Repurposing carrimycin as an antiviral agent against human coronaviruses, including the currently pandemic SARS-CoV-2

COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development. No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections. We report herein that a macrolide antibiotic, carrimycin, potently inhibited the cytopathic effects (CPE) and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229E, OC43, and SARS-CoV-2. Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection. In support of this notion, metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA. Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.

Study on simulation method of knee hydrops based on biologcal impedance / 生物医学工程学杂志

The injury of the knee joint is usually accompanied with the generation of hydrops. The volume of hydrops can be used as a reference to evaluate the extent of knee joint injuries. Based on the principle of bioimpedance detection, in this paper, a new method is proposed to detect knee joint hydrops. Firstly, a three-dimensional model of the knee joint was established according to the physiological and anatomical structure of the knee joint. Secondly, a knee impedance detection system was constructed based on the four-electrode theory, and the relationship between the knee impedance change and the volume of hydrops was calculated by linear regression. Finally, the model of rat knee joint hydrops was established, and the knee joint impedance was measured under different hydrops content to deduce the relationship between the fluid content and the knee joint impedance. The fluid volume in the joint was calculated by measuring the knee joint impedance, and the error rate was less than 10%. The experimental results show that the method proposed in this paper can establish the relationship between the impedance of the knee and the volume of fluid and realize the detection of the fluid volume.

Sulfur-enriched alkaloids from the root of

Five new sulfur-enriched alkaloids isatithioetherins A-E (-), and two pairs of scalemic enantiomers (+)- and (-)-isatithiopyrin B ( and ) and isoepigoitrin and isogoitrin and ), along with the known scalemic enantiomers epigoitrin and goitrin ( and ), were isolated and characterized from an aqueous extract of the roots. Their structures were determined by extensive spectroscopic data analysis, including 2D NMR and theoretical calculations of electronic circular dichroism (ECD) spectra based on the quantum-mechanical time-dependent density functional theory (TDDFT). Compounds - represent a novel group of sulfur-enriched alkaloids, biogenetically originating from stereoselective assemblies of epigoitrin-derived units. Isolation and structure characterization of and support the postulated biosynthetic pathways for the diastereomers and a rare thio-Diels-Alder reaction. Compounds and showed antiviral activity against the influenza virus A/Hanfang/359/95 (H3N2, IC 0.60 and 1.92 μmol/L) and the herpes simplex virus 1 (HSV-1, IC 3.70 and 2.87 μmol/L), and also inhibited Coxsackie virus B3 (IC 0.71 μmol/L).

Aromatic compounds from an aqueous extract of "ban lan gen" and their antiviral activities

A pair of new diphenyl glycerol ether enantiomers (-)-and (+)-and two new methyl benzamidobenzoatesand, named (-)-()- and (+)-()-isatindigotrioic acid [(-)-and (+)-] and isatindigoticamides A () and B (), respectively, were isolated from an aqueous decoction of the roots of(ban lan gen). Their structures were elucidated by spectroscopic data analysis including 2D NMR experiments. The absolute configurations of (-)-and (+)-were assigned based on the CD exciton chirality method. Compoundsandexhibited antiviral activities against HSV-1 with ICvalues of 4.87 and 25.87 μmol/L, respectively. Compoundwas also found active against Coxsackie virus B3 and LPS-induced NO production.

Indole alkaloid sulfonic acids from an aqueous extract ofroots and their antiviral activity

Six new indole alkaloid sulfonic acids (-), together with two analogues (and) that were previously reported as synthetic products, were isolated from an aqueous extract of theroot. Their structures including the absolute configurations were determined by spectroscopic data analysis, combined with enzyme hydrolysis and comparison of experimental circular dichroism and calculated electronic circular dichroism spectra. In the preliminary assay, compoundsandshowed antiviral activity against Coxsackie virus B3 and influenza virus A/Hanfang/359/95 (H3N2), respectively.

