Integration of transcriptomics and metabolomics reveals toxicological mechanisms of ZhuRiHeng drop pill in the 180-day repeated oral toxicity study.

Background: ZhuRiHeng Drop Pill (ZRH) is a traditional Mongolian medicinal preparation. Despite its long history of use for the treatment of coronary heart disease, there have been few toxicological studies of the safety profile of ZRH. Purpose: In order to comprehensively elucidate the underlying mechanisms behind the observed toxicity of ZRH on rat livers in the 180-day repeated oral toxicity study, we conducted a comprehensive analysis by integrating transcriptomic and metabolomic data. Methods: High-resolution mass spectrometry was conducted to evaluate the constituents of ZRH. For the acute oral toxicity study, mice were administered a dose of 32 g/(kg·d) of ZRH, while rats were instead orally administered 0.934, 1.868, or 3.736 g/(kg·d) of ZRH over a 180-day period in a 180-day repeated oral toxicity study. Conventional index and organ weights/histology were then monitored to detect any potential ZRH treatment-related toxicity. To identify key genes and metabolites involved in ZRH toxicological processes, we performed transcriptomic and metabolomic analyses of liver tissue upon ZRH treatment using RNA-seq techniques, qPCR and liquid chromatography-mass spectrometry analyses. Results: A total of 60 compounds in ZRH were identified and speculated in positive and negative ion modes. Mice in the acute toxicity study exhibited no signs of ZRH-related toxicity. In a protracted oral toxicity investigation spanning 180 days, discernible elevations in liver ratios were noted in both male and female rats across all three dose cohorts, relative to the control group (p < 0.05 or p < 0.01). Upon subjecting to ZRH treatment, our transcriptomic and qPCR analyses unveiled notable upregulation of crucial genes, exemplified by Abcb1b and Cyp2b2, known for theirs involvement in liver drug transport and metabolism function. Furthermore, our untargeted metabolomic analysis provided supplementary insights, revealing significant regulation in pyrimidine metabolism, as well as alanine, aspartate, and glutamate metabolism pathways. Conclusion: Our study unveils a panoramic understanding of the temporal, dosage-specific, and gene dimensions surrounding the metabolic and transcriptional shifts induced by ZRH exposure. As we peer into the future, recommendations emerge for further exploration, encompassing aspects such as time dynamics, dosage considerations, and gene-centric avenues to enhance therapeutic efficacy.

Plasma thrombomodulin as a candidate biomarker for the diagnosis and prognosis of HBV-related acute-on-chronic liver failure.

Background and Aim: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a complicated syndrome with high short-term mortality. Effective biomarkers are required for its early diagnosis and prognosis. This study aimed to determine the diagnostic and prognostic value of thrombomodulin (TM) in patients with HBV-ACLF. Methods: The expression of TM during disease progression was evaluated through transcriptomics analysis. The plasma TM concentrations of 393 subjects with HBV-ACLF (n=213), acute-on-chronic hepatic dysfunction (ACHD, n=50), liver cirrhosis (LC, n=50) or chronic hepatitis B (CHB, n=50), and normal controls (NC, n=30) from a prospective multicenter cohort, were measured to verify the diagnostic and prognostic significance of plasma TM for HBV-ACLF patients by enzyme-linked immunosorbent assay (ELISA). Results: TM mRNA was highly expressed in the HBV-ACLF group compared with the ACHD group (AUROC=0.710). High expression of TM predicted poor prognosis for HBV-ACLF patients at 28/90 days (AUROCs=0.823/0.788). Functional analysis showed that TM was significantly associated with complement activation and the inflammatory signaling pathway. External validation confirmed its high diagnostic accuracy for HBV-ACLF patients (AUROC=0.796). Plasma TM concentrations were correlated with organ failure, including coagulation and kidney failure. Plasma TM concentrations showed a potential prognostic value for 28-day mortality rates (AUROC=0.702). Risk stratification specifically identified HBV-ACLF patients with a high risk of death as having a plasma TM concentration of ≥8.4 ng/mL. Conclusion: This study reveals that the plasma TM can be a candidate biomarker for early diagnosis and prognosis of HBV-ACLF, and might play a vital role in coagulation and inflammation.

