scholarly journals Luteolin Alleviates Methamphetamine-Induced Hepatotoxicity by Suppressing the p53 Pathway-Mediated Apoptosis, Autophagy, and Inflammation in Rats

2021 ◽  
Vol 12 ◽  
Author(s):  
Kai-Kai Zhang ◽  
Hui Wang ◽  
Dong Qu ◽  
Li-Jian Chen ◽  
Li-Bin Wang ◽  
...  
Keyword(s):  
Sodium Dodecyl ◽  
Control Group ◽  
Sequencing Data ◽  
Protective Mechanisms ◽  
P53 Pathway ◽  
P53 Signaling ◽  
Tnf Α ◽  
Biochemical Analyses ◽  
P53 Signaling Pathway ◽  
Luteolin Treatment

Misuse of the psychostimulant methamphetamine (METH) could induce serious hepatotoxicity. Our previous study revealed the effects of luteolin on alleviating METH-induced hepatotoxicity, however, the detailed mechanisms have not been elucidated. In this study, rats were orally pretreated with 100 mg/kg luteolin or sodium dodecyl sulfate water, and then METH (15 mg/kg, intraperitoneal [i.p.]) or saline was administered. Histopathological and biochemical analyses were used to determine the alleviative effects of luteolin. Based on the RNA-sequencing data, METH induced 1859 differentially expressed genes (DEGs) in comparison with the control group, which were enriched into 11 signaling pathways. Among these DEGs, 497 DEGs could be regulated through luteolin treatment and enriched into 16 pathways. The p53 signaling pathway was enriched in both METH administered and luteolin pretreated rats. Meanwhile, luteolin significantly suppressed METH-induced elevation of p53, caspase9, caspase3, cleaved caspase3, the ratio of Bax/Beclin-2, as well as autophagy-related Beclin-1, Atg5, and LC3-II. Luteolin also relieved METH-induced hepatotoxicity by decreasing inflammation factors, including TNF-α, IL-1β, and IL-18. Moreover, the levels of PI3K, p-Akt, and the normalized ratio of p-Akt/Akt declined after METH administration, whereas luteolin pretreatment failed to reverse these effects. Our results suggest that luteolin alleviates METH-induced hepatic apoptosis, autophagy, and inflammation through repressing the p53 pathway. It further illustrates the protective mechanisms of luteolin on METH-induced hepatotoxicity and provides a research basis for clinical treatment.

scholarly journals The spliceosome factor sart3 regulates hematopoietic stem/progenitor cell development in zebrafish through the p53 pathway

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Yan Zhao ◽  
Mei Wu ◽  
Jing Li ◽  
Ping Meng ◽  
Jiakui Chen ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Causative Gene ◽  
P53 Pathway ◽  
Hematopoietic Stem ◽  
Cell Lineages ◽  
P53 Signaling ◽  
Rna Expression Profiling ◽  
Mechanistic Basis ◽  
P53 Signaling Pathway ◽  
Definitive Hematopoiesis

AbstractHematopoietic stem cells (HSCs) possess the potential for self-renew and the capacity, throughout life, to differentiate into all blood cell lineages. Yet, the mechanistic basis for HSC development remains largely unknown. In this study, we characterized a zebrafish smu471 mutant with hematopoietic stem/progenitor cell (HSPC) defects and found that sart3 was the causative gene. RNA expression profiling of the sart3smu471 mutant revealed spliceosome and p53 signaling pathway to be the most significantly enriched pathways in the sart3smu471 mutant. Knock down of p53 rescued HSPC development in the sart3smu471 mutant. Interestingly, the p53 inhibitor, mdm4, had undergone an alternative splicing event in the mutant. Restoration of mdm4 partially rescued HSPC deficiency. Thus, our data suggest that HSPC proliferation and maintenance require sart3 to ensure the correct splicing and expression of mdm4, so that the p53 pathway is properly inhibited to prevent definitive hematopoiesis failure. This study expands our knowledge of the regulatory mechanisms that impact HSPC development and sheds light on the mechanistic basis and potential therapeutic use of sart3 in spliceosome-mdm4-p53 related disorders.

scholarly journals MALAT1 Activates the P53 Signaling Pathway by Regulating MDM2 to Promote Ischemic Stroke

