Endocrine, metabolic & immune disorders drug targets最新文献

Background: Adrenocorticotropic Hormone (ACTH)-secreting tumors account for 5- 10% of Cushing syndrome cases and are often difficult to diagnose and treat.

Case report: A 44-year-old man presented with arterial hypertension and weight gain. On the physical examination, he exhibited central obesity, abdominal striae rubrae, and facial plethora. Due to the clinical suspicion of Cushing syndrome, the Nugent test and Liddle-1 test were performed, which showed a lack of cortisol suppression. ACTH levels were also high (138 pg/mL), so pituitary MRI and dynamic tests were performed, including the Corticotropin-releasing Hormone (CRH) stimulation test and Liddle-2. MRI showed a 3 mm pituitary microadenoma, but hormonal testing suggested ectopic ACTH production. Chest CT detected a 10-mm nodule in the upper lobe of the right lung, suspicious for a carcinoid tumor. However, the nodule did not exhibit any enhancement on 68-Gallium-DOTATOC PET-CT, and further, 18-FDG PET-CT was inconclusive. In addition, the nodule was deemed non-biopsiable due to its location. Meanwhile, the patient developed osteoporosis, resulting in two vertebral fractures and one rib fracture, which was treated with zoledronate. Furthermore, the patient developed acute aortic insufficiency. During bioprosthetic valve replacement, the thoracic surgeon performed wedge resection of the right upper lung lobe. The histological examination of the lesion revealed a typical lung carcinoid (1.2x0.9 cm, pT1bNXR0, Ki671%, ACTH positive in 95% of neoplastic elements). ACTH levels dropped to 4 pg/mL on the fourth postoperative day.

Conclusion: ACTH-secreting tumors are particularly challenging diseases. A comprehensive hormonal and instrumental valuation is often required, necessitating a multidisciplinary approach.

Obesity and prediabetes affect a substantial part of the general population, but are largely underdiagnosed, underestimated, and undertreated. Prediabetes differs from diabetes only in the degree of hyperglycaemia consequent to the progressive decline in residual beta-cell function. Both prediabetes and diabetes occur as a consequence of insulin resistance that starts several years before the clinical onset of overt diabetes. Macrovascular complications in patients with diabetes are mainly caused by insulin resistance. This is why in prediabetes, the overall cardiovascular risk is, by all means, similar to that in patients with diabetes. It is important, therefore, to identify prediabetes and treat patients not only to prevent or delay the onset of diabetes, but to reduce the cardiovascular risk associated with prediabetes. This review provides an overview of the pathophysiology of prediabetes in patients with obesity and the progression toward overt diabetes. We have reviewed nutritional and pharmacological approaches to the management of obesity and reduced glucose tolerance, and the treatment of the major comorbidities in these patients, including hypertension, dyslipidaemia, and Metabolic dysfunction-associated Steatotic Liver Disease (MASLD), has also been reviewed. In patients with obesity and prediabetes, the nutritional approach is similar to that adopted for patients with obesity and diabetes; treatments of dyslipidaemia and hypertension also have the same targets compared to patients with diabetes. MASLD is a critical issue in these patients; in the prediabetic state, MASLD rarely progresses into fibrosis. This highlights the importance of the early recognition of this pathological condition before patients become diabetic when the risk of fibrosis is much higher. It is necessary to raise awareness of the clinical relevance of this pathological condition in order to prompt early intervention before complications occur. The single most important therapeutic goal is weight loss, which must be early and persistent.

Objective: Primary Hyperparathyroidism (PHPT) is a common disease, frequently diagnosed in post-menopausal women, among whom Osteoporosis (OP) is a common finding. To date, no study has specifically evaluated the asymptomatic PHPT (aPHPT) patients without OP, in particular post-menopausal women who are exposed to an increased risk of developing OP.

Design: This study involved a retrospective cross-sectional evaluation.

Patients: From our database of 500 consecutive patients diagnosed with PHPT, 178 postmenopausal aPHPT were retrieved.

