The Therapeutic Potential of (+)-Afzelechin for Alleviating Sepsis-Associated Pulmonary Injury.

Sepsis-induced acute lung injury (ALI) poses a common and formidable challenge in clinical practice, currently lacking efficacious therapeutic approaches. This study delves into the evaluation of (+)-afzelechin (AZC), a natural compound derived from Bergenia ligulata with a diverse array of properties, encompassing antioxidant, anticancer, antimicrobial, and cardiovascular effects to ascertain its effectiveness and underlying mechanisms in mitigating sepsis-induced ALI through animal experimentation. An ALI mouse model induced by sepsis was established through lipopolysaccharide (LPS) administration, and various analytical techniques, including quantitative real-time polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assay were employed to gauge inflammatory cytokine levels, lung injury, and associated signaling pathways. The animal experiments revealed that AZC offered safeguards against lung injury induced by LPS while reducing inflammatory cytokine levels in both blood serum and lung tissue. Western blotting experiments revealed AZC's downregulation of the toll-like receptor (TLR)4/NF-κB pathway and the upregulation of PI3K/Akt, coupled with inhibition of the Hippo and Rho signaling pathways. These findings underscore AZC's efficacy in ameliorating sepsis-induced ALI by modulating cytokine storms and curtailing inflammation via the regulation of TLR4/NF-κB, PI3K/Akt, Hippo, and Rho signaling pathways. This work serves as a foundation for additional exploration into AZC's mechanisms and its potential as a therapy for sepsis-induced ALI. Animals in accordance with Kyungpook National University (IRB No. KNU 2022-174).

Jujuboside B Inhibited High Mobility Group Box Protein 1-Mediated Severe Inflammatory Responses in Human Endothelial Cells and Mice.

High mobility group box protein 1 (HMGB1) is a biomolecule that acts as an alerting signal of late sepsis by accelerating the production of proinflammatory cytokines, and eventually leads to various inflammation-related symptoms. When released into plasma at high concentration, it disrupts precise diagnosis and prognosis and worsens the survival of patients with systemic inflammatory conditions. Jujuboside B (JB) is a natural compound pressed from the seed of Zizyphi Spinosi Semen, which is known for its medical efficacies in treating various conditions such as hyperlipidemia, hypoxia, and platelet aggregation. Nevertheless, the medicinal activity of JB on HMGB1-involved inflammatory response in vascular cells in the human body is still ambiguous. Therefore, we hypothesized that JB could regulate the lipopolysaccharide (LPS)-induced dynamics of HMGB1 and its mediated cascade in inflammatory responses in human umbilical vein endothelial cells (HUVECs). In this experiment, JB and HMGB1 were administered in that order. In vitro and in vivo permeability, and cell viability, adhesion, and excavation of leukocytes, development of cell adhesion molecules, and lastly production of proinflammatory substances were investigated on human endothelial cells and mouse disease models to investigate the efficacy of JB in inflammatory condition. JB substantially blocked the translocation of HMGB1 from HUVECs and controlled HMGB1-induced adhesion and extravasation of the neutrophils through LPS-treated HUVECs. Moreover, JB decreased the formation of HMGB1 receptors and continually prevented HMGB1-induced proinflammatory mechanisms by blocking transcription of nuclear factor-κB and synthesis of tumor necrosis factor-α. In conclusion, JB demonstrated preventive effects against inflammatory pathologies and showed the potential to be a candidate substance for various inflammatory diseases by regulating HMGB1-mediated cellular signaling.

Hepatoprotective functions of jujuboside B.

Jujuboside B (JB) found in the seeds of Zizyphi Spinosi Semen possesses pharmacological functions, such as anti-inflammatory, antiplatelet aggregation, and antianxiety potentials. This study evaluated the effect of JB on liver failure in cecal ligation and puncture (CLP)-induced sepsis. First, we observed histopathological changes in the liver by optical microscopy and the activity of enzymes in serum such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST). We further measured the levels of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, nitric oxide (NO), and antioxidative parameters in liver homogenate. The expression of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2), and glucocorticoid receptor (GR) in the liver was observed by Western blotting. CLP enhanced the migration of inflammatory cells, ALT and AST concentrations, and necrosis, which were reduced by JB. In addition, JB reduced 11ß-HSD2 expression and levels of inflammatory mediators (TNF-α, IL-1ß, and NO) in the liver, increased GR expression, enhanced endogenous antioxidative capacity. These results further suggest that JB may protect the liver against CLP-induced damage by regulating anti-inflammatory responses, downregulating 11ß-HSD2 expression and antioxidation, and up-regulating GR expression.

