ABSTRACT
The animal phyla and their associated body plans originate from a singular burst of evolution occurring during the Cambrian period, over 500 million years ago1. The phylum Bryozoa, the colonial 'moss animals', have been the exception: convincing skeletons of this biomineralizing clade have been absent from Cambrian strata, in part because potential bryozoan fossils are difficult to distinguish from the modular skeletons of other animal and algal groups2,3. At present, the strongest candidate4 is the phosphatic microfossil Protomelission5. Here we describe exceptionally preserved non-mineralized anatomy in Protomelission-like macrofossils from the Xiaoshiba Lagerstätte6. Taken alongside the detailed skeletal construction and the potential taphonomic origin of 'zooid apertures', we consider that Protomelission is better interpreted as the earliest dasycladalean green alga-emphasizing the ecological role of benthic photosynthesizers in early Cambrian communities. Under this interpretation, Protomelission cannot inform the origins of the bryozoan body plan; despite a growing number of promising candidates7-9, there remain no unequivocal bryozoans of Cambrian age.
Subject(s)
Bryozoa , Chlorophyta , Fossils , Phylogeny , Animals , Bryozoa/anatomy & histology , Bryozoa/classification , Phosphates/metabolism , Chlorophyta/anatomy & histology , Chlorophyta/classification , Photosynthesis , ChinaABSTRACT
The SysteMHC Atlas v1.0 was the first public repository dedicated to mass spectrometry-based immunopeptidomics. Here we introduce a newly released version of the SysteMHC Atlas v2.0 (https://systemhc.sjtu.edu.cn), a comprehensive collection of 7190 MS files from 303 allotypes. We extended and optimized a computational pipeline that allows the identification of MHC-bound peptides carrying on unexpected post-translational modifications (PTMs), thereby resulting in 471K modified peptides identified over 60 distinct PTM types. In total, we identified approximately 1.0 million and 1.1 million unique peptides for MHC class I and class II immunopeptidomes, respectively, indicating a 6.8-fold increase and a 28-fold increase to those in v1.0. The SysteMHC Atlas v2.0 introduces several new features, including the inclusion of non-UniProt peptides, and the incorporation of several novel computational tools for FDR estimation, binding affinity prediction and motif deconvolution. Additionally, we enhanced the user interface, upgraded website framework, and provided external links to other resources related. Finally, we built and provided various spectral libraries as community resources for data mining and future immunopeptidomic and proteomic analysis. We believe that the SysteMHC Atlas v2.0 is a unique resource to provide key insights to the immunology and proteomics community and will accelerate the development of vaccines and immunotherapies.
Subject(s)
Databases, Protein , Peptides , Proteomics , Mass Spectrometry , Peptides/chemistry , Peptides/immunology , Protein Processing, Post-Translational , Proteomics/methods , Databases, Protein/standards , Internet , Humans , AnimalsABSTRACT
Porcine deltacoronavirus (PDCoV) has caused enormous economic losses to the global pig industry. However, the immune escape mechanism of PDCoV remains to be fully clarified. Transcriptomic analysis revealed a high abundance of interferon (IFN)-induced protein with tetratricopeptide repeats 3 (IFIT3) transcripts after PDCoV infection, which initially implied a correlation between IFIT3 and PDCoV. Further studies showed that PDCoV nsp5 could antagonize the host type I interferon signaling pathway by cleaving IFIT3. We demonstrated that PDCoV nsp5 cleaved porcine IFIT3 (pIFIT3) at Gln-406. Similar cleavage of endogenous IFIT3 has also been observed in PDCoV-infected cells. The pIFIT3-Q406A mutant was resistant to nsp5-mediated cleavage and exhibited a greater ability to inhibit PDCoV infection than wild-type pIFIT3. Furthermore, we found that cleavage of IFIT3 is a common characteristic of nsp5 proteins of human coronaviruses, albeit not alphacoronavirus. This finding suggests that the cleavage of IFIT3 is an important mechanism by which PDCoV nsp5 antagonizes IFN signaling. Our study provides new insights into the mechanisms by which PDCoV antagonizes the host innate immune response.IMPORTANCEPorcine deltacoronavirus (PDCoV) is a potential emerging zoonotic pathogen, and studies on the prevalence and pathogenesis of PDCoV are ongoing. The main protease (nsp5) of PDCoV provides an excellent target for antivirals due to its essential and conserved function in the viral replication cycle. Previous studies have revealed that nsp5 of PDCoV antagonizes type I interferon (IFN) production by targeting the interferon-stimulated genes. Here, we provide the first demonstration that nsp5 of PDCoV antagonizes IFN signaling by cleaving IFIT3, which affects the IFN response after PDCoV infection. Our findings reveal that PDCoV nsp5 is an important interferon antagonist and enhance the understanding of immune evasion by deltacoronaviruses.
