Triptolide Attenuates Vascular Calcification by Upregulating Expression of miRNA-204

Background: Triptolide (TP), a naturally derived compound from Tripterygium wilfordii, has been proven effective in protecting against cardiovascular system, but the molecular mechanisms underlying its protective effects are poorly understood. In the current study, we sought to test the potential protective role of TP in the regulation of vascular calcification in a rat model and explore whether TP attenuates medial vascular calcification by upregulating miRNA-204.Methods: Vitamin D3 plus nicotine (VDN) was used to induce a vascular calcification (VC) model of rat aorta. Von Kossa and Hematoxylin-Eosin staining were applied to assess the degree of calcification of rat aortas. Calcium content and alkaline phosphatase activity were measured. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was applied to quantify miRNA-204 expression. The localization of runt-related transcription factor-2 (RUNX2) and bone morphogenetic protein-2 (BMP2) expressions were detected by immunohistochemistry and western blotting.Results: Administration of TP greatly reduced vascular calcification in a dose-dependent manner compared with VC controls. The increase in ALP activity and calcium content was ameliorated by TP. Moreover, protein expression levels of BMP2 and RUNX2 were significantly reduced in calcified aortas. MiRNA-204 expression was increased in the TP-treated groups compared with VC controls and the effects of TP were reversed by the intravenous injection of miRNA-204-interfering lentivirus. However, the miRNA-204-overexpressing lentivirus had no additional effects on ALP activity, calcium content, BMP2 and RUNX2 expressions compared with those from TP group.Conclusion: TP inhibited BMP2 and RUNX2 expression and attenuated vascular calcification via upregulating the level of miRNA-204. TP appears to be a potential new therapeutic option for treating vascular calcification.

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Protective Effect of Pyrus ussuriensis Maxim. Extract against Ethanol-Induced Gastritis in Rats

Antioxidants ◽

10.3390/antiox10030439 ◽

2021 ◽

Vol 10 (3) ◽

pp. 439

Author(s):

Naila Boby ◽

Muhammad Aleem Abbas ◽

Eon-Bee Lee ◽

Zi-Eum Im ◽

Walter H. Hsu ◽

...

Keyword(s):

Therapeutic Option ◽

Adenosine Monophosphate ◽

Ethanol Ingestion ◽

Dependent Manner ◽

Protective Effects ◽

Gastric Mucosal Lesions ◽

Cellular Degeneration ◽

Mucosal Lesions ◽

Pyrus Ussuriensis Maxim

Pyrus ussuriensis Maxim (Korean pear) has been used for hundreds of years as a traditional herbal medicine for asthma, cough, and atopic dermatitis in Korea and China. Although it was originally shown to possess anti-inflammatory, antioxidant, and antiatopic properties, its gastroprotective effects have not been investigated. In the present study, we evaluated the protective effects of Pyrus ussuriensis Maxim extract (PUE) against ethanol-induced gastritis in rats. The bioactive compound profile of PUE was determined by gas chromatography mass spectroscopy (GC-MS) and high-performance liquid chromatography (HPLC). The gastroprotection of PUE at different doses (250 and 500 mg/kg body weight) prior to ethanol ingestion was evaluated using an in vivo gastritis rat model. Several endpoints were evaluated, including gastric mucosal lesions, cellular degeneration, intracellular damage, and immunohistochemical localization of leucocyte common antigen. The gastric mucosal injury and ulcer score were determined by evaluating the inflamed gastric mucosa and by histological examination. To identify the mechanisms of gastroprotection by PUE, antisecretory action and plasma prostaglandin E2 (PGE2), gastric mucosal cyclic adenosine monophosphate (cAMP), and histamine levels were measured. PUE exhibited significant antioxidant effects with IC50 values of 56.18 and 22.49 µg/mL for 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′- azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid (ABTS) inhibition (%), respectively. In addition, GC/MS and HPLC analyses revealed several bioactive compounds of PUE. Pretreatment with PUE significantly (P < 0.05) decreased the ulcer index by preventing gastric mucosal lesions, erosion, and cellular degeneration. An immunohistochemical analysis revealed that PUE markedly attenuated leucocyte infiltration in a dose-dependent manner. The enhancement of PGE2 levels and attenuation of cAMP levels along with the inhibition of histamine release following PUE pretreatment was associated with the cytoprotective and healing effects of PUE. In contrast, the downregulation of the H+/K+ ATPase pathway as well as muscarinic receptor (M3R) and histamine receptor (H2R) inhibition was also involved in the gastroprotective effects of PUE; however, the expression of cholecystokinin-2 receptors (CCK2R) was unchanged. Finally, no signs of toxicity were observed following PUE treatment. Based on our results, we conclude that PUE represents an effective therapeutic option to reduce the risk of gastritis and warrants further study.

