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Xanthoxylin, a bioactive phenolic compound extracted from the traditional herbal medicine Penthorum Chinense Pursh, is renowned for its anti-inflammatory effects. While previous studies have highlighted the anti-inflammatory and antioxidant properties of Xanthoxylin, its precise mechanisms, particularly concerning immune response and organ protection, remain underexplored. This study aimed to elucidate the effects of Xanthoxylin on inflammation and associated signaling pathways in a mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). ALI was induced via intratracheal administration of LPS, followed by intraperitoneal injections of Xanthoxylin at doses of 1, 2.5, 5, and 10 mg/kg, administered 30 min post-LPS exposure. Lung tissues were harvested for analysis 6 h after LPS challenge. Xanthoxylin treatment significantly mitigated lung tissue damage, pathological alterations, immune cell infiltration, and the production of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Additionally, Xanthoxylin modulated the expression of key proteins in the protein kinase B (Akt)/hypoxia-inducible factor 1-alpha (HIF-1α)/nuclear factor-kappa B (NF-κB) signaling pathway, as well as nuclear factor erythroid 2-related factor 2 (Nrf2) and oxidative markers such as superoxide dismutase (SOD) and malondialdehyde (MDA) in the context of LPS-induced injury. This study demonstrates that Xanthoxylin exerts protective and anti-inflammatory effects by down-regulating and inhibiting the Akt/HIF-1α/NF-κB pathways, suggesting its potential as a therapeutic target for the prevention and treatment of ALI or acute respiratory distress syndrome (ARDS).
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Lesión Pulmonar Aguda , Subunidad alfa del Factor 1 Inducible por Hipoxia , Lipopolisacáridos , Factor 2 Relacionado con NF-E2 , FN-kappa B , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Animales , Lipopolisacáridos/efectos adversos , Lipopolisacáridos/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , FN-kappa B/metabolismo , Ratones , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/metabolismo , Lesión Pulmonar Aguda/patología , Transducción de Señal/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Estrés Oxidativo/efectos de los fármacosRESUMEN
In recent years, gene therapy has been made possible with the success of nucleic acid drugs against sepsis and its related organ dysfunction. Therapeutics based on nucleic acids such as small interfering RNAs (siRNAs), microRNAs (miRNAs), messenger RNAs (mRNAs), and plasmid DNAs (pDNAs) guarantee to treat previously undruggable diseases. The advantage of nucleic acid-based therapy against sepsis lies in the development of nanocarriers, achieving targeted and controlled gene delivery for improved efficacy with minimal adverse effects. Entrapment into nanocarriers also ameliorates the poor cellular uptake of naked nucleic acids. In this study, we discuss the current state of the art in nanoparticles for nucleic acid delivery to treat hyperinflammation and apoptosis associated with sepsis. The optimized design of the nanoparticles through physicochemical property modification and ligand conjugation can target specific organs-such as lung, heart, kidney, and liver-to mitigate multiple sepsis-associated organ injuries. This review highlights the nanomaterials designed for fabricating the anti-sepsis nanosystems, their physicochemical characterization, the mechanisms of nucleic acid-based therapy in working against sepsis, and the potential for promoting the therapeutic efficiency of the nucleic acids. The current investigations associated with nanoparticulate nucleic acid application in sepsis management are summarized in this paper. Noteworthily, the potential application of nanotherapeutic nucleic acids allows for a novel strategy to treat sepsis. Further clinical studies are required to confirm the findings in cell- and animal-based experiments. The capability of large-scale production and reproducibility of nanoparticle products are also critical for commercialization. It is expected that numerous anti-sepsis possibilities will be investigated for nucleic acid-based nanotherapeutics in the future.
