Construction and Application of PLP Self-sufficient Biocatalysis System for Threonine Aldolase.

A number of organic synthesis involve threonine aldolase (TA), a pyridoxal phosphate (PLP)-dependent enzyme. Although the addition of exogenous PLP is necessary for the reactions, it increases the cost and complicates the purification of the product. This work constructed a PLP self-sufficient biocatalysis system for TA, which included an improvement of the intracellular PLP level and co-immobilization of TA with PLP. Engineered strain BL-ST was constructed by introducing PLP synthase PdxS/T to Escherichia coli BL21(ED3). The intracellular PLP concentration of the strain increased approximately fivefold to 48.5 µmol/gDCW. l-TA, from Bacillus nealsonii (BnLTA), was co-expressed in the strain BL-ST with PdxS/T, resulting in the engineered strain BL-BnLTA-ST. Compared with the control strain BL-BnLTA (254.1 U/L), the enzyme activity of the strain BL-BnLTA-ST reached 1518.4 U/L without the addition of exogenous PLP. An efficient co-immobilization system was then designed. The epoxy resin LX-1000HFA wrapped by polyethyleneimine (PEI) acted as a carrier to immobilize the crude enzyme solution of the strain BL-BnLTA-ST mixed with an extra 100 µM of exogenous PLP, resulting in the catalyst HFAPEI-BnLTA-STPLP 100. HFAPEI-BnLTA-STPLP 100 exhibited a half-life of approximately 450 h, and the application of the catalyst in the continuous biosynthesis of 3-[4-(methylsulfonyl) phenyl] serine had more than 180 batch reactions (>60%conv) without the extra addition of exogenous PLP. The excellent compatibility and stability of the system were further confirmed by other TAs. This work introduced a PLP self-sufficient biocatalysis system that can reduce the cost of PLP and contribute to the industrial application of TA. In addition, the system may also be applied in other PLP-dependent enzymes.

[Consideration on establishing evaluation system of clinical practice guidelines in traditional Chinese medicine].

Standardization is the technical support for the development of traditional Chinese medicine(TCM), and the guidelines have become the main component of the core standards of TCM technology. With the rise and development of evidence-based medicine in China, more than 500 guidelines have been issued in China, and the number is still increasing, but the quality of guidelines still lags far behind the international level. Similarly, the formulation of evidence-based clinical practice guidelines for TCM has gradually attracted the attention of the industry, but the quality is not so good, and most guidelines are not really evidence-based guidelines. Only reliable guidelines can fully and effectively play the role of clinical guidance. In order to comprehensively improve the scientificity and credibility of the guidelines, guideline evaluation can be used as a means to improve the quality of the guidelines. For the development of traditional Chinese medicine, it has become an urgent task to establish a complete evaluation standard system of guidelines, especially the evaluation standard system that conforms to the technical characteristics of traditional Chinese medicine. In this paper, the advantages and limitations of a series of domestic and foreign guideline evaluation tools were systematically analyzed, and the thinking and difficulties to establish the evaluation system of TCM guidelines were put forward, with a purpose to further improve the quality of TCM clinical practice guidelines, so that they can be better applied in clinical practice to enhance the clinical efficacy of TCM and ensure the quality of medical services.

[Quality evaluation recommendation list and interpretation of traditional Chinese medicine clinical practice guidelines].

Based on the idea of establishing a complete guideline evaluation system applicable to the field of traditional Chinese medicine(TCM), the author believes that a complete guideline evaluation system of traditional Chinese medicine clinical practice should be divided into three parts: quality evaluation, clinical applicability evaluation and clinical application investigation. According to the different purposes, different evaluators, different evaluation methods and different evaluation time points in the guideline evaluation, the quality evaluation recommendation list, the clinical applicability evaluation recommendation list and the clinical application questionnaire were formed. Among them, the purpose of quality evaluation is to evaluate the methodological quality in the guideline development process, in order to measure whether the entire guideline development process is scientifically rigorous. The evaluators must be the methodologists with an evidence-based medicine background. Therefore, a logical, detailed and comprehensive guideline quality evaluation list will provide good evaluation tools for the TCM guideline formulation team and play an important role in promoting the quality and application of the guidelines. By referring to the internationally recognized development process and methods of evaluation tools, as well as the proof by authoritative TCM clinical experts and methodologists, the author worked out the quality evaluation list of clinical practice guidelines applicable to the field of TCM by considering the characteristics of TCM field. In this paper, the author introduces the whole list of quality evaluation recommendations, and interprets each item in details, hoping to provide reference for the standardization of TCM clinical practice guidelines in the future.

