A simple and sensitive ultra-high performance liquid chromatography tandem mass spectrometry method for the quantitative analysis of VX-548 in monkey plasma: Method validation and application to pharmacokinetic study.

VX-548 is an orally active and highly selective NaV 1.8 inhibitor that is undergoing development for the treatment of acute pain. The aim of this study was to develop a liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for the measurement of VX-548 in monkey plasma. VX-548 was extracted from the plasma using acetonitrile-mediated protein precipitation. The quantitative analysis was performed on a Thermo Vantage TSQ mass spectrometer with ibrutinib as an internal standard. Chromatography was performed on a Waters ACQUITY UPLC BEH C18 column with 0.1% aqueous formic acid and acetonitrile as mobile phase. The precursor-to-product ion transitions were m/z 474.2 > 165.0 and m/z 441.2 > 138.1 for VX-548 and internal standard, respectively. This developed method was successfully validated in the concentration range of 1-1000 ng/mL. The calibration curve showed excellent linearity with a correlation coefficient of >0.999. The precision expressed as relative standard deviation (RSD) was <8.4%, whereas the accuracy denoted as relative error (RE) ranged from -5.0% to 9.1%. The mean recovery was >84%. VX-548 was stable in monkey plasma after storage under certain conditions. The validated method was successfully applied to the pharmacokinetic study of VX-548 in monkey plasma after single oral (2 mg/kg) and intravenous (1 mg/kg) administrations.

Correction: Noncovalent wedging effect catalyzed the cis to syn transformation of a surface-adsorbed polymer backbone toward an unusual thermodynamically stable supramolecular product.

Correction for 'Noncovalent wedging effect catalyzed the cis to syn transformation of a surface-adsorbed polymer backbone toward an unusual thermodynamically stable supramolecular product' by Zhi-Xuan Liu et al., Phys. Chem. Chem. Phys., 2022, 24, 30010-30016, https://doi.org/10.1039/D2CP04184G.

Scalable Asymmetric Synthesis of MK-8998, a T-Type Calcium Channel Antagonist.

Two scalable and efficient synthetic routes for the synthesis of a T-type calcium channel antagonist MK-8998 were developed from a simple pyridine building block. The key step to set the stereochemistry relied on either chiral rhodium catalyst-mediated asymmetric hydrogenation of an enamide or transamination of an arylketone that provided the corresponding product in high enantioselectivity and high yield.

Noncovalent wedging effect catalyzed the cis to syn transformation of a surface-adsorbed polymer backbone toward an unusual thermodynamically stable supramolecular product.

The significant influence of noncovalent interactions on catalytic processes has been recently appreciated but is still in its infancy. In this report, it is found that wedging Me-PTCDI (small-molecule) between the alkyl chains of PffBT4T-2OD (polymer) and a graphite substrate can reduce the energy barrier of flipping over the surface-adsorbed alkylthiophene group from the cis to syn conformation, revealing the catalytic role of Me-PTCDI via a noncovalent wedging effect. The wedging of Me-PTCDI brings the interactions between the alkyl chains and substrate to a very weak level by lifting up the alkyl chains, which eliminates the major hindrance of the flipping process to one main factor: the torsion of the dihedral angles of the thiophene group. The Me-PTCDI/syn PffBT4T-2OD arrangement shows unusual stability compared to the cis one because the syn conformation allows the alkyl chains to construct dense lamella and facilitates interactions between Me-PTCDI and the syn PffBT4T-2OD backbones. The results are helpful for boosting the development of noncovalent catalysis and bottom-up fabrications toward devices functionalized at a molecular level.

The role of MAPK11/12/13/14 (p38 MAPK) protein in dopamine agonist-resistant prolactinomas.

