Long-term outcomes and predictors of patients with ST elevated versus non-ST elevated myocardial infarctions in non-obstructive coronary arteries: a retrospective study in Northern China.

Background: Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a heterogeneous disease entity with diverse etiologies and no uniform treatment protocols. Patients with MINOCA can be clinically classified into two groups based on whether they have an ST-segment elevation (STE) or non-ST segment elevation (NSTE), based on electrocardiogram (ECG) results, whose clinical prognosis is unclear. This study aimed to compare the outcomes and predictors of patients with STE and NSTE in the MINOCA population. Methods: We collected the data for 196 patients with MINOCA (115 with STE and 81 with NSTE) in China. Clinical characteristics, prognoses, and predictors of major adverse cardiovascular events (MACE) were analyzed during the follow-up of all patients. Results: The proportion of patients with STE was greater than that with NSTE in the MINOCA population. Patients with NSTE were older and had a higher incidence of hypertension. No differences were observed in the outcomes between the STE and NSTE groups during a median follow-up period of 49 (37,46) months. No significant differences were observed in those with MACE (24.35% vs 22.22%, P = 0.73) and those without MACE. The multivariable predictors of MACE in the NSTE groups were Killip grades ≥ 2 (HR 9.035, CI 95% [1.657-49.263], P = 0.011), reduced use of ß-blockers during hospitalization (HR 0.238, CI 95% [0.072-0.788], P = 0.019), and higher levels of low-density lipoprotein cholesterol (LDL-C) (HR 2.267, CI 95% [1.008-5.097], P = 0.048); the reduced use of ß-blockers during hospitalization was the only independent risk factor of MACE in the STE group. Conclusions: There were differences between the clinical characteristics of patients with STE and NSTE in the MINOCA population, even though outcomes during follow-up were similar. Independent risk factors for major adverse cardiac events were not identical in the STE and NSTE groups, which could be attributable to the differences in disease pathogenesis.

Genome-wide analysis of MIKCC-type MADS-box genes and roles of CpFUL/SEP/AGL6 superclade in dormancy breaking and bud formation of Chimonanthus praecox.

Wintersweet (Chimonanthus praecox), a Magnoliidae tree, is popular for its unique fragrant aroma and winter-flowering characteristics, which is widely used in gardens and pots, or for cut flowers, essential oil, medicine, and edible products. MIKCC-type of MADS-box gene family play a crucial role in plant growth and development process, particularly in controlling flowering time and floral organ development. Although MIKCC-type genes have been well studied in many plant species, the study of MIKCC-type is poorly in C. praecox. In this study, we identified 30 MIKCC-type genes of C. praecox on gene structures, chromosomal location, conserved motifs, phylogenetic relationships based on bioinformatics tools. Phylogenetic relationships analysis with Arabidopsis (Arabidopsis thaliana), rice (Oryza sativa Japonica), Amborella trichopoda and tomato (Solanum lycopersicum) showed that CpMIKCCs were divided into 13 subclasses, each subclass containing 1 to 4 MIKCC-type genes. The Flowering locus C (FLC) subfamily was absent in C. praecox genome. CpMIKCCs were randomly distributed into eleven chromosomes of C. praecox. Besides, the quantitative RT-PCR (qPCR) was performed for the expression pattern of several MIKCC-type genes (CpFUL, CpSEPs and CpAGL6s) in seven bud differentiation stages and indicated that they were involved in dormancy breaking and bud formation. Additionally, overexpression of CpFUL in Arabidopsis Columbia-0 (Col-0) resulted in early flowering and showed difference in floral organs, leaves and fruits. These data could provide conducive information for understanding the roles of MIKCC-type genes in the floral development and lay a foundation for screening candidate genes to validate function.

Correction of the High Fold in Difficult Secondary Blepharoplasty Through Retro-Orbicularis Oculi Fat Transposition and Augmentation in Asians.

