New labdane diterpenoids from Alpinia galanga: A new type of GLP-1 secretagogues targeting the PKA-CREB and PI3K-Akt signaling axes.

Glucagon-like peptide-1 (GLP-1) secretagogues are fascinating pharmacotherapies to overcome the defects of GLP-1 analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors in treating diabetes and obesity. To discover new GLP-1 secretagogues from natural sources, alpigalangols A-Q (1-17), 17 new labdane diterpenoids including four unusual nor-labdane and N-containing ones, were isolated from the fruits of Alpinia galanga. Most of the isolates showed GLP-1 promotive effects in NCl-H716 cells, of which compounds 3, 4, 12, and 14-17 were revealed with high promoting rates of 246.0%-413.8% at 50 µM. A mechanistic study manifested that the most effective compound 12 upregulated the mRNA expression of Gcg and Pcsk1, and the protein phosphorylation of PKA, CREB, and GSK3ß, but was inactive on GPBAR and GPR119 receptors. Network pharmacology analysis indicated that the PI3K-Akt pathway was involved in the GLP-1 stimulation of 12, which was highly associated with AKT1, CASP3, PPARG, and ICAM1 proteins. This study suggests that A. galanga is rich in diverse labdane diterpenoids with GLP-1 promoting effects, representing a new type of antidiabetic candidates from natural sources.

Sesquiterpenoids from Alpinia oxyphylla with GLP-1 Stimulative Effects through Ca2+/CaMKII and PKA Pathways and Multiple-Enzyme Inhibition.

Six new sesquiterpenoids (1-6), a pair of enantiomers (7a and 7b), and six known ones (8-13) were isolated from the fruits of Alpinia oxyphylla. The structures of the new compounds were elucidated by extensive spectroscopic data and ECD calculations. The stereochemistry of 7a and 7b was reported for the first time. All compounds showed significant GLP-1 stimulation in NCI-H716 cells with promoting ratios ranging from 90.4 to 668.9% at 50 µM. Mechanism study indicated that compound 6 stimulated GLP-1 secretion mainly by regulating the transcription and the shearing process of proglucagon, while compound 13 exerted its effects through up-regulating prkaca levels. Interestingly, the GLP-1 stimulative effects of 6 and 13 were both closely related with Ca2+/CaMKII and PKA pathways but irrelevant to TGR5 and GPR119 receptors. Moreover, most compounds exhibited inhibitory activity against α-glucosidase and PTP1B at concentrations of 100 and 200 µM, while showing no activity against GPa. Compounds 3, 9, 11, and 13 could suppress α-glucosidase with IC50 values of 190.0, 204.0, 181.8, and 159.6 µM, equivalent to acarbose (IC50 = 212.0 µM). This study manifests that A. oxyphylla contains diverse sesquiterpenoids with multiple activities.

Diarylheptanoids with hypoglycemic potency from the rhizomes of Kaempferia galanga.

Five new diarylheptanoids, kaemgalangins A-E (1-5), and seven known ones were isolated from the rhizomes of Kaempferia galanga. The structures of new compounds were identified by spectroscopic analyses involving 1D and 2D NMR, HRESIMS, IR, UV, [α]D, ECD calculations, and chemical methods. All compounds were tested for their hypoglycemic effects against α-glucosidase, Gpa and PTP1B enzymes, and stimulative effects on GLP-1 secretion. Kaemgalangins A (1) and E (5) showed significant inhibition on α-glucosidase with IC50 values of 45.3 and 116.0 µM; renealtin B (8) showed inhibition on GPa with an IC50 value of 68.1 µM; whereas all compounds were inactive to PTP1B. Docking study manifested that 1 well located in the catalytic pocket of α-glucosidase and OH-4″ played important roles in maintaining activity. Moreover, all compounds showed obviously stimulative effects on GLP-1 with promoting rates of 826.9%-1738.3% in NCI-H716 cells. This study suggests that the diarylheptanoids in K. galanga have antidiabetic potency by inhibiting α-glucosidase and Gpa enzymes, and promoting GLP-1 secretion.

