Relationship between the consumption of wholegrain and nonalcoholic fatty liver disease: The TCLSIH cohort study.

BACKGROUND & AIMS: Wholegrain contributes a range of beneficial nutrients and is considered to play a role in the prevention of chronic diseases, but evidence of their influence on nonalcoholic fatty liver disease (NAFLD) is limited. We conducted this study to investigate the prospective association between daily wholegrain consumption and NAFLD in the general population. METHODS: This prospective cohort study included a total of 14,968 (42.2% men) inhabitants living in Tianjin, China. Participants without a history of CVD, cancer, alcoholic fatty liver disease, other liver diseases, or NAFLD were followed up for 1-6 years with a median follow-up duration of 4.2 years. Wholegrain consumption was assessed using a validated self-administered food frequency questionnaire. NAFLD was diagnosed with the results of liver ultrasonography without significant alcohol consumption and other causes of liver disease. Cox proportional hazards regression models were used to estimate the association between wholegrain consumption and NAFLD. RESULTS: A total of 3505 (2171 men) first incident cases of NAFLD occurred during 53,303 person-years of follow-up (median follow-up of 4.2 years). After adjusting for several potential confounders and setting "almost never" as the control group, the multivariable hazard ratios (95% confidence intervals) of the NAFLD were 0.82 (0.73, 0.92) when they consuming ≤1 time/week, 0.78 (0.69, 0.88) when they consuming 2-6 time/week and 0.77 (0.66, 0.90) when they consuming ≥1 time/day (p for trend <0.001). CONCLUSION: The results from our prospective study demonstrated that the higher consumption of wholegrain is associated with a decreased risk of NAFLD in Chinese adults.

Association between edible mushrooms consumption and handgrip strength: A large-scale population based on the TCLSIH cohort study.

BACKGROUND & AIMS: Edible mushrooms can be referred to as a "super food" and are recommended as a valuable constituent of the daily diet. Animal studies have suggested that mushroom intake can increase muscle endurance due to its abundant nutrients, and anti-inflammatory properties. However, no studies have explored the association between edible mushrooms consumption and muscle strength in the general population. We aimed to investigate the association of edible mushrooms consumption with handgrip strength (HGS) among Chinese adults. METHODS: A cross-sectional study was performed with 32,308 adults (17,290 men), in Tianjin, China. Mushrooms consumption was assessed via a self-administered food frequency questionnaire. Handgrip strength was measured using a handheld digital dynamometer. Analysis of covariance were used to evaluate the association between edible mushrooms consumption and handgrip strength. RESULTS: After adjusting potential confounding factors [age, body mass index, smoking status, alcohol-consumption status, education levels, employment status, household income, physical activity, family history of diseases (cardiovascular disease, hypertension, hyperlipidemia, and diabetes), metabolic syndromes, total energy intake, and dietary pattern], the least square means (95% confidence intervals) of HGS across consumption of edible mushrooms in males were 42.3 (41.0, 43.6) kg for ≤1 time/week, 43.4 (42.1, 44.6) kg for 2-3 times/week, and 43.2 (41.9, 44.4) kg for ≥4 times/week (P for trend <0.001). In females, least square means were 25.1 (24.0, 26.2) kg for ≤1 time/week, 25.7 (24.7, 26.8) kg for 2-3 times/week, and 25.7 (24.7, 26.8) kg for ≥4 times/week (P for trend <0.001). Similar associations were also observed for weight-adjusted HGS. CONCLUSIONS: The study firstly revealed a positive association between edible mushrooms consumption and handgrip strength in both males and females. Further studies are needed to explore the casual relationship. TRIAL REGISTERED: UMIN Clinical Trials Registry. Reg no UMIN000027174. Trial registration website https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000031137.

Green tea consumption and risk of depressive symptoms: Results from the TCLSIH Cohort Study.

