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Macrocycles often exhibit good biological properties and potential druggability, which lead to versatile applications in the pharmaceutical industry. Herein, we report a highly efficient and practical methodology for the functionalization and macrocyclization of Trp and Trp-containing peptides

We report here a radical hydrotrifluoromethylation of ynamides to provide an alternative route toward β-CF3 enamides.

Arenaviruses are a large family of enveloped negative-strand RNA viruses that include several causative agents of severe hemorrhagic fevers. Currently, there are no FDA-licensed drugs to treat arenavirus infection except for the off-labeled use of ribavirin. Here, we performed antiviral drug screening against the Old World arenavirus lymphocytic choriomeningitis virus (LCMV) using an FDA-approved drug library. Five drug candidates were identified, including mycophenolic acid, benidipine hydrochloride, clofazimine, dabrafenib, and apatinib, for having strong anti-LCMV effects. Further analysis indicated that benidipine hydrochloride inhibited LCMV membrane fusion, and an adaptive mutation on the LCMV glycoprotein D414 site was found to antagonize the anti-LCMV activity of benidipine hydrochloride. Mycophenolic acid inhibited LCMV replication by depleting GTP production. We also found mycophenolic acid, clofazimine, dabrafenib, and apatinib can inhibit the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Owing to their FDA-approved status, these drug candidates can potentially be used rapidly in the clinical treatment of arenavirus and SARS-CoV-2 infection.

Given the significant clinical potential of human plasminogen Kringle 5 on tumours, it is crucial to seek its receptors for a thorough comprehension of its physiological functions and mechanism. Eleven candidates have been screened out in our previous works. In the present work, we further inquired whether the candidate, von Willebrand factor type A domain 1 in coagulation factor C homology protein (abbr. vWA1), was a potential receptor of Kringle 5, and investigated their binding mechanism by bio-specific experiments, frontal affinity analysis (FA), and molecular dynamic simulation (MDS). After the potential was validated by bio-specific experiments, the FA results stated that vWA1 exhibited a strong interaction towards Kringle 5 in the proportion of 1:1 with the binding constant of 4.18 × 10

OBJECTIVE: To investigate the active compounds from Saussurea involucrata on the heart and brain of mice at simulated high altitude. METHODS: Fifty healthy male adult BALB/c mice were randomly divided into normal control group, hypoxic model group, acetazolamide group, petroleum ether extract of Saussurea involucrata (PESI) group and octacosan group with 10 mice in each group. Acetazolamide group, PESI group and octacosan group were treated with acetazolamide (200 mg/kg), PESI (200 mg/kg) or octacosan (100 mg/kg) by single tail vein injection, respectively. Except normal control group, the mice were exposed to a simulated high altitude of 6000 m for 8 h in an animal decompression chamber. After the mice were sacrificed by cervical dislocation, the heart and brain were histologically observed by HE staining; superoxide dismutase (SOD) activity, total anti-oxidant capacity (T-AOC) and the content of malondialdehyde (MDA) in plasma, heart and brain tissues were detected by WST-1 method, ABTS method and TBA method, respectively; lactic acid and lactate dehydrogenase (LDH) activity in plasma, heart and brain tissues were detected by colorimetric method and microwell plate method, respectively; ATP content and ATPase activity in heart and brain tissues were detected by colorimetric method. RESULTS: PESI and octacosane significantly attenuated the pathological damages of heart and brain tissue at simulated high altitude; increased SOD activity, T-AOC and LDH activity, and decreased the contents of MDA and lactic acid in plasma, heart and brain tissues; increased the content of ATP in heart and brain tissues; increased the activities of Na (+)-K (+) ATPase, Mg (2+) ATPase, Ca (2+) ATPase and Ca (2+)-Mg (2+) ATPase in myocardial tissue; and increased the activities of Mg (2+) ATPase, Ca (2+)-Mg (2+) ATPase in brain tissue. CONCLUSION: PESI and octacosan exert anti-hypoxic activity by improving the antioxidant capacity, reducing the free radical levels, promoting the anaerobic fermentation, and alleviating the energy deficiency and metabolic disorders caused by hypoxia in mice.

