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1.
Antioxidants (Basel) ; 12(1)2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36671000

RESUMO

Type 2 diabetes reduces muscle mass and function. Chronic inflammation and mitochondrial dysfunction play critical roles in muscle atrophy pathogenesis. Here, we investigated the effects of bavachin and corylifol A from Psoralea corylifolia L. seeds on muscle atrophy in dexamethasone-treated mice and in db/db mice. Bavachin and corylifol A enhanced muscle strength and muscle mass in dexamethasone-treated mice. In diabetic mice, they enhanced muscle strength and cross-sectional areas. Bavachin and corylifol A suppressed inflammatory cytokine (interleukin-6 and tumor necrosis factor-α) expression levels by downregulating nuclear factor-κB phosphorylation. They decreased the muscle atrophic factor (myostatin, atrogin-1, and muscle RING finger-1) expression levels. They activated the AKT synthetic signaling pathway and induced a switch from fast-type glycolytic fibers (type 2B) to slow-type oxidative fibers (types I and 2A). They increased mitochondrial biogenesis and dynamic factor (optic atrophy-1, mitofusin-1/2, fission, mitochondrial 1, and dynamin 1-like) expression levels via the AMP-activated protein kinase-peroxisome proliferator-activated receptor gamma coactivator 1-alpha signaling pathway. They also improved mitochondrial quality by upregulating the mitophagy factor (p62, parkin, PTEN-induced kinase-1, and BCL2-interacting protein-3) expression levels. Therefore, bavachin and corylifol A exert potential therapeutic effects on muscle atrophy by suppressing inflammation and improving mitochondrial function.

2.
Life Sci ; 311(Pt B): 121201, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36400203

RESUMO

AIMS: Psoriasis is a chronic inflammatory skin disease and lysophosphatidic acid (LPA) has recently been reported to contribute to its pathogenesis through keratinocyte proliferation. In this study, we investigated the metabolic changes in the LPA-induced keratinocyte hyperproliferation and underlying mechanisms. MAIN METHODS: HaCaT or HEKa cells were treated with LPA in the presence or absence of various chemical inhibitors. The glycolysis stress was measured using the Seahorse extracellular flux analyzer. Gene knockdown by siRNA transfection was used to investigate the role of LPAR1, PGAM1, and HIF-1α in LPA-induced metabolic changes. We confirmed the expression of PGAM1 and HIF-1α in imiquimod (IMQ)-induced psoriasis-like BALB/c mice. KEY FINDINGS: LPA increased aerobic glycolysis; however, treatment with ki16425, or LPAR1 knockdown inhibited LPA-induced glycolysis in HaCaT cells. LPA increased the expression of glycolytic enzyme PGAM1 through LPAR1. PGAM1 knockdown in HaCaT cells suppressed LPA-induced cell proliferation, changes in cell cycle factor expression, and inhibited LPA-induced aerobic glycolysis. LPA sequentially activated AKT, mTOR, its downstream target, p70 S6K, and increased HIF-1α expression through LPAR1. HIF-1α knockdown inhibited LPA-induced PGAM1 expression and aerobic glycolysis. A6730 also decreased LPA-induced activation of mTOR and p70 S6K and LPA-induced increases in HIF-1α and PGAM1 expression. Ki16425 suppressed the increased expression of PGAM1 and HIF-1α in the lesions of IMQ-induced psoriasis-like mice. In primary keratinocytes, LPA/LPAR1 signaling also induced AKT-mediated aerobic glycolysis. SIGNIFICANCE: Collectively, the results demonstrated that LPA induces aerobic glycolysis via AKT/mTOR/HIF-1α-dependent PGAM1 expression during keratinocytes proliferation and this might be one of the mechanisms of psoriasis development.


Assuntos
Proteínas Proto-Oncogênicas c-akt , Psoríase , Animais , Camundongos , Serina-Treonina Quinases TOR , Proliferação de Células , Glicólise , Queratinócitos , Psoríase/induzido quimicamente
3.
Int J Mol Sci ; 23(18)2022 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-36142408