BACKGROUND: The prospective studies on the effect of particular type of tea consumption, especially green tea, on depressive symptoms are limited. OBJECTIVE: The aim of this study is to investigate the prospective association between green tea consumption and depressive symptoms in a large general adult population. METHODS: This prospective cohort study investigated 7524 participants aged 25 to 90 years from May 2013 to December 2018 and they were free of cardiovascular disease, cancer, and depressive symptoms at baseline. Green tea consumption was obtained through a validated food frequency questionnaire. Depressive symptoms were assessed by using the Self-Rating Depressive Scale (SDS). The association between green tea consumption and depressive symptoms was analyzed by Cox proportional hazards regression models. RESULTS: A total of 1064 first incident cases of depressive symptoms (SDS ≥45) occurred during 14,661 person-years of follow-up (median follow-up of 2.0 years). In the crude model, the hazard ratios (95% confidence intervals) were 1.00 (reference), 0.95 (0.81, 1.12), 0.97 (0.83, 1.14) and 0.95 (0.79, 1.14), respectively. After adjusting for demographic characteristics, lifestyle factors, and dietary intake, the multivariable adjusted hazard ratios (95% confidence intervals) were 1.00 (reference), 0.88 (0.74, 1.05), 0.84 (0.69, 1.02) and 0.78 (0.63, 0.97), respectively. CONCLUSIONS: The prospective study suggests that frequent green tea consumption is associated with a decreased risk of depressive symptoms in the general Chinese population.

Polysaccharide from Scutellaria barbata D. Don attenuates inflammatory response and microbial dysbiosis in ulcerative colitis mice.

This study aimed to evaluate the effect of polysaccharides from Scutellaria barbata D. Don (PSB) on dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) in C57BL/6 mice. PSB was isolated, and its chemical composition was preliminarily identified. The average molecular weight of PSB was 1.25 × 104 Da and it was mainly comprised of arabinose, galacturonic acid, galactose, glucose, and glucuronic acid in molar ratios of 1.00:2.09:4.52:4.73:4.90. PSB (25 and 50 mg/kg) and sulfasalazine (200 mg/kg) significantly relieved weight loss and symptoms and alleviated colonic pathological injury in mice with UC. In addition, PSB decreased the levels of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-1ß (IL-1ß), IL-6, and IL-18 in the colon and suppressed DSS-induced activation of the nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways. The improvement in the abundance of several bacterial genera, such as the Lachnospiraceae_NK4A136_group, Ruminococcus, Bacteroides, Parasutterella, and Eisenbergiella might be closely related to the reduction in the intestinal inflammatory response after PSB treatment. These results revealed that PSB could potentially be utilized to treat UC and other diseases associated with an imbalance in the intestinal flora.

Changes of Beclin-1 and ULK1 in retina of mice model in oxygen-inducedretinopathy.

Purpose: To observe the expression differences and potential effects of autophagy-related Beclin1 (mammalian Atg6) and Uncoordinated-51 like kinase 1 (ULK1) in the oxygen-induced retinopathy (OIR) model. Materials and methods: Thirty-three C57BL/6 mice in OIR model group were exposed to 75 â€‹± â€‹0.5% oxygen from postnatal day-of-life 7 (P7) to P12, and were then brought into normal room environment (relative hypoxia stage) and raised to P17. Thirty-three control mice were kept in a normal room environment. The expression of autophagy in the retina tissue was assessed by Western blot analysis. The thickness and ultrastructural of retina were observed by light microscopy and transmission electron microscope (TEM) on P17. Results: In the hyperoxia stage (P8-P11), the expression of Beclin1, ULK1 and Autophagy 5 (Atg5) in retina showed no significant difference between the OIR model group and the control group. In the relatively hypoxia stage (P14 to P17), however, the protein level of Beclin1, ULK1, and Bcl-2-associated X protein (Bax) were upregulated in the retina of the OIR model group, whereas B-cell lymphoma 2 (Bcl-2) was downregulated. The autophagosomes in the photoreceptors of retina in the OIR mice were observed. The inner-segment/out-segment (IS/OS) layer in OIR model group was thinner than that the control group on P17. Conclusions: The expression of Beclin-1 and ULK1 in retina has changed in the OIR model, and the change of Beclin-1 and ULK1 expression is related to the change of oxygen concentration.

Immune Checkpoint Inhibitors and Survival Outcomes in Brain Metastasis: A Time Series-Based Meta-Analysis.

