Therapeutic and Preventive Effects of Morphine Against Leishmania Major and Evaluation the Expression of TLRs and Cytokines in Infected Macrophages in Vitro and in BALB/c Mice

Abstract Purpose: Toll-Like Receptors (TLRs) and cytokines play key roles in infection control. They also enhance phagocytosis and killing of parasites. Morphine can modify host immunity and defense against infectious diseases. Methods: In this study, we assessed Therapeutic and preventive effects of morphine against Leishmania major and then we evaluated the expression of TLRs and pro and anti-inflamatory cytokines in both healthy macrophages and those infected with Leishmania major in vitro and in BALB/c mice. Results: Morphine showed preventive effect and no lesions were observed in the group that was taken morphine before being challenged with promastigotes. TLR2 expression decreased in drug-treated healthy macrophages, whereas TLR4 expression increased. TLR7 expression decreased in healthy macrophages. TLR9 expression was the highest in the groups treated with morphine in infected macrophages. Our findings revealed that healthy macrophages produce higher TNFα and lower IL6; the infected macrophages show a reverse pattern by producing higher IL6 and lower TNFα. We found that treatment with morphine strengthen defensive reactions against leishmaniasis. In mouse macrophages, the highest level of TLR9 expression was induced by morphine. Conclusion: TLR9 has critical role for recognition and control of microbial infection. No lesions were developed in mice treated with morphine before challenge which suggests a protective role for morphine in leishmaniasis. The positive role of morphine in decreasing IL-10 expression and increasing the expression of inflammatory cytokines such as TNF-α and therefore its preventing role in Leishmania disease.

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Combined Stimulation of Toll-Like Receptor 5 and NOD1 Strongly Potentiates Activity of NF-κB, Resulting in Enhanced Innate Immune Reactions and Resistance to Salmonella enterica Serovar Typhimurium Infection

Infection and Immunity ◽

10.1128/iai.00525-13 ◽

2013 ◽

Vol 81 (10) ◽

pp. 3855-3864 ◽

Cited By ~ 23

Author(s):

Amir I. Tukhvatulin ◽

Ilya I. Gitlin ◽

Dmitry V. Shcheblyakov ◽

Natalia M. Artemicheva ◽

Lyudmila G. Burdelya ◽

...

Keyword(s):

Critical Role ◽

Immune Defense ◽

Innate Immune ◽

Microbial Infection ◽

Immune Reactions ◽

Content Type ◽

Essential Components ◽

Stimulation Of

ABSTRACTPathogen recognition receptors (PRRs) are essential components of host innate immune systems that detect specific conserved pathogen-associated molecular patterns (PAMPs) presented by microorganisms. Members of two families of PRRs, transmembrane Toll-like receptors (TLRs 1, 2, 4, 5, and 6) and cytosolic NOD receptors (NOD1 and NOD2), are stimulated upon recognition of various bacterial PAMPs. Such stimulation leads to induction of a number of immune defense reactions, mainly triggered via activation of the transcription factor NF-κB. While coordination of responses initiated via different PRRs sensing multiple PAMPS present during an infection makes clear biological sense for the host, such interactions have not been fully characterized. Here, we demonstrate that combined stimulation of NOD1 and TLR5 (as well as other NOD and TLR family members) strongly potentiates activity of NF-κB and induces enhanced levels of innate immune reactions (e.g., cytokine production) bothin vitroandin vivo. Moreover, we show that an increased level of NF-κB activity plays a critical role in formation of downstream responses. In live mice, synergy between these receptors resulting in potentiation of NF-κB activity was organ specific, being most prominent in the gastrointestinal tract. Coordinated activity of NOD1 and TLR5 significantly increased protection of mice against enteroinvasiveSalmonellainfection. Obtained results suggest that cooperation of NOD and TLR receptors is important for effective responses to microbial infectionin vivo.

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HDAC4 Regulates the Proliferation, Differentiation and Apoptosis of Chicken Skeletal Muscle Satellite Cells

Animals ◽

10.3390/ani10010084 ◽

2020 ◽

Vol 10 (1) ◽

pp. 84 ◽

Cited By ~ 3

Author(s):

Jing Zhao ◽

Xiaoxu Shen ◽

Xinao Cao ◽

Haorong He ◽

Shunshun Han ◽

...

