Biotransformation and disposition characteristics of HSK7653, a novel long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes.

AIM: To investigate the metabolism and disposition characteristics of HSK7653 in healthy male Chinese participants. METHODS: A single oral dose of 80 µCi (25 mg) [14C]HSK7653 capsules was administered to six healthy participants, and blood, plasma, urine and faeces were collected. Quantitative and qualitative analysis was conducted to investigate the pharmacokinetics, blood-to-plasma ratio, mass balance and metabolism of HSK7653. RESULTS: The drug was well absorbed and reached a maximum concentration at 1.25 h. The drug-related components (HSK7653 and its metabolites) were eliminated slowly, with a half-life (t1/2) of 111 h. Unchanged HSK7653 contributed to more than 97% of the total radioactivity in all plasma samples. The blood-to-plasma ratio (0.573-0.845) indicated that HSK7653 did not tend to distribute into blood cells. At 504 h postdose, up to 95.9% of the dose was excreted, including 79.8% in urine and 16.1% in faeces. Most of the radioactivity (75.5% dose) in excreta was unchanged HSK7653. In addition, nine metabolites were detected in urine and faeces. The most abundant metabolite was M6-2, a dioxidation product of HSK7653, which accounted for 4.73% and 2.63% of the dose in urine and faeces, respectively. The main metabolic pathways of HSK7653 in vivo included oxidation, pyrrole ring opening and sulphonamide hydrolysation. CONCLUSION: HSK7653 was well absorbed, slightly metabolized and slowly excreted in humans. The high plasma exposure and long t1/2 of HSK7653 may contribute to its long-lasting efficacy as a long-acting dipeptidyl peptidase-4 inhibitor.

Effect of the serum of rats treated with Suo Quan pill on embryonic stem cells.

Suo Quan pill(SQP), a well-known and classical traditional Chinese medicine compound, consists of three traditional Chinese medicine: Alpinia oxyphylla Miq., Lindera aggregata (Sims) Kosterm., Dioscorea opposite. Its effect was summarized as supplementing kidney-yang and shrinkaging urination. This study evaluated the effects of the serum of rats treated with Suo Quan pill on embryonic stem cells(ES cells). Cell proliferation was detected by MTT assay. Cell cycle and apoptosis of ES cells were evaluated with flow cytometry. Nanog mRNA expression was verified by fluorescence quantitative PCR and Nanog protein in ES cells was determined by Western blot. The serum of SQP-treated rats not only promoted ES cells proliferation and Nanog expression in ES cells, but also inhibited H202 stimulated cell apoptosis. Furthermore, the serum of rats containing SQP affected the cell cycle distribution of ES cells, reducing the percentage of cells in G0/G1phase and increasing the percentage of cells in G2/M phase, increasing the proliferation index of ES cells. These results illustrate that the enhanced effect of SQP on ES cells proliferation is in part due to the increased expression of Nanog in ES cells, the accelerated cell cycle period and the inhibited apoptosis of ES cells.

[Effects of Suoquan Wan and Shenqi Wan on Urethra Function and ß-AR Function of Detrusor in Natural Aged Rats].

OBJECTIVE: To investigate the effect of Suoquan Wan(SQW) and Jinkui Shenqi Wan(JKSQW) on urethra function and ß6-AR function of detrusor in natural aged rats. METHODS: young rats(3 months) and Aged rats(15 months) were chosen. Young rats were chosen as control, aged rats were randomly divided into three groups: model, JKSQW and SQW groups, 12 rats in each group. JKSQW and SQW were given the appropriate concentration once a day for six weeks. The effects of SQW and JKSQW on relaxation function of bladder detrusor was investigated, and their effects on bladder induced by ß3-AR agonist and ß3-AR agonist were further studied. Then, their effects on pressure of urethra were observed. RESULTS: Compared with the young group, detrusor compliance of natural aged model rats was increased, Emax and IA of agonist of ß3-AR including BRL37344 and ISO were decreased(P <0. 01), while PA2 of antagonist of ß3-AR were increased(P <0. 05). Compared with model group, SQW and JKSQW decreased the bladder compliance(P <0. 05), and increased Emax, IA and PD2 due to sensitivity of detrusor to agonist of ß3-AR and ß3-AR including BRL37344 and ISO(P <0. 05 or P < 0. 01) ,while decreased PA2 of antagonist of ß3-AR(P <0. 05). MUCP, MUP and FUL of aged rats were lower than those of normal rats. But SQW and JKSQW increased MUCP and MUP, and JKSQW increased FUL of aged rats(P <0. 05 or P <0. 01). CONCLUSION: SQW and JKSQW can remarkably adjust ß3-AR function on the detrusor and improve the closure ability of bladder detrusor of the natural aged rats.

