Publications by authors named "Matam Vijay-Kumar"

109 Publications

Impact of Nutritional Epigenetics in Essential Hypertension: Targeting microRNAs in the Gut-Liver Axis.

Curr Hypertens Rep 2021 05 7;23(5):28. Epub 2021 May 7.

Microbiome Consortium, Center for Hypertension and Precision Medicine, Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Block Health Science Bldg, 3000 Arlington Ave, Toledo, OH, 43614, USA.

Purpose Of Review: To review the current knowledge on interactions between dietary factors and microRNAs (miRNAs) in essential hypertension (EH) pathogenesis.

Recent Findings: There exists an integration of maintenance signals generated by genetic, epigenetic, immune, and environmental (e.g., dietary) factors that work to sustain balance in the gut-liver axis. It is well established that an imbalance in this complex, intertwined system substantially increases the risk for EH. As such, pertinent research has been taken to decipher how each signal operates in isolation and together in EH progression. Recent literature indicates that both macro- and micronutrients interrupt regulatory miRNA expressions and thus, alter multiple cellular processes that contribute to EH and its comorbidities. We highlight how carbohydrates, lipids, proteins, salt, and potassium modify miRNA signatures during EH. The disruption in miRNA expression can negatively impact communication systems such as over activating the renin-angiotensin-aldosterone system, modulating the vascular smooth muscle cell phenotype, and promoting angiogenesis to favor EH. We also delineate the prognostic value of miRNAs in EH and discuss the pros and cons of surgical vs dietary prophylactic approaches in EH prevention. We propose that dietary-dependent perturbation of the miRNA profile is one mechanism within the gut-liver axis that dictates EH development.
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http://dx.doi.org/10.1007/s11906-021-01142-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105193PMC
May 2021

Bacterial Swarmers Enriched During Intestinal Stress Ameliorate Damage.

Gastroenterology 2021 Mar 16. Epub 2021 Mar 16.

Department of Medicine, Genetics and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York. Electronic address:

Background And Aims: Bacterial swarming, a collective movement on a surface, has rarely been associated with human pathophysiology. This study aims to define a role for bacterial swarmers in amelioration of intestinal stress.

Methods: We developed a polymicrobial plate agar assay to detect swarming and screened mice and humans with intestinal stress and inflammation. From chemically induced colitis in mice, as well as humans with inflammatory bowel disease, we developed techniques to isolate the dominant swarmers. We developed swarm-deficient but growth and swim-competent mutant bacteria as isogenic controls. We performed bacterial reinoculation studies in mice with colitis, fecal 16S, and meta-transcriptomic analyses, as well as in vitro microbial interaction studies.

Results: We show that bacterial swarmers are highly predictive of intestinal stress in mice and humans. We isolated a novel Enterobacter swarming strain, SM3, from mouse feces. SM3 and other known commensal swarmers, in contrast to their mutant strains, abrogated intestinal inflammation in mice. Treatment of colitic mice with SM3, but not its mutants, enriched beneficial fecal anaerobes belonging to the family of Bacteroidales S24-7. We observed SM3 swarming associated pathways in the in vivo fecal meta-transcriptomes. In vitro growth of S24-7 was enriched in presence of SM3 or its mutants; however, because SM3, but not mutants, induced S24-7 in vivo, we concluded that swarming plays an essential role in disseminating SM3 in vivo.

Conclusions: Overall, our work identified a new but counterintuitive paradigm in which intestinal stress allows for the emergence of swarming bacteria; however, these bacteria act to heal intestinal inflammation.
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http://dx.doi.org/10.1053/j.gastro.2021.03.017DOI Listing
March 2021

Atypical immunometabolism and metabolic reprogramming in liver cancer: Deciphering the role of gut microbiome.

Adv Cancer Res 2021 19;149:171-255. Epub 2020 Nov 19.

Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States. Electronic address:

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related mortality worldwide. Much recent research has delved into understanding the underlying molecular mechanisms of HCC pathogenesis, which has revealed to be heterogenous and complex. Two major hallmarks of HCC include: (i) a hijacked immunometabolism and (ii) a reprogramming in metabolic processes. We posit that the gut microbiota is a third component in an entanglement triangle contributing to HCC progression. Besides metagenomic studies highlighting the diagnostic potential in the gut microbiota profile, recent research is pinpointing the gut microbiota as an instigator, not just a mere bystander, in HCC. In this chapter, we discuss mechanistic insights on atypical immunometabolism and metabolic reprogramming in HCC, including the examination of tumor-associated macrophages and neutrophils, tumor-infiltrating lymphocytes (e.g., T-cell exhaustion, regulatory T-cells, natural killer T-cells), the Warburg effect, rewiring of the tricarboxylic acid cycle, and glutamine addiction. We further discuss the potential involvement of the gut microbiota in these characteristics of hepatocarcinogenesis. An immediate highlight is that microbiota metabolites (e.g., short chain fatty acids, secondary bile acids) can impair anti-tumor responses, which aggravates HCC. Lastly, we describe the rising 'new era' of immunotherapies (e.g., immune checkpoint inhibitors, adoptive T-cell transfer) and discuss for the potential incorporation of gut microbiota targeted therapeutics (e.g., probiotics, fecal microbiota transplantation) to alleviate HCC. Altogether, this chapter invigorates for continuous research to decipher the role of gut microbiome in HCC from its influence on immunometabolism and metabolic reprogramming.
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http://dx.doi.org/10.1016/bs.acr.2020.10.004DOI Listing
November 2020

Innate Immune Cells and Hypertension: Neutrophils and Neutrophil Extracellular Traps (NETs).

Compr Physiol 2021 02 12;11(1):1575-1589. Epub 2021 Feb 12.

Program in Physiological Genomics, UT Microbiome Consortium, Center for Hypertension & Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, USA.

