Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma.

Multiple myeloma (MM) is a malignancy that is often driven by MYC and that is sustained by IRF4, which are upregulated by super-enhancers. IKZF1 and IKZF3 bind to super-enhancers and can be degraded using immunomodulatory imide drugs (IMiD). Successful IMiD responses downregulate MYC and IRF4; however, this fails in IMiD-resistant cells. MYC and IRF4 downregulation can also be achieved in IMiD-resistant tumors using inhibitors of BET and EP300 transcriptional coactivator proteins; however, in vivo these drugs have a narrow therapeutic window. By combining IMiDs with EP300 inhibition, we demonstrate greater downregulation of MYC and IRF4, synergistic killing of myeloma in vitro and in vivo, and an increased therapeutic window. Interestingly, this potent combination failed where MYC and IRF4 expression was maintained by high levels of the AP-1 factor BATF. Our results identify an effective drug combination and a previously unrecognized mechanism of IMiD resistance. SIGNIFICANCE: These results highlight the dependence of MM on IKZF1-bound super-enhancers, which can be effectively targeted by a potent therapeutic combination pairing IMiD-mediated degradation of IKZF1 and IKZF3 with EP300 inhibition. They also identify AP-1 factors as an unrecognized mechanism of IMiD resistance in MM. See related article by Neri, Barwick, et al., p. 56. See related commentary by Yun and Cleveland, p. 5. This article is featured in Selected Articles from This Issue, p. 4.

Sustainable valorizing high-protein feather waste utilization through solid-state fermentation by keratinase-enhanced Streptomyces sp. SCUT-3 using a novel promoter.

Feather waste, a rich source of proteins, has traditionally been processed through high-temperature puffing and acid-base hydrolysis, contributing to generation of greenhouse gases and H2S. To address this issue, we employed circular economy techniques to recover the nutritional value of feather waste. Streptomyces sp. SCUT-3, an efficient proteolytic and chitinolytic bacterium, was isolated for feather degradation previously. This study aimed to valorize feather waste for feed purposes by enhancing its feather transformation ability through promoter optimization. Seven promoters were identified through omics analysis and compared to a common Streptomyces promoter ermE*p. The strongest promoter, p24880, effectively enhanced the expression of three candidate keratinases (Sep39, Sep40, and Sep53). The expression efficiency of double-, triple-p24880 and sandwich p24880-sep39-p24880 promoters were further verified. The co-overexpression strain SCUT-3-p24880-sep39-p24880-sep40 exhibited a 16.21-fold increase in keratinase activity compared to the wild-type. Using this strain, a solid-state fermentation process was established that increased the feather/water ratio (w/w) to 1:1.5, shortened the fermentation time to 2.5 days, and increased soluble peptide and free amino acid yields to 0.41 g/g and 0.14 g/g, respectively. The resulting has high protein content (90.49 %), with high in vitro digestibility (94.20 %). This method has the potential to revolutionize the feather waste processing industry.

[Preparation of vitexin albumin nanoparticles and its pharmacokinetic study].

This study aims to prepare vitexin albumin nanoparticles(VT-BSA-NPs) to alleviate the low bioavailability of vitexin(VT) in vivo due to its poor water solubility. VT micro powders were prepared by the antisolvent crystallization method, and the morphology, size, and physicochemical properties of VT micro powders were studied. The results showed that the VT micro powder had a particle size of(187.13±7.15) nm, an approximate spherical morphology, and a uniform size distribution. Compared with VT, the chemical structure of VT micro powders has not changed. VT-BSA-NPs were prepared from VT micro powders by desolvation-crosslinking curing method. The preparation process was screened by single factor test and orthogonal test, and the quality evaluation of the optimal prescription particle size, PDI, Zeta potential, EE, and morphology was performed. The results showed that the average particle size of VT-BSA-NPs was(124.33±0.47) nm; the PDI was 0.184±0.012; the Zeta potential was(-48.83±2.20) mV, and the encapsulation rate was 83.43%±0.39%, all of which met the formulation-related requirements. The morphological results showed that the VT-BSA-NPs were approximately spherical in appearance, regular in shape, and without adhesion on the surface. In vitro release results showed a significantly reduced release rate of VT-BSA-NPs compared with VT, indicating a good sustained release effect. LC-MS/MS was used to establish an analytical method for in vivo analysis of VT and study the plasma pharmacokinetics of VT-BSA-NPs in rats. The results showed that the specificity of the analytical method was good, and the extraction recovery was more than 90%. Compared with VT and VT micro powders, VT-BSA-NPs could significantly increase AUC, MRT, and t_(1/2), which was beneficial to improve the bioavailability of VT.