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Ligustrazine activate the PPAR-γ pathway and play a protective role in vascular calcification

Vascular ◽

10.1177/17085381211051477 ◽

2021 ◽

pp. 170853812110514

Author(s):

Hui Li ◽

Min Yang

Keyword(s):

Vascular Calcification ◽

Chondrogenic Differentiation ◽

Calcium Content ◽

Protective Role ◽

Peroxisome Proliferation ◽

Rt Pcr ◽

Alizarin Red ◽

Ppar Γ ◽

Related Proteins

Objective The purpose of this study was to explore the role of ligustrazine in vascular calcification. Methods After β-GP stimulation, vascular smooth muscle cells (VSMCs) were detected by Alizarin Red Staing staining. Calcium content and alkaline phosphatase (ALP) activity were detected by intracellular calcium assay kit and ALP assay kit, respectively. The expression of peroxisome proliferation-activated receptor (PPAR-γ) pathway–related proteins was detected by Western blot. PPAR-γ, MSX2, osteopontin (OPN), sclerostin, and BGP were detected by RT-PCR. Results β-GP induced the decreased activity and expression of PPAR-γ and ALP in VSMCs, while ligustrazine activated the expression of PPAR-γ. Through activation of PPAR-γ, ligustrazine decreased β-GP–induced VSMC calcification, decreased the expression of markers of osteogenesis and chondrogenic differentiation, and increased the expression of VSMC markers. Conclusion Ligustrazine activates the PPAR-γ pathway and plays a protective role in vascular calcification.

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Protective role of vitamins A, C, and E against the genotoxic damage induced by aflatoxin B1 in cultured human lymphocytes

Toxicology and Industrial Health ◽

10.1177/0748233709106068 ◽

2009 ◽

Vol 25 (3) ◽

pp. 183-188 ◽

Cited By ~ 12

Author(s):

L Alpsoy ◽

G Agar ◽

M Ikbal

Keyword(s):

Vitamin A ◽

Vitamin C ◽

Human Lymphocytes ◽

Mutagenic Effect ◽

Treated Group ◽

Protective Role ◽

Effective Concentration ◽

Dependent Manner ◽

Protective Effects ◽

Aflatoxin B

In this study, we aimed to evaluate the effect of vitamins A, C, and E against aflatoxin B1 (AFB1) on blood cultures in relation to induction of sister chromatid exchange (SCE). The results indicated genotoxic and mutagenic damage in cultured human lymphocytes exposed to AFB1. The results showed that 5 μM concentration of AFB1 increased SCE. When vitamins A, C, and E were added to AFB1, the frequency of SCE decreased. These results suggest that vitamins A, C, and E could effectively inhibit AFB1-induced SCE, which may partially responsible for its mutagenic effect of AFB1. Besides, the protective effect of vitamins A, C, and E against AFB1 was increased in a dose-dependent manner (i.e., as the doses increased, their protective effects also increased). There was a significant decrease in the SCE frequency in AFB1-treated group compared with the groups receiving AFB1 and also vitamins A, C, and E. The most effective concentration was 100 microM vitamin C, and the lowest effective concentration was 0.5 microM vitamin A. Vitamin C has the most effective concentration of 100 μM, and vitamin A has the lowest effective concentration of 0.5 μM. The order of the decreasing effect of the SCE frequency of vitamins was as follows: vitamin C > vitamin E > vitamin A.

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Vascular Protective Effects of Xanthotoxin and Its Action Mechanism in Rat Aorta and Human Vascular Endothelial Cells

Journal of Vascular Research ◽

10.1159/000509112 ◽

2020 ◽

Vol 57 (6) ◽

pp. 313-324

Author(s):

Li-Hua Cao ◽

Ho Sub Lee ◽

Zhe-Shan Quan ◽

Yun Jung Lee ◽

Yu Jin

Keyword(s):

