KLF12 interacts with TRIM27 to affect cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma by regulating L1CAM expression.

Krüppel-like factor 12 (KLF12) has been characterized as a transcriptional repressor, and previous studies have unveiled its roles in angiogenesis, neural tube defect, and natural killer (NK) cell proliferation. However, the contribution of KLF12 to cancer treatment remains undefined. Here, we show that KLF12 is downregulated in various cancer types, and KLF12 downregulation promotes cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma (ESCC). Mechanistically, KLF12 binds to the promoters of L1 Cell Adhesion Molecule (L1CAM) and represses its expression. Depletion of L1CAM abrogates cisplatin resistance and cancer metastasis caused by KLF12 loss. Moreover, the E3 ubiquitin ligase tripartite motif-containing 27 (TRIM27) binds to the N-terminal region of KLF12 and ubiquitinates KLF12 at K326 via K33-linked polyubiquitination. Notably, TRIM27 depletion enhances the transcriptional activity of KLF12 and consequently inhibits L1CAM expression. Overall, our study elucidated a novel regulatory mechanism involving TRIM27, KLF12 and L1CAM, which plays a substantial role in cisplatin resistance and cancer metastasis in ESCC. Targeting these genes could be a promising approach for ESCC treatment.

H2B Lys34 Ubiquitination Induces Nucleosome Distortion to Stimulate Dot1L Activity.

Ubiquitination-dependent histone crosstalk plays critical roles in chromatin-associated processes and is highly associated with human diseases. Mechanism studies of the crosstalk have been of the central focus. Here our study on the crosstalk between H2BK34ub and Dot1L-catalyzed H3K79me suggests a novel mechanism of ubiquitination-induced nucleosome distortion to stimulate the activity of an enzyme. We determined the cryo-electron microscopy structures of Dot1L-H2BK34ub nucleosome complex and the H2BK34ub nucleosome alone. The structures reveal that H2BK34ub induces an almost identical orientation and binding pattern of Dot1L on nucleosome as H2BK120ub, which positions Dot1L for the productive conformation through direct ubiquitin-enzyme contacts. However, H2BK34-anchored ubiquitin does not directly interact with Dot1L as occurs in the case of H2BK120ub, but rather induces DNA and histone distortion around the modified site. Our findings establish the structural framework for understanding the H2BK34ub-H3K79me trans-crosstalk and highlight the diversity of mechanisms for histone ubiquitination to activate chromatin-modifying enzymes.

Finite element analysis of a customized coronoid prosthesis for traumatic coronoid deficiency.

BACKGROUND: Traumatic coronoid deficiency with persistent elbow instability is a challenging condition. Autologous bone graft reconstruction is often associated with a range of additional clinical problems and the outcome is often unpredictable. The purpose of this study was to design a prosthetic device that can reconstruct coronoid deficiency of any height and to evaluate its mechanical properties using finite element analysis. MATERIALS AND METHODS: A customized coronoid prosthesis was designed based on image registration, automatic measurement, and computer-aided design. After pilot study and sample size calculation, image data collected from 6 patients who underwent bilateral complete upper extremity CT scans were reconstructed. The test was divided into 3 groups: coronoid intact, prosthesis and autograft. Regan-Morrey type II and autologous olecranon osteotomy models were established. The prosthesis and autogenous olecranon were assembled to the coronoid base. Stress was applied axially along the proximal humeral diaphysis and implant micromotion and contact mechanics of the humeroulnar joint were measured at 30°, 45°, 60° and 90° of joint flexion respectively. RESULTS: At all flexion angles, the maximum stress on the coronoid articular surface was significantly reduced in the prosthesis and autograft groups, with the reduction being more significant in the latter (P < .001). With increasing flexion, the maximum stress at the coronoid articular surface increased significantly after autograft reconstruction (7.2 to 68 MPa, P < .001), whereas the humeroulnar joint obtained a similar contact mechanics pattern to that of the control group after prosthetic reconstruction. As the flexion angle increased, the relative micromotion of both the prosthesis and autograft increased significantly (0.5-1.6 vs. 0.2-1.2, Pmeasure time < 0.001, Pgroups < 0.001). Contact pressure and center-of-force paths of the humeroulnar joint experience abrupt stress changes at approximately 60° of flexion. CONCLUSION: The contact stress pattern in the humeroulnar joint is similar in prosthesis and intact coronoid groups. Autograft reconstruction increases contact stresses at the articular surface and alters the joint center-of-force path. The "stress surge phenomenon" in the humeroulnar joint surface before and after 60° of flexion may be one of the mechanisms of traumatic elbow degeneration.