Benzoylpaeoniflorin Activates Anti-Inflammatory Mechanisms to Mitigate Sepsis in Cell-Culture and Mouse Sepsis Models.

Xuebijing injection (XBJI) (comprising of five herbs) is a widely used traditional Chinese medicine for sepsis treatment. However, the bioactive components of XBJI and the mechanisms responsible for its sepsis-mitigating action have not been experimentally determined. One of the main bioactive compounds in XBJI-benzoylpaeoniflorin (BPF)-inhibits the expressions of key mediators of inflammation such as nuclear factor kappa B (NF-κB), cyclooxygenase-1 (COX-1), and COX-2. However, its effects on sepsis have not been determined yet. Therefore, here, we investigated the immunomodulatory effect of BPF on severely inflamed endothelial cells, THP-1 macrophages, peritoneal macrophages, and mice. Human umbilical vein endothelial cells (HUVECs) and THP-1-macrophages were activated using lipopolysaccharide (LPS) after pretreatment with BPF. Subsequently, changes in the expression profiles of pro-inflammatory molecules including inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were determined using quantitative real-time polymerase chain reaction (qPCR) and Western blot analysis. Furthermore, we monitored the phosphorylation of NF-kB and mitogen-activated protein kinases (MAPKs) to determine their activation levels. Using the LPS-induced mouse model of sepsis, we studied the effects of BPF on inflammatory cytokine production, pulmonary histopathology, and survival rates. Finally, we evaluated whether BPF protects against cecal ligation and puncture (CLP)-induced sepsis, as it closely mimics human sepsis. BPF pretreatment inhibited LPS-induced increase in mRNA and protein levels of iNOS, TNF-α, and IL-6 in HUVECs and THP-1-macrophages. It also suppressed LPS-mediated phosphorylation of p65, p38, JNK, and ERK. Mice with LPS-induced-sepsis who were treated with BPF had lower serum levels of IL-6, TNF-α, IL-1ß, CXCL1, and CXCL2 than the control mice treated with BPF. Histopathology revealed that BPF treatment alleviated LPS-induced lung damage. In addition, in mice given a lethal dose of LPS, BPF treatment showed a dose-dependent improvement in survival rates. BPF treatment dose-dependently inhibited the LPS-induced IL-6, TNF-α, and CXCL1 production in peritoneal macrophages. BPF treatment also dose-dependently improved the survival rates in mice with CLP-induced sepsis. These results show that BPF alleviates LPS-stimulated septic conditions and protects mice from CLP-induced sepsis. Our research marks BPF as a potential drug in the treatment of sepsis and various inflammatory diseases.

Cirsilineol Treatment Attenuates PM2.5-Induced Lung Injury in Mice.

Ultrafine particulate matter with less than 2.5 µm diameter (PM2.5) is an air pollutant that causes severe lung damage. Currently, effective treatment and preventive methods for PM2.5-induced lung damage are limited. Cirsilineol (CSL) is a small natural compound isolated from Artemisia vestita. In this study, the efficacy of CSL on PM2.5-induced lung toxicity was tested, and its mechanism was identified. Lung injury was caused by intratracheal administration of PM2.5 suspension in animal models. Two days after PM2.5 pretreatment, CSL was injected via mouse tail vein for two days. The effects of CSL on PM2.5-induced lung damage, autophagy, apoptosis, and pulmonary inflammation in a mouse model and their mechanisms were investigated. CSL significantly suppressed histological lung damage and lung wet/dry weight proportion. CSL also significantly reduced PM2.5-induced autophagy dysfunction, apoptosis, lymphocyte suppression, and inflammatory cytokine levels in bronchoalveolar fluid (BALF). Furthermore, CSL increased mammalian target of rapamycin (mTOR) phosphorylation and significantly inhibited the expression of Toll-like receptors (TLR) 2 and 4, MyD88, and the autophagy proteins, Beclin1 and LC3II. Thus, CSL exerts protective effects on pulmonary damage by regulating mTOR and TLR2,4-myD88 autophagy pathways. Therefore, CSL can be used as an effective treatment for PM2.5-induced lung damage.