Simultaneous determination of multiple constituents, serum composition, and tissue distribution of Qingshen granule using ultra-high performance liquid chromatography-quadrupole-orbitrap high-resolution mass spectrometry.

Qingshen granule, composed of 14 herbal drugs, is primarily used as the assistant therapy for chronic kidney disease. Qingshen granule chemical composition was complex, but its chemical constituents and the pharmacodynamic material basis remain unreported. Ultra-high-performance liquid chromatography (UHPLC)-quadrupole-orbitrap high-resolution mass spectrometry was applied to recognize the chemical constituents of Qingshen granule. The analysis was performed using the ACQUITY UHPLC BEH C18 column (2.1 × 50 mm, 1.7 µm) with acetonitrile-0.1% formic acid as the mobile phase for gradient elution. The data were collected using heated electrospray ionization in positive and negative ion modes. This study successfully applied the UPHLC-quadrupole-orbitrap high-resolution mass spectrometry technique with the Compound Discoverer 3.3 platform to analyze Qingshen granule chemical composition. A total of 127 and 42 chemical components were identified in Qingshen granule in vitro and in vivo, respectively. In the tissue distribution of Qingshen granule, 9, 10, 11, 10, and 18 prototype components were detected in the heart, liver, spleen, lungs, and kidneys, respectively. Qingshen granule chemical constituents were characterized rapidly for the first time in this study, laying a foundation for further research on the substance basis and quality control of Qingshen granule in treating chronic kidney disease.

Role of G-protein coupled receptors in cardiovascular diseases.

Cardiovascular diseases (CVDs) are the leading cause of death globally, with CVDs accounting for nearly 30% of deaths worldwide each year. G-protein-coupled receptors (GPCRs) are the most prominent family of receptors on the cell surface, and play an essential regulating cellular physiology and pathology. Some GPCR antagonists, such as ß-blockers, are standard therapy for the treatment of CVDs. In addition, nearly one-third of the drugs used to treat CVDs target GPCRs. All the evidence demonstrates the crucial role of GPCRs in CVDs. Over the past decades, studies on the structure and function of GPCRs have identified many targets for the treatment of CVDs. In this review, we summarize and discuss the role of GPCRs in the function of the cardiovascular system from both vascular and heart perspectives, then analyze the complex ways in which multiple GPCRs exert regulatory functions in vascular and heart diseases. We hope to provide new ideas for the treatment of CVDs and the development of novel drugs.

Roles of Nuclear Receptors in Esophageal Cancer.

BACKGROUND: Esophageal cancer (EC), including esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), is a highly prevalent malignancy that occurs predominantly in the Asian region and is related to ethnicity, genetics, diet, and lifestyle. The nuclear receptor (NR) superfamily consists of 48 members of the human body. It is a collection of a large class of transcription factors, including Peroxisome proliferator-activated receptors (PPARs), Farnesol X receptor (FXR), Vitamin D receptor (VDR), Retinoic acid receptor (RAR), Pregnane X receptor (PXR), Androgen receptor (AR) and so on. Several NRs have been detected as oncogenes or tumor suppressors in EC progression. OBJECTIVES: NRs are associated with the progression of many cancers, including EC. Some NRs, such as PPARs and FXR, play an important role in EC. Studying the molecular mechanism of NRs in EC is helpful for further understanding the development of EC. Preclinical research and development of small molecule compound drugs targeting NRs have provided new ideas for the potential targeted therapy of EC. METHODS: This review summarizes the studies on NRs in EC in recent years, mainly including in vitro cell experiments and in vivo animal experiments. RESULTS: NRs influence EC progress in a variety of ways. They mainly affect the proliferation, migration and drug resistance of EC cells by affecting key cancer cell signaling pathways. Activation or inhibition of NRs inhibits or promotes EC progression, depending on EC types and tumor stages. Preclinical studies mainly focus on the development of small molecule drugs for targeting NRs (such as PPARγ agonists, PPARδ inhibitors, and FXR agonists), and agonists or inhibitors of NRs will become a potential therapeutic regimen for EC. CONCLUSION: The studies on the roles of NRs in EC have provided a theoretical basis for us to further understand the pathogenesis of EC and develop potential therapeutic drugs targeting NRs for the treatment of different diseases.