A New Lunar Lineament Extraction Method Based on Improved UNet++ and YOLOv5.

Lineament is a unique geological structure. The study of Lunar lineament structure has great significance on understanding its history and evolution of Lunar surface. However, the existing geographic feature extraction methods are not suitable for the extraction of Lunar lineament structure. In this paper, a new lineament extraction method is proposed based on improved-UNet++ and YOLOv5. Firstly, new lineament dataset is created containing lineaments structure based on CCD data from LROC. At same time the residual blocks are replaced with the VGG blocks in the down sample part of the UNet++ with adding the attention block between each layer. Secondly, the improved-UNet++ and YOLO networks are trained to execute the object detection and semantic segmentation of lineament structure respectively. Finally, a polygon-match strategy is proposed to combine the results of object detection and semantic segmentation. The experiment result indicate that this new method has relatively better and more stable performance compared with current mainstream networks and the original UNet++ network in the instance segmentation of lineament structure. Additionally, the polygon-match strategy is able to perform preciser edge detail in the instance segmentation of lineament structure result.

Mask, the Drosophila ankyrin repeat and KH domain-containing protein, affects microtubule stability.

Proper regulation of microtubule (MT) stability and dynamics is vital for essential cellular processes, including axonal transportation and synaptic growth and remodeling in neurons. In the present study, we demonstrate that the Drosophila ankyrin repeat and KH domain-containing protein Mask negatively affects MT stability in both larval muscles and motor neurons. In larval muscles, loss-of-function of mask increases MT polymer length, and in motor neurons, loss of mask function results in overexpansion of the presynaptic terminal at the larval neuromuscular junctions (NMJs). mask genetically interacts with stathmin (stai), a neuronal modulator of MT stability, in the regulation of axon transportation and synaptic terminal stability. Our structure-function analysis of Mask revealed that its ankyrin repeats domain-containing N-terminal portion is sufficient to mediate Mask's impact on MT stability. Furthermore, we discovered that Mask negatively regulates the abundance of the MT-associated protein Jupiter in motor neuron axons, and that neuronal knocking down of Jupiter partially suppresses mask loss-of-function phenotypes at the larval NMJs. Taken together, our studies demonstrate that Mask is a novel regulator for MT stability, and such a role of Mask requires normal function of Jupiter.

Factors related to dietary quality among older stroke high-risk population in Tianjin community, China: a multicenter study.

BACKGROUND: Stroke is a common and frequently-occurring disease in older people. It has the characteristics of high morbidity, high mortality, high recurrence rate and high disability rate. Most stroke risk studies are based on pathophysiology, however psychosocial factors such as diet quality are often understudied. The aim of this study was to assess stroke risk in urban community residents in Tianjin and investigate the factors that affect the dietary quality of older stroke high-risk populations. METHODS: Using a cross-sectional, multicenter study, recruit people aged 60 to 80 in Tianjin. Dietary intake data were obtained through a validated food frequency questionnaire, which were used to calculate Alternate Healthy Eating Index-2010 (AHEI-2010) and to analyze its association with sociodemographic characteristics, stroke risk factors and health marker variables. RESULTS: A total of 1068 participants from 4 community health service centers in Tianjin were recruited, including 300 low-risk individuals and 768 high-risk individuals. Compared with the low-risk group (62.75 ± 3.59), the AHEI-2010 mean score of the high-risk group (56.83 ± 6.54) was significantly lower. The top three most common risk factors among participants were dyslipidemia (80.3%), hypertension (60.6%), and physical inactivity (58.2%). Multiple logistic regression showed that diet quality was independently and significantly associated with stroke risk (OR = 0.765; 95%CI: 0.690-0.848, p < 0.001). CONCLUSION: The diet quality of high-risk stroke population in Tianjin is far from ideal. At the same time, public health knowledge needs to be disseminated and educated, especially among those at high risk of cerebrovascular disease, with a focus on improving psychosocial factors such as diet quality.

