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Sepsis, a life-threatening condition characterized by dysregulated immune responses, remains a significant clinical challenge. Myricanol, a natural compound, plays a variety of roles in regulating lipid metabolism, anti-cancer, anti-neurodegeneration, and it could act as an Sirtuin 1 (SIRT1) activator. This study aimed to explore the therapeutic potential and underlying mechanism of myricanol in the lipopolysaccharide (LPS)-induced sepsis model. In vivo studies revealed that myricanol administration significantly improved the survival rate of LPS-treated mice, effectively mitigating LPS-induced inflammatory responses in lung tissue. Furthermore, in vitro studies demonstrated that myricanol treatment inhibited the expression of pro-inflammatory cytokines, attenuated signal pathway activation, and reduced oxidative stress in macrophages. In addition, we demonstrated that myricanol selectively enhances SIRT1 activation in LPS-stimulated macrophages, and all of the protective effect of myricanol were reversed through SIRT1 silencing. Remarkably, the beneficial effects of myricanol against LPS-induced sepsis were abolished in SIRT1 myeloid-specific knockout mice, underpinning the critical role of SIRT1 in mediating myricanol's therapeutic efficacy. In summary, this study provides significant evidence that myricanol acts as a potent SIRT1 activator, targeting inflammatory signal pathways and oxidative stress to suppress excessive inflammatory responses. Our findings highlight the potential of myricanol as a novel therapeutic agent for the treatment of LPS-induced sepsis.
Assuntos
Inflamação , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2 , NF-kappa B , Sepse , Transdução de Sinais , Sirtuína 1 , Regulação para Cima , Animais , Sirtuína 1/metabolismo , Sepse/tratamento farmacológico , Sepse/metabolismo , Camundongos , Lipopolissacarídeos/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Transdução de Sinais/efeitos dos fármacos , NF-kappa B/metabolismo , Regulação para Cima/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Masculino , Estresse Oxidativo/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Células RAW 264.7 , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Anti-Inflamatórios/farmacologiaRESUMO
Macrophage inflammation plays a central role during the development and progression of sepsis, while the regulation of macrophages by parthanatos has been recently identified as a novel strategy for anti-inflammatory therapies. This study was designed to investigate the therapeutic potential and mechanism of pimpinellin against LPS-induced sepsis. PARP1 and PAR activation were detected by western blot or immunohistochemistry. Cell death was assessed by flow cytometry and western blot. Cell metabolism was measured with a Seahorse XFe24 extracellular flux analyzer. C57, PARP1 knockout, and PARP1 conditional knock-in mice were used in a model of sepsis caused by LPS to assess the effect of pimpinellin. Here, we found that pimpinellin can specifically inhibit LPS-induced macrophage PARP1 and PAR activation. In vitro studies showed that pimpinellin could inhibit the expression of inflammatory cytokines and signal pathway activation in macrophages by inhibiting overexpression of PARP1. In addition, pimpinellin increased the survival rate of LPS-treated mice, thereby preventing LPS-induced sepsis. Further research confirmed that LPS-induced sepsis in PARP1 overexpressing mice was attenuated by pimpinellin, and PARP1 knockdown abolished the protective effect of pimpinellin against LPS-induced sepsis. Further study found that pimpinellin can promote ubiquitin-mediated degradation of PARP1 through RNF146. This is the first study to demonstrate that pimpinellin inhibits excessive inflammatory responses by promoting the ubiquitin-mediated degradation of PARP1.
Assuntos
Lipopolissacarídeos , Metoxaleno , Sepse , Animais , Camundongos , Inflamação/metabolismo , Macrófagos , Metoxaleno/análogos & derivados , Camundongos Endogâmicos C57BL , Sepse/induzido quimicamente , Sepse/tratamento farmacológico , Ubiquitinação , Ubiquitinas/metabolismoRESUMO
Obesity, as a worldwide healthcare problem, has attracted more and more attention. Here we identify a long non-coding RNA NRON, which is highly conserved across species, as an important regulator of glucose/lipid metabolism and whole-body energy expenditure. Depletion of Nron leads to metabolic benefits in DIO (diet-induced obesity) mice, including reduced body weight and fat mass, improved insulin sensitivity and serum lipid parameters, attenuated hepatic steatosis and enhanced adipose function. Mechanistically, Nron deletion improves hepatic lipid homeostasis via PER2/Rev-Erbα/FGF21 axis coupled with AMPK activation, and enhances adipose function via activating the process of triacylglycerol hydrolysis and fatty acid re-esterification (TAG/FA cycling) and coupled metabolic network. These interactive and integrative effects cooperatively account for a healthier metabolic phenotype in NKO (Nron knockout) mice. Genetic or pharmacological inhibition of Nron may have potential for future therapy of obesity.
