Transient Folate Deprivation in Combination with Small-molecule Compounds Facilitates the Generation of Somatic Cell-derived Pluripotent Stem Cells in Mice

Induced pluripotent stem cells （iPSCs） can be propagated indefinitely, while maintaining the capacity to differentiate into all cell types in the body except for the extra-embryonic tissues. This iPSC technology not only represents a new way to use individual-specific stem cells for regenerative medicine but also constitutes a novel method to obtain large numbers of disease-specific cells for biomedical re- search. However, the low efficiency of reprogramming and genomic integration of oncogenes and viral vectors limit the potential application of iPSCs. Chemical-induced reprogramming offers a novel ap- proach to generating iPSCs. In this study, a new combination of small-molecule compounds （SMs） （so- dium butyrate, A-83-01, CHIR99021, Y-27632） under conditions of transient folate deprivation was used to generate iPSC. It was found that transient folate deprivation combined with SMs was sufficient to permit reprogramming from mouse embryonic fibroblasts （MEFs） in the presence of transcription factors, Oct4 and Klf4, within 25 days, replacing Sox2 and c-Myc, and accelerated the generation of mouse iPSCs The resulting cell lines resembled mouse embryonic stem （ES） cells with respect to proliferation rate, morphology, pluripotency-associatedmarkers and gene expressions. Deprivation of folic acid, combined with treating MEFs with SMs, can improve the inducing efficiency of iPSCs and reduce their carcino- genicity and the use of exogenous reprogramming factors.

SYNTHESIS AND CHARACTERIZATION OF NOVEL MULTIFUNCTIONAL HOST COMPOUNDS.1.β-CYCLODEXTRIN DERIVATIVE BEARING DIETHANOLAMINE MOIETY

A novel β-cyclodextrin(β-CD)derivative bearing diethanolamine moiety was synthesized by a convenient method with 63% yield,and the new host compound was characterized by (13)~C-NMR,FT-IR spectra etc,

STUDIES ON ORGANOPHOSPHORUS COMPOUNDS 69.A NOVEL SYNTHESIS OF 5-SUBSTITUTED 3-(1'-DIETHOXYPHOSPHORYLALKYL)-2-ISOXAZOLINES

Additions of diethyl phosphite to α-nitroalkenes followed by the introduction of trimethylchlorosilane and an activated alkene, gave the corresponding title compounds via regioselective 1,3-dipolar cycloaddition in moderate yield.

Synthesis and Herbicidal Activity of 1-Phenoxyacetyl-3-arylimidazolidine-2,4-dione Compounds

In order to find new herbicidal compounds, twelve novel 1-phenoxyacetyl-3-arylimidazolidine-2,4-dione compounds were designed and synthesized by substructure combination strategy using 3-arylimidazolidine-2,4-dione as the intermediate. The structures of the target compounds were confirmed by;H NMR and IR. The preliminary bioassay results showed that most of the target compounds had good inhibition against rape and barnyardgrass at the concentration of 100 mg/L. Especially, compound H3 and H5 showed 100% inhibitory activity against rape.

Theory of pleiotropic action of biologically active compounds and medicines—Basic principles and practical application

This article represents the main positions of the theory of pleiotropic action of biologically active compounds (BACs) and medicines, which has been designed by the author based on her own experimental researches. The term “pleiotropy” means the ability of the BACs and medicines to implement more than one mechanism of action resulting in the specific biological (pharmacological) effect. The interaction of these mechanisms forms a distinct pattern of biological response (pleiotropic pattern), which reflects the change in his character with the increased dose (concentration)-dependent efficacy of BACs and medicines. The article consists of description of different pleiotropic patterns established in experiments on the model of reactive oxygen species (ROS) generation by macrophages dependent on activity of specialized enzyme called Nox2-NAD(P)H oxidase (Nox2, EC 1.6.3.1). Moreover, it consists of explanation of pharmacodynamic nature of pleiotropic patterns by means of application Chou-Talalay median effect equalization and combination index (CI) theory. The novel theory explains unsolved until now universal aspects of activity BACs and medicines, such as slope angles of “dose-effect” dependences in the conditions relevant in vivo, and it is of fundamental interest. However, it has applications in experimental pharmacology, as it allows defining the choice of the individual compounds and combinations, modulating the trust effect selectively and efficiently. This knowledge opens up new approaches to medicines discovery and evaluation, their rational dosing and combining.