Modern lifestyle factors (high-caloric food rich in fat) and daily chronic stress are important risk factors for metabolic disturbances. Increased hypothalamic-pituitary-adrenal (HPA) axis activity and the subsequent excess production of glucocorticoids (GCs) in response to chronic stress (CS) leads to increases in metabolic complications, such as type 2 diabetes and insulin resistance (IR). Melatonin (MLT), which protects several regulatory components of the HPA axis from GC-induced deterioration, might improve glucose homeostasis. Piromelatine is a melatonin receptor-1/melatonin receptor-2 (MT1/MT2) agonist with high affinity for MLT receptors and a longer duration of action than MLT. The objective of the present study was to explore the potential effects of piromelatine on glucose and lipid metabolism and insulin sensitivity in rats with IR induced by a high-fat diet combined with CS (CF). The results showed that piromelatine prevented the suppression of body weight gain and energy intake induced by CF and normalized CF-induced hyperglycemia and homeostasis model assessment-IR index, which suggests that piromelatine prevented whole-body IR. Piromelatine also prevented CF-induced dysregulation of genes involved in glucose and lipid metabolism, including proinflammatory cytokines, in adipose tissue. In addition, piromelatine also attenuated CF-induced excess free corticosterone release, increased glucocorticoid receptor expression, and decreased 11β-hydroxysteroid dehydrogenase-1 expression, suggesting that piromelatine might ameliorate impaired glucose metabolism and prevent IR by normalizing HPA-axis functions. In conclusion, piromelatine might be a novel therapeutic agent for glucose intolerance and IR.

Excessive glucocorticoid (GC) in type 2 diabetes mellitus (T2DM) reduces insulin sensitivity, impairs β-cell function, increases gluconeogenesis and glycogenolysis, impairs glucose uptake and metabolism, and reduces the insulinotropic effects of glucagon-like peptide 1. Melatonin, which serves as a physiological regulator of the hypothalamic-pituitary-adrenal (HPA) axis, has been suggested to have anti-diabetic effects. The objective of the present study was to investigate the effect of the MT1/MT2 melatonin agonist Neu-P11 on glucose and lipid metabolism in T2DM rats induced by a high fat diet combined with low doses of streptozotocin. T2DM rats were intragastrically administered melatonin (20mg/kg), Neu-P11 (20, 10, 5mg/kg), or a vehicle for 4 weeks. The results showed that the increased food intake, water consumption, hyperglycemia, glucose intolerance, and insulin resistance in T2DM rats were all improved by Neu-P11 treatment. Neu-P11 increased GC receptor expression and suppressed 11β-hydroxysteroid dehydrogenase 1 activity in the hippocampus by enhancing GC sensitivity and HPA feedback, thus decreasing the high GC levels. Transcript levels of the glucose metabolism-related genes peroxisome proliferator-activated receptor-γ, glucose transporter type-4, and adiponectin in adipose tissue were significantly increased after Neu-P11 treatment, while leptin mRNA was significantly decreased. Furthermore, MT1 and MT2 protein levels were enhanced by Neu-P11. These data suggest that normalization of the hyperactivated HPA axis by melatonin and Neu-P11 in T2DM regulates metabolic profiles and insulin sensitivity, which may attenuate insulin resistance and glucose homeostasis. Because Neu-P11 has superior pharmacokinetics and a longer half-life than melatonin, it might be beneficial in treating obesity and T2DM.

The aim of this study was to determine whether the Rehmannia glutinosa oligosaccharides (ROS) ameliorate the impaired glucose metabolism and the potential mechanism in chronic stress rats fed with high-fat diet. The rats were fed by a high-fat diet and simultaneously stimulated by chronic stress over 5 weeks. Body weight, fasting plasma glucose, intraperitoneal glucose tolerance test (IPGTT), plasma lipids, gluconeogenesis test (GGT), glycogen content, and corticosterone, insulin and leptin levels were measured. The results showed that ROS administration (100, 200 mg/kg, i.g.) for 5 weeks exerted the effects of increasing the organ weights of thymus and spleen, lowering the fasting plasma glucose level, improving impaired glucose tolerance, increasing the contents of liver and muscle glycogen, decreasing the gluconeogenesis ability, plasma-free fatty acid's level, as well as plasma triglyceride and total cholesterol levels in chronic stress and high-fat fed rats, especially in the group of 200mg/kg; while the plasma corticosterone level was decreased, and plasma leptin level was increased. These results suggest that ROS exert an ameliorating effect of impaired glucose metabolism in chronic stress rats fed with high-fat diet, and the potential mechanism may be mediated through rebuilding the glucose homeostasis in the neuroendocrine immuno-modulation (NIM) network through multilinks and multitargets.

