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This review deals with the roles of calcium ions and ATP in the control of the normal functions of the different cell types in the exocrine pancreas as well as the roles of these molecules in the pathophysiology of acute pancreatitis. Repetitive rises in the local cytosolic calcium ion concentration in the apical part of the acinar cells not only activate exocytosis but also, via an increase in the intramitochondrial calcium ion concentration, stimulate the ATP formation that is needed to fuel the energy-requiring secretion process. However, intracellular calcium overload, resulting in a global sustained elevation of the cytosolic calcium ion concentration, has the opposite effect of decreasing mitochondrial ATP production, and this initiates processes that lead to necrosis. In the last few years it has become possible to image calcium signaling events simultaneously in acinar, stellate, and immune cells in intact lobules of the exocrine pancreas. This has disclosed processes by which these cells interact with each other, particularly in relation to the initiation and development of acute pancreatitis. By unraveling the molecular mechanisms underlying this disease, several promising therapeutic intervention sites have been identified. This provides hope that we may soon be able to effectively treat this often fatal disease.
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Trifosfato de Adenosina/fisiologia , Cálcio/fisiologia , Pâncreas Exócrino/fisiologia , Pancreatopatias/fisiopatologia , Animais , Sinalização do Cálcio , Humanos , Pâncreas Exócrino/fisiopatologiaRESUMO
Neutrophils are the most abundant innate immune cells in human blood, emerging as important players in a variety of diseases. Mitochondria are bioenergetic, biosynthetic, and signaling organelles critical for cell fate and function. Mitochondria have been overlooked in neutrophil research owing to the conventional view that neutrophils contain few, if any, competent mitochondria and do not rely on these organelles for adenosine triphosphate production. A growing body of evidence suggests that mitochondria participate in neutrophil biology at many levels, ranging from neutrophil development to chemotaxis, effector function, and cell death. Moreover, mitochondria and mitochondrial components, such as mitochondrial deoxyribonucleic acid, can be released by neutrophils to eliminate infection and/or shape immune response, depending on the specific context. In this review, we provide an update on the functional role of mitochondria in neutrophils, highlight mitochondria as key players in modulating the neutrophil phenotype and function during infection and inflammation, and discuss the possibilities and challenges to exploit the unique aspects of mitochondria in neutrophils for disease treatment.
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Mitocôndrias , Neutrófilos , Humanos , Mitocôndrias/metabolismo , Inflamação , Diferenciação Celular , QuimiotaxiaRESUMO
In contrast to molecular changes associated with increased inflammatory responses, little is known about intracellular counter-regulatory mechanisms that control signaling cascades associated with functional responses of neutrophils. Active RHO GTPases are typically considered as effector proteins that elicit cellular responses. Strikingly, we show here that RHOH, although being constitutively GTP-bound, limits neutrophil degranulation and the formation of neutrophil extracellular traps (NETs). Mechanistically, RHOH is induced under inflammatory conditions and binds to non-muscle myosin heavy chain IIA (NMHC IIA) in activated neutrophils in order to inhibit the transport of mitochondria and granules along actin filaments, which is partially reverted upon disruption of the interaction with NMHC IIA by introducing a mutation in RhoH at lysine 34 (RhoHK34A). In parallel, RHOH inhibits actin polymerization presumably by modulating RAC1 activity. In vivo studies using Rhoh-/- mice, demonstrate an increased antibacterial defense capability against Escherichia coli (E. coli). Collectively, our data reveal a previously undefined role of RHOH as a molecular brake for actomyosin-mediated neutrophil effector functions, which represents an intracellular regulatory axis involved in controlling the strength of an antibacterial inflammatory response.
