A Multicenter Real-World Study Evaluating the Hepatoprotective Effect of Polyene Phosphatidylcholine Against Chronic Hepatitis B.

Background: Polyene phosphatidylcholine (PPC) has been widely used to treat liver diseases in China. However, there is a lack of post-marketing evidence demonstrating its liver-protective efficiency among patients infected with hepatitis B virus (HBV). This study analyzed the multicenter real-world data to compare the effectiveness of PPC with those of magnesium isoglycyrrhizinate (IsoMag) and glutathione (GSH) in patients with liver injury. Methods: This study comprised the real-world data analysis of a multicenter, retrospective observational cohort. The data were retrieved from the Cooperative Registry of the Hospital Prescription in China between 1 October 2018, and 30 September 2019. A growth curve analysis was performed to compare the effects of different treatments on liver function longitudinally for up to 30 days after treatment commencement. In addition, the dose effect of the PPC treatment was investigated. Results: The final cohort included 6,052 patients with approximately 8% infected with HBV (N = 471). There were 1,649, 1,750, and 2,653 patients in the PPC, GSH, and IsoMag groups, respectively, with an average age of 53.9 years. In patients with HBV infection, the PPC treatment was associated with a significant decline in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (slopes: -3.7, 95% CI, -6.0 to -1.5 U/L/day; -2.4, 95% CI, -4.5 to -0.3 U/L/day, respectively). However, there were no significant differences in the effects among the three groups. In patients without HBV infection, the PPC treatment decreased ALT, AST, γ-glutamyl transferase (GGT), and albumin levels (-5.2, 95% CI, -5.8 to -4.5 U/L/day; -3.5, 95% CI, -4.2 to -2.7 U/L/day; -4.9, 95% CI, -6.2 to -3.7 U/L/day, -0.07, 95% CI, -0.09 to -0.04 g/L/day, respectively) and showed a stronger effect on lowering ALT levels than GSH (-2.6, 95% CI, -3.3 to -1.8 U/L/day, p < 0.05), as well as a stronger effect on lowering GGT levels than IsoMag (-1.4, 95% CI, -2.4 to -0.4 U/L/day, p < 0.05). PPC had no impact on prothrombin activity levels in patients with or without HBV infection. High-dose PPC exhibited a stronger effect on lowering ALT and AST levels than low-dose PPC. Conclusion: This was the first real-world multicenter study to demonstrate that PPC efficiently lowers ALT and AST levels in patients with liver diseases regardless of the status of HBV infection. PPC treatment showed a comparable or better effect compared with GSH and IsoMag treatments. High-dose PPC resulted in a stronger effect than low-dose PPC.

Attenuation of secondary damage and Aß deposits in the ipsilateral thalamus of dMCAO rats through reduction of cathepsin B by bis(propyl)-cognitin, a multifunctional dimer.

Delayed secondary degeneration in the non-ischemic sites such as ipsilateral thalamus would occur after cortical infarction. Hence, alleviating secondary damage is considered to be a promising novel target for acute stroke therapy. In the current study, the neuroprotective effects of bis(propyl)-cognitin (B3C), a multifunctional dimer, against secondary damage in the VPN of ipsilateral thalamus were investigated in a distal middle cerebral artery occlusion (dMCAO) stroke model in adult rats. It was found that B3C (0.5 and 1 mg/kg, ip) effectively improved neurological function of rats at day 7 and day 14 after dMCAO. Additionally, the treatment with B3C alleviated neuronal loss and gliosis in ipsilateral VPN after dMCAO, as evidenced by the higher immunoreactivity of neuron-specific nuclear-binding protein (NeuN) as well as lower immunostaining intensity of glial fibrillary acidic protein (GFAP) and cluster of differentiation 68 (CD68). Most encouragingly, immunohistochemistry and western blotting further revealed that B3C treatment greatly reduced Aß deposits and cathepsin B expression in the VPN of ipsilateral thalamus at day 7 and day 14 after dMCAO. In parallel, we demonstrated herein that the neuroprotective effects of B3C in dMCAO model were similar to L-3-trans-(Propyl-carbamoyloxirane-2-carbonyl)- L-isoleucyl-l-proline methyl ester (CA-074Me), a specific inhibitor of cathepsin B, suggesting that B3C attenuated secondary damage and Aß deposits in the VPN of ipsilateral thalamus after dMCAO possibly through the reduction of cathepsin B. These findings taken together provide novel molecular sights into the potential application of B3C for the treatment of secondary degeneration after cortical infarction.

