mTOR inhibition as a possible pharmacological target in the management of systemic inflammatory response and associated neuroinflammation by lipopolysaccharide challenge in rats

2021 ◽  
Author(s):  
Demet Sinem Guden ◽  
Meryem Temiz-Resitoglu ◽  
Sefika Pınar Senol ◽  
Deniz Kibar ◽  
Sakir Necat Yilmaz ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Microglial Activation ◽  
Critical Role ◽  
Mammalian Target Of Rapamycin ◽  
Hypoxia Inducible Factor ◽  
B Cell Lymphoma ◽  
Nuclear Factor Κb ◽  
Systemic Inflammatory Response ◽  
Mtor Inhibition ◽  
Factor Α

Neuroinflammation plays a critical role during sepsis triggered by microglial activation. Mammalian target of rapamycin (mTOR) has gained attraction in neuroinflammation, however, the mechanism remains unclear. Our goal was to assess the effects of mTOR inhibition by rapamycin on inflammation, microglial activation, oxidative stress, and apoptosis associated with the changes in the inhibitor-κB (IκB)-α/nuclear factor-κB (NF-κB)/hypoxia-inducible factor-1α (HIF-1α) pathway activity following a systemic challenge with lipopolysaccharide (LPS). Rats received saline (10 ml/kg), LPS (10 mg/kg), and/or rapamycin (1 mg/kg) via intraperitoneally. Inhibition of mTOR by rapamycin blocked phosphorylated form of ribosomal protein S6, NF-κB p65 activity by increasing degradation of IκB-α in parallel with HIF-1α expression increased by LPS in the kidney, heart, lung, and brain tissues. Rapamycin attenuated the increment in the expression of tumor necrosis factor-α and interleukin-1β, the inducible nitric oxide synthase, gp91<sup>phox</sup>, and p47<sup>phox</sup> in addition to nitrite levels elicited by LPS in tissues or sera. Concomitantly, rapamycin treatment reduced microglial activation, brain expression of caspase-3, and Bcl-2-associated X protein while increased expression of B-cell lymphoma 2 induced by LPS. Overall, this study supports the hypothesis that mTOR contributes to the detrimental effect of LPS-induced systemic inflammatory response associated with neuroinflammation via IκB-α/NF-κB/HIF-1α signaling pathway.

Localized pancreatic NF-κB activation and inflammatory response in taurocholate-induced pancreatitis

2001 ◽  
Vol 280 (6) ◽  
pp. G1197-G1208 ◽  
Author(s):  
Eva Vaquero ◽  
Ilya Gukovsky ◽  
Vjekoslav Zaninovic ◽  
Anna S. Gukovskaya ◽  
Stephen J. Pandol
Keyword(s):  
Transcription Factor ◽  
Inflammatory Response ◽  
Pancreatic Head ◽  
Pancreatic Injury ◽  
Nuclear Factor Κb ◽  
Saline Infusion ◽  
Activator Protein 1 ◽  
Local Inflammatory Response ◽  
Monocyte Chemoattractant Protein 1 ◽  
Factor Α

Transcription factor nuclear factor-κB (NF-κB) is activated in cerulein pancreatitis and mediates cytokine expression. The role of transcription factor activation in other models of pancreatitis has not been established. Here we report upregulation of NF-κB and inflammatory molecules, and their correlation with local pancreatic injury, in a model of severe pancreatitis. Rats received intraductal infusion of taurocholate or saline, and the pancreatic head and tail were analyzed separately. NF-κB and activator protein-1 (AP-1) activation were assessed by gel shift assay, and mRNA expression of interleukin-6, tumor necrosis factor-α, KC, monocyte chemoattractant protein-1, and inducible nitric oxide synthase was assessed by semiquantitative RT-PCR. Morphological damage and trypsin activation were much greater in the pancreatic head than tail, in parallel with a stronger activation of NF-κB and cytokine mRNA. Saline infusion mildly affected these parameters. AP-1 was strongly activated in both pancreatic segments after either taurocholate or saline infusion. NF-κB inhibition with N-acetylcysteine ameliorated the local inflammatory response. Correlation between localized NF-κB activation, cytokine upregulation, and tissue damage suggests a key role for NF-κB in the development of the inflammatory response of acute pancreatitis.

scholarly journals Targeting Multiple Signaling Pathways in Cancer: The Rutin Therapeutic Approach

