Publications by authors named "Aihua Zhang"

482 Publications

Two unusual cases of autologous HSCT related TMA with kidney injury.

Ann Palliat Med 2021 Jul 8. Epub 2021 Jul 8.

Department of Nephrology, Xuanwu Hospital, Capital Medical University, Beijing, China.

Kidney injury caused by transplant-associated thrombotic microangiopathy (TA-TMA) in patients who underwent allogeneic hematopoietic stem cell transplantation (allo HSCT) is relatively frequent. However, it is rarely reported in patients undergoing autologous HSCT (aHSCT). There are a few studies reported that TA-TMA could occur in pediatric patients undergoing aHSCT, but the condition in adult patients is rarely described. Furthermore, almost all the patients who suffered from TA-TMA developed typical and severe manifestations which should be treated with aggressive target therapy. Nevertheless, we presented two cases of kidney injury caused by TA-TMA after aHSCT with specific clinical features. Case 1, a 33-year-old Chinese male diagnosed with Hodgkin's lymphoma developed TA-TMA -associated kidney injury 4 months after transplantation. Case 2, a 49-year-old Chinese female with central nervous lymphoma developed TA-TMA-related kidney injury 3 months after transplantation. Both patients presented "mild" and atypical features of TA-TMA and their kidney function was managed effectively with low-dose prednisone therapy. TA-TMA related kidney injury can occur in patients who underwent aHSCT. Patients with TA-TMA could develop atypically "mild" features. Low-dose prednisone may be effective in place of routine eculizumab treatment regimen. We recommend that clinicians prompt an investigation for TA-TMA in patients presenting kidney injury in the background of aHSCT to facilitate early diagnosis.
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http://dx.doi.org/10.21037/apm-21-226DOI Listing
July 2021

Anti-anemia drug FG4592 retards the AKI-to-CKD transition by improving vascular regeneration and antioxidative capability.

Clin Sci (Lond) 2021 Jul;135(14):1707-1726

Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, China.

Acute kidney injury (AKI) is a known risk factor for the development of chronic kidney disease (CKD), with no satisfactory strategy to prevent the progression of AKI to CKD. Damage to the renal vascular system and subsequent hypoxia are common contributors to both AKI and CKD. Hypoxia-inducible factor (HIF) is reported to protect the kidney from acute ischemic damage and a novel HIF stabilizer, FG4592 (Roxadustat), has become available in the clinic as an anti-anemia drug. However, the role of FG4592 in the AKI-to-CKD transition remains elusive. In the present study, we investigated the role of FG4592 in the AKI-to-CKD transition induced by unilateral kidney ischemia-reperfusion (UIR). The results showed that FG4592, given to mice 3 days after UIR, markedly alleviated kidney fibrosis and enhanced renal vascular regeneration, possibly via activating the HIF-1α/vascular endothelial growth factor A (VEGFA)/VEGF receptor 1 (VEGFR1) signaling pathway and driving the expression of the endogenous antioxidant superoxide dismutase 2 (SOD2). In accordance with the improved renal vascular regeneration and redox balance, the metabolic disorders of the UIR mice kidneys were also attenuated by treatment with FG4592. However, the inflammatory response in the UIR kidneys was not affected significantly by FG4592. Importantly, in the kidneys of CKD patients, we also observed enhanced HIF-1α expression which was positively correlated with the renal levels of VEGFA and SOD2. Together, these findings demonstrated the therapeutic effect of the anti-anemia drug FG4592 in preventing the AKI-to-CKD transition related to ischemia and the redox imbalance.
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http://dx.doi.org/10.1042/CS20210100DOI Listing
July 2021

Imbalanced inflammatory response in subchronic arsenic-induced liver injury and the protective effects of Ginkgo biloba extract in rats: Potential role of cytokines mediated cell-cell interactions.

Environ Toxicol 2021 Jul 12. Epub 2021 Jul 12.

The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guiyang, China.

Arsenic is a well-known environmental toxicant and carcinogen, which has been epidemiologically proved related to the increased hepatic disorders. Researches have shown that aseptic inflammation and abnormal immune response are associated with arsenic-induced liver injury. However, the immunotoxic effects of liver have not been extensively characterized. Ginkgo biloba extract (GBE), a natural products of G. biloba leaves with proven anti-inflammatory and potential immunoregulatory activities, was used as intervention agent to explore its protective effects on arsenic-induced hepatotoxicity. Thus, the underlying mechanism of the immunotoxic effects on arsenic-induced liver injury were investigated in 2.5, 5.0, and 10.0 mg/kg NaAsO of Wistar rats for 16 weeks. Subsequently, GBE was used as intervention agent in 50 mg/kg for 6 weeks after cessation of arsenic exposure. The ratio of Th17 to Treg cells in peripheral blood as well as the secretion of inflammatory cytokines IL-17A, IL-6, TGF-β1, and IL-10 in serum and liver were detected. Meanwhile, the notable activation of aseptic inflammation-related molecule TLR4 and its downstream targets MyD88 and NF-κB in the liver were observed. In this work, we confirmed that subchronic exposed to arsenic triggered the infiltration of inflammatory cells in rat liver, coupled with obvious histopathological changes and aberrant hepatic serum biochemical parameters. Meanwhile, imbalanced immune response was verified by the notable abnormal ratio of Th17 to Treg cells in peripheral blood as well as the secretion of inflammatory cytokines IL-17A, IL-6, TGF-β1, and IL-10 in serum and liver of arsenic exposed rats. Further, the level of TLR4, MyD88, and NF-κB in liver both transcription and translation activity were raised. Subsequently, GBE markedly mitigated arsenic-induced liver injury, most impressively, post treatment with GBE prominently suppressed the overactivated inflammatory-related TLR4-MyD88-NF-κB pathway and evidently decreased the secretion of inflammation cytokines. Meanwhile, the disturbance of pro- and anti-inflammatory response was reversed. We concluded that the disruption of pro- and anti-inflammatory T-cells balance caused by cytokines mediated cell-cell interactions may be one of the mechanisms underlying arsenic-induced liver injury and that GBE intervention exerts an evidence protective effects, which might be closely associated with the suppression of inflammatory-related TLR4 pathway.
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http://dx.doi.org/10.1002/tox.23324DOI Listing
July 2021

Epidemiology of hemorrhagic fever with renal syndrome in Tai'an area.