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Actomiosina , Neutrófilos , Fatores de Transcrição , Proteínas rho de Ligação ao GTP , Citoesqueleto de Actina/metabolismo , Actinas/metabolismo , Actomiosina/metabolismo , Animais , Antibacterianos , Proteínas do Citoesqueleto/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Guanosina Trifosfato , Lisina , Camundongos , Cadeias Pesadas de Miosina/metabolismo , Neutrófilos/metabolismo , Fatores de Transcrição/metabolismo , Proteínas rho de Ligação ao GTP/genética , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
Spin-crossover (SCO) materials exhibit remarkable potential as bistable switches in molecular devices. However, the spin transition temperatures (Tc) of known compounds are unable to cover the entire ambient temperature spectrum, largely limiting their practical utility. This study reports an exemplary two-dimensional SCO solid solution system, [FeIII(H0.5LCl)2-2x(H0.5LF)2x]·H2O (H0.5LX = 5-X-2-hydroxybenzylidene-hydrazinecarbothioamide, X = F or Cl, x = 0 to 1), in which the adjacent layers are adhered via hydrogen bonding. Notably, the Tc of this system can be fine-tuned across 90 K (227-316 K) in a linear manner by modulating the fraction x of the LF ligand. Elevating x results in strengthened hydrogen bonding between adjacent layers, which leads to enhanced intermolecular interactions between adjacent SCO molecules. Single-crystal diffraction analysis and periodic density functional theory calculations revealed that such a special kind of alteration in interlayer interactions strengthens the FeIIIN2O2S2 ligand field and corresponding SCO energy barrier, consequently resulting in increased Tc. This work provides a new pathway for tuning the Tc of SCO materials through delicate manipulation of molecular interactions, which could expand the application of bistable molecular solids to a much wider temperature regime.
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The enzyme AKR1C3 plays a crucial role in hormone and drug metabolism and is associated with abnormal expression in liver cancer, leading to tumor progression and poor prognosis. Nanoparticles modified with HSA can modulate the tumor microenvironment by enhancing photodynamic therapy to induce apoptosis in tumor cells and alleviate hypoxia. Therefore, exploring the potential regulatory mechanisms of resveratrol on AKR1C3 through the construction of HSA-RSV NPs carriers holds significant theoretical and clinical implications for the treatment of liver cancer. The aim of this study is to investigate the targeted regulation of AKR1C3 expression through the loading of resveratrol (RSV) on nanomaterials HSA-RSV NPs (Nanoparticles) in order to alleviate tumor hypoxia and inhibit the progression of hepatocellular carcinoma (HCC), and to explore its molecular mechanism. PubChem database and PharmMapper server were used to screen the target genes of RSV. HCC-related differentially expressed genes (DEGs) were analyzed through the GEO dataset, and relevant genes were retrieved from the GeneCards database, resulting in the intersection of the three to obtain candidate DEGs. GO and KEGG enrichment analyses were performed on the candidate DEGs to analyze the potential cellular functions and molecular signaling pathways affected by the main target genes. The cytohubba plugin was used to screen the top 10 target genes ranked by Degree and further intersected the results of LASSO and Random Forest (RF) to obtain hub genes. The expression analysis of hub genes and the prediction of malignant tumor prognosis were conducted. Furthermore, a pharmacophore model was constructed using PharmMapper. Molecular docking simulations were performed using AutoDockTools 1.5.6 software, and ROC curve analysis was performed to determine the core target. In vitro cell experiments were carried out by selecting appropriate HCC cell lines, treating HCC cells with different concentrations of RSV, or silencing or overexpressing AKR1C3 using lentivirus. CCK-8, clone formation, flow cytometry, scratch experiment, and Transwell were used to measure cancer cell viability, proliferation, migration, invasion, and apoptosis, respectively. Cellular oxygen consumption rate was analyzed using the Seahorse XF24 analyzer. HSA-RSV NPs were prepared, and their characterization and cytotoxicity were evaluated. The biological functional changes of HCC cells after treatment were detected. An HCC subcutaneous xenograft model was established in mice using HepG2 cell lines. HSA-RSV NPs were injected via the tail vein, with a control group set, to observe changes in tumor growth, tumor targeting of NPs, and biological safety. TUNEL, Ki67, and APC-hypoxia probe staining were performed on excised tumor tissue to detect tumor cell proliferation, apoptosis, and hypoxia. Lentivirus was used to silence or overexpress AKR1C3 simultaneously with the injection of HSA-RSV NPs via the tail vein to assess the impact of AKR1C3 on the regulation of HSA-RSV NPs in HCC progression. Bioinformatics analysis revealed that AKR1C3 is an important target gene involved in the regulation of HCC by RSV, which is associated with the prognosis of HCC patients and upregulated in expression. In vitro cell experiments showed that RSV significantly inhibits the respiratory metabolism of HCC cells, suppressing their proliferation, migration, and invasion and promoting apoptosis. Silencing AKR1C3 further enhances the toxicity of RSV towards HCC cells. The characterization and cytotoxicity experiments of nanomaterials demonstrated the successful construction of HSA-RSV NPs, which exhibited stronger inhibitory effects on HCC cells. In vivo, animal experiments further confirmed that targeted downregulation of AKR1C3 by HSA-RSV NPs suppresses the progression of HCC and tumor hypoxia while exhibiting tumor targeting and biological safety. Targeted downregulation of AKR1C3 by HSA-RSV NPs can alleviate HCC tumor hypoxia and inhibit the progression of HCC.