BACKGROUND: Prolactinoma is a functional pituitary adenoma that secretes excessive prolactin. Dopamine agonists (DAs) such as bromocriptine (BRC) are the first-line treatment for prolactinomas, but the resistance rate is increasing year by year, creating a clinical challenge. Therefore, it is urgent to explore the molecular mechanism of bromocriptine resistance in prolactinomas. Activation of the P38 MAPK pathway affects multidrug resistance in tumours. Our previous studies have demonstrated that inhibiting MAPK14 can suppress the occurrence of prolactinoma, but the role of MAPK11/12/13/14 (p38 MAPK) signalling in dopamine agonist-resistant prolactinomas is still unclear. METHODS: A prolactinoma rat model was established to determine the effect of bromocriptine on MAPK11/12/13/14 signalling. DA-resistant GH3 cells and DA-sensitive MMQ cells were used, and the role of MAPK11/12/13/14 in bromocriptine-resistant prolactinomas was preliminarily verified by western blot, RT-qPCR, ELISA, flow cytometry and CCK-8 experiments. The effects of MAPK11 or MAPK14 on bromocriptine-resistant prolactinomas were further verified by siRNA transfection experiments. RESULTS: Bromocriptine was used to treat rat prolactinoma by upregulating DRD2 expression and downregulating the expression level of MAPK11/12/13/14 in vivo experiments. The in vitro experiments showed that GH3 cells are resistant to bromocriptine and that MMQ cells are sensitive to bromocriptine. Bromocriptine could significantly reduce the expression of MAPK12 and MAPK13 in GH3 cells and MMQ cells. Bromocriptine could significantly reduce the expression of MAPK11, MAPK14, NF-κB p65 and Bcl2 in MMQ but had no effect on MAPK11, MAPK14, NF-κB p65 and Bcl2 in GH3 cells. In addition, knockdown of MAPK11 and MAPK14 in GH3 cells by siRNA transfection reversed the resistance of GH3 cells to bromocriptine, and haloperidol (HAL) blocked the inhibitory effect of bromocriptine on MAPK14, MAPK11, and PRL in MMQ cells. Our findings show that MAPK11 and MAPK14 proteins are involved in bromocriptine resistance in prolactinomas. CONCLUSION: Bromocriptine reduces the expression of MAPK11/12/13/14 in prolactinomas, and MAPK11 and MAPK14 are involved in bromocriptine resistance in prolactinomas by regulating apoptosis. Reducing the expression of MAPK11 or MAPK14 can reverse bromocriptine resistance in prolactinomas.

[Progress in the Treatment of Tachyarrhythmia by Pulsed Electric Field Ablation Catheter Ablation].

Pulsed electric field(PEF) provides high-energy instantaneous pulse and release energy to myocardial cell membrane, resulting in irreversible electroporation and causes myocardial cell contents leakage, destruction of intracellular homeostasis, cell death, and slight inflammatory response. PEF as non-thermal energy promotes the design and application of arrhythmia ablation catheter to enter a new stage. There are currently limited clinical studies that have proved the safety and effectieness of Farawave PEF catheter, PVAC GOLD PEF catheter, Lattice-tip Sphere-9 PEF and radiofrequency (RF) catheter used for atrial fibrillation ablation, but still need further discussion. The research of atrial fibrillation ablation with PEF is under study in China. In this paper, the design and application of PEF ablation for tachyarrhythmia are reviewed.

Plant transcriptome analysis reveals specific molecular interactions between alfalfa and its rhizobial symbionts below the species level.

BACKGROUND: Leguminous plants alter patterns of gene expression in response to symbiotic colonization and infection by their cognate rhizobial bacteria, but the extent of the transcriptomic response has rarely been examined below the species level. Here we describe the identification of 12 rhizobial biotypes of Ensifer meliloti, which form nitrogen-fixing nodules in the roots of alfalfa (Medicago sativa L.), followed by a comparative RNA-seq analysis of four alfalfa cultivars each inoculated with two E. meliloti strains varying in symbiotic performance and phylogenetic relatedness. RESULTS: Rhizobial biotypes were identified on the basis of their symbiotic performance, particularly shoot dry weight. Differentially expressed genes (DEGs) and metabolic pathways were determined by comparing the RNA-seq data with that of the uninoculated control plant. Significant differences were found between DEGs generated in each cultivar with the inoculation of two rhizobial strains in comparison (P < 0.01). A total of 8111 genes was differentially expressed, representing ~ 17.1% of the M. sativa genome. The proportion of DEGs ranges from 0.5 to 12.2% for each alfalfa cultivar. Interestingly, genes with predicted roles in flavonoid biosynthesis and plant-pathogen interaction (NBS-LRR) were identified as the most significant DEGs. Other DEGs include Medsa002106 and genes encoding nodulins and NCR peptides whose expression is specifically induced during the development of nitrogen-fixing nodules. More importantly, strong significant positive correlations were observed between plant transcriptomes (DEGs and KEGG pathways) and phylogenetic distances between the two rhizobial inoculants. CONCLUSIONS: Alfalfa expresses significantly distinct sets of genes in response to infection by different rhizobial strains at the below-species levels (i.e. biotype or strain). Candidate genes underlying the specific interactions include Medsa002106 and those encoding nodulins and NCR peptides and proteins in the NBS-LRR family.

