Mining of high throughput screening database reveals AP-1 and autophagy pathways as potential targets for COVID-19 therapeutics.

The recent global pandemic of the Coronavirus disease 2019 (COVID-19) caused by the new coronavirus SARS-CoV-2 presents an urgent need for the development of new therapeutic candidates. Many efforts have been devoted to screening existing drug libraries with the hope to repurpose approved drugs as potential treatments for COVID-19. However, the antiviral mechanisms of action of the drugs found active in these phenotypic screens remain largely unknown. In an effort to deconvolute the viral targets in pursuit of more effective anti-COVID-19 drug development, we mined our in-house database of approved drug screens against 994 assays and compared their activity profiles with the drug activity profile in a cytopathic effect (CPE) assay of SARS-CoV-2. We found that the autophagy and AP-1 signaling pathway activity profiles are significantly correlated with the anti-SARS-CoV-2 activity profile. In addition, a class of neurology/psychiatry drugs was found to be significantly enriched with anti-SARS-CoV-2 activity. Taken together, these results provide new insights into SARS-CoV-2 infection and potential targets for COVID-19 therapeutics, which can be further validated by in vivo animal studies and human clinical trials.

Biological activity-based modeling identifies antiviral leads against SARS-CoV-2.

Computational approaches for drug discovery, such as quantitative structure-activity relationship, rely on structural similarities of small molecules to infer biological activity but are often limited to identifying new drug candidates in the chemical spaces close to known ligands. Here we report a biological activity-based modeling (BABM) approach, in which compound activity profiles established across multiple assays are used as signatures to predict compound activity in other assays or against a new target. This approach was validated by identifying candidate antivirals for Zika and Ebola viruses based on high-throughput screening data. BABM models were then applied to predict 311 compounds with potential activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of the predicted compounds, 32% had antiviral activity in a cell culture live virus assay, the most potent compounds showing a half-maximal inhibitory concentration in the nanomolar range. Most of the confirmed anti-SARS-CoV-2 compounds were found to be viral entry inhibitors and/or autophagy modulators. The confirmed compounds have the potential to be further developed into anti-SARS-CoV-2 therapies.

Two new geranylphenylacetate glycosides from the barks of Cinnamomum cassia.

Two new glycosides, cinnacassides F (1) and G (2), with a rare geranylphenylacetate carbon skeleton, were isolated from the barks of Cinnamomum cassia, along with three known analogues, cinnacassides A (3), B (4) and C (5). The structures of the new compounds were elucidated on the basis of extensive NMR spectroscopic analyses and chemical method. Compounds 1-5 were investigated for their immunomodulatory activities, and compounds 1, 3 and 4 showed differential immunosuppressive activities against murine lymphocytes.

A Computational Method for Optimizing Experimental Environments for Phellinus igniarius via Genetic Algorithm and BP Neural Network.

Flavones, the secondary metabolites of Phellinus igniarius fungus, have the properties of antioxidation and anticancer. Because of the great medicinal value, there are large demands on flavones for medical use and research. Flavones abstracted from natural Phellinus can not meet the medical and research need, since Phellinus in the natural environment is very rare and is hard to be cultivated artificially. The production of flavones is mainly related to the fermentation culture of Phellinus, which made the optimization of culture conditions an important problem. Some researches were made to optimize the fermentation culture conditions, such as the method of response surface methodology, which claimed the optimal flavones production was 1532.83 µg/mL. In order to further optimize the fermentation culture conditions for flavones, in this work a hybrid intelligent algorithm with genetic algorithm and BP neural network is proposed. Our method has the intelligent learning ability and can overcome the limitation of large-scale biotic experiments. Through simulations, the optimal culture conditions are obtained and the flavones production is increased to 2200 µg/mL.

Further Advances in Optimizing (2-Phenylcyclopropyl)methylamines as Novel Serotonin 2C Agonists: Effects on Hyperlocomotion, Prepulse Inhibition, and Cognition Models.

A series of novel compounds with two halogen substituents have been designed and synthesized to further optimize the 2-phenylcyclopropylmethylamine scaffold in the quest for drug-like 5-HT2C agonists. Compound (+)-22a was identified as a potent 5-HT2C receptor agonist, with good selectivity against the 5-HT2B and the 5-HT2A receptors. ADMET assays showed that compound (+)-22a possessed desirable properties in terms of its microsomal stability, and CYP and hERG inhibition, along with an excellent brain penetration profile. Evaluation of (+)-22a in animal models of schizophrenia-related behaviors revealed that it had a desirable activity profile, as it reduced d-amphetamine-stimulated hyperlocomotion in the open field test, it restored d-amphetamine-disrupted prepulse inhibition, it induced cognitive improvements in the novel object recognition memory test in NR1-KD animals, and it produced very little catalepsy relative to haloperidol. These data support the further development of (+)-22a as a drug candidate for the treatment of schizophrenia.

Silencing synapses with DREADDs.