Results: The clinical, biochemical, and imaging data of the 85 patients without OP were not different from those of the 93 with OP, except for bone alkaline phosphatase (significantly higher in the latter group). Among these 85 patients without OP, the 45 patients meeting surgical criteria for parathyroidectomy had significantly higher values of serum PTH (240 vs. 99 ng/L, p =0.03) and calcium (total, 11.2 ± 0.7 vs. 10.6 ± 0.4 mg/dL, p <0.001; ionized, 1.45 ± 0.12 vs. 1.36 ± 0.8 mmol/L, p =0.044) and lower values of serum phosphate (2.57 ± 0.7 vs. 2.94 ± 0.5 mg/dL, p =0.009) and eGFR (68.5 ± 23.8 vs 80.8 ± 14.4 mL/min/1.73 m2, p =0.006) than the 40 aPHPT patients not meeting surgical criteria, without any difference in densitometric data and calculated fracture risk.

Conclusion: In our series, post-menopausal aPHPT patients without OP accounted for almost a sixth of the whole PHPT series. About half of these patients did not meet surgical criteria, but their T scores and 10-year fracture risk calculated by FRAX were not significantly different from post-menopausal aPHPT without OP meeting surgical criteria.

Background: The effects of thyroid hormone on patients hospitalized in coronary intensive care units are still controversial.

Objective: We retrospectively examined thyroid hormone levels and their impact on cardiovascular morbidity in patients admitted to coronary intensive care units.

Methods: A total of 208 (Female/Male; 46.6%/53.4%) patients without any history of thyroid disease were enrolled and screened. Patients with specific heart disease and existing thyroid hormone parameters were included in the study. Low triiodothyronine syndrome is characterized by reduced serum total or free T3 (fT3) concentrations in normal free T4 (fT4) and TSH levels.

Results: The common diagnosis of the patients in the coronary care unit is acute coronary syndrome (n=59, 28.2 %) and heart failure (n=46, 23.3%). Patients were divided into two groups according to left ventricular ejection fraction percentages (LVEF ≤39% vs LVEF ≥40%). Plasma fT3 levels were significantly correlated with low LVEF (≤39%) (p =0.002). fT3 (r=-0.183, p =0.013) and hospitalization etiology (r=-0.161, p =0.023) were also the most critical parameters affecting the length of hospitalization.

Conclusion: Low fT3 was associated with reduced ejection fraction and prolonged hospitalization, which may lead to potential morbidities in HF patients and may be useful in risk stratification and treatment strategies.

Background: The dysregulation of the innate immune system plays a crucial role in the development of Diabetic Retinopathy (DR). To gain an insight into the underlying mechanism of DR, it is essential to identify specific biomarkers associated with immune cell infiltration.

Methods: In this study, we retrieved the GSE94019 and GSE60436 datasets from the Gene Expression Omnibus (GEO) database. By utilizing CIBERSORT, MCPcounter, and xCell algorithms, we conducted a comprehensive analysis of the immune cell infiltration landscape in DR. The limma package was employed to identify Differentially Expressed Necroptosis-related Genes (DENRGs). Subsequently, enrichment analysis was performed to investigate the potential functions of the DENRGs. To identify the core DENRGs, the CytoHubba plug-in in Cytoscape software was utilized. The expression levels of these core DENRGs were verified in an independent dataset.

Results: Our analysis identified 213 DENRGs, and among them, Platelet-derived Growth Factor subunit A (PDGFA) was identified as a core DENRG. Notably, the expression of PDGFA was found to be upregulated in DR, and this finding was further validated in the GSE102485 dataset. Additionally, the results of GSVA and GSEA revealed that in the high PDGFA group, there was activation of pathways related to inflammation and the immune system. Moreover, analysis of immune infiltration demonstrated a significant association between PDGFA gene expression and the infiltration levels of specific immune cells, including basophils, macrophages M1, macrophages, neutrophils, monocytes, NK cells, and B cells.

Conclusion: The involvement of neutrophils in the development and progression of DR is suggested. PDGFA has emerged as a potential marker and is linked to the infiltration of immune cells in DR. These findings shed new light on the underlying mechanisms of DR.