Chinese herbal medicine compound Yi-Zhi-Hao pellet inhibits replication of influenza virus infection through activation of heme oxygenase-1

As a leading cause of respiratory disease, influenza A virus (IAV) presents a pandemic threat in annual seasonal outbreaks. Given the limitation of existing anti-influenza therapies, there remains to be a requirement for new drugs. Compound Yi-Zhi-Hao pellet (CYZH) is a famous traditional Chinese medicine (TCM) used in the clinic, whose formula has been recorded into treat common cold. In this study, we found that CYZH exhibited a broad-spectrum anti-influenza activity and inhibited the expression of viral RNA and proteins. Mechanistically, CYZH had no inhibitory activities against viral protein hemagglutinin and IAV RNA-dependent RNA polymerase. Instead, it induced activation of erythroid 2-related factor 2 (Nrf2) and nuclear factor kappa B (NF-B), which subsequently upregulated heme oxygenase-1 (HO-1) expression. Also, CYZH protected cells from oxidative damage induced by reactive oxygen series. In conclusions, CYZH inhibits IAV replication, at least partly by activating expression of the Nrf2/HO-1 pathway.

Synthesis and antiviral activity of a series of novel N-phenylbenzamide and N-phenylacetophenone compounds as anti-HCV and anti-EV71 agents

A series of novel N-phenylbenzamide and N-phenylacetophenone compounds were synthesized and evaluated for their antiviral activity against HCV and EV71 (strain SZ-98). The biological results showed that three compounds (23, 25 and 41) exhibited considerable anti-HCV activity (IC50=0.57-7.12 μmol/L) and several compounds (23, 28, 29, 30, 31 and 42) displayed potent activity against EV71 with the IC50 values lower than 5.00 μmol/L. The potency of compound 23 (IC50=0.57 μmol/L) was superior to that of reported compounds IMB-1f (IC50=1.90 μmol/L) and IMB-1g (IC50=1.00 μmol/L) as anti-HCV agents, and compound 29 possessed the highest anti-EV71 activity, comparable to the comparator drug pirodavir. The efficacy in vivo and antiviral mechanism of these compounds warrant further investigations.

Glucosylated caffeoylquinic acid derivatives from the flower buds of Lonicera japonica

Three new glucosylated caffeoylquinic acid isomers (1-3), along with six known compounds, have been isolated from an aqueous extract of the flower buds of Lonicera japonica. Structures of the new compounds were determined by spectroscopic and chemical methods as (-)-4-O-(4-O-β-d-glucopyranosylcaffeoyl)quinic acid (1), (-)-3-O-(4-O-β-d-glucopyranosylcaffeoyl)quinic acid (2), and (-)-5-O-(4-O-β-d-glucopyranosylcaffeoyl)quinic acid (3), respectively. In the preliminary in vitro assays, two known compounds methyl caffeate and 2'-O-methyladenosine showed inhibitory activity against Coxsackie virus B3 with IC50 values of 3.70 μmol/L and 6.41 μmol/L and SI values of 7.8 and 12.1, respectively.

Antitumor activity of a novel survivin siRNA

Breast cancer resistance to therapy can result from expression of antiapoptotic genes. Survivin is an antiapoptotic gene that is over expressed in most human tumors. RNA interference using short interfering RNA [siRNA] can be used to specifically inhibit survivin expression. A novel siRNA targeting survivin was used to process MCF-7 cells. Cellular survivin mRNA and protein levels were determined by real-time qRT-PCR and Western blot, respectively. Cellular morphology and cell cycle were determined by fluorescence microscopy and flow cytometry. Cell proliferation was measured by MTT assay. Our data showed that the novel survivin-targeted siRNA could efficiently knockdown the expression of survivin, inhibit cell proliferation and cell cycle, especially at the G2/M checkpoint. These data suggest that the siRNA has potential for therapeutic applications

The recent advances in the host targets of anti-influenza drugs / 药学学报

The challenge of the emergence of drug-resistant influenza strains, which is caused by wide spread utilization of direct-acting antivirals (DAAs), accelerates the research and exploration towards host targeted agents. In contrast to DAAs targeting viral replication components, host targeted agents, which regulate host factors and pathways linked to viral replication, can interfere the replication of influenza. Additionally, the innate immune system is activated by influenza during the early stage of infection, so manipulating the innate immune response may prevent the viral infection. However, the excessive inflammatory response induced at the late phase of influenza infection would lead to severe tissue injures. Thus, it is very important to explore drugs with anti-inflammatory actions to suppress these immune imbalances and tissue injures. Here we overview the current progresses about host targets related to anti-influenza drugs.