Subject(s)
Coronavirus 3C Proteases , Coronavirus Infections , Deltacoronavirus , Interferon Type I , Intracellular Signaling Peptides and Proteins , Swine Diseases , Swine , Animals , Humans , Coronavirus 3C Proteases/metabolism , Coronavirus Infections/immunology , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Deltacoronavirus/enzymology , Deltacoronavirus/metabolism , Deltacoronavirus/pathogenicity , Immunity, Innate , Interferon Type I/antagonists & inhibitors , Interferon Type I/biosynthesis , Interferon Type I/immunology , Intracellular Signaling Peptides and Proteins/chemistry , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Proteolysis , Signal Transduction/immunology , Swine/immunology , Swine/virology , Swine Diseases/immunology , Swine Diseases/metabolism , Swine Diseases/virology , Transcription Factors/metabolism , Viral Zoonoses/immunology , Viral Zoonoses/virology , Virus ReplicationABSTRACT
The hepatic sinusoids are composed of liver sinusoidal endothelial cells (LSECs), which are surrounded by hepatic stellate cells (HSCs) and contain liver-resident macrophages called Kupffer cells, and other patrolling immune cells. All these cells communicate with each other and with hepatocytes to maintain sinusoidal homeostasis and a spectrum of hepatic functions under healthy conditions. Sinusoidal homeostasis is disrupted by metabolites, toxins, viruses, and other pathological factors, leading to liver injury, chronic liver diseases, and cirrhosis. Alterations in hepatic sinusoids are linked to fibrosis progression and portal hypertension. LSECs are crucial regulators of cellular crosstalk within their microenvironment via angiocrine signaling. This review discusses the mechanisms by which angiocrine signaling orchestrates sinusoidal homeostasis, as well as the development of liver diseases. Here, we summarise the crosstalk between LSECs, HSCs, hepatocytes, cholangiocytes, and immune cells in health and disease and comment on potential novel therapeutic methods for treating liver diseases.
Subject(s)
Endothelial Cells , Hepatic Stellate Cells , Homeostasis , Liver Diseases , Signal Transduction , Humans , Homeostasis/physiology , Liver Diseases/metabolism , Liver Diseases/physiopathology , Signal Transduction/physiology , Hepatic Stellate Cells/metabolism , Hepatic Stellate Cells/physiology , Endothelial Cells/metabolism , Endothelial Cells/physiology , Liver/metabolism , Liver/pathology , Animals , Hepatocytes/metabolism , Cell Communication/physiology , Kupffer Cells/physiology , Kupffer Cells/metabolismABSTRACT
Epithelial mesenchymal transition (EMT) is a critical process implicated in the pathogenesis of retinal fibrosis and the exacerbation of diabetic retinopathy (DR) within retinal pigment epithelium (RPE) cells. Apigenin (AP), a potential dietary supplement for managing diabetes and its associated complications, has demonstrated inhibitory effects on EMT in various diseases. However, the specific impact and underlying mechanisms of AP on EMT in RPE cells remain poorly understood. In this study, we have successfully validated the inhibitory effects of AP on high glucose-induced EMT in ARPE-19 cells and diabetic db/db mice. Notably, our findings have identified CBP/p300 as a potential therapeutic target for EMT in RPE cells and have further substantiated that AP effectively downregulates the expression of EMT-related genes by attenuating the activity of CBP/p300, consequently reducing histone acetylation alterations within the promoter region of these genes. Taken together, our results provide novel evidence supporting the inhibitory effect of AP on EMT in RPE cells, and highlight the potential of specifically targeting CBP/p300 as a strategy for inhibiting retinal fibrosis in the context of DR.