RESUMO

The epithelial-mesenchymal transition (EMT) is a differentiation process associated with fibrogenesis in diabetic nephropathy (DN). Lysophosphatidic acid (LPA) is a small, naturally occurring glycerophospholipid implicated in the pathogenesis of DN. In this study, we investigated the role of LPA/LPAR1 signaling in the EMT of tubular cells as well as the underlying mechanisms. We observed a decrease in E-cadherin and an increase in vimentin expression levels in the kidney tubules of diabetic db/db mice, and treatment with ki16425 (LPAR1/3 inhibitor) inhibited the expression of these EMT markers. Ki16425 treatment also decreased the expression levels of the fibrotic factors fibronectin and alpha-smooth muscle actin (α-SMA) in db/db mice. Similarly, we found that LPA decreased E-cadherin expression and increased vimentin expression in HK-2 cells, which was reversed by treatment with ki16425 or AM095 (LPAR1 inhibitor). In addition, the expression levels of fibronectin and α-SMA were increased by LPA, and this effect was reversed by treatment with ki16425 and AM095 or by LPAR1 knockdown. Moreover, LPA induced the expression of the transcription factor, Krüppel-like factor 5 (KLF5), which was decreased by AM095 treatment or LPAR1 knockdown. The expression levels of EMT markers and fibrotic factors induced by LPA were decreased upon KLF5 knockdown in HK-2 cells. Inhibition of the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and serine-threonine kinase (AKT) pathways decreased LPA-induced expression of KLF5 and EMT markers. In conclusion, these data suggest that LPA contributes to the pathogenesis of diabetic nephropathy by inducing EMT and renal tubular fibrosis via regulation of KLF5 through the LPAR1.


Assuntos
Nefropatias Diabéticas , Actinas/metabolismo , Animais , Caderinas/metabolismo , Nefropatias Diabéticas/metabolismo , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fator V , Fibronectinas/metabolismo , Fibrose , Glicerofosfolipídeos/metabolismo , Isoxazóis , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Túbulos Renais/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Lisofosfolipídeos , Camundongos , Propionatos , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Vimentina/metabolismo
4.
J Ethnopharmacol ; 296: 115490, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-35728709

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The seeds of Psoralea corylifolia (PCS), also called "Boh-Gol-Zhee" in Korean, have been used in traditional medicine. PCS is effective for the treatment of vitiligo, cancer, inflammatory diseases, neurodegenerative diseases, kidney diseases, and musculoskeletal diseases. AIM OF THE STUDY: In this study, we validated the beneficial effects of PCS extract on dexamethasone (DEX)-induced muscle atrophy in mice. MATERIALS AND METHODS: DEX (20 mg/kg/day, 10 days) was intraperitoneally injected into C57BL/6 male mice to induce muscular atrophy. Oral administration of PCS extract (200 or 500 mg/kg/day) was started 2 days before DEX injection and continued for 12 days. RESULTS: PCS extract inhibited DEX-induced decrease in body and muscle weight, grip strength, and cross-sectional area of the tibialis anterior. PCS extract significantly increased the mRNA and protein expression levels of myosin heavy chain 1, 2A, and 2X in DEX-administered mice. DEX administration significantly increased the levels of muscle atrophy factors atrogin-1, muscle RING-finger protein-1, and myostatin, which were inhibited by the PCS extract. Additionally, PCS extract increased the expression of muscle regeneration factors, such as myoblast determination protein 1, myogenin, and embryonic myosin heavy chain, and muscle synthesis markers, such as protein kinase B and mammalian target of rapamycin signaling molecules. PCS extract also significantly decreased the DEX-induced production of 4-hydroxynonenal, an oxidative stress marker. Furthermore, PCS extract recovered superoxide dismutase 2, glutathione peroxidase, and catalase activities, which were significantly reduced by DEX administration. Moreover, DEX-induced activation of nuclear factor kappa-light-chain-enhancer of activated B cells and expression of cytokines, such as tumor necrosis factor α and monocyte chemoattractant protein-1, significantly decreased after PCS extract administration. CONCLUSIONS: Here, we demonstrated that PCS extract administration protected against DEX-induced muscle atrophy. This beneficial effect was mediated by suppressing the expression of muscle degradation factors and increasing the expression of muscle regeneration and synthesis factors. This effect was probably due to the inhibition of oxidative stress and inflammation. These results highlight the potential of PCS extract as a protective and therapeutic agent against muscle dysfunction and atrophy.


Assuntos
Dexametasona , Atrofia Muscular , Extratos Vegetais , Psoralea , Animais , Dexametasona/efeitos adversos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Mamíferos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/tratamento farmacológico , Atrofia Muscular/prevenção & controle , Cadeias Pesadas de Miosina/metabolismo , Estresse Oxidativo , Extratos Vegetais/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Psoralea/metabolismo , Sementes/metabolismo
5.
J Biomed Sci ; 29(1): 31, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35538534

