Infiltration and activation of peripheral immune cells are critical in the progression of multiple sclerosis and its experimental animal model, experimental autoimmune encephalomyelitis (EAE). This study investigates the role of high mobility group box 1 (HMGB1) in oligodendrocyte precursor cells (OPCs) in modulating pathogenic T cells infiltrating the central nervous system through the blood-brain barrier (BBB) by using OPC-specific HMGB1 knockout (KO) mice. We found that HMGB1 released from OPCs promotes BBB disruption, subsequently allowing increased immune cell infiltration. The migration of CD4+ T cells isolated from EAE-induced mice was enhanced when co-cultured with OPCs compared to oligodendrocytes (OLs). OPC-specific HMGB1 KO mice exhibited lower BBB permeability and reduced immune cell infiltration into the CNS, leading to less damage to the myelin sheath and mitigated EAE progression. CD4+ T cell migration was also reduced when co-cultured with HMGB1 knock-out OPCs. Our findings reveal that HMGB1 secretion from OPCs is crucial for regulating immune cell infiltration and provides insights into the immunomodulatory function of OPCs in autoimmune diseases.
Animals ; Encephalomyelitis, Autoimmune, Experimental/metabolism* ; HMGB1 Protein/deficiency* ; Mice, Knockout ; Oligodendrocyte Precursor Cells/immunology* ; Mice, Inbred C57BL ; CD4-Positive T-Lymphocytes/immunology* ; Cell Movement ; Blood-Brain Barrier/immunology* ; Mice ; Myelin Sheath/pathology* ; Disease Models, Animal ; Coculture Techniques ; Oligodendroglia/metabolism* ; Female ; Cells, Cultured

Introduction: The purpose of this study is to determine the validity, reliability, and responsiveness of the Malay Shoulder Pain and Disability Index (M-SPADI) in Malay speakers suffering from shoulder pain. Materials and methods: The M-SPADI, the Numerical Rating Scale (NRS), and measurements of shoulder active range of motion (AROM) were completed by 140 patients with shoulder pain (68 with rotator cuff pathology and 72 with other shoulder pathology). Thirty-four patients were retested for test-retest reliability with M-SPADI after an average of 9.2 days. M-SPADI was performed on twenty-one individuals three months after completing treatment for rotator cuff disorders to assess response. Results: The results of exploratory factor analysis revealed a bidimensional structure for M-SPADI. M-SPADI disability score was significantly greater in patients with rotator cuff pathologies (median = 31.87, IQR 82.50) than in patients with other shoulder pathologies (median = 20.00, IQR 23.84). In multi-group factor analysis, measurement invariance revealed no significant difference between the two groups (p>0.05). There was a significant positive correlation between M-SPADI and NRS (Pain = 0.86, Disability = 0.75, Total = 0.82, p=0.005), and a significant negative correlation between M-SPADI and shoulder AROM (Pain = -0.34 to -0.67, Disability =-0.44 to -0.73, Total =- 0.43 to -0.72, p=0.005). M-SPADI had a high degree of internal consistency (Cronbach's 0.92 for pain and 0.95 for disability). Test-retest reliability was moderate to excellent (ICC Pain = 0.84, ICC Disability = 0.78, ICC Total = 0.81, p=0.001), and the smallest detectable change ranges (Pain = 8.74, Disability = 3.21, Total = 3.83) were less than the minimal detectable change ranges (Pain = 21.57, Disability = 6.82, Total = 8.79). The area under the receiver operating characteristic curve (AUC) for M-SPADI was greater than 0.90 (Pain = 0.99, Disability = 0.94, Total = 0.96). Conclusion: The M-SPADI has established construct validity, internal consistency, test-retest reliability, and responsiveness. The M-SPADI is a reliable and valid instrument for evaluating shoulder pain among Malayspeaking individuals. In addition, the M-SPADI disability subscale may be useful for monitoring functional score changes in patients with rotator cuff pathology.

Background: Risk assessment tools have been actively studied, and they summarize key predictors with relative weights/importance for a disease. Currently, standardized screening scores for type 2 diabetes mellitus (DM) and chronic kidney disease (CKD)—two key global health problems—are available in United States and Korea. We aimed to compare and evaluate screening scores for DM (or combined with prediabetes) and CKD, and assess the risk in contemporary United States and Korean populations. Methods: Four (2×2) models were evaluated in the United States-National Health and Nutrition Examination Survey (NHANES 2015–2018) and Korea-NHANES (2016–2018)—8,928 and 16,209 adults. Weighted statistics were used to describe population characteristics. We used logistic regression for predictors in the models to assess associations with study outcomes (undiagnosed DM and CKD) and diagnostic measures for temporal and cross-validation. Results: Korean adult population (mean age 47.5 years) appeared to be healthier than United States counterpart, in terms of DM and CKD risks and associated factors, with exceptions of undiagnosed DM, prediabetes and prehypertension. Models performed well in own country and external populations regarding predictor-outcome association and discrimination. Risk tests (high vs. low) showed area under the curve >0.75, sensitivity >84%, specificity >45%, positive predictive value >8%, and negative predictive value >99%. Discrimination was better for DM, compared to the combined outcome of DM and prediabetes, and excellent for CKD due to age. Conclusion Four easy-to-use screening scores for DM and CKD are well-validated in contemporary United States and Korean populations. Prevention of DM and CKD may serve as first-step in public health, with these self-assessment tools as basic tools to help health education and disparity.