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Nanopartículas , Ácidos Nucleicos , Sepsis , Sepsis/tratamiento farmacológico , Sepsis/terapia , Humanos , Ácidos Nucleicos/uso terapéutico , Ácidos Nucleicos/administración & dosificación , Animales , Nanopartículas/química , Terapia Genética/métodos , Insuficiencia Multiorgánica/terapia , Insuficiencia Multiorgánica/tratamiento farmacológico , Técnicas de Transferencia de GenRESUMEN
Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome (ARDS), are characterized by uncontrolled inflammatory responses, neutrophil activation and infiltration, damage to the alveolar capillary membrane, and diffuse alveolar injury. Neutrophil extracellular traps (NETs), formed by activated neutrophils, contribute significantly to various inflammatory disorders and can lead to tissue damage and organ dysfunction. Corilagin, a compound found in Phyllanthus urinaria, possesses antioxidative and anti-inflammatory properties. In this study, we investigated the protective effects and underlying mechanisms of corilagin in hydrochloric acid (HCl)/lipopolysaccharide (LPS)-induced lung injury. Mice received intraperitoneal administration of corilagin (2.5, 5, or 10 mg/kg) or an equal volume of saline 30 min after intratracheal HCl/LPS administration. After 20 h, lung tissues were collected for analysis. Corilagin treatment significantly mitigated lung injury, as evidenced by reduced inflammatory cell infiltration, decreased production of proinflammatory cytokines, and alleviated oxidative stress. Furthermore, corilagin treatment suppressed neutrophil elastase expression, reduced NET formation, and inhibited the expression of ERK, p38, AKT, STAT3, and NOX2. Our findings suggest that corilagin inhibits NET formation and protects against HCl/LPS-induced ALI in mice by modulating the STAT3 and NOX2 signaling pathways.
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This study aimed to investigate network-level brain functional changes in breast cancer patients and their relationship with fear of cancer recurrence (FCR). Resting-state functional MRI was collected from 43 patients with breast cancer and 40 healthy controls (HCs). Graph theory analyses, whole-brain voxel-wise functional connectivity strength (FCS) analyses and seed-based functional connectivity (FC) analyses were performed to identify connection alterations in breast cancer patients. Correlations between brain functional connections (i.e. FCS and FC) and FCR level were assessed to further reveal the neural mechanisms of FCR in breast cancer patients. Graph theory analyses indicated a decreased clustering coefficient in breast cancer patients compared to HCs (P = 0.04). Patients with breast cancer exhibited significantly higher FCS in both higher-order function networks (frontoparietal, default mode, and dorsal attention systems) and primary somatomotor networks. Among the hyperconnected regions in breast cancer, the left inferior frontal operculum demonstrated a significant positive correlation with FCR. Our findings suggest that breast cancer patients exhibit less segregation of brain function, and the left inferior frontal operculum is a key region associated with FCR. This study offers insights into the neural mechanisms of FCR in breast cancer patients at the level of brain connectome.
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Neoplasias Encefálicas , Neoplasias de la Mama , Conectoma , Humanos , Femenino , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias Encefálicas/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , MiedoRESUMEN
Stachydrine, a prominent bioactive alkaloid derived from Leonurus heterophyllus, is a significant herb in traditional medicine. It has been noted for its anti-inflammatory and antioxidant characteristics. Consequently, we conducted a study of its hepatoprotective effect and the fundamental mechanisms involved in acetaminophen (APAP)-induced liver injury, utilizing a mouse model. Mice were intraperitoneally administered a hepatotoxic dose of APAP (300 mg/kg). Thirty minutes after APAP administration, mice were treated with different concentrations of stachydrine (0, 2.5, 5, and 10 mg/kg). Animals were sacrificed 16 h after APAP injection for serum and liver tissue assays. APAP overdose significantly elevated the serum alanine transferase levels, hepatic pro-inflammatory cytokines, malondialdehyde activity, phospho-extracellular signal-regulated kinase (ERK), phospho-protein kinase B (AKT), and macrophage-stimulating protein expression. Stachydrine treatment significantly decreased these parameters in mice with APAP-induced liver damage. Our results suggest that stachydrine may be a promising beneficial target in the prevention of APAP-induced liver damage through attenuation of the inflammatory response, inhibition of the ERK and AKT pathways, and expression of macrophage-stimulating proteins.
