Repurposing disulfiram with CuET nanocrystals: Enhancing anti-pyroptotic effect through NLRP3 inflammasome inhibition for treating inflammatory bowel diseases.

Drug repurposing offers a valuable strategy for identifying new therapeutic applications for existing drugs. Recently, disulfiram (DSF), a drug primarily used for alcohol addiction treatment, has emerged as a potential treatment for inflammatory diseases by inhibiting pyroptosis, a form of programmed cell death. The therapeutic activity of DSF can be further enhanced by the presence of Cu2+, although the underlying mechanism of this enhancement remains unclear. In this study, we investigated the mechanistic basis of Cu2+-induced enhancement and discovered that it is attributed to the formation of a novel copper ethylthiocarbamate (CuET) complex. CuET exhibited significantly stronger anti-pyroptotic activity compared to DSF and employed a distinct mechanism of action. However, despite its potent activity, CuET suffered from poor solubility and limited permeability, as revealed by our druggability studies. To overcome these intrinsic limitations, we developed a scalable method to prepare CuET nanocrystals (CuET NCs) using a metal coordination-driven self-assembly approach. Pharmacokinetic studies demonstrated that CuET NCs exhibited a 6-fold improvement in bioavailability. Notably, CuET NCs exhibited high biodistribution in the intestine, suggesting their potential application for the treatment of inflammatory bowel diseases (IBDs). To evaluate their therapeutic efficacy in vivo, we employed a murine model of DSS-induced colitis and observed that CuET NCs effectively attenuated inflammation and ameliorated colitis symptoms. Our findings highlight the discovery of CuET as a potent anti-pyroptotic agent, and the development of CuET NCs represents a novel approach to enhance the druggability of CuET.

A New Strategy for Targeting UCP2 to Modulate Glycolytic Reprogramming as a Treatment for Sepsis A New Strategy for Targeting UCP2.

Sepsis is a severe and life-threatening disease caused by infection, characterized by a dysregulated immune response. Unfortunately, effective treatment strategies for sepsis are still lacking. The intricate interplay between metabolism and the immune system limits the treatment options for sepsis. During sepsis, there is a profound shift in cellular energy metabolism, which triggers a metabolic reprogramming of immune cells. This metabolic alteration impairs immune responses, giving rise to excessive inflammation and immune suppression. Recent research has demonstrated that UCP2 not only serves as a critical target in sepsis but also functions as a key metabolic switch involved in immune cell-mediated inflammatory responses. However, the regulatory mechanisms underlying this modulation are complex. This article focuses on UCP2 as a target and discusses metabolic reprogramming during sepsis and the complex regulatory mechanisms between different stages of inflammation. Our research indicates that overexpression of UCP2 reduces the Warburg effect, restores mitochondrial function, and improves the prognosis of sepsis. This discovery aims to provide a promising approach to address the significant challenges associated with metabolic dysfunction and immune paralysis.

The current status and future of PD-L1 in liver cancer.

The application of immunotherapy in tumor, especially immune checkpoint inhibitors (ICIs), has played an important role in the treatment of advanced unresectable liver cancer. However, the efficacy of ICIs varies greatly among different patients, which has aroused people's attention to the regulatory mechanism of programmed death ligand-1 (PD-L1) in the immune escape of liver cancer. PD-L1 is regulated by multiple levels and signaling pathways in hepatocellular carcinoma (HCC), including gene variation, epigenetic inheritance, transcriptional regulation, post-transcriptional regulation, and post-translational modification. More studies have also found that the high expression of PD-L1 may be the main factor affecting the immunotherapy of liver cancer. However, what is the difference of PD-L1 expressed by different types of cells in the microenvironment of HCC, and which type of cells expressed PD-L1 determines the effect of tumor immunotherapy remains unclear. Therefore, clarifying the regulatory mechanism of PD-L1 in liver cancer can provide more basis for liver cancer immunotherapy and combined immune treatment strategy. In addition to its well-known role in immune regulation, PD-L1 also plays a role in regulating cancer cell proliferation and promoting drug resistance of tumor cells, which will be reviewed in this paper. In addition, we also summarized the natural products and drugs that regulated the expression of PD-L1 in HCC.

Global cluster analysis and network visualization in organoids in cancer research: a scientometric mapping from 1991 to 2021.