Recombinant human interferon alpha 2b broad-spectrum anti-respiratory viruses pharmacodynamics study in vitro / 药学学报

This study is to investigate the effect of recombinant human interferon alpha 2b against broad-spectrum respiratory viruses in vitro. At the cellular level, the effect of the recombinant human interferon alpha 2b on influenza A virus was detected using real-time fluorescence quantitative RT-PCR. The effects of the recombinant human interferon alpha 2b on influenza B virus, parainfluenza virus, respiratory syncytial virus (RSV) and coronavirus were detected using cytopathic effect (CPE) method. In this study, the therapeutic index of recombinant human interferon alpha 2b anti-HPIV was 1476.63, the therapeutic index of recombinant human interferon alpha 2b anti-RSV was 141.37, the therapeutic index of recombinant human interferon alpha 2b anti-coronavirus was more than 2820.76, and the antiviral effect of recombinant human interferon alpha 2b was better than ribavirin (RBV). Recombinant human interferon alpha 2b has a stronger inhibitory effect on different influenza A virus RNA than drug control. The therapeutic index of recombinant human interferon alpha 2b anti-influenza B virus was 2.74, with modest effect. Recombinant human interferon alpha 2b in vitro has broad spectrum antiviral activities, low toxicity and high therapeutic index. Recombinant human interferon alpha 2b is expected to become the efficient medicine in clinical against respiratory viruses, as well as provide better services for prevention and treatment of respiratory viruses' infections.

The antiviral effect of jiadifenoic acids C against coxsackievirus B3

Coxsackievirus B type 3 (CVB3) is one of the major causative pathogens associated with viral meningitis and myocarditis, which are widespread in the human population and especially prevalent in neonates and children. These infections can result in dilated cardiomyopathy (DCM) and other severe clinical complications. There are no vaccines or drugs approved for the prevention or therapy of CVB3-induced diseases. During screening for anti-CVB3 candidates in our previous studies, we found that jiadifenoic acids C exhibited strong antiviral activities against CVB3 as well as other strains of Coxsackie B viruses (CVBs). The present studies were carried out to evaluate the antiviral activities of jiadifenoic acids C. Results showed that jiadifenoic acids C could reduce CVB3 RNA and proteins synthesis in a dose-dependent manner. Jiadifenoic acids C also had a similar antiviral effect on the pleconaril-resistant variant of CVB3. We further examined the impact of jiadifenoic acids C on the synthesis of viral structural and non-structural proteins, finding that jiadifenoic acids C could reduce VP1 and 3D protein production. A time-course study with Vero cells showed that jiadifenoic acids C displayed significant antiviral activities at 0-6 h after CVB3 inoculation, indicating that jiadifenoic acids C functioned at an early step of CVB3 replication. However, jiadifenoic acids C had no prophylactic effect against CVB3. Taken together, we show that jiadifenoic acids C exhibit strong antiviral activities against all strains of CVB, including the pleconaril-resistant variant. Our study could provide a significant lead for anti-CVB3 drug development.

Synthesis and antiviral activity of some novel indole-2-carboxylate derivatives

A series of novel indole-2-carboxylate derivatives were synthesized and assayed to determine their in vitro broad-spectrum antiviral activities. The biological results showed that some of the synthesized compounds exhibited potent broad-spectrum antiviral activity. Notably, compound 8f showed the highest SI value (17.1) to Cox B3 virus. Compound 14f showed both potent inhibitory activity against influenza A (IC50=7.53 μmol/L) and the highest SI value (12.1). SAR results showed that the alkyloxy at the 4-position of indole ring was not crucial to the antiviral activities. Incorporation of an acetyl substituent at the amino group disfavored antiviral activity towards RNA viruses.

