Attenuation of Epileptogenesis and Cognitive Deficits by a Selective and Potent Kv7 Channel Opener in Rodent Models of Seizures.

Targeting neuronal Kv7 channels by pharmacological activation has been proven to be an attractive therapeutic strategy for epilepsy. Here, we show that activation of Kv7 channels by an opener SCR2682 dose-dependently reduces seizure activity and severity in rodent models of epilepsy induced by a GABAa receptor antagonist pentylenetetrazole (PTZ), maximal electroshock, and a glutamate receptor agonist kainic acid (KA). Electroencephalographic recordings of rat cerebral cortex confirm that SCR2682 also decreases epileptiform discharges in KA-induced seizures. Nissl and neuronal nuclei staining further demonstrates that SCR2682 also protects neurons from injury induced by KA. In Morris water maze navigation and Y-maze tests, SCR2682 improves PTZ- and KA-induced cognitive impairment. Taken together, our findings demonstrate that pharmacological activation of Kv7 by novel opener SCR2682 may hold promise for therapy of epilepsy with cognitive impairment. SIGNIFICANCE STATEMENT: A neuronal Kv7 channel opener SCR2682 attenuates epileptogenesis and seizure-induced cognitive impairment in rodent models of seizures, thus possessing a developmental potential for effective therapy of epilepsy with cognitive impairment.

Activation of Neuronal Voltage-Gated Potassium Kv7/KCNQ/M-Current by a Novel Channel Opener SCR2682 for Alleviation of Chronic Pain.

Treatment of chronic pain remains an unmet medical need. The neuronal voltage-gated potassium Kv7/KCNQ/M channel has been implicated as a therapeutic target for chronic pain. However, whether pharmacological activation of the Kv7 channel can alleviate pain remains elusive. In this study, we show that selective activation of native M-currents by a novel channel opener SCR2682 reduces repetitive firings of dorsal root ganglia (DRG) sensory neurons. Intraperitoneal administration of SCR2682 relieves mechanical allodynia and thermal hyperalgesia in rat models of pain induced by complete Freund's adjuvant (CFA) or spared nerve injury (SNI) in a dose-dependent manner without affecting locomotor activity. The antinociceptive efficacy of SCR2682 can be reversed by the channel-specific blocker XE991. Furthermore, SCR2682 increases Kv7.2/KCNQ2 mRNA and protein expression in DRG neurons from rats in the SNI model of neuropathic pain. Taken together, pharmacological activation of neuronal Kv7 channels by opener SCR2682 can alleviate pain in rats, thus possessing therapeutic potential for chronic pain or hyperexcitability-related neurologic disorders. SIGNIFICANCE STATEMENT: A novel voltage-gated potassium Kv7 channel opener SCR2682 inhibits action potential firings in dorsal root ganglia sensory neurons and exhibits efficacy in antinociception, thus possessing a developmental potential for treatment of chronic pain or epilepsy.

Dimeric 1,4-benzoquinone Derivatives with Cytotoxic Activities from the Marine-Derived Fungus Penicillium sp. L129.

Two new dimeric 1,4-benzoquinone derivatives, peniquinone A (1) and peniquinone B (2), a new dibenzofuran penizofuran A (3), and a new pyrazinoquinazoline derivative quinadoline D (4), together with 13 known compounds (5-17), were isolated from a marine-derived fungus Penicillium sp. L129. Their structures, including absolute configurations, were elucidated by extensive spectroscopic data and electronic circular dichroism calculations. Compound 1 exhibited cytotoxicity against the MCF-7, U87 and PC3 cell lines with IC50 values of 12.39 µM, 9.01 µM and 14.59 µM, respectively, while compound 2 displayed relatively weak cytotoxicity activities against MCF-7, U87 and PC3 cell lines with IC50 values of 25.32 µM, 13.45 µM and 19.93 µM, respectively. Furthermore, compound 2 showed weak quorum sensing inhibitory activity against Chromobacterium violaceum CV026 with an MIC value of 20 µg/well.

Functional role of RRS1 in breast cancer cell proliferation.