Immune checkpoint inhibitors (ICIs) have shown potential to improve the prognosis of patients with brain metastasis (BM) caused by advanced cancers. However, controversies still exist in regard to its survival benefits. In the present work, a time series-based meta-analysis based on the phase I/II/III trials and observational studies were performed to investigate the differences in mortality of ICI-treated BM patients. A number of public library databases, including MEDLINE, EMBASE, OVID, and COCHRANE, were systemically searched by March 2019. The quality of included studies was evaluated by the Newcastle-Ottawa Scale (NOS) scoring. Outcome measures here established were mortality and progression-free survival (PFS) at different follow-up endpoints. Survival rates and curve data were pooled for further analysis. To detect the data heterogeneity, subgroup analyses were conducted according to tumor and ICI types. Eighteen studies, 6 trials, and 12 controlled cohorts were assessed, involving a total of 1330 ICI-treated BM patients. The 6-month survival rate and PFS were 0.67 (95%CI: 0.59-0.74) and 0.36 (95%CI: 0.24-0.49), respectively. According to the tumor type (melanoma, NSCLC, and RCC), subgroup analyses indicated that melanoma presented the lowest survival rates among the three groups here selected. In regard to the type of ICIs, the anti-CTLA-4 combined with the anti-PD-1/PD-L1 showed the best survival outcome among these groups. The 12-month survival rate and PFS showed a consistent pattern of findings. In the long-term, the 24-month survival rate and PFS were 0.20 (95%CI: 0.12-0.31) and 0.18 (0.05-0.46) in BM patients. Hence, ICI therapy may be associated with an improved prognosis of BM patients. Nevertheless, current research presented a limited study design. Multicenter randomized trials may later assist in validating ICI-based therapies for a better outcome of BM patients.

Nigella A ameliorates inflammation and intestinal flora imbalance in DSS induced colitis mice.

Nigella A, also named Sieboldianoside A, has been extracted from many kinds of Traditional Chinese Medicine (TCM), such as Nigella glandulifera, Stauntonia chinensis DC., and the leaves of Acanthopanax sieboldianus. Nigella A exhibited potential analgesic, anti-inflammatory, anti-tumor, and antioxidant activities. However, whether Nigella A could treat ulcerative colitis (UC) is still unknown. As saponins always be regarded as the kinds of ingredients that could regulate immunity and intestinal flora. This research aimed to investigate the therapeutic effect of Nigella A on UC and explore its effect on intestinal flora. We noted that Nigella A and Sulfasalazine (SASP) could significantly improve the signs and symptoms, alleviate colonic pathological injury in DSS-induced mice. The changing of many specific bacterial genus such as Lactobacillus, Porphyromonadaceae, Bacteroides and Escherichia might closely related to the recovery of intestinal inflammatory response. This study initially confirmed the therapeutic effect of Nigella A and SASP on DSS-induced colitis by improving the diversity of intestinal microbial composition. Nigella A has the potential to be developed for the treatment of UC and other disorders related to the imbalance of intestinal flora.

Anti-colitic effects of Physalin B on dextran sodium sulfate-induced BALB/c mice by suppressing multiple inflammatory signaling pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Physalin B is one of the main active withanolide existed in Physalis alkekengi L. var. franchetii (Mast.) Makino, a famous traditional Chinese food and herbal medicine, which has been widely used as heat-clearing and toxin-resolving medicine for the treatment of various inflammatory disease, such as cough, excessive phlegm, pharyngitis, sore throat, pemphigus, eczema, and jaundice. AIM OF THE STUDY: We aimed to confirm the therapeutic effects of Physalin B on ulcerative colitis (UC) and enrich the further application of its traditional anti-inflammatory effect. MATERIALS AND METHODS: The anti-UC effects of Physalin B were evaluated in Balb/c mice with dextran sulfate sodium (DSS) induction. The body weight, colon length, disease activity index (DAI) and pathological changes of colon tissue were measured. Cytokine levels were detected by ELISA. NF-κB pathway and protein levels of related pathways, such as signal transducer and activator of transcription 3 (STAT3), ß-arrestin1 and NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome were detected by western blot. RESULTS: The dose of Physalin B that is not cytotoxic could dramatically reduce the levels of TNF-α, IL-6 and IL-1ß on LPS-stimulated RAW 264.7 cells. Meanwhile, Physalin B dramatically improved clinical signs and symptoms, alleviated body weight loss and colon length shortening in DSS-induced UC mice. Meanwhile, Physalin B also dramatically relieved the pathological damage, reduced in the activity of myeloperoxidase (MPO) and reestablished the balance of pro-inflammatory cytokines. Physalin B could suppress DSS-induced activation of NF-κB. Moreover, Physalin B also markedly suppressed the activation of STAT3, ß-arrestin1 and NLRP3 inflammasome. CONCLUSION: This study preliminary confirmed the therapeutic effect of Physalin B on experimental acute UC mice and provided robust evidence support for the anti-inflammatory effect of Physalin B, suggesting that Physalin B might be a potential agent for the therapeutic efficacy on UC.

