Fatostatin ameliorates inflammation without affecting cell viability.

The mature form of sterol regulatory element-binding protein (SREBP)1 is a transcription factor involved in lipid synthesis, which participates in toll like receptor 4-triggered inflammatory pathways during the resolution phase of inflammation in macrophages. SREBP1 has thus attracted interest as a candidate target molecule for ameliorating inflammation. Fatostatin is a small molecule that inhibits the maturation and function of SREBP, and its role in regulating inflammation is poorly understood. To evaluate the anti-inflammatory effect of fatostatin, we compared body weight, footpad and hock dimensions, and arthritis scores between K/BxN serum-induced arthritis mice treated with fatostatin and those treated with dimethyl sulfoxide as the vehicle control. We performed hematoxylin and eosin staining of joints of distal paws to assess tissue inflammation. Moreover, inflammatory cytokine production levels and cell viability were measured in lipopolysaccharide-responsive human embryonic kidney 293 cells (293/hTLR4A-MD2-CD14 cells) after fatostatin administration. In K/BxN serum-induced arthritis mice, fatostatin treatment significantly reduced the arthritis scores and hyperplasia. In vitro analysis revealed that fatostatin significantly inhibited the secretion of inflammatory cytokines from cells activated with lipopolysaccharide, without affecting cell viability. This is the first study to demonstrate that fatostatin is an anti-inflammatory agent that modulates the processing of lipid transcription factors without affecting cell viability. Accordingly, the study reveals the potential of anti-inflammatory therapeutics that link lipid regulation and inflammation.

Increased Ratio of CD14++CD80+ Cells/CD14++CD163+ Cells in the Infrapatellar Fat Pad of End-Stage Arthropathy Patients.

Objectives: This study sought to identify the ratio of M1/M2 cells in the infrapatellar fat pads (IFP) and subcutaneous fat tissues (SC) of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. The clinical features of OA and RA patients treated with or without biological disease-modifying anti-rheumatic drugs (bDMARDs) were also assessed. Methods: IFP and SC were collected from patients with OA and RA who are undergoing total knee arthroplasty (TKA). CD14-positive cells were then isolated from these samples. Flow cytometry was used to determine the number of CD14++CD80+ cells and CD14++CD163+ cells. The expression levels of lipid transcription factors, such as sterol regulatory element-binding protein 1 (SREBP1) and liver X receptor alpha (LXRA), and inflammatory cytokines were also evaluated. Results: Twenty OA patients and 22 RA patients were enrolled in this study. Ten of the RA patients (45.4%) received bDAMRDs before TKA. On average, a fivefold increase in the number of CD14-positive cells and lower expression levels of SREBP1C and LXRA were observed in OA IFP relative to OA SC; however, these results were not obtained from the RA samples. The median ratio of CD14++CD80+ cells/CD14++CD163+ cells of OA IFP was 0.87 (0.76-1.09, interquartile range), which is higher to that of OA SC with a lower ratio (p = 0.05835). Conclusions: The quantity and quality of CD14-positive cells differed between IFP and SC in arthropathy patients. To our knowledge, this is the first study to characterize the ratio of M1/M2 cells in the IFP and SC of end-stage OA and RA patients. The increased ratio of CD14++CD80+ cells/CD14++CD163+ cells in the IFP from patients with OA and RA treated with bDMARDs indicated that inflammation was localized in the IFP. As adipose tissue-derived innate immune cells were revealed as one of the targets for regulating inflammation, further analysis of these cells in the IFP may reveal new therapeutic strategies for inflammatory joint diseases.

Anti-PDHA1 antibody is detected in a subset of patients with schizophrenia.

Autoantibodies have been implicated in schizophrenia aetiology. Here, novel autoantibodies were isolated from patients with schizophrenia. Autoantibody candidates were searched using two-dimensional gel electrophoresis and western blotting with rat brain proteins as antigens and two sera pools (25 schizophrenia patients versus 25 controls) as antibodies. Immunoreactive antigens were identified by mass spectrometry. Antibody prevalence were evaluated by western blotting using human recombinant proteins. Furthermore, brain magnetic resonance imaging data (regional brain volumes and diffusion tensor imaging measures) were compared. Two proteins of the mitochondrial respiration pathway were identified as candidate antigens. Three patients with schizophrenia, but no controls, expressed antibodies targeting one of the candidate antigens, i.e., pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial (PDHA1, EC 1.2.4.1), which is related to mitochondrial energy production. Anti-PDHA1 antibody-positive patients (n = 3) had increased volumes in the left occipital fusiform gyrus compared to both controls (n = 23, p = 0.017) and antibody-negative patients (n = 16, p = 0.009), as well as in the left cuneus compared to antibody-negative patients (n = 16, p = 0.018). This is the first report of an anti-PDHA1 antibody in patients with schizophrenia. Compatible with recent findings of mitochondrial dysfunction in schizophrenia, this antibody may be involved in the pathogenesis of a specific subgroup of schizophrenia.