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Secoeudesma sesquiterpenes lactone A (SESLA) is a sesquiterpene derived fromTo set up a GThis study demonstrated that SESLA treatment significantly reduced the levels of inflammatory cytokines stimulated by PGN, Pam3CSK4 or even MRSAThe present study validated the notable anti-inflammatory activity of SESLA and discovered its previously uncharacterized immunoregulatory role and the underlying mechanism in G

Tuberculosis (TB) remains a leading threat to public health worldwide with Mycobacterium tuberculosis (Mtb) infections causing long-term abnormal and excessive inflammatory responses, which in turn lead to lung damage and fibrosis, and ultimately death. Host-directed therapy (HDT) has been shown to be an effective anti-TB strategy in the absence of effective anti-TB drugs. Here, we used an in vitro macrophage model of Mtb infection to evaluate the effects of andrographolide (Andro), extracted from Andrographis paniculata, on pyroptosis in Mtb-infected macrophages. We evaluated the molecular mechanisms underlying these outcomes. These evaluations revealed that Andro downregulated the expression of proinflammatory miR-155-5p, which then promoted the expression of Nrf2 to suppress pyroptosis in Mtb-infected macrophages. Further study also demonstrated that siNrf2 could attenuate the inhibitory effect of Andro on TXNIP, validating our mechanistic studies. Thus, our data suggest that Andro may be a potential candidate adjuvant drug for anti-TB therapy as it inhibits pyroptosis in Mtb-infected macrophages, potentially improving clinical outcomes.

Diets rich in quercitrin show a neuroprotective effect, but the mechanism is not very clear at present. The objective of this study is to explore the effect and mechanism of quercitrin in the treatment of alzheimer's disease (AD).5XFAD transgenic mice were fed with a diet supplemented with quercitrin for three consecutive months. Behavioral experiments were conducted to assess the cognitive ability, luminex liquid chip technology was used to assess the production of proinflammatory cytokines and immunohistochemistry was used to elucidate the activation of microglia.Quercitrin increased the frequency in exploring new objects, shortened the escape latency and increased the frequency crossing the platform in AD model mice. Quercitrin inhibited the activation and proliferation of microglia, inhibited the secretion of inflammatory cytokines and chemokines and reduced the accumulation of amyloid-β plaques in AD model mice.Quercitrin improved mice cognitive impairment through alleviating the intensity of inflammatory response and is a promising medicinal plant extract in the treatment of AD.

The genus Glycyrrhiza is a small perennial herb that has been traditionally used to treat many diseases across the world. Licorice (Gancao in Chinese) is the dried root and rhizome of G. glabra, G. uralensis or G. inflata. Licorice plays an important role in traditional Chinese medicine (TCM), and is the most frequently used in Chinese herbal formulas. Isoliquiritigenin (ISL) is a flavonoid extracted from licorice, and has been evaluated for its various biological activities, including anti-inflammatory, anti-tumor and anti-oxidant activities. Excessive and persistent inflammation in the Mycobacterium tuberculosis (Mtb) infection is not conducive to the elimination of Mtb, but contributes to serious pulmonary dysfunction.This study aimed to examine the anti-inflammatory effects of ISL in the Mtb infection.In vitro models of Mtb-infected macrophages were established. Murine macrophage Raw 264.7 cells and primary peritoneal macrophages were used in this study. Cell viability was determined by the cell counting kit-8 (CCK-8) assay. The effects of ISL on the secretion levels of interleukin -1β (IL-1β), tumor necrosis factor -α (TNF-α), and interleukin -6 (IL-6) were detected by the enzyme-linked immunosorbent assay (ELISA). The expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2) were measured by the real time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot. Western blot was used to assess the effects of ISL on the activation of NLRP3 inflammasome and Notch1/NF-κB and MAPK signaling pathways. Immunofluorescence assays was used to detected the translocation of phosphorylation of p65 subunit of NF-κB.It was revealed that ISL inhibited the secretion of IL-1β and the activation of pore-forming protein (gasdermin D, GSDMD) by suppressing the activation of NLPR3 inflammasome induced by Mtb infection. ISL was also shown to have promising inhibitory effects on inflammatory factors, such as TNF-α, IL-6, iNOS and COX2. Regarding the anti-inflammatory mechanism of ISL, it was found that ISL exerted its anti-inflammatory effects by inhibiting the activation of Notch1/NF-κB and MAPK signaling pathways.ISL reduced Mtb-induced inflammation through the Notch1/NF-κB and MAPK signaling pathways. ISL might be used as a potential adjuvant drug to treat tuberculosis by adjusting host immune responses.