Subject(s)
Apigenin , Epithelial-Mesenchymal Transition , Glucose , Histones , Retinal Pigment Epithelium , Epithelial-Mesenchymal Transition/drug effects , Retinal Pigment Epithelium/drug effects , Retinal Pigment Epithelium/metabolism , Retinal Pigment Epithelium/pathology , Animals , Apigenin/pharmacology , Acetylation/drug effects , Humans , Glucose/metabolism , Glucose/toxicity , Histones/metabolism , Cell Line , Mice , p300-CBP Transcription Factors/metabolism , p300-CBP Transcription Factors/antagonists & inhibitors , Mice, Inbred C57BL , Diabetic Retinopathy/metabolism , Diabetic Retinopathy/pathology , Diabetic Retinopathy/drug therapy , E1A-Associated p300 Protein/metabolism , Male , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Epithelial Cells/pathology , CREB-Binding Protein/metabolism , CREB-Binding Protein/geneticsABSTRACT
Hematopoietic stem cells (HSCs) have reduced capacities to properly maintain and replenish the hematopoietic system during myelosuppressive injury or aging. Expanding and rejuvenating HSCs for therapeutic purposes has been a long-sought goal with limited progress. Here, we show that the enzyme Sphk2 (sphingosine kinase 2), which generates the lipid metabolite sphingosine-1-phosphate, is highly expressed in HSCs. The deletion of Sphk2 markedly promotes self-renewal and increases the regenerative potential of HSCs. More importantly, Sphk2 deletion globally preserves the young HSC gene expression pattern, improves the function, and sustains the multilineage potential of HSCs during aging. Mechanistically, Sphk2 interacts with prolyl hydroxylase 2 and the Von Hippel-Lindau protein to facilitate HIF1α ubiquitination in the nucleus independent of the Sphk2 catalytic activity. Deletion of Sphk2 increases hypoxic responses by stabilizing the HIF1α protein to upregulate PDK3, a glycolysis checkpoint protein for HSC quiescence, which subsequently enhances the function of HSCs by improving their metabolic fitness; specifically, it enhances anaerobic glycolysis but suppresses mitochondrial oxidative phosphorylation and generation of reactive oxygen species. Overall, targeting Sphk2 to enhance the metabolic fitness of HSCs is a promising strategy to expand and rejuvenate functional HSCs.
Subject(s)
Hematopoietic Stem Cells , Sphingosine , Glycolysis/genetics , Hematopoietic Stem Cells/metabolism , Phosphotransferases (Alcohol Group Acceptor) , Prolyl Hydroxylases/metabolism , Reactive Oxygen Species/metabolismABSTRACT
BACKGROUND: Surgical therapy is the most optimal treatment for hepatocellular carcinoma (HCC) combined with bile duct tumor thrombus (BDTT) patients. However, whether to perform bile duct resection (BDR) is still controversial. The purpose of this multicenter research is to compare the effect of BDR on the prognosis of extrahepatic BDTT patients. METHODS: We collected the data of 111 HCC patients combined with extrahepatic BDTT who underwent radical hepatectomy from June 1, 2004 to December 31, 2021. Those patients had either received hepatectomy with extrahepatic bile duct resection (BDR group) or hepatectomy without bile duct resection (NBDR group). Inverse probability of treatment weighting (IPTW) was used to reduce the potential bias between two groups and balance the influence of confounding factors in baseline data. Then compare the prognosis between the two groups of patients. Cox regression model was used for univariate and multivariate analysis to further determine the independent risk factors that influence the prognosis of HCC-BDTT patients. RESULTS: There were 38 patients in the BDR group and 73 patients in the NBDR group. Before and after IPTW, there were no statistical significance in OS, RFS and intraoperative median blood loss between the two groups (all P > 0.05). Before IPTW, the median postoperative hospital stay in the NBDR group was shorter (P = 0.046) and the grade of postoperative complications was lower than BDR group (P = 0.014). After IPTW, there was no difference in postoperative hospital stay between the two groups (P > 0.05). The complication grade in the NBDR group was still lower than that in the BDR group (P = 0.046). The univariate analysis showed that TNM stage and portal vein tumor thrombus (PVTT) were significantly correlated with OS (both P < 0.05). Preoperative AFP level, TNM stage and prognostic nutritional index (PNI) were significantly correlated with postoperative RFS (all P < 0.05). Multivariate analysis showed that tumor TNM stage was an independent risk factor for the OS rate (P = 0.014). TNM stage, PNI and AFP were independent predictors of RFS after radical hepatectomy (all P < 0.05). CONCLUSIONS: For HCC-BDTT patients, hepatocellular carcinoma resection combined with choledochotomy to remove the tumor thrombus may benefit more.
