Publications by authors named "Marthandam Asokan Shibu"

66 Publications

miR-145-5p targets paxillin to attenuate angiotensin II-induced pathological cardiac hypertrophy via downregulation of Rac 1, pJNK, p-c-Jun, NFATc3, ANP and by Sirt-1 upregulation.

Mol Cell Biochem 2021 Apr 22. Epub 2021 Apr 22.

Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan.

Pathological cardiac hypertrophy is associated with many diseases including hypertension. Recent studies have identified important roles for microRNAs (miRNAs) in many cardiac pathophysiological processes, including the regulation of cardiomyocyte hypertrophy. However, the role of miR-145-5p in the cardiac setting is still unclear. In this study, H9C2 cells were overexpressed with microRNA-145-5p, and then treated with Ang-II for 24 h, to study the effect of miR-145-5p on Ang-II-induced myocardial hypertrophy in vitro. Results showed that Ang-II treatment down-regulated miR-145-5p expression were revered after miR-145-5p overexpression. Based on results of bioinformatics algorithms, paxillin was predicted as a candidate target gene of miR-145-5p, luciferase activity assay revealed that the luciferase activity of cells was substantial downregulated the following co-transfection with wild paxillin 3'UTR and miR-145-5p compared to that in scramble control, while the inhibitory effect of miR-145-5p was abolished after transfection of mutant paxillin 3'UTR. Additionally, overexpression of miR-145-5p markedly inhibited activation of Rac-1/ JNK /c-jun/ NFATc3 and ANP expression and induced SIRT1 expression in Ang-II treated H9c2 cells. Jointly, our study suggested that miR-145-5p inhibited cardiac hypertrophy by targeting paxillin and through modulating Rac-1/ JNK /c-jun/ NFATc3/ ANP / Sirt1 signaling, therefore proving novel downstream molecular pathway of miR-145-5p in cardiac hypertrophy.
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http://dx.doi.org/10.1007/s11010-021-04100-wDOI Listing
April 2021

Cardioprotective effects of transplanted adipose-derived stem cells under Ang II stress with Danggui administration augments cardiac function through upregulation of insulin-like growth factor 1 receptor in late-stage hypertension rats.

Environ Toxicol 2021 Apr 21. Epub 2021 Apr 21.

Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.

In aging hypertensive conditions, deterioration of insulin-like growth factor 1 receptor (IGF1R) cause a pathological impact on hypertensive hearts with an increased Ang II level. Recovering these adverse conditions through transplanted adipose-derived stem cells is a challenging approach. Moreover, Danggui, a Traditional Chinese medicine (TCM), is used for the treatment of cardioprotective effects. In this study, to evaluate whether the combined effect of MSCs and TCM can recover the cardiac function in late-stage hypertension rats. We observed that lower dose of Danggui crude extract treatment showed an increased level of cell viability with maintained stemness properties and growth rate in rat adipose-derived stem cells (rADSCs). Further, we cocultured the H9c2 cells with rADSCs and the results revealed that Danggui-treated MSCs enhanced the IGF1R expression and attenuated the hypertrophy in H9c2 cells against Ang II challenge by immunoblot and rhodamine-phalloidin staining. In addition, Danggui crude extract was also quantified and characterized by HPLC and LC-MS analysis. Furthermore, the in vivo study was performed by considering 11 months old rats (n = 7). Importantly, the oral administration of Danggui crude extract with stem cells intravenous injection in SHR-D-ADSCs group showed a combination effect to augment the cardiac function through enhancement of ejection fraction, fractional shortening, contractility function in the late-stage hypertension conditions. We have also observed a decreased apoptosis rate in the heart tissue of SHR-D-ADSCs group. Taken together, these results indicate that the combinatorial effects of Danggui crude extract and stem cell therapy enhanced cardiac function in late-stage SHR rats.
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http://dx.doi.org/10.1002/tox.23145DOI Listing
April 2021

Regulating inflammation associated Ferroptosis-a treatment strategy for Parkinson disease.

Curr Med Chem 2021 Apr 19. Epub 2021 Apr 19.

Institute of Research and Development, Duy Tan University, Da Nang. Vietnam.

Ferroptosis plays a critical regulatory role for a new kind of cell death initiating and developing an array of disorders like neurological diseases, acute injury of kidney, tumors and ischemia etc. This selective deposition of iron is one of the pathogenic reasons for PD and although it's underlying mechanism is still unknown. In this review, the role of neuroinflammation in Parkinson's disease (PD) leading to neurodegeneration has been discussed in detail. The accumulation of brain iron has been found in many chronic neurological disorders including PD. We have also discussed the unique features of Ferroptosis as compared to other cellular death pathways and it links in aggravating the pathology of PD. Further, the concept of targeting Ferroptosis for PD pathology and inducers and inhibitors, pharmacological drugs and clinical trials for PD candidates in phase IV stage in completed status are detailed in the respective sections.
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http://dx.doi.org/10.2174/0929867328666210419125032DOI Listing
April 2021

Small Molecule Compound Nerolidol attenuates Hypertension induced hypertrophy in spontaneously hypertensive rats through modulation of Mel-18-IGF-IIR signalling.

Phytomedicine 2021 Apr 4;84:153450. Epub 2021 Jan 4.

Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan; Department of Biological Science and Technology, Asia University, Taichung, Taiwan; Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien 970, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan. Electronic address:

Background: Cardiovascular diseases are caused by multitudes of stress factors like hypertension and their outcomes are associated with high mortality and morbidity worldwide. Nerolidol, a naturally occurring sesquiterpene found in several plant species, embodies various pharmacological benefits against numerous health disorders. However, their effects on hypertension induced cardiac complications are not completely understood.

Purpose: The present study is to elucidate the efficacy of nerolidol against hypertension related cardiac hypertrophy in spontaneously hypertensive rats (SHRs).

Study Design: For preliminary in vitro studies, H9c2 cardiomyoblasts cells were challenged with 200 nM Angiotensin-II (AngII) for 12 h and were then treated with nerolidol for 24 h. The hypertrophic effect in H9c2 cells were analyzed by actin staining and the modulations in hypertrophic protein markers and mediators were determined by Western blotting analysis. For in vivo experiments, sixteen week-old male Wistar Kyoto (WKY) and SHRs were segregated into five groups (n = 9): Control WKY, hypertensive SHRs, SHRs with low dose (75 mg/kg b.w/day) nerolidol, SHRs with high dose (150 mg/kg b.w/day) nerolidol and SHR rats treated with an anti-hypertensive drug captopril (50 mg/kg b.w/day). Nerolidol treatment was given orally for 8 weeks and were analysed through Echocardiography. After euthanasia, hematoxylin and eosin staining, Immunohistochemical analysis and Western blotting was performed on left ventricle tissue.