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Metal-organic frameworks (MOFs) show unique advantages in simulating the dynamics and fidelity of natural coordination. Inspired by zinc finger protein, a second linker was introduced to affect the homogeneous MOF system and thus facilitate the emergence of diverse functionalities. Under the systematic identification of 12 MOF species (i.e., metal ions, linkers) and 6 second linkers (trigger), a dissipative system consisting of Co-BDC-NO2 and o-phenylenediamine (oPD) was screened out, which can rapidly and in situ generate a high photothermal complex (η = 36.9%). Meanwhile, both the carboxylation of epigenetic modifications and metal ion (Fe3+, Ni2+, Cu2+, Zn2+, Co2+ and Mn2+) screening were utilized to improve the local coordination environment so that the adaptable Co-MOF growth on the DNA strand was realized. Thus, epigenetic modification information on DNA was converted to an amplified metal ion signal, and then oPD was further introduced to generate bimodal dissipative signals by which a simple, high-sensitivity detection strategy of 5-hydroxymethylcytosine (LOD = 0.02%) and 5-formylcytosine (LOD = 0.025) was developed. The strategy provides one low-cost method (< 0.01 $/sample) for quantifying global epigenetic modifications, which greatly promotes epigenetic modification-based early disease diagnosis. This work also proposes a general heterocoordination design concept for molecular recognition and signal transduction, opening a new MOF-based sensing paradigm.
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Cobalto , DNA , Epigênese Genética , Estruturas Metalorgânicas , Fenilenodiaminas , Estruturas Metalorgânicas/química , Cobalto/química , DNA/química , Fenilenodiaminas/química , 5-Metilcitosina/química , 5-Metilcitosina/análise , 5-Metilcitosina/análogos & derivados , Citosina/química , Citosina/análogos & derivados , Limite de DetecçãoRESUMO
Efficient, mild, and reversible adsorption of nucleic acids onto nanomaterials represents a promising analytical approach for medical diagnosis. However, there is a scarcity of efficient and reversible nucleic acid adsorption nanomaterials. Additionally, the lack of comprehension of the molecular mechanisms governing their interactions poses significant challenges. These issues hinder the rational design and analytical applications of the nanomaterials. Herein, we propose an ultra-efficient nucleic acid affinity nanomaterial based on programmable lanthanide metal-organic frameworks (Ln-MOFs). Through experiments and density functional theory calculations, a rational design guideline for nucleic acid affinity of Ln-MOF was proposed, and a modular and flexible preparation scheme was provided. Then, Er-TPA (terephthalic acid) MOF emerged as the optimal candidate due to its pore size-independent adsorption and desorption capabilities for nucleic acids, enabling ultra-efficient adsorption (about 150% mass ratio) within 1 min. Furthermore, we elucidate the molecular-level mechanisms underlying the Ln-MOF adsorption of single- and double-stranded DNA and G4 structures. The affinity nanomaterial based on Ln-MOF exhibits robust nucleic acid extraction capability (4-fold higher than commercial reagent kits) and enables mild and reversible CRISPR/Cas9 functional regulation. This method holds significant promise for broad application in DNA/RNA liquid biopsy and gene editing, facilitating breakthroughs in analytical chemistry, pharmacy, and medical research.