Coronavirus disease-2019 (COVID-19) is a respiratory disease in which Spike protein from SARS-CoV-2 plays a key role in transferring virus genomic code into target cells. Spike protein, which is found on the surface of the SARS-CoV-2 virus, latches onto angiotensin-converting enzyme 2 receptors (ACE2r) on target cells. The RNA genome of coronaviruses, with an average length of 29 kb, is the longest among all RNA viruses and comprises six to ten open reading frames (ORFs) responsible for encoding replicase and structural proteins for the virus. Each component of the viral genome is inserted into a helical nucleocapsid surrounded by a lipid bilayer. The Spike protein is responsible for damage to several organs and tissues, even leading to severe impairments and long-term disabilities. Spike protein could also be the cause of the long-term post-infectious conditions known as Long COVID-19, characterized by a group of unresponsive idiopathic severe neuro- and cardiovascular disorders, including strokes, cardiopathies, neuralgias, fibromyalgia, and Guillaume-Barret's like-disease. In this paper, we suggest a pervasive mechanism whereby the Spike proteins either from SARS-CoV-2 mRNA or mRNA vaccines, tend to enter the mature cells, and progenitor, multipotent, and pluripotent stem cells (SCs), altering the genome integrity. This will eventually lead to the production of newly affected clones and mature cells. The hypothesis presented in this paper proposes that the mRNA integration into DNA occurs through several components of the evolutionarily genetic mechanism such as retrotransposons and retrotransposition, LINE-1 or L1 (long interspersed element-1), and ORF-1 and 2 responsible for the generation of retrogenes. Once the integration phase is concluded, somatic cells, progenitor cells, and SCs employ different silencing mechanisms. DNA methylation, followed by histone modification, begins to generate unlimited lines of affected cells and clones that form affected tissues characterized by abnormal patterns that become targets of systemic immune cells, generating uncontrolled inflammatory conditions, as observed in both Long COVID-19 syndrome and the mRNA vaccine.

Gestational Diabetes Mellitus (GDM) is a common endocrine condition associated with adverse pregnancy outcomes. In recent years, a growing number of risk factors associated with gestational diabetes mellitus have been defined. GDM poses a serious threat to maternal health. The etiology is complex and multifactorial and can be divided into inherent and modifiable factors. The inherent factors have been described in other literature, while the modifiable factors are mainly the risk of lifestyle habits. In this study, we performed a narrative review of the progress of risk factors associated with gestational diabetes mellitus.

Introduction: Metabolism of sulfur amino acids requires an optimal interplay between nutritional demand, enzymes, transporters, and adequate dietary intake of B vitamins. Insufficient intake and excess are detrimental, and concentrations depend on health status. However, plasma aminothiol concentrations, previously reported in healthy subjects using highly sensitive methods, vary considerably, and age- and gender differences were observed. Therefore, defining age- and gender-specific ranges for each population is crucial to evaluate the meaning of plasma thiol redox state in health and disease.

Methods: A healthy Portuguese pediatric population (n=90), aged 9- (n=38) and 17-year-old (n=52), was evaluated. Plasma aminothiols, total homocysteine (tHcy), cysteine (tCys), glutathione (tGSH) and γ-glutamylcysteine (tγ-Glu-Cys), were analysed as SBD-F derivatives by HPLC with fluorescence detection.

Results/case report: Mean plasma concentrations (SD) for the 9- and the 17-year-old groups, were as following: tHcy = 4.58 (0.98); 8.13 (3.27) µM, p <0.001; tCys = 207.34 (32.07); 198.59 (21.24) µM, p = 0.274; tGSH = 4.54 (1.08); 5.20 (1.84) µM, p = 0.123 and tγ-Glu-Cys = 1.47 (0.30); 1.06 (0.28) µM, p < 0.001, respectively. No statistically significant differences were found between males and females in the 9-year-old group. However, in the 17-year-old group, significant differences between genders were observed for tHcys (p < 0.001) and tγ-Glu-Cys (p = 0.039), with males presenting the highest concentrations. When correlating the four thiols' plasma concentrations, only the precursors of glutathione, tγ-Glu-Cys and tCys, were positively correlated (r = 0.450, p < 0.001).

