Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Online First

This study aimed to explore the differential expression of the co-stimulatory molecule CD226 in lymphocytes from patients with New-Onset Graves' Disease (NOGD) and its correlation with clinical indicators.

Sixty-eight participants were recruited for the discovery experiment (NOGD: healthy control (HC) = 39:29). Peripheral Blood Mononuclear Cells (PBMCs) were isolated. Flow cytometry was performed to detect CD226 expression on multiple lymphocyte subtypes. CD226 mRNA expression in PBMCs was detected by qPCR. Fifty-eight participants were recruited for the validation experiment (NOGD: HC=35:23). CD4+ T cells were isolated, and the level of CD226 mRNA in CD4+ T cells was detected. Five cases of each of Graves' disease (GD) thyroid and control thyroid were collected for CD226 immunohistochemical staining.

CD226 expression was the highest in monocytes (NOGD: 94.1% vs. HC: 94.8%) and the lowest in CD8+ T cells (NOGD: 65.3% vs. HC: 64.9%). Compared with HC, CD226 expression on the CD4+ T cells increased in the peripheral blood of NOGD patients and correlated with TPO-Ab. Meanwhile, CD226 mRNA levels were elevated in CD4+ T cells and positively correlated with TR-Ab. CD226 expression was significantly increased in the thyroid tissues of GD patients.

This study demonstrates for the first time the elevated expression of CD226 in CD4+ T cells and thyroid tissue of NOGD. The abnormal elevation of CD226 is correlated with clinical indicators. It suggests that the co-stimulatory molecule CD226 is involved in the pathogenesis of GD.

TAP-1 and TAP-2 are crucial proteins for loading antigenic peptides after proteasome-mediated endogenous processing of the MHC-I (Major Histocompatibility Complex-I) pathway. Our study aimed to explore the Transporter Associated with Antigen Processing proteins (TAP-1 and TAP-2) in oral squamous cell carcinoma and premalignant oral lesions.

We recruited a total of 135 subjects from the outpatient department of the ENT unit of our institute. Real-time Polymerase Chain Reaction (PCR) was used to evaluate the levels of TAP-1 and TAP-2 gene expression in pre-cancerous and oral squamous carcinoma samples. Additionally, we measured the circulating levels of inflammatory markers using an automated biochemistry analyzer.

In the current study, we found that the subjects with oral squamous cell carcinoma had lower expressions of the TAP 1 and TAP 2 genes than precancerous oral subjects of OSMF, leukoplakia, and OLP. In oral squamous carcinoma subjects, we found a 1.7- and 2.1-fold change in gene expression of TAP-1 and TAP-2, respectively, compared to control subjects. Furthermore, we observed an increase in levels of metabolic inflammatory biomarkers of CRP, ESR, and ferritin in oral squamous carcinoma subjects compared to premalignant cases and controls, indicating the presence and aggravation of systemic inflammation.

The study revealed that subjects with oral squamous cell carcinoma have lower TAP 1 and TAP 2 gene expression than premalignant control subjects, thus affecting MHC-I processing, which ultimately affects the functioning of the immune system. These results have the potential to improve our understanding of disease pathophysiology and provide more targeted treatment options.

Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer, and myocardial infarction (MI) is an acute cardiovascular disease resulting from the disruption of coronary blood supply. Recent studies have suggested that these two diseases may share common molecular mechanisms.

The aim of this study was to discover common diagnostic genes for LUAD and MI and analyze their molecular functions and potential drug values by applying bioinformatics analysis.

The objective was to provide a theoretical basis for further research on the pathological mechanisms of LUAD and MI, contributing to the development of novel diagnostic and therapeutic strategies for the two diseases.

In this study, the datasets of LUAD and MI were obtained from TCGA and GEO databases, and differential expression analysis was performed to screen significantly differentially expressed genes (DEGs). Subsequently, disease-related genes were identified using WGCNA analysis, and the biological functions of these genes were explored by functional enrichment analysis. After screening key genes using the protein-protein interaction (PPI) network and the cytoHubba algorithm, biomarkers were determined by LASSO and SVM-RFE machine-learning methods. Finally, immune infiltration analysis and drug prediction were performed, and biomarker expression was verified by single-cell sequencing analysis.

A total of 158 differentially upregulated genes were identified between LUAD and MI. WGCNA analysis screened 86 genes that were significantly associated with both diseases and were enriched in an inflammatory response and immune regulation-related pathways, such as the IL-17 signaling pathway. Ten significant genes were identified by the PPI network and cytoHubba and then reduced to 4 using LASSO and SVM-RFE. Noticeably, MMP9 was significantly overexpressed in both diseases. Immune infiltration analysis showed that MMP9 was significantly related to multiple immune cell infiltration. Drug prediction and molecular docking analysis predicted Ilomastat and Osthole as the potential target drugs. Single-cell sequencing analysis revealed that MMP9 was high-expressed in the macrophages in LUAD tissues.