Analysis of activated brain areas in uncertain rewarding processing of decision making on healthy volunteers / 中华行为医学与脑科学杂志

Objective To research the activated brain areas of decision making under uncertainty reward processing on healthy volunteers.Method The E-Prime programs were presented 3 kinds of tasks of the decision under uncertain reward processing.15 right-handed healthy volunteers made a response after receiving the task.At the same time,the GE 3.0T magnetic resonance scanner scanned the brains areas of subjects.Individual analysis and group analysis was done with SPM8 software,then the brain activating regions and the peak intensity were gotten.Results Orbitofrontal cortex was activated in certainty,peak intensity 2.4328 ± 0.1949 (P ＜ 0.05).Prefrontal cortex,occipital lobe,parietal lobe,posterior lobe of cerebellum,limbic lobe and midbrain were activated under the risk reward processing,peak intensity 2.4228 ± 1.3762 (P ＜ 0.05).When under ambiguity reward processing,prefrontal cortex,temporal lobe,occipital lobe,left inferior frontal gyrus and posterior lobe of cerebellum were activated,peak intensity 2.4056 ± 0.4222 (P ＜ 0.05).Compared with the task under certainty,posterior lobe of cerebellum,gyri subtemporalis and gyri fusiformis,inferior parietal lobule,anterior central convolution,orbitofrontal cortex,ventrolateral prefrontal cortex,both frontopolar and supramarginal gyrus were activated in task under risk (P ＜0.05) ;and both frontopolar were activated in task under ambiguity (P ＜ 0.05).Compared with the task under risk,dorsolateral prefrontal cortex and posterior lobe of cerebellum were activated in task under ambiguity (P ＜ 0.05).Conclusion There are differences in different types of reward processing of decision making.

Establishment of EV71 animal models with 2-week-old BALB/c mice / 药学学报

Animal model is very important for anti-EV71 (enterovirus 71) drug and vaccine development. 1-day-old suckling EV71 mouse model is the main in vivo model used in China. 1-day-old suckling EV71 mouse is too small to perform antiviral experiment. And the route of administration and dosage capacity are also restricted. A strong virulence EV71 virus strain was selected after screening from five EV71 strains with 1-day-old suckling mice. A mouse-adapted EV71 strain with increased virulence in 12-day-old suckling mice, EV71-M5, was generated after five serial passages of the parental EV71 strain in mice. Virus titers of EV71 infected mice heart, liver, spleen, lung, kidney, small intestine, brain and muscle tissue were determined by cytopathic effect (CPE) assay. The virus used in this model is the first isolated EV71 strain in China. And 2-week-old suckling mice were used in this model. This is a supplement for the EV71 animal model in China. Establishment of this EV71 model will provide an attractive platform for anti-EV71 vaccine and drug development.

A comparative study of escitalopram angumentation with psychoanalysis in the treatment of refractory depression / 中华行为医学与脑科学杂志

Objective To investigate the efficacy of escitalopram combined with psychoanalysis in the treatment of refractory depression. Methods A total of 63 patients were randomly divided into escitalopram group ( n = 32) and escitalopram combined with psychoanalysis group( n = 31 ). All patients were evaluated with Hamilton depression Rating Scale(HAMD). Results After treatment,the scores of HAMD in two groups were both significantly lower than those before treatment. In the 8th ( ( HAMD ( 17.35 ± 2.98 ) ), 12th ( ( HAMD (9. 26 ±3.46) )weekend of treatment, the scores of HAMD in study group were significanlly lower than those in control group(8 th:21.97 ± 3.26; 12 th: 15.28 ± 3. 18 ). There were no significant differences in side effects between study group and control group. Conclusion Escitalopram angumented with psychoanalysis takes effects better than escitalopram single and doesn't increase side effects in the treatment of refractory depression.