[Applicability evaluation recommendation list and interpretation of traditional Chinese medicine clinical practice guidelines].

The development of the guidelines should not only meet the rigorous methodological requirements, but also ensure the credibility or enforceability of the guideline recommendations when they are applied in clinical practice. Based on the idea of establi-shing a perfect guideline evaluation system applicable to the field of traditional Chinese medicine(TCM), the author believed that a complete evaluation system of clinical practice guidelines in the field of TCM shall be divided into three parts: quality evaluation, applicability evaluation and clinical application investigation. Among them, applicability evaluation refers to the evaluation of the degree of fit between the guideline and clinical practice, that is, whether the guidelines have good readability and clinical applicability to promote clinical application. The evaluators are clinical experts in the related fields of TCM. Therefore, a logical, detailed and comprehensive guideline quality evaluation list will provide good evaluation tools for the TCM guideline formulation team and play an important role in promoting the quality and application of the guidelines. Based on the internationally recognized development process and methods of evaluation tools, as well as the proof by authoritative TCM clinical experts and methodologists, the author worked out the quality evaluation list of clinical practice guidelines applicable to the field of TCM. In this paper, the author introduces the whole list of quality evaluation, and interprets each item in details, hoping to provide reference for the standardization of TCM clinical practice guidelines in the future.

[Systematic review on clinical efficacy and safety of Cheezheng Pain Relieving Plaster for soft tissue injury].

To systematically evaluate the clinical efficacy and safety of Cheezheng Pain Relieving Plaster in the treatment of soft tissue injury. Four Chinese databases(namely CNKI, WanFang, VIP, CBM) and 2 English databases(namely PubMed, Cochrane Library) were retrieved from the establishment of each database to March 2019. The randomized controlled trials of Cheezheng Pain Relieving Plaster compared with routine therapy in treatment of soft tissue injury were included. The quality of the included studies was assessed using the Cochrane Risk Assessment Tool. Five studies were included, and 367 patients were enrolled. None of the included studies reported randomized concealment, blinding, follow-up and dropping off. The results showed that Cheezheng Pain Relieving Plaster may have advantages in alleviating joint pain, swelling, tenderness and dysfunction and other symptoms, with no serious adverse reaction. Compared with routine therapy, Cheezheng Pain Relieving Plaster may have advantages in the treatment of soft tissue injury. However, due to the quality of the included RCTs, the conclusions of this study were limited. In addition, to produce high-quality evidences for the clinical application of Cheezheng Pain Relieving Plaster, the conclusions of this study shall be further verified with large-sample, scientifically designed and strictly implemented clinical trials.

An expert consensus to standardize acupuncture treatment for knee osteoarthritis.

BACKGROUND: Acupuncture has been advocated for as a potentially effective therapy for patients with knee osteoarthritis (KOA) in systematic reviews and guidelines. However, there is still a lack of agreement on the optimal therapeutic protocol for acupuncture. This aim of this study was to develop an expert consensus regarding the therapeutic protocol of acupuncture to guide doctors in clinical practice. METHODS: An initial list of items was based on an overview of research evidence from four databases and clinical problem investigation with a multidisciplinary panel. A two-step process was used to optimize the list, including semi-structured interviews with three acupuncture clinical experts and a three-round Delphi consensus survey with the voting panel. A nine-point Likert-type scale (1 = strongly disagree, 9 = strongly agree) was used to measure agreement. RESULTS: In total, 52 professionals (response rate: 52%) confirmed their participation in the voting panel. The initial list including 28 items was evaluated. Following a three-round Delphi survey, a consensus was achieved including 37 items that can be broadly categorized into six domains: (1) main treatment principles, (2) acupuncture treatment, (3) dose of acupuncture intervention, (4) primary outcomes, (5) adverse events and (6) others. CONCLUSION: This expert consensus could be used to guide doctors in clinical practice and help patients with KOA gain access to appropriate and coordinated acupuncture treatment.

