Ecological risk assessment of potentially toxic elements in selenium-rich soil with different land-use types.

Dashan Village area is one of the representative areas in China with high selenium concentration in the natural environment. A total of 133 topsoil samples have been collected in the Dashan Village area to explore the potential toxic elements (PTEs) background concentrations in soils under different land-use types for a comprehensive PTEs risk assessment (arsenic, cadmium, chromium, copper, mercury, nickel, lead, selenium and zinc). The results show that the geometric mean concentrations of As, Cr, Cu, Hg, Ni, Pb, Se and Zn found in the soil of the Dashan Village area were lower than the control standard for soil contamination risk in agricultural land. However, the geometric mean concentrations of Cd exceeded their corresponding standard values. For different land-use types, geometric mean concentrations of As, Cd, Cu, Hg, Ni and Pb in the arable soils were higher than in woodland soils and tea garden soils. Based on the potential ecological risk assessment, the woodland, arable and tea garden were at low-risk levels. Cadmium posed the highest ecological risk, while the other PTEs were of low risk in soils. Multiple statistical analyses and geostatistical analysis indicated that the concentrations of Cr, Ni, Pb, Cu, Zn and Se originated mainly from natural sources, while the concentrations of Cd, As and Hg could be influenced by anthropogenic activities. These results provide scientific support for the safe utilization and ecological sustainability of selenium-rich land resources.

Structural annotation, semi-quantification and toxicity prediction of pyrrolizidine alkaloids from functional food: In silico and molecular networking strategy.

Many traditional Chinese herbs contain pyrrolizidine alkaloids (PAs), which have been reported to be toxic to livestock and humans. However, the lack of PAs standards makes it difficult to effectively conduct a risk assessment in the varied components of traditional Chinese medicine. It is necessary to propose a suitable strategy to obtain the representative occurrence data of PAs in complex systems. A comprehensive approach for annotating the structures, concentration, and mutagenicity of PAs in three Chinese herbs has been proposed in this article. First, feature-based molecular networking (FBMN) combined with network annotation propagation (NAP) on the Global Natural Products Social Molecular Networking web platform speeds up the process of annotating PAs found in Chinese herbs. Second, a semi-quantitative prediction model based on the quantitative structure and ionization intensity relationship (QSIIR) is used to forecast the amounts of PAs in complex substrates. Finally, the T.E.S.T. was used to provide predictions regarding the mutagenicity of annotated PAs. The goal of this study was to develop a strategy for combining the results of several computer models for PA screening to conduct a comprehensive analysis of PAs, which is a crucial step in risk assessment of unknown PAs in traditional Chinese herbal preparations.

Effect of folic acid supplementation on the change of plasma S-adenosylhomocysteine level in Chinese hypertensive patients: a randomized, double-blind, controlled clinical trial.

The relationship between folic acid and S-adenosylhomocysteine (SAH) is controversial. This study aims to explore the effect of different doses of folic acid supplementation on SAH levels in hypertensive patients and the modification of methylene-tetrahydrofolate reductase (MTHFR) C677T gene polymorphism. A randomized, double-blind, controlled clinical trial was conducted. Hypertensive patients aged 45-75 years without a history of stroke and cardiovascular disease were selected, who were randomly assigned to one of 8 dose groups. This trial has been registered with Trial Number: ChiCTR1800016135. In the total population, folic acid supplementation of 0.4-2.0 mg/day had no effect on SAH level (ß = 0.47, 95% CI: -0.86-1.79, p = 0.491), while folic acid supplementation of 2.4 mg/day significantly increased SAH level (ß = 1.93, 95% CI: 0.22-3.64, p = 0.027). Stratified analysis found that MTHFR C677T genotype CC supplemented with 2.4 mg/day folic acid had no effect on SAH level (ß = 0.30, 95% CI: -2.74-3.34, p = 0.847), while CT and TT genotype supplemented with 2.4 mg/day folic acid showed a significant increase in SAH level (CT: ß = 2.98, 95% CI: 0.34-5.62, p = 0.027; TT: ß = 3.00, 95% CI: -0.51-6.51, p = 0.095; CT combined with TT: ß = 2.99, 95% CI: 0.90-5.09, p = 0.005). In conclusion, supplementation of 2.4 mg/day folic acid can lead to increased SAH levels, especially in MTHFR C677T genotype CT and TT.