Uncontrolled immune system activation amplifies end-organ injury in hypertension. Nonetheless, the exact mechanisms initiating this exacerbated inflammatory response, thereby contributing to further increases in blood pressure (BP), are still being revealed. While participation of lymphoid-derived immune cells has been well described in the hypertension literature, the mechanisms by which myeloid-derived innate immune cells contribute to T cell activation, and subsequent BP elevation, remains an active area of investigation. In this article, we critically analyze the literature to understand how monocytes, macrophages, dendritic cells, and polymorphonuclear leukocytes, including mast cells, eosinophils, basophils, and neutrophils, contribute to hypertension and hypertension-associated end-organ injury. The most abundant leukocytes, neutrophils, are indisputably increased in hypertension. However, it is unknown how (and why) they switch from critical first responders of the innate immune system, and homeostatic regulators of BP, to tissue-damaging, pro-hypertensive mediators. We propose that myeloperoxidase-derived pro-oxidants, neutrophil elastase, neutrophil extracellular traps (NETs), and interactions with other innate and adaptive immune cells are novel mechanisms that could contribute to the inflammatory cascade in hypertension. We further posit that the gut microbiota serves as a set point for neutropoiesis and their function. Finally, given that hypertension appears to be a key risk factor for morbidity and mortality in COVID-19 patients, we put forth evidence that neutrophils and NETs cause cardiovascular injury post-coronavirus infection, and thus may be proposed as an intriguing therapeutic target for high-risk individuals. © 2021 American Physiological Society. Compr Physiol 11:1575-1589, 2021.
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http://dx.doi.org/10.1002/cphy.c200020DOI Listing
February 2021

Intrinsic Exercise Capacity and Mitochondrial DNA Lead to Opposing Vascular-Associated Risks.

Function (Oxf) 2021 3;2(1):zqaa029. Epub 2020 Nov 3.

Department of Pharmacology and Physiology, University of Toledo College of Medicine and Life Sciences.

Exercise capacity is a strong predictor of all-cause morbidity and mortality in humans. However, the associated hemodynamic traits that link this valuable indicator to its subsequent disease risks are numerable. Additionally, exercise capacity has a substantial heritable component and genome-wide screening indicates a vast amount of nuclear and mitochondrial DNA (mtDNA) markers are significantly associated with traits of physical performance. A long-term selection experiment in rats confirms a divide for cardiovascular risks between low- and high-capacity runners (LCR and HCR, respectively), equipping us with a preclinical animal model to uncover new mechanisms. Here, we evaluated the LCR and HCR rat model system for differences in vascular function at the arterial resistance level. Consistent with the known divide between health and disease, we observed that LCR rats present with resistance artery and perivascular adipose tissue dysfunction compared to HCR rats that mimic qualities important for health, including improved vascular relaxation. Uniquely, we show by generating conplastic strains, which LCR males with mtDNA of female HCR (LCR-mt/Tol) present with improved vascular function. Conversely, HCR-mt/Tol rats displayed indices for cardiac dysfunction. The outcome of this study suggests that the interplay between the nuclear genome and the maternally inherited mitochondrial genome with high intrinsic exercise capacity is a significant factor for improved vascular physiology, and animal models developed on an interaction between nuclear and mtDNA are valuable new tools for probing vascular risk factors in the offspring.
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http://dx.doi.org/10.1093/function/zqaa029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749784PMC
November 2020

Enterobactin induces the chemokine, interleukin-8, from intestinal epithelia by chelating intracellular iron.

Gut Microbes 2020 11;12(1):1-18

UT Microbiome Consortium, Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences , Toledo, OH, USA.

Iron is an indispensable nutrient for both mammals and microbes. Bacteria synthesize siderophores to sequester host iron, whereas lipocalin 2 (Lcn2) is the host defense protein that prevent this iron thievery. Enterobactin (Ent) is a catecholate-type siderophore that has one of the strongest known affinities for iron. Intestinal epithelial cells (IECs) are adjacent to large microbial population and are in contact with microbial products, including Ent. We undertook this study to investigate whether a single stimulus of Ent could affect IEC functions. Using three human IEC cell-lines with differential basal levels of Lcn2 (. HT29 < DLD-1 < Caco-2/BBe), we demonstrated that iron-free Ent could induce a dose-dependent secretion of the pro-inflammatory chemokine, interleukin 8 (IL-8), in HT29 and DLD-1 IECs, but not in Caco-2/BBe. Ent-induced IL-8 secretion was dependent on chelation of the labile iron pool and on the levels of intracellular Lcn2. Accordingly, IL-8 secretion by Ent-treated HT29 cells could be substantially inhibited by either saturating Ent with iron or by adding exogenous Lcn2 to the cells. IL-8 production by Ent could be further potentiated when co-stimulated with other microbial products (i.e. flagellin, lipopolysaccharide). Water-soluble microbial siderophores did not induce IL-8 production, which signifies that IECs are specifically responding to the lipid-soluble Ent. Intriguingly, formyl peptide receptor (FPR) antagonists (i.e. Boc2, cyclosporine H) abrogated Ent-induced IL-8, implicating that such IEC response could be, in part, dependent on FPR. Taken together, these results demonstrate that IECs sense Ent as a danger signal, where its recognition results in IL-8 secretion.
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http://dx.doi.org/10.1080/19490976.2020.1841548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671005PMC
November 2020

Microbiota Introduced to Germ-Free Rats Restores Vascular Contractility and Blood Pressure.

Hypertension 2020 12 19;76(6):1847-1855. Epub 2020 Oct 19.

From the UT Microbiome Consortium, Center for Hypertension and Precision Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH.