Subject(s)
Bile Ducts, Extrahepatic , Carcinoma, Hepatocellular , Hepatectomy , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/surgery , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/complications , Male , Female , Liver Neoplasms/surgery , Liver Neoplasms/pathology , Liver Neoplasms/mortality , Liver Neoplasms/complications , Middle Aged , Prognosis , Bile Ducts, Extrahepatic/surgery , Bile Ducts, Extrahepatic/pathology , Thrombosis/surgery , Thrombosis/etiology , Thrombosis/pathology , Retrospective Studies , Bile Duct Neoplasms/surgery , Bile Duct Neoplasms/pathology , Bile Duct Neoplasms/complications , Bile Duct Neoplasms/mortality , Aged , AdultABSTRACT
Ever since the isolation of Amycolatopsis mediterranei in 1957, this strain has been the focus of research worldwide. In the last 60 years or more, our understanding of the taxonomy, development of cloning vectors and conjugation system, physiology, genetics, genomics, and biosynthetic pathway of rifamycin B production in A. mediterranei has substantially increased. In particular, the development of cloning vectors, transformation system, characterization of the rifamycin biosynthetic gene cluster, and the regulation of rifamycin B production by the pioneering work of Heinz Floss have made the rifamycin polyketide biosynthetic gene cluster (PKS) an attractive target for extensive genetic manipulations to produce rifamycin B analogues which could be effective against multi-drug-resistant tuberculosis. Additionally, a better understanding of the regulation of rifamycin B production and the application of newer genomics tools, including CRISPR-assisted genome editing systems, might prove useful to overcome the limitations associated with low production of rifamycin analogues.
Subject(s)
Actinomycetales , Rifamycins , Amycolatopsis , Biosynthetic Pathways/genetics , Rifamycins/metabolismABSTRACT
Cross-species transmission of viruses from wildlife animal reservoirs poses a marked threat to human and animal health 1 . Bats have been recognized as one of the most important reservoirs for emerging viruses and the transmission of a coronavirus that originated in bats to humans via intermediate hosts was responsible for the high-impact emerging zoonosis, severe acute respiratory syndrome (SARS) 2-10 . Here we provide virological, epidemiological, evolutionary and experimental evidence that a novel HKU2-related bat coronavirus, swine acute diarrhoea syndrome coronavirus (SADS-CoV), is the aetiological agent that was responsible for a large-scale outbreak of fatal disease in pigs in China that has caused the death of 24,693 piglets across four farms. Notably, the outbreak began in Guangdong province in the vicinity of the origin of the SARS pandemic. Furthermore, we identified SADS-related CoVs with 96-98% sequence identity in 9.8% (58 out of 591) of anal swabs collected from bats in Guangdong province during 2013-2016, predominantly in horseshoe bats (Rhinolophus spp.) that are known reservoirs of SARS-related CoVs. We found that there were striking similarities between the SADS and SARS outbreaks in geographical, temporal, ecological and aetiological settings. This study highlights the importance of identifying coronavirus diversity and distribution in bats to mitigate future outbreaks that could threaten livestock, public health and economic growth.