Inhibiting MAPK14 showed anti-prolactinoma effect.

BACKGROUND: The specific underlying pathogenesis of prolactinoma has not been clarified yet, to the best of our knowledge. p38 mitogen-activated protein kinase (MAPK) signaling including p38α MAPK (MAPK14), p38ß (MAPK11), p38γ (MAPK12) and p38δ (MAPK13) is associated with the development and progression of several types of cancer. METHODS: Immunofluorescence analysis was performed on the prolactin (PRL) and MAPK14 expressions of pituitary gland in C57BL/6 mice and human prolactinoma specimen. In the present study, the role of MAPK14 in prolactinoma was determined using estradiol-induced mice and dopamine D2 receptor knockout (DRD2-/-) mice models in C57BL/6 wild-type (WT), MAPK14-/- and DRD2-/-MAPK14+/- mice. GH3 cells were transfected with different sets of MAPK14 small interfering RNA, which to study MAPK14 and PRL expression in GH3 cells. RESULTS: Immunofluorescence analysis showed that PRL and MAPK14 expression were colocalized and increased in the pituitary gland of mice and human prolactinoma specimen compared with the control specimen. It was shown that PRL and MAPK14 expression was colocalized and increased significantly in the pituitary gland of estradiol-injected prolactinoma mice compared with the control mice. Knockout of MAPK14 significantly inhibited tumor overgrowth, and PRL expression was decreased in estradiol-induced mice. Furthermore, MAPK14 knockout of DRD2-/-MAPK14+/- mice significantly reduced the overgrowth of pituitary gland and PRL production and secretion compared with DRD2-/- mice. MAPK14 knockout using siRNA inhibited PRL production in GH3 cells. CONCLUSION: These results suggest that MAPK14 serves a promoting role in the formation of prolactinoma, and highlights the potential of MAPK14 as a potential therapeutic target in the treatment of prolactinoma.

Drug-Induced Liver Injury: Clinical and Etiologic Features at a Large Tertiary Teaching Hospital in China.

BACKGROUND Since the epidemiological profile of drug-induced liver injury (DILI) in China, especially the western of China, it has rarely been studied. The aim of this study was to analyze the characteristics of DILI patients in a large tertiary teaching hospital at Chongqing, a municipality in western China. MATERIAL AND METHODS The medical records of hospitalized patients which diagnosed with DILI between January 2011 and December 2016 were searched retrospectively, and demographic, clinical data, and laboratory data were retrieved for analysis. RESULTS A total of 1811 patients had been diagnosed with DILI, accounting for 0.248% of the total admissions during the same period. Among the 1096 patients included in our analysis, DILI was caused by "medications" in 462 cases (42.15%), "herbs" in 391 cases (35.68%), and combined medications in 189 cases (17.24%). The profiles for each etiology were distinctive for age, sex, clinical features, laboratory features, and types and severity of DILI. CONCLUSIONS Our study provides a systematic etiological profile of DILI in Chinese patients, which can represent references for prevention, diagnosis and treatment, supporting and promoting efforts to ease the burden of this liver disease in China.

Analysis of the clinical characteristics, drug treatments and prognoses of 136 patients with coronavirus disease 2019.