Objective: In the last three decades, there has been a surge in research on cancer organoids using 3D culture technologies, which has resulted in the development of physiological human cancer models. This study aims to provide an overview of the global trends and frontiers in research on cancer organoids. Methods: A total of 3189 publications on organoids in cancer research from 1991 to 2021 were collected from the Science Citation Index-Expanded (SCIE) of Web of Science (WoS). Bibliometric methods such as the R package "Bibliometrix," Citespace, and VOS viewer software were employed to investigate and visualize bibliographic coupling, co-citation, co-authorship, and co-occurrence trends, as well as publication trends in the field of organoids in cancer research. Results: From 1991 to 2021, there has been a significant increase in publications on cancer organoids, with most articles being from North America, Eastern Asia, and Western Europe. The USA had the highest number of publications, citations, prolific authors, and research funding globally. Cancers was the journal with the most publications, while Nature had the best total link strength. Harvard University were the most contributive institutions. The global research in this field could be classified into five clusters: chemotherapy study, organoids for drug screening, different models, molecular mechanism study, and organoid construction. These areas are expected to remain hotspots for future research. Conclusions: The number of publications on organoids in cancer research is expected to increase based on current global trends.

pH-Responsive doxorubicin-loaded magnetosomes for magnetic resonance-guided focused ultrasound real-time monitoring and ablation of breast cancer.

MR-guided focused ultrasound surgery (MRgFUS) is driving a new direction in non-invasive thermal ablation therapy with spatial specificity and real-time temperature monitoring. Although widely used in clinical practice, it remains challenging to completely ablate the tumor margin due to fear of damaging the surrounding tissues, thus leading to low efficacy and a series of complications. Herein, we have developed novel pH-responsive drug-loading magnetosomes (STPSD nanoplatform) for increasing the T2-contrast and improved the ablation efficiency with a clinical MRgFUS system. Specifically, this STPSD nanoplatform is functionalized by pH-responsive peptides (STP-TPE), encapsulating superparamagnetic iron oxide (SPIO) and doxorubicin (DOX), which can cause drug release and SPIO deposition at the tumor site triggered by acidity and MRgFUS. Under MRgFUS treatment, the increased vascular permeability caused by hyperthermia can improve the uptake of SPIO and DOX by tumor cells, so as to enhance ultrasound energy absorption and further enhance the efficacy of chemotherapy to completely ablate tumor margins. Moreover, we demonstrated that a series of MR sequences including T2-weighted imaging (T2WI), contrast-enhanced T1WI imaging (T1WI C+), maximum intensity projection (MIP), volume rendering (VR) and ADC mapping can be further utilized to monitor the MRgFUS ablation effect in rat models. Overall, this smart nanoplatform has the capacity to be a powerful tool to promote the therapeutic MRgFUS effect and minimize the side effects to surrounding tissues.

Extracellular Vesicles and Hypertension.

Hypertension implicates multiple organs and systems, accounting for the majority of cardiovascular diseases and cardiac death worldwide. Extracellular vesicles derived from various types of cells could transfer a variety of substances such as proteins, lipids, and nucleic acids from cells to cells, playing essential roles in both physiological and pathological processes. Extracellular vesicles are demonstrated to be closely associated with the development of essential hypertension by mediating the renin-angiotensin-aldosterone system and crosstalk between multiple vascular cells. Extracellular vesicles also participate in various kinds of pathogenesis of secondary hypertensions including acute kidney injury, renal parenchymal diseases, kidney transplantation, secretory diseases (primary aldosteronism, pheochromocytoma and paraganglioma, Cushing's syndrome), and obstructive sleep apnea. Extracellular vesicles have been proved to have the potential to be served as new biomarkers in the diagnosis, treatment, and prognosis assessment of hypertension. In the future, large multicenter cohorts are highly in demand for further verifying the sensitivity and specificity of extracellular vesicles as biomarkers.

