FASEB bioAdvances最新文献

{"title":"“Student-led workshop strengthens perceived discussion skills and community in an interdisciplinary graduate program”","authors":"Catharine Shipps,&nbsp;Kyra L. Thrush,&nbsp;Clorice R. Reinhardt,&nbsp;Sara A. Siwiecki,&nbsp;Jennifer L. Claydon,&nbsp;Dorottya B. Noble,&nbsp;Corey S. O'Hern","doi":"10.1096/fba.2021-00165","DOIUrl":"10.1096/fba.2021-00165","url":null,"abstract":"<p>The Integrated Graduate Program in Physical and Engineering Biology (IGPPEB) at Yale University brings together Ph.D. students from the physical, engineering, and biological sciences. The main goals of this program are for students to become comfortable working in an interdisciplinary and collaborative research environment and adept at communicating with scientists and nonscientists. To fill a student-identified learning gap in engaging in inclusive discussions, IGPPEB students developed a communication workshop to improve skills in visual engagement, citing specific content, constructive conversation entrances, and encouragement of peers. Based on short- and long-term assessment of the workshop, 100% of students reported that it should be offered to future cohorts and 63% of students perceived it to be personally helpful. Additionally, 92% of participants reported using one or more of the core skills beyond the course, with skills in “Encouraging peers” and “Constructive conversation entrances” rated the highest in perceived improvement. Based on the highest average rating of 76 ± 24 (on a scale of 0–100), students agreed that the workshop made them feel more welcome in the IGPPEB community. With a rating of 68 ± 13, they also agreed that the workshop had a positive impact on their graduate school experience. Participants provided suggestions for future improvements, such as increasing student involvement in leading discussions of course material. This study demonstrates that a student-led workshop can improve perceived discussion skills and build community across an interdisciplinary program in the sciences.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"5 1","pages":"1-12"},"PeriodicalIF":2.7,"publicationDate":"2022-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fba.2021-00165","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10535605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"When women win, we all win—Call for a gendered global NCD agenda","authors":"Christine Ngaruiya","doi":"10.1096/fba.2021-00140","DOIUrl":"10.1096/fba.2021-00140","url":null,"abstract":"<p>Gender is a social determinant of health, interacting with other factors such as income, education, and housing and affects health care access and health care outcomes. This paper reviews key literature and policies on health disparities and gender disparities within health. It examines noncommunicable disease (NCD) health outcomes through a gender lens and challenges existing prevailing measures of success for NCD outcomes that focus primarily on mortality. Chronic respiratory disease, one of the four leading contributors to NCD mortality, is highlighted as a case study to demonstrate the gender gap. Women have different risk factors and higher morbidity for chronic respiratory disease compared to men but morbidity is shadowed by a penultimate research focus on mortality, which results in less attention to the gap in women's NCD outcomes. This, in turn, affects how resources, programs, and interventions are implemented. It will likely slow progress in reducing overall NCD burden if we do not address risk factors in an equitable fashion. The article closes with recommendations to address these gender gaps in NCD outcomes. At the policy level, increasing representation and inclusion in global public health leadership, prioritizing NCDs among marginalized populations by global health societies and political organizations, aligning the gendered global NCD agenda with other well-established movements will each catalyze change for gender-based disparities in global NCDs specifically. Lastly, incorporating gender-based indicators and targets in major NCD-related goals and advancing gender-based NCD research will strengthen the evidence base for women's unique NCD risks and health outcomes.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"4 12","pages":"741-757"},"PeriodicalIF":2.7,"publicationDate":"2022-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9721093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9170260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ralph A. Bradshaw: Scholar, leader, entrepreneur","authors":"Philip D. Stahl","doi":"10.1096/fba.2022-00088","DOIUrl":"10.1096/fba.2022-00088","url":null,"abstract":"&lt;p&gt;Ralph Bradshaw, sage colleague, entrepreneur, gifted editor, and prescient scientist, recently stepped down as the Editor in Chief of &lt;i&gt;FASEB BioAdvances&lt;/i&gt;. This presents the opportunity to pause and reflect on the career of an extraordinary individual, whose continuing commitment to science, science publishing, and the scholarly societies that represent and advocate for us all, illustrates the exceptional. Ralph's career reflects an unyielding dedication to those goals that we all strive to achieve—scholarship with high standards, leadership, service, and entrepreneurship.