Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 592
Filter
Add more filters

Publication year range
1.
Nature ; 629(8012): 679-687, 2024 May.
Article in English | MEDLINE | ID: mdl-38693266

ABSTRACT

Pancreatic intraepithelial neoplasias (PanINs) are the most common precursors of pancreatic cancer, but their small size and inaccessibility in humans make them challenging to study1. Critically, the number, dimensions and connectivity of human PanINs remain largely unknown, precluding important insights into early cancer development. Here, we provide a microanatomical survey of human PanINs by analysing 46 large samples of grossly normal human pancreas with a machine-learning pipeline for quantitative 3D histological reconstruction at single-cell resolution. To elucidate genetic relationships between and within PanINs, we developed a workflow in which 3D modelling guides multi-region microdissection and targeted and whole-exome sequencing. From these samples, we calculated a mean burden of 13 PanINs per cm3 and extrapolated that the normal intact adult pancreas harbours hundreds of PanINs, almost all with oncogenic KRAS hotspot mutations. We found that most PanINs originate as independent clones with distinct somatic mutation profiles. Some spatially continuous PanINs were found to contain multiple KRAS mutations; computational and in situ analyses demonstrated that different KRAS mutations localize to distinct cell subpopulations within these neoplasms, indicating their polyclonal origins. The extensive multifocality and genetic heterogeneity of PanINs raises important questions about mechanisms that drive precancer initiation and confer differential progression risk in the human pancreas. This detailed 3D genomic mapping of molecular alterations in human PanINs provides an empirical foundation for early detection and rational interception of pancreatic cancer.


Subject(s)
Genetic Heterogeneity , Genomics , Imaging, Three-Dimensional , Pancreatic Neoplasms , Precancerous Conditions , Single-Cell Analysis , Adult , Female , Humans , Male , Clone Cells/metabolism , Clone Cells/pathology , Exome Sequencing , Machine Learning , Mutation , Pancreas/anatomy & histology , Pancreas/cytology , Pancreas/metabolism , Pancreas/pathology , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Precancerous Conditions/genetics , Precancerous Conditions/pathology , Workflow , Disease Progression , Early Detection of Cancer , Oncogenes/genetics
2.
Am J Pathol ; 2024 Jul 26.
Article in English | MEDLINE | ID: mdl-39069170

ABSTRACT

Remote ischemic preconditioning (RIPC) exerts a protective role on myocardial ischemia reperfusion (I/R) injury by the release of various humoral factors. Lactate is a common metabolite in ischemic tissues. Nevertheless, little is known about the role lactate plays in myocardial I/R injury and its underlying mechanism. This investigation revealed that RIPC elevated the level of lactate in blood and myocardium. Furthermore, AZD3965, a selective monocarboxylate transporter 1 (MCT1) inhibitor and 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor, mitigated the effects of RIPC-induced elevated lactate in the myocardium and prevented RIPC against myocardial I/R injury. In an in vitro hypoxia reoxygenation (H/R) model, lactate markedly mitigated H/R-induced cell damage in H9c2 cells. Meanwhile, further studies suggested that lactate contributed to RIPC rescuing I/R-induced autophagy deficiency by promoting TFEB translocation to the nucleus through activating the AMPK-mTOR pathway without influencing the PI3K-Akt pathway, thus reducing cardiomyocytes damage. Interestingly, we also found that lactate upregulated the mRNA and protein expression of CX43 by facilitating the binding of TFEB to CX43 promoter in the myocardium. Functionally, silencing of TFEB attenuated the protective effect of lactate on cell damage, which was reversed by overexpression of CX43. Further mechanistic studies suggested lactate facilitated CX43-regulated autophagy via AMPK-mTOR-TFEB signaling pathway. Collectively, our research demonstrates that RIPC protects against myocardial I/R injury through lactate-mediated myocardial autophagy via AMPK-mTOR-TFEB-CX43 axis.

3.
BMC Genomics ; 25(1): 593, 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38867153

ABSTRACT

BACKGROUND: Terpenes are important components of plant aromas, and terpene synthases (TPSs) are the key enzymes driving terpene diversification. In this study, we characterized the volatile terpenes in five different Chrysanthemum nankingense tissues. In addition, genome-wide identification and expression analysis of TPS genes was conducted utilizing an improved chromosome-scale genome assembly and tissue-specific transcriptomes. The biochemical functions of three representative TPSs were also investigated. RESULTS: We identified tissue-specific volatile organic compound (VOC) and volatile terpene profiles. The improved Chrysanthemum nankingense genome assembly was high-quality, including a larger assembled size (3.26 Gb) and a better contig N50 length (3.18 Mb) compared to the old version. A total of 140 CnTPS genes were identified, with the majority representing the TPS-a and TPS-b subfamilies. The chromosomal distribution of these TPS genes was uneven, and 26 genes were included in biosynthetic gene clusters. Closely-related Chrysanthemum taxa were also found to contain diverse TPS genes, and the expression profiles of most CnTPSs were tissue-specific. The three investigated CnTPS enzymes exhibited versatile activities, suggesting multifunctionality. CONCLUSIONS: We systematically characterized the structure and diversity of TPS genes across the Chrysanthemum nankingense genome, as well as the potential biochemical functions of representative genes. Our results provide a basis for future studies of terpene biosynthesis in chrysanthemums, as well as for the breeding of improved chrysanthemum varieties.