RESUMO

BACKGROUND: Mesangial cell fibrosis, a typical symptom of diabetic nephropathy (DN), is a major contributor to glomerulosclerosis. We previously reported that the pharmacological blockade of lysophosphatidic acid (LPA) signaling improves DN. Although LPA signaling is implicated in diabetic renal fibrosis, the underlying molecular mechanisms remain unclear. Here, the role of carbohydrate-responsive element-binding protein (ChREBP) in LPA-induced renal fibrosis and the underlying mechanisms were investigated. METHODS: Eight-week-old wild-type and db/db mice were intraperitoneally injected with the vehicle or an LPAR1/3 antagonist, ki16425 (10 mg/kg), for 8 weeks on a daily basis, following which the mice were sacrificed and renal protein expression was analyzed. SV40 MES13 cells were treated with LPA in the presence or absence of ki16425, and the expression of ChREBP and fibrotic factors, including fibronectin, TGF-ß, and IL-1ß, was examined. The role of ChREBP in the LPA-induced fibrotic response was investigated by ChREBP overexpression or knockdown. The involvement of Smad ubiquitination regulatory factor-2 (Smurf2), an E3 ligase, in LPA-induced expression of ChREBP and fibrotic factors was investigated by Smurf2 overexpression or knockdown. To identify signaling molecules regulating Smurf2 expression by LPA, pharmacological inhibitors such as A6370 (Akt1/2 kinase inhibitor) and Ly 294002 (PI3K inhibitor) were used. RESULTS: The renal expression of ChREBP increased in diabetic db/db mice, and was reduced following treatment with the ki16425. Treatment with LPA induced the expression of ChREBP and fibrotic factors, including fibronectin, TGF-ß, and IL-1ß, in SV40 MES13 cells, which were positively correlated. The LPA-induced expression of fibrotic factors increased or decreased following ChREBP overexpression and knockdown, respectively. The production of reactive oxygen species (ROS) mediated the LPA-induced expression of ChREBP and fibrotic factors, and LPA decreased Smurf2 expression via Traf4-mediated ubiquitination. The LPA-induced expression of ubiquitinated-ChREBP increased or decreased following Smurf2 overexpression and knockdown, respectively. Additionally, Smurf2 knockdown significantly increased the expression of ChREBP and fibrotic factors. The pharmacological inhibition of Akt signaling suppressed the LPA-induced alterations in the expression of ChREBP and Smurf2. CONCLUSION: Collectively, the results demonstrated that the ROS/Akt-dependent downregulation of Smurf2 and the subsequent increase in ChREBP expression might be one of the mechanisms by which LPA induces mesangial cell fibrosis in DN.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Nefropatias Diabéticas , Lisofosfolipídeos , Células Mesangiais , Proteínas Proto-Oncogênicas c-akt , Espécies Reativas de Oxigênio , Ubiquitina-Proteína Ligases , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Regulação para Baixo , Feminino , Fibronectinas/metabolismo , Fibrose , Masculino , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/metabolismo , Células Mesangiais/patologia , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator 4 Associado a Receptor de TNF/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
6.
Int J Mol Sci ; 22(19)2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34639115

RESUMO

Psoriasis is a chronic inflammatory skin disease. Recently, lysophosphatidic acid (LPA)/LPAR5 signaling has been reported to be involved in both NLRP3 inflammasome activation in macrophages and keratinocyte activation to produce inflammatory cytokines, contributing to psoriasis pathogenesis. However, the effect and molecular mechanisms of LPA/LPAR signaling in keratinocyte proliferation in psoriasis remain unclear. In this study, we investigated the effects of LPAR1/3 inhibition on imiquimod (IMQ)-induced psoriasis-like mice. Treatment with the LPAR1/3 antagonist, ki16425, alleviated skin symptoms in IMQ-induced psoriasis-like mouse models and decreased keratinocyte proliferation in the lesion. It also decreased LPA-induced cell proliferation and cell cycle progression via increased cyclin A2, cyclin D1, cyclin-dependent kinase (CDK)2, and CDK4 expression and decreased p27Kip1 expression in HaCaT cells. LPAR1 knockdown in HaCaT cells reduced LPA-induced proliferation, suppressed cyclin A2 and CDK2 expression, and restored p27Kip1 expression. LPA increased Rho-associated protein kinase 2 (ROCK2) expression and PI3K/AKT activation; moreover, the pharmacological inhibition of ROCK2 and PI3K/AKT signaling suppressed LPA-induced cell cycle progression. In conclusion, we demonstrated that LPAR1/3 antagonist alleviates IMQ-induced psoriasis-like symptoms in mice, and in particular, LPAR1 signaling is involved in cell cycle progression via ROCK2/PI3K/AKT pathways in keratinocytes.


Assuntos
Proliferação de Células , Regulação da Expressão Gênica/efeitos dos fármacos , Imiquimode/toxicidade , Queratinócitos/citologia , Lisofosfolipídeos/farmacologia , Psoríase/tratamento farmacológico , Animais , Apoptose , Biomarcadores/metabolismo , Ciclo Celular , Células Cultivadas , Humanos , Indutores de Interferon/toxicidade , Queratinócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Psoríase/induzido quimicamente , Psoríase/metabolismo , Psoríase/patologia , Receptores de Ácidos Lisofosfatídicos/genética , Receptores de Ácidos Lisofosfatídicos/metabolismo , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo
7.
Nutrients ; 13(10)2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34684339

