ABSTRACT
Porcine deltacoronavirus (PDCoV) is an emerging enteropathogenic coronavirus. It causes mortality in neonatal piglets and is of growing concern because of its broad host range, including humans. To date, the mechanism of PDCoV infection remains poorly understood. Here, based on a genome-wide CRISPR screen of PDCoV-infected cells, we found that HSP90AB1 (heat shock protein 90 alpha family class B1) promotes PDCoV infection. Knockdown or KO of HSP90AB1 in LLC-PK cells resulted in a significantly suppressed PDCoV infection. Infected cells treated with HSP90 inhibitors 17-AAG and VER-82576 also showed a significantly suppressed PDCoV infection, although KW-2478, which does not affect the ATPase activity of HSP90AB1, had no effect on PDCoV infection. We found that HSP90AB1 interacts with the N, NS7, and NSP10 proteins of PDCoV. We further evaluated the interaction between N and HSP90AB1 and found that the C-tail domain of the N protein is the HSP90AB1-interacting domain. Further studies showed that HSP90AB1 protects N protein from degradation via the proteasome pathway. In summary, our results reveal a key role for HSP90AB1 in the mechanism of PDCoV infection and contribute to provide new host targets for PDCoV antiviral research.
Subject(s)
HSP90 Heat-Shock Proteins , Virus Replication , Animals , Humans , Deltacoronavirus , Host Specificity , HSP90 Heat-Shock Proteins/genetics , HSP90 Heat-Shock Proteins/metabolism , Swine , HEK293 CellsABSTRACT
It is widely believed that the discrete breather (DB) can only be created when the nonlinearity is strong in nonlinear systems. However, we here establish that this belief is incorrect. In this work, we systemically investigate the generation of DBs induced by coupling of the defects and nonlinearity for Bose-Einstein condensates in dissipative optical lattices. The results show that, only in a clean lattice is strong nonlinearity a necessary condition for generating of DB; whereas, if the lattice has a defect, the DBs can also be discovered even in weak nonlinearity, and its generation turns out to be controllable. In addition, we further reveal a critical interval of the defect in weak nonlinearity, within which DBs can be found, while outside DBs do not exist. Furthermore, we also explore the impact of multiple defects on the generation of DBs, and analyze the underlying physical mechanisms of these interesting phenomena. The results not only have the potential to be used for more precise engineering in the DB experiments, but also suggest that the DB may be ubiquitous since the defects and dissipation are unavoidable in real physics.
ABSTRACT
The ability to detect the polarization information of light is often crucial for various applications in optical systems. However, conventional polarization-sensitive photodetectors struggle to simultaneously achieve a wide band coverage and high-precision detection, severely hindering the development of polarization detectors. In this study, a reflective metasurface with full-Stokes detection capabilities over a wide range is proposed. It integrates four linear polarization filters and two circular polarization filters operating in the near-infrared region. By dynamically adjusting the refractive index of the liquid crystal covering the detector surface, high performance full-Stokes parameter detection can be achieved between 730-770 nm with detection error below 0.07. Therefore, this study provides a design approach for the potential application of Stokes polarization detection over a broadband spectrum. .
ABSTRACT
Dioxin(-like) exposures are linked to adverse health effects, including cancer. However, metabolic alterations induced by these chemicals remain largely unknown. Beyond known dioxin(-like) compounds, we leveraged a chemical-wide approach to assess chlorinated co-exposures and parent compound products [termed dioxin(-like)-related compounds] among 137 occupational workers. Endogenous metabolites were profiled by untargeted metabolomics, namely, reversed-phase chromatography with negative electrospray ionization (C18-negative) and hydrophilic interaction liquid chromatography with positive electrospray ionization (HILIC-positive). We performed a metabolome-wide association study to select dioxin(-like) associated metabolic features using a 20% false discovery rate threshold. Metabolic features were then characterized by pathway enrichment analyses. There are no significant features associated with polychlorinated dibenzo-p-dioxins (PCDDs), a subgroup of known dioxin(-like) compounds. However, 3,110 C18-negative and 2,894 HILIC-positive features were associated with at least one of the PCDD-related compounds. Abundant metabolic changes were also observed for polychlorinated dibenzofuran-related and polychlorinated biphenyl-related compounds. These metabolic features were primarily enriched in pathways of amino acids, lipid and fatty acids, carbohydrates, cofactors, and nucleotides. Our study highlights the potential of chemical-wide analysis for comprehensive exposure assessment beyond targeted chemicals. Coupled with advanced endogenous metabolomics, this approach allows for an in-depth exploration of metabolic alterations induced by environmental chemicals.