Commensal gut microbiota are strongly correlated with host hemodynamic homeostasis but only broadly associated with cardiovascular health. This includes a general correspondence of quantitative and qualitative shifts in intestinal microbial communities found in hypertensive rat models and human patients. However, the mechanisms by which gut microbes contribute to the function of organs important for blood pressure (BP) control remain unanswered. To examine the direct effects of microbiota on BP, we conventionalized germ-free (GF) rats with specific pathogen-free rats for a short-term period of 10 days, which served as a model system to observe the dynamic responses when reconstituting the holobiome. The absence of microbiota in GF rats resulted with relative hypotension compared with their conventionalized counterparts, suggesting an obligatory role of microbiota in BP homeostasis. Hypotension observed in GF rats was accompanied by a marked reduction in vascular contractility. Both BP and vascular contractility were restored by the introduction of microbiota to GF rats, indicating that microbiota could impact BP through a vascular-dependent mechanism. This is further supported by the decrease in actin polymerization in arteries from GF rats. Improved vascular contractility in conventionalized GF rats, as indicated through stabilized actin filaments, was associated with an increase in cofilin phosphorylation. These data indicate that the vascular system senses the presence (or lack of) microbiota to maintain vascular tone via actin polymerization. Overall, these results constitute a fundamental discovery of the essential nature of microbiota in BP regulation.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666075PMC
December 2020

Critical Role of Innate Immunity to Flagellin in the Absence of Adaptive Immunity.

J Infect Dis 2021 Apr;223(8):1478-1487

Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.

Background: Bacterial flagellin is a major target of innate and adaptive immunity, both of which can promote and/or compensate for deficiencies in each other's function.

Methods: To investigate the role of innate immune detection of flagellin irrespective of adaptive immunity, we examined the consequences of loss of Toll-like receptor 5 (T5) and/or Nod-like receptor 4 (N4) upon a Rag1-deficient background.

Results: Mice lacking Toll-like receptor 5 and Rag1 (T5/Rag-DKO) exhibited frequent lethal Pasteurellaceae-containing abscesses that prevented breeding of these mice. Mice lacking Toll-like receptor 5, Nod-like receptor 4, and Rag1 (T5/N4/Rag-TKO) also resulted in sporadic lethal abdominal abscesses caused by similar Pasteurellaceae. In the absence of such infections, relative to Rag1-KO, T5/N4/Rag-TKO mice exhibited microbiota encroachment, low-grade inflammation, microbiota dysbiosis, and, moreover were highly prone to Citrobacter infection and developed severe colitis when adoptively transferred with colitogenic T cells. Relative proneness of T5/N4/Rag-TKO mice to T-cell colitis was ablated by antibiotics while fecal microbiota transplant from T5/N4/Rag-TKO mice to wild-type mice transferred proneness to Citrobacter infection, indicating that dysbiosis in T5/N4/Rag-TKO mice contributed to these phenotypes.

Conclusions: These results demonstrate a critical role for innate immune detection of flagellin, especially in the intestinal tract and particularly in hosts deficient in adaptive immunity.
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http://dx.doi.org/10.1093/infdis/jiaa521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064054PMC
April 2021

Lipocalin 2 deficiency-induced gut microbiota dysbiosis evokes metabolic syndrome in aged mice.

Physiol Genomics 2020 08 6;52(8):314-321. Epub 2020 Jul 6.

Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio.

Lipocalin 2 (Lcn2) is a multifunctional innate immune protein that limits microbial overgrowth. Our previous study demonstrated that the gut microbiota directly induces intestinal Lcn2 production, and Lcn2-deficient () mice exhibit gut dysbiosis. Coincidentally, gut dysbiosis is associated with metabolic syndrome pathogenesis, and elevated Lcn2 levels has been considered a potential clinical biomarker of metabolic syndrome. Yet whether Lcn2 mitigates or exacerbates metabolic syndrome remains inconclusive. Our objective was to determine whether Lcn2 deficiency-induced compositional changes in gut microbiota contribute to gain in adiposity in aged mice. Utilizing mice and their wild-type (WT) littermates, we measured metabolic markers, including fasting blood glucose, serum lipids, fat pad weight, and insulin resistance at ages 3, 6, and 9 mo old. Relative to WT mice, aged mice exhibited a gain in adiposity associated with numerous features of metabolic syndrome, including insulin resistance and dyslipidemia. Surprisingly, supplementation with a high-fat diet did not further aggravate metabolic syndrome that spontaneously occurs in mice by 6 mo of age. Interestingly, chow-fed mice displayed marked differences in the bacterial abundance and metabolomic profile of the gut microbiota compared with WT mice. Overall, our results demonstrate that Lcn2 is essential to maintain metabolic and gut microbiotal homeostasis, where deficiency induces spontaneous delayed onset of metabolic syndrome.
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http://dx.doi.org/10.1152/physiolgenomics.00118.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473890PMC
August 2020

Fermentable fiber-induced hepatocellular carcinoma in mice recapitulates gene signatures found in human liver cancer.

PLoS One 2020 19;15(6):e0234726. Epub 2020 Jun 19.

Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States of America.

Hepatocellular carcinoma (HCC), the most malignant form of primary liver cancer, is the fourth most prevalent cause of cancer mortality globally. It was recently discovered that the dietary fermentable fiber, inulin, can reprogram the murine liver to favor HCC development in a gut microbiota-dependent manner. Determining the molecular pathways that are either over expressed or repressed during inulin-induced HCC would provide a platform of potential therapeutic targets. In the present study, we have combined analysis of the novel inulin-induced HCC murine model and human HCC samples to identify differentially expressed genes (DEGs) in hepatocarcinogenesis. Hepatic transcriptome profiling revealed that there were 674 DEGs in HCC mice compared to mice safeguarded from HCC. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis uncovered enrichment in ECM-receptor interaction, steroid hormone biosynthesis, PPAR signaling pathway, focal adhesion and protein digestion and absorption during inulin-induced HCC. Tandem mass tag based quantitative, multiplexed proteomic analysis delineated 57 differentially expressed proteins, where the over-expressed proteins were associated with cell adhesion molecules, valine, leucine and isoleucine degradation and ECM-receptor interaction. After obtaining the human orthologs of the mouse genes, we did a comparison analysis to level 3 RNA-seq data found in the Cancer Genome Atlas (TCGA) database, corresponding to human HCC (n = 361) and healthy liver (n = 50) samples. Out of the 549 up-regulated and 68 down-regulated human orthologs identified, 142 genes (137 significantly over-expressed and 5 significantly under-expressed) were associated with human HCC. Using univariate survival analysis, we found 27 over-expressed genes involved in cell-cell adhesion and cell division that were associated with poor HCC patient survival. Overall, the genetic and proteomics signatures highlight potential underlying mechanisms in inulin-induced HCC and support that this murine HCC model is human relevant.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234726PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304627PMC
September 2020

Diurnal Timing Dependent Alterations in Gut Microbial Composition Are Synchronously Linked to Salt-Sensitive Hypertension and Renal Damage.

