Croton tiglium L. seeds ameliorate loperamide-induced constipation via regulating gastrointestinal hormones and gut microbiota before and after processing.

ETHNOPHARMACOLOGICAL RELEVANCE: Crotonis Fructus (CF), the seeds of Croton tiglium L., have been commonly used in the treatment of constipation for more than two thousand years in traditional Chinese medicine (TCM). CF needs to be processed before clinical use and Crotonis Semen Pulveratum (CP) is the processed cream of CF, which could reduce the drastic purgative action and gastrointestinal damages. However, the mechanism of CF and CP in the treatment of constipation is still unclear. AIM OF THE STUDY: This study was to evaluate the effects of CF and CP on loperamide-induced constipation and the underlying mechanism. MATERIALS AND METHODS: The chemical compositions of CF and CP were analyzed by UPLC-Q-TOF-MS. Constipated mouse model was established by loperamide (9.6 mg/kg, b.w., i.g.) for two weeks. After successful modeling, the mice were treated with CF or CP (45.5 and 136.5 mg/kg, b.w., i.g.) once a day for seven days. The physiological status, defecation indices, defecation time, and intestinal propulsion rate in mice were measured. Histopathologic examination and serum biochemical parameters were further estimated. 16S rDNA gene sequencing was carried out to characterize the effects of CF and CP on intestinal microbiome structure. Spearman correlation analysis was also performed to explore the association between gut microbiotic abundance and serum indices. RESULTS: The results verified the therapeutic effects of CF and CP on loperamide-induced constipation. CF and CP could significantly ameliorate the reduction of fecal number, fecal weight, fecal water content, and intestinal propulsion rate in mice with constipation, and the first stool defecation time was also obviously reduced. Moreover, CF and CP could regulate the secretion of gastrointestinal hormones and inflammatory factors induced by constipation. Histopathologic examination showed that CP was superior to CF in relieving pathological injury and inflammatory cell infiltration. According to 16S rDNA sequencing, CF and CP treatment could improve gut microbiota disturbance in mice with constipation and the abundance of opportunistic pathogens such as Parabacteroides, Parasutterella and Bacillus remarkably declined, while the levels of beneficial bacterial such as Candidatus_Arthromitus significantly increased. Besides, CP may play a better role in correcting the intestinal flora disorder than CF, which was more obvious in the high-dose group. In addition, phytochemical analysis revealed the presence of diterpenoids and alkaloids in CF and CP. CONCLUSIONS: CF and CP could ameliorate loperamide-induced constipation by regulating gastrointestinal hormones secretion, reducing the levels of inflammatory cytokines and improving the disturbance of gut microbiota. Moreover, CP was superior to CF in the enrichment of beneficial bacteria and reduction of harmful bacteria and histopathological damage induced by constipation, which may be related to the changes in the species and content of diterpenoids after processing. The study provides new evidence for the processing mechanism and clinical application of CF and CP.

Obesity-related gut hormones and cancer: novel insight into the pathophysiology.

The number of cancers attributed to obesity is increasing over time. The mechanisms classically implicated in cancer pathogenesis and progression in patients with obesity involve adiposity-related alteration of insulin, sex hormones, and adipokine pathways. However, they do not fully capture the complexity of the association between obesity-related nutritional imbalance and cancer. Gut hormones are secreted by enteroendocrine cells along the gastrointestinal tract in response to nutritional cues, and act as nutrient sensors, regulating eating behavior and energy homeostasis and playing a role in immune-modulation. The dysregulation of gastrointestinal hormone physiology has been implicated in obesity pathogenesis. For their peculiar function, at the cross-road between nutrients intake, energy homeostasis and inflammation, gut hormones might represent an important but still underestimated mechanism underling the obesity-related high incidence of cancer. In addition, cancer research has revealed the widespread expression of gut hormone receptors in neoplastic tissues, underscoring their implication in cell proliferation, migration, and invasion processes that characterize tumor growth and aggressiveness. In this review, we hypothesize that obesity-related alterations in gut hormones might be implicated in cancer pathogenesis, and provide evidence of the pathways potentially involved.

Implications of gastrointestinal hormones in the pathogenesis of obesity in prepubertal children.

