BindingSiteDTI: differential-scale binding site modelling for drug-target interaction prediction.

MOTIVATION: Enhanced by contemporary computational advances, the prediction of drug-target interactions (DTIs) has become crucial in developing de novo and effective drugs. Existing deep learning approaches to DTI prediction are frequently beleaguered by a tendency to overfit specific molecular representations, which significantly impedes their predictive reliability and utility in novel drug discovery contexts. Furthermore, existing DTI networks often disregard the molecular size variance between macro molecules (targets) and micro molecules (drugs) by treating them at an equivalent scale that undermines the accurate elucidation of their interaction. RESULTS: We propose a novel DTI network with a differential-scale scheme to model the binding site for enhancing DTI prediction, which is named as BindingSiteDTI. It explicitly extracts multiscale substructures from targets with different scales of molecular size and fixed-scale substructures from drugs, facilitating the identification of structurally similar substructural tokens, and models the concealed relationships at the substructural level to construct interaction feature. Experiments conducted on popular benchmarks, including DUD-E, human, and BindingDB, shown that BindingSiteDTI contains significant improvements compared with recent DTI prediction methods. AVAILABILITY AND IMPLEMENTATION: The source code of BindingSiteDTI can be accessed at https://github.com/MagicPF/BindingSiteDTI.

Prevalence and risk factors of long COVID 6-12 months after infection with the Omicron variant among nonhospitalized patients in Hong Kong.

Long COVID has been reported among patients with COVID-19, but little is known about the prevalence and risk factors associated with long COVID 6-12 months after infection with the Omicron variant. This is a large-scale retrospective study. A total of 6242 out of 12 950 nonhospitalized subjects of all ages with SARS-CoV-2 infection (confirmed by polymerase chain reaction/rapid antigen test) during the Omicron dominant outbreak (December 31, 2021-May 6, 2022) in Hong Kong were included. Prevalence of long COVID, frequencies of symptoms, and risk factors were analyzed. Three thousand four hundred and thirty (55.0%) subjects reported at least one long COVID symptom. The most reported symptom was fatigue (1241, 36.2%). Female gender, middle age, obesity, comorbidities, vaccination after infection, having more symptoms, and presenting fatigue/chest tightness/headache/diarrhea in the acute stage of illness were identified as associated risk factors for long COVID. Patients who had received three or more doses of vaccine were not associated with a lower risk of long COVID (adjusted odds ratio 1.105, 95% confidence interval 0.985-1.239, p = 0.088). Among patients with at least three doses of vaccine, there was no significant difference in the risk of long COVID between the CoronaVac vaccine and BNT162b2 vaccine (p > 0.05). Omicron infection can lead to long COVID in a significant proportion of nonhospitalized patients 6-12 months after infection. Further investigation is needed to uncover the mechanisms underlying the development of long COVID and determine the impact of various risk factors such as vaccines.

Weekly symptom profiles of nonhospitalized individuals infected with SARS-CoV-2 during the Omicron outbreak in Hong Kong: A retrospective observational study from a telemedicine center.

Omicron BA.2.2 is the dominant variant in the Hong Kong outbreak since December 31, 2021. There is no study reporting the weekly symptom profile after infection. In this retrospective study, participants who tested positive for SARS-CoV-2 after December 31, 2021, and registered in the telemedicine system between March 14 and May 6, 2022, were analyzed. Among registered 12 950 self-quarantined COVID-19-positive patients, 11 776 symptomatic patients were included for weekly symptom profile analysis. A total of 4718 (40.1%) patients reported symptoms in the first week after a positive test, 2501 (21.2%) in the second week, 1498 (12.7%) in the third week, 1048 (8.9%) in the fourth week, and 2011 (17.1%) in over 4 weeks. Cough was the most common symptom in all participants. Patients in the first week had higher odds of reporting fever (0.206, 95% confidence interval [CI]: 0.161-0.263, p < 0.001) and sore throat (0.228, 95% CI: 0.208-0.252, p < 0.001). Patients in over 4 weeks had higher odds of reporting fatigue (1.263, 95% CI: 1.139-1.402, p < 0.001). Further, having at least two vaccine doses linked to lower odds of having fever (0.675, 95% CI: 0.562-0.811, p < 0.001), but not associated with the presence of cough and fatigue. Diabetic patients had higher odds of reporting diarrhea (1.637, 95% CI: 1.351-1.982, p < 0.001). Symptoms from Omicron infection may last for more than 4 weeks and symptom profiles vary from week to week. Vaccination and comorbidity affect the symptom profiles.