Subject(s)
Alphacoronavirus/isolation & purification , Alphacoronavirus/pathogenicity , Animal Diseases/epidemiology , Animal Diseases/virology , Chiroptera/virology , Coronavirus Infections/veterinary , Diarrhea/veterinary , Swine/virology , Alphacoronavirus/classification , Alphacoronavirus/genetics , Animal Diseases/transmission , Animals , Biodiversity , China/epidemiology , Coronavirus Infections/epidemiology , Coronavirus Infections/transmission , Diarrhea/pathology , Diarrhea/virology , Disease Reservoirs/veterinary , Disease Reservoirs/virology , Genome, Viral/genetics , Humans , Jejunum/pathology , Jejunum/virology , Phylogeny , Severe Acute Respiratory Syndrome/epidemiology , Severe Acute Respiratory Syndrome/veterinary , Severe Acute Respiratory Syndrome/virology , Spatio-Temporal Analysis , Zoonoses/epidemiology , Zoonoses/transmission , Zoonoses/virologyABSTRACT
BACKGROUND: Canine circovirus (CanineCV), a non-enveloped virus with a circular DNA genome, has been identified in various avian and mammalian species, including domestic and wild canids. This study aimed to comprehensively analyze the prevalence of CanineCV across diverse animal species in 11 provinces of China. RESULTS: A total of 1,666 serum samples were collected, revealing a 5.82% prevalence of CanineCV in dogs, with the highest rates being observed in southern and eastern China. Phylogenetic analysis of 266 global CanineCV genomes sourced from the NCBI identified six distinct genotypes, elucidating the complex dynamics of their evolution. Evidence suggested a potential bat origin for CanineCV, with positive selection and high rates of evolution being observed. Recombination analysis revealed dynamic genetic exchange, highlighting the intricate nature of CanineCV evolution. Mutational analysis identified key amino acid substitutions likely to influence the virus's adaptation. Additionally, glycosylation, palmitoylation, and SUMOylation sites were predicted, shedding light on crucial functional properties of the virus. CONCLUSIONS: This study provides a global perspective on the origin, genetic diversity, and evolutionary dynamics of CanineCV. Understanding these factors is crucial for elucidating its epidemiology and potential health risks.
Subject(s)
Circoviridae Infections , Circovirus , Dog Diseases , Phylogeny , Animals , Circovirus/genetics , Circovirus/classification , Dogs , Dog Diseases/virology , Dog Diseases/epidemiology , China/epidemiology , Circoviridae Infections/veterinary , Circoviridae Infections/epidemiology , Circoviridae Infections/virology , Evolution, Molecular , Genome, Viral , Genetic Variation , Prevalence , GenotypeABSTRACT
Tree- and linear-shaped cell differentiation trajectories have been widely observed in developmental biologies and can be also inferred through computational methods from single-cell RNA-sequencing datasets. However, trajectories with complicated topologies such as loops, disparate lineages and bifurcating hierarchy remain difficult to infer accurately. Here, we introduce a density-based trajectory inference method capable of constructing diverse shapes of topological patterns including the most intriguing bifurcations. The novelty of our method is a step to exploit overlapping probability distributions to identify transition states of cells for determining connectability between cell clusters, and another step to infer a stable trajectory through a base-topology guided iterative fitting. Our method precisely re-constructed various benchmark reference trajectories. As a case study to demonstrate practical usefulness, our method was tested on single-cell RNA sequencing profiles of blood cells of SARS-CoV-2-infected patients. We not only re-discovered the linear trajectory bridging the transition from IgM plasmablast cells to developing neutrophils, and also found a previously-undiscovered lineage which can be rigorously supported by differentially expressed gene analysis.
