ETCM v2.0:An update with comprehensive resource and rich annotations for traditional Chinese medicine

Existing traditional Chinese medicine(TCM)-related databases are still insufficient in data standardization,integrity and precision,and need to be updated urgently.Herein,an Encyclopedia of Traditional Chinese Medicine version 2.0(ETCM v2.0,http://www.tcmip.cn/ETCM2/front/#/)was constructed as the latest curated database hosting 48,442 TCM formulas recorded by ancient Chinese medical books,9872 Chinese patent drugs,2079 Chinese medicinal materials and 38,298 ingredients.To facilitate the mechanistic research and new drug discovery,we improved the target identification method based on a two-dimensional ligand similarity search module,which provides the confirmed and/or potential targets of each ingredient,as well as their binding activities.Importantly,five TCM formulas/Chinese patent drugs/herbs/ingredients with the highest Jaccard similarity scores to the submitted drugs are offered in ETCM v2.0,which may be of significance to identify prescriptions/herbs/ingredients with similar clinical efficacy,to summarize the rules of prescription use,and to find alternative drugs for endangered Chinese medicinal materials.Moreover,ETCM v2.0 provides an enhanced Java Script-based network visualization tool for creating,modifying and exploring multi-scale biological networks.ETCM v2.0 may be a major data warehouse for the quality marker identification of TCMs,the TCM-derived drug discovery and repurposing,and the pharmacological mechanism investigation of TCMs against various human diseases.

Hybrid transcytosis nanopomegranates for sensitizing breast cancer radiotherapy in deep tumor tissue

As a standard cancer treatment method,radiotherapy(RT)has cured or alleviated over half cancer bearing patients worldwide more than 100 years.However,the therapeutic outcome is seriously hindered by the resistant tumor microenvironment(TME).Hypoxia is a critical factor of vicious TME that causes radiation resistance owing to the insufficiency of oxygen for DNA damage maintenance.Moreover,severe vascular dysfunction and pyknomorphic extracellular matrix(ECM)in deep tumor tissues substantially limit radiosensitizer penetration and oxygen diffusion from vessels into tightly packed tumor core.In this study,we develop a hybrid transcytosis nanopomegranate(HTP)with high transcytosis potential in response to TME condition.HTP is architected by self-assembly of small CuS and Au nanoparticles(NPs)at normal physiological condition.HTP can rapidly collapse to transcytosis NPs(CuS and Au NPs)in TME with cationized surface,which enables excellent transcytosis potential and effectively elevates the penetration of CuS and Au into deep tumor tissues.Following the second near-infrared(NIR(II))biowindow laser irradiation,CuS heats the tumor and enhances blood perfusion,eliciting tumor hypoxia alleviation and DNA damage aggravation.Moreover,Au NPs enriched in deep tumor tissues effectively sensitize radio-therapeutic response.Our study provides a new and potential nano-platform to ameliorate tumor hypoxia and sensitize deep tumor tissue radiotherapy.

Preventive and therapeutic benefits of nelfinavir in rhesus macaques and human beings infected with SARS-CoV-2

Effective drugs with broad spectrum safety profile to all people are highly expected to combat COVID-19 caused by SARS-CoV-2.Here we report that nelfinavir,an FDA approved drug for the treatment of HIV infection,is effective against SARS-CoV-2 and COVID-19.Preincubation of nelfinavir could inhibit the activity of the main protease of the SARS-CoV-2(IC50=8.26μM),while its antiviral activity in Vero E6 cells against a clinical isolate of SARS-CoV-2 was determined to be 2.93μM(EC50).In comparison with vehicle-treated animals,rhesus macaque prophylactically treated with nelfinavir had significantly lower temperature and significantly reduced virus loads in the nasal and anal swabs of the animals.At necropsy,nelfinavir-treated animals had a significant reduction of the viral replication in the lungs by nearly three orders of magnitude.A prospective clinic study with 37 enrolled treatment-naive patients at Shanghai Public Health Clinical Center,which were randomized(1:1)to nelfinavir and control groups,showed that the nelfinavir treatment could shorten the duration of viral shedding by 5.5 days(9.0 vs.14.5 days,P=0.055)and the duration of fever time by 3.8 days(2.8 vs.6.6 days,P=0.014)in mild/moderate COVID-19 patients.The antiviral efficiency and clinical benefits in rhesus macaque model and in COVID-19 patients,together with its well-established good safety profile in almost all ages and during pregnancy,indicated that nelfinavir is a highly promising medication with the potential of preventative effect for the treatment of COVID-19.

源自针灸的靶标发现之科学路径:以针刺防治哮喘为例

针灸学如何传承精华,实现守正创新.本文在长期工作积累基础上,系统建立了源自针灸的靶标发现科学路径,包括经验传承、临床疗效、效应调节、生物过程、物质基础、靶标发现,并对未来可期的新药创制进行了展望.

D3Targets-2019-nCoV: a webserver for predicting drug targets and for multi-target and multi-site based virtual screening against COVID-19

A highly effective medicine is urgently required to cure coronavirus disease 2019(COVID-19).For the purpose,we developed a molecular docking based webserver,namely D3 Targets-2019-nCoV,with two functions,one is for predicting drug targets for drugs or active compounds observed from clinic or in vitro/in vivo studies,the other is for identifying lead compounds against potential drug targets via docking.This server has its unique features,(1)the potential target proteins and their different conformations involving in the whole process from virus infection to replication and release were included as many as possible;(2)all the potential ligand-binding sites with volume larger than 200 A^3 on a protein structure were identified for docking;(3)correlation information among some conformations or binding sites was annotated;(4)it is easy to be updated,and is accessible freely to public(https://www.d3 pharma.com/D3 Targets-2019-nCoV/index.php).Currently,the webserver contains 42 proteins[20 severe acute respiratory syndrome-related coronavirus 2(SARS-CoV-2)encoded proteins and 22 human proteins involved in virus infection,replication and release]with 69 different conformations/structures and 557 potential ligand-binding pockets in total.With 6 examples,we demonstrated that the webserver should be useful to medicinal chemists,pharmacologists and clinicians for efficiently discovering or developing effective drugs against the SARS-CoV-2 to cure COVID-19.