This study identified MMP9 as a common diagnostic gene and potential therapeutic target for both LUAD and MI and revealed its role in inflammation and immune regulation through comprehensive bioinformatics analysis. These findings provided a theoretical basis for further research on the pathological mechanisms of LUAD and MI, contributing to the development of novel diagnostic and therapeutic strategies.

Immune Checkpoint Inhibitor (ICPi) therapy has revolutionized cancer treatment but can lead to immune-related adverse events (irAE), including thyroid dysfunction. The impact of ICPi on patients with pre-existing autoimmune thyroid diseases (PATD), particularly the development of Graves' disease, remains poorly understood.

We provide the first complete case of Graves' disease with ICPi therapy in a patient who already had Hashimoto's thyroiditis.. The patient, a 52-year-old male, was diagnosed with lung adenocarcinoma and received Atezolizumab. Clinical evaluation revealed hyperthyroidism, confirmed by elevated thyroid hormones and autoantibodies (TRAb and TSAb). The patient was managed with methimazole and demonstrated a transient hyperthyroid phase followed by persistent hypothyroidism. Only 16 confirmed cases of Graves' disease induced by ICPi were reported. We conducted a review to investigate the clinical characteristics, risk factors, and prognosis trends associated with ICPi-induced Graves disease in PTAD patients. Additionally, changes in thyroid function and autoantibodies during and after ICPi treatment are examined.

This case underscores the importance of monitoring thyroid function and autoantibodies in patients with PATD undergoing ICPi therapy. The findings suggest distinct differences in the humoral immune response between ICPi-induced and spontaneous Graves' disease, necessitating further research into autoantibody dynamics and their relationship with cellular immunity in these patients.

Combination therapy with levothyroxine (L-T4) and slow-release T3 (SRT3) in the treatment of hypothyroidism results in a normal triiodothyronine/thyroxine (T3/T4) ratio above that of L-T4 monotherapy. No clinical study has been reported on SRT3 monotherapy for hypothyroidism.

This study was conducted in two parts. In the first part, 20 patients with primary hypothyroidism and serum thyrotropin (TSH) >30 mU/L were randomized into three groups receiving 1.6 μg/kg L-T4, equivalent doses of SRT3 or L-T3 of 0.55 μg/kg for 4 weeks. Their fasting serum-free T4 [fT4], T3, and TSH were measured weekly before taking medication for up to 4 weeks. In the second part, in 9 hypothyroid patients on L-T4 therapy and normal serum TSH, L-T4 therapy was discontinued, and a once-daily dose of SRT3 of 0.55 μg/kg was replaced. Serum fT4, T3, and TSH were measured weekly.

In part one, in patients treated with L-T3 and L-T4, serum TSH decreased to normal values after 4 weeks of intervention. In 7 patients on SRT3, serum T3 increased from 47±12 at baseline to 110±16 ng/dL, and serum TSH decreased from 60±11 at baseline to 24±10 and 26±7 mU/L, respectively, at 14 and 21 days after intervention. At the end of 28 days, mean serum T3 was 110±16, 168±74, and 96±18 ng/dL in SRT3, L-T3, and L-T4 groups, respectively (p < 0.001). In part two, serum fT4 decreased from 1.43±0.7 to 0.41±0.14 ng/dl, and serum T3 increased from 86±21 to 113±27 ng/dL by 21 days. Mean serum TSH remained normal until 14 days but increased to 15.1±7.6 mU/L at 21 days. In the end, mean serum fT4, T3, and TSH were 0.35±0.17 ng/dl, 77.4±8.9 ng/dL, and 35±11 mU/L, respectively.

In patients with primary hypothyroidism, SRT3 monotherapy with an equivalent dose to L-T4 maintained normal serum T3 but could not sustain normal serum TSH concentration.

IRCT20100922004794N12.

Crohn’s Disease (CD) is a chronic inflammatory gastrointestinal disease. Ustekinumab (UST) has been utilized as a therapeutic option for CD patients. However, approximately 40-60% of patients exhibit an inadequate response to UST. Accumulating evidence has confirmed the involvement of oral bacteria in the development of CD. Nevertheless, the relationship between oral microbiota and the efficacy of UST therapy in CD patients has remained unexplored.

We recruited 28 healthy individuals and 53 CD patients, 47 of whom completed the entire UST therapy. Oral samples and clinical data were collected. The clinical response and clinical remission were defined based on the CDAI score. Oral samples were analyzed by 16S rRNA gene sequencing. The analysis of sequence data was performed by QIIME and R.