Coptidis rhizoma and evodiae fructus against lipid droplet deposition in nonalcoholic fatty liver disease-related liver cancer by AKT.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. NAFLD has become one of the major factors contributing to hepatocellular carcinoma (HCC) development. However, there are no clear targets and therapeutic drugs for NAFLD-related liver cancer. This study explored the active compounds, target and mechanism of coptidis rhizoma and evodiae fructus in the treatment of NAFLD-related liver cancer based on the network pharmacology and experimental verification. There were 455 intersection targets of NAFLD-related liver cancer, and 65 drug-disease common targets. AKT1 has the highest degree, indicating that it may be a key target of coptidis rhizoma and evodiae fructus in the treatment of NAFLD-related liver cancer. The expression level of AKT1 was high in high-risk group, and the overall survival rate was lower than that in low-risk group. After oleic acid induction, p-AKT expression and lipid droplet deposition were promoted in HepG2 cells. Quercetin and resveratrol reduced lipid droplet deposition in vivo. Moreover, quercetin inhibited p-AKT expression, resveratrol both reduced the expression of p-AKT and AKT. The overall findings suggested that quercetin inhibited AKT in the treatment of NAFLD-related liver cancer.

Focus on T cell exhaustion: new advances in traditional Chinese medicine in infection and cancer.

In chronic infections and cancers, T lymphocytes (T cells) are exposed to persistent antigen or inflammatory signals. The condition is often associated with a decline in T-cell function: a state called "exhaustion". T cell exhaustion is a state of T cell dysfunction characterized by increased expression of a series of inhibitory receptors (IRs), decreased effector function, and decreased cytokine secretion, accompanied by transcriptional and epigenetic changes and metabolic defects. The rise of immunotherapy, particularly the use of immune checkpoint inhibitors (ICIs), has dramatically changed the clinical treatment paradigm for patients. However, its low response rate, single target and high immunotoxicity limit its clinical application. The multiple immunomodulatory potential of traditional Chinese medicine (TCM) provides a new direction for improving the treatment of T cell exhaustion. Here, we review recent advances that have provided a clearer molecular understanding of T cell exhaustion, revealing the characteristics and causes of T cell exhaustion in persistent infections and cancers. In addition, this paper summarizes recent advances in improving T cell exhaustion in infectious diseases and cancer with the aim of providing a comprehensive and valuable source of information on TCM as an experimental study and their role in collaboration with ICIs therapy.

Determination of the Optimal Volume of Programmed Intermittent Epidural Bolus When Combined With the Dural Puncture Epidural Technique for Labor Analgesia: A Random-Allocation Graded Dose-Response Study.

BACKGROUND: The dural puncture epidural (DPE) and the programmed intermittent epidural bolus (PIEB) techniques are recent innovations for labor analgesia. The optimal volume of PIEB during traditional epidural analgesia has been investigated previously but it is unknown whether these findings are applicable to DPE. This study aimed to determine the optimal volume of PIEB for effective labor analgesia after initiation of analgesia using DPE. METHODS: Parturients requesting labor analgesia received dural puncture with a 25-gauge Whitacre spinal needle and then had analgesia initiated with 15 mL of ropivacaine 0.1% with sufentanil 0.5 µg/mL. Analgesia was maintained using the same solution delivered by PIEB with boluses given at a fixed interval of 40 minutes starting 1 hour after the completion of the initial epidural dose. Parturients were randomized to 1 of 4 PIEB volume groups: 6, 8, 10, or 12 mL. Effective analgesia was defined as no requirement for a patient-controlled or manual epidural bolus for 6 hours after the completion of the initial epidural dose or until full cervical dilation. The PIEB volumes for effective analgesia in 50% of parturients (EV50) and 90% of parturients (EV90) were determined using probit regression. RESULTS: The proportions of parturients with effective labor analgesia were 32%, 64%, 76%, and 96% in the 6-, 8-, 10-, and 12-mL groups, respectively. The estimated values for EV50 and EV90 were 7.1 (95% confidence interval [CI], 5.9-7.9) mL and 11.3 (95% CI, 9.9-15.2) mL, respectively. There were no differences in side effects, including hypotension, nausea and vomiting, and fetal heart rate (FHR) abnormalities among groups. CONCLUSION: Under the conditions of the study, after initiation of analgesia using DPE, the EV90 of PIEB for effective labor analgesia using ropivacaine 0.1% with sufentanil 0.5 µg/mL was approximately 11.3 mL.

Intestinal Epithelial Cell-specific Deletion of Cytokine-inducible SH2-containing Protein Alleviates Experimental Colitis in Ageing Mice.

