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1.
FASEB J ; 34(2): 2792-2811, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31912559

RESUMO

While adipose tissue is required to maintain glucose metabolism, excessive calorie intake induces obesity via mechanisms including accelerated proliferation and differentiation of preadipocytes, leading to insulin resistance. Here, we investigated the role of myoferlin (MYOF), a ferlin family protein, in regulating glucose metabolism by mainly focusing on its unknown role in adipose tissue. Whereas young MYOF knockout (KO) mice on a normal diet showed aggravated glucose tolerance and insulin sensitivity, those on a high-fat diet (HFD) showed preserved glucose tolerance with an attenuated gain of body weight, reduced visceral fat deposits, and less severe fatty liver. The Adipose MYOF expression was reduced by aging but was restored by an HFD along with the retained expression of NFAT transcription factors. Loss-of-function of MYOF in preadipocytes suppressed proliferation and differentiation into mature adipocytes along with the decreased expression of genes involved in adipogenesis. The MYOF expression in preadipocytes was reduced with differentiation. Attenuated obesity in MYOF KO mice on an HFD was also accompanied with increased oxygen consumption by an unidentified mechanism and with reduced adipose inflammation due to less inflammatory macrophages. These insights suggest that the multifunctional roles of MYOF involve the regulation of preadipocyte function and affect glucose metabolism bidirectionally depending on consumed calories.

2.
AAPS PharmSciTech ; 21(1): 19, 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31820256

RESUMO

DNA vaccination can be applied to the treatment of various infectious diseases and cancers; however, technical difficulties have hindered the development of an effective delivery method. The efficacy of a DNA vaccine depends on optimal antigen expression by the injected plasmid DNA. The pyro-drive jet injector (PJI) is a novel system that allows for adjustment of injection depth and may, thus, provide a targeted delivery approach for various therapeutic or preventative compounds. Herein, we investigated its potential for use in delivering DNA vaccines. This study evaluated the optimal ignition powder dosage, as well as its delivery effectiveness in both rat and mouse models, while comparing the results of the PJI with that of a needle syringe delivery system. We found that the PJI effectively delivered plasmid DNA to intradermal regions in both rats and mice. Further, it efficiently transfected plasmid DNA directly into the nuclei, resulting in higher protein expression than that achieved via needle syringe injection. Moreover, results from animal ovalbumin (OVA) antigen induction models revealed that animals receiving OVA expression plasmids (pOVA) via PJI exhibited dose-dependent (10 µg, 60 µg, and 120 µg) production of anti-OVA antibodies; while only low titers (< 1/100) of OVA antibodies were detected when 120 µg of pOVA was injected via needle syringe. Thus, PJI is an effective, novel method for delivery of plasmid DNA into epidermal and dermal cells suggesting its promise as a tool for DNA vaccination.

3.
Geriatr Gerontol Int ; 2019 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-31837250

RESUMO

More than 50 years ago, Hayflick et al. found that no long-lived, proliferative cells remained in long-term cell culture experiments; this phenomenon is called "cellular senescence." This finding has allowed us to understand basic individual tissue aging and cancer inhibition from the view of cellular aging. Senescent cells survive and accumulate in the body, and secrete various inflammatory cytokines or chemokines, which is different from the cell fate in apoptosis. These phenomena describe the so-called senescence-associated secretory phenotype, and chronic inflammation and carcinogenesis are induced in the surrounding tissue through senescence-associated secretory phenotype factors. For example, senescence-associated T cells are an age-dependent CD4(+ ) T-cell subpopulation with a PD-1(+ ) memory phenotype; these cells do not proliferate in response to T-cell receptor stimulation, and produce abundant osteopontin, as well as inflammatory cytokines. Senescence-associated T cells are also increased in adipose tissue under a high-fat diet, which might be related to the progress of obesity or diabetes. These series of findings might allow us to connect senescent cells and tissue aging, leading to individual aging. Interestingly, the depletion of senescent cells in the body, called senolysis, successfully increases lifespan and attenuates age-related diseases. This novel therapy is now moving forward to translational research from the bench toward clinical trials. Geriatr Gerontol Int 2019; ••: ••-••.

