RESUMO
BACKGROUND: Gender is a significant risk factor for late-onset Alzheimer's disease (AD), often attributed to the decline of estrogen. The plant estrogen secoisolariciresinol diglucoside (SDG) has demonstrated anti-inflammatory and neuroprotective effects. However, the protective effects and mechanisms of SDG in female AD remain unclear. METHODS: Ten-month-old female APPswe/PSEN1dE9 (APP/PS1) transgenic mice were treated with SDG to assess its potential ameliorative effects on cognitive impairments in a female AD model through a series of behavioral and biochemical experiments. Serum levels of gut microbial metabolites enterodiol (END) and enterolactone (ENL) were quantified using HPLC-MS. Correlation analysis and broad-spectrum antibiotic cocktail (ABx) treatment were employed to demonstrate the involvement of END and ENL in SDG's cognitive improvement effects in female APP/PS1 mice. Additionally, an acute neuroinflammation model was constructed in three-month-old C57BL/6J mice treated with lipopolysaccharide (LPS) and subjected to i.c.v. injection of G15, an inhibitor of G protein-coupled estrogen receptor (GPER), to investigate the mediating role of the estrogen receptor GPER in the cognitive benefits conferred by SDG. RESULTS: SDG administration resulted in significant improvements in spatial, recognition, and working memory in female APP/PS1 mice. Neuroprotective effects were observed, including enhanced expression of CREB/BDNF and PSD-95, reduced ß-amyloid (Aß) deposition, and decreased levels of TNF-α, IL-6, and IL-10. SDG also altered gut microbiota composition, increasing serum levels of END and ENL. Correlation analysis indicated significant associations between END, ENL, cognitive performance, hippocampal Aß-related protein mRNA expression, and cortical neuroinflammatory cytokine levels. The removal of gut microbiota inhibited END and ENL production and eliminated the neuroprotective effects of SDG. Furthermore, GPER was found to mediate the inhibitory effects of SDG on neuroinflammatory responses. CONCLUSION: These findings suggest that SDG promotes the production of gut microbial metabolites END and ENL, which inhibit cerebral ß-amyloid deposition, activate GPER to enhance CREB/BDNF signaling pathways, and suppress neuroinflammatory responses. Consequently, SDG exerts neuroprotective effects and ameliorates cognitive impairments associated with AD in female mice.
Assuntos
Doença de Alzheimer , Fator Neurotrófico Derivado do Encéfalo , Butileno Glicóis , Disfunção Cognitiva , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Microbioma Gastrointestinal , Glucosídeos , Camundongos Transgênicos , Doenças Neuroinflamatórias , Receptores de Estrogênio , Receptores Acoplados a Proteínas G , Animais , Feminino , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Camundongos , Microbioma Gastrointestinal/efeitos dos fármacos , Butileno Glicóis/farmacologia , Butileno Glicóis/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Receptores de Estrogênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Modelos Animais de DoençasRESUMO
Secoisolariciresinol diglucoside (SDG) has a strong anti-inflammatory effect, which depends partly on the participation of gut microbiota. We studied the effect of SDG on colonic inflammation caused by a common poor diet, high-fat diet (HFD), and the regulation of gut microbiota as well as its metabolites. Considering the difference of sources, prices, and possible bioactivity, we compared the effects of a single compound and the extract of SDG on colon inflammation. The results displayed that both the single compound and the extract ameliorated morphologic damage of the colon and improved intestinal barrier integrity. In addition, SDG suppressed the mRNA expressions of inflammatory cytokines in the colon, and the inhibitory effect of a single compound was stronger than that of the extract. The results of 16S rRNA sequencing showed that SDG altered the diversity and composition of gut microbiota, particularly the abundance of inflammation-related bacteria, and the effect of the extract was greater than that of a single compound. The analysis of short-chain fatty acids (SCFAs) manifested the improved concentration with the intervention of SDG. These results confirmed that SDG, including a single compound and extract, exerted protective effects against colon inflammation, which might be partly explained by the gut microbiome. Our research could provide a positive nutritional intervention for chronic intestinal inflammation.