Subject(s)
Alkyl and Aryl Transferases , Chrysanthemum , Genome, Plant , Multigene Family , Terpenes , Alkyl and Aryl Transferases/genetics , Alkyl and Aryl Transferases/metabolism , Chrysanthemum/genetics , Chrysanthemum/enzymology , Terpenes/metabolism , Phylogeny , Volatile Organic Compounds/metabolism , Plant Proteins/genetics , Plant Proteins/metabolism , Transcriptome
4.
Br J Cancer ; 131(1): 184-195, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38762674

ABSTRACT

BACKGROUND: Immune checkpoint blockade (ICB) therapy provides remarkable clinical benefits for multiple cancer types. However, the overall response rate to ICB therapy remains low in esophageal squamous cell carcinoma (ESCC). This study aimed to identify biomarkers of ICB therapy for ESCC and interrogate its potential clinical relevance. METHODS: We investigated gene expression in 42 treatment-naïve ESCC tumor tissues and identified differentially expressed genes, tumor-infiltrating lymphocytes and immune-related genes signatures associated with differential immunotherapy responses. We systematically assessed the tumor microenvironment using the NanoString GeoMx digital spatial profiler, single-cell RNA-seq and multiplex immunohistochemistry in ESCC. Finally, we evaluated the associations between HLA-A-positive tertiary lymphoid structures (TLSs) and patients' responses to ICB in 60 ESCC patients. RESULTS: Tumor infiltrating B lymphocytes and several immune-related gene signatures, such as the antigen presenting machinery (APM) signature, are significantly elevated in ICB treatment responders. Multiplex immunohistochemistry identified the presence of HLA-A+ TLSs and showed that TLS-resident cells increasingly express HLA-A as TLSs mature. Most TLS-resident HLA-A+ cells are tumor-infiltrating T (TIL-T) or tumor-infiltrating B (TIL-B) lymphocytes. Digital spatial profiling of spatially distinct TIL-T lymphocytes and single-cell RNA-seq data from 60 ESCC tumor tissues revealed that CXCL13-expressing exhausted TIL-Ts inside TLSs are reactivated with elevated expression of the APM signature as TLSs mature. Finally, we demonstrated that HLA-A+ TLSs and their major cellular components, TIL-Ts and TIL-Bs, are associated with a clinical benefit from ICB treatment for ESCC. CONCLUSIONS: HLA-A+ TLSs are present in ESCC tumor tissues. TLS-resident TIL-Ts with elevated expression of the APM signature may be reactivated. HLA-A+ TLSs and their major cellular components, TIL-Ts and TIL-Bs, may serve as biomarkers for ICB-treated ESCC patients.


Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , HLA-A Antigens , Immunotherapy , Lymphocytes, Tumor-Infiltrating , Tertiary Lymphoid Structures , Tumor Microenvironment , Humans , Lymphocytes, Tumor-Infiltrating/immunology , Esophageal Squamous Cell Carcinoma/immunology , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/therapy , Esophageal Squamous Cell Carcinoma/genetics , Tertiary Lymphoid Structures/immunology , Tertiary Lymphoid Structures/pathology , Esophageal Neoplasms/immunology , Esophageal Neoplasms/pathology , Esophageal Neoplasms/therapy , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/genetics , Immunotherapy/methods , Tumor Microenvironment/immunology , HLA-A Antigens/immunology , HLA-A Antigens/genetics , Female , Male , Immune Checkpoint Inhibitors/therapeutic use , Immune Checkpoint Inhibitors/pharmacology , Middle Aged , Aged , Biomarkers, Tumor/metabolism
5.
Anal Chem ; 96(29): 11853-11861, 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-38989993