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2276 ◽  
Author(s):  
Zeinab Nouri ◽  
Sajad Fakhri ◽  
Keyvan Nouri ◽  
Carly E. Wallace ◽  
Mohammad Hosein Farzaei ◽  
...  
Keyword(s):  
Medicinal Plants ◽  
Signaling Pathways ◽  
Anticancer Agents ◽  
Molecular Mechanisms ◽  
Critical Evaluation ◽  
B Cell Lymphoma ◽  
Nuclear Factor Κb ◽  
Anticancer Effects ◽  
Factor Α ◽  
Endothelial Growth Factor

Multiple dysregulated signaling pathways are implicated in the pathogenesis of cancer. The conventional therapies used in cancer prevention/treatment suffer from low efficacy, considerable toxicity, and high cost. Hence, the discovery and development of novel multi-targeted agents to attenuate the dysregulated signaling in cancer is of great importance. In recent decades, phytochemicals from dietary and medicinal plants have been successfully introduced as alternative anticancer agents due to their ability to modulate numerous oncogenic and oncosuppressive signaling pathways. Rutin (also known as rutoside, quercetin-3-O-rutinoside and sophorin) is an active plant-derived flavonoid that is widely distributed in various vegetables, fruits, and medicinal plants, including asparagus, buckwheat, apricots, apples, cherries, grapes, grapefruit, plums, oranges, and tea. Rutin has been shown to target various inflammatory, apoptotic, autophagic, and angiogenic signaling mediators, including nuclear factor-κB, tumor necrosis factor-α, interleukins, light chain 3/Beclin, B cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein, caspases, and vascular endothelial growth factor. A comprehensive and critical analysis of the anticancer potential of rutin and associated molecular targets amongst various cancer types has not been performed previously. Accordingly, the purpose of this review is to present an up-to-date and critical evaluation of multiple cellular and molecular mechanisms through which the anticancer effects of rutin are known to be exerted. The current challenges and limitations as well as future directions of research are also discussed.

scholarly journals HIF-1α is a negative regulator of interferon regulatory factors: Implications for interferon production by hypoxic monocytes

2021 ◽  
Vol 118 (26) ◽  
pp. e2106017118
Author(s):  
Travis Peng ◽  
Shin-Yi Du ◽  
Myoungsun Son ◽  
Betty Diamond
Keyword(s):  
Inflammatory Cytokines ◽  
Cell Function ◽  
Hypoxia Inducible Factor ◽  
Human Monocyte ◽  
Nuclear Factor Κb ◽  
Negative Regulator ◽  
Type I ◽  
Hypoxic Conditions ◽  
Stressed Cells ◽  
Factor Α

Patients with severe COVID-19 infection exhibit a low level of oxygen in affected tissue and blood. To understand the pathophysiology of COVID-19 infection, it is therefore necessary to understand cell function during hypoxia. We investigated aspects of human monocyte activation under hypoxic conditions. HMGB1 is an alarmin released by stressed cells. Under normoxic conditions, HMGB1 activates interferon regulatory factor (IRF)5 and nuclear factor-κB in monocytes, leading to expression of type I interferon (IFN) and inflammatory cytokines including tumor necrosis factor α, and interleukin 1β, respectively. When hypoxic monocytes are activated by HMGB1, they produce proinflammatory cytokines but fail to produce type I IFN. Hypoxia-inducible factor-1α, induced by hypoxia, functions as a direct transcriptional repressor of IRF5 and IRF3. As hypoxia is a stressor that induces secretion of HMGB1 by epithelial cells, hypoxia establishes a microenvironment that favors monocyte production of inflammatory cytokines but not IFN. These findings have implications for the pathogenesis of COVID-19.

scholarly journals Dlg1 Knockout Inhibits Microglial Activation and Alleviates Lipopolysaccharide-Induced Depression-Like Behavior in Mice

2021 ◽  
Author(s):  
Zhixin Peng ◽  
Xiaoheng Li ◽  
Jun Li ◽  
Yuan Dong ◽  
Yuhao Gao ◽  
...  
Keyword(s):  
Microglial Activation ◽  
Neurological Diseases ◽  
Critical Role ◽  
Adaptor Protein ◽  
Nuclear Factor Κb ◽  
Cell Polarization ◽  
Mitogen Activated Protein Kinase ◽  
Treatment Of Depression ◽  
Discs Large ◽  
Mitogen Activated Protein

