{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T02:22:37Z","timestamp":1783477357017,"version":"3.55.0"},"reference-count":51,"publisher":"American Physiological Society","issue":"6","funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences (NIGMS)","doi-asserted-by":"publisher","award":["SC1GM121282"],"award-info":[{"award-number":["SC1GM121282"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"NIDDK","doi-asserted-by":"crossref","award":["R21DKO76704"],"award-info":[{"award-number":["R21DKO76704"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100006545","name":"NIMHD","doi-asserted-by":"crossref","award":["5U54MD007593-09"],"award-info":[{"award-number":["5U54MD007593-09"]}],"id":[{"id":"10.13039\/100006545","id-type":"DOI","asserted-by":"crossref"}]},{"name":"K22","award":["1K22CA197074"],"award-info":[{"award-number":["1K22CA197074"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2018,12,1]]},"abstract":"<jats:p> An impaired nitrergic system and altered redox signaling contribute to gastric dysmotility in diabetics. Our earlier studies show that NF-E2-related factor 2 (NRF2) and phase II antioxidant enzymes play a vital role in gastric neuronal nitric oxide synthase (nNOS) function. This study aims to investigate whether supplementation of sepiapterin (SEP), a precursor for tetrahydrobiopterin (BH<jats:sub>4<\/jats:sub>) (a cofactor of NOS) via the salvage pathway, restores altered nitrergic systems and redox balance in spontaneous diabetic (DB) female rats. Twelve-week spontaneous DB and age-matched, non-DB rats, with and without dietary SEP (daily 20 mg\/kg body wt for 10 days) treatment, were used in this study. Gastric antrum muscular tissues were excised to investigate the effects of SEP in nitrergic relaxation and the nNOS-nitric oxide (NO)-NRF2 pathway(s). Dietary SEP supplementation significantly ( P &lt; 0.05) reverted diabetes-induced changes in nNOS dimerization and function; nitric oxide (NO) downstream signaling molecules; HSP-90, a key regulator of nNOS\u03b1 activity and dimerization; miRNA-28 that targets NRF2 messenger RNA (mRNA), and levels of microRNA (miRNA) biogenesis pathway components, such as DGCR8 (DiGeorge Syndrome Critical Region Gene 8) and TRBP (HIV1-1 transactivating response RNA-binding protein). These findings emphasize the importance of the BH<jats:sub>4<\/jats:sub> pathway in regulating gastric motility functions in DB animals by modulating nNOS\u03b1 dimerization in association with changes in enteric NRF2 and NO downstream signaling. Our results also identify a new pathway, wherein SEP regulates NRF2 mRNA turnover by suppressing elevated miRNA-28, which could be related to alterations in miRNA biogenesis pathway components. <\/jats:p><jats:p> NEW &amp; NOTEWORTHY This study is the first to show a causal link between NF-E2-related factor 2 (NRF2) and neuronal nitric oxide synthase (nNOS) in gastric motility function. Our data demonstrate that critical regulators of the miRNA biosynthetic pathway are upregulated in the diabetic (DB) setting; these regulators were rescued by sepiapterin (SEP) treatment. Finally, we show that low dihydrofolate reductase expression may lead to impaired nNOS dimerization\/function-reduced nitric oxide downstream signaling and elevate oxidative stress by suppressing the NRF2\/phase II pathway through miRNA; SEP treatment restored all of the above in DB gastric muscular tissue. We suggest that tetrahydrobiopterin supplementation may be a useful therapy for patients with diabetes, as well as women with idiopathic gastroparesis. <\/jats:p>","DOI":"10.1152\/ajpgi.00152.2018","type":"journal-article","created":{"date-parts":[[2018,10,4]],"date-time":"2018-10-04T16:45:09Z","timestamp":1538671509000},"page":"G980-G990","source":"Crossref","is-referenced-by-count":12,"title":["Sepiapterin alleviates impaired gastric nNOS function in spontaneous diabetic female rodents through NRF2 mRNA turnover and miRNA biogenesis pathway"],"prefix":"10.1152","volume":"315","author":[{"given":"Pandu R.","family":"Gangula","sequence":"first","affiliation":[{"name":"Department of Oral Diagnostic Sciences and Research, School of Dentistry, Meharry Medical College, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kishore B.","family":"Challagundla","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, and Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalpana","family":"Ravella","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnostic Sciences and Research, School of Dentistry, Meharry Medical College, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sutapa","family":"Mukhopadhyay","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnostic Sciences and Research, School of Dentistry, Meharry Medical College, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijayakumar","family":"Chinnathambi","sequence":"additional","affiliation":[{"name":"Veterinary Training and Research Centre, Chennai, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mukul K.","family":"Mittal","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology and Hepatology, Vanderbilt University Medical Center, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. 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