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DNA , Elementos da Série dos Lantanídeos , Estruturas Metalorgânicas , Estruturas Metalorgânicas/química , Elementos da Série dos Lantanídeos/química , Adsorção , DNA/química , DNA/isolamento & purificação , Ácidos Ftálicos/química , Nanoestruturas/química , Teoria da Densidade Funcional , HumanosRESUMO
Prenylation plays a pivotal role in the diversification and biological activities of natural products. This study presents the functional characterization of TolF, a multiple prenyltransferase from Tolypocladium inflatum. The heterologous expression of tolF in Aspergillus oryzae, coupled with feeding the transformed strain with paxilline, resulted in the production of 20- and 22-prenylpaxilline. Additionally, TolF demonstrated the ability to prenylated the reduced form of paxilline, ß-paxitriol. A related prenyltransferase TerF from Chaunopycnis alba, exhibited similar substrate tolerance and regioselectivity. In vitro enzyme assays using purified recombinant enzymes TolF and TerF confirmed their capacity to catalyze prenylation of paxilline, ß-paxitriol, and terpendole I. Based on previous reports, terpendole I should be considered a native substrate. This work not only enhances our understanding of the molecular basis and product diversity of prenylation reactions in indole diterpene biosynthesis, but also provides insights into the potential of fungal indole diterpene prenyltransferase to alter their position specificities for prenylation. This could be applicable for the synthesis of industrially useful compounds, including bioactive compounds, thereby opening up new avenues for the development of novel biosynthetic strategies and pharmaceuticals. KEY POINTS: ⢠The study characterizes TolF as a multiple prenyltransferase from Tolypocladium inflatum. ⢠TerF from Chaunopycnis alba shows similar substrate tolerance and regioselectivity compared to TolF. ⢠The research offers insights into the potential applications of fungal indole diterpene prenyltransferases.
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Dimetilaliltranstransferase , Diterpenos , Hypocreales , Dimetilaliltranstransferase/metabolismo , Prenilação , Indóis/metabolismo , Diterpenos/metabolismo , Especificidade por SubstratoRESUMO
The application of deep learning methods, specifically the utilization of Large Language Models (LLMs), in the field of plant biology holds significant promise for generating novel knowledge on plant cell systems. The LLM framework exhibits exceptional potential, particularly with the development of Protein Language Models (PLMs), allowing for in-depth analyses of nucleic acid and protein sequences. This analytical capacity facilitates the discernment of intricate patterns and relationships within biological data, encompassing multi-scale information within DNA or protein sequences. The contribution of PLMs extends beyond mere sequence patterns and structure--function recognition; it also supports advancements in genetic improvements for agriculture. The integration of deep learning approaches into the domain of plant sciences offers opportunities for major breakthroughs in basic research across multi-scale plant traits. Consequently, the strategic application of deep learning methodologies, particularly leveraging the potential of LLMs, will undoubtedly play a pivotal role in advancing plant sciences, plant production, plant uses and propelling the trajectory toward sustainable agroecological and agro-food transitions.
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Aprendizado Profundo , Processamento de Linguagem Natural , Plantas , Plantas/genética , Plantas/metabolismoRESUMO
Exosomes are vital mediators for intercellular communications in the tumor microenvironment to accelerate colon cancer progression. Leucine-rich repeat-containing 8A (LRRC8A), the core component of the volume-regulated anion channel, is closely associated with acquiring heterogeneity for tumor cells. However, the role of LRRC8A in the exosomes remains largely unknown. Here, we reported that LRRC8A was one of the compositions in the exosomes released from colon cancer HCT116 cells. Down-regulation of LRRC8A proteins inhibited ex vivo cell growth and induced apoptosis. Consistently, chloride channel blockers DCPIB and NPPB inhibited cell growth and induced cell apoptosis in a time or concentration-dependent manner. Interestingly, the total amounts and proportions of different diameter exosomes released in 6â h were not altered by the treatment of DCPIB and NPPB in HCT116 cells. In contrast with the inhibition of LRRC8A, overexpression of LRRC8A proteins in HCT116 cells released significantly more distinct populations of exosomes. Importantly, the switches of ratios for exosomes in a hypotonic challenge were eliminated by DCPIB treatment. Collectively, our results uncovered that LRRC8A proteins were responsible for the exosome generation and sorted into exosomes for monitoring the volume regulation.
