RESUMO
The global burden of chronic kidney disease is increasing, and the majority of these diseases are progressive. Special site-targeted drugs are emerging as alternatives to traditional drugs. Oligonucleotides (ODNs) have been proposed as effective therapeutic tools in specific molecular target therapies for several diseases. We designed ring-type non-coding RNAs (ncRNAs), also called mTOR ODNs to suppress mammalian target rapamycin (mTOR) translation. mTOR signaling is associated with excessive cell proliferation and fibrogenesis. In this study, we examined the effects of mTOR suppression on chronic renal injury. To explore the regulation of fibrosis and inflammation in unilateral ureteral obstruction (UUO)-induced injury, we injected synthesized ODNs via the tail vein of mice. The expression of inflammatory-related markers (interleukin-1ß, tumor necrosis factor-α), and that of fibrosis (α-smooth muscle actin, fibronectin), was decreased by synthetic ODNs. Additionally, ODN administration inhibited the expression of autophagy-related markers, microtubule-associated protein light chain 3, Beclin1, and autophagy-related gene 5-12. We confirmed that ring-type ODNs inhibited fibrosis, inflammation, and autophagy in a UUO mouse model. These results suggest that mTOR may be involved in the regulation of autophagy and fibrosis and that regulating mTOR signaling may be a therapeutic strategy against chronic renal injury.
Assuntos
Insuficiência Renal Crônica , Obstrução Ureteral , Actinas/metabolismo , Animais , Autofagia/genética , Proteína Beclina-1/metabolismo , Modelos Animais de Doenças , Fibronectinas/metabolismo , Fibrose , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Rim/metabolismo , Mamíferos/metabolismo , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Oligonucleotídeos/farmacologia , RNA não Traduzido/metabolismo , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/genética , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Obstrução Ureteral/complicações , Obstrução Ureteral/genética , Obstrução Ureteral/metabolismoRESUMO
Acne vulgaris is the most common disease of the pilosebaceous unit. The pathogenesis of this disease is complex, involving increased sebum production and perifollicular inflammation. Understanding the factors that regulate sebum production is important in identifying novel therapeutic targets for the treatment of acne. Bee Venom (BV) and melittin have multiple effects including antibacterial, antiviral, and anti-inflammatory activities in various cell types. However, the anti-lipogenic mechanisms of BV and melittin have not been elucidated. We investigated the effects of BV and melittin in models of Insulin-like growth factor-1 (IGF-1) or Cutibacterium acnes (C. acnes)-induced lipogenic skin disease. C. acnes or IGF-1 increased the expression of sterol regulatory element-binding protein-1 (SREBP-1) and proliferator-activated receptor gamma (PPAR-γ), transcription factors that regulate numerous genes involved in lipid biosynthesis through the protein kinase B (Akt)/mammalian target of rapamycin (mTOR)/SREBP signaling pathway. In this study using a C. acnes or IGF-1 stimulated lipogenic disease model, BV and melittin inhibited the increased expression of lipogenic and pro-inflammatory factor through the blockade of the Akt/mTOR/SREBP signaling pathway. This study suggests for the first time that BV and melittin could be developed as potential natural anti-acne agents with anti-lipogenesis, anti-inflammatory, and anti-C. acnes activity.
Assuntos
Acne Vulgar , Venenos de Abelha , Acne Vulgar/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Venenos de Abelha/farmacologia , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Meliteno/farmacologia , Propionibacterium acnes , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Sirolimo/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
Renal fibrosis is a common process of various kidney diseases. Autophagy is an important cell biology process to maintain cellular homeostasis. In addition, autophagy is involved in the pathogenesis of various renal disease, including acute kidney injury, glomerular diseases, and renal fibrosis. However, the functional role of autophagy in renal fibrosis remains poorly unclear. The mammalian target of rapamycin (mTOR) plays a negative regulatory role in autophagy. Signal transducer and activator of transcription 3 (STAT3) is an important intracellular signaling that may regulate a variety of inflammatory responses. In addition, STAT3 regulates autophagy in various cell types. Thus, we synthesized the mTOR/STAT3 oligodeoxynucleotide (ODN) to regulate the autophagy. The aim of this study was to investigate the beneficial effect of mTOR/STAT3 ODN via the regulation of autophagy appearance on unilateral ureteral obstruction (UUO)-induced renal fibrosis. This study showed that UUO induced inflammation, tubular atrophy, and tubular interstitial fibrosis. However, mTOR/STAT3 ODN suppressed UUO-induced renal fibrosis and inflammation. The autophagy markers have no statistically significant relation, whereas mTOR/STAT3 ODN suppressed the apoptosis in tubular cells. These results suggest the possibility of mTOR/STAT3 ODN for preventing renal fibrosis. However, the role of mTOR/STAT3 ODN on autophagy regulation needs to be further investigated.
