Explore the vast range of titles available.

Therapy for Clostridioides difficile infections includes the use of antibiotics, immunosuppressors, and fecal microbiota transplantation. However, these treatments have several drawbacks, including the loss of colonization resistance, the promotion of autoimmune disorders, and the potential for unknown pathogens in donor samples. To date, the potential benefits of microbial metabolites in CDI-induced colitis have not been fully investigated. Here, we report for the first time that the microbial metabolite urolithin A has the potential to block toxin production from C. difficile and enhance gut barrier function to mitigate CDI-induced colitis.

Cytochrome P450 Family 1 Subfamily A Member 1 (CYP1A1) pathway, which is regulated by aryl hydrocarbon receptor (AhR) plays an important role in chemical carcinogenesis and xenobiotic metabolism. Recently, we demonstrated that the microbial metabolite Urolithin A (UroA) mitigates colitis through its gut barrier protective and anti-inflammatory activities in an AhR-dependent manner. Here, we explored role of CYP1A1 in UroA-mediated gut barrier and immune functions in regulation of inflammatory bowel disease (IBD). To determine the role of CYP1A1 in UroA-mediated protectives activities against colitis, we subjected C57BL/6 mice and mice to dextran sodium sulphate (DSS)-induced acute colitis model. The phenotypes of the mice were characterized by determining loss of body weight, intestinal permeability, systemic and colonic inflammation. Further, we evaluated the impact of UroA on regulation of immune cell populations by flow cytometry and confocal imaging using both and model systems. UroA treatment mitigated DSS-induced acute colitis in the wildtype mice. However, UroA-failed to protect mice against colitis, as evident from non-recovery of body weight loss, shortened colon lengths and colon weight/length ratios. Further, UroA failed to reduce DSS-induced inflammation, intestinal permeability and upregulate tight junction proteins in mice. Interestingly, UroA induced the expansion of T-reg cells in a CYP1A1-dependent manner both and models. Our results suggest that CYP1A1 expression is essential for UroA-mediated enhanced gut barrier functions and protective activities against colitis. We postulate that CYP1A1 plays critical and yet unknown functions beyond xenobiotic metabolism in the regulation of gut epithelial integrity and immune systems to maintain gut homeostasis in IBD pathogenesis.

Environmental chemicals such as inorganic arsenic (iAs) significantly contribute to redox toxicity in the human body by enhancing oxidative stress. Imbalanced oxidative stress rapidly interferes with gut homeostasis and affects variety of cellular processes such as proliferation, apoptosis, and maintenance of intestinal barrier integrity. It has been shown that gut microbiota are essential to protect against iAs 3+ -induced toxicity. However, the effect of microbial metabolites on iAs 3+ -induced toxicity and loss of gut barrier integrity has not been investigated. The objectives of the study are to investigate impact of iAs on gut barrier function and determine benefits of gut microbial metabolite, urolithin A (UroA) against iAs 3+ -induced adversaries on gut epithelium. We have utilized both colon epithelial cells and in a human intestinal 3D organoid model system to investigate iAs 3+ -induced cell toxicity, oxidative stress, and gut barrier dysfunction in the presence or absence of UroA. Here, we report that treatment with UroA attenuated iAs 3+ -induced cell toxicity, apoptosis, and oxidative stress in colon epithelial cells. Moreover, our data suggest that UroA significantly reduces iAs 3+ -induced gut barrier permeability and inflammatory markers in both colon epithelial cells and in a human intestinal 3D organoid model system. Mechanistically, UroA protected against iAs 3+ -induced disruption of tight junctional proteins in intestinal epithelial cells through blockade of oxidative stress and markers of inflammation. Taken together, our studies for the first time suggest that microbial metabolites such as UroA can potentially be used to protect against environmental hazards by reducing intestinal oxidative stress and by enhancing gut barrier function. Highlights The gut microbial metabolite Urolithin A (UroA) enhances cell viability during inorganic arsenic (iAs 3+ ) exposure and prevents arsenite-induced cell death in colon epithelial cells. UroA reduced iAs 3+ -induced oxidative stress in intestinal epithelial cells. UroA alleviated iAs 3+ -induced barrier dysfunction in both colon epithelial cell monolayers and a human 3D small intestinal tissue model. The protective effect of UroA is associated with enhanced accumulation of tight junctional proteins including Zonula occludens-1, Occludin, and Claudin-4 to repair iAs 3+ -induced intestinal barrier damage.