Acute non-traffic traumatic spinal cord injury in the aging population: Analysis of the National Inpatient Sample 2005-2018.

BACKGROUND: This study aimed to determine risk factors for poor in-hospital outcomes in a large cohort of older adult patients with acute non-traffic traumatic spinal cord injury (tSCI). METHODS: This is a population-based, retrospective, observational study. Data of older adults ≥65 years with a primary discharge diagnosis of acute non-traffic tSCI were extracted from the US National Inpatient Sample (NIS) database 2005-2018. Traffic-related tSCI admissions or patients lacking complete data on age, sex and outcomes of interest were excluded. Univariate and multivariate logistic regression analysis was used to determine associations between variables and in-hospital outcomes. RESULTS: Data of 49,449 older patients (representing 246,939 persons in the US) were analyzed. The mean age was 79.9 years. Multivariable analyses revealed that severe International Classification of Disease (ICD)-based injury severity score (ICISS) (adjusted odds ratio [aOR] = 3.14, 95% confidence interval [CI]: 2.77-3.57), quadriplegia (aOR = 2.79, 95%CI: 2.34-3.32), paraplegia (aOR = 2.60, 95%CI:1.89-3.58), cervical injury with vertebral fracture (aOR = 2.19, 95%CI: 1.90-2.52), and severe liver disease (aOR = 2.33, 95%CI: 1.34-4.04) were all strong independent predictors of in-hospital mortality. In addition, malnutrition (aOR = 3.19, 95% CI: 2.93-3.48) was the strongest predictors of prolonged length of stay (LOS). CONCLUSIONS: Several critical factors for in-hospital mortality, unfavorable discharge, and prolonged LOS among US older adults with acute non-traffic tSCI were identified. In addition to the factors associated with initial severity, the presence of severe liver disease and malnutrition emerged as strong predictors of unfavorable outcomes, highlighting the need for special attention for these patient subgroups.

How can we establish animal models of HIV-associated lymphoma?

Human immunodeficiency virus (HIV) infection is strongly associated with a heightened incidence of lymphomas. To mirror the natural course of human HIV infection, animal models have been developed. These models serve as valuable tools to investigate disease pathobiology, assess antiretroviral and immunomodulatory drugs, explore viral reservoirs, and develop eradication strategies. However, there are currently no validated in vivo models of HIV-associated lymphoma (HAL), hampering progress in this crucial domain, and scant attention has been given to developing animal models dedicated to studying HAL, despite their pivotal role in advancing knowledge. This review provides a comprehensive overview of the existing animal models of HAL, which may enhance our understanding of the underlying pathogenesis and approaches for malignancies linked to HIV infection.

Petersen's hernia after gastric cancer surgery: Unravelling clinical characteristics and optimal management approaches.

INTRODUCTION: Petersen's hernia is a rare and serious complication that can occur after radical gastrectomy and digestive tract reconstruction for gastric cancer. This article summarises the symptoms, diagnosis and treatment of Petersen's hernia after surgery for gastric cancer. PATIENTS AND METHODS: A retrospective analysis was conducted on 11 male patients who were diagnosed with Petersen's hernia and underwent surgical treatment at our hospital from January 2020 to December 2022. Their clinical manifestations, perioperative conditions and follow-up after treatment were collected. RESULTS: The median age was 58.5 years (range: 45-73), and the median time since gastrectomy was 24 months (range: 4-125). Open distal gastrectomy (45.5%) and open total gastrectomy (27.3%) were the most common procedures. Roux-en-Y (81.8%) was the predominant anastomosis method. All patients underwent emergency surgery within a median time of 30 h (range: 4-45). Intestine necrosis occurred in 36.4% of cases, with a perioperative death rate of 27.3%. CONCLUSION: Petersen's hernia after gastric cancer surgery can quickly lead to necrotising intestinal obstruction and poor prognosis. Enhanced abdominal computed tomography should be performed as soon as possible, and early exploratory laparotomy should be done to avoid intestinal necrosis. Routine closure of the mesenteric defect after gastric cancer resection can prevent the occurrence of Petersen's hernia. This article highlights the need for increased awareness and preventive measures to minimise the occurrence of Petersen's hernia in gastric cancer patients. It emphasises the importance of early detection and appropriate management strategies for improved patient outcomes.