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disorder that causes excess lipid accumulation in the liver and is the leading cause of end-stage liver disease. Liriope platyphylla is a medicinal herb that has long been used to treat cough, obesity, and diabetes. However, the effect of Liriope platyphylla on NAFLD has not been studied. The aim of this study was to investigate the effect of Liriope platyphylla root ethanolic extract (LPE) on hepatic lipid accumulation in high-fat diet (HFD)-induced obese mice. Six-week-old C57BL/6 male mice were fed a HFD for 8 weeks and then treated with LPE (100 or 250 mg/kg/day) by oral gavage for another 8 weeks. Body weight gain and liver weight were significantly lower in the 250 mg/kg LPE-treated HFD group than in the vehicle-treated HFD group. Histological analysis of liver sections demonstrated that LPE treatment reduced lipid accumulation compared to the vehicle treatment. The serum total cholesterol, AST, and ALT levels significantly decreased in the LPE-treated HFD group compared to those in the vehicle-treated HFD group. The LPE significantly decreases the protein expression levels of SREBP1, ACC, p-ACC, FAS, and SCD1, which are involved in lipogenesis, and PPARγ, CD36/FAT, and FATP5, which are involved in fatty acid uptake, both in vivo and in vitro. Thus, LPE may attenuate HFD-induced NAFLD by decreasing lipid accumulation by inhibiting lipogenesis and fatty acid uptake.


Assuntos
Dieta Hiperlipídica , Etanol/química , Lipídeos/sangue , Lipogênese , Liriope (Planta)/química , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Raízes de Plantas/química , Animais , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica , Células Hep G2 , Humanos , Lipogênese/genética , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Extratos Vegetais/farmacologia , Triglicerídeos/sangue , Aumento de Peso
8.
Aging (Albany NY) ; 13(18): 21962-21974, 2021 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-34537761

RESUMO

Dulaglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effects on muscle wasting due to aging are poorly understood. In the current study, we investigated the therapeutic potential and underlying mechanism of dulaglutide in muscle wasting in aged mice. Dulaglutide improved muscle mass and strength in aged mice. Histological analysis revealed that the cross-sectional area of the tibialis anterior (TA) in the dulaglutide-treated group was thicker than that in the vehicle group. Moreover, dulaglutide increased the shift toward middle and large-sized fibers in both young and aged mice compared to the vehicle. Dulaglutide increased myofiber type I and type IIa in young (18.5% and 8.2%) and aged (1.8% and 19.7%) mice, respectively, compared to the vehicle group. Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, decreased but increased by dulaglutide in aged mice. The expression of atrophic factors such as myostatin, atrogin-1, and muscle RING-finger protein-1 was decreased in aged mice, whereas that of the myogenic factor, MyoD, was increased in both young and aged mice following dulaglutide treatment. In aged mice, optic atrophy-1 (OPA-1) protein was decreased, whereas Toll-like receptor-9 (TLR-9) and its targeting inflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor-α [TNF-α]) were elevated in the TA and quadriceps (QD) muscles. In contrast, dulaglutide administration reversed this expression pattern, thereby significantly attenuating the expression of inflammatory cytokines in aged mice. These data suggest that dulaglutide may exert beneficial effects in the treatment of muscle wasting due to aging.


Assuntos
Envelhecimento/metabolismo , Peptídeos Semelhantes ao Glucagon/análogos & derivados , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Músculo Esquelético/fisiopatologia , Proteínas Recombinantes de Fusão/administração & dosagem , Sarcopenia/tratamento farmacológico , Sarcopenia/imunologia , Receptor Toll-Like 9/imunologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Animais , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/imunologia , Peptídeos Semelhantes ao Glucagon/administração & dosagem , Humanos , Hipoglicemiantes/administração & dosagem , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Camundongos , Proteínas Musculares/genética , Proteínas Musculares/imunologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/imunologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/imunologia , Proteínas Ligases SKP Culina F-Box/genética , Proteínas Ligases SKP Culina F-Box/imunologia , Sarcopenia/etiologia , Sarcopenia/genética , Transdução de Sinais/efeitos dos fármacos , Receptor Toll-Like 9/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
9.
Oxid Med Cell Longev ; 2021: 5511881, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33859775