Structural basis for zinc-induced activation of a zinc uptake transcriptional regulator.

The zinc uptake regulator (Zur) is a member of the Fur (ferric uptake regulator) family transcriptional regulators that plays important roles in zinc homeostasis and virulence of bacteria. Upon zinc perception, Zur binds to the promoters of zinc responsive genes and controls their transcription. However, the mechanism underlying zinc-mediated Zur activation remains unclear. Here we report a 2.2-Å crystal structure of apo Zur from the phytopathogen Xanthomonas campestris pv. campestris (XcZur), which reveals the molecular mechanism that XcZur exists in a closed inactive state before regulatory zinc binding. Subsequently, we present a 1.9-Å crystal structure of holo XcZur, which, by contrast, adopts an open state that has enough capacity to bind DNA. Structural comparison and hydrogen deuterium exchange mass spectrometry (HDX-MS) analyses uncover that binding of a zinc atom in the regulatory site, formed by the hinge region, the dimerization domain and the DNA binding domain, drives a closed-to-open conformational change that is essential for XcZur activation. Moreover, key residues responsible for DNA recognition are identified by site-directed mutagenesis. This work provides important insights into zinc-induced XcZur activation and valuable discussions on the mechanism of DNA recognition.

Urinary microbiota and metabolic signatures associated with inorganic arsenic-induced early bladder lesions.

Inorganic arsenic (iAs) contamination in drinking water is a global public health problem, and exposure to iAs is a known risk factor for bladder cancer. Perturbation of urinary microbiome and metabolome induced by iAs exposure may have a more direct effect on the development of bladder cancer. The aim of this study was to determine the impact of iAs exposure on urinary microbiome and metabolome, and to identify microbiota and metabolic signatures that are associated with iAs-induced bladder lesions. We evaluated and quantified the pathological changes of bladder, and performed 16S rDNA sequencing and mass spectrometry-based metabolomics profiling on urine samples from rats exposed to low (30 mg/L NaAsO2) or high (100 mg/L NaAsO2) iAs from early life (in utero and childhood) to puberty. Our results showed that iAs induced pathological bladder lesions, and more severe effects were noticed in the high-iAs group and male rats. Furthermore, six and seven featured urinary bacteria genera were identified in female and male offspring rats, respectively. Several characteristic urinary metabolites, including Menadione, Pilocarpine, N-Acetylornithine, Prostaglandin B1, Deoxyinosine, Biopterin, and 1-Methyluric acid, were identified significantly higher in the high-iAs groups. In addition, the correlation analysis demonstrated that the differential bacteria genera were highly correlated with the featured urinary metabolites. Collectively, these results suggest that exposure to iAs in early life not only causes bladder lesions, but also perturbs urinary microbiome composition and associated metabolic profiles, which shows a strong correlation. Those differential urinary genera and metabolites may contribute to bladder lesions, suggesting a potential for development of urinary biomarkers for iAs-induced bladder cancer.

Co-exposure to arsenic and fluoride to explore the interactive effect on oxidative stress and autophagy in myocardial tissue and cell.

Co-contamination of arsenic and fluoride is widely distributed in groundwater. However, little is known about the interactively influence of arsenic and fluoride, especially the combined mechanism in cardiotoxicity. Cellular and animal models exposure to arsenic and fluoride were established to assess the oxidative stress and autophagy mechanism of cardiotoxic damage using the factorial design, a widely used statistical method for assessing two factor interventions. In vivo, combined exposure to high arsenic (50 mg/L) and high fluoride (100 mg/L) induced myocardial injury. The damage is accompanied by accumulation of myocardial enzyme, mitochondrial disorder, and excessive oxidative stress. Further experiment identified that arsenic and fluoride induced the accumulation of autophagosome and increased expression level of autophagy related genes during the cardiotoxicity process. These findings were further demonstrated through the in vitro model of arsenic and fluoride-treated the H9c2 cells. Additionally, combined of arsenic-fluoride exposure possesses the interactively influence on oxidative stress and autophagy, contributing to the myocardial cell toxicity. In conclusion, our data suggest that oxidative stress and autophagy are involved in the process of cardiotoxic injury, and that these indicators showed interaction effect in response to the combined exposure of arsenic and fluoride.