Mϕs are the main innate immune cells in the lung at homeostasis, with important roles in host defence and immune modulation. Alveolar Mϕs (AMs) and interstitial Mϕs (IMs) are the two lung Mϕ subsets, so called according to the sites they reside in. These subsets are also defined by their origins and immunological microenvironment, which endow these cells with distinct features and plasticity. This review summarizes the latest definitions and functions of lung Mϕs during homeostasis and provides exemplar of their divergent roles in lung fibrosis.

Discussion on the identification of GPER as a potential therapeutic target for asthma through Chinese herb-driven drug discovery strategy.

Growing evidence indicates that silibinin (SLB), a main component extracted from Chinese herb Silybum marianum, can effectively antagonize doxorubicin (DOX) induced myocardial injury (DIMI), but the specific molecular mechanism is still unelucidated. Herein, DOX induced human AC16 cardiomyocyte injury model and Network Pharmacology are used to predict and verify the potential mechanism. The analysis results of the core PPI network of SLB against DIMI show that JAK/STAT signaling pathway and autophagy are significantly enriched. Molecular docking results indicate that SLB has stronger binding ability to signaling key proteins IL6ST, JAK2 and STAT3 (affinity ≤ -7.0 kcal/mol). The detection results of pathway activation and autophagy level demonstrate that SLB significantly alleviates DOX induced IL6ST/JAK2/STAT3 signaling pathway inhibition and autophagy inhibition, reduces the death rate of cardiomyocytes. This protective effect of SLB is eliminated when key pathway proteins (IL6ST, JAK2, STAT3) are knocked down or autophagy is inhibited (3-MA or Beclin1 knockdown). These results suggest that the regulation of IL6ST/JAK2/STAT3 signaling pathway and autophagy may be important mechanism for SLB's protective effect on DOX injured cardiomyocytes. Further experimental results prove that knockdown of IL6ST, JAK2 and STAT3 eliminate the mitochondrial ROS scavenging effect and autophagy promoting effect of SLB. In sum, SLB can decrease the mitochondrial ROS and restore autophagy to antagonize DOX-induced cardiomyocyte injury by activating IL6ST/JAK2/STAT3 signaling pathway.

Background The traditional Chinese medicine (TCM) formula Qing-Fei-Pai-Du decoction (QFPDD) was the most widely used prescription in China's campaign to contain COVID-19, which has exhibited positive effects. However, the underlying mode of action is largely unknown. Purpose A systems pharmacology strategy was proposed to investigate the mechanisms of QFPDD against COVID-19 from molecule, pathway and network levels. Study design and methods The systems pharmacological approach consisted of text mining, target prediction, data integration, network study, bioinformatics analysis, molecular docking, and pharmacological validation. Especially, we proposed a scoring method to measure the confidence of targets identified by prediction and text mining, while a novel scheme was used to identify important targets from 4 aspects. Results 623 high-confidence targets of QFPDD's 12 active compounds were identified, 88 of which were overlapped with genes affected by SARS-CoV-2 infection. These targets were found to be involved in biological processes related with the development of COVID-19, such as pattern recognition receptor signaling, interleukin signaling, cell growth and death, hemostasis, and injuries of the nervous, sensory, circulatory, and digestive systems. Comprehensive network and pathway analysis were used to identify 55 important targets, which regulated 5 functional modules corresponding to QFPDD's effects in immune regulation, anti-infection, anti-inflammation, and multi-organ protection, respectively. Four compounds (baicalin, glycyrrhizic acid, hesperidin, and hyperoside) and 7 targets (AKT1, TNF-α, IL6, PTGS2, HMOX1, IL10, and TP53) were key molecules related to QFPDD's effects. Molecular docking verified that QFPDD's compounds may bind to 6 host proteins that interact with SARS-CoV-2 proteins, further supported the anti-virus effect of QFPDD. At last, in intro experiments validated QFPDD's important effects, including the inhibition of IL6, CCL2, TNF-α, NF-κB, PTGS1/2, CYP1A1, CYP3A4 activity, the up-regulation of IL10 expression, and repressing platelet aggregation. Conclusion This work illustrated that QFPDD could exhibit immune regulation, anti-infection, anti-inflammation, and multi-organ protection. It may strengthen the understanding of QFPDD and facilitate more application of this formula in the campaign to SARS-CoV-2., Graphical abstract Image, graphical abstract

The nuclear Dbf2-related (NDR) kinases NDR1 and NDR2 belong to the NDR/LATS (large tumor suppressor) subfamily in the Hippo signaling pathway. They are highly conserved from yeast to humans. It is well-known that NDR1/2 control important cellular processes, such as morphological changes, centrosome duplication, cell proliferation, and apoptosis. Recent studies revealed that NDR1/2 also play important roles in the regulation of infection and inflammation. In this review, we summarized the roles of NDR1/2 in the modulation of inflammation induced by cytokines and innate immune response against the infection of bacteria and viruses, emphasizing on how NDR1/2 regulate signaling transduction through Hippo pathway-dependent and -independent manners.

