@article {2400, title = {Inflammation-specific targeted carriers for local drug delivery to inflammatory bowel disease.}, journal = {Biomaterials}, volume = {281}, year = {2022}, month = {2022 Jan 05}, pages = {121364}, abstract = {

Delivering drugs directly to the inflamed intestinal sites to treat inflammatory bowel disease (IBD), particularly Crohn{\textquoteright}s and ulcerative colitis, is highly challenging. Recent advances in colitis therapy medications are expanding opportunities for improving local on-site drug availability by minimising the associated systemic side-effects. Drug delivery with targeted carrier systems has shown the potential to increase site-specificity, stability, and therapeutic efficacy. Herein, we report the development of a strong anionic charged inflammation targeted nanocarriers (IT-NCs) loaded with an immunosuppressant model drug. This system showed preferential adhesion on a charge-modified surface in vitro, and in both dextran sulfate sodium (DSS) and TNBS colitis mice in vivo models. IT-NCs showed improved colitis phenotype therapeutic efficacy in both animal models compared to free drug. Furthermore, ex vivo study of colon tissue biopsies from patients with colitis revealed that IT-NCs adhered preferentially to inflamed biopsies compared to normal. Together, our results suggest that IT-NCs have promising therapeutic potential as delivery carriers{\textquoteright} in colitis management.

}, issn = {1878-5905}, doi = {10.1016/j.biomaterials.2022.121364}, author = {Kotla, Niranjan G and Singh, Rajbir and Baby, Becca V and Rasala, Swetha and Rasool, Jawad and Hynes, Sean O and Martin, Darrell and Egan, Laurence J and Vemula, Praveen K and Jala, Venkatakrishna R and Rochev, Yury and Pandit, Abhay} } @article {2883, title = {Microbial metabolite restricts 5-fluorouracil-resistant colonic tumor progression by sensitizing drug transporters via regulation of FOXO3-FOXM1 axis.}, journal = {Theranostics}, volume = {12}, year = {2022}, month = {2022}, pages = {5574-5595}, abstract = {

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.

}, keywords = {Animals, Antimetabolites, Antineoplastic, ATP Binding Cassette Transporter, Subfamily G, Member 2, Azoxymethane, Cell Line, Tumor, Colonic Neoplasms, Coumarins, Drug Resistance, Neoplasm, Fluorouracil, Forkhead Box Protein M1, Forkhead Box Protein O3, Gastrointestinal Microbiome, Humans, Mice, Neoplasm Proteins}, issn = {1838-7640}, doi = {10.7150/thno.70754}, author = {Ghosh, Sweta and Singh, Rajbir and Vanwinkle, Zachary Matthew and Guo, Haixun and Vemula, Praveen Kumar and Goel, Ajay and Haribabu, Bodduluri and Jala, Venkatakrishna Rao} } @article {2107, title = {Microbial Metabolite Urolithin B Inhibits Recombinant Human Monoamine Oxidase A Enzyme.}, journal = {Metabolites}, volume = {10}, year = {2020}, month = {2020 Jun 19}, abstract = {

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{\textquoteright}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 IC value of 0.88 {\textmu}M, and displaying a mixed mode of inhibition. However, all tested compounds exhibited higher IC (\>100 {\textmu}M) for MAO-B enzyme.

}, issn = {2218-1989}, doi = {10.3390/metabo10060258}, author = {Singh, Rajbir and Chandrashekharappa, Sandeep and Vemula, Praveen Kumar and Haribabu, Bodduluri and Jala, Venkatakrishna Rao} } @article {1603, title = {Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway.}, journal = {Nat Commun}, volume = {10}, year = {2019}, month = {2019 01 09}, pages = {89}, abstract = {

The importance of gut microbiota in human health and pathophysiology is undisputable. Despite the abundance of metagenomics data, the functional dynamics of gut microbiota in human health and disease remain elusive. Urolithin A (UroA), a major microbial metabolite derived from polyphenolics of berries and pomegranate fruits displays anti-inflammatory, anti-oxidative, and anti-ageing activities. Here, we show that UroA and its potent synthetic analogue (UAS03) significantly enhance gut barrier function and inhibit unwarranted inflammation. We demonstrate that UroA and UAS03 exert their barrier functions through activation of aryl hydrocarbon receptor (AhR)- nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent pathways to upregulate epithelial tight junction proteins. Importantly, treatment with these compounds attenuated colitis in pre-clinical models by remedying barrier dysfunction in addition to anti-inflammatory activities. Cumulatively, the results highlight how microbial metabolites provide two-pronged beneficial activities at gut epithelium by enhancing barrier functions and reducing inflammation to protect from colonic diseases.