4.
Nihon Yakurigaku Zasshi ; 154(5): 270-274, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31735757

RESUMO

In the 18th century, Edward Jenner proposed the vaccine for smallpox as a first vaccine therapy based on the legend that a vaccinia prevents the infection with smallpox. Recently, the therapeutic target of vaccine will expand from infectious diseases to various diseases, such as amyloid ß or tau vaccine for Alzheimer's disease. We are now going to develop a therapeutic vaccine to lifestyle-related diseases (i.e. high blood pressure), and aim to realize a novel therapy which will be injected once or twice per year from a daily medication. For this purpose, the appropriate choice of an antigen, carrier and adjuvants should be required to activate hormonal immunity by the vaccine, leading to efficient antibody production without toxicity, because the therapeutic target of our vaccine is an endogenous protein (i.e. hormone). The clinical advantage of this therapeutic vaccine is to improve the medical adherence and drug management because the multiple drug users are increased in particular old patients, so called polypharmacy. If the vaccine will take place of a part of medicine in future, it may give us a novel therapeutic option with several social benefits.


Assuntos
Hipertensão/terapia , Estilo de Vida , Vacinas/uso terapêutico , Humanos
5.
Geriatr Gerontol Int ; 19(11): 1118-1123, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31746528

RESUMO

AIM: An investigator-initiated clinical study was carried out to evaluate the therapeutic potency of SR-0379 for the treatment of leg ulcers in patients with Werner syndrome. METHODS: A multicenter, open-label study was carried out from September 2017 to February 2018. The inclusion criteria for leg ulcers were: (i) leg ulcers in patients with Werner syndrome, diabetes or critical limb ischemia/venous stasis; and (ii) a wound size of >1 cm and <6 cm in diameter. Four individuals with Werner syndrome and diabetic ulcers, respectively, were enrolled. SR-0379 (0.1%) was sprayed on skin ulcers once per day for 4 weeks. Efficacy was evaluated by determining the rate of wound size reduction as a primary end-point at 4 weeks after the first treatment compared with the pretreatment wound size. As secondary end-points, the DESIGN-R score index, the 50% wound size reduction ratio, time to wound closure and quantification of wound bacteria were also evaluated. The safety of SR-0379 was evaluated during the study period. RESULTS: The reduction rate of ulcer size treated with 0.1% SR-0379 was 22.90% (mean) in the Werner syndrome ulcers group (n = 4) and 35.70% (mean) in the diabetic ulcers group (n = 4), respectively. The DESIGN-R score decreased by 4.0 points in the Werner syndrome ulcers group and 4.3 points in the diabetic ulcers group. Two mild adverse events were reported in two patients, and causal relationships were denied in any events. CONCLUSION: Treatment with SR-0379 was safe, well-tolerated, and effective for leg ulcers of both Werner syndrome and diabetes patients. Geriatr Gerontol Int 2019; 19: 1118-1123.

