A comprehensive review of BET-targeting PROTACs for cancer therapy.

Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) has emerged as an effective strategy for drug discovery, given their unique advantages over target protein inhibition. The bromodomain and extra-terminal (BET) family proteins play a key role in regulating oncogene expression and are considered attractive therapeutic targets for cancer therapy. Considering the therapeutic potential of BET proteins in cancer and the marked attractiveness of PROTACs, BET-targeting PROTACs have been extensively pursued. Recently, BET-targeting PROTACs based on new E3 ligases and novel strategies, such as light-activated, macrocyclic, folate-caged, aptamer-PROTAC conjugation, antibody-coupling, and autophagy-targeting strategies, have emerged. In the present review, we provide a comprehensive summary of advances in BET-targeting PROTACs.

[Evaluation of methodological and reporting quality of domestic clinical guidelines for hyperuricemia].

This study aims to evaluate the methodological and reporting quality of diagnosis and treatment guidelines for hyperuricemia as well as the expert consensuses and promote the understanding and application of the diagnosis and treatment guidelines for hyperuricemia. With "hyperuricemia" "guidelines" "consensus" "recommendations" as the key words in titles, the authors searched for the published clinical guidelines on hyperuricemia in Chinese against CNKI, Wanfang, VIP, Medlive and the official website of the industry association. The retrieval time limit was until May 31, 2021. The appraisal of guidelines for research and evaluation Ⅱ(AGREEⅡ) and the reporting items for practice guidelines in health care(RIGHT) were employed to evaluate the methodological quality and reporting quality of 14 guidelines/consensuses included. The average scores of the guidelines/consensuses were 80.85%(48.61%-98.61%) for the domain of scope and purpose, 34.52%(0-69.44%) for the domain of stakeholder involvement, 35.53%(6.25%-92.19%) for the domain of rigor of development, 55.85%(23.61%-86.11%) for the domain of clarity of presentation, 26.19%(0-76.04%) for the domain of applicability, and 21.42%(0-50.00%) for the domain of editorial independence. Nine guidelines/consensuses were of medium overall quality with grade B recommendation, and five guidelines/consensuses were of poor quality with grade C recommendation. The RIGHT classified the fourteen guidelines/consensuses into one of high reporting quality, three of medium reporting quality, and ten of low reporting quality. The results of this study indicate that the standardization and rigor of the methodological quality and the reporting quality of the clinical guidelines/consensuses for hyperuricemia in China remain to be strengthened.

Acupuncture for functional gastrointestinal disorders: A systematic review and meta-analysis.

OBJECTIVES: The therapeutic effect of acupuncture treatments (AT) on functional gastrointestinal disorders (FGIDs) is contentious. A meta-analysis was conducted to assess the efficacy and safety of acupuncture for FGIDs. METHODS: The Cochrane Library, EMBASE, PUBMED, Web of Science, Wanfang Database, China National Knowledge Infrastructure, and VIP Database were searched through December 31, 2019 with no language restrictions. Risk ratio (RR) with 95% confidence interval (CI) was calculated to determine the improvement in symptom severity after treatment. RESULTS: A total of 61 randomized controlled trials (RCTs) on FGIDs were included. The pooled results illustrated the following: compared to pharmacotherapy (RR 1.13, 95% CI 1.09-1.17), placebo acupuncture (RR 1.69, 95% CI 1.37-2.08), no specific treatment (RR 1.86, 95% CI 1.31-2.62), and AT as an adjuvant intervention to other active treatments (RR 1.25, 95% CI 1.21-1.30), AT had more favorable improvements in symptom severity; sub-group analysis results classified according to functional dyspepsia, irritable bowel syndrome, and functional constipation also supported this finding; and the incidence of adverse events was lower in AT than in other treatments (RR 0.75, 95% CI 0.56-0.99). CONCLUSIONS: This meta-analysis found that AT was significantly associated with relief of FGIDs symptoms; however, the evidence level was moderate or low. Further data from rigorously designed and well powered RCTs are needed to verify the effectiveness and safety of AT as a FGIDs treatment. PROSPERO PROTOCOL NUMBER: CRD42020169508.