The role of circular RNA during the urological cancer metastasis: exploring regulatory mechanisms and potential therapeutic targets.

Metastasis is a major contributor to treatment failure and death in urological cancers, representing an important biomedical challenge at present. Metastases form as a result of cancer cells leaving the primary site, entering the vasculature and lymphatic vessels, and colonizing clones elsewhere in the body. However, the specific regulatory mechanisms of action underlying the metastatic process of urological cancers remain incompletely elucidated. With the deepening of research, circular RNAs (circRNAs) have been found to not only play a significant role in tumor progression and prognosis but also show aberrant expression in various tumor metastases, consequently impacting tumor metastasis through multiple pathways. Therefore, circRNAs are emerging as potential tumor markers and treatment targets. This review summarizes the research progress on elucidating how circRNAs regulate the urological cancer invasion-metastasis cascade response and related processes, as well as their role in immune microenvironment remodeling and circRNA vaccines. This body of work highlights circRNA regulation as an emerging therapeutic target for urological cancers, which should motivate further specific research in this regard.

Cellular heterogeneity and dynamics of the human uterus in healthy premenopausal women.

The human uterus is a complex and dynamic organ whose lining grows, remodels, and regenerates in every menstrual cycle or upon tissue damage. Here we applied single-cell RNA sequencing to profile more the 50,000 uterine cells from both the endometrium and myometrium of 5 healthy premenopausal individuals, and jointly analyzed the data with a previously published dataset from 15 subjects. The resulting normal uterus cell atlas contains more than 167K cells representing the lymphatic endothelium, blood endothelium, stromal, ciliated epithelium, unciliated epithelium, and immune cell populations. Focused analyses within each major cell type and comparisons with subtype labels from prior studies allowed us to document supporting evidence, resolve naming conflicts, and to propose a consensus annotation system of 39 subtypes. We release their gene expression centroids, differentially expressed genes, and mRNA patterns of literature-based markers as a shared community resource. We find many subtypes show dynamic changes over different phases of the cycle and identify multiple potential progenitor cells: compartment-wide progenitors for each major cell type, transitional cells that are upstream of other subtypes, and potential cross-lineage multipotent stromal progenitors that may be capable of replenishing the epithelial, stromal, and endothelial compartments. When compared to the healthy premenopausal samples, a postpartum and a postmenopausal uterus sample revealed substantially altered tissue composition, involving the rise or fall of stromal, endothelial, and immune cells. The cell taxonomy and molecular markers we report here are expected to inform studies of both basic biology of uterine function and its disorders. SIGNIFICANCE: We present single-cell RNA sequencing data from seven individuals (five healthy pre-menopausal women, one post-menopausal woman, and one postpartum) and perform an integrated analysis of this data alongside 15 previously published scRNA-seq datasets. We identified 39 distinct cell subtypes across four major cell types in the uterus. By using RNA velocity analysis and centroid-centroid comparisons we identify multiple computationally predicted progenitor populations for each of the major cell compartments, as well as potential cross-compartment, multi-potent progenitors. While the function and interactions of these cell populations remain to be validated through future experiments, the markers and their "dual characteristics" that we describe will serve as a rich resource to the scientific community. Importantly, we address a significant challenge in the field: reconciling multiple uterine cell taxonomies being proposed. To achieve this, we focused on integrating historical and contemporary knowledge across multiple studies. By providing detailed evidence used for cell classification we lay the groundwork for establishing a stable, consensus cell atlas of the human uterus.

Hemostasis Using Prothrombin Complex Concentrate in Patients Undergoing Cardiac Surgery: Systematic Review with Meta-Analysis.