AbstractMicroglia-mediated neuroinflammation is widely perceived as a contributor to numerous neurological diseases and mental disorders including depression. Discs large homolog 1 (Dlg1), an adaptor protein, regulates cell polarization and the function of K+ channels, which are reported to regulate the activation of microglia. However, little is known about the role of Dlg1 in microglia and the maintenance of central nervous system homeostasis. In this study, we found that Dlg1 knockdown suppressed lipopolysaccharide (LPS)-induced inflammation by down-regulating the activation of nuclear factor-κB signaling and the mitogen-activated protein kinase pathway in microglia. Moreover, using an inducible Dlg1 microglia-specific knockout (Dlg1flox/flox; CX3CR1CreER) mouse line, we found that microglial Dlg1 knockout reduced the activation of microglia and alleviated the LPS-induced depression-like behavior. In summary, our results demonstrated that Dlg1 plays a critical role in microglial activation and thus provides a potential therapeutic target for the clinical treatment of depression.

Signal Pathways and Therapeutic Prospects of Diffuse Large B Cell Lymphoma

2020 ◽  
Vol 19 (17) ◽  
pp. 2047-2059
Author(s):  
Feifei Sun ◽  
Xiaosheng Fang ◽  
Xin Wang
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Mammalian Target Of Rapamycin ◽  
B Cell Lymphoma ◽  
Nuclear Factor Κb ◽  
Janus Kinase ◽  
Signal Pathways ◽  
Non Hodgkin Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Background: Diffuse Large B Cell Lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma which is heterogeneous both clinically and morphologically. Over the past decades, significant advances have been made in the understanding of the molecular genesis, leading to the identification of multiple pathways and molecules that can be targeted for clinical benefit. Objective: The current review aims to present a brief overview of signal pathways of DLBCL, which mainly focus on B-cell antigen Receptor (BCR), Nuclear Factor-κB (NF-κB), Phosphatidylinositol-3-Kinase (PI3K) – protein kinase B (Akt) – mammalian Target of Rapamycin (mTOR), Janus Kinase (JAK) – Signal Transducer and Activator (STAT), Wnt/β-catenin, and P53 pathways. Methods: Activation of signal pathways may contribute to the generation, development, chemotherapy sensitivity of DLBCL, and expression of pathway molecules is associated with the prognosis of DLBCL. Some agents targeting these pathways have been proved effective and relevant clinical trials are in progress. These agents used single or combined with chemotherapy/each other might raise the possibility of improving clinical outcomes in DLBCL. Conclusion: This review presents several signal pathways of DLBCL and targeted agents had a tendency to improve the curative effect, especially in high-risk or relapsed/refractory DLBCL.

scholarly journals The anti-inflammatory drug BAY 11-7082 suppresses the MyD88-dependent signalling network by targeting the ubiquitin system

2013 ◽  
Vol 451 (3) ◽  
pp. 427-437 ◽  
Author(s):  
Sam Strickson ◽  
David G. Campbell ◽  
Christoph H. Emmerich ◽  
Axel Knebel ◽  
Lorna Plater ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Hypoxia Inducible Factor ◽  
B Cell Lymphoma ◽  
Nuclear Factor Κb ◽  
Polyubiquitin Chains ◽  
Il Interleukin ◽  
Ubiquitin System ◽  
Ubiquitin Conjugation ◽  
Anti Inflammatory ◽  
In Cells

The compound BAY 11-7082 inhibits IκBα [inhibitor of NF-κB (nuclear factor κB)α] phosphorylation in cells and has been used to implicate the canonical IKKs (IκB kinases) and NF-κB in >350 publications. In the present study we report that BAY 11-7082 does not inhibit the IKKs, but suppresses their activation in LPS (lipopolysaccharide)-stimulated RAW macrophages and IL (interleukin)-1-stimulated IL-1R (IL-1 receptor) HEK (human embryonic kidney)-293 cells. BAY 11-7082 exerts these effects by inactivating the E2-conjugating enzymes Ubc (ubiquitin conjugating) 13 and UbcH7 and the E3 ligase LUBAC (linear ubiquitin assembly complex), thereby preventing the formation of Lys63-linked and linear polyubiquitin chains. BAY 11-7082 prevents ubiquitin conjugation to Ubc13 and UbcH7 by forming a covalent adduct with their reactive cysteine residues via Michael addition at the C3 atom of BAY 11-7082, followed by the release of 4-methylbenzene-sulfinic acid. BAY 11-7082 stimulated Lys48-linked polyubiquitin chain formation in cells and protected HIF1α (hypoxia-inducible factor 1α) from proteasomal degradation, suggesting that it inhibits the proteasome. The results of the present study indicate that the anti-inflammatory effects of BAY 11-7082, its ability to induce B-cell lymphoma and leukaemic T-cell death and to prevent the recruitment of proteins to sites of DNA damage are exerted via inhibition of components of the ubiquitin system and not by inhibiting NF-κB.

scholarly journals Is There a Role for Mammalian Target of Rapamycin Inhibition in Renal Failure due to Mesangioproliferative Nephrotic Syndrome?