6.
Sci Rep ; 9(1): 15434, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659208

RESUMO

We recently developed a partial peptide of receptor activator of nuclear factor-кB ligand (RANKL) known as microglial healing peptide 1 (MHP1-AcN), that inhibits Toll-like receptor (TLR)-related inflammation through RANKL/RANK signaling in microglia and macrophages without promoting osteoclast activation. The abnormal activation of TLRs contributes to the initiation and maintenance of psoriasis, which is a chronic inflammatory skin disease that involves the aberrant expression of proinflammatory cytokines and the subsequent dermal γδ T cell and T helper 17 (Th17) cell responses. The inhibition of TLR-mediated inflammation provides an important strategy to treat psoriasis. Here, we examined the preventative effects of MHP1-AcN in a mouse model of imiquimod (a TLR 7/8 agonist)-induced psoriasis. Topical imiquimod application induced psoriasis-like skin lesions on the ear and dorsal skin. Systemic administration of MHP1-AcN by daily subcutaneous injection significantly prevented the development of skin lesions, including erythema, scaling and thickening. Mice treated with MHP1-AcN showed reduced levels of skin Il6 mRNA at 32 h and reduced levels of Il23 and Il17a mRNA at d9. Serum levels of IL-6 and IL-23 were reduced at 32 h, and IL-17A was reduced at d9. These results indicated that MHP1-AcN could decrease imiquimod-induced IL-6, IL-23 and IL-17A production. MHP1-AcN is potentially an alternative treatment for psoriasis.

7.
PLoS One ; 14(5): e0215482, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31048856

RESUMO

Although T cells play important roles in the pathophysiology of ischemic stroke, the dynamics of T cells remains unclear. In cancer, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) contribute to the maintenance of the tumor microenvironment by suppressing T cells. However, the presence of these cells has never been examined in ischemic brain. Therefore, we examined the temporal and spatial profiles of PMN-MDSCs, which are defined as the CD11b+Ly6ClowLy6G+ cells with higher expression levels of Nox2 and C/EBP Homologous Protein (CHOP) mRNA than normal neutrophil. Fluorescence-activated cell sorter (FACS) analysis showed that the count of CD11b+Ly6ClowLy6G+ cells was increased in the ischemic hemisphere and bone marrow at 72 hours, as well as in the spleen 24 hours after transient middle cerebral artery occlusion in mice. In contrast, the contralateral hemisphere, normal bone marrow, and normal spleen contained few CD11b+Ly6ClowLy6G+ cells. Real-time reverse transcription polymerase chain reaction revealed that CD11b+Ly6ClowLy6G+ cells sorted from brain and spleen 72 hours after ischemia had greater expression of Nox2 and CHOP mRNA than neutrophils in bone marrow, suggesting that these cells constitute PMN-MDSCs. Immunohistochemistry showed that CD11b+Ly6G+ cells were located in the ischemic core and border zone, indicating that PMN-MDSCs might be endemic to these regions. Although neutrophils are believed to invade infarct regions 48-72 hours after ischemia, the present study suggested that some of these cells are in fact PMN-MDSCs. Further studies on the function of PMN-MDSCs might unveil the unknown mechanisms of T cell activation and recruitment in ischemic stroke.


Assuntos
Isquemia Encefálica/patologia , Células Supressoras Mieloides/metabolismo , Neutrófilos/metabolismo , Animais , Antígenos Ly/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Isquemia Encefálica/imunologia , Isquemia Encefálica/veterinária , Antígeno CD11b/metabolismo , Citocinas/metabolismo , Citometria de Fluxo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/imunologia , NADPH Oxidase 2/genética , NADPH Oxidase 2/metabolismo , Neutrófilos/citologia , Neutrófilos/imunologia , Baço/citologia , Baço/imunologia , Baço/metabolismo , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo
9.
Sci Rep ; 9(1): 3858, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30846754

RESUMO

We previously demonstrated that cellular aging signals upregulated a secreted class 3 semaphorin E (Sema3E) and its receptor plexinD1 in the adipose tissue of a murine model of dietary obesity and that Sema3E was a chemoattractant, mediating its biological effects by inducing infiltration of plexinD1-positive inflammatory macrophages into the visceral white adipose tissue. This study was performed to develop a peptide vaccine for Sema3E and test its therapeutic potential in a murine model of dietary obesity. Two antigenic peptides were selected to generate neutralizing antibodies for a vaccine. These peptides were conjugated to keyhole limpet hemocyanin (KLH), and were administered with Freund's adjuvant to obese wild-type male mice. The Sema3E antibody titer was analyzed by ELISA, and the biological effects of the peptides were tested in mice with dietary obesity. Among the two candidate peptides, the Sema3E antibody titer was significantly increased by injection of KLH-conjugated HKEGPEYHWS (Sema3E vaccine). Administration of Sema3E vaccine suppressed the infiltration of plexinD1-positive cells, ameliorated chronic inflammation in visceral white adipose tissue, and improved systemic glucose intolerance in mice with dietary obesity, suggesting that Sema3E vaccine has the potential to become a next generation therapy for obesity and diabetes.