OBJECTIVE: The purpose of present study was to comprehensívely explore the efficacy and safety of prothrombín complex concentrate (PCC) to treat massíve bleedíng in patíents undergoing cardiac surgery. METHODS: PubMed®, Embase, and Cochrane Líbrary databases were searched for studíes ínvestigating PCC administratíon duríng cardiac surgery published before September 10, 2022. Mean dífference (MD) wíth 95% confidence interval (CI) was applíed to analyze continuous data, and dichotomous data were analyzed as risk ratio (RR) with 95% CI. RESULTS: Twelve studies were included in the meta-analysis. Compared with other non-PCC treatment regimens, PCC was not assocíated with elevated mortality (RR=1.18, 95% CI=0.86-1.60, P=0.30, I2=0%), shorter hospital stay (MD=-2.17 days; 95% CI=-5.62-1.28, P=0.22, I2=91%), reduced total thoracic drainage (MD=-67.94 ml, 95% CI=-239.52-103.65, P=0.44, I2=91%), thromboembolíc events (RR=1.10, 95% CI=0.74-1.65, P=0.63, I2=39%), increase ín atríal fibríllatíon events (RR=0.73, 95% CI=0.52-1.05, P=0.24, I2=29%), and myocardial infarction (RR=1.10, 95% CI=0.80-1.51, P=0.57, I2=81%). However, PCC use was associated with reduced intensive care unit length of stay (MD=-0.81 days, 95% CI=-1.48- -0.13, P=0.02, I2=0%), bleeding (MD=-248.67 ml, 95% CI=-465.36- -31.97, P=0.02, I2=84%), and intra-aortic balloon pump/extracorporeal membrane oxygenation (RR=0.65, 95% CI=0.42-0.996, P=0.05, I2=0%) when compared with non-PCC treatment regimens. CONCLUSION: The use of PCC in cardiac surgery did not correlate with mortality, length of hospítal stay, thoracic drainage, atríal fibríllatíon, myocardíal ínfarction, and thromboembolíc events. However, PCC sígnificantly improved postoperatíve intensíve care unít length of stay, bleedíng, and intra-aortic balloon pump/ extracorporeal membrane oxygenation outcomes ín patients undergoing cardíac surgery.

Recent advances in photothermal nanomaterials-mediated detection of circulating tumor cells.

Photothermal materials have shown great potential for cancer detection and treatment due to their excellent photothermal effects. Circulating tumor cells (CTCs) are tumor cells that are shed from the primary tumor into the blood and metastasize. In contrast to other tumor markers that are free in the blood, CTCs are a collective term for all types of tumor cells present in the peripheral blood, a source of tumor metastasis, and clear evidence of tumor presence. CTCs detection enables early detection, diagnosis and treatment of tumors, and plays an important role in cancer prevention and treatment. This review summarizes the application of various photothermal materials in CTC detection, including gold, carbon, molybdenum, phosphorus, etc. and describes the significance of CTC detection for early tumor diagnosis and tumor prognosis. Focus is also put on how various photothermal materials play their roles in CTCs detection, including CT, imaging and photoacoustic and therapeutic roles. The physicochemical properties, shapes, and photothermal properties of various photothermal materials are discussed to improve the detection sensitivity and efficiency and to reduce the damage to normal cells. These photothermal materials are capable of converting radiant light energy into thermal energy for highly-sensitive CTCs detection and improving their photothermal properties by various methods, and have achieved good results in various experiments. The use of photothermal materials for CTCs detection is becoming more and more widespread and can be of significant help in early cancer screening and later treatment.

Effective dose of intranasal remimazolam for preoperative sedation in preschool children: a dose-finding study using Dixon's up-and-down method.

Background: Most preschool children are distressed during anesthesia induction. While current pharmacological methods are useful, there is a need for further optimization to an "ideal" standard. Remimazolam is an ultra-short-acting benzodiazepine, and intranasal remimazolam for pre-induction sedation may be promising. Methods: This study included 32 preschool children who underwent short and minor surgery between October 2022 and January 2023. After pretreatment with lidocaine, remimazolam was administered to both nostrils using a mucosal atomizer device. The University of Michigan Sedation Score (UMSS) was assessed for sedation 6, 9, 12, 15, and 20 min after intranasal atomization. We used Dixon's up-and-down method, and probit and isotonic regressions to determine the 50% effective dose (ED50) and 95% effective dose (ED95) of intranasal remimazolam for pre-induction sedation. Results: Twenty-nine pediatric patients were included in the final analysis. The ED50 and ED95 of intranasal remimazolam for successful pre-induction sedation, when processed via probit analysis, were 0.65 (95% confidence interval [CI], 0.59-0.71) and 0.78 mg/kg (95% CI, 0.72-1.07), respectively. In contrast, when processed by isotonic regression, they were 0.65 (95% CI: 0.58-0.72 mg/kg) and 0.78 mg/kg (95% CI: 0.69-1.08 mg/kg), respectively. At 6 min after intranasal remimazolam treatment, 81.2% (13/16) of "positive" participants were successfully sedated with a UMSS ≧ 1. All the "positive" participants were successfully sedated within 9 min. Conclusion: Intranasal remimazolam is feasible for preschool children with a short onset time. For successful pre-induction sedation, the ED50 and ED95 of intranasal remimazolam were 0.65 and 0.78 mg/kg, respectively.