Subject(s)
COVID-19 , Single-Cell Analysis , Humans , Single-Cell Analysis/methods , SARS-CoV-2 , COVID-19/genetics , Cell Differentiation/geneticsABSTRACT
OBJECTIVE: Tobacco has been identified as a significant contributory element to the development of breast cancer. Our objective was to evaluate the spatiotemporal trends of tobacco-related breast cancer at the global, regional, and national scales during 1990-2019. METHODS: We extracted data on mortality, disability adjusted of life years (DALYs), age-standardized mortality rate (ASMR), and age-standardized DALYs rate (ASDR) from the Global Burden of Disease (GBD) study 2019. Estimated annual percentage change (EAPC) was computed to assess the temporal change in ASDR and ASMR. RESULTS: In 2019, the deaths and DALYs attributed to tobacco-related breast cancer were estimated to be 35,439 (95% UI: 22,179-48,119) and 1,060,590 (95% UI: 622,550-1,462,580), respectively. These figures accounted for 5.1% and 5.2% of the total burden of breast cancer. ASMR and ASDR increased in low SDI regions, remained stable in low-middle and middle SDI regions and declined in high and high-middle SDI regions. The burden of breast cancer attributable to tobacco varied notably among regions and nations. Oceania, Southern Latin America, and Central Europe were the GBD regions with the highest number of ASMR and DALYs. There was a positive relationship between age-standardized rate and SDI value in 2019 across 204 nations or territories. A negative association was observed between the EAPC in ASMR or ASDR and the human development index (HDI) in 2019 (R = -0.55, p < 0.01 for ASMR; R = -0.56, p < 0.01 for ASDR). CONCLUSION: Tobacco is one important and modifiable risk factor for breast cancer. The heterogeneity in both the spatial and temporal distribution can be attributed to factors such as aging, population growth, and SDI. These findings substantiate the necessity of expediting the enforcement of tobacco-free legislation in order to safeguard populations from the detrimental effects of tobacco.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/epidemiology , Breast Neoplasms/etiology , Global Burden of Disease , Cost of Illness , Breast , Tobacco ProductsABSTRACT
OBJECTIVES: The epidemiological trends of cardiovascular disease (CVD) burden attributed to low physical activity (LPA) across various regions and countries are poorly understood. Hence, we assessed the global, regional, and national spatiotemporal trends of LPA-related CVD from 1990 to 2019. STUDY DESIGN: We conducted a secondary analysis of the Global Burden of Disease Study 2019. The data on LPA-related CVD were examined with regard to sex, age, year, and Socio-Demographic Index (SDI). METHODS: We assessed the temporal changes in age-standardized mortality rate (ASMR) and age-standardized death rate (ASDR) using the estimated annual percentage change (EAPC) over a 30-year period. RESULTS: There were a staggering 0.64 million deaths and 9.99 million disability-adjusted life-years globally attributed to LPA-related CVD in 2019. The majority of the LPA-related CVD burden was observed in the population aged ≥80 years. It also indicated a high disease burden of LPA-related CVD in Central Asia, Arabian Peninsula, and North Africa. Although there has been a decline in ASMR and ASDR associated with LPA-related CVD on a global scale, the countries experiencing the most substantial increase in LPA-related CVD burden are Uzbekistan, Tajikistan, and Azerbaijan. The ASMR and ASDR remained stable in regions with low, low-middle, and middle SDI levels. The EAPCs of ASMR and ASDR were negatively linked with SDI in 2019. CONCLUSIONS: From 1990 to 2019, LPA led to a significant and escalating burden of CVD in certain regions, namely, Uzbekistan, Tajikistan, and Azerbaijan. It is imperative for governments and policymakers to implement regulatory measures and strategic interventions aimed at mitigating this burden.
Subject(s)
Cardiovascular Diseases , Humans , Cardiovascular Diseases/epidemiology , Global Burden of Disease , Social Perception , Africa, Northern , Exercise , Global Health , Quality-Adjusted Life YearsABSTRACT
Nineteen isosteviol derivatives were designed and synthesized by C-16, C-19 and D-ring modifications of isosteviol. These compounds were screened for their cytotoxic activities against Hela and A549 cells in vitro. Among them, the inhibitory effect of compounds 3b and 16 on Hela cells was comparable to that of the positive control gefitinib, and the compounds 3b (IC50=7.84 ± 0.84 µM) and 7a (IC50=6.89 ± 0.33 µM) exhibited significant cytotoxicity superior to gefitinib (IC50=11.02 ± 3.27 µM) against A549 cells.