Hypertension 2020 07 26;76(1):59-72. Epub 2020 May 26.

From the Microbiome Consortium, Center for Hypertension and Precision Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH; and Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH (S.J., J.M., X.C., S.G., A.H., P.S., B.S.Y., B.M., J.-Y.Y., M.V-K., T.Y., B.J.).

Alterations of diurnal rhythms of blood pressure (BP) and reshaping of gut microbiota are both independently associated with hypertension. However, the relationships between biorhythms of BP and gut microbial composition are unknown. We hypothesized that diurnal timing-associated alterations of microbial compositions are synchronous with diurnal rhythmicity, dip in BP, and renal function. To test this hypothesis, Dahl salt-sensitive (S) rats on low- and high-salt diets were examined for time of day effects on gut microbiota, BP, and indicators of renal damage. Major shifts in night and day patterns of specific groups of microbiota were observed between the dark (active) and light (rest) phases, which correlated with diurnal rhythmicity of BP. The diurnal abundance of Firmicutes, Bacteroidetes, and Actinobacteria were independently associated with BP. Discrete bacterial taxa were observed to correlate independently or interactively with one or more of the following 3 factors: (1) BP rhythm, (2) dietary salt, and (3) dip in BP. Phylogenetic Investigation of Communities revealed diurnal timing effects on microbial pathways, characterized by upregulated biosynthetic processes during the active phase of host, and upregulated degradation pathways of metabolites in the resting phase. Additional metagenomics functional pathways with rhythm variations were noted for aromatic amino acid metabolism and taurine metabolism. These diurnal timing dependent changes in microbiota, their functional pathways, and BP dip were associated with concerted effects of the levels of renal lipocalin 2 and kidney injury molecule-1 expression. These data provide evidence for a firm and concerted diurnal timing effects of BP, renal damage, and select microbial communities.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289684PMC
July 2020

Gnotobiotic Rats Reveal That Gut Microbiota Regulates Colonic mRNA of , the Receptor for SARS-CoV-2 Infectivity.

Hypertension 2020 07 19;76(1):e1-e3. Epub 2020 May 19.

From the Department of Physiology and Pharmacology, Microbiome Consortium, Center for Hypertension and Precision Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH (T.Y., S.C., P.S., B.M., X.C., J.-Y.Y., X.M., G.Z., J.M., R.G., B.S.Y., C.G.M., C.W., M.V.-K., B.J.).

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379164PMC
July 2020

Distinct iron homeostasis in C57BL/6 and Balb/c mouse strains.

Physiol Rep 2020 05;8(9):e14441

Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA.

C57BL/6 (BL6) and Balb/c mice exhibit prototypical Th1- and Th2-dominant immune predispositions, respectively. Iron is a proinflammatory metal ion; however, limited information is documented on the differences in iron homeostasis between BL6 and Balb/c strains. The objective of this study was to investigate the extent to which strain-level differences in these mice dictates the regulation of iron homeostasis during physiologic and inflammatory conditions. At basal levels, Balb/c mice displayed significantly higher levels of iron in systemic circulation and tissue compared to BL6 mice. Moreover, Balb/c mice had greater iron absorption as indicated by higher gene expressions of duodenal DcytB, DMT1, Fpn, SFT, and Heph. Similarly, hepatic Tf, TfR1, TfR2, and DMT1 expressions were augmented in Balb/c mice. Interestingly, there was no change in hepatic Hamp expression between the two strains, suggesting that the disparity in their maintenance of iron is independent of hepcidin. Additionally, the basal levels of intracellular labile iron pool in Balb/c intestinal epithelial cells, and bone marrow-derived macrophages and neutrophils, were higher compared to BL6 mice. When mice were challenged with lipopolysaccharide, the acute inflammatory response in BL6 mice was more pronounced than in Balb/c mice, as indicated by the more rapid development of hypoferremia and upregulation of serum IL-6 and TNF-α levels in BL6 mice. In conclusion, this study underscores that iron homeostasis is distinct between BL6 and Balb/c strains under both physiologic and inflammatory conditions.
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http://dx.doi.org/10.14814/phy2.14441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210116PMC
May 2020

Metabolites and Hypertension: Insights into Hypertension as a Metabolic Disorder: 2019 Harriet Dustan Award.

Hypertension 2020 06 27;75(6):1386-1396. Epub 2020 Apr 27.

From the Center for Hypertension and Precision Medicine and Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Ohio.

For over 100 years, essential hypertension has been researched from different perspectives ranging from genetics, physiology, and immunology to more recent ones encompassing microbiology (microbiota) as a previously underappreciated field of study contributing to the cause of hypertension. Each field of study in isolation has uniquely contributed to a variety of underlying mechanisms of blood pressure regulation. Even so, clinical management of essential hypertension has remained somewhat static. We, therefore, asked if there are any converging lines of evidence from these individual fields that could be amenable for a better clinical prognosis. Accordingly, here we present converging evidence which support the view that metabolic dysfunction underlies essential hypertension.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.13896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225070PMC
June 2020

Beneficial and detrimental effects of processed dietary fibers on intestinal and liver health: health benefits of refined dietary fibers need to be redefined!

Gastroenterol Rep (Oxf) 2020 Apr 20;8(2):85-89. Epub 2020 Jan 20.

UT-Microbiome Consortium, Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, OH, USA.