10.
Transl Res ; 205: 17-32, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30720435

RESUMO

Lipid metabolic disorders play critical roles in atherogenesis. Traditionally, it has been suggested that reduced high density lipoprotein (HDL) levels might be an important morbidity indicator for cardiovascular diseases. Therefore, it has been argued that therapeutically raising HDL levels may reduce atherogenesis in patients with dyslipidemia. However, recent clinical trials to elevate serum HDL levels by pharmacologic approaches failed to demonstrate clinical efficacy. Thus, to investigate the functionality of HDL and to explore the possible clinical relevance as well as to define an effective indicator that can represent HDL function may provide another key and reference to disclose the clinical treatment of dyslipidemia. We analyzed the association between the data of dichlorofluorescein assay (assay the functionality of HDL), the effect of HDL on oxidized low density lipoprotein (oxLDL)-stimulated endothelial progenitor cells (EPCs) in vitro, levels of circulating EPCs, and ex vitro EPC colony forming units of each case, we defined the indicator (relative HDL index (RHDL index) = dichlorofluorescein assay result of each subject/dichlorofluorescein assay reading of our young healthy controls) that may represent functionality of HDL. HDL from healthy adults protected oxLDL-treated EPCs by modulating p38 mitogen-activated protein kinase and Rho activation and by promoting nitric oxide production. HDL from subject with RHDL index ≧2 also failed to restore the functionality of oxLDL-treated EPCs via cell-signaling pathways in vitro. The RHDL index significantly correlated with patients' circulating EPC number or EPC colony forming units ex vivo. In conclusions, we explored the RHDL index as a score to predict a patient's EPC functions in vivo and ex vitro.


Assuntos
Células Progenitoras Endoteliais/efeitos dos fármacos , Lipoproteínas HDL/fisiologia , Lipoproteínas LDL/farmacologia , Adulto , Idoso , Dislipidemias/sangue , Ativação Enzimática , Feminino , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Lipoxigenase/metabolismo , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/biossíntese , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Quinases Associadas a rho/metabolismo
11.
Biochem Biophys Res Commun ; 508(4): 1168-1174, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30554661

RESUMO

Cardiovascular disease is one of the leading causes of death in the elderly, and novel therapeutic targets against atherogenesis are urgent. The initiation of atherosclerotic changes of monocyte adhesion on the vascular endothelium and subsequent foam cell formation are noteworthy pathophysiologies when searching for strategies to prevent the progression of age-related atherosclerosis. We report the significance of the deubiquitinating enzyme cylindromatosis (CYLD) in vascular remodeling by interference with inflammatory responses regulated by NF-κB signaling. The purpose of this study was to elucidate the pathological functions of CYLD in the early phase of atherogenesis associated with aging. Treatment with inflammatory cytokines induced endogenous CYLD in aortic endothelial cells (HAECs) and THP-1 cells. siRNA-mediated CYLD silencing led to enhanced monocyte adhesion along with increased adhesion molecules in HAECs treated with TNFα. In siRNA-mediated CYLD silenced RAW 264.7 macrophages treated with oxidized LDL (oxLDL), augmented lipid accumulation was observed, along with increased expression of the class A macrophage scavenger receptor (SR-A), lectin-like oxidized LDL receptor-1 (LOX-1), CD36, fatty acid binding protein 4 (FABP4), the cholesterol ester synthase acyl-CoA cholesterol acyltransferase (ACAT1), MCP-1, and IL-1ß and decreased expression of scavenger receptor class B type I (SR-BI). Intriguingly, CYLD gene expression was significantly reduced in bone marrow-derived macrophages of aged mice compared that of young mice, as well as in senescent HAECs compared with young cells. These findings suggest that age-related attenuation of CYLD expression in endothelial cells (ECs) and macrophages triggers the initiation of age-related atherogenesis by exacerbating monocyte adhesion on the endothelium and foam cell formation. CYLD in the vasculature may be a novel therapeutic target, especially in the early preventive intervention against the initiation of age-related atherogenesis.