Assuntos
Anti-Inflamatórios/farmacologia , Butileno Glicóis/farmacologia , Glucosídeos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Butileno Glicóis/química , Butileno Glicóis/uso terapêutico , Colite/prevenção & controle , Dieta Hiperlipídica , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Glucosídeos/química , Glucosídeos/uso terapêutico , Inflamação , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Preeclampsia is a hypertensive pregnancy disorder with no treatment beyond management of symptoms and delivery of the fetus and placenta. Chronic hypertension increases the risk of developing superimposed preeclampsia. Previous reports showed that 1,3-butanediol attenuates hypertension in rodents; however, the therapeutic potential of 1,3-butanediol for the prevention of preeclampsia has not been investigated. This study tested the hypothesis that attenuating hypertension before pregnancy and through the placentation period via 1,3-butanediol prevents the onset of preeclampsia in female Dahl salt-sensitive (SS/Jr) rats. Female Dahl SS/Jr rats were divided into two groups: 1,3-butanediol treated (20% via drinking water) and control (ad libitum water). Both groups were maintained on low-salt rodent chow (Teklad 7034, 0.3% NaCl; n = 8/group). Animals were treated with 1,3-butanediol for 7 wk (baseline), mated, and treated through day 12 of pregnancy. 1,3-Butanediol treatment increased plasma ß-hydroxybutyrate (metabolite of 1,3-butanediol) that negatively correlated with maternal body weight in late pregnancy. Mean arterial pressure was lower in the treated group at baseline, early, and mid pregnancy, but no difference was observed in late pregnancy after treatment ended. Uterine artery resistance index (UARI) was reduced in the treated dams. No adverse fetal effects were observed, and there were no differences in pup weight or length. Placentas from treated dams had decreased vascular endothelial growth factor levels as well as decreased placental basal zone thickness and increased labyrinth zone thickness. These findings support the therapeutic role of physiological ketosis via 1,3-butanediol as a potential therapeutic approach for managing chronic hypertension, thereby preventing and mitigating adverse pregnancy outcomes associated with preeclampsia.NEW & NOTEWORTHY A ketogenic diet or increased ß-hydroxybutyrate levels can reduce hypertension, but the potential of 1,3-butanediol, a ß-hydroxybutyrate precursor, for treatment of preeclampsia is unknown. We hypothesized that attenuating hypertension before and during pregnancy via 1,3-butanediol prevents preeclampsia in Dahl Salt-sensitive rats. 1,3-Butanediol significantly lowered blood pressure and improved uterine artery resistance with no observable adverse fetal effects. Physiological ketosis via 1,3-butanediol may be a potential therapeutic approach for managing hypertension and mitigating adverse pregnancy outcomes.
Assuntos
Butileno Glicóis/uso terapêutico , Pré-Eclâmpsia/tratamento farmacológico , Ácido 3-Hidroxibutírico/sangue , Animais , Peso Corporal , Butileno Glicóis/administração & dosagem , Butileno Glicóis/efeitos adversos , Suplementos Nutricionais , Feminino , Cetose , Fenótipo , Placenta/metabolismo , Pré-Eclâmpsia/prevenção & controle , Gravidez , Ratos , Ratos Endogâmicos Dahl , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Exposure to Libby amphibole (LA) asbestos-like fibers is associated with increased risk of asbestosis, mesothelioma, pulmonary disease, and systemic autoimmune disease. LGM2605 is a small molecule antioxidant and free radical scavenger, with anti-inflammatory effects in various disease models. The current study aimed to determine whether the protective effects of LGM2605 persist during the late inflammatory phase post-LA exposure. Male and female C57BL/6 mice were administered daily LGM2605 (100 mg/kg) via gel cups for 3 days before and 14 days after a 200 µg LA given via intraperitoneal (i.p.) injection. Control mice were given unsupplemented gel cups and an equivalent dose of i.p. saline. On day 14 post-LA treatment, peritoneal lavage was assessed for immune cell influx, cytokine concentrations, oxidative stress biomarkers, and immunoglobulins. During the late inflammatory phase post-LA exposure, we noted an alteration in trafficking of both innate and adaptive immune cells, increased pro-inflammatory cytokine concentrations, induction of immunoglobulin isotype switching, and increased oxidized guanine species. LGM2605 countered these changes similarly among male and female mice, ameliorating late inflammation and altering immune responses in late post-LA exposure. These data support possible efficacy of LGM2605 in the prolonged treatment of LA-associated disease and other inflammatory conditions.
Assuntos
Amiantos Anfibólicos/toxicidade , Butileno Glicóis/uso terapêutico , Glucosídeos/uso terapêutico , Inflamação/prevenção & controle , Imunidade Adaptativa/efeitos dos fármacos , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Butileno Glicóis/farmacologia , Quimiocina CCL2/metabolismo , Feminino , Glucosídeos/farmacologia , Imunidade Inata/efeitos dos fármacos , Isotipos de Imunoglobulinas/metabolismo , Imunoglobulinas/metabolismo , Inflamação/induzido quimicamente , Inflamação/patologia , Interleucina-6 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Leptin is an adipocyte-derived hormone that regulates appetite and energy expenditure via the hypothalamus. Since the majority of obese subjects are leptin resistant, leptin sensitizers, rather than leptin itself, are expected to be anti-obesity drugs. Endoplasmic reticulum (ER) stress in the hypothalamus plays a key role in the pathogenesis of leptin resistance. ATP-deficient cells are vulnerable to ER stress and ATP treatment protects cells against ER stress. Thus, we investigated the therapeutic effects of oral 1,3-butanediol (BD) administration, which increases plasma ß-hydroxybutyrate and hypothalamic ATP concentrations, in diet induced obese (DIO) mice with leptin resistance. BD treatment effectively decreased food intake and body weight in DIO mice. In contrast, BD treatment had no effect in leptin deficient ob/ob mice. Co-administration experiment demonstrated that BD treatment sensitizes leptin action in both DIO and ob/ob mice. We also demonstrated that BD treatment attenuates ER stress and leptin resistance at the hypothalamus level. This is the first report to confirm the leptin sensitizing effect of BD treatment in leptin resistant DIO mice. The present study provides collateral evidence suggesting that the effect of BD treatment is mediated by the elevation of hypothalamic ATP concentration. Ketone bodies and hypothalamic ATP are the potential target for the treatment of obesity and its complications.