Inhibitory Activities of Rare Ginsenoside Rg4 on Cecal Ligation and Puncture-Induced Sepsis.

Sepsis is an uncontrolled response to inflammatory infection and is associated with high levels of mortality and morbidity. Rg4 is a rare ginsenoside mainly found in the leaves of Panax ginseng C. A. Meyer and the major protopanaxatriol-type ginsenoside of black ginseng. In this study, we determined whether Rg4 affects cecal ligation and puncture (CLP)-induced sepsis. Animals were separated into the following six groups: control group, CLP-operated group, CLP plus maslinic acid (MA), and CLP plus Rg4 (5, 10, or 15 mg/kg). Survival rate, body weight changes, inflammatory cytokines, and histological analyses were assessed. Human endothelial cells were activated with the high-mobility group box 1 (HMGB1) protein and Rg4. Cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Enzyme-linked immunosorbent assay (ELISA) and Western blot analysis were used to assess inflammation and gene expression, respectively. After CLP surgery, the Rg4-administered group exhibited a higher survival rate and body weight compared with the untreated control group. Rg4 treatment reduced cytokine levels, including tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, as well as nitric oxide (NO) levels and renal inflammation. After Rg4 treatment of HMGB1-activated cells, the expressions of toll-like receptor (TLR) 4 and TNF-α were decreased, and the activation of phosphoinositide 3-kinase (PI3K)/AKT signaling increased cell viability. In summary, Rg4 inhibited inflammation and exhibited a protective effect against CLP-induced sepsis, thereby reinforcing cell survival against septic responses.

Anti-Inflammatory and Anti-oxidant Functions of Cornuside by Regulating NF-[Formula: see text]B, STAT-1, and Nrf2-HO-1 Pathways.

Cornuside (CNS), found in the fruit of Cornus officinalis Seib, is a natural bisiridoid glucoside that possesses therapeutic effects by suppressing inflammation. This study aimed to determine whether CNS could inhibit the inflammatory response induced by lipopolysaccharide (LPS) in human umbilical vein endothelial cells (HUVECs) and mice, as well as to decipher the mechanisms. After activating HUVECs with LPS, the cells were treated with CNS. Cells were then isolated for protein or mRNA assays to analyze signaling and inflammatory molecules. In addition, mice received an intraperitoneal injection of LPS, followed by an intravenously administered dose of CNS. CNS inhibited cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) expressions induced by LPS. CNS decreased phosphorylated signal transducer and activator of transcription 1 (STAT1)-1 by promoting HO-1 expression, inhibiting nuclear factor (NF)-[Formula: see text]B-luciferase activity, and decreasing COX-2/prostaglandin E2 (PGE2) and iNOS/NO. Furthermore, CNS treatment in LPS-activated HUVECs increased the nuclear translocation of nuclear factor erythrocyte 2-related factor 2 (Nrf2) and combined Nrf2 to anti-oxidant response elements and decreased IL-1[Formula: see text] production. Reduced iNOS/NO expression by CNS was restored when HO-1 RNAi inhibited heme oxygenase-1 (HO-1). After CNS treatment in vivo, iNOS levels in lung tissue and tumor necrosis factor (TNF)-[Formula: see text] expression in the bronchoalveolar lavage fluid were significantly decreased. The results indicated that CNS increased HO-1 expression, reduced LPS-activated NF-[Formula: see text]B-luciferase activity, and inhibited iNOS/NO and COX-2/PGE2, all of which contributed to the inhibition of STAT-1 phosphorylation. Thus, CNS can be a potential new substance for treating inflammatory disorders.

Inhibition of factor Xa activity, platelet aggregation, and experimentally induced thrombosis by Sparstolonin B.