BACKGROUND: There is a worsening high prevalence of global obesity. Special attention has been paid to the gut-endocrine system, represented by the regulators of appetite. In particular, it has been suggested that ghrelin ("hunger" peptide), and obestatin and glucagon-like peptide-1 (GLP-1) ("satiety" peptides) could play important roles in the pathogenesis of obesity. OBJECTIVES: The aims of this study were to compare fasting plasma ghrelin, obestatin, and GLP-1 levels between obese and nonobese prepubertal children, and to assess their relations with fatness indexes and insulin resistance (IR). SUBJECTS AND METHODS: Fifty-two prepubertal obese children and 22 controls were enrolled. Fasting levels of gastrointestinal hormones (ghrelin, obestatin, and GLP-1), glucose, and insulin were evaluated. IR was assessed using the homeostasis model assessment of IR (HOMA-IR) index. Analysis was performed by Mann-Whitney U-test, Kruskal-Wallis test, and Spearman's correlation. RESULTS: Obese prepubertal children and normal-weight controls had similar age distribution. Obese children were more insulin resistant when compared to controls (HOMA-IR: p < 0.01 ). GLP-1 levels were significantly lower in obese children than in controls (p < 0.01). Obestatin was significantly higher in obese than normal-weight children (p < 0.01), while ghrelin was not different. There was a negative correlation between GLP-1 and standard deviation score-body mass index (r = -0.36, p = 0.009) and between GLP-1 and waist circumference (r = -0.45, p = 0.001), while no association was observed with HOMA-IR. CONCLUSIONS: GLP-1 levels have been shown to be correlated with adiposity indexes, but not with HOMA-IR, suggesting that this hormone could play an important role in the early development of obesity.

Impaired nociception and inflammatory pain sensation in mice lacking the prokineticin receptor PKR1: focus on interaction between PKR1 and the capsaicin receptor TRPV1 in pain behavior.

Bv8, prokineticin-1 or EG-VEGF (endocrine gland-derived vascular endothelial growth factor), and prokineticin-2, are naturally occurring peptide agonists of two G-protein-coupled receptors (GPCRs), prokineticin receptor 1 (PKR1) and PKR2. PKRs are expressed in neurons in the CNS and peripheral nervous system and many dorsal root ganglion (DRG) cells expressing PKRs also express transient receptor potential vanilloid receptor-1 (TRPV1). Mice lacking the pkr1 gene were generated to explore the role of the PKR1 receptor in nociceptive signaling and in nociceptor sensitization. When compared with wild-type littermates, mice lacking the pkr1 gene showed impaired responsiveness to noxious heat, mechanical stimuli, capsaicin, and protons. In wild-type mice, activation of PKRs by the PKR agonist Bv8 caused hyperalgesia and sensitized to the actions of capsaicin. pkr1-null mice exhibited impaired responses to Bv8 but showed normal hyperalgesic responses to bradykinin and PGE2 (prostaglandin E2). Conversely, trpv1-null mice showed a reduced pronociceptive response to Bv8. Additionally, pkr1-null mice showed diminished thermal hyperalgesia after acute inflammation elicited by mustard oil and reduced pain behavior after chronic inflammation produced by complete Freund's adjuvant. The number of neurons that responded with a [Ca2+]i increase to Bv8 exposure was five times lower in pkr1-null DRG cultures than in wild-type cultures. Furthermore, Bv8-responsive neurons from pkr1-null mice showed a significant reduction in the [Ca2+]i response to capsaicin. These findings indicate a modulatory role of PKR1 in acute nociception and inflammatory pain and disclose a pharmacological interaction between PKR1 and TRPV1 in nociceptor activation and sensitization.

Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon.

BACKGROUND & AIMS: Glucagon-like peptide 2 (GLP-2) is intestinotrophic, antisecretory, and transit-modulating in rodents, and it is mainly secreted from the intestinal mucosa of the terminal ileum and colon after food ingestion. We assessed the effect of GLP-2 on the gastrointestinal function in patients without a terminal ileum and colon who have functional short-bowel syndrome with severe malabsorption of wet weight (>1.5 kg/day) and energy (>2.3 MJ/day) and no postprandial secretion of GLP-2. METHODS: Balance studies were performed before and after treatment with GLP-2, 400 microg subcutaneously twice a day for 35 days, in 8 patients (4-17 years from last bowel resection; 6 with Crohn's disease). Four patients received home parenteral nutrition (mean residual jejunum, 83 cm), and 4 did not (mean ileum resection, 106 cm). Biopsy specimens were taken from jejunal/ileal stomas, transit was measured by scintigraphy, and body composition was measured by dual-energy x-ray absorptiometry. RESULTS: Treatment with GLP-2 improved the intestinal absorption of energy 3.5% +/- 4.0% (mean +/- SD) from 49.9% to 53.4% (P = 0.04), wet weight 11% +/- 12% from 25% to 36% (P = 0.04), and nitrogen 4.7% +/- 5.4% from 47.4% to 52.1% (P = 0.04). Body weight increased 1.2 +/- 1.0 kg (P = 0.01), lean body mass increased 2.9 +/- 1.9 kg (P = 0.004), fat mass decreased 1.8 +/- 1.3 kg (P = 0.007), and 24-hour urine creatinine excretion increased (P = 0.02). The time to 50% gastric emptying of solids increased 30 +/- 16 minutes from 89 to 119 minutes (P < 0.05). Small bowel transit time was not changed. Crypt depth and villus height were increased in 5 and 6 patients, respectively. CONCLUSIONS: Treatment with GLP-2 improves intestinal absorption and nutritional status in short-bowel patients with impaired postprandial GLP-2 secretion in whom the terminal ileum and the colon have been resected.