[Effect of Zhuangyao Jianshen Wan (ZYJCW) on P2X1 and P2X3 mRNA expressions in rats with diuresis caused by kidney deficiency].

To investigate the urination-reducing effect and mechanism of Zhuangyao Jianshen Wan (ZYJCW). In this study, SI rats were subcutaneously injected with 150 mg · kg(-1) dose of D-galactose to prepare the sub-acute aging model and randomly divided into the model group, the Suoquan Wan group (1.17 g · kg(-1) · d(-1)), and ZYJCW high, medium and low dose groups (2.39, 1.20, 0.60 g · kg(-1) · d(-1)) , with normal rats in the blank group. They were continuously administered with drugs for eight weeks. The metabolic cage method was adopted to measure the 24 h urine volume and 5 h water load urine volume in rats. The automatic biochemistry analyzer was adopted to detect urine concentrations of Na+, Cl-, K+. The ELISA method was used to determine serum aldosterone (ALD) and antidiuretic hormone (ADH). The changes in P2X1 and P2X3 mRNA expressions in bladder tissues of rats were detected by RT-PCR. According to the results, both ZYJCW high and medium dose groups showed significant down-regulations in 24 h urine volume and 5 h water load urine volume in (P <0.05, P <0.01), declines in Na+ and Cl- concentrations in urine (P <0.01), notable rises in plasma ALD and ADH contents (P <0.05, P <0.01) and remarkable down-regulations in the P2X1 and P2X3 mRNA expressions in bladder tissues (P <0.01). The ZYJCW low dose group revealed obvious reductions in Na+ and Cl- concentrations in urine (P <0.01). The results indicated that ZYJCW may show the urination-reducing effect by down-regulating the P2X1 and P2X3 mRNA expressions in bladder tissues of rats with diuresis caused by kidney deficiency.

Gastroprotective and anti-Helicobacter pylori potential of herbal formula HZJW: safety and efficacy assessment.

BACKGROUND: A traditional Chinese Medicine (TCM) formula, HZJW, has been applied in clinics in China for gastrointestinal disorders. However, the therapeutic mechanism underlying its efficacy and safety remained to be defined. The present investigation was undertaken to evaluate the formula HZJW for its gastroprotective potential, possible effect on Helicobacter pylori along with safety to justify its anti-ulcer action and safe clinical application. METHODS: The gastroduodenal cytoprotective potential was evaluated in rodent experimental models (HCl/Ethanol and NSAID-induced ulcer protocols). The anti-H. pylori property was assessed by agar dilution assay in vitro and analysis in vivo including rapid urease test, immunogold test and histopathology. For toxicity assessment, acute toxicity study was performed according to fixed dose procedure with a single oral administration of HZJW to mice. In the oral chronic toxicity, rats (80 males, 80 females) were administrated HZJW orally in 0, 1000, 2500, or 5000 mg/kg/day doses for 26 weeks (n = 40/group of each sex). Clinical signs, mortality, body weights, feed consumption, ophthalmology, hematology, serum biochemistry, gross findings, organ weights and histopathology were examined at the end of the 13- and 26-week dosing period, as well as after the 4-week recovery period. RESULTS: In the HCl/Ethanol-induced ulcer model, it was observed that oral administration with HZJW (260, 520 and 1040 mg/kg) and ranitidine (250 mg/kg) significantly reduced the ulcerative lesion index (116.70 ± 36.4, 102.20 ± 18.20, 84.10 ± 12.1 and 73.70 ± 16.70) in a dose-dependent manner, respectively, with respect to control group (134.10 ± 31.69). Significant inhibition was also observed in ulcerative index from aspirin-induced ulcer model, with decreases of 35.40 ± 5.93, 31.30 ± 8.08, 26.80 ± 8.27and 20.40 ± 6.93 for the groups treated with HZJW and ranitidine, in parallel to controls (41.60 ± 10.80). On the other hand, treatment with HZJW efficaciously eradicated H. pylori in infected mice in rapid urease test (RUT) and immunogold antibody assay, as further confirmed by reduction of H. pylori presence in histopathological analysis. In the in vitro assay, MICs for HZJW and amoxicillin (positive control) were 125 and 0.12 µg/mL respectively. The LD50 of HZJW was over 18.0 g/kg for mice. No drug-induced abnormalities were found as clinical signs, body weight, food consumption, hematology, blood biochemistry, ophthalmology and histopathology results across three doses. No target organ was identified. The No Observed Adverse Effect Level (NOAEL) of HZJW was determined to be 5,000 mg/kg/day for both sexes, a dose that was equivalent to 50 times of human dose. CONCLUSIONS: These results suggested the efficacy and safety of HZJW in healing peptic ulcer and combating H. pylori, which corroborated their conventional indications and contributed to their antiulcer pharmacological validation, lending more credence to its clinical application for the traditional treatment of stomach complaints symptomatic of peptic ulcer disease (PUD). HZJW might have the potential for further development as a safe and effective alternative/complementary to conventional medication in treating gastrointestinal (GI) disorders.