Background and AimsExcessive alcohol consumption poses a significant global health concern, ranking as the world’s third-largest risk factor for diseases and disabilities, contributing to 5.9% of all deaths worldwide. Among various disorders linked to alcohol misuse, alcohol-associated liver disease (ALD) is the most prominent. ALD patients often exhibit increased intestinal permeability, systemic inflammation, gut dysbiosis, and hepatic steatosis. No FDA-approved therapies are available to treat ALD or to resolve the pathological domains of alcohol-induced gut barrier dysfunction, inflammation, and steatosis. The goal of this study is to investigate the potential therapeutic role of the microbial metabolite Urolithin A’ (UroA), in alleviating ALD.MethodsCaco-2 (monolayer colon epithelial) cells and AML12 (hepatocytes) cells were used to test the protective activities of UroA against EtOH-induced gut barrier dysfunction and lipid accumulation in vitro. Preclinical ALD mouse models were used to test the therapeutic potential of UroA against EtOH exposure. Additionally, we generated cell-specific deletion mice with aryl hydrocarbon receptor (AHR) deletion to define the role of intestinal epithelial cell AHR in UroA-mediated protective activities against ALD.ResultsThe results presented here demonstrate the efficacy of UroA as a potential therapeutic agent to protect against EtOH-induced disruption of tight junction proteins, inflammation, and lipogenesis both in vitro and in vivo models.ConclusionOur findings suggest that the simultaneous targeting of gut barrier dysfunction, inflammation, and hepatic steatosis by treatment with UroA may offer new possibilities for combating ALD. Moreover, our results suggest that UroA-mediated protective activities against EtOH-induced gut barrier dysfunction and inflammation in ALD are dependent on intestinal epithelial cell-AHR.

Background G-protein-coupled estrogen receptor (GPER/GPR30) was reported to bind 17β-estradiol (E 2 ), tamoxifen, and ICI 182,780 (fulvestrant) and promotes activation of epidermal growth factor receptor (EGFR)-mediated signaling in breast, endometrial and thyroid cancer cells. Although lung adenocarcinomas express estrogen receptors α and β (ERα and ERβ), the expression of GPER in lung cancer has not been investigated. The purpose of this study was to examine the expression of GPER in lung cancer. Methods The expression patterns of GPER in various lung cancer lines and lung tumors were investigated using standard quantitative real time PCR (at mRNA levels), Western blot and immunohistochemistry (IHC) methods (at protein levels). The expression of GPER was scored and the pairwise comparisons (cancer vs adjacent tissues as well as cancer vs normal lung tissues) were performed. Results Analysis by real-time PCR and Western blotting revealed a significantly higher expression of GPER at both mRNA and protein levels in human non small cell lung cancer cell (NSCLC) lines relative to immortalized normal lung bronchial epithelial cells (HBECs). The virally immortalized human small airway epithelial cell line HPL1D showed higher expression than HBECs and similar expression to NSCLC cells. Immunohistochemical analysis of tissue sections of murine lung adenomas as well as human lung adenocarcinomas, squamous cell carcinomas and non-small cell lung carcinomas showed consistently higher expression of GPER in the tumor relative to the surrounding non-tumor tissue. Conclusion The results from this study demonstrate increased GPER expression in lung cancer cells and tumors compared to normal lung. Further evaluation of the function and regulation of GPER will be necessary to determine if GPER is a marker of lung cancer progression.

Inflammatory bowel disease (IBD) treatment often involves systemic administration of anti-inflammatory drugs or biologics such as anti-TNF-α antibodies. However, current drug therapies suffer from limited efficacy due to unresponsiveness and adverse side effects. To address these challenges, we developed inflammation-targeting nanoparticles (ITNPs) using biopolymers derived from the gum kondagogu ( Cochlospermum gossypium ) plant. These ITNPs enable selective drug delivery to inflamed regions, offering improved therapeutic outcomes. We designed ITNPs that specifically bind to inflamed regions in both human and mouse intestines, facilitating more effective, uniform, and prolonged drug delivery within the inflamed tissues. Furthermore, we demonstrated that oral administration of ITNPs loaded with urolithin A (UroA), a microbial metabolite or its synthetic analogue UAS03 significantly attenuated chemical- and immune checkpoint inhibitor- induced colitis in pre-clinical models. In conclusion, ITNPs show great promise for delivering UroA or its analogues while enhancing therapeutic efficacy at lower doses and reduced frequency compared to free drug administration. This targeted approach offers a potential solution to enhance IBD treatment while minimizing systemic side effects. Significance Inflammatory Bowel Disease (IBD) is a complex medical condition characterized by alternating phases of inflammation and remission in the gastrointestinal tract. Despite the success of immune checkpoint inhibitors (ICI) in cancer therapy, ICI-mediated colitis remains a challenge for cancer patients. Current treatments targeting systemic inflammation have limitations and adverse effects. To overcome these challenges, we have developed inflammation-targeted nanoparticles from natural compounds to deliver the microbial metabolite urolithin A or its synthetic analog UAS03 to inflammatory sites to ameliorate colitis. Our data showed that oral treatment with these nanoparticles attenuated chemically induced and ICI-triggered colitis in preclinical models. These studies highlight the utilization of these inflammation-targeted nanoparticles to deliver urolithin A will have significant implications for the treatment of IBD.