Subject(s)
Dioxins , Neoplasms , Polychlorinated Biphenyls , Polychlorinated Dibenzodioxins , Humans , Polychlorinated Biphenyls/analysis , Polychlorinated Biphenyls/chemistry , MetabolomeABSTRACT
In the modern "omics" era, measurement of the human exposome is a critical missing link between genetic drivers and disease outcomes. High-resolution mass spectrometry (HRMS), routinely used in proteomics and metabolomics, has emerged as a leading technology to broadly profile chemical exposure agents and related biomolecules for accurate mass measurement, high sensitivity, rapid data acquisition, and increased resolution of chemical space. Non-targeted approaches are increasingly accessible, supporting a shift from conventional hypothesis-driven, quantitation-centric targeted analyses toward data-driven, hypothesis-generating chemical exposome-wide profiling. However, HRMS-based exposomics encounters unique challenges. New analytical and computational infrastructures are needed to expand the analysis coverage through streamlined, scalable, and harmonized workflows and data pipelines that permit longitudinal chemical exposome tracking, retrospective validation, and multi-omics integration for meaningful health-oriented inferences. In this article, we survey the literature on state-of-the-art HRMS-based technologies, review current analytical workflows and informatic pipelines, and provide an up-to-date reference on exposomic approaches for chemists, toxicologists, epidemiologists, care providers, and stakeholders in health sciences and medicine. We propose efforts to benchmark fit-for-purpose platforms for expanding coverage of chemical space, including gas/liquid chromatography-HRMS (GC-HRMS and LC-HRMS), and discuss opportunities, challenges, and strategies to advance the burgeoning field of the exposome.
Subject(s)
Mass Spectrometry , Humans , Mass Spectrometry/methods , Exposome , Metabolomics , Proteomics/methods , Environmental ExposureABSTRACT
Parkinson's disease (PD), a neurodegenerative disorder with an unknown etiology, is primarily characterized by the degeneration of dopamine (DA) neurons. The prevalence of PD has experienced a significant surge in recent years. The unidentified etiology poses limitations to the development of effective therapeutic interventions for this condition. Helicobacter pylori (H. pylori) infection has affected approximately half of the global population. Mounting evidences suggest that H. pylori infection plays an important role in PD through various mechanisms. The autotoxin produced by H. pylori induces pro-inflammatory cytokines release, thereby facilitating the occurrence of central inflammation that leads to neuronal damage. Simultaneously, H. pylori disrupts the equilibrium of gastrointestinal microbiota with an overgrowth of bacteria in the small intestinal known as small intestinal bacterial overgrowth (SIBO). This dysbiosis of the gut flora influences the central nervous system (CNS) through microbiome-gut-brain axis. Moreover, SIBO hampers levodopa absorption and affects its therapeutic efficacy in the treatment of PD. Also, H. pylori promotes the production of defensins to regulate the permeability of the blood-brain barrier, facilitating the entry of harmful factors into the CNS. In addition, H. pylori has been found to induce gastroparesis, resulting in a prolonged transit time for levodopa to reach the small intestine. H. pylori may exploit levodopa to facilitate its own growth and proliferation, or it can inflict damage to the gastrointestinal mucosa, leading to gastrointestinal ulcers and impeding levodopa absorption. Here, this review focused on the role of H. pylori infection in PD from etiology, pathogenesis to levodopa bioavailability.