The efficacy and safety of Zengxiao Jiandu decoction combined with definitive concurrent chemoradiotherapy for unresectable locally advanced non-small cell lung cancer: a randomized, double-blind, placebo-controlled clinical trial.

Background: Traditional Chinese medicine (TCM) makes a synergistic and attenuative effect when combined with chemoradiotherapy. However, strong evidence-based studies are lacking. The study sought to investigate whether Zengxiao Jiandu decoction as an adjunctive therapy is superior to definitive concurrent chemoradiotherapy (DCCRT) alone in unresectable, locally advanced (LA), stage III non-small cell lung cancer (NSCLC). Methods: Patients with unresectable LA-NSCLC were randomly assigned to receive DCCRT either combined with Zengxiao Jiandu decoction (TCM arm) or placebo therapy (Control arm), by computer-generated random assignment lists using a central randomization system. The patients were routinely followed-up every 3 months for the first 2 years after the therapy, and every 6 months for the subsequent 3 years, or earlier if clinically indicated. The primary endpoint was grade ≥3 chemoradiotherapy-related toxicities, while secondary endpoints included the completion rate of chemoradiotherapy, the clinical objective response rate (ORR), and survival. The placebo achieved full consistency in color, aroma, taste and appearance with the Zengxiao Jiandu decoction. Results: From February 2019 to December 2020, 163 patients were randomly allocated to TCM arm (n=82) or Control arm (n=81). Fifty-nine (72.0%) patients in TCM arm finished chemoradiotherapy per protocol and 79 (96.3%) received protocol-specified Zengxiao Jiandu decoction. Forty-two patients in Control arm finished chemoradiotherapy per protocol. The incidence of grade ≥3 chemoradiotherapy-related toxicities was higher in Control arm than TCM arm (44.4% vs. 31.7%, P=0.094). Grade ≥3 radiation pneumonitis occurred more frequently in Control arm than TCM arm (13.6% vs. 3.7%, P=0.024). The completion rate of the protocol-specified chemotherapy was significantly higher in TCM arm than Control arm (79.3% vs. 64.2%, P=0.033), but the completion rates of the definitive-dose radiotherapy were similar. There were no significant differences in ORR between the 2 arms. The progression-free survival (PFS) of TCM arm was significantly better than Control arm (median PFS, 12.0 vs. 9.0 months, P=0.035). However, Zengxiao Jiandu decoction was not found to produce any significant benefit in overall survival. Conclusions: The Zengxiao Jiandu decoction adjunctive therapy, as compared to DCCRT alone, reduced grade ≥3 radiation pneumonitis, improved the completion rate of DCCRT, and prolonged PFS for unresectable LA-NSCLC. Trial Registration: Chinese Clinical Trial Registry ChiCTR2000031667.

Three new acylphloroglucinol glucosides from the roots of Lysidice rhodostegia and their antioxidant activities.

Three new acylphloroglucinol glucosides, rhodosides A-C (1-3), and three known ones (4-6) were isolated from the roots of Lysidice rhodostegia. The new structures were identified by MS, NMR, and acid hydrolysis. In addition, the antioxidant capacities of the isolated compounds were evaluated using DPPH radical-scavenging assay, and compounds 1-6 exhibited obvious antioxidant activities with IC50 values of 24.65 ± 1.27 to 38.11 ± 1.35 µM.

Allicin Reversed the Process of Frailty in Aging Male Fischer 344 Rats With Osteoporosis.

The research and development of pharmaceutical intervention is insufficient for the frail older adults, especially in preclinical stage for the frail individuals with osteoporosis. Garlic exerts an antiosteoporotic effect and its vital component allicin could protect organisms against aging. The present study aimed to investigate the effect of long-term intragastric administration of allicin (low dose of 4 mg·kg-1·d-1; middle dose of 8 mg·kg-1·d-1; high dose of 16 mg·kg-1·d-1) on frailty with osteoporosis in aging male Fischer 344 rats. Frailty was assessed with a 27-item frailty index based on quantifying health-related deficits in adult male rats varied from 13 to 21 months and in control rats from 6 to 9 months. Osteoporosis was appraised by bone mineral density detected by dual-energy X-ray absorptiometry, biomechanical properties measured by a three-point bending test, and bone metabolic analysis using ELISA. Allicin could attenuate frailty index scores by reducing the accumulation of health deficits in aging male Fischer 344 rats. Meanwhile, allicin could protect against senile osteoporosis, and the underlying mechanism may involve in increasing low bone turnover through elevation of both bone formation and bone resorption, and subsequently lead to increase of bone mineral density, contributing to reversing deleterious bone biomechanical features associated with aging. The present study reveals firstly that long-term oral administration with allicin attenuated frailty with osteoporosis during the process of aging, which provides a preclinical evidence for intervention of frailty.