A cross-sectional study of the endorsement proportion of reporting guidelines in 1039 Chinese medical journals.

BACKGROUND: Reporting quality is a critical issue in health sciences. Adopting the reporting guidelines has been approved to be an effective way of enhancing the reporting quality and transparency of clinical research. In 2012, we found that only 7 (7/1221, 0.6%) journals adopted the Consolidated Standards of Reporting Trials (CONSORT) statement in China. The aim of the study was to know the implementation status of CONSORT and other reporting guidelines about clinical studies in China. METHODS: A cross-sectional bibliometric study was conducted. Eight medical databases were systematically searched, and 1039 medical journals published in mainland China, Hong Kong, Macau, and Taiwan were included. The basic characteristics, including subject, language, publication place, journal-indexed databases, and journal impact factors were extracted. The endorsement of reporting guidelines was assessed by a modified 5-level evaluation tool, namely i) positive active, ii) positive weak, iii) passive moderate, iv) passive weak and v) none. RESULTS: Among included journals, 24.1% endorsed CONSORT, and 0.8% endorsed CONSORT extensions. For STROBE (STrengthening the Reporting of Observational Studies in Epidemiology), PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), STARD (An Updated List of Essential Items for Reporting Diagnostic Accuracy Studies), CARE (CAse REport guidelines), the endorsement proportion were 17.2, 16.6, 16.4, and 14.8% respectively. The endorsement proportion for SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials), TRIPOD (Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis), AGREE (Appraisal of Guidelines, Research, and Evaluation), and RIGHT (Reporting Items for Practice Guidelines in Healthcare) were below 0.7%. CONCLUSIONS: Our results showed that the implementation of reporting guidelines was low. We suggest the following initiatives including i) enhancing the level of journal endorsement for reporting guidelines; ii) strengthening the collaboration among authors, reviewers, editors, and other stakeholders; iii) providing training courses for stakeholders; iv) establishing bases for reporting guidelines network in China; v) adopting the endorsement of reporting guidelines in the policies of the China Periodicals Association (CPA); vi) promoting Chinese medical journals into the international evaluation system and publish in English.

Reporting quality of randomized controlled trials of angina pectoris with integrated traditional Chinese and western medicine interventions: a cross-sectional study.

BACKGROUND AND OBJECTIVE: Integrated traditional Chinese and western medicine (ITCWM), as a representative type of complex intervention, is commonly used for the treatment of angina pectoris (AP) in clinical practice. However, it is unclear whether the details of ITCWM interventions, such as rationale for selection and design, implementation and potential interactions for different therapies, were adequately reported. Therefore, this study aimed to describe the reporting characteristics and quality in randomized controlled trials (RCTs) of AP with ITCWM interventions. METHODS: Through a search of 7 electronic databases, we identified RCTs of AP with ITCWM interventions published in both English and Chinese from 1st Jan 2017 to 6th Aug 2022. The general characteristics of included studies were summarized, further, the quality of reporting was assessed based on three Checklists, including the CONSORT with 36 items (except for one item 1b about abstract), the CONSORT for abstracts (17 items), and a self-designed ITCWM-related checklist (21 items covering rationale and details of interventions, outcome assessment and analysis). The quality of RCTs published in English and Chinese, as well as journals and dissertations were also compared. RESULTS: A total of 451 eligible RCTs were included. For the reporting compliance, the mean score (95% Confidence Interval) of the CONSORT (72 scores in total), CONSORT for abstract (34 scores in total), and ITCWM-related (42 scores in total) checklists was 27.82 (27.44-28.19), 14.17 (13.98-14.37) and 21.06 (20.69-21.43), respectively. More than half items were evaluated as poor quality (reporting rate < 50%) among each Checklist. Moreover, the reporting quality of publications in English journals was higher than that in Chinese journals in terms of the CONSORT items. The reporting of published dissertations was better than that in journal publications regarding both the CONSORT and ITCWM-specific items. CONCLUSION: Although the CONSORT appears to have enhanced the reporting of RCTs in AP, the quality of ITCWM specifics is variable and in need of improvement. Reporting guideline of the ITCWM recommendations should be developed thus to improve their quality.