The dual-functional memantine nitrate MN-08 alleviates cerebral vasospasm and brain injury in experimental subarachnoid haemorrhage models.

BACKGROUND AND PURPOSE: Cerebral vasospasm and neuronal apoptosis after subarachnoid haemorrhage (SAH) is the major cause of morbidity and mortality in SAH patients. So far, single-target agents have not prevented its occurrence. Memantine, a non-competitive NMDA re3ceptor antagonist, is known to alleviate brain injury and vasospasm in experimental models of SAH. Impairment of NO availability also contributes to vasospasm. Recently, we designed and synthesized a memantine nitrate MN-08, which has potent dual functions: neuroprotection and vasodilation. Here, we have tested the therapeutic effects of MN-08 in animal models of SAH. EXPERIMENTAL APPROACH: Binding to NMDA receptors (expressed in HEK293 cells), NO release and vasodilator effects of MN-08 were assessed in vitro. Therapeutic effects of MN-08 were investigated in vivo, using rat and rabbit SAH models. KEY RESULTS: MN-08 bound to the NMDA receptor, slowly releasing NO in vitro and in vivo. Consequently, MN-08 relaxed the pre-contracted middle cerebral artery ex vivo and increased blood flow velocity in small vessels of the mouse cerebral cortex. It did not, however, lower systemic blood pressure. In an endovascular perforation rat model of SAH, MN-08 improved the neurological scores and ameliorated cerebral vasospasm. Moreover, MN-08 also alleviated cerebral vasospasm in a cisterna magna single-injection model in rabbits. MN-08 attenuated neural cell apoptosis in both rat and rabbit models of SAH. Importantly, the therapeutic benefit of MN-08 was greater than that of memantine. CONCLUSION AND IMPLICATIONS: MN-08 has neuroprotective potential and can ameliorate vasospasm in experimental SAH models.

Shift of microbial diversity and function in high-efficiency performance biotrickling filter for gaseous xylene treatment.

Xylene is the main component of many volatile industrial pollution sources, and the use of biotechnology to remove volatile organic compounds (VOCs) has become a growing trend. In this study, a biotrickling filter for gaseous xylene treatment was developed using activated sludge as raw material to study the biodegradation process of xylene. Reaction conditions were optimized, and long-term operation was performed. The optimal pH was 7.0, gas-liquid ratio was 15:1 (v/v), and temperature was 25 °C. High-throughput sequencing technique was carried out to analyze microbial communities in the top, middle, and bottom layers of the reactor. Characteristics of microbial diversity were elucidated, and microbial functions were predicted. The result showed that the removal efficiency (RE) was stable at 86%-91%, the maximum elimination capacity (EC) was 303.61 g·m-3·hr-1, residence time was 33.75 sec, and the initial inlet xylene concentration was 3000 mg·m-3, which was the highest known degradation concentration reported. Kinetic analysis of the xylene degradation indicated that it was a very high-efficiency-activity bioprocess. The rmax was 1059.8 g·m-3·hr-1, and Ks value was 4.78 g·m-3 in stationary phase. In addition, microbial community structures in the bottom and top layers were significantly different: Pseudomonas was the dominant genus in the bottom layer, whereas Sphingobium was dominant in the top layer. The results showed that intermediate metabolites of xylene could affect the distribution of community structure. Pseudomonas sp. can adapt to high concentration xylene-contaminated environments. Implications: We combined domesticated active sludge and reinforced microbial agent on biotrickling filter. This system performed continuously under a reduced residence time at 33.75 sec and high elimination capacity at 303.61 g·m-3·hr-1 in the biotrickling reactor for about 260 days. In this case, predomestication combined with reinforcing of microorganisms was very important to obtaining high-efficiency results. Analysis of microbial diversity and functional prediction indicated a gradient distribution along with the concentration of xylene. This implied a rational design of microbial reagent and optimizing the inoculation of different sites of reactor could reduce the preparation period of the technology.

In Situ Growth of CuS/SiO2-Based Multifunctional Nanotherapeutic Agents for Combined Photodynamic/Photothermal Cancer Therapy.