Emodin Ameliorates High Glucose-Induced Podocyte Apoptosis via Regulating AMPK/mTOR-Mediated Autophagy Signaling Pathway.

OBJECTIVE: To investigate the effect of emodin on high glucose (HG)-induced podocyte apoptosis and whether the potential anti-apoptotic mechanism of emodin is related to induction of adenosine-monophosphate-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)-mediated autophagy in podocytes (MPC5 cells) in vitro. METHODS: MPC5 cells were treated with different concentrations of HG (2.5, 5, 10, 20, 40, 80 and 160 mmol/L), emodin (2, 4, 8 µ mol/L), or HG (40 mmol/L) and emodin (4 µ mol/L) with or without rapamycin (Rap, 100 nmol/L) and compound C (10 µ mol/L). The viability and apoptosis of MPC5 cells were detected using cell counting kit-8 (CCK-8) assay and flow cytometry analysis, respectively. The expression levels of cleaved caspase-3, autophagy marker light chain 3 (LC3) I/II, and AMPK/mTOR signaling pathway-related proteins were determined by Western blot. The changes of morphology and RFP-LC3 fluorescence were observed under microscopy. RESULTS: HG at 20, 40, 80 and 160 mmol/L dose-dependently induced cell apoptosis in MPC5 cells, whereas emodin (4 µ mol/L) significantly ameliorated HG-induced cell apoptosis and caspase-3 cleavage (P<0.01). Emodin (4 µ mol/L) significantly increased LC3-II protein expression levels and induced RFP-LC3-containing punctate structures in MPC5 cells (P<0.01). Furthermore, the protective effects of emodin were mimicked by rapamycin (100 nmol/L). Moreover, emodin increased the phosphorylation of AMPK and suppressed the phosphorylation of mTOR. The AMPK inhibitor compound C (10 µ mol/L) reversed emodin-induced autophagy activation. CONCLUSION: Emodin ameliorated HG-induced apoptosis of MPC5 cells in vitro that involved induction of autophagy through the AMPK/mTOR signaling pathway, which might provide a potential therapeutic option for diabetic nephropathy.

[Optimization of ethanol precipitation process of Nauclea officinalis extract based on concept of quality by design(QbD)].

The ethanol precipitation process of Nauclea officinalis extract was optimized based on the concept of quality by design(QbD). Single factor tests were carried out to determine the levels of test factors. The ethanol volume fraction, pre-ethanol precipitation drug concentration, and ethanol precipitation time were taken as critical process parameters(CPPs). With the comprehensive scores of strictosamide transfer rate and solid removal rate as the critical quality attributes(CQAs), Box-Behnken design was employed to establish the mathematical models and space design between CPPs and CQAs, and the obtained optimal operating space was validated. The optimal operating space included ethanol volume fraction of 65%-70%, pre-ethanol precipitation drug concentration of 22-27 mg·mL~(-1), and ethanol precipitation time of 12 h. Based on the concept of QbD, this study adopted the design space to optimize the ethanol precipitation process of N. officinalis extract, which provided a reliable theoretical basis for the quality control in the production process of N. officinalis preparations. Moroever, this study provided a reference value for guiding the research and industrial production of traditional Chinese medicines.

An IGF1-expressing endometrial stromal cell population is associated with human decidualization.