ABSTRACT
Metal exposure has been suggested as a possible environmental risk factor for Parkinson disease (PD). We searched the PubMed, EMBASE, and Cochrane databases to systematically review the literature on the relationship between metal exposure and PD risk and to examine the overall quality of each study and the exposure assessment method. A total of 83 case-control studies and 5 cohort studies published during the period 1963-July 2021 were included, of which 73 were graded as being of low or moderate overall quality. Investigators in 69 studies adopted self-reported exposure and biomonitoring after disease diagnosis for exposure assessment approaches. The meta-analyses showed that concentrations of copper and iron in serum and concentrations of zinc in either serum or plasma were lower, while concentrations of magnesium in CSF and zinc in hair were higher, among PD cases as compared with controls. Cumulative lead levels in bone were found to be associated with increased risk of PD. We did not find associations between other metals and PD. The current level of evidence for associations between metals and PD risk is limited, as biases from methodological limitations cannot be ruled out. High-quality studies assessing metal levels before disease onset are needed to improve our understanding of the role of metals in the etiology of PD.
Subject(s)
Metals , Parkinson Disease , Humans , Cohort Studies , Copper/adverse effects , Copper/blood , Lead/adverse effects , Lead/blood , Parkinson Disease/epidemiology , Parkinson Disease/etiology , Zinc/adverse effects , Zinc/blood , Metals/adverse effects , Metals/bloodABSTRACT
INTRODUCTION: Lipopolysaccharide (LPS) is the outer membrane component of Gram-negative bacteria. LPS-binding protein (LBP) is an acute-phase reactant that mediates immune responses triggered by LPS and has been used as a blood marker for LPS. LBP has recently been indicated to be associated with Parkinson's disease (PD) in small-scale retrospective case-control studies. We aimed to investigate the association between LBP blood levels with PD risk in a nested case-control study within a large European prospective cohort. METHODS: A total of 352 incident PD cases (55% males) were identified and one control per case was selected, matched by age at recruitment, sex and study center. LBP levels in plasma collected at recruitment, which was on average 7.8 years before diagnosis of the cases, were analyzed by enzyme linked immunosorbent assay. Odds ratios (ORs) were estimated for one unit increase of the natural log of LBP levels and PD incidence by conditional logistic regression. RESULTS: Plasma LBP levels were higher in prospective PD cases compared to controls (median (interquartile range) 26.9 (18.1-41.0) vs. 24.7 (16.6-38.4) µg/ml). The OR for PD incidence per one unit increase of log LBP was elevated (1.46, 95% CI 0.98-2.19). This association was more pronounced among women (OR 2.68, 95% CI 1.40-5.13) and overweight/obese subjects (OR 1.54, 95% CI 1.09-2.18). CONCLUSION: The findings suggest that higher plasma LBP levels may be associated with an increased risk of PD and may thus pinpoint to a potential role of endotoxemia in the pathogenesis of PD, particularly in women and overweight/obese individuals.
