Publications by authors named "Hsin-Hsueh Shen"

12 Publications

  • Page 1 of 1

Milk thistle seed cold press oil attenuates markers of the metabolic syndrome in a mouse model of dietary-induced obesity.

J Food Biochem 2020 12 12;44(12):e13522. Epub 2020 Oct 12.

Department of Medicine, New York Medical College, Valhalla, NY, USA.

Milk thistle cold press oil (MTO) is an herbal remedy derived from Silybum marianum which contains a low level of silymarin and mixture of polyphenols and flavonoids. The effect of MTO on the cardiovascular and metabolic complications of obesity was studied in mice that were fed a high-fat diet (HFD) for 20 weeks and treated with MTO for the final 8 weeks of the diet. MTO treatment attenuated HFD-induced obesity, fasting hyperglycemia, hypertension, and induced markers of mitochondrial fusion and browning of white adipose. Markers of inflammation were also attenuated in both adipose and the liver of MTO-treated mice. In addition, MTO resulted in the improvement of liver fibrosis. These results demonstrate that MTO has beneficial actions to attenuate dietary obesity-induced weight gain, hyperglycemia, hypertension, inflammation, and suggest that MTO supplementation may prove beneficial to patients exhibiting symptoms of metabolic syndrome. PRACTICAL APPLICATIONS: Natural supplements are increasingly being considered as potential therapies for many chronic cardiovascular and metabolic diseases. Milk thistle cold press oil (MTO) is derived from Silybum marianum which is used as a dietary supplement in different parts of the world. The results of the present study demonstrate that MTO supplementation normalizes several metabolic and cardiovascular complications arising from dietary-induced obesity. MTO supplementation also had anti-inflammatory actions in the adipose as well as the liver. These results suggest that supplementation of MTO into the diet of obese individuals may afford protection against the worsening of cardiovascular and metabolic disease and improve inflammation and liver fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jfbc.13522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770619PMC
December 2020

Involvement of HO-1 and Autophagy in the Protective Effect of Magnolol in Hepatic Steatosis-Induced NLRP3 Inflammasome Activation In Vivo and In Vitro.

Antioxidants (Basel) 2020 Sep 27;9(10). Epub 2020 Sep 27.

Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei 11490, Taiwan.

Magnolol (MG) is the main active compound of and exerts a wide range of biological activities. In this study, we investigated the effects of MG using tyloxapol (Tylo)-induced (200 mg/kg, i.p.) hyperlipidemia in rats and palmitic acid (PA)-stimulated (0.3 mM) HepG2 cells. Our results showed that Tylo injection significantly increased plasma levels of triglyceride and cholesterol as well as superoxide anion in the livers, whereas MG pretreatment reversed these changes. MG reduced hepatic lipogenesis by attenuating sterol regulatory element-binding protein-1c (SREBP-1c) and fatty acid synthase (FAS) proteins and , , , and mRNA expression as well as upregulated the lipolysis-associated genes , , and . Furthermore, MG reduced plasma interleukin-1β (IL-1β) and protein expression of NLR family pyrin domain-containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), and caspase 1 as well as upregulated nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and induction of heme oxygenase-1 (HO-1) in hepatocytes of Tylo-treated rats. Enhanced autophagic flux by elevation of autophagy related protein 5-12 (ATG5-12), ATG7, Beclin1, and microtubule-associated protein light chain 3 B II (LC3BII)/LC3BI ratio, and reduction of sequestosome-1 (SQSTM1/p62) and phosphorylation of mTOR was observed by MG administration. However, autophagy inhibition with 3-methyladenine (3-MA) in HepG2 cells drastically abrogated the MG-mediated suppression of inflammation and lipid metabolism. In conclusion, MG inhibited hepatic steatosis-induced NLRP3 inflammasome activation through the restoration of autophagy to promote HO-1 signaling capable of ameliorating oxidative stress and inflammatory responses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/antiox9100924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600324PMC
September 2020

Cold Press Pomegranate Seed Oil Attenuates Dietary-Obesity Induced Hepatic Steatosis and Fibrosis through Antioxidant and Mitochondrial Pathways in Obese Mice.

