Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 24, Issue 14, 2024

Gestational diabetes mellitus (GDM) is considered a risk factor for heart metabolic disorder in future mothers and offspring. Ferroptosis is a new type of programmed cell death, which may participate in the occurrence and development of GDM.

This study aims to identify ferroptosis-related genes in GDM by bioinformatics methods and to explore their clinical diagnostic value.

The dataset GSE103552 was analyzed using the Gene Expression Omnibus (GEO) database to screen for differentially expressed genes (DEGs) in GDM. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and protein-protein interaction (PPI) network were performed. Gene sets for ferroptosis were retrieved in MSigDB and GSVA gene set analysis was performed on the database. Finally, logistic regression was performed to differentiate between GDM patients and controls to screen for diagnostic markers.

A total of 179 DEGs were identified in the expression profile of GDM. GO and KEGG enrichment analysis revealed significant enrichment in the TGF-β, p53 signaling pathway, platelet activation, glutathione metabolism, sensory perception of taste, and leukocyte and vascular endothelial cell migration regulation. DEGs (n = 107) associated with the ferroptosis gene set were screened by GSVA analysis. The screened DEGs for disease and DEGs for ferroptosis scores were intersected and 35 intersected genes were identified. PPI identified two key genes associated with GDM as CCNB2 and CDK1. Wilcox-test showed low expression of CCNB2 and CDK1 in GDM. The area under the ROC curve (AUC) of the CCNB2 and CDK1 prognostic model was 0.822.

The genes associated with ferroptosis in GDM were CCNB2 and CDK1, which can be used as valid indicators for the diagnosis of GDM.

In complementary and alternative medicinal systems, the Arsenicum album in ultra-high dilution was used in various therapeutic conditions, considering its effects on the body’s immune system, including the COVID-19 pandemic. However, scientific evidence regarding its immunomodulatory effects is insufficient.

The current study aimed to investigate the immunomodulatory effects of Arsenicum album in an experimental mouse model.

Immunomodulatory activity of potentized dilutions of Arsenicum album i.e., 6C, 30C, 200C in BALB/c mice was evaluated by humoral antibody titer and delayed-type hypersensitivity assays wherein a fixed concentration (0.5 ml of 1× 10⁹ cells/ml) of freshly prepared sheep RBC was administered as a foreign antigen to generate primary and secondary antibodies.

Arsenicum album showed significant immunomodulatory activity by increasing primary antibody titer evaluated on day 21 of the treatment in all the dilutions as compared to SRBC and vehicle control group in humoral immune response assay without showing any effect on delayed-type hypersensitivity.

The results of this preliminary study indicate that oral administration of Arsenicum album has the potential to augment primary humoral response at all dilutions. Hence, the possibility of using the Arsenicum album could be explored to treat immunological conditions, infections, etc., as an alternative therapy alongwith modern medicines.

The purpose of this study was to identify predictive and risk factors for the development of immune-related endocrinopathies and to analyze the incidence and characteristics of immune-related endocrinopathies in our population.

A retrospective, single-centre cohort carried out at Gregorio Marañón Hospital between January 2018 -December 2019.

A total of 163 patients were enrolled. In January 2018 and December 2019, we treated patients who underwent ICI treatment in the Medical Oncology Department of General University Hospital Gregorio Marañón, a tertiary care public hospital in Madrid, as part of an observational, retrospective, single-center cohort study.

Endocrinopathies were diagnosed in 19.5% of the patients (n = 32). The tumours with the highest incidence of endocrinopathies were non-small cell lung cancer (25,9%), kidney cell cancer (25%) and hepatocarcinoma (20%). Among the 32 patients who developed endocrinopathy, 18,8%, 19,13%, and 21,28% received anti-CTLA-4, anti-PD-1 and anti-PDL-1, respectively. Thyroid dysfunction was the most frequent endocrinopathy (12,8%). A higher percentage of patients with negative antiTPO and antiTG antibodies developed G1 hypothyroidism compared to patients with positive antibodies who developed a higher proportion of G2 hypothyroidism. The presence of an initial phase of thyrotoxicity was not related to greater severity. We observed longer progression-free survival in patients who developed thyroid dysfunction.

Pre-existing antibodies were independently associated with endocrinopathies. Moreover, our study let us conclude that the presence of thyroid autoantibodies may be related to its severity. It is important to determine anti-thyroid antibodies prior to the start of immunotherapy as a risk factor for thyroid dysfunction, which in turn is a prognostic marker.

Obesity-linked insulin resistance (IR) is an important risk factor for metabolic diseases, and anthropometric indices are commonly used for risk assessment.

The study aimed to assess possible differences between women and men in the predictive value and association of nine obesity indices with IR, as assessed by HOMA-IR, in a non-diabetic adult population.

The cross-sectional study included individuals recruited from a hospital in Mexico City. Indices evaluated were waist circumference (WC), hip circumference (HC), body mass index (BMI), waist-to-hip ratio, waist-to-height ratio, visceral adiposity index, body adiposity index (BAI), relative fat mass (RFM), and conicity index (CI). Fasting plasma glucose and insulin were measured to calculate HOMA-IR. Correlation analysis was performed between obesity indices and HOMA-IR. Receiver operating characteristics curve analyses were performed to determine predictive accuracy and cut-off values of obesity indices for IR. A binary logistic regression (BLR) analysis with OR calculation was performed to determine the strength of association with HOMA-IR.