WHAT IS KNOWN AND OBJECTIVE: Since the December 2019 discovery of several cases of coronavirus disease 2019 (COVID-19) in Wuhan, China, the infection has spread worldwide. Our aim is to report on the clinical characteristics, treatments and prognoses of COVID-19. METHODS: This was a retrospective, single-centre, case series of 136 patients who were diagnosed with COVID-19 at Wuhan Third Hospital in Wuhan, China, between 28 January 2020 and 12 February 2020. The clinical characteristics, laboratory tests, treatment features and prognoses were summarized. RESULTS AND DISCUSSION: The 136 patients were divided into a moderate (M) group (n = 103, 75.7%) and a severe and critical (SC) group (n = 33, 24.3%). There were significant differences in the incidences of concomitant chronic medical illnesses (eg, hypertension, diabetes and cardiovascular disease), fever, dry cough and dyspnoea among the two groups (P < .05). Compared with those in the M group, lymphocyte count (LYM) decreased significantly in the SC group, while the serum levels of C-reactive protein (CRP), procalcitonin (PCT), creatinine (Cre), D-dimer, lactic dehydrogenase (LDH), myoglobin (MB) and troponin I (cTnl) increased significantly in the SC group (P < .05). The main therapeutic drugs were antivirals, antibiotics, glucocorticoids, immunomodulators, traditional Chinese medicine preparations and symptomatic support drugs. There were significant differences in the incidences of shock, myocardial injury, acute respiratory distress syndrome (ARDS) and renal injury among the two groups (P < .05). Among the 136 patients, 99 (72.7%) were cured, 14 (10.3%) were transferred to other hospital and 23 (16.9%) died. WHAT IS NEW AND CONCLUSION: Elderly patients with chronic diseases are more likely to develop severe or critical COVID-19 with multiple organ damage or systemic injuries. The improvement of LYM and CRP may be associated with the prognoses of COVID-19. The combined use of three or more antiviral drugs is to be avoided. The combination of broad-spectrum antibacterial drugs is not recommended and the risk of drug-induced liver injury should be monitored. Throughout a patient's hospitalization, their treatment plan should be evaluated and adjusted according to their vital signs, clinical symptoms, laboratory tests and imaging changes. Patients should receive effective psychological counselling.

Resveratrol inhibits oral squamous cell carcinoma cells proliferation while promoting apoptosis through inhibition of CBX7 protein.

As a natural compound, resveratrol (Res) is confirmed to be promising drug for the treatment of malignant tumors. Therefore, our study aimed to observe the impacts of Res on the proliferation and apoptosis of oral squamous cell carcinoma cells (HSC-3 cells) as well as the mechanism involving chromobox protein homolog 7 (CBX7) signal transduction. HSC-3 cells were treated with Res, Akt agonist (AL3818) and p16 inhibitor (SC79), and transfected with CBX7 mimics and inhibitor plasmids. The CCK-8 assay was used to detect cell proliferation, flow cytometry was performed to assess cell cycle and apoptosis, and cell colonies and histone DNA level were also measured. Western blot analysis was used to determine the expression levels of related proteins. HSC-3 cells showed decreased cell proliferation, colonies, BrdU-counled cells and increased apoptosis, histone DNA level, the activities of caspase-3 and caspase-9 when treated with Res. Western blot analysis revealed elevated Cle-PARP and Cle-caspase 3 expression and reduced t-PARP expression in HSC-3 cells treated with Res compared with control. AL3818 and SC79 could decrease the inhibitory effects of Res on the growth of HSC-3 cells. Furthermore, CBX7 overexpression could also partly reverse the roles of Res in the growth of HSC-3 cells, and Akt and p16 signal transduction. Our results demonstrate that Res suppresses the proliferation, and induces the apoptosis of oral squamous cell carcinoma cells through the inhibition of CBX7/Akt and the activation of p16 cascades.

[Analysis of 131 cases of COVID-19 treated with Ganlu Xiaodu Decoction].

In this study, Donghua Hospital information management system and Meikang clinical pharmacy management system were used to collect medical records of all inpatients diagnosed as coronavirus disease 2019(COVID-19) in Wuhan Third Hospital. The statistics was based on the data of the cases treated with Ganlu Xiaodu Decoction, including demographic statistics, clinical cha-racteristics before medication, outcome of after medication and efficacy of drug combination. Excel 2003 and SPSS Clementine 12.0 software were used to conduct statistics on the included cases, and Apriori algorithm and association rules were used for the association analysis on drug combination. A total of 131 cases of COVID-19 were treated with Ganlu Xiaodu Decoction combined with Chinese and Western medicine. All of the patients were cured and discharged. The drug combination mainly included Ganlu Xiaodu Decoction, abidor, Lianhua Qingwen, moxifloxacin, Qiangli Pipa Lu, vitamin C, glycyrrhizinate diammonium, pantoprazole and Shufeng Jiedu. There is a certain regularity and effectiveness in the treatment of COVID-19 infection patients with the combination of Ganlu Xiaodu Decoction and other drugs, but the rationality and safety still need to be further verified.

[Self-made metal freezing plate for cryopreservation of human epididymal sperm: An experimental study].