Assessment of heavy metals, fungicide quintozene and its hazardous impurity residues in medical Panax notoginseng (Burk) F.H.Chen root.

A quick, easy, cheap, effective, rugged, and safe extraction approach and gas chromatography/tandem mass spectrometry with programmed temperature vaporization sampling technology were used to determine fungicide quintozene and its hazardous impurity hexachlorobenzene (HCB) in Panax notoginseng root, which is commonly used as a rare traditional Chinese medicine worldwide. The mean recoveries were in the ranges of 94-125 and 84-119% for quintozene and HCB with relative standard deviations of 6.2-16.1% at three concentrations: 0.01, 0.1 and 1 mg kg-1 . Heavy metals arsenic, cadmium, copper and lead were simultaneously detected by an inductively coupled plasma-mass spectrometry approach after digestion with nitric acid. The above methods were used to analyze 50 samples of P. notoginseng roots collected at markets and planting bases from the special local producing areas, namely, Honghe, Kunming and Wenshan in Yunnan province, China. Quintozene and HCB in root samples were determined at <0.0015-1.50 and <0.0015-0.125 mg kg-1 . In the 50 samples, 60, 16, 56, 2 and 6% exceeded the maximum permissible levels in medicinal plants (WM/T2-2004) for quintozene, arsenic, cadmium, lead and copper. The results showed that the method is robust and suitable for measuring quintozene, its hazardous impurity and heavy metals in P. notoginseng roots.

Transcriptomic Comparison Reveals Candidate Genes for Triterpenoid Biosynthesis in Two Closely Related Ilex Species.

Native to Southern China, Ilex pubescens and Ilex asprella are frequently used in traditional Chinese medicine. Both of them produce a large variety of ursane-type triterpenoid saponins, which have been demonstrated to have different pharmacological effects. However, little is known about their biosynthesis. In this study, transcriptomic analysis of I. pubescens and comparison with its closely related specie I. asprella were carried out to identify potential genes involved in triterpenoid saponin biosynthesis. Through RNA sequencing (RNA-seq) and de novo transcriptome assembly of I. pubescens, a total of 68,688 UniGene clusters are obtained, of which 32,184 (46.86%) are successfully annotated by comparison with the sequences in major public databases (NCBI, Swiss-Prot, and KEGG). It includes 128 UniGenes related to triterpenoid backbone biosynthesis, 11 OSCs (oxidosqualene cyclases), 233 CYPs (cytochrome P450), and 269 UGTs (UDP-glycosyltransferases). By homology-based blast and phylogenetic analysis with well-characterized genes involved in triterpenoid saponin biosynthesis, 5 OSCs, 14 CYPs, and 1 UGT are further proposed as the most promising candidate genes. Transcriptomic comparison between two Ilex species using blastp and OrthoMCL method reveals high sequence similarity. All OSCs and UGTs as well as most CYPs are classified as orthologous genes, while only 5 CYPs in I. pubescens and 3 CYPs in I. asprella are species-specific. One of OSC candidates, named as IpAS1, was successfully cloned and expressed in Saccharomyces cerevisiae INVSc1. Analysis of the yeast extract by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) shows IpAS1 is a mixed amyrin synthase, producing α-amyrin and ß-amyrin at ratio of 5:1, which is similar to its ortholog IaAS1 from I. asprella. This study is the first exploration to profile the transcriptome of I. pubescens, the generated data and gene models will facilitate further molecular studies on the physiology and metabolism in this plant. By comparative transcriptomic analysis, a series of candidate genes involved in the biosynthetic pathway of triterpenoid saponins are identified, providing new insight into their biosynthesis at transcriptome level.

Tenuifolin, a saponin derived from Radix Polygalae, exhibits sleep-enhancing effects in mice.