[Bibliometric analysis and quality assessment of clinical evidence on Xiaotong Tiegao].

Many clinical studies on Cheezheng Xiaotong Tiegao have been accumulated since it was launched in 1993,but they have not been comprehensively analyzed and evaluated. This study systematically retrieved relevant studies in six databases at home and abroad as of December 2017. This study analyzed the statistics of the included studies in several aspects,including publication time,region,fund,disease category and type of study. In this study,various tools were used to evaluate the methodological quality of included studies,such as the Cochrane collaboration's tool for assessing the risk of bias in randomized trials,MINORS,IHE,AMSTAR2.The results showed that the literatures were mainly published from 2010 to 2011,and a total of 28 projects were financially supported.The most involved disease was arthropathy. The randomized controlled trials were the majority in the included studies,but the quality was low,and most of the literatures didn't report the allocation concealment and blinding. This study comprehensively reflected the current situations and shortcomings of the clinical studies of Cheezheng Xiaotong Tiegao,and put forward several suggestions,in the expectation of providing a reference for the future clinical research direction of Cheezheng Xiaotong Tiegao.

Docking-based 3D-QSAR and pharmacophore studies on diarylpyrimidines as non-nucleoside inhibitors of HIV-1 reverse transcriptase.

Diarylpyrimidines (DAPYs), a type of effective HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), have been considered as one of the most successful agents for treating AIDS. A number of structurally diverse DAPYs have been designed and synthesized in the past decade, and most of them exhibited potent anti-HIV-1 activities; however, the structure-activity relationships of recently reported DAPYs and their pharmacophore features that interacted with HIV-1 reverse transcriptase (RT) remain to be studied. In the present study, molecular docking studies were first performed on three novel classes of DAPYs to study their binding pattern in the HIV-1 RT. Based on the docking conformations of these DAPYs, 3D-QSAR models were constructed using CoMSIA and Topomer CoMFA methods, and pharmacophore models were also built using distance comparison technique. All selected DAPYs presented preferred U- or L-shaped conformations while being docked into the non-nucleoside inhibitor-binding pocket of the HIV-1 RT. The best CoMSIA model exhibited powerful predictivity, with satisfactory statistical parameters such as a q2 of 0.572, an r2 of 0.952, and an [Formula: see text] of 0.728. Contour maps of the best CoMSIA model were in accordance with those of the Topomer CoMFA model, giving the insight into the feature requirements of DAPYs for the anti-HIV-1 activity. Three potential pharmacophore models were constructed, and each of them was consisted of five hypothesis features. All results suggested that the aromatic ring on the left wing of DAPYs and the central pyrimidine ring contained key pharmacophore features for the anti-HIV-1 activity, and also indicated that the right wing of DAPYs had potential for further structural modification to improve activity. Eight novel DAPY molecules with potential anti-HIV-1 activities were designed on the basis of the obtained results. The findings in this study might provide important information for further design and development of novel HIV-1 NNRTIs.