We included 378 individuals (59% females, mean age 46.38 ±12.25 years). The highest Pearson coefficient value was observed for BMI among women, while among men, the highest values were found for BMI and BAI. WC among women, and BAI and RFM among men showed the highest sensitivity, while the highest specificity was observed for WHR among women and WC among men with respect to insulin prediction. In the adjusted BLR model, BMI, WC, and WHR among women and WC and RFM and BAI among men were independently associated with IR, showing the highest odds ratio (OR).

In Mexican adults, WC, WHR, RFM and BAI could be complementary tools for BMI in screening for IR.

Diabetic retinopathy (DR) is a major cause of vision loss in working-age individuals worldwide. Cell-to-cell communication between retinal cells and retinal pigment epithelial cells (RPEs) in DR is still unclear, so this study aimed to generate a single-cell atlas and identify receptor‒ligand communication between retinal cells and RPEs.

A mouse single-cell RNA sequencing (scRNA-seq) dataset was retrieved from the GEO database (GSE178121) and was further analyzed with the R package Seurat. Cell cluster annotation was performed to further analyze cell‒cell communication. The differentially expressed genes (DEGs) in RPEs were explored through pathway enrichment analysis and the protein‒protein interaction (PPI) network. Core genes in the PPI were verified by quantitative PCR in ARPE-19 cells.

We observed an increased proportion of RPEs in STZ mice. Although some overall intercellular communication pathways did not differ significantly in the STZ and control groups, RPEs relayed significantly more signals in the STZ group. In addition, THBS1, ITGB1, COL9A3, ITGB8, VTN, TIMP2, and FBN1 were found to be the core DEGs of the PPI network in RPEs. qPCR results showed that the expression of ITGB1, COL9A3, ITGB8, VTN, TIMP2, and FBN1 was higher and consistent with scRNA-seq results in ARPE-19 cells under hyperglycemic conditions.

Our study, for the first time, investigated how signals that RPEs relay to and from other cells underly the progression of DR based on scRNA-seq. These signaling pathways and hub genes may provide new insights into DR mechanisms and therapeutic targets.

The most aggressive form of breast cancer (BC) is Triple-Negative BC (TNBC), with the poorest prognosis, accounting for nearly 15% of all cases. Since there is no effective treatment, novel strategies, especially targeted therapies, are essential to treat TNBC. Exosomes are nano-sized microvesicles derived from cells and transport various intracellular cargoes, including microRNAs (miRNAs). MiRNAs, small non-coding RNA, are an influential factor in the development of cancerous transformations in cells.

Bioinformatics analysis of genes related to TNBC revealed that PTEN plays a crucial role in the disease. Relative expression of this gene was analyzed with RT-qPCR in 14 TNBC clinical samples. Electroporation was used to load miRNA antagomir into exosomes extracted from the conditioned medium. Then, the expression of miR-155 and PTEN was evaluated in MDA-MB-231 cells treated with antagomir-loaded exosomes.

Based on the bioinformatics analysis, miR-155 is a potent inhibitor of PTEN. Following treatment with antagomir-loaded exosomes, RT-qPCR showed significantly reduced miR-155 and increased PTEN levels in MDA-MB-231 cells.

Based on the results of this study, exosomes can be effectively used as a cargo of oligonucleotides like miRNA mimics and antagomirs in targeted therapies.

COVID-19 is a potentially serious new infection first reported in North East Italy in Spring, 2020. Patients with adrenal insufficiency (AI) have a known increased risk of infections that could precipitate to adrenal crisis. Even COVID-19-related psycho-social impact could affect their health, requiring a dynamic adaptation of daily glucocorticoid (GC) therapy. The aim of this study was to evaluate the incidence of COVID-19 infection and self-reported outcomes in AI patients after the first pandemic waves.

It was an open-label, cross-sectional monocentric study on 84 (65 primary, 19 secondary) AI patients resident in Veneto and followed-up in our clinical Endocrine Unit. All patients underwent serological investigation of anti-SARS-CoV2 IgG, answered the purpose-built “ADDI-COVID” questionnaire in August, 2020, and were re-contacted to reevaluate COVID-19 infection occurrence in March-April, 2021.

All patients resulted negative to the serological test for anti-SARS-CoV2 IgG at the end of the first pandemic wave. After the third wave, COVID-19 infection occurred in 8 patients without the need for hospitalization. Half patients felt an increased risk of COVID-19 infection, significantly associated with increased stress and GC stress dose. Only one patient reported stress-correlated adrenal crisis. The majority of AI workers changed working habits, significantly reducing COVID-19-related stress.

AI patients did not show an increased incidence of COVID-19, but the perception of increased COVID-19 infection risk significantly impacted their psychological well-being, working habits, and GC daily doses. Therapeutic patient education is crucial, especially for AI workers, to prevent and treat situations that could lead to an adrenal crisis.