A leading cause of death worldwide is sepsis that develops as a dysregulated immune response to infection. Serious infection caused by methicillin-resistant Staphylococcus aureus (MRSA) increases the difficulty of treatment in septic patients. Host-directed therapy (HDT) is an emerging approach to bacterial infections. Xuebijing injection (XBJ), a commercialized injectable prescription from traditional Chinese medicine, has been used as adjuvant therapy for sepsis with a history of 15 years. Whether it plays a protective role in severe infection caused by antibiotic-resistant bacteria is still unknown. In this study, XBJ significantly improved the survival of MRSA-induced sepsis mice. In MRSA-infected mouse model, XBJ down-regulated the expression of inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, MCP-1, MIP-2, and IL-10 in sera. Besides that, it decreased the bacterial load in spleens, livers, and alleviated tissue damage of lung, liver, and kidney. The combination of XBJ with vancomycin or dexamethasone exhibited a better down-regulatory role of the inflammatory response. Then, the protective mechanism of XBJ was further investigated. XBJ inhibited heat-killed MRSA-induced IL-6 and TNF-α production in mouse macrophages. XBJ also decreased Pam3CSK4 (a synthetic tripalmitoylated lipopeptide mimicking bacterial lipoproteins)-stimulated expression of IL-6, TNF-α, IL-1β, IL-12, etc. in mouse macrophages. Furthermore, XBJ down-regulated the activation of NF-κB, MAPK, and PI3K/Akt pathways in Pam3CSK4-stimulated mouse macrophages. In conclusion, our findings demonstrated that XBJ played a protective role in MRSA-challenged mice and down-regulated the inflammatory response and the activation of signaling pathways initiated by Pam3CSK4. It enlarged the clinical application of XBJ in the treatment of severe bacterial infection, e.g. caused by MRSA.

Idiopathic pulmonary fibrosis (IPF) is the most severe form of lung fibrosis. It is progressive, and has an extremely poor outcome and limited treatment options. The disease exclusively affects the lungs, and thus less attention has been focused on blood-borne immune cells. which could be a more effective therapeutic target than lung-based cells. Here, we questioned if circulating monocytes, which has been shown to be increased in IPF, bore abnormalities that might contribute to its pathogenesis. We found that levels of circulating monocytes correlated directly with the extent of fibrosis in the lungs, and increased further during acute clinical deterioration. Monocytes in IPF were phenotypically distinct, displaying increased expression of CD64, a type 1 IFN gene expression signature and a greater magnitude of type 1 IFN response when stimulated. These abnormalities were accompanied by markedly raised CSF-1 levels in the serum, prolonged survival of monocytesex vivo, and increased numbers of monocytes in lung tissue. Our study defines the key monocytic abnormalities in IPF, proposing type 1 IFN-primed monocytes as a potential driver of an aberrant repair response and fibrosis. It provides a rationale for targeting monocytes and identifies monocytic CD64 as a potential specific therapeutic target for IPF.

Cell specific and cytokine targeted therapeutics have underperformed in systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs) have emerged as a novel therapy to address the dysregulation in autoimmune diseases but also have limitations. Human gingiva derived MSCs (GMSCs) are superior in regulating immune responses. Here, we demonstrate that the adoptive transfer of GMSCs homes to and maintains in the kidney and has a robust therapeutic effect in a spontaneous lupus nephritis model. Specifically, GMSCs limits the development of autoantibodies as well as proteinuria, decreases the frequency of plasma cells and lupus nephritis histopathological scores by directly suppressing B cells activation, proliferation and differentiation. The blockage of CD39