BACKGROUND: Sparstolonin B (SsnB) is an isocumarin compound extracted from medicinal plants such as Sparganium stoloniferum and Scirpus yagara with well documented anti-inflammatory activity. Here we examined if SsnB also possesses antithrombotic activity and the underlying mechanisms. METHODS: Anti-thrombotic effects of SsnB were determined by measuring in vitro/ex vivo/in vivo clotting times, platelet aggregation assay, production and activity of factor Xa, nitric oxide, and expressions of relative proteins. RESULTS: Treatment with SsnB prolonged the clotting time of human platelet-poor serum at concentrations comparable to the clinical anticoagulant rivaroxaban (as a positive control) and inhibited human platelet aggregation induced by adenosine diphosphate (ADP) or the thromboxane A2 analog U46619. SsnB also inhibited U46619-induced and ADP-induced phosphorylation of phospholipase C (PLC)γ2/protein kinase C (PKC) and intracellular calcium mobilization, both of which are required for platelet aggregation. In addition, SsnB inhibited expression of the cell adhesion factors P-selectin and PAC-1. SsnB increased production of the vasodilator nitric oxide and suppressed secretion of the vasoconstrictor endothelin-1 from ADP- or U46619-treated human umbilical vein endothelial cells. Further, SsnB reduced coagulation factor Xa (FXa) catalytic activity and production by endothelial cells as well as FXa-induced platelet aggregation. CONCLUSION: Finally, SsnB injection reduced thrombus formation time, number, size, and related mortality in mouse models of thromboembolism. SsnB is a promising antithrombotic agent targeting both FXa and platelet aggregation pathways, which can overcome the side effects of existing antithrombotic agents.

Inhibitory functions of cornuside on TGFBIp-mediated septic responses.

Transforming growth factor ß-induced protein (TGFBIp), as an extracellular matrix protein, is expressed TGF-ß in some types of cells. Experimental sepsis is mediated by expressed and released TGFBIp in primary human umbilical vein endothelial cells (HUVECs). Cornuside (CNS) is a bisiridoid glucoside compound found in the fruit of Cornus officinalis SIEB. et ZUCC. Based on the known functions of CNS, such as the immunomodulatory and anti-inflammatory activities, we tested whether TGFBIp-mediated septic responses were suppressed by CNS in human endothelial cells and mice and investigated the underlying anti-septic mechanisms of CNS. Data showed that the secretion of TGFBIp by lipopolysaccharide (LPS) and severe septic responses by TGFBIp were effectively inhibited by CNS. And, TGFBIp-mediated sepsis lethality and pulmonary injury were reduced by CNS. Therefore, the suppression of TGFBIp-mediated septic responses by CNS suggested that CNS may be used as a potential therapeutic agent for several vascular inflammatory diseases, with the inhibition of the TGFBIp signaling pathway as the mechanism of action.

Suppressive activity of RGX-365 on HMGB1-mediated septic responses

Abstract RGX-365 is the main fraction of black ginseng conmprising protopanaxatriol (PPT)-type rare ginsenosides (ginsenosides Rg4, Rg6, Rh4, Rh1, and Rg2). No studies on the antiseptic activity of RGX-365 have been reported. High mobility group box 1 (HMGB1) is recognized as a late mediator of sepsis, and the inhibition of HMGB1 release and recovery of vascular barrier integrity have emerged as attractive therapeutic strategies for the management of sepsis. In this study, we examined the effects of RGX-365 on HMGB1-mediated septic responses and survival rate in a mouse sepsis model. RGX-365 was administered to the mice after HMGB1 challenge. The antiseptic activity of RGX-365 was assessed based on the production of HMGB1, measurement of permeability, and septic mouse mortality using a cecal ligation and puncture (CLP)-induced sepsis mouse model and HMGB1-activated human umbilical vein endothelial cells (HUVECs). We found that RGX-365 significantly reduced HMGB1 release from LPS- activated HUVECs and CLP-induced release of HMGB1 in mice. RGX-365 also restored HMGB1-mediated vascular disruption and inhibited hyperpermeability in the mice. In addition, treatment with RGX-365 reduced sepsis-related mortality in vivo. Our results suggest that RGX- 365 reduces HMGB1 release and septic mortality in vivo, indicating that it is useful in the treatment of sepsis.

The Decursin Analog, CYJ-27, Suppresses Inflammation Via the Downregulation of NF-κB and STAT-1.