Nephrotoxicity of Tripterygium wilfordii Hook. f Preparations: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the incidence rate of nephrotoxicity in Tripterygium wilfordii Hook. f (TwHF) preparations approved by the China Food and Drug Administration and the potential risk factors. METHODS: CENTRAL, PubMed, SinoMed, Chinese National Knowledge Infrastructure, VIP, China Important Conference Papers Database, China Dissertation Database, and online clinical trial registry websites were searched for articles that reported on nephrotoxicity of TwHF preparations until November 23, 2017. There was no limitation for study design. RESULTS: A total of 36 articles involving 2,017 participants were included. Results showed that the incidence of nephrotoxicity associated with TwHF preparations was 5.81% (95% confidence interval: 4.43-7.57). Subgroup analysis showed that the disease type, combined medication, duration, and study design were not correlated with the incidence of nephrotoxicity. CONCLUSION: The incidence rate of nephrotoxicity in TwHF preparations was 5.81%. The possible risk factors, such as disease type, the combination with other drugs, medication time, and study design, were not found to be correlated with the incidence of nephrotoxicity. However, due to the limited number of included articles, the limited sample size, and the poor methodology quality, the incidence rate of nephrotoxicity of TwHF preparations might be overestimated, and more prospective articles are needed to explore the potential influence factor.

Pediatric Tui Na for acute diarrhea in children under 5 years old: A systematic review and meta-analysis of randomized clinical trials.

OBJECTIVE: To evaluate the benefits and harms of pediatric Tui Na as a non-pharmaceutical Chinese medicine therapy for acute diarrhea in children under 5 years of age. DESIGN: Systematic review and meta-analysis of randomized clinical trials. METHODS: We searched seven major English and Chinese databases from their inception to January 2018 for randomized clinical trials (RCTs) comparing pediatric Tui Na therapy with conventional medicine (montmorillonite/diosmectite or probiotics used alone or in combination). Two authors extracted data and assessed the Cochrane risk of bias, independently. The primary outcomes are clinical cure rate and diarrhea duration from admission to the cessation of diarrhea. 'Clinical cure' is defined as the frequency, timing and character of stool back to normal status, as well as disappearance of diarrhea symptoms. We present dichotomous data as risk ratio (RR), and continuous data as mean difference (MD) with their 95% confidence interval (CI). We used the Cochrane's Revman software (v.5.3) for data analysis. Trial sequential analysis (TSA) was applied to calculate the required sample size in a meta-analysis and detect the robustness of the results. The GRADEpro was used to generate a summary of finding table. RESULTS: Totally 26 RCTs were included, involving 2410 children with acute diarrhea. Most of the included trials had high or unclear risk of bias in terms of random sequence generation, blinding, and incomplete outcome reporting. The pooled results demonstrated that pediatric Tui Na was superior to montmorillonite after three-session treatment (RR 1.45, 95% CI 1.29-1.62, n = 772, 10 trials), and also superior to montmorillonite combined with probiotics after three-session treatment (RR 2.04, 95% CI 1.49-2.78, n = 533, 7 trials) and after six-session treatment (RR 1.52, 95% CI 1.34-1.73, n = 631, 5 trials) in improving clinical cure rate. Pediatric Tui Na significantly decreased the duration of acute diarrhea (hrs) (MD -0.40 h, 95% CI -15.31 to -5.48 h, n = 410, 6 trials) and daily stool frequency (MD -1.71times, 95% CI -2.37 to -1.04, n = 217, 3 trials, after three-session treatment). No adverse event related to pediatric Tui Na was reported in the included trials. The quality of evidence of included trials was generally moderate to low. TSA for cure rate demonstrated that the pooled data reached a sufficient power regarding both numbers of trials and participants. CONCLUSIONS: This review shows pediatric Tui Na appears to be effective and safe in improving clinical cure rate and shortening diarrhea duration in childhood aged less than five years of age with acute diarrhea. However, rigorously designed well-reported RCTs are warranted to confirm the findings.

[Current research situation of nephrotoxicity of Chinese herbal medicine].