Int J Mol Sci 2020 Jul 31;21(15). Epub 2020 Jul 31.

Departments of Medicine and Pharmacology, New York Medical College, Valhalla, NY 10595, USA.

Aim: Obesity is associated with metabolic syndrome, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes. In this study, we investigated whether the dietary supplementation of pomegranate seed oil (PSO) exerted a protective effect on liver lipid uptake, fibrosis, and mitochondrial function in a mouse model of obesity and insulin resistance.

Method: In this in vivo study, eight-week-old C57BL/6J male mice were fed with a high fat diet (HFD) for 24 weeks and then were divided into three groups as follows: group (1) Lean; group ( = 6) (2) HF diet; group ( = 6) (3) HF diet treated with PSO (40 mL/kg food) ( = 6) for eight additional weeks starting at 24 weeks. Physiological parameters, lipid droplet accumulation, inflammatory biomarkers, antioxidant biomarkers, mitochondrial biogenesis, insulin sensitivity, and hepatic fibrosis were determined to examine whether PSO intervention prevents obesity-associated metabolic syndrome.

Results: The PSO group displayed an increase in oxygen consumption, as well as a decrease in fasting glucose and blood pressure ( < 0.05) when compared to the HFD-fed mice group. PSO increased both the activity and expression of hepatic HO-1, downregulated inflammatory adipokines, and decreased hepatic fibrosis. PSO increased the levels of thermogenic genes, mitochondrial signaling, and lipid metabolism through increases in Mfn2, OPA-1, PRDM 16, and PGC1α. Furthermore, PSO upregulated obesity-mediated hepatic insulin receptor phosphorylation Tyr-, p-IRB tyr, and pAMPK, thereby decreasing insulin resistance.

Conclusions: These results indicated that PSO decreased obesity-mediated insulin resistance and the progression of hepatic fibrosis through an improved liver signaling, as manifested by increased insulin receptor phosphorylation and thermogenic genes. Furthermore, our findings indicate a potential therapeutic role for PSO in the prevention of obesity-associated NAFLD, NASH, and other metabolic disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21155469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432301PMC
July 2020

Cold-Pressed Oil Standardized to 3% Thymoquinone Potentiates Omega-3 Protection against Obesity-Induced Oxidative Stress, Inflammation, and Markers of Insulin Resistance Accompanied with Conversion of White to Beige Fat in Mice.

Antioxidants (Basel) 2020 Jun 4;9(6). Epub 2020 Jun 4.

Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.