OBJECTIVE: To study the effect of a new human sperm freezing method on the sperm recovery rate and search for an optimal method for cryopreservation of human epididymal sperm. METHODS: We collected semen samples from 76 men with obstructive azoospermia by percutaneous epididymal sperm aspiration and divided each sample into two parts to be cryopreserved with a self-made metal freezing plate (the experimental group) or by slow freezing (the control group), respectively. We measured the percentage of progressively motile sperm (PMS) with the computer-assisted semen analysis system and compared the membrane function, DNA fragmentation index (DFI), acrosin activity and morphological abnormality of the sperm between the two groups before and after cryopreservation. RESULTS: After thawing, both the percentages of PMS and hypotonically swollen sperm were significantly higher in the experimental than in the control group (ï¼»12.0 ± 7.5ï¼½% vs ï¼»8.0 ± 5.1ï¼½%, P < 0.05; ï¼»22.0 ± 17.5ï¼½% vs ï¼»18.0 ± 20.5ï¼½%, P < 0.05), though both decreased in comparison with the pre-freezing parameters (ï¼»20.7 ± 8.8ï¼½% and ï¼»30.0 ± 13.5ï¼½%) (P < 0.05). The sperm acrosin activity was remarkably higher in the experimental than in the control group after thawing (ï¼»75.2 ± 9.5ï¼½ vs ï¼»55.7 ± 8.3ï¼½ µIU/106sperm, P < 0.05), though decreased as compared with the baseline (ï¼»120.0 ± 10.5ï¼½ µIU/106 sperm, P < 0.05). No statistically significant differences were observed between the experimental and the control groups after thawing in the percentage of morphologically abnormal sperm (ï¼»98.7 ± 8.8ï¼½% vs ï¼»98.5±9.2ï¼½%, P > 0.05) or sperm DFI ï¼»38.2 ± 8.5ï¼½% vs ï¼»39.5 ± 10.2ï¼½%, P > 0.05), though both markedly elevated in comparison with the pre-freezing parameters (ï¼»97.2 ± 9.5ï¼½% and ï¼»30.8 ± 9.7ï¼½%) (P < 0.05). The post-thaw recovery rate of sperm was significantly higher in the experimental than in the control group (ï¼»65.2 ± 12.0ï¼½% vs ï¼»52.3 ± 18.0ï¼½%, P < 0.05). CONCLUSIONS: The self-made metal freezing plate, with its advantages of low cost, high efficiency, and easy operation, can be used as an effective method for cryopreservation of human sperm to achieve a high post-thaw sperm recovery rate, progressive sperm motility, and sperm acrosin activity.

NLRP3 Inflammasome Is Involved in Q-VD-OPH Induced Necroptosis Following Cerebral Ischemia-Reperfusion Injury.

Necroptosis is a manner of caspase-independent cell death,which accounts for delayed ischemic cerebral injury, and can be used as a novel tool to expand the treatment time window in ischemic cerebral injury. Q-VD-OPH, a novel pan caspase inhibitor, has been identified as an inducer of necroptosis. In this study, we determined the optimal dose of Q-VD-OPH, which induces necroptosis in rats by the middle cerebral artery occlusion, followed by reperfusion. Furthermore, we report that the NLRP3 inflammasome is involved in necroptosis, with levels of NLRP3 inflammasome proteins as well as inflammatory cytokines, such as IL-1ß, being elevated. We also demonstrated that NLRP3 was not only expressed in microglia and vascular endothelial cell, but also in neurons when necroptosis is induced with Q-VD-OPH. Inhibition of NLRP3 by glyburide strongly suppressed the expression of NLRP3 inflammasome proteins and IL-1ß, and markedly reduced brain tissue damage. Our findings provide evidence that pretreatment with Q-VD-OPH suppresses apoptosis and induces necroptosis in the cerebral ischemia-reperfusion model. We also identified that the NLRP3 inflammasome plays an important role in neuronal necroptosis, and that NLRP3 inflammasome deficiency reduces brain tissue damage after cerebral ischemia-reperfusion injury in rats.

DFT insight into the effect of potassium on the adsorption, activation and dissociation of CO2 over Fe-based catalysts.