Assuntos
Peso Corporal/efeitos dos fármacos , Butileno Glicóis/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Leptina/farmacologia , Obesidade/tratamento farmacológico , Ácido 3-Hidroxibutírico/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Butileno Glicóis/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Obesos , Obesidade/metabolismoRESUMO
Thirty-seven million people in the United States are estimated to have chronic kidney disease (CKD). Hypertension (HTN) is the second leading risk factor for developing kidney disease. A recent study reported that increasing levels of ß-hydroxybutyrate levels by administration of its precursor, 1,3-butanediol, decreased salt-induced HTN in male Dahl salt-sensitive (S) rats. The effect of 1,3-butanediol on hypertensive kidney disease in female rats or the absence of high salt has not been investigated. This study tested the hypothesis that 1,3-butanediol attenuates HTN and the progression of CKD in female S-SHR(11) rats. The S-SHR(11) strain is a congenic rat strain generated from genetic modification of the Dahl S rat, previously characterized as a model of accelerated renal disease. Rats received 1,3-butanediol (20% via drinking water) or control for 10 wk and were maintained on a 0.3% NaCl rodent diet (n = 12-14 rats/group). Blood pressure was measured after 6 and 9 wk of treatment by tail-cuff plethysmography; after 10 wk, urine and tissues were collected. Activity of the treatment was confirmed by measuring plasma ß-hydroxybutyrate levels, which were greater in the treated group. The 1,3-butanediol-treated group had lower systolic blood pressure, proteinuria, plasma creatinine, and renal fibrosis after 9 wk of treatment compared with controls. The treated group had significantly smaller spleens and increased the renal anti-inflammatory molecules interleukin-10 and granulocyte-macrophage colony-stimulating factor, suggesting reduced inflammation. The present data demonstrate that 1,3-butanediol lowers blood pressure and renal injury in female rats and could be a novel nutritional intervention for the treatment of CKD.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Butileno Glicóis/uso terapêutico , Hipertensão/tratamento farmacológico , Rim/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Butileno Glicóis/farmacologia , Progressão da Doença , Feminino , Hipertensão/fisiopatologia , Rim/fisiopatologia , Ratos , Ratos Endogâmicos SHR , Insuficiência Renal Crônica/fisiopatologiaRESUMO
We conducted a multiinstitutional, placebo-controlled phase IIB trial of the lignan secoisolariciresinol diglucoside (SDG) found in flaxseed. Benign breast tissue was acquired by random periareolar fine needle aspiration (RPFNA) from premenopausal women at increased risk for breast cancer. Those with hyperplasia and ≥2% Ki-67 positive cells were eligible for randomization 2:1 to 50 mg SDG/day (Brevail) versus placebo for 12 months with repeat bio-specimen acquisition. The primary endpoint was difference in change in Ki-67 between randomization groups. A total of 180 women were randomized, with 152 ultimately evaluable for the primary endpoint. Median baseline Ki-67 was 4.1% with no difference between arms. Median Ki-67 change was -1.8% in the SDG arm (P = 0.001) and -1.2% for placebo (P = 0.034); with no significant difference between arms. As menstrual cycle phase affects proliferation, secondary analysis was performed for 117 women who by progesterone levels were in the same phase of the menstrual cycle at baseline and off-study tissue sampling. The significant Ki-67 decrease persisted for SDG (median = -2.2%; P = 0.002) but not placebo (median = -1.0%). qRT-PCR was performed on 77 pairs of tissue specimens. Twenty-two had significant ERα gene expression changes (<0.5 or >2.0) with 7 of 10 increases in placebo and 10 of 12 decreases for SDG (P = 0.028), and a difference between arms (P = 0.017). Adverse event incidence was similar in both groups, with no evidence that 50 mg/day SDG is harmful. Although the proliferation biomarker analysis showed no difference between the treatment group and the placebo, the trial demonstrated use of SDG is tolerable and safe.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Butileno Glicóis/uso terapêutico , Glucosídeos/uso terapêutico , Hiperplasia/tratamento farmacológico , Lignanas/uso terapêutico , Pré-Menopausa , Adulto , Neoplasias da Mama/patologia , Feminino , Linho/química , Seguimentos , Humanos , Hiperplasia/patologia , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Fatores de Risco , Adulto JovemRESUMO