Diastereomeric resolution of racemic o-chloromandelic acid.

The separation of rac-o-chloromandelic acid 1 with enantiopure aryloxypropylamine via diastereomeric salt formation was investigated. (R)-o-chloromandelic acid (R)-1, a key intermediate for the antithrombotic agent clopidogrel, was obtained in 65% yield and 98% ee by Dutch resolution of rac-1 with (S)-2-hydroxyl-3-(p-chlorophenoxy) propylamine (S)-5 as resolving agent and (S)-2-hydroxyl-3-(o-nitrophenoxy) propylamine (S)-4 as nucleation inhibitor.

Recent strategies targeting Embryonic Ectoderm Development (EED) for cancer therapy: Allosteric inhibitors, PPI inhibitors, and PROTACs.

The polycomb repressive complex 2 (PRC2), which comprised of the core subunits: Enhancer of Zeste Homolog 2 (EZH2), Suppressor of Zeste 12 (SUZ12), and Embryonic Ectoderm Development (EED), is an essential epigenetic gene silencer responsible for depositing repressive histone H3 lysine 27 trimethylation (H3K27me3) marks on chromatin. The aberrant activity of PRC2 is closely involved in tumorigenesis and progression, making its inhibition a viable strategy for epigenetic cancer therapy. Although the clinical development of small PRC2 inhibitors has made impressive progress, with one EZH2 inhibitor approved for cancer therapy and several other candidates in clinical trials, current EZH2 inhibitors are limited to treating certain hematological malignancies and have acquired drug resistance. EED is essential for PRC2 stabilization and allosterically stimulating PRC2 activity because it functions as a scaffold protein and an H3K27me3-recognizing protein. Thus, due to its novel mechanism of action, targeting EED provides a promising new strategy for inhibiting PRC2 function and exhibits the potential to overcome the issues encountered by EZH2 inhibitors. This review provides a comprehensive overview of available cancer therapy strategies that target EED, including allosteric inhibitors, protein-protein interaction (PPI) inhibitors, and proteolysis-targeting chimeras (PROTACs).

Research progress of dual inhibitors targeting crosstalk between histone epigenetic modulators for cancer therapy.

Abnormal epigenetics is a critical hallmark of human cancers. Anticancer drug discovery directed at histone epigenetic modulators has gained impressive advances with six drugs available for cancer therapy and numerous other candidates undergoing clinical trials. However, limited therapeutic profile, drug resistance, narrow safety margin, and dose-limiting toxicities pose intractable challenges for their clinical utility. Because histone epigenetic modulators undergo intricate crosstalk and act cooperatively to shape an aberrant epigenetic profile, co-targeting histone epigenetic modulators with a different mechanism of action has rapidly emerged as an attractive strategy to overcome the limitations faced by the single-target epigenetic inhibitors. In this review, we summarize in detail the crosstalk of histone epigenetic modulators in regulating gene transcription and the progress of dual epigenetic inhibitors targeting this crosstalk.

Uncovering the pathophysiology of irritable bowel syndrome by exploring the gut-brain axis: a narrative review.