Analysis of novel coronavirus pneumonia treatment with Chinese herbal compound

Objective: To analyze the prescription law of TCM compound in the treatment of new coronavirus pneumonia, and provides reference for the clinical treatment of new coronavirus pneumonia. Methods: Collected Collected 24 novel coronavirus pneumonia related diagnostic and therapeutic plans issued by the National Health Council and the Chinese medicine authority from January 26, 2020 to March 8th ,the filtered solution involved in the formula, establishing database of traditional Chinese medicine compound prescription for the treatment of new crown pneumonia, the frequency of using frequency analysis methods of analysis and clustering analysis and association rules analysis to sort out data mining analysis of traditional Chinese medicine compound. Results: In this study, a total of 159 TCM compounds were included in the treatment of new crown pneumonia from the country and 23 provinces, municipalities and autonomous regions, involving 189 TCM compounds. A total of 62 high-frequency traditional Chinese medicines (frequency ≥ 11) were obtained, mainly including licorice, almond, ephedra, gypsum, Poria cocos, Huoxiang, etc The drug types are mainly heat-clearing drugs, vacuous drugs, moisture-curing drugs, and surfactant drugs. The main effect of the medicine was warm, cold, lukewarm and flat, the main effect of the medicine was bitter and bitter, and the main effect of the medicine was the lung, stomach and spleen. Cluster analysis results according to the performance of traditional Chinese medicine treatment of new crown pneumonia high frequency drugs into 7 classes;Association rule analysis results in 29 common drug pairs. Conclusion: In the treatment of pneumonia caused by new coronavirus infection with traditional Chinese medicine, the following characteristics are presented: the number of times of supplementing qi and Yin is more than that of attacking evil and maintaining health;The method of dispersing and solving the attack of wet, beneficial, wet, permeable and wet medicine fully embodies a variety of ways to drive away evil;In terms of drugs, heat-clearing drugs, deficiency drugs, dampness drugs and surface drugs are the main ones, highlighting that the basic treatment method is to dissolve dampness and detoxify, and replenish qi and Yin. In summary, this study can provide reference for guiding clinical drug use and developing new drugs.

Exact Traveling Wave Solutions for the (1 + 1)-Dimensional Compound KdVB Equation via the Novel (G'/G)-Expansion Method

In this work, while applying a new and novel (G'/G)-expansion version technique, we identify four families of the traveling wave solutions to the (1 + 1)-dimensional compound KdVB equation. The exact solutions are derived, in terms of hyperbolic, trigonometric and rational functions, involving various parameters. When the parameters are tuned to special values, both solitary, and periodic wave models are distinguished. State of the art symbolic algebra graphical representations and dynamical interpretations of the obtained solutions physics are provided and discussed. This in turn ends up revealing salient solutions features and demonstrating the used method efficiency.

A network pharmacology approach to explore the mechanism of action of Yiqi Fumai lyophilized injection in the treatment of novel coronavirus disease

Background:Shengmai decoction,which has been included in the diagnosis and treatment of coronavirus disease 2019(COVID-19),is effective in the early treatment of patients with severe COVID-19.Yiqi Fumai lyophilized injection(YQFM)is a modern Chinese medicine preparation of the Shengmai decoction.The mechanism of its intervention at the molecular level in the severe stage of COVID-19 remains unclear.Therefore,it is necessary to investigate the mechanism of YQFM in the treatment of patients with severe COVID-19.Methods:The corresponding target genes of the main active ingredients in YQFM and COVID-19 were obtained by using multiple databases and literature retrieval.A protein-protein interaction network was constructed,and enrichment analysis of the target was performed using Cytoscape 3.8.1.Lastly,the docking of all the identified compounds with angiotensin-converting enzyme II was confirmed by applying molecular docking technology.Results:YQFM has anti-inflammatory effects on RAW267.4 macrophages.The main active compounds of YQFM are all effective anti-inflammatory agents,and these active compounds also show beneficial physiological functions,such as anti-oxidation,anti-bacterial,and anticancer activities.Gene Ontology analysis showed enrichment in the following pathways:lipopolysaccharides,interleukins,NF-kappa B,interleukin-2 and others,revealing that YQFM may play a role in the treatment of patients with severe COVID-19 through these pathways.Conclusion:YQFM has multicomponent and multitarget characteristics,and it could reduce lung injury by inhibiting inflammatory reactions,promoting antiviral activities,and regulating immunity,among other functions,to treat patients with severe COVID-19.