Inflammatory bowel disease (IBD) is a chronic and recurrent intestinal inflammatory disease with high risks for colorectal cancer and extremely affect people's health. Secoisolariciresinol diglucoside (SDG), a major component of lignans, exerts anti-inflammatory effects against digestive system diseases through a multi-target mechanism. However, the effect of SDG on IBD is not clear. In the present study, we aimed to investigate the effects of SDG on IBD and elucidate the underlying mechanism. The Dextran Sulfate Sodium Salt (DSS)-induced colitis model and lipopolysaccharide (LPS) stimulated RAW264.7 mouse macrophages cellular inflammation model were established. Morphological and pathological changes in colitis tissue in mice were observed by HE staining. Macrophage infiltration was detected by flow cytometry. The levels of nucleotide oligomerization domain-like receptor protein 1 (NLRP1) inflammasome complexes, nuclear factor-kappa B (NF-κB) and inflammatory cytokines were determined using quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. The results showed that SDG significantly attenuated the pathological severity and the number of macrophage infiltration of colitis in mice. Besides, SDG decreased the levels of inflammatory cytokines (IL-1ß, IL-18 and TNF-α) and inhibited the activation of the NLRP1 inflammasome in DSS-induced colitis mice and RAW264.7 mouse macrophages. Moreover, the inhibitory effect of SDG was partly dependent on the disruption of NF-κB activation. Our results indicated that SDG relieves colitis by inhibiting NLRP1 inflammasome, and partly dependent on the disruption of NF-κB activation. Therefore, SDG may be a potential treatment option for IBD.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Anti-Inflamatórios/uso terapêutico , Proteínas Reguladoras de Apoptose/antagonistas & inibidores , Butileno Glicóis/uso terapêutico , Colite/tratamento farmacológico , Glucosídeos/uso terapêutico , Inflamassomos/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Anti-Inflamatórios/farmacologia , Proteínas Reguladoras de Apoptose/imunologia , Butileno Glicóis/farmacologia , Colite/induzido quimicamente , Colite/imunologia , Colite/patologia , Colo/efeitos dos fármacos , Colo/imunologia , Colo/patologia , Citocinas/imunologia , Sulfato de Dextrana , Glucosídeos/farmacologia , Inflamassomos/imunologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7RESUMO
BACKGROUND: In medicinal chemistry, the discovery of small organic molecules that can be optimized and lead to a future drug capable of effectively modulating the biological activity of a therapeutic target remains a major challenge. Because of the harmful secondary effects of synthesized therapeutic molecules, the development of research has been oriented towards phytomedicines. Phenolic compounds from medicinal plants are constantly explored for new therapeutic use. METHODS: In this paper, we studied interactions between main enzymes responsible for causing type 2 diabetes mellitus (T2DM) and phenolic compounds from nettle (Urtica dioica L.) using molecular Docking with Molecular Operating Environment Software (MOE). RESULTS: Docking results show a common molecule (secoisolariciresinol), which may form stable complexes with depeptidyl peptidase 4 (DPP-4), alpha-amylase and beta-glucosidase with binding energy of -7.04732084 kcal/mol, -3.82946181 kcal/mol and -4.16077089 kcal/mol respectively. Besides secoisolariciresinol, other phenolic compounds give better docking score than the original co-crystallized ligand for alpha-amylase (PDB ID 5U3A) and beta-glucosidase (PDB ID 1OGS). CONCLUSION: The obtained results are promising for the discovery of new alpha-amylase and betaglucosidase inhibitors. This study also confirms the folk use of nettle as antidiabetic agent.
Assuntos
Butileno Glicóis/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Lignanas/farmacologia , Extratos Vegetais/farmacologia , Urtica dioica/química , Glicemia/metabolismo , Butileno Glicóis/química , Butileno Glicóis/uso terapêutico , Cristalografia por Raios X , Diabetes Mellitus Tipo 2/enzimologia , Dipeptidil Peptidase 4/metabolismo , Dipeptidil Peptidase 4/ultraestrutura , Descoberta de Drogas/métodos , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Lignanas/química , Lignanas/uso terapêutico , Simulação de Acoplamento Molecular , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/metabolismo , alfa-Amilases/ultraestrutura , beta-Glucosidase/antagonistas & inibidores , beta-Glucosidase/metabolismo , beta-Glucosidase/ultraestruturaRESUMO
Flaxseed is a rich source of the omega-3 fatty acid, alpha linolenic acid, the lignan secoisolariciresinol diglucoside and fiber. These compounds provide bioactivity of value to the health of animals and humans through their anti-inflammatory action, anti-oxidative capacity and lipid modulating properties. The characteristics of ingesting flaxseed or its bioactive components are discussed in this article. The benefits of administering flaxseed or the individual bioactive components on health and disease are also discussed in this review. Specifically, the current evidence on the benefits or limitations of dietary flaxseed in a variety of cardiovascular diseases, cancer, gastro-intestinal health and brain development and function, as well as hormonal status in menopausal women, are comprehensive topics for discussion.
Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Dieta , Linho/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Sementes/química , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Butileno Glicóis/farmacologia , Butileno Glicóis/uso terapêutico , Doenças Cardiovasculares/terapia , Fibras na Dieta/farmacologia , Fibras na Dieta/uso terapêutico , Suplementos Nutricionais , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-3/uso terapêutico , Feminino , Alimento Funcional , Gastroenteropatias/terapia , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Hormônios/metabolismo , Humanos , Lignanas/farmacologia , Lignanas/uso terapêutico , Neoplasias/terapia , Ácido alfa-Linolênico/farmacologia , Ácido alfa-Linolênico/uso terapêuticoRESUMO
Sepsis is the overwhelming systemic immune response to infection, which can result in multiple organ dysfunction and septic shock. Myocardial dysfunction during sepsis is associated with advanced disease and significantly increased in-hospital mortality. Our group has shown that energetic failure and excess reactive oxygen species (ROS) generation constitute major components of myocardial dysfunction in sepsis. Because ROS production is central to cellular metabolic health, we tested if the synthetic anti-oxidant lignan secoisolariciresinol diglucoside (SDG; LGM2605) would alleviate septic cardiac dysfunction and investigated the underlying mechanism. Using the cecal ligation and puncture (CLP) mouse model of peritonitis-induced sepsis, we observed impairment of cardiac function beginning at 4â¯h post-CLP surgery. Treatment of mice with LGM2605 (100â¯mg/kg body weight, i.p.) 6â¯h post-CLP surgery reduced cardiac ROS accumulation and restored cardiac function. Assessment of mitochondrial respiration (Seahorse XF) in primary cardiomyocytes obtained from adult C57BL/6 mice that had undergone CLP and treatment with LGM2605 showed restored basal and maximal respiration, as well as preserved oxygen consumption rate (OCR) associated with spare capacity. Further analyses aiming to identify the cellular mechanisms that may account for improved cardiac function showed that LGM2605 restored mitochondria abundance, increased mitochondrial calcium uptake and preserved mitochondrial membrane potential. In addition to protecting against cardiac dysfunction, daily treatment with LGM2605 and antibiotic ertapenem (70â¯mg/kg) protected against CLP-associated mortality and reversed hypothermia when compared against mice receiving ertapenem and saline. Therefore, treatment of septic mice with LGM2605 emerges as a novel pharmacological approach that reduces cardiac ROS accumulation, protects cardiac mitochondrial function, alleviates cardiac dysfunction, and improves survival.
Assuntos
Butileno Glicóis/síntese química , Butileno Glicóis/uso terapêutico , Cardiomiopatias/complicações , Cardiomiopatias/tratamento farmacológico , Glucosídeos/síntese química , Glucosídeos/uso terapêutico , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/metabolismo , Sepse/complicações , Sepse/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Autofagia/efeitos dos fármacos , Biomarcadores/metabolismo , Butileno Glicóis/química , Butileno Glicóis/farmacologia , Cálcio/metabolismo , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Ceco/patologia , Linhagem Celular , Citocinas/sangue , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Glucosídeos/química , Glucosídeos/farmacologia , Humanos , Mediadores da Inflamação/metabolismo , Ligadura , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Mitocôndrias Cardíacas/efeitos dos fármacos , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , NF-kappa B/metabolismo , Biogênese de Organelas , Estresse Oxidativo/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Punções , Sepse/genética , Sepse/fisiopatologiaRESUMO
BACKGROUND: Recent studies indicated that ketone ester R,S-1,3-butanediol acetoacetate diester (BD-AcAc2) may be effective in preventing central nervous system oxygen toxicity (CNS-OT) and concomitant acute lung injury, a serious medical problem to be faced when breathing hyperbaric oxygen (HBO). This study aimed to further investigate the protective effects of BD-AcAc2 against CNS-OT and concomitant acute lung injury (ALI) in mice. METHODS: Mice were treated with BD-AcAc2 in peanut oil vehicle (2.5, 5.0 or 10.0 g·kg⻲ body weight) by gavage 20 minutes before 600 kPa HBO exposure. Control mice received the vehicle only. Seizure latency was recorded. Malondialdehyde content in brain and lung tissues, total protein level in bronchoalveolar lavage fluid (BLF) and lung water content were measured 60 minutes after the hyperbaric exposure. Histopathology of lung tissue was undertaken. RESULTS: Compared with the vehicle alone, BD-AcAc2 prolonged seizure latency in a dose-dependent manner (P < 0.01). The HBO-induced increase in brain malondialdehyde, BLF protein and lung water were significantly reduced by BD-AcAc2 (P < 0.01). CONCLUSION: Oral administration of the ketone ester BD-AcAc2 significantly protected against CNS-OT and concomitant ALI. Alleviation of oxidative stress may be one underlying mechanism providing this effect.
Assuntos
Acetoacetatos/uso terapêutico , Lesão Pulmonar Aguda , Encéfalo/efeitos dos fármacos , Butileno Glicóis/uso terapêutico , Oxigenoterapia Hiperbárica , Acetoacetatos/farmacologia , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Oxigenoterapia Hiperbárica/efeitos adversos , Camundongos , Oxigênio , Ratos Sprague-Dawley , Convulsões/tratamento farmacológicoRESUMO
