CMAUP: a database of collective molecular activities of useful plants.

The beneficial effects of functionally useful plants (e.g. medicinal and food plants) arise from the multi-target activities of multiple ingredients of these plants. The knowledge of the collective molecular activities of these plants facilitates mechanistic studies and expanded applications. A number of databases provide information about the effects and targets of various plants and ingredients. More comprehensive information is needed for broader classes of plants and for the landscapes of individual plant's multiple targets, collective activities and regulated biological pathways, processes and diseases. We therefore developed a new database, Collective Molecular Activities of Useful Plants (CMAUP), to provide the collective landscapes of multiple targets (ChEMBL target classes) and activity levels (in 2D target-ingredient heatmap), and regulated gene ontologies (GO categories), biological pathways (KEGG categories) and diseases (ICD blocks) for 5645 plants (2567 medicinal, 170 food, 1567 edible, 3 agricultural and 119 garden plants) collected from or traditionally used in 153 countries and regions. These landscapes were derived from 47 645 plant ingredients active against 646 targets in 234 KEGG pathways associated with 2473 gene ontologies and 656 diseases. CMAUP (http://bidd2.nus.edu.sg/CMAUP/) is freely accessible and searchable by keywords, plant usage classes, species families, targets, KEGG pathways, gene ontologies, diseases (ICD code) and geographical locations.

Discovery of novel dual VEGFR2 and Src inhibitors using a multistep virtual screening approach.

AIM: Simultaneous inhibition of VEGFR2 and Src may enhance the efficacy of VEGFR2-targeted cancer therapeutics. Hence, development of dual inhibitors on VEGFR2 and Src can be a useful strategy for such treatments. MATERIALS & METHODS: A multistep virtual screening protocol, comprising ligand-based support vector machines method, drug-likeness rules filter and structure-based molecular docking, was developed and employed to identify dual inhibitors of VEGFR2 and Src from a large commercial chemical library. Kinase inhibitory assays and cell viability assays were then used for experimental validation. RESULTS: A set of compounds belonging to six different molecular scaffolds was identified and sent for biological evaluation. Compound 3c belonging to the 2-amino-3-cyanopyridine scaffold exhibited good antiproliferative effect and dual-target activities against VEGFR2 and Src. CONCLUSION: This study demonstrated the ability of the multistep virtual screening approach to identify novel multitarget agents.

Is sham acupuncture as effective as traditional Chinese acupuncture? It's too early to say / 中国结合医学杂志

Many clinical trials and experimental studies claim that sham acupuncture is as effective as traditional Chinese acupuncture. However, these studies have no standard sham acupuncture control and many other factors can affect the clinical effect. These factors include needle retention time, treatment frequency, and the total number of treatments needed for satisfactory results, and all can change the clinical effect. The majority of existing acupuncture treatment studies do not consider these factors and lack standard dosage criteria. Therefore, it is still too early to conclude that sham acupuncture is as effective as traditional Chinese acupuncture. This article investigates the factors that influence the curative effect of acupuncture as to help set a standard for acupuncture studies in the future.

Inhibition of the PI3K/AKT pathway reduces tumor necrosis factor-alpha production in the cellular response to wear particles in vitro.

Joint replacement is the most effective treatment for end-stage osteoarticular disease. However, macrophage-mediated aseptic loosening of joint prosthesis severely hampers the clinical effects of joint replacement. Until now, the mechanism by which macrophages regulate the secretion of inflammatory cytokines after particle stimulation is not clear. It is well known that the PI3K/AKT pathway participates in multiple cellular processes, including cell growth, survival, and inflammation. However, whether the PI3K/AKT pathway participates in the proinflammatory response of macrophages after particle stimulation and secondary aseptic loosening is still unknown. In this study, ceramic and titanium particles of different sizes were prepared to stimulate macrophages. LY294002, a specific inhibitor of PI3K, was pretreated prior to particle stimulation. The expression of tumor necrosis factor-alpha (TNF-α) and all the subunits of PI3K and AKT were detected by real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot. The result showed that LY294002 could suppress the RNA and protein expression of TNF-α in RAW264.7 cells after stimulation of different particles. The subunits of PI3K (p110ß and p85ß), followed by activation of phosphor-AKT (Ser473), participated in the regulation of activating macrophages by wear particles, ultimately resulting in the secretion of TNF-α.

What does it take to synergistically combine sub-potent natural products into drug-level potent combinations?

There have been renewed interests in natural products as drug discovery sources. In particular, natural product combinations have been extensively studied, clinically tested, and widely used in traditional, folk and alternative medicines. But opinions about their therapeutic efficacies vary from placebo to synergistic effects. The important questions are whether synergistic effects can sufficiently elevate therapeutic potencies to drug levels, and by what mechanisms and at what odds such combinations can be assembled. We studied these questions by analyzing literature-reported cell-based potencies of 190 approved anticancer and antimicrobial drugs, 1378 anticancer and antimicrobial natural products, 99 natural product extracts, 124 synergistic natural product combinations, and 122 molecular interaction profiles of the 19 natural product combinations with collective potency enhanced to drug level or by >10-fold. Most of the evaluated natural products and combinations are sub-potent to drugs. Sub-potent natural products can be assembled into combinations of drug level potency at low probabilities by distinguished multi-target modes modulating primary targets, their regulators and effectors, and intracellular bioavailability of the active natural products.