A New Lunar Dome Detection Method Based on Improved YOLOv7.

Volcanism is an important geological evolutionary process on the Moon. The study of lunar volcanic features is of great significance and value to understanding the geological evolution of the Moon better. Lunar domes are one of the essential volcanic features of the Moon. However, the existing lunar dome detection methods are still traditional manual or semiautomatic identification approaches that require extensive prior knowledge and have a complex identification process. Therefore, this paper proposes an automatic detection method based on improved YOLOv7 for lunar dome detection. First, a new lunar dome dataset was created by digital elevation model (DEM) data, and the effective squeeze and excitation (ESE) attention mechanism module was added to the backbone and neck sections to reduce information loss in the feature map and enhance network expressiveness. Then, a new SPPCSPC-RFE module was proposed by adding the receptive field enhancement (RFE) module into the neck section, which can adapt to dome feature maps of different shapes and sizes. Finally, the bounding box regression loss function complete IOU (CIOU) was replaced by wise IOU (WIOU). The WIOU loss function improved the model's performance for the dome detection effect. Furthermore, this study combined several data enhancement strategies to improve the robustness of the network. To evaluate the performance of the proposed model, we conducted several experiments using the dome dataset developed in this study. The experimental results indicate that the improved method outperforms related methods with a mean average precision (mAP@0.5) value of 88.7%, precision (P) value of 85.6%, and recall (R) value of 86.4%. This study provides an effective solution for lunar dome detection.

Structural brain network measures in elderly patients with cerebral small vessel disease and depressive symptoms.

OBJECTIVES: To investigate the relationship between diffusion tensor imaging (DTI) indicators and cerebral small vessel disease (CSVD) with depressive states, and to explore the underlying mechanisms of white matter damage in CSVD with depression. METHOD: A total of 115 elderly subjects were consecutively recruited from the neurology clinic, including 36 CSVD patients with depressive state (CSVD+D), 34 CSVD patients without depressive state (CSVD-D), and 45 controls. A detailed neuropsychological assessment and multimodal magnetic resonance imaging (MRI) were performed. Based on tract-based spatial statistics (TBSS) analysis and structural network analysis, differences between groups were compared, including white matter fiber indicators (fractional anisotropy and mean diffusivity) and structural brain network indicators (global efficiency, local efficiency and network strength), in order to explore the differences and correlations of DTI parameters among the three groups. RESULTS: There were no significant differences in terms of CSVD burden scores and conventional imaging findings between the CSVD-D and CSVD+D groups. Group differences were found in DTI indicators (p <  0.05), after adjusting for age, gender, education level, and vascular risk factors (VRF), there were significant correlations between TBSS analysis indicators and depression, including: fractional anisotropy (FA) (r = - 0.291, p <  0.05), mean diffusivity (MD) (r = 0.297, p < 0.05), at the same time, between structural network indicators and depression also show significant correlations, including: local efficiency (ELocal) (r = - 0.278, p < 0.01) and network strength (r = - 0.403, p < 0.001). CONCLUSIONS: Changes in FA, MD values and structural network indicators in DTI parameters can predict the depressive state of CSVD to a certain extent, providing a more direct structural basis for the hypothesis of abnormal neural circuits in the pathogenesis of vascular-related depression. In addition, abnormal white matter alterations in subcortical neural circuits probably affect the microstructural function of brain connections, which may be a mechanism for the concomitant depressive symptoms in CSVD patients.

Gait Disorders and Magnetic Resonance Imaging Characteristics in Older Adults with Cerebral Small Vessel Disease.