In this issue of Neuron, Stachniak et al. (2014) determine that the chemogenetic silencer hM4Di-DREADD suppresses presynaptic glutamate release, and by generating an axon-targeted hM4Di variant they demonstrate that it can be used to locally silence synaptic transmission in neural circuits.

Bacterial Quorum Sensing Inhibition Activity of the Traditional Chinese Herbs, Ficus carica L. and Perilla frutescens.

BACKGROUND: Quorum sensing (QS), as the basis of bacterial cell-to-cell communication, is a promising approach to reduce the incidence of multidrug resistance. The objective of this study was to search for novel quorum sensing inhibitors from plants and control detrimental infections. METHODS: The crude extracts of Ficus carica and Perilla frutescens were examined for their anti-QS properties. Powdered plant samples were treated sequentially with organic solvents of increasing polarity. The extracts of each solvent were concentrated in vacuo to give crude extracts and tested against Chromobacterium violaceum CV026 and Pseudomonas aeruginosa PA01 especially. Anti-QS activity was measured by quantifying violacein production and swarming motility. RESULTS: All extracts of these two plants display anti-QS ability. Interestingly, the extract of F. carica with dichloromethane and of P. frutescens with MeOH exhibited the most pronounced inhibition of QS activity. CONCLUSIONS: These two plants can offer bioactive natural products with potential for attenuating pathogens.

Clinical evaluation study on long-term effect of acupuncture with pattern/syndrome differentiation on functional dyspepsia / 中国针灸

<p><b>OBJECTIVE</b>To compare the efficacy difference in the treatment of functional dyspepsia between acupuncture at the acupoints selected by pattern/syndrome differentiation and domperidone.</p><p><b>METHODS</b>Seventy cases were randomized into an acupuncture group (35 cases) and a western medication group (35 cases). In the acupuncture group, Zusanli (ST 36) and Neiguan (PC 6) were selected. Taichong (LR 3) and Neiting (ST 44) were added for excess syndrome while Gongsun (SP 4) and Yinlingquan (SP 9) were added for deficiency syndrome. A pair of electrodes was attached to one acupoint and an assistant point (2 mm next to the acupoint centripetally) and stimulated with disperse-dense wave at 2 Hz/100 Hz, once a day. In the western medication group, domperidone was prescribed for oral administration, 10 mg each time, three times a day. In the two groups, the treatment of 5 days made one session and 4 sessions were required totally. Nepean dyspepsia index (NDI) was compared after treatment, 1, 2, 3, 4 and 5 months after treatment between the two groups respectively.</p><p><b>RESULTS</b>The score of symptom and score of life quality in NDI after treatment and at each follow-up time point were improved obviously in the acupuncture group as compared with those before treatment (all P < 0.01). In the western mediation group, the score of symptom and the score of life quality in NDI after treatment and in follow-up of 1, 2 and 3 months were improved obviously as compared with those before treatment (all P < 0.01), but the differences were not significant in follow-up of 4 and 5 months (both P > 0.05). Compared with the western medication group, the symptom score of NDI was reduced obviously after treatment and in each time point of follow-up in the acupuncture group (P < 0.05, P < 0.01), and the score of life quality was increased obviously (P < 0.05, P < 0.01).</p><p><b>CONCLUSION</b>Acupuncture at the acupoints selected by pattern/syndrome differentiation and domperidone are effective in the treatment of functional dyspepsia. Domperidone is unsatisfactory in the long-term effect, but acupuncture achieves the positive short-term and long-term effects on functional dyspepsia.</p>

Observation on analgesia effect of electroacupuncture during gynecologic outpatient operation / 中国针灸

<p><b>OBJECTIVE</b>To verify the feasibility of electroacupuncture analgesia applied to gynecologic outpatient operation.</p><p><b>METHODS</b>Two hundred patients were randomly divided into an electroacupuncture analgesia group and an intravenous anesthesia group, 100 cases in each group. Operation types included artificial abortion, diagnostic curettage and remove of intrauterine divice. The electroacupuncture analgesia group was treated with electroacupuncture at bilateral Hegu (LI 4) and Neiguan (PC 6), and the routine gynecologic outpatient operation was performed under patients' waking state. The intravenous anesthesia group was treated with routine gynecologic outpatient operation after intravenous injection of fentanyl and propofol.</p><p><b>RESULTS</b>The excellent rate and the effective rate of analgesia were 88.0% (88/100) and 100.0% (100/100) in the electroacupuncture analgesia group, and 94.0% (94/100) and 100.0% (100/100) in the intravenous anesthesia group, with no statistically significant differences between the two groups (all P > 0.05). There was no adverse reaction in the electroacupuncture anesthesia group, but 11 cases of adverse reactions in the intravenous anesthesia group.</p><p><b>CONCLUSION</b>Electroacupuncture analgesia can effectively alleviate the pain during gynecologic outpatient operation and it is simple and safe without adverse reactions.</p>

Inhibition of quorum sensing in the opportunistic pathogenic bacterium Chromobacterium violaceum by an extract from fruiting bodies of Lingzhi or Reishi medicinal mushroom, Ganoderma lucidum (W.Curt.:Fr.) P. Karst. (higher Basidiomycetes).