Whole fresh fruit intake and risk of incident diabetes in different glycemic stages: a nationwide prospective cohort investigation.

PURPOSE: Fruit intake is beneficial to several chronic diseases, but controversial in diabetes. We aimed to investigate prospectively the associations of whole fresh fruit intake with risk of incident type 2 diabetes (T2D) in subjects with different glucose regulation capacities. METHODS: The present study included 79,922 non-diabetic participants aged ≥ 40 years from an ongoing nationwide prospective cohort in China. Baseline fruit intake information was collected by a validated food frequency questionnaire. Plasma HbA1c, fasting and 2 h post-loading glucose levels were measured at both baseline and follow-up examinations. Cox proportional hazards models were used to calculate hazard ratio (HR) and 95% confidence intervals (CI) for incident diabetes among participants with normal glucose tolerance (NGT) and prediabetes, after adjusted for multiple confounders. Restricted cubic spline analysis was applied for dose-response relation. RESULTS: During a median 3.8-year follow-up, 5886 (7.36%) participants developed diabetes. Overall, we identified a linear and dose-dependent inverse association between dietary whole fresh fruit intake and risk of incident T2D. Each 100 g/d higher fruit intake was associated with 2.8% lower risk of diabetes (HR 0.972, 95%CI [0.949-0.996], P = 0.0217), majorly benefiting NGT subjects with 15.2% lower risk (HR 0.848, 95%CI [0.766-0.940], P = 0.0017), while not significant in prediabetes (HR 0.981, 95%CI 0.957-4.005, P = 0.1268). Similarly, the inverse association was present in normoglycemia individuals with a 48.6% lower risk of diabetes when consuming fruits > 7 times/week comparing to those < 1 time/week (HR 0.514, 95% CI [0.368-0.948]), but not in prediabetes (HR 0.883, 95% CI [0.762-1.023]). CONCLUSION: These findings suggest that higher frequency and amount of fresh fruit intake may protect against incident T2D, especially in NGT, but not in prediabetes, highlighting the dietary recommendation of higher fresh fruit consumption to prevent T2D in normoglycemia population.

[Terpenoids from fruits of Amomum villosum and their hypoglycemic activity].

Eight terpenoids were isolated from the fruits of Amomum villosum by silica gel, Sephadex LH-20, Rp-C_(18), MCI GEL CHP20 P column chromatography, preparative TLC, and HPLC. Their structures were identified by HR-ESI-MS, ~1H and ~(13)C-NMR, IR, UV, [α]_D, and ECD spectroscopic data as kravanhin A 3-O-ß-D-glucopyranoside(1), kravanhin B(2), 6-eudesmene-1ß,4ß-diol(3), oplodiol(4), vicodiol(5),(1R,2S,4R,7S)-vicodiol 9-O-ß-D-glucopyranoside(6),(1R,2S,4S,5R)-angelicoidenol 2-O-ß-D-glucopyranoside(7), and(1S,2S,4R,6S)-bornane-2,6-diol 2-O-ß-D-glucopyranoside(8). Compound 1 was a new compound, and compounds 2-5 were isolated from A. villosum for the first time. Their hypoglycemic activity was tested based on STC-1 cell model and two enzymatic models(GPa and PTP1 B). The results showed that compounds 1, 7, and 8 could stimulate GLP-1 with the secretion rates of 692.8%, 398.6%, and 483.3% at 25.0 µmol·L~(-1), and compound 6 showed inhibitory activity against GPa with an IC_(50) value of 78.6 µmol·L~(-1).

Oligostilbenes from the seeds of Paeonia lactiflora as potent GLP-1 secretagogues targeting TGR5 receptor.