RESUMO

Diabetic nephropathy is a microvascular complication induced by diabetes, and methylglyoxal (MGO) is a reactive carbonyl species causing oxidative stress that contributes to the induction of inflammatory response in kidney cells. Cudrania tricuspidata (CT), cultivated in Northeast Asia, has been used as traditional medicine for treating various diseases, including neuritis, liver damage, and cancer. In this study, we determined whether a CT root extract (CTRE) can prevent MGO-induced reactive oxygen species (ROS) production and inflammation and assessed underlying mechanisms using a kidney epithelial cell line, HK-2. We observed that CTRE inhibited MGO-induced ROS production. Additionally, CTRE ameliorated the activation of MGO-induced inflammatory signaling pathways such as p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), and c-JUN N-terminal kinase (JNK). Consistent with these results, expressions of p-nuclear factor-kappa B (NFκB) and inflammatory cytokines, tumor necrosis factor-α, interleukin- (IL-) 1ß, and IL-6, were decreased when compared with MGO-only exposed HK-2 cells. CTRE alleviated the MGO-induced decrease in nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and antioxidant enzyme mRNA expressions. MGO induced the expression of NADPH oxidase 4 (NOX4); CTRE pretreatment inhibited this induction. Further studies revealed that the NOX4 expression was inhibited owing to the suppression of MGO-induced protein kinase C (PKC) activation following CTRE treatment. Collectively, our data suggest that CTRE attenuates MGO-induced inflammation and oxidative stress via inhibition of PKC activation and NOX4 expression, as well as upregulating the Nrf2-antioxidant enzyme pathway in HK-2 cells.


Assuntos
Inflamação/prevenção & controle , Rim/efeitos dos fármacos , Moraceae/química , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Aldeído Pirúvico/farmacologia , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular , Humanos , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Rim/metabolismo , Rim/patologia , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , NADPH Oxidase 4/metabolismo , Extratos Vegetais/química , Raízes de Plantas/química , Proteína Quinase C/metabolismo , Espécies Reativas de Oxigênio/metabolismo
10.
Antioxidants (Basel) ; 10(2)2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33572166

RESUMO

Pancreatic ß-cell loss is critical in diabetes pathogenesis. Up to now, no effective treatment has become available for ß-cell loss. A polyphenol recently isolated from Polysiphonia japonica, 5-Bromoprotocatechualdehyde (BPCA), is considered as a potential compound for the protection of ß-cells. In this study, we examined palmitate (PA)-induced lipotoxicity in Ins-1 cells to test the protective effects of BPCA on insulin-secreting ß-cells. Our results demonstrated that BPCA can protect ß-cells from PA-induced lipotoxicity by reducing cellular damage, preventing reactive oxygen species (ROS) overproduction, and enhancing glucose-stimulated insulin secretion (GSIS). BPCA also improved mitochondrial morphology by preserving parkin protein expression. Moreover, BPCA exhibited a protective effect against PA-induced ß-cell dysfunction in vivo in a zebrafish model. Our results provide strong evidence that BPCA could be a potential therapeutic agent for the management of diabetes.

11.
Med Hypotheses ; 144: 110186, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33254506

RESUMO

COVID-19, caused by the novel coronavirus SARS-CoV-2, is an abbreviated name for coronavirus disease 2019. COVID-19 became a global pandemic in early 2020. It predominantly affects not only the upper and lower respiratory tract, but also multiple organs, including the kidney, heart, and brain. The mortality of COVID-19 patients is high in men and in elderly patients with age-related diseases such as hypertension and diabetes. The angiotensin converting enzyme-2 (ACE-2), a component in the renin-angiotensin-aldosterone system (RAAS), plays as cell surface receptors for SARS-CoV-2. A recent study proved that coronavirus SARS-CoV-2 also uses dipeptidyl peptidase-4 (DPP4, also known as adenosine deaminase complexing protein 2, CD26) as a co-receptor when entering cells. In addition, DPP4 is also implicated in the regulation of the immune response. Thus, the combination of DPP4 inhibition and suppression of ACE-2/RAAS may be a novel therapeutic strategy for combating this pandemic.


Assuntos
Tratamento Farmacológico da COVID-19 , Dipeptidil Peptidase 4/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Idoso , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/complicações , Citocinas/metabolismo , Complicações do Diabetes/tratamento farmacológico , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Sistema Imunitário , Inflamação , Masculino , SARS-CoV-2/fisiologia , Internalização do Vírus , Replicação Viral
12.
Mar Drugs ; 18(9)2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32962167

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease, encompassing a range of conditions caused by lipid deposition within liver cells, and is also associated with obesity and metabolic diseases. Here, we investigated the protective effects of diphlorethohydroxycarmalol (DPHC), which is a polyphenol isolated from an edible seaweed, Ishige okamurae, on palmitate-induced lipotoxicity in the liver. DPHC treatment repressed palmitate-induced cytotoxicity, triglyceride content, and lipid accumulation. DPHC prevented palmitate-induced mRNA and protein expression of SREBP (sterol regulatory element-binding protein) 1, C/EBP (CCAAT-enhancer-binding protein) α, ChREBP (carbohydrate-responsive element-binding protein), and FAS (fatty acid synthase). In addition, palmitate treatment reduced the expression levels of phosphorylated AMP-activated protein kinase (AMPK) and sirtuin (SIRT)1 proteins, and DPHC treatment rescued this reduction. Moreover, DPHC protected palmitate-induced liver toxicity and lipogenesis, as well as inflammation, and enhanced AMPK and SIRT1 signaling in zebrafish. These results suggest that DPHC possesses protective effects against palmitate-induced toxicity in the liver by preventing lipogenesis and inflammation. DPHC could be used as a potential therapeutic or preventive agent for fatty liver diseases.