Acupuncture for post-stroke depression: a systematic review and network meta-analysis.

BACKGROUND: Patients with post-stroke depression (PSD) usually experience anxiety, hopelessness, and insomnia, which have a negative impact on their daily activities and post-stroke rehabilitation. Acupuncture (AC), as a minimally invasive technique, has become a popular choice for improving depression symptoms. However, it is still unclear which therapy is associated with the best outcomes for PSD. In this review, we aimed to explore the impact of AC in alleviating symptoms of PSD and to evaluate the difference in effectiveness between AC combined with pharmacotherapies and various non-pharmacotherapies. METHODS: Six databases and three clinical trials registration platforms were searched from inception to March 2023. Randomized clinical trial comparing needle-based AC with pharmacotherapy, and other non-pharmacotherapy or invalid group were included. Two independent reviewers identified eligible studies, and collected data using a pre-made form. A Bayesian network meta-analysis was conducted to assess and compare different techniques using RStudio 3.6.0 with the package 'GEMTC' V.0.8.1. The primary outcome was the efficacy for PSD assessed by scales measuring depressive symptoms. The secondary outcomes were effectiveness for neurological function and the quality of life. The ranking probabilities for all treatment interventions was performed using the Surface Under the Cumulative Ranking curve (SUCRA). The risk of bias was assessed by using the Revised Cochrane Risk of Bias tool 2. RESULTS: Sixty-two studies, involving 5308 participants published from 2003 to 2022, were included. The results showed that compared with western medicine (WM) (defined as pharmacotherapy for PSD), AC alone or with repetitive transcranial magnetic stimulation (RTMS), Traditional Chinese medicine (TCM) alone or with WM, were superior for alleviating depression symptoms. Compared to Usual Care, AC alone or plus other therapies could significantly decrease scores on the Hamilton Depression Rating scale. According to result of SUCRA, AC plus RTMS had the highest probability of improving depressive symptoms with a probability of 49.43%. CONCLUSIONS: The results of this study indicate that AC alone or combined with other therapies appears to be effective in improving depression symptoms of stroke survivors. Moreover, in comparison to WM, AC alone or plus RTMS, TCM, TCM with WM, or WM, were more effective in improving depression symptoms of PSD. Also, AC with RTMS seems to be the most effective with the highest probability. REGISTRATION: This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database in November 2020 and updated in July 2021. The registration number is CRD42020218752.

Combination of artesunate and WNT974 induces KRAS protein degradation by upregulating E3 ligase ANACP2 and ß-TrCP in the ubiquitin-proteasome pathway.

BACKGROUND: KRAS mutation is one of the dominant gene mutations in colorectal cancer (CRC). Up to present, targeting KRAS for CRC treatment remains a clinical challenge. WNT974 (LGK974) is a porcupine inhibitor that interferes Wnt signaling pathway. Artesunate (ART) is a water-soluble semi-synthetic derivative of artemisinin. METHODS: The synergistic effect of ART and WNT974 combination in reducing CRC cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RT-PCR was utilized for the mRNA levels of KRAS, CUL7, ANAPC2, UBE2M, RNF123, SYVN1, or ß-TrCP. Western blot assay was utilized for the protein levels of NRAS, HRAS, KRAS, ANAPC2, ß-TrCP, GSK-3ß, p-Akt (Ser473), t-Akt, p-PI3K (Tyr458), t-PI3K, p-mTOR (Ser2448), t-mTOR. Xenograft mouse model assay was performed for the anti-CRC effect of combination of ART and WNT974 in vivo. IHC assay was utilized for the levels of KRAS, ß-TrCP, GSK-3ß or ANAPC2 in tumor tissues. RESULTS: Our study shows that the combination of WNT974 and ART exhibits synergistic effect in reducing CRC growth. The combination treatment significantly reduces KRAS protein level and activity in CRC cells. Interestingly, the combination treatment increases E3 ligases ANAPC2 expression. Our data show that overexpression of ANAPC2 significantly reduces KRAS protein levels, which is reversed by MG132. Knockdown of ANAPC2 in CRC abolishes the combination treatment-reduce KRAS expression. Besides, the treatment also increases the expressions of GSK-3ß and E3 ligase ß-TrCP that is known to degrade GSK-3ß-phosphorylated KRAS protein. Knockdown of ß-TrCP- and inhibition of GSK-3ß abolish the combination treatment-induce KRAS ubiquitination and reduction in expression. Last but not least, combination treatment suppresses PI3K/Akt/m-TOR signaling pathway. CONCLUSIONS: Our data clearly show that the combination treatment significantly enhances KRAS protein degradation via the ubiquitination ubiquitin-proteasome pathway, which is also demonstrated in xenograft mouse model. The study provides strong scientific evidence for the development of the combination of WNT974 and ART as KRAS-targeting therapeutics for CRC treatment. Video Abstract.