Assuntos
Envelhecimento/patologia , Aterosclerose/fisiopatologia , Cisteína Endopeptidases/metabolismo , Enzima Desubiquitinante CYLD/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Macrófagos/metabolismo , Envelhecimento/genética , Animais , Aterosclerose/genética , Aterosclerose/patologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Adesão Celular/efeitos dos fármacos , Citocinas/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/efeitos dos fármacos , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Inativação Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Lipoproteínas LDL/farmacologia , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Células RAW 264.7 , RNA Interferente Pequeno/metabolismo , Células THP-1 , Regulação para Cima/efeitos dos fármacos
12.
Sci Rep ; 8(1): 17770, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30538259

RESUMO

Although the regulation of post-ischemic inflammation is an important strategy to treat ischemic stroke, all clinical trials have failed to show its efficacy. To solve the problem, we previously developed a novel partial peptide of RANKL, microglial healing peptide 1 (MHP1), which could reduce ischemic injury by inhibiting Toll-like receptor (TLR) induced inflammation. However, optimization of the peptide was necessary to increase the stability and efficacies for clinical use. According to information gathered through HPLC/MS in serum, we have newly designed a series of modified MHP1 peptides and have found that N-terminal acetylation and C-terminal amidation in MHP1 (MHP1-AcN), can strengthen its anti-inflammatory effects and increase its stability with anti-osteoclastogenic effects. Anti-TLR activity was reported to be reduced in MHP1 when incubated at 37 °C for 24 hrs, but MHP1-AcN could keep the activity under the same condition. The therapeutic effect of MHP1-AcN was observed in transient ischemic stroke model at lower dose than MHP1. Importantly, MHP1-AcN did not affect thrombolytic effects of tissue plasminogen activator (tPA) and inhibited tPA-induced hemorrhagic transformation. These findings indicated that MHP1-AcN was stable and effective anti-TLR signal peptide and could be a promising agent for treating stroke patients receiving tPA and endovascular therapy.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Ligante RANK/uso terapêutico , Acidente Vascular Cerebral/terapia , Sequência de Aminoácidos , Animais , Fibrinolíticos/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microglia/fisiologia , Peptídeos/uso terapêutico , Ativador de Plasminogênio Tecidual/administração & dosagem
13.
Hypertension ; 72(6): 1355-1364, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30571223

RESUMO

Decreased adherence to daily ingestion of antiplatelet drugs is a critical issue, increasing mortality and morbidity in poststroke patients. As vaccination could be a promising approach to solving this, we designed an antiplatelet vaccine that inhibited S100A9 (S100 calcium-binding protein A9)/CD36 (cluster of differentiation 36) signaling in platelets, which was reported to be a key signal in arterial thrombosis, but not hemostasis. Immunization with this vaccine induced a sustainable increase in the anti-S100A9 antibody titer for >2 months and an additional booster immunization enhanced the antibody production further. The middle cerebral artery occlusion time was successfully prolonged in the vaccinated mice, which was comparable to that in mice treated with clopidogrel. The antithrombotic effect lasted for 84 days after the last vaccination, as well as after the booster immunization. Importantly, the bleeding time was not affected in the immunized mice. The antithrombotic effect was also observed in the common carotid artery, which was similar to that found in CD36-/- mice. Vascular injury increased the expression of S100A9 in the serum and phosphorylation of JNK (c-Jun N-terminal kinase) and VAV1 in the platelets, but these increases were inhibited in the immunized mice. Moreover, the S100A9 vaccine did not induce cell-mediated autoimmunity, as demonstrated by the enzyme-linked immunosorbent spot assay. Thus, immunization with the S100A9 vaccine resulted in long-term inhibition of thrombus formation through inhibition of increased S100A9/CD36 signaling without risk of bleeding or adverse autoimmune responses. Vaccination against S100A9 might be a novel therapy to prevent recurrent ischemic stroke.