A scalable and low-cost strategy is developed to fabricate a novel CuS/SiO2-based nanotherapeutic agent for dual-model imaging-guided photothermal/photodynamic combined therapy. In this design, mesoporous silica nanoparticles (MSNs) with CuS bundled in the channel are obtained in aqueous solution via in situ growth route for the first time. Furthermore, to achieve a more efficient therapy, photosensitizer (complex Ir-2) and bovine serum albumin are sequentially assembled via layer-by-layer method. The as-prepared complex Ir-2 presents a remarkably high 1O2 generation (ΦΔ = 1.3) under light illumination to offer effective photodynamic cell killing, and MSN/CuS exhibits high photothermal conversion efficiency (η = 31.7%) under illumination by 808 nm light to offer hyperthermia tumor ablation. In vitro and in vivo analyses show that the as-obtained nanotherapeutic agents exhibit excellent performance in tumor therapy even under irradiation with low power because of the high yield of 1O2 combined with the high photothermal conversion efficiency. Additionally, the nanotherapeutic agents are readily visualized in vivo via near-infrared fluorescence and thermal imaging. More importantly, based on the strategy of in situ growth and layer-by-layer assembly developed in this study, the development of other "all-in-one" multifunctional theranostic platform with high efficiency can be predictable.

Potent Protection Against MPP+-Induced Neurotoxicity via Activating Transcription Factor MEF2D by a Novel Derivative of Naturally Occurring Danshensu/Tetramethylpyrazine.

Danshensu (DSS) and tetramethylpyrazine (TMP) are active ingredients of Salvia miltiorrhiza Bge. and Ligusticum chuanxiong Hort that are widely used in oriental medicine. Structural combination of compounds with known biological activity may lead to the formation of a molecule with multiple properties or new function profile. In the current study, the neuroprotective effects of DT-010, a novel analogue in which TMP was coupled to DSS through an ester bond and two allyl groups at the carboxyl group, were evaluated in a cellular model of Parkinson's disease (PD). As evidenced by the increase in cell survival, as well as the decrease in the number of Hoechst-stained apoptotic nuclei and the level of intracellular accumulation of reactive oxygen species, DT-010 at 3-30 µM substantially protected against MPP+-induced neurotoxicity in both PC12 cells and primary cerebellar granule neurons, a protection that was more potent and efficacious than its parent molecules DSS and TMP. Very encouragingly, we found that DT-010, but not DSS or TMP, could enhance myocyte enhancer factor 2D (MEF2D) transcriptional activity using luciferase reporter gene assay. The neuroprotective effects of DT-010 could be blocked by pharmacologic inhibition of PI3K pathways with LY294002, or MEF2D pathway with short hairpin RNA-mediated knockdown of MEF2D. Furthermore, western blot analysis revealed that DT-010 potentiates Akt protein expression against MPP+ to down-regulate MEF2D inhibitor GSK3ß. Taken together, the results suggest that DT-010 prevents MPP+-induced neurotoxicity via enhancing MEF2D through the activation of PI3K/Akt/GSK3ß pathway. DT-010 may be a potential candidate for further preclinical study for preventing and treating PD.

Gartanin Protects Neurons against Glutamate-Induced Cell Death in HT22 Cells: Independence of Nrf-2 but Involvement of HO-1 and AMPK.

Oxidative stress mediates the pathogenesis of neurodegenerative disorders. Gartanin, a natural xanthone of mangosteen, possesses multipharmacological activities. Herein, the neuroprotection capacity of gartanin against glutamate-induced damage in HT22 cells and its possible mechanism(s) were investigated for the first time. Glutamate resulted in cell death in a dose-dependent manner and supplementation of 1-10 µM gartanin prevented the detrimental effects of glutamate on cell survival. Additional investigations on the underlying mechanisms suggested that gartanin could effectively reduce glutamate-induced intracellular ROS generation and mitochondrial depolarization. We further found that gartanin induced HO-1 expression independent of nuclear factor erythroid-derived 2-like 2 (Nrf2). Subsequent studies revealed that the inhibitory effects of gartanin on glutamate-induced apoptosis were partially blocked by small interfering RNA-mediated knockdown of HO-1. Finally, the protein expression of phosphorylation of AMP-activated protein kinase (AMPK) and its downstream signal molecules, Sirtuin activator (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), increased after gartanin treatment. Taken together, these findings suggest gartanin is a potential neuroprotective agent against glutamate-induced oxidative injury partially through increasing Nrf-2-independed HO-1 and AMPK/SIRT1/PGC-1α signaling pathways.