Trajectory of gestational weight gain is related to birthweight: The TAWS cohort study in China.

Few studies have reported the timing and amount of gestational weight gain (GWG) to prevent large-for-gestational-age (LGA) or small-for-gestational-age (SGA). This study aimed to evaluate the association of GWG velocity in each trimester with LGA or SGA based on data from the Taicang and Wuqiang cohort study (TAWS, n = 2008). We used a linear mixed model to evaluate the association of trimester-specific GWG velocity with birthweight categories and stratified by prepregnancy body mass index category and parity. For normal-weight pregnant women, mothers with LGA births had higher GWG velocities than mothers with appropriate-for-gestational-age (AGA) births in the first trimester (0.108 vs. 0.031 kg/week, p < 0.01), second trimester (0.755 vs. 0.631 kg/week, p < 0.01) and third trimester (0.664 vs. 0.594 kg/week, p < 0.01); in contrast, mothers with SGA births had lower GWG velocities than mothers with AGA births in the second trimester (0.528 vs. 0.631 kg/week, p < 0.01) and third trimester (0.541 vs. 0.594 kg/week, p < 0.01). For normal-weight pregnant women with AGA births, multiparous women had lower GWG velocities than primiparous women in the second (0.602 vs. 0.643 kg/week, p < 0.01) and third trimesters (0.553 vs. 0.606 kg/week, p < 0.01). Therefore, for normal-weight women, LGA prevention would begin in early pregnancy and continue until delivery and the second and third trimesters may be critical periods for preventing SGA; in addition, among normal-weight pregnant women with AGA births, multiparous women tend to have lower weight gain velocities than primiparous women.

Tiam1-mediated maladaptive plasticity underlying morphine tolerance and hyperalgesia.

Opioid pain medications, such as morphine, remain the mainstay for treating severe and chronic pain. Prolonged morphine use, however, triggers analgesic tolerance and hyperalgesia (OIH), which can last for a long period after morphine withdrawal. How morphine induces these detrimental side effects remains unclear. Here, we show that morphine tolerance and OIH are mediated by Tiam1-coordinated synaptic structural and functional plasticity in the spinal nociceptive network. Tiam1 is a Rac1 GTPase guanine nucleotide exchange factor (GEF) that promotes excitatory synaptogenesis by modulating actin cytoskeletal dynamics. We found that prolonged morphine treatment activated Tiam1 in the spinal dorsal horn and Tiam1 ablation from spinal neurons eliminated morphine antinociceptive tolerance and OIH. At the same time, the pharmacological blockade of Tiam1-Rac1 signaling prevented the development and reserved the established tolerance and OIH. Prolonged morphine treatment increased dendritic spine density and synaptic NMDA receptor (NMDAR) activity in spinal dorsal horn neurons, both of which required Tiam1. Furthermore, co-administration of the Tiam1 signaling inhibitor NSC23766 was sufficient to abrogate morphine tolerance in chronic pain management. These findings identify Tiam1-mediated maladaptive plasticity in the spinal nociceptive network as an underlying cause for the development and maintenance of morphine tolerance and OIH and provide a promising therapeutic target to reduce tolerance and prolong morphine use in chronic pain management.

A novel exosome-related prognostic risk model for thyroid cancer.