RRS1 (human regulator of ribosome synthesis 1), an essential nuclear protein involved in ribosome biogenesis, is overexpressed in some human cancers, yet its role in breast cancer remains unclear. Here, we report a functional analysis of RRS1 in breast cancer and its likely mechanism. Immunohistochemistry (IHC) and RT-qPCR analyses indicated that RRS1 was commonly overexpressed in breast cancer tissues. The copy numbers of RRS1 were higher in tumours compared with those for normal tissues. And there was a significant correlation between copy number and mRNA expression. In addition, RRS1 overexpression was significantly correlated with lymph node metastasis and poor survival. RRS1 mRNA and protein levels were also significantly increased in a panel of human breast cancer cell lines. RRS1 knockdown inhibited proliferation and induced apoptosis and cell cycle arrest in all three cell lines. Furthermore, RRS1 knockdown suppressed the tumour formation and growth of MDA-MB-231 cells in nude mice. Additionally, RRS1 knockdown activated p53 and p21 in MCF-7 cells. A marked increase in the quantity of ribosome-free RPL11 was detected by Western blot. Moreover, co-immunoprecipitation (CoIP) experiments showed that RRS1 knockdown activated p53 by facilitating the direct contact of MDM2 and RPL11/RPL5. Taken together, our results suggest that RRS1 may contribute to breast cancer proliferation through RPL11/MDM2-mediated p53 activation. Therefore, RRS1 may be a promising target for breast cancer therapy.

Isatin inhibits SH-SY5Y neuroblastoma cell invasion and metastasis through MAO/HIF-1α/CXCR4 signaling.

Isatin was reported to possess anticancer activities through its effect on tumor proliferation, apoptosis, and metastasis in vitro and in vivo. This study aimed to elucidate the underlying mechanism behind isatin's ability to inhibit neuroblastoma cell metastasis. Our results demonstrated that isatin could inhibit neuroblastoma cell proliferation, invasion, and migration in a dose-dependent manner. Moreover, isatin inhibited the expression level of monoamine oxidase A as well as that of its downstream protein hypoxia-inducible factor 1α. Further study indicated that isatin inhibited reactive oxygen species production, extracellular signal-regulated kinase activation, vascular endothelial growth factor receptor-1 phosphorylation, and chemokine receptor type 4 expression. All results support the potential antimetastatic effect of isatin in neuroblatoma cells.

Anti-oxidation and Antiapoptotic Effects of Chondroitin Sulfate on 6-Hydroxydopamine-Induced Injury Through the Up-Regulation of Nrf2 and Inhibition of Mitochondria-Mediated Pathway.

The purpose of the study was to investigate the protective effect and molecular mechanism of chondroitin sulfate (CS) against 6-hydroxydopamine (6-OHDA) induced toxicity in the human neuroblastoma cell line SH-SY5Y. The results showed that CS could protect SH-SY5Y cells against 6-OHDA-induced injury. The subsequent mechanism study showed that the anti-oxidation of CS may partly be mediated through inhibiting the intracellular reactive oxygen species overproduction, recovering the reduction of nuclear NF-E2-related factor-2 (Nrf2) expression and the reduction of antioxidants activity induced by 6-OHDA. Furthermore, CS pretreatment significantly attenuated 6-OHDA-induced cell apoptosis and nuclear condensation. 6-OHDA-induced dysfunctions, including the decrease of mitochondrial membrane potential (ΔΨm), increase of intracellular free Ca(2+), imbalance of Bcl-2/Bax ratio, release of Cyt-c from the mitochondria and activation of caspase-3 and caspase-9 were attenuated by CS pretreatment, which demonstrated that CS suppressed 6-OHDA-induced apoptosis in SH-SY5Y cells possibly through mitochondria protection. These results suggest that CS exhibits anti-oxidation through the up-regulation of Nrf2 along with endogenous antioxidant, and reduces apoptosis via inhibiting the mitochondrial pathway to protect SH-SY5Y cells damaged by 6-OHDA.

Dairy foods intake and risk of Parkinson's disease: a dose-response meta-analysis of prospective cohort studies.