Results: Western blotting analysis revealed that nerolidol significantly attenuates AngII induced expression of hypertrophic markers ANP and BNP in H9c2 cardiomyoblasts. In addition, actin staining further ascertained the potential of nerolidol to ameliorate AngII induced cardiac hypertrophy. Moreover, nerolidol administration suppressed the hypertrophic signalling mediators like calcineurin, GATA4, Mel-18, HSF-2 and IGFIIR in a dose-dependent fashion. In silico studies also ascertained the role of Mel-18 in the ameliorative effects of nerolidol. Further, these intriguing in vitro results were further confirmed in in vivo SHR model. Oral neraolidol in SHRs efficiently reduced blood pressure and ameliorated hypertension induced cardiac hypertrophic effects by effectively reducing the levels of proteins involved in cardiac MeL-18-HSF2-IGF-IIR signalling.

Conclusion: Collectively, the data reveals that the cardioprotective effect of nerolidol against hypertension induced hypertrophy involves reduction in blood pressure and regulation of the cardiac Mel-18-IGFIIR signalling cascade.
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http://dx.doi.org/10.1016/j.phymed.2020.153450DOI Listing
April 2021

Cardioprotective potential of amygdalin against angiotensin II induced cardiac hypertrophy, oxidative stress and inflammatory responses through modulation of Nrf2 and NF-κB activation.

Environ Toxicol 2021 May 15;36(5):926-934. Epub 2021 Jan 15.

Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.

Heart failure (HF) and cardiac hypertrophy is an unfavorable outcome of pathological cardiac remodeling and represents the most important contributing factor for HF and cardiac hypertrophy. Amygdalin (AMG) is a cyanogenic glycoside derived from bitter almonds. Accumulating evidences have highlighted their pharmacological potentials against various diseases. However, there is no report delineating the potential of AMG against angiotensin (Ang II) induced cardiac injuries. Thus, the present study was performed to explore whether AMG could ameliorate Ang II induced cardiomyopathies and thereby ascertain the underlying mechanisms thereof. To this end, H9c2 cells were treated with Ang II and thereafter treated with various concentration of AMG and finally the cardio-protective effects of AMG were analyzed through Western blotting, immunofluorescence, and insilico analysis. Our results showed that the cardiomyocyte cell size, inflammatory markers and cytokines(pNF-κB, TNF-α, iNOS and COX-2) were markedly increased following Ang II treatment; nevertheless, treatment with AMG led to considerable decrement in the Ang II induced enlargement of the cardiomyocytes, and attenuate the expression of hypertrophic markers(ANP, BNP and MHC-7), inflammatory markers and cytokines. Additionally, oxidative stress related proteins (Nrf2, catalase, SOD-2, and GPX-4) were markedly increased following AMG treatment. Molecular docking reveals the interaction of AMG with Nrf2 possessing good binding affinity. Cumulatively, our study highlights the cardio-protective role of AMG against Ang II induced cardiomyopathies, including oxidative stress and inflammation effects. The intriguing in vitro results warrants the need of further animal studies to truly ascertain their potentialities.
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http://dx.doi.org/10.1002/tox.23094DOI Listing
May 2021

Platycodin D reverses histone deacetylase inhibitor resistance in hepatocellular carcinoma cells by repressing ERK1/2-mediated cofilin-1 phosphorylation.

Phytomedicine 2021 Feb 23;82:153442. Epub 2020 Dec 23.

Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; Center of Stem Cell & Precision Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan; Department of Biological Science and Technology, Asia University, Taichung, Taiwan; Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien 970, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan. Electronic address:

Background: Chemoresistance remains the main obstacle in hepatocellular carcinoma (HCC) therapy. Despite significant advances in HCC therapy, HCC still has a poor prognosis. Thus, there is an urgent need to identify a treatment target to reverse HCC chemotherapy resistance. Platycodon grandiflorus (PG) is a perennial herb that has been used as food and traditional Chinese medicine for thousands of years in Northeast Asia. Platycodin D (PD), a main active triterpenoid saponin found in the root of PG, has been reported to possess anticancer properties in several cancer cell lines, including HCC; however, the reversal effect of this molecule on HCC chemoresistance remains largely unknown.

Purpose: This study aimed to investigate the role and the mechanism of PD-mediated reversal of the histone deacetylase inhibitor (HDACi) resistance in HCC cells.

Methods: Human HCC cells (HA22T) and HDACi-resistant (HDACi-R) cells were used. Cell viability was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Combination index was used to calculate the synergism potential. Expression of ERK1/2 (total/phospho), cofilin-1 (total/phospho) and apoptosis-related protein was determined using western blotting. Mitochondrial membrane potential was assessed using the JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine iodide) probe. Apoptosis was detected using the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Mitochondrial reactive oxygen species generation was measured using the MitoSOX Red fluorescent probe.

Results: We found that PD treatment inhibited cell viability both in HA22T HCC and HDACi-R cells. Inhibition of ERK1/2 by PD98059 could reverse drug resistance in HDACi-R cells treated with PD98059 and PD. Nevertheless, pre-treatment with U46619, an ERK1/2 activator, rescued PD-induced apoptosis by decreasing levels of apoptosis-related proteins in HCC cells. The combined treatment of PD with apicidin a powerful HDACi, dramatically enhanced the apoptotic effect in HDACi-R cells.

Conclusion: For the first time, we showed that PD reversed HDACi resistance in HCC by repressing ERK1/2-mediated cofilin-1 phosphorylation. Thus, PD can potentially be a treatment target to reverse HCC chemotherapy resistance in future therapeutic trials.
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http://dx.doi.org/10.1016/j.phymed.2020.153442DOI Listing
February 2021

Exercise training restores IGFIR survival signaling in d-galactose induced-aging rats to suppress cardiac apoptosis.

J Adv Res 2021 Feb 20;28:35-41. Epub 2020 Jun 20.

School of Chinese Medicine, College of Chinese Medicine, China Medical University, 40402 Taichung, Taiwan.

Introduction: Insulin-like growth factor-I receptor (IGF1R) mediated survival signaling is a crucial mechanism for cellular endurance and a potential indicator of recuperation in deteriorating hearts.

Objective: This study evaluates the impact of long-term exercise training in enhancing cardiac survival mechanism in D-galactose-induced toxicity associated aging rats.

Methods: Forty-eight male SD-rats were segregated into 4 groups (n=9) and were named as control, exercise training groups, aging group and aging group with exercise training. Aging was induced by intraperitoneal (IP) D-galactose (150 mL/kg) injection for 8 weeks and for exercise training, the rats were left to swim in warm water for 60 min every day and 5 times/week. Western blotting of proteins from the left ventricles was performed to identify the modulations in the survival signaling. Tissue sections were analyzed to determine the extent of fibrosis and apoptosis.