Assuntos
Autofagia/efeitos dos fármacos , Fibrose/prevenção & controle , Rim/lesões , Oligodesoxirribonucleotídeos/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Modelos Animais de DoençasRESUMO
Kidney fibrosis is a common process of various kidney diseases leading to end-stage renal failure irrespective of etiology. Myofibroblasts are crucial mediators in kidney fibrosis through production of extracellular matrix (ECM), but their origin has not been clearly identified. Many study proposed that epithelial and endothelial cells become myofibroblasts by epithelial dedifferentiation and endothelial-mesenchymal transition (EndoMT). TGF-ß1/Smad signaling plays a crucial role in partly epithelial-mensencymal transition (EMT) and EndoMT. Thus, we designed the TGF-ß1/Smad oligodeoxynucleotide (ODN), a synthetic short DNA containing complementary sequence for Smad transcription factor and TGF-ß1 mRNA. Therefore, this study investigated the anti-fibrotic effect of synthetic TGF-ß1/Smad ODN on UUO-induced kidney fibrosis in vivo model and TGF-ß1-induced in vitro model. To examine the effect of TGF-ß1/Smad ODN, we performed various experiments to evaluate kidney fibrosis. The results showed that UUO induced inflammation, ECM accumulation, epithelial dedifferentiation and EndoMT processes, and tubular atrophy. However, synthetic TGF-ß1/Smad ODN significantly suppressed UUO-induced fibrosis. Furthermore, synthetic ODN attenuated TGF-ß1-induced epithelial dedifferentiation and EndoMT program via blocking TGF-ß1/Smad signaling. In conclusion, this study demonstrated that administration of synthetic TGF-ß1/Smad ODN attenuates kidney fibrosis, epithelial dedifferentiation, and EndoMT processes. The findings propose the possibility of synthetic ODN as a new effective therapeutic tool for kidney fibrosis.
Assuntos
Desdiferenciação Celular , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal , Fibrose/prevenção & controle , Nefropatias/prevenção & controle , Oligodesoxirribonucleotídeos/farmacologia , Proteínas Smad/genética , Fator de Crescimento Transformador beta1/genética , Animais , Células Epiteliais/metabolismo , Fibrose/genética , Fibrose/patologia , Técnicas In Vitro , Nefropatias/genética , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obstrução Ureteral/genética , Obstrução Ureteral/patologia , Obstrução Ureteral/prevenção & controleRESUMO
Acute kidney injury (AKI) is a dose-limiting side effect of cisplatin therapy in cancer patients. However, effective therapies for cisplatin-induced AKI are not available. Oxidative stress, tubular cell death, and inflammation are known to be the major pathological processes of the disease. 6-Shogaol is a major component of ginger and exhibits anti-oxidative and anti-inflammatory effects. Accumulating evidence suggest that 6-shogaol may serve as a potential therapeutic agent for various inflammatory diseases. However, whether 6-shogaol exerts a protective effect on cisplatin-induced renal side effect has not yet been determined. The aim of this study was to evaluate the effect of 6-shogaol on cisplatin-induced AKI and to investigate its underlying mechanisms. An administration of 6-shogaol after cisplatin treatment ameliorated renal dysfunction and tubular injury, as shown by a reduction in serum levels of creatinine and blood urea nitrogen and an improvement in histological abnormalities. Mechanistically, 6-shogaol attenuated cisplatin-induced oxidative stress and modulated the renal expression of prooxidant and antioxidant enzymes. Apoptosis and necroptosis induced by cisplatin were also suppressed by 6-shogaol. Moreover, 6-shogaol inhibited cisplatin-induced cytokine production and immune cell infiltration. These results suggest that 6-shogaol exhibits therapeutic effects against cisplatin-induced AKI via the suppression of oxidative stress, tubular cell death, and inflammation.