BACKGROUND: Decidualization refers to the process of transformation of endometrial stromal fibroblast cells into specialized decidual stromal cells that provide a nutritive and immunoprivileged matrix essential for blastocyst implantation and placental development. Deficiencies in decidualization are associated with a variety of pregnancy disorders, including female infertility, recurrent implantation failure (RIF), and miscarriages. Despite the increasing number of genes reportedly associated with endometrial receptivity and decidualization, the cellular and molecular mechanisms triggering and underlying decidualization remain largely unknown. Here, we analyze single-cell transcriptional profiles of endometrial cells during the window of implantation and decidual cells of early pregnancy, to gains insights on the process of decidualization. RESULTS: We observed a unique IGF1+ stromal cell that may initiate decidualization by single-cell RNA sequencing. We found the IL1B+ stromal cells promote gland degeneration and decidua hemostasis. We defined a subset of NK cells for accelerating decidualization and extravillous trophoblast (EVT) invasion by AREG-IGF1 and AREG-CSF1 regulatory axe. Further analysis indicates that EVT promote decidualization possibly by multiply pathways. Additionally, a systematic repository of cell-cell communication for decidualization was developed. An aberrant ratio conversion of IGF1+ stromal cells to IGF1R+ stromal cells is observed in unexplained RIF patients. CONCLUSIONS: Overall, a unique subpopulation of IGF1+ stromal cell is involved in initiating decidualization. Our observations provide deeper insights into the molecular and cellular characterizations of decidualization, and a platform for further development of evaluation of decidualization degree and treatment for decidualization disorder-related diseases.

Diagnostic and therapeutic strategies for non-alcoholic fatty liver disease.

The global incidence rate of non-alcoholic fatty liver disease (NAFLD) is approximately 25%. With the global increase in obesity and its associated metabolic syndromes, NAFLD has become an important cause of chronic liver disease in many countries. Despite recent advances in pathogenesis, diagnosis, and therapeutics, there are still challenges in its treatment. In this review, we briefly describe diagnostic methods, therapeutic targets, and drugs related to NAFLD. In particular, we focus on evaluating carbohydrate and lipid metabolism, lipotoxicity, cell death, inflammation, and fibrosis as potential therapeutic targets for NAFLD. We also summarized the clinical research progress in terms of drug development and combination therapy, thereby providing references for NAFLD drug development.

Wafer-scale ultra-broadband perfect absorber based on ultrathin Al-SiO2 stack metasurfaces.

Broadband absorbers with high absorption, ultrathin thickness, and lithography-free planar structure have a wide range of potential applications, such as clocking and solar energy harvesting. For plasmonic metal materials, achieving perfect ultra-broadband absorption remains a challenge owing to the intrinsically narrow bandwidth. In this study, wafer-scale Al-SiO2 stack metasurfaces were experimentally fabricated to realize perfect ultra-broadband absorption. The experimental results show that the absorption for Al-SiO2 stack metasurfaces can reach up to 98% for the wavelength range from the ultraviolet to the near-infrared (350-1400 nm). It was experimentally verified that the absorption performance of Al-SiO2 stack metasurfaces is dependent on the layer number and is superior to that of other metal-based stack metasurfaces. This study will pave the way for development of plasmonic metal-based ultra-broadband absorbers as in low cost and high performance robust solar energy devices.

Application of symptom-based mind mapping combined with PBL teaching method in emergency trauma standardized resident training in MDT model.

Explore the feasibility and effectiveness of accepting mind mapping combined with problem-based learning (PBL) teaching method in the standardized training of emergency surgery residents in the multi-disciplinary team (MDT) model of emergency trauma. Eighty-nine doctors under training who rotated in the Department of Emergency Surgery of the First Affiliated Hospital of Anhui Medical University from January 2021 to January 2022 were selected as the study subjects, and randomly divided into a group receiving mind mapping combined with PBL teaching and a group receiving traditional lecture-based learning teaching. Mini-clinical evaluation exercise (Mini-CEX), direct observation of procedural skills (DOPS), teaching adherence, and satisfaction assessments were completed at the time of discharge from the department. There were no significant differences between the observation and control group trainees in terms of gender, age, education, and entry grades. Both groups of doctors were better able to participate in their respective teaching modes and made significant progress. The participants in the observation group had significantly higher Mini-CEX, DOPS, and teaching satisfaction scores than the control group (P < .05). Under the MDT model of emergency trauma, the combination of mind mapping and PBL teaching can improve the comprehensive clinical ability of the trainees more than participating in the traditional lecture-based learning teaching, which is worth promoting and implementing in the clinical standardized training.