Results: Western-blot analysis performed on the excised left ventricles (LV) showed that proteins of the cardiac survival pathway including IGF1R and Akt and the pro-survival Bcl-2 showed significant decrease in the aging group, whereas the levels were restored in the aging rats subjected to exercise training. In addition, aging groups showed increased interstitial space and collagen accumulation. Further, TUNEL assay showed higher number of apoptotic cells in the LV of aging group, which was correlated with increase in the proteins involved in FAS-FADD-dependent apoptosis. However, these aging associated effects were ameliorated upon exercise training in the D-galactose-induced aging rats that showed elevated IGF1R/Akt signaling.

Conclusion: The results suggest that IGFIR survival signaling cascadeis elevated in following long-term exercise training and thereby provide cardio-protective benefits in D-galactose induced aging rats.
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http://dx.doi.org/10.1016/j.jare.2020.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753223PMC
February 2021

Nerolidol improves cardiac function in spontaneously hypertensive rats by inhibiting cardiac inflammation and remodelling associated TLR4/ NF-κB signalling cascade.

Food Chem Toxicol 2021 Jan 17;147:111837. Epub 2020 Nov 17.

Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 404, Taiwan; Department of Biological Science and Technology, Asia University, Taichung, Taiwan; Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, 970, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan. Electronic address:

Toll-like receptor 4 (TLR4) is an important mediator of hypertension and AngII induced cardiac inflammation and remodelling. In this study, the potential of nerolidol to ameliorate hypertension induced cardiac injuries and the underlying mechanism of action was explored by using in vitro and in vivo models. The in vitro analysis was performed on AngII challenged H9c2 cells and their ability to overcome cardiac inflammation and cardiac remodelling effects was determined by evaluating TLR4/NF-κB signalling cascade using Western blot analysis and immunofluorescence. The results were further ascertained using in vivo experiments. Eighteen week old male rats were randomly allocated into different groups i.e. Wistar Kyoto (WKY) rats, hypertensive SHRs, SHRs treated with a low-dose (75 mg/kg b.w) and high-dose of nerolidol (150 mg/kg b.w) and SHRs treated with captopril (50 mg/kg b.w) through oral gauge and finally analysed through echocardiography, histopathological techniques and molecular analysis. The results show that nerilodol target TLR4/NF-κB signalling and thereby attenuate hypertension associated inflammation and oxidative stress thereby provides effective cardioprotection. Echocardiography analysis showed that nerolidol improved cardiac functional characteristics including Ejection Fraction and Fractional Shortening in the SHRs. Collectively, the data of the study demonstrates nerolidol as a cardio-protective agent against hypertension induced cardiac remodelling.
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http://dx.doi.org/10.1016/j.fct.2020.111837DOI Listing
January 2021

Leech extract: A candidate cardioprotective against hypertension-induced cardiac hypertrophy and fibrosis.

J Ethnopharmacol 2021 Jan 4;264:113346. Epub 2020 Sep 4.

Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan; Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan. Electronic address:

Ethnopharmacological Relevance: The prevalence of cardiovascular diseases (CVDs) has been increasing worldwide. Despite significant improvements in therapeutics and on-going developments of novel targeted-treatment regimens, cardiac diseases lack effective preventive and curative therapies with minimal side effects. Therefore, there is an urgent need to identify and propagate alternative and complementary therapies against cardiovascular diseases. Some traditional Chinese medicines can contribute to the prevention and treatment of CVDs and other chronic diseases, with few side effects. Hirudo, a medicinal leech, has been acclaimed for improving blood circulation and overcoming blood stagnation; however, the precise molecular mechanisms of leech extract treatment against pathological cardiac remodeling remain elusive. In this study, we aimed to delineate the molecular mechanisms of medicinal leech extract in the treatment of cardiac hypertrophy and fibrosis, using both in vitro and in vivo assessments.

Materials And Methods: We conducted in vitro and in vivo animal experiments, including cell-viability assays, fluorescence microscopy, immunoblotting, immunohistochemistry, and Masson's trichrome staining.

Results: Pre-treatment with leech extract conferred a survival benefit to spontaneously-hypertensive rats (SHRs) and significantly reduced angiotensin II (ANG II)-induced cardiac hypertrophy and fibrosis. ANG II-stimulated cardiac hypertrophy markers were attenuated by leech extract treatment, versus controls. Translational expression of stress-associated mitogen-activated protein kinases (MAPKs) was also repressed. In vivo, leech extract treatment significantly ameliorated the cardiac hypertrophy phenotype in SHRs and diminished interstitial fibrosis, accompanied with reduced fibrosis markers.

Conclusion: Leech extract treatment under a hypertensive condition exerted significant cardio-protective benefits by reducing the expression of cardiac hypertrophy-related transcription factors, stress-associated MAPKs, and fibrosis mediators. Our findings imply that medicinal leach extract may be effective against hypertension-induced cardiac hypertrophy and fibrosis.
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http://dx.doi.org/10.1016/j.jep.2020.113346DOI Listing
January 2021

D-galactose-induced toxicity associated senescence mitigated by alpinate oxyphyllae fructus fortified adipose-derived mesenchymal stem cells.

Environ Toxicol 2020 Sep 5. Epub 2020 Sep 5.

Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.

This study addresses the effect of D-galactose-induced toxicity associated senescence mitigated by alpinate oxyphyllae fructus (AOF; Alpinia oxyphylla Miq) extracts fortified with adipose-derived mesenchymal stem cells (ADMSCs) in rats. Male 18 week-old Wistar Kyoto (WKY) rats were used in this study. We analyzed cardiac fibrosis by Masson's trichrome staining. The tissue sections were dyed using hematoxylin and eosin (H&E). Tissue sections were stained for the restoration of Nrf2 expression in treatment groups by immunohistochemistry. Immunohistochemistry and western blotting analysis showed that AOF with ADMSCs could significantly reduce aging-induced oxidative stress in D-galactose-induced aging rat hearts by inducing Nrf2 pathway. Reduction in ROS resulted in the suppression of inflammatory signals (p-NF-κB and IL-6). Histopathological studies were showed an increased interstitium and collagen accumulation in aging-induced heart sections. However, AOF and ADMSCs treated hearts were recovered from cardiac remodeling. Furthermore, hypertrophy and fibrosis associated markers were also significantly reduced (P < .05) in treatment groups. We speculate that ADMSCs might activate certain paracrine factors, which could target the upstream activator of aging associated cardiac complications and AOF might provide homing for these stem cells.
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http://dx.doi.org/10.1002/tox.23014DOI Listing
September 2020

Inhibition of cell death-inducing p53 target 1 through miR-210-3p overexpression attenuates reactive oxygen species and apoptosis in rat adipose-derived stem cells challenged with Angiotensin II.

Biochem Biophys Res Commun 2020 11 1;532(3):347-354. Epub 2020 Sep 1.