Conclusion: Our results showed significant differences in tHcy and tγ-Glu-Cys levels across both age groups, which increased and decreased with age, respectively. It is interesting to highlight that in the 17-year-old group, tHcy and tγ-Glu-Cys levels were higher in males than in females. These observations showed that age and gender influence plasma levels of thiols, which may impact cellular oxidative status. In conclusion, setting age and gender distinct ranges for each specific population is of utmost importance for understanding disease mechanisms and the effectiveness of therapeutic interventions.

Introduction: Mitochondrial oxidative phosphorylation (OXPHOS) is a cellular process that generates most of the cellular energy required by the body. Disorders affecting OXPHOS are multisystem diseases caused by pathogenic variants in more than 50 genes. In 2017, biallelic variants in the MRPS34 gene were shown to cause combined oxidative phosphorylation deficiency type 32 (COPD32) (OMIM#617664); however, only 7 patients have been reported in the literature up to this moment. COPD32 is characterized mainly by a severe Leigh-like syndrome.

Methods: Whole-exome sequencing identified a homozygous pathogenic variant in the MRPS34 gene, c.322-10G>A. Only the mother was heterozygous for this variant. SNP-array analysis was performed, which revealed a region of absence of heterozygosity in variant 16q with 9.8Mb, compatible with maternal uniparental disomy.

Results/case report: We report the case of an 18-year-old female with unremarkable family history. The pregnancy was complicated by oligohydramnios, and the neonatal period was unremarkable. She evolved with low weight, mild-moderate developmental delay/intellectual disability, and hypogonadotropic hypogonadism. On examination, she had slender habitus, joint laxity, and kyphoscoliosis. The cardiac evaluation was normal, and the head MRI showed bilateral olivary nucleus degeneration that was not confirmed subsequently. Extensive metabolic studies documented only mild lactate and pyruvate elevation, and the chromosomal microarray was normal.

Conclusion: We have reported the case of the first patient with COPD32 due to partial maternal uniparental disomy of chromosome 16, being first in Portugal and seventh in the literature. Contrarily to previous patients, who died in the first months of life or survived with severe DD/ID, and had a Leigh-like syndrome, this case is significantly milder, contributing to a better characterization of the phenotypic spectrum. Recurrence risk is unexpectedly low in this instance. This case illustrates the importance of segregation analysis in patients with homozygous recessive mutations.

Background: Soccer match requires anaerobic and aerobic energetic metabolism. The aim of this pilot study was to investigate the changes in blood lactate concentration in young male soccer players in different playing roles at different time points after the soccer match.

Methods: Following an initial screening of 134 young soccer athletes, 8 male athletes (average age of 15.5 ± 5 SD) were chosen for their characteristics similar to those of competitive athletes. Players were categorized as goalkeeper, central defender, central midfielder, and forward. Blood lactate concentrations were determined using a portable device at different times (10 min, 5 and 16 h) after the soccer match by a maximum effort test on a treadmill. The data were analyzed by one-way analysis of variance ANOVA, followed by Bonferroni's post-hoc test.

Results: The following results (mean ± SD) were obtained: VO_2max (%) 60.33 ± 3.10; blood lactate (mM) end match (10 min) 2.17 ± 0.78, post-match-early (after 5 h) 2.2 ± 0.42, postmatch- late (16 h) 3.2 ± 0.84. ANOVA analysis indicated that the blood LA concentrations at end-match (10 min) and post-match-early (5 h) were statistically significative lower than those determined at post-match-late (16 h) (p < 0.05).

Conclusion: These results suggest that aerobic mechanisms can also use LA as an energy source, contributing to the reduction of its blood concentration. This effect can be due to reduced maximal work during a soccer match and to the LA removal during exercise at reduced intensity. These data can provide indications for planning suitable training strategies for young male soccer players.