BACKGROUND: Radix Polygalae, the dried root of Polygala tenuifolia, has been extensively used as a traditional Chinese medicine for promoting intelligence and tranquilization. Polygalasaponins extracted from the root of P. tenuifolia possess evident anxiolytic and sedative-hypnotic activities. Previous studies have reported that tenuifolin was a major constituent of polygalasaponins. PURPOSE: The currently study aims to investigate the hypnotic effect and possible mechanism of tenuifolin in freely moving mice. DESIGN/METHODS: The hypnotic effects of tenuifolin (20, 40 and 80mg/kg, p.o.) were assessed by electroencephalographic (EEG) and electromyographic (EMG) analysis. Double-staining immunohistochemistry test was performed to evaluate the neuronal activity of sleep-wake regulating brain areas. High performance liquid chromatograph- electrochemical detection (HPLC-ECD) and ultrafast liquid chromatography-mass spectrometry (UFLC-MS) were used for the detection of neurotransmitters. Locomotor activity was measured by Open-field Test. RESULTS: Tenuifolin at doses of 40 and 80mg/kg (p.o.) significantly prolonged the total sleep time by increasing the amount of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep, associated with the significant increase in the bouts of episodes respectively. After administration of tenuifolin, the cortical EEG power spectral densities during NREM and REM sleep were similar to that of natural sleep (vehicle) and thus compatible with physiological sleep. Double-immunohistochemistry staining test showed that tenuifolin increased the c-Fos positive ratios of GABAergic NREM sleep-promoting neurons in ventrolateral preoptic area (VLPO), cholinergic REM sleep-promoting neurons in laterodorsal tegmental area (LDT) and pontomesencephalic tegmental area (PPT) and decreased the c-Fos positive ratios in wake-promoting neurons (locus coeruleus (LC) and perifornical area (Pef)). Neurotransmitter detections revealed that tenuifolin significantly reduced the noradrenaline (NA) levels in LC, VLPO, PPT and LDT, elevated the GABA levels in VLPO, LC and Pef and increased the acetylcholine (Ach) levels in LDT and PPT. In addition, tenuifolin did not cause any change to locomotor activity. CONCLUSION: Taken together, these results provide the first experimental evidence of the significant sleep-enhancing effect of tenuifolin in mice. This effect appears to be mediated, at least in part, by the activation of GABAergic systems and/or by the inhibition of noradrenergic systems. Moreover, this study adds new scientific evidence and highlights the therapeutic potential of the medicinal plant P. tenuifolia in the development of phytomedicines with hypnotic properties.

Computational analysis and enzyme assay of inhibitor response to disease single nucleotide polymorphisms (SNPs) in lipoprotein lipase.

Lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of the triglyceride (TG) core of circulating TG-rich lipoproteins, chylomicrons, and very low-density lipoproteins. The enzyme has been established as an efficacious and safe therapeutic target for the management of obesity. Here, a systematic profile of the lipase inhibitor response of three anti-obesity agents (Orlistat, Lipstatin, and Cetilistat) to clinical LPL missense mutations arising from disease single nucleotide polymorphisms (SNPs) was established by integrating complex structure modeling, virtual mutagenesis, molecular dynamics (MD) simulations, binding energy analysis, and radiolabeled TG hydrolysis assays. The profile was then used to characterize the resistance and sensitivity of systematic mutation-inhibitor pairs. It is suggested that the Orlistat and Lipstatin have a similar response profile to the investigated mutations due to their homologous chemical structures, but exhibit a distinct profile to that of Cetilistat. Most mutations were predicted to have a modest or moderate effect on inhibitor binding; they are located far away from the enzyme active site and thus can only influence the binding limitedly. A number of mutations were found to sensitize or cause resistance for lipase inhibitors by directly interacting with the inhibitor ligands or by indirectly addressing allosteric effect on enzyme active site. Long-term MD simulations revealed a different noncovalent interaction network at the complex interfaces of Orlistat with wild-type LPL as well as its sensitized mutant H163R and resistant mutant I221T.

Phosphorylation of CaMKII in the rat dorsal raphe nucleus plays an important role in sleep-wake regulation.