Background: In recent years, long non-coding RNAs (lncRNAs) are emerging as crucial regulators in the immunological process of liver hepatocellular carcinoma (LIHC). Increasing studies have found that some lncRNAs could be used as a diagnostic or therapeutic target for clinical management, but little research has investigated the role of immune-related lncRNA in tumor prognosis. In this study, we aimed to develop an immune lncRNA signature for the precise diagnosis and prognosis of liver hepatocellular carcinoma. Methods: Gene expression profiles of LIHC samples obtained from TCGA were screened for immune-related genes using two reference gene sets. The optimal immune-related lncRNA signature was built via correlational analysis, univariate and multivariate cox analysis. Then the Kaplan-Meier plot, ROC curve, clinical analysis, gene set enrichment analysis, and principal component analysis were carried out to evaluate the capability of immune lncRNA signature as a prognostic indicator. Results: Six long non-coding RNA MSC−AS1, AC009005.1, AL117336.3, AL031985.3, AL365203.2, AC099850.3 were identified via correlation analysis and cox regression analysis considering their interactions with immune genes. Next, tumor samples were separated into two risk groups by the signature with different clinical outcomes. Stratification analysis showed the prognostic ability of this signature acted as an independent factor. The AUC value of ROC curve was 0.779. The Kaplan-Meier method was used in survival analysis and results showed a statistical difference between the two risk groups. The predictive performance of this signature was validated by principal component analysis (PCA). Data from gene set enrichment analysis (GSEA) further unveiled several potential biological processes of these biomarkers may involve in. Conclusion: In summary, the study demonstrated the potential role of the six-lncRNA signature served as an independent prognostic factor for LIHC patients.

Portulaca oleracea L. is a traditional Chinese medicine, which has been used as adjuvant therapy for inflammatory bowel disease (IBD). However, the mechanism of its activity in IBD still remains unclear. Since previous studies have documented the anti-inflammatory effect of peroxisome proliferator activated receptors-γ (PPAR-γ), Portulaca regulation of PPAR-γ in inflammation was examined in current study. Ulcerative colitis (UC) was generated by 5% dextran sulfate sodium (DSS) in mice and four groups were established as normal control, DSS alone, DSS plus mesalamine, and DSS plus Portulaca. Severity of UC was evaluated by body weight, stool blood form, and length of colorectum. Inflammation was examined by determination of inflammatory cytokines (TNF-a, IL-6, and IL-1a). Portulaca extract was able to attenuate development of UC in DSS model similar to the treatment of mesalazine. Moreover, Portulaca extract inhibited proinflammatory cytokines release and reduced the level of DSS-induced NF-κB phosphorylation. Furthermore, Portulaca extract restored PPAR-γ level, which was reduced by DSS. In addition, Portulaca extract protected DSS induced apoptosis in mice. In conclusion, Portulaca extract can alleviate colitis in mice through regulation of inflammatory reaction, apoptosis, and PPAR-γ level; therefore, Portulaca extract can be a potential candidate for the treatment of IBD.

Mycobacterium tuberculosis(Mtb) remains a significant menace to global health as it induces granulomatous lung lesions and systemic inflammatory responses during active tuberculosis (TB). Micheliolide (MCL), a sesquiterpene lactone, was recently reported to have a function of relieving LPS-induced inflammatory response, but the regulative role of MCL on the immunopathology of TB still remains unknown. In this experiment, we examined the inhibitory effect of MCL on Mtb-induced inflammatory response in mouse macrophage-like cell line Raw264.7 by downregulating the activation of nuclear factor kappa B (NF-κB) and NLRP3 inflammasome. Evidences showed that MCL decreased the secretion of Mtb-induced inflammatory cytokines (IL-1βand TNF-α) in a dose-dependent manner. Meanwhile, MCL dramatically suppressed Mtb-induced activation of iNOS and COX2 as well as subsequent production of NO. Furthermore, MCL inhibited Mtb-induced phosphorylation of Akt (Ser 473) in Raw264.7. According to our results, MCL plays an important role in modulating Mtb-induced inflammatory response through PI3K/Akt/NF-κB pathway and subsequently downregulating the activation of NLRP3 inflammasome. Therefore, MCL may represent as a potential drug candidate in the adjuvant treatment of TB by regulating host immune response.

Tuberculosis is a serious public health problem aggravated by the slow progress in the development of new anti-tuberculosis drugs. The hyper-reactive TB patients have suffered from chronic inflammation which could cause deleterious effects on their bodies. Therefore, it is imperative to develop an adjunctive therapy based on inflammatory modulation during Mycobacterium tuberculosis (Mtb) infection. The present study aims to investigate the immune regulatory effects of Andrographolide (Andro) on Mtb-infected macrophages and its underlying mechanisms. The results showed that Andro inhibits the production of IL-1β and other inflammatory cytokines in a dose-dependent manner. The down-regulation of IL-1β expression causes the declining expression of IL-8 and MCP-1 in lung epithelial cells which were co-cultured with Mtb-infected macrophages. The inhibition of the activation of NF-κB pathway, but not the inhibition of MAPK signaling pathway, accounts for the anti-inflammatory role of Andro. Further studies elucidated that Andro could evoke the activation of autophagy to degrade NLRP3, which ultimately inhibited inflammasome activation and subsequent IL-1β production. Finally, the relevant results demonstrated that Andro inhibited the Notch1 pathway to down-regulate the phosphorylation of Akt/mTOR and NF-κB p65 subunit. Taken together, Andro has been found to suppress the Notch1/Akt/NF-κB signaling pathway. Both Akt inhibition-induced autophagy and inhibition of the NF-κB pathway contributed to restraining the activation of NLRP3 inflammasome and subsequent IL-1β production. Then, the decreased production of IL-1β influenced chemokine expression in lung epithelial cells. Based on these results, anti-inflammatory effect of Andro in TB infection is merit further investigation.