SARS-CoV-2 Omicron RBD shows weaker binding affinity than the currently dominant Delta variant to human ACE2

Dear Editor,SARS-coronavirus-2(SARS-CoV-2)Omicron variant(B.1.1.529)is of great concern to the world due to its multiple mutations that may have an impact on transmissibility and immune evasion.1 Compared to the wild type(WT),Omicron carries as many as 30 single point mutations,3 deletion mutation and one insertion mutation on its spike protein.Strikingly,there are 15 mutations observed in the Omicron receptor-binding domain(RBD),10 of which are in the receptor-binding motif(RBM)that human angiotensin-converting enzyme 2(ACE2)and most monoclonal antibodies(mAbs)interact directly with.As a comparison,the currently dominant variant Delta(B.1.617.2)has only 2 mutations(L452R and T478K)in its RBM and additional K417N and E484K mutations sometimes.Therefore,Omicron variant may significantly impact the binding affinity to ACE2 and effectiveness of currently available mAbs.Consequently,Omicron mutant has aroused wide concern,many countries have taken measures on entry restrictions to prevent its rapid spread.However,the transmissibility and immune evasion risk of Omicron have not been properly evaluated.

Facile Synthesis of 7-epi-Taxane and Its Derivatives and Preliminary Evaluation of Anticancer Activity

7-epi-Taxane has been achieved efficiently in gram scale from natural taxane via inversion of the 7-hydroxyl group simply using Ag20 as catalyst and DMF as solvent. The catalyst could he quantitatively recovered by filtra- tion without loss of catalytic activity. This condition is also applicable to the direct epimerization of taxane derivatives （e.g., docetaxel and paclitaxel） to 7-epi-taxane derivatives （e.g., 7-epi-docetaxel and 7-epi-paclitaxel）. Furthermore, 33 ester derivatives of 7-epi-taxane with different amino acid moieties at the position of C-13 were successfully synthesized via esterification without protecting C-7-OH. Bioassay results revealed that compounds 13 and 18 have good selectivity against prostatic cancer cell line DU145, with ICs0 value as low as 15.9 nmol/L for 18.

A Novel Sarsolenane Diterpene as a PTPIB Inhibitor from Hainan Soft Coral Sarcophyton trocheliophorum Marenzeller

A novel sarsolenane diterpene, named secodihydrosarsolenone （1）, as a minor component was obtained from the South China Sea soft coral Sarcophyton trocheliophorum Marenzeller. Its structure was elucidated by detailed spectroscopic analysis. Compound 1 exhibited moderate inhibitory activity （IC50= 13.7 μmol·L^-1） against protein tyrosine phosphatase 1B （PTP1B）, a key target for the treatment of type 2 diabetes, representing the first report of PTP1B inhibitory activity for sarsolenane diterpenes. This discovery promotes computational prediction of binding mode between the enzyme and the metabolite, suggesting a crucial role of the residues Tyr46, Ser216 and Arg221 in the binding action.

Advances in studying of the pharmacological activities and structure–activity relationships of natural C-glycosylflavonoids

C-glycosylflavonoids are characterized by a bond between the anomeric carbon of a sugar moiety and the C-6 or C-8 position of a flavonoid A ring.These compounds are widespread in nature and have become the subject of increasing research interest due to their high biological potential.This review focuses on the biological effects of various C-glycosylflavonoids and their structure–activity relationships(SAR)as elucidated over the last 5 years.

A novel silicone derivative of natural osalmid(DCZ0858)induces apoptosis and cell cycle arrest in diffuse large B-cell lymphoma via the JAK2/STAT3 pathway

Diffuse large B-cell lymphoma(DLBCL)is a highly heterogeneous malignant tumor characterized by diffuse growth.DCZ0858 is a novel small molecule with excellent antitumor effects in DLBCL.This study explored in depth the inhibitory effect of DCZ0858 on DLBCL cell lines.Cell Counting Kit-8(CCK-8)and plate colony formation assays were used to evaluate cell proliferation levels.Flow cytometry was employed to analyze apoptosis and the cell cycle,and western blotting was used to quantify the expression of cell cycle regulators.The results indicated that DCZ0858 inhibited cell growth in a concentration-dependent and time-dependent manner while inducing no significant toxicity in normal cells.Moreover,DCZ0858 initiated cell apoptosis via both internal and external apoptotic pathways.DCZ0858 also induced cell cycle arrest in the G0/G1 phase,thereby controlling cell proliferation.Further investigation of the molecular mechanism showed that the JAK2/STAT3 pathway was involved in the DCZ0858-mediated antitumor effects and that JAK2 was the key target for DCZ0858 treatment.Knockdown of JAK2 partly weakened the DCZ0858-mediated antitumor effect in DLBCL cells,while JAK2 overexpression strengthened the effect of DCZ0858 in DLBCL cells.Moreover,a similar antitumor effect was observed for DCZ0858 and the JAK2 inhibitor ruxolitinib,and combining the two could significantly enhance cancer-suppressive signaling.Tumor xenograft models showed that DCZ0858 inhibited tumor growth in vivo and had low toxicity in important organs,findings that were consistent with the in vitro data.In summary,DCZ0858 is a promising drug for the treatment of DLBCL.