Assuntos
Injúria Renal Aguda/tratamento farmacológico , Antioxidantes/farmacologia , Catecóis/farmacologia , Cisplatino/toxicidade , Zingiber officinale/química , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Animais , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Substâncias Protetoras/farmacologiaRESUMO
Hyperlipidemia is a chronic disorder that plays an important role in the development of cardiovascular diseases, type II diabetes, atherosclerosis, hypertension, and non-alcoholic fatty liver disease. Hyperlipidemias have created a worldwide health crisis and impose a substantial burden not only on personal health but also on societies and economies. Transcription factors in the sterol regulatory element binding protein (SREBP) family are key regulators of the lipogenic genes in the liver. SREBPs regulate lipid homeostasis by controlling the expression of a range of enzymes required for the synthesis of endogenous cholesterol, fatty acids, triacylglycerol, and phospholipids. Thereby, SREBPs have been considered as targets for the treatment of metabolic diseases. The aim of this study was to investigate the beneficial functions and the possible underlying molecular mechanisms of SREBP decoy ODN, which is a novel inhibitor of SREBPs, in high-fat diet (HFD)-fed hyperlipidemic mice. Our studies using HFD-induced hyperlipidemia animal model revealed that SREBB decoy ODN inhibited the increased expression of fatty acid synthetic pathway, such as SREBP-1c, FAS, SCD-1, ACC1, and HMGCR. In addition, SREBP decoy ODN decreased pro-inflammatory cytokines, including TNF-α, IL-1ß, IL-8, and IL-6 expression. These results suggest that SREBP decoy ODN exerts its anti-hyperlipidemia effects in HFD-induced hyperlipidemia mice by regulating their lipid metabolism and inhibiting lipogenesis through inactivation of the SREPB pathway.
Assuntos
Modelos Animais de Doenças , Hiperlipidemias/prevenção & controle , Oligodesoxirribonucleotídeos/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/antagonistas & inibidores , Animais , Vias Biossintéticas/efeitos dos fármacos , Vias Biossintéticas/genética , Citocinas/genética , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperlipidemias/etiologia , Hiperlipidemias/genética , Mediadores da Inflamação/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Masculino , Camundongos Endogâmicos C57BL , Oligodesoxirribonucleotídeos/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoRESUMO
Fibrosis is a common pathological feature in most kinds of chronic kidney disease. Transforming growth factor ß1 (TGF-ß1) signaling is the master pathway regulating kidney fibrosis pathogenesis, in which mothers against decapentaplegic homolog 3 (SMAD3) with signal transducer and activator of transcription 3 (STAT3) act as the integrator of various pro-fibrosis signals. We examine the effects of pomolic acid (PA) on mice with unilateral ureteral obstruction (UUO) and TGF-ß1 stimulated kidney fibroblast cells. UUO mice were observed severe tubular atrophy, and tubulointerstitial fibrosis and extracellular matrix (ECM) deposition at seven days postoperatively. However, PA-treated UUO mice demonstrated only moderate injury, minimal fibrosis, and larger reductions in the expression of ECM protein and epithelial-mesenchymal transition (EMT) progress. PA inhibited the SMAD-STAT phosphorylation in UUO mice. PA effects were also confirmed in TGF-ß1 stimulated kidney fibroblast cells. In this study, we first demonstrated that PA ameliorates fibroblast activation and renal interstitial fibrosis. Our results indicate that PA may be useful as a potential candidate in the prevention of chronic kidney disease.
Assuntos
Fibroblastos/citologia , Ácido Oleanólico/análogos & derivados , Insuficiência Renal Crônica/tratamento farmacológico , Fatores de Transcrição STAT/metabolismo , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Animais , Linhagem Celular , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Proteínas da Matriz Extracelular/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Ácido Oleanólico/administração & dosagem , Ácido Oleanólico/farmacologia , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Hepatic fibrosis is the wound-healing process of chronic hepatic disease that leads to the end-stage of hepatocellular carcinoma and demolition of hepatic structures. Epithelialâ»mesenchymal transition (EMT) has been identified to phenotypic conversion of the epithelium to mesenchymal phenotype that occurred during fibrosis. Smad decoy oligodeoxynucleotide (ODN) is a synthetic DNA fragment containing a complementary sequence of Smad transcription factor. Thus, this study evaluated the antifibrotic effects of Smad decoy ODN on carbon tetrachloride (CCl4)-induced hepatic fibrosis in mice. As shown in histological results, CCl4 treatment triggered hepatic fibrosis and increased Smad expression. On the contrary, Smad decoy ODN administration suppressed fibrogenesis and EMT process. The expression of Smad signaling and EMT-associated protein was markedly decreased in Smad decoy ODN-treated mice compared with CCl4-injured mice. In conclusion, these data indicate the practicability of Smad decoy ODN administration for preventing hepatic fibrosis and EMT processes.