Endothelial Cells ◽

Cell Adhesion ◽

Adhesion Molecule ◽

Molecular Mechanisms ◽

Umbilical Vein ◽

Neuroprotective Effect ◽

Intercellular Adhesion Molecule ◽

Dependent Manner ◽

Protective Effects ◽

Concentration Dependent Manner

Objective: Xanthotoxin (XAT) is a linear furanocoumarin mainly extracted from the plants Ammi majus L. XAT has been reported the apoptosis of tumor cells, anti-convulsant, neuroprotective effect, antioxidative activity, and vasorelaxant effects. This study aimed to investigate the vascular protective effects and underlying molecular mechanisms of XAT. Methods: XAT’s activity was studied in rat thoracic aortas, isolated with aortic rings, and human umbilical vein endothelial cells (HUVECs). Results: XAT induced endothelium-dependent vasodilation in a concentration-dependent manner in the isolated rat thoracic aortas. Removal of endothelium or pretreatment of aortic rings with L-NAME, 1H-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one, and wortmannin significantly inhibited XAT-induced relaxation. In addition, treatment with thapsigargin, 2-aminoethyl diphenylborinate, Gd3+, and 4-aminopyridine markedly attenuated the XAT-induced vasorelaxation. XAT increased nitric oxide production and Akt- endothelial NOS (eNOS) phosphorylation in HUVECs. Moreover, XAT attenuated the expression of TNF-α-induced cell adhesion molecules such as intercellular adhesion molecule, vascular cell adhesion molecule-1, and E-selectin. However, this effect was attenuated by the eNOS inhibitors L-NAME and asymmetric dimethylarginine. Conclusions: This study suggests that XAT induces vasorelaxation through the Akt-eNOS-cGMP pathway by activating the KV channel and inhibiting the L-type Ca2+ channel. Furthermore, XAT exerts an inhibitory effect on vascular inflammation, which is correlated with the observed vascular protective effects.

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miR-135b Plays a Neuroprotective Role by Targeting GSK3β in MPP+-Intoxicated SH-SY5Y Cells

Disease Markers ◽

10.1155/2017/5806146 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 10

Author(s):

Jianlei Zhang ◽

Wei Liu ◽

Yabo Wang ◽

Shengnan Zhao ◽

Na Chang

Keyword(s):

Cell Proliferation ◽

Glycogen Synthase ◽

Underlying Mechanism ◽

Protective Role ◽

Luciferase Reporter ◽

Dependent Manner ◽

Protective Effects ◽

Inflammatory Cytokine Production ◽

Protein Levels

miR-135a-5p was reported to play a crucial role in the protective effects of hydrogen sulfide against Parkinson’s disease (PD) by targeting rho-associated protein kinase 2 (ROCK2). However, the role of another member of miR-135 family (miR-135b) and the underlying mechanism in PD are still unclear. qRT-PCR and western blot showed that miR-135 was downregulated and glycogen synthase kinase 3β (GSK3β) was upregulated at mRNA and protein levels in MPP+-intoxicated SH-SY5Y cells in a dose- and time-dependent manner. MTT, TUNEL, and ELISA assays revealed that miR-135b overexpression significantly promoted cell proliferation and inhibited apoptosis and production of TNF-α and IL-1β in SH-SY5Y cells in the presence of MPP+. Luciferase reporter assay demonstrated that GSK3β was a direct target of miR-135b. Moreover, sodium nitroprusside (SNP), a GSK3β activator, dramatically reversed the effects of miR-135b upregulation on cell proliferation, apoptosis, and inflammatory cytokine production in MPP+-intoxicated SH-SY5Y cells. Taken together, miR-135b exerts a protective role via promotion of proliferation and suppression of apoptosis and neuroinflammation by targeting GSK3β in MPP+-intoxicated SH-SY5Y cells, providing a potential therapeutic target for the treatment of PD.

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Melatonin attenuates vascular calcification by activating mitochondrial fusion and mitophagy via an AMPK/OPA1 signaling pathway

10.21203/rs.2.17699/v1 ◽

2019 ◽

Author(s):

chenweiren chen ◽

jia qi yang ◽

fang liu ◽

xue qin shen ◽

yuan sha

Keyword(s):

