Core outcome sets for myocardial infarction in clinical trials of traditional Chinese medicine and Western medicine.

BACKGROUND: Clinical trials of traditional Chinese medicine (TCM) and Western medicine showed there was heterogeneity of outcome reporting in myocardial infarction (MI). Developing a core outcome set (COS) might improve the consistency of outcome reporting in future clinical trials. METHODS: A list of outcomes was developed based on a systematic review of randomized controlled trials (RCTs) of MI and semistructured interviews with MI patients. Two rounds of Delphi survey for clinicians, researchers, journal editors, and methodologists were conducted. An online questionnaire sent to nurses. After an online consensus meeting, a COS for MI RCTs was developed. RESULTS: After extracted data from clinical trials and discussed, 216 outcomes were included in round 1 of the Delphi survey. Seventy-four participants completed round 1 of the Delphi survey. Sixty-five participants completed round 2 of the Delphi survey. Twenty-two nurses completed the online questionnaire. Fifteen participants attended the online consensus meeting, and 14 of them voted and determined the final COS. For all types of MI, it was recommended that left ventricular ejection fraction and quality of life be measured and reported. For acute MI, the participants in the consensus meeting recommended the following core outcomes: death from cardio-cerebrovascular disease, cardiogenic shock, heart failure, troponin I, troponin T, creatine kinase isoenzyme, Killip class, target vessel revascularization, and emergency CABG. For previous MI, recurrent MI, recurrent angina pectoris, and heart failure readmission were recommended. CONCLUSIONS: The COS for MI in RCTs provides recommendations for clinical trials that seek to improve outcomes for patients with MI.

Risk prediction models for mortality and readmission in patients with acute heart failure: A protocol for systematic review, critical appraisal, and meta-analysis.

INTRODUCTION: A considerable number of risk models, which predict outcomes in mortality and readmission rates, have been developed for patients with acute heart failure (AHF) to help stratify patients by risk level, improve decision making, and save medical resources. However, some models exist in a clinically useful manner such as risk scores or online calculators, while others are not, providing only limited information that prevents clinicians and patients from using them. The reported performance of some models varied greatly when predicting at multiple time points and being validated in different cohorts, which causes model users uncertainty about the predictive accuracy of these models. The foregoing leads to users facing difficulties in the selection of prediction models, and even sometimes being reluctant to utilize models. Therefore, a systematic review to assess the performance at multiple time points, applicability, and clinical impact of extant prediction models for mortality and readmission in AHF patients is essential. It may facilitate the selection of models for clinical implementation. METHOD AND ANALYSIS: Four databases will be searched from their inception onwards. Multivariable prognostic models for mortality and/or readmission in AHF patients will be eligible for review. Characteristics and the clinical impact of included models will be summarized qualitatively and quantitatively, and models with clinical utility will be compared with those without. Predictive performance measures of included models with an analogous clinical outcome appraised repeatedly, will be compared and synthesized by a meta-analysis. Meta-analysis of validation studies for a common prediction model at the same time point will also be performed. We will also provide an overview of critical appraisal of the risk of bias, applicability, and reporting transparency of included studies using the PROBAST tool and TRIPOD statement. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42021256416.

Integrated analysis of genome-wide association studies and 3D epigenomic characteristics reveal the BMP2 gene regulating loin muscle depth in Yorkshire pigs.