The standard methods of treatment often do not lead to the expected effects. Mechanistically, the enhanced response correlated with a decrease in the percentage of tumor-associated granulocytic cells, upregulation in MHC class II expression by intratumoral macrophages and an increase in tumor infiltration by effector T cells. A comparative, temporal in vitro analysis of these strains revealed a substantial reduction of cytokine activity in chromosome-based constructs.

Diabetic nephropathy (DN) remains the leading cause of vascular morbidity and mortality in diabetes patients. Despite the progress in understanding the diabetic disease process and advanced management of nephropathy, a number of patients still progress to end-stage renal disease (ESRD). The underlying mechanism still needs to be clarified. Gaseous signaling molecules, so-called gasotransmitters, such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S), have been shown to play an essential role in the development, progression, and ramification of DN depending on their availability and physiological actions. Although the studies on gasotransmitter regulations of DN are still emerging, the evidence revealed an aberrant level of gasotransmitters in patients with diabetes. In studies, different gasotransmitter donors have been implicated in ameliorating diabetic renal dysfunction. In this perspective, we summarized an overview of the recent advances in the physiological relevance of the gaseous molecules and their multifaceted interaction with other potential factors, such as extracellular matrix (ECM), in the severity modulation of DN. Moreover, the perspective of the present review highlights the possible therapeutic interventions of gasotransmitters in ameliorating this dreaded disease.

Urolithins are gut microbial metabolites derived from ellagitannins (ET) and ellagic acid (EA), and shown to exhibit anticancer, anti-inflammatory, anti-microbial, anti-glycative and anti-oxidant activities. Similarly, the parent molecules, ET and EA are reported for their neuroprotection and antidepressant activities. Due to the poor bioavailability of ET and EA, the in vivo functional activities cannot be attributed exclusively to these compounds. Elevated monoamine oxidase (MAO) activities are responsible for the inactivation of monoamine neurotransmitters in neurological disorders, such as depression and Parkinson’s disease. In this study, we examined the inhibitory effects of urolithins (A, B and C) and EA on MAO activity using recombinant human MAO-A and MAO-B enzymes. Urolithin B was found to be a better MAO-A enzyme inhibitor among the tested urolithins and EA with an IC50 value of 0.88 µM, and displaying a mixed mode of inhibition. However, all tested compounds exhibited higher IC50 (>100 µM) for MAO-B enzyme.

The survival rate of colorectal cancer patients is adversely affected by the selection of tumors resistant to conventional anti-cancer drugs such as 5-fluorouracil (5FU). Although there is mounting evidence that commensal gut microbiota is essential for effective colon cancer treatment, the detailed molecular mechanisms and the role of gut microbial metabolites remain elusive. The goal of this study is to decipher the impact and mechanisms of gut microbial metabolite, urolithin A (UroA) and its structural analogue, UAS03 on reversal of 5FU-resistant (5FUR) colon cancers. We have utilized the SW480 and HCT-116 parental (5FU-sensitive) and 5FUR colon cancer cells to examine the chemosensitization effects of UroA or UAS03 by using both and models. The effects of mono (UroA/UAS03/5FU) and combinatorial therapy (UroA/UAS03 + 5FU) on cell proliferation, apoptosis, cell migration and invasion, regulation of epithelial mesenchymal transition (EMT) mediators, expression and activities of drug transporters, and their regulatory transcription factors were examined using molecular, cellular, immunological and flowcytometric methods. Further, the anti-tumor effects of mono/combination therapy (UroA or UAS03 or 5FU or UroA/UAS03 + 5FU) were examined using pre-clinical models of 5FUR-tumor xenografts in NRGS mice and azoxymethane (AOM)-dextran sodium sulfate (DSS)-induced colon tumors. Our data showed that UroA or UAS03 in combination with 5FU significantly inhibited cell viability, proliferation, invasiveness as well as induced apoptosis of the 5FUR colon cancer cells compared to mono treatments. Mechanistically, UroA or UAS03 chemosensitized the 5FUR cancer cells by downregulating the expression and activities of drug transporters (MDR1, BCRP, MRP2 and MRP7) leading to a decrease in the efflux of 5FU. Further, our data suggested the UroA or UAS03 chemosensitized 5FUR cancer cells to 5FU treatment through regulating FOXO3-FOXM1 axis. Oral treatment with UroA or UAS03 in combination with low dose i.p. 5FU significantly reduced the growth of 5FUR-tumor xenografts in NRGS mice. Further, combination therapy significantly abrogated colonic tumors in AOM-DSS-induced colon tumors in mice. In summary, gut microbial metabolite UroA and its structural analogue UAS03 chemosensitized the 5FUR colon cancers for effective 5FU chemotherapy. This study provided the novel characteristics of gut microbial metabolites to have significant translational implications in drug-resistant cancer therapeutics.