OBJECTIVE: To improve the pathophysiological understanding of irritable bowel syndrome (IBS) by exploring the gut-brain axis. BACKGROUND: Disorders of gut-brain interaction (DGBIs) are gastrointestinal (GI) disorders in which alterations in bowel functions occur. IBS, which is one of the most studied DGBIs, is linked with abdominal distress or pain without obvious structural or biochemical anomalies. METHODS: The etiology of IBS has not been clearly described but is known to be multifactorial, involving GI motility changes, post-infectious reactivity, visceral hypersensitivity, gut-brain interactions, microbiota dysbiosis, small intestinal bacterial overgrowth, food sensitivity, carbohydrate malabsorption, and intestinal inflammation. CONCLUSIONS: One of the main features of IBS is the occurrence of structural and functional disruptions in the gut-brain axis, which alter reflective and perceptual nervous system reactions. Herein, we provide a brief summary of this topic. Furthermore, we discuss animal models, which are important in the study of IBS, especially as it is linked with stressors. These animal models cannot fully represent the human disease but serve as important tools for understanding this complicated disorder. In the future, technologies, such as organ-on-a-chip models and metabolomics, will provide novel information regarding the pathophysiology of IBS, which will play an important role in treatment development. Finally, we take a brief glance at how acupuncture treatments may hold potential for patients with IBS.

Design, synthesis, and biological evaluation of novel dual inhibitors targeting lysine specific demethylase 1 (LSD1) and histone deacetylases (HDAC) for treatment of gastric cancer.

LSD1 and HDAC are physical and functional related to each other in various human cancers and simultaneous pharmacological inhibition of LSD1 and HDAC exerts synergistic anti-cancer effects. In this work, a series of novel LSD1/HDAC bifunctional inhibitors with a styrylpyridine skeleton were designed and synthesized based on our previously reported LSD1 inhibitors. The representative compounds 5d and 5m showed potent activity against LSD1 and HDAC at both molecular and cellular level and displayed high selectivity against MAO-A/B. Moreover, compounds 5d and 5m demonstrated potent antiproliferative activities against MGC-803 and HCT-116 cancer cell lines. Notably, compound 5m showed superior in vitro anticancer potency against a panel of gastric cancer cell lines than ORY-1001 and SP-2509 with IC50 values ranging from 0.23 to 1.56 µM. Compounds 5d and 5m significantly modulated the expression of Bcl-2, Bax, Vimentin, ZO-1 and E-cadherin, induced apoptosis, reduced colony formation and suppressed migration in MGC-803 cancer cells. In addition, preliminary absorption, distribution, metabolism, excretion (ADME) studies revealed that compounds 5d and 5m showed acceptable metabolic stability in human liver microsomes with minimal inhibition of cytochrome P450s (CYPs). Those results indicated that compound 5m could be a promising lead compound for further development as a therapeutic agent in gastric cancers via LSD1 and HDAC dual inhibition.

[Investigation of determining strontium in M. nitida Benth. var. hirsutissima. Z. Wei. by flame atomic absorption spectra].

The present paper is aimed to establish the method of determining the strontium in M. nitida Benth. var. hirsutissima. Z. Wei. by means of air-acetylene flame atomic absorption spectra, and also provide reference for the determination of the strontium in other traditional Chinese medicine. M. Nitida Benthvarhirsutissima Z. Wei. was taken as the object. The authors used nitric-perchloric acid as digestion solution to digest samples by microwave which was controlled by pressure, and used EDTA-2Na as the releasing agent to add in the samples for determining the strontium in M. nitida Benth. var. hirsutissima. Z. Wei. by FAAS. The results showed that the samples were entirely digested by microwave. The working curve was Y = 0.036 5x -0.001 1, r = 0.999 4, the range was 0-1.6 microg x mL(-1), the average recovery rate was 101.5% with RSD 2.04%, and the method detection limit was 0.008 2 microg x mL(-1) (n = 21). It is concluded that this method is simple and accurate. It has high sensitivity and can be effectively used for determining the strontium in this traditional Chinese medicine.

Retention of volunteers and factors influencing program performance of the Senior Care Volunteers Training Program in Jiangsu, China.