To provide the basis for the future research on the nephrotoxicity of Chinese herbal medicine through systematic and comprehensive summary of all the Chinese herbal medicines which may lead to nephrotoxicity. Foreign resources included PubMed and Cochrane library， and domestic research resources was China Food and Drug Administration(CDFA) Adverse Drug Reaction Monitoring Center database. The databases were searched from establishment to January 1， 2017. There was no limitation on research type. 28 English studies were found， including 97 Chinese herbs or prescriptions with the risk of nephrotoxicity. The following six Chinese herbal medicines with the risk of nephrotoxicity had a large number of studies： aristolochic acid(5 studies)， Tripterygium wilfordii(4 studies)， Erycibe obtusifolia(2 studies)， Rheum palmatum(2 studies)， Ephedra sinica(2 studies)， and Atractylodes lances(2 studies). The remaining 91 Chinese medicines were reported with risk of nephrotoxicity in only 1 study respectively. CDFA reported 16 Chinese herbal medicines with the risk of nephrotoxicity， including Ganmaoqing Pian(capsule)， Zhenju Jiangya Pian， T. wilfordii preparation， Vc-Yinqiao Pian， Chuanhuning injection， Shuanghuanglian injection， Qingkailing injection， Lianbizhi injection， herbal decoction containing Aristolochiae Radix， Guanxin Suhe Wan， Shugan Liqi Wan， Ershiwuwei Songshi Wan， herbal decoction containing Aristolochia Fangchi， herbal granules containing root of Kaempfer Dutchmanspipe， Ganmaotong(tablets)， and Longdan Xiegan Wan. Currently， in addition to aristolochic acids， the most reported Chinese herbal medicine with the risk of nephrotoxicity is T. wilfordii preparation.

[Evaluation of reporting quality of RCT on nephrotoxicity of Tripterygium wilfordii preparations according to CONSORT HARMs statement].

To evaluate the quality of randomized controlled trials(RCT) on nephrotoxicity of Tripterygium wilfordii preparations according to the CONSORT HARMs statement. The report quality of each included study was evaluated according to the CONSORT HARMs statement， and the number of entries that comply with CONSORT HARMs statement was calculated in each study to evaluate the report quality on nephrotoxicity-related adverse reactions of T. wilfordii preparations and summarize the problems in domestic studies on nephrotoxicity-related adverse reactions. A total of 16 RCTs were included， with an average of 7 entries complying with CONSORT HARMs statement per study. The report of the nephrotoxic-associated RCT of T. wilfordii preparations was of poor quality and the most non-repeating entries included the following ones： using validated tools to report adverse effects， standards for coding of the adverse reactions， describing how and when to collect data on adverse reactions in Method， describing how adverse reactions are attributed to T. wilfordii， clearly stating who has reported the adverse reactions， describing the analysis method of adverse reactions， describing the method of collecting recurrent adverse reaction data， describing any subgroup analysis and exploratory analysis associated with the hazard. We suggest that the studies on adverse reactions of traditional Chinese medicine should strictly report the entries according to the CONSORT HARMs statement， and take the characteristics of traditional Chinese medicine into account to report the details of the Chinese medicine like compositions， dose， taking time， combined medication and the dialectical typology of research objects.

[Evidence-based evaluation on safety of Tripterygium wilfordii preparations].

The study was aimed to conduct an evidence-based evaluation on the safety of Tripterygium wilfordii(TW) preparations through a method combined bibliometrics research with evidence-based evaluation research， to provide evidence-based safety information of the TW preparations(nephrotoxicity) for the government decision-making and clinical application， and to provides methods and suggestions for evaluating nephrotoxicity of Chinese herbal medicine(CHM) in the future. We searched relevant databases at home and abroad systematically， and six Chinese and English databases including CNKI， SinoMed， VIP， WanFang， PubMed， and Cochrane library were comprehensively searched. All types of research documents about the safety of TW preparations. Literature were screened and extracted based on inclusion and exclusion criteria. The methodology quality of all included studies were assessed by internationally recognized evaluation tools or standards. The incidence rate was analyzed by using R software. Subgroup analysis were conducted according to the type of disease treated， drug delivery way， medication time， and study types.

[Application of evidence-based rapid review in studying nephrotoxicity of Tripterygium wilfordii preparation].