[Study on efficacy and mechanism of weiyangning pills against experimental gastric ulcer].

OBJECTIVE: To study the efficacy and mechanism of Weiyangning pills against experimental gastric ulcer. METHOD: The gastric ulcer model were established by acetic acid, water-immersion stress, aspirin induction, pyloric ligation in rats, in order to observe the effect of Weiyangning pills against experimental gastric ulcer and study its effect on the content of nitric oxide (NO) and epidermal growth factor (EGF), gastric mucosal blood flow, the content of PGE2, gastric secretion, gastric acid content and the activity of pepsin. RESULT: Weiyangning pills markedly reduced index of gastric ulcers of various types, increased the content of NO, EGF, PGE2 and gastric mucosal blood flow, inhibited gastric secretion and gastric acid content, and decreased the activity of pepsin. CONCLUSION: Weiyangning pills has a significant effect against experimental gastric ulcer, which is related to the reduction of gastric mucosa damage factors (gastric acid and pepsin) and the increase in gastric mucosa's function as a barrier and its recovery effects, such as NO, EGF, PGE2 and gastric mucosal blood flow.

Corrigendum: Combination effect of three main constituents from Sarcandra glabra inhibits oxidative stress in the mice following acute lung injury: a role of MAPK-NF-κB pathway.

[This corrects the article DOI: 10.3389/fphar.2020.580064.].

[Effect of Huangqi gegen decoction (HGD) on TGF-beta1/Smad3 pathway in diabetic cardiomyopathy rats].

OBJECTIVE: To study the effect of HGD on diabetic cardiomyopathy and its mechanism. METHODS: The T2-DM rats model was established by combining high fat diet with STZ. The blood glucose, insulin, myocardial fibrosis and TGF-beta1/Smad3 signaling pathway were observed; TGF-beta1 and Smad3 mRNA expression were detected by RT-PCR method, protein expression detected by immunohistochemical method. RESULTS: HGD obviously reduced fasting blood glucose, insulin, improved insulin resistance, reduced myocardial hydroxyproline contents, lowered cardiac index, significantly inhibited over-expression of TGF-beta1/SMAD3 mRNA and protein in diabetic rats cardiac. CONCLUSION: HGD can obviously prevent experimental diabetic myocardial fibrosis through the regulation effect on TGFbeta1/Smad3 signaling pathway.

[The influence of suoquan capsule on the mRNA expression of CYP11B2 in deficiency of the kidney and diuresis rats].

OBJECTIVE: To explore the mechanism of nourishing kidney and reducing urine effect of suoquan capsule by discussing the adjusting action on ALD synthase. METHODS: Built the model of deficiency of the kidney and diuresis by adenine,inspectd the contents of Cort, ALD in blood and the mRNA expression of CYP11B2 with ELISA and RT-PCR technology of the mice. RESULTS: Compared with model group, Suoquan capsule could remarkedly increase the contents of Cort, ALD in blood and the mRNA expression of CYP1 1 B2 of model rats. CONCLUSIONS: Suoquan capsule can increase the contents of Cort, ALD in blood and the mRNA expression of CYP11B2 in deficiency of the kidney and diuresis rats. Promote the combining of ALD by adjusting the ALD synthase may be the mechanism of nourishing the kidney and reducing urine of Souquan capsule from ALD synthase approach.

Combination Effect of Three Main Constituents From Sarcandra glabra Inhibits Oxidative Stress in the Mice Following Acute Lung Injury: A Role of MAPK-NF-κB Pathway.