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Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Enfermedad Hepática Inducida por Sustancias y Drogas , Prolina , Animales , Ratones , Acetaminofén/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hígado/metabolismo , Macrófagos/metabolismo , Estrés Oxidativo , Prolina/análogos & derivados , Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Factor Estimulante de Colonias de Macrófagos/efectos de los fármacos , Factor Estimulante de Colonias de Macrófagos/metabolismoRESUMEN
PURPOSE: Delayed awakening after anesthetic discontinuation during awake craniotomy is associated with somnolence during functional brain mapping. However, predictors of delayed awakening in patients receiving monitored anesthesia care for awake craniotomy are unknown. METHODS: This retrospective cohort study analyzed 117 adult patients with supratentorial glioma in or near eloquent areas who received monitored anesthesia care for awake craniotomy between July 2020 and January 2023 at Linkou Chang Gung Memorial Hospital. These patients were divided into two groups according to their time to awakening (ability to speak their names) after propofol cessation: longer or shorter than 20 min (median duration). Because propofol was solely used anesthetic from skin incision to dural opening, parameters in Schnider model for propofol target-controlled infusion, such as age, sex, and BMI, were adjusted or propensity-matched to compare their anesthetic, surgical, and histopathological profiles. RESULTS: After propensity-matched comparisons of age and BMI, significant predictors of delayed awakening included IDH1 wild-type tumors and repeated craniotomies. Subgroup analysis revealed that older age and larger T2 volume were predictors in patients undergoing the first craniotomy, while lower preoperative Karnofsky performance scale scores and depression were predictors in repeated craniotomy cases. Delayed awakening was also associated with somnolence and a lower gross total resection rate. CONCLUSION: Our retrospective analysis of patients receiving monitored anesthesia care for awake craniotomy revealed that delayed awakening after propofol discontinuation occurred more often in patients with IDH1 wild-type tumors and repeated craniotomies. Also, delayed awakening was associated with somnolence during functional mapping and a lower gross total resection rate.
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Anestesia , Anestésicos , Neoplasias Encefálicas , Glioma , Propofol , Humanos , Adulto , Estudios Retrospectivos , Vigilia , Somnolencia , Glioma/cirugía , Glioma/patología , Craneotomía , Neoplasias Encefálicas/cirugía , Neoplasias Encefálicas/patologíaRESUMEN
Recent experimental studies have highlighted the beneficial effects of curcumin on liver injury induced by acetaminophen (APAP). However, the specific molecular mechanisms underlying curcumin's hepatoprotective effects against APAP-induced liver injury remain to be fully elucidated. This study aimed to investigate the therapeutic effect of curcumin on APAP-induced liver injury using a mouse model. In the experiment, mice were subjected to an intraperitoneal hepatotoxic dose of APAP (300 mg/kg) to induce hepatotoxicity. After 30 min of APAP administration, the mice were treated with different concentrations of curcumin (0, 10, 25, or 50 mg/kg). After 16 h, mice with hepatotoxicity showed elevated levels of serum alanine transaminase (ALT), aspartate transaminase (AST), hepatic myeloperoxidase (MPO), TNF-α, and IL-6, and decreased levels of glutathione (GSH). Moreover, there was an increased infiltration of neutrophils and macrophages following intraperitoneal injection of APAP. However, curcumin-treated mice displayed a pronounced reduction in serum ALT, AST, hepatic MPO, TNF-α, and IL-6 levels, coupled with a notable elevation in GSH levels compared to the APAP-treated hepatotoxic mice. Moreover, curcumin treatment led to reduced infiltration of neutrophils and macrophages. Additionally, curcumin inhibited the phosphorylation of ERK and NF-kB proteins while reducing the expression of cyclooxygenase-2 (COX-2). These findings highlight the hepatoprotective potential of curcumin against APAP-induced liver injury through the suppression of the ERK, NF-kB, and COX-2 signaling pathways.