Subject(s)
Lipopolysaccharides , Parkinson Disease , Male , Humans , Female , Case-Control Studies , Overweight , Parkinson Disease/epidemiology , Prospective Studies , Retrospective Studies , Acute-Phase ProteinsABSTRACT
BACKGROUND: Metals have been postulated as environmental concerns in the etiology of Parkinson's disease (PD), but metal levels are typically measured after diagnosis, which might be subject to reverse causality. OBJECTIVE: The aim of this study was to investigate the association between prediagnostic blood metal levels and PD risk. METHODS: A case-control study was nested in a prospective European cohort, using erythrocyte samples collected before PD diagnosis. RESULTS: Most assessed metals were not associated with PD risk. Cadmium has a suggestive negative association with PD (odds ratio [95% confidence interval] for the highest quartile, 0.70 [0.42-1.17]), which diminished among never smokers. Among current smokers only, lead was associated with decreased PD risk (0.06 [0.01-0.35]), whereas arsenic showed associations toward an increased PD risk (1.85 [0.45-7.93]). CONCLUSIONS: We observe no strong evidence to support a role of metals in the development of PD. In particular, smoking may confound the association with tobacco-derived metals. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Subject(s)
Parkinson Disease , Humans , Parkinson Disease/diagnosis , Parkinson Disease/epidemiology , Parkinson Disease/etiology , Prospective Studies , Case-Control Studies , CausalityABSTRACT
China's marine satellite infrared radiometer SST remote sensing observations began relatively late. Thus, it is essential to evaluate and correct the SST observation data of the Ocean Color and Temperature Scanner (COCTS) onboard the China HY-1C satellite in the Southeast Asia seas. We conducted a quality assessment and correction work on the SST of the China COCTS/HY-1C in Southeast Asian seas based on multisource satellite SST data and temperature data measured by Argo buoys. The accuracy evaluation results of the COCTS SST indicated that the bias, Std, and RMSE of the daytime SST data for HY-1C were -0.73 °C, 1.38 °C, and 1.56 °C, respectively, while the bias, Std, and RMSE of the nighttime SST data were -0.95 °C, 1.57 °C, and 1.83 °C, respectively. The COCTS SST accuracy was significantly lower than that of other infrared radiometers. The effect of the COCTS SST zonal correction was most significant, with the Std and RMSE approaching 1 °C. After correction, the RMSE of the daytime SST and nighttime SST data decreased by 32.52% and 42.04%, respectively.
ABSTRACT
Transmissible gastroenteritis virus (TGEV) is an important swine enteric coronavirus causing viral diarrhea in pigs of all ages. Currently, the development of antiviral agents targeting host proteins to combat viral infection has received great attention. The heat shock protein 90 (HSP90) is a critical host factor and has important regulatory effects on the infection of various viruses. However, its roles in porcine coronavirus infection remain unclear. In this study, the effect of HSP90 on TGEV infection was evaluated. In addition, the influence of its inhibitor VER-82576 on proinflammatory cytokine (IL-6, IL-12, TNF-α, CXCL10, and CXCL11) production induced by TGEV infection was further analyzed. The results showed that the knockdown of HSP90AB1 and HSP90 inhibitor VER-82576 treatment resulted in a reduction in TGEV M gene mRNA levels, the N protein level, and virus titers in a dose-dependent manner, while the knockdown of HSP90AA1 and KW-2478 treatment had no significant effect on TGEV infection. A time-of-addition assay indicated that the inhibitory effect of VER-82576 on TGEV infection mainly occurred at the early stage of viral replication. Moreover, the TGEV-induced upregulation of proinflammatory cytokine (IL-6, IL-12, TNF-α, CXCL10, and CXCL11) expression was significantly inhibited by VER-82576. In summary, these findings indicated that HSP90AB1 is a host factor enhancing TGEV infection, and the HSP90 inhibitor VER-82576 could reduce TGEV infection and proinflammatory cytokine production, providing a new perspective for TGEV antiviral drug target design.
Subject(s)
Gastroenteritis, Transmissible, of Swine , Transmissible gastroenteritis virus , Swine , Animals , Transmissible gastroenteritis virus/genetics , Gastroenteritis, Transmissible, of Swine/genetics , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/pharmacology , Interleukin-6/pharmacology , Cytokines/genetics , Cytokines/pharmacology , Interleukin-12/pharmacologyABSTRACT
OBJECTIVES: To determine the performance of machine learning (ML)-based ultrasomic analysis of subacromial impingement syndrome (SIS) stage evaluation. METHODS: In this retrospective study, 324 patients with SIS were included. The SIS stage was evaluated with a Neer test. Regions of the musculi supraspinatus were manually segmented by an experienced radiologist. Then, 5936 ultrasomic features were extracted from the Ultrasomics Platform software. The Wilcoxon test was used to identify differentially expressed radiomic features. Then, these differentially expressed features were submitted to the least absolute shrinkage and selection operator (LASSO) for model construction. The area under the curve (AUC) of the receiver operating characteristic was used to evaluate the performance of the ultrasonic model for SIS stage evaluation. RESULTS: Finally, a total of 223 early-stage and 101 advanced-stage SIS patients were randomly divided into a training cohort (n = 227) and a validation cohort (n = 97). After feature-dimensionality reduction, a total of 28 radiomic features were submitted to LASSO analysis. Finally, 10 radiomic features were finally included for radiomics model construction. The AUC results showed that the ultrasomics model had moderate performance for SIS stage evaluation in both the training cohort (AUC = 0.839) and the validation cohort (AUC = 0.789). CONCLUSIONS: ML-derived ultrasomics can discriminate the SIS stage in patients with SIS. This noninvasive and low-cost approach may be helpful in the preliminary screening of shoulder pain.