BACKGROUND AND AIMS: The incidence of inflammatory bowel disease [IBD] in the elderly has increased in recent years. However, the mechanisms underlying the ageing-related IBD susceptibility remain elusive. Cytokine-inducible SH2-containing protein [CISH] is involved in regulating metabolism, the expansion of intestinal tuft cells and type-2 innate lymphoid cells, and ageing-related airway inflammation. Here, we investigated the role of CISH in ageing-related colitis susceptibility. METHODS: CISH and phosphorylated signal transducer and activator of transcription-3 [p-STAT3] levels were evaluated in the colons of ageing mice and older ulcerative colitis [UC] patients. Mice with intestinal epithelial cell-specific knockout of Cish [CishΔIEC] and Cish-floxed mice were administered dextran sodium sulphate [DSS] or trinitrobenzene sulphonic acid [TNBS] to induce colitis. Colonic tissues were analysed in quantitative real-time polymerase chain reaction, immunoblotting, immunohistochemical, and histological staining experiments. Differentially expressed genes from colonic epithelia were analysed by RNA sequencing. RESULTS: Ageing increased the severity of DSS-induced colitis and the expression of colonic epithelial CISH in mice. CishΔIEC prevented DSS- or TNBS-induced colitis in middle-aged mice but not in young mice. RNA-sequencing analysis revealed that CishΔIEC significantly suppressed DSS-induced oxidative stress and proinflammatory responses. During ageing in the CCD841 cell model, knockdown of CISH decreased ageing-induced oxidative stress and proinflammatory responses, whereas these effects were compromised by knocking down or inhibiting STAT3. The increase in CISH expression was higher in the colonic mucosa of older patients with UC than in that of healthy controls. CONCLUSIONS: CISH might be a proinflammatory regulator in ageing; therefore, targeted therapy against CISH may provide a novel strategy for treating ageing-related IBD.

Six Cell Cycle-related Genes Serve as Potential Prognostic Biomarkers and Correlated with Immune Infiltrates in Hepatocellular Carcinoma.

Background: Cell cycle-related genes (CDK1, CDK5, CDC20, CCNA2, CCNB1, and CCNB2) play important roles in the regulation of mitotic cell cycle in eukaryotes. However, the correlation between cell cycle-related genes and tumor-infiltrating and prognosis of hepatocellular carcinoma (HCC) needs further investigation. Methods: Two public websites, Tumor Immune Estimate Resource (TIMER) and Oncomine, were used to assess the expression levels of cycle-related genes. We also analyzed the protein expression levels of six cell cycle-related genes using the HPA database. In addition, Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA) database were used to investigate the impact of cell cycle-related gene expression levels on the clinical prognosis of HCC. The correlation between cell cycle-related genes and cancer immune infiltrates was analyzed through TIMER site. Subsequently, GEPIA and TIMER database were used to assess the correlation between the expression of six cell cycle-related genes and polygenic markers in monocytes and macrophages, respectively. The cell cycle-related genes were also analyzed to find the associated genes with the highest alteration frequency, by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) approaches of Metascape and String database, respectively. Results: The expression levels of cell cycle-related genes were up-regulated in tumor tissues compared with normal tissues. Subsequently, the expression of high cell cycle-related genes was positively correlated with poor overall survival (OS) and progression-free survival (PFS) in HCC, for CDK1 (OS: HR = 2.15, P = 1.1E-05 PFS: HR = 2.03, P = 2.3E-06), CDK5 (OS: HR = 1.85, P = 0.0035 PFS: HR = 1.26, P = 0.17), CDC20 (OS: HR = 2.49, P = 5.1E-07 PFS: HR = 1.77, P = 0.00012), CCNA2 (OS: HR = 1.92, P = 0.00018 PFS: HR = 1.96, P = 5.2E-06), CCNB1 (OS: HR = 2.34, P = 3.4E-05 PFS: HR = 1.97, P = 5.3E-06), and CCNB2 (OS: HR = 1.91, P = 0.0013 PFS: HR = 1.63, P = 0.0011), respectively. Furthermore, the transcription level of cell cycle-related genes was significantly correlated with immune infiltrating levels of CD4+ T and CD8+ T cells, neutrophils, macrophages, and dendritic cells (DCs) in HCC, respectively. Amongst them, the expression levels of CDK1, CDC20, CCNA2, CCNB1 and CCNB2 manifest strongly correlated with diverse immune marker sets in HCC. Conclusions: Our results demonstrated that cell cycle-related genes played key roles in the prognosis of HCC. Meanwhile, they were significantly correlated with immune infiltrating levels of CD4+ T cells, CD8+ T cells, neutrophils, macrophages and DCs in HCC, respectively. In addition, CDK1, CDC20, CCNA2, CCNB1 and CCNB2 expressions may be involved in the regulation of monocytes and tumor-associated macrophages (TAMs) in HCC, respectively. These findings strongly suggested that cell cycle-related genes could be used as novel biomarkers for exploring the prognosis and immune cells infiltration of HCC.