AIM: The aim was to build an exosome-related gene (ERG) risk model for thyroid cancer (TC) patients. METHODS: Note that, 510 TC samples from The Cancer Genome Atlas database and 121 ERGs from the ExoBCD database were obtained. Differential gene expression analysis was performed to get ERGs in TC (TERGs). Functional enrichment analyses including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were conducted on the TERGs. Then we constructed a model based on LASSO Cox regression analysis. Kaplan-Meier survival analysis was applied and a Nomogram model was also built. The immune landscape was evaluated by CIBERSORT. RESULTS: Thirty-eight TERGs were identified and their functions were enriched on 591 GO terms and 30 KEGG pathways. We built a Risk Score model based on FGFR3, ADRA1B, and POSTN. Risk Scores were significantly higher in T4 than in other stages, meanwhile, it didn't significantly differ in genders and TNM N or M classifications. The nomogram model could reliably predict the overall survival of TC patients. The mutation rate of BRAF and expression of cytotoxic T-lymphocyte-associated protein 4 were significantly higher in the high-risk group than in the low-risk group. The risk score was significantly correlated to the immune landscape. CONCLUSION: We built a Risk Score model using FGFR3, ADRA1B, and POSTN which could reliably predict the prognosis of TC patients.

Silver Surface-Assisted Dehydrobrominative Cross-Coupling between Identical Aryl Bromides.

Cross-coupling reactions represent an indispensable tool in chemical synthesis. An intriguing challenge in this field is to achieve selective cross-coupling between two precursors with similar reactivity or, to the limit, the identical molecules. Here we report an unexpected dehydrobrominative cross-coupling between 1,3,5-tris(2-bromophenyl)benzene molecules on silver surfaces. Using scanning tunneling microscopy, we examine the reaction process at the single-molecular level, quantify the selectivity of the dehydrobrominative cross-coupling, and reveal the modulation of selectivity by substrate lattice-related catalytic activity or molecular assembly effect. Theoretical calculations indicate that the dehydrobrominative cross-coupling proceeds via regioselective C-H bond activation of debrominated TBPB and subsequent highly selective C-C coupling of the radical-based intermediates. The reaction kinetics plays an important role in the selectivity for the cross-coupling. This work not only expands the toolbox for chemical synthesis but also provides important mechanistic insights into the selectivity of coupling reactions on the surface.

Neutrophil extracellular traps promote acetaminophen-induced acute liver injury in mice via AIM2.

Excessive acetaminophen (APAP) can induce neutrophil activation and hepatocyte death. Along with hepatocyte dysfunction and death, NETosis (a form of neutrophil-associated inflammation) plays a vital role in the progression of acute liver injury (ALI) induced by APAP overdose. It has been shown that activated neutrophils tend to migrate towards the site of injury and participate in inflammatory processes via formation of neutrophil extracellular traps (NETs). In this study we investigated whether NETs were involved in hepatocyte injury and contributed to APAP-induced ALI progression. ALI mouse model was established by injecting overdose (350 mg/kg) of APAP. After 24 h, blood and livers were harvested for analyses. We showed that excessive APAP induced multiple programmed cell deaths of hepatocytes including pyroptosis, apoptosis and necroptosis, accompanied by significantly increased NETs markers (MPO, citH3) in the liver tissue and serum. Preinjection of DNase1 (10 U, i.p.) for two consecutive days significantly inhibited NETs formation, reduced PANoptosis and consequently alleviated excessive APAP-induced ALI. In order to clarify the communication between hepatocytes and neutrophils, we induced NETs formation in isolated neutrophils, and treated HepaRG cells with NETs. We found that NETs treatment markedly increased the activation of GSDMD, caspase-3 and MLKL, while pre-treatment with DNase1 down-regulated the expression of these proteins. Knockdown of AIM2 (a cytosolic innate immune receptor) abolished NETs-induced PANoptosis in HepaRG cells. Furthermore, excessive APAP-associated ALI was significantly attenuated in AIM2KO mice, and PANoptosis occurred less frequently. Upon restoring AIM2 expression in AIM2KO mice using AAV9 virus, both hepatic injury and PANoptosis was aggravated. In addition, we demonstrated that excessive APAP stimulated mtROS production and mitochondrial DNA (mtDNA) leakage, and mtDNA activated the TLR9 pathway to promote NETs formation. Our results uncover a novel mechanism of NETs and PANoptosis in APAP-associated ALI, which might serve as a therapeutic target.

A promising future of metal-N-heterocyclic carbene complexes in medicinal chemistry: The emerging bioorganometallic antitumor agents.