Consumption of processed foods-which are generally composed of nutritionally starved refined ingredients-has increased exponentially worldwide. A rise in public health awareness that low fiber intake is strongly linked to new-age disorders has spurred food manufacturers to fortify processed foods with refined dietary fibers (RDFs). Consumption of whole foods rich in natural fibers undoubtedly confers an array of health benefits. However, it is not clear whether RDFs extracted from the whole plant, kernel, and fruit peels exert similar physiological effects to their naturally occurring counterparts. Recent studies caution that RDFs are not universally beneficial and that inappropriate consumption of RDFs may risk both gastrointestinal and liver health. Herein, we briefly summarize the beneficial and detrimental effects of RDFs on digestive health and discuss the contribution of metabolites derived from microbial fermentation of RDFs in driving such positive or negative health outcomes.
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http://dx.doi.org/10.1093/gastro/goz072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136706PMC
April 2020

Harnessing innate immunity to eliminate SARS-CoV-2 and ameliorate COVID-19 disease.

Physiol Genomics 2020 05 10;52(5):217-221. Epub 2020 Apr 10.

UT Microbiome Consortium, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio.

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http://dx.doi.org/10.1152/physiolgenomics.00033.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200864PMC
May 2020

Vancomycin prevents fermentable fiber-induced liver cancer in mice with dysbiotic gut microbiota.

Gut Microbes 2020 07 30;11(4):1077-1091. Epub 2020 Mar 30.

Microbiome Consortium, Center for Hypertension and Precision Medicine, University of Toledo College of Medicine and Life Sciences , Toledo, OH, USA.

Owing to their health benefits, dietary fermentable fibers, such as refined inulin, are increasingly fortified in processed foods to enhance their nutritional value. However, we previously demonstrated that when inulin was fed to Toll-like receptor 5 deficient (T5KO) mice susceptible to dysbiosis, a subset of them developed cholestasis and subsequently liver cancer in a gut microbiota-dependent manner. Therefore, we hypothesized that clearance of bacterial taxa, and thereby gut metabolites, involved in the onset and progression to liver cancer could abate the disease in these mice. Such a reshaping of microbiota by vancomycin treatment was sufficient to halt the development of liver cancer in inulin-fed T5KO mice; however, this intervention did not remedy disease penetrance for cholestatic liver injury and its sequelae, including hyperbilirubinemia, hypolipidemia, cholemia and liver fibrosis. Selective depletion of gut bacterial communities was observed in vancomycin-treated mice, including Gram-positive and belonging to the phylum Firmicutes, of the phylum Actinobacteria, which ferment fibers, and Clostridium cluster XIVa, which produce secondary bile acids. Lack of liver cancer in vancomycin-treated mice strongly correlated with the substantial loss of secondary bile acids in circulation. Although cholemia was unabated by vancomycin, the composition of serum bile acids shifted toward an abundance of hydrophilic primary bile acids, denoted by the increase in conjugated-to-unconjugated bile acid ratio. Taken together, the present study suggests that microbiotal regulation of bile acid metabolism is one of the critical mediators of fermentable fiber-induced liver cancer in dysbiotic mice.
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http://dx.doi.org/10.1080/19490976.2020.1743492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524287PMC
July 2020

Fermentable fibers induce rapid macro- and micronutrient depletion in Toll-like receptor 5-deficient mice.

Am J Physiol Gastrointest Liver Physiol 2020 05 23;318(5):G955-G965. Epub 2020 Mar 23.

Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio.

Functional fermentable fibers are considered essential for a healthy diet. Recently, we demonstrated that gut microbiota dysbiotic mice fed an inulin-containing diet (ICD) developed hepatocellular carcinoma (HCC) within 6 mo. In particular, a subset of Toll-like receptor 5-deficient (T5KO) mice prone to HCC exhibited rapid onset of hyperbilirubinemia (HB) and cholemia; these symptoms provide rationale that ICD induces cholestasis. Our objective in the present study was to determine whether inulin-fed T5KO-HB mice exhibit other known consequences of cholestasis, including essential fatty acid and fat-soluble vitamin deficiencies. Here, we measured hepatic fatty acids and serum vitamin A and D levels from wild-type (WT), T5KO low bilirubin (LB) and T5KO-HB mice fed ICD for 4 wk. Additionally, hepatic RNAseq and proteomics were performed to ascertain other metabolic alterations. Compared with WT and T5KO-LB, T5KO-HB mice exhibited steatorrhea, i.e., ~50% increase in fecal lipids. This could contribute to the significant reduction of linoleate in hepatic neutral lipids in T5KO-HB mice. Additionally, serum vitamins A and D were ~50% reduced in T5KO-HB mice, which was associated with metabolic compromises. Overall, our study highlights that fermentable fiber-induced cholestasis is further characterized by depletion of macro-and micronutrients. Feeding a dietary, fermentable fiber diet to a subset of Toll-like receptor 5 deficient (T5KO) mice induces early onset hyperbilirubinemia and cholemia that later manifests to hepatocellular carcinoma (HCC). Our study highlights that fermentable fiber-induced cholestasis is characterized with modest macro- and micronutrient deficiencies that may further contribute to hepatic biliary disease. Compared with chemical induction, immunization, surgery, or genetic manipulation, these findings provide a novel approach to study the cholestatic subtype of HCC.
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http://dx.doi.org/10.1152/ajpgi.00349.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276927PMC
May 2020

Altered nutrient status reprograms host inflammation and metabolic health via gut microbiota.

J Nutr Biochem 2020 06 22;80:108360. Epub 2020 Feb 22.