Assuntos
Plaquetas/imunologia , Isquemia Encefálica/prevenção & controle , Calgranulina B/imunologia , Trombose/prevenção & controle , Vacinação/efeitos adversos , Animais , Isquemia Encefálica/imunologia , Hemorragias Intracranianas/induzido quimicamente , Camundongos , Fosforilação , Prevenção Secundária , Trombose/imunologia
15.
J Cachexia Sarcopenia Muscle ; 9(5): 975-986, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30207087

RESUMO

BACKGROUND: A pharmacologic strategy for age-related muscle weakness is desired to improve mortality and disability in the elderly. Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II into angiotensin 1-7, a peptide known to protect against acute and chronic skeletal muscle injury in rodents. Since physiological aging induces muscle weakness via mechanisms distinct from other muscle disorders, the role of ACE2-angiotensin 1-7 in age-related muscle weakness remains undetermined. Here, we investigated whether deletion of ACE2 alters the development of muscle weakness by aging and whether angiotensin 1-7 reverses muscle weakness in older mice. METHODS: After periodic measurement of grip strength and running distance in male ACE2KO and wild-type mice until 24 months of age, we infused angiotensin 1-7 or vehicle for 4 weeks, and measured grip strength, and excised tissues. Tissues were also excised from younger (3-month-old) and middle-aged (15-month-old) mice. Microarray analysis of RNA was performed using tibialis anterior (TA) muscles from middle-aged mice, and some genes were further tested using RT-PCR. RESULTS: Grip strength of ACE2KO mice was reduced at 6 months and was persistently lower than that of wild-type mice (p < 0.01 at 6, 12, 18, and 24-month-old). Running distance of ACE2KO mice was shorter than that of wild-type mice only at 24 months of age [371 ± 26 vs. 479 ± 24 (m), p < 0.01]. Angiotensin 1-7 improved grip strength in both types of older mice, with larger effects observed in ACE2KO mice (% increase, 3.8 ± 1.5 and 13.3 ± 3.1 in wild type and ACE2KO mice, respectively). Older, but not middle-aged ACE2KO mice had higher oxygen consumption assessed by a metabolic cage than age-matched wild-type mice. Angiotensin 1-7 infusion modestly increased oxygen consumption in older mice. There was no difference in a wheel-running activity or glucose tolerance between ACE2KO and wild-type mice and between mice with vehicle and angiotensin 1-7 infusion. Analysis of TA muscles revealed that p16INK4a, a senescence-associated gene, and central nuclei of myofibers increased in middle-aged, but not younger ACE2KO mice. p16INK4a and central nuclei increased in TA muscles of older wild-type mice, but the differences between ACE2KO and wild-type mice remained significant (p < 0.01). Angiotensin 1-7 did not alter the expression of p16INK4a or central nuclei in TA muscles of both types of mice. Muscle ACE2 expression of wild-type mice was the lowest at middle age (2.6 times lower than younger age, p < 0.05). CONCLUSIONS: Deletion of ACE2 induced the early manifestation of muscle weakness with signatures of muscle senescence. Angiotensin 1-7 improved muscle function in older mice, supporting future application of the peptide or its analogues in the treatment of muscle weakness in the elderly population.