Flaxseeds are used to treat metabolic diseases such as type 2 diabetes, fatty liver, hyperlipidemia and obesity. Secoisolariciresinol diglucoside (SDG) is a main substance of lignan which belongs to the phytoestrogen family and exists abundantly in flaxseeds. In this study, SDG reduced the body weight and size of adipose tissue, and decreased protein expressions of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding protein α (C/EBPα) in the high fat diet-fed-induced obese mice model. In the vitro study, we examined the anti-adipogenic effect of SDG during differentiation of 3T3-L1 cells into adipocytes. 3T3-L1 preadipocytes were differentiated and treated with various concentrations of SDG. Oil Red O staining was done to measure the quantity of lipid contents. As a result, SDG reduced lipid accumulation and decreased the expressions of adipogenic-related genes such as adipocyte fatty-acid-binding protein 2, adiponectin, and resistin. SDG also decreased the mRNA and protein levels of PPARγ and C/EBPα. Furthermore, phosphorylation levels of AMP-activated protein kinase α (AMPK α) and its upstream activator, liver kinase B1, were significantly increased by SDG in 3T3-L1 cells. These results suggest that SDG inhibits adipogenesis by activating AMPKα, suggesting it could be an attractive therapeutic candidate for the treatment of obesity.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adipogenia/efeitos dos fármacos , Butileno Glicóis/farmacologia , Glucosídeos/farmacologia , Células 3T3-L1 , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Animais , Butileno Glicóis/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Glucosídeos/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacosRESUMO
Radiation therapy for the treatment of thoracic malignancies has improved significantly by directing of the proton beam in higher doses on the targeted tumor while normal tissues around the tumor receive much lower doses. Nevertheless, exposure of normal tissues to protons is known to pose a substantial risk in long-term survivors, as confirmed by our work in space-relevant exposures of murine lungs to proton radiation. Thus, radioprotective strategies are being sought. We established that LGM2605 is a potent protector from radiation-induced lung toxicity and aimed in the current study to extend the initial findings of space-relevant, proton radiation-associated late lung damage in mice by looking at acute changes in human lung. We used an ex vivo model of organ culture where tissue slices of donor living human lung were kept in culture and exposed to proton radiation. We exposed donor human lung precision-cut lung sections (huPCLS), pretreated with LGM2605, to 4 Gy proton radiation and evaluated them 30 min and 24 h later for gene expression changes relevant to inflammation, oxidative stress, and cell cycle arrest, and determined radiation-induced senescence, inflammation, and oxidative tissue damage. We identified an LGM2605-mediated reduction of proton radiation-induced cellular senescence and associated cell cycle changes, an associated proinflammatory phenotype, and associated oxidative tissue damage. This is a first report on the effects of proton radiation and of the radioprotective properties of LGM2605 on human lung.
Assuntos
Anti-Inflamatórios/uso terapêutico , Butileno Glicóis/uso terapêutico , Glucosídeos/uso terapêutico , Prótons/efeitos adversos , Pneumonite por Radiação/prevenção & controle , Protetores contra Radiação/uso terapêutico , Anti-Inflamatórios/farmacologia , Butileno Glicóis/farmacologia , Pontos de Checagem do Ciclo Celular , Senescência Celular , Glucosídeos/farmacologia , Humanos , Pulmão/efeitos dos fármacos , Pulmão/efeitos da radiação , Estresse Oxidativo , Pneumonite por Radiação/tratamento farmacológico , Pneumonite por Radiação/etiologia , Protetores contra Radiação/farmacologiaRESUMO
BACKGROUND: The interaction of asbestos with macrophages drives two key processes that are linked to malignancy: (1) the generation of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and (2) the activation of an inflammation cascade that drives acute and chronic inflammation, with the NLRP3 inflammasome playing a key role. Synthetic secoisolariciresinol diglucoside (SDG), LGM2605, is a nontoxic lignan with anti-inflammatory and antioxidant properties and was evaluated for protection from asbestos in murine peritoneal macrophages (MF). METHODS: MFs were exposed to crocidolite asbestos ± LGM2605 given 4 hours prior to exposure and evaluated at various times for NLRP3 expression, secretion of inflammasome-activated cytokines (IL-1ß and IL-18), proinflammatory cytokines (IL-6, TNFα, and HMGB1), NF-κB activation, and levels of total nitrates/nitrites. RESULTS: Asbestos induces a significant (p < 0.0001) increase in the NLRP3 subunit, release of proinflammatory cytokines, NLRP3-activated cytokines, NF-κB, and levels of nitrates/nitrites. LGM2605 significantly reduced NLRP3 ranging from 40 to 81%, IL-1ß by 89-96%, and TNFα by 67-78%, as well as activated NF-κB by 48-49% while decreasing levels of nitrates/nitrites by 85-93%. CONCLUSIONS: LGM2605 reduced asbestos-induced NLRP3 expression, proinflammatory cytokine release, NF-κB activation, and nitrosative stress in MFs supporting its possible use in preventing the asbestos-induced inflammatory cascade leading to malignancy.
Assuntos
Amianto/efeitos adversos , Butileno Glicóis/uso terapêutico , Glucosídeos/uso terapêutico , Inflamassomos/efeitos adversos , Macrófagos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Butileno Glicóis/farmacologia , Glucosídeos/farmacologia , CamundongosRESUMO
Background: 5% minoxidil solution is approved for the treatment of male androgenetic alopecia (AGA). However, there have been occasional reports of adverse events that were caused mostly by propylene glycol sensitivity. As an alternative treatment, Siriraj hair team developed a proprietary preparation referred to as "minoxidil milky lotion" that uses butylene glycol as a substitute for propylene glycol. Objective: To compare the efficacy and safety of 5% minoxidil solution with 5% minoxidil milky lotion in the treatment of male AGA. Materials and Method: Twenty males with AGA were recruited for this prospective randomized study. Subjects were randomly treated with 5% minoxidil solution or 5% minoxidil milky lotion. Clinical outcomes and adverse events were recorded at 8, 16, and 24 weeks. Results: The mean age of subjects was 43.5±12.5 years (range, 26-65 years). Percentage increase in hair density at 8 weeks after receiving 5% minoxidil solution and 5% minoxidil milky lotion was 8.8% and 37.4%, respectively (p = 0.01). However, there was no statistically significant difference between the two preparations at the 16 and 24 week visits. Mild irritation was reported in 1 case in the 5% minoxidil milky lotion group. Study limitation: Small sample size. Conclusion: Both formulations were found to be effective and safe in the treatment of male AGA. 5% minoxidil milky lotion may be an alternative treatment in propylene glycol-sensitive patients, with efficacy that is comparable to that of 5% minoxidil solution.