BACKGROUND: The lack of integrated analysis of genome-wide association studies (GWAS) and 3D epigenomics restricts a deep understanding of the genetic mechanisms of meat-related traits. With the application of techniques as ChIP-seq and Hi-C, the annotations of cis-regulatory elements in the pig genome have been established, which offers a new opportunity to elucidate the genetic mechanisms and identify major genetic variants and candidate genes that are significantly associated with important economic traits. Among these traits, loin muscle depth (LMD) is an important one as it impacts the lean meat content. In this study, we integrated cis-regulatory elements and genome-wide association studies (GWAS) to identify candidate genes and genetic variants regulating LMD. RESULTS: Five single nucleotide polymorphisms (SNPs) located on porcine chromosome 17 were significantly associated with LMD in Yorkshire pigs. A 10 kb quantitative trait locus (QTL) was identified as a candidate functional genomic region through the integration of linkage disequilibrium and linkage analysis (LDLA) and high-throughput chromosome conformation capture (Hi-C) analysis. The BMP2 gene was identified as a candidate gene for LMD based on the integrated results of GWAS, Hi-C meta-analysis, and cis-regulatory element data. The identified QTL region was further verified through target region sequencing. Furthermore, through using dual-luciferase assays and electrophoretic mobility shift assays (EMSA), two SNPs, including SNP rs321846600, located in the enhancer region, and SNP rs1111440035, located in the promoter region, were identified as candidate SNPs that may be functionally related to the LMD. CONCLUSIONS: Based on the results of GWAS, Hi-C, and cis-regulatory elements, the BMP2 gene was identified as an important candidate gene regulating variation in LMD. The SNPs rs321846600 and rs1111440035 were identified as candidate SNPs that are functionally related to the LMD of Yorkshire pigs. Our results shed light on the advantages of integrating GWAS with 3D epigenomics in identifying candidate genes for quantitative traits. This study is a pioneering work for the identification of candidate genes and related genetic variants regulating one key production trait (LMD) in pigs by integrating genome-wide association studies and 3D epigenomics.

Bamboo leaf: A review of traditional medicinal property, phytochemistry, pharmacology, and purification technology.

ETHNOPHARMACOLOGICAL RELEVANCE: Bamboos are perennial evergreen plants that belong to the subfamily Bambusoideae of the true grass family Poaceae, with more than thousands of species distributed around the world. They are used as a traditional medicine with demonstrated effects of anti-oxidation, free radical scavenging, anti-inflammatory, liver protection and ameliorating cognitive deficits. Bamboo leaf is mainly used for the treatment of atherosclerotic, diabetic and nervous system diseases. AIM OF THE STUDY: This review aims to provide up-to-date information on the traditional medicinal properties, phytochemistry, pharmacology, and purification technologies of bamboo leaf. MATERIALS AND METHODS: Relevant information on bamboo leaf was obtained by an online search of worldwide accepted scientific databases (Web of Science, ScienceDirect, Elsevier, SpringerLink, ACS Publications, Wiley Online Library and CNKI). RESULTS: More than 100 chemical compounds, including flavonoids and flavonoid glycosides, volatile components, phenolic acids, polysaccharide, coenzyme Q10, phenylpropanoid and amino acids have been reported to be present. These compounds were usually extracted by column chromatography and membrane separation technologies. Preparative high performance liquid chromatography (PHPLC), high-speed counter-current chromatography (HSCCC), simulated moving bed chromatography (SMB) and dynamic axial compression chromatography (DAC) were the advanced separation technologies have been used to isolate C-glycosides from bamboo leaf flavonoid, the main bioactive ingredient of bamboo leaf. Currently, bamboo leaf is mainly used for the treatment of atherosclerotic, diabetic, hepatic diseases and nervous system related symptoms, which are attributed to the presence of bioactive components of bamboo leaf. CONCLUSIONS: Phytochemical and pharmacological analyses of bamboo leaf have been revealed in recent studies. However, most of the pharmacological studies on bamboo leaf have focused on bamboo leaf flavonoids. Further studies need to pay more attention to other phytochemical components of bamboo leaf. In addition, there is lack of sufficient clinical data and toxicity studies on bamboo leaf. Therefore, more clinical and toxicity researches on this plant and constituents are recommended.

Two polyamines -responsive WRKY transcription factors from Anoectochilus roxburghii play opposite functions on flower development.