Natural Xanthones from Garcinia mangostana with Multifunctional Activities for the Therapy of Alzheimer's Disease.

Natural xanthones have diversity pharmacological activities. Here, a series of xanthones isolated from the pericarps of Garcinia mangostana Linn, named α-Mangostin, 8-Deoxygartanin, Gartanin, Garciniafuran, Garcinone C, Garcinone D, and γ-Mangostin were investigated. Biological screening performed in vitro and in Escherichia coli cells indicated that most of the xanthones exhibited significant inhibition of self-induced ß-amyloid (Aß) aggregation and also ß-site amyloid precursor protein-cleaving enzyme 1, acted as potential antioxidants and biometal chelators. Among these compounds, α-Mangostin, Gartanin, Garcinone C and γ-Mangostin showed better antioxidant properties to scavenge Diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH) free radical than Trolox, and potent neuroprotective effects against glutamate-induced HT22 cell death partly by up-regulating HO-1 protein level and then scavenging reactive oxygen species. Moreover, Gartanin, Garcinone C and γ-Mangostin could be able to penetrate the blood-brain barrier (BBB) in vitro. These findings suggest that the natural xanthones have multifunctional activities against Alzheimer's disease (AD) and could be promising compounds for the therapy of AD.

Plant Natural Product Formononetin Protects Rat Cardiomyocyte H9c2 Cells against Oxygen Glucose Deprivation and Reoxygenation via Inhibiting ROS Formation and Promoting GSK-3ß Phosphorylation.

The opening of mitochondrial permeability transition pore (mPTP) is a major cause of cell death in ischemia reperfusion injury. Based on our pilot experiments, plant natural product formononetin enhanced the survival of rat cardiomyocyte H9c2 cells during oxygen glucose deprivation (OGD) and reoxygenation. For mechanistic studies, we focused on two major cellular factors, namely, reactive oxygen species (ROS) and glycogen synthase kinase 3ß (GSK-3ß), in the regulation of mPTP opening. We found that formononetin suppressed the formation of ROS and superoxide in a concentration-dependent manner. Formononetin also rescued OGD/reoxygenation-induced loss of mitochondrial membrane integrity. Further studies suggested that formononetin induced Akt activation and GSK-3ß (Ser9) phosphorylation, thereby reducing GSK-3ß activity towards mPTP opening. PI3K and PKC inhibitors abolished the effects of formononetin on mPTP opening and GSK-3ß phosphorylation. Immunoprecipitation experiments further revealed that formononetin increased the binding of phosphor-GSK-3ß to adenine nucleotide translocase (ANT) while it disrupted the complex of ANT with cyclophilin D. Moreover, immunofluorescence revealed that phospho-GSK-3ß (Ser9) was mainly deposited in the space between mitochondria and cell nucleus. Collectively, these results indicated that formononetin protected cardiomyocytes from OGD/reoxygenation injury via inhibiting ROS formation and promoting GSK-3ß phosphorylation.

Miracle Fruit (Synsepalum dulcificum) Exhibits as a Novel Anti-Hyperuricaemia Agent.

Miracle fruit (Synsepalum dulcificum) belongs to the Sapotaceae family. It can change flavors on taste buds, transforming acidic tastes to sweet. We evaluated various miracle fruit extracts, including water, butanol, ethyl acetate (EA), and hexane fractions, to determine its antioxidant effects. These extracts isolated from miracle fruit exerted potential for reduction of uric acid and inhibited xanthine oxidase activity in vitro and in monosodiumurate (MSU)-treated RAW264.7 macrophages. Moreover, we also found that the butanol extracts of miracle fruit attenuated oxonic acid potassium salt-induced hyperuricaemia in ICR mice by lowering serum uric acid levels and activating hepatic xanthine oxidase. These effects were equal to those of allopurinol, suggesting that the butanol extract of miracle fruit could be developed as a novel anti-hyperuricaemia agent or health food.

Dimeric bis (heptyl)-Cognitin Blocks Alzheimer's ß-Amyloid Neurotoxicity Via the Inhibition of Aß Fibrils Formation and Disaggregation of Preformed Fibrils.