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This study aimed to evaluate the antibacterial activity of isopropoxy benzene guanidine (IBG) against C. perfringens based on pharmacokinetics/pharmacodynamics (PK/PD) modeling in broilers. The PK parameters of IBG in the plasma and ileal content of C. perfringens-infected broilers following oral administration at 2, 30, and 60 mg/kg body weight were investigated. in vivo PD studies were conducted over oral administration ranging from 2 to 60 mg/kg and repeated every 12 h for 3 days. The inhibitory I max model was used for PK/PD modeling. Results showed that the MIC of IBG against C. perfringens was 0.5-32 mg/L. After oral administration of IBG, the peak concentration (C max ), maximum concentration time (T max ), and area under the concentration-time curve (AUC) in ileal content of broilers were 10.97-1,036.64 mg/L, 2.39-4.27 h, and 38.31-4,266.77 mg·h/L, respectively. After integrating the PK and PD data, the AUC0 - 24h /MIC ratios needed for the bacteriostasis, bactericidal activity, and bacterial eradication were 4.00, 240.74, and 476.98 h, respectively. For dosage calculation, a dosage regimen of 12.98 mg/kg repeated every 12 h for 3 days was be therapeutically effective in broilers against C. perfringens with MIC ≤ 2 mg/L. In addition, IBG showed potent activity against C. perfringens, which may be responsible for cell membrane destruction. These results can facilitate the evaluation of the use of IBG in the treatment of intestinal diseases in broilers caused by C. perfringens.
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Endothelial cells (ECs) are vital regulators of inflammatory processes, there is the potential for inhibition of EC inflammation to be a therapeutic target in chronic inflammatory diseases. This study aimed to investigate the effect of 7-methoxyisoflavone (7-Mif) on endothelial inflammation. Our results showed that 7-Mif have no cytotoxicity on HUVECs. Pretreatment with 5 µM, 10 µM and 50 µM 7-Mif significantly reduced IL-1ß-induced ICAM-1 (28.1% ± 4.1%, 25.9 ± 2.5% and 32.0% ± 3.2%, respectively) and VCAM-1 (48.0% ± 5.6%, 40.1 ± 3.1% and 39.6% ± 3.1%, respectively) mRNA expression. And pretreatment with 10 µM and 50 µM 7-Mif significantly reduced IL-1ß-induced ICAM-1 (45.1% ± 4.4% and 33.6 ± 4.4%, respectively) and VCAM-1 (53.0% ± 3.7% and 53.7 ± 5.1%, respectively) protein levels. Furthermore, pretreatment with 50 µM 7-Mif inhibited monocyte-endothelial cell adhesion (50.2% ± 4.2%). Mechanistically, our results showed that 7-Mif reversed IL-1ß-induced NF-κB activation and p65 translocation to the nucleus, therefore inhibiting endothelial cell inflammation. In addition, we confirmed that 7-Mif 10 mg/kg and 20 mg/kg reduced LPS-induced ICAM-1 (47.3% ± 1.3% and 39.0% ± 3.2%, respectively) and VCAM-1 (56.5 ± 2.8% and 47.8 ± 4.3%, respectively) expression and attenuated inflammatory injury in mice. In conclusion, we showed the inhibitory effect of 7-Mif on endothelial inflammation by suppressing the expression of endothelial adhesion molecules and monocyte adhesion. Our data illustrated that 7-Mif could positively regulate the process of endothelial inflammation.
Assuntos
Flavonas/farmacologia , Molécula 1 de Adesão Intercelular , Molécula 1 de Adesão de Célula Vascular , Animais , Adesão Celular , Células Cultivadas , Células Endoteliais , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , NF-kappa B/metabolismo , RNA Mensageiro/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Isopropoxy benzene guanidine (IBG) is a novel substituted benzene guanidine analogue with antibacterial activity against multidrug-resistant bacteria. However, the bioavailability of IBG is not optimal due to its finite aqueous solubility, thus hampering its potential therapeutic exploitation. In this study, we prepared IBG/hydroxypropyl-ß-CD (IBG/HP-ß-CD) complex, and characterized it by differential scanning calorimetry, Fourier transform infrared spectroscopy, powder X-ray diffraction, and scanning electron microscopy. Physicochemical characterization indicated that the crystal morphology of IBG transformed into an amorphous state, thus forming IBG/HP-ß-CD inclusion complexes. Complexation with HP-ß-CD significantly improve the aqueous solubility, pharmaceutical properties, absorption, and bioavailability of IBG.