To investigate the feasibility of applying the evidence-based rapid review in studying the nephrotoxicity of Tripterygium wilfordii preparation. We used four methods in relevant studies on the nephrotoxicity of T. wilfordii preparation. The first method had no limitation on any search terms， which was a traditional approach to retrieve systematic reviews. The second method limited the relevant search terms of T. wilfordii preparation to "all of CHMs containing T. wilfordii preparation approved by CFDA". The third method was to limit the relevant retrieval terms of nephrotoxicity as the "most frequently reported terms related to nephrotoxicity found in the study literature screening process in the early stage of systematic review". The fourth method was to limit the search terms relating to both T. wilfordii preparation and nephrotoxicity. Finally， the results of the last three search methods were compared with those of the first search method， and the feasibility of the rapid review method in the study for the nephrotoxicity of CHM was discussed. For the total number of literatures searched， the fourth method had the smallest number of literatures. For the number of articles in line with the inclusion criteria， the second method had the largest number of eligible literatures. For the type of literatures included， the forth method had a higher coincidence degree. The forth method was the best one， because it was not only consistent with the results， but also could minimize the workload. Rapid review is feasible in the study of nephrotoxicity of T. wilfordii.

Design, syntheses and lipid accumulation inhibitory activities of novel resveratrol mimics.

Hispidine was initially discovered from Ficus Hispida for cardiovascular protection. In this paper, hispidine derivatives, which contain a novel resveratrol-like scaffold, have been designed, synthesized, and assayed as agents against lipid accumulations in 3T3-L1 pre-adipocytes. Six hispidine derivatives have the activity of reducing TG in 3T3-L1 adipocytes in dosage-dependent manner. The most active compound can reduce the lipid accumulation up to 78.4% at 10 µM qPCR and Western blotting results demonstrate that the two most active compounds inhibit both lipodenesis and adipogenesis in 3T3-L1 cells through (1) increasing the phosphorylations of AMPK and ACC, promoting SIRT1 expression. These three proteins are key regulators for lipogenesis and energy metabolism. (2) Decreasing the expressions of PPARγ, sREBP-1c, and FABP4, which are pivotal regulators for adipogenesis. Overall, this work proves that hispidine derivatives diminish the lipid accumulation in 3T3-L1 cell line by downregulating lipogenic and adipogenic pathways.

[Manual for the clinical experts consensus of Chinese patent medicine].

Chinese patent medicine is widely used in clinical practice, but improper use will not only weaken the efficacy of drugs, but even cause adverse consequences. Evidence-based medicine provides guidance for clinical practice based on the best available evidence, experience of experts and needs of patients. However, considering the situation of "insufficient evidence" or "very low quality" in Chinese medicine research, experts consensus is the main basis for clinical decision-making, but expert opinions on which the consensus depends are susceptible to various subjective biases. Therefore, a reliable and scientific consensus-making process is needed to maximally avoid bias on consensus. Unlike the clinical practice guidelines, there is no unified formulating process for consensus in the world today. This article learns from a set of formulating processes from some international consensus formulating institutions/associations, combined with the characteristics and current situation of traditional Chinese medicine, and draws up a set of standard process that is suitable for the clinical experts consensus on Chinese patent medicine, with the expect of providing evidence and reference for consensus makers, and then bringing evidence-based assistance for the clinical standardized application of Chinese patent medicines.

[Discussion on issues related to clinical experts consensus of Chinese patent medicine].

The promulgation of standardized documents on traditional Chinese medicine has promoted the formulation of industrial standards of traditional Chinese medicine, including clinical practice guidelines and clinical expert consensus. In order to adapt to the current research situation of "insufficient evidence" or "very low quality" when developing clinical practice guideline in the field of traditional Chinese medicine, the author has made a retrospective study on the development of guidelines and consensus, and found that the consensus is more suitable for the current research status of Chinese patent medicine, as the stage of lack of high-quality clinical evidence will remain for a long time. However, unlike clinical practice guidelines, domestic scholars and consensus makers have insufficient understanding of the clinical experts consensus. This article will introduce the origin and status of the clinical experts consensus, the differences between clinical experts consensus and the clinical practice guidelines, and the basic principles that should be followed in the formulation of the clinical experts consensus of Chinese patent medicine, expecting to provide theory basis and reference for the normative formulation of clinical experts consensus.