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Neoplasias do Colo , Exossomos , Humanos , Proteínas de Membrana/metabolismo , Exossomos/genética , Exossomos/metabolismo , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Proteínas de Repetições Ricas em Leucina , Microambiente TumoralRESUMO
BACKGROUND: MicroRNA (miRNA) which can act as post-transcriptional regulators of mRNAs via base-pairing with complementary sequences within mRNAs is involved in processes of the complex interaction between immune system and tumors. In this research, we elucidated the profiles of miRNAs and target mRNAs expression and their associations with the phenotypic hallmarks of colorectal cancers (CRC) by integrating transcriptomic, immunophenotype, methylation, mutation and survival data. RESULTS: We conducted the analysis of differential miRNA/mRNA expression profile by GEO, TCGA and GTEx databases and the correlation between miRNA and targeted mRNA by miRTarBase and TarBase. Then we detected using qRT-PCR and validated the diagnostic value of miRNA-mRNA regulator pairs by the ROC, calibration curve and DCA. Phenotypic hallmarks of regulatory pairs including tumor-infiltrating lymphocytes, tumor microenvironment, tumor mutation burden, global methylation and gene mutation were also described. The expression levels of miRNAs and target mRNAs were detected in 80 paired colon tissue samples. Ultimately, we picked up two pivotal regulatory pairs (miR-139-5p/ STC1 and miR-20a-5p/ FGL2) and verified the diagnostic value of the complex model which is the combination of 4 signatures above-mentioned in 3 testing GEO datasets and an external validation cohort. CONCLUSIONS: We found that 2 miRNAs by targeting 2 metastasis-related mRNAs were correlated with tumor-infiltrating macrophages, HRAS, and BRAF gene mutation status. Our results established the diagnostic model containing 2 miRNAs and their respective targeted mRNAs to distinguish CRCs and normal controls and displayed their complex roles in CRC pathogenesis especially tumor immunity.
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Neoplasias Colorretais , MicroRNAs , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Regulação Neoplásica da Expressão Gênica , Perfilação da Expressão Gênica/métodos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Redes Reguladoras de Genes , Microambiente Tumoral/genética , Fibrinogênio/genética , Fibrinogênio/metabolismoRESUMO
Three-dimensional (3D) cages in the mesopore regime (2-50 nm) assembled from molecular building blocks are highly desirable in biological applications; however, their synthesis in crystalline form is quite challenging, as well as their structure characterization. Here, we report the synthesis of extremely large 3D cages in MOF crystals, with internal cage sizes of 6.9, and 8.5 nm in MOF-929; 9.3 and 11.4 nm in MOF-939, in cubic unit cells, a = 17.4 and 22.8 nm, respectively. These cages are constructed from relatively short organic linkers with the lengths of 0.85 and 1.3 nm, where the influence from molecular motion is minimized, thus favoring their crystallization. A 0.45 nm linker length elongation leads to a maximum 2.9 nm increase in cage size, giving a supreme efficiency in cage expansion. The spatial arrangements of these 3D cages were visualized by both X-ray diffraction and transmission electron microscopy. The efforts to obtain these cages in crystals pushed forward the size boundary for the construction of 3D cages from molecules and also exploited the limit of the area in space possibly supported per chemical bond, where the expansion efficiencies of the cages were found to play a critical role. These extremely large 3D cages in MOFs were useful in the complete extraction of long nucleic acid, such as total RNA and plasmid from aqueous solution.
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The replication of HBV in hepatocytes can be effectively inhibited by lifelong antiviral therapy. Because of the long-term presence of HBV reservoirs, the virus rebound frequently occurs once the treatment is stopped, which poses a considerable obstacle to the complete removal of the virus. In terms of gene composition, regulation of B cell action and function, CXCR5+ CD8+ T cells are similar to CXCR5+ CD4+ T follicular helper cells, while these cells are characterized by elevated programmed cell death 1 and cytotoxic-related proteins. CXCR5+ CD8+ T cells are strongly associated with progression in inflammatory and autoimmune diseases. In addition, CXCR5 expression on the surface of CD8+ T cells is mostly an indicator of memory stem cell-like failure in progenitor cells in cancer that are more responsive to immune checkpoint blocking therapy. Furthermore, the phenomena have also been demonstrated in some viral infections, highlighting the duality of the cellular immune response of CXCR5+ CD8+ T cells. This mini-review will focus on the function of CXCR5+ CD8+ T cells in HBV infection and discuss the function of these CD8+ T cells and the potential of associated co-stimulators or cytokines in HBV therapeutic strategies.