Sepsis was redefined as life-threatening organ dysfunction caused by a dysregulated host response to infection in 2016. One of its most common causes is Staphylococcus aureus, especially methicillin-resistant Staphylococcus aureus (MRSA), which leads to a significant increase in morbidity and mortality. Therefore, innovative and effective approaches to combat MRSA infection are urgently needed. Recently, host-directed therapy (HDT) has become a new strategy in the treatment of infectious diseases, especially those caused by antibiotic-resistant bacteria. Baicalin (BAI) is the predominant flavonoid and bioactive compound isolated from the roots of Radix Scutellariae (Huang Qin), a kind of traditional Chinese medicine. It has been reported that BAI exhibits multiple biological properties such as anti-oxidant, antitumor, and anti-inflammatory activities. However, the therapeutic role of BAI in MRSA infection is still unknown. In this study, it is found that BAI treatment inhibited the production of IL-6, TNF-α, and other cytokines from MRSA- or bacterial mimics-stimulated Mϕs and dendritic cells (DCs). BAI played an anti-inflammatory role by inhibiting the activation of ERK, JNK MAPK, and NF-κB pathways. Moreover, the serum level of TNF-α was decreased, whereas IL-10 was increased, in mice injected with MRSA. Furthermore, the bacterial load in livers and kidneys were further decreased by the combination of BAI and vancomycin (VAN), which might account for the amelioration of tissue damage. BAI reduced the high mortality rate caused by MRSA infection. Collectively, the results suggested that BAI may be a viable candidate of HDT strategy against severe sepsis caused by antibiotic-resistant bacteria such as MRSA.

Cell specific and cytokine targeted therapeutics have underperformed in systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs) have emerged as a novel therapy to address the dysregulation in autoimmune diseases but also have limitations. Human gingiva derived MSCs (GMSCs) are superior in regulating immune responses. Here, we demonstrate that the adoptive transfer of GMSCs homes to and maintains in the kidney and has a robust therapeutic effect in a spontaneous lupus nephritis model. Specifically, GMSCs limits the development of autoantibodies as well as proteinuria, decreases the frequency of plasma cells and lupus nephritis histopathological scores by directly suppressing B cells activation, proliferation and differentiation. The blockage of CD39-CD73 pathway dramatically abrogates the suppressive capacities of GMSCs in vitro and in vivo and highlights the significance of this signaling pathway in SLE. Collectively, manipulation of GMSCs provides a promising strategy for the treatment of patients with SLE and other autoimmune diseases.

Ethnopharmacological relevance Secoeudesma sesquiterpenes lactone A (SESLA) is a sesquiterpene compound isolated from Inula japonica Thunb. (I. japonica). It is an herb widely distributed in Asian countries often used for the treatment of various conditions including tumors, bronchitis and bacterial and viral infections. It has been reported that SESLA could significantly inhibit the production of nitric oxide (NO) by lipopolysaccharide (LPS) in Raw264.7 cells. However, the mechanism responsible for this anti-inflammatory role and its role in the treatment of antibiotic-resistant bacterial infection, e.g., carbapenem-resistant Klebsiella pneumoniae (CRKP), remain to be investigated. Aim of the study This study was carried out to investigate the protective anti-inflammatory role and the underlying molecular mechanisms of SESLA in LPS or CRKP evoked inflammation. Materials and methods ELISA and PCR were utilized to detect the expression of inflammatory mediators in LPS or heat-killed CRKP (HK CRKP)-stimulated immune cells containing different concentrations of SESLA. The protective role of SESLA was observed in mice challenged with a lethal dose of CRKP. Mice were intraperitoneally injected with CRKP to create a septic mouse model to evaluate the protective role of SESLA in vivo. Phosphorylated proteins, which represented the activation of signaling pathways, were examined by Western blot. Results SESLA was showed to inhibit the expression of inflammatory mediators in various macrophages and dendritic cells upon stimulation of LPS or HK CRKP. It also facilitated phagocytosis of bacteria by Raw264.7 cells. The combined use of SELSA and the ineffective antibiotic, meropenem, increased the survival rate of CRKP infected mice from 25% to 50%. ERK, NF-κB and PI3K/Akt pathways accounted for the anti-inflammatory role of SESLA with the stimulation of LPS. Conclusion According to the notable anti-inflammatory effect in vitro and its joint protective effects on a septic mouse model, SESLA might act as an adjuvant drug candidate for sepsis, even those caused by antibiotic-resistant bacteria, e.g., CRKP.