ABSTRACT

Cardiac myosin-binding protein C (cMyBP-C) is a novel cardiac marker of acute myocardial infarction (AMI) and acute cardiac injuries (ACI). Construction of point-of-care testing techniques capable of sensing cMyBP-C with high sensitivity and precision is urgently needed. Herein, we synthesized an Au@NGQDs@Au/Ag multi-shell nanoUrchins (MSNUs), and then applied it in a colorimetric/SERS dual-mode immunoassay for detection of cMyBP-C. The MSNUs displayed superior stability, colorimetric brightness, and SERS enhancement ability with an enhanced factor of 5.4 × 109, which were beneficial to improve the detection capability of test strips. The developed MSNU-based test strips can achieve an ultrasensitive immunochromatographic assay of cMyBP-C in both colorimetric and SERS modes with the limits of detection as low as 19.3 and 0.77 pg/mL, respectively. Strikingly, this strip was successfully applied to analyze actual plasma samples with significantly better sensitivity, negative predictive value, and accuracy than commercially available gold test strips. Notably, this method possessed a wide range of application scenarios via combining with a color recognizer application named Color Grab on the smartphone, which can meet various needs of different users. Overall, our MSNU-based test strip as a mobile health monitoring tool shows excellent sensitivity, reproducibility, and rapid detection of the cMyBP-C, which holds great potential for the early clinic diagnosis of AMI and ACI.


Subject(s)
Carrier Proteins , Gold , Humans , Immunoassay/methods , Carrier Proteins/blood , Gold/chemistry , Limit of Detection , Colorimetry/methods , Metal Nanoparticles/chemistry , Myocardial Infarction/diagnosis , Myocardial Infarction/blood , Spectrum Analysis, Raman/methods
6.
J Transl Med ; 22(1): 97, 2024 01 23.
Article in English | MEDLINE | ID: mdl-38263066

ABSTRACT

Atherosclerosis is a chronic, progressive, inflammatory disease that occurs in the arterial wall. Despite recent advancements in treatment aimed at improving efficacy and prolonging survival, atherosclerosis remains largely incurable. In this review, we discuss emerging single-cell sequencing techniques and their novel insights into atherosclerosis. We provide examples of single-cell profiling studies that reveal phenotypic characteristics of atherosclerosis plaques, blood, liver, and the intestinal tract. Additionally, we highlight the potential clinical applications of single-cell analysis and propose that combining this approach with other techniques can facilitate early diagnosis and treatment, leading to more accurate medical interventions.


Subject(s)
Atherosclerosis , Plaque, Atherosclerotic , Humans , Precision Medicine , Arteries , Liver
7.
J Biochem Mol Toxicol ; 38(1): e23610, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38091339

ABSTRACT

Although epidemiological studies have evaluated the association between ambient air pollution and chronic kidney disease (CKD), the results remain mixed. To clarify the nature of the association, we conducted a comprehensive systematic review and meta-analysis to assess the global relationship between air pollution and CKD. The Web of Science, PubMed, Embase and Cochrane Library databases systematically were searched for studies published up to July 2023 and included 32 studies that met specific criteria. The random effects model was used to derive overall risk estimates for each pollutant. The meta-analysis estimated odds ratio (ORs) of risk for CKD were 1.42 (95% confidence interval [CI]: 1.31-1.54) for each 10 µg/m3 increase in PM2.5 ; 1.20 (95% CI: 1.14-1.26) for each 10 µg/m3 increase in PM10 ; 1.07 (95% CI: 1.05-1.09) for each 10 µg/m3 increase in NO2 ; 1.03 (95% CI: 1.02-1.03) for each 10 µg/m3 increase in NOX ; 1.07 (95% CI: 1.01-1.12) for each 1 ppb increase in SO2 ; 1.03 (95% CI: 1.00-1.05) for each 0.1 ppm increase in CO. Subgroup analysis showed that this effect varied by gender ratio, age, study design, exposure assessment method, and income level. Furthermore, PM2.5 , PM10 , and NO2 had negative effects on CKD even within the World Health Organization-recommended acceptable concentrations. Our results further confirmed the adverse effect of air pollution on the risk of CKD. These findings can contribute to enhance the awareness of the importance of reducing air pollution among public health officials and policymakers.


Subject(s)
Air Pollutants , Air Pollution , Renal Insufficiency, Chronic , Humans , Air Pollutants/adverse effects , Particulate Matter/adverse effects , Nitrogen Dioxide/analysis , Environmental Exposure/adverse effects , Air Pollution/adverse effects , Air Pollution/analysis , Renal Insufficiency, Chronic/etiology , Renal Insufficiency, Chronic/chemically induced
8.
BMC Anesthesiol ; 24(1): 77, 2024 Feb 26.
Article in English | MEDLINE | ID: mdl-38408913

ABSTRACT

BACKGROUND: Extensive metastatic and refractory cancer pain is common, and exhibits a dissatisfactory response to the conventional intrathecal infusion of opioid analgesics. CASE PRESENTATION: The present study reports a case of an extensive metastatic esophageal cancer patient with severe intractable pain, who underwent translumbar subarachnoid puncture with intrathecal catheterization to the prepontine cistern. After continuous infusion of low-dose morphine, the pain was well-controlled with a decrease in the numeric rating scale (NRS) of pain score from 9 to 0, and the few adverse reactions to the treatment disappeared at a low dose of morphine. CONCLUSIONS: The patient achieved a good quality of life during the one-month follow-up period.