Assuntos
Compostos Heterocíclicos com 3 Anéis/farmacologia , Inflamação/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Phaeophyceae/química , Células Hep G2 , Compostos Heterocíclicos com 3 Anéis/isolamento & purificação , Humanos , Inflamação/patologia , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Palmitatos/toxicidade
13.
Ann Transl Med ; 8(8): 561, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32775362

RESUMO

BACKGROUND: Islet transplantation might be a logical strategy to restore insulin secretion for the treatment of diabetes, however, the scarcity of donors poses an obstacle for such a treatment. As an alternative islet source, differentiation of stem cells into insulin-producing cells (IPCs) has been tried. Many protocols have been developed to improve the efficiency of differentiation of stem cells into IPCs. In this study, we investigated whether glucosamine supplementation during differentiation of human adipose-derived stem cells (hADSCs) into IPCs can improve the insulin secretory function. METHODS: Glucosamine was added to the original differentiation medium at different stages of differentiation of hADSCs into IPCs for 12 days and insulin secretion was analyzed. RESULTS: Addition of glucosamine alone to the growth medium of hADSCs did not affect the differentiation of hADSCs to IPCs. Supplementation of the differentiation medium with glucosamine at a later stage (protocol G3) proved to have the greatest effect on IPC differentiation. Basal and glucose-stimulated insulin secretion (GSIS) was significantly increased and the expression of insulin and C-peptide was increased in differentiated IPCs as compared with that in differentiated IPCs using the conventional protocol (protocol C). In addition, the expression of beta-cell specific transcription factors such as pancreatic and duodenal homeobox1 (PDX1) and neurogenin 3 (NGN3) was also increased. Furthermore, the expression of genes related to insulin secretion, including synaptotagmin 4 (Syt4), glucokinase (Gck) and glucose transporter 2 (Glut2), was also increased. CONCLUSIONS: We conclude that glucosamine supplementation potentiates the differentiation of hADSCs into IPCs.

14.
J Ginseng Res ; 44(4): 619-626, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32617042

RESUMO

BACKGROUND: The effects of diol-ginsenoside fraction (Diol-GF) and triol-ginsenoside fraction (Triol-GF) from Korean Red Ginseng on the development of type 1 diabetes (T1D) were examined in diabetes-prone biobreeding (DP-BB) rats that spontaneously develop T1D through an autoimmune process. METHODS: DP-BB female rats were treated with Diol-GF or Triol-GF daily from the age of 3-4 weeks up to 11-12 weeks (1 mg/g body weight). RESULTS: Diol-GF delayed the onset, and reduced the incidence, of T1D. Islets of Diol-GF-treated DP-BB rats showed significantly lower insulitis and preserved higher plasma and pancreatic insulin levels. Diol-GF failed to change the proportion of lymphocyte subsets such as T cells, natural killer cells, and macrophages in the spleen and blood. Diol-GF had no effect on the ability of DP-BB rat splenocytes to induce diabetes in recipients. Diol-GF and diol-ginsenoside Rb1 significantly decreased tumor necrosis factor α production, whereas diol-ginsenosides Rb1 and Rd decreased interleukin 1ß production in RAW264.7 cells. Furthermore, mixed cytokine- and chemical-induced ß-cell cytotoxicity was greatly inhibited by Diol-GF and diol-ginsenosides Rc and Rd in RIN5mF cells. However, nitric oxide production in RAW264.7 cells was unaffected by diol-ginsenosides. CONCLUSION: Diol-GF, but not Triol-GF, significantly delayed the development of insulitis and T1D in DP-BB rats. The antidiabetogenic action of Diol-GF may result from the decrease in cytokine production and increase in ß-cell resistance to cytokine/free radical-induced cytotoxicity.

15.
Artigo em Inglês | MEDLINE | ID: mdl-32714420

RESUMO

Polygonum multiflorum Thunb. (PM) root extracts have been used for treating graying hair in Oriental medicine; however, the molecular mechanisms underlying the melanogenic effects of PM root have not been fully understood. In the present study, we investigated the melanogenic effects of an ethanolic extract of PM root (PME) and the mechanisms involved. We examined the effects of PME on cell viability, cellular melanin content, and tyrosinase activity in B16F10 cells. The melanogenic mechanism of PME was explored using signaling inhibitors and examining the expression of melanogenic genes and signaling molecules by western blot and RT-qPCR analyses. PME did not exhibit any cytotoxicity in B16F10 cells compared to that in control cells. PME treatment significantly increased melanin production and tyrosinase activity. In addition, PME induced the expression of cyclooxygenase-2 (COX2) as well as that of melanogenic genes, such as microphthalmia-associated transcription factor (MiTF), tyrosinase-related protein (Trp) 1, Trp2, and tyrosinase, in B16F10 cells. PME treatment increased the level of phosphorylated p38 mitogen-activated protein kinase (MAPK), and pretreatment with SB 203580, a p38 MAPK inhibitor, significantly suppressed this PME-induced increase in the expression of COX2 and melanogenic genes. These results indicate that PME induced the expression of melanogenic genes by inducing COX2 expression via the activation of the p38 MAPK pathway, thereby contributing to the enhancement of melanogenesis.