The Ca(2+) modulation in the dorsal raphe nucleus (DRN) plays an important role in sleep-wake regulation. Calmodulin-dependent kinase II (CaMKII) is an important signal-transducing molecule that is activated by Ca(2+) . This study investigated the effects of intracellular Ca(2+) /CaMKII signaling in the DRN on sleep-wake states in rats. Maximum and minimum CaMKII phosphorylation was detected at Zeitgeber time 21 (ZT 21; wakefulness state) and ZT 3 (sleep state), respectively, across the light-dark rhythm in the DRN in rats. Six-hour sleep deprivation significantly reduced CaMKII phosphorylation in the DRN. Microinjection of the CAMKII activation inhibitor KN-93 (5 or 10 nmol) into the DRN suppressed wakefulness and enhanced rapid-eye-movement sleep (REMS) and non-REM sleep (NREMS). Application of a high dose of KN-93 (10 nmol) increased slow-wave sleep (SWS) time, SWS bouts, the mean duration of SWS, the percentage of SWS relative to total sleep, and delta power density during NREMS. Microinjection of CaCl2 (50 nmol) in the DRN increased CaMKII phosphorylation and decreased NREMS, SWS, and REMS. KN-93 abolished the inhibitory effects of CaCl2 on NREMS, SWS, and REMS. These data indicate a novel wake-promoting and sleep-suppressing role for the Ca(2+) /CaMKII signaling pathway in DRN neurons. We propose that the intracellular Ca(2+) /CaMKII signaling in the dorsal raphe nucleus (DRN) plays wake-promoting and sleep-suppressing role in rats. Intra-DRN application of KN-93 (CaMKII activation inhibitor) suppressed wakefulness and enhanced rapid-eye-movement sleep (REMS) and non-REMS (NREMS). Intra-DRN application of CaCl2 attenuated REMS and NREMS. We think these findings should provide a novel cellular and molecular mechanism of sleep-wake regulation.

Capsaicin Enhances the Drug Sensitivity of Cholangiocarcinoma through the Inhibition of Chemotherapeutic-Induced Autophagy.

Cholangiocarcinoma (CCA), a devastating cancer with a poor prognosis, is resistant to the currently available chemotherapeutic agents. Capsaicin, the major pungent ingredient found in hot red chili peppers of the genus Capsicum, suppresses the growth of several malignant cell lines. Our aims were to investigate the role and mechanism of capsaicin with respect to the sensitivity of CCA cells to chemotherapeutic agents. The effect of capsaicin on CCA tumor sensitivity to 5-fluorouracil (5-FU) was assessed in vitro in CCA cells and in vivo in a xenograft model. The drug sensitivity of QBC939 to 5-FU was significantly enhanced by capsaicin compared with either agent alone. In addition, the combination of capsaicin with 5-FU was synergistic, with a combination index (CI) < 1, and the combined treatment also suppressed tumor growth in the CCA xenograft to a greater extent than 5-FU alone. Further investigation revealed that the autophagy induced by 5-FU was inhibited by capsaicin. Moreover, the decrease in AKT and S6 phosphorylation induced by 5-FU was effectively reversed by capsaicin, indicating that capsaicin inhibits 5-FU-induced autophagy by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway in CCA cells. Taken together, these results demonstrate that capsaicin may be a useful adjunct therapy to improve chemosensitivity in CCA. This effect likely occurs via PI3K/AKT/mTOR pathway activation, suggesting a promising strategy for the development of combination drugs for CCA.

Glucocorticoid receptors in the locus coeruleus mediate sleep disorders caused by repeated corticosterone treatment.

Stress induced constant increase of cortisol level may lead to sleep disorder, but the mechanism remains unclear. Here we described a novel model to investigate stress mimicked sleep disorders induced by repetitive administration of corticosterone (CORT). After 7 days treatment of CORT, rats showed significant sleep disturbance, meanwhile, the glucocorticoid receptor (GR) level was notably lowered in locus coeruleus (LC). We further discovered the activation of noradrenergic neuron in LC, the suppression of GABAergic neuron in ventrolateral preoptic area (VLPO), the remarkable elevation of norepinephrine in LC, VLPO and hypothalamus, as well as increase of tyrosine hydroxylase in LC and decrease of glutamic acid decarboxylase in VLPO after CORT treatment. Microinjection of GR antagonist RU486 into LC reversed the CORT-induced sleep changes. These results suggest that GR in LC may play a key role in stress-related sleep disorders and support the hypothesis that repeated CORT treatment may decrease GR levels and induce the activation of noradrenergic neurons in LC, consequently inhibit GABAergic neurons in VLPO and result in sleep disorders. Our findings provide novel insights into the effect of stress-inducing agent CORT on sleep and GRs' role in sleep regulation.