Micro/nano-modified titanium surfaces accelerate osseointegration via Rab7-dependent mitophagy.

To achieve rapid and successful osseointegration of titanium (Ti) implants, the underlying mechanisms of surface modification-mediated bone metabolism need to be clarified. Given that the microenvironment surrounding Ti implants may be altered after implant insertion, mitophagy as a key control system for cellular homeostasis is most likely to regulate osseointegration. Recent findings suggest that PTEN-induced putative kinase 1 (Pink1)/Parkin-mediated mitophagy plays a key role in bone metabolism. Since the micro/nano-modified surfaces of Ti implants have been widely appreciated for osseointegration acceleration, we used two common micro/nano-modified techniques and demonstrated elevations of both the osteo-differentiation potential and Pink1/Parkin pathway of osteoblasts. Moreover, the Pink1/Parkin pathway exhibited an upward trend during osteoblast differentiation. However, when osteoblasts were treated with CCCP, a Pink1/Parkin inducer, the osteo-differentiation potential decreased. Our further study showed that the small GTPase Rab7, which was inhibited by CCCP, was essential for the Pink1/Parkin pathway. Upon Pink1 or Rab7 knockdown, the pro-osteogenic effect of micro/nano-modified Ti surfaces was significantly weakened. The present results demonstrated that Rab7 activation was essential for active mitophagy and osteogenesis. In addition, Rab7 was confirmed to mediate the process of autophagosome formation. Our findings provide novel insights into new targets for osseointegration promotion, regardless of Ti surface characteristics.

Randomized Assessment of the Optimal Time Interval Between Programmed Intermittent Epidural Boluses When Combined With the Dural Puncture Epidural Technique for Labor Analgesia.

BACKGROUND: The dural puncture epidural (DPE) and programmed intermittent epidural bolus (PIEB) techniques are recent advances in neuraxial labor analgesia. Previous studies have investigated the PIEB optimal interval for effective analgesia when a standard epidural technique is used to initiate labor analgesia. However, it is unknown whether these findings are applicable when DPE is used. METHODS: Patients were randomized into 1 of 5 groups with PIEB intervals of 35, 40, 45, 50, or 55 minutes. Labor analgesia was initiated on request with a DPE technique by epidural injection over 2 minutes of 15 mL of ropivacaine 0.1% with sufentanil 0.5 µg/mL after a dural puncture with a 25-gauge Whitacre needle. Effective analgesia was defined as no additional requirement for a patient-controlled bolus during the first stage of labor. The PIEB interval that was effective in 50% of patients (EI50) and 90% of patients (EI90) was estimated using probit regression. RESULTS: One hundred laboring parturients received the DPE technique of whom 93 proceeded to have analgesia maintained with PIEB using 10 mL boluses of ropivacaine 0.1% and sufentanil 0.5 µg/mL. Totals of 89.5% (17/19), 84.2% (16/19), 82.4% (14/17), 52.6% (11/19), and 36.8% (7/19) of patients in groups 35, 40, 45, 50, and 55, respectively, received effective PIEB analgesia. The estimated values for EI50 and EI90 were 52.5 (95% CI, 48.4-62.6) minutes and 37.0 (95% CI, 28.4-40.9) minutes, respectively. CONCLUSION: The estimate of the PIEB optimal interval for effective analgesia after the DPE technique was comparable to that reported in previous studies when analgesia was initiated using a conventional epidural technique.