Assuntos
Alopecia/tratamento farmacológico , Minoxidil/uso terapêutico , Administração Tópica , Adulto , Idoso , Butileno Glicóis/administração & dosagem , Butileno Glicóis/efeitos adversos , Butileno Glicóis/uso terapêutico , Emolientes/administração & dosagem , Emolientes/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Minoxidil/administração & dosagem , Minoxidil/efeitos adversos , Estudos Prospectivos , Resultado do Tratamento , Vasodilatadores/administração & dosagem , Vasodilatadores/efeitos adversos , Vasodilatadores/uso terapêuticoRESUMO
Secoisolariciresinol diglucoside (SDG), a lignan extracted from flaxseed, has been shown to suppress benign prostatic hyperplasia (BPH). However, little is known about the mechanistic basis for its anti-BPH activity. The present study showed that enterolactone (ENL), the mammalian metabolite of SDG, shared the similar binding site of G1 on a new type of membranous estrogen receptor, G-protein-coupled estrogen eceptor 1 (GPER), by docking simulations method. ENL and G1 (the specific agonist of GPER) inhibited the proliferation of human prostate stromal cell line WPMY-1 as shown by MTT assay and arrested cell cycle at the G0/G1 phase, which was displayed by propidium iodide staining following flow cytometer examination. Silencing GPER by short interfering RNA attenuated the inhibitory effect of ENL on WPMY-1 cells. The therapeutic potential of SDG in the treatment of BPH was confirmed in a testosterone propionate-induced BPH rat model. SDG significantly reduced the enlargement of the rat prostate and the number of papillary projections of prostatic alveolus and thickness of the pseudostratified epithelial and stromal cells when comparing with the model group. Mechanistic studies showed that SDG and ENL increased the expression of GPER both in vitro and in vivo. Furthermore, ENL-induced cell cycle arrest may be mediated by the activation of GPER/ERK pathway and subsequent upregulation of p53 and p21 and downregulation of cyclin D1. This work, in tandem with previous studies, will enhance our knowledge regarding the mechanism(s) of dietary phytochemicals on BPH prevention and ultimately expand the scope of adopting alternative approaches in BPH treatment.
Assuntos
4-Butirolactona/análogos & derivados , Antineoplásicos Fitogênicos/metabolismo , Butileno Glicóis/metabolismo , Linho/química , Glucosídeos/metabolismo , Lignanas/metabolismo , Modelos Moleculares , Hiperplasia Prostática/metabolismo , Receptores Acoplados a Proteínas G/agonistas , 4-Butirolactona/química , 4-Butirolactona/metabolismo , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/uso terapêutico , Sítios de Ligação , Butileno Glicóis/química , Butileno Glicóis/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células , Suplementos Nutricionais , Regulação Neoplásica da Expressão Gênica , Glucosídeos/química , Glucosídeos/uso terapêutico , Glicosídeos/química , Glicosídeos/metabolismo , Glicosídeos/uso terapêutico , Humanos , Lignanas/química , Lignanas/uso terapêutico , Masculino , Simulação de Acoplamento Molecular , Proteínas de Neoplasias/agonistas , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Próstata/metabolismo , Próstata/patologia , Hiperplasia Prostática/dietoterapia , Hiperplasia Prostática/patologia , Interferência de RNA , Distribuição Aleatória , Ratos , Ratos Wistar , Receptores de Estrogênio/química , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Sementes/químicaRESUMO
BACKGROUND: There is increased risk of colon cancer in both men and women having diabetes. The objective of the study was to evaluate the role of Secoisolariciresinol diglucoside rich extract(SRE) of L.usissatisimum(flaxseed) in colon cancer associated with type 2 diabetes mellitus. MATERIAL AND METHODS: Diabetes was induced by administering high fat diet with low dose streptozotocin model. After 6 weeks, diabetes was confirmed and 1,2 dimethylhydrazine(25mg/kg, sc) weekly administration was from 6th to 18th weeks. Rats were treated with the SRE(500mg/kg) orally from 6th to 24th week. After 24 weeks, various biochemical and enzymatic parameters were estimated. Animals were sacrificed and colon tissue was separated and subjected to analysis of histopathological, PCNA studies and mRNA expression of CDK4. RESULTS: Disease control rats depicted hyperglycaemia, hyperinsulinaemia, elevated pro-inflammatory cytokines and cancer biomarker levels, and marked presence of proliferating cells. Treatment with SRE controlled hyperglycaemia, hyperinsulinaemia, reduced pro-inflammatory cytokines and cancer biomarker levels, and decreased no. of proliferating cells. We found that disease control rats depicted over expression of CDK4 mRNA levels which were reduced by SRE treatment. CONCLUSIONS: SRE of L. usitatissimum exhibited chemopreventive effect in colon cancer associated with type 2 diabetes mellitus which might be mediated through inhibition of CDK4.