Characterisation of two oxidosqualene cyclases responsible for triterpenoid biosynthesis in Ilex asprella.

Ilex asprella, a plant widely used as a folk herbal drug in southern China, produces and stores a large amount of triterpenoid saponins, most of which are of the α-amyrin type. In this study, two oxidosqualene cyclase (OSC) cDNAs, IaAS1 and IaAS2, were cloned from the I. asprella root. Functional characterisation was performed by heterologous expression in the yeast Saccharomyces cerevisiae. Analysis of the resulting products by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) showed that both genes encode a mixed amyrin synthase, producing α-amyrin and ß-amyrin at different ratios. IaAS1, which mainly produces α-amyrin, is the second triterpene synthase so far identified in which the level of α-amyrin produced is ≥80% of total amyrin production. By contrast, IaAS2 mainly synthesises ß-amyrin, with a yield of 95%. Gene expression patterns of these two amyrin synthases in roots and leaves of I. asprella were found to be consistent with the content patterns of total saponins. Finally, phylogenetic analysis and multiple sequence alignment of the two amyrin synthases against several known OSCs from other plants were conducted to further elucidate their evolutionary relationship.

A retrospective analysis of carbapenem-resistant Acinetobacter baumannii-mediated nosocomial pneumonia and the in vitro therapeutic benefit of cefoperazone/sulbactam.

BACKGROUND: Acinetobacter baumannii has been reported increasingly as a significant causative organism of various nosocomial infections, including hospital-acquired pneumonia (HAP). The aim of this study was to investigate the clinical characteristics of HAP induced by carbapenem-resistant A. baumannii (CRAB) in elderly patients and the in vitro antimicrobial effects of cefoperazone/sulbactam combination therapy. METHODS: Seventy-one elderly patients in the geriatric ward of the General Hospital of the People's Liberation Army (PLAGH) with CRAB-induced HAP were analyzed retrospectively. The checkerboard method was used to determine the in vitro drug sensitivity of 60 CRAB strains to antimicrobial combinations (cefoperazone/sulbactam with meropenem, minocycline, or levofloxacin). The occurrence of carbapenemase genes was detected by PCR. RESULTS: CRAB-induced HAP occurred mostly in patients with underlying diseases. Prior to onset, most patients had received antimicrobial therapies including broad-spectrum ß-lactams, invasive mechanical ventilation, and catheterization. The 30-day survival rate was 95.1% in patients using cefoperazone/sulbactam, with or without combination with antimicrobial drugs, and 73.3% in patients not using cefoperazone/sulbactam (p<0.05). When cefoperazone/sulbactam was used in combination with minocycline, levofloxacin, and meropenem, minimum inhibitory concentrations MIC50 and MIC90 were reduced for each drug. The genes OXA-23 and OXA-51 were amplified in 96.7% of the strains, but the genes OXA-24, OXA-58, SIM, VIM, and IMP were not amplified. CONCLUSIONS: CRAB-induced HAP occurred mostly in patients with anemia or decreased levels of serum albumin, but with elevated levels of C-reactive protein and creatinine. Cefoperazone/sulbactam in combination with minocycline, meropenem, and levofloxacin had a synergistic and additive in vitro bacteriostatic action on CRAB.

A Chinese herbal formula, Wuzi Yanzong pill, improves spermatogenesis by modulating the secretory function of Sertoli cells.

