• Biomolecules & Therapeutics
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• v.21 no.1
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• pp.66-71
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• 2013

Broussonetia papyrifera and Lonicera japonica have long been used in the treatment of inflammatory disorders in Chinese medicine, especially respiratory inflammation. Previously, a new phytoformula (BL) containing B. papyrifera and L. japonica was found to exert strong anti-inflammatory activity against several animal models of inflammation, especially against an animal model of acute bronchitis. In the present investigation, the effects of BL on animal models of septic inflammation and chronic bronchitis are examined. Against lipopolysaccharide (LPS)-induced septic inflammation in mice, BL (200-400 mg/kg) reduced the induction of some important proinflammatory cytokines. At 1 h after LPS treatment, BL was found to considerably inhibit TNF-${\alpha}$ production when measured by cytokine array. At 3 h after LPS treatment, BL inhibited the induction of several proinflammatory cytokines, including IFN-${\gamma}$ and IL-$1{\beta}$, although dexamethasone, which was used as a reference, showed a higher inhibitory action on these biomarkers. Against chronic bronchitis induced by LPS/elastase instillation in rats for 4 weeks, BL (200-400 mg/kg/day) significantly inhibited cell recruitment in bronchoalveolar lavage fluid. Furthermore, BL considerably reduced lung injury, as revealed by histological observation. Taken together, these results indicate that BL may have a potential to treat systemic septic inflammation as well as chronic bronchitis.

• YAKHAK HOEJI
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• v.51 no.6
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• pp.476-481
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• 2007

A polymorphic fungus, Candida albicans, causes various forms of infections such as disseminated candidiasis and vaginitis. Recent reports indicate that the fungus is a main etiological agent for the arthritis. In search of new sources for treatment of the fungal arthritis, we examined $18{\beta}$-glycyrrhetinic acid ($18{\beta}$-GA) against C. albicans-caused septic arthritis. The compound is isolated from Glycyrrhizae Radix that is known to have various immunomodulating activities and is one of the most popular herbal medicines. For induction of animal model of a septic arthritis, mice were given an emulsion form of C. albicans cell wall mixed with Complete Freund's Adjuvant (CFA) via footpad-injection. To determine prophylactic and therapeutic effects, the component was given to the animals before or after the induction of the arthritis, respectively. Data showed that intraperitoneal administration of $18{\beta}$-GA resulted in reduction of the inflammation, indicating the component had both prophylactic and therapeutic activities. For investigation of mechanism of the $18{\beta}$-GA, inhibitory effects on NO (nitiric oxide) and on T-lymphocyte proliferation were determined. Results demonstrated that $18{\beta}$-GA suppressed NO production from LPS (lipopolysaccharide)-treated macrophages and also inhibited proliferation of Con A (concanavalin A)activated T-cells. Taken together, $18{\beta}$-GA, a pentacyclic triterpene, has anti-arthritic activity against C. albicans-caused septic arthritis, possibly by blocking NO production and T-cell suppression.

• The Korean Journal of Physiology and Pharmacology
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• v.26 no.6
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• pp.511-518
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• 2022

Sepsis-associated myocardial injury, an invertible myocardial depression, is a common complication of sepsis. Neogambogic acid is an active compound in garcinia and exerts anthelmintic, anti-inflammatory, and detoxification properties. The role of neogambogic acid in sepsis-associated myocardial injury was assessed. Firstly, mice were pretreated with neogambogic acid and then subjected to lipopolysaccharide treatment to induce sepsis. Results showed that lipopolysaccharide treatment induced up-regulation of biomarkers involved in cardiac injury, including lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), and troponin I (cTnI). However, pretreatment with neogambogic acid reduced levels of LDH, CK-MB, and cTnI, and ameliorated histopathological changes in the heart tissues of septic mice. Secondly, neogambogic acid also improved cardiac function in septic mice through reduction in left ventricular end-diastolic pressure, and enhancement of ejection fraction, fractional shortening, and left ventricular systolic mean pressure. Moreover, neogambogic acid suppressed cardiac apoptosis and inflammation in septic mice and reduced cardiac fibrosis. Lastly, protein expression of p-p38, p-JNK, and p-NF-κB in septic mice was decreased by neogambogic acid. In conclusion, neogambogic acid exerted anti-apoptotic, anti-fibrotic, and anti-inflammatory effects in septic mice through the inactivation of MAPK/NF-κB pathway.

• YAKHAK HOEJI
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• v.45 no.1
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• pp.16-22
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• 2001

Novel yakuchinone derivatives have been designed, synthesized and evaluated their inhibitory activity of NO production in lipopolysaccharide (LPS)-activated macrophages. From this study, some enone compounds have been found to be highly active in the assay. In view of the importance of NO in septic shock and inflammation, these compounds may be useful candidates for the development of new drug to treat endotoxemia and inflammation accompanying overproduction of NO.