}, keywords = {Animals, Basic Helix-Loop-Helix Transcription Factors, Caco-2 Cells, Coumarins, Epithelial Cells, Gene Expression Regulation, HT29 Cells, Humans, Intestinal Mucosa, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-E2-Related Factor 2, Receptors, Aryl Hydrocarbon, Specific Pathogen-Free Organisms, Tight Junction Proteins}, issn = {2041-1723}, doi = {10.1038/s41467-018-07859-7}, author = {Singh, Rajbir and Chandrashekharappa, Sandeep and Bodduluri, Sobha R and Baby, Becca V and Hegde, Bindu and Kotla, Niranjan G and Hiwale, Ankita A and Saiyed, Taslimarif and Patel, Paresh and Vijay-Kumar, Matam and Langille, Morgan G I and Douglas, Gavin M and Cheng, Xi and Rouchka, Eric C and Waigel, Sabine J and Dryden, Gerald W and Alatassi, Houda and Zhang, Huang-Ge and Haribabu, Bodduluri and Vemula, Praveen K and Jala, Venkatakrishna R} } @article {1200, title = {Targeted delivery of microbial metabolite, urolithin A protects from chemically (DSS or TNBS) induced colitis in pre-clinical models}, journal = {The Journal of Immunology}, volume = {198}, year = {2017}, pages = {65.6{\textendash}65.6}, abstract = {

Epidemiological data suggests that consumption of diets rich in phytochemicals are protective in inflammatory bowel diseases (IBDs). However, the beneficial effects are not uniform among individuals and attributed to variations in gut microbiota, and altered capacity to generate certain metabolites. Urolithin A (UroA) (3,8-dihydroxybenzo[c]chromen-6-one) is a microbial metabolite, derived from ellagic acid and ellagitannins, major poly phenolic components in berries and pomegranates. Here, we examined therapeutic applications of UroA and mechanisms of action in IBDs. Our studies suggested that UroA significantly reduced LPS induced inflammatory mediators (e.g., IL-6, TNF-alpha and IL-12) as well as ROS production in mouse bone marrow-derived macrophages (BMDMs), dendritic and THP1 cells. Most importantly, UroA also reduced LPS induced systemic inflammation in mouse models. Next, we examined therapeutic applications of UroA in dextran sodium sulphate (DSS)-induced, 2,4,6-Trinitrobenzenesulfonic acid (TNBS)-induced colitis models. Treatment with UroA significantly reduced both acute and chronic DSS-induced colitis as well as TNBS induced colitis in mouse models. Most importantly, delivery of UroA utilizing inflammation targeting oral nano-particles (single treatment regimen) effectively mitigated the colitis in both models. In summary, these results highlight even presence of single microbial metabolite at right location at right time will have significant beneficial effects to protect from adverse inflammatory activities.

}, issn = {0022-1767}, url = {http://www.jimmunol.org/content/198/1_Supplement/65.6}, author = {Singh, Rajbir and Hegde, Bindu and Von Baby, Becca and Sadeep, C and Kotla, Niranjan and Chandrasekar, Bhargavi and Marepally, Srujan and Bodduluri, Haribabu and Vemula, Praveen K and Jala, Venkatakrishna R} } @article {617, title = {Gut Microbiota Conversion of Dietary Ellagic Acid into Bioactive Phytoceutical Urolithin A Inhibits Heme Peroxidases.}, journal = {PLoS One}, volume = {11}, year = {2016}, month = {2016}, pages = {e0156811}, abstract = {

Numerous studies signify that diets rich in phytochemicals offer many beneficial functions specifically during pathologic conditions, yet their effects are often not uniform due to inter-individual variation. The host indigenous gut microbiota and their modifications of dietary phytochemicals have emerged as factors that greatly influence the efficacy of phytoceutical-based intervention. Here, we investigated the biological activities of one such active microbial metabolite, Urolithin A (UA or 3,8-dihydroxybenzo[c]chromen-6-one), which is derived from the ellagic acid (EA). Our study demonstrates that UA potently inhibits heme peroxidases i.e. myeloperoxidase (MPO) and lactoperoxidase (LPO) when compared to the parent compound EA. In addition, chrome azurol S (CAS) assay suggests that EA, but not UA, is capable of binding to Fe3+, due to its catechol-like structure, although its modest heme peroxidase inhibitory activity is abrogated upon Fe3+-binding. Interestingly, UA-mediated MPO and LPO inhibition can be prevented by innate immune protein human NGAL or its murine ortholog lipocalin 2 (Lcn2), implying the complex nature of host innate immunity-microbiota interactions. Spectral analysis indicates that UA inhibits heme peroxidase-catalyzed reaction by reverting the peroxidase back to its inactive native state. In support of these in vitro results, UA significantly reduced phorbol myristate acetate (PMA)-induced superoxide generation in neutrophils, however, EA failed to block the superoxide generation. Treatment with UA significantly reduced PMA-induced mouse ear edema and MPO activity compared to EA treated mice. Collectively, our results demonstrate that microbiota-mediated conversion of EA to UA is advantageous to both host and microbiota i.e. UA-mediated inhibition of pro-oxidant enzymes reduce tissue inflammation, mitigate non-specific killing of gut bacteria, and abrogate iron-binding property of EA, thus providing a competitive edge to the microbiota in acquiring limiting nutrient iron and thrive in the gut.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0156811}, author = {Saha, Piu and Yeoh, Beng San and Singh, Rajbir and Chandrasekar, Bhargavi and Vemula, Praveen Kumar and Haribabu, Bodduluri and Vijay-Kumar, Matam and Jala, Venkatakrishna R} }