Retrospect and reflection on the construction of large-scale technology platform of the State Key Laboratory of Natural and Biomimetic Drugs in 2018–2020

The State Key Laboratory of Natural and Biomimetic Drugs was approved for a funding of nearly 100 million yuan specifically aimed at the purchase and maintenance of equipment and instruments from 2018 to 2020,which is a record high.The Laboratory focuses on two major directions of scientific research,the"basic scientific problems of drug resistance of complex components of natural products"and the"key biomimetic scientific problems of endogenous substances therapeutic functions".The selection of scientific instruments and equipment,trial production,upgrading,as well as high level of technical and management personnel allocation and other aspects are critical to meet the development needs of the Key Laboratory and to maintain the advantages and leading role in these two major directions of scientific research.

Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia:randomized trials and multiomics analysis

Background:Choosing the appropriate antipsychotic drug(APD)treatment for patients with schizophrenia(SCZ)can be challenging,as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers.Previous studies have indicated the association between treatment response and genetic and epigenetic factors,but no effective biomarkers have been identified.Hence,further research is imperative to enhance precision medicine in SCZ treatment.Methods:Participants with SCZ were recruited from two randomized trials.The discovery cohort was recruited from the CAPOC trial(n=2307)involved 6 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,Quetiapine,Aripiprazole,Ziprasidone,and Haloperidol/Perphenazine(subsequently equally assigned to one or the other)groups.The external validation cohort was recruited from the CAPEC trial(n=1379),which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine,Risperidone,and Aripiprazole groups.Additionally,healthy controls(n=275)from the local community were utilized as a genetic/epigenetic reference.The genetic and epigenetic(DNA methylation)risks of SCZ were assessed using the polygenic risk score(PRS)and polymethylation score,respectively.The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis,methylation quantitative trait loci,colocalization,and promoteranchored chromatin interaction.Machine learning was used to develop a prediction model for treatment response,which was evaluated for accuracy and clinical benefit using the area under curve(AUC)for classification,R^(2) for regression,and decision curve analysis.Results:Six risk genes for SCZ(LINC01795,DDHD2,SBNO1,KCNG2,SEMA7A,and RUFY1)involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response.The developed and externally validated prediction model,which incorporated clinical information,PRS,genetic risk score(GRS),and proxy methylation level(proxyDNAm),demonstrated positive benefits for a wide range of patients receiving different APDs,regardless of sex[discovery cohort:AUC=0.874(95%CI 0.867-0.881),R^(2)=0.478;external validation cohort:AUC=0.851(95%CI 0.841-0.861),R^(2)=0.507].Conclusions:This study presents a promising precision medicine approach to evaluate treatment response,which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ.Trial registration Chinese Clinical Trial Registry(https://www.chictr.org.cn/),18 Aug 2009 retrospectively registered:CAPOC-ChiCTR-RNC-09000521(https://www.chictr.org.cn/showproj.aspx?proj=9014),CAPEC-ChiCTRRNC-09000522(https://www.chictr.org.cn/showproj.aspx?proj=9013).

Natural products as a crucial source of anti-inflammatory drugs: recent trends and advancements

Natural active molecules are key sources of modern innovative drugs. Particularly, a great amount of natural active molecules have been reported to possess promising therapeutic effects on inflammatory diseases, including asthma, rheumatoid arthritis, hepatitis, enteritis, metabolic disorders and neurodegenerative diseases. However, these natural active molecules with various molecular structures usually exert anti-inflammatory effects through diversiform pharmacological mechanisms, which is necessary to be summarized systematically. In this review, we introduced the current major anti-inflammatory natural active molecules based on their chemical structures, and discussed their pharmacological mechanisms including anti-inflammatory molecular signaling pathways and potential target proteins, which providing a referential significance on the development of novel anti-inflammatory drugs, and also revealing new therapeutic strategies for inflammatory diseases.