Sci Rep 2021 Jul 5;11(1):11596. Epub 2021 Jul 5.

Department of Health Management, The First Affiliated Hospital, Shandong Provincial Qianfoshan Hospital, Shandong Engineering Laboratory for Health Management, Shandong Medicine and Health Key Laboratory of Laboratory Medicine, Shandong First Medical University, Jinan, Shandong, People's Republic of China.

Hemorrhagic fever with renal syndrome (HFRS), a serious threat to human health, is mainly transmitted by rodents in Eurasia. The risk of disease differs according to sex, age, and occupation. Further, temperature and rainfall have some lagging effects on the occurrence of the disease. The quantitative data for these factors in the Tai'an region of China are still unknown. We used a forest map to calculate the risk of HFRS in different populations and used four different mathematical models to explain the relationship between time factors, meteorological factors, and the disease. The results showed that compared with the whole population, the relative risk in rural medical staff and farmers was 5.05 and 2.00, respectively (p < 0.05). Joinpoint models showed that the number of cases decreased by 33.32% per year from 2005 to 2008 (p < 0.05). The generalized additive model showed that air temperature was positively correlated with disease risk from January to June, and that relative humidity was negatively correlated with risk from July to December. From January to June, with an increase in temperature, after 15 lags, the cumulative risk of disease increased at low temperatures. From July to December, the cumulative risk decreased with an increase in the relative humidity. Rural medical staff, farmers, men, and middle-aged individuals were at a high risk of HFRS. Moreover, air temperature and relative humidity are important factors that affect disease occurrence. These associations show lagged and differing effects according to the season.
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http://dx.doi.org/10.1038/s41598-021-91029-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257732PMC
July 2021

PD-1 Coexpression Gene Analysis and the Regulatory Network in Endometrial Cancer Based on Bioinformatics Analysis.

Biomed Res Int 2021 25;2021:9923434. Epub 2021 May 25.

Tianjin Central Hospital of Gynecology and Obstetrics, Tianjin, China.

Gynecological malignancies are tumors of the female reproductive system, mainly cervical cancer, endometrial cancer, and ovarian cancer. Endometrial cancer (EC) is the most common gynecological malignant tumor in developed countries. The aim of this study was to construct a network of programmed cell death protein 1 (PD-1) coexpressed genes through bioinformatics analysis and screen the potential biomarkers of PD-1 in endometrial cancer. In addition, genes and pathways involved in PD-1 and modulating tumor immune status were identified. We select the EC transcriptomic dataset in TCGA to retrieve gene sets on the cBioPortal platform, and the PD-1 coexpressed genes were obtained on the platform. GO and KEGG enrichment analysis of coexpressed genes was performed using the DAVID database. The target protein-protein interaction (PPI) network was constructed using Cytoscape 3.7.1 software, and the hub genes were then screened. A total of 976 coexpression genes were obtained. The enrichment analysis showed that PD-1 coexpressed genes were significantly enriched in overall components of the cell structure, the interaction of cytokines with cytokine receptors, chemokine signaling pathways, and cell adhesion molecules (CAMs). Ten hub genes were obtained by node degree analysis. CD3E gene is involved in the prognosis and immune process of EC, and the expression level is related to PD-1 (Pearson correlation coefficient is 0.82, < 0.01). Patients with low CD3E gene expression in EC have a poor prognosis. The coexpression hub genes of PD-1 are related to immunity, in which CD3E is a prognostic marker that is involved in the PD-1/PD-L1-induced tumor immune escape. This study provides a new area to study the mechanism of PD-1/PD-L1 in EC and the precise treatment with targeted drugs.
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http://dx.doi.org/10.1155/2021/9923434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172290PMC
May 2021

The push-to-open mechanism of the tethered mechanosensitive ion channel NompC.

Elife 2021 Jun 8;10. Epub 2021 Jun 8.

Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China.

NompC is a mechanosensitive ion channel responsible for the sensation of touch and balance in . Based on a resolved cryo-EM structure, we performed all-atom molecular dynamics simulations and electrophysiological experiments to study the atomistic details of NompC gating. Our results showed that NompC could be opened by compression of the intracellular ankyrin repeat domain but not by a stretch, and a number of hydrogen bonds along the force convey pathway are important for the mechanosensitivity. Under intracellular compression, the bundled ankyrin repeat region acts like a spring with a spring constant of ~13 pN nm by transferring forces at a rate of ~1.8 nm ps. The linker helix region acts as a bridge between the ankyrin repeats and the transient receptor potential (TRP) domain, which passes on the pushing force to the TRP domain to undergo a clockwise rotation, resulting in the opening of the channel. This could be the universal gating mechanism of similar tethered mechanosensitive TRP channels, which enable cells to feel compression and shrinkage.
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http://dx.doi.org/10.7554/eLife.58388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186909PMC
June 2021

Assessing the potential value and mechanism of . On coal-fired arsenic-induced skin damage: In vitro and human evidence.

Hum Exp Toxicol 2021 Jun 4:9603271211021887. Epub 2021 Jun 4.

The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education & School of Public Helath, Guizhou Medical University, Guiyang, China.

Exposure through arsenic-contaminated air and food caused by the burning of coal is a major environmental public health concern in Guizhou Province of China. Previous studies have shown that immunological dysfunction is involved in the pathogenesis and carcinogenesis of arsenic; however, knowledge regarding effective prevention measures have not been fully examined. The effect of extract (EGb761) on arsenic-induced skin damage of human immortalized keratinocyte cells (HaCaT) was first evaluated in this study. The results showed that 200 μg/mL EGb761 can reduce the expression of miR-155-5p, and the indicators reflecting arsenic-induced skin damage (Krt1, Krt6c and Krt10) in arsenic-exposed cells ( 0.05), the expression levels of NF-AT1; the indicators reflecting arsenic-induced immunological dysfunction (IL-2, IFN-γ) in cells; and the levels of secreted IL-2 and IFN-γ in cell supernatants were significantly increased ( 0.05). Further randomized controlled double-blind experiments showed that compared to the placebo control group, the expression level of miR-155-5p in the plasma of the intervention group, the indicators in the serum reflecting arsenic-induced skin damage (Krt1, Krt6c, and Krt10) and the epithelial-mesenchymal transformation (EMT) vimentin were significantly reduced ( 0.05), but the levels of NF-AT1 and the indicators reflecting arsenic-induced immunological dysfunction (IL-2, IFN-γ) and EMT (E-cadherin) in serum were significantly increased ( 0.05). Our study provides some limited evidence that can increase the expression of NF-AT1 by downregulating the level of miR-155-5p, alleviating immunological dysfunction, and decreasing the expression of EMT biomarkers, thus indirectly improving arsenic-induced skin damage.
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http://dx.doi.org/10.1177/09603271211021887DOI Listing
June 2021

miR-486-3p regulates CyclinD1 and promotes fluoride-induced osteoblast proliferation and activation.

