The Effects of a PPAR&lt;i&gt;&amp;alpha;&lt;/i&gt; Agonist on Myocardial Damage in Obese Diabetic Mice With Heart Failure

Chen, Rui; Liang, Feng-Xia; Morimoto, Shigeto; Li, Qian; Moriya, Junji; Yamakawa, J; Takahashi, Takashi; Iwai, Kunimitsu; Kanda, Tsugiyasu

doi:10.1536/ihj.51.199

Cited by 12 publications

(13 citation statements)

References 29 publications

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“…Activity Eight-week old BALB/c mice (female, 20-24 g, CLEA Japan, Tokyo, Japan) were housed singly in previously described cages 8,9) including running wheels and counters. The cages were maintained under a light-dark photoperiod (lights on from 09:00 to 17:00), and daily spontaneous running activity defined by the number of wheel turns was measured at 09:00 when environmental lighting was turned on.…”

Section: Animals Living Conditions and Spontaneous Runningmentioning

confidence: 99%

Resveratrol Improves Hippocampal Atrophy in Chronic Fatigue Mice by Enhancing Neurogenesis and Inhibiting Apoptosis of Granular Cells

Moriya

Chen

Yamakawa

et al. 2011

Biological & Pharmaceutical Bulletin

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Chronic fatigue is reported in more than 20% of patients examined in primary care, and this common problem affects the quality of life and work productivity.1) A large part of the chronic fatigue population meets the diagnostic criteria for chronic fatigue syndrome (CFS), which is defined by unexplained physical or mental fatigue of at least 6-month duration and a combination of nonspecific symptoms.2) Several CFS symptoms including impaired concentration, attention, and memory as well as headache suggest that the central nervous system (CNS) may be involved in CFS pathophysiology.3) Moreover, neuroimaging evidence indicates that structural and/or functional abnormalities exist in the CNS of CFS patients. For example, marked reductions in the gray matter volume are observed; 4) Cook et al. 5) found an association between subjective feelings of mental fatigue and brain responses during a fatiguing cognitive task; CFS patients always have reduced concentrations of N-acetylaspartate in the hippocampus, a putative marker of neuronal metabolism 6) ; and a 23% reduction in 5-HT 1A receptor number and affinity was found in the hippocampus of CFS patients. 7) However, neural mechanisms, especially the hippocampal substrates in CFS, are unclear in part due to the lack of a suitable animal model.In our previous study, a chronic fatigue mouse model was induced by six repeated injections of fixed killed Brucella abortus antigen solution via the tail vein every 2 weeks. 8,9) We found that brain atrophy and reduction of the hippocampal Bcl-2 and brain-derived neurotrophic factor (BDNF) mRNA expression levels were accompanied by lower spontaneous activity.8) However, the hippocampal weight was not measured in those previous studies.Resveratrol (RSV), an active component of grapevines and peanuts, is recognized as a polyphenolic activator of sirtuin 1 (Sirt1), a protein deacetylase.10) It can enhance running activity of high fat diet-fed mice two-fold by activating Sirt1. 11)Moreover, Sirt1 can protect neurons from DNA damageinduced apoptosis by downregulating p53 acetylation, an apoptotic mediator.12) RSV treatment of neural progenitor cells (NPCs) is capable of increasing differentiation and directing neurogenesis through a mechanism requiring Sirt1.13) Thus RSV may be beneficial for physical activity of our fatigue mice and even play a role in improving structural and/or functional defects of the hippocampus.We aimed to clarify the hippocampal structural and/or functional defects in this fatigue model. Another purpose of our study was to determine whether RSV intervention could improve the fatigue and reverse the abnormalities by antiapoptosis and promoting neurogenesis. MATERIALS AND METHODS Animals, Living Conditions, and Spontaneous RunningActivity Eight-week old BALB/c mice (female, 20-24 g, CLEA Japan, Tokyo, Japan) were housed singly in previously described cages 8,9) including running wheels and counters. The cages were maintained under a light-dark photoperiod (lights on from 09:00 to 17:00), and daily spontaneous ...

