Ginkgoghrelins, unique acylated flavonoid diglycosides in Folium Ginkgo, stimulate growth hormone secretion via activation of the ghrelin receptor.

ETHNOPHARMACOLOGICAL RELEVANCE: Folium Ginkgo, the dried leaf of Ginkgo biloba L. is a traditional Chinese medicine listed in the Pharmacopoeia of the People's Republic of China with several therapeutic effects, including prevention of aging. It is used as herbal medicine for the treatment of several aging-related diseases. The therapeutic effects of Folium Ginkgo on aging-related diseases are suspected to be similar to the anti-aging effects of growth hormone release induced by ghrelin. MATERIALS AND METHODS: Candidate components responsible for the anti-aging effects via the ghrelin receptor-activated pathway were searched from the known compounds found in Folium Ginkgo. Two acylated flavonoid diglycosides, tentatively named ginkgoghrelins in this study, were selected and isolated from the methanol extract of Folium Ginkgo, and their chemical structures were confirmed by spectroscopic analysis. These two compounds were examined for their capability of stimulating growth hormone release of rat primary anterior pituitary cells via activation of the ghrelin receptor. The major metabolites of ginkgoghrelins in rat bile were detected after intravenous injection and structurally analyzed by mass spectroscopy. Molecular modeling of ginkgoghrelins docking to the ghrelin receptor was exhibited to explore the possible interaction within the binding pocket. RESULTS: Similar to growth hormone-releasing hormone-6 (GHRP-6), a synthetic analog of ghrelin, ginkgoghrelins were demonstrated to stimulate growth hormone secretion of rat primary anterior pituitary cells in a dose dependent manner, and the stimulation was inhibited by [d-Arg1, d-Phe5, d-Trp7,9, Leu11]-substance P, an inverse agonist of the ghrelin receptor. Putative metabolites of ginkgoghrelins via glucuronidation and methylation were detected in bile of rats after intravenous injection. Molecular modeling and docking showed that ginkgoghrelins as well as GHRP-6 could fit in and adequately interact with the binding pocket of the ghrelin receptor. CONCLUSION: The results suggest that ginkgoghrelins are putative components partly accounting for the anti-aging effects of Folium Ginkgo possibly via activation of the ghrelin receptor, and possess great potential to be developed as non-peptidyl analogs of ghrelin.

Association Between Use of Dipeptidyl Peptidase-4 Inhibitors and the Risk of Acute Kidney Injury: A Nested Case-Control Study.

OBJECTIVE: To examine the risk of acute kidney injury (AKI) in a nationwide cohort of patients with type 2 diabetes initiating dipeptidyl peptidase-4 (DPP-4) inhibitors. PATIENTS AND METHODS: This nested case-control study of a cohort of adult DPP-4 inhibitor users with type 2 diabetes who were hospitalized for AKI between January 1, 2010, and December 31, 2013, was conducted using Taiwan's National Health Insurance Research Database. Each AKI case was matched with one control subject according to duration of follow-up, age, sex, urbanization level, monthly income, comorbidity severity, and well-known predisposing factors for AKI. Odds ratios (ORs) for AKI were calculated according to current, recent, or past use of DPP-4 inhibitors. RESULTS: A total of 6752 cases with AKI and 6752 matched controls were analyzed. The exposure prevalence of DPP-4 inhibitor use in the previous year was higher among patients with AKI (adjusted OR, 1.20; 95% CI, 1.05-1.36; P=.006). In a stratified analysis, the association was significant for current DPP-4 inhibitor use (adjusted OR, 1.26; 95% CI, 1.08-1.48; P=.004), but not for recent or past use. CONCLUSION: In this large contemporary cohort, DPP-4 inhibitor users had an increased risk of AKI development compared with nonusers. Further research is warranted to investigate the mechanism underlying this association.

Association of sleep apnoea with chronic kidney disease in a large cohort from Taiwan.