新型查尔酮衍生物抗乳腺癌活性的3D-QSAR模型构建及分子设计

为了获得较高抗乳腺癌活性的新型化合物,对18个新型查尔酮衍生物抗乳腺癌活性(pIC_(50))进行了三维定量构效关系(3D-QSAR)研究。其中14个化合物作为训练集用于构建3D-QSAR模型,其余化合物(含模板分子)作为测试集对所建模型进行验证。所建3D-QSAR模型的交叉验证系数R^(2)_(CV)为0.569,非交叉验证系数R^(2)为0.974,说明所建模型具有良好的稳定性和预测能力。该模型中立体场、静电场对pIC_(50)的贡献分别为58.8%和41.2%,表明影响该类化合物抗肿瘤活性的主要因素是取代基的疏水性、空间位阻和电荷分布。通过对模型的分析,设计了5个具有较高pIC_(50)的新化合物,有待通过后续医学实验加以验证。

伐莫洛酮治疗Duchenne型肌营养不良症的研究进展

Duchenne型肌营养不良症(DMD)是进行肌营养不良症的最常见类型,也是中国最常见的X连锁隐性遗传的肌病,发病率约30/10万男婴,主要表现为缓慢进行性加重的躯干肌肉及肢体肌肉无力及萎缩、肌肉的假性肥大,大多数还会有心肌损害,一般患儿在12岁左右不能行走,后期会出现呼吸肌无力,由于DMD目前无特异性治疗方法,多数患者在20~30岁因呼吸道感染、心力衰竭而死亡。糖皮质激素对DMD运动和心功能有明显改善作用,目前临床建议早期使用,但糖皮质激素存在较多的不良反应,临床应用有较多限制。近十余年国外临床研究发现伐莫洛酮对DMD有同糖皮质激素一样的疗效,但没有与糖皮质激素相关的不良反应(生长发育迟缓、骨疾病、肌肉萎缩等)。本文就目前关于伐莫洛酮治疗DMD的作用机制、治疗方案及不良反应做一总结。

Therapeutic strategies of targeting nonapoptotic regulated cell death (RCD) with smallmolecule compounds in cancer

Regulated cell death(RCD)is a controlled form of cell death orchestrated by one or more cascading signaling pathways,making it amenable to pharmacological intervention.RCD subroutines can be categorized as apoptotic or non-apoptotic and play essential roles in maintaining homeostasis,facilitating development,and modulating immunity.Accumulating evidence has recently revealed that RCD evasion is frequently the primary cause of tumor survival.Several non-apoptotic RCD subroutines have garnered attention as promising cancer therapies due to their ability to induce tumor regression and prevent relapse,comparable to apoptosis.Moreover,they offer potential solutions for overcoming the acquired resistance of tumors toward apoptotic drugs.With an increasing understanding of the underlying mechanisms governing these non-apoptotic RCD subroutines,a growing number of small-molecule compounds targeting single or multiple pathways have been discovered,providing novel strategies for current cancer therapy.In this review,we comprehensively summarized the current regulatory mechanisms of the emerging non-apoptotic RCD subroutines,mainly including autophagy-dependent cell death,ferroptosis,cuproptosis,disulfidptosis,necroptosis,pyroptosis,alkaliptosis,oxeiptosis,parthanatos,mitochondrial permeability transition(MPT)-driven necrosis,entotic cell death,NETotic cell death,lysosome-dependent cell death,and immunogenic cell death(ICD).Furthermore,we focused on discussing the pharmacological regulatory mechanisms of related small-molecule compounds.In brief,these insightful findings may provide valuable guidance for investigating individual or collaborative targeting approaches towards different RCD subroutines,ultimately driving the discovery of novel small-molecule compounds that target RCD and significantly enhance future cancer therapeutics.

新型农抗N2对采后柑橘的保鲜效果研究

【目的】研究新型抗真菌剂-农抗N2对柑橘采后保鲜效果的影响,以期为柑橘采后的防腐保鲜技术提供材料与理论参考。【方法】使用5.77 mg/L农抗N2对采摘后柑橘进行浸泡处理,晾干后使用聚乙烯薄膜进行单果包装,于25℃、相对湿度90%~95%条件下储存60 d,以无菌水浸泡的柑橘为阴性对照,以200 mg/L抑霉唑浸泡处理的柑橘为阳性对照,测定柑橘的腐烂率及失重率,可溶性固形物、可滴定酸、抗坏血酸以及酚类与黄酮类化合物含量,研究农抗N2对柑橘采后的保鲜效果。【结果】农抗N2处理后的柑橘,其失重率与腐烂率显著低于无菌水处理组(CK组),且与抑霉唑处理组无显著性差异;农抗N2处理后的柑橘,其果实可溶性固形物含量在贮存40 d后显著高于CK组;果实可滴定酸与抗坏血酸含量在60 d的贮存期内与CK组无显著性差异;柑橘果皮总酚与黄酮含量在储存50 d后显著高于阴性对照组。【结论】农抗N2能显著降低采后柑橘的失重率以及腐烂率,有效延长采后柑橘的货架期。此外,农抗N2在60 d的贮存期内能显著提高柑橘果实的可溶性固形物含量以及柑橘果皮的酚类与黄酮类化合物含量,有效维持柑橘果实的品质与营养价值。