Environ Toxicol 2021 Jun 3. Epub 2021 Jun 3.

School of Public Health, The key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, China.

Fluoride is a persistent environmental pollutant, and its excessive intake contributes to skeletal and dental fluorosis. The mechanisms underlying fluoride-induced abnormal osteoblast proliferation and activation, which are related to skeletal fluorosis, have not yet been fully clarified. As important epigenetic regulators, microRNAs (miRNAs) participate in bone metabolism. On the basis of our previous miRNA-seq results and bioinformatics analysis, this study investigated the role and specific molecular mechanism of miR-486-3p in fluoride-induced osteoblast proliferation and activation via CyclinD1. Herein, in the fluoride-challenged population, we observed that miR-486-3p expression decreased while CyclinD1 and transforming growth factor (TGF)-β1 increased, and miR-486-3p level correlated negatively with the expression of CyclinD1 and TGF-β1 genes. Further, we verified that sodium fluoride (NaF) decreases miR-486-3p expression in human osteoblasts and overexpression of miR-486-3p reduces fluoride-induced osteoblast proliferation and activation. Meanwhile, we demonstrated that miR-486-3p regulates NaF-induced upregulation of CyclinD1 by directly targeting its 3'-untranslated region (3'-UTR). In addition, we observed that NaF activates the TGF-β1/Smad2/3/CyclinD1 axis and miR-486-3p mediates transcriptional regulation of CyclinD1 by TGF-β1/Smad2/3 signaling pathway via targeting TGF-β1 3'-UTR in vitro. This study, thus, contributes significantly in revealing the mechanism of miR-486-3p-mediated CyclinD1 upregulation in skeletal fluorosis and sheds new light on endemic fluorosis treatment.
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http://dx.doi.org/10.1002/tox.23302DOI Listing
June 2021

Lower serum irisin levels are associated with the increasing mortality of cardiovascular and cerebrovascular diseases in hemodialysis patients.

Ann Palliat Med 2021 Jun 18;10(6):6052-6061. Epub 2021 May 18.

Department of Nephrology, Xuanwu Hospital, Capital Medical University, Beijing, China.

Background: Irisin is a recently discovered myokine/adipokine and lower levels of irisin were proved to be associated with adverse outcomes of cardiovascular and cerebrovascular diseases (CCVD) in general population. A significant decrease of irisin concentrations were also detected in patients with chronic kidney disease (CKD). In the present study, we investigated whether the serum irisin levels were associated with cardiovascular and cerebrovascular mortality in hemodialysis (HD) patients.

Methods: This retrospective cohort study enrolled 152 HD patients. Kaplan-Meier analysis was used to estimate the cumulative mortality of CCVD. The differences between the survival curves were compared by log-rank test. A multivariable Cox regression analysis was employed to identify the predictors of CCVD related deaths.

Results: Among 152 HD patients, 55 patients died and 18 of them died of CCVD, 97 HD patients survived. Compared with the survival group, patients died of CCVD had significantly lower serum irisin levels [23.6 (2.2, 319.4) vs. 45.7 (2.1, 367.8) ng/mL, P<0.05]. The Kaplan-Meier survival curves showed that patients with lower levels of irisin had higher CCVD mortality. The Cox regression analysis indicated lower irisin level as an independent risk factor for CCVD mortality in HD patients but not for all-cause mortality.

Conclusions: Our results provided an association between lower irisin level and CCVD mortality in HD patients. Lower levels of irisin increased the mortality of CCVD in HD patients.
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http://dx.doi.org/10.21037/apm-21-406DOI Listing
June 2021

Clinical and Functional Characterization of Novel INSR Variants in Two Families With Severe Insulin Resistance Syndrome.

Front Endocrinol (Lausanne) 2021 29;12:606964. Epub 2021 Apr 29.

Department of Endocrinology, Children's Hospital of Nanjing Medical University, Nanjing, China.

Objective: Defects in the insulin receptor () gene cause various severe insulin resistance conditions, including Donohue syndrome (DS), Rabson-Mendenhall syndrome (RMS) and type A insulin resistance (type A-IR). This study aimed to investigate the clinical characterization and molecular defects in three Chinese children with -related insulin resistance syndrome.

Methods: We reviewed the clinical data of three Chinese children with -related insulin resistance syndrome from two unrelated kindreds. Genetic analysis was performed using whole-exome sequencing and the effects of the novel variants were further assessed by functional assays.

Results: The proband with type A-IR presented with acanthosis nigricans, hypertrichosis, and euglycemia with mild insulin resistance in early childhood. His sister presented with features typical of type A-IR and was diagnosed with diabetes mellitus with severe insulin resistance at the age of 9.8 years. The proband with DS showed typical dysmorphic characteristics, severe intrauterine growth retardation, extreme insulin resistance, fasting hypoglycemia and postprandial hyperglycemia from birth. The heterozygote variants c.[3670G>A]; c.[3614C>T] were identified in both siblings with type A-IR; and c.[749_751del]; c.[3355C>T] in the patient with DS. studies showed that the novel variant c.749_751del [p.(Thr250del)] in the α-subunit, reduced expression of the mature INSR protein and severely impaired INSR function. In contrast, the novel variant c.3670G>A [p.(Val1224Met)] in the β-subunit had no effect on total protein expression and phosphorylation of INSR and Akt, suggesting that the variant p.Val1224Met appeared to be tolerated and was not responsible for the severe insulin resistance.

Conclusion: Our study detailed the clinical features of three patients with type A-IR and DS, and identified two novel variants in the gene. Functional assays indicated the novel variant p.Thr250del was pathogenic. In contrast, the novel variant p.Val1224Met was suggested to be tolerated by our experimental data, even though bioinformatics analyses predicted the variant as deleterious.
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http://dx.doi.org/10.3389/fendo.2021.606964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8117416PMC
April 2021

let-7c-5p regulates CyclinD1 in fluoride-mediated osteoblast proliferation and activation.