Dairy foods have been linked to Parkinson's disease (PD), and a meta-analysis of prospective cohort studies on dairy foods intake and PD risk was conducted. Eligible studies were identified in a literature search of EMBASE and PubMed up to April 2014. Seven results from prospective studies were included, including 1,083 PD cases among 304,193 subjects. The combined risk of PD for highest vs. lowest level of dairy foods intake was 1.40 (1.20-1.63) overall, 1.66 (1.29-2.14) for men and 1.15 (0.85-1.56) for women. For highest vs. lowest level, the PD risk was 1.45 (1.23-1.73) for milk, 1.26 (0.99-1.60) for cheese, 0.95 (0.76-1.20) for yogurt and 0.76 (0.51-1.13) for butter. The linear dose-response relationship showed that PD risk increased by 17% [1.17 (1.06-1.30)] for every 200 g/day increment in milk intake (Pfor non-linearity = 0.22), and 13% [1.13 (0.91-1.40)] for every 10 g/day increment in cheese intake (Pfor non-linearity = 0.39). The absolute risk differences were estimated to be 2-4 PD cases per 100,000 person-years for every 200 g/day increment in milk intake, and 1-3 PD cases per 100,000 person-years for every 10 g/day increment in cheese intake. Dairy foods (milk, cheese) might be positively associated with increased risk of PD, especially for men.

The Kv7 channel opener Retigabine reduces neuropathology and alleviates behavioral deficits in APP/PS1 transgenic mice.

Hyperexcitability of neuronal networks is central to the pathogenesis of Alzheimer's disease (AD). Pharmacological activation of Kv7 channels is an effective way to reduce neuronal firing. Our results showed that that pharmacologically activating the Kv7 channel with Retigabine (RTG) can alleviate cognitive impairment in mice without affecting spontaneous activity. RTG could also ameliorate damage to the Nissl bodies in cortex and hippocampal CA and DG regions in 9-month-old APP/PS1 mice. Additionally, RTG could reduce the Aß plaque number in the hippocampus and cortex of both 6-month-old and 9-month-old mice. By recordings of electroencephalogram, we showed that a decrease in the number of abnormal discharges in the brains of the AD model mice when the Kv7 channel was opened. Moreover, Western blot analysis revealed a reduction in the expression of the p-Tau protein in both the hippocampus and cortex upon Kv7 channel opening. These findings suggest that Kv7 channel opener RTG may ameliorate cognitive impairment in AD, most likely by reducing brain excitability.

[Protective effects of total epimedium flavonoids against QA-induced toxicity in SH-SY5Y cells].

OBJECTIVE: To investigate the protective effects and its mechanisms of total epimedium flavonoids (TEF) against Quindinince acid (QA)-induced toxicity in SH-SY5Y cells. METHODS: The MT assay was used to detect the toxicity of QA and the cell viability of pretreatment of TEF and co-incubation with QA in SH-SY5Y cells; Cell apoptosis was observed by Hochest33258 staining; SOD and GSH-Px activities as well as MDA content were measured by colorimetric method; The mitochondrial membrane potential (delta psi m) and intracellular free calcium concentration ([Ca2+]i) were monitored by FCM. RESULTS: TEF increased the cell viability of SH-SY5Y cells, reduced apoptosis cells significantly, improved SOD and GSH-Px activities, decreased MDA content, increased the mitochondrial membrane potential and reduced intracellular free calcium concentration( [Ca2+]i ). CONCLUSION: TEF has significant protective effects against QA-induced toxicity in SH-SY5Y cells,the action mechanism may be associated with resisting oxidative stress, decreasing the [Ca2]i and up-regulating delta psi m.

Inhibition of neuronal Kv7 channels ameliorates MK-801-induced cognitive dysfunction in mice via up-regulating NAMPT expression.

PURPOSE: Abnormal energy metabolism affects cognitive function in schizophrenia. Nicotinamide phosphoribosyltransferase (NAMPT), as the rate-limiting enzyme of nicotinamide adenine dinucleotide (NAD+), is involved in energy metabolism by regulating the synthesis of NAD+. This study aims to clarify whether inhibition of Kv7 channels improves cognitive impairment by up-regulating NAMPT expression to increase the level of NAD+. METHODS: The dominant negative pore mutation of KCNQ2 in transgenic mice was achieved by mutating residual 279-Gly to Ser (rQ2-G279S). A cognitive deficit model was established by injecting MK-801 into C57BL/6J mice. Y-maze and prepulse inhibition (PPI) tests were performed to evaluate cognitive ability. Gene and protein expression of NAMPT in the mouse hippocampus, cortex, and PC-12 cells were measured by qRT-PCR and Western blot. The level of NAD+ was measured by a WST-8 assay. RESULTS: The Y-maze and PPI results showed that genetic or pharmacological inhibition of Kv7 channels by XE991 enhanced cognitive function in mice. Furthermore, inhibition of Kv7 channels increased the gene and protein expression of NAMPT and the level of NAD+ in the hippocampus and cortex of the above animal model. Similarly, XE991 treatment increased NAMPT expression and NAD+ levels in PC-12 cells. NAMPT inhibitor FK866 and Kv7 channel opener retigabine reversed the effects of XE991 in vivo and in vitro. In addition, XE991 increased pAMPK protein expression in PC-12 cells, while AMPK inhibitor Compound C counteracted the effect of XE991 on increasing NAMPT expression and NAD+ levels. CONCLUSIONS: Suppression of Kv7 channel function improved spatial working memory and PPI impairment. This result may be achieved by activating AMPK to up-regulate NAMPT expression and thus increase NAD+ levels.

