Selective antagonism of somatostatin receptor type 2 (SSTR2) normalizes glucagon and corticosterone responses to hypoglycemic clamp in diabetic rats. The purpose of this study was to determine whether SSTR2 antagonism (SSTR2a) ameliorates hypoglycemia in response to overinsulinization in diabetic rats previously exposed to recurrent hypoglycemia. Streptozotocin diabetic rats (n = 19), previously subjected to five hypoglycemia events over 3 days, received an insulin bolus (10 units/kg i.v.) plus insulin infusion (50 mU/kg/min i.v.) until hypoglycemia ensued (≤3.9 mmol/L) (experimental day 1 [Expt-D1]). The next day (Expt-D2), rats were allocated to receive either placebo treatment (n = 7) or SSTR2a infusion (3,000 nmol/kg/min i.v., n = 12) 60 min prior to the same insulin regimen. On Expt-D1, all rats developed hypoglycemia by ∼90 min, while on Expt-D2, hypoglycemia was attenuated with SSTR2a treatment (nadir = 3.7 ± 0.3 vs. 2.7 ± 0.3 mmol/L in SSTR2a and controls, P < 0.01). Glucagon response to hypoglycemia on Expt-D2 deteriorated by 20-fold in the placebo group (P < 0.001) but improved in the SSTR2a group (threefold increase in area under the curve [AUC], P < 0.001). Corticosterone response deteriorated in the placebo-treated rats on Expt-D2 but increased twofold in the SSTR2a group. Catecholamine responses were not affected by SSTR2a. Thus, SSTR2 antagonism after recurrent hypoglycemia improves the glucagon and corticosterone responses and largely ameliorates insulin-induced hypoglycemia in diabetic rats.
Somatostatin may inhibit gastric exocrine functions independent of blockade of gastrin secretion. In order to further investigate this suppressive effect, somatostatin derivatives were injected to cats bearing a cannulated gastric fistula under pentagastrin stimulation. Results showed that somatostatin-14 was more potent than somatostatin-28 in this particular model. Analogues with substituted residues exhibited a variable spectrum of actions on hormone release and gastric function. A cyclic pentapeptide was deprived of gastric or GH inhibitory properties whereas the related peptide with a benzyl-protecting group on Thr was only devoid of gastric effect. The octapeptide SMS 201-995 was described as a potent inhibitor of gastric secretion in comparison with natural somatostatin in rats and also in humans, but was unable to induce maximal suppression of acid output in the cat model. Differences in gastric effect of different derivatives could be explained on the basis of binding to a selective subset of receptors, since at least two binding sites have been identified in the stomach mucosa. Serial studies with short cyclic somatostatin should help to establish a clear relationship between peptide structure and inhibition of gastric secretion.
We determined whether pituitary adenylate cyclase-activating polypeptide 38 (PACAP38) prevents contrast-induced nephropathy using human renal proximal tubule epithelial (HK-2) cells and homozygous endothelial nitric oxide synthase-deficient (eNOS(-/-)) mice as a novel in vivo model. Cultured HK-2 cells were pretreated with 10(-9)-10(-6) mol/L PACAP or vasoactive intestinal peptide (VIP) for 1 h, and then exposed to ionic (Urografin) or nonionic (iohexol) contrast media at 50 mg iodine/mL for 24 h. Male eNOS(-/-) mice received Urografin (1.85 g iodine/kg) intravenously after water deprivation for 24 h, and PACAP38 (10 μg) intraperitoneally 1 h before and 12 h after Urografin injection. Urografin and iohexol increased lactate dehydrogenase and kidney injury molecule 1 in the culture medium, induced apoptosis, and inhibited cell proliferation in HK-2 cell cultures. PACAP38 and VIP reduced these changes in a dose-dependent manner. PACAP38 was more potent than VIP. In eNOS(-/-) mice, Urografin raised serum creatinine and cystatin C levels, caused renal tubule damage, induced apoptosis, and promoted neutrophil influx. Urografin also increased kidney protein levels of proinflammatory cytokines, and kidney mRNA levels of proinflammatory cytokines, kidney injury biomarkers, and enzymes responsible for reactive oxygen and nitrogen species. PACAP38 significantly reduced these Urografin-induced changes in eNOS(-/-) mice. This study shows that both Urografin and iohexol are toxic to HK-2 cells, but Urografin is more toxic than iohexol. Urografin causes acute kidney injury in eNOS(-/-) mice. PACAP38 protects HK-2 cells and mouse kidneys from contrast media and is a potential therapeutic agent for contrast-induced nephropathy.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthesis and biological properties of [2-L-.beta.-(pyrazolyl-3)alanine]-luteinizing hormone-releasing hormoneDavid H. Coy, Esther J. Coy, Yoshihiro Hirotsu, and Andrew V. SchallyCite this: J. Med. Chem. 1974, 17, 1, 140–142Publication Date (Print):January 1, 1974Publication History Published online1 May 2002Published inissue 1 January 1974https://pubs.acs.org/doi/10.1021/jm00247a030https://doi.org/10.1021/jm00247a030research-articleACS PublicationsRequest reuse permissionsArticle Views42Altmetric-Citations15LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