BACKGROUND AND OBJECTIVE: Recent observational studies have shown that sleep apnoea (SA) is associated with increased risk of incident CKD. However, the contribution of SA relative to common traditional CKD risk factors remains unknown. The aims of this study were to investigate the long-term risk of incident CKD events following SA diagnosis and compare the relative contributions of SA, diabetes and hypertension. METHODS: Data were retrieved from Taiwan's National Health Insurance Research Database during the period between 2000 and 2010 for this retrospective cohort study. The cohorts are composed of patients (age ≥ 20 years) newly diagnosed with SA and matched subjects without SA. The two cohorts were followed until the occurrence of CKD, death or the end of 2010. RESULTS: The sample is composed of 43,434 individuals (8687 patients with SA and 34,747 matched non-SA subjects). A total of 157 new CKD events in patients with SA and 298 events in the matched non-SA cohort were recorded during a mean follow-up period of 3.9 years (incidence rates, 4.5 and 2.2/per 1000 person-years). The risk of CKD development was greater among patients with SA than in the matched non-SA cohort (adjusted hazard ratio (aHR) 1.58, 95% confidence interval ( CI): 1.29-1.94). The contribution of SA to the CKD hazard was similar to that of hypertension (aHR 1.17, 95% CI: 0.68-2.01, P = 0.56), whereas that of diabetes remained significantly higher (aHR 2.17, 95% CI: 1.21-3.90, P = 0.01). CONCLUSION: SA was associated with an increase in the risk of CKD incidence similar to that of hypertension. See article, page 578.

Association of hypoglycemia with incident chronic kidney disease in patients with type 2 diabetes: a nationwide population-based study.

This article aims to investigate the long-term risk of incident chronic kidney disease (CKD) in type 2 diabetes mellitus (T2DM) patients with hypoglycemia.This nationwide, population-based, propensity score (PS)-matched cohort study involved 2 cohorts: a hypoglycemic cohort and a matched cohort without hypoglycemia. Data from 1.3 million patients with newly diagnosed T2DM between 2000 and 2010 were extracted from Taiwan's National Health Insurance Research Database. Hypoglycemic events were collected using inpatient, outpatient, and emergency department diagnoses. Patients aged <20 years and those with previous histories of CKD were excluded. The association between hypoglycemia and subsequent CKD risk in patients with T2DM was examined using Cox regression analysis after PS matching.During the mean follow-up period of 4.2 years, a total of 15,036 (1.7 %) patients experienced at least 1 episode of hypoglycemia and 15,036 matched controls without hypoglycemia were identified among 906,368 eligible patients. The incidence rates of subsequent CKD were 26.1 and 14.8 events per 1000 person-years in the hypoglycemic and matched cohorts, respectively. The hazard ratio (HR) of hypoglycemia for incident CKD was 1.77 (95% confidence interval [CI], 1.63-1.92; P < 0.001). Compared with those without hypoglycemia, HRs for 1 to 3 and ≥4 episodes of hypoglycemia for CKD were 1.65 (95% CI, 1.50-1.81) and 1.75 (95% CI, 1.34-2.29), respectively (P for trend <0.001).Our study supports the association of hypoglycemia with CKD development among patients with T2DM, possibly in a dose-dependent relationship.

Identification of biosynthetic intermediates of teaghrelins and teaghrelin-like compounds in oolong teas, and their molecular docking to the ghrelin receptor.

Teaghrelins are unique acylated flavonoid tetraglycosides found in Chin-shin oolong tea, and have been demonstrated to be promising oral ghrelin analogues. The biosynthetic pathway of teaghrelins from quercetin-3-O-rutinoside (rutin) or kaempferol-3-O-rutinoside (nicotiflorin) was proposed to comprise three enzymatic steps according to the identification of putative intermediates in Chin-shin oolong tea. In addition to the two known teaghrelins in Chin-shin oolong tea, four teaghrelin-like compounds with different attachments of glycosides were identified in various oolong teas. Molecular modeling and docking were used to evaluate theoretically whether the putative biosynthetic intermediates of teaghrelins and the four teaghrelin-like compounds could be potential candidates of ghrelin analogues. The results showed that the attachment of a coumaroyl group was crucial for these tea compounds to bind to the ghrelin receptor. However, the additional attachment of a rhamnosyl glycoside to the flavonoid backbone of teaghrelin-like compounds at C-7 significantly reduced their binding affinity with the ghrelin receptor.

Emoghrelin, a unique emodin derivative in Heshouwu, stimulates growth hormone secretion via activation of the ghrelin receptor.