BACKGROUND: This study aims to explore the features of gait disorders with cerebral small vessel disease (CSVD), and results from magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) were analyzed. METHODS: The 139 patients with CSVD were divided into two groups by the Tinetti scale scores: the gait disorder (GD) group with a score <24 (63 patients) and the normal gait (GN) group with a score ≥24 (76 patients). A series of scales and 3.0T MRI with DTI were used to analyze the correlation between the abnormal gaits and imaging findings. RESULTS: The differences in the Barthel Index, Unified Parkinson's Disease Rating Scale part III, and Montreal Cognitive Assessment (MoCA) scores between the two groups were significant (p < 0.05), and there were significant correlations between MoCA and total gait scores (r = 0.201, p = 0.002). The GD group had a more degraded gait score, widened gait base, and degraded gait length than the GN group (p < 0.05). There were significant differences between the two groups (p < 0.05) in white matter (WM) hyperintensities (WMH) of the Fazekas scale grade 2-3 and lacunes. The GD group had a greater total MRI burden than the GN group (p < 0.05). In DTI parameters, the GD group had lower fractional anisotropy (FA) and higher mean diffusion (MD) values in WM tracts in many areas around the ventricles (family-wise error corrected, p < 0.05). Significant correlations were observed between FA and the total gait score (r = 0.467, p < 0.01), and also between MD and total gait score (r  = -0.422, p < 0.01). CONCLUSIONS: Patients with CSVD with gait disorders had more WMH of Fazekas scale grade 2-3, lacunes, and total MRI burden than the GN patients, and those with gait disorders may suffer from demyelination of nerve fibers and damage to the fibers' microstructures.

Expedient Synthesis of Ubiquitin-like Protein ISG15 Tools through Chemo-Enzymatic Ligation Catalyzed by a Viral Protease Lbpro.

Ubiquitin (Ub)-like protein ISG15 (interferon-stimulated gene 15) regulates innate immunity and links with the evasion of host response by viruses such as SARS-CoV-2. Dissecting ISGylation pathways recently received increasing attention which can inform related disease interventions, but such studies necessitate the preparation and development of various ISG15 protein tools. Here, we find that the leader protease (Lbpro ) encoded by foot-and-mouth disease virus can promote ligation reactions between recombinant ISG15 and synthetic glycyl compounds, generating protein tools such as ISG15-propargylamide and ISG15-rhodamine110, which are needed for cellular proteomic studies of deISGylases, and the screening and evaluation of inhibitors against SARS-CoV-2 papain-like protease (PLpro). Furthermore, this strategy can be also used to load ISG15 onto the lysine of a synthetic peptide through an isopeptide bond, and prepare Ub and NEDD8 (ubiquitin-like protein Nedd8) protein tools.

Rapid gut dysbiosis induced by stroke exacerbates brain infarction in turn.

OBJECTIVE: Stroke is a leading cause of death and disability worldwide. Neuroprotective approaches have failed in clinical trials, thus warranting therapeutic innovations with alternative targets. The gut microbiota is an important contributor to many risk factors for stroke. However, the bidirectional interactions between stroke and gut microbiota remain largely unknown. DESIGN: We performed two clinical cohort studies to capture the gut dysbiosis dynamics after stroke and their relationship with stroke prognosis. Then, we used a middle cerebral artery occlusion model to explore gut dysbiosis post-stroke in mice and address the causative relationship between acute ischaemic stroke and gut dysbiosis. Finally, we tested whether aminoguanidine, superoxide dismutase and tungstate can alleviate post-stroke brain infarction by restoring gut dysbiosis. RESULTS: Brain ischaemia rapidly induced intestinal ischaemia and produced excessive nitrate through free radical reactions, resulting in gut dysbiosis with Enterobacteriaceae expansion. Enterobacteriaceae enrichment exacerbated brain infarction by enhancing systemic inflammation and is an independent risk factor for the primary poor outcome of patients with stroke. Administering aminoguanidine or superoxide dismutase to diminish nitrate generation or administering tungstate to inhibit nitrate respiration all resulted in suppressed Enterobacteriaceae overgrowth, reduced systemic inflammation and alleviated brain infarction. These effects were gut microbiome dependent and indicated the translational value of the brain-gut axis in stroke treatment. CONCLUSIONS: This study reveals a reciprocal relationship between stroke and gut dysbiosis. Ischaemic stroke rapidly triggers gut microbiome dysbiosis with Enterobacteriaceae overgrowth that in turn exacerbates brain infarction.

Co-exposure to fluoride and arsenic disrupts intestinal flora balance and induces testicular autophagy in offspring rats.