Generation of Hepatocytes and Nonparenchymal Cell Codifferentiation System from Human-Induced Pluripotent Stem Cells.

To date, hepatocytes derived from human-induced pluripotent stem cells (hiPSC) provide a potentially unlimited resource for clinical application and drug development. However, most hiPSC-derived hepatocyte-like cells initiated differentiation from highly purified definitive endoderm, which are insufficient to accurately replicate the complex regulation of signals among multiple cells and tissues during liver organogenesis, thereby displaying an immature phenotypic and short survival time in vitro. Here, we described a protocol to achieve codifferentiation of endoderm-derived hepatocytes and mesoderm-derived nonparenchymal cells by the inclusion of BMP4 into hepatic differentiation medium, which has a beneficial effect on the hepatocyte maturation and lifespan in vitro. Our codifferentiation system suggests the important role of nonparenchymal cells in liver organogenesis. Hopefully, these hepatocytes described here provide a promising approach in the therapy of liver diseases.

CT-based transformer model for non-invasively predicting the Fuhrman nuclear grade of clear cell renal cell carcinoma.

Background: Clear cell Renal Cell Carcinoma (ccRCC) is the most common malignant tumor in the urinary system and the predominant subtype of malignant renal tumors with high mortality. Biopsy is the main examination to determine ccRCC grade, but it can lead to unavoidable complications and sampling bias. Therefore, non-invasive technology (e.g., CT examination) for ccRCC grading is attracting more and more attention. However, noise labels on CT images containing multiple grades but only one label make prediction difficult. However, noise labels exist in CT images, which contain multiple grades but only one label, making prediction difficult. Aim: We proposed a Transformer-based deep learning algorithm with CT images to improve the diagnostic accuracy of grading prediction and to improve the diagnostic accuracy of ccRCC grading. Methods: We integrate different training models to improve robustness and predict Fuhrman nuclear grade. Then, we conducted experiments on a collected ccRCC dataset containing 759 patients and used average classification accuracy, sensitivity, specificity, and AreaUnderCurve as indicators to evaluate the quality of research. In the comparative experiments, we further performed various current deep learning algorithms to show the advantages of the proposed method. We collected patients with pathologically proven ccRCC diagnosed from April 2010 to December 2018 as the training and internal test dataset, containing 759 patients. We propose a transformer-based network architecture that efficiently employs convolutional neural networks (CNNs) and self-attention mechanisms to extract a persuasive feature automatically. And then, a nonlinear classifier is applied to classify. We integrate different training models to improve the accuracy and robustness of the model. The average classification accuracy, sensitivity, specificity, and area under curve are used as indicators to evaluate the quality of a model. Results: The mean accuracy, sensitivity, specificity, and Area Under Curve achieved by CNN were 82.3%, 89.4%, 83.2%, and 85.7%, respectively. In contrast, the proposed Transformer-based model obtains a mean accuracy of 87.1% with a sensitivity of 91.3%, a specificity of 85.3%, and an Area Under Curve (AUC) of 90.3%. The integrated model acquires a better performance (86.5% ACC and an AUC of 91.2%). Conclusion: A transformer-based network performs better than traditional deep learning algorithms in terms of the accuracy of ccRCC prediction. Meanwhile, the transformer has a certain advantage in dealing with noise labels existing in CT images of ccRCC. This method is promising to be applied to other medical tasks (e.g., the grade of neurogliomas and meningiomas).

Inhibition of HIPK2 protects stress-induced pathological cardiac remodeling.