Tuberculosis (TB) remains a leading killer worldwide among infectious diseases and the effective control of TB is still challenging. Autophagy is an intracellular self-digestion process which has been increasingly recognized as a major host immune defense mechanism against intracellular microorganisms like Mycobacterium tuberculosis (Mtb) and serves as a key negative regulator of inflammation. Clinically, chronic inflammation surrounding Mtb can persist for decades leading to lung injury that can remain even after successful treatment. Adjunct host-directed therapy (HDT) based on both antimycobacterial and anti-inflammatory interventions could be exploited to improve treatment efficacy and outcome. Autophagy occurring in the host macrophages represents a logical host target. Here, we show that herbal medicine, baicalin, could induce autophagy in macrophage cell line Raw264.7 and caused increased killing of intracellular Mtb. Further, baicalin inhibited Mtb-induced NLRP3 inflammasome activation and subsequent inflammasome-derived IL-1β. To investigate the molecular mechanisms of baicalin, the signaling pathways associated with autophagy were examined. Results indicated that baicalin decreased the levels of phosphorylated protein kinase B (p-Akt) and phosphorylated mammalian target of rapamycin (p-mTOR) at Ser473 and Ser2448, respectively, but did not alter the phosphorylation of p38, JNK, or ERK both in Raw264.7 and primary peritoneal macrophages. Moreover, baicalin exerted an obvious inhibitory effect on nuclear factor-kappa B (NF-κB) activity. Finally, immunofluorescence studies demonstrated that baicalin promoted the co-localization of inflammasome with autophagosome may serve as the underlying mechanism of autophagic degradative effect on reducing inflammasome activation. Together, baicalin definitely induces the activation of autophagy on the Mtb-infected macrophages through PI3K/Akt/mTOR pathway instead of MAPK pathway. Furthermore, baicalin inhibited the PI3K/Akt/NF-κB signal pathway, and both autophagy induction and NF-κB inhibition contribute to limiting the NLRP3 inflammasome as well as subsequent production of pro-inflammatory cytokine IL-1β. Based on these results, we conclude that baicalin is a promising antimycobacterial and anti-inflammatory agent which can be a novel candidate for the development of new adjunct drugs targeting HDT for possible improved treatment.

Staphylococcus aureus is a Gram-positive (G+) bacterium that causes a wide range of diseases in humans and livestock. Therefore, the development of innovative and effective therapies is essential for the treatment of S. aureus-induced severe infections. Ephedrine hydrochloride (EH) is a compound derived from ephedrine and is widely used for the management of cardiovascular diseases and hypotension. The results of our previous studies demonstrated that EH has anti-inflammatory activity in macrophages and protects against endotoxic shock. However, whether EH regulates the function of dendritic cells (DCs) and the immune response in S. aureus-induced infection is unknown. In this study, the anti-inflammatory and regulatory activity of EH on DCs was evaluated. EH increased the production of anti-inflammatory cytokine IL-10 and decreased the production of proinflammatory cytokines TNF-α and IL-12 in DCs stimulated with peptidoglycan (PGN), the main cell wall component in G+ bacteria. The PI3K/Akt and p38 MAPK signaling pathways controlled EH-induced IL-10 expression and EH-inhibited TNF-α expression, respectively. The PGN-induced expression of co-stimulatory molecules CD40, CD80, CD86, and MHC class II molecule Iab was down-regulated in DCs by EH. Furthermore, EH protected the liver and kidney and increased the survival rate of mice with S. aureus-induced peritonitis. In conclusion, EH helps to keep immune homeostasis and alleviate organ damage during S. aureus-induced peritonitis. Therefore, EH may be a promising drug candidate in the treatment of S. aureus-induced severe infections and other invasive G+ bacterial infections.