Anoectochilus roxburghii is a rare and precious plant with medicinal and healthcare functions. Embryo abortion caused the lack of resources. Polyamine promoted its flowering and stress resistance in our previous study. But the mechanism remains unclear. The WRKY transcription factor family has been linked to a variety of biological processes in plants. In this study, two WRKY TFs (ArWRKY5 and ArWRKY20) of A. roxburghii, which showed significant response to Spd treatment, were identified and functionally analyzed. Tissue specific expression analyzation showed both of them mostly present in the flower. And ArWRKY5 expressed highest in the flower bud stage (-1 Flowering), while ArWRKY20 showed the highest expression in earlier flower bud stage (-2 Flowering) and the expression gradually decreased with flowering. The transcriptional activation activity assay and subcellular localization revealed that ArWRKY5 and ArWRKY20 were located in the nucleus and ArWRKY20 showed transcriptional activity. The heterologous expression of ArWRKY5 in Arabidopsis thaliana showed earlier flowering, while overexpression of ArWRKY20 delayed flowering. But the OE-ArWRKY20 lines had a robust body shape and a very significant increase in the number of rosette leaves. Furthermore, stamens and seed development were positively regulated by these two ArWRKYs. These results indicated that ArWRKY5 and ArWRKY20 not only play opposite roles in the floral development, but also regulate the plant growth and seed development in A. thaliana. But their specific biological functions and mechanism in A. roxburghii need to be investigated further.

Developing a core outcome set for assessing clinical safety outcomes of cardiovascular diseases in clinical trials of integrated traditional Chinese medicine and Western medicine: study protocol.

BACKGROUND: Integrative medicine is commonly used in China. Researchers prefer to report efficacy outcomes rather than safety outcomes in clinical trials; thus, evidence regarding safety in integrative medicine is unclear. Developing a core outcome set (COS) for safety outcomes is necessary. In this study, a representative example of the methodology for developing COS to assess safety outcomes of cardiovascular diseases in clinical trials investigating integrated medicine will be developed. METHODS AND ANALYSIS: Safety information will be extracted from package inserts and through systematic reviews of treatments for cardiovascular diseases (including angina pectoris, myocardial infarction, heart failure, arrhythmia, and hypertension) to develop an extensive list of safety outcomes, which will then be categorized according to whether subjective or objective outcomes. Questionnaires for clinician-reported safety outcomes and patient-reported safety outcomes will be developed. Two rounds of the Delphi survey will then be conducted for different stakeholders (traditional Chinese medicine clinicians and researchers in cardiovascular diseases, Western medicine clinicians and researchers in cardiovascular diseases, integrated medicine clinicians and researchers of cardiovascular diseases, pharmacologists, methodologists of evidence-based medicine, and patients). After round 2 of the Delphi analysis, a face-to-face consensus meeting will be held to determine the final COS for assessing safety outcomes in cardiovascular diseases. DISCUSSION: A COS for safety outcomes in cardiovascular diseases may improve the consistency of reporting results and will help identify potential bias of selective reporting in the future. TRIAL REGISTRATION: This study was registered in the Core Outcome Measures in Effectiveness Trials database as study 1564 .