BACKGROUND: As the country with the largest aging population, China faces an enormous challenge with its elderly support and care. One of the proposed solutions is the development of volunteerism for elderly care. The Senior Care Volunteers Training Program (SCVTP) was initiated by the Red Cross Society of China with the purpose of training volunteers to care for community seniors. As one of the four pilot provinces, Jiangsu Province launched the program since 2017. AIMS: The present study was conducted to investigate the dropout rate of trained volunteer group leaders, the characteristics of the retained trained volunteer group leaders and the activities that their groups conducted. Additionally, the exploration of the factors influencing the SCVTP's performance was listed as another aim. METHODS: A cross-sectional study was designed. The study used purposive sampling to select participants who meet the criteria from all the trained volunteer group leaders (n = 623). Demographic questionnaire, volunteer role identity (VRI) scale, attitude toward helping others (AHO) scale, team climate and atmosphere (TCA) scale, and volunteer program performance evaluation (VPPE) questionnaire were used to collect the data online. Descriptive statistics were used to determine the dropout rate and general characteristics of the retained volunteers and the activities. A multiple linear regression equation was developed to study the factors that influence program performance. RESULTS: In total, 307 questionnaires were valid in the study. About 67.9%, 53.7%, and 30.0% of the trained volunteer group leaders dropped out of the program in the year of 2017, 2018, and 2019, respectively. The retained trained volunteer group leaders were more likely to be females (84.7%), those in excellent health (75.2%) and with a bachelor's degree or above (87.6%). Less attention has been paid to frailty care (n = 76) than other volunteer caring activities (e.g., safe care: n = 277, diet care: n = 250, drug management care: n = 226). VRI (ß = 0.118, p = 0.017), AHO (ß = 0.134, p = 0.021), TCA (ß = 0.459, p<0.001), and financial sustainability (ß = 0.179, p<0.001) affected the SCVTP's performance significantly (adjusted R2 = 0.356). CONCLUSION: High rate of trained volunteer group leaders' dropout should be brought to the policymaker's attention. The characteristics of the retained trained volunteer group leaders provide a useful reference for the recruitment of trainees in the future. Frailty care may need more training by the volunteer service provider. In order to enhance program performance, a better team climate and atmosphere, financial sustainability, and volunteers with appropriate attitude and role identity are also necessary for the volunteer program.

Brain functional connectivity network studies of acupuncture: a systematic review on resting-state fMRI.

BACKGROUND: Functional magnetic resonance imaging (fMRI) is a novel method for studying the changes of brain networks due to acupuncture treatment. In recent years, more and more studies have focused on the brain functional connectivity network of acupuncture stimulation. OBJECTIVE: To offer an overview of the different influences of acupuncture on the brain functional connectivity network from studies using resting-state fMRI. SEARCH STRATEGY: The authors performed a systematic search according to PRISMA guidelines. The database PubMed was searched from January 1, 2006 to December 31, 2016 with restriction to human studies in English language. INCLUSION CRITERIA: Electronic searches were conducted in PubMed using the keywords "acupuncture" and "neuroimaging" or "resting-state fMRI" or "functional connectivity". DATA EXTRACTION AND ANALYSIS: Selection of included articles, data extraction and methodological quality assessments were respectively conducted by two review authors. RESULTS: Forty-four resting-state fMRI studies were included in this systematic review according to inclusion criteria. Thirteen studies applied manual acupuncture vs. sham, four studies applied electro-acupuncture vs. sham, two studies also compared transcutaneous electrical acupoint stimulation vs. sham, and nine applied sham acupoint as control. Nineteen studies with a total number of 574 healthy subjects selected to perform fMRI only considered healthy adult volunteers. The brain functional connectivity of the patients had varying degrees of change. Compared with sham acupuncture, verum acupuncture could increase default mode network and sensorimotor network connectivity with pain-, affective- and memory-related brain areas. It has significantly greater connectivity of genuine acupuncture between the periaqueductal gray, anterior cingulate cortex, left posterior cingulate cortex, right anterior insula, limbic/paralimbic and precuneus compared with sham acupuncture. Some research had also shown that acupuncture could adjust the limbic-paralimbic-neocortical network, brainstem, cerebellum, subcortical and hippocampus brain areas. CONCLUSION: It can be presumed that the functional connectivity network is closely related to the mechanism of acupuncture, and central integration plays a critical role in the acupuncture mechanism.

