scholarly journals Target Sestrin2 to Rescue the Damaged Organ: Mechanistic Insight into Its Function

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Moein Ala ◽  
Seyed Parsa Eftekhar
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Energy Homeostasis ◽  
Macrophage Polarization ◽  
Negative Regulator ◽  
Cellular Damage ◽  
M2 Macrophage ◽  
Nonalcoholic Fatty Liver ◽  
Cord Injury

Sestrin2 is a stress-inducible metabolic regulator and a conserved antioxidant protein which has been implicated in the pathogenesis of several diseases. Sestrin2 can protect against atherosclerosis, heart failure, hypertension, myocardial infarction, stroke, spinal cord injury neurodegeneration, nonalcoholic fatty liver disease (NAFLD), liver fibrosis, acute kidney injury (AKI), chronic kidney disease (CKD), and pulmonary inflammation. Oxidative stress and cellular damage signals can alter the expression of Sestrin2 to compensate for organ damage. Different stress signals such as those mediated by P53, Nrf2/ARE, HIF-1α, NF-κB, JNK/c-Jun, and TGF-β/Smad signaling pathways can induce Sestrin2 expression. Subsequently, Sestrin2 activates Nrf2 and AMPK. Furthermore, Sestrin2 is a major negative regulator of mTORC1. Sestrin2 indirectly regulates the expression of several genes and reprograms intracellular signaling pathways to attenuate oxidative stress and modulate a large number of cellular events such as protein synthesis, cell energy homeostasis, mitochondrial biogenesis, autophagy, mitophagy, endoplasmic reticulum (ER) stress, apoptosis, fibrogenesis, and lipogenesis. Sestrin2 vigorously enhances M2 macrophage polarization, attenuates inflammation, and prevents cell death. These alterations in molecular and cellular levels improve the clinical presentation of several diseases. This review will shed light on the beneficial effects of Sestrin2 on several diseases with an emphasis on underlying pathophysiological effects.

Therapeutic Effects of Azithromycin on Spinal Cord Injury in Male Wistar Rats: A Role for Inflammatory Pathways

2021 ◽  
Author(s):  
Ali Rismanbaf ◽  
Khashayar Afshari ◽  
Mehdi Ghasemi ◽  
Abolfazl Badripour ◽  
Arvin Haj-Mirzaian ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Wistar Rats ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Therapeutic Effects ◽  
Spinal Cord Tissue ◽  
Cord Injury ◽  
Male Wistar Rats

Abstract Background Inflammatory responses, including macrophages/microglia imbalance, are associated with spinal cord injury (SCI) complications. Accumulating evidence also suggests an anti-inflammatory property of azithromycin (AZM). Material and Methods Male Wistar rats were subjected to T9 vertebra laminectomy. SCI was induced by spinal cord compression at this level with an aneurysmal clip for 60 seconds. They were divided into three groups: the sham-operated group and two SCI treatment (normal saline as a vehicle control vs. AZM at 180 mg/kg/d intraperitoneally for 3 days postsurgery; first dose: 30 minutes after surgery) groups. Locomotor scaling and behavioral tests for neuropathic pain were evaluated and compared through a 28-day period. At the end of the study, tissue samples were taken to assess neuroinflammatory changes and neural demyelination using ELISA and histopathologic examinations, respectively. In addition, the proportion of M1/M2 macrophage polarization was assessed by using flow cytometry. Results Post-SCI AZM treatment (180 mg/kg/d for 3 days) significantly improved locomotion (p < 0.01) and decreased sensitivity to mechanical (p < 0.01) and thermal allodynia (p < 0.001). Moreover, there was a significant tumor necrosis factor-α (TNF-α) decline (p < 0.01) and interleukin-10 (IL-10) elevation (p < 0.01) in the spinal cord tissue of the AZM-treated group compared with the control groups 28 days post-SCI. AZM significantly improved neuroinflammation as evidenced by reduction of the M1 expression, elevation of M2 macrophages, and reduction of the M1/M2 ratio in both the dorsal root ganglion and the spinal cord tissue after SCI compared with controls (p < 0.01). Conclusion AZM treatment can be considered a therapeutic agent for SCI, as it could reduce neuroinflammation and SCI sensory/locomotor complications.