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Vírus da Hepatite B , Hepatite B , Humanos , Linfócitos T CD8-Positivos , Citocinas/metabolismo , Linfócitos B , Hepatite B/complicações , Receptores CXCR5/genética , Receptores CXCR5/metabolismoRESUMO
AIMS: This study investigated the association between serum calcium levels and the prevalence of T2D using a cross-sectional study and Mendelian randomization analysis. METHODS: Cross-sectional data were obtained from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018. Serum calcium levels were divided into three groups (low, medium and high groups) according to the tertiles. Logistic regression was used to estimate the association between serum calcium levels and T2D prevalence. Instrumental variables for serum calcium levels were obtained from the UK Biobank and a two-sample MR analysis was performed to examine the causal relationship between genetically predicted serum calcium levels and the risk of T2D. RESULTS: A total of 39,645 participants were available for cross-sectional analysis. After adjusting for covariates, participants in the high serum calcium group had significantly higher odds of T2D (OR = 1.18, 95% CI = 1.07, 1.30, p = 0.001) than those in the moderate group. Restricted cubic spline plots showed a J-shaped curve relationship between serum calcium level and prevalence of T2D. Consistently, Mendelian randomization analysis showed that higher genetically predicted serum calcium levels were causally associated with a higher risk of T2D (OR = 1.16, 95% CI: 1.01, 1.33, p = 0.031). CONCLUSIONS: The results of this study suggest that higher serum calcium levels are causally associated with a higher risk of T2D. Further studies are needed to clarify whether intervening in high serum calcium could reduce the risk of T2D.
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Diabetes Mellitus Tipo 2 , Humanos , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Estudos Transversais , Cálcio , Inquéritos Nutricionais , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Estudo de Associação Genômica AmplaRESUMO
Iodide (I-) is crucial to thyroid function, and its regulation in thyrocytes involves ion transporters and reactive oxygen species (ROS). However, the extent of 2Cl-/H+ exchanger (ClC-3) involvement in the iodide (I-) efflux from thyrocytes remains unclear. Therefore, we examined the effects of ClC-3 on I- efflux. ClC-3 expression was found to significantly alter the serum TT3 and TT4 concentrations in mice. We further found that excess I- stimulation affected ClC-3 expression, distribution, and I- efflux in FRTL-5 cells. Immunofluorescence analyses indicated that ClC-3 mainly accumulated in the cell membrane and co-localized with ß-tubulins after 24â h of excess I- treatment, and that this process depended on ROS production. Thus, ClC-3 may be involved in I- efflux at the apical pole of thyrocytes via excess I--induced ROS production and ß-tubulin polymerization. Our results reveal novel insights into the role of ClC-3 in I- transport and thyroid function.