Keyword(s):

Skeletal Muscle ◽

Satellite Cells ◽

Muscle Development ◽

Critical Role ◽

Muscle Growth ◽

Positive Role ◽

Muscle Satellite Cells ◽

Skeletal Muscle Satellite Cells ◽

Chicken Skeletal Muscle

The development of skeletal muscle satellite cells (SMSCs) is a complex process that could be regulated by many genes. Previous studies have shown that Histone Deacetylase 4 (HDAC4) plays a critical role in cell proliferation, differentiation, and apoptosis in mouse. However, the function of HDAC4 in chicken muscle development is still unknown. Given that chicken is a very important meat-producing animal that is also an ideal model to study skeletal muscle development, we explored the functions of HDAC4 in chicken SMSCs after the interference of HDAC4. The results showed that HDAC4 was enriched in embryonic skeletal muscle, and it was highly expressed in embryonic muscle than in postnatal muscles. Meanwhile, knockdown of HDAC4 could significantly inhibit the proliferation and differentiation of chicken SMSCs but had no effect on the apoptosis of SMSCs as observed in a series of experiment conducted in vitro. These results indicated that HDAC4 might play a positive role in chicken skeletal muscle growth and development.

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Protective role of microRNA-9-5p in oxygen glucose deprivation/reperfusion-induced injury in liver sinusoidal endothelial cell

10.21203/rs.3.rs-19922/v1 ◽

2020 ◽

Author(s):

Yi Duan ◽

Zhifeng Gao ◽

Xiaoyu Wang ◽

Yuanyuan Meng ◽

Huan Zhang

Keyword(s):

Inflammatory Response ◽

Ischemia Reperfusion ◽

Critical Role ◽

Glucose Deprivation ◽

Protective Role ◽

Liver Sinusoidal Endothelial Cell ◽

Liver Sinusoidal Endothelial Cells ◽

Hepatic Ischemia

Abstract Background: Maintenance of the function and survival of liver sinusoidal endothelial cells (LSECs) play a crucial role in hepatic ischemia/reperfusion (I/R) injury, a major cause of liver impairment during surgical treatment. Emerging evidence indicate a critical role of microRNAs in I/R injury. This study aims to investigate whether miR-9-5p exert a protective effect on LSECs in vitro .Methods: We transfected LSECs with miR-9-5p mimic or mimic NC. LSECs were treated with oxygen and glucose deprivation (OGD, 5% CO2 and 95% N2), followed by glucose-free DMEM medium for 6 h, and high-glucose (HG, 30 mmol/L glucose) DMEM medium for 12 h. The biological role of miR-9-5p in I/R-induced LSEC injury was determined. Results: In the in vitro model of OGD/HG injury in LSECs, the expression levels of miR-9-5p were significantly downregulated and those of CXC chemokine receptor-4 (CXCR4) upregulated. LSEC I/R injury led to deteriorated cell death, enhanced oxidative stress and excessive inflammatory response. Mechanistically, we showed that miR-9-5p overexpression significantly upregulated both mRNA and protein levels of CXCR4, followed by rescue of LSECs, ameliorated inflammatory response, and deactivation of pro-apoptotic signaling pathways.Conclusion: miR-9-5p promotes LSEC survival and inhibits apoptosis and inflammatory response in LSECs following OGD/HG injury via downregulation of CXCR4.

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Leishmania major Promastigotes Inhibit Dendritic Cell Motility In Vitro

Infection and Immunity ◽

10.1128/iai.70.2.1023-1026.2002 ◽

2002 ◽

Vol 70 (2) ◽

pp. 1023-1026 ◽

Cited By ~ 24

Author(s):

Heather Jebbari ◽

Andrew J. Stagg ◽

Robert N. Davidson ◽

Stella C. Knight

Keyword(s):

Dendritic Cells ◽

Dendritic Cell ◽

Cell Motility ◽

Leishmania Major ◽

Protective Role ◽

Transwell Migration Assay ◽

Migration Assay ◽

Dose Dependent

ABSTRACT Using an in vitro transwell migration assay, we have demonstrated that products secreted by Leishmania major promastigotes inhibit the motility of dendritic cells (DC) by up to 93%. Inhibition was dose dependent and reversible. By inhibiting DC migration in vivo, L. major may therefore subvert DC from their potentially protective role during leishmaniasis.