Cell death mechanisms induced by synergistic effects of halofuginone and artemisinin in colorectal cancer cells.

Our previous study found that the combination of halofuginone (HF) and artemisinin (ATS) synergistically arrest colorectal cancer (CRC) cells at the G1/G0 phase of the cell cycle; however, it remains unclear whether HF-ATS induces cell death. Here we report that HF-ATS synergistically induced caspase-dependent apoptosis in CRC cells. Specifically, both in vitro and in vivo experiments showed that HF or HF-ATS induces apoptosis via activation of caspase-9 and caspase-8 while only caspase-9 is involved in ATS-induced apoptosis. Furthermore, we found HF or HF-ATS induces autophagy; ATS can't induce autophagy until caspase-9 is blocked. Further analyzing the crosstalk between autophagic and caspase activation in CRC cells, we found autophagy is essential for activation of caspase-8, and ATS switches to activate capase-8 via induction of autophagy when caspase-9 is inhibited. When apoptosis is totally blocked, HF-ATS switches to induce autophagic cell death. This scenario was then confirmed in studies of chemoresistance CRC cells with defective apoptosis. Our results indicate that HF-ATS induces cell death via interaction between apoptosis and autophagy in CRC cells. These results highlight the value of continued investigation into the potential use of this combination in cancer therapy.

Reactivation of Epstein-Barr virus by a dual-responsive fluorescent EBNA1-targeting agent with Zn2+-chelating function.

Epstein-Barr nuclear antigen 1 (EBNA1) plays a vital role in the maintenance of the viral genome and is the only viral protein expressed in nearly all forms of Epstein-Barr virus (EBV) latency and EBV-associated diseases, including numerous cancer types. To our knowledge, no specific agent against EBV genes or proteins has been established to target EBV lytic reactivation. Here we report an EBNA1- and Zn2+-responsive probe (ZRL5P4) which alone could reactivate the EBV lytic cycle through specific disruption of EBNA1. We have utilized the Zn2+ chelator to further interfere with the higher order of EBNA1 self-association. The bioprobe ZRL5P4 can respond independently to its interactions with Zn2+ and EBNA1 with different fluorescence changes. It can selectively enter the nuclei of EBV-positive cells and disrupt the oligomerization and oriP-enhanced transactivation of EBNA1. ZRL5P4 can also specifically enhance Dicer1 and PML expression, molecular events which had been reported to occur after the depletion of EBNA1 expression. Importantly, we found that treatment with ZRL5P4 alone could reactivate EBV lytic induction by expressing the early and late EBV lytic genes/proteins. Lytic induction is likely mediated by disruption of EBNA1 oligomerization and the subsequent change of Dicer1 expression. Our probe ZRL5P4 is an EBV protein-specific agent that potently reactivates EBV from latency, leading to the shrinkage of EBV-positive tumors, and our study also suggests the association of EBNA1 oligomerization with the maintenance of EBV latency.

The level and prevalence of depression and anxiety among patients with different subtypes of irritable bowel syndrome: a network meta-analysis.