&lt;/p&gt;&lt;p&gt;Ralph grew up in the Boston area and attended Colby College, where he majored in chemistry; he completed his doctorate with Robert Hill in the Biochemistry Department at Duke, where his thesis work focused on protein chemistry. His postdoctoral work at Indiana University in the laboratory of Frank Gurd and the University of Washington in the laboratory of Hans Neurath allowed him to refine his repertoire of protein sequencing and analytic methodologies. P. Roy Vagelos (former CEO of Merck and former department head at Washington University) recruited Ralph to the Department of Biological Chemistry at Washington University as Roy began a highly successful renovation and rebuilding of the department after the long reign of Carl Cori. This is where I first met Ralph, as we were newly appointed assistant professors in biochemistry and physiology, respectively, and shared our interest in graduate education.&lt;/p&gt;&lt;p&gt;In 1973, Vagelos and colleagues at Washington University advanced a novel approach to graduate education in the biological and biomedical sciences, the Division of Biology and Biomedical Sciences (DBBS)—recently named the Roy and Diana Vagelos Division of Biology and Biomedical Sciences. The idea was based on the ongoing diversification of medical and biological research, where the traditional departmental boundaries that separated disparate “fields of research” were increasingly seen as hardened silos that suppressed innovation and reduced opportunities for graduate research. By creating programs built on common faculty interests rather than departmental affiliation, cross disciplinary opportunities for graduate research flourished—this approach in one form or another is now common among nearly all research institutions. Ralph Bradshaw played a key role in getting the DBBS off the ground—perhaps a precursor to his now well appreciated organizational skills. He was appointed the first chair of the newly formed graduate admissions committee, an enthusiastic recruiter of talented students to the programs and the principal investigator on one of the first NIH training grants under this new umbrella. Roy Vagelos commented, “Bradshaw was an enthusiastic and very effective recruiter of graduate students to Washington University. When the DBBS faculty decided that the University should have greater diversity among its graduate students, Ralph led a small group of facu","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"4 11","pages":"691-693"},"PeriodicalIF":2.7,"publicationDate":"2022-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9635006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40673514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bone marrow-derived extracellular vesicles modulate the abundance of infiltrating immune cells in the brain and exert an antiviral effect against the Japanese encephalitis virus","authors":"Naina Soni,&nbsp;Aarti Tripathi,&nbsp;Sriparna Mukherjee,&nbsp;Suchi Gupta,&nbsp;Sujata Mohanty,&nbsp;Anirban Basu,&nbsp;Arup Banerjee","doi":"10.1096/fba.2022-00071","DOIUrl":"10.1096/fba.2022-00071","url":null,"abstract":"<p>Mesenchymal stem cells (MSCs) have regenerative capacity and have reported a beneficial effect on the Japanese encephalitis virus (JEV) in an encephalitis model. However, the MSCs do not cross the blood–brain barrier and have other disadvantages limiting their therapeutic utility scope. Recently, there has been a shift in concept from a cell-based to a cell-free approach using MSCs-derived extracellular vesicles (MSC-EVs). The MSC-EVs retain regenerative and immunomodulatory capacity as their parental cells. However, the role of MSC-EVs in limiting JEV pathology remains elusive. In this study, we have used Bone marrow (BM)-derived EV (BM-EVs) and assessed their effect on JEV replication and pathogenesis in primary neuronal stem cells and a murine model. The in vitro and in vivo studies suggested that BM-derived EVs delay JEV-induced symptoms and death in mice, improve the length of survival, accelerate neurogenesis in primary neuronal stem cells, reduce JEV-induced neuronal death, and attenuate viral replication. BM-EVs treatment upregulated interferon-stimulated genes. Flow cytometry analysis revealed a reduction in the frequency of macrophages. At the same time, CD4+ T cells and neutrophils were significantly augmented, accompanied by the alteration of cytokine expression with the administration of BM-EVs, reinforcing the immunomodulatory role of EVs during JEV-induced encephalitis. In conclusion, our study describes the beneficial role of BM-EVs in limiting JEV pathology by attenuating virus replication, enhancing antiviral response, and neurogenesis in primary neuronal stem cells. However, BM-EVs do not seem to protect BBB integrity and alter immune cell infiltration into the treated brain.