Drug discovery prospect from untapped species: indications from approved natural product drugs.

Due to extensive bioprospecting efforts of the past and technology factors, there have been questions about drug discovery prospect from untapped species. We analyzed recent trends of approved drugs derived from previously untapped species, which show no sign of untapped drug-productive species being near extinction and suggest high probability of deriving new drugs from new species in existing drug-productive species families and clusters. Case histories of recently approved drugs reveal useful strategies for deriving new drugs from the scaffolds and pharmacophores of the natural product leads of these untapped species. New technologies such as cryptic gene-cluster exploration may generate novel natural products with highly anticipated potential impact on drug discovery.

In vitro comparison of the biological activity of alumina ceramic and titanium particles associated with aseptic loosening.

Prosthetic wear particles are thought to play a central role in the initiation and development of periprosthetic osteolysis, leading to aseptic loosening of prostheses. This study aimed to compare the biological activity of ceramic and titanium particles that are associated with particle-induced, aseptic joint loosening. Different sizes of alumina-ceramic particles and titanium particles were prepared to stimulate murine macrophage cells RAW 264.7, of which the expressions of tumor necrosis factor alpha (TNF-alpha) and receptor activator of nuclear factor-κB ligand (RANKL) were measured by qPCR and ELISA at various time points. In the presence of all particles, the expression of TNF-alpha increased in a time-dependent manner, whereas the expression of RANKL showed no regular expression patterns. Notably, particles of smaller sizes provoked significantly higher levels of TNF-alpha and RANKL than those of larger sizes. Compared to the titanium particles, the ceramic particles provoked a significantly lower production of TNF-alpha. Thus, the bioactivities of titanium and alumina ceramic particles were inversely proportional to the sizes of the particles, and the expression of RANKL was not parallel to that of TNF-alpha. The successful outcome of ceramic-on-ceramic artificial joint prostheses may be attributed to the low biological activity of ceramic particles, as evidenced here.

Clustered patterns of species origins of nature-derived drugs and clues for future bioprospecting.

Many drugs are nature derived. Low drug productivity has renewed interest in natural products as drug-discovery sources. Nature-derived drugs are composed of dozens of molecular scaffolds generated by specific secondary-metabolite gene clusters in selected species. It can be hypothesized that drug-like structures probably are distributed in selective groups of species. We compared the species origins of 939 approved and 369 clinical-trial drugs with those of 119 preclinical drugs and 19,721 bioactive natural products. In contrast to the scattered distribution of bioactive natural products, these drugs are clustered into 144 of the 6,763 known species families in nature, with 80% of the approved drugs and 67% of the clinical-trial drugs concentrated in 17 and 30 drug-prolific families, respectively. Four lines of evidence from historical drug data, 13,548 marine natural products, 767 medicinal plants, and 19,721 bioactive natural products suggest that drugs are derived mostly from preexisting drug-productive families. Drug-productive clusters expand slowly by conventional technologies. The lack of drugs outside drug-productive families is not necessarily the result of under-exploration or late exploration by conventional technologies. New technologies that explore cryptic gene clusters, pathways, interspecies crosstalk, and high-throughput fermentation enable the discovery of novel natural products. The potential impact of these technologies on drug productivity and on the distribution patterns of drug-productive families is yet to be revealed.

Treatment of Diabetic Nephropathy with Acupuncture / 针灸推拿医学（英文版）

Objective: to observe the clinical efficacy of acupuncture on diabetic nephropathy.Methods: altogether 54 cases were randomly allocated into acupuncture group (30 cases) and control group of western medications (24 cases), the latter was treated with routine western medication, while the former was combined acupuncture based on routine western medication,and the treatment course of the two groups were both 30 days. Results: the effect of treatment group was superior to the control group (P＜0.05). Conclusion: acupuncture can improve symptoms of diabetic nephropathy, lower blood glucose, urine albumin, blood urine nitrogen,and creatinine and improve the function of kidney.

Clinical observation on acupuncture for treatment of diabetic nephropathy / 中国针灸

<p><b>OBJECTIVE</b>To observe the clinical therapeutic effect of acupuncture on early metaphase diabetic nephropathy.</p><p><b>METHODS</b>Fifty-four cases of diabetes were randomly divided into an acupuncture group (n=30) and a control group (n=24). The patients in the two groups were all treated by oral administration of Gliguidon or subcutaneous injection of insulin with acupuncture at Ganshu (BL 18), Weiwanxiashu (EX-B 3), Shenshu (BL 23), Guanyuan (CV 4) and other acupoints added in the acupuncture group, for 30 days.</p><p><b>RESULTS</b>The total effective rate was 93.3% in the acupuncture group and 66.7% in the control group. After treatment, blood beta2-microglobulin (beta2-MG), and urine beta2-MG in the acupuncture group decreased significantly with a significant difference as compared with those in the control group; total cholesterol (TC) and triglyceride (TG) significantly decreased and high density lipoprotein (HDL) significantly increased in the acupuncture group with significant differences compared with the control group.</p><p><b>CONCLUSION</b>Acupuncture can improve lipid metabolism and protect the renal function of the patient with early metaphase diabetes.</p>