[Reporting criteria for clinical experts consensus of Chinese medicine].

Due to its own characteristics and research status, traditional Chinese medicine research often faces the reality of "insufficient evidence" or "very low quality" when making clinical practice guidelines. Therefore, in many cases, clinical decision-making of traditional Chinese medicine should rely mainly on expert consensus to achieve. A clear and detailed list of expert consensus report specifications will provide a good reporting tool for Chinese clinical expert consensus makers, which is very important for promoting the quality of consensus production and the promotion and application of consensus results. The author consulted the internationally published authoritative expert consensus, summarized the main points of the reports, combined with the formulation process of the clinical experts consensus of Chinese medicine, and the demonstration of clinical experts and methodologists, and then formulated the list of items for clinical expert consensus reports adapt to the field of Chinese medicine. This article introduces the entire list of items and elaborates on the key parts. It is expected to provide reference for the standardization of future clinical expert consensus reports.

Synthesis and anti-neuroinflammatory activity of lactone benzoyl hydrazine and 2-nitro-1-phenyl-1h-indole derivatives as p38α MAPK inhibitors.

Inhibition of p38 mitogen-activated protein kinases (MAPKs) would allow significant modulation of the neuroinflammation condition associated with Alzheimer's disease (AD). Inspired from the pharmacophore of natural NF-κB and p38α MAPK inhibitor 5,6-dehydrokawain and p38α MAPK inhibitors 1a, 1-pyrazolyl-3-(4-((2-anilinopyrimidin-4-yl)oxy)napththalen-1-yl)ureas, and 1b, a class of indole-pyrimidinyl compounds which were patented respectively, we designed, de novo synthesized, and evaluated two kinds of novel series of lactone benzoyl hydrazine derivatives and 2-nitro-1-phenyl-1H-indole derivatives in an effort to develop pharmacologically tractable agents to alleviate the progression of AD. Fourteen of the seventeen synthesized compounds exhibit significant inhibitory effect on the nitric oxide (NO) production induced by lipopolysaccharide (LPS)-induced microglia activation with IC50 less than the control 5,6-dehydrokawain. Notably, compound 27, 6-methoxy-2-nitro-1-(1H-1, 2, 3-triazol-1-yl)-1H-indole, with IC50 values of 1.6 µm can markedly inhibit p38α MAPK and NO release in BV-2 microglial cells. The molecular dynamic (MD) simulations demonstrate that compound 27 inhibits p38α MAPK through binding to the Glu71 and Asp168 residues. Moreover, in vitro study shows that all compounds can easily cross the blood-brain barrier (BBB) and did not exhibit any acute cellular toxicity checked by MTT assay. These investigations provide promising chemical lead candidate as anti-neuroinflammatory agents for AD.

Synthesis, antitumor activity, and mechanism of action of 6-acrylic phenethyl ester-2-pyranone derivatives.

Based on the scaffolds of caffeic acid phenethyl ester (CAPE) as well as bioactive lactone-containing compounds, 6-acrylic phenethyl ester-2-pyranone derivatives were synthesized and evaluated against five tumor cell lines (HeLa, C6, MCF-7, A549, and HSC-2). Most of the new derivatives exhibited moderate to potent cytotoxic activity. Moreover, HeLa cell lines showed higher sensitivity to these compounds. In particular, compound showed potent cytotoxic activity (IC50 = 0.50-3.45 µM) against the five cell lines. Further investigation on the mechanism of action showed that induced apoptosis, arrested the cell cycle at G2/M phases in HeLa cells, and inhibited migration through disruption of the actin cytoskeleton. In addition, ADMET properties were also calculated in silico, and compound showed good ADMET properties with good absorption, low hepatotoxicity, and good solubility, and thus, could easily be bound to carrier proteins, without inhibition of CYP2D6. A structure-activity relationship (SAR) analysis indicated that compounds with ortho-substitution on the benzene ring exhibited obviously increased cytotoxic potency. This study indicated that compound is a promising compound as an antitumor agent.