scholarly journals Decursinol Angelate Inhibits LPS-Induced Macrophage Polarization through Modulation of the NFκB and MAPK Signaling Pathways

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 1880 ◽  
Author(s):  
Salman Islam ◽  
Jung Lee ◽  
Adeeb Shehzad ◽  
Eun-Mi Ahn ◽  
You Lee ◽  
...  
Keyword(s):  
Map Kinase ◽  
Signaling Pathways ◽  
Inflammatory Cytokines ◽  
Macrophage Polarization ◽  
Raw 264.7 Cells ◽  
M2 Macrophage ◽  
Raw 264.7 ◽  
Decursinol Angelate ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Inflammation is considered the root cause of various inflammatory diseases, including cancers. Decursinol angelate (DA), a pyranocoumarin compound obtained from the roots of Angelica gigas, has been reported to exhibit potent anti-inflammatory effects. In this study, the anti-inflammatory effects of DA on the MAP kinase and NFκB signaling pathways and the expression of pro-inflammatory cytokines were investigated in phorbol 12-myristate 13-acetate (PMA)-activated human promyelocytic leukemia (HL-60) and lipopolysaccharide (LPS)-stimulated macrophage (Raw 264.7) cell lines. PMA induced the activation of the MAP kinase-NFκB pathway and the production of pro-inflammatory cytokines in differentiated monocytes. Treatment with DA inhibited the activation of MAP kinases and the translocation of NFκB, and decreased the expression and exogenous secretion of IL-1β and IL-6. Furthermore, LPS-stimulated Raw 264.7 cells were found to have increased expression of M1 macrophage-associated markers, such as NADPH oxidase (NOX) and inducible nitric oxide synthase (iNOS), and the M2 macrophage-associated marker CD11b. LPS also activated pro-inflammatory cytokines and Erk-NFκB. Treatment with DA suppressed LPS-induced macrophage polarization and the inflammatory response by blocking Raf-ERK and the translocation of NFκB in Raw 264.7 cells. Treatment with DA also inhibited the expression of pro-inflammatory cytokines, such as IL-1β and IL-6, NOX, and iNOS in Raw 264.7 cells. These results suggest that DA has the potential to inhibit macrophage polarization and inflammation by blocking the activation of pro-inflammatory signals. These anti-inflammatory effects of DA may contribute to its potential use as a therapeutic strategy against various inflammation-induced cancers.

scholarly journals The Role of Tissue Macrophage-Mediated Inflammation on NAFLD Pathogenesis and Its Clinical Implications

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Anna Alisi ◽  
Guido Carpino ◽  
Felipe L. Oliveira ◽  
Nadia Panera ◽  
Valerio Nobili ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Macrophage Polarization ◽  
Experimental Studies ◽  
Inflammatory Factors ◽  
M2 Macrophage ◽  
Low Grade ◽  
Nonalcoholic Fatty Liver ◽  
Tissue Macrophage ◽  
Phenotype Switch

The obese phenotype is characterized by a state of chronic low-grade systemic inflammation that contributes to the development of comorbidities, including nonalcoholic fatty liver disease (NAFLD). In fact, NAFLD is often associated with adipocyte enlargement and consequent macrophage recruitment and inflammation. Macrophage polarization is often associated with the proinflammatory state in adipose tissue. In particular, an increase of M1 macrophages number or of M1/M2 ratio triggers the production and secretion of various proinflammatory signals (i.e., adipocytokines). Next, these inflammatory factors may reach the liver leading to local M1/M2 macrophage polarization and consequent onset of the histological damage characteristic of NAFLD. Thus, the role of macrophage polarization and inflammatory signals appears to be central for pathogenesis and progression of NAFLD, even if the heterogeneity of macrophages and molecular mechanisms that govern their phenotype switch remain incompletely understood. In this review, we discuss the role of adipose and liver tissue macrophage-mediated inflammation in experimental and human NAFLD. This focus is relevant because it may help researchers that approach clinical and experimental studies on this disease advancing the knowledge of mechanisms that could be targeted in order to revert NAFLD-related fibrosis.