Nanoparticles based on hydrophobic alginate derivative as nutraceutical delivery vehicle: vitamin D3 loading.

We report the application of Vitamin D3 (VD(3)) in nanoparticles of oleoyl alginate ester (OAE)(OAE-VD(3)). The internalization of fluorescent OAE-VD(3) by Caco-2 cells was visualized by confocal laser scanning microscopy. In vivo pharmacokinetic studies showed that incorporation into OAE nanoparticles resulted in increased absorption of VD(3). Its application in the treatment of rickets was assayed using a model of nutritionally induced vitamin D-deficiency rickets. The results showed that the encapsulated VD(3) had better efficacy than that of the free drug in vivo. Our studies provide evidence that OAE nanoparticles are valuable as nutraceutical delivery vehicles to enhance the absorption of VD(3).

JWX-A0108, a positive allosteric modulator of α7 nAChR, attenuates cognitive deficits in APP/PS1 mice by suppressing NF-κB-mediated inflammation.

Neuroinflammation plays an early and prominent role in the pathology of Alzheimer's disease (AD). Studies have shown that cholinergic lesion is a contributor for the pathophysiology of AD. The α7 nicotinic acetylcholine receptors (nAChRs), a subtype of nAChRs, are abundantly expressed in the brain regions related to cognition and memory, such as hippocampus and frontal cortex. The α7 nAChR is rapidly activated and desensitized by agonists. JWX-A0108 is a type I positive allosteric modulator (PAM) of α7 nAChR, which mainly enhances agonist-evoked peak currents. Here, we used the Morris Water Maze to evaluate the effect of JWX-A0108 on cognition and memory functions in APP/PS1 mice, and the mechanism related to anti-inflammatory effect. The results showed that JWX-A0108 could improve the learning and memory function of APP/PS1 transgenic mice in Morris water maze, decrease the expression of IL-1ß, TNF-α, IL-6 in the brain and lower the phosphorylation level of IκBα (Ser32/36) and NF-κB p65 (Ser536), decrease the expression of Iba1, the microglia activation marker. Nissl staining showed that the CA3 and DG regions of hippocampus were damaged in APP/PS1 mice, which was improved by JWX-A0108. All of these effects of JWX-A0108 were reversed by MLA (α7 nAChR specific blocker). Taken together, the results reveal that JWX-A0108 improved the learning and memory function of APP/PS1 mice by enhancing the anti-inflammatory effect of the endogenous choline system through α7 nAChR, inhibited the activation of the NF-κB signaling pathway by inhibiting IκB phosphorylation, and ultimately inhibited inflammatory responses.

Antidiabetic effect and mechanism of chitooligosaccharides.