2018 ◽  
Vol 50 (6) ◽  
pp. 2216-2228 ◽  
Author(s):  
Ting Zhang ◽  
Hongmei Wang ◽  
Qiang Li ◽  
Jianliang Fu ◽  
Jiankang Huang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Ischemic Stroke ◽  
Signaling Pathway ◽  
Bioinformatics Analysis ◽  
Mrna Levels ◽  
P53 Pathway ◽  
P53 Signaling ◽  
Related Proteins ◽  
P53 Signaling Pathway

Background/Aims: This study focused on evaluating the effect of MALAT1 and MDM2 on ischemic stroke through regulation of the p53 signaling pathway. Materials: Bioinformatics analysis was performed to identify abnormally expressed lncRNAs, mRNAs and their associated pathways. Oxygen-glucose deprivation/reoxygenation (OGD/R) in cells and middle cerebral artery occlusion/reperfusion (MCAO/R) in mice were performed to simulate an ischemic stroke environment. Western blot and qRT-PCR were used to examine lncRNA expression and mRNA levels. Fluorescence in situ hybridization (FISH) LncRNA was used to locate mRNA. MTT and flow cytometry were performed to examine cell proliferation and apoptosis. Finally, immunohistochemistry was used to observe the expression of genes in vivo. Results: MALAT1 and MDM2, which exhibit strong expression in stroke tissues, were subjected to bioinformatics analysis, and the p53 pathway was chosen for further study. MALAT1, MDM2 and p53 signaling pathway-related proteins were all up regulated in OGD/R cells. Furthermore, Malat1, Mdm2 and p53 pathway related-proteins were also up regulated in MCAO/R mice. Both MALAT1 and MDM2 were localized in the nuclei. Down regulation of MALAT1 and MDM2 enhanced cell proliferation ability and reduced apoptosis, resulting in decreased infarct size in MCAO/R brains. Conclusion: These results indicate that MALAT1/MDM2/p53 signaling pathway axis may provide more effective clinical therapeutic strategy for patients with ischemic stroke.

scholarly journals Mild Hypothermia Therapy Lowers the Inflammatory Level and Apoptosis Rate of Myocardial Cells of Rats with Myocardial Ischemia-Reperfusion Injury via the NLRP3 Inflammasome Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Renjun Gao ◽  
Hongye Zhao ◽  
Xianyan Wang ◽  
Bo Tang ◽  
Yu Cai ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Ischemia Reperfusion Injury ◽  
Mild Hypothermia ◽  
Therapy Group ◽  
Ischemia Reperfusion ◽  
P53 Signaling ◽  
Tnf Α ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion ◽  
P53 Signaling Pathway

Objective. To explore the protective effects and mechanism of mild hypothermia treatment in the treatment of myocardial ischemia-reperfusion injury. Material and Methods. A total of 20 Sprague-Dawley (SD) rats were assigned to 4 groups: the blank control group, sham operation group, ischemia reperfusion group, and mild hypothermia therapy group (each n = 5 ). Some indexes were detected. In addition, myocardial cell models of oxygen-glucose deprivation/reoxygenation injury (OGD) were established. The expression of mRNA IL-6 and TNF-α and the key enzyme levels of apoptosis (cleaved-Caspase-3) and the NLRP3 inflammasome/p53 signaling pathway in the models were determined. Results. The expression of serum IL-6 and TNF-α in the mild hypothermia therapy group was significantly lower than that in the ischemia reperfusion group. The mild hypothermia therapy group also showed a significantly lower TUNEL cell count and NLRP3 and p53 phosphorylation levels than the ischemia reperfusion group (all p < 0.05 ). The in vitro mild hypothermia + OGD group also showed significantly lower mRNA expression of IL-6 and TNF-α and levels of cleaved Caspase-3, NLRP3, and phosphorylated p53 protein than the OGD group (all p < 0.05 ). Conclusion. In conclusion, mild hypothermia therapy can inhibit the apoptosis and myocardial inflammation of cells induced by MI/R injury in rats and inhibiting the activity of the NLRP3 inflammasome pathway and p53 signaling pathway may be the mechanism.