Anti-breast cancer and toxicity studies of total secondary saponin from Anemone raddeana Rhizome on MCF-7 cells via ROS generation and PI3K/AKT/mTOR inactivation.

ETHNOPHARMACOLOGICAL RELEVANCE: The rhizome of Anemone raddeana Regel (A. raddeana) is a famous traditional Chinese medicine (TCM) recorded in Chinese Pharmacopoeia for the treatment of carbuncle and swelling. Carbuncle swollen is an explanation of tumor in the theory of TCM and softening and resolving hard mass effects are one of the important pharmacological activities of A. raddeana. AIM OF THE STUDY: We investigated the potential anti-breast cancer effect and toxicological properties of alkali-ethanol extract from A. raddeana, namely total secondary saponin (TSS). MATERIALS AND METHODS: Anti-proliferative effect of total saponin of A. raddeana (ATS) and TSS were tested using MTT assay. Hoechst staining, flow cytometry analysis, DCFH-DA fluorescence microscopy and western blot were carried out to evaluate the mechanisms of action of TSS. The potential anti-breast cancer activity and toxicological properties of TSS were tested in vivo. RESULTS: ATS and TSS could inhibit the proliferation of A549, HepG2, MCF-7, MDA-MB-231 and SKBr-3 cells, especially for MCF-7 cells. Flow cytometry analysis revealed that TSS (10, 12 and 15 µg/ml) could induce cell cycle arrest on G0/G1 phase and promote apoptosis of MCF-7 cells. TSS could increase Bax/Bcl-2 ratio, elevate cytochrome c levels in cytosol and activate caspase-3/9. In addition, TSS also induced ROS generation and inactivated PI3K/AKT/mTOR pathway which may involved in the mitochondrial dysfunction of MCF-7 cells. TSS showed slight toxic at the dosage of 100 and 200 mg/kg by oral administration without any toxic potential for 28 days. TSS (50, 100 and 200 mg/kg) showed significant inhibitory effect on growth of transplanted tumor in mice. At last, twenty-three C-3 monosaccharide oleanane-type triterpene saponins were tentatively identified, which may contributed to the anti-cancer activity of TSS. CONCLUSION: This study demonstrated that TSS exhibited anti-proliferative and pro-apoptosis activities on MCF-7 cells via ROS-mediated activation of mitochondrial apoptosis pathway. TSS might be used as chemotherapeutic agent for the treatment of breast cancer with relatively low toxicity.

Potential Cytotoxicity, Pharmacokinetics, and Excretion Properties of Sapindoside B from the Seeds of Nigella sativa var. hispidula.

The seeds of Nigella sativa var. hispidula are widely used in food preparation by the Uighur people in western China. Recently, series of oleanane triterpenoid saponins were extracted from the seeds of Nigella sativa var. hispidula, especially α-hederin as representative that exhibited strong antitumor activity. Compared to α-hederin, sapindoside B has just 1 more terminal xylopyranose in the 3-O position and displays similar effects against various human cancer cell lines with cisplatin. Considering this potential cytotoxic activity, a reliable LC-MS/MS method was developed to quantify sapindoside B in rat plasma, urine, and feces. Chromatographic separation was conducted on an Agilent Zorbax SB-Aq (3.0 × 150 mm, 3.5 µm) column via an isocratic elution procedure with acetonitrile and water containing 0.1% formic acid. Mass spectrometric detection was coupled with an electrospray ionization source in the MRM mode. The linear range of calibration curves was 15 ~ 3000 ng/mL in plasma/urine and 30 ~ 3000 ng/g in feces. The intra-day and inter-day precision was less than 11.1%, and accuracy ranged from 92.2% to 108.7%. The proposed method was validated and shown to be reliable, precise, and accurate and was successfully applied to its pharmacokinetics and excretion studies. Sapindoside B exhibited dosage-dependent pharmacokinetics in the range of 2.5 mg/kg to 12.5 mg/kg, and only about 2% of intravenous dose of sapindoside B was excreted by the feces and urine in its unchanged form over 48 h. These results provide further data support for evaluating the druggability of sapindoside B.