Subject(s)
Cancer Pain , Neoplasms , Pain, Intractable , Humans , Morphine , Pain, Intractable/etiology , Pain, Intractable/chemically induced , Cancer Pain/drug therapy , Quality of Life , Analgesics, Opioid , Injections, Spinal/adverse effects
9.
Acta Biochim Biophys Sin (Shanghai) ; 56(1): 34-43, 2024 01 25.
Article in English | MEDLINE | ID: mdl-38151998

ABSTRACT

Cisplatin resistance is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). p32 and OPA1 are the key regulators of mitochondrial morphology and function. This study aims to investigate the role of the p32/OPA1 axis in cisplatin resistance in NSCLC and its underlying mechanism. The levels of p32 protein and mitochondrial fusion protein OPA1 are higher in cisplatin-resistant A549/DDP cells than in cisplatin-sensitive A549 cells, which facilitates mitochondrial fusion in A549/DDP cells. In addition, the expression of p32 and OPA1 protein is also upregulated in A549 cells during the development of cisplatin resistance. Moreover, p32 knockdown effectively downregulates the expression of OPA1, stimulates mitochondrial fission, decreases ATP generation and sensitizes A549/DDP cells to cisplatin-induced apoptosis. Furthermore, metformin significantly downregulates the expressions of p32 and OPA1 and induces mitochondrial fission and a decrease in ATP level in A549/DDP cells. The co-administration of metformin and cisplatin shows a significantly greater decrease in A549/DDP cell viability than cisplatin treatment alone. Moreover, D-erythro-Sphingosine, a potent p32 kinase activator, counteracts the metformin-induced downregulation of OPA1 and mitochondrial fission in A549/DDP cells. Taken together, these findings indicate that p32/OPA1 axis-mediated mitochondrial dynamics contributes to the acquired cisplatin resistance in NSCLC and that metformin resensitizes NSCLC to cisplatin, suggesting that targeting p32 and mitochondrial dynamics is an effective strategy for the prevention of cisplatin resistance.


Subject(s)
Antineoplastic Agents , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Metformin , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Cisplatin/pharmacology , Cisplatin/therapeutic use , Mitochondrial Dynamics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Drug Resistance, Neoplasm , Cell Line, Tumor , Apoptosis , A549 Cells , Proteins , Metformin/pharmacology , Adenosine Triphosphate , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Proliferation , GTP Phosphohydrolases/genetics
10.
Ecotoxicol Environ Saf ; 272: 116076, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38335577

ABSTRACT

Cr(VI) is known to be seriously toxic and carcinogenic. Hypoxia-inducible factor-1α (HIF-1α) is a crucial regulator to promote tumor development. In this study, we found that Cr(VI) significantly increased the expression of HIF-1α in A549 cells and in lung of BALB/c mice but not in HELF cells. Treatment with Lificiguat (YC-1), HIF-1α inhibitor, or CoCl2, HIF-1α inducer, could alter Cr(VI)-induced autophagy, glycolysis, and cell growth in A549 cells but not in HELF cells, validating the involvement of HIF-1α in these effects of Cr(VI) in A549 cells. Co-treatments of pcATG4B with YC-1, or siATG4B with CoCl2 demonstrated the role of HIF-1α / autophagy axis in inducing glycolysis and cell growth in A549 cells. In HELF cells, however, only autophagy but not HIF-1α played a role in inducing glycolysis. The protein level of p53 was significantly lower in A549 cells than in HELF cells. RITA, a p53 inducer, attenuated Cr(VI)-induced HIF-1α and LC3-II in A549 cells, suggesting that p53 might be the mechanism underlying the different effects of Cr(VI) on HIF-1α in A549 and HELF cells. Thus, p53-dependent HIF-1α / autophagy-mediated glycolysis plays a role in facilitating Cr(VI)-induced carcinogenesis.