Expression and Significance of Th17 Cells and Related Factors in Patients with Autoimmune Hepatitis

2019 ◽  
Vol 22 (4) ◽  
pp. 232-237 ◽  
Author(s):  
Jihong An
Keyword(s):  
Autoimmune Hepatitis ◽  
Peripheral Blood ◽  
Th17 Cells ◽  
Treg Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Serum Total Bilirubin ◽  
Study Group ◽  
Related Factors ◽  
Tnf Α

Objective: This study aims to investigate the expression and clinical significance of Th17 cells and related factors in peripheral blood of patients with Autoimmune Hepatitis (AIH). Methods: A retrospective selection of 100 patients with AIH were included as a study group, and 100 healthy volunteers in the outpatient clinic were selected as the control group. The levels of IL- 17, IL-6, IL-21 and TNF-α in peripheral blood of all subjects were detected by enzyme-linked immunosorbent assay and the frequency of Th17 cells and Treg cells was detected by flow cytometry. Results: Results showed that the study group had higher levels of serum total bilirubin (TBil), alkaline phosphatase (ALP), γ -glutamyltranspeptidase (γ-GT), immunoglobulin G (IgG), immunoglobulin M (IgM), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) than the control group, as well as higher levels of IL-17, IL-6, IL-21 and TNF-α in serum. The frequency of Th17 cells in peripheral blood was higher in the study group, while the frequency of Treg cells was lower. Also, serum IL-17, TNF-α levels and Th17 cells frequency were positively correlated with ALT and AST, whereas Treg cells frequency were negatively correlated with ALT and AST levels. Conclusion: Our finding demonstrates that Th17 cell frequency and their related factors IL-17 and TNF-α, are associated with liver damage, which might be used to monitor AIH disease severity.

Effect of Chinese Herbal Monomer Hairy Calycosin on Nonalcoholic Fatty Liver Rats and its Mechanism

2019 ◽  
Vol 22 (3) ◽  
pp. 194-200 ◽  
Author(s):  
Xiang Liu ◽  
Zhi-Hong Xie ◽  
Chen-Yuan Liu ◽  
Ying Zhang
Keyword(s):  
Fatty Liver ◽  
Liver Tissue ◽  
Liver Homogenate ◽  
Control Group ◽  
Necrosis Factor Alpha ◽  
Alcoholic Fatty Liver ◽  
Nonalcoholic Fatty Liver ◽  
Chinese Herbal ◽  
Tnf Α ◽  
Model Control

Background: Chinese herbal monomer hairy Calycosin is a flavonoid extracted from Radix astragali. Aims and Scope: The aim of the research was to investigate the effect and mechanism of Hairy Calycosin on Non-Alcoholic Fatty Liver Dieases (NAFLD) in rats. Materials and Methods: 60 rats were randomly divided into 6 groups, then NAFLD rat models were prepared and treated with different doses of Hairy Calycosin (0.5, 1.0, 2.0 mg/kg) or Kathyle relatively. Results: Both 1.0 mg/kg and 2.0 mg/kg Hairy Calycosin treatment could significantly increase the serum Superoxide Dismutase (SOD) content of the model rats and reduce the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), Free Fatty Acid (FFA), IL-6, tumor necrosis factor-alpha (TNF-α) and liver homogenate malondialdehyde (MDA), while 2.0 mg/kg Hairy Calycosin can down-regulate liver tissue cytochrome p450 2E1 (CYP2E1). In the electron microscope, compared with the model control group, the mitochondrial swelling in the hepatocytes of Hairy Calycosin (1.0, 2.0 mg/kg) treatment group was significantly reduced, the ridge on the inner membrane of mitochondria increased, and the lipid droplets became much smaller. Conclusion: Hairy Calycosin can effectively control the lipid peroxidation in liver tissues of rats with NAFLD, and reduce the levels of serum TNF-α, IL-6, MDA and FFA, effectively improve the steatosis and inflammation of liver tissue, and down-regulate the expression of CYP2E1, inhibit apoptosis of hepatocytes.