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BACKGROUND: During biological aging, significant metabolic dysregulation in the central nervous system may lead to cognitive decline and neurodegeneration. However, the metabolomics of the aging process in cerebrospinal fluid (CSF) has not been thoroughly explored. METHODS: In this cohort study of CSF metabolomics using liquid chromatography-mass spectrometry (LC-MS), fasting CSF samples collected from 92 cognitively unimpaired adults aged 20-87 years without obesity or diabetes were analyzed. RESULTS: We identified 37 metabolites in these CSF samples with significant positive correlations with aging, including cysteine, pantothenic acid, 5-hydroxyindoleacetic acid (5-HIAA), aspartic acid, and glutamate; and two metabolites with negative correlations, asparagine and glycerophosphocholine. The combined alterations of asparagine, cysteine, glycerophosphocholine, pantothenic acid, sucrose, and 5-HIAA showed a superior correlation with aging (AUC = 0.982). These age-correlated changes in CSF metabolites might reflect blood-brain barrier breakdown, neuroinflammation, and mitochondrial dysfunction in the aging brain. We also found sex differences in CSF metabolites with higher levels of taurine and 5-HIAA in women using propensity-matched comparison. CONCLUSIONS: Our LC-MS metabolomics of the aging process in a Taiwanese population revealed several significantly altered CSF metabolites during aging and between the sexes. These metabolic alterations in CSF might provide clues for healthy brain aging and deserve further exploration.
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Envejecimiento , Cromatografía Liquida , Cisteína , Metaboloma , Espectrometría de Masas en Tándem , Femenino , Humanos , Masculino , Envejecimiento/líquido cefalorraquídeo , Envejecimiento/metabolismo , Asparagina/líquido cefalorraquídeo , Cromatografía Liquida/métodos , Estudios de Cohortes , Cisteína/líquido cefalorraquídeo , Ácido Hidroxiindolacético/líquido cefalorraquídeo , Ácido Pantoténico/líquido cefalorraquídeo , Espectrometría de Masas en Tándem/métodos , Voluntarios Sanos , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Cognición/fisiología , Ayuno/líquido cefalorraquídeo , Ayuno/metabolismoRESUMEN
Acetaminophen (APAP) overdose causes acute liver injury via oxidative stress, uncontrolled inflammatory response, and subsequent hepatocyte death. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is a potent source of cellular reactive oxygen species (ROS) and may contribute to oxidative stress in many inflammatory processes. Corilagin, a component of Phyllanthus urinaria, possesses antioxidant, anti-inflammatory, and hepatoprotective effects. We evaluated the mechanisms underlying the protective effect of corilagin against acetaminophen-induced liver injury. Mice were intraperitoneally administrated 300 mg/kg APAP or equal volume of saline (control), with or without various concentrations of corilagin (0, 1, 5, or 10 mg/kg) administered after 30 min. All animals were sacrificed 16 h after APAP administration, and serum and liver tissue assays including histology, immunohistochemistry, and Western blot assay were performed. Corilagin post-treatment significantly attenuated APAP-induced liver injury (p < 0.005), inflammatory cell infiltration, hepatic proinflammatory cytokine levels, and hepatic oxidative stress. Furthermore, corilagin attenuated the protein levels of NOX1, NOX2, signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B (NF-κB) in APAP-induced liver injury. These results indicated that the antioxidant, anti-inflammatory, and protective effects of corilagin in APAP-induced liver injury might involve the regulation of interleukin (IL)-6/STAT3 and mitogen-activated protein kinase (MAPK)/NF-κB signaling pathways through NOX-derived ROS.
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PURPOSE: This prospective study investigated the preventive effect of transcutaneous electrical nerve stimulation (TENS) for postoperative thirst. DESIGN: This experimental study was conducted with the CONSORT checklist. METHODS: A total of 105 surgical patients who received general anesthesia were recruited from a medical center. Each patient was randomly assigned to the experimental group (n = 53; 20 min of TENS) or the control group (n = 52; routine care). In each group, oral moisture wetness was measured at 1 min, 20 min, and 50 min post-surgery. Descriptive and inferential statistics (Chi-square test, t test, one-way ANOVA, and generalized estimating equation (GEE) regression analysis) were performed to assess the proposed relationships. FINDINGS: The two groups showed similar characteristics at baseline. The oral moisture wetness was significantly higher in the experimental group than the control group at each post-surgery assessment time (all P < .001). The GEE results showed that patients in the experimental group reported more oral moisture wetness than patients in the control group. CONCLUSIONS: This study demonstrated that TENS can reduce thirst reported by patients after general anesthesia. Thus, this method may have clinical applications for managing postoperative thirst.