Subject(s)
Carcinogenesis , Chromium , Cobalt , Tumor Suppressor Protein p53 , Animals , Mice , Tumor Suppressor Protein p53/genetics , Autophagy , Cell Movement , Glycolysis , Cell Line, Tumor
11.
Ecotoxicol Environ Saf ; 276: 116318, 2024 May.
Article in English | MEDLINE | ID: mdl-38626609

ABSTRACT

Perfluorooctane sulfonate (PFOS), an officially listed persistent organic pollutant, is a widely distributed perfluoroalkyl substance. Epidemiological studies have shown that PFOS is intimately linked to the occurrence of insulin resistance (IR). However, the detailed mechanism remains obscure. In previous studies, we found that mitochondrial calcium overload was concerned with hepatic IR induced by PFOS. In this study, we found that PFOS exposure noticeably raised lysosomal calcium in L-02 hepatocytes from 0.5 h. In the PFOS-cultured L-02 cells, inhibiting autophagy alleviated lysosomal calcium overload. Inhibition of mitochondrial calcium uptake aggravated the accumulation of lysosomal calcium, while inhibition of lysosomal calcium outflowing reversed PFOS-induced mitochondrial calcium overload and IR. Transient receptor potential mucolipin 1 (TRPML1), the calcium output channel of lysosomes, interacted with voltage-dependent anion channel 1 (VDAC1), the calcium intake channel of mitochondria, in the PFOS-cultured cells. Moreover, we found that ATP synthase F1 subunit beta (ATP5B) interacted with TRPML1 and VDAC1 in the L-02 cells and the liver of mice under PFOS exposure. Inhibiting ATP5B expression or restraining the ATP5B on the plasma membrane reduced the interplay between TRPML1 and VDAC1, reversed the mitochondrial calcium overload and deteriorated the lysosomal calcium accumulation in the PFOS-cultured cells. Our research unveils the molecular regulation of the calcium crosstalk between lysosomes and mitochondria, and explains PFOS-induced IR in the context of activated autophagy.


Subject(s)
Alkanesulfonic Acids , Autophagy , Calcium , Fluorocarbons , Insulin Resistance , Liver , Lysosomes , Mitochondria , Mitochondrial Proton-Translocating ATPases , Alkanesulfonic Acids/toxicity , Fluorocarbons/toxicity , Animals , Lysosomes/drug effects , Lysosomes/metabolism , Autophagy/drug effects , Calcium/metabolism , Mice , Mitochondrial Proton-Translocating ATPases/metabolism , Liver/drug effects , Liver/metabolism , Mitochondria/drug effects , Mitochondria/metabolism , Male , Voltage-Dependent Anion Channel 1/metabolism , Cell Line , Hepatocytes/drug effects , Hepatocytes/metabolism , Environmental Pollutants/toxicity , TRPM Cation Channels/metabolism , Mice, Inbred C57BL
12.
Ecotoxicol Environ Saf ; 278: 116435, 2024 Jun 15.
Article in English | MEDLINE | ID: mdl-38714084

ABSTRACT

The compound known as Sodium arsenite (NaAsO2), which is a prevalent type of inorganic arsenic found in the environment, has been strongly associated with liver fibrosis (LF), a key characteristic of nonalcoholic fatty liver disease (NAFLD), which has been demonstrated in our previous study. Our previous research has shown that exposure to NaAsO2 triggers the activation of hepatic stellate cells (HSCs), a crucial event in the development of LF. However, the molecular mechanism is still unknown. N6-methyladenosine (m6A) modification is the most crucial post-transcriptional modification in liver disease. Nevertheless, the precise function of m6A alteration in triggering HSCs and initiating LF caused by NaAsO2 remains unknown. Here, we found that NaAsO2 induced LF and HSCs activation through TGF-ß/Smad signaling, which could be reversed by TGF-ß1 knockdown. Furthermore, NaAsO2 treatment enhanced the m6A modification level both in vivo and in vitro. Significantly, NaAsO2 promoted the specific interaction of METTL14 and IGF2BP2 with TGF-ß1 and enhanced the TGF-ß1 mRNA stability. Notably, NaAsO2-induced TGF-ß/Smad pathway and HSC-t6 cells activation might be avoided by limiting METTL14/IGF2BP2-mediated m6A modification. Our findings showed that the NaAsO2-induced activation of HSCs and LF is made possible by the METTL14/IGF2BP2-mediated m6A methylation of TGF-ß1, which may open up new therapeutic options for LF brought on by environmental hazards.