Stability and infectivity of coronaviruses in inanimate environments

Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is a highly contagious virus that can transmit through respiratory droplets,aerosols,or contacts.Frequent touching of contaminated surfaces in public areas is therefore a potential route of SARS-CoV-2 transmission.The inanimate surfaces have often been described as a source of nosocomial infections.However,summaries on the transmissibility of coronaviruses from contaminated surfaces to induce the coronavirus disease 2019 are rare at present.This review aims to summarize data on the persistence of different coronaviruses on inanimate surfaces.The literature was systematically searched on Medline without language restrictions.All reports with experimental evidence on the duration persistence of coronaviruses on any type of surface were included.Most viruses from the respiratory tract,such as coronaviruses,influenza,SARS-CoV,or rhinovirus,can persist on surfaces for a few days.Persistence time on inanimate surfaces varied from minutes to up to one month,depending on the environmental conditions.SARSCoV-2 can be sustained in air in closed unventilated buses for at least 30 min without losing infectivity.The most common coronaviruses may well survive or persist on surfaces for up to one month.Viruses in respiratory or fecal specimens can maintain infectivity for quite a long time at room temperature.Absorbent materials like cotton are safer than unabsorbent materials for protection from virus infection.The risk of transmission via touching contaminated paper is low.Preventive strategies such as washing hands and wearing masks are critical to the control of coronavirus disease 2019.

A biomimetic antitumor nanovaccine based on biocompatible calcium pyrophosphate and tumor cell membrane antigens

Currently,the cancer immunotherapy has made great progress while antitumor vaccine attracts substantial attention.Still,the selection of adjuvants as well as antigens are always the most crucial issues for better vaccination.In this study,we proposed a biomimetic antitumor nanovaccine based on biocompatible nanocarriers and tumor cell membrane antigens.Briefly,endogenous calcium pyrophosphate nanogranules with possible immune potentiating effect are designed and engineered,both as delivery vehicles and adjuvants.Then,these nanocarriers are coated with lipids and B16-OVA tumor cell membranes,so the biomembrane proteins can serve as tumor-specific antigens.It was found that calcium pyrophosphate nanogranules themselves were compatible and possessed adjuvant effect,while membrane proteins including tumor associated antigen were transferred onto the nanocarriers.It was demonstrated that such a biomimetic nanovaccine could be well endocytosed by dendritic cells,promote their maturation and antigen-presentation,facilitate lymph retention,and trigger obvious immune response.It was confirmed that the biomimetic vaccine could induce strong T-cell response,exhibit excellent tumor therapy and prophylactic effects,and simultaneously possess nice biocompatibility.In general,the present investigation might provide insights for the further design and application of antitumor vaccines.

Simultaneous determination of 35 constituents and elucidation of effective constituents in a multi-herb Chinese medicine formula Xiaoer-Feire-Kechuan

Xiaoer-Feire-Kechuan(XFK) is an 11-herb Chinese medicine formula to treat cough and pulmonary inflammation.The complicated composition rendered its chemical analysis and effective-component elucidation.In this study,we combined quantitative analysis and bioactivity test to reveal the antiinflammatory constituents of XFK.First,UPLC-DAD and UHPLC/Q-Orbitrap-MS methods were established and validated to quantify 35 analytes(covering 9 out of 11 herbs) in different XFK formulations.Parallel reaction monitoring mode built in Q-Orbitrap-MS was used to improve the sensitivity and selectivity.Then,anti-inflammatory activities of the 35 analytes were analyzed using in vitro COX-2 inhibition assay.Finally,major analytes forsythosides H,I,A(8-10),and baicalin(15)(total contents varied from 21.79 to 91.20 mg/dose in different formulations) with significant activities(inhibitory rate ≥ 80%) were proposed as the anti-inflammatory constituents of XFK.The present study provided an effective strategy to discover effective constituents of multi-herb formulas.