Caffeoylquinic acids, coumarins and dicaffeoyl derivatives are considered to be three kinds of the most abundant bioactive components in Sarcandra glabra, an anti-inflammatory herb mainly found in Southern Asia. The combined anti-inflammatory effect of three typical constituents C + R + I (chlorogenic acid + rosmarinic acid + isofraxidin) from this plant has been investigated. The result implies that targeting the MAPK-NF-κB pathway would be one of the major mechanisms involved, using LPS stimulated RAW 264.7 cells as in vitro model and LPS-induced acute lung injury in mice as in vivo model. C + R + I can significantly suppress the levels of nitric oxide (NO), pro-inflammatory cytokines, and inhibit iNOS and COX-2 expression in LPS-treated RAW264.7 macrophage cells. Western blot analysis showed that C + R + I suppressed phosphorylation of NF-κB and MAPK, including phosphorylation of p65-NF-κB, IKB, ERK, JNK and P38. Besides, C + R + I suppressed MPO protein expression, but promoted SOD and HO-1 expression, and the related targets for C, R, and I were also predicted by molecular docking. This indicated that C + R + I could alleviate oxidative stress induced by LPS, which were further verified in the in vivo model of mice with acute lung injury through the measurement of corresponding inflammatory mediators and the analysis of immunehistochemistry.

[Impacts of the formula of Suoquanwan(SQW) on expression of AQP-2 mRNA and AVPR-V2 mRNA in the kidney of rat polyuria model of Yang-deficiency].

OBJECTIVE: To observe the impacts of the formula of Suoquanwan (SQW) on the expression of AQP-2 mRNA and AVPR-V2 mRNA in the kidney of rat polyuria model of Yang-deficiency. METHODS: The model rats were induced by adenine (250 mg/kg) for 4 weeks, then treated respectively with SQW or dDAVP. The expression of AQP-2 mRNA and AVPR-V2 mRNA in kidney of Yang-deficiency model by realtime fluorescence quantitative PCR method were investigated. RESULTS: In model rats, the expression of AQP-2 mRNA and AVPR-V2 mRNA in the kidney decreased, dDAVP and SQW high dose could increased the expression of AQP-2 mRNA and AVPR-V2 mRNA in the kidney. The others had no influence on the expression of AQP-2 mRNA and AVPR-V2 mRNA in the kidney. CONCLUSION: SQW can increase the expression of AQP-2 mRNA and AVPR-V2 mRNA in the kidney of rat polyuria model of Yang-deficiency.

[Influence of FPS on the expression of LDL-R mRNA in the liver tissues of hyperlipidemic rats].

OBJECTIVE: To explore the effect of FPS on low-density lipoprotein acceptor (LDL-R) mRNA in the liver tissues of hyperlipidemic rats. METHODS: Sixty healthy male SD rats were randomly divided into six groups: normal control, model control, Gynostemma pentaphyllum, FPS low dosage, FPS moderate dosage, and FPS high dosage group. Excepting the rats in the normal control group, the ones in other groups were all made rats' hyperlipidemic model by irrigating hyperlipidemic emulsion into the stomach and observed the expression of LDL-R mRNA in the liver tissues of rats of each group. RESULTS: Relative content of LDL-RmRNA in low and moderate dosage groups was notably higher than that inmodel group. The contents's difference was not remarkable between FPS moderate dosage group and Gynostemma pentaphyllum group. CONCLUSION: FPS can appreciably increase the expression of LDL-R mRNA in the liver tissues of hyperlipidemic rats and promote the elimination ofLDL-C to reduce serum cholesterol notably.

[A questionnaire-based survey on attitude and behavior of sex among rural women in Hainan province].

OBJECTIVE: To define the profile and risk factors of sexual attitude and behavior of rural women. METHODS: Using stratified cluster sampling, tape-recorded interviews and face to face interviews were carried out among 606 rural women. RESULTS: 24.6% of the women being studied accepted the idea of "premarital sexual intercourse" and thought "premarital sexual intercourse between a couple" acceptable accounted for 34.2%, 14.7% and 4% of the women reported having had premarital sexual intercourse and premarital induced abortion respectively. 5.0% of the women admitted having had sexual intercourse during menstruation. 4% and 3% of the women under study accepted "extramarital sexual intercourse" and "paid sexual intercourse" if they were in need of money. None of the women reported ever having had extramarital sex or paid sex. The results derived from two different methods did not differ significantly. Logistic rgression suggested that age, education and ethnicity were associated with attitude towards premarital sex, and age was associated with premarital sexual behavior. CONCLUSION: Sex education need to be promoted and targeted among rural population at early age. "Tape-recorded interview" method did not show a better validity in this study.