While numerous studies have shown that fluoride or arsenic exposure may damage the reproductive system, there are few reports of co-exposure to fluoride and arsenic. In addition, the literature on autophagy and intestinal flora composition in reproductive toxicity studies of co-exposure to fluoride and arsenic is insufficient. In this study, we developed a rat model of fluoride and arsenic exposure via drinking water from pre-pregnancy to 90 days postnatal. Sprague-Dawley rats were randomly divided into sterile water control group, fluoride group (100 mg/L NaF), arsenic group (50 mg/L NaAsO2) and combined exposure group (100 mg/L NaF+50 mg/L NaAsO2). Our results showed that fluoride and arsenic exposure caused a reduction in testicular weight and significant pathological damage to tissue. We found that the levels of follicle-stimulating hormone, luteinizing hormone, and testosterone were reduced to varying degrees. Meanwhile experiments showed that fluoride and arsenic exposure can modulate autophagic flux, causing increased levels of Beclin1 and LC3 expression and decreased p62 expression. Analogously, by performing 16S sequencing of rat feces, we found 24 enterobacterial genera that differed significantly among the groups. Furthermore, the flora associated with testicular injury were identified by correlation analysis of hormonal indices and autophagy alterations with intestinal flora composition at the genus level, respectively. In summary, our study shows that fluoride and arsenic co-exposure alters autophagic flux in the testis, causes testicular injury, and reveals an association between altered intestinal flora composition and testicular injury.

Proteomics and transcriptomics jointly identify the key role of oxidative phosphorylation in fluoride-induced myocardial mitochondrial dysfunction in rats.

The regulation of mitochondrial function, which is dominated by oxidative phosphorylation (OXPHOs), is important in fluoride induced cardiovascular disease. Based on the previous study of fluoride-induced mitochondrial structure and membrane potential abnormalities, this study integrated ITRAQ protein quantification and RNA-Seq methods to analyze the sequencing data of rat myocardial tissue under fluoride exposure (0, 30, 60 and 90 mg/L). A total of 22 differentially expressed genes associated with the OXPHOs pathway were screened by Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) co-enrichment analysis, and were localizated by Interaction Network and calculated inter-genes and inter-omics correlations by Pearson correlation. In general, fluoride exposure can down-regulate genes related OXPHOs, particularly affecting the assembly of the complex I including Ndufa10, resulting in abnormal mitochondrial ATP synthesis and reduced myocardial energy supply. Most importantly, this study shows that the enriched information from the proteomics can explain the change process of energy production, but the specific molecules involved in energy supply cannot be obtained via transcriptomics information alone. Based on the results of transcriptional and protein analysis, our findings contribute to an innovative understanding of the pathways and molecular changes of myocardial injury induced by fluorosis.

Effects of arsenic exposure on lipid metabolism: a systematic review and meta-analysis.

Lipid metabolism dysfunction is a risk factor for cardiovascular diseases. Reportedly, arsenic exposure could affect lipid metabolism, but this finding remains controversial. Herein, we updated and reevaluated evidence regarding the relationship between arsenic exposure and lipid metabolism. Electronic and manual searches were performed to determine the effect of arsenic exposure on lipid metabolism from inception up to 30 November 2019. Overall, five studies were included in our meta-analysis. Two reviewers independently extracted information. Standardized mean difference (SMD) and 95% confidence intervals (CI) were used to analyze the combined effects of four indicators related to lipid metabolism (total cholesterol [TC], triglyceride [TG], high-density lipoprotein [HDL], low-density lipoprotein [LDL]). Afterwards, subgroup and sensitivity analyses were performed to explore the source of heterogeneity. Publication bias was tested using funnel plots and Begg's test. In this study, we observed that arsenic exposure can affect lipid metabolism by reducing serum HDL levels and increasing serum LDL levels. Following subgroup analysis, the arsenic concentration appeared to affect lipid metabolism. Funnel plot and Begg's test suggested no asymmetry. In conclusion, we recommend that potential influencing factors, including age, exposure time, and multiple concentration gradients, should be considered to further explore the relationship between arsenic exposure and lipid metabolism.

Deregulation of autophagy is involved in nephrotoxicity of arsenite and fluoride exposure during gestation to puberty in rat offspring.