This chapter introduces a practical application of early warning system at grassroots level in Baiyin City, Gansu Province, China, which is named Real-time Monitoring and Alert System on Infectious Diseases in Baiyin City (B-Alert System). The system aims at early detection of potential outbreaks for 44 infectious diseases at a small area, which adopts the stratified fixed-value method (SFM) to detect any aberration on each targeted disease at the geographic area on a daily basis and at each administrative level from county to township, village and school. Each signal generated by the B-Alert System would be verified and investigated by the local public health staff. The data sources, algorithm, workflow, and operation mechanism of the system were introduced, and the warning results of the system during 2007–2014 were also presented.

In this review, the literature data on the phytochemical and biological investigations on the genus of Meconopsis are summarized from 49 references. Up to now, more than 95 compounds were isolated from 19 Meconopsis plant species. The chemical constituents are mostly alkaloids, flavonoids, phenols, steroids, and terpenes, together with minor constituents of essential oil, and others. The crude extracts and metabolites have been found to possess various bioactivities including antitumor activity, central action, cardiovascular system effects, antibiosis, antiviral activity, anti-inflammatory effects, and other biological activities.

Lamiophlomis rotata (Benth.) Kudo is a perennial herb (Labiatae) used as the Tibetan traditional medicine with the effects of alleviating pain, detumescence, hemostasis, promoting blood circulation to remove blood stasis and reinforcing marrow. In this study, we investigated the antinociceptive and anti-inflammatory activities of iridoid glycosides extract of L. rotata (IGLR) in mice. Our results showed that the iridoid glycosides extract could decrease acetic-acid-induced writhings times and formalin-induced lickings times, inhibit carrageenan-induced hind paw edema and xylene-induced ear swelling, and suppress peritoneal capillary permeability and leukocyte infiltration also induced by acetic acid in mice. All of these results suggested that the iridoid glycosides extract possesses the significant antinociceptive and anti-inflammatory activities.

Lamiophlomis rotata (Benth.) Kudo (LR) is a traditional drug used by Chinese minorities such as Tibetans, Mongolians and Na Xi with the beneficial effects of hemostasis and alleviating pain. Flavonoids ingredients (P(1)), iridoid glycosides ingredients (P(2)) and maximus polarity components ingredients (P(3)) were isolated from the aqueous extract of LR (AELR) with polyamide and macroporous adsorptive resins chromatographic columns. The hemostatic activity of these ingredients was estimated by the changes in bleeding time (BT), clotting time (CT) and blood coagulation parameters in mice or rats. RP-HPLC was used to analyze the chemical composition of P(2). As a result, AELR and P(2) significantly shortened BT, CT and thrombin time (TT), and increased fibrinogen (FIB), but P(1) and P(3) showed no hemostatic effect during the experiment. Moreover, P(2) showed satisfactory hemostatic effect with dose-effect relationship and low toxicity in mice. 8-Dehydroxy shanzhiside, phloyoside II, shanzhiside methylester, loganin, and 8-O-acetylshanzhiside methylester were detected as the main iridoid glycosides in P(2) by RP-HPLC. Our results suggest that iridoid glycosides may be the hemostatic activity ingredients of L. rotata and are a potential hemostatic medicine.

8-deoxyshanzhiside was extracted from Lamiophlomis rotata (Benth.) Kudo. Extensive NMR spectroscopy techniques were used to fully assign the (1)H and (13)C spectra. X-ray investigation was used to identify its conformation, and absolute configuration.

Lamiophlomis rotata (Benth.) Kudo (LR) is a traditional drug used by Chinese minorities such as Tibetans, Mongolians and Na Xi with the beneficial effects of hemostasis and alleviating pain. Flavonoids ingredients (P(1)), iridoid glycosides ingredients (P(2)) and maximus polarity components ingredients (P(3)) were isolated from the aqueous extract of LR (AELR) with polyamide and macroporous adsorptive resins chromatographic columns. The hemostatic activity of these ingredients was estimated by the changes in bleeding time (BT), clotting time (CT) and blood coagulation parameters in mice or rats. RP-HPLC was used to analyze the chemical composition of P(2). As a result, AELR and P(2) significantly shortened BT, CT and thrombin time (TT), and increased fibrinogen (FIB), but P(1) and P(3) showed no hemostatic effect during the experiment. Moreover, P(2) showed satisfactory hemostatic effect with dose-effect relationship and low toxicity in mice. 8-Dehydroxy shanzhiside, phloyoside II, shanzhiside methylester, loganin, and 8-O-acetylshanzhiside methylester were detected as the main iridoid glycosides in P(2) by RP-HPLC. Our results suggest that iridoid glycosides may be the hemostatic activity ingredients of L. rotata and are a potential hemostatic medicine.