Assuntos
Cirrose Hepática/patologia , Oligodesoxirribonucleotídeos/farmacologia , Proteínas Smad/genética , Animais , Sequência de Bases , Tetracloreto de Carbono/efeitos adversos , Modelos Animais de Doenças , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Matriz Extracelular/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Masculino , Camundongos , Oligodesoxirribonucleotídeos/síntese química , Oligodesoxirribonucleotídeos/química , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/química , Proteínas Smad/metabolismo , TransfecçãoRESUMO
Periodontitis is a chronic inflammatory disease that contributes to the destruction of the gingiva. Porphyromonas gingivalis (P. gingivalis) can cause periodontitis via its pathogenic lipopolysaccharides (LPS). Melittin, a major component of bee venom, is known to have anti-inflammatory and antibacterial effects. However, the role of melittin in the inflammatory response has not been elucidated in periodontitis-like human keratinocytes. Therefore, we investigated the anti-inflammatory effects of melittin on a P. gingivalis LPS (PgLPS)-treated HaCaT human keratinocyte cell line. The cytotoxicity of melittin was measured using a human keratinocyte cell line, HaCaT, and a Cell Counting Kit-8. The effect of melittin on PgLPS-induced inflammation was determined with Western blot, real-time quantitative PCT, and immunofluorescence. PgLPS increased the expression of toll-like receptor (TLR) 4 and proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, and interferon-γ (IFN-γ). Moreover, PgLPS induced activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), extracellular signal-regulated kinase (ERK), and protein kinase B/Akt. Melittin also inhibited the expression of proinflammatory cytokines by suppressing the activation of the NF-κB signaling pathway, ERK, and Akt. Melittin attenuates the PgLPS-induced inflammatory response and could therefore be applied in the treatment of periodontitis for anti-inflammatory effects.
Assuntos
Anti-Inflamatórios/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Queratinócitos/efeitos dos fármacos , Lipopolissacarídeos/antagonistas & inibidores , Meliteno/farmacologia , Porphyromonas gingivalis/metabolismo , Linhagem Celular Transformada , Regulação da Expressão Gênica/imunologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Interleucina-8/genética , Interleucina-8/imunologia , Queratinócitos/imunologia , Queratinócitos/patologia , Lipopolissacarídeos/isolamento & purificação , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/imunologia , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Porphyromonas gingivalis/patogenicidade , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Periodontitis is a chronic inflammatory disease that leads to destruction of tooth supporting tissues. Porphyromonas gingivalis (P. gingivalis), especially its lipopolysaccharides (LPS), is one of major pathogens that cause periodontitis. Bee venom (BV) has been widely used as a traditional medicine for various diseases. Previous studies have demonstrated the anti-inflammatory, anti-bacterial effects of BV. However, a direct role and cellular mechanism of BV on periodontitis-like human keratinocytes have not been explored. Therefore, we investigated the anti-inflammatory mechanism of BV against P. gingivalis LPS (PgLPS)-induced HaCaT human keratinocyte cell line. The anti-inflammatory effect of BV was demonstrated by various molecular biological methods. The results showed that PgLPS increased the expression of Toll-like receptor (TLR)-4 and pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-8, and interferon (IFN)-γ. In addition, PgLPS induced activation of the signaling pathways of inflammatory cytokines-related transcription factors, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP-1). BV effectively inhibited those pro-inflammatory cytokines through suppression of NF-κB and AP-1 signaling pathways. These results suggest that administration of BV attenuates PgLPS-induced inflammatory responses. Furthermore, BV may be a useful treatment to anti-inflammatory therapy for periodontitis.