Overexpression of synuclein-gamma confers resistance to antimicrotubule drugs against human hepatoma cells / 药学学报

Liver cancer is one of the most common neoplastic diseases with high mortality in China. Currently, antimicrotubule drugs such as paclitaxel (PTX) and vincristine (VCR), are used as the common agents in the clinical chemotherapy for liver cancer. However, the responses of patients to these drugs vary markedly. Successful identification of intracellular factors influencing liver cancer's sensitivity to antimicrotubule drugs would be of great clinical importance. In this study, by engineering human hepatoma cell HepG2 to overexpress synuclein-gamma (SNCG), we investigated if SNCG is a molecular factor associated with the sensitivity to antimicrotubule drug treatment. Real-time RT-PCR and Western blotting assays showed SNCG was successfully overexpressed in HepG2/ SNCG cells compared with HepG2/Neo cells. The overexpressed SNCG altered the proliferation activity in HepG2 cells, which was 66% higher than that of HepG2/Neo cells through MTT method. The overexpressed SNCG also reduced sensitivity of HepG2 cells to antimicrotubule drugs: after PTX or VCR treatment, the proportion of HepG2/SNCG cells in G2/M arrest was significantly lower than that in HepG2/Neo cells. Correspondingly, HepG2/SNCG cells showed significantly lower mitotic index than HepG2/Neo cells. Meanwhile, HepG2/SNCG cells showed higher resistance to PTX and VCR than HepG2/Neo cells, with resistance index 21 and 15 respectively. Our studies suggested that the overexpression of SNCG could confer resistance to antimicrotubule drugs in hepatoma cells; and it indicated that SNCG may be as a potential response marker for antimicrotubule drugs in liver cancer chemotherapy.

In vitro and in vivo anti-influenza virus activity of ribavirin injection / 药学学报

Ribavirin is a broad-spectrum inhibitor against several unrelated DNA or RNA viruses in vitro and in vivo. In this paper the in vitro and in vivo study of anti-influenza virus activity of ribavirin (RBV) injection had been reported. The in vitro antiviral activity of ribavirin injection against influenza virus A and B was studied by CPE. The in vivo protective action of ribavirin injection against influenza A/FM/1/47(H1N1) mouse adapted strain infected mouse was studied with mouse model. The results showed ribavirin injection has strong inhibitory activity against 7 virus strains tested in vitro. Ribavirin injection could significantly increase virus infected mouse survival rate and survival days and improve lung pathogen and lung index.

In vitro anti-influenza virus activity of 10 traditional Chinese medicines / 药学学报

Influenza virus is a virus causing upper respiratory tract infection disease with high morbidity and mortality. China is considered as an area with high rate of influenza morbidity. Prevention and treatment of influenza currently rely on vaccines and antiviral agents in the world. In addition, traditional Chinese medicines also have been used in clinical for influenza therapy. In vitro anti-influenza virus activities of 10 traditional Chinese medicines were studied by cytopathic effect (CPE). Qingre Jiedu oral liquid (factory H) had strong antiviral activity against influenza virus A/Guangdong Luohu/219/2006 (H1N1); Yinhuang oral liquid had strong antiviral activity against influenza virus A/Hanfang/359/95 and A/Yuefang/243/72 (H3N2). Qingkailing oral liquid (factory G) had strong antiviral activity against influenza virus A/Jifang/15/90 (H3N2). Qingre Jiedu oral liquid (factory H) had strong antiviral activity against influenza virus A/Jifang/15/90, A/Yuefang/243/72 (H3N2) and virus B.

Antiviral activities of cycloheximide and its derivatives / 药学学报

Cycloheximide (CHX) inhibits protein synthesis in most eukaryotic cells and it is a well-known tool commonly used in biochemical research. In this paper, the antiviral spectrum of CHX against several DNA and RNA viruses have been evaluated. CHX showed strong inhibitory activities against several RNA viruses such as HIV-1, influenza viruses, coxsackie B virus, enterovirus (EV71) and several DNA viruses such as HSV and HCMV. Especially the strong inhibitory activities of CHX against coxsackie B virus and enterovirus caught our attention, since effective drugs available in clinic are limited. The SAR of CHX derivatives also has been discussed in the paper. The hydroxyl group at C-2' and carbonyl group at C-2" of CHX are essential for its antiviral activity. And modification to these groups results its derivatives' antiviral activities reduced or lost.