Subject(s)
Shoulder Impingement Syndrome , Area Under Curve , Humans , Machine Learning , ROC Curve , Retrospective Studies , Shoulder Impingement Syndrome/diagnostic imagingABSTRACT
PDCoV is an emerging enteropathogenic coronavirus that mainly causes acute diarrhea in piglets, seriously affecting pig breeding industries worldwide. To date, the molecular mechanisms of PDCoV-induced immune and inflammatory responses or host responses in LLC-PK cells in vitro are not well understood. HSP90 plays important roles in various viral infections. In this study, HSP90AB1 knockout cells (HSP90AB1KO) were constructed and a comparative transcriptomic analysis between PDCoV-infected HSP90AB1WT and HSP90AB1KO cells was conducted using RNA sequencing to explore the effect of HSP90AB1 on PDCoV infection. A total of 1295 and 3746 differentially expressed genes (DEGs) were identified in PDCoV-infected HSP90AB1WT and HSP90AB1KO cells, respectively. Moreover, most of the significantly enriched pathways were related to immune and inflammatory response-associated pathways upon PDCoV infection. The DEGs enriched in NF-κB pathways were specifically detected in HSP90AB1WT cells, and NF-κB inhibitors JSH-23, SC75741 and QNZ treatment reduced PDCoV infection. Further research revealed most cytokines associated with immune and inflammatory responses were upregulated during PDCoV infection. Knockout of HSP90AB1 altered the upregulated levels of some cytokines. Taken together, our findings provide new insights into the host response to PDCoV infection from the transcriptome perspective, which will contribute to illustrating the molecular basis of the interaction between PDCoV and HSP90AB1.
Subject(s)
Coronavirus Infections/veterinary , Deltacoronavirus , Gene Expression Profiling , HSP90 Heat-Shock Proteins/genetics , Immunity/genetics , Swine Diseases/etiology , Transcriptome , Animals , Computational Biology/methods , Disease Susceptibility , Gene Knockdown Techniques , Gene Ontology , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , NF-kappa B/metabolism , SwineABSTRACT
OBJECTIVE: This study investigated the role of radiomics in evaluating the alterations of oncogenic signaling pathways in head and neck cancer. METHODS: Radiomics features were extracted from 106 enhanced computed tomography images with head and neck squamous cell carcinoma. Support vector machine-recursive feature elimination was used for feature selection. Support vector machine algorithm was used to develop radiomics scores to predict genetic alterations in oncogenic signaling pathways. The performance was evaluated by the area under the curve (AUC) of the receiver operating characteristic curve. RESULTS: The alterations of the Cell Cycle, HIPPO, NOTCH, PI3K, RTK RAS, and TP53 signaling pathways were predicted by radiomics scores. The AUC values of the training cohort were 0.94, 0.91, 0.94, 0.93, 0.87, and 0.93, respectively. The AUC values of the validation cohort were all greater than 0.7. CONCLUSIONS: Radiogenomics is a new method for noninvasive acquisition of tumor molecular information at the genetic level.