Assuntos
Venenos de Abelha/farmacologia , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , NF-kappa B/metabolismo , Polissacarídeos Bacterianos/farmacologia , Porphyromonas gingivalis/química , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição AP-1/metabolismo , Linhagem Celular Tumoral , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
INTRODUCTION: This study inquired into any significant difference in blood lead levels (BLLs) among aircraft maintenance crews at the air-bases, each with a different aviation fuel in use, and confirmed an environmental impact of leaded aviation gasoline (AVGAS). METHODS: This study included a total of 256 male aircraft maintenance personnel, among whom 105 used only AVGAS as their aviation fuel, while 151 used only jet propellant 8 (JP-8), a kerosene variety. BLLs were measured and the data on related factors were obtained. RESULTS: The arithmetic and geometric means of BLLs of the personnel at the airbases that used only AVGAS were 4.20 microg x dl(-1) and 4.01 microg x dl(-1) and that used only JP-8 were 3.79 microg x dl(-1) and 3.57 microg x dl(-1), respectively. The BLLs of the maintenance crew of the main workspace that was located within a 200-m distance from the runway were higher than those of the main workspace that was located 200 m or farther from the runway. The longer the work hours in the runway or the longer the work duration, the higher the BLLs of the maintenance crew. DISCUSSION: This investigation exposed the fact that a body's BLL could be increased by AVGAS emissions through the examination of aircraft maintenance crew. This result is in agreement with results of previous studies that suggest proximity to an airport may be associated with elevated BLLs for adults and children. Collectively, the results of the current study and previous research suggest that long-duration inhabitation and/or activities in close proximity to an air facility should be limited given that lead poses known health risks.
Assuntos
Aviação , Gasolina , Querosene , Chumbo/sangue , Saúde Ocupacional , Adulto , Aeroportos , Exposição Ambiental , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Atopic dermatitis (AD) is a common inflammatory skin disease caused by an immune disorder. Mast cells are known to be activated and granulated to maintain an allergic reaction, including rhinitis, asthma, and AD. Although hypoxia-inducible factor-1 alpha (HIF-1α) and signal transducer and activator of transcription 5 (STAT5) play crucial roles in mast cell survival and granulation, their effects need to be clarified in allergic disorders. Thus, we designed decoy oligodeoxynucleotide (ODN) synthetic DNA, without open ends, containing complementary sequences for HIF-1α and STAT5 to suppress the transcriptional activities of HIF-1α and STAT5. In this study, we demonstrated the effects of HIF-1α/STAT5 ODN using AD-like in vivo and in vitro models. The HIF-1α/STAT5 decoy ODN significantly alleviated cutaneous symptoms similar to AD, including morphology changes, immune cell infiltration, skin barrier dysfunction, and inflammatory response. In the AD model, it also inhibited mast cell infiltration and degranulation in skin tissue. These results suggest that the HIF-1α/STAT5 decoy ODN ameliorates the AD-like disorder and immunoglobulin E (IgE)-induced mast cell activation by disrupting HIF-1α/STAT5 signaling pathways. Taken together, these findings suggest the possibility of HIF-1α/STAT5 as therapeutic targets and their decoy ODN as a potential therapeutic tool for AD.
RESUMO
Atherosclerosis is a progressive chronic inflammatory condition that is the cause of most cardiovascular and cerebrovascular diseases. The transcription factor nuclear factorκB (NFκB) regulates a number of genes involved in the inflammatory responses of cells that are critical to atherogenesis, and signal transducer and activator of transcription (STAT)3 is a key transcription factor in immunity and inflammation. Decoy oligodeoxynucleotides (ODNs) bind to sequencespecific transcription factors and limit gene expression by interfering with transcription in vitro and in vivo. The present study aimed to investigate the beneficial functions of STAT3/NFκB decoy ODNs in liposaccharide (LPS)induced atherosclerosis in mice. Atherosclerotic injuries of mice were induced via intraperitoneal injection of LPS and the mice were fed an atherogenic diet. Ringtype STAT3/NFκB decoy ODNs were designed and administered via an injection into the tail vein of the mice. To investigate the effect of STAT3/NFκB decoy ODNs, electrophoretic mobility shift assay, western blot analysis, histological analysis with hematoxylin and eosin staining, VerhoeffVan Gieson and Masson's trichrome staining were performed. The results revealed that STAT3/NFκB decoy ODNs were able to suppress the development of atherosclerosis by attenuating morphological changes and inflammation in atherosclerotic mice aortae, and by reducing proinflammatory cytokine secretion through inhibition of the STAT3/NFκB pathway. In conclusion, the present study provided novel insights into the antiatherogenic molecular mechanism of STAT3/NFκB decoy ODNs, which may serve as an additional therapeutic intervention to combat atherosclerosis.