A Phase I Comparative Pharmacokinetic and Safety Study of Two Intravenous Formulations of Vinorelbine in Patients With Advanced Non-Small Cell Lung Cancer.

Purpose: The aim of this study was to compare the pharmacokinetics and safety between two vinorelbine formulations [a new oil-in-water emulsion formulation (ANX) versus a previously marketed solution formulation (Navelbine)] in Chinese patients with advanced non-small cell lung cancer (NSCLC). Method: This was a single-center, randomized, open-label study. Eligible patients aged 18-70 years who had histologically or cytologically confirmed NSCLC were enrolled. In cycle 1, the patients alternatively received the two formulations (30 mg/m2, given as a 10-min infusion) with a 7-day interval. Samples for pharmacokinetic analysis were taken during cycle 1. For all subsequent 21-day cycles (maximum four cycles), ANX was administered on days 1 and day 8. Bioequivalence analysis was performed on Cmax, AUClast, and AUCinf. The safety profiles and anti-tumor effects were also determined. Results: From March 2013 to January 2015, 24 patients were enrolled and 20 were eligible for pharmacokinetic evaluation. The 20 subjects in the pharmacokinetic analysis set had a median age of 61 years (range, 37-70 years), and 15 patients were male (75%). Mean vinorelbine Cmax values for ANX and Navelbine were 1,317.40 and 1,446.30 ng/mL, respectively. Corresponding AUClast values were 797.08 and 924.26 ng·h/mL, respectively. AUCinf values were 830.14 and 957.16 ng·h/mL, respectively. Treatment ratios of the geometric means were 90.00% (90% CI, 83.22-99.07%) for Cmax, 86.92% (90% CI, 80.91-93.37%) for AUClast, and 87.44% (90% CI, 82.08-93.16%) for AUCinf. These results met the required 80-125% bioequivalence criteria. The most frequently reported adverse events after vinorelbine administration were neutropenia, leucopenia, neutropenic fever, and constipation. Conclusion: At therapeutic dosage levels, pharmacokinetic behavior and safety profiles were similar for both formulations. Chinese National Registry Code: ChiCTR-IPR-15005856.

Physalin B induces G2/M cell cycle arrest and apoptosis in A549 human non-small-cell lung cancer cells by altering mitochondrial function.

Physalin B (PB) is one of the major constituents of Physalis alkekengi var. franchetii, a well-known Chinese traditional herb. In this study, we demonstrated for the first time that PB exhibits significant antiproliferative and apoptotic activity in A549 human lung cancer cells in a concentration-dependent and time-dependent manner. Flow cytometric analyses indicated that PB-induced G2/M arrest through down-regulation of cyclin B1 and cell division control protein cyclin-dependent kinase 1, and up-regulation of p21. The reduction in the level of cyclin B1/cyclin-dependent kinase 1 complex down-regulated oxidative phosphorylation multisubunit activity to reduce mitochondrial energetic homeostasis. Moreover, defects in mitochondrial ATP synthesis and mitochondrial membrane potential were found in PB-treated cell lines. These abnormalities led to an increase in intracellular superoxide and apoptosis. Thus, as an inhibitor of mitochondrial energetic homeostasis, PB demonstrates potent antitumor activities and may be developed as an alternative therapeutic agent against non-small-cell lung cancer.

Downregulation of CPT2 promotes tumorigenesis and chemoresistance to cisplatin in hepatocellular carcinoma.