The aim of this study was to observe the antidiabetic effect and mechanism of chitooligosaccharides (COS). Type 2 diabetic rats were fed a high-energy diet together with an injection of streptozotocin (STZ). After 8 weeks of COS treatment, the changes in glycometabolism, insulin sensitivity, serum hepatic marker enzyme levels, liver glycogen content, expressions of glucose transporter GLUT-4, malonaldehyde content, superoxide dismutase activity and morphology of the pancreas were observed. The results showed that COS significantly reduced fasting blood glucose (FBG), fasting insulin (FINS), increased the insulin sensitivity index (ISI) and improved oral glucose tolerance. COS increased liver glucokinase activity and glycogen content and upregulated the expressions of GLUT-4 mRNA in adipose and soleus muscle. They also raised the superoxide dismutase activity and reduced the malonaldehyde content in pancreas homogenate. Pancreas hematoxylin/eosin (HE) staining of the diabetic rats showed ruptured islet, but changes of pancreatic islet in the animals were minimized by administration of COS. The effect of COS on pancreatic beta cell (INS-1) in vitro was also examined. It was found that COS played important roles in INS-1 cells by promoting proliferation, increasing glucose stimulated insulin release, upregulating the expressions of GLUT-2 mRNA and protecting against STZ-induced apoptosis. The results from the present study indicate COS have protective effect for type 2 diabetes by ameliorating insulin resistance, promoting the proliferation of beta cells, increasing insulin secretion and protecting beta cells.

Prefrontal inhibition of neuronal Kv 7 channels enhances prepulse inhibition of acoustic startle reflex and resistance to hypofrontality.

BACKGROUND AND PURPOSE: Dysfunction of the prefrontal cortex (PFC) is involved in the cognitive deficits in neuropsychiatric diseases, such as schizophrenia, characterized by deficient neurotransmission known as NMDA receptor hypofrontality. Thus, enhancing prefrontal activity may alleviate hypofrontality-induced cognitive deficits. To test this hypothesis, we investigated the effect of forebrain-specific suppression or pharmacological inhibition of native Kv 7/KCNQ/M-current on glutamatergic hypofrontality induced by the NMDA receptor antagonist MK-801. EXPERIMENTAL APPROACH: The forebrain-specific inhibition of native M-current was generated by transgenic expression, in mice, of a dominant-negative pore mutant G279S of Kv 7.2/KCNQ2 channels that suppresses channel function. A mouse model of cognitive impairment was established by single i.p. injection of 0.1 mg·kg-1 MK-801. Mouse models of prepulse inhibition (PPI) of acoustic startle reflex and Y-maze spontaneous alternation test were used for evaluation of cognitive behaviour. Hippocampal brain slice recordings of LTP were used to assess synaptic plasticity. Hippocampus and cortex were dissected for detecting protein expression using western blot analysis. KEY RESULTS: Genetic suppression of Kv 7 channel function in the forebrain or pharmacological inhibition of Kv 7 channels by the specific blocker XE991 enhanced PPI and also alleviated MK-801 induced cognitive decline. XE991 also attenuated MK-801-induced LTP deficits and increased basal synaptic transmissions. Western blot analysis revealed that inhibiting Kv 7 channels resulted in elevation of pAkt1 and pGSK-3ß expressions in both hippocampus and cortex. CONCLUSIONS AND IMPLICATIONS: Both genetic and pharmacological inhibition of Kv 7 channels alleviated PPI and cognitive deficits. Mechanistically, inhibition of Kv 7 channels promotes synaptic transmission and activates Akt1/GSK-3ß signalling.

Isatin inhibits the invasion of human neuroblastoma SH­SY5Y cells, based on microarray analysis.

Neuroblastoma is the fourth most common type of extracranial malignant solid tumor in children. Isatin had been demonstrated to have inhibitory effects on neuroblastoma tumors in vivo and in vitro. The aim of the present study was to investigate the molecular mechanism related to the anti­invasion effect of isatin on SH­SY5Y cells using microarray analysis. The microarray data identified a number of genes to be differentially upregulated or downregulated between isatin­treated cells and untreated controls. A large number of these genes were associated with the mTOR signaling pathway. The differentially expressed genes involved in the mTOR signaling pathway were verified further, as well as their downstream genes associated with autophagy. The results of the present study provided an insight into the potential inhibitory mechanism of isatin on neuroblastoma metastasis.

Overexpression of TIPE2, a Negative Regulator of Innate and Adaptive Immunity, Attenuates Cognitive Deficits in APP/PS1 Mice.