Extracts of Lingzhi or Reishi medicinal mushroom, Ganoderma lucidum, inhibited quorum sensing in Chromobacterium violaceum CV026. G. lucidum fruiting bodies were milled and extracted with ethyl acetate. The crude extract was dissolved in an appropriate concentration of methanol, sterilized by filtration through a 0.22-µm membrane filter, and added to Ch. Violaceum CV026 cultures, which were used as an indicator to monitor quorum sensing inhibition. Inhibitory activity was measured by quantifying violacein production using a microplate reader. Methanol-soluble compounds extracted from G. lucidum significantly inhibited quorum sensing-controlled behavior in Ch. Violaceum in a concentration-dependent manner. The results suggest that compounds in G. lucidum might be useful to control and handle detrimental infections caused by human, animal, and plant pathogens. Further studies are in progress in our lab to isolate the specific compounds from G. lucidum extract, evaluate them as quorum sensing inhibitors, and analyze their mechanism of action.

Inhibiting effect of bioactive metabolites produced by mushroom cultivation on bacterial quorum sensing-regulated behaviors.

AIMS: This study aimed to search for novel quorum sensing (QS) inhibitors from mushroom and to analyze their inhibitory activity, with a view to their possible use in controlling detrimental infections. METHODS: The bioactive metabolites produced by mushroom cultivation were tested for their abilities to inhibit QS-regulated behavior. All mushroom strains were cultivated in potato-dextrose medium by large-scale submerged fermentation. The culture supernatant was condensed into 0.2 vol by freeze-drying. The condensed supernatant was sterilized by filtration through a 0.22-µm membrane filter and added to Chromobacterium violaceum CV026 cultures, which were used to monitor QS inhibition. Inhibitory activity was measured by quantifying violacein production using a microplate reader. RESULTS: The results have revealed that, of 102 mushroom strains, the bioactive metabolites produced by 14 basidiomycetes were found to inhibit violacein production, a QS-regulated behavior in C. violaceum. CONCLUSIONS: Higher fungi can produce QS-inhibitory compounds.

[Study on the chemical constituents of Phryma leptostachya].

OBJECTIVE: To study the chemical constituents of Phryma leptostachya. METHODS: The chemical constituents were isolated and purified by silica gel column, recrystallization and Pre-RP-HPLC and their structwes were elucidated by spectroscopic methods. RESULTS: Five compounds were obtained and identified as ursolic acid (1), quercetin (2), isovanillic acid (3), p-hydroxybenzoic acid (4), adenine arabinoside (5). CONCLUSION: Compounds 2 - 5 are isolated from this genus for the first time.

Application of UV similarity in quality control of Chinese medical injection / 中国中药杂志

<p><b>OBJECTIVE</b>To propose an algorithm of the similarity between UV-spectra for controlling the quality of Chinese medical injection.</p><p><b>METHOD</b>The similarity is calculated base on the data of two UV-spectrum curves, thus the sample quality is evaluated according to the average value of the similarity of the UV-spectra between sample with each of standard samples; the proposed algorithm of the similarity is compared with cosine of vectorial angle and relative coefficient; the proposed method for quality evaluation of traditional Chinese injection is discussed with the method according to the chromatographic fingerprint similarity.</p><p><b>RESULT</b>The calculated similarity with the proposed method can be sensitive to show the difference between UV-spectra. This proposed method for quality evaluation was applied for assessing quality of 14 batches of Xiangdan injection and the results well coincident with sample quality.</p><p><b>CONCLUSION</b>The proposed method can be used to evaluate the quality of the Chinese medical injection according to the similarity of two UV-spectrum curves.</p>

Correlation studies of contents of copper and organic components in Astragalus roots / 中国中药杂志

<p><b>OBJECTIVE</b>To study the relationship between copper and organic components, total flavonoids of Astragalus (TFA), total saponins of Astragalus (TSA) and total polysaccharide of Astragalus (TPA).</p><p><b>METHOD</b>TFA, TSA and TPA were extracted from Astragalus roots using different organic solvents, and determined by colorimetry. The concentration of copper in extracts was determined by graphite furnace atomic absorption spectrometry (GFAAS).</p><p><b>RESULT</b>Copper was found in TFA, TPA and TSA, and its concentration in TFA and TPA was higher; the content of copper was correlated significantly to that of TFA and TPA (r1(2) = 0.754 8, F1 = 57.202, P < 0.01 and r2(2) = 0.499, F2 = 21.906, P < 0.01), while not to that of TSA ( r3(2) = 0.0026, F3 = 0.041, P > 0.1).</p><p><b>CONCLUSION</b>Correlation analysis could reveal the relationship of copper with organic components in Astragalus roots; contents and structure characteristics of organic components might be important factors influencing the distribution of copper in Astragalus roots.</p>