One unusual stilbene trimer-flavonoid hybrid, paeonilactiflobenoid (1), together with six known stilbenes (2-7) were isolated from the seeds of Paeonia lactiflora. The structure of 1 was elucidated with the aid of HRESIMS, 1D and 2D NMR, [α]D spectroscopic data and ECD calculation. Compounds 2-7 showed stimulative effects on GLP-1 secretion with promoting rates of 79.8%-880.4% (25 µM) and 217.6%-1089.4% (50 µM), more potent than the positive control, oleoylethanolamide (250.2% at 50 µM). Moreover, compounds 4 and 6 exhibited agonistic activity on the G protein-coupled receptor (GPCR) TGR5 with stimulative ratios of 40.2% and 40.5% at 50 µM, and 54.2% and 49.1% at 100 µM, respectively. Docking study manifested that 6 well located in the catalytic pocket of TGR5 by hydrogen-bond and hydrophobic interactions. The GLP-1 promotion of 6 could be attenuated by IP3, Ca2+/CaMKII and MEK/ERK pathway inhibitors, suggesting that these pathways played important roles in GLP-1 secretion. Thus, stilbenes in peony seeds maybe regarded as potential GLP-1 secretagogues through TGR5-IP3-Ca2+/CaMKII-MEK/ERK pathways.

Norlignans as potent GLP-1 secretagogues from the fruits of Amomum villosum.

The dried fruit of Amomum villosum (Amomi Fructus) is an important spices and traditional Chinese medicine. In this study, the EtOH extract of Amomi Fructus was revealed with hypoglycemic effects on db/db mice by increasing plasma insulin levels. After extracted with EtOAc, the EtOAc fraction showed increased activity in stimulating glucagon-like peptide-1 (GLP-1) secretion compared with the EtOH extract. In order to clarify the antidiabetic constituents, four undescribed norlignans, amovillosumins A‒D, were isolated from the EtOAc fraction, and the subsequent chiral resolution yielded three pairs of enantiomers. Their structures were determined by extensive spectroscopic data (1D and 2D NMR, HRESIMS, IR, UV and [α]D) and ECD calculations. Amovillosumins A and B significantly stimulated GLP-1 secretion by 375.1% and 222.7% at 25.0 µM, and 166.9% and 62.7% at 12.5 µM, representing a new type of GLP-1 secretagogues.

New diarylheptanoid dimers as GLP-1 secretagogues and multiple-enzyme inhibitors from Alpinia katsumadai.

Ten new diarylheptanoid dimers, katsumadainols C1 - C10 (1-10), were isolated from the seeds of Alpinia katsumada and elucidated by extensive spectroscopic methods, ECD calculations, and single-crystal X-ray diffraction. Their antidiabetic effects were evaluated by the stimulation of GLP-1 secretion in STC-1 cells and inhibition against four diabetes-related enzymes, GPa, α-glucosidase, PTP1B, and DPP4. Compounds 1-5 and 7-10 significantly stimulated GLP-1 secretion by 267.5-433.1% (25.0 µM) and 117.8-348.2% (12.5 µM). Compounds 1-4 exhibited significant inhibition on GPa with IC50 values of 18.0-31.3 µM; compounds 1-5 showed obvious inhibition on α-glucosidase with IC50 values of 6.9-18.2 µM; compounds 1-5 and 10 possessed PTP1B inhibitory activity with IC50 values ranging from 35.5 to 80.1 µM. This investigation first disclosed compounds 1-4 as intriguing GLP-1 secretagogues and GPa, α-glucosidase, and PTP1B inhibitors, which provided valuable clues for searching multiple-target antidiabetic candidates from Zingiberaceae plants.

Inverted U-Shaped Associations between Glycemic Indices and Serum Uric Acid Levels in the General Chinese Population: Findings from the China Cardiometabolic Disease and Cancer Cohort (4C) Study.