OBJECTIVE: To evaluate the effects of the Chinese herbal formula Wuzi Yanzong Pill (, WYP) on the spermatogenesis and specific secretory functions of Sertoli cells in rat model and to investigate the underlying mechanism. METHODS: Five groups of male Sprague-Dawley rats including the control group, the model group, the low-dose WYP group, the medium-dose WYP group and the high-dose WYP group (5 in each group) were treated daily with vehicle, multiglycosides of Tripterygium wilfordii Hook f (GTW) either alone (20 mg/kg) or followed by WYP (0.5, 1.0, or 2.0 g/kg daily), respectively for 30 days. Serum levels of follicle-stimulating hormone (FSH), inhibin B (INHB) and testosterone (T) were evaluated using enzyme-linked immunosorbent assay. Androgen-binding protein (ABP) gene expression and transferrin (TF) protein expression in testis tissue specimens of all rats were determined using real-time reverse transcriptase polymerase chain reaction and Western blotting analysis, respectively. Histopathological alterations in the testis were determined using Johnsen's score. RESULTS: The toxicity of GTW towards Sertoli cell secretory functions and spermatogenesis was accompanied by increased serum FSH concentrations and decreased INHB and T concentrations. Upregulated ABP mRNA levels, and decreased TF protein expression and Johnsen's scores were detected in the model group compared with the control group P<0.05 or P<0.01). Oral high-dose WYP administrations to GTW-treated rats effectively alleviated all of the GTW-induced changes in specific secretory functions of Sertoli cells (ABP, INHB and TF). Furthermore, serum T level and Johnsen's score of the testis increased greatly compared with the model group (P<0.01). CONCLUSION: WYP has the ability to improve the spermatogenesis, possibly through modulating the secretory proteins expression of Sertoli cells.

EGFR inhibitors with concurrent thoracic radiation therapy for locally advanced non-small cell lung cancer.

Currently, a combination of chemotherapy and radiotherapy is the standard treatment approach for locally advanced non-small cell lung cancer (NSCLC). However, the clinical outcomes are still disappointing, with the 5-year survival rate being only approximately 20%. Further improvement in treatment outcome for patients with locally advanced NSCLC will require the development of more effective combined-modality therapies. Increasing attention has focused on the integration of targeted agents into current therapies. Many preclinical studies in this area have targeted the epidermal growth factor receptor (EGFR) signaling pathway to increase radiosensitivity. The in vitro rationale for targeting EGFR and concurrent ionizing radiation is well established, but to date, rare clinical data could provide proof-of-principle. In this review article, we briefly discuss pre-clinical data and the rationale and report all the different published clinical trials focusing on efficacy and toxicity in order to clarify and to summarize the present state-of-the-art of this particular combination in NSCLC.

[Metabolism-based interaction of diphenytriazol and flavone compounds].

OBJECTIVE: To observe the metabolism-based interaction of diphenytriazol and flavone compounds. METHODS: Flavone compounds kaempferol, isoharmnten and Elsholtzia blanda benth extract were chosen as the substrate of glucuronidation in the phase II metabolism. The metabolism was investigated in different rat liver microsome incubates pretreated with beta-naphthoflavone (BNF), diphenytriazol and tea oil (control). The concentrations of residual substrate were determined by HPLC. Quercetin and kaempferol were coincubated with diphenytriazol in control microsome to evaluate the inhibition for phase I metabolism. The concentration of diphenytriazol was determined by HPLC. RESULT: The phase II metabolic activity of kaempferol, isoharmnten and Elsholtzia blanda benth extract in diphenytriazol-treated microsome was more potent than that in BNF-treated microsome (P<0.01). The phase I metabolism of diphenytriazol was markedly inhibited by quercetin and kaempferol, with the inhibition constants (Ki) (12.41 +/-0.26)microg . ml(-1) and (7.97 +/-0.08)microg . ml(-1), respectively. CONCLUSION: Diphenytriazol demonstrates metabolism-based interaction with flavone compounds in vitro.

The effect of blue light exposure on the expression of circadian genes: bmal1 and cryptochrome 1 in peripheral blood mononuclear cells of jaundiced neonates.

The purpose of this study was to investigate the effect of blue light phototherapy on the expression of circadian genes in peripheral blood mononuclear cells (PBMC) and plasma melatonin levels in neonates. Real-time reverse-transcriptase polymerase chain reaction (RT-PCR) was used to determine the expression of Bmal1 and Cry1 in PBMC, and an enzyme-linked immunosorbent assay was used to determine plasma melatonin levels in 32 breast-milk jaundiced neonates before and after phototherapy, compared with 29 control neonates. The results showed that the expression of Bmal1 was decreased and Cry1 increased significantly after phototherapy. Plasma melatonin levels were decreased after phototherapy. There was no statistical difference in Bmal1 and Cry1 gene expression and plasma melatonin levels in the control group. In conclusion, phototherapy does affect the expression of the circadian genes Bmal1 and Cry1 in PBMC and plasma melatonin concentration in jaundiced neonates. Our results suggest that phototherapy should be timed according to circadian rhythms when treating jaundiced neonates.