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Thymosin β4 protect against LPS induced lung injury and inflammation and subsequent fibrosis in mice

10.21203/rs.3.rs-139980/v2 ◽

2021 ◽

Author(s):

Zhen Tian ◽

Naijuan Yao ◽

Fei Wang ◽

Litao Ruan

Keyword(s):

Pulmonary Fibrosis ◽

Lung Injury ◽

Critical Role ◽

Protective Role ◽

Inflammasome Activation ◽

Thymosin Β4 ◽

Mesenchymal Transition ◽

Tgf Β1

Abstract Background: Inflammation plays a critical role in the progression of pulmonary fibrosis. Thymosin β4 (Tβ4) has antioxidant, anti-inflammatory and antifibrotic effects. Although the potent protective role of Tβ4 in bleomycin-induced pulmonary fibrosis has been validated, the mechanism is not clear, and its impact on lipopolysaccharide (LPS)-induced lung injury/fibrosis has not been reported. Method: Expression of Tβ4 in fibrotic lung tissues was assessed by real-time quantitative reverse transcriptase PCR (RQ-PCR), immunohistochemistry (IHC) and Western Blotting. The effects of intraperitoneal adeno-associated virus-Tβ4 (AAV-Tβ4) on LPS-induced lung injury and fibrosis were observed through the evaluation of collagen deposition and α-smooth muscle actin (SMA) expression. In vitro tests with HPAEpiC and HLF-1 cells were performed to confirm the effects of Tβ4.Results: In this study, we evaluated the role of Tβ4 in pulmonary fibrosis and explored the possible underlying mechanisms. We found that Tβ4 was markedly upregulated in human or mouse fibrotic lung tissues. AAV-Tβ4 markedly alleviated LPS-induced oxidative damage, lung injury, inflammation, and fibrosis in mice. Our in vitro experiments also showed that LPS inhibited mitophagy and promoted inflammation via oxidative stress in HPAEpiC, and usage of Tβ4 significantly attenuated LPS-induced mitophagy inhibition, inflammasome activation and transforming growth factor-β (TGF)-β1 induced epithelial-mesenchymal transition (EMT) in HPAEpiC. Moreover, we found that Tβ4 suppressed the proliferation and attenuated the TGF-β1-induced activation of HLF-1 cells. Conclusions: In conclusion, Tβ4 alleviates LPS-induced lung injury, inflammation, and subsequent fibrosis in mice, suggesting a protective role of Tβ4 in disease pathogenesis of pulmonary fibrosis (PF). Tβ4 involves in attenuating oxidative injury, promoting mitophagy, and then alleviating inflammation and fibrosis. Modulating of Tβ4 might be a novel strategy for treating PF.

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Levosimendan Protects against Doxorubicin-Induced Cardiotoxicity by Regulating the PTEN/Akt Pathway

BioMed Research International ◽

10.1155/2020/8593617 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Ling-Li Li ◽

Li Wei ◽

Ning Zhang ◽

Wen-Ying Wei ◽

Can Hu ◽

...

Keyword(s):