• BMB Reports
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• v.48 no.6
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• pp.336-341
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• 2015

Sepsis is a life-threatening, infectious, systemic inflammatory disease. In this study, we investigated the therapeutic effect of α-cubebenoate, a novel compound isolated from Schisandra chinensis against polymicrobial sepsis in a cecal ligation and puncture (CLP) experimental model. Administration of α-cubebenoate strongly enhanced survival in the CLP model. α-cubebenoate administration also markedly blocked CLP-induced lung inflammation and increased bactericidal activity by enhancing phagocytic activity and hydrogen peroxide generation in mouse bone marrow-derived macrophages and neutrophils. Expression of two important inflammatory cytokines, IL-1 and IL-6, was strongly increased in the CLP model, and this was dramatically blocked by α-cubebenoate. Lymphocyte apoptosis and caspase-3 activation, which are associated with immune paralysis during sepsis, were markedly attenuated by α-cubebenoate. Taken together, our findings indicate that α-cubebenoate, a natural compound isolated from Schisandra chinensis, is a powerful potential anti-septic agent. [BMB Reports 2015; 48(6): 336-341]

• YAKHAK HOEJI
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• v.56 no.1
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• pp.20-25
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• 2012

In Northeast Asia, Paeoniae Radix has been used in treatments of inflammation-causing diseases such as arthritis for many centuries. Paeoniflorin, one of the principle bioactive monoterpene glucosides from the paeony root, is reported to be mostly responsible for the effectiveness of the treatments. However, the anti-inflammatory effect of a monoterpene, paeoniflorigenone (PFG) which partially has the moiety of paeoniflorin minus a glucose structure is unknown. Thus, the aim of this work was to investigate anti-inflammatory activity of PFG. For the investigation, PFG activity on the NO (nitric oxide) production from LPS-stimulated macrophages, and the anti-inflammatory effect was tested in the animal model of septic arthritis caused by Candida albicans, a major etiological agent for septic arthritis. For induction of the arthritis, mice were administered with an emulsion of C. albicans cell wall (CACW) mixed with Complete Freund's Adjuvant (CFA) via footpad-injection (Day 0); PFG at a dose of 0.5 or 1 mg/mouse (25 or 50 mg/kg of body-weight) was given to the animals on Day 3, 6, and 9; footpads were scored for arthritis. Moreover, the PFG effect on proliferation of T-lymphocyte that causes aggravation of arthritis was additionally tested. Data resulting from those tests showed that PFG inhibited the NO production from the stimulated macrophage in a dose dependent manner (P<0.05), indicating that PFG is an anti-inflammatory. To confirm the in-vitro results, anti-inflammatory activity of PFG was determined against C. albicans-caused septic arthritis. Data showed that PFG-treatment reduced footpad-swelling which indicates that PFG has anti-arthritic effect (P<0.05), which is therapeutic. The anti-arthritic effect appeared to be mediated by PFG suppression of T-cell proliferation. Ultimately, PFG, a monoterpene component, has anti-inflammatory activity analogous to paeoniflorin. The anti-inflammatory activity treats the septic arthritis due to a pathogenic fungus C. albicans.

• Tuberculosis and Respiratory Diseases
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• v.47 no.4
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• pp.451-459
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• 1999

Background : In sepsis, excessive generation of reactive oxygen species plays key roles in the pathogenesis of acute lung injury. The serum antioxidants such as catalase and MnSOD are elevated in sepsis and considered as predictors of acute respiratory distress syndrome(ARDS) and prognostic factors of sepsis. Peroxiredoxin(Prx) has recently been known as an unique and major intracellular antioxidant. In this study, we evaluated the expression of Prx I and Prx II in mouse monocyte-macrophage cells(RAW 267.7) after treatment of oxidative stress and endotoxin and measured the amount of Prx I, Prx II and thioredoxin(Trx) in peritoneal and bronchoalveolar lavage fluid of septic animal model. Methods : Using immunoblot analysis with specific antibodies against Prx I, Prx II and Trx, we evaluated the distribution of Prx I and Prx II in human neutrophil, alveolar macrophage and red blood cell. We evaluated the expression of Prx I and Prx II in mouse monocyte-macrophage cells after treatment of $5\;{\mu}M$ menadione and $1\;{\mu}g/ml$ lipopolysaccharide(LPS) and measured the amount of Prx I, Prx II and Trx in peritoneal lavage fluid of intraperitoneal septic animals(septic animal model induced with intraperitoneal 6 mg/Kg LPS injection) and those in bronchoalveolar lavage fluid of intraperitoneal septic animals and intravenous septic animals(septic animal model induced with intravenous 5 mg/Kg LPS injection) and compared with the severity of lung inflammation. Results : The distribution of Prx I and Prx II were so different among human neutrophil, alveolar macrophage and red blood cell. The expression of Prx I in mouse monocyte-macrophage cells was increased after treatment of $5\;{\mu}M$ menadione and $1\;{\mu}g/ml$ lipopolysaccharide but that of Prx II was not increased. The amount of Prx I, Prx II and Trx were increased in peritoneal lavage fluid of intraperitoneal septic animals but were not increased in bronchoalveolar lavage fluid of intraperitoneal and intravenous septic animals regardless of the severity of lung inflammation. Conclusion : As intracellular antioxidant, the expression of Prx I is increased in mouse monocyte-macrophage cells after treatment of oxidative stress and endotoxin. The amount of Prx I, Prx II and Trx are increased in local inflammatory site but not increased in injured lung of septic animal model.