Vascular Calcification ◽

Mitochondrial Fusion ◽

Calcium Deposition ◽

Protective Effects ◽

Melatonin Treatment ◽

Western Blots ◽

Alizarin Red ◽

Mitofusin 2 ◽

Alp Activity ◽

Compound C

Abstract Background: Mitochondrial fusion/mitophagy play a role in cardiovascular calcification. Melatonin has been shown to protect against cardiovascular disease. This study sought to explore whether melatonin attenuates vascular calcification by regulating mitochondrial fusion/mitophagy via an AMP activated protein kinase/ Optic atrophy 1 (AMPK/OPA1) signaling pathway.Methods: The effects of melatonin on vascular calcification were investigated in vascular smooth muscle cells (VSMCs). Calcium deposits were visualised by Alizarin red staining. Calcium content and alkaline phosphatase (ALP) activity were used to evaluate osteogenic differentiation. Western blots were used to measure expression of runt-related transcription factor 2 (Runx2), mitofusin 2 (Mfn2), mito-light chain 3 II (LC3II) and cleaved caspase3. Results: Melatonin markedly reduced calcium deposition and ALP activity. Runx2 and cleaved caspase3 were found to be down-regulated and Mfn2 or mito-LC3II was found to be enhanced in response to melatonin, together with a decrease in mitochondrial superoxide levels. Melatonin also maintained mitochondrial function and promoted mitochondrial fusion/mitophagy via OPA1 pathway. But OPA1 deletion abolished the protective effects of melatonin on VSMC calcification. Melatonin treatment significantly increased the p-AMPK and OPA1 protein expression. Treatment with compound C ablated the benefit observed with melatonin treatment. Conclusions: Melatonin protects VSMC against calcification by promoting mitochondrial fusion/mitophagy via AMPK/OPA1 pathway.

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Molecular Mechanisms Underlying Protective Role of Quercetin on Copper Sulfate-Induced Nephrotoxicity in Mice

Frontiers in Veterinary Science ◽

10.3389/fvets.2020.586033 ◽

2021 ◽

Vol 7 ◽

Author(s):

Xinyan Peng ◽

Chongshan Dai ◽

Min Zhang ◽

Subhajit Das Gupta

Keyword(s):

Molecular Mechanism ◽

Copper Sulfate ◽

Molecular Mechanisms ◽

Protective Role ◽

Potential Candidate ◽

Dependent Manner ◽

Oxidative Stress Biomarkers ◽

Tubular Necrosis ◽

Gene And Protein Expression ◽

Copper Overload

Copper overload is an established cause of nephrotoxicity, but the precise molecular mechanism remains unknown. Our study aimed to investigate the molecular mechanism of copper sulfate (CuSO4)-induced nephrotoxicity and the protective effect of the natural compound quercetin using a mouse model. Mice were orally administered CuSO4 only (200 mg/kg per day), or co-administered CuSO4 (200 mg/kg per day) plus quercetin (25, 50, or 100 mg/kg per day), or quercetin only (100 mg/kg per day), or vehicle for 28 days. The blood and kidneys were collected for the examination of serum biomarkers, oxidative stress biomarkers, changes in histopathology and gene and protein expression. Our results show that quercetin supplementation attenuates CuSO4-induced renal dysfunction and tubular necrosis in a dose-dependent manner. Quercetin supplementation at 50 and 100 mg/kg significantly attenuated CuSO4-induced oxidative damage. Quercetin supplementation also inhibited the activities of caspases-9 and−3, and the expression of p53 and Bax mRNAs. Furthermore, quercetin supplementation markedly activated the expression of Nrf2 and HO-1 mRNAs, but inhibited the expression of NF-κB, IL-1β, IL-6, and TNF-α mRNAs. In conclusion, our results revealed that quercetin supplementation could inhibit CuSO4-induced nephrotoxicity in mice via the inhibition of mitochondrial apoptotic and NF-κB pathways and the activation of Nrf2/HO-1 pathway. Our study highlights quercetin as a potential candidate in treating copper overload-induced nephrotoxicity.

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IcarisideII facilitates the differentiation of ADSCs to SCs via let-7i/STAT3 axis to preserve erectile function

Biological Research ◽

10.1186/s40659-019-0262-3 ◽

2019 ◽

Vol 52 (1) ◽

Author(s):

Pingyu Ge ◽

Yinxue Guo ◽

Jun Shen

Keyword(s):