Excessive lipid accumulation in white adipose tissue (WAT) results in adipocyte hypertrophy and chronic low-grade inflammation, which is the major cause of obesity-associated insulin resistance and consequent metabolic disease. The development of beige adipocytes in WAT (browning of WAT) increases energy expenditure and has been considered as a novel strategy to counteract obesity. Thymoquinone (TQ) is the main bioactive quinone derived from the plant and has antioxidative and anti-inflammatory capacities. Fish oil omega 3 (ω3) enhances both insulin sensitivity and glucose homeostasis in obesity, but the involved mechanisms remain unclear. The aim of this study is to explore the effects of TQ and ω3 PUFAs (polyunsaturated fatty acids) on obesity-associated inflammation, markers of insulin resistance, and the metabolic effects of adipose tissue browning. 3T3-L1 cells were cultured to investigate the effects of TQ and ω3 on the browning of WAT. C57BL/6J mice were fed a high-fat diet (HFD), supplemented with 0.75% TQ, and 2% ω3 in combination for eight weeks. In 3T3-L1 cells, TQ and ω3 reduced lipid droplet size and increased hallmarks of beige adipocytes such as uncoupling protein-1 (UCP1), PR domain containing 16 (PRDM16), fibroblast growth factor 21 (FGF21), Sirtuin 1 (Sirt1), Mitofusion 2 (Mfn2), and heme oxygenase 1 (HO-1) protein expression, as well as increased the phosphorylation of Protein Kinase B (AKT) and insulin receptors. In the adipose tissue of HFD mice, TQ and ω3 treatment attenuated levels of inflammatory adipokines, Nephroblastoma Overexpressed (NOV/CCN3) and Twist related protein 2 (TWIST2), and diminished adipocyte hypoxia by decreasing HIF1α expression and hallmarks of beige adipocytes such as UCP1, PRDM16, FGF21, and mitochondrial biogenesis markers Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), Sirt1, and Mfn2. Increased 5' adenosine monophosphate-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) phosphorylation and HO-1 expression were observed in adipose with TQ and ω3 treatment, which led to increased pAKT and pIRS1 Ser expression. In addition to the adipose, TQ and ω3 also increased inflammation and markers of insulin sensitivity in the liver, as demonstrated by increased phosphorylated insulin receptor (pIR tyr), insulin receptor beta (IRβ), UCP1, and pIRS1 Ser and reduced NOV/CCN3 expression. Our data demonstrate the enhanced browning of WAT from TQ treatment in combination with ω3, which may play an important role in decreasing obesity-associated insulin resistance and in reducing the chronic inflammatory state of obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/antiox9060489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346210PMC
June 2020

Alpha-Lipoic Acid Protects Cardiomyocytes against Heat Stroke-Induced Apoptosis and Inflammatory Responses Associated with the Induction of Hsp70 and Activation of Autophagy.

Mediators Inflamm 2019 3;2019:8187529. Epub 2019 Dec 3.

Department and Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan.

Heat stroke (HS) is a life-threatening illness and defined as when body temperature elevates above 40°C accompanied by the systemic inflammatory response syndrome that results in multiple organ dysfunctions. -Lipoic acid (ALA) acts as a cofactor of mitochondrial enzymes and exerts anti-inflammatory and antioxidant properties in a variety of diseases. This study investigates the beneficial effects of ALA on myocardial injury and organ damage caused by experimental HS and further explores its underlying mechanism. Male Wistar rats were exposed to 42°C until their rectal core temperature reached 42.9°C and ALA was pretreared 40 or 80 mg/kg (i.v.) 1.5 h prior to heat exposure. Results showed that HS-induced lethality and hypothermia were significantly alleviated by ALA treatment that also improved plasma levels of CRE, LDH, and CPK and myocardial injury biomarkers myoglobin and troponin. In addition, ALA reduced cardiac superoxide anion formation and protein expression of cleaved caspase 3 caused by HS. Proinflammatory cytokine TNF- and NF-B pathways were significantly reduced by ALA treatment which may be associated with the upregulation of Hsp70. ALA significantly increased the Atg5-12 complex and LC3B II/LC3B I ratio, whereas the p62 and p-mTOR expression was attenuated in HS rats, indicating the activation of autophagy by ALA. In conclusion, ALA ameliorated the deleterious effects of HS by exerting antioxidative and anti-inflammatory capacities. Induction of Hsp70 and activation of autophagy contribute to the protective effects of ALA in HS-induced myocardial injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/8187529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914879PMC
June 2020

Raloxifene inhibits adipose tissue inflammation and adipogenesis through Wnt regulation in ovariectomized rats and 3 T3-L1 cells.

J Biomed Sci 2019 Aug 31;26(1):62. Epub 2019 Aug 31.

Department and Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan.

Background: Loss of ovarian function, as in menopause or after ovariectomy (OVX), is closely associated with obesity and white adipose tissue (WAT) inflammation. Estrogen replacement protects against postmenopausal obesity but increases the risks of carcinogenesis. In the present study, we investigated the effects of long-term treatment of raloxifene (RAL), a selective estrogen receptor modulator, on the features of estrogen deficiency-induced obesity and explored the involvement of canonical and non-canonical Wnt regulation in vivo and in vitro.