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Canais de Cloreto/metabolismo , Células Epiteliais da Tireoide , Animais , Transporte Biológico , Iodetos , Camundongos , Prótons , Espécies Reativas de Oxigênio , Tubulina (Proteína)RESUMO
BACKGROUND: Environmental noise is becoming increasingly recognized as an urgent public health problem, but the quality of current studies needs to be assessed. To evaluate the significance, validity and potential biases of the associations between environmental noise exposure and health outcomes. METHODS: We conducted an umbrella review of the evidence across meta-analyses of environmental noise exposure and any health outcomes. A systematic search was done until November 2021. PubMed, Cochrane, Scopus, Web of Science, Embase and references of eligible studies were searched. Quality was assessed by AMSTAR and Grading of Recommendations, Assessment, Development and Evaluation (GRADE). RESULTS: Of the 31 unique health outcomes identified in 23 systematic reviews and meta-analyses, environmental noise exposure was more likely to result in a series of adverse outcomes. Five percent were moderate in methodology quality, the rest were low to very low and the majority of GRADE evidence was graded as low or even lower. The group with occupational noise exposure had the largest risk increment of speech frequency [relative risk (RR): 6.68; 95% confidence interval (CI): 3.41-13.07] and high-frequency (RR: 4.46; 95% CI: 2.80-7.11) noise-induced hearing loss. High noise exposure from different sources was associated with an increased risk of cardiovascular disease (34%) and its mortality (12%), elevated blood pressure (58-72%), diabetes (23%) and adverse reproductive outcomes (22-43%). In addition, the dose-response relationship revealed that the risk of diabetes, ischemic heart disease (IHD), cardiovascular (CV) mortality, stroke, anxiety and depression increases with increasing noise exposure. CONCLUSIONS: Adverse associations were found for CV disease and mortality, diabetes, hearing impairment, neurological disorders and adverse reproductive outcomes with environmental noise exposure in humans, especially occupational noise. The studies mostly showed low quality and more high-quality longitudinal study designs are needed for further validation in the future.
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Doenças Cardiovasculares , Exposição Ocupacional , Humanos , Estudos Longitudinais , Revisões Sistemáticas como Assunto , Exposição Ambiental/efeitos adversos , Ruído/efeitos adversos , Exposição Ocupacional/efeitos adversos , Doenças Cardiovasculares/etiologiaRESUMO
BACKGROUND AND AIMS: Myofibroblasts play a pivotal role in the development and progression of HCC. Here, we aimed to explore the role and mechanism of myofibroblast Musashi RNA binding protein 2 (MSI2) in HCC progression. APPROACH AND RESULTS: Myofibroblast infiltration and collagen deposition were detected and assessed in the tissues from 117 patients with HCC. Transgenic mice (Msi2ΔCol1a1 ) with floxed Msi2 allele and collagen type I alpha 1 chain (Col1a1)-ligand inducible Cre recombinases (CreER) were constructed to generate a myofibroblast-specific Msi2 knockout model. Mouse HCC cells were orthotopically transplanted into the Msi2ΔCol1a1 or the control mice (Msi2F/F ). We found that the deposition of collagen fibers, the main product of myofibroblasts, predicted a poor prognosis for HCC; meanwhile, we detected high MSI2 expression in the peritumoral infiltrated myofibroblasts. Conditional deletion of Msi2 in myofibroblasts significantly inhibited the growth of orthotopically implanted HCC, reduced both intrahepatic and lung metastasis, and prolonged the overall survival of tumor-bearing mice (P = 0.002). In vitro analysis demonstrated that myofibroblasts promoted cell proliferation, invasion, and epithelial-mesenchymal transformation of HCC cells, whereas Msi2 deletion in myofibroblasts reversed these effects. Mechanically, Msi2 knockout decreased myofibroblast-derived IL-6 and IL-11 secretion by inhibiting the extracellular signal-regulated kinase 1/2 pathway, and thus attenuated the cancer stem cell-promoting effect of myofibroblasts. Interestingly, we found that the simultaneous knockout of Msi2 in myofibroblasts and knockdown of Msi2 in HCC cells could not further attenuate the implanted HCC progression. CONCLUSIONS: Myofibroblast-specific Msi2 knockout abrogated the tumor-promoting function of myofibroblasts and inhibited HCC progression in mouse models. Targeting myofibroblast MSI2 expression may therefore prove to be a therapeutic strategy for HCC treatment in the future.
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Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Miofibroblastos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Técnicas de Silenciamento de Genes , Humanos , Fígado/patologia , Camundongos , Camundongos Knockout , Miofibroblastos/patologia , Proteínas de Ligação a RNA/genéticaRESUMO
Food safety is a global problem, and methods to reliably and sensitivity detect contaminants could be transformative. Herein, we synthesized a novel Porphyrin NanoMoFs (NanoPCN-223(Fe)) with excellent dispersion and peroxidase-like activity. The Km value of NanoPCN-223(Fe) was 2.0 × 10-4 M toward the H2O2 substrate during the catalytic process. We use the NanoPCN-223(Fe) to construct an enhanced dispersion MOF-linked immunosorbent assay (Ed-MOFLISA) to sensitive detect AFB1 in milk. The optimized Ed-MOFLISA displayed a broad quantitative range from 0.05 to 10 ng/mL and a limit of detection of 0.003 ng/mL. Spiked peanut and soy milk recovery ranged from 91.22% to 97.63%. Intra-assay and inter-assay coefficient of variation values ranged from 0.78 to 3.85%, demonstrating the outstanding reproducibility and accuracy of Ed-MOFLISA. We applied the Ed-MOFLISA assay to test the milk samples, demonstrating its potential use for monitoring food quality.