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"4 12","pages":"798-815"},"PeriodicalIF":2.7,"publicationDate":"2022-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9721092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10433263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic regulation of the transcriptome and proteome of the equine embryo during maternal recognition of pregnancy","authors":"Alba Rudolf Vegas,&nbsp;Giorgia Podico,&nbsp;Igor F. Canisso,&nbsp;Heinrich Bollwein,&nbsp;Thomas Fröhlich,&nbsp;Stefan Bauersachs,&nbsp;Carmen Almiñana","doi":"10.1096/fba.2022-00063","DOIUrl":"10.1096/fba.2022-00063","url":null,"abstract":"<p>During initial maternal recognition of pregnancy (MRP), the equine embryo displays a series of unique events characterized by rapid blastocyst expansion, secretion of a diverse array of molecules, and transuterine migration to interact with the uterine surface. Up to date, the intricate transcriptome and proteome changes of the embryo underlying these events have not been critically studied in horses. Thus, the objective of this study was to perform an integrative transcriptomic (including mRNA, miRNAs, and other small non-coding RNAs) and proteomic analysis of embryos collected from days 10 to 13 of gestation. The results revealed dynamic transcriptome profiles with a total of 1311 differentially expressed genes, including 18 microRNAs (miRNAs). Two main profiles for mRNAs and miRNAs were identified, one with higher expression in embryos ≤5 mm and the second with higher expression in embryos ≥7 mm. At the protein level, similar results were obtained, with 259 differentially abundant proteins between small and large embryos. Overall, the findings demonstrated fine-tuned transcriptomic and proteomic regulations in the developing embryo associated with embryo growth. The identification of specific regulation of mRNAs, proteins, and miRNAs on days 12 and 13 of gestation suggested these molecules as pivotal for embryo development and as involved in MRP, and in establishment of pregnancy in general. In addition, the results revealed new insights into prostaglandin synthesis by the equine embryo, miRNAs and genes potentially involved in modulation of the maternal immune response, regulation of endometrial receptivity and of late implantation in the mare.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"4 12","pages":"775-797"},"PeriodicalIF":2.7,"publicationDate":"2022-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9721094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10433264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fusion of the β2-adrenergic receptor with either Gαs or βarrestin-2 produces constitutive signaling by each pathway and induces gain-of-function in BEAS-2B cells","authors":"Emilio Y. Lucero-Garcia Rojas,&nbsp;Arfaxad Reyes-Alcaraz,&nbsp;Kehe Ruan,&nbsp;Bradley K. McConnell,&nbsp;Richard A. Bond","doi":"10.1096/fba.2022-00038","DOIUrl":"10.1096/fba.2022-00038","url":null,"abstract":"<p>The β₂AR is a prototypical G protein-coupled receptor (GPCR) known to orchestrate different cellular responses by the stimulation of specific signaling pathways. The best-established signaling pathways for the β₂AR are the canonical Gs pathway and the alternative β arrestin 2 (βarr2) pathway. Exploring each pathway separately remains a challenging task due to the dynamic nature of the receptor. Here, we fused the β₂AR with its cognate transducers, Gαs and βarr2, using short linkers as a novel approach for restricting the conformation of the receptor and preferentially activating one of its two signaling pathways. We characterized the behavior of our fusion proteins β₂AR-Gαs and β₂AR-βarr2 in HEK293 cells by measuring their constitutive activity, transducer recruitment, and pharmacological modulation. Our fusion proteins show (a) steric hindrance from the reciprocal endogenous transducers, (b) constitutive activity of the β₂AR for the signaling pathway activated by the tethered transducer, and (c) pharmacologic modulation by β₂AR ligands. Based on these characteristics, we further explored the possibility of a gain-of-function mechanism in the human lung non-tumorigenic epithelial cell line, BEAS-2B cells. This immortalized human bronchial epithelial cell line has immunomodulatory properties through cytokine release mediated by β₂AR stimulation. Our findings suggest that each signaling pathway of the β₂AR is biased toward either the Th1 or Th2 inflammatory response suggesting a role in regulating the immune phenotype of respiratory diseases. Our data imply that our fusion proteins can be used as tools to isolate the function elicited by a single signaling pathway in physiologically relevant cell types.