Critical Role ◽

Cardiac Injury ◽

Protective Role ◽

Akt Inhibitor ◽

Morphological Examination ◽

Phosphatase And Tensin Homolog ◽

Tensin Homolog ◽

Myocardial Apoptosis

Background and Aims. Myocyte apoptosis plays a critical role in the development of doxorubicin- (DOX-) induced cardiotoxicity. In addition to its cardiotonic effect, laboratory evidence indicates that levosimendan can inhibit apoptosis, but its role in DOX-induced cardiac injury remains unclear. Therefore, the present study is aimed at exploring whether levosimendan could attenuate DOX-induced cardiotoxicity. Methods. Levosimendan (1 mg/kg) was administered to mice through oral gavage once daily for 4 weeks, and the mice were also subjected to an intraperitoneal injection of DOX (5 mg/kg) or saline, once a week for 4 weeks, to create a chronic model of DOX-induced cardiotoxicity. A morphological examination and biochemical analysis were used to evaluate the effects of levosimendan. H9C2 cells were used to verify the protective role of levosimendan in vitro. And an Akt inhibitor was utilized to verify the cardioprotection of levosimendan. Results. Levosimendan reduced the cardiac dysfunction and attenuated the myocardial apoptosis induced by DOX in vivo and in vitro. Levosimendan also inhibited the activation of phosphatase and tensin homolog (PTEN) and upregulated P-Akt expression both in vivo and in vitro. And inhibition of Akt abolished the cardioprotection of levosimendan in vitro. Conclusion. Levosimendan may protect against DOX-induced cardiotoxicity via modulation of the PTEN/Akt signaling pathway.

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hPER3 promotes adipogenesis via hHSP90AA1-mediated inhibition of Notch1 pathway

Cell Death and Disease ◽

10.1038/s41419-021-03584-0 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Xinxing Wan ◽

Liyong Zhu ◽

Liling Zhao ◽

Lin Peng ◽

Jing Xiong ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Stromal Cells ◽

Critical Role ◽

Human Adipose Tissue ◽

Positive Role ◽

Positive Regulator ◽

Adipose Derived Stromal Cells

AbstractThe period circadian regulator 3 (PER3) has been reported to play a negative role in human immortalized bone marrow-derived Scp-1 cells (iBMSCs) and patient adipose-derived stromal cells (PASCs) or a negative/positive role in mice adipogenesis. However, human PER3 (hPER3) was identified as a positive regulator of human adipose tissue-derived stromal cells (hADSCs) adipogenesis in this study. Silencing or overexpression of hPER3 in hADSCs inhibited and promoted adipogenesis in vitro. In vivo, the overexpression of hPER3 increased high-fat diet-induced inguinal white adipose tissue (iWAT) and epididymal white adipose tissue (eWAT) forms, increasing systemic glucose intolerance and insulin resistance. Molecularly, hPER3 does not interact with hPPARγ, but represses Notch1 signaling pathway to enhance adipogenesis by interacting with hHSP90AA1, which is able to combine with the promoter of hNotch1 and inactivate its expression. Thus, our study revealed hPER3 as a critical positive regulator of hADSCs adipogenesis, which was different from the other types of cells, providing a critical role of it in treating obesity.

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TRIM25 Identification in the Chinese Goose: Gene Structure, Tissue Expression Profiles, and Antiviral Immune Responses In Vivo and In Vitro

BioMed Research International ◽

10.1155/2016/1403984 ◽

2016 ◽

Vol 2016 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

Yunan Wei ◽

Hao Zhou ◽

Anqi Wang ◽

Lipei Sun ◽

Mingshu Wang ◽

...

Keyword(s):

Rna Virus ◽

Expression Profiles ◽

Critical Role ◽

Coiled Coil ◽

Poly I:C ◽

Positive Role ◽

Antiviral Immune Response ◽

Polycytidylic Acid

The retinoic acid-inducible gene I (RIG-I) and the RIG-I-like receptor (RLR) protein play a critical role in the interferon (IFN) response during RNA virus infection. The tripartite motif containing 25 proteins (TRIM25) was reported to modify caspase activation and RIG-I recruitment domains (CARDs) via ubiquitin. These modifications allow TRIM25 to interact with mitochondrial antiviral signaling molecules (MAVs) and form CARD-CARD tetramers. Goose TRIM25 was cloned from gosling lungs, which possess a 1662 bp open reading flame (ORF). This ORF encodes a predicted 554 amino acid protein consisting of a B-box domain, a coiled-coil domain, and a PRY/SPRY domain. The protein sequence has 89.25% sequence identity withAnas platyrhynchosTRIM25, 78.57% withGallus gallusTRIM25, and 46.92% withHomo sapiensTRIM25. TRIM25 is expressed in all gosling and adult goose tissues examined. QRT-PCR revealed that goose TRIM25 transcription could be induced by goose IFN-α, goose IFN-γ, and goose IFN-λ, as well as a35 s polyinosinic-polycytidylic acid (poly(I:C)), oligodeoxynucleotides 2006 (ODN 2006), and resiquimod (R848) in vitro; however, it is inhibited in H9N2 infected goslings for unknown reasons. These data suggest that goose TRIM25 might play a positive role in the regulation of the antiviral immune response.