Assessment of Key Elements in the Innate Immunity System Among Patients with HIV, HCV, and Coinfections of HIV/HCV

2020 ◽  
Vol 18 (3) ◽  
pp. 194-200
Author(s):  
Maryam Moradi ◽  
Alireza Tabibzadeh ◽  
Davod Javanmard ◽  
Saied Ghorbani ◽  
Farah Bokharaei-Salim ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Mononuclear Cells ◽  
Hiv Infections ◽  
Control Group ◽  
Peripheral Blood Mononuclear ◽  
Hiv Coinfection ◽  
Tnf Α ◽  
Immunity Genes ◽  
Healthy Control ◽  
Hcv Coinfection

Background: Coinfection of Hepatitis C virus (HCV) with human immunodeficiency virus (HIV) has a higher risk of mortality than HCV or HIV monoinfection. HCV and HIV infections are specified by systemic inflammation, but the inflammation process in HCV/HIV coinfection is much complicated and is not well characterized. Objective: The aim of this study was to analyze the expression of TLR-3, TLR-7, IL-10, IFN-1 (IFN-α, IFN-β), and TNF-α in HIV, HCV and HIV/HCV co-infected patients. Methods: Forty-five patients including HIV group (n=15), HCV group (n=15), HIV/HCV coinfection group (n=15) and healthy control group (n=15) participated. Peripheral blood mononuclear cells (PBMCs) were obtained. PBMC-RNA, HCV and HIV RNA were extracted from all subjects and cDNA was synthesized. The viral load analyzed by reverse transcription-quantitative PCR (RT-qPCR), and the expression levels of IFN-α, IFN-β, TLR-3, TLR-7, TNF, and IL-10 mRNA were quantified in PBMCs. Results: The levels of IFN-I, IL-10, and TNF-α were overexpressed in all patients’ groups (P<0.05), TLR-7 was upregulated in all groups, but this upregulation was not statistically significant (p>0.05). TLR-3 showed a decrease in all patient groups (P<0.05). The statistical analysis demonstrated that TLR-3 has a negative correlation with HIV load, whereas other genes positively correlated with HIV load. In addition, TLR-3, TNF-α, and IFN-I were negatively correlated with HCV load, whereas TLR-7 and IL-10 s were positively correlated with HCV load. Conclusion: Our results showed a significant relationship between the expression level of innate immunity genes and inflammation in HCV, HIV, and HIV/HCV coinfected patients.

Melatonin Improves Erythropoietin Hyporesponsiveness via Suppression of Inflammation

2019 ◽  
Vol 14 (3) ◽  
pp. 203-208
Author(s):  
Evan Noori Hameed ◽  
Haydar F. Hadi AL Tukmagi ◽  
Hayder Ch Assad Allami
Keyword(s):  
Iron Status ◽  
Transferrin Saturation ◽  
Control Group ◽  
Base Line ◽  
Inadequate Response ◽  
Inflammatory Parameters ◽  
Tnf Α ◽  
Before And After ◽  
And Control ◽  
Controlled Clinical Study

Background: Inadequate response to Erythropoietin Stimulating Agents (ESA) despite using relatively larger doses regimen represents a potential risk factor of Cardiovascular (CV) related mortality in addition to health-care economic problems in anemic patients with Chronic Kidney Disease (CKD). Erythropoietin (EPO) hyporesponsiveness related to inflammation has been increased progressively. Melatonin is well known as a potent anti-inflammatory agent. Therefore, the current study was designed to evaluate whether melatonin could improve anemic patients response to EPO. Methods: This single controlled clinical study was carried out in 41 CKD patients with hemoglobin (Hb) levels less than 11g/dl divided randomly in a 1:1 ratio into 2 groups; treatment group who received 5mg melatonin plus their regular treatments and control group who received their regular treatments only. Hematological and iron status parameters include Hb level, serum iron (S. iron), Transferrin Saturation Ratio (TSAT) and serum ferritin (S. ferritin) in addition to inflammatory parameters that include tissue necrotic factor alfa (TNF-α), interleukin-1beta (IL-1β) and interleukin-6 (IL-6) determined before and after 12 weeks of treatment. Results: Melatonin remarkably increases the Hb level with a significant increase in S. iron and TSAT compared to baseline. The elevation of S. iron and TSAT was significantly higher in the melatonin group. Additionally, all inflammatory markers estimated were reduced significantly by melatonin compared to base line and control group. Conclusion: The results of the current study showed that melatonin has an advantageous effect on improving EPO response in anemic patients with CKD.