The appliances and prospects of aurum nanomaterials in biodiagnostics, imaging, drug delivery and combination therapy

Aurum nanomaterials(ANM), combining the features of nanotechnology and metal elements, have demonstrated enormous potential and aroused great attention on biomedical applications over the past few decades. Particularly, their advantages, such as controllable particle size, flexible surface modification, higher drug loading, good stability and biocompatibility, especially unique optical properties, promote the development of ANM in biomedical field. In this review, we will discuss the advanced preparation process of ANM and summarize their recent applications as well as their prospects in diagnosis and therapy. Besides, multi-functional ANM-based theranostic nanosystems will be introduced in details, including radiotherapy(RT), photothermal therapy(PTT), photodynamic therapy(PDT), immunotherapy(IT), and so on.

Intestinal Absorption of Ergostane and Lanostane Triterpenoids from Antrodia cinnamomea Using Caco-2 Cell Monolayer Model

Antrodia cinnamomea is a precious medicinal mushroom.It exhibits promising therapeutic effects on cancer,intoxication,hypertension,hepatitis,and inflammation.Its major bioactive constituents are ergostane and lanostane triterpenoids.In this study,we used intestinal Caco-2 cell monolayer model to reveal the intestinal absorption property of 14 representative triterpenoids from A.cinnamomea.The bidirectional transport through the monolayer at different time points was monitored by a fully validated LC/MS/MS method.In the case of pure compounds,ergostanes 5(25R-antcin H),6(25Santcin H)and 10(25R-antcin B)could readily pass through the Caco-2 cell layer,whereas lanostanes 13(dehydroeburicoic acid)and 14(eburicoic acid)could hardly pass through.When the cells were treated with A.cinnamomea extract,antcins A,B,C,H and K(1–6 and 9–11)were absorbed via passive transcellular diffusion,and showed high PAB and PBA values(>2.5×10^(-5) cm/s).Meanwhile,the lanostanes dehydrosulphurenic acid(8),15a-acetyldehydrosulphurenic acid(12),13 and 14 exhibited poor permeability.Transport features of these compounds were consistent with their pharmacokinetic behaviors in rats.This study could also be helpful in predicting the intestinal absorption of A.cinnamomea in human.

Optimize the combination regimen of Trastuzumab and Nab-paclitaxel in HER2-positive tumors via modulating Caveolin-1 expression by lovastatin

The combination regimen of trastuzumab(Tras)plus Nab-paclitaxel(Nab)is recommended to treat HER2-positive(HER2+)cancers.However,they exert effects in different mechanisms:Tras need to stay on cell membranes,while Nab need to be endocytosed,therefore the concurrent combination regimen may not be the best one in HER2+tumors treatment.Caveolin-1(Cav-1)is a key player in mediating their endocytosis and is associated with their efficacy,but few researches noticed the opposite effect of Cav-1 expression on the combination efficacy.Herein,we systematically studied the Cav-1 expression level on the combination efficacy and proposed an optimized and clinically feasible combination regimen for HER2+Cav-1 High tumor treatment.In the regimen,lovastatin(Lova)was introduced to modulate the Cav-1 expression and the results indicated that Lova could downregulate Cav-1 expression,increase Tras retention on cell membrane and enhance the in vitro cytotoxicity of Tras in HER2+Cav-1 High cells but not in HER2+Cav-1 Low cells.Therefore,by exchanging the dosing sequence of Nab and Tras,and by adding Lova at appropriate time points,the precise three-drug-sequential regimen(PTDS,Nab(D1)-Lova(D2)-Lova&Tras(D2+12 h))was established.Compared with the concurrent regimen,the PTDS regimen exhibited a higher in vitro cytotoxicity and a stronger tumor growth inhibition in HER2+Cav-1 High tumors,which might be a promising combination regimen for these patients in clinics.

A New Sesquiterpene from Transformation of Curdione by Cell Suspension Culture of Platycodon Grandiflorum

A new sesquiterpene was isolated from transformation of curdione by cell suspension culture of Platycodon grandiflorum. The structure of the new compound was elucidated on the basis of spectral methods including 2D NMR.