Toxicol Sci 2021 May 12. Epub 2021 May 12.

School of Public Health, The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 550025, China.

Endemic fluorosis is caused by the intake of high environmental fluoride levels, which causes dental and skeletal fluorosis. Osteoblast proliferation and activation is closely related to skeletal fluorosis and is tightly regulated by the cell cycle. Several biological processes, including bone metabolism and osteoblast proliferation and activation, are regulated by a type of non-coding RNA called microRNAs (miRNAs). However, the understanding of miRNA functions in skeletal fluorosis is limited. Based on our previous miRNA sequencing results and bioinformatics analysis, we investigated the function of the miRNA let-7c-5p to regulate CyclinD1 in fluoride-induced osteoblast proliferation and activation. We designed population experiments as well as in vitro studies using EdU, flow cytometry, immunofluorescence, dual-luciferase reporters, and chromatin immunoprecipitation. The population-based analysis showed a decrease in let-7c-5p expression as fluoride exposure increased. In addition, let-7c-5p levels were negatively correlated with CyclinD1 and Wnt9a (another let-7c-5p target). We verified in vitro that let-7c-5p participates in the fluoride-induced proliferation and activation of human osteoblasts by directly targeting CyclinD1. Furthermore, we demonstrated that let-7c-5p regulates CyclinD1 expression via the Wnt/β-catenin signaling pathway. This study demonstrated the participation of let-7c-5p in fluoride-induced proliferation and activation of human osteoblasts by regulation of CyclinD1 expression at the post-transcriptional and transcriptional levels. We report for the first time that the Wnt9a/β-catenin/CyclinD1 axis is involved in fluorosis development.
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http://dx.doi.org/10.1093/toxsci/kfab054DOI Listing
May 2021

Response to comment on "Nuclear receptor PXR targets AKR1B7 to protect mitochondrial metabolism and renal function in AKI".

Sci Transl Med 2021 05;13(593)

Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.

The nuclear pregnane X receptor protects against bilateral renal ischemia/reperfusion-induced acute kidney injury in mice.
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http://dx.doi.org/10.1126/scitranslmed.abf9849DOI Listing
May 2021

Estrogen-Related Receptor γ Agonist DY131 Ameliorates Lipopolysaccharide-Induced Acute Liver Injury.

Front Pharmacol 2021 23;12:626166. Epub 2021 Apr 23.

Department of Pediatrics, School of Medicine, Southeast University, Nanjing, China.

Sepsis-associated liver dysfunction remains a challenge in clinical practice with high mortality and limited specific therapies. DY131 is a pharmacological agonist of the orphan receptor estrogen-related receptor (ERR) γ which plays a crucial role in regulating energy generation, oxidative metabolism, cell apoptosis, inflammatory responses, etc. However, its role in acute liver injury is unknown. In this study, we evaluated the effect of DY131 on lipopolysaccharide (LPS)-induced liver injury. Mice were pretreated with DY131 through intraperitoneal injection at a dose of 5 mg/kg/day for 3 days prior to LPS challenge (10 mg/kg). 24 h later, they were anesthetized and sacrificed. Blood and liver tissues were collected for further studies. In a separate experiment, mice were treated with saline (vehicle) or DY131 for 3 days to evaluate the toxicity of DY131. We found that ERRγ was downregulated in the liver tissues from LPS-treated mice. Pretreatment with DY131 ameliorated LPS-induced liver injury as demonstrated by reduced liver enzyme release (ALT, AST, and LDH), improved liver morphological damage, and attenuated oxidative stress, inflammation and apoptosis. Meanwhile, DY131 had no significant side effects on hepatic and renal functions in mice. Finally, transcriptomics analysis revealed that the dysregulated pathways associated with inflammation and metabolism were significantly reversed by DY131 in LPS-treated mice, providing more evidence in favor of the protective effect of DY131 against LPS-induced liver injury. Altogether, these findings highlighted the protective effect of DY131 on LPS-induced hepatotoxicity possibly via suppressing oxidative stress, inflammation, and apoptosis.
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http://dx.doi.org/10.3389/fphar.2021.626166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104008PMC
April 2021

miR-21 in EVs from pulmonary epithelial cells promotes myofibroblast differentiation via glycolysis in arsenic-induced pulmonary fibrosis.

Environ Pollut 2021 Apr 29;286:117259. Epub 2021 Apr 29.

Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China; China International Cooperation Center for Environment and Human Health, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, People's Republic of China. Electronic address:

As an environmental toxicant, arsenic causes damage to various organs and systems of the body and has attracted worldwide attention. It is well-known that exposure to arsenic can induce pulmonary fibrosis, but the molecular mechanisms are elusive. Glycolysis is involved in the process of various diseases, including pulmonary fibrosis. Extracellular vehicles (EVs) are mediators of cell communication through transporting miRNAs. The potential of miRNAs in EVs as liquid biopsy biomarkers for various diseases has been reported, and they have been applied in clinical diagnoses. In the present investigation, we focused on the roles and mechanisms of miR-21 in EVs on arsenic-induced glycolysis and pulmonary fibrosis through experiments with human populations, experimental animals, and cells. The results for arsenicosis populations showed that the serum levels of hydroxyproline, lactate, and EVs-miRNAs were elevated and that EVs-miR-21 levels were positively related to the levels of hydroxyproline and lactate. For mice, chronic exposure to arsenite led to high levels of miR-21, AKT activation, elevated glycolysis, and pulmonary fibrosis; however, these effects were blocked by the depletion of miR-21 in miR-21 knockout (miR-21) mice. After MRC-5 cells were co-cultured with arsenite-treated HBE cells, the levels of miR-21, AKT activation, glycolysis, and myofibroblast differentiation were enhanced, effects that were blocked by reducing miR-21 and by inhibiting the EVs in HBE cells. The down-regulation of PTEN in MRC-5 cells and primary lung fibroblasts (PLFs) reversed the blocking effect of inhibiting miR-21 in HBE cells. Thus, miR-21 down-regulates PTEN and promotes glycolysis via activating AKT, which is associated with arsenite-induced myofibroblast differentiation and pulmonary fibrosis. Our results provide a new approach for the construction of clinical diagnosis technology based on analysis of the mechanism of arsenite-induced pulmonary fibrosis.
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http://dx.doi.org/10.1016/j.envpol.2021.117259DOI Listing
April 2021

Assessing the risk of coal-burning arsenic-induced liver damage: a population-based study on hair arsenic and cumulative arsenic.