ETHNOPHARMACOLOGICAL RELEVANCE: Heshouwu, the root of Polygonum multiflorum, is an anti-aging Chinese traditional medicine. Fresh (raw) Heshouwu is commonly converted to processed Heshouwu by specialized heating to alleviate its side effects of diarrhea presumably caused by anthraquinones. However, raw Heshouwu has been noted to be better than processed Heshouwu regarding anti-aging effects. The therapeutic effects of raw Heshouwu on aging-related diseases were somehow similar to the anti-aging effects of growth hormone release induced by ghrelin MATERIALS AND METHODS: Major ingredients in the methanol extract from raw Heshouwu were separated and identified. Emodin-8-O-(6'-O-malonyl)-glucoside, a unique anthraquinone glycoside known to be completely eliminated in the conversion process of Heshouwu was isolated. This emodin derivative, tentatively named emoghrelin, was examined for its cytotoxicity and capability of stimulating growth hormone release of rat primary anterior pituitary cells via activation of the ghrelin receptor. Moreover, molecular modeling of emoghrelin docking to the ghrelin receptor was exhibited to explore the possible interaction within the binding pocket. RESULTS: No apparent cytotoxicity was observed for emoghrelin of 10(-7)-10(-4)M. Similar to growth hormone-releasing hormone-6 (GHRP-6), a synthetic analog of ghrelin, emoghrelin was demonstrated to stimulate growth hormone secretion of rat primary anterior pituitary cells in a dose dependent manner, and the stimulation was inhibited by [d-Arg(1), d-Phe(5), d-Trp(7,9), Leu(11)]-substance P, an antagonist of the ghrelin receptor. Molecular modeling and docking showed that emoghrelin as well as GHRP-6 could fit in and adequately interact with the binding pocket of the ghrelin receptor. CONCLUSION: The results suggest that emoghrelin is a key ingredient accounting for the anti-aging effects of Heshouwu, and possesses great potential to be a promising non-peptidyl analog of ghrelin.

Teaghrelins, unique acylated flavonoid tetraglycosides in Chin-shin oolong tea, are putative oral agonists of the ghrelin receptor.

Chin-shin oolong tea, a popular tea in Taiwan, was empirically perceived to induce hunger and accelerate gastric emptying in a manner similar to the physiological effects of ghrelin, an endogenous acylated peptide known as the hunger hormone. Two unique acylated flavonoid tetraglycosides previously identified in Chin-shin oolong tea were demonstrated to induce hunger of rats in a food intake assay and, thus, named teaghrelin-1 and teaghrelin-2. Similar to GHRP-6, a synthetic analogue of ghrelin, teaghrelin-1 stimulated growth hormone secretion of rat primary anterior pituitary cells in a dose-dependent manner, and the stimulation was inhibited by [D-Arg(1),D-Phe(5),D-Trp(7,9),Leu(11)]-substance P, an antagonist of the ghrelin receptor. While teaghrelin-2 remained unmodified, a meta-O-methylated metabolite of teaghrelin-1 was detected in bile of rats after intravenous injection. Presumably, teaghrelins are promising oral agonists of the ghrelin receptor.

Adrenocortical carcinoma initially presenting with hypokalemia and hypertension mimicking hyperaldosteronism: a case report.

BACKGROUND: Adrenocortical carcinoma is a rare malignancy and rare cause of Cushing's syndrome. CASE PRESENTATION: A 65-year-old seemingly well male patient was referred to our clinic under the suspicion of hyperaldosteronism due to hypertension combined with hypokalemia. However, his serum aldosterone and plasma renin activity were within normal limits. Instead, Cushing's syndrome was diagnosed by elevated urine free cortisol and a non-suppressible dexamethasone test. Abdominal computed tomography showed a 7.8 × 4.8 cm mass lesion at the right adrenal gland with liver invasion. Etomidate infusion was performed to reduce his cortisol level before the patient received a right adrenalectomy and liver wedge resection. The pathology report showed adrenocortical carcinoma with liver and lymph node metastasis. According to the European Network for the Study of Adrenal Tumors (ENSAT) staging system, the tumor was classified as T4N1M1, stage IV. Recurrent hypercortisolism was found shortly after surgery. The patient died of Fournier's gangrene with septic shock on the 59th day after diagnosis. CONCLUSIONS: We report a case of rapidly progressive stage IV adrenocortical carcinoma with initial presentations of hypokaelmia and hypertension, mimicking hyperaldosteronism.

Transcatheter arterial embolization with trisacryl gelatin microspheres (Embosphere(®)) leads to life-threatening tumor lysis syndrome in a rectal carcinoid patient with hepatic metastases.

The incidence of gastrointestinal carcinoids appears to be increasing, and the rectum is the third most common location. Transcatheter arterial embolization (TAE) with trisacryl gelatin microspheres (Embosphere(®)) has been reported as an effective method for hepatic metastases of rectal carcinoids. Complications are uncommon and usually of minor consequence. We report an unusual case of a 34-year-old man with tumor lysis syndrome following TAE with Embosphere(®) in a patient with multiple hepatic metastases of a rectal carcinoid. Early detection and effective treatment are essential for this rare but potentially catastrophic complication.