Establishment of organoid models based on a nested array chip for fast and reproducible drug testing in colorectal cancer therapy

The conventional microwell-based platform for construction of organoid models exhibits limitations in precision oncology applications because of low-speed growth and high variability. Here, we established organoid models on a nested array chip for fast and reproducible drug testing using 50% matrigel. First, we constructed mouse small intestinal and colonic organoid models. Compared with the conventional microwell-based platform, the mouse organoids on the chip showed accelerated growth and improved reproducibility due to the nested design of the chip. The design of the chip provides miniaturized and uniform shaping of the matrigel that allows the organoid to grow in a concentrated and controlled manner. Next, a patient-derived organoid(PDO) model from colorectal cancer tissues was successfully generated and characterized on the chip. Finally, the PDO models on the chip, from three patients, were implemented for high-throughput drug screening using nine treatment regimens. The drug sensitivity testing on the PDO models showed good quality control with a coefficient of variation under 10% and a Z’ factor of more than 0.7. More importantly, the drug responses on the chip recapitulate the heterogeneous response of individual patients, as well as showing a potential correlation with clinical outcomes. Therefore,the organoid model coupled with the nested array chip platform provides a fast and reproducible means for predicting drug responses to accelerate precise oncology.

One-pot preparation of nanodispersion with readily available components for localized tumor photothermal and photodynamic therapy

Photothermal(PTT) and photodynamic(PDT) combined therapy has been hindered to clinical translation, due to the lack of available biomaterials, difficult designs of functions,and complex chemical synthetic or preparation procedures. To actualize a high-efficiency combination therapy for cancer via a feasible approach, three readily available materials are simply associated together in one-pot, namely the single-walled carbon nanohorns(SWCNH), zinc phthalocyanine(ZnPc), and surfactant TPGS. The established nanodispersion is recorded as PCT. The association of SWCNH/ZnPc/TPGS was confirmed by energy dispersive spectrum, Raman spectrum and thermogravimetric analysis. Under lighting, PCT induced a temperature rising up to about 60 ℃ due to the presence of SWCNH, production a 7-folds of singlet oxygen level elevation because of ZnPc, which destroyed almost all4T1 tumor cells in vitro. The photothermal effect of PCT depended on both laser intensity and nanodispersion concentration in a linear and nonlinear manner, respectively. After a single peritumoral injection in mice and laser treatment, PCT exhibited the highest tumor temperature rise(to 65 ℃) among all test groups, completely destroyed primary tumor without obvious toxicity, and inhibited distant site tumor. Generally, this study demonstrated the high potential of PCT nanodispersion in tumor combined therapy.

Effects of parasitic plant Cistanche deserticola on chlorophyll a fluorescence and nutrient accumulation of host plant Haloxylon ammodendron in the Taklimakan Desert

The parasitic plant Cistanche deserticola attaches to Haloxylon ammodendron, a perennial shrub with high tolerance to salinity and drought. However, little was known about the parasite-host relation between the two species. Effects of the parasite on chlorophyll a fluorescence and nutrient accumulation in the host plant （H. am- modendron） were investigated in the Taklimakan Desert. Some photosynthetic parameters of both host and non-host H. ammodendron plants were measured by in vivo chlorophyll a fluorescence technology in the field. The assimilating branches of host and non-host plants were collected and nutrient and inorganic ion contents were analyzed. The results from field experiments showed that the infection of C. deserticola reduced the non-photochemical quenching of the variable chlorophyll fluorescence （NPQ） and the potential maximum quantum yield for primary photochemistry （Fv/Fm） of the host. Compared with non-host plants, the host H. ammodendron had low nutrient, low inorganic ion contents （Na~ and K~） and low K~/Na~ ratios in the assimilating branches. It suggested that C. deserticola infection reduced the nutrient acquisition and caused damage to the photoprotection through thermal dissipation of the energy of the photosystem II in the host, resulting in a decrease in the tolerance to salinity and high radiation. It was concluded that the attachment of the parasite plant （C. deserticola） had negative effects on the growth of its host.