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Estimulación Eléctrica Transcutánea del Nervio , Humanos , Estimulación Eléctrica Transcutánea del Nervio/métodos , Estudios Prospectivos , SedRESUMEN
Diabetic kidney disease (DKD) is the major cause of end stage renal disease in patients with type 2 diabetes mellitus (T2DM). The subtle metabolic changes in plasma and cerebrospinal fluid (CSF) might precede the development of DKD by years. In this longitudinal study, CSF and plasma samples were collected from 28 patients with T2DM and 25 controls, during spinal anesthesia for elective surgery in 2017. These samples were analyzed using liquid chromatography-mass spectrometry (LC-MS) in 2017, and the results were correlated with current DKD in 2017, and the development of new-onset DKD, in 2021. Comparing patients with T2DM having new-onset DKD with those without DKD, revealed significantly increased CSF tryptophan and plasma uric acid levels, whereas phosphatidylcholine 36:4 was lower. The altered metabolites in the current DKD cases were uric acid and paraxanthine in the CSF and uric acid, L-acetylcarnitine, bilirubin, and phosphatidylethanolamine 38:4 in the plasma. These metabolic alterations suggest the defective mitochondrial fatty acid oxidation and purine and phospholipid metabolism in patients with DKD. A correlation analysis found CSF uric acid had an independent positive association with the urine albumin-to-creatinine ratio. In conclusion, these identified CSF and plasma biomarkers of DKD in diabetic patients, might be valuable for monitoring the DKD progression.
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Ovarian cancer is the second most common cause of death from gynecologic cancer. The aim of this study was to estimate the incidence of ovarian cancer and the trend of mortality in different histological subtypes of ovarian cancer in Taiwan. Patient information regarding ovarian cancer was provided by the Taiwan National Health Insurance database. The histological subtypes of ovarian cancer were retrieved from the Taiwan Cancer Registry database, while the survival rates were extracted from the National Death Registry database. In this population-based cohort study, the annual prevalence, incidence, and overall mortality of ovarian cancer during 2002-2015 were determined. The trend in the incidence and the mortality rate of different histologic subtypes were estimated using joinpoint regression analysis. It was found that age-standardized incidence of ovarian cancer increased from 9.46 in 2002 to 11.92 per 100,000 person-years in 2015, with an average annual percentage change of 2.0 (95% CI = 1.5-2.5). The 1-, 3-, and 5-year mortality rates of overall ovarian cancer declined progressively during the study period, especially the group of Charlson comorbidity index ≤ 1. Ovarian serous carcinoma was the most common histological subtype in Taiwan, comprising 30.9% of ovarian cancer patients in 2002-2015. This study provides valuable information for use in developing healthcare policies for ovarian cancer.
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BACKGROUND: In previous literature, reference values for cerebrospinal fluid (CSF) may be based on patients who were not truly healthy, other species, or outdated information. In the present study, we performed a lumbar puncture in patients requiring spinal anesthesia by a reasonable indication to evaluate CSF parameters in healthy adults. METHODS: All patients between the ages of 20 and 70 years scheduled for elective orthopedic or urologic surgery requiring spinal anesthesia were enrolled in this study. We measured electrolytes and gas tension analysis in CSF and whole blood samples in adult humans. RESULTS: A total of 28 patients were included with an average age of 44.2 years. The concentration of Na^+ in blood was slightly lower when compared with that in CSF. There were significantly higher levels of K^+ and Ca^(2+) in the blood when we compared with CSF. Significantly lower levels of Cl^- and Mg^(2+) in the blood were observed when compared with CSF. The glucose level of CSF was about half of that in blood. CONCLUSIONS: We provided updated reference values for various solutes in blood and CSF in adults. Analysis of CSF parameters and relevant paired blood samples is highly informative, helping clinicians diagnose a variety of central nervous system diseases.