UT Microbiome Consortium, Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614. Electronic address:

The metabolism of macro- and micronutrients is a complex and highly regulated biological process. An imbalance in the metabolites and their signaling networks can lead to nonresolving inflammation and consequently to the development of chronic inflammatory-associated diseases. Therefore, identifying the accumulated metabolites and altered pathways during inflammatory disorders would not only serve as "real-time" markers but also help in the development of nutritional therapeutics. In this review, we explore recent research that has delved into elucidating the effects of carbohydrate/calorie restriction, protein malnutrition, lipid emulsions and micronutrient deficiencies on metabolic health and inflammation. Moreover, we describe the integrated stress response in terms of amino acid starvation and lipemia and how this modulates new age diseases such as inflammatory bowel disease and atherosclerosis. Lastly, we explain the latest research on metaflammation and inflammaging. This review focuses on multiple signaling pathways, including, but not limited to, the FGF21-β-hydroxybutryate-NLRP3 axis, the GCN2-eIF2α-ATF4 pathway, the von Hippel-Lindau/hypoxia-inducible transcription factor pathway and the TMAO-PERK-FoxO1 axis. Additionally, throughout the review, we explain how the gut microbiota responds to altered nutrient status and also how antimicrobial peptides generated from nutrient-based signaling pathways can modulate the gut microbiota. Collectively, it must be emphasized that metabolic starvation and inflammation are strongly regulated by both environmental (i.e., nutrition, gut microbiome) and nonenvironmental (i.e., genetics) factors, which can influence the susceptibility to inflammatory disorders.
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http://dx.doi.org/10.1016/j.jnutbio.2020.108360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242157PMC
June 2020

Functional MAIT Cells Are Associated With Reduced Simian-Human Immunodeficiency Virus Infection.

Front Immunol 2019 17;10:3053. Epub 2020 Jan 17.

Emory Vaccine Center, Emory University, Atlanta, GA, United States.

Mucosa-associated invariant T (MAIT) cells are recently characterized as a novel subset of innate-like T cells that recognize microbial metabolites as presented by the MHC-1b-related protein MR1. The significance of MAIT cells in anti-bacterial defense is well-understood but not clear in viral infections such as SIV/HIV infection. Here we studied the phenotype, distribution, and function of MAIT cells and their association with plasma viral levels during chronic SHIV infection in rhesus macaques (RM). Two groups of healthy and chronic SHIV-infected macaques were characterized for MAIT cells in blood and mucosal tissues. Similar to human, we found a significant fraction of macaque T cells co-expressing MAIT cell markers CD161 and TCRVα-7.2 that correlated directly with macaque MR1 tetramer. These cells displayed memory phenotype and expressed high levels of IL-18R, CCR6, CD28, and CD95. During chronic infection, the frequency of MAIT cells are enriched in the blood but unaltered in the rectum; both blood and rectal MAIT cells displayed higher proliferative and cytotoxic phenotype post-SHIV infection. The frequency of MAIT cells in blood and rectum correlated inversely with plasma viral RNA levels and correlated directly with total CD4 T cells. MAIT cells respond to microbial products during chronic SHIV infection and correlated positively with serum immunoreactivity to flagellin levels. Tissue distribution analysis of MAIT cells during chronic infection showed significant enrichment in the non-lymphoid tissues (lung, rectum, and liver) compared to lymphoid tissues (spleen and LN), with higher levels of tissue-resident markers CD69 and CD103. Exogenous cytokine treatments during chronic SHIV infection revealed that IL-7 is important for the proliferation of MAIT cells, but IL-12 and IL-18 are important for their cytolytic function. Overall our results demonstrated that MAIT cells are enriched in blood but unaltered in the rectum during chronic SHIV infection, which displayed proliferative and functional phenotype that inversely correlated with SHIV plasma viral RNA levels. Treatment such as combined cytokine treatments could be beneficial for enhancing functional MAIT cells during chronic HIV infection .
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http://dx.doi.org/10.3389/fimmu.2019.03053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978843PMC
November 2020

Exposure to Amoxicillin in Early Life Is Associated With Changes in Gut Microbiota and Reduction in Blood Pressure: Findings From a Study on Rat Dams and Offspring.

J Am Heart Assoc 2020 01 11;9(2):e014373. Epub 2020 Jan 11.

Program in Physiological Genomics, Microbiome Consortium and Center for Hypertension and Precision Medicine Department of Physiology and Pharmacology University of Toledo College of Medicine and Life Sciences Toledo OH.

Background Pediatric hypertension is recognized as an emerging global health concern. Although new guidelines are developed for facilitating clinical management, the reasons for the prevalence of hypertension in children remain unknown. Genetics and environmental factors do not fully account for the growing incidence of pediatric hypertension. Because stable bacterial flora in early life are linked with health outcomes later in life, we hypothesized that reshaping of gut microbiota in early life affects blood pressure (BP) of pediatric subjects. Methods and Results To test this hypothesis, we administered amoxicillin, the most commonly prescribed pediatric antibiotic, to alter gut microbiota of young, genetically hypertensive rats (study 1) and dams during gestation and lactation (study 2) and recorded their BP. Reshaping of microbiota with reductions in Firmicutes/Bacteriodetes ratio were observed. Amoxicillin treated rats had lower BP compared with untreated rats. In young rats treated with amoxicillin, the lowering effect on BP persisted even after antibiotics were discontinued. Similarly, offspring from dams treated with amoxicillin showed lower systolic BP compared with control rats. Remarkably, in all cases, a decrease in BP was associated with lowering of Veillonellaceae, which are succinate-producing bacteria. Elevated plasma succinate is reported in hypertension. Accordingly, serum succinate was measured and found lower in animals treated with amoxicillin. Conclusions Our results demonstrate a direct correlation between succinate-producing gut microbiota and early development of hypertension and indicate that reshaping gut microbiota, especially by depleting succinate-producing microbiota early in life, may have long-term benefits for hypertension-prone individuals.
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http://dx.doi.org/10.1161/JAHA.119.014373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033837PMC
January 2020

Microbiota are critical for vascular physiology: Germ-free status weakens contractility and induces sex-specific vascular remodeling in mice.

Vascul Pharmacol 2020 Feb - Mar;125-126:106633. Epub 2019 Dec 13.