Synthesis of New Flavanone Derivatives of Farrerol and Preliminary SAR Studies on Anti-VSMCs Vegetation Activity

A series of new flavanone derivatives of farrerol was designed and synthesized as a potent inhibitor of vascular smooth muscle cells（VSMCs） vegetation according to a convenient method. The structures of all the synthesized compounds were confirmed by 1H NMR, 13C NMR and EIHR-MS. The biological activities of these compounds against VSMCs in vitro were evaluated. The assay results indicate that two compounds, 5,7-dihydroxy-6,8-dimethyl- 2-（2-nitrophenyl）chroman-4-one（7f） and 2,3-dibromo-4,5-dihydroxydiphenylmethanone（7j） exhibited high activity against VSMCs in vitro with IC50 values of 9.9 and 6.7 μmol/L, respectively, and the preliminary structure-activity relationship（SAR） was described.

Baoyuan decoction alleviates myocardial infarction through the regulation of metabolic dysfunction and the mitochondria-dependent caspase-9/3 pathway

Objective:Baoyuan decoction(BYD)is a traditional Chinese formula with myocardial protection efficacy validated by modern pharmacological tests.The present study aimed to investigate the effect and mechanism of BYD on alleviating myocardial infarction(MI).Methods:Nuclear magnetic resonance-based serum and urinary metabolomics were employed to explore the metabolic regulation effects of BYD in rats with MI induced by left anterior descending ligation.Oxygen-glucose deprivation/recovery(OGD/R)model in H9c2 cells and multiple molecular biology approaches were used to clarify the underlying action mechanisms of BYD.Results:BYD treatment recovered the serum and urinary metabolite profiles of the MI rats toward normal metabolic status and significantly improved mitochondrial energy metabolism and apoptosis pathways perturbed by MI.Analysis of the molecular mechanism of BYD indicated that it suppressed OGD/R-induced H9c2 cell apoptosis in a concentration-dependent manner by inhibiting the mitochondria-dependent caspase-9/3-poly ADP-ribose polymerase pathway.Conclusions:Our results demonstrate that BYD protects against myocardial apoptosis via the mitochondrial metabolic and apoptosis pathways.They also provide novel insights into the clinical application of BYD for the treatment of ischemic heart diseases.

Effects of Ce^(3+),Nd^(3+),Gd^(3+), Tb^(3+) and Lu^(3+) ions on Formation of CaCO_3

The effects of lanthanides at various concentrations on CaCO 3 crystal growth were studied by X ray diffraction (XRD), infrared spectra (IR), X ray photoelectric energy spectra (XPS) and inductively coupled plasma mass spectrometry (ICP MS). It was found that the calcite, a stable form of CaCO 3 in thermodynamics, is the predominant species. The research indicates that lanthanide ions (Ln 3+ ) can partly substitute the Ca 2+ in the lattice of CaCO 3 crystals, and change the crystal characterization and direct the ordinal growth of CaCO 3 crystals.

The role of natural products in regulating pyroptosis

In recent years,large numbers of novel cell death types have been reported such as autophagic death,paraptosis,mitosis,oncosis and pyroptosis.As a new type of proinflammatory programmed cell death,pyroptosis has attracted increasing attentions gradually,and its morphological characteristics and molecular mechanisms are significantly different from other cell death types such as necrosis and apoptosis.Many research groups have demonstrated the association between pyroptosis and various human diseases including immunological disease,cancer,atherosclerosis,infectious disease,and cardiovascular and cerebrovascular disease.Natural products are small molecules synthetized in organisms including primary and secondary metabolites.Natural products are important sources of modern innovative drugs discovery and can be used as key tools to explore the molecular mechanism of cell fate.The aim of this study is to review the molecular mechanisms and pathways of pyroptosis,and to categorize and conclude research results on the correlation between different natural products and pyroptosis in recent years.In this study,a total of 39 papers were enrolled in analyses.The molecular pathways and mechanisms of pyroptosis were clearly described.Fourteen types of natural products,their sources,effects,mechanisms and therapeutic potentials are categorized and illuminated.It is showed that a variety of natural products and pyroptosis have close correlations.They negatively or positively affect or act on different positions of pyroptosis inflammatory pathways,indicating that they may have certain potential therapeutic effects on pyroptosis-related diseases.Pyroptosis,a relatively new way of cell death,is closely associated with a variety of diseases.Natural products can have obvious effects on the process of pyroptosis as potential sources of new drugs.In-depth studies using natural products to investigate pyroptosis will help to enhance our understandings of human diseases and establish effective prevention and treatment strategies.

