The cytosolic iron–sulfur (Fe-S) cluster assembly (CIA) pathway delivers Fe-S clusters to nuclear and cytosolic Fe-S proteins involved in essential cellular functions. Although the delivery process ...is regulated by the availability of iron and oxygen, it remains unclear how CIA components orchestrate the cluster transfer under varying cellular environments. Here, we utilized a targeted proteomics assay for monitoring CIA factors and substrates to characterize the CIA machinery. We find that nucleotide-binding protein 1 (NBP35), cytosolic iron–sulfur assembly component 3(CIAO3) (NARFL), and CIA substrates associate with nucleotide-binding protein 2 (CFD1), a component of the CIA scaffold complex. We also show that nucleotide-binding protein 2 weakly associates with the CIA targeting complex (MMS19, CIAO1, and CIAO2B) indicating the possible existence of a higher order complex. Interactions between CIAO3 and the CIA scaffold complex are strengthened upon iron supplementation or low oxygen tension, while iron chelation and reactive oxygen species weaken CIAO3 interactions with CIA components. We further demonstrate that CIAO3 mutants defective in Fe-S cluster binding fail to integrate into the higher order complexes. However, these mutants exhibit stronger associations with CIA substrates under conditions in which the association with the CIA targeting complex is reduced suggesting that CIAO3 and CIA substrates may associate in complexes independently of the CIA targeting complex. Together, our data suggest that CIA components potentially form a metabolon whose assembly is regulated by environmental cues and requires Fe-S cluster incorporation in CIAO3. These findings provide additional evidence that the CIA pathway adapts to changes in cellular environment through complex reorganization.
Paederia scandens (Lour.) Merr. (P. scandens) has been traditionally used to treat the pain of rheumatism.
The purpose of this study was to investigate the possible influences of P. scandens on the ...progression of rheumatoid arthritis (RA), inflammatory responses and gut bacterial communities in RA mouse model.
collagen-induced arthritis (CIA) mice were orally administered with P. scandens extract (PSE) for 24 days. Then, pro-inflammatory cytokine levels in the serum were measured, and gut microbiota was examined with Illumina HiSeq.
Compared with the vehicle group, PSE significantly inhibited paw swelling and reduced arthritis score. Histological examination of ankle soft tissue of demonstrated PSE effectively inhibited the tissue fibrosis and inflammatory cell infiltration. The increased serum levels of TNF-α, IL-1β, IL-6, IL-7, and IL-23 in RA mice were significantly suppressed by PSE. Moreover, PSE treatment help restore gut microbial ecosystem altered in RA mice including decreasing relative abundance of inflammatory related microorganisms, Desulfovibrio, Mucispirillum, Helicobacter, and Lachnospiraceae.
These results suggest that PSE has therapeutic effects in RA mice with CIA, showing the potential as anti-arthritis reagent.
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Current research suggests that synovial phagocytic cells remove excessive amounts of free oxygen radicals (reactive oxygen species ROS), thereby preventing damage to synovial tissues. Moreover, ROS ...may affect the expression of growth arrest and DNA damage inducible α (GADD45A), thus further promoting the activation of synovial fibroblasts. Male adult rats were assessed for progression of collagen‐induced arthritis (CIA) using a macroscopic arthritis scoring system of the hind paws and by measuring the changes in the rat's body weight, and activity level before and after diagnosis of CIA. Rats were intraperitoneally injected twice daily with edaravone at doses of 3, 6, and 9 mL/kg. Samples were taken at 2, 4, and 6 weeks, respectively. Edaravone was found to significantly reduce macroscopic arthritis and microscopic pathology scores in CIA rats. The concentration of endothelial nitric oxide synthase‐6, glutathione, and heme oxygenase‐1 in the serum of rats decreased, as was the production of ROS around the synovium and inflammatory factors. Moreover, ROS‐1 increased the expression of the nuclear factor‐κB (NF‐κB) p65 protein by altering the expression level of GADD45A, causing aggravation of tissue damage. Edaravone also significantly improved the physiological condition of CIA rats, including appetite, weight changes, and loss of fur, as well as limb mobility. We believe that edaravone acts to reduce the expression of NF‐ĸB p65 by clearing ROS, which causes reduced expression of GADD45A, and subsequently reduces the level of apoptosis and inflammatory response proteins, thereby reducing the symptoms of CIA. We, therefore, propose that edaravone is an effective option for clinical treatment of rheumatic arthritis.
This study sought to elucidate the role of edaravone as an effective scavenger of reactive oxygen species (ROS) in the synovial tissues of rheumatoid arthritis patients through the use of a rat model of collagen‐induced arthritis. Our results suggest that edaravone served to effectively reduce the macroscopic presentation and microscopic pathology scores in collagen‐induced arthritis (CIA) rats.
This article first describes the intelligence landscape in Iran in the mid-and late 1970s where intelligence services from three countries, the USA, the Soviet Union, and Iran, were involved in a ...standoff. It offers an in-depth overview of these organizations and explores their history, emergence, and expansion. Then, the article dwells on approaches and methods that the U.S. intelligence agencies employed for the recruitment and co-option of would-be renegades. In particular, the article focuses on the concepts of psychological vulnerabilities and 'MICE' and how they were applied to find people who are already mentally defected and manipulate them toward betrayal. Two cases of the Soviet officials in Iran who became targets of recruitment approaches are analyzed in depth. Besides, ethical considerations in recruitment operations are examined briefly.