Neuroinflammation plays an early and prominent role in the pathology of Alzheimer's disease (AD). Tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) has been identified as a negative regulator of innate and adaptive immunity. However, whether TIPE2 affects cognitive functions in AD-like mouse models remains unknown. In this study, we compared the gene and protein expressions of TIPE2 between the APP/PS1 mice and the age-matched wild type (WT) mice at different stages of development using western blot and RT-qPCR. The hippocampal expression of the TIPE2 mRNA and protein in APP/PS1 mice was higher than that of the WT mice starting from 6 months to 10 months. However, the difference of the TIPE2 expression between the APP/PS1 mice and the WT mice declined in a time-dependent manner. The spatial learning and memory deficit from the 8-month-old APP/PS1 mice was observed in the Y-maze test and fear conditioning task. Interestingly, overexpression of TIPE2 by intra-hippocampal injection of AAV-TIPE2 into APP/PS1 mice resulted in an improvement of learning and memory and reduced expression of inflammatory cytokines, such as TNF-α, IL-6 and IL-1ß, and increased expression of anti-inflammatory cytokines, such as IL-10 and Arg-1. Taken together, our findings show that the TIPE2 expression level was negatively correlated with the pathogenesis of Alzheimer's disease, and overexpression of TIPE2 attenuates cognitive deficits in APP/PS1 mice, suggesting TIPE2 is a potential target for pharmacological intervention and improvement of cognitive deficits. Graphical Abstract .

Antitumor effects of Isatin on human neuroblastoma cell line (SH-SY5Y) and the related mechanism.

The purpose of the study was to investigate the antitumor effects of Isatin and the related mechanism. Human neuroblastoma cells (SH-SY5Y) were exposed to Isatin at different concentrations for 48 h. Apoptotic features were demonstrated by means of nuclei staining with Hoechst 33258 and flow cytometry with propidium iodide (PI). Expressions of Bcl-2, Bax and vascular endothelial growth factor (VEGF) mRNA were analyzed via RT-PCR. Expressions of Bcl-2, Bax proteins and phosphorylated extracellular signal regulated protein kinases (ERKs, p42/p44) were analyzed via Western blot. Activation of caspase-3 was assayed by flow cytometry with anti-active caspase-3-McAb-PE. VEGF protein was determined by ELISA kits. And the results showed that apoptosis of SH-SY5Y cells were induced by Isatin in a dose-dependent manner. Expressions of Bcl-2, VEGF mRNA and Bcl-2, VEGF proteins were down-regulated, while expressions of Bax mRNA and Bax protein were not changed obviously. Expression of phosphorylated ERKs decreased, but the level of activated caspase-3 increased after treatment of Isatin. These results suggest that Isatin promotes the apoptosis of neuroblastoma cells, therefore, it might be a potential candidate for the treatment of neuroblastoma.

Anti-inflammatory drugs ameliorate opposite enzymatic changes in ileal 5-hydroxytryptamine metabolism in the delayed phase after cisplatin administration to rats.

The effects of anti-inflammatory drugs on ileal 5-hydroxytryptamine (5-HT) metabolic dynamics at 72 h after a single administration of cisplatin were investigated in rats. Cisplatin 5 mg/kg i.p. caused pathological changes, with an inflammatory response occurring 72 h after its administration. The inflammatory response was associated with the induction of cyclooxygenase-2, but not cyclooxygenase-1, in the ileal mucosa at 72 h after the cisplatin administration. Daily treatment with meloxicam 3 mg/kg s.c. ameliorated the cisplatin-induced mucosal damage, whereas dexamethasone 1 mg/kg s.c. did not. Cisplatin administration also caused a significant increase in cyclooxygenase-2 mRNA expression at 72 h after administration, which was blunted by dexamethasone, but not by meloxicam. Cisplatin increased the content of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), but had no effect on 5-HT turnover (5-HIAA/5-HT ratio). Meloxicam and dexamethasone did not significantly decrease 5-HT and 5-HIAA content. Cisplatin significantly decreased monoamine oxidase activity but increased tryptophan hydroxylase (TPH) activity and TPH(1) mRNA expression in ileal tissue. Meloxicam and dexamethasone significantly restored the decreased monoamine oxidase activity and inhibited the cisplatin-induced increase in tryptophan hydroxylase activity toward the control levels. These drugs also decreased the cisplatin-induced increase in TPH(1) mRNA expression. Neither cisplatin nor the anti-inflammatory drugs had significant effect on mRNA expression of the serotonin re-uptake transporter. These results suggest that the inflammatory response associated with cyclooxygenase-2 induction is involved in the opposite change in ileal tryptophan hydroxylase and monoamine oxidase activities in the delayed phase after single administration of cisplatin to rats.