Catalytic conversion of CO2 including hydrogenation has attracted great attention as a method for chemical fixation of CO2 in combination with other techniques such as CO2 capture and storage. Potassium is a well-known promotor for many industrial catalytic processes such as in Fischer-Tropsch synthesis. In this work, we performed density functional theory (DFT) calculations to investigate the effect of potassium on the adsorption, activation, and dissociation of CO2 over Fe(100), Fe5C2(510) and Fe3O4(111) surfaces. The function of K was analyzed in terms of electronic interactions between co-adsorbed CO2 and K-surfaces which showed conspicuous promotion in the presence of K of the adsorption and activation of CO2. The adsorption strength of CO2 on these surfaces ranks as oct2-Fe3O4(111) > Fe(100) > Fe5C2(510). Generally, we observed a direct proportional correlation between the adsorption strength and the charges on the adsorbates. Adding K on the catalyst surface also reduces the kinetic barrier for CO2 dissociation. CO2 dissociation is more facile to occur on Fe(100) and Fe5C2(510) in the presence of K whereas the Fe3O4(111) surfaces impede CO2 dissociation regardless of the existence of K. Instead, a stable CO3- species is formed upon CO2 adsorption on Fe3O4(111) which will be directly hydrogenated when sufficient H* are available on the surface. Our results highlight the origin of the promotion effect of potassium and provide insight for the future design of K-promoted Fe-based catalysts for CO2 hydrogenation.

Structures and Spectroscopic Properties of F-(H2O) n with n = 1-10 Clusters from a Global Search Based On Density Functional Theory.

Using a genetic algorithm incorporated in density functional theory, we explore the ground state structures of fluoride anion-water clusters F-(H2O) n with n = 1-10. The F-(H2O) n clusters prefer structures in which the F- anion remains at the surface of the structure and coordinates with four water molecules, as the F-(H2O) n clusters have strong F--H2O interactions as well as strong hydrogen bonds between H2O molecules. The strong interaction between the F- anion and adjacent H2O molecule leads to a longer O-H distance in the adjacent molecule than in an individual water molecule. The simulated infrared (IR) spectra of the F-(H2O)1-5 clusters obtained via second-order vibrational perturbation theory (VPT2) and including anharmonic effects reproduce the experimental results quite well. The strong interaction between the F- anion and water molecules results in a large redshift (600-2300 cm-1) of the adjacent O-H stretching mode. Natural bond orbital (NBO) analysis of the lowest-energy structures of the F-(H2O)1-10 clusters illustrates that charge transfer from the lone pair electron orbital of F- to the antibonding orbital of the adjacent O-H is mainly responsible for the strong interaction between the F- anion and water molecules, which leads to distinctly different geometric and vibrational properties compared with neutral water clusters.

Pelargonidin induces antitumor effects in human osteosarcoma cells via autophagy induction, loss of mitochondrial membrane potential, G2/M cell cycle arrest and downregulation of PI3K/AKT signalling pathway.

PURPOSE: Osteosarcoma is the most common type of primary malignancy of bone in children and adults. The treatment options for osteosarcoma are limited and are associated with a number of drawbacks. Therefore there is an urgent need to look for more efficient options for the treatment of this disease. Flavonoids have been considered as important anticancer agents due to their efficacy and lower cytotoxicity. In the present study we evaluated the anticancer effects of pelargonidin in U2OS osteosarcoma cell line. METHODS: Cell viability was assessed by MTT assay. Reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and cell cycle analysis was done by flow cytometry. Expression of proteins was examined by western blotting. RESULTS: Pelargonidin exhibited significant anticancer effects on osteosarcoma U2OS cell line with an IC50 of 15 µM. The anticancer effects of pelargonidin were due to induction of autophagy as evidenced from the expression of LC3-I, LC-3II and Beclin-1. Moreover, pelargonidin triggered ROSinduced reduction in MMP and triggered G2/M cell cycle arrest. In addition, pelargonidin inhibited the expression of p-PI3K and p-AKT in a concentration-dependent manner. CONCLUSIONS: Taken together, these results indicated that pelargonidin may prove a potential lead drug for the treatment of osteosarcoma.

Asymmetric Formal Synthesis of the Long-Acting DPP-4 Inhibitor Omarigliptin.

A highly efficient asymmetric synthesis of the key tetrahydropyranol intermediate of DPP-4 inhibitor omarigliptin (1) is described. The successful development of a protecting-group- and precious-metal-free synthesis was achieved via the discovery of a practical asymmetric Henry reaction and the application of a one-pot nitro-Michael-lactolization-dehydration through-process. Other features of the synthesis include a highly efficient MsCl-mediated dehydration and a crystallization-induced dynamic resolution for exceptional ee and dr upgrade. The synthesis of this complex intermediate utilizes simple starting materials and proceeds in four linear steps.