Assuntos
Angiotensina I/metabolismo , Debilidade Muscular/etiologia , Debilidade Muscular/metabolismo , Músculo Esquelético/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/deficiência , Fatores Etários , Animais , Biomarcadores , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Teste de Tolerância a Glucose , Camundongos , Camundongos Knockout , Debilidade Muscular/fisiopatologia , Músculo Esquelético/fisiopatologia , Consumo de Oxigênio , Condicionamento Físico Animal , Transcriptoma
16.
Biomed Res Int ; 2018: 4637084, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30151382

RESUMO

Microglial healing peptide 1, "MHP1", is a newly developed synthetic peptide composed of the DE and a part of the EF loop of the receptor activator of nuclear factor-кB (NFκB) ligand (RANKL). Our previous report demonstrated that MHP1 significantly inhibits Toll-like receptor (TLR) 2- and 4-induced inflammation in microglia/macrophages through RANK signaling without osteoclast activation. However, its inhibitory effects on ischemic stroke when administered intravenously have not been clarified. First, we examined whether MHP1 could penetrate the brain parenchyma. Intravenous injection of FITC-conjugated MHP1 demonstrated that MHP1 could cross the blood-brain-barrier in peri-infarct regions, but not in intact regions. Because MHP1 in the parenchyma was reduced at 60 minutes after injection, we speculated that continuous injection was necessary to achieve the therapeutic effects. To check the possible deactivation of MHP1 by continuous injection, the anti-inflammatory effects were checked in MG6 cells after incubation in 37°C for 24 hours. Although the inhibitory effects for IL6 and TNFα were reduced compared to nonincubated MHP1, its anti-inflammatory efficacy remained, indicating that continuous administration with pump was possible. The single and successive continuous administration of MHP1 starting from 4 or 6 hours after cerebral ischemia successfully reduced infarct volume and prevented the exacerbation of neurological deficits with reduced activation of microglia/macrophages and inflammatory cytokines. Different from recombinant RANKL, MHP1 did not activate osteoclasts in the paralytic arm. Although further modification of MHP1 is necessary for stabilization, the MHP1 could be a novel agent for the treatment ischemic stroke.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Peptídeos/uso terapêutico , Ligante RANK/agonistas , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Camundongos , Microglia , Osteoclastos
17.
Curr Hypertens Rep ; 20(3): 22, 2018 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-29556794

RESUMO

PURPOSE OF REVIEW: Vaccines are commonly used as preventive methods, primarily against infectious diseases. The goal of our study is to develop the therapeutic vaccine for hypertension. RECENT FINDINGS: We and others recently reported that an angiotensin II (AngII) vaccine for hypertension successfully attenuated elevated blood pressures in an animal model without any immunogenic side effects. In this system, an immunogenic molecule (i.e., KLH) with adjuvants provides an antigen that supports the activation of helper T cells. In addition, pretreatment with the AngII vaccine exerts neuroprotective effects in a cerebral ischemia model and cardioprotective effects in a myocardial infarction model. In the early phase of clinical trial, the administration of an AngII vaccine (AngQb-Cyt006) successfully decreased blood pressure in hypertensive patients with the increase of anti-AngII antibody titer. Increasing the effectiveness of drug adherence interventions in the clinical setting may have a large impact on the health of the population, which can be improved by using successful therapeutic vaccines. In this review, we describe the concept of therapeutic vaccines for hypertension and future directions for therapeutic vaccines.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Hipertensão/terapia , Oligopeptídeos/farmacologia , Vacinas/uso terapêutico , Angiotensina II/imunologia , Angiotensina II/farmacologia , Animais , Pressão Sanguínea/imunologia , Modelos Animais de Doenças , Humanos , Hipertensão/imunologia
18.
NPJ Aging Mech Dis ; 4: 2, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29449960