We revealed the oral microbial difference between the Healthy Control (HC) group and the CD group. The enrichment of Fusobacteria, Leptotrichia, Capnocytophaga, and Campylobacter, and the diminution of Haemophilus and Rothia were observed in the CD group. Differences in oral microbiota were also identified among patients with different efficacy of UST. Compared to the response and remission groups, both the non-response and non-remission groups showed significantly higher levels of Fusobacteria and Leptotrichia. Predictive models for clinical response and clinical remission in UST were developed based on oral microbiota, with the Area Under the Curve (AUC) value of 0.944 and 0.930, respectively.

Oral microbiota was relevant to the UST efficacy in patients with CD based on the predictive model. These findings suggest that oral microbiota could serve as a non-invasive prognostic biomarker for UST treatment in CD patients.

There is still no conclusive understanding of whether the glucokinase regulator (GCKR) gene rs780094 and rs1260326 polymorphisms predispose to gestational diabetes mellitus (GDM).

This systematic review and meta-analysis aimed to determine the effect of the GCKR polymorphisms on GDM susceptibility.

Seven literature databases were searched (from inception to February 17, 2024) to locate relevant studies included in further meta-analysis. Odds ratio (OR) and 95% confidence intervals (CI) in the pooled population were estimated to assess the effects of the variant allele on GDM risk.

For the rs780094 polymorphism, 13 datasets with 3443 GDM cases and 5930 nondiabetic controls were included. The pooled estimates in the allele model (OR: 1.19, 95% CI: 1.07~1.32), homozygote model (OR: 1.27, 95% CI: 1.10~1.47), dominant model (OR: 1.16, 95% CI: 1.03~1.31), and recessive model (OR: 1.31, 95% CI: 1.09~1.57) suggested that the C allele carriers were prone to GDM. For the rs1260326 polymorphism, five datasets with 1495 cases and 2678 controls were integrated. The statistically significant effect of the C allele was evident in the allele model (OR: 1.12, 95% CI: 1.01~1.24) and the homozygote model (OR: 1.26, 95% CI: 1.03~1.54).

This meta-analysis suggested that the C allele of the rs780094 and rs1260326 polymorphisms in the GCKR gene are significantly associated with increased risk of GDM.

Hepatic inflammation, e.g., Nonalcoholic Fatty Liver Diseases (NAFLD) and the severe form of steatohepatitis (NASH), has been associated with a higher risk of MetS in the general population.

This study aimed to investigate the associations of chronic hepatitis B (CHB) and fatty liver diseases with the incidence of metabolic syndrome (MetS) in young adults, which have not been verified before.

The associations between NAFLD, NASH, and CHB and the incidence of new-onset MetS remain inconclusive in young adults.

This cohort study included 2,614 military personnel aged 18-39 years who were free of baseline MetS in 2014 and were followed for the incidence of MetS in each annual health examination until the end of 2020. CHB was defined by the presence of the hepatitis B surface antigen with an established diagnosis history. NAFLD and NASH were defined by the ultrasound finding with an elevated alanine transaminase (27–53.9 and ≥54 U/L in men and 15–29.9 and ≥30 U/L in women, respectively). MetS was defined based on the International Diabetes Federation criteria. Multivariable Cox regression analysis was used to determine the associations between hepatitis and incident MetS.

During a mean follow-up of 6.0 years, 582 new-onset MetS cases occurred (22.3%). NAFLD and NASH were associated with a greater risk of new-onset MetS (hazard ratios (HRs) and 95% confidence intervals: 1.47 (1.21-1.79) and 1.66 (1.16-2.39), respectively), while no association for CHB was found (HR: 1.31 (0.88-1.96)).

This study found that NAFLD and NASH, while not CHB, were independent risk factors of new-onset MetS with adjustments for potential covariates, e.g., physical activity and fitness in young adults.

Gaucheromas, pseudotumors composed of Gaucher cells, are rare complications of Gaucher’s Disease (GD). They are usually seen in patients receiving enzyme replacement. Surgery is generally not recommended for these benign masses in treatment management. Most patients treated with Enzyme Replacement Therapy (ERT) show organ enlargement and improvement in laboratory values. In our case, no change in the size of the lesions was observed despite 4 years of standard dose ERT.

A 27-year-old female, not having a known chronic disease and occasionally consulting doctors due to bone pain, weakness, and fatigue, visited the emergency department with the complaint of a nosebleed four years ago. The patient was found to have hepatosplenomegaly in physical examination and was referred to the hematology clinic because of pancytopenia. According to the physical examination and laboratory results, the desired leukocyte glucocerebrosidase level was 0.4 micromol/lt/hour (normal range > 2.5). Homozygous mutations of p.L483P and L483P were observed in genetic tests. Based on these results, the patient was diagnosed with GD. Although the patient received regular weekly treatment for 4 years, no significant change was observed in the spleen size. The patient was admitted to the hospital in April 2022 with complaints of abdominal fullness and indigestion. Her quality of life was deteriorating due to massive splenomegaly. A splenectomy was performed on the patient. In our case, splenic gaucheroma, a rare complication of Gaucher’s disease, was found to be present.