CYJ-27, a synthetic analog of decursin, prevents the generation of proinflammatory cytokines and oxidative stress. In this study, the effects of CYJ-27 on the regulation of inducible nitric oxide synthase (iNOS), heme oxygenase (HO)-1, and cyclooxygenase (COX-)2 were characterized in lipopolysaccharide (LPS)-treated human umbilical vein endothelial cells (HUVECs). In addition, the effects of CYJ-27 on the production of iNOS and representative proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, were tested in the lung tissues of LPS-treated mice. CYJ-27 promoted the expression of HO-1, suppressed NF-κB-luciferase activity, and reduced COX-2/PGE2 and iNOS/NO, resulting in a diminution in phosphorylated-STAT-1. Furthermore, CYJ-27 promoted the nuclear translocation of Nrf2, enhanced the combination of Nrf2 to antioxidant response elements, and diminished IL-1ß production in LPS-activated HUVECs. CYJ-27-downregulated iNOS/NO expression was rescued after the RNAi suppression of HO-1. In LPS-treated mice, CYJ-27 significantly diminished iNOS production in the lung tissues and TNF-α expression in the bronchoalveolar lavage fluid. These findings indicate that CYJ-27 exerts anti-inflammatory activities by regulating iNOS through downregulation of both NF-κB activation and phosphorylated-STAT-1. Hence, it can act as a template for the development of novel substances to treat inflammatory diseases.

Impacts of Drug Interactions on Pharmacokinetics and the Brain Transporters: A Recent Review of Natural Compound-Drug Interactions in Brain Disorders.

Natural compounds such as herbal medicines and/or phyto-compounds from foods, have frequently been used to exert synergistic therapeutic effects with anti-brain disorder drugs, supplement the effects of nutrients, and boost the immune system. However, co-administration of natural compounds with the drugs can cause synergistic toxicity or impeditive drug interactions due to changes in pharmacokinetic properties (e.g., absorption, metabolism, and excretion) and various drug transporters, particularly brain transporters. In this review, natural compound-drug interactions (NDIs), which can occur during the treatment of brain disorders, are emphasized from the perspective of pharmacokinetics and cellular transport. In addition, the challenges emanating from NDIs and recent approaches are discussed.

Natural Antioxidant and Anti-Inflammatory Compounds in Foodstuff or Medicinal Herbs Inducing Heme Oxygenase-1 Expression.

Heme oxygenase-1 (HO-1) is an inducible antioxidant enzyme that catalyzes heme group degradation. Decreased level of HO-1 is correlated with disease progression, and HO-1 induction suppresses development of metabolic and neurological disorders. Natural compounds with antioxidant activities have emerged as a rich source of HO-1 inducers with marginal toxicity. Here we discuss the therapeutic role of HO-1 in obesity, hypertension, atherosclerosis, Parkinson's disease and hepatic fibrosis, and present important signaling pathway components that lead to HO-1 expression. We provide an updated, comprehensive list of natural HO-1 inducers in foodstuff and medicinal herbs categorized by their chemical structures. Based on the continued research in HO-1 signaling pathways and rapid development of their natural inducers, HO-1 may serve as a preventive and therapeutic target for metabolic and neurological disorders.

Fisetin Suppresses Pulmonary Inflammatory Responses Through Heme Oxygenase-1 Mediated Downregulation of Inducible Nitric Oxide Synthase.

The effects of a mixture of fisetin on cytokine-mediated pulmonary damages have not been studied, despite its known antiviral, neuroprotective, and anti-inflammatory activities. Using lipopolysaccharide (LPS)-activated human pulmonary artery endothelial cells (HPAECs), we determined the effects of fisetin on the induction of heme oxygenase-1 (HO-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). In the lung tissue of LPS-treated mice, fisetin was also evaluated for its effect on the regulation of iNOS and tumor necrosis factor (TNF)-α. In LPS-activated HPAECs, fisetin increased nuclear factor erythrocyte 2-related factor 2-antioxidant response element (Nrf2-ARE) reporter activity through the nuclear translocation of Nrf2, and the expression of HO-1, and decreased IL-1ß and iNOS/NO production. In particular, the suppression of iNOS/NO expression by the administration of fisetin was dependent on HO-1. Current findings indicate that the anti-inflammatory activity of fisetin was due to its HO-1 dependent downregulation of p-STAT-1 and nuclear factor kappa B (NF-κB) and the resultant inhibition of iNOS, and also suggest TNF-α as a potential target for HO-1. We propose that administration of fisetin may be a novel approach, ideal for the treatment of inflammatory pulmonary disease.