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Lnc-C2orf63-4-1 Confers VSMC Homeostasis and Prevents Aortic Dissection Formation via STAT3 Interaction

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.792051 ◽

2021 ◽

Vol 9 ◽

Author(s):

Song Zhang ◽

Shiqi Zhao ◽

Xuejie Han ◽

Yun Zhang ◽

Xuexin Jin ◽

...

Keyword(s):

Aortic Dissection ◽

Vascular Remodeling ◽

Critical Role ◽

Protective Role ◽

Phenotypic Switching ◽

Ang Ii ◽

Downstream Effector ◽

Induced Apoptosis

Emerging evidence indicates that long non-coding RNAs (lncRNAs) serve as a critical molecular regulator in various cardiovascular diseases. Here, we aimed to identify and functionally characterize lncRNAs as potential mediators in the development of thoracic aortic dissection (TAD). We identified that a novel lncRNA, lnc-C2orf63-4-1, was lowly expressed in aortic samples of TAD patients and angiotensin II (Ang II)-challenged vascular smooth muscle cells (VSMCs), which was correlated with clinically aortic expansion. Besides, overexpression of lnc-C2orf63-4-1 significantly attenuated Ang II-induced apoptosis, phenotypic switching of VSMCs and degradation of extracellular matrix both in vitro and in vivo. A customized transcription factor array identified that signal transducer and activator of transcription 3 (STAT3) functioned as the main downstream effector. Mechanistically, dual-luciferase report analysis and RNA antisense purification (RAP) assay indicated that lnc-C2orf63-4-1 directly decreased the expression of STAT3, which was depend on the reduced stabilization of STAT3 mRNA. Importantly, up-regulation of STAT3 efficiently reversed the protective role of lnc-C2orf63-4-1 against Ang II-mediated vascular remodeling. Therefore, lnc-C2orf63-4-1 negatively regulated the expression of STAT3 and prevented the development of aortic dissection. Our study revealed that lnc-C2orf63-4-1 played a critical role in vascular homeostasis, and its dysfunction exacerbated Ang II-induced pathological vascular remodeling.

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STING Contributes to Host Defense Against Staphylococcus aureus Pneumonia Through Suppressing Necroptosis

Frontiers in Immunology ◽

10.3389/fimmu.2021.636861 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhen-Zhen Liu ◽

Yong-Jun Yang ◽

Cheng-Kai Zhou ◽

Shi-Qing Yan ◽

Ke Ma ◽

...

Keyword(s):

Cell Death ◽

Host Defense ◽

Early Stage ◽

Critical Role ◽

Adaptor Protein ◽

Tunel Staining ◽

Microbial Infection

STING (Stimulator of interferon genes) is known as an important adaptor protein or direct sensor in the detection of nucleotide originating from pathogens or the host. The implication of STING during pulmonary microbial infection remains unknown to date. Herein, we showed that STING protected against pulmonary S.aureus infection by suppressing necroptosis. STING deficiency resulted in increased mortality, more bacteria burden in BALF and lungs, severe destruction of lung architecture, and elevated inflammatory cells infiltration and inflammatory cytokines secretion. STING deficiency also had a defect in bacterial clearance, but did not exacerbate pulmonary inflammation during the early stage of infection. Interestingly, TUNEL staining and LDH release assays showed that STING-/- mice had increased cell death than WT mice. We further demonstrated that STING-/- mice had decreased number of macrophages accompanied by increased dead macrophages. Our in vivo and in vitro findings further demonstrated this cell death as necroptosis. The critical role of necroptosis was detected by the fact that MLKL-/- mice exhibited decreased macrophage death and enhanced host defense to S.aureus infection. Importantly, blocking necroptosis activation rescued host defense defect against S.aureus pneumonia in STING-/- mice. Hence, these results reveal an important role of STING in suppressing necroptosis activation to facilitate early pathogen control during pulmonary S.aureus infection.

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