RESUMO

SR-0379 is a functional peptide that has wound healing effect with anti-microbial action, making it an ideal drug to prevent infection. To evaluate the safety, efficacy, and pharmacokinetics of SR-0379 for the treatment of leg ulcers, a physician-initiated, phase I/IIa, first-in-patient clinical study was designed. A multi-center, double-blind, randomized clinical study was conducted from October 2015 to September 2016. The inclusion criteria for leg ulcers were (1) diabetes or critical limb ischemia and (2) wound size <6 cm in diameter. Twelve patients were randomized into four groups and administered 0.02%, 0.1%, or 0.5% SR-0379 or placebo treatment on skin ulcers once per day for 28 days. Efficiency was evaluated by determining the rate of wound size reduction as a primary endpoint at 4 weeks after the first treatment compared with the pre-treatment wound size. As a secondary endpoint, the DESIGN-R score index, time to wound closure, and the 50% wound size reduction ratio were also evaluated. The safety of SR-0379 was evaluated during the study period. In the evaluation of efficiency, the skin ulcer reduction rates at the last evaluation were 44.73% for the 0.02% SR-0379 group, 68.25% for the 0.1% group, and 71.61% for the 0.5% group, compared with 9.95% for the placebo group. Six adverse events were reported in four patients, of which one occurred in the placebo group, and causal relationships to study drugs were denied for all six events. Treatment with SR-0379 for chronic leg ulcers was safe, well tolerated, and effective.

19.
PLoS One ; 13(2): e0191895, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29438441

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates expression of low-density lipoprotein (LDL) receptors via receptor internalization and subsequent lysosomal degradation. Thus, an anti-PCSK9 antibody is well known as an anti-hyperlipidemia drug. Here, we aimed to develop vaccine for a long-term treatment of dyslipidemia targeted to PCSK9. In This study, we designed a peptide vaccine for mouse PCSK-9, which consisted of short peptides conjugated to keyhole limpet hemocyanin (KLH) as a carrier protein. Vaccines were administered to male apolipoprotein E (ApoE) deficient mice with adjuvants and significantly elicited an antibody response against PCSK9. The PCSK9 vaccines were administered to mice three times in 2-week intervals, and antibody titers and lipoprotein levels were evaluated up to 24 weeks after the first immunization to determine the therapeutic effect. Anti-PCSK9 antibody titers reached peak levels 6 weeks after the first immunization, and theses titers were maintained for up to 24 weeks. Decreased plasma levels of total cholesterol, very low-density lipoprotein (VLDL), and chylomicron (CM) were maintained for up to 24 weeks. Immunized mice exhibited a significant increase in cell-surface LDL receptor expression. Stimulation with KLH, but not PCSK9, induced the production of INF-gamma and interleukin-4 (IL-4), as determined with ELISPOT assays, thus indicating that PCSK9 vaccine did not elicit T-cell activation in our vaccine system. The present anti-PCSK9 vaccine induced long-lasting anti-PCSK9 antibody production and improved lipoprotein profiles. Thus, anti-PCSK9 vaccine could become a new option for the treatment of dyslipidemia as a long-acting therapy in future.


Assuntos
Dislipidemias/prevenção & controle , Pró-Proteína Convertase 9/química , Vacinas/imunologia , Animais , Ensaio de Imunoadsorção Enzimática , Camundongos , Pró-Proteína Convertase 9/imunologia
20.
Cardiovasc Endocrinol Metab ; 7(1): 4-9, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31646271

RESUMO

Diabetes mellitus elicits cellular, epigenetic, and post-translational changes that directly or indirectly affect the biology of the vasculature and other metabolic systems resulting in the apparition of cardiovascular disease. In this review, we provide a current perspective on the most recent discoveries in this field, with particular focus on hyperglycemia- induced pathology in the cardiovascular system. We also provide perspective on the clinical importance of molecular targeting of cardiovascular and diabetes mellitus therapies to treat hyperglycemia, inflammation, thrombosis, dyslipidemia, atherosclerosis, and hypertension.

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