Inhibitory functions of cardamonin against particulate matter-induced lung injury through TLR2,4-mTOR-autophagy pathways.

Particulate matter with an aerodynamic diameter equal to or less than 2.5 µm (PM2.5) is a form of air pollutant that causes significant lung damage when inhaled. Cardamonin, a flavone found in Alpinia katsumadai Heyata seeds, has been reported to have anti-inflammatory and anticoagulative activity. The aim of this study was to determine the protective effects of cardamonin on PM2.5-induced lung injury. Mice were treated with cardamonin via tail-vein injection 30 min after the intratracheal instillation of PM2.5. The results showed that cardamonin markedly reduced the pathological lung injury, lung wet/dry weight ratio, and hyperpermeability caused by PM2.5. Cardamonin also significantly inhibited PM2.5-induced myeloperoxidase (MPO) activity in lung tissue, decreased the levels of PM2.5-induced inflammatory cytokines and effectively attenuated PM2.5-induced increases in the number of lymphocytes in the bronchoalveolar lavage fluid (BALF). And, cardamonin increased the phosphorylation of mammalian target of rapamycin (mTOR) and dramatically suppressed the PM2.5-stimulated expression of toll-like receptor 2 and 4 (TLR 2,4), MyD88, and the autophagy-related proteins LC3 II and Beclin 1. In conclusion, these findings indicate that cardamonin has a critical anti-inflammatory effect due to its ability to regulate both the TLR2,4-MyD88 and mTOR-autophagy pathways and may thus be a potential therapeutic agent against PM2.5-induced lung injury.

Inhibitory effect of oolonghomobisflavan B on osteoclastogenesis by suppressing p38 MAPK activation.

Suppression of differentiation and/or function of osteoclasts is considered an effective therapeutic strategy for osteolytic bone diseases such as periodontitis and osteoporosis. Evidence regarding the health benefits of oolong tea consumption is accumulating, and tea polyphenols have various pharmacological properties such as anti-cancer and anti-diabetes effects. In this study, we investigated the effect of oolonghomobisflavan B (OFB), a polyphenolic compound in oolong tea, on osteoclast differentiation. OFB suppressed receptor activator of nuclear factor-κB (RANKL)-induced formation of tartate-resistant acid phosphatase-positive multinuclear cells without cytotoxicity. OFB also significantly attenuated p38 phosphorylation, which is essential for RANKL-induced osteoclastogenesis, and inhibited the expressions of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) and osteoclast-specific target genes, including dendritic cell-specific transmembrane protein and cathepsin K. Our findings suggest that OFB exhibits an anti-osteoclastogenic activity by inhibiting RANKL-mediated p38 activation, which is useful for the prevention and treatment of osteolytic bone diseases.

[Formula: see text], a Rare Protopanaxatriol-Type Ginsenoside Fraction from Black Ginseng, Suppresses Inflammatory Gene iNOS via the Iinhibition of p-STAT-1 and NF-[Formula: see text]B.

Black ginseng (BG), which is ginseng that has been steamed and dried nine times, and its main protopanaxatriol-type ginsenosides Rg4, Rg6, Rh4, and Rg2 have been reported to exhibit various forms of biological activity, including antiseptic, antidiabetic, wound-healing, immune-stimulatory, and anti-oxidant activity. The aim of the this study was to examine the effects of [Formula: see text] (a rare protopanaxatriol-type ginsenoside fraction; Rg2, Rg4, Rg6, Rh1, and Rh4) on heme oxygenase-1 (HO-1) induction and on the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-)2 in lipopolysaccharide (LPS)-activated human pulmonary artery endothelial cells (HPAECs). [Formula: see text] was tested to determine its effect on iNOS protein expression and inflammatory markers (interleukin [IL]-1[Formula: see text] and tumor necrosis factor [TNF]-[Formula: see text] in the lung tissue of LPS-treated mice. The results showed that [Formula: see text] induced the expression of HO-1, reduced LPS-activated NF-[Formula: see text]B-luciferase activity, and inhibited iNOS/NO and COX-2/PGE2, which contributed to the inhibition of STAT-1 phosphorylation. In particular, [Formula: see text] induced the translocation of Nrf2 from the cytosol to the nucleus by increasing Nrf2-ARE activity and decreased IL-1[Formula: see text] production in LPS-activated HPAECs. This reduction in iNOS/NO expression due to [Formula: see text] was reversed by siHO-1 RNA transfection. In LPS-treated mice, [Formula: see text] significantly reduced lung tissue iNOS protein levels and TNF-[Formula: see text] levels in the bronchoalveolar lavage fluid. In conclusion, these findings indicate that [Formula: see text] has a critical anti-inflammatory effect due to its ability to regulate iNOS via the inhibition of p-STAT-1 and NF-[Formula: see text]B, and thus it may be suitable for the treatment of inflammatory disease.