Polycystic Ovary Syndrome (PCOS) is a highly prevalent, complex, heterogeneous, polygenic endocrine disorder characterized by metabolic and reproductive dysfunction that affects 8-13% of women of reproductive age worldwide. The pathogenesis of PCOS has not been fully clarified and includes genetics, obesity, and insulin resistance (IR). Oxidative stress (OS) of PCOS is independent of obesity. It can induce IR through post-insulin receptor defects, impair glucose uptake in muscle and adipose tissue, and exacerbate IR by reducing insulin secretion from pancreatic β-cells.

To investigate the effects of Calorie Restricted Diet (CRD), High Protein Diet (HPD), and High Protein and High Dietary Fiber Diet (HPD+HDF) on body composition, insulin resistance, and oxidative stress in overweight/obese PCOS patients.

A total of 90 overweight/obese patients with PCOS were selected to receive an 8-week medical nutrition weight loss intervention at our First Hospital of Peking University, and we randomly divided them into the CRD group (group A), the HPD group (group B), and the HPD+HDF group (group C), with 30 patients in each group. We measured their body composition, HOMA-IR index, and oxidative stress indicators. The t-test, Mann-Whitney U test, analysis of variance (ANOVA), and Kruskal-Wallis H test were used to compare the efficacy of the three methods.

After eight weeks, the body weights of the three groups decreased by 6.32%, 5.70% and 7.24%, respectively, and the Visceral Fat Area (VFA) values decreased by 6.8 cm², 13.4 cm² and 23.45 cm², respectively, especially in group C (p <0.05). The lean body mass (LBM), also known as the Fat-Free Mass (FFM) values of group B and group C after weight loss, were higher than that of group A (p <0.05). After weight loss, the homeostatic model assessment of insulin resistance (HOMA-IR) index and malondialdehyde (MDA) were decreased. Superoxide dismutase (SOD) was increased in all three groups (p <0.05), and the changes in SOD and MDA in group B and group C were more significant (p <0.05). HOMA-IR index positively correlated with body mass index (BMI) (r=0.195; p <0.05); MDA positively correlated with percent of body fat (PBF) (r=0.186; p <0.05) and HOMA-IR index (r=0.422; p <0.01); SOD positively correlated with LMI/FFMI (r=0.195; p <0.05), negatively correlated with HOMA-IR index (r=-0.433; p <0.01).

All three diets were effective in reducing the body weight of overweight/obese patients with PCOS by more than 5% within 8 weeks and could improve both insulin resistance and oxidative stress damage. Compared with CRD, HPD and HPD+HDF diets could better retain lean body mass and significantly improve oxidative stress damage.

ChiCTR2100054961.

This study reported a case of micropenis caused by a novel hemizygous mutation in the ADGRG2 gene, which aimed to expand the understanding of sexual dysplasia caused by ADGRG2 gene mutation.

We present the clinical data and genetic test results of a patient with micropenis admitted in September, 2022, to the Tongji Hospital. The patient was a 9-year-10-month-old male whose chief complaint was the presence of a short penis over a period of three years. In April 2016, the patient underwent corrective surgery for a clubbed penis. Upon admission to the study hospital, his height and weight were 145.0 cm (75-90^th percentile) and 37.8 kg (50-75^th percentile), respectively, and his BA was 12 years old. His physical characteristics included a normal face, bilateral testicle size of 2 ml, and penile length of about 3 cm. A gonadotrophin-releasing hormone-stimulating test revealed normal hypothalamic-pituitary-gonadal axis function. An HCG stimulation test indicated normal sperm production in the testis. Key abnormalities from auxiliary examinations included low testosterone and high ACTH, dehydroepiandrosterone sulfate, androstenedione, and 17-OH-P levels. Genetic testing revealed a new hemizygous mutation, a splicing mutation in intron 4 of the ADGRG2 gene (ChrX: 19040187 (NM_001079858.3): c.154 + 2T > A, inherited from the mother.

This study reported a case of micropenis caused by a new hemizygous mutation in the ADGRG2 gene. This indicates the importance of genetic testing and gene-guided treatments to improve prognosis.

Adrenal Hypoplasia Congenita (AHC) is a rare subtype of primary adrenal insufficiency (PAI) that can go undiagnosed easily. In this article, we report two brothers with hypogonadotropic hypogonadism and novel mutations in the NR0B1 gene who were misdiagnosed and mismanaged as having congenital adrenal hypoplasia (CAH) for several years.

Herein, we describe two brothers with similar histories; first, they were diagnosed with CAH and treated for that; however, after several years, they showed symptoms of lack of testosterone despite receiving CAH treatment. Low levels of testosterone and LH were detected in both, and a genetic test of CAH was negative for the first brother. Thereafter, DAX-1 deficiency was suspected, and their genetic tests (the NR0B1 gene) confirmed the diagnosis of DAX-1.

The diagnosis of CAH in case of low levels of 17- OHP, testosterone, and LH, as well as central hypogonadotropic hypogonadism, should be studied, and further investigations are mandatory to evaluate other subtypes of PAI, especially AHC.