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Hernán Trimarchi ◽  
Mariano Forrester ◽  
Fernando Lombi ◽  
Vanesa Pomeranz ◽  
Romina Iriarte ◽  
...  
Keyword(s):  
Critical Role ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Target Of Rapamycin ◽  
Mtor Inhibition ◽  
Primary Glomerulonephritis ◽  
Glomerular Proteinuria ◽  
Mesangioproliferative Glomerulonephritis ◽  
Stage Renal Disease ◽  
End Stage

Primary glomerulonephritis stands as the third most important cause of end-stage renal disease, suggesting that appropriate treatment may not be as effective as intended to be. Moreover, proteinuria, the hallmark of glomerular damage and a prognostic marker of renal damage progression, is frequently resistant to thorough control. In addition, proteinuria may be the common end pathway in which different pathogenetic mechanisms may converge. This explains why immunosuppressive and nonimmunosuppressive approaches are partly not sufficient to halt disease progression. One of the commonest causes of primary glomerulonephritis is mesangioproliferative glomerulonephritis. Among the triggered intracellular pathways involved in mesangial cell proliferation, the mammalian target of rapamycin (mTOR) plays a critical role in cell growth, in turn regulated by many cytokines, disbalanced by the altered glomerulopathy itself. However, when inhibition of mTOR was studied in rodents and in humans with primary glomerulonephritis the results were contradictory. In light of these controversial data, we propose an explanation for these results, to dilucidate under which circumstances mTOR inhibition should be considered to treat glomerular proteinuria and finally to propose mTOR inhibitors to be prospectively assessed in clinical trials in patients with primary mesangioproliferative glomerulonephritis, for which a satisfactory standard immunosuppressive regimen is still pending.

Ameliorative Effect of Rhoifolin in Cisplatin-Induced Nephrotoxicity via Regulating Nuclear Factor-κB Pathway

2020 ◽  
Vol 18 (3) ◽  
pp. 266-272
Author(s):  
Song Yanfang ◽  
Yan Shufang ◽  
Zhang Hong ◽  
Liu Rui ◽  
An Xin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Inflammatory Response ◽  
Signaling Pathway ◽  
Renal Damage ◽  
Nuclear Translocation ◽  
Intraperitoneal Administration ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Ameliorative Effect ◽  
Factor Α

Dose-dependent nephrotoxicity limits the therapeutic use of cisplatin in tumor chemotherapy. Natural compounds show a protective effect against cisplatin-induced nephrotoxicity. Rhoifolin is a flavone glycoside that demonstrates antioxidant and antiproliferative effects. The influence and mechanism of rhoifolin on cisplatin-induced nephrotoxicity were investigated in this study. First, a rat model of cisplatin-induced nephrotoxicity was established. Intraperitoneal administration of cisplatin induced renal damage in rats as demonstrated by a decrease in body weight, increase in blood urea, nitrogen and creatinine, and destruction of histological integrity. However, treatment with rhoifolin attenuated cisplatin-induced nephrotoxicity. Second, cisplatin induced oxidative stress and inflammatory response in rats as demonstrated by a decrease in superoxide dismutase, glutathione, glutathione S-transferase and catalase, and an increase in malondialdehyde, tumor necrosis factor-α, and interleukin-6. Also, the administration of rhoifolin led to alleviation of cisplatin-induced oxidative stress and inflammatory response. Finally, cisplatin activated the nuclear factor-kappa B signaling pathway via degradation and phosphorylation of IκBα (inhibitor of kappa B). Administration of rhoifolin inhibited nuclear translocation of NF-κB via down-regulation of phospho-IκBα and phospho-p65, as well as up-regulation of IκBα. In conclusion, the administration of rhoifolin attenuated cisplatin-induced renal damage, oxidative stress and inflammatory response through inhibition of the NF-κB signaling pathway, suggesting a potential adjunct candidate for cisplatin in tumor treatment.

Sign in / Sign up

Export Citation Format

Share Document