stilbenes and Sepsis

Our previous study confirmed that polydatin (PD) can alleviate sepsis-induced multiorgan dysfunction (in the vascular endothelium, kidney, and small intestine) by activating Sirt1 and that PD protects against traumatic brain injury in rats via increased Sirt1 and inhibition of the p38-mediated mitogen-activated protein kinase (MAPK) pathway. We aim to investigate whether PD may also attenuate sepsis-associated encephalopathy (SAE).. In this study, we constructed an SAE mouse model by cecal ligation and puncture (CLP) and measured Sirt1 protein activity, p38 phosphorylation, brain tissue pathological damage, pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), mitochondrial function (mitochondrial membrane potential, ATP content, and reactive oxygen species), neurological function, and animal survival time. Sirt1 selective inhibitor Ex527 and p38 inhibitor SB203580 were used to explore the possible mechanism of PD in SAE.. We confirmed that PD inhibits neuroinflammation evidenced by reduced proinflammatory cytokines. In addition, PD protects mitochondria as demonstrated by restored mitochondrial membrane potential and adenosine triphosphate (ATP) content, and decreased reactive oxygen species (ROS) level. As we expected, p38 inhibition reduces neuroinflammation and mitochondrial damage. In contrast, Sirt1 inhibition aggravates cerebral cortex mitochondrial damage and neuroinflammation and promotes phosphorylation of p38. Mechanistically, PD treatment suppressed p38 phosphorylation and consequently reduced the neuroinflammatory response, and these effects were blocked by the Sirt selective inhibitor Ex527.. This study, to the best of our knowledge, is the first to demonstrate that PD alleviates SAE, at least partially, by upregulating Sir1-mediated neuroinflammation inhibition and mitochondrial function protection.

Topics: Adenosine Triphosphate; Animals; Cytokines; Glucosides; Mice; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Reactive Oxygen Species; Sepsis; Sepsis-Associated Encephalopathy; Sirtuin 1; Stilbenes

Our previous studies showed that silent mating-type information regulation 2 homologue-1 (SIRT1, a deacetylase) upregulation could attenuate sepsis-induced acute kidney injury (SAKI). Upregulated SIRT1 can deacetylate certain autophagy-related proteins (Beclin1, Atg5, Atg7 and LC3) in vitro. However, it remains unclear whether the beneficial effect of SIRT1 is related to autophagy induction and the underlying mechanism of this effect is also unknown. In the present study, caecal ligation and puncture (CLP)-induced mice, and an LPS-challenged HK-2 cell line were established to mimic a SAKI animal model and a SAKI cell model, respectively. Our results demonstrated that SIRT1 activation promoted autophagy and attenuated SAKI. SIRT1 deacetylated only Beclin1 but not the other autophagy-related proteins in SAKI. SIRT1-induced autophagy and its protective effect against SAKI were mediated by the deacetylation of Beclin1 at K430 and K437. Moreover, two SIRT1 activators, resveratrol and polydatin, attenuated SAKI in CLP-induced septic mice. Our study was the first to demonstrate the important role of SIRT1-induced Beclin1 deacetylation in autophagy and its protective effect against SAKI. These findings suggest that pharmacologic induction of autophagy via SIRT1-mediated Beclin1 deacetylation may be a promising therapeutic approach for future SAKI treatment.

Topics: Acetylation; Acute Kidney Injury; Animals; Autophagy; Beclin-1; Cell Line; Disease Models, Animal; Enzyme Activation; Enzyme Activators; Glucosides; Humans; Kidney Tubules, Proximal; Male; Mice, Inbred C57BL; Resveratrol; Sepsis; Signal Transduction; Sirtuin 1; Stilbenes; Time Factors

Sepsis-induced myocardial dysfunction (SIMD) represents one of the serious complications secondary to sepsis, which is a leading cause of the high mortality rate among septic cases. Subsequent cardiomyocyte apoptosis, together with the uncontrolled inflammatory response, has been suggested to be closely related to SIMD. Piceatannol (PIC) is verified with potent anti-apoptotic and anti-inflammatory effects, but its function and molecular mechanism in SIMD remain unknown so far. This study aimed to explore the potential role and mechanism of action of PIC in resisting SIMD. The interaction of PIC with JAK2 proteins was evaluated by molecular docking, molecular dynamics (MD) simulation and surface plasmon resonance imaging (SPRi). The cecal ligation and puncture-induced septicemia mice and the LPS-stimulated H9C2 cardiomyocytes were prepared as the models in vivo and in vitro, separately. Molecular docking showed that JAK2-PIC complex had the -8.279 kcal/mol binding energy. MD simulations showed that JAK2-PIC binding was stable. SPRi analysis also showed that PIC has a strong binding affinity to JAK2. PIC treatment significantly ameliorated the cardiac function, attenuated the sepsis-induced myocardial loss, and suppressed the myocardial inflammatory responses both in vivo and in vitro. Further detection revealed that PIC inhibited the activation of the JAK2/STAT3 signaling, which was tightly associated with apoptosis and inflammation. Importantly, pre-incubation with a JAK2 inhibitor (AG490) partially blocked the cardioprotective effects of PIC. Collectively, the findings demonstrated that PIC restored the impaired cardiac function by attenuating the sepsis-induced apoptosis and inflammation via suppressing the JAK2/STAT3 pathway both in septic mice and H9C2 cardiomyocytes.

Topics: Animals; Apoptosis; Cardiomyopathies; Cardiotonic Agents; Cell Line; Disease Models, Animal; Inflammation; Janus Kinase 2; Male; Mice, Inbred C57BL; Molecular Docking Simulation; Molecular Dynamics Simulation; Myocytes, Cardiac; Rats; Sepsis; Signal Transduction; STAT3 Transcription Factor; Stilbenes; Tyrphostins

We have reported that polydatin (PD) alleviates mitochondrial dysfunction in rat models of sepsis-induced acute kidney injury (SI-AKI), but the mechanism is not well understood. Here, we investigated the role of Parkin-mediated mitophagy in the protective effects of PD in SI-AKI in mice.. Sepsis was induced in the mice by caecal ligation and puncture. Mitophagy was determined by mitochondrial mass. NLRP3 inflammasome activation was determined by NLRP3, ASC and caspase-1. Mitophagy was blocked by treatment with mitochondrial division inhibitor-1 and Parkin knockout.. PD treatment increased the sepsis-induced loss of mitochondrial mass, indicating the upregulation of mitophagy. Furthermore, PD treatment mediated Parkin translocation from the cytoplasm to the mitochondria. This suggests that Parkin-mediated mitophagy is an underlying mechanism. This was confirmed by the suppression of PD-induced mitophagy in Parkin-/- mice and in mice that were treated with a mitophagy inhibitor. PD-induced Parkin translocation and mitophagy were blocked by inhibiting SIRT1; thus, activation of SIRT1 might be an important molecular mechanism that is triggered by PD. Additionally, PD treatment protected against sepsis-induced kidney injury. These effects were blocked by inhibition of Parkin-dependent mitophagy. Furthermore, PD also protected against mitochondrial dysfunction and mitochondria-dependent apoptosis, and the effect was blocked when Parkin-dependent mitophagy was inhibited. Finally, PD suppressed NLRP3 inflammasome activation that was also dependent on Parkin-mediated mitophagy.. These findings indicate that Parkin-mediated mitophagy is important for the protective effect of PD in SI-AKI, and the underlying mechanisms include the inhibition of mitochondrial dysfunction and NLRP3 inflammasome activation.

Topics: Acute Kidney Injury; Animals; Glucosides; Mice; Mitophagy; Rats; Sepsis; Stilbenes; Ubiquitin-Protein Ligases

Sepsis is a life-threatening condition. Polydatin (PD), a small natural compound from Polygonum cuspidatum, possesses antioxidant and anti-inflammatory properties. However, the protective mechanism of PD on sepsis-induced acute myocardial damage is still unclear. The aim of this study was to investigate the effect and mechanism of action of PD on lipopolysaccharide (LPS)-induced H9c2 cells and in a rat model of sepsis, and explored the role of PD-upregulated sirtuin (SIRT)6. LPS-induced H9c2 cells were used to simulate sepsis. Cecal ligation and puncture (CLP)-induced sepsis in rats were used to verify the protective effect of PD. ELISA, western blotting, immunofluorescence, immunohistochemistry, and flow cytometry were used to study the protective mechanism of PD against septic myocardial injury. PD pretreatment suppressed LPS-induced H9c2 cell apoptosis by promotion of SIRT6-mediated autophagy. Downregulation of SIRT6 or inhibition of autophagy reversed the protective effect of PD on LPS-induced apoptosis. PD pretreatment also suppressed LPS-induced inflammatory factor expression. CLP-induced sepsis in rats showed that PD pretreatment decreased CLP-induced myocardial apoptosis and serum tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 expression. 3-Methyladenine (autophagy inhibitor) pretreatment prevented the protective effect of PD on septic cardiomyopathy. SIRT6 expression was increased with PD treatment, which confirmed that PD attenuates septic cardiomyopathy by promotion of SIRT6-mediated autophagy. All these results indicate that PD has potential therapeutic effects that alleviate septic myocardial injury by promotion of SIRT6-mediated autophagy.

Topics: Animals; Autophagy; Cardiomyopathies; Cell Line; Glucosides; Lipopolysaccharides; Male; Myocardium; Rats; Rats, Sprague-Dawley; Sepsis; Sirtuins; Stilbenes

Sepsis is characterized by injury to the microvasculature and the microvascular endothelial cells, leading to barrier dysfunction. However, the specific role of injury in septic endothelial barrier dysfunction remains to be elucidated. In the present study, it was hypothesized that endothelial cell inflammatory injury is likely required for barrier dysfunction under septic conditions in vitro. 2,3,5,4'‑Tetrahydroxystilbene‑2‑O‑β‑D‑glucoside (TSG), a compound extracted from Chinese herbs, is able to inhibit the inflammatory injury of septic‑serum in endothelial cells. In the present study, cell viability was assayed by CCK‑8 method; mRNA and protein expression was identified by RT‑qPCR, western blot or Elisa, respectively and the production of reactive oxygen species was observed by a fluorescence microscope. The present study indicated that septic serum significantly decreased the cell viability of pulmonary aortic endothelial cells (PAECs) following co‑cultivation for 6 h, which occurred in a time‑dependent manner. TSG notably increased the viability of PAECs in a time‑ and concentration‑dependent manner. Further investigations revealed that septic serum increased the secretion of interleukin (IL)‑1β, IL‑6 and C‑reactive protein in PAECs, whereas pretreatment with TSG significantly decreased the secretion of these inflammatory factors. These data indicated that septic serum increased inflammatory injury to the PAECs, and TSG decreased this injury via the reactive oxygen species‑mitogen‑activated protein kinase‑nuclear factor‑κB signaling pathway.

Topics: Animals; Aorta; Cell Survival; Cells, Cultured; Cytokines; Endothelial Cells; Glucosides; Inflammation; Lung; Male; Mitogen-Activated Protein Kinases; NF-kappa B; Phosphorylation; Rats, Sprague-Dawley; Reactive Oxygen Species; RNA, Messenger; Sepsis; Signal Transduction; Stilbenes; Superoxides

BACKGROUND Resveratrol (Res) is a type of polyphenol found in many plants, which can protect important organs from the damage induced by sepsis. However, the exact mechanism of its protective effect has not been established. This study investigated the effect of Res on the PI3K/Nrf2/HO-1 signaling pathway in rats with sepsis-induced acute lung injury (ALI). MATERIAL AND METHODS Male Wistar rats were treated with 30 mg/kg Res by intraperitoneal administration for 1 hour immediately after cecal ligation and puncture. Levels of MIP-2, IL-18, and IL-10 in bronchoalveolar lavage fluid (BALF) were determined. Lung tissues were collected to measure the wet-to-dry (W/D) ratios, oxidative stress index, and lung injury scores. Expression levels of Akt, p-Akt, HO-1, Nrf-2, and active caspase-3 proteins were determined by western blotting; expression of HO-1 mRNA was determined by RT-PCR. RESULTS Treatment with Res significantly decreased the levels of MIP-2 and IL-18 and increased IL-10 in the BALF of rats with sepsis-induced ALI. In addition, Res also effectively reduced the W/D lung weight ratio, lung injury score, and the levels of MDA (malondialdehyde) and 8-OHdG. Conversely, Res increased SOD (superoxide dismutase) activity in the lung tissue. Moreover, Res significantly induced higher HO-1 mRNA expression, upregulated HO-1 and Nrf-2 protein expression, and the phosphorylation of Akt in the lung tissue. In contrast, the levels of activated caspase-3 protein were decreased in Res-treated rats (P<0.05). CONCLUSIONS Res could inhibit inflammation, oxidative stress, and cell apoptosis to alleviate ALI in septic rats through the inhibition of the PI3K/Nrf2/HO-1 signaling pathway.

Topics: Acute Lung Injury; Animals; Apoptosis; Bronchoalveolar Lavage Fluid; Chemokine CXCL2; Heme Oxygenase-1; Interleukin-10; Interleukin-18; Male; NF-E2-Related Factor 2; Oxidative Stress; Phosphatidylinositol 3-Kinase; Random Allocation; Rats; Rats, Wistar; Resveratrol; Sepsis; Signal Transduction; Stilbenes

Resveratrol, a polyphenol compound derived from various edible plants, protects against sepsis-induced acute kidney injury (AKI) via its anti-inflammatory activity, but the underlying mechanisms remain largely unknown. In this study, a rat model of sepsis was established by cecal ligation and puncture (CLP), 30 mg/kg resveratrol was intraperitoneally administrated immediately after the CLP operation. HK-2 cells treated by 1 μg/ml lipopolysaccharide, 0.2 μM tunicamycin, 2.5 mM irestatin 9389 and 20 μM resveratrol were used for in vitro study. The results demonstrated that resveratrol significantly improved the renal function and tubular epithelial cell injury and enhanced the survival rate of CLP-induced rat model of sepsis, which was accompanied by a substantial decrease of the serum content and renal mRNA expressions of TNF-α, IL-1β and IL-6. In addition, resveratrol obviously relieved the endoplasmic reticulum stress, inhibited the phosphorylation of inositol-requiring enzyme 1(IRE1) and nuclear factor-κB (NF-κB) in the kidney. In vitro studies showed that resveratrol enhanced the cell viability, reduced the phosphorylation of NF-κB and production of inflammatory factors in lipopolysaccharide and tunicamycin-induced HK-2 cells through inhibiting IRE1 activation. Taken together, administration of resveratrol as soon as possible after the onset of sepsis could protect against septic AKI mainly through inhibiting IRE1-NF-κB pathway-triggered inflammatory response in the kidney. Resveratrol might be a readily translatable option to improve the prognosis of sepsis.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents; Biomarkers; Cell Line; Cytokines; Disease Models, Animal; Endoplasmic Reticulum Stress; Humans; Inflammation Mediators; Kidney Function Tests; Lipopolysaccharides; Male; Membrane Proteins; NF-kappa B; Protein Serine-Threonine Kinases; Rats; Resveratrol; Sepsis; Signal Transduction; Stilbenes

Extracellular vesicles (EVs) are nanoscale membrane-formed compartments naturally secreted from cells, which are intercellular mediators regulating physiology and pathogenesis, therefore they could be a novel therapeutic carrier for targeted delivery. However, the translation of EVs is hindered by the heterogeneous composition, low yield, inefficient drug loading and unlikely scalability. Here we report a strategy to generate EVs using nitrogen cavitation (NC-EVs) that instantly disrupts neutrophils to form nanosized membrane vesicles. NC-EVs are similar to naturally secreted EVs (NS-EVs), but contain less subcellular organelles and nuclear acids. The production of NC-EVs was increased by 16 folds and is easy to scale up for clinical use compared to NS-EVs. To examine the usefulness of NC-EVs as a drug delivery platform, piceatannol (an anti-inflammation drug) was remotely loaded in NC-EVs via the pH gradient. We found that piceatannol-loaded NC-EVs dramatically alleviated acute lung inflammation/injury and sepsis induced by lipopolysaccharide (LPS). Our studies reveal that nitrogen cavitation is a novel approach to efficiently generate EVs from any cell type and could be exploited for personalized nanomedicine.

Topics: Animals; Cell-Derived Microparticles; Cells, Cultured; Extracellular Vesicles; HL-60 Cells; Humans; Inflammation; Lipopolysaccharides; Mice; Neutrophils; Sepsis; Stilbenes

Liver injury occurs frequently during sepsis. Pterostilbene (Pte), a natural dimethylated analog of resveratrol from blueberries, exerts anti-inflammatory and anti-apoptotic effects in various diseases. However, the role of Pte in sepsis-induced liver injury and its underlying mechanisms remain unknown. The current study aimed to evaluate the protective effects of Pte on sepsis-induced liver injury and its potential mechanisms. Sepsis was induced using cecal ligation and puncture (CLP) in C57BL/6 mice. Mice were administered Pte (5, 10, 15mg/kg, i.p.) at 0.5h, 2h, and 8h after CLP induction. The pathological changes of the liver were evaluated using hematoxylin and eosin (H&E) staining. The serum levels of alanine transaminase (ALT) and aspartate aminotransferase (AST) were measured. The levels of tumor necrosis factor-alpha (TNF-α), interleukin (IL-6), myeloperoxidase (MPO), p38 mitogen-activated protein kinase (p38MAPK), Bax, and B-cell lymphoma 2 (Bcl-2) were also evaluated. Pte treatment attenuated the CLP-induced liver injury, as evidenced by the attenuated histopathologic injuries and the decreased serum aminotransferase levels. Pte reduced the serum inflammatory cytokine (TNF-α and IL-6) levels and hepatic mRNA levels of TNF-α and IL-6. Pte also reduced MPO activity and p38MAPK activation in the liver. Additionally, Pte significantly inhibited Bax expression and increased Bcl-2 expression. Moreover, Pte increased the expression of sirtuin-1 (SIRT1) and reduced the expression of acetylated forkhead box O1 (Ac-FoxO1), acetylated Ac-p53, and acetylated nuclear factor-kappa beta (Ac-NF-κB). However, SIRT1 small interfering RNA (siRNA) abolished Pte's effects on the expression levels of those protein. Notably, Pte improved the survival rate in septic mice. In conclusion, Pte alleviates sepsis-induced liver injury by reducing inflammatory response and inhibiting hepatic apoptosis, and the potential mechanism is associated with SIRT1 signaling activation.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents; Aspartate Aminotransferases; Blueberry Plants; Cecum; Cytokines; Disease Models, Animal; Inflammation Mediators; Liver; Male; Mice; Mice, Inbred C57BL; RNA, Small Interfering; Sepsis; Signal Transduction; Sirtuin 1; Stilbenes

The aim of the study is to investigate protective effect of resveratrol (Res) on acute kidney injury (AKI) in sepsis.. Rats in sham group received sham operation; in sham + Res received sham operation and Res (3 mg/kg); in cecal ligation and puncture (CLP) established as sepsis; in CLP + Res (3 mg/kg) with sepsis and Res (3 mg/kg); and in CLP + Res (10 mg/kg) with sepsis and Res (10 mg/kg). Survival rate, serum indexes, inflammatory factors, NF-κB-P65, and SIRT1 were detected. Lipopolysaccharide (LPS) mesangial cell was with Res and SIRT1 silencing.. (1) Res intervention improved survival rate of CLP rat. (2) Compared to sham, serum creatinine, blood urine nitrogen, serum cystatin C, neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, tumor necrosis factor-α, interleukin-1β, IL-6, and renal injury index increased in CLP group, while decreased in CLP + Res (3 mg/kg) and CLP + Res (10 mg/kg), significantly, as dose-dependent ( p < 0.05). (3) With Res, NF-κB-P65 and de-acetylated SIRT1 decreased, while SIRT1 and de-acetylated Nuclear factor kB-p65 9 NF-κB-P65) increased, significantly ( p < 0.05). (4) SIRT1 and de-acetylated NF-κB-P65 decreased in LPS cells, while SIRT1 increased after Res intervention, significantly ( p < 0.05). After silencing SIRT1, de-acetylated NF-κB-P65 increased, significantly ( p < 0.05).. Res increases the survival rate of septic rats by inhibiting inflammatory factors to ease AKI and promotes NF-κB-P65 de-acetylation by upregulating SIRT1.

Topics: Acute Kidney Injury; Animals; Cytokines; Glomerular Filtration Rate; Kidney; Male; Protective Agents; Rats, Sprague-Dawley; Renal Circulation; Resveratrol; Sepsis; Sirtuin 1; Stilbenes; Transcription Factor RelA

Sepsis is a severe inflammatory response to systemic infection that frequently affects the myocardium. Previous studies have suggested that resveratrol (RESV) is protective in sepsis. The present study aimed to investigate the role of sirtuin 1 (Sirt1) signaling in the protective effect of intraperitoneally administered RESV against sepsis‑induced myocardial injury. Cecal ligation and puncture, or a sham operation, were performed in male Sprague‑Dawley rats, and the levels of tumor necrosis factor (TNF)‑α and myeloperoxidase (MPO) were assessed by ELISA and an MPO activity kit, respectively. The extent of myocardial apoptosis was assessed by TUNEL staining. The protein expression levels of Sirt1, acetylated (Ac)‑Forkhead box O1 (FoxO1), B cell lymphoma 2 apoptosis regulator (Bcl‑2) and Bcl‑2 associated protein X apoptosis regulator (Bax) were detected by western blot analysis. RESV was demonstrated to attenuate myocardial apoptosis and decrease the production of TNF‑α and MPO. Additionally, RESV upregulated the expression of Sirt1 and Bcl‑2, and downregulated the expression of Ac‑FoxO1 and Bax. The protective effects of RESV were abolished by EX527, a Sirt1 inhibitor. RESV has therefore been demonstrated to attenuate myocardial injury in sepsis by decreasing neutrophil accumulation, TNF‑α expression, and myocardial apoptosis via activation of Sirt1 signaling. These results suggest a novel therapeutic strategy for the clinical treatment of sepsis.

Topics: Animals; Apoptosis; Cardiomyopathies; Disease Models, Animal; Male; Neutrophil Infiltration; Neutrophils; Rats; Resveratrol; Sepsis; Sirtuin 1; Stilbenes; Tumor Necrosis Factor-alpha

Sepsis is a systemic inflammatory response resulting from the excessive production of pro-inflammatory cytokines, including tumor necrosis factor (TNF)‑α. Sirtuin 1 (SirT1) actively deacetylates histone proteins, and facilitates chromatin compaction and gene silencing. In the present study, a cell model of sepsis, comprising lipopolysaccharide (LPS)‑tolerant THP‑1 cells, was used to investigate whether the SirT1 activator, resveratrol, repressed the transcription of TNF‑α. Chromatin immunoprecipitation and real‑time PCR were used to determine the transcription of the TNF‑α promoter. The result revealed that the binding of SirT1 to the TNF‑α promoter was decreased by LPS stimulation in normal cells. However, in LPS‑tolerant cells, nuclear protein levels of SirT1 remained elevated, and LPS stimulation had no significant effect on the binding of SirT1 to the TNF‑α promoter. However, the activity of SirT1 was increased and binding of ace‑H4K16 to the TNF‑α promoter was decreased with resveratrol treatment in the tolerant cells. It was concluded that resveratrol stimulated sirtuin activity in LPS‑tolerant THP‑1 cells, and repressed TNF‑α transcription through the deacetylation of H4K16, without affecting the methylation of H3K9. Resveratrol offers potential as an infective candidate to alleviate inflammation in patients with sepsis.

Topics: Acetylation; Cell Line; Drug Resistance, Neoplasm; Enzyme Activation; Gene Expression Regulation; Histones; Humans; Macrophages; Promoter Regions, Genetic; Protein Binding; Resveratrol; RNA, Messenger; Sepsis; Sirtuin 1; Stilbenes; Transcription, Genetic; Tumor Necrosis Factor-alpha

Sepsis often results in damage to multiple organ systems, possibly due to severe mitochondrial dysfunction. Two members of the sirtuin family, SIRT1 and SIRT3, have been implicated in the reversal of mitochondrial damage. The aim of this study was to determine the role of SIRT1/3 in acute kidney injury (AKI) following sepsis in a septic rat model. After drug pretreatment and cecal ligation and puncture (CLP) model reproduction in the rats, we performed survival time evaluation and kidney tissue extraction and renal tubular epithelial cell (RTEC) isolation. We observed reduced SIRT1/3 activity, elevated acetylated SOD2 (ac-SOD2) levels and oxidative stress, and damaged mitochondria in RTECs following sepsis. Treatment with resveratrol (RSV), a chemical SIRT1 activator, effectively restored SIRT1/3 activity, reduced acetylated SOD2 levels, ameliorated oxidative stress and mitochondrial function of RTECs, and prolonged survival time. However, the beneficial effects of RSV were greatly abrogated by Ex527, a selective inhibitor of SIRT1. These results suggest a therapeutic role for SIRT1 in the reversal of AKI in septic rat, which may rely on SIRT3-mediated deacetylation of SOD2. SIRT1/3 activation could therefore be a promising therapeutic strategy to treat sepsis-associated AKI.

Topics: Acetylation; Acute Kidney Injury; Animals; Apoptosis; Carbazoles; Cecum; Disease Models, Animal; Enzyme Activation; Epithelial Cells; Female; Histone Deacetylase Inhibitors; Kidney Tubules; Ligation; Male; Mitochondria; Oxidative Stress; Punctures; Rats, Sprague-Dawley; Resveratrol; Sepsis; Signal Transduction; Sirtuin 1; Sirtuins; Stilbenes; Superoxide Dismutase

Obesity, a sirtuin-1 (SIRT-1) -deficient state, increases morbidity and resource utilization in critically ill patients. SIRT-1 deficiency increases microvascular inflammation and mortality in early sepsis. The objective of the study was to study the effect of resveratrol (RSV), a SIRT-1 activator, on microvascular inflammation in obese septic mice.. ob/ob and C57Bl/6 (WT) mice were pretreated with RSV versus dimethyl sulfoxide (DMSO) (vehicle) prior to cecal ligation and puncture (sepsis). We studied (1) leukocyte/platelet adhesion, (2) E-selectin, ICAM-1, and SIRT-1 expression in small intestine, and (3) 7-day survival. A group of RSV-treated mice received SIRT-1 inhibitor (EX-527) with sepsis induction, and leukocyte/platelet adhesion and E-selectin/ICAM-1 expression were studied. We treated endothelial (HUVEC) cells with RSV to study E-selectin/ICAM-1 and p65-acetylation (AC-p65) in response to lipopolysaccharide (LPS).. RSV treatment decreased leukocyte/platelet adhesion and E-selectin/ICAM-1 expression with increased SIRT-1 expression in septic ob/ob and WT mice, decreased E-selectin/ICAM-1 expression via increased SIRT-1 expression, and decreased AC-p65 expression in HUVEC. EX-527 abolished RSV-induced attenuation of microvascular inflammation in ob/ob septic mice. Finally, ob/ob mice in the sepsis+RSV group had significantly increased 7-day survival versus the sepsis+vehicle group.. RSV increases SIRT-1 expression in ob/ob septic mice to reduce microvascular inflammation and improves survival.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cecum; Cell Adhesion Molecules; Female; Inflammation; Intercellular Adhesion Molecule-1; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Platelet Adhesiveness; Resveratrol; Sepsis; Sirtuin 1; Stilbenes

Mitochondrial injury is a major cause of sepsis-induced organ failure. Polydatin (PD), a natural polyphenol, demonstrates protective mitochondrial effects in neurons and arteriolar smooth muscle cells during severe shock. In this study, we investigated the effects of PD on renal tubular epithelial cell (RTEC) mitochondria in a rat model of sepsis-induced acute kidney injury.. Rats underwent cecal ligation and puncture (CLP) to mimic sepsis-induced acute kidney injury. Rats were randomly divided into sham, CLP + normal saline, CLP + vehicle, and CLP + PD groups. Normal saline, vehicle, and 30 mg/kg PD were administered at 6, 12, and 18 hours after CLP or sham surgery via the tail vein. Mitochondrial morphology, metabolism, and function in RTECs were then assessed. Serum cytokines, renal function, survival, and histologic changes in the kidney were also evaluated.. CLP increased lipid peroxide content, lysosomal instability, and opening of the mitochondrial permeability transition pore and caused mitochondrial swelling. Moreover, mitochondrial membrane potential (ΔΨm) was decreased and ATP levels reduced after CLP. PD inhibited all the above effects. It also inhibited the inflammatory response, improved renal function, attenuated histologic indicators of kidney damage, and prolonged survival.. PD protects RTECs against mitochondrial dysfunction and prolongs survival in a rat model of sepsis-induced acute kidney injury. These effects may partially result from reductions in interleukin-6 and oxidative stress.

Topics: Acute Kidney Injury; Animals; Disease Models, Animal; Drugs, Chinese Herbal; Epithelial Cells; Glucosides; Kidney Tubules; Membrane Potential, Mitochondrial; Mitochondria; Rats; Rats, Sprague-Dawley; Sepsis; Stilbenes

To investigate the influence of resveratrol (RES) on myocardial energy metabolism in sepsis rats and its mechanism.. Twenty Sprague-Dawley (SD) rats were divided into four groups according to the random number table, 5 rats in each group. The sepsis model was reproduced by intraperitoneal injection of lipopolysaccharide (LPS) 10 mg/kg, and the rats in sham group were injected intraperitoneally with the same amount of saline. The rats in RES treatment group (RES group) were injected RES 8 mg/kg 10 minutes before LPS injection, and those in RES combined with the silent information regulator 1 (sirti) inhibitor group (RES + sirtinol group) were injected sirtinol 1 mg/kg followed by RES 8 mg/kg 10 minutes before LPS injection. The rats were sacrificed 6 hours later, and the heart was harvested. The myocardial ultrastructure was observed by transmission electron microscope. The expression of sirt1 protein was detected by Western Blot. The cytochrome C oxidase (CCO) activity was determined by ultraviolet spectrophotometry. The content of adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP) were detected by high-performance liquid chromatography (HPLC).. Under transmission electron microscopy, the mitochrondria in myocardium in sham group was normal, and mitochrondria was swollen and derangement in LPS group and RES + sirtinol group, but it was not significant in RES group. Compared with sham group, the siit1 protein expression in LPS group was decreased (gray value: 0.602 ± 0.038 vs. 0.902 ± 0.037, P < 0.05), the CCO activity was declined (U/mg: 0.344 ± 0.019 vs. 0.600 ± 0.023, P < 0.05), the contents of ATP, ADP, and AMP were decreased [ATP (µg/g): 89.958 ± 7.570 vs. 157.460 ± 6.737, ADP (µg/g): 164.658 ± 6.742 vs. 251.608 ± 5.191, AMP (µg/g): 179.926 ± 7.303 vs. 276.262 ± 5.546 all P < 0.05]. Compared with LPS group, the sirt1 protein expression in RES group was increased (gray value: 0.874 ± 0.017 vs. 0.602 ± 0.038, P < 0.05), the CCO activity was increased (U/mg: 0.574 ± 0.013 vs. 0.344 ± 0.019, P < 0.05), the contents of ATP, ADP, and AMP were increased [ATP (µg/g): 97.942 ± 11.257 vs. 147.686 ± 8.853, ADP (µG/G): 168.888 ± 8.965 VS. 245.860 ± 7.111, AMP (µg/g): 175.498 ± 6.993 vs. 271.260 ± 6.658, all P < 0.05].

Topics: Animals; Energy Metabolism; Heart; Lipopolysaccharides; Mitochondria, Heart; Myocardium; Random Allocation; Rats; Rats, Sprague-Dawley; Resveratrol; Sepsis; Stilbenes

Nitric oxide (NO) can induce mitochondrial biogenesis in cultured cells, through increased guanosine 3',5'-monophosphate (cGMP), and activation of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). We sought to determine the role of NO, heme oxygenase-1 (HO-1), and its reaction product (carbon monoxide [CO]) in the induction of mitochondrial biogenesis by the natural antioxidant resveratrol.. S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, induced mitochondrial biogenesis in HepG2 hepatoma cells, and in vivo, through stimulation of PGC-1α. NO-induced mitochondrial biogenesis required cGMP, and was mimicked by the cGMP analogue (8-bromoguanosine 3',5'-cyclic monophosphate [8-Br-cGMP]). Activation of mitochondrial biogenesis by SNAP required HO-1, as it could be reversed by genetic interference of HO-1; and by treatment with the HO inhibitor tin-protoporphyrin-IX (SnPP) in vitro and in vivo. Cobalt protoporphyrin (CoPP)-IX, an HO-1 inducing agent, stimulated mitochondrial biogenesis in HepG2 cells, which could be reversed by the CO scavenger hemoglobin. Application of CO, using the CO-releasing molecule-3 (CORM-3), stimulated mitochondrial biogenesis in HepG2 cells, in a cGMP-dependent manner. Both CoPP and CORM-3-induced mitochondrial biogenesis required NF-E2-related factor-2 (Nrf2) activation and phosphorylation of Akt. The natural antioxidant resveratrol induced mitochondrial biogenesis in HepG2 cells, in a manner dependent on NO biosynthesis, cGMP synthesis, Nrf2-dependent HO-1 activation, and endogenous CO production. Furthermore, resveratrol preserved mitochondrial biogenesis during lipopolysaccharides-induced hepatic inflammation in vivo.. The complex interplay between endogenous NO and CO production may underlie the mechanism by which natural antioxidants induce mitochondrial biogenesis. Strategies aimed at improving mitochondrial biogenesis may be used as therapeutics for the treatment of diseases involving mitochondrial dysfunction.

Topics: Animals; Antioxidants; Carbon Monoxide; Disease Models, Animal; Hep G2 Cells; Humans; Injections, Intraperitoneal; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Mitochondria, Liver; Nitric Oxide; Resveratrol; Sepsis; Stilbenes; Tumor Cells, Cultured

High-mobility group protein box 1 (HMGB1) is essential in the response to injury during sepsis. We hypothesized that resveratrol (RESV) administration would inhibit nuclear-cytoplasmic HMGB1 translocation in hepatocytes, which is associated with sirtuin 1 (SIRT1) upregulation. We investigated the regulatory role of SIRT1 in HMGB1 nucleocytoplasmic translocation and its effect on sepsis-induced liver injury.. Rats were randomly assigned to pretreatment with RESV (60 mg/kg per day), nicotinamide (60 mg/kg per day), or vehicle (olive oil), which was administered by gavage for 3 days directly before cecal ligation and puncture was performed to induce sepsis. Parallel control groups were established. Rats were killed 24 h after surgery, and cytokine production, histology, apoptosis, SIRT1, serum HMGB1, nuclear and cytoplasmic HMGB1/ac-HMGB1, and the interaction between SIRT1 and HMGB1 were evaluated. In vitro evaluations were performed in human liver L02 cells subjected to lipopolysaccharide-induced injury, and siRNA-mediated SIRT1 knockdown experiments were performed.. Sepsis-induced serum aminotransferase activities and proinflammatory chemokine levels were reduced by RESV pretreatment, which also improved liver histological parameters in association with SIRT1 upregulation. Resveratrol inhibited HMGB1 cytoplasmic translocation. Nicotinamide, an SIRT1 inhibitor, reduced the SIRT1-mediated suppression of HMGB1 translocation and aggravated cecal ligation and puncture-induced liver damage. Sirtuin 1 knockdown in vitro confirmed that RESV increased the SIRT1-mediated repression of HMGB1 translocation. In vivo, SIRT1 and HMGB1 physically interacted in the nucleus, and SIRT1 regulated HMGB1 acetylation in response to septic liver injury.. Resveratrol protects against sepsis-induced liver injury through the SIRT1-mediated HMGB1 nucleocytoplasmic translocation pathway, a new potential therapeutic target in sepsis-induced liver injury.

Topics: Acetylation; Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Cell Nucleus; Cells, Cultured; Cytoplasm; Drug Evaluation, Preclinical; Gene Knockdown Techniques; Hepatocytes; HMGB1 Protein; Male; Molecular Targeted Therapy; Oxidative Stress; Rats, Sprague-Dawley; Resveratrol; Sepsis; Sirtuin 1; Stilbenes; Translocation, Genetic; Up-Regulation

The present study was carried out to investigate the effects and mechanisms of polydatin (PD) in septic mice. The model of cecal ligation and puncture (CLP-)induced sepsis was employed. Pretreatment of mice with PD (15, 45, and 100 mg/kg) dose-dependently reduced sepsis-induced mortality and lung injury, as indicated by alleviated lung pathological changes and infiltration of proteins and leukocytes. In addition, PD inhibited CLP-induced serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production, lung cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase isoform (iNOS) protein expressions and NF-κB activation. Notably, PD upregulated the expression and activity of heme oxygenase (HO-)1 in lung tissue of septic mice. Further, the protective effects of PD on sepsis were abrogated by ZnPP IX, a specific HO-1 inhibitor. These findings indicated that PD might be an effective antisepsis drug.

Topics: Animals; Bronchoalveolar Lavage Fluid; Glucosides; Heme Oxygenase-1; Interleukin-6; Lung Injury; Mice; Nitric Oxide; Random Allocation; Sepsis; Stilbenes; Transcription Factor RelA; Tumor Necrosis Factor-alpha

The development of acute lung injury (ALI) during sepsis almost doubles the mortality rate of patients. The efficacy of current treatment strategies is low as treatment is usually initiated following the onset of symptoms. Inflammation is one of the main mechanisms of autoimmune disorders and is a common feature of sepsis. The suppression of inflammation is therefore an important mechanism for the treatment of sepsis. Sirtuin 1 (Sirt1) has been demonstrated to play a role in the regulation of inflammation. Resveratrol, a potent Sirt1 activator, exhibits anti‑inflammatory properties. However, the role of resveratrol for the treatment of ALI during sepsis is not fully understood. In the present study, the anti‑inflammatory role of Sirt1 in the lipopolysaccharide (LPS)‑induced TC‑1 cell line and its therapeutic role in ALI was investigated in a mouse model of sepsis. The upregulation of matrix metalloproteinase-9, interleukin (IL)‑1β, IL‑6 and inducible nitric oxide synthase was induced by LPS in the mouse model of sepsis and the TC‑1 cell line, and resveratrol suppressed the overexpression of these proinflammatory molecules in a dose‑dependent manner. Resveratrol decreased pulmonary edema in the mouse model of sepsis induced by LPS. In addition, resveratrol improved lung function and reduced pathological alterations in the mouse model of sepsis. Knockdown of Sirt1 by RNA interference resulted in an increased susceptibility of TC‑1 cells to LPS stimulation and diminished the anti‑inflammatory effect of resveratrol. These results demonstrated that resveratrol inhibits LPS‑induced ALI and inflammation via Sirt1, and indicated that Sirt1 is an efficient target for the regulation of LPS‑induced ALI and inflammation. The present study provides insights into the treatment of ALI during sepsis.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Disease Models, Animal; Inflammation; Interleukin-1beta; Interleukin-6; Lipopolysaccharides; Male; Matrix Metalloproteinase 9; Mice; Nitric Oxide Synthase Type II; Resveratrol; RNA Interference; RNA, Small Interfering; Sepsis; Sirtuin 1; Stilbenes; Up-Regulation

To investigate the protective effects of polydatin on sepsis-induced acute liver injury (ALI) in mice, and to preliminarily study its mechanisms.. The sepsis model was established using cecal ligation and puncture (CLP).A sham-operation control group was also set up. Polydatin (50, 100, and 300 mg/kg, respectively) was administrated to mice 1 h before CLP. The survival and liver injury were evaluated subsequently per 6 h after CLP. The survived mice were scarified 24 h later. The serum and the liver tissue sample were collected. The serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected by colorimetric method. The content of tumor necrosis factor-alpha (TNF-alpha) was assayed by ELISA. The cyclooxygenase-2 (COX-2) expression in the liver tissue was detected by Western blot. The pathological changes of the hepatic tissue were analyzed by hematoxylin and eosin stain.. The mortality of mice reached as high as 50% at 24 h after CLP. The biochemical indices and the pathological changes of the liver tissue showed obvious lesion. The success rate of modeling was 90%. Compared with the sham-operation control group, the serum ALT,AST activity, the TNF-alpha content, and the hepatic COX-2 protein expression markedly increased in the CLP group (P < 0.01). Polydatin improved the sepsis-induced mortality dose-dependently, inhibited increased ALT, AST activity and TNF-alpha, decreased the hepatic COX-2 protein expression, and attenuated the pathological injury of the liver (P < 0.05).. Polydatin could effectively protect sepsis-induced ALI, which might be achieved possibly through inhibiting serum TNF-alpha production and hepatic COX-2 expression.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Cyclooxygenase 2; Disease Models, Animal; Glucosides; Liver; Mice; Mice, Inbred Strains; Sepsis; Stilbenes; Tumor Necrosis Factor-alpha

Sepsis, often initiated by an infection, is a state of disrupted inflammatory homeostasis. There is increasing evidence that oxidative stress has an important role in the development of sepsis-induced multiorgan failure. Resveratrol (RV) is a polyphenolic compound found in the skin of red fruits, such as mulberries and red grapes, and in peanuts. RV has been reported to have an antioxidant, antiproliferative, and anti-inflammatory properties in various models. It has also been found to inhibit the proliferation of a variety of human cancer cell lines, including breast, prostate, colon, pancreatic, and thyroid. This study has been undertaken to assess the role of RV on the sepsis-induced oxidative DNA damage in the lymphocytes of Wistar albino rats by the standard and formamidopyrimidine DNA glycosylase (Fpg)-modified comet assays. The parameters of tail length, tail intensity, and tail moment were evaluated for the determination of DNA damage. According to the study, the DNA damage was found to be significantly higher in the sepsis-induced rats when compared with the control rats (p < 0.05). The parameters were significantly decreased in the RV-treated sepsis-induced group when compared with the sepsis-induced group. The parameters in the sepsis-induced rats were found to be significantly higher in the Fpg-modified comet assay when compared with the standard comet assay (p < 0.05), and RV treatment decreases the DNA damage in the sepsis-induced rats, suggesting that the oxidative stress is likely to be responsible for DNA damage and RV might have a role in the prevention of sepsis-induced oxidative DNA damage.

Topics: Animals; Antimutagenic Agents; Comet Assay; DNA Damage; DNA-Formamidopyrimidine Glycosylase; Lymphocytes; Rats; Rats, Wistar; Resveratrol; Sepsis; Stilbenes

To determine the effects of resveratrol on the ileal smooth muscle reactivity in polymicrobial sepsis.. Polimicrobial sepsis was induced by the cecal ligation and perforation (CLP) procedure. Sprague Dawley rats were divided into three groups. Rats in resveratrol group received resveratrol after CLP (100 mg/kg, i.p.). Rats received saline immediately after CLP in the sepsis group. Control group rats underwent sham operation. The rats were sacrificed and the ileum was excised 24 h after the operation. Contractile and relaxant responses in isolated smooth muscle strips (SMS) were determined using an in vitro muscle technique. TNFα and IL-6 levels were measured in blood samples.. Contractile responses to carbachol and KCl and relaxant responses to transmural electrical field stimulation (EFS) were significantly decreased in the sepsis group compared with control and resveratrol groups. No significant changes were observed for smooth muscle reactivity in the resveratrol and control groups. Sodium nitroprusside (SNP) or papaverine-induced relaxations were similar in the all groups. Resveratrol treatment supressed increased TNFα and IL-6 levels in blood seen in sepsis group.. Ileal smooth muscle reactivity was improved after resveratrol treatment in rats with sepsis. The results of the present study indicate that the beneficial effects of resveratrol might be, at least in part, attributed to its effects on non-adrenergic non-cholinergic pathway and/or anti-inflammatory and antioxidant activity.

Topics: Animals; Antioxidants; Cecum; Ileum; Interleukin-1; Ligation; Male; Muscle, Smooth; Rats; Rats, Wistar; Resveratrol; Sepsis; Stilbenes; Tumor Necrosis Factor-alpha

The mortality rate of patients who develop acute kidney injury during sepsis nearly doubles. The effectiveness of therapy is hampered because it is usually initiated only after the onset of symptoms. As renal microvascular failure during sepsis is correlated with the generation of reactive nitrogen species, the therapeutic potential of resveratrol, a polyphenol vasodilator that is also capable of scavenging reactive nitrogen species, was investigated using the cecal ligation and puncture (CLP) murine model of sepsis-induced acute kidney injury. Resveratrol when given at 5.5 h following CLP reversed the decline in cortical capillary perfusion, assessed by intravital microscopy, at 6 h in a dose-dependent manner. Resveratrol produced the greatest improvement in capillary perfusion and increased renal blood flow and the glomerular filtration rate without raising systemic pressure. A single dose at 6 h after CLP was unable to improve renal microcirculation assessed at 18 h; however, a second dose at 12 h significantly improved microcirculation and decreased the levels of reactive nitrogen species in tubules, while improving renal function. Moreover, resveratrol given at 6, 12, and 18 h significantly improved survival. Hence, resveratrol may have a dual mechanism of action to restore the renal microcirculation and scavenge reactive nitrogen species, thus protecting the tubular epithelium even when administered after the onset of sepsis.

Topics: Acute Kidney Injury; Animals; Antioxidants; Blood Pressure; Disease Models, Animal; Epithelium; Glomerular Filtration Rate; Heart Rate; Kidney; Kidney Tubules; Male; Mice; Mice, Inbred C57BL; Microcirculation; Reactive Nitrogen Species; Resveratrol; Sepsis; Stilbenes; Survival Analysis; Time Factors; Vasodilator Agents

Oxidant stress and compromised microcirculation underlie renal pathophysiology in septic acute kidney injury (AKI). Holthoff et al. report that resveratrol ameliorates these coupled abnormalities. They did not establish the primacy of either defect in septic AKI. However, tubule mitochondrial defects were recently reported to be involved in septic AKI pathogenesis, and resveratrol targets PGC-1α and respiratory enzymes. Together, these findings open new avenues for research into long-unresolved issues in the pathophysiology of septic AKI.

Topics: Acute Kidney Injury; Animals; Antioxidants; Kidney; Male; Microcirculation; Resveratrol; Sepsis; Stilbenes

We hypothesized that resveratrol administration would reverse sepsis-dependent downregulation of peroxisome proliferator activated receptor-γ coactivator 1α, preserve mitochondrial integrity, and rescue animals from sepsis-induced myocardial failure.. Teaching hospital research laboratory.. Cecal ligation and puncture in mice was performed to induce sepsis. Mice that underwent cecal ligation and puncture were randomly assigned to receive resveratrol (30 mg/kg or 60 mg/kg) or vehicle 1 mL sodium chloride 0.9% subcutaneously in the scruff of the neck directly after surgery and at 16, 24, and 40 hrs, respectively.. Forty-eight hrs after cecal ligation and puncture, cardiac performance was established using echocardiography. Mitochondrial integrity was evaluated with electron microscopy, and changes in gene expression were evaluated with microarray analysis. Survival at 48 hrs was just under 50% and comparable between groups. Myocardial contractile function significantly improved after resveratrol treatment. Resveratrol-treated mice developed focal areas of edema, whereas vehicle-treated mice developed significant, diffuse myocardial edema. Electron microscopy revealed widespread swollen mitochondria with ruptured outer membranes, autophagosomes, and vacuolation of the internal compartment, which were significantly attenuated in resveratrol-treated animals. Resveratrol treatment significantly increased cardiac expression of peroxisome proliferator-activated receptor-γ coactivator 1a. Microarray analysis revealed that resveratrol treatment resulted in upregulation of the peroxisome proliferator-activated receptor-γ coactivator gene set containing genes known to be regulated by this transcriptional coactivator. Our data strongly suggest that administration of resveratrol modulates bioenergy metabolism, substrate utilization, oxidative stress, and detoxification pathways associated with both mitochondrial and cardiac pathological conditions, but does not alter mortality from sepsis.. The salutary effects of resveratrol on cecal ligation and puncture-induced myocardial dysfunction are associated with increased peroxisome proliferator-activated receptor-γ coactivator 1a abundance and function. Preservation of myocardial energy production capacity, prevention of secondary injury, mitigation of inflammation, and reversal of sepsis-induced myocardial remodeling are likely to underlie its beneficial effects. This however, does not result in improved survival.

Topics: Animals; Cardiomyopathies; Cecum; Down-Regulation; Edema; Gene Expression; Heart Failure; Ligation; Male; Mice; Mice, Inbred C57BL; Mitochondria, Heart; Myocardial Contraction; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Random Allocation; Resveratrol; Sepsis; Stilbenes; Trans-Activators; Transcription Factors; Vasodilator Agents

Topics: Animals; Heart Failure; Male; Myocardial Contraction; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Resveratrol; Sepsis; Stilbenes; Trans-Activators; Transcription Factors; Vasodilator Agents

The high mortality index due to sepsis and the lack of an effective treatment requires the search for new compounds that can serve as therapy for this disease. Resveratrol, a well-known anti-inflammatory natural compound, might be a good candidate for the treatment of sepsis. The aim of this work was to study the effects of oral administration of resveratrol, before and after sepsis initiation, on inflammation markers in a murine model of endotoxin-induced sepsis.. Sprague-Dawley male rats were treated with resveratrol the 3 days prior to LPS administration and 45 min later. Hematological parameters, TNF-α, IL-1β and CINC-1, FRAP and TBARS levels were determined. Resveratrol and resveratrol-derived metabolites profile in plasma was compared after oral and intraperitoneal administration.. Oral treatment with resveratrol had no apparent systemic protective effects. However, resveratrol reduced the levels of lipid peroxidation in the small intestine and colon. Importantly, the administration of LPS caused a decrease in resveratrol absorption. When resveratrol bioavailability after i.p. administration was compared to that observed after oral administration, a different profile of resveratrol metabolites was found in plasma.. These results highlight the importance of studying the bioavailability of the assayed compounds in the experimental models used to be able to choose the best route of administration depending on the target organ and to determine which compounds or derived metabolites are effective treating the studied disease.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Antioxidants; Chromatography, Liquid; Endotoxins; Inflammation; Interleukin-1beta; Lipid Peroxidation; Lipopolysaccharides; Male; Rats; Rats, Sprague-Dawley; Resveratrol; Sepsis; Stilbenes; Tandem Mass Spectrometry; Thiobarbituric Acid Reactive Substances; Tumor Necrosis Factor-alpha

Host-parasite contact is a prerequisite for the acute cytotoxicity of Vibrio vulnificus, which is mediated primarily by RtxA1, a repeat in toxin (RTX) toxin. We found that resveratrol (at 10 or 30 microM), a natural polyphenol, protected HeLa cells from V. vulnificus cytotoxicity. To further characterize the underlying mechanism, the effect of resveratrol was investigated at the level of the host-microbe interactions. We studied the effects of resveratrol on adhesion, motility, cytotoxicity, and RtxA1 toxin expression of V. vulnificus. In addition, the effect of resveratrol on mouse mortality caused by V. vulnificus was investigated. Resveratrol inhibited V. vulnificus motility and the microbe adhesion to host cells, critical virulence traits for many bacteria. Resveratrol also down-regulated the expression of RtxA1 toxin at the transcriptional level and thereby protected the host cells from becoming rounded and damaged. In addition, resveratrol (20mg/kg) protected CD-1 mice from V. vulnificus infection. Taken together, these results suggest that resveratrol, a modulator of host-microbe interactions, has potential for development as a new paradigm drug to treat infectious diseases.

Topics: Animals; Bacterial Adhesion; Bacterial Toxins; Down-Regulation; Gene Expression Regulation, Bacterial; HeLa Cells; Host-Pathogen Interactions; Humans; Mice; Movement; Resveratrol; RNA, Messenger; Sepsis; Stilbenes; Vibrio Infections; Vibrio vulnificus

Resveratrol (3,5,4'-trans-trihydroxystilbene), a natural phytoalexin, has various pharmacological effects, including anti-inflammatory properties via inhibition of oxidation, leukocyte priming, and expression of inflammatory mediators. The present study was aimed to investigate the possible beneficial activities of resveratrol on lung and kidney damage in a rat model of sepsis.. Sepsis was induced to Sprague-Dawley rats of both sexes (200-250 g) by cecal ligation and perforation. The rats were treated with resveratrol (30 mg/kg; i.p.) or saline after induction of sepsis and at 16 h. Twenty-four hours after the sepsis-induction, all rats were decapitated. Blood was collected for the measurement of tumor necrosis factor-alpha level and lactate dehydrogenase activity. Lung and kidney samples were taken for histological assessment and for the measurement of malondialdehyde, glutathione level, myeloperoxidase activity, and collagen content.. Sepsis caused a significant increase in malondialdehyde levels, myeloperoxidase activity, and collagen content of the lung and kidney tissues with a concomitant reduction in glutathione levels. Microscopic examination revealed severe destruction of regular morphology in both lung and kidney tissues. Serum tumor necrosis factor-alpha and lactate dehydrogenase levels also were higher in rats with sepsis compared to those of the sham group. Resveratrol treatment reversed these biochemical parameters and preserved tissue morphology as evidenced by histological evaluation.. Resveratrol, a phenolic compound, reduces sepsis-induced remote organ injury, at least in part, through its ability to balance oxidant-antioxidant status, to inhibit neutrophil infiltration and to regulate the release of inflammatory mediators.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cecum; Collagen; Disease Models, Animal; Female; Glutathione; Kidney; Kidney Diseases; L-Lactate Dehydrogenase; Ligation; Lung; Lung Diseases; Male; Malondialdehyde; Peroxidase; Rats; Rats, Sprague-Dawley; Resveratrol; Sepsis; Stilbenes; Tumor Necrosis Factor-alpha

Interferon regulatory factor 3 (IRF3) mediates the transcriptional induction of interferon-stimulated genes (ISGs) in response to viral and bacterial infections. Here we show that the hydroxystilbene piceatannol inhibits the LPS-mediated activation of IRF3 and subsequent ISG induction. Consequently, piceatannol blocks the LPS-induced up-regulation of critical mediators of the inflammatory response such as interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), intercellular adhesion molecule 1 (ICAM-1), and macrophage chemoattractant protein (MCP-1). Furthermore, the LPS-mediated induction of tissue factor (TF), a cell surface protein responsible for initiating the coagulation cascade, is also inhibited by piceatannol. The effectiveness of piceatannol in blocking both the inflammatory response and the coagulation pathway is evidenced by its ability to confer protection against LPS-induced septic shock in a murine model. Thus, IRF3 appears to be a promising target for pharmacologic intervention in the prevention or treatment of septic shock syndrome.

Topics: Animals; Cell Line; Cell Line, Tumor; Chemokine CCL2; DNA-Binding Proteins; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interferon Regulatory Factor-3; Interferons; Interleukin-6; Lipopolysaccharides; Mice; Protein-Tyrosine Kinases; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleases; Sepsis; Shock; Stilbenes; Time Factors; Transcription Factors; Transcription, Genetic; Transfection; Tumor Necrosis Factor-alpha

Sepsis-induced suppression in T-cell proliferation follows deranged Ca(2+) signaling in adult rats. In preliminary studies, we observed suppression in T-cell proliferation in septic neonatal rats as well. In this study, we assessed splenic T-cell cytosolic Ca(2+) concentration, [Ca(2+)](i), as its elevation plays an important role in T-cell proliferation. Also, we investigated the role of PGE(2) in sepsis-related changes in T-cell [Ca(2+)](i) in animals pretreated with cyclooxygenase-1 (COX-1) inhibitor (resveratrol) and cyclooxygenase-2 (COX-2) inhibitor (NS-398). Sepsis was induced in 15-day-old rat pups by intraperitoneal implantation of fecal pellets containing Escherichia coli and Bacteroides fragilis. The sham group consisted of pups implanted with sterile fecal pellets. Septic and sham pups were sacrificed 24 h after implantation and their spleens were removed. The spleens from sham and septic pups, along with spleens from unoperated control pups, were processed for single cell suspensions, and T cells were isolated using nylon wool columns. Fura-2 fluorophotometry was employed for the measurement of [Ca(2+)](i) (in nM units) in T cells stimulated with concanavalin A (ConA). Our results show that ConA-mediated T-cell [Ca(2+)](i) response is significantly suppressed in septic neonatal rats. Pretreatment of pups with COX-2, but not COX-1 inhibitor, prevented the decrease in the [Ca(2+)](i) response. These findings suggest that PGE(2) might induce the attenuation in T-cell Ca(2+) signaling during sepsis in neonatal rats.

Topics: Animals; Animals, Newborn; Bacteroides Infections; Calcium; Concanavalin A; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Escherichia coli Infections; Isoenzymes; Lymphocyte Activation; Membrane Proteins; Nitrobenzenes; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Resveratrol; Sepsis; Signal Transduction; Spleen; Stilbenes; Sulfonamides; T-Lymphocytes