Assuntos
Aterosclerose , NF-kappa B , Animais , Camundongos , NF-kappa B/metabolismo , Lipopolissacarídeos , Transdução de Sinais , Oligodesoxirribonucleotídeos/farmacologia , Oligodesoxirribonucleotídeos/uso terapêutico , Oligodesoxirribonucleotídeos/genética , Inflamação/patologia , Fatores de Transcrição , Aterosclerose/tratamento farmacológico , Aterosclerose/genéticaRESUMO
Acne vulgaris has a pathogenesis that involves increased sebum production and perifollicular inflammation. Sterol regulatory element-binding protein-1 (SREBP-1) and peroxisome proliferator activated receptor-γ (PPAR-γ) are transcription factors that regulate numerous genes involved in lipid biosynthesis. To improve a new therapeutic approach, we designed the SREBP/PPAR decoy oligodeoxynucleotide (ODN), a synthetic short DNA containing complementary sequences for the SREBP and PPAR transcription factors. We aim to investigate the beneficial functions and the molecular mechanisms of the synthetic SREBP/PPAR decoy ODN in lipogenic models. C. acnes was intradermally injected with a 1.0 × 107 colony forming unit/20 µL. The synthetic SREBP/PPAR decoy ODN or scrambled decoy ODN (10 µg) was transferred via the mouse tail vein injection. SZ95 cells were transfected with 2 µg of synthetic ODNs. After transfection, the SZ95 cells were cultured in serum-free medium containing 20 ng/µL of insulin-like growth factor-1 (IGF)-1 for 24 h. To investigate the expression of gene and signaling pathways, we performed Western blotting. The distribution of the chimeric decoy ODN was confirmed by EMSA. Lipid levels were assessed by Nile red and Oil Red O staining. The cytokine levels were measured by ELISA kit. This study showed that C. acnes-injected mice and IGF-1-stimulated SZ95 cells exhibited increased expression of SREBP-1 and PPAR-γ compared to the normal controls. In contrast, the administration of the SREBP/PPAR chimeric decoy ODN significantly suppressed the upregulation of lipogenic genes. Furthermore, the SREBP/PPAR decoy ODN decreased the plasma cytokines and cytokine levels of total protein. These results suggested that the SREBP/PPAR decoy ODN exerts its anti-lipogenic effects by regulating lipid metabolism and by inhibiting lipogenesis through the inactivation of the SREBP and PPAR pathways. Therefore, the synthetic SREBP/PPAR ODN demonstrates substantial therapeutic feasibility for the treatment of acne vulgaris.
Assuntos
Acne Vulgar , Lipogênese , Animais , Camundongos , Lipogênese/genética , Oligodesoxirribonucleotídeos/genética , PPAR gama/genética , PPAR gama/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Acne Vulgar/genética , Citocinas/metabolismo , LipídeosRESUMO
The use of cisplatin, a chemotherapy drug, is often limited due to its renal side effects such as acute kidney injury (AKI). However, there are no validated medications to prevent or treat cisplatin-induced AKI. Oridonin is the major bioactive component of Isodon rubescens (Rabdosia rubescens) and exhibits anticancer, antioxidative, and anti-inflammatory effects. Recent studies have shown that oridonin alleviated a variety of inflammatory diseases, including renal diseases, in rodents. This study was aimed at investigating the potential renoprotective effect of oridonin on cisplatin-induced AKI. Male C57BL/6 mice were administered with cisplatin (20 mg/kg) with or without oridonin (15 mg/kg). Oridonin administration to mice after cisplatin injection attenuated renal dysfunction and histopathological changes. Upregulation of tubular injury markers was also suppressed by oridonin. Mechanistically, oridonin suppressed lipid peroxidation and reversed the decreased ratio of reduced to oxidized glutathione in cisplatin-injected mice. The increase in cisplatin-induced apoptosis was also alleviated by the compound. Moreover, oridonin inhibited cytokine overproduction and attenuated immune cell infiltration in cisplatin-injected mice. Altogether, these data demonstrated that oridonin alleviates cisplatin-induced kidney injury via inhibiting oxidative stress, apoptosis, and inflammation.