Microbiome Consortium, Center for Hypertension and Precision Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine & Life Sciences, Toledo, OH, USA. Electronic address:

Commensal microbiota within a holobiont contribute to the overall health of the host via mutualistic symbiosis. Disturbances in such symbiosis is prominently correlated with a variety of diseases affecting the modern society of humans including cardiovascular diseases, which are the number one contributors to human mortality. Given that a hallmark of all cardiovascular diseases is changes in vascular function, we hypothesized that depleting microbiota from a holobiont would induce vascular dysfunction. To test this hypothesis, young mice of both sexes raised in germ-free conditions were examined vascular contractility and structure. Here we observed that male and female germ-free mice presented a decrease in contraction of resistance arteries. These changes were more pronounced in germ-free males than in germ-free females mice. Furthermore, there was a distinct change in vascular remodeling between males and females germ-free mice. Resistance arteries from male germ-free mice demonstrated increased vascular stiffness, as shown by the leftward shift in the stress-strain curve and inward hypotrophic remodeling, a characteristic of chronic reduction in blood flow. On the other hand, resistance arteries from germ-free female mice were similar in the stress-strain curves to that of conventionally raised mice, but were distinctly different and showed outward hypertrophic remodeling, a characteristic seen in aging. Interestingly, we observed that reactive oxygen species (ROS) generation from bone marrow derived neutrophils is blunted in female germ-free mice, but it is exacerbated in male germ-free mice. In conclusion, these observations indicate that commensal microbiota of a holobiont are central to maintain proper vascular function and structure homeostasis, especially in males.
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http://dx.doi.org/10.1016/j.vph.2019.106633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036036PMC
October 2020

Vertical selection for nuclear and mitochondrial genomes shapes gut microbiota and modifies risks for complex diseases.

Physiol Genomics 2020 01 25;52(1):1-14. Epub 2019 Nov 25.

Microbiome Consortium and Center for Hypertension and Precision Medicine, Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio.

Here we postulate that the heritability of complex disease traits previously ascribed solely to the inheritance of the nuclear and mitochondrial genomes is broadened to encompass a third component of the holobiome, the microbiome. To test this, we expanded on the selectively bred low capacity runner/high capacity runner (LCR/HCR) rat exercise model system into four distinct rat holobiont model frameworks including matched and mismatched host nuclear and mitochondrial genomes. Vertical selection of varying nuclear and mitochondrial genomes resulted in differential acquisition of the microbiome within each of these holobiont models. Polygenic disease risk of these novel models were assessed and subsequently correlated with patterns of acquisition and contributions of their microbiomes in controlled laboratory settings. Nuclear-mitochondrial-microbiotal interactions were not for exercise as a reporter of health, but significantly noted for increased adiposity, increased blood pressure, compromised cardiac function, and loss of long-term memory as reporters of disease susceptibility. These findings provide evidence for coselection of the microbiome with nuclear and mitochondrial genomes as an important feature impacting the heritability of complex diseases.
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http://dx.doi.org/10.1152/physiolgenomics.00089.2019DOI Listing
January 2020

"Western Diet"-Induced Adipose Inflammation Requires a Complex Gut Microbiota.

Cell Mol Gastroenterol Hepatol 2020 5;9(2):313-333. Epub 2019 Oct 5.

Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia. Electronic address:

Background & Aims: Consumption of a low-fiber, high-fat, Western-style diet (WSD) induces adiposity and adipose inflammation characterized by increases in the M1:M2 macrophage ratio and proinflammatory cytokine expression, both of which contribute to WSD-induced metabolic syndrome. WSD-induced adipose inflammation might result from endoplasmic reticulum stress in lipid-overloaded adipocytes and/or dissemination of gut bacterial products, resulting in activation of innate immune signaling. Hence, we aimed to investigate the role of the gut microbiota, and its detection by innate immune signaling pathways, in WSD-induced adipose inflammation.

Methods: Mice were fed grain-based chow or a WSD for 8 weeks, assessed metabolically, and intestinal and adipose tissue were analyzed by flow cytometry and quantitative reverse transcription polymerase chain reaction. Microbiota was ablated via antibiotics and use of gnotobiotic mice that completely lacked microbiota (germ-free mice) or had a low-complexity microbiota (altered Schaedler flora). Innate immune signaling was ablated by genetic deletion of Toll-like receptor signaling adaptor myeloid differentiation primary response 88.

Results: Ablation of microbiota via antibiotic, germ-free, or altered Schaedler flora approaches did not significantly impact WSD-induced adiposity, yet dramatically reduced WSD-induced adipose inflammation as assessed by macrophage populations and cytokine expression. Microbiota ablation also prevented colonic neutrophil and CD103 dendritic cell infiltration. Such reduced indices of inflammation correlated with protection against WSD-induced dysglycemia, hypercholesterolemia, and liver dysfunction. Genetic deletion of myeloid differentiation primary response 88 also prevented WSD-induced adipose inflammation.

Conclusions: These results indicate that adipose inflammation, and some aspects of metabolic syndrome, are not purely a consequence of diet-induced adiposity per se but, rather, may require disturbance of intestine-microbiota interactions and subsequent activation of innate immunity.
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http://dx.doi.org/10.1016/j.jcmgh.2019.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957826PMC
May 2021

Inflammation induces stress erythropoiesis through heme-dependent activation of SPI-C.

Sci Signal 2019 09 10;12(598). Epub 2019 Sep 10.

Intercollege Graduate Program in Genetics, Penn State University, University Park, PA 16802, USA.

Inflammation alters bone marrow hematopoiesis to favor the production of innate immune effector cells at the expense of lymphoid cells and erythrocytes. Furthermore, proinflammatory cytokines inhibit steady-state erythropoiesis, which leads to the development of anemia in diseases with chronic inflammation. Acute anemia or hypoxic stress induces stress erythropoiesis, which generates a wave of new erythrocytes to maintain erythroid homeostasis until steady-state erythropoiesis can resume. Although hypoxia-dependent signaling is a key component of stress erythropoiesis, we found that inflammation also induced stress erythropoiesis in the absence of hypoxia. Using a mouse model of sterile inflammation, we demonstrated that signaling through Toll-like receptors (TLRs) paradoxically increased the phagocytosis of erythrocytes (erythrophagocytosis) by macrophages in the spleen, which enabled expression of the heme-responsive gene encoding the transcription factor SPI-C. Increased amounts of SPI-C coupled with TLR signaling promoted the expression of and , both of which encode ligands that initiate the expansion of stress erythroid progenitors (SEPs) in the spleen. Furthermore, despite their inhibition of steady-state erythropoiesis in the bone marrow, the proinflammatory cytokines TNF-α and IL-1β promoted the expansion and differentiation of SEPs in the spleen. These data suggest that inflammatory signals induce stress erythropoiesis to maintain erythroid homeostasis when inflammation inhibits steady-state erythropoiesis.
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http://dx.doi.org/10.1126/scisignal.aap7336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904953PMC
September 2019

Enterobactin, an iron chelating bacterial siderophore, arrests cancer cell proliferation.