Characteristic fragmentation behavior of the analogs of endomorphin-2 with phenylglycine in position 3 or 4 by ESI-FT tandem mass spectrometry

A series of analogs of endomorphin-2 （EM-2） with phenylglycine （Phg） in position 3 or 4 were synthesized. In electrospray ionization Fourier transform ion cyclotron resonance （ESI-Fr-ICR） MS/MS spectra of these compounds, some b, y, a, and internal ions were observed and slight mass differences between the calculated and observed results are obtained. Their sequences were derived successfully. However, the MS/MS patterns of these analogs with Dphg and Lphg were very similar. It is hard to distinguish them by MS/MS spectra. Moreover, if the third position was substituted by phenylglycine （L or D）, a rearrangement could occur in MS/MS experiment to lose proline residue.

ERG3 potassium channel-mediated suppression of neuronal intrinsic excitability and prevention of seizure generation in mice

The input-output relationship of neuronal networks depends heavily on the intrinsic properties of their neuronal elements.Profound changes in intrinsic properties have been observed in various physiological and pathological processes,such as learning,memory and epilepsy.However,the cellular and molecular mechanisms underlying acquired changes in intrinsic excitability are still not fully understood.Here,we demonstrate that ERG3 channels are critically involved in the regulation of intrinsic excitability in hippocampal CA1 pyramidal neurons and DG granule cells.Knock-down of ERG3 channels significantly increases neuronal intrinsic excitability,which is mainly caused by decreased fast afterhyperpolarization,delayed time to the generation of an action potential and enhanced summation of somatic excitatory post-synaptic potentials.Interestingly,the expression level of ERG3 protein is significantly reduced in human and mouse brain tissues with temporal lobe epilepsy.Moreover,ERG3 channel knock-down in hippocampus significantly enhanced seizure susceptibility,while mice treated with ERG3 channel activator NS1643 were less prone to epileptogenesis.Taken together,our results suggest ERG3 channels play an important role in determining the excitability of hippocampal neurons and dysregulation of these channels may be involved in the generation of epilepsy.ERG3 channels may thus be a novel therapeutic target for the prevention of epilepsy.

Advances in anti-inflammatory and immunoregulatory mechanisms of sinomenine

Sinomenine,a major active ingredient from traditional Chinese medicine Qingfengteng(Sinomenium acutum(Thunb.)Rehd.et Wils.),has been proven to have anti-inflammatory,analgesic,anti-tumor,immunomodulatory and other pharmacological effects,and is clinically used for various inflammatory and autoimmune diseases.However,due to complex molecular mechanisms and pathological characteristics in inflammatory and immune responses,the precise anti-inflammatory and immunological mechanisms of sinomenine are still unclear.This review summarizes the anti-inflammatory and immunoregulatory mechanisms of sinomenine during recent years in rheumatoid arthritis,respiratory system,nervous system,digestive system and organ transplant rejection.The molecular pharmacological mechanisms of sinomenine responsible for anti-inflammatory and immunosuppressive effects were in detail introduced based on 3 aspects including cytokines induction,signal pathways modulation and immune cells function regulation.Moreover,this review also raises some concerns and challenges in future sinomenine study,which will contribute to crucial theoretical and practical significance for in-depth development and utilization of sinomenine as medicinal resource.