BACKGROUND: Cancer cells often have characteristic changes in metabolism. Besides Warburg effect, abnormal lipid metabolism is also considered as one of the most typical metabolic symbols of cancer. Thus, understanding the mechanisms of cell metabolic reprogramming may provide a potential avenue for cancer treatment. MATERIALS AND METHODS: In total, 41 pairs of matched samples of primary hepatocellular carcinoma (HCC) and adjacent non-cancerous liver tissues were collected. Afterward, we performed quantitative reverse transcriptase polymerase chain reaction to investigate carnitine palmitoyltransferase-2 (CPT2) expression and then systematically analyzed its relationship with clinicopathologic features. We further performed proliferation, colony formation, migration and invasion, drug resistance, and lipogenesis assays to determine the function of CPT2 in HCC. RESULTS: In this study, we have identified CPT2 which is the rate-limiting enzyme of fatty acid oxidation, downregulated in HCC and was significantly associated with tumor histological differentiation and venous invasion. In vitro studies demonstrated that knockdown of CPT2 remarkably enhanced the tumorigenic activity and metastatic potential of hepatoma cells. In addition, CPT2 silencing induced chemoresistance to cisplatin. Mechanistically, low expression of CPT2 promoted cancer cell lipogenesis via upregulation of stearoyl-CoA desaturase-1, the key enzyme involved in the synthesis of monounsaturated fatty acids, at both mRNA and protein levels in hepatoma cell line. CONCLUSION: Altogether, our findings demonstrate that CPT2 has a critical role in HCC progression and chemoresistance and may potentially serve as a novel prognostic marker and therapeutic target for HCC treatment.

Ethnopharmacological uses, phytochemistry, biological activities, and therapeutic applications of Alpinia oxyphylla Miquel: A review.

ETHNOPHARMACOLOGICAL USAGES: Fructus Alpiniae oxyphyllae (A. oxyphylla) is an important medicinal plant that is used not only as an edible fruit, but also as an important traditional medicine for benefiting cognitive performance and alleviating a wide spectrum of diseases. Such as; warming kidney, securing essence and arresting polyuria, as well as warming the spleen and stopping diarrhea and saliva. AIMS: The purpose of this review is to provide updated, comprehensive and categorized information on the traditional uses, phytochemistry and pharmacological research of A. oxyphylla in order to explore their therapeutic potential and establish a solid foundation for directing future research. MATERIALS AND METHODS: All the available information on A. oxyphylla was collected via electronic search (using Pubmed, SciFinder, Scirus, Google Scholar and Web of Science) and additionally a number of unpublished resources, (e.g. books, Ph.D. and M.Sc. dissertations, government reports). RESULTS: Phytochemical research on A. oxyphylla has led to the isolation of components such as essential oils, terpenes, diarylheptanoids, flavones, nucleobases and nucleosides, steroids and others. Crude extracts, fractions and phytochemical constituents isolated from A. oxyphylla showed a wide spectrum of in vitro and in vivo pharmacological activities like neuroprotective, anti-diarrheal, anti-diuretic, anti-neoplastic, anti-oxidant, anti-inflammatory, anti-allergic, viscera protective and anti-diabetic activities. Neuroprotective, anti-cancer, anti-diarrheal and anti-diuretic effects are major areas of research conducted on A. oxyphylla. CONCLUSIONS: Modern pharmacological studies have supported many traditional uses of A. oxyphylla, including nervous system, urinary system and gastrointestinal system disease. There was convincing evidence in experimental animal models in support of its neuroprotection, secure essence, reduce urination, and anti-carcinogenic effects. However, all the reported pharmacological activities were carried out at pre-clinical level and the authors urge further investigation in clinical trials about these therapeutic fields of A. oxyphylla.

Simultaneous pharmacokinetics and stability studies of physalins in rat plasma and intestinal bacteria culture media using liquid chromatography with mass spectrometry.

Physalins are the major steroidal constituent of Physalis plants and display a range of biological activities. For this study, a rapid and sensitive high-performance liquid chromatography with triple quadrupole mass spectrometry method was developed for the simultaneous quantification of six physalins. Specifically, it was for the quantification of physalin A, physalin B, physalin D, physalin G, 4,7-didehydroneophysalin B, and isophysalin B in rat plasma and rat intestinal bacteria. After a solid-phase extraction, analytes and internal standards (prednisolone) were separated on a Shield reverse-phase C18 column (measuring 3 mm × 150 mm with an internal diameter of 3.5 µm) and determined using multiple reactions in a monitoring mode with a positive-ion electrospray ionization source. The mobile phase was a mixture of 0.1% formic acid in water (A) and acetonitrile (B) and was used at a flow rate of 0.6 mL/min. The intra- and interday precisions were within 15% with accuracies ranging from 86.2 to 114%. The method was validated and successfully applied to pharmacokinetics and stability studies of six physalins in rat plasma and rat intestinal bacteria, respectively. The results showed that physalin B and isophysalin B could not be absorbed by rats, and rat intestinal bacteria could quickly transform physalins.