Cell Proliferation ◽

Erectile Function ◽

Molecular Mechanisms ◽

Therapeutic Option ◽

Luciferase Reporter ◽

Dependent Manner ◽

Regulatory Relationship ◽

Rat Models ◽

Protein Levels ◽

Dose Dependent

Abstract Background IcarisideII (ICAII) could promote the differentiation of adipose tissue-derived stem cells (ADSCs) to Schwann cells (SCs), leading to improvement of erectile function (EF) and providing a realistic therapeutic option for the treatment of erectile dysfunction (ED). However, the underlying molecular mechanisms of ADSCs and ICAII in this process remain largely unclear. Methods ADSCs were treated with different concentrations of ICAII. Cell proliferation was determined by MTT assay. qRT-PCR and western blot were performed to detect expressions of SCs markers, signal transducer and activator of transcription-3 (STAT3), and microRNA-let-7i (let-7i). Luciferase reporter assay was conducted to verify the regulatory relationship between let-7i and STAT3. The detection of intracavernosal pressure (ICP) and the ratio of ICP/mean arterial pressure (MAP) were used to evaluate the EF in bilateral cavernous nerve injury (BCNI) rat models. Results ICAII promoted cell proliferation of ADSCs in a dose-dependent manner. The mRNA and protein levels of SCs markers were increased by ICAII treatment in a dose-dependent manner in ADSCs. Moreover, let-7i was significantly decreased in ICAII-treated ADSCs and upregulation of let-7i attenuated ICAII-induced promotion of SCs markers. In addition, STAT3 was a direct target of let-7i and upregulated in ICAII-treated ADSCs. Interestingly, overexpression of STAT3 abated the let-7i-mediated inhibition effect on differentiation of ADSCs to SCs and rescued the ICAII-mediated promotion effect on it. Besides, combination treatment of ADSCs and ICAII preserved the EF of BCNI rat models, which was undermined by let-7i overexpression. Conclusion ICAII was effective for preserving EF by promoting the differentiation of ADSCs to SCs via modulating let-7i/STAT3 pathway.

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Alpha-lipoic acid improves acute deltamethrin-induced toxicity in rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2014-0280 ◽

2014 ◽

Vol 92 (9) ◽

pp. 773-779 ◽

Cited By ~ 30

Author(s):

Rania H. Abdou ◽

Mohamed M. Abdel-Daim

Keyword(s):

Lipoic Acid ◽

Therapeutic Option ◽

Antioxidant Properties ◽

Free Radical Scavenger ◽

Radical Scavenger ◽

Dependent Manner ◽

Protective Effects ◽

Alpha Lipoic Acid ◽

Pre Treatment ◽

Tissue Lipid Peroxidation

Alpha-lipoic acid (ALA) is a natural dithiol compound, with a free radical scavenger and biological antioxidant properties. The purpose of the current study was to investigate the protective effects of ALA on biochemical alteration and oxidative stress induced by acute deltamethrin intoxication in rats. Markers of liver and kidney injuries in serum of deltamethrin-intoxicated as well as ALA-pretreated rats were analyzed. Moreover, serum and (or) tissue lipid peroxidation, malondialdehyde and antioxidant markers, reduced glutathione, catalase, superoxide dismutase activity, and total antioxidant capacity were evaluated. The results showed that all parameters were altered in the intoxicated group, indicating hepatorenal oxidative damage of deltamethrin. Pre-treatment with ALA reversed the changes in most of the studied parameters in a dose-dependent manner. Histopathological and biochemical findings were parallel. It can be concluded that ALA may be a promising therapeutic option for prevention and (or) treatment of deltamethin toxicity.

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Functional Role of Wogonin in Anti-Angiogenesis

The American Journal of Chinese Medicine ◽

10.1142/s0192415x12500322 ◽

2012 ◽

Vol 40 (02) ◽

pp. 415-427 ◽

Cited By ~ 15

Author(s):

Chiu-Mei Lin ◽

Yen-Hsu Chen ◽

Jiann-Ruey Ong ◽

Hon-Ping Ma ◽

Kou-Gi Shyu ◽

...

Keyword(s):

Molecular Mechanisms ◽

Therapeutic Option ◽

Suppressive Effect ◽

Binding Activity ◽

Janus Kinase ◽

Dependent Manner ◽

Vegf Expression ◽

Concentration Dependent Manner ◽

Biologically Relevant

Constitutive activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway occurs commonly in cancer cells and endothelial cells, and contributes to angiogenesis. Wogonin is a compound with many biologically relevant properties. We previously reported that wogonin blocked IL-6-induced angiogenesis through suppression of VEGF expression, an important regulator of angiogenesis. However, the pathway involved in the suppressive effect of wogonin on IL-6-induced VEGF has not been completely clarified. This study aimed to investigate the molecular mechanisms participating in the suppression of wogonin on IL-6-induced VEGF in vitro, focusing on IL-6R/JAK1/STAT3/VEGF pathway. Both STAT3 siRNA and wogonin treatment resulted in an abolition of the expression of VEGF. Moreover, our data revealed that wogonin treatment after STAT3 knock-down did not further suppress VEGF expression. The addition of IL-6R siRNA or wogonin resulted in a decrease in the expression level of the phosphorylated JAK1 protein. Furthermore, wogonin significantly decreased the amount of phosphorylated STAT3. Finally, by EMSA, wogonin suppressed IL-6-induced STAT3 binding activity in a concentration-dependent manner. Taken together, our results show that wogonin suppresses IL-6-induced VEGF by modulating the IL-6R/JAK1/STAT3 signaling pathway. Based on this study, we suggest that wogonin may provide a new potential therapeutic option for treatment of IL-6-related pathological angiogenesis.

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