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Section: Animals Living Conditions and Spontaneous Runningmentioning

confidence: 99%

Resveratrol Improves Hippocampal Atrophy in Chronic Fatigue Mice by Enhancing Neurogenesis and Inhibiting Apoptosis of Granular Cells

Moriya

Chen

Yamakawa

et al. 2011

Biological & Pharmaceutical Bulletin

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“…The treatment of the aldehyde 23 7) with glycine tert-butyl ester under reflux conditions to form the imine, followed by the reduction with NaBH 4 gave secondary amine 24. Alkylation of 24 with 4-(chloromethyl)-5-methyl-2-phenyl-1,3-oxazole as the lipophilic tail chloride in the presence of K 2 CO 3 in DMF, followed Reagents and conditions: (a) 4 M HCl in EtOAc, 4a: 81%, 4b: 85%, 4c: 47%; (b) POCl 3 , CHCl 3 , 5a: 79%, 5b: 14%, 5c: 42%; (c) 1 M BH 3 -THF solution, THF, 87%; (d) NBS, PPh 3 , DCM, 92%; (e) NBS, AIBN, CCl 4 , 45%; (f) NaNO 2 , AcOH; (g) 10% Pd/C, 1 N HCl-EtOH solution; (h) Corresponding acid chloride reagent, TEA, DCM, 14a: 48% (3 steps), 14b: 78% (3 steps), 14c: 67% (3 steps); (i) POCl 3 , 15a: 63%, 15b: 88%, 15c: 90%; (j) LiBH 4 , THF; (k) SOCl 2 , CHCl 3 , 17a: 18% (2 steps), 17b: 86% (2 steps), 17c: 89% (2 steps); (l) Corresponding lipophilic tail moieties, EDCI, HOBt, DMF or K 2 CO 3 , DMF, 22-91%; (m) 1 M BH 3 -THF solution, THF, 50%; (n) 1 N NaOH aq.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, some PPARα agonists have been reported to reduce weight gain in rodents without an effect on food intake. 7,8) Therefore, PPARα/γ dual agonists are expected to improve blood glucose levels and lipid parameters, together with lowering side effects, i.e. weight gain, caused by PPARγ activation.…”

Section: Synthesis and Structure-activity Relationships Of Novel Zwitmentioning

confidence: 99%

Synthesis and Structure–Activity Relationships of Novel Zwitterionic Compounds as Peroxisome Proliferator Activated Receptor α/γ Dual Agonists with Improved Physicochemical Properties

Shibata

Kagechika

Yamaguchi

et al. 2013

CHEMICAL & PHARMACEUTICAL BULLETIN

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We describe herein the design, syntheses and structure-activity relationships (SAR) of novel zwitterionic compounds as non-thiazolidinedion (TZD) based peroxisome proliferator activated receptor (PPAR) α/γ dual agonists. In the previous report, we obtained compound 1 showing potent PPARα/γ dual agonistic activities, together with a great glucose lowering effect in the db/db mice. However, this compound possessed fatal issues such as potent cytochrome P450 (CYP)3A4 direct inhibitory activity. Thus, we carried out the medicinal optimization to improve these while maintaining the potent PPAR agonistic activity. As a result, the issues were addressed by changing the furan ring to a low lipophilic 1,3,4-oxadiazole ring. Additionally, these oxadiazole derivatives exhibited a significant decrease in plasma glucose and plasma triglyceride levels without marked weight gain.Key words peroxisome proliferator activated receptor; cytochrome P450; drug-drug interactionThe number of people living with diabetes is growing rapidly worldwide. While the number of individuals with diabetes was 151 million in 2002, this number is 366 million at present and is estimated to be 552 million by 2030.1) Of these cases, type 2 diabetes is the majority in both developing and developed countries, whose populations currently account for >90% of all diabetes worldwide.2) In the type 2 diabetic people who show it, insulin resistence poses a cardiovascular risk factor including dyslipidemia, coagulopathy, hypertension and obesity.3) Many drug targets have been investigated to treat type 2 diabetes such as peroxisome proliferator-activated receptor (PPAR), dipeptidyl peptidase IV (DPP-4), glucagonlike peptides-1 (GLP-1), etc. Among these, PPAR is noted as a worthy target to improve metabolic syndrome. PPARs consist of three isoforms, i.e. PPARα, PPARγ and PPARδ, which are members of the superfamily of nuclear transcription factors that include the receptors for steroid, retinoid and thyroid hormones. Activation of PPARγ leads to mitigated insulin resistance by promoting hypertrophied adipocyte differentiation and improving the balance of physiological active substances. 4,5) However their activation has been plagued by adverse effects including weight gain, fluid retention and edema.6) On the other hand, PPARα activation has been identified to mediate the lipid-lowering activity in the study with the fibrate class of hypolipidemic drugs. Furthermore, some PPARα agonists have been reported to reduce weight gain in rodents without an effect on food intake. 7,8) Therefore, PPARα/γ dual agonists are expected to improve blood glucose levels and lipid parameters, together with lowering side effects, i.e. weight gain, caused by PPARγ activation.In the previous report, 9) we obtained zwitterionic compounds showing the PPARα/γ dual agonistic activities. Especially, compound 1 provided highly potent dual activities (α: EC 50 =1.7 nM, γ: EC 50 =4.7 nM, shown in Fig. 1), accompanied by a great glucose lowering effect in the db/db mice. Moreover, it remedied ...