Graduate Institute of Basic Medical Science, China Medical University, Taichung City, 40402, Taiwan; Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 970, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan; Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, 970, Taiwan. Electronic address:

Hypoxic preconditioning is a well-known strategy to improve the survival and therapeutic potential of stem cells against various challenges including hemodynamic and neurohormonal modulations. However, the mechanism involved in hypoxia-induced benefits on stem cells is still ambiguous. In pathological hypertension, the elevation of the neurohormonal mediator Angiotensin II (Ang II) causes the adverse effects to stem cells. In this study, we investigate the effect and mechanism of action of short term hypoxia-inducible miRNA in suppressing the effects of AngII on stem cells. According to the results obtained, Ang II affects the normal cell cycle and triggers apoptosis in rADSCs with a corresponding increase in the expression of cell death-inducing p53 target 1 (CDIP1) protein. However, the short term hypoxia-inducible miRNA-miR-210-3p was found to target CDIP1 and reduce their levels upon the Ang II challenge. CDIP1 induces stress-mediated apoptosis involving the extrinsic apoptosis pathway via Bid/Bax/cleaved caspase3 activation. Administration of mimic miR-210-3p targets CDIP1 mRNA by binding to the 3' UTR region as confirmed by dual luciferase assay and also reduced Ang II-induced mitochondrial ROS accumulation as analyzed by MitoSOX staining. Moreover, the present study demonstrates the mechanism of miR-210-3p in the regulation of Ang II-induced CDIP1-associated apoptotic pathway in rADSCs.
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http://dx.doi.org/10.1016/j.bbrc.2020.07.052DOI Listing
November 2020

Adipose derived mesenchymal stem cells along with Alpinia oxyphylla extract alleviate mitochondria-mediated cardiac apoptosis in aging models and cardiac function in aging rats.

J Ethnopharmacol 2021 Jan 22;264:113297. Epub 2020 Aug 22.

Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 970, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 404, Taiwan; Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, 970, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 404, Taiwan; Department of Biotechnology, Asia University, Taichung, 413, Taiwan. Electronic address:

Ethnopharmacological Relevance: The Fructus (Alpinia oxyphylla MIQ) known as Yi Zhi Ren in Chinese medicine has been used as a food and herbal medicinal substance in China for centuries; in the year 2015 Chinese Pharmacopoeia Commission reported water extracts of Alpinia oxyphyllae Fructus (AoF) as a popular medication for aging-related diseases in the form of tonic, aphrodisiac, and health-care food in south China.

Aim Of The Study: Adipose mesenchymal stem cells are physiologically and therapeutically associated with healthy vascular function and cardiac health. However aging conditions hinder stem cell function and increases the vulnerability to cardiovascular diseases. In this study, the effect of the anti-aging herbal medicine AoF to enhance the cardiac restorative function of adipose-derived mesenchymal stem cells (ADMSCs) in aging condition was investigated.

Materials And Methods: Low dose (0.1 μM) Doxorubicin and D-galactose (150 mg/kg/day for 8 weeks) were used to respectively induce aging in vitro and in vivo. For In vivo studies, 20 week old WKY rats were divided into Control, Aging induced (AI), AI + AoF, AI + ADMSC, AI + AoF Oral + ADMSC, and AI + AoF treated ADMSC groups. AoF (100 mg/kg/day) was administered orally and ADMSCs (1 × 10 cells) were injected (IV).

Results: AoF preconditioned ADMSC showed reduction in low dose Dox induced mitochondrial apoptosis and improved DNA replication in H9c2 cardiomyoblasts. In vivo experiments confirmed that both a combined treatment with AoF-ADMSCs and with AoF preconditioned ADMSCs reduced aging associated cardiac damages which was correlated with reduction in apoptosis and expression of senescence markers (P21 and β-gal). Survival and longevity markers were upregulated up on combined administration of AoF and ADMSCs. The cardiac performance of the aging-induced rats was improved significantly in the treatment groups. AoF along with ADMSCs might activate paracrine factors to restore the performance of an aging heart.

Conclusion: Hence, we propose that ADMSCs combined with AoF have promising therapeutic properties in the treatment of healthy aging heart.
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http://dx.doi.org/10.1016/j.jep.2020.113297DOI Listing
January 2021

Induction of Autophagy by Vasicinone Protects Neural Cells from Mitochondrial Dysfunction and Attenuates Paraquat-Mediated Parkinson's Disease Associated α-Synuclein Levels.

Nutrients 2020 Jun 7;12(6). Epub 2020 Jun 7.

Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan.

Mitochondrial dysfunction and disturbed mitochondrial dynamics were found to be common phenomena in the pathogenesis of Parkinson's disease (PD). Vasicinone is a quinazoline alkaloid from . Here, we investigated the autophagy/mitophagy-enhancing effect of vasicinone and explored its neuroprotective mechanism in paraquat-mimic PD modal in SH-SY5Y cells. Vasicinone rescued the paraquat-induced loss of cell viability and mitochondrial membrane potential. Subsequently, the accumulation of mitochondrial reactive oxygen species (ROS) was balanced by an increase in the expression of antioxidant enzymes. Furthermore, vasicinone restored paraquat-impaired autophagy and mitophagy regulators DJ-1, PINK-1 and Parkin in SH-SY5Y cells. The vasicinone mediated autophagy pathways were abrogated by treatment with the autophagy inhibitor 3-MA, which lead to increases α-synuclein accumulation and decreased the expression of p-ULK and ATG proteins and the autophagy marker LC3-II compared to that observed without 3-MA treatment. These results demonstrated that vasicinone exerted neuroprotective effects by upregulating autophagy and PINK-1/Parkin mediated mitophagy in SH-SY5Y cells.
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http://dx.doi.org/10.3390/nu12061707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352463PMC
June 2020

Chemoresistance-Associated Silencing of miR-4454 Promotes Colorectal Cancer Aggression through the and Pathway.

Cancers (Basel) 2020 May 14;12(5). Epub 2020 May 14.

Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan.

Guanine nucleotide-binding protein-like-3-like () is a crucial regulator of signaling that is aberrantly activated during diverse chemoresistance-associated cellular processes. However, the molecular mechanisms of tumor initiation and resistant state are largely unknown. Moreover, the identification of predictive biomarkers is necessary to effectively generate therapeutic strategies for metastatic human colorectal cancer (CRC). This study aims to identify how cells acquire resistance to anticancer drugs and whether the downregulation of miR-4454 is associated with the progression of CRC. Here, we have shown that the overexpression of miR-4454 in resistant tumors is a crucial precursor for the posttranscriptional repression of in human chemoresistant CRC progression, and we used doxycycline induced miR-4454 overexpression that significantly reduced tumor volume in a subcutaneous injection nude mice model. Together, these observations highlight that the downregulation of miR-4454 in resistant clones is prominently responsible for maintaining their resistance against anticancer drug therapy. Our study indicates that the development of miR-4454 as a microRNA-based therapeutic approach to silence may remarkably reduce oncogenic cell survival that depends on signaling, making miR-4454 a candidate for treating metastatic human CRC.
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http://dx.doi.org/10.3390/cancers12051231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281507PMC
May 2020

Selective Activation of ZAK β Expression by 3-Hydroxy-2-Phenylchromone Inhibits Human Osteosarcoma Cells and Triggers Apoptosis via JNK Activation.