BACKGROUND: Secondary blepharoplasty to correct a high crease is considered challenging for most surgeons, especially in patients who show overly excessive removal of eyelid tissue in Asians. Therefore, we define a typical difficult secondary blepharoplasty as when patients present too high eyelid fold with excessive tissue resection and preaponeurotic fat deficiency. This study provides the technique of retro-orbicularis oculi fat (ROOF) transferring and volume augmentation to reconstruct eyelid anatomical structure on the base of a series of difficult secondary blepharoplasty cases in Asians and assess the effectiveness of the method in the meanwhile. METHOD: This was a secondary blepharoplasty cases-based retrospective observational study. From October 2016 to May 2021, a total of 206 cases were performed blepharoplasty revision surgery to correct high folds. Among them, a total of 58 cases (6 men, 52 women) diagnosed with difficult blepharoplasty were applied ROOF transferring and volume augmentation to correct high folds and were followed up on time. Depending on the distribution of ROOF of different thicknesses, we designed 3 different methods of harvesting and transferring ROOF flaps. The mean follow-up for patients in our study was 9 months, a range of 6 to 18 months. The postoperative results were reviewed, graded, and analyzed. RESULT: Most patients (89.66%) were satisfied. No postoperative complications were observed, such as infection, dehiscence of incision, tissue necrosis, levator dysfunction, or multiple creases. The mean height of the mid, medial, and lateral eyelid folds decreased from 8.96 ± 0.43, 8.21 ± 0.58, and 7.96 ± 0.53 mm to 6.77 ± 0.55, 6.27 ± 0.57, and 6.65 ± 0.61 mm, respectively. CONCLUSIONS: Retro-orbicularis oculi fat transposition or/and its enhancement contributes significantly to the reconstruction of the physiology of the eyelid structure and provides an available surgical option for the correction of too high folds in blepharoplasty.

Multi-omics insights into the interplay between gut microbiota and colorectal cancer in the "microworld" age.

Colorectal cancer (CRC) is a multifactorial heterogeneous disease largely due to both genetic predisposition and environmental factors including the gut microbiota, a dynamic microbial ecosystem inhabiting the gastrointestinal tract. Elucidation of the molecular mechanisms by which the gut microbiota interacts with the host may contribute to the pathogenesis, diagnosis, and promotion of CRC. However, deciphering the influence of genetic variants and interactions with the gut microbial ecosystem is rather challenging. Despite recent advancements in single omics analysis, the application of multi-omics approaches to integrate multiple layers of information in the microbiome and host to introduce effective prevention, diagnosis, and treatment strategies is still in its infancy. Here, we integrate host- and microbe-based multi-omics studies, respectively, to provide a strategy to explore potential causal relationships between gut microbiota and colorectal cancer. Specifically, we summarize the recent multi-omics studies such as metagenomics combined with metabolomics and metagenomics combined with genomics. Meanwhile, the sample size and sample types commonly used in multi-omics research, as well as the methods of data analysis, were also generalized. We highlight multiple layers of information from multi-omics that need to be verified by different types of models. Together, this review provides new insights into the clinical diagnosis and treatment of colorectal cancer patients.

Graphene Biointerface for Cardiac Arrhythmia Diagnosis and Treatment.

Heart rhythm disorders, known as arrhythmias, cause significant morbidity and are one of the leading causes of mortality. Cardiac arrhythmias are frequently treated by implantable devices, such as pacemakers and defibrillators, or by ablation therapy guided by electroanatomical mapping. Both implantable and ablation therapies require sophisticated biointerfaces for electrophysiological measurements of electrograms and delivery of therapeutic stimulation or ablation energy. In this work, we report for the first time on graphene biointerface for in vivo cardiac electrophysiology. Leveraging sub-micrometer thick tissue-conformable graphene arrays, we demonstrate sensing and stimulation of the open mammalian heart both in vitro and in vivo. Furthermore, we demonstrate the graphene biointerface treatment of atrioventricular block (the kind of arrhythmia where the electrical conduction from the atria to the ventricles is interrupted). The graphene arrays show effective electrochemical properties, namely interface impedance down to 40 Ohm×cm2 at 1 kHz, charge storage capacity up to 63.7 mC/cm2 , and charge injection capacity up to 704 µC/cm2 . Transparency of the graphene structures allows for simultaneous optical mapping of cardiac action potentials, calcium transients, and optogenetic stimulation while performing electrical measurements and stimulation. Our report presents evidence of the significant potential of graphene biointerfaces for advanced cardiac electrophysiology and arrhythmia therapy. This article is protected by copyright. All rights reserved.

Discovery of YH677 as a cancer stemness inhibitor that suppresses triple-negative breast cancer growth and metastasis by regulating the TGFß signaling pathway.

Triple-negative breast cancer (TNBC) has a poor prognosis due to the lack of specific and highly effective therapeutic agents. Cancer stem cells (CSCs) are one of the main factors contributing to TNBC relapse and metastasis. Therefore, targeting CSCs selectively with small molecules is a novel strategy for drug development. In this study, the natural product harmine (HM) was identified as a hit compound from 2632 natural product monomers based on phenotypic screening of a 2D assay and patient-derived organoid (PDO) model that was established from a patient who had multiple drug resistance and various visceral and contralateral breast metastases. Next, harmine was further modified and optimized to obtain a lead compound (YH677) with a tetrahydro-ß-carboline scaffold. YH677 showed potent antiproliferative and antimigratory activities against several TNBC cell lines in vitro. In addition, YH677 inhibited epithelial mesenchymal transition (EMT) and stem cell marker expression in a dose-dependent manner. More importantly, YH677 suppressed breast cancer growth and metastasis in orthotopic, metastatic xenograft and patient-derived xenograft (PDX) models in vivo. Mechanistic studies showed that YH677 inhibits the expansion of CSCs by regulating the TGFß/Smad signaling pathway. These preclinical data provide a basis for the development of YH677 as a lead compound for TNBC treatment.

Improved LSTM-based deep learning model for COVID-19 prediction using optimized approach.

Individuals in any country are badly impacted both economically and physically whenever an epidemic of infectious illnesses breaks out. A novel coronavirus strain was responsible for the outbreak of the coronavirus sickness in 2019. Corona Virus Disease 2019 (COVID-19) is the name that the World Health Organization (WHO) officially gave to the pneumonia that was caused by the novel coronavirus on February 11, 2020. The use of models that are informed by machine learning is currently a major focus of study in the field of improved forecasting. By displaying annual trends, forecasting models can be of use in performing impact assessments of potential outcomes. In this paper, proposed forecast models consisting of time series models such as long short-term memory (LSTM), bidirectional long short-term memory (Bi-LSTM), generalized regression unit (GRU), and dense-LSTM have been evaluated for time series prediction of confirmed cases, deaths, and recoveries in 12 major countries that have been affected by COVID-19. Tensorflow1.0 was used for programming. Indices known as mean absolute error (MAE), root means square error (RMSE), Median Absolute Error (MEDAE) and r2 score are utilized in the process of evaluating the performance of models. We presented various ways to time-series forecasting by making use of LSTM models (LSTM, BiLSTM), and we compared these proposed methods to other machine learning models to evaluate the performance of the models. Our study suggests that LSTM based models are among the most advanced models to forecast time series data.

Beneficial insights into postbiotics against colorectal cancer.

Colorectal cancer (CRC) is one of the most prevalent and life-threatening cancer types with limited therapeutic options worldwide. Gut microbiota has been recognized as the pivotal determinant in maintaining gastrointestinal (GI) tract homeostasis, while dysbiosis of gut microbiota contributes to CRC development. Recently, the beneficial role of postbiotics, a new concept in describing microorganism derived substances, in CRC has been uncovered by various studies. However, a comprehensive characterization of the molecular identity, mechanism of action, or routes of administration of postbiotics, particularly their role in CRC, is still lacking. In this review, we outline the current state of research toward the beneficial effects of gut microbiota derived postbiotics against CRC, which will represent the key elements of future precision-medicine approaches in the development of novel therapeutic strategies targeting gut microbiota to improve treatment outcomes in CRC.

Proteomic characterization and comparison of milk fat globule membrane proteins of Saanen goat milk from 3 habitats in China using SWATH-MS technique.

Saanen goats are among the major dairy goats in China. In present study, variation of milk fat globule membrane proteins profile of Saanen goat milk caused by geographic location was investigated using sequential window acquisition of all theoretical fragment ions data-independent acquisition mass spectrometry based proteomic approach. A total of 1,001 proteins were quantified in goat milk collected from 3 habitats of China [Guangdong (GD); Inner Mongolia (IM); Shannxi (SX)]. Most of the proteins were found to act cellular process of biological process, cell of cellular component, binding of molecular function after Gene Ontology annotation and metabolic of pathway indicated by Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Differentially expressed proteins (DEP) for GD versus IM, GD versus SX, IM versus SX were identified to be 81, 91, and 44, respectively. Gene Ontology enrichment analysis showed that the greatest DEP for 3 groups (GD vs. IM, GD vs. SX, IM vs. SX) were cellular process, cellular process and organonitrogen compound biosynthetic process/immune system process for biological process. For cellular component, the largest number of DEP for 3 comparison groups were organelle, organelle and organelle/intracellular. For molecular function, DEP of the 3 comparison groups were expressed most in structural molecule activity, binding and anion binding, respectively. Pathways with the majority of DEP were ribosome, systemic lupus erythematosus and primary immunodeficiency/systemic lupus erythematosus/amoebiasis/PI3K-Akt signaling pathway for GD versus IM, GD versus SX and IM versus SX, severally. Protein-protein interaction network analysis showed that DEP interacted most were 40S ribosomal protein S5, fibronectin and Cytochrome b-c1 complex subunit 2, mitochondrial for GD versus IM, GD versus SX and IM versus SX, separately. Data may give useful information for goat milk selection and milk authenticity in China.

Unraveling the effect of differential leadership on employee performance: Evidence from China.

This paper examines how differential leadership influences employee performance via perceived organizational support and individual-organizational fit. The psychological contract theory was used to investigate how differential leadership influences the performance of employees. The information was obtained by means of surveys distributed to various types of Chinese firms. A total of 358 complete responses for statistical analysis were received and examined. A structural equation model was used, which we believed would be the most appropriate model for testing the proposed study model. The evidence suggests that differentiated leadership promotes employee performance. The association between leadership differences and employee performance is positively mediated by perceived organizational support. Individual-organizational fit lowers the positive effect of differential leadership on employee performance and reduces the positive effect of organizational support perception on employee performance. The results of this research contribute to a better understanding of Chinese culture's differentiated interpersonal cordial leadership construct.

Outcome of COVID-19 Infection in Patients With Multiple Sclerosis Who Received Disease-Modifying Therapies: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: A systematic review and meta-analysis was performed of the outcome of Coronavirus disease 2019 (COVID-19) infection in patients with multiple sclerosis (MS) who received disease-modifying therapies (DMTs). METHODS: Relevant studies published before November 2022 in the PubMed, Cochrane Library, Chinese National Knowledge Infrastructure, and Web of Science databases were retrieved using the following search expression: ("multiple sclerosis" OR "MS") AND ("DMT" OR "disease modifying therapies") AND ("COVID-19"). Two authors independently screened the articles and extracted the data. Qualitative analyses and a meta-analysis constituted 22 of the 794 retrieved articles. Differences in the hospitalization and mortality rates were used as the main measures of efficacy, and the meta-analysis was performed using RevMan software. RESULTS: 22 clinical trials were selected. The hospitalization rate was lower in the 3,216 patients who received DMTs than in the 774 patients who did not receive any treatment, with a moderate effect size of 0.43 (p<0.00001). The mortality rate was also lower among patients with MS treated using DMTs than in controls (odds ratio [OR]=0.19, 95% confidence interval [CI]=0.13-0.27, p<0.00001). The hospitalization rates for COVID-19 infection in patients with MS treated with anti-CD20 therapy also increased markedly (OR=3.32, 95% CI=2.63-4.20, p<0.00001). However, there was no significant difference between patients with MS who did and did not receive DMTs. CONCLUSIONS: In summary, the application of DMTs was found to be valuable for patients with MS infected with COVID-19. However, more clinical studies are needed to determine the use of anti-CD20 drugs in patients with MS during the COVID-19 pandemic.

Selective Electroreductive Hydroboration of Olefins with B2pin2.

Organoboron showed great potential in the synthesis of various high-value chemical compounds. Direct hydroboration of olefins has been witnessed over time as a mainstream method for the synthesis of organoboron compounds. In this work, an electroreductive anti-Markovnikov hydroboration approach of olefins with readily available B2pin2 to synthesize valuable organoboron compounds with high chemo- and regioselectivities under metal catalyst-free conditions was reported. This protocol exhibited broad substrate scope and good functional-group tolerance on styrenes and heteroaromatic olefins, providing synthetically useful alkylborons with high efficiency and even various deuterium borylation products with good D-incorporation when CD3CN was employed as solvent. Furthermore, gram-scale reactions and extensive functional derivatization further highlighted the potential of this method.

A Smart Benzothiazole-Based Conjugated Polymer Nanoplatform with Multistimuli Response for Enhanced Synergistic Chemo-Photothermal Cancer Therapy.

The combination of chemotherapy and phototherapy has received tremendous attention in multimodal cancer therapy. However, satisfactory therapeutic outcomes of chemo-photothermal therapy (chemo-PTT) still remain challenging. Herein, a biocompatible smart nanoplatform based on benzothiazole-linked conjugated polymer nanoparticles (CPNs) is rationally designed, for effectively loading doxorubicin (DOX) and Mo-based polyoxometalate (POM) through both dynamic chemical bond and intermolecular interactions, with an expectation to obtain new anticancer drugs with multiple stimulated responses to the tumor microenvironment (TME) and external laser irradiation. Controlled drug release of DOX from the obtained nanoformulation (CPNs-DOX-PEG-cRGD-BSA@POM) triggered by both endogenous stimulations (GSH and low pH) and exogenous laser irradiation has been well demonstrated by pharmacodynamics investigations. More intriguingly, incorporating POM into the nanoplatform not only enables the nanomedicine to achieve mild hyperthermia but also makes it exhibit self-assembly behavior in acidic TME, producing enhanced tumor retention. Benefiting from the versatile functions, the prepared CPNs-DOX-PEG-cRGD-BSA@POM exhibited excellent tumor targeting and therapeutic effects in murine xenografted models, showing great potential in practical cancer therapy.

Targeting the chemokine ligand 2-chemokine receptor 2 axis provides the possibility of immunotherapy in chronic pain.

Chronic pain affects patients' physical and psychological health and quality of life, entailing a tremendous public health challenge. Currently, drugs for chronic pain are usually associated with a large number of side effects and poor efficacy. Chemokines in the neuroimmune interface combine with their receptors to regulate inflammation or mediate neuroinflammation in the peripheral and central nervous system. Targeting chemokines and their receptor-mediated neuroinflammation is an effective means to treat chronic pain. In recent years, growing evidence has shown that the expression of chemokine ligand 2 (CCL2) and its main chemokine receptor 2 (CCR2) is involved in its occurrence, development and maintenance of chronic pain. This paper summarises the relationship between the chemokine system, CCL2/CCR2 axis, and chronic pain, and the CCL2/CCR2 axis changes under different chronic pain conditions. Targeting chemokine CCL2 and its chemokine receptor CCR2 through siRNA, blocking antibodies, or small molecule antagonists may provide new therapeutic possibilities for managing chronic pain.

Effect of ultrasound-supported wound debridement in subjects with diabetic foot ulcers: A meta-analysis.

A meta-analysis study to assess the effect of ultrasound-supported wound debridement (USSD) in subjects with diabetic foot ulcer (DFU). A comprehensive literature examination till January 2023 was implemented and 1873 linked studies were appraised. The picked studies contained 577 subjects with DFUs in the studies' baseline, 282 of them were using USSD, 204 were using standard care, and 91 were using a placebo. Odds ratio (OR) in addition to 95% confidence intervals (CIs) were used to calculate the consequence of USSD in subjects with DFUs by the dichotomous styles and a fixed or random effect model. The USSD applied to DFU caused a significantly higher wound healing rate compared with the standard care (OR, 3.08; 95% CI, 1.94-4.88, P < .001) with no heterogeneity (I2  = 0%) and the placebo (OR, 7.61; 95% CI, 3.11-18.63, P = .02) with no heterogeneity (I2  = 0%). The USSD applied to DFUs caused a significantly higher wound healing rate compared with the standard care and the placebo. Though precautions should be taken when commerce with the consequences as all of the picked studies for this meta-analysis was with low sample sizes.

Magnetic nanoparticles enhance the cellular immune response of dendritic cell tumor vaccines by realizing the cytoplasmic delivery of tumor antigens.

Dendritic cells (DCs)-based tumor vaccines have the advantages of high safety and rapid activation of T cells, and have been approved for clinical tumor treatment. However, the conventional DC vaccines have some severe problems, such as poor activation of DCs in vitro, low level of antigen presentation, reduced cell viability, and difficulty in targeting lymph nodes in vivo, resulting in poor clinical therapeutic effects. In this research, magnetic nanoparticles Fe3O4@Ca/MnCO3 were prepared and used to actively and efficiently deliver antigens to the cytoplasm of DCs, promote antigen cross-presentation and DC activation, and finally enhance the cellular immune response of DC vaccines. The results show that the magnetic nanoparticles can actively and quickly deliver antigens to the cytoplasm of DCs by regulating the magnetic field, and achieve cross-presentation of antigens. At the same time, the nanoparticles degradation product Mn2+ enhanced immune stimulation through the interferon gene stimulating protein (STING) pathway, and another degradation product Ca2+ ultimately promoted cellular immune response by increasing autophagy. The DC vaccine constructed with the magnetic nanoparticles can more effectively migrate to the lymph nodes, promote the proliferation of CD8+ T cells, prolong the time of immune memory, and produce higher antibody levels. Compared with traditional DC vaccines, cytoplasmic antigen delivery with the magnetic nanoparticles provides a new idea for the construction of novel DC vaccines.

Dirigent gene editing of gossypol enantiomers for toxicity-depleted cotton seeds.

Axial chirality of biaryls can generate varied bioactivities. Gossypol is a binaphthyl compound made by cotton plants. Of its two axially chiral isomers, (-)-gossypol is the bioactive form in mammals and has antispermatogenic activity, and its accumulation in cotton seeds poses health concerns. Here we identified two extracellular dirigent proteins (DIRs) from Gossypium hirsutum, GhDIR5 and GhDIR6, which impart the hemigossypol oxidative coupling into (-)- and (+)-gossypol, respectively. To reduce cotton seed toxicity, we disrupted GhDIR5 by genome editing, which eliminated (-)-gossypol but had no effects on other phytoalexins, including (+)-gossypol, that provide pest resistance. Reciprocal mutagenesis identified three residues responsible for enantioselectivity. The (-)-gossypol-forming DIRs emerged later than their enantiocomplementary counterparts, from tandem gene duplications that occurred shortly after the cotton genus diverged. Our study offers insight into how plants control enantiomeric ratios and how to selectively modify the chemical spectra of cotton plants and thereby improve crop quality.

Visible-Light-Driven Organocatalytic Alkoxylation of Benzylic C-H Bonds.

A variety of strategies for direct alkoxylation of the benzyl C-H bond have been developed toward the construction of benzyl ethers. The light-induced benzyl C-H bond alkoxylation provides an alternative strategy for the synthesis of these important intermediates. The photocatalyzed alkoxylation of the benzyl C-H bond has dominated by metal-catalyzed methods. Herein, we reported a light-driven organocatalytic approach for alkoxylation of the benzyl C-H bond by the use of 9,10-dibromoanthracene as a photocatalyst and employing N-fluorobenzenesulfonimide as an oxidant. This reaction proceeds at room temperature and is capable of converting a variety of alkyl biphenyl and coupling partners, including a variety of alcohol and carboxylic acid, as well as peroxide, to the desired products under 400 nm light irradiation.

Shouhui Tongbian Capsules induce regression of inflammation to improve intestinal barrier in mice with constipation by targeted binding to Prkaa1: With no obvious toxicity.

Constipation arising from the poor bowel movement is a rife enteric health problem. Shouhui Tongbian Capsule (SHTB) is a traditional Chinese medicine (TCM) which effectively improve the symptoms of constipation. However, the mechanism has not been fully evaluated. The purpose of this study was to evaluate the effect of SHTB on the symptoms and intestinal barrier of mice with constipation. Our data showed that SHTB effectively improved the constipation induced by diphenoxylate, which was confirmed by shorter first defecation time, higher internal propulsion rate and fecal water content. Additionally, SHTB improved the intestinal barrier function, which was manifested by inhibiting the leakage of Evans blue in intestinal tissues and increasing the expression of occludin and ZO-1. SHTB inhibited NLRP3 inflammasome signaling pathway and TLR4/NF-κB signaling pathway, reduced the number of proinflammatory cell subsets and increased the number of immunosuppressive cell subsets to relieve inflammation. The photochemically induced reaction coupling system combined with cellular thermal shift assay and central carbon metabolomics technology confirmed that SHTB activated AMPKα through targeted binding to Prkaa1 to regulate Glycolysis/Gluconeogenesis and Pentose Phosphate Pathway, and finally inhibited intestinal inflammation. Finally, no obvious toxicity related to SHTB was found in a repeated drug administration toxicity test for consecutive 13 weeks. Collectively, we reported SHTB as a TCM targeting Prkaa1 for anti-inflammation to improve intestinal barrier in mice with constipation. These findings broaden our knowledge of Prkaa1 as a druggable target protein for inflammation inhibition, and open a new avenue to novel therapy strategy for constipation injury.

Study Protocol of a Multicenter, Randomized, Single-Blind Trial: Efficacy and Safety of Remimazolam Tosylate for Sedation in ICU Patients.

INTRODUCTION: Pharmacodynamic and pharmacokinetic studies in animal experiments and a phase 1 study suggested remimazolam tosylate as an effective and safe sedation/anesthetic agent. However, the effects and safety dose of remimazolam for light sedation in intensive care unit (ICU) patients are not clear and should be confirmed in a phase 2 study. METHODS: Sixty ICU patients requiring sedation treatment and undergoing mechanical ventilation will be enrolled and randomly assigned to a high dose group (HD group, 30 cases) and a low dose group (LD group, 30 cases) in a 1:1 ratio. Patients in both groups will be sedated using remimazolam tosylate in a primary dose of 0.08 mg/kg and a range of 0-2.0 mg/kg/h after randomization. Dose adjustment will be made at the range of every 0.1 mg/kg/h in the LD group and 0.2 mg/kg/h in the HD group to maintain the target Richmond Agitation and Sedation Score (RASS) at - 2 to + 1. The primary outcome will be the proportion of subjects that meet the following conditions: the time within the range of RASS (- 2 to + 1) accounts for 70% of the study drug administration time; without other rescue treatments. Secondary outcomes including the percentage time to reach the sedation goal; the proportion of subjects receiving rescue sedation and/or analgesic, and the mean dose of rescue drug throughout the study period; duration of mechanical ventilation; recovery time to full consciousness and nursing scores. Evaluations of safety including adverse events (AEs), serious AEs, physical examination, laboratory examination, etc. OUTCOME: The results of this study will provide crucial information for the use of remimazolam tosylate for ICU sedation. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT05152303.