Subject(s)
Adenosine , Arsenites , Hepatic Stellate Cells , Liver Cirrhosis , Sodium Compounds , Transforming Growth Factor beta1 , Arsenites/toxicity , Hepatic Stellate Cells/drug effects , Sodium Compounds/toxicity , Liver Cirrhosis/pathology , Liver Cirrhosis/chemically induced , Animals , Transforming Growth Factor beta1/metabolism , Adenosine/analogs & derivatives , Methyltransferases/genetics , Methyltransferases/metabolism , Male , RNA-Binding Proteins/metabolism , RNA-Binding Proteins/genetics , Signal Transduction/drug effects , Mice , Humans , Mice, Inbred C57BL
13.
Ecotoxicol Environ Saf ; 280: 116553, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-38850699

ABSTRACT

The incidence of nonalcoholic steatohepatitis (NASH) is related with perfluorooctane sulfonate (PFOS), yet the mechanism remains ill-defined. Mounting evidence suggests that ferroptosis plays a crucial role in the initiation of NASH. In this study, we used mice and human hepatocytes L-02 to investigate the role of ferroptosis in PFOS-induced NASH and the effect and molecular mechanism of PFOS on liver ferroptosis. We found here that PFOS caused NASH in mice, and lipid accumulation and inflammatory response in the L-02 cells. PFOS induced hepatic ferroptosis in vivo and in vitro, as evidenced by the decrease in glutathione peroxidase 4 (GPX4), and the increases in cytosolic iron, acyl-CoA synthetase long-chain family member 4 (ACSL4) and lipid peroxidation. In the PFOS-treated cells, the increases in the inflammatory factors and lipid contents were reversed by ferroptosis inhibitor. PFOS-induced ferroptosis was relieved by autophagy inhibitor. The expression of mitochondrial calcium uniporter (MCU) was accelerated by PFOS, leading to subsequent mitochondrial calcium accumulation, and inhibiting autophagy reversed the increase in MCU. Inhibiting mitochondrial calcium reversed the variations in GPX4 and cytosolic iron, without influencing the change in ACSL4, induced by PFOS. MCU interacted with ACSL4 and the siRNA against MCU reversed the changes in ACSL4,GPX4 and cytosolic iron systemically. This study put forward the involvement of hepatic ferroptosis in PFOS-induced NASH and identified MCU as the mediator of the autophagy-dependent ferroptosis.


Subject(s)
Alkanesulfonic Acids , Autophagy , Calcium , Coenzyme A Ligases , Ferroptosis , Fluorocarbons , Non-alcoholic Fatty Liver Disease , Ferroptosis/drug effects , Fluorocarbons/toxicity , Animals , Alkanesulfonic Acids/toxicity , Mice , Non-alcoholic Fatty Liver Disease/chemically induced , Non-alcoholic Fatty Liver Disease/pathology , Autophagy/drug effects , Coenzyme A Ligases/metabolism , Humans , Calcium/metabolism , Calcium Channels/metabolism , Male , Mice, Inbred C57BL , Mitochondria/drug effects , Mitochondria/metabolism , Cell Line , Hepatocytes/drug effects
14.
Int J Mol Sci ; 25(2)2024 Jan 05.
Article in English | MEDLINE | ID: mdl-38255764

ABSTRACT

Inflammatory bowel disease (IBD) is a group of intestinal inflammatory diseases characterized by chronic, recurrent, remitting, or progressive inflammation, which causes the disturbance of the homeostasis between immune cells, such as macrophages, epithelial cells, and microorganisms. Intestinal macrophages (IMs) are the largest population of macrophages in the body, and the abnormal function of IMs is an important cause of IBD. Most IMs come from the replenishment of blood monocytes, while a small part come from embryos and can self-renew. Stimulated by the intestinal inflammatory microenvironment, monocyte-derived IMs can interact with intestinal epithelial cells, intestinal fibroblasts, and intestinal flora, resulting in the increased differentiation of proinflammatory phenotypes and the decreased differentiation of anti-inflammatory phenotypes, releasing a large number of proinflammatory factors and aggravating intestinal inflammation. Based on this mechanism, inhibiting the secretion of IMs' proinflammatory factors and enhancing the differentiation of anti-inflammatory phenotypes can help alleviate intestinal inflammation and promote tissue repair. At present, the clinical medication of IBD mainly includes 5-aminosalicylic acids (5-ASAs), glucocorticoid, immunosuppressants, and TNF-α inhibitors. The general principle of treatment is to control acute attacks, alleviate the condition, reduce recurrence, and prevent complications. Most classical IBD therapies affecting IMs function in a variety of ways, such as inhibiting the inflammatory signaling pathways and inducing IM2-type macrophage differentiation. This review explores the current understanding of the involvement of IMs in the pathogenesis of IBD and their prospects as therapeutic targets.