OBJECTIVE: The relationship between serum uric acid (SUA) levels and glycemic indices, including plasma glucose (FPG), 2-hour postload glucose (2h-PG), and glycated hemoglobin (HbA1c), remains inconclusive. We aimed to explore the associations between glycemic indices and SUA levels in the general Chinese population. METHODS: The current study was a cross-sectional analysis using the first follow-up survey data from The China Cardiometabolic Disease and Cancer Cohort Study. A total of 105,922 community-dwelling adults aged ≥ 40 years underwent the oral glucose tolerance test and uric acid assessment. The nonlinear relationships between glycemic indices and SUA levels were explored using generalized additive models. RESULTS: A total of 30,941 men and 62,361 women were eligible for the current analysis. Generalized additive models verified the inverted U-shaped association between glycemic indices and SUA levels, but with different inflection points in men and women. The thresholds for FPG, 2h-PG, and HbA1c for men and women were 6.5/8.0 mmol/L, 11.0/14.0 mmol/L, and 6.1/6.5, respectively (SUA levels increased with increasing glycemic indices before the inflection points and then eventually decreased with further increases in the glycemic indices). CONCLUSION: An inverted U-shaped association was observed between major glycemic indices and uric acid levels in both sexes, while the inflection points were reached earlier in men than in women.

Dithiolation of [70]Fullerene with Aliphatic Primary Thiols in the Presence of n-Butylamine via Aerobic Oxidation Reaction.

Aerobic oxidation reaction of [70]fullerene with aliphatic primary thiols in the presence of n-butylamine was studied. The reaction afforded both the fullerene dithiol (2) and dithiol epoxide (3) compounds, which were characterized by 1H and 13C NMR, HRMS and UV-vis spectroscopies. In situ vis-NIR spectral measurement showed absorption bands due to anionic fullerene species, indicating that the reaction was likely initiated with the addition of thiolate anions to C70. Computational calculations were performed to rationalize the structure of the dithiol epoxide compounds. The electrochemical property of 2,5-( n-C5H11S)2C70 (2a) was compared with two analogue compounds of 2,5-Bn2C70 and 2-MeO-5-BnC70 that had identical addition pattern and number of addends. The result showed that the dithiol compound was more electron deficient than the other two derivatives.

Copper-Catalyzed Aerobic Oxidative Reaction of C60 with Aliphatic Primary Amines and CS2.

A novel type of fullerene derivatives, [60]fullerothiazolidinethiones (2), were obtained from the copper-catalyzed aerobic oxidative reaction of C60 with aliphatic primary amines and CS2 in 4:1 v/v DMF and o-DCB. The obtained products were fully characterized with the X-ray single-crystal diffraction and spectroscopic methods. Control experiment with maleic anhydride, an analogue to C60, also afforded thiazolidinethione product, but via a mechanism different from that of C60 judging from the structure difference between the two types of thiazolidinethione compounds, demonstrating the unique reactivity of C60.

Dicussion on the Innovation Development by Blood-supply Requirements: Based on the 6 Requirements of Supply Side Structural Reform Guidance for Deepening Eonomics Development / 中国卫生经济

Objective:To discuss innovative development under the "6 requirements" guidance of supply-side structural reform,and provide direction of development reference for promoting the development of blood collection and supply.Methods:It reviewed the development of blood collection and supply in a certain blood center,analyzed the integrating degree between the main business development measures and "6 requirements" of supply-side structural reform.Results:There was a better compatibility between the main measures and "6 requirements" of supply-side structural reform.Conclusion:Based on the "6 requirements" guidance of supply-side structural reform,innovative development could be led to effectively break the current bottleneck at blood collection and supplyment.

Reductive Activation of C70 Equatorial Carbons and Structurally Characterized C70 δ-Adduct with Closed [5,6]-Ring Fusion.

The C70 δ-adducts with closed [5,6]-ring fusion are an important type of compound in classifying bond delocalization in the equatorial belt of C70. However, the formation of such compounds is severely restricted due to the low reactivity of the carbon atoms in the flat equatorial region. Such a restriction is lifted when reduced anionic C70 species are used, where the inert equatorial carbon atoms are activated.