Biochem Pharmacol 2019 10 19;168:71-81. Epub 2019 Jun 19.

Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA; Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, OH 43614, USA. Electronic address:

Iron is essential for many biological functions, including being a cofactor for enzymes involved in cell proliferation. In line, it has been shown that cancer cells can perturb their iron metabolism towards retaining an abundant iron supply for growth and survival. Accordingly, it has been suggested that iron deprivation through the use of iron chelators could attenuate cancer progression. While they have exhibited anti-tumor properties in vitro, the current therapeutic iron chelators are inadequate due to their low efficacy. Therefore, we investigated whether the bacterial catecholate-type siderophore, enterobactin (Ent), could be used as a potent anti-cancer agent given its strong iron chelation property. We demonstrated that iron-free Ent can exert cytotoxic effects specifically towards monocyte-related tumor cell lines (RAW264.7 and J774A.1), but not primary cells, i.e. bone marrow-derived macrophages (BMDMs), through two mechanisms. First, we observed that RAW264.7 and J774A.1 cells preserve a bountiful intracellular labile iron pool (LIP), whose homeostasis can be disrupted by Ent. This may be due, in part, to the lower levels of lipocalin 2 (Lcn2; an Ent-binding protein) in these cell lines, whereas the higher levels of Lcn2 in BMDMs could prevent Ent from hindering their LIP. Secondly, we observed that Ent could dose-dependently impede reactive oxygen species (ROS) generation in the mitochondria. Such disruption in LIP balance and mitochondrial function may in turn promote cancer cell apoptosis. Collectively, our study highlights Ent as an anti-cancer siderophore, which can be exploited as an unique agent for cancer therapy.
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http://dx.doi.org/10.1016/j.bcp.2019.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733644PMC
October 2019

Pressure From the Bugs Within.

Hypertension 2019 05;73(5):977-979

Microbiome Consortium, Center for Hypertension and Precision Medicine, University of Toledo College of Medicine and Life Sciences, OH (S.C., M.V.-K., B.J.).

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.12685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478159PMC
May 2019

Adaptive Immunity Induces Tolerance to Flagellin by Attenuating TLR5 and NLRC4-Mediated Innate Immune Responses.

Front Cell Infect Microbiol 2019 19;9:29. Epub 2019 Feb 19.

Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, United States.

The host immune system is constantly exposed to diverse microbial ligands, including flagellin (FliC; a ligand for TLR5 and NLRC4) and lipopolysaccharide (LPS; a ligand for TLR4), which could induce immune tolerance to subsequent exposure. Herein, we investigated the extent to which FliC induces self-tolerance and the role of adaptive immunity in mediating such effect. Mice pre-treated with FliC displayed attenuated serum keratinocyte-derived chemokine (KC), interleukin (IL)-6 and IL-18 responses to secondary challenge of FliC. A negative correlation was observed between high anti-FliC titer and reduced KC, IL-6, and IL-18 responses upon FliC re-challenge in WT mice, but not KO mice, suggesting that adaptive immunity could tolerize TLR5 and NLRC4. However, administration of LPS during FliC pre-treatment impaired the generation of anti-FliC antibodies and resulted in a partial loss of self-tolerance to FliC re-challenge. These findings may be relevant in the context of bacterial infection, as we observed that anti-FliC response are protective against systemic infection by . Taken together, our study delineates a distinct co-operative and reciprocal interaction between the innate and adaptive arms of immunity in modulating their responses to a bacterial protein.
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http://dx.doi.org/10.3389/fcimb.2019.00029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390806PMC
November 2019

Deoxyribonuclease I Activity, Cell-Free DNA, and Risk of Liver Cancer in a Prospective Cohort.

JNCI Cancer Spectr 2018 Dec 21;2(4):pky083. Epub 2019 Feb 21.

Background: Circulating cell-free DNA (cfDNA) is a proposed latent biomarker for several cancers, including liver cancer. Deoxyribonucleases (DNases) facilitate the timely and efficient degradation of cfDNA, leading us to hypothesize that DNase I and/or II might be a more sensitive early biomarker than cfDNA. To test this hypothesis, a study was conducted in a large, prospective cohort.

Methods: A nested case-control study (224 liver cancer case patients and 224 matched control subjects) was conducted in a cohort of Finnish male smokers, followed from baseline (1985-1988) to 2014. The associations among DNase I activity, cfDNA, and the risk of liver cancer were assessed using multivariable-adjusted conditional logistic regression.

Results: DNase I activity, whether measured as radius (mm) or as units per milliliter, was statistically significantly associated with increased risk of liver cancer ( <.01). DNase I activity in the highest quartile was associated with a greater than threefold risk of developing liver cancer (DNase I activity radius >2.7 mm, hazard ratio [HR] = 3.03, 95% confidence interval [CI] = 1.59 to 5.77; DNase I activity >2.72 units/mL, HR = 3.30, 95% CI = 1.64 to 6.65). The strength of this association was not substantially altered by exclusion of cases diagnosed within the first five years of follow-up or those with hepatitis C virus (HCV) infection. In contrast, cfDNA and DNase II was not statistically significantly associated with risk of liver cancer.

Conclusions: DNase I activity was a superior latent biomarker of liver cancer than cfDNA. These findings advance the goal of developing a means to detect liver cancer years well before the development of clinical manifestations.
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http://dx.doi.org/10.1093/jncics/pky083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383694PMC
December 2018