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Anestesia Raquidea , Punción Espinal , Humanos , Adulto , Adulto Joven , Persona de Mediana Edad , Anciano , Electrólitos/líquido cefalorraquídeo , Sodio , Valores de ReferenciaRESUMEN
Acute lung injury (ALI) and acute respiratory distress syndrome are clinically life-threatening diseases. Corilagin, a major polyphenolic compound obtained from the herb Phyllanthus urinaria, has anti-inflammatory and antioxidant properties, and in this study, we sought to evaluate the protective effects and mechanisms of corilagin on lipopolysaccharide (LPS)-induced ALI in mice. ALI was induced in the mice by the intratracheal administration of LPS, and following 30 min of LPS challenge, corilagin (5 and 10 mg/kg body weight) was administered intraperitoneally. At 6 h post-LPS administration, lung tissues were collected for analysis. Corilagin treatment significantly attenuated inflammatory cell infiltration, the production of pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß, and oxidative stress in lung tissues. In addition, corilagin inhibited the LPS-induced expression of NOX2, ERK, and NF-κB. Corilagin has anti-oxidative and anti-inflammatory effects, and can effectively reduce ALI via attenuation of the NOX2 and ERK/NF-κB signaling pathways.
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The over-activated neutrophils through G-protein-coupled receptors (GPCRs) caused inflammation or tissue damage. Therefore, GPCRs or their downstream molecules are major targets for inhibiting uncontrolled neutrophil activation. Our studies investigate the action and underlying mechanism of larixol, a diterpene extract from the root of euphorbia formosana, on fMLP-induced neutrophil respiratory burst, chemotaxis, and granular release. The immunoprecipitation assay was performed to investigate whether larixol inhibits fMLP-induced respiratory burst by interfering with the interaction of fMLP receptor Gi-protein ßγ subunits with its downstream molecules. Briefly, larixol inhibited fMLP (0.1 µM)-induced superoxide anion production (IC50:1.98 ± 0.14 µM), the release of cathepsin G (IC50:2.76 ± 0.15 µM) and chemotaxis in a concentration-dependent manner; however, larixol did not inhibit these functions induced by PMA (100 nM). Larixol inhibited fMLP-induced Src kinase phosphorylation. Therefore, larixol attenuated the downstream signaling of Src kinases, ERK1/2, p38, and AKT phosphorylation. Moreover, larixol inhibited fMLP-induced intracellular calcium mobilization, PKC phosphorylation, and p47phox translocation from the cytosol to the plasma membrane. Larixol inhibited the interaction of the ßγ subunits of Gi-protein of fMLP receptor with Src kinase or with PLCß by the immunoprecipitation and duolink assay. Furthermore, larixol did not antagonize the formyl peptide receptors. Larixol did not increase cyclic nucleotide levels in neutrophils. These results suggest that larixol modulated fMLP-induced neutrophils superoxide anion production, chemotaxis, and granular releases by interrupting the interaction of the ßγ subunits of Gi-protein with downstream signaling of the fMLP receptor.
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Diterpenos , Receptores de Formil Péptido , Quimiotaxis , Humanos , N-Formilmetionina Leucil-Fenilalanina/metabolismo , N-Formilmetionina Leucil-Fenilalanina/farmacología , NADPH Oxidasas/metabolismo , Neutrófilos/metabolismo , Fosforilación , Receptores de Formil Péptido/metabolismo , Superóxidos/metabolismo , Familia-src Quinasas/metabolismoRESUMEN
Gastrodin is a major active phenolic glycoside extract from Gastrodia elata, an important herb used in traditional medicine. Previous research has reported that gastrodin possesses anti-inflammatory and anti-oxidant properties. Therefore, we aimed to investigate its hepatoprotective effects and mechanisms on acetaminophen (APAP)-induced liver injury in a mouse model. Mice included in this study were intraperitoneally administered with a hepatotoxic APAP dose (300 mg/kg). At 30 min after APAP administration, gastrodin was intraperitoneally injected at concentrations of 0, 15, 30, and 45 mg/kg. Then, all mice were sacrificed at 16 h after APAP injection for further analysis. The results showed that gastrodin treatment ameliorated acute liver injury caused by APAP, as indicated by serum alanine aminotransferase level, hepatic myeloperoxidase activity, and cytokine (TNF-α, IL-1ß, and IL-6) production. It also significantly decreased hepatic malondialdehyde activity but increased superoxide dismutase activity. In addition, gastrodin decreased ERK/JNK MAPK expression but promoted Nrf2 expression. These results demonstrated that gastrodin may be a potential therapeutic target for the prevention of APAP-induced hepatotoxicity via amelioration of the inflammatory response and oxidative stress, inhibition of ERK/JNK MAPK signaling pathways, and activation of Nrf2 expression levels.