Assuntos
Injúria Renal Aguda , Cisplatino , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/patologia , Animais , Apoptose , Cisplatino/farmacologia , Diterpenos do Tipo Caurano , Feminino , Humanos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse OxidativoRESUMO
Streptococcus pyogenes (S. pyogenes) bacteria cause almost all primary skin infections in humans. Bee venom (BV) and melittin (Mel) have multiple effects, including antibacterial and anti-inflammatory activities. This study aims to demonstrate their effects on bacterial mouse skin infection using S. pyogenes. The dorsal skin was tape-stripped, then S. pyogenes was topically applied. BV or Mel were topically applied to the lesion. The tissues were stained with hematoxylin and eosin, while immunohistochemical staining was performed with anti-neutrophil. S. pyogenes-infected skin revealed increased epidermal and dermal layers, but it was reduced in the BV and Mel groups. Finding increased neutrophils in the mice infected with S. pyogenes, but the BV and Mel mice showed decreased expression. These results suggest that BV and Mel treatments could reduce the inflammatory reactions and help improve lesions induced by S. pyogenes skin infection. This study provides additional assessment of the potential therapeutic effects of BV and Mel in managing skin infection caused by S. pyogenes, further suggesting that it could be a candidate for developing novel treatment alternative for streptococcal skin infections.
Assuntos
Venenos de Abelha , Dermatopatias Bacterianas , Humanos , Camundongos , Animais , Meliteno/farmacologia , Meliteno/uso terapêutico , Venenos de Abelha/farmacologia , Venenos de Abelha/uso terapêutico , Streptococcus pyogenes , Amarelo de Eosina-(YS) , Hematoxilina , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Dermatopatias Bacterianas/tratamento farmacológico , Antibacterianos/uso terapêuticoRESUMO
Renal fibrosis is a progressive and chronic process that influences kidneys with chronic kidney disease (CKD), irrespective of cause, leading to irreversible failure of renal function and end-stage kidney disease. Among the signaling related to renal fibrosis, transforming growth factor-ß1 (TGF-ß1) signaling is a major pathway that induces the activation of myofibroblasts and the production of extracellular matrix (ECM) molecules. Apamin, a component of bee venom (BV), has been studied in relation to various diseases. However, the effect of apamin on renal interstitial fibrosis has not been investigated. The aim of this study was to estimate the beneficial effect of apamin in unilateral ureteral obstruction (UUO)-induced renal fibrosis and TGF-ß1-induced renal fibroblast activation. This study revealed that obstructive kidney injury induced an inflammatory response, tubular atrophy, and ECM accumulation. However, apamin treatment suppressed the increased expression of fibrotic-related genes, including α-SMA, vimentin, and fibronectin. Administration of apamin also attenuated the renal tubular cells injury and tubular atrophy. In addition, apamin attenuated fibroblast activation, ECM synthesis, and inflammatory cytokines such as TNF-α, IL-1ß, and IL-6 by suppressing the TGF-ß1-canonical and non-canonical signaling pathways. This study showed that apamin inhibits UUO-induced renal fibrosis in vivo and TGF-ß1-induced renal fibroblasts activation in vitro. Apamin inhibited the inflammatory response, tubular atrophy, ECM accumulation, fibroblast activation, and renal interstitial fibrosis through suppression of TGF-ß1/Smad2/3 and STAT3 signaling pathways. These results suggest that apamin might be a potential therapeutic agent for renal fibrosis. KEY MESSAGES: UUO injury can induce renal dysfunction; however, apamin administration prevents renal failure in UUO mice. Apamin inhibited renal inflammatory response and ECM deposition in UUO-injured mice. Apamin suppressed the activation of myofibroblasts in vivo and in vitro. Apamin has the anti-fibrotic effect on renal fibrosis via regulation of TGF-ß1 canonical and non-canonical signaling.