scholarly journals Polyphenols Targeting MAPK Mediated Oxidative Stress and Inflammation in Rheumatoid Arthritis

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6570
Author(s):  
Tapan Behl ◽  
Tanuj Upadhyay ◽  
Sukhbir Singh ◽  
Sridevi Chigurupati ◽  
Amal M. Alsubayiel ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Oxidative Stress ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Bone Erosion ◽  
Mapk Signaling ◽  
Future Research ◽  
Pathophysiological Mechanism ◽  
Critical Function ◽  
Research Perspectives

Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune disorder, predominantly symmetric, which causes joint inflammation, cartilage degeneration and bone erosion, resulting in deformity and the loss of physical function. Although the management of RA has steadily improved, the pathophysiological mechanism is incompletely elucidated, and therapeutic options are still limited. Due to shortcomings in the efficacy or safety profiles of conventional RA therapies, therapeutic alternatives have been considered. Therefore, natural extracts containing polyphenolic compounds can become promising adjuvant agents for RA global management, due to their antioxidant, anti-inflammatory and apoptotic properties. Polyphenols can regulate intracellular signaling pathways in RA and can generate different immune responses through some key factors (i.e., MAPK, interleukins (ILs 1 and 6), tumor necrosis factor (TNF), nuclear factor light k chain promoter of activated receptor (NF-κB), and c-Jun N-terminal kinases (JNK)). The critical function of the Toll like-receptor (TLR)-dependent mitogen-activating protein kinase (MAPK) signaling pathway in mediating the pathogenic characteristics of RA has been briefly discussed. Oxidative stress can trigger a change in transcription factors, which leads to the different expression of some genes involved in the inflammatory process. This review aims to provide a comprehensive perspective on the efficacy of polyphenols in mitigating RA by inhibiting signaling pathways, suggesting future research perspectives in order to validate their use.

scholarly journals Ubiquitination of interleukin-1α is associated with increased pro-inflammatory polarization of murine macrophages deficient in the E3 ligase ITCH

2020 ◽  
Vol 295 (33) ◽  
pp. 11764-11775
Author(s):  
Xi Lin ◽  
Hengwei Zhang ◽  
Brendan F. Boyce ◽  
Lianping Xing
Keyword(s):  
Signaling Pathways ◽  
Macrophage Polarization ◽  
E3 Ligase ◽  
Negative Regulator ◽  
Inflammatory Signaling ◽  
Protein Ubiquitination ◽  
Inflammatory Status ◽  
Interleukin 1Α ◽  
Inflammatory Macrophages ◽  
Macrophage Subsets

Macrophages play critical roles in homeostasis and inflammation. Macrophage polarization to either a pro-inflammatory or anti-inflammatory status is controlled by activating inflammatory signaling pathways. Ubiquitination is a posttranslational modification that regulates these inflammatory signaling pathways. However, the influence of protein ubiquitination on macrophage polarization has not been well studied. We hypothesized that the ubiquitination status of key proteins in inflammatory pathways contributes to macrophage polarization, which is regulated by itchy E3 ubiquitin ligase (ITCH), a negative regulator of inflammation. Using ubiquitin proteomics, we found that ubiquitination profiles are different among polarized murine macrophage subsets. Interestingly, interleukin-1α (IL-1α), an important pro-inflammatory mediator, was specifically ubiquitinated in lipopolysaccharide-induced pro-inflammatory macrophages, which was enhanced in ITCH-deficient macrophages. The ITCH-deficient macrophages had increased levels of the mature form of IL-1α and exhibited pro-inflammatory polarization, and reduced deubiquitination of IL-1α protein. Finally, IL-1α neutralization attenuated pro-inflammatory polarization of the ITCH-deficient macrophages. In conclusion, ubiquitination of IL-1α is associated with increased pro-inflammatory polarization of macrophages deficient in the E3 ligase ITCH.

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