Roles of gastrointestinal hormones in pancreatic cancer.

Several gastrointestinal (GI) hormones, such as gastrin, cholecystokinin, and bombesin, have been reported to affect the development of pancreatic cancer. The receptors for these hormones are found in normal and neoplastic pancreatic cells. Activation of these receptors enhances pancreatic carcinogenesis and promotes the growth of established pancreatic carcinoma either in vitro or in vivo. On the other hand, some studies have shown that these GI hormones may have no effect or may play an inhibitory role in the development of pancreatic cancer. The reasons for the apparent discrepancies in the published literature are discussed in this review. In recent years, increasing emphasis has been placed on the effects of GI hormones on cancer invasion and metastasis. As the transition from noninvasion to the invasive state is the crucial event in cancer development, further investigation of the way in which GI hormones affect the invasion and metastasis of pancreatic cancer may be important for the development of new therapeutic approaches with eventual clinical utility.

Different effects of octreotide by continuous night infusion at increasing rate or by evening injections at different times on morning hyperglycemia and growth hormone levels in insulin-dependent diabetic patients.

The effect of octreotide on morning hyperglycemia and GH levels was evaluated in eight insulin-dependent diabetic patients. Octreotide (50 mcg) was administered through subcutaneous injections at different hours (20:00, 22:00 and 24:00 h) or through continuous subcutaneous night infusion from midnight to 08:00 at increasing rate between 03:00 and 08:00 h. After octreotide injection at midnight we noticed a sharp decrease of both glycemia (p < 0.005) and GH (p < 0.05) at 04:00 h, but not at 08:00 h. Only the night continuous infusion at increasing rate was able to reduce glycemia and GH at 04:00 and at 08:00 h (p < 0.001 and p < 0.01 respectively). The injections of octreotide at 20:00 and 22:00 h lowered GH values at 24:00 h (p < 0.01 and p < 0.05 vs insulin alone) but did not show any significant effect on blood glucose levels and GH at 04:00 and 08:00 h. In conclusion, only the continuous subcutaneous night infusion of octreotide at increasing rate during the last hours of the night was able to reduce simultaneously morning hyperglycemia and GH levels in insulin-dependent diabetic patients, whereas evening subcutaneous injections at different times did not show any appreciable effect.

Gastrointestinal hormones as potential adjuvant treatment of exocrine pancreatic adenocarcinoma.

CONCLUSION: Gastrointestinal hormones and their antagonists can alter the growth of pancreatic adenocarcinoma in vitro and in vivo. The potential clinical benefit of this approach deserves further study. BACKGROUND: Epithelial cell growth is normally under hormonal control. Hormones also affect the growth of many epithelial cancers, and this fact is used to modify tumor growth. Pancreatic epithelial cell growth is under the influence of gastrointestinal hormones. This article reviews experiments designed to determine the effect of gastrointestinal hormones on the growth of pancreatic adenocarcinoma. METHODS: Eighty-eight articles were identified from a Medline search using the terms pancreatic adenocarcinoma and the individual names of gastrointestinal hormones. The experimental design and results of these studies are reviewed. RESULTS: In general, somatostatin, vasoactive intestinal polypeptide, pancreatic polypeptide, and pancreastatin inhibit pancreatic adenocarcinoma growth. Cholecystokinin, secretin, bombesin, gastrin, EGF, TGF-alpha, insulin, and IGF-1 have a growth-promoting effect.

Effects of subcutaneous glucagon-like peptide 1 (GLP-1 [7-36 amide]) in patients with NIDDM.