Int J Mol Sci 2020 May 9;21(9). Epub 2020 May 9.

Graduate Institute of Biomedical Science, China Medical University, Taichung 404, Taiwan.

Although various advancements in radical surgery and neoadjuvant chemotherapy have been developed in treating osteosarcoma (OS), their clinical prognosis remains poor. A synthetic chemical compound, 3-hydroxylflavone, that is reported to regulate ROS production is known to inhibit human bone osteosarcoma cells. However, its role and mechanism in human OS cells remains unclear. In this study, we have determined the potential of 3-Hydroxy-2-phenylchromone (3-HF) against OS using human osteosarcoma (HOS) cells. Our previous studies showed that Zipper sterile-alpha-motif kinase (ZAK), a kinase member of the MAP3K family, was involved in various cellular events such as cell proliferation and cell apoptosis, and encoded two transcriptional variants, ZAKα and β. In this study, we show that 3-HF induces the expression of ZAK and thereby enhances cellular apoptosis. Using gain of function and loss of function studies, we have demonstrated that ZAK activation by 3-HF in OS cells is confined to a ZAKβ form that presumably plays a leading role in triggering ZAKα expression, resulting in an aggravated cancer apoptosis. Our results also validate ZAKβ as the predominant form of ZAK to drive the anticancer mechanism in HOS cells.
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http://dx.doi.org/10.3390/ijms21093366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247666PMC
May 2020

Andrographolide mitigates cardiac apoptosis to provide cardio-protection in high-fat-diet-induced obese mice.

Environ Toxicol 2020 Jun 5;35(6):707-713. Epub 2020 Feb 5.

Cardiovascular and Mitochondria Related Diseases Research Center, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan.

Excessive intake of high fat diet (HFD) and associated obese conditions are critical contributors of cardiac diseases. In this study, an active metabolite andrographolide from Andrographis paniculata was found to ameliorate HFD-induced cardiac apoptosis. C57/BL6 mouse were grouped as control (n = 9), obese (n = 8), low dose (25 mg/kg/d) andrographolide treatment (n = 9), and high dose (50 mg/kg/d) andrographolide treatment (n = 9). The control group was provided with standard laboratory chow and the other groups were fed with HFD. Andrographolide was administered through oral gavage for 1 week. Histopathological analysis showed increase in apoptotic nuclei and considerable cardiac-damages in the obese group signifying cardiac remodeling effects. Further, Western blot results showed increase in pro-apoptotic proteins and decrease in the proteins of IGF-1R-survival signaling. However, feeding of andrographolide significantly reduced the cardiac effects of HFD. The results strongly suggest that andrographolide supplementation can be used for prevention and treatment of cardiovascular disease in obese patients.
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http://dx.doi.org/10.1002/tox.22906DOI Listing
June 2020

Tetramethylpyrazine reverses high-glucose induced hypoxic effects by negatively regulating HIF-1α induced BNIP3 expression to ameliorate H9c2 cardiomyoblast apoptosis.

Nutr Metab (Lond) 2020 31;17:12. Epub 2020 Jan 31.

2College of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan.

Background: Diabetic patients are highly vulnerable to hypoxic injury, which is associated with hypoxia induced BNIP3 expression that subsequently activate apoptosis. Our previous research show that Tetramethylpyrazine (TMP), a food flavoring agent, represses the hypoxia induced BNIP3 expression attenuate myocardial apoptosis. In this study, we evaluate the effect of TMP to provide protection against hypoxia aggravated high-glucose associated cellular apoptosis.

Methods: The cytoprotective effect of TMP against high glucose induced cellular damages was determined on embryo derived H9c2 cardiomyoblast cells that were subjected to 5% hypoxia for 24 h and subjected to different duration of 33 mM high glucose challenge. Further, the involvement of HIF-1α and BNIP3 in cellular damage and the mechanism of protection of TMP were determined by overexpression and silencing HIF-1α and BNIP3 protein expression.

Results: The results show that hypoxic effects on cell viability aggravates with high glucose challenge and this augmentative effect is mediated through BNIP3 in H9c2 cardiomyoblast cells. However, TMP administration effectively reversed the augmented HIF-1α levels and BNIP3 elevation. TMP improved the survival of H9c2 cells and effectively suppressed apoptosis in H9c2 cells. Further comparison on the effects of TMP on H9c2 cells challenged with high glucose and those challenged with hypoxia show that TMP precisely regulated the hypoxic intensified apoptotic effects in high-glucose condition.

Conclusion: The results clearly show that flavoring agent-TMP attenuates cytotoxicity amplified by hypoxia challenge in high glucose condition by destabilizing HIF-1α.
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http://dx.doi.org/10.1186/s12986-020-0432-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995207PMC
January 2020

Design, Synthesis, and Structure-Activity Relationships of 1,2,3-Triazole Benzenesulfonamides as New Selective Leucine-Zipper and Sterile-α Motif Kinase (ZAK) Inhibitors.

J Med Chem 2020 03 17;63(5):2114-2130. Epub 2019 Jun 17.

International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.

ZAK is a new promising target for discovery of drugs with activity against antihypertrophic cardiomyopathy (HCM). A series of 1,2,3-triazole benzenesulfonamides were designed and synthesized as selective ZAK inhibitors. One of these compounds, binds tightly to ZAK protein ( = 8.0 nM) and potently suppresses the kinase function of ZAK with single-digit nM (IC = 4.0 nM) and exhibits excellent selectivity in a KINOMEscan screening platform against a panel of 403 wild-type kinases. This compound dose dependently blocks p38/GATA-4 and JNK/c-Jun signaling and demonstrates promising in vivo anti-HCM efficacy upon oral administration in a spontaneous hypertensive rat (SHR) model. Compound may serve as a lead compound for new anti-HCM drug discovery.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00664DOI Listing
March 2020

Pheretima aspergillum extract attenuates high-KCl-induced mitochondrial injury and pro-fibrotic events in cardiomyoblast cells.

Environ Toxicol 2019 Aug 7;34(8):921-927. Epub 2019 May 7.

Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.