Subject(s)
Head and Neck Neoplasms/diagnostic imaging , Radiographic Image Interpretation, Computer-Assisted/methods , Signal Transduction/genetics , Squamous Cell Carcinoma of Head and Neck/diagnostic imaging , Tomography, X-Ray Computed/methods , Adult , Aged , Aged, 80 and over , Cohort Studies , Female , Head and Neck Neoplasms/genetics , Humans , Imaging Genomics/methods , Male , Middle Aged , Squamous Cell Carcinoma of Head and Neck/genetics , Support Vector Machine , Young AdultABSTRACT
BACKGROUND: The molecular biomarkers of breast ductal carcinoma in situ (DCIS) have important guiding significance for individualized precision treatment. This study was intended to explore the significance of radiomics based on ultrasound images to predict the expression of molecular biomarkers of mass type of DCIS. METHODS: 116 patients with mass type of DCIS were included in this retrospective study. The radiomics features were extracted based on ultrasound images. According to the ratio of 7:3, the data sets of molecular biomarkers were split into training set and test set. The radiomics models were developed to predict the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), Ki67, p16, and p53 by using combination of multiple feature selection and classifiers. The predictive performance of the models were evaluated using the area under the curve (AUC) of the receiver operating curve. RESULTS: The investigators extracted 5234 radiomics features from ultrasound images. 12, 23, 41, 51, 31 and 23 features were important for constructing the models. The radiomics scores were significantly (P < 0.05) in each molecular marker expression of mass type of DCIS. The radiomics models showed predictive performance with AUC greater than 0.7 in the training set and test set: ER (0.94 and 0.84), PR (0.90 and 0.78), HER2 (0.94 and 0.74), Ki67 (0.95 and 0.86), p16 (0.96 and 0.78), and p53 (0.95 and 0.74), respectively. CONCLUSION: Ultrasonic-based radiomics analysis provided a noninvasive preoperative method for predicting the expression of molecular markers of mass type of DCIS with good accuracy.
Subject(s)
Biomarkers, Tumor/analysis , Breast Neoplasms/chemistry , Breast Neoplasms/diagnostic imaging , Carcinoma, Intraductal, Noninfiltrating/chemistry , Carcinoma, Intraductal, Noninfiltrating/diagnostic imaging , Ultrasonography/methods , Adult , Aged , Aged, 80 and over , Cyclin-Dependent Kinase Inhibitor p16/analysis , Female , Humans , Ki-67 Antigen/analysis , Middle Aged , Receptor, ErbB-2/analysis , Receptors, Estrogen/analysis , Receptors, Progesterone/analysis , Retrospective Studies , Tumor Suppressor Protein p53/analysisABSTRACT
WHAT IS KNOWN AND OBJECTIVE: We have previously shown that the saponins of Sanguisorba parviflora (Maxim.) Takeda (Sp. T) relieved cyclophosphamide-induced myelosuppression in leukopenic mice. Haematopoietic cell-specific protein 1-associated protein X-1 (HAX-1) participated in the survival of neutrophils through the regulation of mitochondrial function. The aim of the present study was to comprehensively identify the role of HAX-1 in the mechanism of leukopenia alleviation by Sp. T. METHODS: HAX-1 gene and protein expression levels in peripheral blood neutrophils were examined using real-time quantitative reverse transcription-polymerase chain reaction, western blot and immunohistochemical assays. Neutrophil apoptosis was measured using flow cytometry. Mitochondrial function was determined via assessments of the reactive oxygen species (ROS) generation and mitochondrial membrane potential (ΔΨm) integrity levels. RESULTS AND DISCUSSION: The HAX-1 gene expression level in the peripheral blood neutrophils was significantly lower in patients with leukopenia than in healthy donors. The saponins of Sp. T induced HAX-1 expression and promoted myeloid progenitor cell (mEB8-ER cell) viability. HAX-1 overexpression reduced the production of ROS and maintained ΔΨm integrity. Cyclophosphamide-induced mitochondrial dysfunction and apoptosis could be abrogated by treatment with Sp. T or metformin. WHAT IS NEW AND CONCLUSION: Our data suggest a mechanism through which Sp. T protects against chemotherapy-induced leukopenia by regulating HAX-1 gene expression in a mitochondrial-dependent manner.