BACKGROUND: Irritable bowel syndrome (IBS) is a very common functional bowel disorder. However, the difference of depression and anxiety comorbidities among different IBS subtypes is still not well evaluated. This study aims to investigate the difference in the level and prevalence of depression and anxiety among healthy controls and patients with different subtypes of IBS. METHODS: PubMed, EMBASE and the Cochrane library were searched systematically until August 17, 2020. Studies that investigated depression and/or anxiety levels or prevalence among different IBS-subtype patients measured at baseline or the same point were included. Network meta-analysis was conducted to analyze standardized mean difference (SMD) of anxiety and depression levels, and single arm meta-analysis was performed for prevalence of anxiety and depression among different IBS subtypes. RESULTS: Eighteen studies involving 7095 participants were included. Network meta-analyses results showed healthy controls had a lower level of depression than IBS with mixed symptoms of constipation and diarrhea (IBS-M) [SMD = - 1.57; 95% confidence interval (CI) - 2.21, - 0.92], IBS with constipation (IBS-C) (SMD = - 1.53; 95% CI - 2.13, - 0.93) and IBS with diarrhea (IBS-D)(SMD = - 1.41; 95% CI - 1.97, - 0.85), while no significant difference was found between IBS unclassified (IBS-U) and healthy controls (SMD = - 0.58; 95% CI - 2.15, 1.00). There was also no significant difference in the level of depression among different IBS subtypes patients. The results of anxiety were similar to depression. Ranking probability showed that IBS-M was associated with the highest level of depression and anxiety symptoms, followed by IBS-C/IBS-D and IBS-U. Single-arm meta-analysis showed IBS-C had the highest prevalence of depression (38%) and anxiety (40%), followed by IBS-D, IBS-M and IBS-U. CONCLUSION: The results indicated that IBS-M was more likely to be associated with a higher level of depression and anxiety, and the prevalence of depression and anxiety in IBS-C was highest. The psychological screening and appropriate psychotherapy are needed for patients with IBS-C, IBS-D and IBS-M instead of IBS-U.

Gut-Microbial Metabolites, Probiotics and Their Roles in Type 2 Diabetes.

Type 2 diabetes (T2D) is a worldwide prevalent metabolic disorder defined by high blood glucose levels due to insulin resistance (IR) and impaired insulin secretion. Understanding the mechanism of insulin action is of great importance to the continuing development of novel therapeutic strategies for the treatment of T2D. Disturbances of gut microbiota have been widely found in T2D patients and contribute to the development of IR. In the present article, we reviewed the pathological role of gut microbial metabolites including gaseous products, branched-chain amino acids (BCAAs) products, aromatic amino acids (AAAs) products, bile acids (BA) products, choline products and bacterial toxins in regulating insulin sensitivity in T2D. Following that, we summarized probiotics-based therapeutic strategy for the treatment of T2D with a focus on modulating gut microbiota in both animal and human studies. These results indicate that gut-microbial metabolites are involved in the pathogenesis of T2D and supplementation of probiotics could be beneficial to alleviate IR in T2D via modulation of gut microbiota.

Spexin as an anxiety regulator in mouse hippocampus: Mechanisms for transcriptional regulation of spexin gene expression by corticotropin releasing factor.

Spexin (SPX) acts as a neuropeptide with pleiotropic functions that can participate in anxiety regulation. Corticotropin releasing factor (CRF) is widely expressed in brain tissues and associated with depression and anxiety and addiction. With the anxious mice under chronic unpredictable stress, we found SPX mRNA expression level in the hippocampus of the brain was significantly reduced, while local CRF mRNA expression level was increased. Furthermore, CRF injection in the hippocampus could also decrease SPX mRNA expression levels in hippocampus and other brain tissues, including pituitary and hypothalamus. With the primary mouse hippocampal cell model, CRF treatment could decrease SPX mRNA expression at hippocampal cell level and this inhibitory effect was mediated only by corticotropin releasing factor receptor 2 (CRFR2) but not corticotropin releasing factor receptor 1 (CRFR1). In HEK293 cells with CRFR2 over-expression, CRF could also inhibit SPX promoter activity coupling with AC/cAMP/PKA and MEK1/2/Erk1/2 cascades. In addition, Epac was also involved with the CRF-repressed SPX promoter activity and cross-talked with MEK1/2/Erk1/2 pathway. CRF could inhibit SPX gene expression in mouse hippocampus via transcriptional activation at the promoter level with coupling of AC/cAMP and MEK1/2/Erk1/2 signaling, which will be relevant to the anxiety response mediated by SPX in central nervous system.