Subject(s)
Inflammatory Bowel Diseases , Monocytes , Humans , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/etiology , Macrophages , Mesalamine , Anti-Inflammatory Agents , Inflammation
15.
Adv Skin Wound Care ; 37(3): 148-154, 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38393704

ABSTRACT

OBJECTIVE: To comprehensively assess the association between operative positioning with intraoperative-acquired pressure injury (IAPI) development. METHODS: This retrospective cohort study included 455 patients who underwent surgery between October 2020 and January 2021. The authors grouped patients by operative positioning into the prone position and nonprone position groups. They used propensity-score matching at a 1:2 ratio to control for preoperative confounders, applied multiple logistic regression models to analyze the effects between positioning and IAPI, and assessed interactions of positioning and intraoperative factors on IAPI. RESULTS: The final enrollment was 92 cases in the prone position group and 181 in the nonprone position group. Multivariable logistic analysis suggested that the prone position had a 2.92 times higher risk of IAPI than the nonprone position (odds ratio, 2.92; 95% CI, 1.13-7.57; P = .026). Subgroup analysis showed a significant multiplicative interaction between positioning and foam dressing on IAPI (P < .05), which was not observed in other intraoperative factors (P > .05). CONCLUSIONS: This study provides evidence that prone operative positioning can increase IAPI risk. Patients in the prone position may particularly benefit from using dressings in Chinese populations. Further large-sample longitudinal studies are required to confirm these findings.


Subject(s)
Pressure Ulcer , Humans , Retrospective Studies , Pressure Ulcer/etiology , Prone Position , Pressure , Patient Positioning/adverse effects
16.
Glob Chang Biol ; 29(7): 1984-1997, 2023 04.
Article in English | MEDLINE | ID: mdl-36607170

ABSTRACT

The contribution of agriculture to the sustainable development goals requires climate-smart and profitable farm innovations. Increasing the ammonia fertilizer applications to meet the global food demands results in high agricultural costs, environmental quality deterioration, and global warming, without a significant increase in crop yield. Here, we reported that a third microbial ammonia oxidation process, complete ammonia oxidation (comammox), is contributing to a significant ammonia fertilizer loss (41.9 ± 4.8%) at the rate of 3.53 ± 0.55 mg N kg-1 day-1 in agricultural soils around the world. The contribution of comammox to ammonia fertilizer loss, occurring mainly in surface agricultural soil profiles (0-0.2 m), was equivalent to that of bacterial ammonia oxidation (48.6 ± 4.5%); both processes were significantly more important than archaeal ammonia oxidation (9.5 ± 3.6%). In contrast, comammox produced less N2 O (0.98 ± 0.44 µg N kg-1 day-1 , 11.7 ± 3.1%), comparable to that produced by archaeal ammonia oxidation (16.4 ± 4.4%) but significantly lower than that of bacterial ammonia oxidation (72.0 ± 5.1%). The efficiency of ammonia conversion to N2 O by comammox (0.02 ± 0.01%) was evidently lower than that of bacterial (0.24 ± 0.06%) and archaeal (0.16 ± 0.04%) ammonia oxidation. The comammox rate increased with increasing soil pH values, which is the only physicochemical characteristic that significantly influenced both comammox bacterial abundance and rates. Ammonia fertilizer loss, dominated by comammox and bacterial ammonia oxidation, was more intense in soils with pH >6.5 than in soils with pH <6.5. Our results revealed that comammox plays a vital role in ammonia fertilizer loss and sustainable development in agroecosystems that have been previously overlooked for a long term.


Subject(s)
Ammonia , Soil , Fertilizers/analysis , Nitrification , Oxidation-Reduction , Soil Microbiology , Bacteria , Archaea , Agriculture
17.
Chemistry ; 29(1): e202202002, 2023 Jan 02.
Article in English | MEDLINE | ID: mdl-36161734

ABSTRACT

Microbial fuel cell (MFC) is a promising approach that could utilize microorganisms to oxidize biodegradable pollutants in wastewater and generate electrical power simultaneously. Introducing advanced anode nanomaterials is generally considered as an effective way to enhance MFC performance by increasing bacterial adhesion and facilitating extracellular electron transfer (EET). This review focuses on the key advances of recent anode modification materials, as well as the current understanding of the microbial EET process occurring at the bacteria-electrode interface. Based on the difference in combination mode of the exoelectrogens and nanomaterials, anode surface modification, hybrid biofilm construction and single-bacterial surface modification strategies are elucidated exhaustively. The inherent mechanisms may help to break through the performance output bottleneck of MFCs by rational design of EET-related nanomaterials, and lead to the widespread application of microbial electrochemical systems.


Subject(s)
Bioelectric Energy Sources , Nanostructures , Bioelectric Energy Sources/microbiology , Electron Transport , Nanostructures/chemistry , Electricity , Bacteria/metabolism , Electrodes
18.
Neurochem Res ; 48(9): 2607-2620, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37126193

ABSTRACT

Ischemic stroke (IS), a devastating condition characterized by intracranial artery stenosis and middle cerebral artery occlusion leading to insufficient oxygen supply to the brain, is a major cause of death and physical disability worldwide. Recent research has demonstrated the critical role of circular RNAs (circRNAs), a class of covalently enclosed noncoding RNAs that are widespread in eukaryotic cells, in regulating various physiological and pathophysiological cellular processes, including cell apoptosis, autophagy, synaptic plasticity, and neuroinflammation. In the past few years, circRNAs have attracted extensive attention in the field of IS research. This review summarizes the current understanding of the mechanisms underlying the involvement of circRNAs in IS development. A better understanding of circRNA-mediated pathogenic mechanisms in IS may pave the way for translating circRNA research into clinical practice, ultimately improving the clinical outcomes of IS patients.