Zanthoxylum bungeanum seed oil inhibits RANKL-induced osteoclastogenesis by suppressing ERK/c-JUN/NFATc1 pathway and regulating cell cycle arrest in RAW264.7 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Zanthoxylum bungeanum Maxim (ZBM), a traditional Chinese medicine, is traditionally used for osteoporosis treatment recorded in ancient Chinese medicine work Benjingshuzheng and reported to have the anti-bone loss activity in recent studies. However, the anti-osteoporotic activities of the seed of ZBM have not been elucidated yet. Our previous study found that Zanthoxylum bungeanum Maxim seed oil (ZBSO) was rich in polyunsaturated fatty acids (PUFAs), which were reported to prevent bone loss. Thus, we propose a hypothesis that ZBSO could be a potential natural resource for anti-bone loss. AIM OF THE STUDY: To investigate whether ZBSO could prevent bone loss by targeting osteoclastogenesis and investigate the potential mechanisms in receptor-activator of nuclear factor κB ligand (RANKL)-induced RAW264.7 cells. MATERIALS AND METHODS: RAW264.7 cells were treated with RANKL in the presence or absence of ZBSO. The effect of ZBSO on osteoclast differentiation and bone resorption activity of RAW264.7 cells were evaluated by tartrate-resistant acid phosphatase (TRAP) staining, F-actin ring staining, and bone resorption assay. Differentially expression genes (DEGs) and relevant pathways of different cell groups were obtained from RNA sequencing and protein-protein interaction (PPI) network analysis followed by KEGG pathway enrichment analysis. The effect of ZBSO on the RANKL-induced cell cycle change was analyzed by flow cytometry assay, and the expression of genes and proteins related to the selected pathways was further verified by RT-qPCR and western blot analysis. RESULTS: The inhibitory effects of ZBSO on osteoclast differentiation and bone resorption activity in a dose-dependent manner were demonstrated by TRAP staining, F-actin ring staining, and bone resorption assay in RANKL-induced RAW264.7 cells. Osteoclast differentiation and cell cycle pathways were the most enriched pathways based on DEGs enrichment analysis among different cell groups. The reversion effect of ZBSO on the RANKL-induced RAW264.7 cell cycle arrest at the G1 phase was observed by flow cytometry assay. Western blot results showed that ZBSO markedly decreased RANKL-induced activation of ERK, as well as the phosphorylation of c-JUN and NFATc1 expression, and subsequently suppressed osteoclast-specific genes, such as Ctsk, Trap, and Dc-stamp. CONCLUSIONS: ZBSO exhibited an inhibitory effect on osteoclastogenesis via suppressing the ERK/c-JUN/NFATc1 pathway and regulating cell cycle arrest induced by RANKL, suggesting that ZBSO may serve as a promising agent for anti-bone loss.

Transcriptional regulation of plant seed development.

Plant seeds, which are unique reproductive organs of gymnosperms and angiosperms, are used for edible, medicinal, and industrial purposes. Transcription factors (TFs) are master regulators of plant growth, development, and stress responses. This review describes, in detail, the functions of TFs in regulating seed development. Different TFs, or even different TF families, may have similar functions in seed development. For example, WUSCHEL-related homeobox, LEC2/FUS3/ABI3, and HEME ACTIVATOR PROTEIN3 families can control plant seed embryonic initiation and development. In contrast, some members of the same TF family may have completely opposite roles. For instance, AtMYB76 and AtMYB89 inhibit the accumulation of seed oil, whereas AtMYB96 promotes seed fatty acid accumulation in Arabidopsis thaliana. Compared with the number of studies that have addressed regulation by single TFs, only a few have focused on multiple-TF regulatory networks. This review should be useful as a reference for future studies on regulatory networks of TF complexes.

Baihui (DU20)-penetrating-Qubin (GB7) acupuncture regulates microglia polarization through miR-34a-5p/Klf4 signaling in intracerebral hemorrhage rats.

Intracerebral hemorrhage (ICH) is the most devastating subtype of stroke with high morbidity and mortality. The previous study has confirmed the therapeutic effect of Baihui (DU20)-penetrating-Qubin (GB7) acupuncture on ICH, while the related mechanism is left to be revealed. The aim of this study was to investigate the relevant mechanisms. ICH rat models were established utilizing the autologous blood injection method and the beneficial effect was found after DU20-penetrating-GB7 acupuncture along with decreased miR-34a-5p levels in the perihemorrhagic penumbra. Inversely, upregulating miR-34a-5p expression inhibited microglia M2 polarization while accelerated M1 polarization through targeting Krüppel-like factor 4 (Klf4), and thereby diminished the protective effect of DU20-penetrating-GB7 acupuncture on ICH. The results suggested the therapeutic effect of DU20-penetrating-GB7 acupuncture on ICH might be attributed to its modulation on microglia polarization through miR-34a-5p/Klf4 signaling.

Ligustrum robustum Alleviates Atherosclerosis by Decreasing Serum TMAO, Modulating Gut Microbiota, and Decreasing Bile Acid and Cholesterol Absorption in Mice.