Assuntos
Butileno Glicóis/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/prevenção & controle , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Diabetes Mellitus Tipo 2/tratamento farmacológico , Linho/química , Glucosídeos/uso terapêutico , Extratos Vegetais/uso terapêutico , Animais , Biomarcadores Tumorais/metabolismo , Butileno Glicóis/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/enzimologia , Neoplasias do Colo/patologia , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Teste de Tolerância a Glucose , Glucosídeos/farmacologia , Hiperglicemia/complicações , Hiperglicemia/tratamento farmacológico , Hiperglicemia/patologia , Mediadores da Inflamação/metabolismo , Masculino , Compostos Fitoquímicos/análise , Extratos Vegetais/farmacologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-DawleyRESUMO
Peripheral painful neuropathy is one of the most common complications in diabetes and necessitates improved treatment. Secoisolariciresinol diglycoside (SDG), a predominant lignan in flaxseed, has been shown in our previous studies to exert antidepressant-like effect. As antidepressant drugs are clinically used to treat chronic neuropathic pain, this work aimed to investigate the potential analgesic efficacy of SDG against diabetic neuropathic pain in a mouse model of type 1 diabetes. We subjected mice to diabetes by a single intraperitoneal (i.p.) injection of streptozotocin (STZ, 200 mg/kg), and Hargreaves test or von Frey test was used to assess thermal hyperalgesia or mechanical allodynia, respectively. Chronic instead of acute SDG treatment (3, 10 or 30 mg/kg, p.o., twice per day for three weeks) ameliorated thermal hyperalgesia and mechanical allodynia in diabetic mice, and these analgesic actions persisted about three days when SDG treatment was terminated. Although chronic treatment of SDG to diabetic mice did not impact on the symptom of hyperglycemia, it greatly attenuated excessive oxidative stress in sciatic nerve and spinal cord tissues, and partially counteracted the condition of weight decrease. Furthermore, the analgesic actions of SDG were abolished by co-treatment with the reactive oxygen species donor tert-butyl hydroperoxide (t-BOOH), but potentiated by the reactive oxygen species scavenger phenyl-N-tert-butylnitrone (PBN). These findings indicate that chronic SDG treatment can correct neuropathic hyperalgesia and allodynia in mice with type 1 diabetes. Mechanistically, the analgesic actions of SDG in diabetic mice may be associated with its antioxidant activity.
Assuntos
Analgésicos/uso terapêutico , Antioxidantes/metabolismo , Butileno Glicóis/uso terapêutico , Diabetes Mellitus Tipo 1/complicações , Neuropatias Diabéticas/tratamento farmacológico , Linho/química , Lignanas/uso terapêutico , Analgésicos/farmacologia , Animais , Butileno Glicóis/antagonistas & inibidores , Butileno Glicóis/farmacologia , Óxidos N-Cíclicos/farmacologia , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Neuropatias Diabéticas/induzido quimicamente , Neuropatias Diabéticas/complicações , Neuropatias Diabéticas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Glicosídeos/antagonistas & inibidores , Glicosídeos/farmacologia , Glicosídeos/uso terapêutico , Hiperalgesia/complicações , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Lignanas/antagonistas & inibidores , Lignanas/farmacologia , Masculino , Camundongos , Neuralgia/complicações , Neuralgia/tratamento farmacológico , Nervo Isquiático/metabolismo , Medula Espinal/metabolismo , terc-Butil Hidroperóxido/farmacologiaRESUMO
BACKGROUND: Collagen-rich extracellular matrix from land-based mammalian tissues is increasingly used in regenerative medicine. However, its uses are associated with risk of disease transfer and may carry an ethnocultural stigma. In the present study, collagen-rich acellular swim bladder matrix (ASBM) from Rohu fish was prepared using sodium deoxycholate and crosslinked with 1,4-butanediol diglycidyl ether (BDDGE). Wound healing potential of ASBM and ASBM-BDDGE was compared in full-thickness skin wounds in rabbits. MATERIALS AND METHODS: Four full-thickness skin wounds (20 × 20 mm(2) each) were created on the dorsum of 18 rabbits and randomly divided into three equal groups. Wounds were left open, repaired with ASBM and ASBM-BDDGE in groups sham (I), ASBM (II), and ASBM-BDDGE (III), respectively. Planimetry, contracture, immunologic, and histologic observations were carried out to evaluate wound healing. RESULTS: Significantly (P < 0.05) lesser wound contraction was observed in ASBM (II) and ASBM-BDDGE (III) groups compared with sham (I) group. Total immunoglobulin G response in rabbit sera was decreased significantly (P < 0.05) in the ASBM-BDDGE (III) group compared with ASBM (II) group by enzyme-linked immunosorbent assay. Stimulation index of peripheral blood lymphocytes was decreased significantly (P < 0.05) in the ASBM-BDDGE (III) group compared with ASBM (II) group by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Histologically, improved epithelialization, neovascularization, fibroplasia, and best arranged collagen fibers were observed in ASBM (II) and ASBM-BDDGE (III) groups as early as on postimplantation day 21. CONCLUSIONS: Findings of this study indicate that BDDGE crosslinked ASBM derived from Rohu fish has potential for the clinical applications. Furthermore, it is expected that their clinical applications will not be limited by ethnocultural stigma.