Assuntos
Benzeno , beta-Ciclodextrinas , 2-Hidroxipropil-beta-Ciclodextrina , Disponibilidade Biológica , Guanidina , Guanidinas , Água , beta-Ciclodextrinas/químicaRESUMO
Plasmid-borne colistin resistance mediated by mcr-1 is a growing problem, which poses a serious challenge to the clinical application of colistin for Gram-negative bacterial infections. Drug combination is one of the effective strategies to treat colistin-resistant bacteria. Here, we found a guanidine compound, namely, isopropoxy benzene guanidine (IBG), which boosted the efficacy of colistin against mcr-1-positive Salmonella. This study aimed to develop a pharmacokinetics/pharmacodynamics (PK/PD) model by combining colistin with IBG against mcr-1-positive Salmonella in an intestinal infection model. Antibiotic susceptibility testing, checkerboard assays and time-kill curves were used to investigate the antibacterial activity of the synergistic activity of the combination. PK studies of colistin in the intestine were determined through oral gavage of single dose of 2, 4, 8, and 16 mg/kg of body weight in broilers with intestinal infection. On the contrary, PD studies were conducted over 24 h based on a single dose ranging from 2 to 16 mg/kg. The inhibitory effect I max model was used for PK/PD modeling. The combination of colistin and IBG showed significant synergistic activity. The AUC0-24h /MIC index was used to evaluate the relationship between PK and PD, and the correlation was >0.9085. The AUC0-24h /MIC targets in combination required to achieve the bacteriostatic action, 3-log10 kill, and 4-log10 kill of bacterial counts were 47.55, 865.87, and 1894.39, respectively. These results can facilitate the evaluation of the use of IBG as a potential colistin adjuvant in the treatment of intestinal diseases in broilers caused by colistin-resistant Salmonella.
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Doxorubicin (DOX), a commonly used antitumor agent, is often accompanied by its dosage-dependent cardiotoxicity, which incorporates ferroptosis in its pathogenesis. Protein arginine methyltransferase 4 (PRMT4) is a transcription regulator involved in the modulation of oxidative stress and autophagy, but its role in DOX-induced cardiomyopathy (DIC) and ferroptosis remains elusive. Herein, we aimed to investigate the involvement and the underlying mechanisms of PRMT4 in the pathogenesis of DIC. Our present study revealed that the expression level of PRMT4 was markedly decreased in DOX-treated cardiomyocytes. Interestingly, it is noted that PRMT4 overexpression accelerated ferroptosis to aggravate DIC, while its gene disruption or pharmaceutical inhibition exhibited the opposite effect. Mechanistically, our observation demonstrated that PRMT4 interacted with the nuclear factor erythroid 2-related factor 2 (Nrf2) to promote its enzymatic methylation, which restricted the nuclear translocation of Nrf2 and subsequently suppressed the transcription of glutathione peroxidase 4 (GPX4). Importantly, the detrimental role of PRMT4 in DOX-induced cardiomyocyte ferroptosis was abolished by Nrf2 activation or Fer-1 administration. Collectively, our data reveal that PRMT4 inhibits Nrf2/GPX4 signaling to accelerate ferroptosis in DIC, suggesting that targeting PRMT4 may present as a potential preventive strategy against the development of DIC.
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Antineoplásicos , Cardiomiopatias , Ferroptose , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Proteína-Arginina N-Metiltransferases , Humanos , Antineoplásicos/efeitos adversos , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/genética , Doxorrubicina/toxicidade , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Proteína-Arginina N-Metiltransferases/metabolismoRESUMO
The major clinical consequences of atherosclerosis such as myocardial infarction or stroke are because of thrombotic events associated with acute rupture or erosion of an unstable plaque. Here, we identify an lncRNA Noncoding Repressor of NFAT (Nron) as a critical regulator of atherosclerotic plaque stability. Nron overexpression (OE) in vascular smooth muscle cells (VSMC) induces a highly characteristic architecture of more-vulnerable plaques, while Nron knockdown (KD) suppresses the development of atherosclerosis and favors plaque stability. Mechanistically, Nron specifically binds to and negatively regulates NFATc3, thus inhibiting the proliferation and promoting the apoptosis of VSMCs. Moreover, we also provide evidence that Nron increases the production and secretion of VEGFA from VSMCs, which functions as a paracrine factor to enhance intra-plaque angiogenesis. All of these effects contribute to plaque instability. Genetic or pharmacological inhibition of Nron may have potential for future therapy of atherosclerosis.
