ABSTRACT
In the HAX1/HtrA2-OMI/PARL (HOP) mitochondrial protein complex, anti-apoptotic signals are generated by cleavage and activation of the serine protease HtrA2/OMI by the rhomboid protease PARL upon recruitment of both proteases to inner mitochondrial membrane protein HAX1 (HS1-associated protein X-1). Here we report the negative regulation of the HOP complex by human leukemia-associated myeloid leukemia factor 1 (MLF1). We demonstrate that MLF1 physically and functionally associates with HAX1 and HtrA2. Increased interaction of MLF1 with HAX1 and HtrA2 displaces HtrA2 from the HOP complex and inhibits HtrA2 cleavage and activation, resulting in the apoptotic cell death. Conversely, over-expressed HAX1 neutralizes MLF1's effect and inhibits MLF1-induced apoptosis. Importantly, Mlf1 deletion reverses B- and T-cell lymphopenia and significantly ameliorates the progressive striatal and cerebellar neurodegeneration observed in Hax1-/- mice, with a doubling of the lifespan of Mlf1-/-/Hax1-/- animals compared to Hax1-/- animals. Collectively, these data indicate that MLF1 serves as a proapoptotic antagonist that interacts with the HOP mitochondrial complex to modulate cell survival.
Subject(s)
Lymphopenia/genetics , Metalloproteases/genetics , Mitochondria/metabolism , Mitochondrial Proteins/genetics , Proteins/genetics , Serine Endopeptidases/genetics , Animals , Apoptosis , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , COS Cells , Cell Cycle Proteins , Cell Survival , Chlorocebus aethiops , DNA-Binding Proteins , Female , Fibroblasts/cytology , Fibroblasts/metabolism , Gene Deletion , Gene Expression Regulation , HEK293 Cells , High-Temperature Requirement A Serine Peptidase 2 , Humans , Intracellular Signaling Peptides and Proteins , K562 Cells , Lymphopenia/mortality , Lymphopenia/pathology , Lymphopenia/prevention & control , Metalloproteases/metabolism , Mice , Mitochondrial Proteins/metabolism , Proteins/metabolism , Serine Endopeptidases/metabolism , Signal Transduction , Survival Analysis , T-Lymphocytes/metabolism , T-Lymphocytes/pathologyABSTRACT
Myasthenia gravis (MG) is a chronic autoimmune disease caused by autoantigen against the nicotine acetylcholine receptor at the neuromuscular junction. With modern treatment facilities, the treatment effect and outcome for MG has been greatly improved with MG and non-MG patients enjoying the same life expectancy. Many classifications of disease distribution and severity have been set up and tested all over the world, mainly in the western world. However, the absolute and relative scoring system for evaluating the severity and treatment effect of MG in China where traditional Chinese medicine (TCM) has been practiced for thousands of years has not been introduced worldwide. The TCM has achieved a great success in the treatment of MG in the country with a huge population. This article serves to introduce this scoring system to the world.
Subject(s)
Medicine, Chinese Traditional/methods , Myasthenia Gravis/diagnosis , Eye Movements/physiology , Humans , Myasthenia Gravis/physiopathology , Severity of Illness IndexABSTRACT
Purpose. To evaluate the treatment effect and side effect of Shenqi Fuzheng Injection (SFI) on alleviating transient worsening of myasthenia gravis (MG) symptoms caused by high-dose steroids pulse therapy. Methods. Sixty-six consecutive patients with MG were randomly divided into two groups: the treatment group treated with SFI and methylprednisolone pulse therapy (MPT) and the control group treated with MPT alone. The severity of MG before, during, and after MPT and the duration of transient worsening (TW) were evaluated and compared with the clinical absolute scoring (AS) and relative scoring (RS) system. Results. Twenty-nine patients experienced TW in each group. At TW, the AS was significantly increased (P < 0.000) in both groups compared with baseline data, with the AS increase in the treatment group (16.8 ± 2) significantly smaller (P < 0.05) than in the control group (24.9 ± 2.5). At the end of the treatment course, the AS for the treatment group was significantly decreased (7.5 ± 0.9) compared with at TW, although no significant difference compared with the control (9.7 ± 1.1). The TW lasted 1-6 days (mean 3.7) for the treatment group, significantly shorter (P < 0.05) than 2-12 days (mean 7.8) for the control. The RS for the treatment group at the end of treatment was 43.8%-100% (mean 76.8% ± 2.6%), significantly better than the control group: 33.3%-100% (mean 67.2 ± 3.6%). Slight side effects (18.75%) included maldigestion and rash in the treatment group. Conclusion. SFI has a better treatment effect and few side effects and can alleviate the severity and shorten the duration of the transient worsening of MG during steroids pulse therapy.