The angiotensin AT
2
receptor (AT
2
R) is a main receptor of the protective arm of the renin-angiotensin system and exerts for instance anti-inflammatory effects. The impact of AT
2
R stimulation on ...autoimmune diseases such as rheumatoid arthritis (RA) is not yet known. We investigated the therapeutic potential of AT
2
R-stimulation with the selective non-peptide AT
2
R agonist Compound 21 (C21) in collagen-induced arthritis (CIA), an animal model for inflammatory arthritis. Arthritis was induced by immunization of DBA/1J mice with collagen type II (CII). Prophylactic and therapeutic C21 treatment alleviates arthritis severity and incidence in CIA. Joint histology revealed significantly less infiltrates of IL-1 beta and IL-17A expressing cells and a well-preserved articular cartilage in C21- treated mice. In CIA, the number of CD4
+
CD25
+
FoxP3
+
regulatory T (Treg) cells significantly increased upon C21 treatment compared to vehicle. T cell differentiation experiments demonstrated increased expression of FoxP3 mRNA, whereas IL-17A, STAT3 and IFN-gamma mRNA expression were reduced upon C21 treatment. In accordance with the mRNA data, C21 upregulated the percentage of CD4
+
FoxP3
+
cells in Treg polarizing cultures compared to medium-treated controls, whereas the percentage of CD4
+
IL-17A
+
and CD4
+
IFN-gamma
+
T cells was suppressed. To conclude, C21 exerts beneficial effects on T cell-mediated experimental arthritis. We found that C21-induced AT
2
R-stimulation promotes the expansion of CD4
+
regulatory T cells and suppresses IL-17A production. Thus, AT
2
R-stimulation may represent an attractive treatment strategy for arthritis.
•Cancer and chemotherapy-induced anemia is relatively common but underdiagnosed.•Anemia in cancer patients can negatively impact their quality of life and may worsen their prognosis and response to ...treatment particularly when radiation therapy is planned.•Blood transfusion can be offered in severe and symptomatic patients.•ESA should be avoided when cure is the goal in treating cancer patients, specially so if baseline Hb is above 10–12 g m/dL.•Cancer, along with chronic infections and inflammation, may increase the production of hepcidin which may result in poor utilization of iron creating a state of functional iron deficiency.•Intravenous “third-generation” iron formulations are safe and can be utilized in the treatment of both absolute and functional iron deficiency states.
Cancer and chemotherapy-induced anemia (CIA) is commonly encountered among patients undergoing active chemotherapy with or without radiation therapy. Its pathogenesis is complex and is often difficult to identify. Symptoms related to CIA may have a negative impact on quality of life and may influence treatment efficacy, disease progression and even survival. The recent major setback of erythropoietin-stimulating agents (ESAs) and the reluctance to transfuse cancer patients with mild and even moderate anemia, had resulted in significant under-treatment of CIA. The discovery of hepcidin and its role in iron homeostasis has revolutionized our understanding of the pathogenesis of iron deficiency and iron overload states. In the present review we examine the multifactorial pathogenesis of CIA, addressing the main mechanisms by which the tumor and immune system affect anemia. Additionally, we discuss the treatment options with more focus on the utilization of the new intravenous iron formulations for this indication.
Regulatory T (T
reg
) cells are garnering increased attention in research related to autoimmune diseases, including rheumatoid arthritis (RA). They play an essential role in the maintenance of immune ...homeostasis by restricting effector T cell activity. Reduced functions and frequencies of T
reg
cells contribute to the pathogenesis of RA, a common autoimmune disease which leads to systemic inflammation and erosive joint destruction. T
reg
cells from patients with RA are characterized by impaired functions and by an altered phenotype. They show increased plasticity towards Th17 cells and a reduced suppressive capacity. Besides the suppressive function of T
reg
cells, their effectiveness is determined by their ability to migrate into inflamed tissues. In the past years, new mechanisms involved in T
reg
cell migration have been identified. One example of such a mechanism is the phosphorylation of vasodilator-stimulated phosphoprotein (VASP). Efficient migration of T
reg
cells requires the presence of VASP. IL-6, a cytokine which is abundantly present in the peripheral blood and in the synovial tissue of RA patients, induces posttranslational modifications of VASP. Recently, it has been shown in mice with collagen-induced arthritis (CIA) that this IL-6 mediated posttranslational modification leads to reduced T
reg
cell trafficking. Another protein which facilitates T
reg
cell migration is G-protein-signaling modulator 2 (GPSM2). It modulates G-protein coupled receptor functioning, thereby altering the cellular activity initiated by cell surface receptors in response to extracellular signals. The almost complete lack of GPSM2 in T
reg
cells from RA patients contributes to their reduced ability to migrate towards inflammatory sites. In this review article, we highlight the newly identified mechanisms of T
reg
cell migration and review the current knowledge about impaired T
reg
cell homeostasis in RA.
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