The blood hemostatic activity of the Tibetan medicinal herb Lamiophlomis rotata was evaluated in BALB/c mice and Wistar rats. L. rotata aqueous extract (LRAE) was given to mice at concentrations of 0.5, 1.0, 2.0 g/kg body weight and 0.75, 1.5, 3.0 g/kg to rats. The hemostatic activity of LRAE was estimated by changes in bleeding time (BT), prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen (FIB). At the same time hepatic function and blood fat indexes including AST, ALT, Alb, Chol and LDL-C were measured also. The results showed that an appropriate level of LRAE could shorten the BT and TT values and increase the Alb level paralleling that of FIB. However, the shortening of the PT was only possible by a high and long administration of LRAE, and no change in APTT was observed. On the other hand, LRAE showed some effects in improving the liver function and reducing blood lipids by decreasing the levels of AST, ALT, Chol and LDL-C. All these changes had a significant dose-effect and time-effect relationship. These results confirm the hemostatic and thromboplastic effects of L. rotata and these effects might be implemented by improving the synthetic function of the liver.

To screen the antitumor extract from Stellera chamaejasmel L..The means of systematic solvent extraction was used to separate the 95% ethanol extract. The antitumor activities of the different extracts in vitro were analyzed with MTT assay.The petroleum ether extract and the chloroform extract strongly inhibited cell proliferation of human cancer cell lines such as leukemia HL-60, stomach cancer SGC-7901 and hepatocarcinoma BEL-7402, and showed significant dose-dependent response while the n-butanol extract and the methanol extract exhibited low antitumor activities in vitro. The petroleum ether extract was most active.The petroleum ether extract is the principal antitumor extract from Stellera chamaejasmel L..

The hypoglycemic and anti-diabetic effect of Rehmannia glutinosa oligosaccharide (ROS) in glucose-induced hyperglycemic and alloxan-induced diabetic rats and its mechanism was investigated in this paper. It was found that pretreatment of ROS in normal rats with 100 mg/kg for 3 days, i.p., induced a partial prevention of hyperglycemia caused by glucose (2g/kg, i.p.), while when hyperglycemia was induced in adrenalectomized (ADX) rats, the preventive effect of ROS on hyperglycemia was lost. In alloxan-induced diabetic rats, ROS (100 mg/kg for 15 days, i.p.) showed a significant decrease in blood glucose level and hepatic glucose-6-phosphatase activity with an increase in hepatic glycogen content. Furthermore, ROS raised plasma insulin level and lowered plasma corticosterone level in alloxan-induced diabetic rats. The results indicated that oligosaccharide of Rehmannia glutinosa Libosch. exerted a significant hypoglycemic effect in normal and alloxan-induced diabetic rats. The regulatory mechanism of ROS on glucose metabolism was adrenal dependent and had a close relation with the neuroendocrine system.

0009-3130/11/4705-0848 2011 Springer Science+Business Media, Inc. 1) Department of Pharmacy, Lanzhou General Hospital of PLA, Lanzhou, 730050, P. R. China, fax: 86931 266-1767, e-mail: limaox2005@yahoo.com.cn; 2) Department of Pharmacy, Changhai Hospital, Second Military Medical University, Shanghai, 200433, P. R. China; 3) Department of Life Sciences, Lanzhou University, Lanzhou, 730000, P. R. China. Published in Khimiya Prirodnykh Soedinenii, No. 5, pp. 740–741, September–October, 2011. Original article submitted June 15, 2010. Chemistry of Natural Compounds, Vol. 47, No. 5, November, 2011 [Russian original No. 5, September–October, 2011]

An HPLC-photodiode array detector (PAD)-APCI/MS method was developed for the identification of iridoid glycosides in Lamiophlomis rotata (Benth.) Kudo. The regularities of characteristic ions of iridoid glycosides obtained in APCI-MS were analyzed and used to deduce the structure of iridoid glycosides. Compared with the literature on ESI-MS, the deprotonated molecular ions were more outstanding in APCI-MS. Five major active constituents, namely, 8-O-acetylshanzhiside methyl ester, loganin, 8-deoxyshanzhiside, phloyoside II, and shanzhiside methyl ester, were simultaneously determined in ten samples by HPLC. A comprehensive validation of the method included tests of sensitivity, linearity, precision, and accuracy. The linear regressions were acquired with r > 0.999. The precision was evaluated by intra- and inter-day assays, after which relative standard deviation (R.S.D.) values were reported within 2.5%. The recovery studies for the quantified compounds were observed in the range of 95.6-101.2% with R.S.D. values less than 2.1%. The overall procedure may be suitable for the qualitative and quantitative analyses of iridoid glycosides in L. rotata and its preparations.