Subject(s)
Adaptor Proteins, Signal Transducing/biosynthesis , Cyclophosphamide/adverse effects , Leukopenia/chemically induced , Leukopenia/drug therapy , Sanguisorba/chemistry , Saponins/pharmacology , Adult , Apoptosis/drug effects , Female , Humans , Male , Membrane Potential, Mitochondrial/drug effects , Middle Aged , Myeloid Progenitor Cells/drug effects , Neutrophils/drug effects , Reactive Oxygen Species/metabolismABSTRACT
WHAT IS KNOWN AND THE OBJECTIVE: Our previous studies have shown that saponins of Sanguisorba parviflora (Maxim) Takeda (Sp. T) relieved cyclophosphamide-induced myelosuppression in mice with leukopenia. The hematopoietic cell-specific protein 1-associated protein X-1 (HAX-1) participated in the survival of neutrophils through the regulation of mitochondrial function. This study aimed to comprehensively identify the role of HAX-1 in Sp. T to alleviate leukopenia. METHODS: HAX-1 expression was examined in the peripheral blood neutrophils using real-time polymerase chain reaction (PCR), Western blot analysis and immunohistochemical staining. Neutrophil apoptosis was measured by flow cytometry. Mitochondrial function was evaluated via reactive oxygen species (ROS) generation and mitochondrial membrane potential (ΔΨm) integrity. RESULTS AND DISCUSSION: Our study indicated that the expression of the HAX-1 gene was significantly decreased in the peripheral blood neutrophils of leukopenia patients compared with healthy donors. The saponins of Sp. T induced HAX-1 expression and promoted myeloid progenitor cell (mEB8-ER cell) viability, while overexpression of HAX-1 reduced the production of reactive oxygen species (ROS) and maintained the integrity of the mitochondrial membrane potential. Cyclophosphamide-induced mitochondrial dysfunction and apoptosis could be abrogated by treatment with Sp. T or the addition of metformin. WHAT IS NEW AND OUR CONCLUSION: Our data support a mechanism where Sp. T protects against chemotherapy-induced leukopenia by regulating HAX-1 gene expression in a mitochondrial-dependent manner.
Subject(s)
Adaptor Proteins, Signal Transducing/biosynthesis , Cyclophosphamide/adverse effects , Leukopenia/chemically induced , Leukopenia/drug therapy , Sanguisorba/chemistry , Saponins/pharmacology , Adult , Apoptosis/drug effects , Female , Humans , Male , Membrane Potential, Mitochondrial/drug effects , Middle Aged , Neutrophils/drug effects , Reactive Oxygen Species/metabolismABSTRACT
BACKGROUND: Exposure to benzo(a)pyrene (BaP) was associated with cognitive impairments and some Alzheimer's disease (AD)-like pathological changes. However, it is largely unknown whether BaP exposure participates in the disease progression of AD. OBJECTIVES: To investigate the effect of BaP exposure on AD progression and its underlying mechanisms. METHODS: BaP or vehicle was administered to 4-month-old APPswe/PS1dE9 transgenic (APP/PS1) mice and wildtype (WT) mice for 2 months. Learning and memory ability and exploratory behaviors were evaluated 1 month after the initiation/termination of BaP exposure. AD-like pathological and biochemical alterations were examined 1 month after 2-month BaP exposure. Levels of soluble beta-amyloid (Aß) oligomers and the number of Aß plaques in the cortex and the hippocampus were quantified. Gene expression profiling was used to evaluate alternation of genes/pathways associated with AD onset and progression. Immunohistochemistry and Western blot were used to demonstrate neuronal loss and neuroinflammation in the cortex and the hippocampus. Treatment of primary neuron-glia cultures with aged Aß (a mixture of monomers, oligomers, and fibrils) and/or BaP was used to investigate mechanisms by which BaP enhanced Aß-induced neurodegeneration. RESULTS: BaP exposure induced progressive decline in spatial learning/memory