Methods: Adult female rats received bilateral OVX and divided into 5 groups: (1) Sham, (2) OVX, (3) OVX + E: OVX rats were administered with E (50 μg/kg, s.c., 3 times/week), (4) OVX + RAL: OVX rats were treated with RAL (gavage, 1 mg/kg/day) suspended in 0.8% carboxymethylcellulose (CMC), (5) OVX + CMC: 0.8% CMC as vehicle control. All treatments were given for 8 weeks beginning at 1 week after OVX. In 3 T3-L1 cells, the effects of RAL on adipogenesis and lipopolysaccharide (LPS)-induced inflammation were evaluated.

Results: Treatment with RAL significantly decreased body weight, visceral fat pad mass, adipocyte size and plasma levels of glucose but increased plasma adiponectin. RAL reduced the elevation of HIF-1α, VEGF-A and proinflammatory cytokines (MCP-1 and TNF-α) expression by inhibition of NF-κB p65 and JNK cascades in retroperitoneal WAT. This anti-inflammatory capacity of RAL may result from upregulation of secreted frizzle-related protein 5 (SFRP5), an adipokine that repressed Wnt5a signaling. Furthermore, RAL inhibited adipogenic factors such as PPAR-γ, C/EBP-α, and FABP4, and preserved canonical Wnt10b/β-catenin protein expression. In 3 T3-L1 adipocytes, RAL (20 μM) diminished lipid accumulation and inhibited adipogenic factors accompanied with the induction of β-catenin, which were effectively reversed by the β-catenin inhibitor IWR-1-endo. In addition, RAL reduced LPS-induced NF-κB p65 and p-IκB expression as well as TNF-α secretion. Suppression of SFRP5 by small interfering RNA significantly abrogated the anti-inflammatory effects of RAL.

Conclusions: Distinct activation of canonical β-catenin on inhibition of adipogenesis and non-canonical SFRP5 on suppression of WAT inflammation may contribute to the beneficial effects of RAL. Therefore, this study provides a rationale for the therapeutic potential of RAL for postmenopausal obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12929-019-0556-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717377PMC
August 2019

Genistein ameliorated obesity accompanied with adipose tissue browning and attenuation of hepatic lipogenesis in ovariectomized rats with high-fat diet.

J Nutr Biochem 2019 05 19;67:111-122. Epub 2019 Feb 19.

Department and Institute of Pharmacology, National Defense Medical Center, Taipei. Electronic address:

Estrogen deficiency in postmenopausal women is linked to the higher prevalence of obesity, type 2 diabetes and metabolic syndromes. Development of beige adipocytes (browning of WAT) increases energy expenditure and could be a promising strategy for obesity management. This study aimed to investigate the effects of phytoestrogen genistein (GEN) on white adipose tissue (WAT) inflammation, browning and hepatic lipogenesis in ovariectomized rats with high-fat diet (HFD) and further explore the underlying mechanism. Female Wistar rats received ovariectomy (Ovx) and HFD (45% fat) and then were administered with 17β-estradiol (E2, 3 times/week, subcutaneously) or GEN (15 mg/kg or 30 mg/kg, gavage, once daily) for 4 weeks. Administration of GEN decreased Ovx-induced body weight gain and adiposity and improved insulin sensitivity as well as increased insulin signaling p-IRS1 and p-AKT in retroperitoneal WAT. Adipocyte hypertrophy and production of proinflammatory cytokines MCP-1, TNF-α and IL-6 were reduced by GEN. It also suppressed the activation of NF-κB pathway evidenced by attenuation of p65 and phospho-IκB levels. Additionally, GEN elevated myokine irisin and promoted WAT browning by increasing UCP-1, PRDM-16, PGC-1α and CIDEA proteins and Ppargc1a, Ucp-1 and Tbx-1 mRNA in inguinal WAT which is associated with up-regulation of nuclear estrogen receptor-α. Plasma levels of triglyceride and cholesterol were reduced by GEN treatment accompanied with inhibition of lipogenic proteins (p-ACC, SREBP-1, FAS and CD36) in the liver. Long-term treatment with GEN attenuated estrogen-deficiency-induced obesity, WAT inflammation and hepatic lipogenesis and promoted the induction of WAT browning. It may provide a promising approach to prevent obesity during menopause.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jnutbio.2019.02.001DOI Listing
May 2019