Peripheral plasma progestin levels were used to assess luteal function in 13 anestrous ewes following induction of ovulation by use of D-Leu6-des GlyNH120-LHRH ethylamide (D-Leu6 LHRH). Progestin levels in jugular vein plasma were measured by competitive protein binding and compared to plasma progestin levels in these same ewes following natural ovulation. The number of ovulations in each ewe was determined by the presence of corpora lutea (CL) at laparotomy. Eight of 13 ewes ovulated after D-Leu6 LHRH treatment. In ewes which failed to ovulate (n=5), progestin levels remained <1 ng/ml. In treated ewes with one CL (n=3) and two CL (n=5), progestin levels increased from <1 ng/ml on Day 1 to 4.5 ± .5 (mean ± SE), and 5.4 ± .1 ng/ml, respectively, on Day 9, and decreased to <1 ng/ml on Day 15. In cycling ewes with one CL (n=4) and two CL (n=9), progestin levels remained at approximately 1 ng/ml on Days 0 through 3, and then increased slowly to 4.9 ± 1.0 and 4.9 ± .8 ng/ml on Days 9 and 11, respectively. In both cases progestin levels gradually declined to <3 ng/ml on Day 15. Progestin levels across days were similar in ewes that ovulated after treatment with D-Leu6 LHRH and in ewes that ovulated during the natural cycle. These data indicate that CL formed after D-Leu6 LHRH-induced ovulation are functional and appear comparable in terms of progestin secretion to CL formed after natural ovulation.
// Bo Zhu 1, * , Lichun Sun 1, 2, 3, 4, * , Wei Luo 3 , Min Li 4, 5 , David H. Coy 4 , Long Yu 1 , Wenbo Yu 1 1 State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai 200433, China 2 Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China 3 Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China 4 Department of Medicine, School of Medicine, Tulane Health Sciences Center, New Orleans, LA 70112-2699, USA 5 Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China * These authors contributed equally to this work Correspondence to: Lichun Sun, email: peptide612@gmail.com , lsun@tulane.edu Wenbo Yu, email: 12111010012@fudan.edu.cn Keywords: hepatocellular carcinoma, Notch signaling, Notch1, nuclear receptor, NR4A2 Received: November 02, 2016 Accepted: February 13, 2017 Published: February 21, 2017 ABSTRACT Hepatocellular carcinoma (HCC) is one of the most malignant cancers. Conventional therapies are limited due to the human liver being such a unique organ and easily showing side-effects. The unclear molecular mechanisms are tough challenges for scientists searching for new and effective anti-HCC targeting drugs. We identified that the nuclear receptor NR4A2 is a novel oncogene in HCC progression. In this study, we show that NR4A2 and the notch recceptor Notch1 were expressed highly in primary HCC tissues and immortal HCC cells by using qPCR, western blot and immuno-histochemistry assays. Both genes were observed to stimulate HCC cell proliferation, anti-apoptosis and cell cycle arrest by using cell proliferation assays and FACS assays. We also observed that the four notch receptor subtypes (Notch1-4) displayed different effects on HCC cell growth. The over-expression of Notch1 by transiently transfecting the intracellular domain of Notch1 (ICN1, Notch1 active form) increased the expression of NR4A2, with the knockdown of Notch1 decreasing NR4A2. This indicates that NR4A2 is one of the Notch-mediated downstream genes. Moreover, both NR4A2 and Notch1 suppressed the expression of tumor suppressors p21 and p63. These findings support that Notch1/NR4A2 co-regulate HCC cell functions by playing oncogenic roles and regulating the associated downstream signaling pathways. Novel Notch1/NR4A2-mediated oncogenic signaling may provide us a great opportunity for anti-HCC drug development.
The Hippo pathway was initially discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth and fate decision, organ size ...Read More
Abstract The conformations of three somatostatin analogues were compared in methanol at 193 K. A biologically active cyclic analogue, DC13‐116 ( D ‐Nal 5 ‐Cys 6 ‐Tyr 7 ‐ D ‐Trp 8 ‐Lys 9 ‐Val 10 ‐Cys 11 ‐Thr 12 ‐NH 2 ), and two linear analogues, one biologically active, DC25‐24 ( D ‐Phes 5 ‐Cpa 6 ‐Tyr 7 ‐ D ‐Trp 8 ‐Lys 9 ‐Val 10 ‐Phe 11 ‐Thr 12 ‐NH 2 ), and one with poor biological activity, DC23‐89 ( D ‐Phe 5 ‐Ala 6 ‐Phe 7 ‐ D ‐Trp 8 ‐Lys 9 ‐Thr 10 ‐Ala 11 ‐Thr 12 ‐NH 2 ), were compared. The predominant conformation of the linear active analogue is shown to be the same as that of the active cyclic analogue; they both adopt a β 11 turn/β‐sheet structure. The linear analogue with low activity has a similar conformation, which, however, is less stable.
