The pathogenesis and regulatory role of HIF-1 in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a prevalent autoimmune disease that involves the overgrowth and inflammation of synovial tissue, leading to the degeneration and impairment of joints. In recent years, numerous studies have shown a close relationship between the hypoxic microenvironment in joints and the occurrence and progression of RA. The main cause of the pathological changes in RA is widely believed to be the abnormal expression of hypoxia-inducible factor-1 (HIF-1) in joints. This paper describes and illustrates the structure and primary functions of HIF-1 and explains the main regulatory methods of HIF-1, including the PHDs/HIF-1 α/pVHL pathway, factor-inhibiting HIF (FIH), regulation of inflammatory cytokines, and the NF-κB pathway. Furthermore, this paper discusses the mechanism of HIF-1 and its impact on inflammation, angiogenesis, and cartilage destruction in greater detail. We summarize previous research findings on the mechanism of HIF-1 and propose new potential treatments for RA based on the pathogenesis of HIF-1 in RA.

The roles of reactive oxygen species (ROS) and autophagy in the survival and death of leukemia cells.

As a clonal disease of hematopoietic stem cells (HSCs), the etiology and pathogenesis of leukemia is not fully understood. Recent studies suggest that cellular homeostasis plays an essential role in maintaining the function of HSCs because dysregulation of cellular homeostasis is one of the major factors underlying the malignant transformation of HSCs. Reactive oxygen species (ROS) and autophagy, key factors regulating cellular homeostasis, are commonly observed in the human body. Autophagy can be induced by ROS through a variety of signaling pathways, and conversely inhibits ROS-induced damage to cells and tissues. ROS and autophagy coordinate to maintain cellular homeostasis. Previous studies have demonstrated that both of ROS and autophagy play important roles in the development of leukemia and are closely involved in drug resistance in leukemia. Interference with cellular homeostasis by promoting programmed leukemia cell death via ROS and autophagy has been verified to be an efficient technique in the treatment of leukemia. However, the critical roles of ROS and autophagy in the development of leukemia are largely unknown. In this review, we summarize the roles of ROS and autophagy in the pathogenesis of leukemia, which may allow the identification of novel targets and drugs for the treatment of leukemia based on the regulation of HSCs homeostasis through ROS and autophagy.

[Effects of TAK gene silencing on the expressions of IL-6 and IL-8 induced by TNF-α in fibroblast-like synoviocytes].

OBJECTIVE: To investigate the effects of silencing transforming growth factor-ß activating kinase 1 (TAK1)on the expressions of IL-6 and IL-8 induced by TNF-α in fibroblast-like synoviocytes, and to explore the role of TAK1 in rheumatoid arthritis (RA). METHODS: The synthesized TAK1 siRNA and scrambled siRNA (ScRNA) were transferred into cultured RA fibroblast-like synoviocyte line MH7A by lipofectamine. The expressions of the pro-inflammatory mediator IL-6 and IL-8 and the levels of phospho-P38(p-P38), phospho-C-Jun NH2-terminal kinase(p-JNK), phospho-extracellular signal-regulated kinase(p-ERK), phospho-p65(p-p65) and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha(IκBa) were examined. RESULTS: Silencing of TAK was demonstrated in synoviocytes transfected by TAK siRNA. TAK1 silencing markedly attenuated the expression of IL-6 and IL-8 in the presence of TNF-α. TAK1 silencing inhibited the activation of p38 and JNK MAPK. TAK1 silencing also inhibited activation of nuclear factor-κB (NF-κB). CONCLUSIONS: TAK1 silencing attenuated the expression of IL-6 and IL-8 in synoviocytes induced by TNF-α via inhibiting the activation of p38, JNK MAPK and NF-κB.

The role of RIP1 and RIP3 in the development of aplastic anemia induced by cyclophosphamide and busulphan in mice.

This study aimed to investigate the role of RIP1 and RIP3 in the pathogenesis of aplastic anemia (AA) induced by cyclophosphamide and busulphan in mice. Animals were randomly divided into three groups: the control group, the AA group, and the Nec-1 group. Mouse AA model was established by intraperitoneal injection of cyclophosphamide (40 mg/kg/d) and busulfan (20 mg/kg/d) for 12 days. The Nec-1 group mice received intraperitoneal injection of Nec-1 (2 mg/kg/d) for 12 days prior to intraperitoneal injection of cyclophosphamide (40 mg/kg/d) and busulfan (20 mg/kg/d) for 12 days. The control mice received intraperitoneal injection of equal volume of saline. At 12 h after the last intraperitoneal injection, blood and bone marrow tissues were collected from mice. Peripheral blood cells were analyzed using hematology analyzer and the histological changes of bone marrow tissues were examined using scanning electron microscopy (SEM). The levels of RIP3 and RIP3 in bone marrow were measured using Western blot analysis and the interaction of RIP1 and RIP3 proteins was investigated on the basis of immunoprecipitation analysis. ELISA was used to measure the levels of IL-6, TNF-α, and FLT-3L in bone marrow tissue supernatant. Apoptosis and necrosis of bone marrow cells were analyzed using flow cytometry. Western blot showed that the expression of RIP1 and RIP3 was significantly increases in AA mice compared to the normal controls. Immunoprecipitation detected the pro-necrotic RIP1-RIP3 complex, suggesting that RIP1 and RIP3 mediated necroptosis may involved in the damage of bone marrow cells. Compared to the AA mice, Nec-1 group mice exhibited significantly increase of peripheral blood cells and mononuclear cells in bone marrow tissues and decrease of the apoptosis/necrosis of bone marrow cells. In addition, we observed significant decrease of IL-6, TNF-α, and FLT-3L in bone marrow tissue supernatant in the Nec-1 group mice compared to AA mice. Our results suggest that Nec-1 can prevent the development of AA by inhibiting bone marrow cells necrosis and the production of inflammatory mediators. RIP1 and RIP3-mediated necroptosis may involve in the pathogenesis of AA induced by cyclophosphamide and busulfan in mice.

[The effect of Hsp72 on IL-6, IL-8 expression and activation of NF-kappaB in synoviocytes of rheumatoid arthritis].

OBJECTIVE: To investigate the effects of heat shock protein 72 (Hsp72) on the expression of IL-6 and IL-8 and activation of NF-kappaB in synoviocytes from patients suffered from rheumatoid arthritis (RA). METHODS: IL6 and IL8 concentrations in culture supernatants were measured using enzyme-linked immunosorbent assays (ELISA). Nuclear translocation of NF-kappaB and degradation of the inhibitory protein IkappaBalpha were examined using immunohistochemistry and Western blot. RESULTS: Hsp72 down-regulated IL-6 and IL-8 production in RA synoviocytes induced by tumor necrosis factor-alpha (TNF-alpha). Hsp72 inhibited nuclear translocation of NF-kappaB and degradation of IkappaBalpha induced by TNF-alpha. CONCLUSION: Hsp72 has an anti-inflammatory effect on RA by down-regulation of IL-6 and IL-8 in synoviocytes, which is mediated through inhibiting the activation of NF-KalphaB signal pathways.