Comparative proteomic analysis of the brain and colon in three rat models of irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) has been gradually recognized as a disorder of the brain-gut interaction, but the molecular changes in the brain and colon that occur in disease development remain poorly understood. We employed proteomic analysis to identify differentially expressed proteins in both the brain and colon of three IBS models. METHODS: To explore the relevant protein abundance changes in the brain and colon, isobaric tags for relative and absolute quantitation (iTRAQ), liquid chromatography and tandem mass spectrometry (LC-MS) and Western blotting methods were used in three IBS models, including maternal separation (MS, group B), chronic wrap restraint stress (CWRS, group C) and a combination of MS and CWRS (group D). RESULTS: We identified 153, 280, and 239 proteins that were common and differentially expressed in the two tissue types of groups B, C and D, respectively; 43 differentially expressed proteins showed the same expression changes among the three groups, including 25 proteins upregulated in the colon and downregulated in the brain, 7 proteins downregulated in the colon and upregulated in the brain, and 3 proteins upregulated and 8 downregulated in both tissues. Gene ontology analysis showed that the differentially expressed proteins were mainly associated with cellular assembly and organization and cellular function and maintenance. Protein interaction network and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that the differentiated proteins were mainly involved in the protein ubiquitination pathway and mitochondrial dysfunction. CONCLUSIONS: Taken together, the data presented represent a comprehensive and quantitative proteomic analysis of the brain and colon in IBS models, providing new evidence of an abnormal brain-gut interaction in IBS. These data may be useful for further investigation of potential targets in the diagnosis and treatment of IBS.

Apigenin inhibits STAT3/CD36 signaling axis and reduces visceral obesity.

Visceral obesity is the excess deposition of visceral fat within the abdominal cavity that surrounds vital organs. Visceral obesity is directly associated with metabolic syndrome, breast cancer and endometrial cancer. In visceral obese subjects, signal transducer and activator of the transcription 3 (STAT3) in adipocytes is constitutively active. In this study, we aimed to screen for dietary herbal compounds that possess anti-visceral obesity effect. Apigenin is abundant in fruits and vegetables. Our data show that apigenin significantly reduces body weight and visceral adipose tissue (VAT), but not subcutaneous (SAT) and epididymal adipose tissues (EAT), of the high fat diet (HFD)-induced obese mice. Mechanistic studies show that HFD increases STAT3 phosphorylation in VAT, but not in SAT and EAT. Further studies suggest that apigenin binds to non-phosphorylated STAT3, reduces STAT3 phosphorylation and transcriptional activity in VAT, and consequently reduces the expression of STAT3 target gene cluster of differentiation 36 (CD36). The reduced CD36 expression in adipocytes reduces the expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) which is the critical nuclear factor in adipogenesis. Our data show that apigenin reduces CD36 and PPAR-γ expressions and inhibits adipocyte differentiation; overexpression of constitutive active STAT3 reverses the apigenin-inhibited adipogenesis. Taken together, our data suggest that apigenin inhibits adipogenesis via the STAT3/CD36 axis. Our study has delineated the mechanism of action underlying the anti-visceral obesity effect of apigenin, and provide scientific evidence to support the development of apigenin as anti-visceral obesity therapeutic agent.

WHO Trial Registration Data Set (TRDS) extension for traditional Chinese medicine 2020: recommendations, explanation, and elaboration.