The Molecular Docking of Flavonoids Isolated from Daucus carota as a Dual Inhibitor of MDM2 and MDMX

2020 ◽  
Vol 15 (2) ◽  
pp. 154-164 ◽  
Author(s):  
Ijaz Muhammad ◽  
Noor Rahman ◽  
Gul E. Nayab ◽  
Sadaf Niaz ◽  
Mohibullah Shah ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Cancer Therapy ◽  
Natural Product ◽  
Signaling Pathway ◽  
In Silico ◽  
P53 Protein ◽  
Dual Inhibitor ◽  
P53 Signaling ◽  
In Silico Studies ◽  
P53 Signaling Pathway

Background: Cancer is characterized by overexpression of p53 associated proteins, which down-regulate P53 signaling pathway. In cancer therapy, p53 activity can be restored by inhibiting the interaction of MDMX (2N0W) and MDM2 (4JGR) proteins with P53 protein. Objective: In the current, study in silico approaches were adapted to use a natural product as a source of cancer therapy. Methods: In the current study in silico approaches were adapted to use a natural product as a source of cancer therapy. For in silico studies, Chemdraw and Molecular Operating Environment were used for structure drawing and molecular docking, respectively. Flavonoids isolated from D. carota were docked with cancerous proteins. Result: Based on the docking score analysis, we found that compound 7 was the potent inhibitor of both cancerous proteins and can be used as a potent molecule for inhibition of 2N0W and 4JGR interaction with p53. Conclusion: Thus the compound 7 can be used for the revival of p53 signaling pathway function however, intensive in vitro and in vivo experiments are required to prove the in silico analysis.

Can Cytokines be used as an Activation Marker in Rheumatoid Arthritis?

2020 ◽  
Vol 20 ◽  
Author(s):  
Fatih Öner Kaya ◽  
Yeşim Ceylaner ◽  
Belkız Öngen İpek ◽  
Zeynep Güneş Özünal ◽  
Gülbüz Sezgin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Healthy Volunteers ◽  
Venous Blood ◽  
Cross Sectional Study ◽  
Joint Disease ◽  
Control Group ◽  
Cross Sectional ◽  
Positive Correlation ◽  
Das 28 ◽  
Tnf Α

Aims: The etiopathogenesis of Rheumatoid Arthritis (RA) is not clearly understood. However, the role of the cytokines takes an important part in this mechanism. We aimed to bring a new approach to the concept of 'remission' in patients with RA. Background: RA is a chronic, autoimmune, inflammatory disease that involves small joints in the form of symmetrical polyarthritis and progresses with exacerbations and remissions. Pain, swelling, tenderness and morning stiffness are typical of the joints involved. Although it is approached as a primary joint disease, a wide variety of extra-articular involvements may also occur. It is an interesting pathophysiological process, the exact cause of which is still unknown, with many environmental, genetic and potentially undiscovered possible factors in a chaotic manner. Objective: In this cross-sectional study, sedimentation rate (ESR), C- Reactive protein (CRP), Tumor necrosis factor (TNF)-α, soluble-TNF-α receptor (TNF-R), Interleukin (IL)-1B and IL-10 were measured in three groups which were healthy volunteers, patients with RA in the active period, and patients with RA in remission. Disease activity score-28 (DAS-28) was calculated in active RA and RA in remission. Methods: This study included 20 healthy volunteers, 20 remission patients with RA and 20 active RA patients. Venous blood samples were collected from patients in both healthy and RA groups. Results: RA group consisted 43 (71.6%) female and 17 (28.4%) male. Control group consisted 11 (55%) female and 9 (45%) male. TNF-R was significantly high only in the active group according to the healthy group (p=0.002). IL-10 was significantly high in active RA according to RA in remission (p=0.03). DAS-28 was significantly high in active RA according to RA in remission (p=0.001). In the active RA group, ESR and TNF-R had a positive correlation (r:0.442; p=0.048). In the active RA group, there was also a positive correlation between TNF-R and CRP (r:0.621; p=0,003). Both healthy and active RA group had significant positive correlation between ESR and CRP (r: 0.481; p=0.032 and r: 0,697; p=0,001 respectively). Conclusion: TNF-R can be the main pathophysiological factor and a marker showing activation. TNF-R can be very important in revealing the effect of TNF on the disease and the value of this effect in the treatment and ensuring the follow-up of the disease with CRP instead of ESR in activation.

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