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Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Enfermedad Hepática Inducida por Sustancias y Drogas , Acetaminofén , Animales , Antioxidantes/farmacología , Alcoholes Bencílicos , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Modelos Animales de Enfermedad , Glucósidos , Hígado/metabolismo , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Estrés OxidativoRESUMEN
The molecular process of biological aging might be accompanied by significant metabolic derangement, especially in the central nervous system (CNS), since the brain has an enormous energy demand. However, the metabolic signature of the aging process in cerebrospinal fluid (CSF) has not been thoroughly investigated, especially in the Asian population. In this prospective cohort study on CSF metabolomics using proton nuclear magnetic resonance (NMR) spectroscopy, fasting CSF samples from 75 cognitively unimpaired patients aged 20-92 years without diabetes or obesity, undergoing spinal anesthesia for elective surgery were analyzed. Several metabolites in CSF samples were identified as having a significant association with the aging process in cerebral circulation; among the metabolites, the levels of alanine, citrate, creatinine, lactate, leucine, tyrosine, and valine significantly increased in old patients compared to those in young patients. The combined CSF metabolite alterations in citrate, lactate, leucine, tyrosine, and valine had a superior correlation with the aging process in all age groups. In conclusion, our pilot study of aging CSF metabolomics in the Taiwanese population presents significantly altered CSF metabolites with potential relevance to the aging process. These metabolic alterations in CSF samples might imply increasing anaerobic glycolysis, mitochondrial dysfunction, and decreasing glucose utilization in cerebral circulation in aged patients.
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BACKGROUND: Diabetes mellitus (DM) has detrimental effects on the function of microvascular beds, resulting in blood-brain barrier (BBB) dysfunction. The objective of the study was to investigate whether DM affects the brain physiology through composition of cerebrospinal fluid (CSF) and compare gas tension and electrolyte levels in CSF between the diabetic and nondiabetic populations. METHODS: Patients aged between 20 and 70 years scheduled for elective orthopedic or urologic surgery requiring spinal anesthesia were enrolled. They were assigned to either of the two groups (control or type 2 DM). Gas tension and electrolytes in the CSF and whole blood samples were measured in both groups. RESULTS: All 49 enrolled patients (24 in the control and 25 in the DM group) completed the study. The concentrations of Na+ and Mg2+ in the blood were significantly lower in the DM group than those in the control. The levels of pCO2 and HCO 3 - in the CSF were lower in the DM group than in the control group. In addition, there was a marked increase in the glucose level in both the blood and CSF in the DM group. CONCLUSION: The results show that there were some homeostatic changes in blood and CSF in patients with DM.
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Acetaminophen (APAP) overdose is the major cause of drug-induced liver injury and acute liver failure. Approximately 10% of APAP is metabolized by cytochrome P450 (CYP2E1) into toxic N-acetyl-p-benzoquinone imine (NAPQI). CYP2E1 also contributes to ethanol metabolism, especially during conditions of high blood ethanol concentration. Acute and chronic ethanol consumption appears to have opposite effects on APAP-induced liver injury. We determined the effects of different doses, pre- and post-treatment, and various schedules of ethanol exposure in APAP-induced liver injury. Treatment with ethanol (0.5 g/kg) after 1 h of APAP (300 mg/kg) administration decreased serum ALT levels, histopathological features, and inflammatory cell infiltration. Moreover, ethanol treatment 1 h after APAP treatment reduced APAP-induced liver injury compared with later administration. Interestingly, ethanol pretreatment did not provide any protective effect. Furthermore, ethanol treatment was associated with a significant decrease in ERK and AKT phosphorylation during the acute injury phase. Ethanol exposure also increased CYP2E1 expression and decreased PCNA expression during the liver regeneration phase.