Hyperkalemia is often associated with cardiac dysfunction. In this study an earthworm extract (dilong) was prepared from dried Pheretima aspergillum powder and its effect against high-KCl challenge was determined in H9c2 cardiomyoblast cells. H9c2 cells pre-treated with dilong (31.25, 62.5, 125, and 250 mg/mL) for 24 hours, where challenged with different doses of KCl treatment for 3 hours to determine the protective mechanisms of dilong against cardiac fibrosis. High-KCl administration induced mitochondrial injury and elevated the levels of pro-apoptotic proteins. The mediators of fibrosis such as ERK, uPA, SP1, and CTGF were also found to be upregulated in high-KCl condition. However, dilong treatment enhanced IGF1R/PI3k/Akt activation which is associated with cell survival. In addition, dilong also reversed high-KCl induced cardiac fibrosis related events in H9c2 cells and displayed a strong cardio-protective effect. Therefore, dilong is a potential agent to overcome cardiac events associated with high-KCl toxicity.
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http://dx.doi.org/10.1002/tox.22763DOI Listing
August 2019

Antidiabetic Effects of a Short Peptide of Potato Protein Hydrolysate in STZ-Induced Diabetic Mice.

Nutrients 2019 Apr 4;11(4). Epub 2019 Apr 4.

Department of Hospitality Management, College of Agriculture, Tunghai University, Taichung 40704, Taiwan.

Alcalase- generated potato protein hydrolysate (APPH) is a potential bioactive peptide against diabetes mellitus (DM) and DM-associated secondary effects in animal models. The aim of the present study was to find the efficiency of a deca-peptide DIKTNKPVIF (DF) from APPH against DM. Six-week-old male ICR mice were divided into the following groups: Control, Control+DF (received 50 mg/kg DF), streptozotocin (STZ)-induced DM group, DM+Acarbose group (20 mg/kg of acarbose), DM+DF-L (25 mg/kg of DF), DM+DF-H (50 mg/kg of DF), and DM+APPH (50 mg/kg of APPH). Comparable to APPH, treatment with DF effectively regulated blood glucose level and also controlled plasma total glycerol (TG), total cholesterol (TC), insulin, and HbA1c levels in DM animals. DF treatment also showed evidence of ameliorating DM-associated damages in the pancreatic islets and in the liver, heart, and kidney tissues. Therefore, the results demonstrate that the short synthetic peptide-DF may effectively provide protection against DM-associated damages.
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http://dx.doi.org/10.3390/nu11040779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520812PMC
April 2019

ERK1/2 mediates the lipopolysaccharide-induced upregulation of FGF-2, uPA, MMP-2, MMP-9 and cellular migration in cardiac fibroblasts.

Chem Biol Interact 2019 Jun 11;306:62-69. Epub 2019 Apr 11.

Department of Biotechnology, Asia University, Taichung, Taiwan; College of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan; Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan. Electronic address:

Myocardial fibrosis is a critical event during septic shock. Upregulation in the fibrosis signaling cascade proteins such as fibroblast growth factor (FGF), urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA) and activation of matrix metalloproteinases (MMPs) are widely associated with the development of myocardial infarction, dilated cardiomyopathy, cardiac fibrosis and heart failure. However, evidences suggest that the common upstream mediators of fibrosis cascade play little role in cardiac fibrosis induced by LPS; further, it is unknown if LPS directly triggers the expressions and/or activity of FGF-2, uPA, tPA, MMP-2 and MMP-9 in cardiac fibroblasts. In the present study, we treated primary cultures of cardiac fibroblasts with LPS to explore whether LPS upregulates FGF-2, uPA, tPA, MMP-2, MMP-9 and enhance cellular migration. Further the precise molecular and cellular mechanisms behind these LPS induced responses were identified. Inhibition assays on MAPKs using U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor), SP600125 (JNK1/2 inhibitor), CsA (calcineurin inhibitor) and QNZ (NFκB inhibitor) show that LPS-induced upregulation of FGF-2, uPA, MMP-2 and MMP-9 in cardiac fibroblasts was mediated through ERK1/2 signaling. Collectively, our results provide a link between LPS-induced cardiac dysfunction and ERK1/2 signaling pathway and thereby implies ERK1/2 as a possible target to regulate LPS induced upregulation of FGF-2, uPA, MMP-2, MMP-9 and cellular migration in cardiac fibroblasts.
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http://dx.doi.org/10.1016/j.cbi.2019.04.010DOI Listing
June 2019

Taiwanin C elicits apoptosis in arecoline and 4-nitroquinoline-1-oxide-induced oral squamous cell carcinoma cells and hinders proliferation via epidermal growth factor receptor/PI3K suppression.

Environ Toxicol 2019 Jun 18;34(6):760-767. Epub 2019 Mar 18.

Medical Research Center for Exosomes and Mitochondria Related Diseases, China Medical University Hospital, Taichung, Taiwan.

Oral Squamous Cell Carcinoma (OSSC) is a major life-threatening disease with high incidence in the Southeast Asian countries. Chronic exposure to arecoline causes genetic changes in the epithelial cells of the oral mucosa, induces proliferation through activation of the EGF receptor and promotes downstream COX-2 expression. Taiwanin C, a podophyllotoxin derived from Taiwania cryptomerioides Hayata is known to inhibit COX activity and to hinder PGE2 production in macrophages. In this study a tumor cell line T28 and a non-tumor cell line N28 derived from mice OSCC models were used to study the effect of Taiwanin C on PGE associated COX-2 expression and cell cycle regulators. Taiwanin C activated p21 protein expression, down-regulated cell cycle regulatory proteins, elevated apoptosis and down-regulated p-PI3K/p-Akt survival mechanism in T28 oral cancer cells. Our results therefore emphasize the therapeutic potential of Taiwanin C against arecoline-induced oral cancer.
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http://dx.doi.org/10.1002/tox.22742DOI Listing
June 2019

Protective effect of Fisetin against angiotensin II-induced apoptosis by activation of IGF-IR-PI3K-Akt signaling in H9c2 cells and spontaneous hypertension rats.

Phytomedicine 2019 Apr 17;57:1-8. Epub 2018 Sep 17.

Graduate Institute of Basic Medical Science, China Medical University, Taichung, 40402, Taiwan; School of Post-Baccalaureate Chinese Medicine, China Medical University, Taichung, Taiwan; School of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan; Department of Biotechnology, Asia University, Taichung, 41354, Taiwan. Electronic address:

Background: Fisetin, a polyphenolic compound, has drawn notable attention owing to its antioxidant, anti-inflammatory, anti-cancer and neuroprotective effects. However, the cardiac effects of fisetin are not clear yet.

Hypothesis: The aim of the present study is to examine the cardioprotective effect of fisetin against Ang-II induced apoptosis in H9c2 cells and in spontaneous hypertensive rats (SHR).

Methods/study Design: The in vitro protective effect of fisetin was evaluated after the cells were treated with fisetin (50 µM/ml/ 24  h) for 2  h prior or after Ang-II administration to induce apoptosis. For in vivo experiments, SHRs were orally administered with fisetin (10  mg/kg) twice a week for 6 weeks. Cellular apoptosis was analyzed by TUNEL staining assay and the modulation in the expression levels of proteins involved in apoptosis and cell survival were determined by western blotting.