Subject(s)
Brain Ischemia , Ischemic Stroke , Stroke , Humans , RNA, Circular/genetics , Ischemic Stroke/genetics , Brain/pathology , Brain Ischemia/genetics , Brain Ischemia/pathology , Infarction, Middle Cerebral Artery/pathology , Stroke/genetics
19.
Mol Cell Biochem ; 478(7): 1519-1531, 2023 Jul.
Article in English | MEDLINE | ID: mdl-36413334

ABSTRACT

Triple negative breast cancer (TNBC) is a kind of refractory cancer with poor response to conventional chemotherapy. Recently, the combination of baicalein and doxorubicin was reported to exert a synergistic antitumor effect on breast cancer. However, the underlying mechanism how baicalein sensitizes breast cancer cells to doxorubicin remains to be elucidated. Here, it was found that 20 µM baicalein increased the autophagy markers including the ratio of LC3B II/I, GFP-LC3 punctate aggregates and down-regulation of p62 expression, and up-regulated mitophagy marker PINK1 and Parkin in TNBC MDA-MB-231 cells as well. In contrast, doxorubicin decreased the levels of autophagy markers, and significantly up-regulated CDK1 in MDA-MB-231 cells. Pretreatment with baicalein markedly inhibited the doxorubicin-induced decrease in autophagy markers and up-regulation of CDK1, which was reversed by the autophagy inhibitor 3-Methyladenine. Moreover, baicalein alleviated the doxorubicin-induced expression and phosphorylation (at Ser616) of mitochondrial fission protein Drp1. Intriguingly, the autophagy inhibitor 3-Methyladenine also significantly weakened the effect of baicalein on doxorubicin-induced viability decrease and apoptosis in MDA-MB-231 cells. Taken together, our data indicate that baicalein improves the chemosensitivity of TNBC cells to doxorubicin through promoting the autophagy-mediated down-regulation of CDK1, also suggest a novel strategy for prevention of TNBC in the future.


Subject(s)
Triple Negative Breast Neoplasms , Humans , Triple Negative Breast Neoplasms/metabolism , MDA-MB-231 Cells , Down-Regulation , Cell Line, Tumor , Doxorubicin/pharmacology , Autophagy , Apoptosis , Cell Proliferation , CDC2 Protein Kinase/metabolism , CDC2 Protein Kinase/pharmacology
20.
Cell Biol Toxicol ; 39(5): 2165-2181, 2023 10.
Article in English | MEDLINE | ID: mdl-35226250

ABSTRACT

N6-methyladenosine (m6A) messenger RNA methylation is the most widespread gene regulatory mechanism affecting liver functions and disorders. However, the relationship between m6A methylation and arsenic-induced hepatic insulin resistance (IR), which is a critical initiating event in arsenic-induced metabolic syndromes such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), remains unclear. Here, we showed that arsenic treatment facilitated methyltransferase-like 14 (METTL14)-mediated m6A methylation, and that METTL14 interference reversed arsenic-impaired hepatic insulin sensitivity. We previously showed that arsenic-induced NOD-like receptor protein 3 (NLRP3) inflammasome activation contributed to hepatic IR. However, the regulatory mechanisms underlying the role of arsenic toward the post-transcriptional modification of NLRP3 remain unclear. Here, we showed that NLRP3 mRNA stability was enhanced by METTL14-mediated m6A methylation during arsenic-induced hepatic IR. Furthermore, we demonstrated that arsenite methyltransferase (AS3MT), an essential enzyme in arsenic metabolic processes, interacted with NLRP3 to activate the inflammasome, thereby contributing to arsenic-induced hepatic IR. Also, AS3MT strengthened the m6A methylase association with NLRP3 to stabilize m6A-modified NLRP3. In summary, we showed that AS3MT-induced m6A modification critically regulated NLRP3 inflammasome activation during arsenic-induced hepatic IR, and we identified a novel post-transcriptional function of AS3MT in promoting arsenicosis.


Subject(s)
Arsenic , Insulin Resistance , Humans , Arsenic/toxicity , Arsenic/metabolism , Diabetes Mellitus, Type 2/metabolism , Inflammasomes/metabolism , Liver , Methyltransferases/genetics , Methyltransferases/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , NLR Proteins/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL