Cardiac dysfunction, a common consequence of sepsis, is the major contribution to morbidity and mortality in patients. Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of Tanshinone IIA (TA), a main active component of Salvia miltiorrhiza Bunge, which has been widely used in China for the treatment of cardiovascular and cerebral system diseases. In the present study, the effect of STS on sepsis-induced cardiac dysfunction was investigated and its effect on survival rate of rats with sepsis was also evaluated. STS treatment could significantly decrease the serum levels of C-reactive protein (CRP), procalcitonin (PCT), cardiac troponin I (cTn-I), cardiac troponin T (cTn-T), and brain natriuretic peptide (BNP) in cecal ligation and puncture (CLP)-induced) septic rats and improve left ventricular function, particularly at 48 and 72 h after CLP. As the pathogenesis of septic myocardial dysfunction is attributable to dysregulated systemic inflammatory responses, several key cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10) and high mobility group protein B1 (HMGB1), were detected to reveal the possible mechanism of attenuation of septic myocardial dysfunction after being treated by STS. Our study showed that STS, especially at a high dose (15 mg·kg), could efficiently suppress inflammatory responses in myocardium and reduce myocardial necrosis through markedly reducing production of myocardial TNF-α, IL-6 and HMGB1. STS significantly improved the 18-day survival rate of rats with sepsis from 0% to 30% (P < 0.05). Therefore, STS could suppress inflammatory responses and improve left ventricular function in rats with sepsis, suggesting that it may be developed for the treatment of sepsis.
Animals ; C-Reactive Protein ; genetics ; immunology ; Cecum ; surgery ; Drugs, Chinese Herbal ; administration & dosage ; chemistry ; Female ; Heart ; drug effects ; physiopathology ; Humans ; Interleukin-6 ; genetics ; immunology ; Ligation ; adverse effects ; Male ; Myocardium ; immunology ; Phenanthrenes ; administration & dosage ; chemistry ; Punctures ; adverse effects ; Rats ; Salvia miltiorrhiza ; chemistry ; Sepsis ; drug therapy ; etiology ; immunology ; physiopathology ; Troponin T ; genetics ; immunology ; Tumor Necrosis Factor-alpha ; genetics ; immunology

Triptolide (TP) induces severe liver injury, but its hepatotoxicity mechanisms are still unclear. Inflammatory responses may be involved in the pathophysiology. Neutrophils are the first-line immune effectors for sterile and non-sterile inflammatory responses. Thus, the aim of the present study was to investigate the neutrophilic inflammatory response in TP-induced liver injury in C57BL/6 mice. Our results showed that neutrophils were recruited and accumulated in the liver, which was parallel to or slightly after the development of liver injury. Neutrophils induced release of myeloperoxidase and up-regulation of CD11b, which caused cytotoxicity and hepatocyte death. Hepatic expressions of CXL1, TNF-α, IL-6, and MCP1 were increased significantly to regulate neutrophils recruitment and activation. Up-regulation of toll like receptors 4 and 9 also facilitated neutrophils infiltration. Moreover, neutrophils depletion using an anti-Gr1 antibody showed mild protection against TP overdose. These results indicated that neutrophils accumulation might be the secondary response, not the cause of TP-induced liver injury. In conclusion, the inflammatory response including neutrophil infiltration may play a role in TP-induced hepatotoxicity, but may not be severe enough to cause additional liver injury.
Animals ; Chemical and Drug Induced Liver Injury ; etiology ; immunology ; Chemokine CCL2 ; genetics ; immunology ; Diterpenes ; adverse effects ; Drugs, Chinese Herbal ; adverse effects ; Epoxy Compounds ; adverse effects ; Female ; Humans ; Interleukin-6 ; genetics ; immunology ; Intracellular Signaling Peptides and Proteins ; genetics ; immunology ; Liver ; drug effects ; immunology ; Mice ; Mice, Inbred C57BL ; Neutrophil Infiltration ; drug effects ; Neutrophils ; drug effects ; immunology ; Phenanthrenes ; adverse effects ; Tripterygium ; adverse effects ; chemistry ; Tumor Necrosis Factor-alpha ; genetics ; immunology

The saponin ginsenoside Rk1 is a major compound isolated from ginseng. Ginsenoside Rk1 has been reported to have anti-inflammatory and anti-tumor properties and to be involved in the regulation of metabolism. However, the effect and mechanism of anti-inflammatory action of ginsenoside Rk1 has not been fully clarified. We investigated whether ginsenoside Rk1 could suppress the inflammatory response in lipopolysaccharide-stimulated RAW264.7 macrophages and to explore its mechanism of the action. RAW264.7 cells were treated with LPS (1 μg·mL) in the absence or the presence of Ginsenoside Rk1 (10, 20, and 40 μmol·L). Then the inflammatory factors were tested with Griess reagents, ELISA, and RT-PCR. The proteins were analyzed by Western blotting. Ginsenoside Rk1 inhibited lipopolysaccharide-induced expression of nitric oxide (NO), interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, and monocyte chemotactic protein (MCP)-1. Ginsenoside Rk1 inhibited the lipopolysaccharide-stimulated phosphorylation of NF-κB and janus kinase (Jak)2 and signal transducer and activator of transcription (Stat)3 at Ser727 and Tyr705. These data suggested that ginsenoside Rk1 could inhibit expression of inflammatory mediators and suppress inflammation further by blocking activation of NF-κB and the Jak2/Stat3 pathway in LPS-stimulated RAW264.7 cells.
Animals ; Anti-Inflammatory Agents ; pharmacology ; Ginsenosides ; pharmacology ; Interleukin-6 ; genetics ; immunology ; Janus Kinase 2 ; genetics ; immunology ; Lipopolysaccharides ; pharmacology ; Macrophages ; drug effects ; immunology ; Mice ; RAW 264.7 Cells ; STAT3 Transcription Factor ; genetics ; immunology ; Tumor Necrosis Factor-alpha ; genetics ; immunology

The present study was designed to investigate the anti-sepsis effects of physcion 8-O-β-glucopyranoside (POG) isolated from Rumex japonicas and explore its possible pharmacological mechanisms. POG was extracted from R. japonicas by bioactivity-guided isolation with the anti-sepsis agents. Survival analysis in septic mouse induced by LPS and heat-killed Escherichia coli were used to evaluate the protective effect of POG (40 mg·kg, i.p.) on sepsis. Cytokines including TNF-α, IL-1β and IL-6 in RAW 264.7 cells induced by LPS (100 ng·mL) were determined by ELISA. In addition, the proteins expressions of TLR2 and TLR4 were determined by Western blotting assay. Our results demonstrated that POG (40 mg·kg, i.p.) possessed significant protective activity on the endotoxemic mice. The POG treatment (20, 40, and 80 μg·mL) significantly decreased the TNF-α, IL-1β and IL-6 induced by LPS (P < 0.01) in a concentration-dependent manner. Furthermore, the TLR4 and TLR2 proteins were also down-regulated by POG at 20 (P < 0.01), 40 (P < 0.01), and 80 μg·mL (P < 0.01). The present study demonstrated that the POG extracted from R. japonicas possessed significant anti-sepsis effect on endotoxemic mice, and can be developed as a novel drug for treating sepsis in the future.
Animals ; Anti-Inflammatory Agents ; administration & dosage ; Drugs, Chinese Herbal ; administration & dosage ; Emodin ; administration & dosage ; analogs & derivatives ; Glucosides ; administration & dosage ; Humans ; Interleukin-1beta ; genetics ; immunology ; Interleukin-6 ; genetics ; immunology ; Interleukin-8 ; genetics ; immunology ; Macrophages ; drug effects ; immunology ; Male ; Mice ; Mice, Inbred ICR ; RAW 264.7 Cells ; Rumex ; chemistry ; Sepsis ; drug therapy ; genetics ; immunology ; Tumor Necrosis Factor-alpha ; genetics ; immunology

The present study was designed to synthesize 2-Cyano-3, 12-dioxooleana-1, 9(11)-en-28-oate-13β, 28-olide (1), a lactone derivative of oleanolic acid (OA) and evaluate its anti-inflammatory activity. Compound 1 significantly diminished nitric oxide (NO) production and down-regulated the mRNA expression of iNOS, COX-2, IL-6, IL-1β, and TNF-α in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Further in vivo studies in murine model of LPS-induced acute lung injury (ALI) showed that 1 possessed more potent protective effects than the well-known anti-inflammatory drug dexamethasone by inhibiting myeloperoxidase (MPO) activity, reducing total cells and neutrophils, and suppressing inflammatory cytokines expression, and thus ameliorating the histopathological conditions of the injured lung tissue. In conclusion, compound 1 could be developed as a promising anti-inflammatory agent for intervention of LPS-induced ALI.
Acute Lung Injury ; drug therapy ; genetics ; immunology ; Animals ; Anti-Inflammatory Agents ; administration & dosage ; chemical synthesis ; Bronchoalveolar Lavage Fluid ; immunology ; Cyclooxygenase 2 ; genetics ; immunology ; Female ; Humans ; Interleukin-1beta ; genetics ; immunology ; Interleukin-6 ; genetics ; immunology ; Lipopolysaccharides ; adverse effects ; Lung ; drug effects ; immunology ; Macrophages ; drug effects ; immunology ; Male ; Mice ; Mice, Inbred BALB C ; Neutrophils ; drug effects ; immunology ; Oleanolic Acid ; administration & dosage ; analogs & derivatives ; chemical synthesis ; Peroxidase ; genetics ; immunology ; RAW 264.7 Cells ; Tumor Necrosis Factor-alpha ; genetics ; immunology

The present study was designed to examine the anti-hyperuricemic and anti-inflammatory effects and possible mechanisms of vaticaffinol, a resveratrol tetramer isolated from ethanol extracts of Dipterocarpus alatus, in oxonate-induced hyperuricemic mice. At 1 h after 250 mg·kg potassium oxonate was given, vaticaffinol at 20, 40, and 60 mg·kg was intragastrically administered to hyperuricemic mice once daily for seven consecutive days. Vaticaffinol significantly decreased serum uric acid levels and improved kidney function in hyperuricemic mice. It inhibited hepatic activity of xanthine dehydrogenase (XDH) and xanthine oxidase (XOD), regulated renal mRNA and protein levels of urate transporter 1 (URAT1), glucose transporter 9 (GLUT9), organic anion transporter 1 (OAT1), organic cation transporter 1 (OCT1), OCT2, organic cation/carnitine transporter 1 (OCTN1), and OCTN2 in hyperuricemic mice. Moreover, vaticaffinol markedly down-regulated renal protein levels of NOD-like receptor 3 (NLRP3), apoptosis-associated speck-like (ASC), and Caspase-1, resulting in the reduction of interleukin (IL)-1β, IL-18, IL-6 and tumor necrosis factor-α (TNF-α) levels in this animal model. Additionally, HPLC and LC-MS analyses clearly testified the presence of vaticaffinol in the crude extract. These results suggest that vaticaffinol may be useful for the prevention and treatment of hyperuricemia with kidney inflammation.
Animals ; Anti-Inflammatory Agents ; administration & dosage ; Dipterocarpaceae ; chemistry ; Humans ; Hyperuricemia ; blood ; drug therapy ; immunology ; Interleukin-18 ; genetics ; immunology ; Interleukin-1beta ; genetics ; immunology ; Interleukin-6 ; genetics ; immunology ; Kidney ; drug effects ; immunology ; Male ; Mice ; Organic Anion Transport Protein 1 ; genetics ; immunology ; Plant Extracts ; administration & dosage ; Stilbenes ; administration & dosage ; Tumor Necrosis Factor-alpha ; genetics ; immunology ; Uric Acid ; blood

PURPOSE: Acute hepatitis A (AHA) and acute hepatitis B (AHB) are caused by an acute infection of the hepatitis A virus and the hepatitis B virus, respectively. In both AHA and AHB, liver injury is known to be mediated by immune cells and cytokines. In this study, we measured serum levels of various cytokines and T-cell cytotoxic proteins in patients with AHA or AHB to identify liver injury-associated cytokines. MATERIALS AND METHODS: Forty-six patients with AHA, 16 patients with AHB, and 14 healthy adults were enrolled in the study. Serum levels of 17 cytokines and T-cell cytotoxic proteins were measured by enzyme-linked immunosorbent assays or cytometric bead arrays and analyzed for correlation with serum alanine aminotransferase (ALT) levels. RESULTS: Interleukin (IL)-18, IL-8, CXCL9, and CXCL10 were significantly elevated in both AHA and AHB. IL-6, IL-22, granzyme B, and soluble Fas ligand (sFasL) were elevated in AHA but not in AHB. In both AHA and AHB, the serum level of CXCL10 significantly correlated with the peak ALT level. Additionally, the serum level of granzyme B in AHA and the serum level of sFasL in AHB correlated with the peak ALT level. CONCLUSION: We identified cytokines and T-cell cytotoxic proteins associated with liver injury in AHA and AHB. These findings deepen the existing understanding of immunological mechanisms responsible for liver injury in acute viral hepatitis.
Acute Disease ; Adult ; Alanine Transaminase/blood ; Biomarkers/blood ; Cytokines/*blood ; Enzyme-Linked Immunosorbent Assay ; Fas Ligand Protein/blood ; Female ; Hepatitis A/blood/virology ; Hepatitis A virus/*genetics/immunology ; Hepatitis B/blood/virology ; Hepatitis B virus/*genetics/immunology ; Humans ; Interleukin-6/blood ; Interleukin-8/blood ; Interleukins/blood ; Liver Failure/immunology/metabolism/*pathology ; Male ; Middle Aged ; T-Lymphocytes, Cytotoxic/immunology/*metabolism

OBJECTIVETo determine the proportion of Tc17 cells in the lungs of mice with neutrophilic(NEU) asthma, and to investigate the role of Tc17 cells in the pathogenesis of NEU asthma.

METHODSThirty-two C57/B6 mice of clean grade were randomly divided into two groups: NEU asthma and control. The mice in the NEU asthma group were sensitized by airway instillation of ovalbumin (OVA) and lipopolysaccharide (LPS), and challenged with an aerosol of OVA, while those in the control group were sensitized and challenged with normal saline. At 24 hours after the final challenge, bronchoalveolar lavage fluid (BALF) was collected, and the total number and differential counts of nucleated cells and percentage of each type were determined. The lung tissues were separated and hematoxylin-eosin staining was performed to observe the pathological changes of lungs; flow cytometry was applied to determine the percentages of Tc17 and Th17 cells in the lung tissues. Enzyme-linked immunosorbent assay was applied to determine the levels of interleukin-6 (IL-6), transforming growth factor β (TGF-β), and interleukin-17 (IL-17) in BALF.

RESULTSThe NEU asthma group had a significantly higher total number of nucleated cells, a significantly higher percentage of eosinophils, and a significantly higher percentage of neutrophils in BALF than the control group (P<0.01). The NEU asthma group also had significantly higher percentages of Tc17 and Th17 cells than the control group (P<0.01). In the NEU asthma group, the percentage of Tc17 cells was positively correlated with that of Th17 cells (P<0.05). The NEU asthma group had significantly higher concentrations of IL-6, TGF-β, and IL-17 in BALF than the control group (P<0.05).

CONCLUSIONSThe expression of Tc17 cells in the lung tissues increases in mice with NEU asthma, and the increased number of Tc17 cells may be involved in the pathogenesis of NEU asthma. Tc17 cells may play an important role in NEU asthma through IL-17.

Animals ; Asthma ; genetics ; immunology ; CD8-Positive T-Lymphocytes ; immunology ; Female ; Humans ; Interferon-gamma ; immunology ; Interleukin-17 ; genetics ; immunology ; Interleukin-4 ; genetics ; immunology ; Interleukin-6 ; genetics ; immunology ; Lymphocyte Count ; Mice ; Th17 Cells ; immunology

OBJECTIVETo observe effects and mechanism of Dinggui gel paste analgesic anti-inflammatory.

METHODSEighty-four male KM mice weighted from 18 to 22 g and aged 4 to 5 weeks were randomly divided into 7 groups, named blank group, model group, matrix control group, Votalin group, high dosage of Dinggui gel paste group with group, equivalent dosage of Dinggui gel paste group, Dinggui gel paste group, 12 mice in each group. Except blank and model group, the other groups were paste ointment for 7 days, and one time a day, matrix control group were pasted isodose blank matrix gel patch. Pain threshold were tested at 30, 60, 90 and 120 min after the last ad-ministration. Hot plate test were performed by injection of 5% formalin for 20 µL on right hindfoot sole after the last administration. The cumulative time of mice licking right rear foot were observed at stage of I and II, and content of IL-1, TNF-α were tested by ELISA method. Differences of weight between right and left ears were measured by ear swelling method and anti-inflammation experiment.

RESULTSIn hot plate test at 90 min, pain threshold in equivalent dosage of Dinggui gel paste group was (24.87 ± 14.67) s and (15.28 ± 8.23) s in model group; (26.33 ± 15.45) s in high dosage of Dinggui gel paste group and (15.31 ± 5.02) s in model group at 120 min in hot plate test, there were no statistical differences between two groups. Pain period at stage I, licking cumulative time in high dosage of Dinggui gel paste group was (66.70 ± 22.83) s and (101.80 ± 33.65) s in model group,and had significant differences between two groups; there were statistical differences in licking cumulative time at stage I of pain period among high dosage of Dinggui gel paste group (51.30 ± 43.60)s, equivalent dosage of Dinggui gel paste group (64.00 ± 47.27) sand model group (109.50 ± 36.78) s. Content of IL-1 in model group was (28.70 ± 8.24) ng/L and (13.33 ± 2.20) ng/L in high dosage of Dinggui gel paste group, there was obvious meaning between two groups; There were significant differences in TNF-α content among model group (93.60 ± 23.65) ng/L,high dosage of Dinggui gel paste group (63.21 ± 10.54)ng/L and equivalent dosage of Dinggui gel paste group (72.69 ± 16.26) ng/L; while there were no statistical meaning in ear swelling degree among model group (5.73 ± 0.80) mg,high dosage of Dinggui gel paste group (5.42 ± 0.68) mg and equivalent dosage of Dinggui gel paste group (4.98 ± 1.52) mg.

CONCLUSIONDinggui gel paste could increase pain threshold, reduce licking accumulative time, and decrease ear swelling degree, and relief pain by regulating level of TNF-α and IL-1.

Analgesics ; administration & dosage ; Animals ; Anti-Inflammatory Agents, Non-Steroidal ; administration & dosage ; Dosage Forms ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Interleukin-1beta ; genetics ; immunology ; Interleukin-6 ; genetics ; immunology ; Male ; Mice ; Ointments ; Pain ; genetics ; immunology ; Pain Management ; Tumor Necrosis Factor-alpha ; genetics ; immunology

PURPOSE: High mobility group box 1 (HMGB1) plays a central role in the pathogenesis of sepsis and multiple organ dysfunction syndromes. We investigated the associations of a single nucleotide polymorphism (SNP; rs1045411) in HMGB1 with various clinical parameters, severity, and prognosis in patients with sepsis, severe sepsis, or septic shock. MATERIALS AND METHODS: We enrolled 212 adult patients followed for 28 days. All patients were genotyped for rs1045411, and the serum levels of HMGB1 and several cytokines were measured. RESULTS: The proportions of patients according to genotype were GG (71.2%), GA (26.4%), and AA (2.4%). Among patients with chronic lung disease comorbidity, patients with a variant A allele had higher positive blood culture rates and higher levels of various cytokines [interleukin (IL)-1beta, IL-6, IL-10, IL-17, and tumor necrosis factor-alpha] than those with the GG genotype. In the analysis of those with diabetes as a comorbidity, patients with a variant A allele had higher blood culture and Gram-negative culture rates than those with GG genotypes; these patients also had a higher levels of IL-17. In the analysis of those with sepsis caused by a respiratory tract infection, patients with a variant A allele had higher levels of IL-10 and IL-17 (all p<0.05). This polymorphism had no significant impact on patient survival. CONCLUSION: The variant A allele of rs1045411 appears to be associated with a more severe inflammatory response than the GG genotype under specific conditions.
Adult ; Aged ; Alleles ; Asian Continental Ancestry Group/genetics ; China/epidemiology ; Cytokines/*blood/*genetics ; Female ; Genotype ; HMGB1 Protein/blood/*genetics ; Humans ; Interleukin-10/genetics ; Interleukin-17/genetics ; Interleukin-6/blood ; Male ; Middle Aged ; Polymorphism, Genetic/*genetics ; Polymorphism, Single Nucleotide/*genetics ; Prognosis ; Republic of Korea ; Sepsis/immunology/*metabolism/mortality ; Shock, Septic/immunology/*metabolism/mortality ; Survival ; Tumor Necrosis Factor-alpha/genetics