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“…Furthermore, some PPARα agonists have been reported to reduce weight gain in rodents. 8,9) Thus, PPARα/γ dual agonists are expected to be a safer type 2 diabetic agent.…”

Section: Synthesis and Structure-activity Relationships Of 2-aminoacementioning

confidence: 99%

“…Furthermore, some PPARα agonists have been reported to reduce weight gain in rodents. 8,9) Thus, PPARα/γ dual agonists are expected to be a safer type 2 diabetic agent.In our previous report, 10) we obtained zwitterionic compounds showing the PPARα/γ dual agonistic activities. In particular, compound 1 provided highly potent dual activities (α: EC 50 =0.55 nM, γ: EC 50 =18 nM, shown in Fig.…”

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confidence: 99%

Synthesis and Structure–Activity Relationships of 2-Aminoacetamide Derivatives as Peroxisome Proliferator-Activated Receptor α/γ Dual Agonists

Shibata

Kagechika

Ota

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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We describe the design, syntheses, and structure-activity relationships of novel zwitterionic compounds as nonthiazolidinedion-based peroxisome proliferator-activated receptor (PPAR) α/γ dual agonists. In our previous report, we obtained compound 1 showing potent PPARα/γ dual agonistic activities, together with a sufficient glucose-lowering effect in db/db mice. However, this compound possessed an issue, i.e., the 1,3,4-oxadiazole ring was not stable in acidic conditions. Thus, we carried out further optimization to improve the stability while maintaining the other favorable profile features including potent PPARα/γ dual agonistic activity. We addressed the issue by changing the oxadiazole ring to a bioisostere amide group. These amide derivatives were stable in acidic conditions and decreased plasma glucose and plasma triglyceride levels significantly without marked weight gain.Key words peroxisome proliferator-activated receptor; type 2 diabetes; bioisostere In 2014, 4.9 million people died from diabetes.1) Diabetes is a serious health problem since the number of individuals with diabetes is 387 million at present and is estimated to be 592 million by 2035.1) Of these cases, the populations of type 2 diabetes currently account for >90% of all diabetes worldwide.2)The type 2 diabetic people who have insulin resistance are more susceptible to cardiovascular risk factors including dyslipidemia, coagulopathy, hypertension and obesity.3) Furthermore, it has been revealed that type 2 diabetes with insulin resistance and hyperinsulinemia is associated with the risk of cancer in recent years. 4) In fact, the prevention and the treatment of type 2 diabetes becomes more and more important to maintaining the quality of life of people all over the world. Today, we have a wide variety of antidiabetic agents. Among these, the use of the thiazolidinedione (TZD) insulin-sensitizer makes sense for treating patients with type 2 diabetes since TZD activates peroxisome proliferator-activated receptor gamma (PPARγ) and leads to abated insulin resistance by promoting hypertrophied adipocyte differentiation and improving the balance of physiological active substances.5,6) However, its activation also causes adverse effects including weight gain, fluid retention and edema. 7) On the other hand, the activation of another subtype PPARα has been identified to mediate the lipid-lowering activity in studies with the fibrate class of hypolipidemic drugs. Furthermore, some PPARα agonists have been reported to reduce weight gain in rodents. 8,9) Thus, PPARα/γ dual agonists are expected to be a safer type 2 diabetic agent.In our previous report, 10) we obtained zwitterionic compounds showing the PPARα/γ dual agonistic activities. In particular, compound 1 provided highly potent dual activities (α: EC 50 =0.55 nM, γ: EC 50 =18 nM, shown in Fig. 1), accompanied by a pronounced glucose lowering effect and triglyceride remedying effect without body weight gain at 10 mg/kg in the db/db mice. Moreover, the exchange of the ring system into this 1,3,...

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The Effects of a PPAR<i>α</i> Agonist on Myocardial Damage in Obese Diabetic Mice With Heart Failure

Cited by 12 publications

References 29 publications

Resveratrol Improves Hippocampal Atrophy in Chronic Fatigue Mice by Enhancing Neurogenesis and Inhibiting Apoptosis of Granular Cells

Resveratrol Improves Hippocampal Atrophy in Chronic Fatigue Mice by Enhancing Neurogenesis and Inhibiting Apoptosis of Granular Cells

Synthesis and Structure–Activity Relationships of Novel Zwitterionic Compounds as Peroxisome Proliferator Activated Receptor α/γ Dual Agonists with Improved Physicochemical Properties

Synthesis and Structure–Activity Relationships of 2-Aminoacetamide Derivatives as Peroxisome Proliferator-Activated Receptor α/γ Dual Agonists

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