Biology subjects

Major, P.

Publications and source records attributed to Major, P..

3 recordsLinked to original sources

bioRxiv2023

Diosmetin alleviates liver inflammation by improving liver sinusoidal endothelial cell dysfunction.

Background & AimsTumor necrosis factor-alpha (TNF) induces pro-inflammatory activation in liver sinusoidal endothelial cells (LSEC) and liver inflammation. However, knowledge about whether modulating LSEC activation can alleviate liver inflammation is scarce. This study aimed to establish and validate an animal model mimicking LSEC dysfunction observed in patients with elevated plasma levels of TNF, and explore whether vasoactive flavonoid diosmetin could serve as a therapeutic agent for liver inflammation. Approach & ResultsGenetic deletion of Mcpip1 in myeloid leukocytes (Mcpip1fl/flLysMCre) resulted in the development of systemic and liver inflammation in mice. Symptoms were compared with those in liver samples from obese humans with elevated TNF. Mice were treated with diosmetin, and its effectiveness in alleviating liver inflammation was evaluated. Elevated TNF correlated with reduced Mcpip1 expression in peripheral blood mononuclear cells and LSEC dysfunction in obese patients. Mcpip1 knockout in myeloid cells in mice replicated molecular signs observed in human samples. Diosmetin efficiently reduced LSEC activation and liver inflammation in Mcpip1fl/flLysMCre mice. Diosmetins effects may stem from inhibiting NF-{kappa}B-p50 subunit production in TNF-activated endothelial cells. ConclusionsDiosmetin treatment efficiently restricted liver inflammation, despite ongoing systemic inflammation, by diminishing LSEC dysfunction. Mcpip1fl/flLysMCre mice mimic symptoms of liver inflammation observed in humans and can be useful in studies on new anti-inflammatory therapies for the liver. We show that diosmetin, a vasoactive flavonoid that is successfully used in the clinic to treat chronic venous insufficiency, has also strong anti-inflammatory properties in the liver. This suggests that diosmetin treatment may be tested in humans as a supportive therapy for liver inflammation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=186 HEIGHT=200 SRC="FIGDIR/small/563468v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@1c1c841org.highwire.dtl.DTLVardef@1425cb9org.highwire.dtl.DTLVardef@1d583aaorg.highwire.dtl.DTLVardef@b71f40_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

Hepatic MCPIP1 protein levels are reduced in NAFLD patients and are predominantly expressed in cholangiocytes and liver endothelium

Nonalcoholic fatty liver disease (NAFLD) is characterized by the excessive accumulation of fat in hepatocytes. NAFLD can range from simple steatosis to the aggressive form called nonalcoholic steatohepatitis (NASH), which is characterized by both fatty liver and liver inflammation. Without proper treatment, NAFLD may further progress to lifethreatening complications, such as fibrosis, cirrhosis or liver failure. Monocyte chemoattractant protein-induced protein 1 (MCPIP1, alias Regnase 1) is a negative regulator of inflammation, acting through the cleavage of transcripts coding for proinflammatory cytokines and the inhibition of NF{kappa}B activity. In this study, we investigated MCPIP1 expression in the liver and peripheral blood mononuclear cells (PBMCs) collected from a cohort of 36 control and NAFLD patients hospitalized due to bariatric surgery or primary inguinal hernia laparoscopic repair. Based on liver histology data (H&E and Oil Red O staining), 12 patients were classified into the nonalcoholic fatty liver (NAFL) group, 19 into the NASH group and 5 into the control (non-NAFLD) group. Biochemical characterization of patient plasma was followed by expression analysis of genes regulating inflammation and lipid metabolism. The MCPIP1 protein level was reduced in the livers of NAFL and NASH patients in comparison to non-NAFLD control individuals. Additionally, in all groups of patients, immunohistochemical staining showed that the expression of MCPIP1 was higher in the portal fields and bile ducts in comparison to the liver parenchyma and central vein. The liver MCPIP1 protein level negatively correlated with hepatic steatosis but not with patient BMI or any other analyte. The MCPIP1 level in PBMCs did not differ between NAFLD patients and control patients. Similarly, in patients PBMCs there were no differences in the expression of genes regulating {beta}-oxidation (ACOX1, CPT1A, and ACC1) and inflammation (TNF, IL1B, IL6, IL8, IL10, and CCL2), or transcription factors controlling metabolism (FAS, LCN2, CEBPB, SREBP1, PPARA, and PPARG). We have demonstrated that MCPIP1 protein levels are reduced in NAFLD patients, but further research is needed to investigate the specific role of MCPIP1 in NAFL initiation and the transition to NASH.

molecular biology↗

bioRxiv2018

Circuit dysfunction in SOD1-ALS model first detected in sensory feedback prior to motor neuron degeneration is alleviated by BMP signaling

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease whose origin and underlying cellular defects are still not fully understood. While motor neuron degeneration is the signature feature of ALS, it is not yet clear if motor neurons, or other cells of the motor circuit, are the site of disease initiation. To better understand the contribution of multiple cell types in ALS, we made use of a Drosophila Sod1G85R knock-in model, in which all cells harbor the disease allele. End-stage dSod1G85R animals exhibit severe motor deficits with clear degeneration of motor neurons. Interestingly, earlier in dSod1G85R larvae motor function is also compromised, but their motor neurons exhibit only subtle morphological and electrophysiological changes, that are unlikely to cause the observed decrease in locomotion. We analyzed the intact motor circuit and identified a defect in sensory feedback that likely accounts for the altered motor activity of dSod1G85R. Furthermore, we found that the cell-autonomous activation of BMP signaling in proprioceptor sensory neurons that relay the contractile status of muscles back to the central nerve cord, is able to completely rescue early stage motor defects and partially rescue late stage motor function to extend lifespan. Identifying a defect in sensory feedback as a potential initiating event in ALS motor dysfunction, coupled with the ability of modified proprioceptors to alleviate such motor deficits, underscores the critical role that non-motor neurons play in disease progression and highlights their potential as a site to identify early-stage ALS biomarkers and for therapeutic intervention.\n\nSignificance StatementAt diagnosis, many cellular processes are already disrupted in the ALS patient. Identifying the initiating cellular events is critical for achieving an earlier diagnosis in order to slow or prevent disease progression. Our findings indicate that neurons relaying sensory information underlie early stage motor deficits in a Drosophila knock-in model of ALS that best replicates gene dosage in familial ALS (fALS). Importantly, studies on intact motor circuits revealed defects in sensory feedback before evidence of motor neuron degeneration. These findings strengthen our understanding of how neural circuit dysfunctions lead to neurodegeneration and coupled with our demonstration that activation of BMP signaling in proprioceptors alleviates both early and late motor dysfunction, underscores the importance of considering non-motor neurons as therapeutic targets.

neuroscience↗