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Deciphering the molecular and cellular processes involved in foam cell formation is critical for us to understand the pathogenesis of atherosclerosis. Nuclear factor of activated T cells (NFAT) is a transcription factor originally identified as a key player in the differentiation of T cells and maturation of immune system. Nowadays it has been brought into attention that NFAT also regulates multiple pathophysiological processes and targeted intervention in NFAT may be effective in the treatment of some cardiovascular diseases. However, whether NFAT is involved in foam cell formation remains elusive. NFAT in human monocyte-derived macrophage was activated by ox-LDL and translocated from the cytoplasm to the nucleus. NFAT then directly bound to peroxisome proliferator-activated receptor γ (PPARγ) in the nucleus and negatively regulated its transcriptional activity. NFATc2 knockdown or NFAT inhibitor 11R-VIVIT increased cholesterol efflux (by activating PPARγ-LXRα-ABCA1 cascade) and reduced the uptake of modified lipoprotein (in a PPARγ-independent way) in macrophage, thus prevented foam cell formation. Besides, 11R-VIVIT also exerted a protective role in the development of atherosclerosis in western diet-fed ApoE-/- mice. These results suggest NFAT inhibition as a potential therapeutic strategy in atherosclerosis.
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Aterosclerose/prevenção & controle , Dieta/efeitos adversos , Células Espumosas/citologia , Fatores de Transcrição NFATC/antagonistas & inibidores , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/etiologia , Aterosclerose/metabolismo , Núcleo Celular/metabolismo , Colesterol/metabolismo , Humanos , Lipoproteínas LDL/farmacologia , Macrófagos , Masculino , Camundongos , Fatores de Transcrição NFATC/metabolismo , PPAR gama/antagonistas & inibidores , PPAR gama/metabolismoRESUMO
Sleep problems have been demonstrated to cause mental symptoms, such as anxiety. However, research on the association of the night sleep duration and sleep initiation time on anxiety symptoms in rural China is still lacking. The current study, therefore, explored the independent and combined association of the night sleep duration and sleep initiation time on anxiety symptoms. This study included 28, 054 participants from the Henan Rural Cohort. Sleep was measured using the Pittsburgh Sleep Quality Index (PSQI). Anxiety was assessed by the two-item Generalized Anxiety Disorder scale (GAD-2). Multivariable logistic regression models and restricted cubic spline with anxiety symptoms as a dependent variable were fitted. Among the participants in this study, 11, 209 (39.96%) were males, and 16,845 (60.04%) were females, 1574 (5.61%) had anxiety symptoms. Both shorter and longer night sleep duration were significantly related to elevated prevalence of anxiety symptoms. Extreme sleep initiation time was also significantly associated with elevated anxiety symptoms. Additionally, night sleep duration and sleep initiation time had a combined effect on the prevalent anxiety symptoms. In conclusion, there was a dose-response association of night sleep duration and sleep initiation time with anxiety among Chinese rural population. Moreover, they might jointly increase the odds of prevalent anxiety.
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Ansiedade/etiologia , Povo Asiático/psicologia , Distúrbios do Início e da Manutenção do Sono/psicologia , Fatores de Tempo , Adulto , Ansiedade/epidemiologia , Ansiedade/etnologia , China/epidemiologia , Cognição , Estudos de Coortes , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , População Rural , Sono/fisiologia , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Distúrbios do Início e da Manutenção do Sono/etnologia , Adulto JovemRESUMO
OBJECTIVE: Coal miners are exposed to polycyclic aromatic hydrocarbons (PAHs), a group of neurotoxicants formed and released during incomplete combustion of coal. High levels of anxiety and depression have been reported in coal miners, but little is known about neurobehavioral functions in populations that are occupationally exposed to PAHs. We tested neurobehavioral performance in coal miners and correlated it with levels of urinary markers of PAH exposure. METHODS: Levels of urinary PAH metabolites were measured in 652 male coal miners as an indicator of exposure. Subjects were divided into a high-exposure group and a low-exposure group based on the median level of total PAH metabolites. A neurobehavioral core test battery and a questionnaire were used to assess neurobehavioral performance and collect demographic information, respectively. RESULTS: The median level of total PAH metabolites in urine was 4.88 µmol/mol creatinine. Highly exposed workers exhibited more fatigue-inertia than less-exposed workers (p < 0.05), and had lower scores in forward digit span, digit symbol, and Benton visual retention tests (p < 0.05). Multiple linear regression indicated that age, education, and shift work were significantly correlated with test scores. CONCLUSIONS: PAH exposure may be associated with neurobehavioral alterations, which should be monitored in coal miners to prevent neurobehavioral disorders.