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"4 12","pages":"758-774"},"PeriodicalIF":2.7,"publicationDate":"2022-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ca/bb/FBA2-4-758.PMC9721090.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10433260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of insulin-like growth factor 2 mRNA-binding protein 1 sensitizes colorectal cancer cells to chemotherapeutics","authors":"Nicole Betson,&nbsp;Mohammed Hajahmed,&nbsp;Tsige Gebretsadek,&nbsp;Kenneth Ndebele,&nbsp;H. Anwar Ahmad,&nbsp;Paul B. Tchounwou,&nbsp;Vladimir S. Spiegelman,&nbsp;Felicite K. Noubissi","doi":"10.1096/fba.2021-00069","DOIUrl":"10.1096/fba.2021-00069","url":null,"abstract":"<p>Although colorectal cancer (CRC) treatment has seen a remarkable improvement in the recent years, many patients will develop metastasis due to the resistance of cancer cells to chemotherapeutics. Targeting mechanisms driving the resistance of CRC cells to treatment would significantly reduce cases of metastasis and death. Induction of insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), a direct target of the Wnt/β-catenin signaling pathway, might promote resistance of CRC cells to treatment via activation of anti-apoptotic pathways and induction of the multidrug resistance (MDR1) membrane transporter that pumps drugs out of the cells. We hypothesized that inhibition of IGF2BP1 will sensitize CRC cells to chemotherapeutics. We used CRC cell lines with different status of activation of Wnt signaling to show that inhibition of IGF2BP1 potentiates the anti-growth and anti-proliferative effects of chemotherapeutics on CRC cells with activated Wnt/β-catenin signaling pathway. We observed that the inhibition of IGF2BP1 significantly increases apoptosis in the same cells. A remarkable reduction in the migratory capability of those cells was noted as well. We found that inhibition of IGF2BP1 is sufficient to decrease the resistance of chemotherapy-resistant cancer cells with activated Wnt/β-catenin signaling pathway. These findings portray IGF2BP1 as a good candidate for CRC therapy.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"4 12","pages":"816-829"},"PeriodicalIF":2.7,"publicationDate":"2022-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ef/06/FBA2-4-816.PMC9721091.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10433265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transgenic overexpression of α7 integrin in smooth muscle attenuates allergen-induced airway inflammation in a murine model of asthma","authors":"Mariam A. Ba,&nbsp;Annemarie Aiyuk,&nbsp;Karla Hernández,&nbsp;Jon M. Evasovic,&nbsp;Ryan D. Wuebbles,&nbsp;Dean J. Burkin,&nbsp;Cherie A. Singer","doi":"10.1096/fba.2022-00050","DOIUrl":"10.1096/fba.2022-00050","url":null,"abstract":"<p>Asthma is a chronic inflammatory disorder of the lower airways characterized by modulation of airway smooth muscle (ASM) function. Infiltration of smooth muscle by inflammatory mediators is partially regulated by transmembrane integrins and the major smooth muscle laminin receptor α7β1 integrin plays a critical role in the maintenance of ASM phenotype. The goal of the current study was to investigate the role of α7 integrin in asthma using smooth muscle-specific α7 integrin transgenic mice (TgSM-Itgα7) using both acute and chronic OVA sensitization and challenge protocols that mimic mild to severe asthmatic phenotypes. Transgenic over-expression of the α7 integrin in smooth muscle resulted in a significant decrease in airway resistance relative to controls, reduced the total number of inflammatory cells and substantially inhibited the production of crucial Th2 and Th17 cytokines in airways. This was accompanied by decreased secretion of various inflammatory chemokines such as eotaxin/CCL11, KC/CXCL3, MCP-1/CCL2, and MIP-1β/CCL4. Additionally, α7 integrin overexpression significantly decreased ERK1/2 phosphorylation in the lungs of TgSM-Itgα7 mice and affected proliferative, contractile, and inflammatory downstream effectors of ERK1/2 that drive smooth muscle phenotype in the lung. Taken together, these results support the hypothesis that enhanced expression of α7 integrin in vivo inhibits allergic inflammation and airway resistance. Moreover, we identify ERK1/2 as a potential target by which α7 integrin signals to regulate airway inflammation. We conclude that identification of therapeutics targeting an increase in smooth muscle α7 integrin expression could serve as a potential novel treatment for asthma.