BACKGROUND: Although the WHO Trial Registration Data Set (TRDS) has been published for many years, the quality of clinical trial registrations with traditional Chinese medicine (TCM) is still not satisfactory, especially about the inadequate reporting on TCM interventions. The development of the WHO TRDS for TCM Extension 2020 (WHO TRDS-TCM 2020) aims to address this inadequacy. METHODS: A group of clinical experts, methodologists, epidemiologists, and editors has developed this WHO TRDS-TCM 2020 through a comprehensive process, including the baseline survey, draft of the initial items, three-round of Delphi survey, solicitation of comments, revision, and finalization. RESULTS: The WHO TRDS-TCM 2020 statement extends the latest version (V.1.3.1) of TRDS published in November 2017. The checklist includes 11 extended items (including subitems), namely Source(s) of Monetary or Material Support (Item 4), Scientific Title (Item 10a and 10b), Countries of Recruitment (Item 11), Health Condition(s) or Problem(s) Studied (Item 12), Intervention(s) (Item 13a, 13b and 13c), Key Inclusion and Exclusion Criteria (Item 14), Primary and Key Secondary Outcomes (Item 19 to 20), and Lay Summary (Item B1). For Item 13 (Interventions), three common TCM interventions--i.e., Chinese herbal medicine formulas, acupuncture and moxibustion-are elaborated. CONCLUSIONS: The group hopes that the WHO TRDS-TCM 2020 can improve the reporting quality and transparency of TCM trial registrations, assist registries in assessing the registration quality of TCM trials, and help readers understand TCM trial design.

Anti-inflammatory Efficacy of Combined Natural Alkaloid Berberine and S1PR Modulator Fingolimod at Low Doses in Ulcerative Colitis Preclinical Models.

The natural alkaloid berberine is being studied as a drug candidate for the treatment of ulcerative colitis (UC). Fingolimod is an immunomodulator approved for the treatment of multiple sclerosis. Whether fingolimod use can be extended to UC and how it interacts with berberine remain unclear. In the present study, the anti-inflammatory efficacies of berberine, fingolimod, and a combination of half-doses of them was examined in mice with dextran sulfate sodium-induced colitis. In mice with subchronic colitis, 14-day oral administration of fingolimod had greater efficacy than berberine in ameliorating the disease clinical severity and colon shortening. However, in mice with chronic colitis, 30-day oral administration of berberine was more effective than fingolimod except on splenic swelling. Notably, the combination of half-doses of each drug was equally effective as the superior single drugs for two models and resulted in reduced splenic swelling in the chronic colitis model. The inhibition of cytokine expression and STAT3 activation, as well as binding to the sphingosine 1-phosphate receptor by both drugs, contributed to the combination efficacy. Our findings suggest that fingolimod in combination with berberine at reduced doses represents a novel therapy for UC that attains satisfactory efficacy with reduced potentials for adverse effects.

Palmitic acid is an intracellular signaling molecule involved in disease development.

Emerging evidence shows that palmitic acid (PA), a common fatty acid in the human diet, serves as a signaling molecule regulating the progression and development of many diseases at the molecular level. In this review, we focus on its regulatory roles in the development of five pathological conditions, namely, metabolic syndrome, cardiovascular diseases, cancer, neurodegenerative diseases, and inflammation. We summarize the clinical and epidemiological studies; and also the mechanistic studies which have identified the molecular targets for PA in these pathological conditions. Activation or inactivation of these molecular targets by PA controls disease development. Therefore, identifying the specific targets and signaling pathways that are regulated by PA can give us a better understanding of how these diseases develop for the design of effective targeted therapeutics.

Efficacy of MaZiRenWan, a Chinese Herbal Medicine, in Patients With Functional Constipation in a Randomized Controlled Trial.

BACKGROUND & AIMS: The Chinese herbal medicine, MaZiRenWan (MZRW), has been used for more than 2000 years to treat constipation, but it has not been tested in a randomized controlled trial. We performed a trial to evaluate the efficacy and safety of MZRW, compared with the stimulant laxative senna or placebo, for patients with functional constipation (FC). METHODS: We performed a double-blind, double-dummy, trial of 291 patients with FC based on Rome III criteria, seen at 8 clinics in Hong Kong from June 2013 through August 2015. Patients were observed for 2 weeks and then assigned randomly (1:1:1) to groups given MZRW (7.5 g, twice daily), senna (15 mg daily), or placebo for 8 weeks. Patients were then followed for 8 weeks and evaluated at baseline and weeks 4, 8 (end of treatment), and 16 (end of follow up). Participants recorded information on stool form and frequency, feeling of complete evacuation, and research medication taken. Data on individual bowel symptoms, global symptom improvement, and adverse events were collected. A complete response was defined as an increase ≥1 complete spontaneous bowel movement (CSBM)/week from baseline (the primary outcome). Secondary outcomes included response during the follow-up period, colonic transit, individual and global symptom assessments, quality of life measured with 36-item short form Chinese version, and adverse events. RESULTS: Although there was no statistically significant difference in proportions of patients with a complete response to MZRW (68%) vs. senna (57.7%) (P = .14) at week 8, there was a statistically significant difference vs. placebo (33.0%) (P < .005). At the 16-week timepoint (after the 8-week follow-up period), 47.4% of patients had a complete response to MZRW, 20.6% had a complete response to senna, and 17.5% had a complete response to placebo (P < .005 for MZRW vs. placebo). The group that received MZRW group also had significant increases in colonic transit and reduced severity of constipation, straining, incomplete evacuation, and global constipation symptoms compared with the groups that received placebo or senna in (P < .05 for all comparisons). CONCLUSIONS: In a randomized controlled trial of 291 patients with FC, we found MZRW to be well-tolerated and effective in increasing CSBM/week. MZRW did not appear to be more effective than senna and might be considered as an alternative to this drug. ClincialTrials.gov no: NCT01695850.