SCOPE: Atherosclerosis (AS) is closely related to gut microbiota. Previous studies demonstrates that Ligustrum robustum (LR), a flavonoid-rich tea like plant, can mitigate several AS-related risk factors and modulate gut microbiota in animal models and human subjects. But its anti-AS effect and mechanisms remain unclear. Therefore, in this study, impacts of LR on AS development are investigated and the potential underlying mechanisms in C57BL/6J and Apoe-/- mice are explored. METHODS AND RESULTS: Female C57BL/6J and Apoe-/- mice are fed a chow diet or high-choline diet, supplemented with vehicle (water) or LR water extract (700 mg kg-1 ) by gavage for 17 weeks. It is found that LR attenuates diet-induced AS by reducing serum trimethylamine and trimethylamine-N-oxide (TMAO) levels likely by modulating gut microbiota. Moreover, LR increases the abundance of the genus Bifidobacterium, which generates bile salt hydrolase, and thus presumably enhances bile acid (BA) deconjugation and increases fecal BA excretion. Meanwhile, LR increases fecal cholesterol excretion, decreases the levels of serum and hepatic cholesterol, but did not affect short-chain fatty acids in feces. CONCLUSION: LR attenuates AS development presumably by decreasing serum TMAO levels and increasing fecal BA excretion likely via gut microbial modulation. These effects are accompanied by increases in fecal cholesterol excretion and decreases in serum and hepatic cholesterol.

A strategy for component-based Chinese medicines design approach of Polygonum orientale L. against hypoxia/reoxygenation based on uniform design-stepwise regression-simulated annealing.

Presently, optimal proportions and synergistic mechanisms of component-based Chinese medicines are critical for developing novel strategies to treat cardiovascular diseases (CVDs). A new multi-objective optimization algorithm based on uniform design (UD) and stepwise regression (SR) modeling is proposed to find the synergistic effect of orientin (Ori), quercitrin (Que) and vitexin (Vit), the three effective components from Polygonum orientale L., using the H9c2 cells injury induced by hypoxia/reoxygenation (H/R). The optimal proportion of these three components was calculated by simulated annealing (SA). In this research, the excellent combination named OQV-e (Ori: Que: Vit =12.55 µM: 39.99 µM: 19.99 µM) could exert significant cardioprotection against the H9c2 cells injury induced by H/R through increasing cell viability, decreasing leakage rate of lactate dehydrogenase (LDH) and the level of nitric oxide (NO). Moreover, western blot analysis revealed that OQV-e could activate autophagy by inhibiting the p-JNK/JNK signaling pathway, which showed that the method (UD-SR-SA) was a feasible strategy. Mathematical system modeling may be a considerable approach for the powerful mathematical analysis of the complex pharmacological effects of component-based Chinese medicines from herbal medicines, which might greatly enhance the efficiency to find new modern Chinese drugs for CVDs based on Chinese herbal medicine (CHM) with affirmative therapeutic effect.

Protein interactions in T7 DNA replisome inhibit the bypass of abasic site by DNA polymerase.

Abasic site as a common DNA lesion blocks DNA replication and is highly mutagenic. Protein interactions in T7 DNA replisome facilitate DNA replication and translesion DNA synthesis. However, bypass of an abasic site by T7 DNA replisome has never been investigated. In this work, we used T7 DNA replisome and T7 DNA polymerase alone as two models to study DNA replication on encountering an abasic site. Relative to unmodified DNA, abasic site strongly inhibited primer extension and completely blocked strand-displacement DNA synthesis, due to the decreased fraction of enzyme-DNA productive complex and the reduced average extension rates. Moreover, abasic site at DNA fork inhibited the binding of DNA polymerase or helicase onto fork and the binding between polymerase and helicase at fork. Notably and unexpectedly, we found DNA polymerase alone bypassed an abasic site on primer/template (P/T) substrate more efficiently than did polymerase and helicase complex bypass it at fork. The presence of gp2.5 further inhibited the abasic site bypass at DNA fork. Kinetic analysis showed that this inhibition at fork relative to that on P/T was due to the decreased fraction of productive complex instead of the average extension rates. Therefore, we found that protein interactions in T7 DNA replisome inhibited the bypass of DNA lesion, different from all the traditional concept that protein interactions or accessory proteins always promote DNA replication and DNA damage bypass, providing new insights in translesion DNA synthesis performed by DNA replisome.