• Clinical and Experimental Pediatrics
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• v.46 no.8
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• pp.777-783
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• 2003

Purpose : The aim of this study was to evaluate the effect of inhaled nitric oxide(iNO) on gas exchange, hemodynamics and pulmonary inflammation in newborn piglets with E. coli induced septic lung. Methods : Twenty three instrumented and ventilated piglets were randomized into three groups : CON(n=6), PCON(n=9), and PNO(n=8). In the piglets of the PCON and PNO groups, E. coli septic lung was induced by endotracheal instillation of E. coli. Ten ppm iNO was given continuously in the PNO group after endotracheal instillation of E. coli. All animals were mechanically ventilated for six hour with a peak inspiratory pressure of 30 $cmH_2O$, frequency of 25 breaths/min, $FiO_2$ 1.0 and a positive end-expiratory pressure of 4 $cmH_2O$. All measurements were made at one hour intervals during the experiment. At the end of the experiment, lung tissue was harvested for the analysis of myeloperoxidase activity, indicative of lung inflammation. Results : All piglets with pulmonary instillation of E. coli developed E. coli sepsis. Piglets in the PCON group developed progresseve pulmonry hypertension, hypoxemia and hypercarbia compared to the CON group due to increased pulmonary vascular resistance, intrapulmonary shunt fraction and physiologic dead space fraction. iNO did not reverse pulmonary hypertension in the PNO group. However iNO significantly improved oxygenation, which was attributed to marked improvement of venous admixture and partial attenuation of increase in dead space fraction. Increased myeloperoxidase activity in PCON compared to CON was significantly attenuated in PNO. Conclusion : iNO improves oxygenation and lung inflammation in newborn piglets with E. coli induced septic lung.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.203.2-204
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• 2003

Nitric oxide (NO) produced in large amounts by inducible nitric oxide synthase (iNOS) is known to be responsible for the vasodilation and hypotension observed in septic shock and inflammation. Inhibitors of iNOS, thus, may be useful candidate for the treatment of inflammatory diseases accompanied by the overproduction of NO. We prepared alcoholic extracts of woody plants and screened the inhibitory activity of NO production in lipopolysaccharide (LPS)-activated macrophages after the treatment of these extracts. (omitted)

• Journal of Microbiology and Biotechnology
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• v.29 no.11
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• pp.1707-1716
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• 2019

The development of new antimicrobial agents is essential for the effective treatment of diseases such as sepsis. We previously developed a new short peptide, Pap12-6, using the 12 N-terminal residues of papiliocin, which showed potent and effective antimicrobial activity against multidrug-resistant Gram-negative bacteria. Here, we investigated the antimicrobial mechanism of Pap12-6 and a newly designed peptide, Pap12-7, in which the 12^th Trp residue of Pap12-6 was replaced with Val to develop a potent peptide with high bacterial selectivity and a different antibacterial mechanism. Both peptides showed high antimicrobial activity against Gram-negative bacteria, including multidrug-resistant Gram-negative bacteria. In addition, the two peptides showed similar anti-inflammatory activity against lipopolysaccharide-stimulated RAW 264.7 cells, but Pap12-7 showed very low toxicities against sheep red blood cells and mammalian cells compared to that showed by Pap12-6. A calcein dye leakage assay, membrane depolarization, and confocal microscopy observations revealed that the two peptides with one single amino acid change have different mechanisms of antibacterial action: Pap12-6 directly targets the bacterial cell membrane, whereas Pap12-7 appears to penetrate the bacterial cell membrane and exert its activities in the cell. The therapeutic efficacy of Pap12-7 was further examined in a mouse model of sepsis, which increased the survival rate of septic mice. For the first time, we showed that both peptides showed anti-septic activity by reducing the infiltration of neutrophils and the production of inflammatory factors. Overall, these results indicate Pap12-7 as a novel non-toxic peptide with potent antibacterial and anti-septic activities via penetrating the cell membrane.