16.
Int J Mol Sci ; 21(10)2020 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-32429518

RESUMO

Vascular calcification (VC) is commonly associated with bone loss in patients with chronic kidney disease (CKD). The Wingless-related integration site (Wnt) regulates osteoblast activation through canonical signaling pathways, but the common pathophysiology of these pathways during VC and bone loss has not been identified. A rat model of adenine-induced CKD with VC was used in this study. The rats were fed 0.75% adenine (2.5% protein, 0.92% phosphate) with or without intraperitoneal injection of calcitriol (0.08 µg/kg/day) for 4 weeks. Angiotensin II (3 µM)-induced VC was achieved in high phosphate medium (3 mM) through its effect on vascular smooth muscle cells (VSMCs). In an mRNA profiler polymerase chain reaction assay of the Wnt signaling pathway, secreted frizzled-related protein 5 (sFRP5) levels were significantly decreased in the CKD rat model compared with the control group. The repression of sFRP5 on VSMC trans-differentiation was mediated through Rho/Rho-associated coiled coil containing protein kinase (ROCK) and c-Jun N-terminal kinase (JNK) pathways activated by Wnt3a. In a proof of concept study conducted with patients with CKD, serum sFRP5 concentrations were significantly lower in subjects with VC than in those without VC. Our findings suggest that repression of sFRP5 is associated with VC in the CKD environment via activation of the noncanonical Wnt pathway, and thus that sFRP5 might be a novel therapeutic target for VC in CKD.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/sangue , Adipocinas/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Insuficiência Renal Crônica/metabolismo , Calcificação Vascular/metabolismo , Via de Sinalização Wnt/genética , Quinases Associadas a rho/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenina/toxicidade , Adipocinas/genética , Animais , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/genética , Calcificação Vascular/induzido quimicamente , Calcificação Vascular/genética , Via de Sinalização Wnt/efeitos dos fármacos , Quinases Associadas a rho/genética
17.
Nutrients ; 12(5)2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32354126

RESUMO

Muscle wasting is caused by various factors, such as aging, cancer, diabetes, and chronic kidney disease, and significantly decreases the quality of life. However, therapeutic interventions for muscle atrophy have not yet been well-developed. In this study, we investigated the effects of schisandrin A (SNA), a component extracted from the fruits of Schisandra chinensis, on dexamethasone (DEX)-induced muscle atrophy in mice and studied the underlying mechanisms. DEX+SNA-treated mice had significantly increased grip strength, muscle weight, and muscle fiber size compared with DEX+vehicle-treated mice. In addition, SNA treatment significantly reduced the expression of muscle degradation factors such as myostatin, MAFbx (atrogin1), and muscle RING-finger protein-1 (MuRF1) and enhanced the expression of myosin heavy chain (MyHC) compared to the vehicle. In vitro studies using differentiated C2C12 myotubes also showed that SNA treatment decreased the expression of muscle degradation factors induced by dexamethasone and increased protein synthesis and expression of MyHCs by regulation of Akt/FoxO and Akt/70S6K pathways, respectively. These results suggest that SNA reduces protein degradation and increases protein synthesis in the muscle, contributing to the amelioration of dexamethasone-induced muscle atrophy and may be a potential candidate for the prevention and treatment of muscle atrophy.


Assuntos
Ciclo-Octanos/farmacologia , Ciclo-Octanos/uso terapêutico , Dexametasona/efeitos adversos , Expressão Gênica/efeitos dos fármacos , Lignanas/farmacologia , Lignanas/uso terapêutico , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Atrofia Muscular/prevenção & controle , Fitoterapia , Compostos Policíclicos/farmacologia , Compostos Policíclicos/uso terapêutico , Schisandra/química , Animais , Células Cultivadas , Ciclo-Octanos/administração & dosagem , Ciclo-Octanos/isolamento & purificação , Lignanas/administração & dosagem , Lignanas/isolamento & purificação , Masculino , Camundongos Endogâmicos C57BL , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Força Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/induzido quimicamente , Atrofia Muscular/fisiopatologia , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Miostatina/genética , Miostatina/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Compostos Policíclicos/administração & dosagem , Compostos Policíclicos/isolamento & purificação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Ligases SKP Culina F-Box/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Proteínas com Motivo Tripartido/genética , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
18.
Front Pharmacol ; 11: 90, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32153405