Subject(s)
Diterpenes, Kaurane , Drug Screening Assays, Antitumor , Humans , Diterpenes, Kaurane/pharmacology , Diterpenes, Kaurane/chemical synthesis , Diterpenes, Kaurane/chemistry , Molecular Structure , HeLa Cells , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , A549 Cells , Gefitinib/pharmacology , Structure-Activity Relationship , Cell Proliferation/drug effects , Quinazolines/pharmacology , Quinazolines/chemistry , Quinazolines/chemical synthesisABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is the liver component of a cluster of conditions, while its subtype, nonalcoholic steatohepatitis (NASH), emerges as a potentially progressive liver disorder that harbors the risk of evolving into cirrhosis and culminating in hepatocellular carcinoma (HCC). NASH and cardiovascular disease (CVD) have common risk factors, but compared to liver-related causes, the most common cause of death in NASH patients is CVD. Within the pharmacological armamentarium, statins, celebrated for their lipid-modulating prowess, have now garnered attention for their expansive therapeutic potential in NASH. Evidence from a plethora of studies suggests that statins not only manifest anti-inflammatory and antifibrotic properties but also impart a multifaceted beneficial impact on hepatic health. In this review, we used "statin", "NAFLD", "NASH", and "CVD" as the major keywords and conducted a literature search using the PubMed and Web of Science databases to determine the safety and efficacy of statins in patients and animals with NASH and NAFLD, and the mechanism of statin therapy for NASH. Simultaneously, we reviewed the important role of the intestinal microbiota in statin therapy for NASH, as it is hoped that statins will provide new insights into modulating the harmful inflammatory microbiota in the gut and reducing systemic inflammation in NASH patients.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors , Non-alcoholic Fatty Liver Disease , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/metabolism , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Animals , Gastrointestinal Microbiome/drug effects , Treatment Outcome , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/etiologyABSTRACT
Drug-induced liver injury (DILI) is a common clinical pharmacogenic disease. In the United States and Europe, DILI is the most common cause of acute liver failure. Drugs can cause hepatic damage either directly through inherent hepatotoxic properties or indirectly by inducing oxidative stress, immune responses, and inflammatory processes. These pathways can culminate in hepatocyte necrosis. The role of the gut microecology in human health and diseases is well recognized. Recent studies have revealed that the imbalance in the gut microecology is closely related to the occurrence and development of DILI. The gut microecology plays an important role in liver injury caused by different drugs. Recent research has revealed significant changes in the composition, relative abundance, and distribution of gut microbiota in both patients and animal models with DILI. Imbalance in the gut microecology causes intestinal barrier destruction and microorganism translocation; the alteration in microbial metabolites may initiate or aggravate DILI, and regulation and control of intestinal microbiota can effectively mitigate drug-induced liver injury. In this paper, we provide an overview on the present knowledge of the mechanisms by which DILI occurs, the common drugs that cause DILI, the gut microbiota and gut barrier composition, and the effects of the gut microbiota and gut barrier on DILI, emphasizing the contribution of the gut microecology to DILI.
Subject(s)
Chemical and Drug Induced Liver Injury , Gastrointestinal Microbiome , Humans , Gastrointestinal Microbiome/drug effects , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/metabolism , AnimalsABSTRACT
Irisin, a peptide produced during exercise, is believed to play a role in regulating energy levels within the body. Moreover, Irisin has the ability to traverse the blood-brain barrier and engage in various pathophysiological processes within the central nervous system. An increasing body of research identifies Irisin as a significant therapeutic target for neurodegenerative diseases, indicating a strong link between Irisin and the development of cognitive impairments. In this paper, we present a concise review of effects of different types of exercise on Irisin production, and the mechanisms underlying the Irisin's intervention in various diseases including metabolic diseases, kidney injury and depression. Following this, we delve into an in-depth exploration of its role in modulating cognitive dysfunction among patients with Alzheimer's disease (AD), focusing on recent advancements in three critical areas: neuroinflammation, mitochondrial dysfunction, and protein misfolding. Finally, we put forth 3 hypotheses: (1) exercise-induced fibronectin type III domain containing protein 5 (FNDC5) stimulation and subsequent Irisin cleavage may be associated with the stress response in energy metabolism; (2) Irisin, as a myokine, likely plays a role in mitochondrial repair mechanisms to ameliorate cognitive impairment in AD patients; (3) Irisin is a homeostatic factor that maintains energy homeostasis and is closely related to the dynamic stability of the body's internal environment.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Exercise , Fibronectins , Humans , Alzheimer Disease/metabolism , Fibronectins/metabolism , Cognitive Dysfunction/etiology , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/physiopathology , Exercise/physiology , Animals , Mitochondria/metabolismABSTRACT
Necrotic lesions and cavities filled with caseum are a hallmark of mycobacterial pulmonary disease. Bronchocavitary Mycobacterium abscessus disease is associated with poor treatment outcomes. In caseum surrogate, M. abscessus entered an extended stationary phase showing tolerance to killing by most current antibiotics, suggesting that caseum persisters contribute to the poor performance of available treatments. Novel ADP-ribosylation-resistant rifabutin analogs exhibited bactericidal activity against these M. abscessus persisters at concentrations achievable by rifamycins in caseum.