[Multicentric randomized double blinded clinical study of Yiqi Tongmai Oral Liquid against angina pectoris in patients with coronary heart disease].

OBJECTIVE: To study the efficacy and safety of Yiqi Tongmai Oral Liquid (YQTM), a traditional compound Chinese herbal medicine, in treating angina pectoris in patients with coronary heart disease. METHODS: A multicentric, randomized, double blinded and paralleled controlled trial was conducted on 110 patients in trial group treated with YQTM, and 109 patients in control group treated with Shuxin Oral Liquid (SX). Cure and effective rates in both groups were evaluated. Frequency and duration of angina attack were counted and measured. Coronary angiography (CAG), electrocardiogram (ECG) and flat exercise test were taken in both groups. Blood lipid indexes, such as cholesterol (CH), triglyceride (TG), low-density lipoprotein (LDL), high density lipoprotein (HDL), were determined at pre- and post-treatment. The hemodynamic indexes, such as whole blood viscosity (J2), high-shear reduced viscosity (Eh), low-shear reduced viscosity (Ei), red cell aggregation index (Lb), red cell rigidity index (Rh), fibrinogen (Fb), blood sedimentation rate (BSR) and hematocrit (HCT), were determined at pre-and post-treatment. The indicated scores of symptoms and signs of traditional Chinese medicine (TCM) pattern, such as chest pain, chest constriction, breath shortness, palpitation, fatigue, dim complexion, spontaneous perspiration and tongue proper, tongue coating were evaluated in week 0, 1, 2, 3, 4 during the treatment course. The safety indexes, such as body temperature, pulse, respiration and blood pressure were observed. Routine tests of blood, urine and stool, hepatic function test and renal function test were taken at pre- and post-treatment. RESULTS: There was no significant difference between the total effective rate of the trial group and that of the control group, which were 91.82% and 85.32%, respectively (P>0.05). Trial groups percentile of cure rate is significantly higher than that of the control group (P<0.01). The frequency and duration of angina attack, the positive ratio of CAG and flat exercise test of both groups were lowered, while the effect of the trial group on frequency and duration of angina attack was better. No significant difference was found in ECG features between the two groups (P>0.05). The levels of CH, TG and LDL of both groups were lowered significantly (P<0.05). The effect of lowering CH, TG and LDL of the trial group was stronger than that of the control group (P<0.05). The hemodynamic indexes, such as J2, Eh, Ei, Lb, Rh, Fb, BSR and HCT were improved significantly in both groups (P<0.05). The improvements of J2, Eh, Ei, Lb, Rh, Fb and SR in the trial group were greater than those of control group (P<0.05). The TCM symptoms and signs, such as chest pain, chest constriction, breath shortness, palpitation, fatigue, dim complexion, spontaneous perspiration were improved significantly in both groups (P<0.05). The improvements of chest constriction, palpitation, fatigue and spontaneous perspiration in the trial group were greater than those of the control group (P<0.05). The total indicated score of TCM symptoms and signs was lowered more significantly than that of the control group (P<0.01). No significant changes were found at pre- and post-treatment in safety indexes, such as routine tests for blood, urine and stool, hepatic function test and renal function test. There was no significant difference in safety features of both groups (P>0.05). CONCLUSION: Yiqi Tongmai Oral Liquid bears good therapeutic effect on angina pectoris without adverse reaction, and is superior to Shuxin Oral Liquid. Yiqi Tongmai Oral Liquid is a new effective and safe medicine for the treatment of angina pectoris in patients with coronary heart disease.

Research progress on the direct antiviral drugs for hepatitis C virus.

Hepatitis C, caused by the hepatitis C virus (HCV) that attacks the liver and leads to inflammation, is a severe threat to human health. Pegylated interferon α (INF-α) and ribavirin based therapy was once the standard therapy for HCV infection. However, it is suboptimal in efficacy and poorly tolerated in some patients. In the last five years, four classes of direct antiviral drugs (NAAs) that target non-structural proteins (NS) of the virus including NS3/NS4A, NS5A, and NS5B have been developed and opened a new era in HCV treatment as they are more effective and tolerable than the INF-α and ribavirin combination regimen. Importantly, the newly introduced multiple NAAs combination therapy makes it possible to eradicate all genotypes of HCV. We review recent progress on the research and development of DAAs in the present article.