Effect of A disintegrin and metalloproteinase 10 gene silencing on the proliferation, invasion and migration of the human tongue squamous cell carcinoma cell line TCA8113.

The present study aimed to investigate the effect of A disintegrin and metalloproteinase 10 (ADAM10) gene silencing on the proliferation, migration and invasion of the human tongue squamous cell carcinoma cell line TCA8113. RNA interference was used to knock down the expression of ADAM10 in the TCA8113 cell line and the proliferation, migration and invasive ability of the treated cells were observed in vitro. The expression levels of epidermal growth factor receptor (EGFR) and E-cadherin in the treated cells were determined by western blot analysis. The proliferation, migration and invasion abilities of cells in the ADAM10 siRNA-treated group were significantly lower than those in the control groups (P<0.05). In addition, compared with the control groups, the expression levels of EGFR and E-cadherin in the ADAM10 siRNA-treated cells were significantly decreased (P<0.05) and increased (P<0.05), respectively. These results suggested that ADAM10 is important in regulating the proliferation, invasion and migration of the human tongue squamous cell carcinoma cell line TCA8113 and that the mechanism may, at least in part, be associated with the upregulation of EGFR and the downregulation of E-cadherin.

Necrolytic migratory erythema as the first manifestation of pancreatic neuroendocrine tumor.

Necrolytic migratory erythma (NME) is an obligatory paraneoplastic syndrome. Here we describe a woman admitted to the dermatology ward with NME which was later found to be associated with glucagonoma, a slow-growing, rare pancreatic neuroendocrine tumor. Even more rarely, the tumor was located in the pancreas head, while most of such lesions are located in the distal pancreas. The diagnosis of this rare tumor requires an elevated serum glucagon level and imaging confirming a pancreatic tumor. After surgical removal of the tumor, the patient's cutaneous and systemic features resolved. It is therefore imperative that clinicians recognize NME early in order to make an accurate diagnosis and to provide treatment for this rare tumor.

MicroRNA-145 inhibits the proliferation, migration and invasion of the human TCA8113 oral cancer line.

The aim of this study was to investigate the effect of microRNA (miR)-145 on the proliferation, migration and invasion of the human oral cancer line, TCA8113. Expression levels of miR-145 in TCA8113 cells were detected by quantitative PCR. miR-145 was transfected into human TCA8113 oral cancer cells and the proliferation, migration and invasion abilities of treated TCA8113 cells were detected by proliferation, migration and invasion assays, respectively. The expression levels of miR-145 in TCA8113 cells were significantly lower than those in human normal oral keratinocytes (P<0.05). Cellular proliferation, migration and invasion abilities in the miR-145 transfection group were significantly lower than those in the control group (all P<0.05). High miR-145 expression was found to negatively regulate the proliferation, migration and invasion of TCA8113 cells. Results of the present study indicate that the expression of miR-145 may be associated with the genesis and development of human oral cancer.

Tolerance and chimerism and allogeneic bone marrow/stem cell transplantation in liver transplantation.

The liver has particular tolerogenic properties that allow its spontaneous acceptance in some animal species. Liver structure is considered to favor a tolerogenic environment. The peripheral tolerance mechanisms also play a role in spontaneous tolerance to liver graft. In a clinical setting, the main challenge nowadays facing liver transplantation is minimization of immunosuppression with the goal of donor-specific tolerance. Mechanisms involved in tolerance to transplanted organs are complex and partly unknown. A significant mechanism in tolerance induction is chimerism. Chimerism can be induced through transplantation of allogeneic donor bone marrow/stem cells under appropriate host conditioning. This review focuses on the tolerance mechanisms in liver transplantation and highlights the role of chimerism and allogeneic bone marrow/stem cell transplantation in tolerance development.

[Study of the microwave emissivity characteristics over different land cover types].