Nanosecond pulsed electric field (nsPEF) disrupts the structure and metabolism of human Echinococcus granulosus protoscolex in vitro with a dose effect.

The number of interventional treatments for hepatic cystic echinococcosis is increasing, but the chemicals or high temperatures used in these methodologies cause biliary complications, thus limiting their clinical applications. This experimental study aimed to apply a novel, non-thermal, non-chemical ablation method termed nanosecond pulsed electric field (nsPEF) for the treatment of human hepatic cystic echinococcosis. The nsPEF treatment parameters against protoscolices from human hepatic cystic echinococcosis were optimized in vitro. The efficacy and mechanism of nsPEF treatment were also investigated. Fresh protoscolices were isolated from human hepatic cystic echinococcosis and were exposed to 300 ns of nsPEF with different field strengths (0, 7, 14, 21, and 29 kV/cm) and pulse numbers (50 and 100 pulses). Then, the viability of the nsPEF-treated protoscolices was evaluated in vitro. Morphological and ultra-structural changes were visualized with H&E staining and scanning electron microscopy. The membrane enzyme activity of alkaline phosphatase (AP) and gamma-glutamyl-transpeptidase (GGT) was measured. nsPEF caused dose-dependent protoscolex death. One-hundred pulses of nsPEF at 21 kV/cm or higher caused a significant increase in the death rate of protoscolices. nsPEF induced significant lethal damage with 50 pulses at 21 or 29 kV/cm and with 100 pulses at 14, 21, or 29 kV/cm, accompanied by morphological destruction and increased levels of AP and GGT membrane enzymes. Thus, nsPEF induced dose-dependent protoscolex mortality and caused destruction of protoscolices and increased membrane enzymes. The mechanism may involve direct damage to the membrane structures of the protoscolices, promoting enzyme exhaustion and disruption of metabolism.

Therapeutic effects of Qian-Yu decoction and its three extracts on carrageenan-induced chronic prostatitis/chronic pelvic pain syndrome in rats.

BACKGROUND: Qian-Yu decoction (QYD) is a traditional Chinese medicinal recipe composed of Radix astragali (Astragalus membranaceus (Fisch.) Bunge var. mongholicus (Bunge) P.K. Hsiao, Fabaceae ), Herba epimedii (Epimedium brevicornum Maxim., Berberidaceae), Herba leonuri (Leonurus japonicus Houtt., Lamiaceae), Cortex phellodendri (Phellodendron chinense Schneid., Rutaceae) and Radix achyranthis bidentatae (Achyranthes bidentata Bl., Amaranthaceae). This study aimed to evaluate the therapeutic activity of QYD against carrageenan-induced chronic prostatic/chronic pelvic pain syndrome (CP/CPPS) in rats and further elucidate its effective components. METHODS: Three types of components, total polysaccharides, total flavonoids and total saponins were separately extracted from QYD. Carrageenan-induced CP/CPPS rats were intragastrically administered with lyophilized product of QYD, individual extracts and all the combined forms of extracts for three weeks. Prostatic index (PI) was determined and histopathological analysis was performed. The levels of tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1ß), cyclooxygenase-2 (COX-2) and prostaglandin E2 (PEG2) in rat prostate tissues were measured using ELISA. The production of inducible nitric oxide synthase (iNOS) was evaluated by an enzymatic activity assay, and the release of nitric oxide (NO) was determined by a nitrate/nitrite assay. RESULTS: Treatment with QYD significantly ameliorated the histological changes of CP/CPPS rats and reduced the PI by 44.3%, with a marked downregulation of TNF-α (42.8% reduction), IL-1ß (45.3%), COX-2 (36.6%), PGE2 (44.2%), iNOS (54.1%) and NO (46.0%). Each of three extracts attenuated the symptom of CP/CPPS, but much more weakly than QYD. The combined administration of three extracts showed efficacy comparable to that of QYD while better than that of any combination of two extracts. A principal component analysis of the six inflammatory mediators as variables indicated that the effects of TS on CP/CPPS were rather different from those of TF and TP, which were similar. CONCLUSIONS: QYD can be beneficial in prevention and treatment of CP/CPPS. Polysaccharides, flavonoids and saponins, as the major effective components of QYD, exert a cooperative effect on CP/CPPS.