Subject(s)
Mycobacterium Infections, Nontuberculous , Mycobacterium abscessus , Rifamycins , Humans , Rifabutin/pharmacology , Mycobacterium Infections, Nontuberculous/drug therapy , Mycobacterium Infections, Nontuberculous/microbiology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Microbial Sensitivity TestsABSTRACT
Ferroptosis is a type of nonapoptotic necrotic cell death characterized by iron-dependent lipid peroxidation. Saikosaponin A (SsA), a natural bioactive triterpenoid saponin extracted from Radix Bupleuri, has shown potent antitumor activity against various tumors. However, the underlying mechanism of the antitumor activity of SsA remains unclear. Here, we discovered that SsA induced HCC cell ferroptosis in vitro and in vivo. Using RNA-sequence analysis, we found that SsA mainly affected the glutathione metabolic pathway and inhibited the expression of cystine transporter solute carrier family 7 member 11 (SLC7A11). Indeed, SsA increased intracellular malondialdehyde (MDA) and iron accumulation, while it decreased the levels of reduced glutathione (GSH) in HCC. Deferoxamine (DFO), ferrostatin-1 (Fer-1) and GSH could rescue SsA-induced cell death, whereas Z-VAD-FMK was found ineffective in inhibiting SsA-induced cell death in HCC. Importantly, our result indicated that SsA induced the expression of activation transcription factor 3 (ATF3). SsA-induced cell ferroptosis and suppression of SLC7A11 are dependent on ATF3 in HCC. Moreover, we revealed that SsA induced ATF3 upregulation via activation of endoplasmic reticulum (ER) stress. Taken together, our findings support that ATF3-dependent cell ferroptosis mediated the antitumor effects of SsA, opening the possibility to explore SsA as a ferroptosis inducer in HCC.
Subject(s)
Carcinoma, Hepatocellular , Ferroptosis , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/drug therapy , Transcription Factor 3 , Liver Neoplasms/drug therapy , Endoplasmic Reticulum Stress , Glutathione , Iron , Activating Transcription Factor 3/geneticsABSTRACT
Single-cell mRNA sequencing has been adopted as a powerful technique for understanding gene expression profiles at the single-cell level. However, challenges remain due to factors such as the inefficiency of mRNA molecular capture, technical noises and separate sequencing of cells in different batches. Normalization methods have been developed to ensure a relatively accurate analysis. This work presents a survey on 10 tools specifically designed for single-cell mRNA sequencing data preprocessing steps, among which 6 tools are used for dropout normalization and 4 tools are for batch effect correction. In this survey, we outline the main methodology for each of these tools, and we also compare these tools to evaluate their normalization performance on datasets which are simulated under the constraints of dropout inefficiency, batch effect or their combined effects. We found that Saver and Baynorm performed better than other methods in dropout normalization, in most cases. Beer and Batchelor performed better in the batch effect normalization, and the Saver-Beer tool combination and the Baynorm-Beer combination performed better in the mixed dropout-and-batch effect normalization. Over-normalization is a common issue occurred to these dropout normalization tools that is worth of future investigation. For the batch normalization tools, the capability of retaining heterogeneity between different groups of cells after normalization can be another direction for future improvement.