Activation of autophagy is involved in the protective effect of 17β-oestradiol on endotoxaemia-induced multiple organ dysfunction in ovariectomized rats.

J Cell Mol Med 2017 Dec 17;21(12):3705-3717. Epub 2017 Jul 17.

Department of Pharmacology, Taipei Medical University, Taipei, Taiwan, ROC.

Oestrogens have been reported to attenuate acute inflammation in sepsis. In this study, the effects of long-term oestrogen replacement with 17β-oestradiol (E ) on endotoxaemia-induced circulatory dysfunction and multiple organ dysfunction syndrome were evaluated in ovariectomized (Ovx) rats. E (50 μg/kg, s.c., 3 times/week) was administered for 8 weeks, followed by the induction of endotoxaemia by intravenous infusion of lipopolysaccharides (LPS; 30 mg/kg/4 hrs). Oestrogen deficiency induced by ovariectomy for 9 weeks augmented the LPS-induced damage, including endotoxic shock, myocardial contractile dysfunction, renal dysfunction and rhabdomyolysis. Cardiac levels of NF-κB p65, iNOS and oxidized glutathione, free radical production in skeletal muscles, myoglobin deposition in renal tubules, and plasma levels of plasminogen activator inhibitor-1, TNF-α, and IL-6 were more pronounced in the Ovx + LPS group than in the Sham + LPS group. Long-term treatment of E prevented this amplified damage in Ovx rats. Six hours after LPS initiation, activation of the autophagic process, demonstrated by increases in Atg12 and LC3B-II/LC3B-I ratios, and induction of haem oxygenase (HO)-1 and heat-shock protein (HSP) 70 protein expression in myocardium were increased significantly in the Ovx + E  + LPS group. These results suggest that activation of autophagy and induction of HO-1 and HSP70 contribute to the protective effect of long-term E replacement on multiple organ dysfunction syndrome in endotoxaemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jcmm.13280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706505PMC
December 2017

Involvement of HSP70 and HO-1 in the protective effects of raloxifene on multiple organ dysfunction syndrome by endotoxemia in ovariectomized rats.

Menopause 2017 Aug;24(8):959-969

1Department and Institute of Pharmacology 2Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan 3Department of Pharmacy, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan 4Department of Physiology & Biophysics, National Defense Medical Center, Taipei, Taiwan 5Department of Nursing, Hung Kuang University, Taichung, Taiwan 6Department of Pharmacology, Taipei Medical University, Taipei, Taiwan 7Department of Anesthesiology, Catholic Mercy Hospital, Hsinchu, Taiwan.

Objective: Accumulating evidence demonstrates that raloxifene, a selective estrogen receptor modulator, possesses anti-inflammatory action. This study evaluates the preventive effects of long-term treatment of raloxifene on acute inflammation and multiple organ dysfunction syndrome (MODS) in ovariectomized (OVX) rats with endotoxemia and its underlying mechanism of action.

Methods: Adult female rats were OVX bilaterally to induce estrogen insufficiency. OVX rats were administered with raloxifene (1 mg/kg, gavage, once daily) for 8 weeks, beginning 1 week after surgery, followed by induction of sepsis via intravenous infusion of lipopolysaccharides (LPS; 30 mg/kg) for 4 hours. LPS-activated RAW 264.7 cells were used to investigate the mechanism of raloxifene.