AIMS: Fibrillar aggregates of ß-amyloid protein (Aß) are the main constituent of senile plaques and considered to be one of the causative events in the pathogenesis of Alzheimer's disease (AD). Compounds that could inhibit Aß fibrils formation, disaggregate preformed Aß fibrils as well as reduce their associated neurotoxicity might have therapeutic values for treating AD. In this study, the inhibitory effects of bis (heptyl)-cognitin (B7C), a multifunctional dimer derived from tacrine, on aggregation and neurotoxicity of Aß1-40 were evaluated both in vitro and in vivo. METHODS: Thioflavin T fluorescence assay was carried out to evaluate Aß aggregation, MTT and Hoechst-staining assays were performed to investigate Aß-associated neurotoxicity. Fluorescent probe DCFH-DA was used to estimate the accumulation of intracellular reactive oxygen stress (ROS). Morris water maze was applied to determine learning and memory deficits induced by intracerebroventricular infusion of Aß in rats. RESULTS: B7C (0.1-10 µM), but not tacrine, effectively inhibited Aß fibrils formation and disaggregated preformed Aß fibrils following co-incubation of B7C and Aß monomers or preformed fibrils, respectively. In addition, B7C markedly reduced Aß fibrils-associated neurotoxicity in SH-SY5Y cell line, as evidenced by the increase in cell survival, the decrease in Hoechst-stained nuclei and in intracellular ROS. Most encouragingly, B7C (0.1 and 0.2 mg/kg), 10 times more potently than tacrine (1 and 2 mg/kg), inhibited memory impairments after intracerebroventricular infusion of Aß in rats, as evidenced by the decrease in escape latency and the increase in the spatial bias in Morris water maze test along with upregulation of choline acetyltransferase activity and downregulation of acetylcholinesterase activity. CONCLUSION: These findings provide not only novel molecular insight into the potential application of B7C in treating AD, but also an effective approach for screening anti-AD agents.

Examining the neuroprotective effects of protocatechuic acid and chrysin on in vitro and in vivo models of Parkinson disease.

Polypharmacology-based strategies using drug combinations with different mechanisms of action are gaining increasing attention as a novel methodology to discover potentially innovative medicines for neurodegenerative disorders. We used this approach to examine the combined neuroprotective effects of two polyphenols, protocatechuic acid (PCA) and chrysin, identified from the fruits of Alpinia oxyphylla. Our results demonstrated synergistic neuroprotective effects, with chrysin enhancing the protective effects of PCA, resulting in greater cell viability and decreased lactate dehydrogenase release from 6-hydroxydopamine-treated PC12 cells. Their combination also significantly attenuated chemically induced dopaminergic neuron loss in both zebrafish and mice. We examined the molecular mechanisms underlying these collective cytoprotective effects through proteomic analysis of treated PC12 cells, resulting in the identification of 12 regulated proteins. Two were further characterized, leading to the determination that pretreatment with PCA and chrysin resulted in (i) increased nuclear factor-erythroid 2-related factor 2 protein expression and transcriptional activity; (ii) modulation of cellular redox status with the upregulated expression of hallmark antioxidant enzymes, including heme oxygenase-1, superoxide dismutase, and catalase; and (iii) decreased levels of malondialdehyde, a known lipid peroxidation product. Treatment with PCA and chrysin also inhibited activation of nuclear factor-κB and expression of inducible nitric oxide synthase. Our findings suggest that natural products, when used in combination, can be effective potential therapeutic agents for treating diseases such as Parkinson disease. A therapy involving both PCA and chrysin exhibits its enhanced neuroprotective effects through a combination of cellular mechanisms: antioxidant cytoprotection and anti-inflammation.

An analysis of chemical ingredients network of Chinese herbal formulae for the treatment of coronary heart disease.

As a complex system, the complicated interactions between chemical ingredients, as well as the potential rules of interactive associations among chemical ingredients of traditional Chinese herbal formulae are not yet fully understood by modern science. On the other hand, network analysis is emerging as a powerful approach focusing on processing complex interactive data. By employing network approach in selected Chinese herbal formulae for the treatment of coronary heart disease (CHD), this article aims to construct and analyze chemical ingredients network of herbal formulae, and provide candidate herbs, chemical constituents, and ingredient groups for further investigation. As a result, chemical ingredients network composed of 1588 ingredients from 36 herbs used in 8 core formulae for the treatment of CHD was produced based on combination associations in herbal formulae. In this network, 9 communities with relative dense internal connections are significantly associated with 14 kinds of chemical structures with P<0.001. Moreover, chemical structural fingerprints of network communities were detected, while specific centralities of chemical ingredients indicating different levels of importance in the network were also measured. Finally, several distinct herbs, chemical ingredients, and ingredient groups with essential position in the network or high centrality value are recommended for further pharmacology study in the context of new drug development.