BACKGROUND: Homeodomain-Interacting Protein Kinase 2 (HIPK2) has been reported to maintain basal cardiac function, however, its role in pathological cardiac remodeling remains unclear. METHODS: HIPK2 inhibitors (tBID and PKI1H) treated mice and two lines of HIPK2-/- mice were subjected to transverse aortic constriction (TAC). HIPK2 knockdown were performed in neonatal rat cardiomyocytes (NRCMs), neonatal rat cardiac fibroblasts (NRCFs), and human embryonic stem cell-derived cardiomyocytes (hESC-CMs). Microarray analysis was used to screen HIPK2 targets. Overexpression of early growth response 3 (EGR3) and C-type lectin receptor 4D (CLEC4D) were performed in NRCMs, while an activator of Smad3 was used in NRCFs, to rescue the effects of HIPK2 knockdown. Finally, the effects of EGR3 and CLEC4D knockdown by AAV9 in TAC were determined. FINDINGS: HIPK2 was elevated in TAC mice model, as well as cardiomyocyte hypertrophy and NRCFs fibrosis model. Pharmacological and genetic inhibition of HIPK2 improved cardiac function and suppressed cardiac hypertrophy and fibrosis induced by TAC. In vitro, HIPK2 inhibition prevented cardiomyocyte hypertrophic growth and NRCFs proliferation and differentiation. At the mechanistic level, we identified EGR3 and CLEC4D as new targets of HIPK2, which were regulated by ERK1/2-CREB and mediated the protective function of HIPK2 inhibition in cardiomyocytes. Meanwhile, inhibition of phosphorylation of Smad3 was responsible for the suppression of cardiac fibroblasts proliferation and differentiation by HIPK2 inhibition. Finally, we found that inhibition of EGR3 or CLEC4D protected against TAC. INTERPRETATION: HIPK2 inhibition protects against pathological cardiac remodeling by reducing EGR3 and CLEC4D with ERK1/2-CREB inhibition in cardiomyocytes, and by suppressing the phosphorylation of Smad3 in cardiac fibroblasts. FUNDING: This work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to J.X.), National Natural Science Foundation of China (82020108002 and 81911540486 to J.X., 81400647 to MJ Xu), the grant from Science and Technology Commission of Shanghai Municipality (21XD1421300 and 20DZ2255400 to J.X.), the "Dawn" Program of Shanghai Education Commission (19SG34 to J.X.), and Shanghai Sailing Program (21YF1413200 to Q.Z.).

MgCr2O4-Modified CuO/Cu2O for High-Temperature Thermochemical Energy Storage with High Redox Activity and Sintering Resistance.

Metal oxides as high-temperature thermochemical energy storage systems with high energy density based on the gas-solid reaction are a critical demand for the future development of concentrated solar power plants. A copper-based system has high enthalpy change and low cost, but its serious sintering leads to poor reactivity. In this study, MgCr2O4 is decorated on the CuO/Cu2O surface to effectively increase the sintering temperature and alleviate the sintering problem. The re-oxidation degree is increased from 46 to 99.9%, and the reaction time is shortened by 3.7 times. The thermochemical energy density of storage and release reach -818.23 and 812.90 kJ/kg, respectively. After 600 cycles, the oxidation activity remains 98.77%. Material characterization elucidates that nanosized MgCr2O4 is uniformly loaded on the surface of CuO/Cu2O during the reversible reaction, and there is a strong interaction between metal oxides and prompter. Density functional theory (DFT) calculation further confirms that CuO/Cu2O-MgCr2O4 has large binding energy and the formation energy of copper vacancy increases, which can effectively inhibit sintering. The modification mechanism of CuO/Cu2O by MgCr2O4 is revealed, which can provide guidance for the reasonable design of thermochemical energy storage materials with sintering resistance and redox activity.

Hepatic cytokine-inducible SH2-containing protein (CISH) regulates gluconeogenesis via cAMP-responsive element binding protein (CREB).

Impairment of gluconeogenesis is a key factor responsible for hyperglycemia in patients with type 2 diabetes. As an important member of the suppressors of cytokine signaling (SOCS) protein family, many physiological functions of cytokine-inducible SH2-containing protein (CISH) have been described; however, the role of hepatic CISH in gluconeogenesis is poorly understood. In the present study, we observed that hepatic CISH expression was reduced in fasted wild-type (WT) mice. Overexpression of CISH decreased glucose production in mouse primary hepatocytes, while silencing of CISH had the opposite effects. In addition, adenovirus-mediated hepatic CISH overexpression resulted in improved glucose tolerance and decreased gluconeogenesis in WT and leptin receptor-deficient diabetic (db/db) mice. In contrast, adenovirus-mediated hepatic CISH knockdown impaired glucose tolerance and increased gluconeogenesis in WT mice. We also generated liver-specific CISH knockout (LV-CISH KO) mice and discovered that these mice had a similar phenotype in glucose tolerance and gluconeogenesis as mice injected with adenoviruses that knockdown CISH expression. Mechanistically, we found that CISH overexpression decreased and CISH knockdown increased the mRNA and protein levels of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase 1 (PEPCK), two key enzymes involved in gluconeogenesis, in vitro, and in vivo. Moreover, we discovered that the phosphorylation of cAMP-responsive element binding protein 1 (CREB), a transcription factor of G6pase and Pepck, was required for regulating gluconeogenesis by CISH. Taken together, this study identifies hepatic CISH as an important regulator of gluconeogenesis. Our results also provide important insights into the metabolic functions of the SOCS protein family and the potential targets for the treatment of diabetes.