N-取代萘二酰亚胺乙酸类衍生物的合成及生物活性

采用活性基团拼接法,以1,8-萘二甲酸酐为基本骨架,合成了3个具有植株生长调节功能的新型萘二酰亚胺乙酸类衍生物,并经1H NMR、元素分析确定了化合物的结构。室内生物活性测试结果显示:目标化合物4a在质量浓度为1 mg/L时,对绿豆种子的发芽促进率达到254.55%,芽长促进率达到136.36%,根长促进率达到75.00%;在4℃、质量浓度为0.67 mg/L时,对小麦种子的发芽促进率达到240%。目标化合物4a表现出优异的抗低温胁迫和植物生长调节活性。

Targeting autophagy using small-molecule compounds to improve potential therapy of Parkinson’s disease

Parkinson’s disease(PD),known as one of the most universal neurodegenerative diseases,is a serious threat to the health of the elderly.The current treatment has been demonstrated to relieve symptoms,and the discovery of new small-molecule compounds has been regarded as a promising strategy.Of note,the homeostasis of the autolysosome pathway(ALP)is closely associated with PD,and impaired autophagy may cause the death of neurons and thereby accelerating the progress of PD.Thus,pharmacological targeting autophagy with small-molecule compounds has been drawn a rising attention so far.In this review,we focus on summarizing several autophagy-associated targets,such as AMPK,m TORC1,ULK1,IMPase,LRRK2,beclin-1,TFEB,GCase,ERRα,C-Abelson,and as well as their relevant small-molecule compounds in PD models,which will shed light on a clue on exploiting more potential targeted small-molecule drugs tracking PD treatment in the near future.

Molecular mechanism prediction analysis of compound Kushen injection in the treatment of COVID-19 based on network pharmacology and molecular docking

Background:As one of the eight effective traditional Chinese medicines for the treatment of atypical pneumonia,compound Kushen injection(CKI)played an important role in combating pneumonia caused by severe acute respiratory syndrome coronavirus 2 virus in China in 2003.CKI is known to inhibit inflammation,and its main chemical components,namely matrine and oxymatrine,can promote Th cells to recognize and eliminate viruses.In this study,network pharmacology and molecular docking were used to explore the mechanisms of CKI for treating coronavirus disease 2019.Methods:The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform and other related literature were used to screen CKI’s active ingredients in the blood.Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,Swiss Target Prediction and STITCH were used to search for potential targets of the active ingredients.The“ingredient-target”network was constructed using the Cytoscape software.The STRING online database was used to construct a target protein-protein interaction network that can be visualized and analyzed using the Cytoscape software to obtain key targets.Results:Sophocarpine,sophoridine,matrine,(+)-allomatrine,AIDS211310,and sophranol were the six active ingredients.After docking the active ingredients with severe acute respiratory syndrome coronavirus 23CL hydrolase and angiotensin-converting enzyme 2(ACE2),they displayed suitable affinity,which could block viral replication and its binding to ACE2.The key targets mainly involved inflammatory factors,such as interleukin-6(IL-6)and tumor necrosis factor(TNF).Gene Ontology enrichment analysis mainly indicated the IL-6 cytokine-mediated signaling pathway and cytokine-mediated signaling pathway.The Kyoto Encyclopedia of Genes and Genome pathway enrichment analysis mainly indicated steroid hormone biosynthesis and the TNF signaling pathway.Conclusion:The alkaloids in CKI can block viral replication and its binding to severe acute respiratory syndrome coronavirus 2 and ACE2 receptors.They regulate the IL-6-mediated signaling pathway,TNF signaling pathway,and steroid hormone biosynthesis,thereby initiating therapeutic responses against coronavirus disease 2019.