Synergistic inhibition on acetylcholinesterase by the combination of berberine and palmatine originally isolated from Chinese medicinal herbs.

Alzheimer's disease is a multi-factorial neurodegenerative disorder devastatingly affecting the aged population worldwide. Previous studies have shown that medicinal herbs used in traditional Chinese medicine might be benefit to Alzheimer's disease patients. Berberine and palmatine, two isoquinoline alkaloids found in several medicinal herbs, were used for memory enhancement in China. In this study, the inhibitory effects of combined berberine and palmatine on acetylcholinesteras were evaluated using recombinant human acetylcholinesterase. Our results showed that the combination of berberine and palmatine inhibited acetylcholinesterase in a mixed competitive pattern. By the median-effect principle, the calculated combination index of the combination was less than 1, suggesting that berberine and plamatine inhibited acetylcholinesterase synergistically. Furthermore, the drug-reducing index of berberine and palmatine were 2.98 and 2.66, respectively. Taken together, the results showed that the combination of the two alkaloids might potentially be developed as a more effective therapeutic strategy for Alzheimer's disease patients.

New Perspectives on How to Discover Drugs from Herbal Medicines: CAM's Outstanding Contribution to Modern Therapeutics.

With tens of thousands of plant species on earth, we are endowed with an enormous wealth of medicinal remedies from Mother Nature. Natural products and their derivatives represent more than 50% of all the drugs in modern therapeutics. Because of the low success rate and huge capital investment need, the research and development of conventional drugs are very costly and difficult. Over the past few decades, researchers have focused on drug discovery from herbal medicines or botanical sources, an important group of complementary and alternative medicine (CAM) therapy. With a long history of herbal usage for the clinical management of a variety of diseases in indigenous cultures, the success rate of developing a new drug from herbal medicinal preparations should, in theory, be higher than that from chemical synthesis. While the endeavor for drug discovery from herbal medicines is "experience driven," the search for a therapeutically useful synthetic drug, like "looking for a needle in a haystack," is a daunting task. In this paper, we first illustrated various approaches of drug discovery from herbal medicines. Typical examples of successful drug discovery from botanical sources were given. In addition, problems in drug discovery from herbal medicines were described and possible solutions were proposed. The prospect of drug discovery from herbal medicines in the postgenomic era was made with the provision of future directions in this area of drug development.

Bis(12)-hupyridone, a novel acetylcholinesterase inhibitor, protects against glutamate-induced neuronal excitotoxicity via activating α7 nicotinic acetylcholine receptor/phosphoinositide 3-kinase/Akt cascade.

Bis(12)-hupyridone (B12H), derived from the Chinese medicinal component huperzine A, was originally designed as a novel acetylcholinesterase (AChE) inhibitor. In this paper, we report that B12H (24-h pretreatment) effectively blocked glutamate-induced neuronal excitotoxicity in cerebellar granule neurons (CGNs). However, the huge discrepancy between the EC50 value and IC50 value of B12H, to protect against neuronal toxicity (0.09 µM) and to block the NMDA receptor (21.8 µM) respectively, suggests that the neuroprotection of B12H might be not primarily due to the blockade of the NMDA receptor. Pretreatment by specific antagonists of alpha7-nicotinic acetylcholine receptor (α7nAChR), but not muscarinic acetylcholine receptor (mAChR) or α4ß2nAChR, decreased the neuroprotection of B12H. The neuroprotection of B12H could also be abolished by the pretreatment of specific PI3-K inhibitors. Furthermore, B12H restored the suppressed activation of the Akt pathway caused by glutamate as evidenced by the decreased expressions of pSer473-Akt and pSer9-GSK3ß. All these results suggest that B12H substantially protected CGNs against glutamate-induced neuronal excitotoxicity via activating α7nAChR/PI3-K/Akt cascade.