Assuntos
Anti-Inflamatórios/farmacologia , Antifibróticos/farmacologia , Apamina/farmacologia , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Obstrução Ureteral/tratamento farmacológico , Animais , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Fibrose , Rim/metabolismo , Rim/patologia , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Camundongos Endogâmicos C57BL , Fosforilação , Ratos , Transdução de Sinais , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Obstrução Ureteral/complicações , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologiaRESUMO
Autophagy in the proximal tubules may promote fibrosis by activating tubular cell death, interstitial inflammation, and the production of pro-fibrotic factors. The signal transducer and activator of transcription 3 (STAT3) is activated as a potential transcription factor, which mediates the stimulation of renal fibrosis. We investigated the role of the STAT3 in autophagy and its effect on the prevention of interstitial renal fibrosis. In this study, we use synthesized STAT3 decoy oligonucleotides (ODN), which were injected into the tail veins of unilateral ureteral obstruction (UUO) mice, to explore the regulation of autophagy in UUO-induced renal fibrosis. The expression of interleukin-6 (IL-6), interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and collagen were decreased by STAT3 decoy ODN. The autophagy markers microtubule-associated protein light chain 3 (LC3) and fibronectin, were identified through immunofluorescent staining, indicating that they were reduced in the group injected with ODN. The expressions of LC3, Beclin1, p62, and autophagy-related 5-12 (Atg5-12) and hypoxia inducible factor-1α (HIF-1α) were inhibited in the ODN injection group. We determined the inhibitory effect of autophagy in chronic kidney disease and confirmed that STAT3 decoy ODN effectively inhibited autophagy by inhibiting the expression of STAT3 transcription factors in the UUO group.
RESUMO
Bee venom is a natural toxin produced by honeybees and plays an important role in defending bee colonies. Bee venom has several kinds of peptides, including melittin, apamin, adolapamine, and mast cell degranulation peptides. Apamin accounts for about 2%-3% dry weight of bee venom and is a peptide neurotoxin that contains 18 amino acid residues that are tightly crosslinked by two disulfide bonds. It is well known for its pharmacological functions, which irreversibly block Ca2+-activated K+ (SK) channels. Apamin regulates gene expression in various signal transduction pathways involved in cell development. The aim of this study was to review the current understanding of apamin in the treatment of apoptosis, fibrosis, and central nervous system diseases, which are the pathological processes of various diseases. Apamin's potential therapeutic and pharmacological applications are also discussed.
Assuntos
Apamina/uso terapêutico , Aterosclerose/tratamento farmacológico , Venenos de Abelha/química , Sistema Nervoso Central/efeitos dos fármacos , Cirrose Hepática/tratamento farmacológico , Canais de Potássio Cálcio-Ativados/antagonistas & inibidores , Apamina/isolamento & purificação , Apoptose/efeitos dos fármacos , Aterosclerose/metabolismo , Sistema Nervoso Central/patologia , Citocinas/antagonistas & inibidores , Fibrose , Humanos , Cirrose Hepática/patologiaRESUMO
Porphyromonas gingivalis (P. gingivalis) is one of the major periodontal pathogens leading to inflammation and alveolar bone resorption. Bone resorption is induced by osteoclasts, which are multinucleated giant cells. Osteoclastic bone resorption is mediated by enhanced receptor activator of nuclear factor-kappa B ligand (RANKL) signaling. Therefore, the down-regulation of RANKL downstream signals is regarded as an effective therapeutic target in the treatment of bone loss-associated disorders. The aim of this study was to evaluate whether purified bee venom (BV) could attenuate P. gingivalis-induced inflammatory periodontitis and RANKL-induced osteoclast differentiation. Inflammatory periodontitis induced by P. gingivalis increased alveolar bone resorption and increased expression of TNF-α and IL-1ß, while BV treatment resulted in decreased bone loss and pro-inflammatory cytokines. Similarly, RANKL-induced multinucleated osteoclast differentiation and osteoclast-specific gene expression, such as nuclear factor of activated T cells 1 (NFATc1), cathepsin K, tartrate-resistant acid phosphatase (TRAP), and integrin αvß3 were significantly suppressed by treatment with BV. We show that BV reduces P. gingivalis-induced inflammatory bone loss-related periodontitis in vivo and RANKL-induced osteoclast differentiation, activation, and function in vitro. These results suggest that BV exerts positive effects on inflammatory periodontitis associated osteoclastogenesis.