The microwave emissivity over land is very important for describing the characteristics of the lands, and it is also a key factor for retrieving the parameters of land and atmosphere. Different land covers have their emission behavior as a function of structure, water content, and surface roughness. In the present study the global land surface emissivities were calculated using six month (June, 2003-August, 2003, Dec, 2003-Feb, 2004) AMSR-E L2A brightness temperature, MODIS land surface temperature and the layered atmosphere temperature, and humidity and pressure profiles data retrieved from MODIS/Aqua under clear sky conditions. With the information of IGBP land cover types, "pure" pixels were used, which are defined when the fraction cover of each land type is larger than 85%. Then, the emissivity of sixteen land covers at different frequencies, polarization and their seasonal variation were analyzed respectively. The results show that the emissivity of vegetation including forests, grasslands and croplands is higher than that over bare soil, and the polarization difference of vegetation is smaller than that of bare soil. In summer, the emissivity of vegetation is relatively stable because it is in bloom, therefore the authors can use it as its emissivity in our microwave emissivity database over different land cover types. Furthermore, snow cover can heavily impact the change in land cover emissivity, especially in winter.

Magnetic resonance cholangiopancreatography for the detection of pancreatic duct stones in patients with chronic pancreatitis.

AIM: To assess the role of magnetic resonance cholangiopancreatography (MRCP) in detection of pancreatic duct stones (PDS) in patients with chronic pancreatitis (CP). METHODS: Clinical data of 78 CP patients who were treated at the First Affiliated Hospital of Xi'an Jiaotong University (China) between January 2004 and July 2008 were retrospectively analyzed. A predictive model of pancreatic duct stones was established through logistic regression and its effectiveness was verified. Among these patients, MRCP was performed in 60 patients who served as a control group, while 44 patients with a higher predictive value than the entry threshold of the predictive model served as an experimental group. RESULTS: The positive rate of PDS in the 78 patients with CP was 19.2% (15/78). The predictive entry threshold of the predictive model was 5% (P < 0.05). The possibility of existence of PDS could be predicted according to the following 4 indexes: gastrointestinal symptoms, intermittent abdominal pain, diabetes mellitus (DM)/impaired glucose tolerance (IGT) and positive B-mode ultrasound results. The incidence of PDS in the experimental group was higher than that in the control group (P < 0.05). CONCLUSION: MRCP is strongly suggested for the detection of PDS in patients with gastrointestinal symptoms, intermittent abdominal pain, DM/IGT and positive B-mode ultrasound results.

Serum from radiofrequency-injured livers induces differentiation of bone marrow stem cells into hepatocyte-like cells.

BACKGROUND: Roles that bone marrow stem cells (BMSCs) play in liver repair after liver injury and the cell therapy for liver diseases are widely accepted. However, the availability of hepatocyte-like cells from BMSCs and possible animal diseases association with culturing in fetal calf serum (FCS) are the major limitations of clinical therapy. Therefore, this study was designed to search for a new cell source for the treatment of liver injuries through investigating whether serum from radiofrequency ablation-injured rabbit livers can induce the differentiation of BMSCs into hepatocyte-like cells. METHODS: Serum was collected from rabbits 36 h after radiofrequency ablation (RFA) treatment of the liver. BMSCs were isolated from rabbit bone marrow and were cultured in the collected serum. Cellular morphology and cell cycle were observed. Hepatocyte markers of the differentiated cells were detected by immunohistochemistry. RESULTS: After induction for 7 d, spindle-shaped BMSCs turned into round cells that resembled the morphology of hepatocyte-like cells. Flow cytometry showed that the percentage of cells in the S/G2/M phase was higher in the RFA group than that in the FCS group and HGF groups. This result suggests that BMSC can transform into mature cells from stem cell phase. Albumin and CK18 were considered as typical marker of hepatocytes. Following induction for 14 d, the differentiated cells expressed immunofluorescence of FITC-labeled albumin and TRITC-labeled CK18. CONCLUSION: BMSCs treated with serum collected from radiofrequency ablation-injured livers can differentiate into hepatocyte-like cells providing a cell source to cell therapy.