Results: Our results demonstrate the potent cardioprotective efficacy of fisetin against Ang-II induced apoptosis in H9c2 cells and in SHR models. Fisetin administration reduced the apoptotic nuclei considerably And reduced the expression of apoptotic proteins such as TNF- α, Fas L, FADD, Cleaved caspase-3 and Cleaved PARP and increased the cell survival and anti-apoptotic proteins like Bcl-2, Bcl-x p-IGF1R, p-PI3K and p-AKT in both in vitro and in vivo models.

Conclusion: In conclusion, the results of the present study reveal that fisetin activates the IGF-IR-dependent p-PI3K/p-Akt survival signaling pathway and suppresses the caspase dependent apoptosis.
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http://dx.doi.org/10.1016/j.phymed.2018.09.179DOI Listing
April 2019

Exercise training augments Sirt1-signaling and attenuates cardiac inflammation in D-galactose induced-aging rats.

Aging (Albany NY) 2018 12;10(12):4166-4174

Medical Research Center for Exosome and Mitochondria Related Diseases, China Medical University and Hospital, Taichung, Taiwan.

Exercise is known to be beneficial in controlling aging associated disorders however, the consequence of long-term exercise on cardiac health among aging population is not much clear. In this study the protective effect of exercise on aging associated cardiac disorders was determined using a D-galactose-induced aging model. Eight weeks old Sprague Dawley rats were given intraperitoneal injection of 150 mL/kg D-galactose. Swimming exercise was provided in warm water for 60 min/day for five days per week. Hematoxylin and eosin staining of cardiac tissue sections revealed cardiomyocyte disarrangements in the aging rat hearts but long-term exercise training showed improvements in the cardiac histology. Exercise training also enhanced the expression levels of proteins such as SIRT1, PGC-1α and AMPKα1 that are associated with energy homeostasis and further suppressed aging associated inflammatory cytokines. Our results show that long-term exercise training potentially enhances SIRT1 associated anti-aging signaling and provide cardio-protection against aging.
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http://dx.doi.org/10.18632/aging.101714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326662PMC
December 2018

Alpinate Oxyphyllae extracts enhance the longevity and homing of mesenchymal stem cells and augment their protection against senescence in H9c2 cells.

J Cell Physiol 2019 07 4;234(7):12042-12050. Epub 2018 Dec 4.

Medical Research Center for Exosomes and Mitochondria Related Diseases, China Medical University Hospital, Taichung, Taiwan.

Adipose-derived mesenchymal stem cells (ADMSCs) are easily accessible and are attractive mesenchymal stem cells for use in regenerative medicine; however their application is frequently restricted due to various challenges present in the environment they are administered. Therefore ADMSCs are preferably preconditioned with various stimulating factors to overcome the barriers developed in any pathological conditions. Here we used ADMSCs from rat adipose based on the abundance of positive markers and preconditioned the cells with extracts from Alpinate Oxyphyllae Fructus (AOF), a traditional Chinese herb used for antiaging, associated various health benefits. The preconditioned stem cells were tested for their potential to drive H9c2 from doxorubicin (Dox)-induced aging. The AOF-treated stem cells enriched stemness in ADMSCs with respect to their stem cells' positive marker, and enhanced their longevity mechanism and elevated the stem cell homing-associated C-X-C chemokine receptor type 7 (CXCR7). The AOF preconditioned stem cells, when cocultured with H9c2 cells, showed effective protection to Dox-induced senescence and stem cell homing to damaged H9c2 cells. The presence of AOF provided greater protective effects in the Dox environment. In addition, AOF-pretreated ADMSCs showed enhanced migration than those treated with AOF in Dox environment. Therefore, our results show that administration of AOF preconditioned stem cells is potentially an effective strategy in the management of aging-associated cardiac disorders.
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http://dx.doi.org/10.1002/jcp.27867DOI Listing
July 2019

Anti-hypertrophic and anti-apoptotic effects of short peptides of potato protein hydrolysate against hyperglycemic condition in cardiomyoblast cells.

Biomed Pharmacother 2018 Nov 8;107:1667-1673. Epub 2018 Sep 8.

Department of Hospitality Management, College of Agriculture, Tunghai University, Taichung, Taiwan. Electronic address:

Cardiomyocyte hypertrophy is a critical pathological phenomenon observed in diabetic cardiomyopathy. Various molecular events including the Calcineurin/nuclear factor of activated T-cell (NFAT) mediated signaling contributes to the pathogenesis of cardiac hypertrophy. While different new therapeutic interventions are investigated in order to overcome pathological hypertrophic effects, recent studies on peptide hydrolysates from common foods have gained interest. In this study the cytoprotective efficiency of two short peptides DIKTNKPVIF (DF) and a dipeptide IF from a potato protein hydrolysate were evaluated for their anti-hypertrophic effects against high glucose (HG) challenge. Murine cardio myoblast (H9c2) cells were challenges with 33 mM of glucose and after 1 h were treated with DF or IF for 24 h. The results showed enlargement in cell size, elevated ANP and BNP expression induced by HG however the abnormalities were efficiently attenuated by IF and DF. Further, HG increased the levels of calcineurin and NFATC3 which was markedly suppressed by DF and IF in H9c2 cells. The results further showed that DF and IF suppresses the activation of p38 in a dose dependent manner with no notable effects on JNK activation. DF and IF also attenuated the HG induced apoptotic effects in H9c2 cells by suppressing the apoptotic proteins and by enhancing the survival and anti-apoptotic proteins. Further, it should be noted that administration of both the fragments showed similar effects in all the analysis. Our results therefore showed that DF and IF of potato protein hydrolysate possess efficient protective effects against HG-induced cardiomyocyte damages by ameliorating the apoptotic and hypertrophic effects.
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http://dx.doi.org/10.1016/j.biopha.2018.08.070DOI Listing
November 2018

Cryptotanshinone (Dsh-003) from Salvia miltiorrhiza Bunge inhibits prostaglandin E2-induced survival and invasion effects in HA22T hepatocellular carcinoma cells.

Environ Toxicol 2018 Dec 12;33(12):1254-1260. Epub 2018 Sep 12.

Medical Research Center for Exosome and Mitochondria Related Diseases, China Medical University Hospital, Taichung 40402, Taiwan.