Environ Sci Pollut Res Int 2021 May 7. Epub 2021 May 7.

The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, China.

Exposure to arsenic-contaminated air and food caused by the burning of coal in unventilated indoor stoves is a major environmental public health concern in Guizhou Province, China. The liver is one of the main target organs for coal-fired arsenic exposure; however, there is little information about the risk assessment between cumulative arsenic exposure and the prevalence of liver damage. This study first evaluated the chronic daily intake (CDI) for two exposure pathways (inhalation and ingestion) and five environmental media (i.e., indoor and outdoor air, drinking water, rice, corn, and chili peppers) in 1998, 2006, 2014, and 2017. Then, the dose-effect and dose-response relationship between hair arsenic (HA) and cumulative arsenic (CA) levels and liver damage was analyzed. The results clearly show that the CDI in 1998 was 34.9 μg·kg·d, 22.9 μg·kg·d in 2006, 11.7 μg·kg·d in 2014, and 6.7 μg·kg·d in 2017 in the arsenic exposure area. All of these values were higher than the daily baseline level of 3.0 μg·kg·d as recommended by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), and the increased HA and CA can increase the risk of coal-fired arsenic-induced liver damage. In addition, we analyzed the possible maximum acceptable CA exposure level for coal-fired arsenic-induced liver damage using the Bayesian benchmark dose. The recommended maximum acceptable CA exposure level for liver damage caused by coal-burning arsenic is 7120 mg. This study provides scientific insight into understanding the dose-response relationship of liver damage caused by coal-burning arsenic exposure and the monitoring and prevention of arsenic poisoning.
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http://dx.doi.org/10.1007/s11356-021-14273-yDOI Listing
May 2021

Establish a Real-time Responsible Home Quarantine and Monitoring Management mHealth Platform.

AMIA Annu Symp Proc 2020 25;2020:697-706. Epub 2021 Jan 25.

Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan.

Due to the global spreading of the COVID-19 virus, countries all over the world are faced with the need to conduct centralized quarantine or home quarantine for "persons who have been in contact with individuals diagnosed with the COVID-19 virus" and "visitors who have travel histories via COVID-19 hot zones". We have presented the community home quarantine service platform design that was utilized in Nanjing, China when the first wave of citizens returns to work after the Chinese New Year holidays on 10th Feb 2020. The main functions of the home quarantine monitoring system include (1) community grid management,(2) GPS positioning application in home isolation movement management,(3) Bluetooth body temperature patch data transmission integration, (4) health assessment scale (physical and mental health state) and (5) multilingual language options.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075449PMC
May 2021

Atomistic Details of Charge/Space Competition in the Ca Selectivity of Ryanodine Receptors.

J Phys Chem Lett 2021 May 28;12(17):4286-4291. Epub 2021 Apr 28.

Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.

Ryanodine receptors (RyRs) are ion channels responsible for the fast release of Ca from the sarco/endoplasmic reticulum to the cytosol and show a selectivity of Ca over monovalent cations. By utilizing a recently developed multisite Ca model in molecular dynamic simulations, we show that multiple cations accumulate in the upper selectivity filter of RyRs, and the small size and high valence of Ca make it preferable to K in competition for space in this confined region of negative electrostatic potential. The presence of Ca in the upper selectivity filter significantly increases the energy barrier of K permeation, while the presence of K has little impact on the Ca permeation. Our results provide the atomistic details of the charge/space competition mechanism for the ion selectivity of RyRs, which ensures the robustness of their Ca release function. The mechanism could be utilized in protein- and nanoengineering for valence selectivity of ion species.
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http://dx.doi.org/10.1021/acs.jpclett.1c00681DOI Listing
May 2021

Effects of hydrogen as adjuvant treatment for unstable angina.

Exp Biol Med (Maywood) 2021 Apr 25:15353702211009138. Epub 2021 Apr 25.

Key Laboratory of Atherosclerosis in Universities of Shandong and Institute of Atherosclerosis, Shandong First Medical University, Shandong 271000, China.

Oxidative stress and inflammation are closely related to atherosclerotic cardiovascular disease. It is established that hydrogen has significant protective effects on many diseases as a potential antioxidative and anti-inflammatory agent. The purpose of this study is to evaluate the effect of hydrogen on unstable angina An atherosclerosis model was constructed by ox-LDL-induced injury of human umbilical vein endothelial cells and testing indicated hydrogen inhibited ox-LDL-induced oxidative stress and inflammatory response by down-regulating LOX-1/NF-kB signaling pathway. Subsequently, the attenuating effect of hydrogen-rich water intake on unstable angina was further confirmed in clinic. Forty hospitalized subjects with unstable angina were enrolled and consumed either 1000-1200 mL/d hydrogen-rich water or the same amount of placebo pure water in addition to conventional drugs for three months. Clinical analysis showed hydrogen-rich water intake relieved angina symptoms in unstable angina patients. Serum analysis showed that hydrogen-rich water addition resulted in more effective reductions of total-cholesterol, low-density lipoprotein-cholesterol, and apolipoprotein B levels compared with conventional treatment. These results support that hydrogen as adjuvant treatment has a beneficial effect on unstable angina.
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http://dx.doi.org/10.1177/15353702211009138DOI Listing
April 2021

Exposure to fine particulate matter-bound polycyclic aromatic hydrocarbons, male semen quality, and reproductive hormones: The MARCHS study.

Environ Pollut 2021 Jul 20;280:116883. Epub 2021 Mar 20.

Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Institute of Toxicology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China. Electronic address:

Exposure to outdoor fine particulate matter (PM)-bound polycyclic aromatic hydrocarbons (PAHs) is linked to reproductive dysfunction. However, it is unclear which component of PAHs is responsible for the adverse outcomes. In the Male Reproductive Health in Chongqing College Students (MARHCS) cohort study, we measured the exposure levels of 16 PAHs by collecting air PM particles and assessed eight PAHs metabolites from four parent PAHs, including naphthalene, fluorene, phenanthrene, and pyrene in urine samples. We investigated compositional profiles and variation characteristics for 16 PAHs in PM, and then assessed the association between PAHs exposure and semen routine parameters, sperm chromatin structure, and serum hormone levels in 1452 samples. The results showed that naphthalene (95% CI: -17.989, -8.101), chrysene (95% CI: -64.894, -47.575), benzo[a]anthracene (95% CI: -63.227, -45.936) and all the high molecular weight (HMW) PAHs in PM were negatively associated with sperm normal morphology. Most of the low molecular weight (LMW) PAHs, such as acenaphthylene, fluorene, phenanthrene, fluoranthene, pyrene, chrysene, benzo[a]anthracene, ∑LMW PAHs and ∑16 PAHs, were correlated with increased sperm motility (all corrected P < 0.05). On the other hand, sperm normal morphology was all negatively associated with urinary metabolites of ∑OH-Nap (95% CI: -5.611, -0.536), ∑OH-Phe (95% CI: -5.741, -0.957), and ∑OH-PAHs (95% CI: -5.274, -0.361). Urinary concentrations of ∑OH-PAHs were found to be negatively associated with sperm high DNA stainability (HDS) (P = 0.023), while ∑OH-Phe were negatively associated with serum testosterone level and sperm HDS (P = 0.004). Spearman correlation analysis showed that except for the urinary OH-Nap metabolites, the rest of the urinary OH-PAHs metabolites were negatively correlated with their parent PAHs in air. The results of this study suggest that various PAHs' components may affect reproductive parameters differently. Inhalation of PAHs in air, especially HMW PAHs, may be a potential risk factor for male reproductive health.
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http://dx.doi.org/10.1016/j.envpol.2021.116883DOI Listing
July 2021

Clinical and Imaging Analysis of Cerebral Infarction Caused by Spontaneous Cerebral Artery Dissection Based on Augmented Reality Technology.

J Healthc Eng 2021 11;2021:6671121. Epub 2021 Feb 11.

Computer Tomography Room, Cangzhou Central Hospital, Cangzhou 061000, Hebei, China.

In recent years, with the progress of population ageing, the incidence of a stroke caused by spontaneous dissection of the cerebral artery also increases with time. In order to address the health damage caused by a stroke caused by spontaneous dissection of the cerebral artery and to study its effect on human health, this article analyzes the incidence, type, electrocardiogram, and cardiovascular biomarker changes of cerebral infarction through statistical analysis and then discusses cerebral infarction. The pathogenesis and prevention measures of the disease are expected to provide better means for the treatment of cerebral infarction. Based on the case investigation of patients with cerebral infarction caused by spontaneous cerebral artery dissection, a case template was constructed, and a damage assessment matrix was created using a comprehensive quantitative and qualitative analysis method. Experimental results prove that cerebral infarction caused by spontaneous cerebral artery dissection is a great threat to human health, and the fatality rate of patients is extremely high. Enhanced imaging technology is of great help to clinical and image analysis, with a correlation coefficient of 0.87, compared with the other damage rate of cerebral infarction caused by spontaneous cerebral artery dissection which is about 15% higher than that of cerebral infarction caused by different methods. Studies have found that there are great differences in the age of people with cerebral infarction caused by spontaneous cerebral artery dissection, and the patients are generally over 45 years old. This shows that cerebral infarction caused by spontaneous cerebral artery dissection will cause great damage and affect people's health, which requires people's attention.
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http://dx.doi.org/10.1155/2021/6671121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892251PMC
February 2021

The novel STING antagonist H151 ameliorates cisplatin-induced acute kidney injury and mitochondrial dysfunction.

Am J Physiol Renal Physiol 2021 04 22;320(4):F608-F616. Epub 2021 Feb 22.

Nanjing Key Lab of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.

Stimulator of interferon genes (STING) is an important adaptor in cytosolic DNA-sensing pathways. A recent study found that the deletion of STING ameliorated cisplatin-induced acute kidney injury (AKI), suggesting that STING could serve as a potential target for AKI therapy. Up to now, a series of small-molecule STING inhibitors/antagonists have been identified. However, none of the research was performed to explore the role of human STING inhibitors in AKI. Here, we investigated the effect of a newly generated covalent antagonist, H151, which targets both human and murine STING, in cisplatin-induced AKI. We found that H151 treatment significantly ameliorated cisplatin-induced kidney injury as shown by the improvement of renal function, kidney morphology, and renal inflammation. In addition, tubular cell apoptosis and increased renal tubular injury marker neutrophil gelatinase-associated lipocalin induced by cisplatin were also effectively attenuated in H151-treated mice. Moreover, the mitochondrial injury caused by cisplatin was also reversed as evidenced by improved mitochondrial morphology, restored mitochondrial DNA content, and reversed mitochondrial gene expression. Finally, we observed enhanced mitochondrial DNA levels in the plasma of patients receiving platinum-based chemotherapy compared with healthy controls, which could potentially activate STING signaling. Taken together, these findings suggested that H151 could be a potential therapeutic agent for treating AKI possibly through inhibiting STING-mediated inflammation and mitochondrial injury. Although various stimulator of interferon genes (STING) inhibitors have been identified, no research was performed to investigate the role of human STING inhibitors in AKI. Here, we evaluated the effect of H151 targeting both human and murine STING on cisplatin-induced AKI and observed a protection against renal injury possibly through ameliorating inflammation and mitochondrial dysfunction.
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http://dx.doi.org/10.1152/ajprenal.00554.2020DOI Listing
April 2021

Acute effects of short-term exposure to ambient air pollution on reproductive hormones in young males of the MARHCS study in China.

Sci Total Environ 2021 Jun 6;774:145691. Epub 2021 Feb 6.