Inhibitory functions of maslinic acid, a natural triterpene, on HMGB1-mediated septic responses.

BACKGROUND: Maslinic acid (MA), a natural triterpenoid from Olea europaea, prevents oxidative stress and pro-inflammatory cytokine generation. High mobility group box 1 (HMGB1) has been recognized as a late mediator of sepsis, and the inhibition of the release of HMGB1 and the recovery of vascular barrier integrity have emerged as attractive therapeutic strategies for the management of sepsis. METHODS: We tested the hypothesis that MA induces sirtuin 1 and heme oxygenase-1, which inhibit the release of HMGB1 in lipopolysaccharide (LPS)-stimulated cells, thus inhibiting HMGB1-induced hyperpermeability and increasing the survival of septic mice. MA was administered after LPS or HMGB1 challenge, and the antiseptic activity of MA was determined based on permeability, the activation of pro-inflammatory proteins, and the production of markers for tissue injury in HMGB1-activated human umbilical vein endothelial cells (HUVECs) and a cecal ligation and puncture (CLP)-induced sepsis mouse model. RESULTS: MA significantly reduced the release of HMGB1 in LPS-activated HUVECs and attenuated the CLP-induced release of HMGB1. Additionally, MA alleviated HMGB1-mediated vascular disruption and inhibited hyperpermeability in mice, and in vivo analysis revealed that MA reduced sepsis-related mortality and tissue injury. CONCLUSION: Taken together, the present results suggest that MA reduced HMGB1 release and septic mortality and thus may be useful in the treatment of sepsis.

Hepatoprotective effects of vicenin-2 and scolymoside through the modulation of inflammatory pathways.

The aim of this study was to investigate the effects of two structurally related flavonoids found in Cyclopia subternata, vicenin-2 (VCN) and scolymoside (SCL) on lipopolysaccharide (LPS)-induced liver failure in mice and to elucidate underlying mechanisms. Mice were treated intravenously with VCN or SCL at 12 h after LPS treatment. LPS significantly increased mortality, serum levels of alanine transaminase, aspartate transaminase, and inflammatory cytokines, and toll-like receptor 4 (TLR4) protein expression; these effects of LPS were inhibited by VCN or SCL. It also attenuated the LPS-induced activation of myeloid differentiation primary response gene 88 and TLR-associated activator of interferon-dependent signaling pathways of the TLR system. Our results suggest that VCN or SCL protects against LPS-induced liver damage by inhibiting the TLR-mediated inflammatory pathway, indicating its potential to treat liver diseases.

Suppressive functions of collismycin C in TGFBIp-mediated septic responses.

Transforming growth factor ß-induced protein (TGFBIp) is an extracellular matrix protein; its expression by several cell types is greatly increased by TGF-ß. TGFBIp is released by primary human umbilical vein endothelial cells (HUVECs) and functions as a mediator of experimental sepsis. 2,2'-Bipyridine-containing natural products are generally accepted to have antimicrobial, cytotoxic and anti-inflammatory properties. We hypothesized that a 2,2'-bipyridine containing natural product, collismycin C, could reduce TGFBIp-mediated severe inflammatory responses in human endothelial cells and mice. Here we investigated the effects and underlying mechanisms of collismycin C against TGFBIp-mediated septic responses. Collismycin C effectively inhibited lipopolysaccharide-induced release of TGFBIp and suppressed TGFBIp-mediated septic responses. In addition, collismycin C suppressed TGFBIp-induced sepsis lethality and pulmonary injury. This suppression of TGFBIp-mediated and CLP-induced septic responses indicates that collismycin C is a potential therapeutic agent for various severe vascular inflammatory diseases, with inhibition of the TGFBIp signaling pathway as the mechanism of action.