Results: Ovariectomy amplified the endotoxemia-induced hypotensive effect, MODS, and superoxide anion production in the myocardium. The levels of inducible nitric oxide synthase, high mobility group box 1, and nuclear factor-κB p65 protein increased in OVX rats 6 hours after LPS initiation. Raloxifene mitigated MODS, together with reduced inducible nitric oxide synthase induction and fewer superoxide anions in organs. Raloxifene induced high levels of heat shock protein 70 (HSP70) and heme oxygenase 1 (HO-1), which are associated with an increase in the transcription factor heat shock factor-1 and Nrf-2, respectively. Pretreatment with quercetin, an inhibitor of HSP70, or SnPP, an inhibitor of HO-1, reversed the protective effects of raloxifene in septic OVX rats and LPS-activated macrophages.

Conclusions: Long-term treatment with raloxifene reduces the severity of sepsis in OVX rats, attributed from up-regulation of HSP70 and HO-1 to exert the antioxidant and anti-inflammatory capacities. These findings provide new insights into bacterial infection during menopause and the molecular mechanism of raloxifene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/GME.0000000000000864DOI Listing
August 2017

17-DMAG, an HSP90 Inhibitor, Ameliorates Multiple Organ Dysfunction Syndrome via Induction of HSP70 in Endotoxemic Rats.

PLoS One 2016 25;11(5):e0155583. Epub 2016 May 25.

Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.

Sepsis is a systemic inflammatory disorder, accompanied with elevated oxidative stress, leading to multiple organ dysfunction syndrome (MODS), and disseminated intravascular coagulation. 17-Dimethylaminoethylamino- 17-demethoxygeldanamycin (17-DMAG), a heat shock protein (HSP) 90 inhibitor, has been reported to possess anti-inflammatory effects. In this study, the beneficial effects of 17-DMAG on lipopolysaccharide (LPS) induced MODS and DIC was evaluated in anesthetized rats. 17-DMAG (5 mg/kg, i.p.) was significantly increased survival rate, and prevented hypotension in LPS (30 mg/kg i.v. infused for 4 h) induced endotoxemia. The elevated levels of alanine aminotransferase (ALT), creatine phosphokinase (CPK), lactate dehydrogenase, creatinine, nitric oxide (NO) metabolites, IL-6, and TNF-α in LPS-exposed rat plasma were significantly reduced by 17-DMAG. Moreover, 17-DMAG suppressed LPS-induced superoxide anion production and caspase 3 activation in heart tissues. LPS induced the prolongation of prothrombin time, and a pronounced decrease in platelet count, which were improved by 17-DMAG. 17-DMAG markedly induced HSP70 and heme oxygenase (HO)-1, and suppressed inducible nitric oxide synthase (iNOS) and phosphorylated NF-κB p65 protein expression in organs 6 h after LPS initiation. Pretreatment with high dose of quercetin (300 mg/kg, i.p.), as an HSP70 inhibitor, reversed the beneficial effects of 17-DMAG on survival rate, plasma levels of ALT, CPK, creatinine, IL-6, and NO metabolites, iNOS induction, and caspase-3 activation in LPS-treated rats. In conclusion, 17-DMAG possesses the anti-inflammatory and antioxidant effects that were proved through LPS-induced acute inflammation, which is associated with induction of HSP70 and HO-1, leading to prevent MODS in sepsis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0155583PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4880344PMC
July 2017

Alpha-lipoic acid prevents endotoxic shock and multiple organ dysfunction syndrome induced by endotoxemia in rats.

Shock 2015 Apr;43(4):405-11

*Department and Institute of Pharmacology, National Defense Medical Center; and †Department of Pharmacology, Taipei Medical University, Taipei; ‡Department of Anesthesiology, Catholic Mercy Hospital, Hsinchu; §Department of Physiology and Biophysics, National Defense Medical Center, Taipei; ∥Department of Nursing, Tzu Chi College of Technology, Hualien; ¶Department of Biotechnology, HungKuang University, Taichung; and **Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Chi-Mei Medical Center, Tainan, Taiwan.

