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Feb 2025 DOI 10.14302/issn.2326-0793.jpgr-25-5405
Ho Ming-FenCorresponding author
Alcohol use disorder (AUD) is the most prevalent substance use disorder. Excessive alcohol consumption leads to a range of health issues. We set out to identify inflammatory markers linked to alcohol consumption, which might ultimately offer novel insight into genetic underpinnings and have implications for alcohol-associated disease. Alcohol consumption and blood-based multi-omics data were collected by The Mayo Clinic Center for Individualized Treatment of Alcohol Dependence study. Plasma samples from patients with AUD were used for proteomics analysis using the OLINK “Explore Inflammation” panel (n=410). Liver enzymes were also measured. A genome-wide association study (GWAS) was performed to explore the relationship between genetic variants and plasma TREM2 levels. Our findings show thatplasma triggering receptor expressed on myeloid cells 2 (TREM2), a key gene associated with neurodegenerative disease, was the most significant signal correlated with alcohol consumption, and has also been associated with liver enzyme levels in patients with AUD. We identified the rs7232 single nucleotide polymorphism (SNP) in MS4A6A as a key genetic variant associated with plasma TREM2 levels, with the minor allele (A) linked to higher TREM2 levels and increased alcohol consumption, particularly in men. Furthermore, MA4A6A is an ethanol-responsive gene in a SNP-dependent manner, and the variant genotype of the rs7232 SNP was associated with lower expression for MA4A6A due to proteasome-mediated protein degradation. In summary, this study provides insight into the relationship between plasma TREM2 levels, alcohol consumption, and liver function in AUD patients, shedding light on genetic factors underlying alcohol-related diseases.
Oct 2016 DOI 10.14302/issn.2572-3030.jcgb-16-1276
Hayashi TakumaCorresponding author
Dept. of Obstetrics and Gynecology, Shinshu University School of Medicine, Japan,
Human uterine leiomyosarcoma (LMS) is neoplastic malignancy that typically arises in tissues of mesenchymal origin. The identification of novel molecular mechanism leading to human uterine LMS formation and the establishment of new therapies has been hampered by several critical points. We earlier reported that mice with a homozygous deficiency for proteasome beta subunit 9 (PSMB9)/b1i, an interferon (IFN)-g inducible factor, spontaneously develop uterine LMS. The use of research findings of the experiment with mouse model has been successful in increasing our knowledge and understanding of how alterations, in relevant oncogenic, tumour suppressive, and signaling pathways directly impact sarcomagenesis. The IFN-g pathway is important for control of tumour growth and invasion and, has been implicated in several malignant tumours. In this study, experiments with human tissues revealed a defective PSMB9/b1i expression in human uterine LMS that was traced to the IFN-g pathway and the specific effect of somatic mutations of Janus kinase (JAK1) molecule or promoter region on the transcriptional activation of PSMB9/b1i gene. Understanding the molecular mechanisms of human uterine LMS may lead to identification of new diagnostic candidates or therapeutic targets in human uterine LMS.
Jun 2014 DOI 10.14302/issn.2372-6601.jhor-13-379
Hayashi TakumaCorresponding author
Dept. of Immunology and Infectious Disease, Shinshu University, School of Medicine, Matsumoto, Nagano 390-8621, Japan
Sarcomas are neoplastic malignancies that typically arise in tissues of mesenchymal origin. The identification of novel molecular mechanisms leading to sarcoma formation and the establishment of new therapies has been hampered by several critical factors. Human uterine leiomyosarcoma (Ut-LMS) develops more frequently in the muscle tissue layer of the uterine body than in the uterine cervix. Although the development of gynecologic tumors is often correlated with the secretion of female hormones; that of human Ut-LMS does not and its risk factors remain unknown. Importantly, a diagnostic biomarker that can distinguish malignant Ut-LMS from benign tumor uterine leiomyoma (LMA) has yet to be established. Therefore the risk factor(s) associated with human Ut-LMS to establish a diagnosis and novel therapeutic method. Proteasome b-ring subunit LMP2/b1i-deficient mice spontaneously develop Ut-LMS, with a disease prevalence of ~40% by 14 months of age. We shown that LMP2/b1i expression was absent in human Ut-LMS, but present in other human uterine mesenchymal tumors including uterine LMA. Therefore, defective-LMP2/b1i expression may be one of the risk factors for human Ut-LMS. LMP2/b1i is a potential diagnostic biomarker for human Ut-LMS, and may be a targeted-molecule for a new therapeutic approach.
Jun 2014 DOI 10.14302/issn.2328-0182.japst-13-288
Pradhan N.Corresponding author
Sr. Professor and Head, Department of Psychopharmacology, NIMHANS, Bangalore, INDIA, 560001
ALS is the neurodegenerative disease which is caused due to breakdown in interaction between UBL and rpn1. In this study, we explore the interaction of UBL and rpn1 which is involved in protein degradation. Protein recycling system plays a crucial role in degradation of deformed or damaged proteins. Task of degradation of damaged ubiquitinated proteins is completed by proteasome with the help of ubiquilin2 protein which links 19s proteasome and poly-Ub chain attached to damaged protein. More specifically, N-terminal UBL domain interacts with rpn1 subunit of base complex of 19s proteasome and C-terminal UBA domain interacts with tetra poly-Ub chain attached to damaged protein. In present study, UBL domains are docked against homology modeled rpn1 with the help of Patch dock server. Further the docked structures are refined using fire dock server and best docked structure is chosen having global energy -16.71. Best docked structures are analyzed using swiss-pdb viewer software to show hydrogen bonds between interacting proteins. Here we explore a mutation E6A and P11A in UBL structure with the help of YASARA which is significantly increasing the interaction between interacting proteins in terms of hydrogen bonds.