A novel protein tyrosine phosphatase 1B inhibitor with therapeutic potential for insulin resistance

Insulin sensitizing medicines are currently limited, and identification of new drug candidate is a chal- lenge. Protein tyrosine phosphatase 1B （PTP1 B） negatively regulates insulin signaling pathway, and its inhibition is anticipated to improve insulin resistance. This study investigated the pharmacological profiles of compound CX08005, a new PTP1B inhibitor, with therapeutic potential for insulin resistance in vivo and in vitro, respective- ly. Recombinant human PTP1B protein was used to measure the enzyme activity. The docking simulation was per- formed to explore the interactions between the compound and the protein. The insulin sensitivity was evaluated in Diet-induced obesity mice and/or T2DM KKAy mice by glucose tolerance test （GTT）, the blood glucose level, glucose stimulated insulin secretion （GSIS）, homeostasis model assessment of insulin resistance index （HOMA-IR） and the whole-body insulin sensitivity （ISwb） index, respectively. The hyperinsulinemic-euglycemic clamp was performed to evaluate the insulin stimulated glucose disposal both in whole body and in insulin-sensitive tissues （muscle and fat）. Furthermore, its direct effect in muscle, fat and liver cells was observed. We found that CX08005 was a competitive inhibitor of PTP1B with dose-dependent activity （IC50=5.95 × 10^-7 M）. Docking simulation demonstrated that CX08005 binds to PTP1B at the catalytic P-loop through hydrogen bonds. In DIO mice, treatment with CX08005 effectively ameliorated glucose intolerance in a dose-dependent manner （50- 200 mg. kg^-1 · d^-l）, and decreased HOMA-IR values. We also demonstrated that oral administration of 50 mg ~ kg^-1· d^-1 CX08005 improved hyperglycemia, hyperinsulinemia, HOMA-IR and ISwb in KKAy mice. In hyperin- sulinemic-euglycemic clamp test, CX08005 increased glucose infusion rate and glucose uptake in muscle and fat of DIO mice. In 3T3-L1 adipocytes and C2C12 myotubes, CX08005 enhanced insulin-induced glucose uptake. In HepG2 hepatocyte, CX08005 enhanced insulin-stimulated tyrosine phosphorylation of IRβ/IRS1 in a dose-depend- ent manner, respectively; furthermore, the phosphorylation of several downstream molecules, including Akt, Foxol and GSK3β was also increased, indicating this compound could augment insulin＇s ability to suppress hepatic glu- cose output （HGO）. Our results strongly suggest that compound CX08005 directly enhances insulin action in vitro and in vivo with therapeutic potential for insulin resistance.

耐甲氧西林金黄色葡萄球菌感染新型控制策略研究新进展

耐甲氧西林金黄色葡萄球菌(methicillin-resistant staphylococcus aureus,MRSA)是临床常见的多重耐药菌之一,被称为“超级细菌”。随着MRSA耐药机制的不断进化,通过传统抗生素治疗MRSA感染的困难不断增加。近年来,针对MRSA感染的新型控制策略从各个层面不断深入。纳米材料的独特结构具有抗菌活性,也可作为一种高效的抗菌药物输送载体。光动力疗法通过光激活光敏剂(photosensitizer,PS)与分子氧或底物作用产生活性氧(reactive oxygen species,ROS)促进细胞氧化应激。中草药多种机制的抗菌特性已经被广泛证实。免疫疗法在对抗MRSA的免疫逃逸机制、多价疫苗和混合抗体的使用取得了突破。以mecA基因为代表的基因靶点正在不断被发掘。靶向硫醇依赖的氧化还原系统(thiol-dependent redox system,TDRS)尤其是硫氧还蛋白系统(thioredoxin system,Trx system)的新型候选抗菌化合物将是未来充满潜力的生力军。本文将MRSA的新型控制策略进行综述和展望。

Novel inclusion compounds with urea/thiourea/seleno-urea-anion host lattices

The chemistry of inclusion compounds has a long history and is nowadays a subject of wide-ranging and intense study. With the awarding of the 1987 Nobel Prize in Chemistry to Donald J. Cram, Jean-Marie Lehn and Charles J. Pedersen for their fundamental work on 'host-guest' or 'supramolecular' systems, inclusion chemistry has come to the fore front in contemporary researches. Increasing varieties of novel inclusion compounds and new host molecules have been synthesized recently. The term 'crystal engineering' was coined by Schmidt to describe the rational design and control of molecular packing arrangements in the solid state, and the structural study of clathrates has contributed

Syntheses of salvilenone and related compounds——Ⅱ.A novel rearrangement of a tetrahydrophenalenone to a naphthopyranone(?)

The reaction of isopropenyl carbinol(2)with aqueous hydrobromic acid and hydroiodic- acid gave salvilenone(1)and naphthopyranone(3)respectively.The reaction mechanism has been investigated.The formation of(3)was undergone a novel rearrangement of a tetrahydrophenalenone to a naphthopyranone.