Metal complexes based on N-heterocyclic carbene (NHC) ligands have emerged as promising broad-spectrum antitumor agents in bioorganometallic medicinal chemistry. In recent decades, studies on cytotoxic metal-NHC complexes have yielded numerous compounds exhibiting superior cytotoxicity compared to cisplatin. Although the molecular mechanisms of these anticancer complexes are not fully understood, some potential targets and modes of action have been identified. However, a comprehensive review of their biological mechanisms is currently absent. In general, apoptosis caused by metal-NHCs is common in tumor cells. They can cause a series of changes after entering cells, such as mitochondrial membrane potential (MMP) variation, reactive oxygen species (ROS) generation, cytochrome c (cyt c) release, endoplasmic reticulum (ER) stress, lysosome damage, and caspase activation, ultimately leading to apoptosis. Therefore, a detailed understanding of the influence of metal-NHCs on cancer cell apoptosis is crucial. In this review, we provide a comprehensive summary of recent advances in metal-NHC complexes that trigger apoptotic cell death via different apoptosis-related targets or signaling pathways, including B-cell lymphoma 2 (Bcl-2 family), p53, cyt c, ER stress, lysosome damage, thioredoxin reductase (TrxR) inhibition, and so forth. We also discuss the challenges, limitations, and future directions of metal-NHC complexes to elucidate their emerging application in medicinal chemistry.

High SEC61A1 expression predicts poor outcome of acute myeloid leukemia.

The malfunction of SEC61A1 has been linked to several types of cancers, but its role in acute myeloid leukemia (AML) remains poorly understood. In this study, we used a series of bioinformatics analysis techniques, including gene expression profiling and proteomic analysis. Our findings were subsequently validated through a series of in vitro experiments, such as SEC61A1 knockdown in cell lines and RT-qPCR. We discovered a significant up-regulation of SEC61A1 in AML patients compared to healthy controls. AML patients with elevated SEC61A1 expression exhibited reduced overall survival compared to those with lower expression. Moreover, SEC61A1 expression emerged as an independent risk factor for predicting the survival of AML patients undergoing allo-HSCT. Our analysis also revealed an association between high SEC61A1 expression and increased signaling pathways related to cell growth. Our study underscores the importance of SEC61A1 expression as a novel prognostic indicator for predicting survival among AML patients, while also identifying it as a promising therapeutic target.

Efficient Electrochemical Co-Reduction of Carbon Dioxide and Nitrate to Urea with High Faradaic Efficiency on Cobalt-Based Dual-Sites.

Renewable electricity-powered nitrate/carbon dioxide co-reduction reaction toward urea production paves an attractive alternative to industrial urea processes and offers a clean on-site approach to closing the global nitrogen cycle. However, its large-scale implantation is severely impeded by challenging C-N coupling and requires electrocatalysts with high activity/selectivity. Here, cobalt-nanoparticles anchored on carbon nanosheet (Co NPs@C) are proposed as a catalyst electrode to boost yield and Faradaic efficiency (FE) toward urea electrosynthesis with enhanced C-N coupling. Such Co NPs@C renders superb urea-producing activity with a high FE reaching 54.3% and a urea yield of 2217.5 µg h-1 mgcat. -1, much superior to the Co NPs and C nanosheet counterparts, and meanwhile shows strong stability. The Co NPs@C affords rich catalytically active sites, fast reactant diffusion, and sufficient catalytic surfaces-electrolyte contacts with favored charge and ion transfer efficiencies. The theoretical calculations reveal that the high-rate formation of *CO and *NH2 intermediates is crucial for facilitating urea synthesis.

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B-cell activating factor (BAFF), a critical regulator of B cells, is involved in various autoimmune diseases. Inflammatory bowel disease (IBD) is a group of chronic and recurrent intestinal inflammatory disorders with unclear etiology, and its global incidence has been increasing in recent years. Abnormal immune responses triggered by multiple factors are closely related to the pathogenesis of IBD. Previous studies have confirmed the association of B-cell abnormal activation and increased production of autoantibodies with the development of ulcerative colitis. However, the involvement of BAFF in the mechanisms of IBD remains unclear. This review summarizes the potential role of BAFF in the pathogenesis of IBD and provides an overview of targeted therapies on BAFF in IBD, aiming to contribute insights for targeted treatments of IBD.