Sepsis is the principal cause of fatality in the intensive care units worldwide. It involves uncontrolled inflammatory response resulting in multi-organ failure and even death. Micheliolide (MCL), a sesquiterpene lactone, was reported to inhibit dextran sodium sulphate (DSS)-induced inflammatory intestinal disease, colitis-associated cancer and rheumatic arthritis. Nevertheless, the role of MCL in microbial infection and sepsis is unclear. We demonstrated that MCL decreased lipopolysaccharide (LPS, the main cell wall component of Gram-negative bacteria)-mediated production of cytokines (IL-6, TNF-α, MCP-1, etc) in Raw264.7 cells, primary macrophages, dendritic cells and human monocytes. MCL plays an anti-inflammatory role by inhibiting LPS-induced activation of NF-κB and PI3K/Akt/p70S6K pathways. It has negligible impact on the activation of mitogen-activated protein kinase (MAPK) pathways. In the acute peritonitis mouse model, MCL reduced the secretion of IL-6, TNF-α, IL-1β, MCP-1, IFN-β and IL-10 in sera and ameliorated lung and liver damage. MCL down-regulated the high mortality rate caused by lethal LPS challenge. Collectively, our data illustrated that MCL enabled maintenance of immune equilibrium may represent a potentially new anti-inflammatory and immunosuppressive drug candidate in the treatment of sepsis and septic shock.

Background The Mycobacterium tuberculosis (Mtb) proteasome has been established as a viable target for the development of anti-tuberculosis agents. In this study, the inhibitory activities of 100 plant-derived natural products on the Mtb proteasome were analyzed to identify novel potential inhibitors. Methods The fluorescent substrate Suc-Leu-Leu-Val-Tyr-AMC can be hydrolyzed by the proteasome to release free AMC, the fluorescence of which is proportional to the proteasome activity. The inhibitory activities of 100 natural products (each at a final concentration of 200 μM) were detected by this method using MG132 as a positive control. Results Twelve of these natural products (10 of which were flavonoids) inhibited the activity of the Mtb proteasome by more than 65%. Comparison of the structural differences between the flavonoids with good inhibitory activity and those without inhibitory activity revealed that the hydroxyl at the flavonoid C ring C-3 or the hydroxyl/methoxyl at the flavonoid A ring C-6 were critical for the inhibition of proteasomal activity. Conclusions These data indicate that flavonoids represent a basis for rational structural design in the process of novel anti-tuberculosis drug discovery.

All-trans retinoic acid (ATRA) is a revolutionary agent for acute promyelocytic leukemia (APL) treatment via differentiation induction. However, ATRA treatment also increases cytokine, chemokine, and adhesive molecule (mainly ICAM-1) expression, which can cause clinical complications, including a severe situation known as differentiation syndrome (DS) which can cause death. Therefore, it is of clinical significance to find a strategy to specifically blunt inflammatory effects while preserving differentiation. Here we report that the natural compound, celastrol, could effectively block lung infiltrations in DS animal models created by loading ATRA-induced APL cell line NB4. In ATRA-treated NB4 cells, celastrol could potently inhibit ICAM-1 elevation and partially reduce TNF-α and IL-1β secretion, though treatment showed no effects on IL-8 and MCP-1 levels. Celastrol's effect on ICAM-1 in ATRA-treated NB4 was related to reducing MEK1/ERK1 activation. Strikingly and encouragingly, celastrol showed no obvious effects on ATRA-induced NB4 differentiation, as determined by morphology, enzymes, and surface markers. Our results show that celastrol is a promising and unique agent for managing the side effects of ATRA application on APL, and suggest that hyper-inflammatory ability is accompanied by, but not necessary for, APL differentiation. Thus we offered an encouraging novel strategy to further improve differentiation therapy.

Approaches for controlling inflammatory responses and reducing the mortality rate of septic patients remain clinically ineffective; new drugs need to be identified that can induce anti-inflammatory responses. Ephedrine hydrochloride (EH) is a compound that is widely used in cardiovascular diseases, especially to treat hypotension caused by either anesthesia or overdose of antihypertensive drugs. In this study, we reported that EH also plays an important role in the control of the inflammatory response. EH increased IL-10 and decreased proinflammatory cytokine (IL-6, tumor-necrosis factor (TNF)-α, IL-12 and IL-1β) expression in primary peritoneal macrophages and Raw264.7 cells treated with peptidoglycan (PGN), a Gram-positive cell wall component. The anti-inflammatory role of EH was also demonstrated in an experimental mouse model of peritonitis induced by intraperitoneal PGN injection. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway was found to be responsible for the EH-mediated increase in IL-10 production and decrease in IL-6 expression. Therefore, our results illustrated that EH can help maintain immune equilibrium and diminish host damage by balancing the production of pro- and anti-inflammatory cytokines after PGN challenge. EH may be a new potential anti-inflammatory drug that can be useful for treating severe invasive Gram-positive bacterial infection.