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Aflatoxina B1 , Porfirinas , Aflatoxina B1/análise , Ensaio de Imunoadsorção Enzimática , Contaminação de Alimentos/análise , Peróxido de Hidrogênio , Imunoadsorventes , Limite de Detecção , Reprodutibilidade dos TestesRESUMO
The tumor suppressor gene phosphatase and tensin homolog (PTEN) in PI3K/Akt/mTOR pathway is essential in inhibiting tumor growth and metastasis. However, whether the mutation of PTEN gene could induce tumorigenesis and impact the treatment of gastric cancer is still unclear. The purpose of the study was to investigate the combined treatment of gastric tumorigenesis using Rapamycin and Fluorouracil (5-Fu) through interfering with the Akt/mTOR pathway in a mouse model with PTEN conditional deletion. Three groups of mice were exposed for 5 days to Rapamycin and 5-Fu separately and together. The gene expression of the Akt/mTOR pathway, the protein expression of caspase-3 and p-Akt, p-S6K and p-4EBP1, and the pathological changes in stomachs were analyzed. Our study demonstrates that the conditional PTEN deletion in the cells of glandular stomach induces hyperplastic gastric tumors in mice. The combined Rapamycin administration with 5-Fu resulted in better outcomes than their separate administration for the treatment of gastric cancer by inhibiting the mTOR signal pathway. Our study indicates that Rapamycin has a synergistic interaction with chemotherapeutic 5-Fu, and demonstrates a potential therapeutic combination treatment on glandular stomach tumor with PTEN functional absence or aberrantly activated Akt/mTOR pathway. It provides important insights into the inhibition of the Akt/mTOR pathway in gastric cancer clinical therapy.
Assuntos
Neoplasias Gástricas , Animais , Linhagem Celular Tumoral , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Camundongos , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologiaRESUMO
INTRODUCTION AND OBJECTIVES: Circular RNA (circRNA) has attracted extensive attention in studies related to the malignant progression of cancer, including hepatocellular carcinoma (HCC). Therefore, its molecular mechanism in HCC needs to be further explored. MATERIALS AND METHODS: The expression levels of circ_0008285, microRNA (miR)-384 and ribonucleotide reductase subunit M2 (RRM2) mRNA were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation was analyzed using cell counting kit-8 assay and 5-ethynyl-2'-deoxyuridine assay, cell apoptosis was analyzed by flow cytometry, and cell migration and invasion were detected by transwell assay. Protein level was detected by western blot. The relationships between miR-384 and circ_0008285 or RRM2 were predicted by bioinformatics software and validated by dual luciferase reporter assay and RNA immunoprecipitation (RIP) assay. RESULTS: Circ_0008285 expression is elevated to HCC tissues and cell lines. Silencing of circ_0008285 inhibited the proliferation, migration and invasion of HCC cells but accelerated cell apoptosis in vitro and impeded HCC tumorigenesis in vivo. Mechanistically, circ_0008285 directly interacted with miR-384, and miR-384 silencing attenuated the effects of circ_0008285 interference on cell proliferation, migration, invasion, and apoptosis. RRM2 was a direct target of miR-384, and RRM2 overexpression reversed the effects of miR-384 overexpression on cell proliferation, migration, invasion, and apoptosis. In addition, circ_0008285 regulated RRM2 expression by sponging miR-384. CONCLUSION: In this study, circ_0008285 could promote the malignant biological behaviors of HCC cells through miR-384/RRM2 axis and has the potential to become a therapeutic target for HCC, providing a new idea for targeted therapy of HCC.