Deficiency of miRNA-149-3p shaped gut microbiota and enhanced dextran sulfate sodium-induced colitis.

Genetic predisposition and disruption of host gut microbiota and immune system can result in inflammatory bowel disease (IBD). Here, we show that miRNA-149-5p (miR-149-5p) and miRNA-149-3p (miR-149-3p) play crucial roles in IBD. Mice lacking miR-149-3p were considerably more susceptible to dextran sulfate sodium (DSS)-induced colitis than wild-type (WT) mice, accompanied by more serious inflammatory symptoms and increased gene expression of certain inflammatory cytokines. Both miR-149-5p and miR-149-3p suppressed colon inflammatory response in vitro and in vivo. Furthermore, we found significant differences in the composition of the gut microbiota between WT and miR-149-3p-/- mice by 16S rRNA sequencing. Co-housing endowed susceptibility to WT mice against DSS-induced colitis compared with the WT control group. However, susceptibility of miR-149-3p-/- mice against DSS-induced colitis was still present after antibiotic treatment. These findings suggest that the deletion of miR-149-3p altered gut microbiota and influenced pathogenesis of intestinal inflammation, but sensitivity of miR-149-3p-/- mice to DSS-induced colitis is not conferred by microbiota. In addition, we identified the roles of miR-149-5p and miR-149-3p in colon inflammation, which may serve as an attractive therapeutic tool for colitis or IBD, and even colitis-associated carcinoma.

Single-cell transcriptome profiling of the human endometrium of patients with recurrent implantation failure.

Introduction: Despite great advances in assisted reproductive technology (ART), recurrent implantation failure (RIF) cannot be effectively avoided. Notably, cellular characteristics and communication that regulate endometrial receptivity and differentiation, and its disorders in RIF at window of implantation (WOI) remain rudimentary. Objectives: In this study, we profiled the endometrial cells present at the WOI timing in RIF patients and healthy controls using single-cell RNA sequencing (scRNA-seq) and provided a detailed molecular and cellular map of a healthy and RIF endometrium at the WOI. Method: In the current study, the endometrium from RIF patient (n = 6; age range, 32 - 35 years) and control (Ctrl) (n = 3; age range, 29 - 35 years) groups were studied at a single-cell resolution. single-cell RNA-seq and analysis were performed on the endometrium of patients with RIF and Ctrl. Immunofluorescence, flow cytometry assays, and quantitative real-time polymerase chain reaction (qRT-PCR) were performed to verify cellular identity and function. Results: We profiled the transcriptomes of 60222 primary human endometrial cells isolated from control and RIF patients at a single-cell resolution. We discovered dramatic differential expression of endometrial receptivity-related genes in four major endometrial fibroblast-like cells from RIF patients compared to the control endometrium. We observed that CD49a+CXCR4+NK cells were diminished in proportion with RIF. The decrease in subset of CD63highPGRhigh endometrial epithelial cells with high levels of progesterone receptor, autophagy and exosomes should contribute to the decrease in subset of NK cells. Additionally, we characterized aberrant molecular and cellular characteristics and endometrial cell-cell communication disorders in RIF patients. Conclusion: Our study provides deeper insights into endometrial microenvironment disorder of RIF that are potentially applicable to improving the etiological diagnosis and therapeutics of unexplained RIF.

Tentative exploration of pharmacodynamic substances: Pharmacological effects, chemical compositions, and multi-components pharmacokinetic characteristics of ESZWD in CHF-HKYd rats.

The chemical components of Xin'an famous prescription Ershen Zhenwu Decoction (ESZWD) are still unclear. The results showed that ESZWD could significantly reduce left ventricular end diastolic diameter, decrease N-terminal pro-brain natriuretic peptide (NT-proBNP), angiotensinII, aldosterone, reactive oxygen species, and malondialdehyde, increase serum superoxide dismutase, while had no significant effect on inflammatory factors. Ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF-MS) analysis detected 30 prototype components in model rats' serum, mainly including alkaloids, saponins, terpenoids, tanshinones, phenols. UPLC-MS/MS successfully detected the pharmacokinetic parameters of four components, and correlation analysis shows that there are negative correlations between four compounds and serum NT-proBNP. Thirty components of ESZWD may play a therapeutic role in chronic heart failure with heart-kidney Yang deficiency (CHF-HKYd) by improving myocardial injury, reducing oxidative stress levels, and inhibiting activation of the RAAS system in rats. Salsolinol, aconitine, paeoniflorin, and miltrione are equipped with potential characteristics as pharmacodynamic substances for ESZWD in treating CHF-HKYd. Additionally, the constituents of ESZWD in CHF-HKYd rats are different from normal rats, which provided a reference for the selection of subjects for further study.

Poria cocos polysaccharide prevents alcohol-induced hepatic injury and inflammation by repressing oxidative stress and gut leakiness.

Alcoholic liver disease (ALD) is a major worldwide chronic liver disease accompanied by hepatic inflammation, gut leakiness, and abnormal oxidative stress. Our previous study demonstrated substantial hepatoprotective activity of the active Poria cocos polysaccharide (PCP-1C). The present study explored whether PCP-1C protects against ALD among hepatic inflammation, gut leakiness, and abnormal oxidative stress. The results showed that PCP-1C significantly improved alcohol-induced liver injury by decreasing serum biochemical parameters, alleviating hepatic steatosis, and reducing lipid accumulation caused by ALD. Moreover, PCP-1C treatment reduced hepatic inflammation by inhibiting the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway and also improved hepatocyte apoptosis by inhibiting the cytochrome P450 2E1 (CYP2E1)/reactive oxygen species (ROS)/mitogen-activated protein kinases (MAPKs) signaling pathway. Regarding intestinal protection, PCP-1C could repair the intestinal barrier and reduce lipopolysaccharide (LPS) leakage. Generally, PCP-1C exerts a positive therapeutic effect on ALD, which may play a pivotal of decreasing inflammatory factor release, inhibiting oxidative stress and apoptosis, and improving intestinal barrier injury.

Neuroprotective Effect of Taohong Siwu Decoction on Cerebral Ischemia/Reperfusion Injury via Mitophagy-NLRP3 Inflammasome Pathway.

Objective: Globally, cerebral ischemia has been shown to be the second leading cause of death. Our previous studies have shown that Taohong Siwu Decoction (THSWD) exhibits obvious neuroprotective effects on cerebral ischemia/reperfusion (I/R) injury (CIRI). In this study, we further explored the modulatory effect of THSWD on mitochondrial autophagy in CIRI and the relationship between modulatory effect and NLRP3 inflammatory vesicle activation, so as to further explain the mechanism of neuroprotective effect of THSWD. Methods: Middle cerebral artery occlusion reperfusion (MCAO/R) model in rats was built to simulate I/R. Adult male SD rats (220-270 g) were randomly divided into the following four groups: the sham group, the MCAO/R group, the MCAO/R + THSWD group, and the MCAO/R + THSWD + Mitochondrial division inhibitor 1 (Mdivi-1) group. Neurological defect scores were used to evaluate neurological function. 2,3,5-Triphenyltetrazolium chloride (TTC) staining was conducted to measure cerebral infarct volume. Nissl staining, H&E staining and TUNEL staining were executed to detect ischemic cortical neuronal cell viability and apoptosis. Electron microscopy was used to observe the ultrastructural changes of mitochondria. Total Reactive Oxygen Species (ROS) in tissue were measured by fluorescence spectrophotometry, and the activation status of microglia was evaluated by Iba-1/CD16 immunofluorescence staining. The levels of mitophagy-related proteins (LC3, Parkin, PINK1), NLRP3 inflammasome-related proteins (NLRP3, ASC, Pro-caspase-1, Cleaved-caspase-1), and inflammatory cytokines (Pro-IL-18, Pro-IL-1ß, IL-18, IL-1ß) were evaluated by western blotting. Results: The studies showed that THSWD treatment alleviated cerebral infarction and neurological deficiencies. THSWD upregulated the expressions of autophagy markers (LC3-II/LC3-I and Beclin1) mitochondrial autophagy markers (Parkin and PINK1) after CIRI. Furthermore, THSWD treatment attenuated microglia activation and damage to mitochondrial structures, thereby reducing ROS production and NLRP3 inflammasome activation. In contrast, the mitochondrial autophagy inhibitor Mdivi-1 inhibited the above beneficial effects of THSWD. Conclusions: THSWD exhibits neuroprotective effects against MCAO/R in rats by enhancing mitochondrial autophagy and reducing NLRP3 inflammasome activation.

Epidemiological features and dynamic changes in blood biochemical indices for COVID-19 patients in Hebi.

BACKGROUND: Millions of people have died of coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and retrospective studies of the disease in local regions are necessary. AIM: To characterize the epidemiological features and dynamic changes in blood biochemical indices for SARS-CoV-2-infected patients in Hebi, a representative city with a large floating population in North China. METHODS: From January 25 to February 10, 2020, the clinical data of patients who tested positive for SARS-CoV-2 by quantitative real-time polymerase chain reaction in Hebi city (China) were evaluated at admission, and laboratory data for hematologic parameters, inflammatory indices, coagulation function indices, liver function indices, blood lipid indices, renal function indices, myocardial enzyme activities and five blood biochemical markers of immunity were evaluated at admission, upon hospitalization and before discharge. RESULTS: Sixteen confirmed COVID-19 patients developed pneumonia but were cured after adequate treatment. Fever and fatigue were the common symptoms. The most common laboratory abnormalities of patients at admission were leukopenia, eosinopenia, decreased percentage of eosinophils, elevated high sensitivity C-reactive protein and fibrinogen levels, hypoalbuminemia, mildly increased aspartate transferase activity and levels of bilirubin, and increased levels of ß2-microglobulin. Importantly, aggravated liver dysfunction was detected in most patients, which may be partially attributed to virus infection as well as medicinal treatment. CONCLUSION: This study provides several potential diagnostic markers and dynamic biochemical indices of disease progression to better prevent, diagnose and treat COVID-19 infection.

Design, synthesis and evaluation of 3-phenoxypyrazine-2-carboxamide derivatives as potent TGR5 agonists.

TGR5 is emerging as an important and promising target for the treatment of non-alcoholic steatohepatitis, type 2 diabetes mellitus (T2DM), and obesity. A series of novel 3-phenoxypyrazine-2-carboxamide derivatives were designed, synthesized and evaluated in vitro and in vivo. The most potent compounds 18g and 18k exhibited excellent hTGR5 agonist activity, which was superior to those of the reference drug INT-777. In addition, compound 18k could significantly reduce blood glucose levels in C57 BL/6 mice and stimulate GLP-1 secretion in NCI-H716 cells and C57 BL/6 mice.

HGF/c-Met: A Key Promoter in Liver Regeneration.

Hepatocyte growth factor (HGF) is a peptide-containing multifunctional cytokine that acts on various epithelial cells to regulate cell growth, movement and morphogenesis, and tissue regeneration of injured organs. HGF is sequestered by heparin-like protein in its inactive form and is widespread in the extracellular matrix of most tissues. When the liver loses its average mass, volume, or physiological and biochemical functions due to various reasons, HGF binds to its specific receptor c-Met (cellular mesenchymal-epithelial transition) and transmits the signals into the cells, and triggers the intrinsic kinase activity of c-Met. The downstream cascades of HGF/c-Met include JAK/STAT3, PI3K/Akt/NF-κB, and Ras/Raf pathways, affecting cell proliferation, growth, and survival. HGF has important clinical significance for liver fibrosis, hepatocyte regeneration after inflammation, and liver regeneration after transplantation. And the development of HGF as a biological drug for regenerative therapy of diseases, that is, using recombinant human HGF protein to treat disorders in clinical trials, is underway. This review summarizes the recent findings of the HGF/c-Met signaling functions in liver regeneration.