Human hepatocellular carcinoma (HCC) is currently the second most common cancer and one of the leading causes of cancer-related mortality in Taiwan. Previous reports show that the expression of (E-type prostaglandin 2) EP2 and (E-type prostaglandin 4) EP4 are elevated in HCC and further demonstrate that Prostaglandin E2 (PGE2) induces HA22T cell proliferation and metastasis through EP2 and EP4 receptor. Danshen (root of Salvia miltiorrhiza Bunge) is a very important and popular traditional Chinese herbal medicine which is widely and successfully used against breast cancer, leukemia, pancreatic cancer, and head and neck squamous carcinoma cells. In this study, we used Cryptotansinone (Dsh-003) (MW 269.14) from Danshen to investigate their effect and corresponding mechanism of action in PGE2-treated HA22T cells. Dsh-003 inhibited HA22T cell viability and further induced cell apoptosis in PGE2-treated HA22T cells. Furthermore, Dsh-003 inhibited EP2, EP4, and their downstream effector such as p-PI3K and p-Akt expression in HA22T hepatocellular carcinoma cells. We also observed that Dsh-003 blocked PGE2-induced cell migration by down-regulating PGE2-induced β-catenin expression and by up-regulating E-cadherin and GSK3-β expression. All these findings suggest that Dsh-003 inhibit human HCC cell lines and could potentially be used as a novel drug for HCC treatment.
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http://dx.doi.org/10.1002/tox.22633DOI Listing
December 2018

Bioactive Peptide Improves Diet-Induced Hepatic Fat Deposition and Hepatocyte Proinflammatory Response in SAMP8 Ageing Mice.

Cell Physiol Biochem 2018 9;48(5):1942-1952. Epub 2018 Aug 9.

Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.

Background/aims: High-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) poses therapeutic challenges in elderly subjects. Due to lack of efficient drug therapy, plant-based bioactive peptides have been studied as alternative strategy in NAFLD and for less toxicity in elderly. To mimic fatty liver in aging conditions, researchers highly commended the genetically engineered strains SAMP8 (senescence-accelerated mice prone 8). However, there is a paucity of reports about the anti-steatosis effects of bioactive peptides against fatty liver development under a combined action of high-fat diet exposure and aging process. This study was conducted to evaluate the activity of DIKTNKPVIF peptide synthesized from alcalase-generated potato protein hydrolysate (PH), on reducing HFD-driven and steatosis-associated proinflammatory reaction in ageing model.

Methods: Five groups of six-month-old SAMP8 mice (n=4, each) were fed either a normal chow (NC group) for 14 weeks upon sacrifice, or induced with a 6-week HFD feeding, then treated without (HCO group) or with an 8-week simultaneous administration of peptide (HPEP group), protein (HPH group) or probucol (HRX group). Liver organs were harvested from each group for histological analysis and immunoblot assay.

Results: In contrast to NC, extensive fat accumulation was visualized in the liver slides of HCO. Following the trends of orally administered PH, intraperitoneally injected peptide reduces hepatic fat deposition and causes at protein level, a significant decrease in HFD-induced proinflammatory mediators p-p38 MAPK, FGF-2, TNF-α, IL-6 with concomitant reactivation of AMPK. However, p-Foxo1 and PPAR-α levels were slightly changed.

Conclusion: Oral supplementation of PH and intraperitoneal injection of derived bioactive peptide alleviate proinflammatory reaction associated with hepatosteatosis development in elderly subjects, through activation of AMPK.
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http://dx.doi.org/10.1159/000492518DOI Listing
September 2018

Eriobotrya japonica ameliorates cardiac hypertrophy in H9c2 cardiomyoblast and in spontaneously hypertensive rats.

Environ Toxicol 2018 Nov 4;33(11):1113-1122. Epub 2018 Jul 4.

Graduate Institute of Aging Medicine, China Medical University, Taichung, Taiwan.

Eriobotrya japonica (EJ) is a traditional Chinese plant with high medicinal value. EJ extracts are reported to exhibit antioxidant and anti-inflammatory biological attributes. The current study aims to evaluate the prospective efficacy of E. japonica leave extract (EJLE) against Angiotensin-II induced cardiac hypertrophy in H9c2 cardiomyoblast and in spontaneously hypertensive rats (SHRs). For the in vitro studies, Angiotensin-II pretreated H9c2 cells were treated with EJLE and analyzed through Western blotting and rhodamine phalloidin staining for their cardio-protective attributes. In the in vivo studies, 12-week-old SHRs were randomly divided into groups: SHRs supplemented with EJLE, control SHR group supplemented with PBS; in addition, a control group of Wistar-Kyoto rats (WKY) was also employed. All rats were supplemented twice a week for 8 week time interval. Finally, echocardiography, morphological, histology, and Western blot analysis were performed to assess their role against cardiac hypertrophy. Interestingly, we could observe that supplementation of EJLE could rescue Ang-II induced cardiac hypertrophy as evident through Western blot, rhodamine phalloidin staining, and Hematoxylin-Eosin staining. Notably, morphological and echocardiography data provided further supports for their ability to ameliorate cardiac characteristics. Cumulatively, the results clearly suggests that supplementation of EJLE promotes cardio-protective effects through amelioration of cardiac hypertrophy in vitro and in vivo.
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http://dx.doi.org/10.1002/tox.22589DOI Listing
November 2018

ERβ targets ZAK and attenuates cellular hypertrophy via SUMO-1 modification in H9c2 cells.

J Cell Biochem 2018 09 22;119(9):7855-7864. Epub 2018 Jun 22.

Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.

Aberrant expression of leucine zipper- and sterile ɑ motif-containing kinase (ZAK) observed in pathological human myocardial tissue is associated with the progression and elevation of hypertrophy. Our previous reports have correlated high levels of estrogen (E2) and abundant estrogen receptor (ER) α with a low incidence of pathological cardiac-hypertrophy and heart failure in the premenopause female population. However, the effect of elevated ERβ expression is not well known yet. Therefore, in this study, we have analyzed the cardioprotective effects and mechanisms of E2 and/or ERβ against ZAK overexpression-induced cellular hypertrophy. We have used transient transfection to overexpress ERβ into the ZAK tet-on H9c2 cells that harbor the doxycycline-inducible ZAK plasmid. The results show that ZAK overexpression in H9c2 cells resulted in hypertrophic effects, which was correlated with the upregulation of p-JNK and p-p38 MAPKs and their downstream transcription factors c-Jun and GATA-4. However, ERβ and E2 with ERβ overexpressions totally suppressed the effects of ZAK overexpression and inhibited the levels of p-JNK, p-p38, c-Jun, and GATA-4 effectively. Our results further reveal that ERβ directly binds with ZAK under normal conditions; however, ZAK overexpression reduced the association of ZAK-ERβ. Interestingly, increase in ERβ and E2 along with ERβ overexpression both enhanced the binding strengths of ERβ and ZAK and reduced the ZAK protein level. ERβ overexpression also suppressed the E3 ligase-casitas B-lineage lymphoma (CBL) and attenuated CBL-phosphoinositide 3-kinase (PI3K) protein association to prevent PI3K protein degradation. Moreover, ERβ and/or E2 blocked ZAK nuclear translocation via the inhibition of small ubiquitin-like modifier (SUMO)-1 modification. Taken together, our results further suggest that ERβ overexpression strongly suppresses ZAK-induced cellular hypertrophy and myocardial damage.
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http://dx.doi.org/10.1002/jcb.27199DOI Listing
September 2018