Key Lab of Medical Protection for Electromagnetic Radiation, Ministry of Education of China, Institute of Toxicology, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing, China. Electronic address:

Air pollution, which is associated with male reproductive health. However, it is unknown the acute effects of ambient air pollutants exposure on male reproductive hormones. The current study, we measured serum levels of reproductive hormone in 2030 blood samples gathered from The Male Reproductive Health in Chongqing College Students (MARHCS) cohort study. We derived a full coverage of ambient air pollutant (PM, PM, SO, NO, CO and O) concentrations by employing machine learning algorithms, and used a mixed-effect model to estimate single-day and cumulative effects of air pollutants exposure on serum reproductive hormones. Our results showed that (1) PM and PM concentrations were positively associated with estradiol (E) in both single and cumulative lag days, but were negatively associated with the ratio of Testosterone/E (the T/E ratio). NO was positively associated with estradiol at lag day 2 (95% CI: 0.290, 0.881; corrected P = 0.048) and lag 0-2 days (95% CI: 0.523, 1.337; corrected P = 0.003), with progesterone (P) at lag day 2 and lag day 3 (corrected P < 0.05). There was also a positive association between CO exposure and progesterone at lag day 2. (2) SO was inversely associated with E at lag day 3, 4 and lag 0-4 days, and progesterone at lag day 0, 1, 2 and lag 0-1, 0-2, 0-4 days, but positively associated with the T/E ratio at lag day 3, 4 and lag 0-4 days (corrected P < 0.05). O exposure was negatively associated with E at lag day 3 (95% CI: -0.216, -0.074, corrected P = 0.03). (3) No significant associations were found between the cumulative daily average air pollutant exposure of CO, O and hormone outcomes. This study suggests that short-term exposure to air pollutants may thus alter reproductive hormone levels, especially on serum estradiol, progesterone levels and the T/E ratio.
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http://dx.doi.org/10.1016/j.scitotenv.2021.145691DOI Listing
June 2021

Celastrol inhibits intestinal lipid absorption by reprofiling the gut microbiota to attenuate high-fat diet-induced obesity.

iScience 2021 Feb 20;24(2):102077. Epub 2021 Jan 20.

Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Guangzhou Road #72, Nanjing 210008, P. R. of China.

Celastrol, a compound extracted from traditional Chinese medicine, has been reported as a potent anti-obesity agent with controversial mechanisms. Here both C57BL/6J and leptin-deficient () mice fed a high-fat diet (HFD) displayed body weight loss after celastrol therapy, opposing the previous viewpoint that celastrol improves obesity by sensitizing leptin signaling. More importantly, celastrol downregulated lipid transporters in the intestine, increased lipid excretion in feces, and reduced body weight gain in HFD mice. Meanwhile, analysis of gut microbiota revealed that celastrol altered the gut microbiota composition in HFD-fed mice, and modulating gut microbiota by antibiotics or fecal microbiota transplantation blocked the celastrol effect on intestinal lipid transport and body weight gain, suggesting a critical role of the gut microbiota composition in mediating the anti-obesity role of celastrol under HFD. Together, the findings revealed that celastrol reduces intestinal lipid absorption to antagonize obesity by resetting the gut microbiota profile under HFD feeding.
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http://dx.doi.org/10.1016/j.isci.2021.102077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868996PMC
February 2021

Cilomilast Ameliorates Renal Tubulointerstitial Fibrosis by Inhibiting the TGF-β1-Smad2/3 Signaling Pathway.

Front Med (Lausanne) 2020 21;7:626140. Epub 2021 Jan 21.

Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China.

Renal tubulointerstitial fibrosis is the key pathological feature in chronic kidney diseases (CKDs) with no satisfactory therapies in clinic. Cilomilast is a second-generation, selective phosphodiesterase-4 inhibitor, but its role in renal tubulointerstitial fibrosis in CKD remains unclear. Cilomilast was applied to the mice with unilateral ureteric obstruction (UUO) and renal fibroblast cells (NRK-49F) stimulated by TGF-β1. Renal tubulointerstitial fibrosis and inflammation after UUO or TGF-β1 stimulation were examined by histology, Western blotting, real-time PCR and immunohistochemistry. KIM-1 and NGAL were detected to evaluate tubular injury in UUO mice. , immunohistochemistry and western blot data demonstrated that cilomilast treatment inhibited extracellular matrix deposition, profibrotic gene expression, and the inflammatory response. Furthermore, cilomilast prevented tubular injury in UUO mice, as manifested by reduced expression of KIM-1 and NGAL in the kidney. , cilomilast attenuated the activation of fibroblast cells stimulated by TGF-β1, as shown by the reduced expression of fibronectin, α-SMA, collagen I, and collagen III. Cilomilast also inhibited the activation of TGF-β1-Smad2/3 signaling in TGF-β1-treated fibroblast cells. The findings of this study suggest that cilomilast is protective against renal tubulointerstitial fibrosis in CKD, possibly through the inhibition of TGF-β1-Smad2/3 signaling, indicating the translational potential of this drug in treating CKD.
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http://dx.doi.org/10.3389/fmed.2020.626140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859332PMC
January 2021

Gasdermin E deficiency attenuates acute kidney injury by inhibiting pyroptosis and inflammation.

Cell Death Dis 2021 02 1;12(2):139. Epub 2021 Feb 1.

Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, 210008, Nanjing, China.

Pyroptosis, one kind of inflammatory regulated cell death, is involved in various inflammatory diseases, including acute kidney injury (AKI). Besides Gasdermin D (GSDMD), GSDME is a newly identified mediator of pyroptosis via the cleavage of caspase-3 generating pyroptotic GSDME-N. Here, we investigated the role of GSDME in renal cellular pyroptosis and AKI pathogenesis employing GSDME-deficient mice and human tubular epithelial cells (TECs) with the interventions of pharmacological and genetic approaches. After cisplatin treatment, GSDME-mediated pyroptosis was induced as shown by the characteristic pyroptotic morphology in TECs, upregulated GSDME-N expression and enhanced release of IL-1β and LDH, and decreased cell viability. Strikingly, silencing GSDME in mice attenuated acute kidney injury and inflammation. The pyroptotic role of GSDME was also verified in human TECs in vitro. Further investigation showed that inhibition of caspase-3 blocked GSDME-N cleavage and attenuated cisplatin-induced pyroptosis and kidney dysfunction. Moreover, deletion of GSDME also protected against kidney injury induced by ischemia-reperfusion. Taken together, the findings from current study demonstrated that caspase-3/GSDME-triggered pyroptosis and inflammation contributes to AKI, providing new insights into the understanding and treatment of this disease.
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http://dx.doi.org/10.1038/s41419-021-03431-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862699PMC
February 2021

Targeting microsomal prostaglandin E synthase 1 to develop drugs treating the inflammatory diseases.

Am J Transl Res 2021 15;13(1):391-419. Epub 2021 Jan 15.

Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University Nanjing 210008, China.