Artesunate activates the ATF4-CHOP-CHAC1 pathway and affects ferroptosis in Burkitt's Lymphoma.

Currently, there is no effective treatment for Burkitt's lymphoma in patients aged above 60 years, and thus research on effective treatment options for Burkitt's lymphoma has been gaining increasing attention. Artesunate has been identified as a novel effective growth suppressor in Burkitt's lymphoma. Here, we utilized molecular biology, transcriptome analysis, and other techniques to study artesunate-induced death of the Burkitt's lymphoma cells DAUDI and CA-46, the effect of artesunate on gene expression in DAUDI and CA-46 cells, and the effect of artesunate-induced ATF4-CHOP-CHAC1 pathway on ferroptosis. We also studied the inhibitory effects and ferroptosis induction of artesunate on CA-46 cells in mouse xenografts. Results showed that artesunate induced ferroptosis in DAUDI and CA-46 cells, as evidenced by the protective effect of liproxstatin-1, ferrostatin-1, and desferoxamine, resulting in an endoplasmic reticulum stress response, activation of the ATF4-CHOP-CHAC1 pathway enhanced ferroptosis in DAUDI and CA-46 cells. A mouse-transplanted tumor model showed that artesunate can inhibit the proliferation and induce ferroptosis of CA-46 cells in vivo. This study provides a novel perspective for the development of drugs against different types of Burkitt's lymphomas.

Placebo design in WHO-registered trials of Chinese herbal medicine need improvements.

BACKGROUND: Physical identical and pharmacological inert are the basic requirements for placebo design, which are essential in clinical trials to evaluate the efficacy of an intervention. However, it is difficult to makeup a placebo of Chinese herbal medicine (CHM) because of special color, taste and smell, etc. Currently, there is no specific requirements and standards for the creation of a CHM-placebo. The purpose of this study is to review the characteristics of the CHM-placebo design and application in registered clinical trials with CHM interventions and identify the common problems, if any. METHODS: The World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) was systematically searched for CHM interventional trials with placebo-controlled design up to 31 December 2017. Registered information of each included trial was collected from specific registries involved in ICTRP through hyperlinks. Descriptive statistics were used to analyze the characteristics of placebo design in CHM trial registrations. RESULTS: A total of 889 CHM interventional trials were registered from 1999 to 2017, and 40.8% (363) of them included CHM-placebo control design. The common ways of their design were: placebo as sole control (191, 52.6%); placebo as add-on control with baseline treatment (84, 23.1%); and placebo as double-dummy control (57, 15.7%). Among 363 included trials, 46 (12.7%) reported the compositions of placebos, including CHM ingredients (17 trials), excipients and other agents (29 trials). 2 (0.6%) reported pharmacological inert testing, and 52 (14.3%) descripted their placebos to be physically identical with the CHMs. 14 (3.9%) reported quality control of placebos, and 2 (0.6%) provided blinding assessment of placebos. CONCLUSIONS: The placebos included in most CHM trial registrations is not optimal in terms of placebo design, application, evaluation and reporting. Specific guidelines or standards of CHM-placebo design, including usage requirements, preparation specifications, quality assessments and reporting guidelines should be developed thus to improve their quality.