RESUMO

Pathological conditions such as joint immobilization, long-time bed rest, or inactivity may result in disuse-induced muscle wasting and dysfunction. To investigate the effect of dulaglutide, a long-acting glucagon-like peptide-1 receptor agonist, on disuse muscle atrophy, disuse condition was induced by spiral wire immobilization in C57BL/6 mice and the mice were treated with dulaglutide. Dulaglutide treatment effectively improved muscle function and increased muscle mass compared with vehicle treatment. Dulaglutide inhibited the decrease of muscle fiber size and the expression of atrophic factors such as myostatin, atrogin-1/MAFbx, and muscle RING-finger protein-1 in immobilized mice. In addition, dulaglutide inhibited nuclear factor kappa B activation, leading to a decrease in the mRNA levels of proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 in muscle of immobilized mice. Dulaglutide suppressed the expression of apoptotic markers such as caspase-3, cleaved poly-ADP ribose polymerase, and Bax under immobilization condition and increased the expression of heat shock protein 72 (Hsp72), which is related to the amelioration of inflammation and apoptosis during disuse time. Further study showed that dulaglutide could induce Hsp72 expression via the regulation of 5'-AMP-activated protein kinase signaling. Our data suggest that dulaglutide could exert beneficial effects against disuse-induced muscle atrophy.

19.
Aging (Albany NY) ; 12(1): 593-610, 2020 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-31905169

RESUMO

Dipeptidyl peptidase 4 (DPP4) inactivates incretin hormone glucagon-like peptide-1. DPP4 inhibitors may exert beneficial effects on diabetic nephropathy (DN) independently of glycemic control; however, the mechanisms underlying are not fully understood. Here, we investigated the mechanisms of the beneficial effects of DPP4 inhibition on DN using DPP4-deficient (DPP4-def) rats and rat mesangial cells.Blood glucose and HbA1c significantly increased by streptozotocin (STZ) and no differences were between WT-STZ and DPP4-def-STZ. The albumin level in urine decreased significantly and the albumin/creatinine ratio decreased slightly in DPP4-def-STZ. The glomerular volume in DPP4-def-STZ significantly decreased compared with that of WT-STZ. Advanced glycation end products formation, receptor for AGE (RAGE) protein expression, and its downstream inflammatory cytokines and fibrotic factors in kidney tissue, were significantly suppressed in the DPP4-def-STZ compared to the WT-STZ with increasing glyoxalase-1 (GLO-1) expression responsible for the detoxification of methylglyoxal (MGO). In vitro, exendin-4 suppressed MGO-induced AGEs production by enhancing the expression of GLO-1 and nuclear factor-erythroid 2 p45 subunit-related factor 2, resulting in decreasing pro-inflammatory cytokine levels. This effect was abolished by GLO-1 siRNA.Our data suggest that endogenously increased GLP-1 in DPP4-deficient rats contributes to the attenuation of DN partially by regulating AGEs formation via upregulation of GLO-1 expression.


Assuntos
Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Dipeptidil Peptidase 4/deficiência , Lactoilglutationa Liase/metabolismo , Animais , Biomarcadores , Biópsia , Citocinas/metabolismo , Diabetes Mellitus Experimental , Nefropatias Diabéticas/patologia , Modelos Animais de Doenças , Expressão Gênica , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Mediadores da Inflamação/metabolismo , Células Mesangiais/metabolismo , Ratos
20.
Front Cell Dev Biol ; 8: 605110, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33553143

RESUMO

Betacellulin (BTC), an epidermal growth factor family, is known to promote ß-cell regeneration. Recently, pancreatic α-cells have been highlighted as a source of new ß-cells. We investigated the effect of BTC on α-cells. Insulin+glucagon+ double stained bihormonal cell levels and pancreatic and duodenal homeobox-1 expression were increased in mice treated with recombinant adenovirus-expressing BTC (rAd-BTC) and ß-cell-ablated islet cells treated with BTC. In the islets of rAd-BTC-treated mice, both BrdU+glucagon+ and BrdU+insulin+ cell levels were significantly increased, with BrdU+glucagon+ cells showing the greater increase. Treatment of αTC1-9 cells with BTC significantly increased proliferation and cyclin D2 expression. BTC induced phosphorylation of ErbB receptors in αTC1-9 cells. The proliferative effect of BTC was mediated by ErbB-3 or ErbB-4 receptor kinase. BTC increased phosphorylation of ERK1/2, AKT, and mTOR and PC1/3 expression and GLP-1 production in α-cells, but BTC-induced proliferation was not changed by the GLP-1 receptor antagonist, exendin-9. We suggest that BTC has a direct role in α-cell proliferation via interaction with ErbB-3 and ErbB-4 receptors, and these increased α-cells might be a source of new ß-cells.

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