Alpha-lipoic acid (ALA), a naturally occurring disulfide derivative of octanoic acid, serves as a strong antioxidant and has been reported to possess anti-inflammatory effects. The aim of the present study is to investigate the preventive and therapeutic effects of ALA on multiple organ dysfunction syndrome (MODS) caused by endotoxemia in rats. Male Wistar rats were intravenously infused with lipopolysaccharide (LPS) (10 mg/kg) to induce endotoxemia. Alpha-lipoic acid 10, 20, or 40 mg/kg was administered intravenously 60 min before (pretreatment) LPS challenge, and ALA 40 mg/kg was administered intravenously 30 min after (posttreatment) LPS challenge. Pretreatment and posttreatment with ALA significantly improved the deleterious hemodynamic changes 8 h after LPS challenge, including hypotension and bradycardia. Alpha-lipoic acid reduced the plasma levels of glutamic pyruvic transaminase, blood urea nitrogen, lactate dehydrogenase, tumor necrosis factor-α, nitric oxide metabolites, and thrombin-antithrombin complex, which increased markedly after LPS challenge. The induction of inducible nitric oxide synthase both in the liver and the lung and vascular superoxide anion production were also significantly suppressed by ALA. Moreover, ALA significantly attenuated LPS-induced caspase-3 activation in cardiomyocytes and improved survival rate. In conclusion, ALA effectively attenuated LPS-induced acute inflammatory response and improved MODS. The antioxidant and anti-inflammatory effects of ALA may contribute to these beneficial effects. Alpha-lipoic acid might be considered as a novel therapeutic strategy in the prevention of sepsis-induced MODS and inflammatory vascular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SHK.0000000000000295DOI Listing
April 2015

Estrogen deficiency-induced alterations of vascular MMP-2, MT1-MMP, and TIMP-2 in ovariectomized rats.

Am J Hypertens 2009 Jan 20;22(1):27-34. Epub 2008 Nov 20.

Department of Pharmacology, Taipei Medical University, Taipei, Taiwan.

Background: Matrix metalloproteinases (MMPs) activity may modulate hypertension-related accumulation of extracellular matrix (ECM) in arteries. We tested whether estrogen deficiency induces alterations of vascular collagen, MMP-2, membrane-type 1-MMP (MT1-MMP), or tissue inhibitor of metalloproteinases-2 (TIMP-2) expression in ovariectomized rats, which may be associated with postmenopausal hypertension.

Methods: Estrogen deficiency was induced by ovariectomy (Ovx) in female rats. Time-course changes of aortic MMPs protein expression were evaluated. Treatment with tempol or aminoguanidine was used to examine the role of oxidative stress and nitric oxide (NO) on these changes.

Results: The level of the active-form MMP-2 was markedly reduced during 1-4 weeks after Ovx, with a significant increase in collagen accumulation and increased MT1-MMP expression. Although active-form MMP-2 and collagen progressively returned to normal levels, the markedly increased collagen deposition appeared again at 8 weeks and persisted until 12 weeks, followed by induction of MMP-2 and MT1-MMP at 12 weeks. The TIMP-2 level reduced for 2 weeks after Ovx, but soon returned to normal. Treatment with 17beta-estradiol (E(2)), tempol, or aminoguanidine for 6 weeks prevented Ovx-induced blood pressure elevation and apparently reversed the MMPs changes.

Conclusions: In an initial period, E(2) deficiency induces a reduction of active-form MMP-2 leading to collagen accumulation, and induction of MT1-MMP, which may be a compensatory response to degrade collagen. At a latter stage, the concurrent elevation of active-form MMP-2 and MT1-MMP expression may be adaptive responses to regulate ECM composition in the vascular wall. Oxidative stress and NO contribute to activity modulation of vascular MMPs in Ovx rats.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ajh.2008.306DOI Listing
January 2009