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"4 11","pages":"724-740"},"PeriodicalIF":2.7,"publicationDate":"2022-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ef/57/FBA2-4-724.PMC9635010.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40673515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multienzyme activity profiling for evaluation of cell-to-cell variability of metabolic state","authors":"Govind S. Gill,&nbsp;Michael C. Schultz","doi":"10.1096/fba.2022-00073","DOIUrl":"10.1096/fba.2022-00073","url":null,"abstract":"<p>In solid organs, cells of the same “type” can vary in their molecular phenotype. The basis of this state variation is being revealed by characterizing cell features including the expression pattern of mRNAs and the internal distribution of proteins. Here, the variability of metabolic state between cells is probed by enzyme activity profiling. We study individual cells of types that can be identified during the post-mitotic phase of oogenesis in Xenopus laevis. Whole-cell homogenates of isolated oocytes are used for kinetic analysis of enzymes, with a focus on the initial reaction rate. For each oocyte type studied, the activity signatures of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and malate dehydrogenase 1 (MDH1) vary more between the homogenates of single oocytes than between repeat samplings of control homogenates. Unexpectedly, the activity signatures of GAPDH and MDH1 strongly co-vary between oocytes of each type and change in strength of correlation during oogenesis. Therefore, variability of the kinetic behavior of these housekeeping enzymes between “identical” cells is physiologically programmed. Based on these findings, we propose that single-cell profiling of enzyme kinetics will improve understanding of how metabolic state heterogeneity is related to heterogeneity revealed by omics methods including proteomics, epigenomics, and metabolomics.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"4 11","pages":"709-723"},"PeriodicalIF":2.7,"publicationDate":"2022-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/d7/e3/FBA2-4-709.PMC9635011.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40673517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regional brain activation during rectal distention and attenuation with alosetron in a nonhuman primate model of irritable bowel syndrome","authors":"Rintaro Fujii,&nbsp;Yuji Awaga,&nbsp;Kenya Nozawa,&nbsp;Mayumi Matsushita,&nbsp;Aldric Hama,&nbsp;Takahiro Natsume,&nbsp;Hiroyuki Takamatsu","doi":"10.1096/fba.2022-00048","DOIUrl":"10.1096/fba.2022-00048","url":null,"abstract":"<p>Greater understanding of the mechanism that mediates visceral pain and hypersensitivity associated with irritable bowel syndrome (IBS) would facilitate the development of effective therapeutics to manage these symptoms. An objective marker associated with the underlying mechanisms of visceral pain and hypersensitivity could be used to guide therapeutic development. The current study examined brain activation evoked by rectal distention with functional magnetic resonance imaging (fMRI) in a cynomolgus macaque model of visceral hypersensitivity. Male, cynomolgus macaques underwent five four-week treatments of dextran sodium sulfate (DSS)-distilled water (DW), which induced mild–moderate colitis with remission during each treatment cycle. Balloon rectal distention (RD) was performed under anesthesia 14 weeks after the final DSS-DW treatment. Colonoscopy confirmed the absence of colitis prior to the start of RD. In naïve, untreated macaques, 10, 20 and 30 ml RD did not evoke brain activation. However, insular cortex/somatosensory II cortex and cerebellum were significantly activated in DSS-treated macaques at 20 and 30 ml rectal distention. Intra-rectal pressure after DSS treatment was not significantly different from that of naïve, untreated macaques, indicating lack of alteration of rectal functioning following DSS-treatment. Treatment with 5-HT₃ receptor antagonist alosetron (p.o.) reduced distension-evoked brain activation and decreased intra-rectal pressure. The current findings demonstrated activation of brain regions to RD following DSS treatments which was not present in naïve macaques, suggesting visceral hypersensitivity. Brain activation in turn was reduced by alosetron, which could underlie the analgesic effect alosetron in IBS patients.</p>","PeriodicalId":12093,"journal":{"name":"FASEB bioAdvances","volume":"4 11","pages":"694-708"},"PeriodicalIF":2.7,"publicationDate":"2022-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/07/c9/FBA2-4-694.PMC9635009.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40673516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}