New perspectives on chinese herbal medicine (zhong-yao) research and development.

Synthetic chemical drugs, while being efficacious in the clinical management of many diseases, are often associated with undesirable side effects in patients. It is now clear that the need of therapeutic intervention in many clinical conditions cannot be satisfactorily met by synthetic chemical drugs. Since the research and development of new chemical drugs remain time-consuming, capital-intensive and risky, much effort has been put in the search for alternative routes for drug discovery in China. This narrative review illustrates various approaches to the research and drug discovery in Chinese herbal medicine. Although this article focuses on Chinese traditional drugs, it is also conducive to the development of other traditional remedies and innovative drug discovery.

Pharmacological induction of leukotriene B4-12-hydroxydehydrogenase suppresses the oncogenic transformation of human hepatoma HepG2 cells.

Leukotriene B4-12-hydroxydehydrogenase (LTB4DH) is characterized as a chemopreventive and tumor suppressor gene. The aim of this study was to investigate the pharmaco-logical induction of LTB4DH and potential anticancer activity. Using HepG2 cells as a cellular detector, we successfully isolated the active compounds from the herbs Radix Astragali and Radix Paeoniae Rubra through a bioactivity-guided fractionation procedure. Using various analytical techniques including electronic spray ionization-mass spectrometry (ESI-MS) and nuclear magnetic resonance (NMR), gallic acid (GA) was identified as the active compound from Radix Paeoniae Rubra whereas the active compound from Radix Astragali, designated as RA-C, was also purified to the extent that it is now suitable for further identifi-cation. We found that the active compounds from these two different herbs synergistically induced LTB4DH expression in a dose- and time-dependent manner. A key finding was that commercial GA in combination with purified RA-C attenuated the focus formation and anchorage-independent growth, two indexes of in vitro oncogenic transformation, of HepG2 cells via the induction of LTB4DH expression. Moreover, the combination of GA and purified RA-C significantly induced G2/M cell cycle arrest in HepG2 cells. Our results demon-strated for the first time that GA and purified RA-C suppress the in vitro oncogenic transformation of HepG2 cells via the induction of LTB4DH expression. Importantly, pharmaco-logical induction of LTB4DH represents a potential alternative strategy for the therapy of hepatocellular carcinoma.

Protection against 1-methyl-4-phenylpyridinium ion (MPP+)-induced apoptosis by water extract of ginseng (Panax ginseng C.A. Meyer) in SH-SY5Y cells.

ETHNOPHARMACOLOGICAL RELEVANCE: The present study investigates the protective effects of water extract of ginseng (Panax ginseng C.A. Meyer) against 1-methyl-4-phenylpyridinium ion (MPP(+))-induced cytotoxicity in SH-SY5Y human neuroblastoma cells and explores the underlying mechanisms. The approach may be used for screening therapeutic agents for degenerative disorders such as Parkinson's disease. MATERIALS AND METHODS: SH-SY5Y human neuroblastoma cells were used to analyze the protective effects of water extract of ginseng (WEG) against multiple parameters such as MPP(+)-induced viability, oxidative injury, expression of Bax, Bcl-2, cytochrome c and cleaved caspase-3. RESULTS: WEG exerted inhibitory effect on cell death, overproduction of ROS, elevated Bax/Bcl-2 ratio, release of cytochrome c and activation of caspase-3 expression in MPP(+)-treated SH-SY5Y cells. CONCLUSIONS: WEG exhibited significant protective effects against MPP(+)-induced cytotoxicity in SH-SY5Y cells possibly through the suppression of ROS generation and the inhibition of mitochondria-dependent apoptotic pathway.

New perspectives on innovative drug discovery: an overview.

Despite advances in technology, drug discovery is still a lengthy, expensive, difficult, and inefficient process, with a low rate of success. Today, advances in biomedical science have brought about great strides in therapeutic interventions for a wide spectrum of diseases. The advent of biochemical techniques and cutting-edge bio/chemical technologies has made available a plethora of practical approaches to drug screening and design. In 2010, the total sales of the global pharmaceutical market will reach 600 billion US dollars and expand to over 975 billion dollars by 2013. The aim of this review is to summarize available information on contemporary approaches and strategies in the discovery of novel therapeutic agents, especially from the complementary and alternative medicines, including natural products and traditional remedies such as Chinese herbal medicine.