These masses, which are a rare complication of GD, have started to be better recognized by radiologists and clinicians thanks to the case series shared, and it is clear that there is a need for standardization and further research in this field. With an increase in the number of cases and experiences in this field, there will inevitably be different and new developments in follow-up and treatment approaches.

Primary pituitary abscess is a rare disease with no specific symptoms for pituitary abscess alone. A preoperative diagnosis is quite challenging due to unclear imaging findings.

We report the case of a patient with a pituitary lesion who presented with hypopituitarism, diabetes insipidus, and visual field defect and was misdiagnosed as a possible cystic pituitary adenoma. Endoscopic endonasal transsphenoidal surgery (ETSS) was performed, and surprisingly, only pus was found, and complete resection of the lesion was achieved. Coagulase-negative staphylococci were detected in the culture, and appropriate antibiotic therapy was administered for six weeks. Diabetes insipidus and hypopituitarism did not improve. One year later, the abscess recurred, and a second operation with complete resection was performed.

Knowledge of primary pituitary abscess, a rare infectious disease, is essential for early detection and successful treatment. Most patients have a chronic and silent prediagnostic course with symptoms that are not specific to pituitary abscess alone. The primary treatment option is EETS, followed by long-term, relevant antibiotics. The disease can be resistant and recur despite appropriate treatment, especially in patients with risk factors. Therefore, long-term follow-up of patients is essential.

Liquid-Liquid Phase Separation (LLPS) is a process involved in the formation of established organelles and various condensates that lack membranes; however, the relationship between LLPS and Ulcerative Colitis (UC) remains unclear.

This study aimed to comprehensively clarify the correlation between ulcerative colitis (UC) and liquid-liquid phase separation (LLPS).

In this study, bioinformatics analyses and public databases were applied to screen and validate key genes associated with LLPS in UC. Furthermore, the roles of these key genes in UC were comprehensively analyzed.

Based on the single-cell transcriptomic data of UC obtained from the Gene Expression Omnibus (GEO) database, differences between patients with UC and their controls were compared using the limma package. The single-cell data were then filtered and normalized by the ‘Seurat’ package and subjected to dimension reduction by the Uniform Manifold Approximation and Projection (UMAP) algorithm. The LLPS-related genes (LLPSRGs) were searched on the DrLLPS website to obtain cross-correlated genes, which were scored using the ssGSEA algorithm. Next, functional enrichment, interaction network, immune landscape, and diagnostic and drug prediction of the LLPSRGs were comprehensively explored. Finally, the results were validated using external datasets and quantitative real-time PCR (qRT-PCR).

A total of eight cell types in UC were classified, namely, fibroblasts, macrophages, endothelial cells, neutrophils, NK cells, B cells, epithelial cells, and T cells. The intersection between differently expressed genes (DEGs) among the eight cell types identified 44 key genes, which were predominantly enriched in immune- and infection-related pathways. According to receiver operating characteristic (ROC) curves, PLA2G2A, GZMK, CD69, HSP90B1, and S100A11 reached an AUC value of 0.94, 0.95, 0.86, 0.89, and 0.93, respectively. Drug prediction revealed that decitabine, tetrachlorodibenzodioxin, tetradecanoylphorbol acetate, thapsigargin, and cisplatin were the potential small molecular compounds for PLA2G2A, GZMK, CD69, HSP90B1, and S100A11. Immune cell infiltration analysis demonstrated that the infiltration of CD4 memory T cell activation, macrophage M1, T macrophage M0, neutrophils, and mast cell activation was higher in the UC group than in the normal group.

The LLPSRGs play crucial roles in UC and can be used as prognostic and diagnostic markers for UC. The current findings contribute to the management of UC.

Diabetic wounds are major clinical challenges, often complicated by oxidative stress and free radical generation. Hydrogen (H2), a selective antioxidant, offers potential as a therapeutic agent for chronic diabetic wounds. However, its precise mechanisms remain underexplored.

This study aimed to investigate the protective effects of H2 on high glucose-induced oxidative damage and apoptosis in human skin cells.

HaCaT keratinocytes and HSF fibroblasts were treated with high glucose or AGEs. Cell viability, oxidative stress markers, inflammatory cytokines, and apoptosis were analyzed. AGEs/RAGE/NF-κB signaling was evaluated via Western blot.

H2 treatment significantly reduced ROS, MDA, IL-1β, and TNF-α levels, while enhancing SOD and GSH activity. It also inhibited AGEs/RAGE/NF-κB signaling and apoptosis.

Hydrogen therapy protects against oxidative stress and inflammation induced by high glucose or AGEs, offering potential as an adjunctive treatment for diabetic wound healing.