and exploratory behaviors in APP/PS1 mice and WT mice, and APP/PS1 mice showed severer behavioral deficits than WT mice. Moreover, BaP exposure promoted neuronal loss, Aß burden and Aß plaque formation in APP/PS1 mice, but not in WT mice. Gene expression profiling showed most robust alteration in genes and pathways related to inflammation and immunoregulatory process, Aß secretion and degradation, and synaptic formation in WT and APP/PS1 mice after BaP exposure. Consistently, the cortex and the hippocampus of WT and APP/PS1 mice displayed activation of microglia and astroglia and upregulation of inducible nitric oxide synthase (iNOS), glial fibrillary acidic protein (GFAP), and NADPH oxidase (three widely used neuroinflammatory markers) after BaP exposure. Furthermore, BaP exposure aggravated neurodegeneration induced by aged Aß peptide in primary neuron-glia cultures through enhancing NADPH oxidase-derived oxidative stress. CONCLUSION: Our study showed that chronic exposure to environmental pollutant BaP induced, accelerated, and exacerbated the progression of AD, in which elevated neuroinflammation and NADPH oxidase-derived oxidative insults were key pathogenic events.
Subject(s)
Alzheimer Disease/pathology , Benzo(a)pyrene/toxicity , Cognitive Dysfunction/chemically induced , Neurons/drug effects , Plaque, Amyloid/pathology , Amyloid beta-Protein Precursor/genetics , Animals , Behavior, Animal/drug effects , Cognitive Dysfunction/pathology , Disease Models, Animal , Exploratory Behavior/drug effects , Maze Learning/drug effects , Mice , Neurons/pathology , Presenilin-1/genetics , Spatial Memory/drug effectsABSTRACT
[This corrects the article DOI: 10.1186/s12935-020-01298-5.].
ABSTRACT
BACKGROUND: Hydroxysteroid 17-Beta Dehydrogenase 6 (HSD17B6), a key protein involved in synthetizing dihydrotestosterone, is abundant in the liver. Previous studies have suggested a role for dihydrotestosterone in modulating progress of various malignancies, and HSD17B6 dysfunction was associated with lung cancer and prostate cancer. However, little is known about the detailed role of HSD17B6 in hepatocellular carcinoma (HCC). METHODS: Clinical implication and survival data related to HSD17B6 expression in patients with HCC were obtained through TCGA, ICGC, ONCOMINE, GEO and HPA databases. Survival analysis plots were drawn with Kaplan-Meier Plotter. The ChIP-seq data were obtained from Cistrome DB. Protein-Protein Interaction and gene functional enrichment analyses were performed in STRING database. The correlations between HSD17B6 and tumor immune infiltrates was investigated via TIMER and xCell. The proliferation, migration and invasion of liver cancer cells transfected with HSD17B6 were evaluated by the CCK8 assay, wound healing test and transwell assay respectively. Expression of HSD17B6, TGFB1 and PD-L1 were assessed by quantitative RT-PCR. RESULTS: HSD17B6 expression was lower in HCC compared to normal liver and correlated with tumor stage and grade. Lower expression of HSD17B6 was associated with worse OS, PFS, RFS and DSS in HCC patients. HNF4A bound to enhancer and promoter regions of HSD17B6 gene, activating its transcription, and DNA methylation of HSD17B6 promoter negatively controlled the expression. HSD17B6 and its interaction partners were involved in androgen metabolism and biosynthesis in liver. HSD17B6 inhibited tumor cell proliferation, migration and invasion in liver cancer cells and low expression of HSD17B6 correlated with high immune cells infiltration, relative reduction of immune responses and multiple immune checkpoint genes expression in HCC, probably by regulating the expression of TGFB1. CONCLUSIONS: This study indicate that HSD17B6 could be a new biomarker for the prognosis of HCC and an important negative regulator of immune responses in HCC.