Sepsis and its derivative endotoxic shock are still serious conditions with high mortality in the intensive care unit. The mechanisms that ensure the balance of proinflammatory cytokines and anti-inflammatory cytokine production are of particular importance. As an active α- and β-adrenergic agonist, ephedrine hydrochloride (EH) is a widely used agent for cardiovascular diseases, especially boosting blood pressure. Here we demonstrate that EH increased Toll-like receptor 4 (TLR4)-mediated production of interleukin 10 (IL-10) through p38 MAPK activation. Simultaneously, EH negatively regulated the production of proinflammatory cytokines. Consistently, EH increased lipopolysaccharide (LPS)-induced serum IL-10 and inhibited tumor necrotic factor-α (TNFα) production in vivo. As a result, EH treatment protected mice from endotoxic shock by lethal LPS challenge. In brief, our data demonstrated that EH could contribute to immune homeostasis by balancing the production of proinflammatory cytokines and anti-inflammatory cytokine in TLR4 signaling. This study provides a potential usage of EH in autoimmunologic diseases or other severe inflammations.

RIG-I–like helicases and TLRs are critical sensors in the induction of type I IFN and proinflammatory cytokines to initiate innate immunity against invading pathogens. However, the mechanisms for the full activation of TLR and RIG-I–triggered innate response remain to be fully investigated. Grb2-associated binder 1 (Gab1), a member of scaffolding/adaptor proteins, can mediate signal transduction from many receptors, however, whether and how Gab1 is required for TLR and RIG-I–triggered innate responses remain unknown. In this study, we demonstrated that Gab1 significantly enhances TLR4-, TLR3-, and RIG-I–triggered IL-6, IL-1β, and IFN-α/β production in macrophages. Gab1 knockdown in primary macrophages or Gab1 deficiency in mouse embryonic fibroblasts significantly suppresses TLR3/4- and RIG-I–triggered production of IL-6, IL-1β, and IFN-α/β. Consistently, Gab1 deficiency impairs vesicular stomatitis virus (VSV) infection-induced IFN-α/β production. In addition to promoting both MyD88- and TLR/IL-1 receptor domain-containing adaptor protein inducing IFN-β–dependent MAPKs and NF-κB activation, Gab1 enhances PI3K/Akt activation by directly binding p85 in TLR signaling and VSV infection. Accordingly, Gab1 inhibits VSV replication and VSV infection-induced cell damage by inducing type I IFNs and IFN-inducible gene expression via PI3K/Akt pathway. Therefore, Gab1 is needed for full activation of TLR3/4- and RIG-I–triggered innate responses by promoting activation of PI3K/Akt, MAPKs, and NF-κB pathways.

Unbalanced production of proinflammatory cytokines and type I interferons in immune responses may lead to immunopathology; thus, the mechanisms that ensure the beneficial production of proinflammatory cytokines and type I interferons are of particular importance. Here we demonstrate that the phosphatase SHP-1 negatively regulated Toll-like receptor-mediated production of proinflammatory cytokines by inhibiting activation of the transcription factor NF-kappaB and mitogen-activated protein kinase. Simultaneously, SHP-1 increased the production of type I interferon mediated by Toll-like receptors and the helicase RIG-I by directly binding to and inhibiting activation of the kinase IRAK1. Our data demonstrate that SHP-1 contributes to immune homeostasis by balancing the production of proinflammatory cytokines and type I interferons in the innate immune response.

The approaches to control the inflammatory responses and reduce the mortality rate of sepsis are still not very effective in clinics and new potential drugs are needed to be confirmed to be useful in the induction of anti-inflammatory response. Ephedrine hydrochloride (EH) is a compound widely used for cardiovascular diseases, especially to treat hypotension caused by anesthesia or overdose of antihypertensive drugs. In this study, we reported that EH also plays an important role in the control of inflammatory response. It increases interleukin 10 (IL-10) and decreases proinflammatory cytokine (IL-6, TNF-α, IL-12, and IL-1β) expression in response to gram-positive cell wall component peptidoglycan (PGN) in primary peritoneal macrophages and Raw264.7 cells. The anti-inflammatory role of EH was also observed in experimental peritonitis mouse model induced by intraperitoneally PGN injection. Phosphatidylinositol 3-kinase (PI3K)/Akt pathway was found to be responsible for EH-enhanced IL-10 production and EH-decreased IL-6 expression. Therefore, our results illustrated that EH can help to maintain immune equilibrium and diminish host damage by balancing the production of proinflammatory cytokines and anti-inflammatory cytokine after PGN challenge. EH may be a new potential anti-inflammatory drug in treatment of severe invasive gram-positive bacterial infection.

Nat. Immunol. 9, 542–550 (2008); published online 6 April 2008; corrected after print 22 December 2010 In the version of this article initially published, the actin loading control in Figure 6b (left) was incorrect. The correct figure is provided here. The error has been corrected in the HTML and PDF versions of the article.