher (p < 0.01) in the liver relative to muscle. A characteristic occurrence pattern showed PCBs dominating the combined toxic equivalence (TEQ) by >95% in cattle tissues and 78% and 67% in sheep muscle and liver, respectively. A majority of liver samples exceeded regulated maximum limits, and the herds were excluded from the food supply. Subsequent regional monitoring showed regulatory compliance of cattle/sheep meat and liver, but prominence of PCB-TEQ persisted. Concentrations of both contaminants declined strongly in the tissues of both species with increasing age of juveniles but stabilized in older animals (>one year in sheep; 2/3 years in cattle). Although weight gain might partly account for this pattern, the initial decline may also relate to inadequate levels of CYP enzymes in the youngest juveniles, but this would need to be confirmed in both species by targeted toxicokinetic studies during this perinatal period. The expression of these detoxifying enzymes is reported to rise rapidly with increasing postnatal age in many animal species, including sheep. Full article

Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (B[a]P), are major risk factors for lung cancer and other diseases, acting through the aryl hydrocarbon receptor (AHR). Alveolar macrophages (AMs) help regulate the lung microenvironment by responding to inhaled toxicants and resident microbiota. Although small extracellular vesicles (sEVs, aka exosomes) released by AMs mediate intercellular communication and immune responses, the influence of lung microbiota on sEV biogenesis and the mechanisms underlying sEV dysregulation during PAH exposure remain unknown. Here, we investigated the interplay between AMs, B[a]P, and lung microbiota, focusing on sEV-associated miRNAs (exo-miRNAs). Murine AMs (MH-S) were exposed to varying B[a]P concentrations in the presence or absence of murine lung microbiota with or without an AHR antagonist. sEVs from each condition were characterized and profiled for miRNA. Distinct miRNA signatures emerged: high-dose B[a]P enriched miRNAs linked to cancer progression, whereas lung microbiota alone or with low-dose B[a]P induced tumor-suppressor miRNAs that limit proliferation and metastasis and promote apoptosis, an effect enhanced by AHR antagonism. Lung microbiota appeared to counteract high-dose B[a]P by modulating tumor-suppressive exo-miRNAs. This study demonstrates that lung microbiota-induced exo-miRNAs critically shape AM-derived sEV-miRNA signaling during PAH exposure. The identified exosomal miRNAs could serve as important exposure biomarkers and therapeutic targets for mitigating B[a]P-induced toxicity and cancer development. Full article

In the treatment of atopic dermatitis (AD), synergistic activation of the aryl hydrocarbon receptor (AHR)/nuclear factor erythroid 2-related factor 2 (NRF2) pathways represents a promising strategy. However, known dual agonists are limited, and traditional screening methods are inefficient. Therefore, this study developed machine learning models to predict AHR/NRF2 dual agonists using molecular descriptors and fingerprints. All models achieved area under the receiver operating characteristic curve (AUC) values above 0.86, indicating good classification performance. The optimal AHR model showed an accuracy (ACC) of 0.811 and an AUC of 0.878, while the best NRF2 model yielded an ACC of 0.839 and an AUC of 0.907. Based on this model, compounds with a low fraction of sp³-hybridized carbons, moderate hydrophobicity, limited alkyl chains, and highly conjugated structures tend to act as AHR/NRF2 dual agonists. Finally, this study screened 1011 potential natural AHR/NRF2 dual agonists suitable for drug development. Among these, 2-arylbenzofurans, alkaloids, phenanthrenes, flavones, and furocoumarins demonstrated particular advantages. For validation, Indirubin, imperatorin and 3′-O-Methylbutastatin III were first discovered as AHR/NRF2 dual agonists in HaCaT cells. This work provides a robust predictive tool, clarifies key molecular features of dual agonists, and may support the discovery of anti-AD agents. Full article

Chronic inflammatory skin diseases, including atopic dermatitis (AD) and psoriasis, are systemic immune-mediated disorders driven by dysregulated immune responses. The gut–skin axis is a bidirectional network linking intestinal microorganisms, their metabolites, and host immunity. It connects microbiome composition and function with systemic inflammation and cutaneous pathology, shaping disease-specific mechanisms such as Th2/IL-4/IL-13-mediated barrier dysfunction in AD and Th17/IL-23/IL-17-driven hyperproliferation in psoriasis. Microbiota-derived metabolites, including short-chain fatty acids, tryptophan-derived aryl hydrocarbon receptor ligands, and bile acid-dependent FXR/TGR5 signaling, modulate immune homeostasis and epithelial integrity. Gut dysbiosis, impaired metabolite production, and barrier dysfunction disrupt regulatory networks, amplifying inflammation. Microbiota-targeted interventions, including probiotics, synbiotics, postbiotics, and precision nutrition, may serve as adjunctive therapies, although further well-controlled clinical studies are needed. Integrating multi-omics, metabolomics, and functional microbial profiling, alongside investigations of the gut mycobiome and virome, will be critical to identify predictive biomarkers and optimize therapeutic strategies. These concepts remain mechanistically compelling but largely theoretical, requiring validation in longitudinal and interventional studies. Full article

During infection in vitro with the strain 438/06 of bovine coronavirus (BCoV), a β-coronavirus similar to severe acute respiratory syndrome (SARS) CoV-2, treatment with 6-pentyl-α-pyrone (6PP), a fungal metabolite obtained from Trichoderma atroviride, was recently shown to influence viral load by reducing viral entry. Herein, the ability of 6PP to counteract the BCoV infection was further investigated both in vitro and in silico. Following the BCoV (strain 282/23) infection in bovine (MDBK) cells, the 6PP in co-treatment increased cell viability, reduced morphological signs of cell death, and significantly inhibited viral yield, by lessening the expression of the viral spike (S) protein, as well as the gene transcription of the viral nucleocapsid (NP) protein. In addition, a noticeable down-regulation in the expression of aryl hydrocarbon receptor (AhR) signaling, a strategic modulator of CoVs infection, was found. Molecular docking studies were performed to evaluate the potential interaction between 6PP and AhR involved in the BCoV infection. The docking 3D structural model showed that 6PP fits into a binding pocket positioned between the PASB and TAD domains of bovine AhR (bAhR), where the ligand is stabilized through hydrophobic interactions. In addition, the obtained computational data strongly suggest that the bAhR binding mechanism of 6PP is principally mediated by a well-conserved hydrophobic cavity playing a key role in the modulation of the receptor functions. Overall, our findings showed an antiviral action of 6PP versus BCoV infection in vitro and in silico. Full article