Discovery of resveratrol derivatives as novel LSD1 inhibitors: Design, synthesis and their biological evaluation.

Inhibition of lysine-specific demethylase 1 (LSD1) has recently emerged as an attractive therapeutic target for treating cancer and other diseases. As a continuity of our ongoing effort to identify novel small-molecule LSD1-inhibitors, we designed and synthesized a series of resveratrol derivatives, which were shown to be potent inhibitors of LSD1. Among them, compounds 4e and 4m displayed the most potent LSD1-inhibitory activities in enzyme assays, with IC50 values of 121 nM and 123 nM, respectively. Biochemistry study and docking analysis indicated that compounds 4e and 4m were reversible LSD1 inhibitors. High content analysis showed that 4e and 4m induced a dose-dependent increase of dimethylated Lys4 of histone H3 and had no impact on the expression of LSD1 in MGC-803 cells. Furthermore, 4e or 4m could remarkably increase the mRNA level of CD86, a surrogate cellular biomarker for LSD1 activity, in MGC-803 cells, suggesting that they are likely to exhibit LSD1-inhibitory activities intracellularly. These findings should encourage further modification of these compounds to produce more potent LSD1 inhibitors with potential anticancer activity.

Design and synthesis of tranylcypromine derivatives as novel LSD1/HDACs dual inhibitors for cancer treatment.

Lysine specific demethylase 1 (LSD1) and Histone deacetylases (HDACs) are promising drug targets for cancers. Recent studies reveal an important functional interplay between LSD1 and HDACs, and there is evidence for the synergistic effect of combined LSD1 and HDAC inhibitors on cancers. Therefore, development of inhibitors targeting both LSD1 and HDACs might be a promising strategy for epigenetic therapy of cancers. We report herein the synthesis of a series of tranylcypromine derivatives as LSD1/HDACs dual inhibitors. Most compounds showed potent LSD1 and HDACs inhibitory activity, especially compound 7 displayed the most potent inhibitory activity against HDAC1 and HDAC2 with IC50 of 15 nM and 23 nM, as well as potent inhibition against LSD1 with IC50 of 1.20 µM. Compound 7 demonstrated stronger anti-proliferative activities than SAHA with IC50 values ranging from 0.81 to 4.28 µM against MGC-803, MCF-7, SW-620 and A-549 human cancer cell lines. Further mechanistic studies showed that compound 7 treatment in MGC-803 cells dose-dependently increased cellular H3K4 and H3K9 methylation, as well as H3 acetylation, decreased the mitochondrial membrane potential and induced remarkable apoptosis. Docking studies showed that compound 7 can be well docked into the active binding sites of LSD1 and HDAC2. This finding highlights the potential for the development of LSD1/HDACs dual inhibitors as novel anticancer drugs.

Design, synthesis and antiproliferative activity studies of novel 1,2,3-triazole-dithiocarbamate-urea hybrids.

A series of novel 1,2,3-triazole-dithiocarbamate-urea hybrids were designed, synthesized and their antiproliferative activities against four selected human cancer cell lines were evaluated. The results showed that a number of the hybrids exhibited potent activity in selected human cancer cell lines. Among them, compounds 27 and 34 showed broad spectrum anticancer activity with IC50 values ranging from 1.62 to 20.84 µM and 0.76 to 13.55 µM, respectively. Interestingly, compounds 27 and 34, being very potent against MGC-803 cells, exhibited no significant cytotoxicity against normal human embryonic kidney cells at up to 55 µM and 70 µM, respectively. Evidences of cell cycle arrest and apoptosis induction were obtained for the most effective compounds 27 and 34 by means of flow cytometry and microscopic techniques.