Exposure to fluoride (F) or arsenite (As) through contaminated drinking water has been associated with chronic nephrotoxicity in humans. Autophagy is a regulated mechanism ubiquitous for the body in a toxic environment with F and As, but the underlying mechanisms of autophagy in the single or combined nephrotoxicity of F and As are unclear. In the present study, we established a rat model of prenatal and postnatal exposure to F and As with the aim of investigating the mechanism underlying nephrotoxicity of these pollutants in offspring. Rats were randomly divided into four groups that received NaF (100 mg/L), NaAsO2 (50 mg/L), or NaF (100 mg/L) with NaAsO2 (50 mg/L) in drinking water or clean water during pregnancy and lactation; after weaning, pups were exposed to the same treatment as their mothers until puberty. The results revealed that F and As exposure (alone or combined) led to significant increases of arsenic and fluoride levels in blood and bone, respectively. In this context, F and/or As disrupted histopathology and ultrastructure in the kidney, and also altered creatinine (CRE), urea nitrogen (BUN) and uric acid (UA) levels. Intriguingly, F and/or As uptake induced the formation of autophagosomes in kidney tissue and resulted in the upregulation of genes encoding autophagy-related proteins. Collectively, these results suggest that nephrotoxicity of F and As for offspring exposed to the pollutants from in utero to puberty is associated with deregulation of autophagy and there is an antagonism between F and As in the toxicity autophagy process.

ITRAQ-based proteomics reveals the potential mechanism of fluoride-induced myocardial contraction function damage.

Fluorosis is a worldwide public health problem, and its adverse effects on the heart have been confirmed by many studies. Abnormal myocardial contractions are often associated with impairment of cardiac function as a cause or consequence. We designed two-part experiments to search for biomarkers and clarify the underlying molecular mechanism of fluoride on myocardial contraction. First, we used Pressure-volume Loop analysis to evaluate changes in myocardial function indexes with multiple fluoride exposure levels in mice (0, 30, 70, and 150 mg/L) exposed for 4 weeks. The results showed that fluoride exposure affects the heart pump function and reduces cardiac contractility. Then, we established a rat model of fluoride exposure (0, 30, 60, and 90 mg/L) for 6 months to carry out proteomic analysis of fluoride-induced myocardial contractile injury. Hematoxylin-eosin (H&E) staining was used to determine the severity of myocardial injury, and myocardial tissue samples were submitted for isobaric tags for relative and absolute quantitation (ITRAQ) analysis. A total of 1607 proteins were successfully identified with 294 differentially expressed proteins (DEPs) in fluoride treated groups. According to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, 12 DEPs were confirmed to be involved in pathways related to myocardial contraction. Furthermore, we constructed a protein-protein interaction (PPI) network for these 12 core DEPs to illustrate the role and location of each DEP in the myocardial contraction pathway. The results of this study are helpful for identify a potential mechanism and biomarkers of fluoride-induced myocardial contraction function damage, moreover, which can provide a new insight into the heart toxicity of fluoride in animals at the proteomics level.

Revealing the Inhibitory Effect of Ginseng on Mitochondrial Respiration through Synaptosomal Proteomics.

Ginseng, the active ingredients of which are ginsenosides, is the most popular herbal medicine and has potential merit in the treatment of cerebral disorders. To better understand the function of Ginseng in the cerebral system, we examined changes in the protein expression profiles of synaptosomes extracted from the cerebral cortical and hippocampal tissues of rats administered a high or low dose of Ginseng for 2 weeks. More than 5000 proteins belonging to synaptosomes were simultaneously identified and quantitated by an approach combining tandem mass tags with 2D liquid chromatography-mass spectrometry (LC-MS). Regarding differentially expressed proteins, downregulated proteins were much more highly induced than upregulators in the cerebral cortical and hippocampal synaptosomes, regardless of the dose of Ginseng. Bioinformatic analysis indicated the majority of the altered proteins to be located in the mitochondria, directly or indirectly affecting mitochondrial oxidative respiration. Further functional experiments using the substrate-uncoupler inhibitor titration approach confirmed that three representative ginsenosides were able to inhibit oxidative phosphorylation in mitochondria. Our results demonstrate that Ginseng can regulate the function of mitochondria and alter the energy metabolism of cells, which may be useful for the treatment of central nervous disorders.