Incidence and risk of hypertension with bevacizumab in non-small-cell lung cancer patients: a meta-analysis of randomized controlled trials.

AIM: A study was conducted to determine the overall risk and incidence of hypertension with bevacizumab in non-small-cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: Electronic databases such as the Embase, PubMed, and Cochrane Library were searched for related trials. Statistical analyses were conducted to calculate the overall incidence rates, odds ratios (ORs), and 95% confidence intervals (CIs) by using either random-effect or fixed-effect models depending on the heterogeneity. RESULTS: A total of 3,155 subjects from nine studies were included. The overall incidences of all-grade and high-grade hypertension in NSCLC patients were 19.55% (95% CI 10.17%-34.3%) and 6.95% (95% CI 5.81%-8.30%). Bevacizumab use was associated with a significantly increased risk in all-grade hypertension (OR 8.07, 95% CI 3.87-16.85; P=0.0002) and high-grade hypertension (OR 5.93, 95% CI 3.41-10.32; P<0.0001). No evidence of publication bias was determined for the ORs of hypertension in our meta-analysis. CONCLUSION: Bevacizumab is associated with a significantly increased risk of hypertension development in NSCLC patients. Early monitoring and effective management of hypertension might be important steps for the safe use of this drug.

Quantification of an antitumor agent (copen) in rat plasma by liquid chromatography-electrospray ionization tandem mass spectrometry and its application in a preclinical pharmacokinetic study.

Copen is a derivative obtained from the structural modification of osthole, which inhibits tumoral proliferation in many tumor cell lines. A rapid and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established for the quantification of copen in rat plasma. After a simple sample preparation procedure by one-step protein precipitation with methanol, copen and bicalutamide (internal standard, IS) were chromatographed on a Zorbax SB-C18 (4.6×100 mm, 1.8 µm) column with a mobile phase consisting of methanol-5 mm ammonium formate water with 0.1% formic acid (80:20, v/v). MS detection was performed on a triple quadrupole tandem mass spectrometer in the multiple reaction monitoring mode with a positive eletrospray ionization source. The assay was validated in the concentration range of 51.58-20,630 ng/mL, with a limit of quantitation (LOQ) of 51.58 ng/mL. The intra- and inter-day precisions (relative standard deviation) were ≤3.21 and ≤11.3%, respectively, with accuracy (%) in the range of 94.66-102.1%. The method was fully validated in a study of the pharmacokinetics of copen (25 mg/kg) after intragastric administration in rats.

Development and validation of liquid chromatography-tandem mass spectrometry method for quantification of a potential anticancer triterpene saponin from seeds of Nigella glandulifera in rat plasma: application to a pharmacokinetic study.

Nigella glandulifera Freyn et Sit is a folk medicinal plant, whose seeds show significant anticancer activities attributed to triterpene saponins and volatile oil. In this study, an in vitro cytotoxicity assay demonstrated that Nigella A, the major component of triterpene saponins extracted from N. glandulifera, exhibited growth inhibition in the human lung carcinoma A-549 cell line. Due to this potential activity, a reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify Nigella A in rat plasma for a pharmacokinetic study was developed. Nigella A and pravastatin, as internal standard (IS), were extracted from rat plasma using acetonitrile to precipitate protein. Separation was performed on an Agilent Zorbax SB-Aq (3.0 × 150 mm, 3.5 µm) column using a gradient elution method with acetonitrile-0.1% formic acid in water at a flow rate of 0.35 mL/min. Detection was performed using an electrospray ionization in a negative ion multiple reaction monitoring mode. The deprotonated precursor to product ion transitions monitored for Nigella A and IS was at m/z 1352.7→882.6 and m/z 423.1→321.0, respectively. The linear range was 0.240-120 µg/mL with a square regression coefficient (r=0.9996). The intra-day and inter-day precision was less than 6.93%. The simple extraction procedure provided recovery ranged from 92.32 to 95.44% for both analyte and IS. The method was proved to be reliable, precise, and accurate, and was successfully applied to a pharmacokinetic study of Nigella A in rats after i.v. administration via the tail vein at doses of 10, 20, and 30 mg/kg.