Microsomal prostaglandin E synthase 1 (mPGES-1) is the terminal synthase of prostaglandin E2 (PGE2) which plays a crucial role in inflammatory diseases. Thus, mPGES-1 inhibitors are promising agents for their better specificity in blocking the production of PGE2, a potent inflammatory mediator, compared with non-steroidal anti-inflammatory drugs (NSAIDs). Currently, two mPGES-1 inhibitors are undergoing clinical trials and more novel inhibitors are being developed. In this review, we focus on the advances in the development of mPGES-1 inhibitors and the potential of these inhibitors to treat different inflammatory diseases, and discuss the existing challenges. The insights from this review will increase the understanding on the current status of mPGES-1-targeted anti-inflammatory drug development and the potential of these drugs in treating inflammation in diseases.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847505PMC
January 2021

[Design of Radial Artery Simulation Platform Based on Waveform Drive].

Zhongguo Yi Liao Qi Xie Za Zhi 2021 Feb;45(1):26-31

School of Electrical and Information Engineering, Lanzhou University of Technology, Gansu, Lanzhou, 730050.

In order to obtain the three-dimensional pulse information and blood pressure waveform needed in the study, a radial artery simulation platform with programmable controlled injection pump as the core was constructed by using the circulation theory of human cardiovascular system and pulse wave formation mechanism. Gaussian function model was selected to synthesize multi-type pulse wave to program and drive the platform. The three-dimensional pulse information and blood pressure waveform of the simulated radial artery were collected by binocular visual pulse detection system and pressure transmitter respectively, and the platform stability and repeatability were tested by Pearson correlation. The experimental results show that the radial artery simulation platform is stable, reliable and repeatable, and can generate multiple types of three-dimensional pulse information and blood pressure waveform at the simulated radial artery. The platform is simple in structure, low in cost, and produces many types of pulsating flow. It provides an experimental research platform for revealing the relationship between the three-dimensional pulse information of radial artery and the change of pressure inside the vessel, as well as the prediction of blood pressure waveform from the three-dimensional pulse information.
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http://dx.doi.org/10.3969/j.issn.1671-7104.2021.01.006DOI Listing
February 2021

Role of inhibiting Chk1-p53 pathway in hepatotoxicity caused by chronic arsenic exposure from coal-burning.

Hum Exp Toxicol 2021 Jul 27;40(7):1141-1152. Epub 2021 Jan 27.

Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, 74628Guizhou Medical University, Guiyang, Guizhou, People's Republic of China.

Arsenic is a naturally occurring environmental toxicant, chronic exposure to arsenic can cause multiorgan damage, except for typical skin lesions, liver damage is the main problem for health concern in population with arsenic poisoning. Abnormal apoptosis is closely related to liver-related diseases, and p53 is one of the important hallmark proteins in apoptosis progression. This study was to investigate whether arsenic poisoning-induced hepatocyte apoptosis and the underlying role of p53 signaling pathway. A rat model of arsenic poisoning was established by feeding corn powder for 90 days, which was baked with high arsenic coal, then were treated with (GBE) for 45 days by gavage. The results showed that arsenic induced liver damage, increased hepatocyte apoptosis and elevated the expression level of Chk1 and the ratios of p-p53/p53 and Bax/Bcl-2 in liver tissues, which were significantly attenuated by GBE. Additionally, to further demonstrate the potential apoptosis-associated mechanism, L-02 cells were pre-incubated with p53 inhibitor pifithrin-α (PFTα), ataxia telangiectasia-mutated (ATM)/ataxia telangiectasia-mutated and Rad3-related (ATR) inhibitor (CGK733) or GBE, then treated with sodium arsenite (NaAsO) for 24 h. The results showed that GBE, PFTα or CGK733 significantly reduced arsenic-induced Chk1 expression and the ratios of p-p53/p53 and Bax/Bcl-2. In conclusion, Chk1-p53 pathway was involved in arsenic poisoning-induced hepatotoxicity, and inhibiting of Chk1-p53 pathway ameliorated hepatocyte apoptosis caused by coal-burning arsenic poisoning. The study provides a pivotal clue for understanding of the mechanism of arsenic poisoning-induced liver damage, and possible intervention strategies.
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http://dx.doi.org/10.1177/0960327120988880DOI Listing
July 2021

miR-21-regulated M2 polarization of macrophage is involved in arsenicosis-induced hepatic fibrosis through the activation of hepatic stellate cells.

J Cell Physiol 2021 Aug 22;236(8):6025-6041. Epub 2021 Jan 22.

Center for Global Health, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, China.

Arsenicosis induced by chronic exposure to arsenic is recognized as one of the main damaging effects on public health. Exposure to arsenic can cause hepatic fibrosis, but the molecular mechanisms by which this occurs are complex and elusive. It is not known if miRNAs are involved in arsenic-induced liver fibrosis. We found that in the livers of mice exposed to arsenite, there were elevated levels of microRNA-21 (miR-21), phosphorylated mammalian target of rapamycin (p-mTOR), and arginase 1 (Arg1); low levels of phosphatase and tensin homolog (PTEN); and more extensive liver fibrosis. For cultured cells, arsenite-induced miR-21, p-mTOR, and Arg1; decreased PTEN; and promoted M2 polarization of macrophages derived from THP-1 monocytes (THP-M), which caused secretion of fibrogenic cytokines, including transforming growth factor-β1. Coculture of arsenite-treated, THP-M with LX-2 cells induced α-SMA and collagen I in the LX-2 cells and resulted in the activation of these cells. Downregulation of miR-21 in THP-M inhibited arsenite-induced M2 polarization and activation of LX-2 cells, but cotransfection with PTEN siRNA or a miR-21 inhibitor reversed this inhibition. Moreover, knockout of miR-21 in mice attenuated liver fibrosis and M2 polarization compared with WT mice exposed to arsenite. Additionally, LN, PCIII, and HA levels were higher in patients with higher hair arsenic levels, and levels of miR-21 were higher than controls and positively correlated with PCIII, LN, and HA levels. Thus, arsenite induces the M2 polarization of macrophages via miR-21 regulation of PTEN, which is involved in the activation of hepatic stellate cells and hepatic fibrosis. The results establish a previously unknown mechanism for arsenicosis-induced fibrosis.
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http://dx.doi.org/10.1002/jcp.30288DOI Listing
August 2021