Analysis of the close contact management mode and epidemiological characteristics of COVID-19 in Chengdu, China.

With the development of the novel coronavirus disease 2019 (COVID-19) epidemic and the increase in cases, as a potential source of infection, the risk of close contact has gradually increased. However, few studies have analyzed the tracking and management of cross-regional personnel. In this study, we hope to understand the effectiveness and feasibility of existing close contact management measures in Chengdu, so as to provide a reference for further prevention and control of the epidemic. The close contact management mode and epidemiological characteristics of 40,425 close contacts from January 22, 2020, to March 1, 2022, in Chengdu, China, were analyzed. The relationship with index cases was mainly co-passengers (57.58%) and relatives (7.20%), and the frequency of contact was mainly occasional contact (70.39%). A total of 400 (0.99%) close contacts were converted into cases, which were mainly found in the first and second nucleic acid tests (53.69%), and the contact mode was mainly by sharing transportation (63.82%). In terms of close contact management time, both the supposed ((11.93 ± 3.00) days vs. (11.92 ± 7.24) days) and actual ((13.74 ± 17.47) days vs. (12.60 ± 4.35) days) isolation times in Chengdu were longer than those of the outer cities (P < 0.001). For the local clustered epidemics in Chengdu, the relationship with indexed cases was mainly colleagues (12.70%). The tracing and management of close contacts is a two-way management measure that requires cooperation among departments. Enhancing existing monitoring and response capabilities can control the spread of the epidemic to a certain extent.

Determination of the Relative Potency of Norepinephrine and Phenylephrine Given as Infusions for Preventing Hypotension During Combined Spinal-Epidural Anesthesia for Cesarean Delivery: A Randomized Up-And-Down Sequential Allocation Study.

Purpose: The relative potency of norepinephrine and phenylephrine given as boluses to treat hypotension during spinal anesthesia for cesarean delivery has been reported but few data are available for infusions. This study aimed to determine the relative potency of norepinephrine and phenylephrine when given by infusion for preventing hypotension during combined spinal-epidural anesthesia for cesarean delivery. Methods: This was a prospective, randomized, double-blind, up-and-down sequential allocation study. Patients were randomly allocated to receive a prophylactic infusion of norepinephrine or phenylephrine started immediately after induction of anesthesia. The first patients received either norepinephrine 0.1 µg/kg/min or phenylephrine 0.5 µg/kg/min. An effective infusion rate was defined when no hypotension occurred before delivery. For each subsequent patient, the norepinephrine infusion rate was decreased or increased by 0.01 µg/kg/min or the phenylephrine infusion rate was decreased or increased by 0.05 µg/kg/min according to whether the infusion was effective or ineffective respectively in the previous patient. Values for the infusion rate that was effective in preventing hypotension in 50% of patients (ED50) for norepinephrine and phenylephrine were estimated using up-and-down sequential analysis and relative potency was estimated. Probit regression was used as a backup and sensitivity analysis. Results: The ED50 values for norepinephrine and phenylephrine calculated by the up-and-down method were 0.061 (95% CI 0.054-0.068) µg/kg/min and 0.368 (95% CI 0.343-0.393) µg/kg/min respectively. The estimated relative potency ratio for ED50 for norepinephrine to phenylephrine was 6.03:1 (95% CI 5.26:1 to 6.98:1). Conclusion: Under the conditions of this study, norepinephrine given by infusion was about 6 times more potent than phenylephrine. This information is useful for clinical practice and further comparative studies of norepinephrine versus phenylephrine. Clinical Trial Registration: http://www.chictr.org.cn/showproj.aspx, identifier [ChiCTR2200056237].