Intravenous glucagon-like peptide (GLP)-1 [7-36 amide] can normalize plasma glucose in non-insulin-dependent diabetic (NIDDM) patients. Since this is no form for routine therapeutic administration, effects of subcutaneous GLP-1 at a high dose (1.5 nmol/kg body weight) were examined. Three groups of 8, 9 and 7 patients (61 +/- 7, 61 +/- 9, 50 +/- 11 years; BMI 29.5 +/- 2.5, 26.1 +/- 2.3, 28.0 +/- 4.2 kg/m2; HbA1c 11.3 +/- 1.5, 9.9 +/- 1.0, 10.6 +/- 0.7%) were examined: after a single subcutaneous injection of 1.5 nmol/kg GLP [7-36 amide]; after repeated subcutaneous injections (0 and 120 min) in fasting patients; after a single, subcutaneous injection 30 min before a liquid test meal (amino acids 8%, and sucrose 50 g in 400 ml), all compared with a placebo. Glucose (glucose oxidase), insulin, C-peptide, GLP-1 and glucagon (specific immunoassays) were measured. Gastric emptying was assessed with the indicator-dilution method and phenol red. Repeated measures ANOVA was used for statistical analysis. GLP-1 injection led to a short-lived increment in GLP-1 concentrations (peak at 30-60 min, then return to basal levels after 90-120 min). Each GLP-1 injection stimulated insulin (insulin, C-peptide, p < 0.0001, respectively) and inhibited glucagon secretion (p < 0.0001). In fasting patients the repeated administration of GLP-1 normalized plasma glucose (5.8 +/- 0.4 mmol/l after 240 min vs 8.2 +/- 0.7 mmol/l after a single dose, p = 0.0065). With the meal, subcutaneous GLP-1 led to a complete cessation of gastric emptying for 30-45 min (p < 0.0001 statistically different from placebo) followed by emptying at a normal rate. As a consequence, integrated incremental glucose responses were reduced by 40% (p = 0.051). In conclusion, subcutaneous GLP-1 [7-36 amide] has similar effects in NIDDM patients as an intravenous infusion. Preparations with retarded release of GLP-1 would appear more suitable for therapeutic purposes because elevation of GLP-1 concentrations for 4 rather than 2 h (repeated doses) normalized fasting plasma glucose better. In the short term, there appears to be no tachyphylaxis, since insulin stimulation and glucagon suppression were similar upon repeated administrations of GLP-1 [7-36 amide]. It may be easier to influence fasting hyperglycaemia by GLP-1 than to reduce meal-related increments in glycaemia.

Vasoactive intestinal polypeptide (VIP) as a mediator of the watery diarrhea syndrome.

Evidence that VIP is the principal humoral mediator of the watery diarrhea syndrome includes: (a) actions of VIP in experimental anaimals parallel the clinical manifestations of the syndrome; (b) infusions of VIP induce watery diarrhea in intestinal loops of dogs and a picture resembling the clinical syndrome in pigs, at circulating levels of the peptide similar to those observed in human disease; (c) most patients with the watery diarrhea syndrome and underlying tumors have elevated plasma levels of VIP; (d) in those patients in whom pre- and postoperative measurements were made, plasma VIP levels fell to the normal range with removal of the tumor and relief of the diarrhea; and (e) extracts of such tumors are rich in VIP-immunoreactivity and VIP-like biologic activity. A few patients with the syndrome have been reported to have normal plasma VIP levels, and it is possible that other humoral agents (such as pancreatic polypeptide, prostaglandins) may contribute to the production of the diarrhea.

The VIPoma: further confirmation of VIP as the hormonal agent in the WDHA syndrome.

The WDHA syndrome characterized by watery diarrhea, hypokalemia, and achlorhydria is being diagnosed with increasing frequency. The diagnosis has been made to date only due to severe clinical symptomatology. In a review of the literature gastrin, secretin, glucagon, enteroglucagon, gastric inhibitory peptide (GIP), vasoactive intestinal peptide (VIP), and prostaglandins have been variously suggested as a possible etiologic agent for this syndrome. A case of the WDHA syndrome is reported in which hormonal assays of the serum preoperatively and two years postoperatively and tumor for many of the proposed agents is performed. A discussion of possible cross-reactivity among these similary structured polypeptides in the radioimmunoassays systems is used to explain the multitude of possible hormonal agents presented in the literature. Standardization of the VIP assays will result in increasing diagnosis of this diseases state prior to its fulminant clinical presentation.