Hepsin, a transmembrane serine protease abundant in renal endothelial cells, is a promising therapeutic target against several cancers, particularly prostate cancer. It is involved in the release and polymerization of uromodulin in the urine, which plays a role in kidney stone formation. In this work, we design new potential hepsin inhibitors for high activity, improved specificity towards hepsin, and promising ADMET properties. The ligands were developed through a novel hierarchical pipeline. This pipeline explicitly accounts for off-target binding to the related serine proteases matriptase and HGFA (human hepatocyte growth factor activator). We completed the pipeline incorporating ADMET properties of the candidate inhibitors into custom multi-objective optimization functions. The ligands designed show excellent prospects for targeting hepsin the blood stream and the urine and thus enable key experimental studies. The computational pipeline proposed is remarkably cost-efficient and can be easily adapted for designing inhibitors against new drug targets.

Drug-metabolizing enzymes, transporters, and nuclear receptors are essential for the absorption, distribution, metabolism, and excretion (ADME) of drugs and xenobiotics. MicroRNAs participate in the regulation of ADME gene expression imperfect complementary Watson-Crick base pairings with target transcripts. We have previously reported that Cytochrome P450 3A4 (CYP3A4) and ATP-binding cassette sub-family G member 2 (ABCG2) are regulated by miR-27b-3p and miR-328-3p, respectively. Here we employed our newly established RNA bioengineering technology to produce bioengineered RNA agents (BERA), namely BERA/miR-27b-3p and BERA/miR-328-3p, fermentation. When introduced into human cells, BERA/miR-27b-3p and BERA/miR-328-3p were selectively processed to target miRNAs and thus knock down and mRNA and their protein levels, respectively, as compared to cells treated with vehicle or control RNA. Consequently, BERA/miR-27b-3p led to a lower midazolam 1'-hydroxylase activity, indicating the reduction of CYP3A4 activity. Likewise, BERA/miR-328-3p treatment elevated the intracellular accumulation of anticancer drug mitoxantrone, a classic substrate of ABCG2, hence sensitized the cells to chemotherapy. The results indicate that biologic miRNA agents made by RNA biotechnology may be applied to research on miRNA functions in the regulation of drug metabolism and disposition that could provide insights into the development of more effective therapies.

Protein ubiquitination is an important means of post-translational modification which plays an essential role in the regulation of various aspects of leukocyte development and function. The specificity of ubiquitin tagging to a protein substrate is determined by E3 ubiquitin ligases via defined E3-substrate interactions. In this review, we will focus on two E3 ligases, VHL and Itch, to discuss the latest progress in understanding their roles in the differentiation and function of CD4 T helper cell subsets, the stability of regulatory T cells, effector function of CD8 T cells, as well as the development and maturation of innate lymphoid cells. The biological implications of these E3 ubiquitin ligases will be highlighted in the context of normal and dysregulated immune responses including the control of homeostasis, inflammation, auto-immune responses and anti-tumor immunity. Further elucidation of the ubiquitin system in immune cells will help in the design of new therapeutic interventions for human immunological diseases and cancer.

No abstract available.
*Hospitalization ; Humans ; *Liver Cirrhosis

Recent studies indicate that antiviral treatment with pegylated interferon alfa and ribavirin for hepatitis C can be individualized based on viral and host characteristics and the pattern of virologic response during the initial months of antiviral treatment. Patients with a low initial viral load who demonstrate a rapid virologic response to antiviral therapy may be treated with a shorter duration of therapy and are less sensitive to reduced dosing of ribavirin. Patients with delayed virologic response will require a longer duration of therapy - up to 72 weeks for patients with genotype 1 - in order to optimize chances of a sustained virologic response. Patients who were nonresponders or relapsed after an acceptable course of antiviral therapy may be retreated using a more intensive regimen and/or a longer duration of therapy. Previous nonresponders to pegylated interferon alfa and ribavirin are less likely to respond to retreatment unless they demonstrate a virologic response within the first three months of retreatment, lack advanced fibrosis, and can tolerate a more intensive and/or lengthier treatment. Individualized treatment based on viral genotype, viral load, the presence of advanced fibrosis, and initial virologic response can improve therapy for some patients and save resources in others.
Fibrosis ; Genotype ; Hepatitis C ; Humans ; Interferon-alpha ; Interferons ; Retreatment ; Ribavirin ; Viral Load

Molecular Nuclear Neuro - Imaging in "CNS" drug discovery and development can be divided into four categories that are clearly inter-related. (1) Neuroreceptor mapping to examine the involvement of specific neurotransmitter system in CNS diseases, drug occupancy characteristics and perhaps examine mechanisms of action; (2) Structural and spectroscopic imaging to examine morphological changes and their consequences; (3) Metabolic mapping to provide evidence of central activity and "CNS fingerprinting" the neuroanatomy of drug effects; (4) Functional mapping to examine disease-drug interactions. In addition, targeted delivery of therapeutic agents could be achieved by modifying stem cells to release specific drugs at the site of transplantation ('stem cell pharmacology'). Future exploitation of stem cell biology, including enhanced release of therapeutic factors through genetic stem cell engineering, might thus constitute promising pharmaceutical approaches to treating diseases of the nervous system. With continued improvements in instrumentation, identification of better imaging probes by innovative chemistry, molecular nuclear neuro-imaging promise to play increasingly important roles in disease diagnosis and therapy.
Biology ; Central Nervous System Diseases ; Chemistry ; Diagnosis ; Drug Discovery ; Molecular Imaging ; Nervous System ; Neuroanatomy ; Neuroimaging ; Neurotransmitter Agents ; Sensory Receptor Cells ; Stem Cells