Objective. The outcome of directed differentiation for cell-based therapies is profoundly influenced by the starting cell's intrinsic state, or cellular context. How pluripotent versus lineage-primed cells interpret the same developmental cues remains unclear. To address this, we performed a comparative transcriptomic analysis using two mouse cell lines engineered for episomal expression: a pluripotent embryonic stem cell line (PLT-ES) and a multipotent pancreatic stem cell line (PLT-PPPD). Methods. We introduced a core set of pancreatic transcription factors - PMN: Pdx1 (pancreatic and duodenal homeobox 1), MafA (MAF BZIP transcription factor A), and NeuroD1 (neurogenic differentiation 1) - into both cell types and analyzed global gene expression and insulin promoter activity. Results. The two cell types exhibited strikingly divergent fates. In lineage-primed PLT-PPPD cells, PMN expression induced a mixed pancreatic/hepatic phenotype. In stark contrast, PMN expression in pluripotent PLT-ES cells failed to initiate an endodermal program, instead robustly driving differentiation towards mesodermal lineages. Intriguingly, reporter assays revealed that the PMN factors could activate the insulin promoter in both PLT-ES and PLT-PPPD cells, regardless of the overall differentiation outcome. Conclusions. Our findings demonstrate that cellular context is a paramount determinant of cell fate. The activation of a single promoter is insufficient to orchestrate a complete differentiation program. While pancreatic stem cells exhibit plasticity within the endodermal lineage, pluripotent cells are misdirected towards entirely different germ layers if not appropriately primed. This study underscores the critical importance of using lineage-committed cells for predictable therapeutic outcomes.
Objective. Glioblastomas are the most common and highly aggressive malignant brain tumors that are difficult to treat. Hypoxia is a significant factor in glioblastoma growth. Previous studies have shown that the inhibition of ERN1 (endoplasmic reticulum to nucleus signaling 1) significantly suppresses the glioblastoma cell proliferation and modifies the hypoxic regulation. The present study aimed to investigate the impact of hypoxia on the expression of endoplasmic reticulum stress-dependent genes including EGLN1 in U87MG glioblastoma cells in relation to ERN1 inhibition to reveal a possible role of the ERN1 signaling pathway in the hypoxic regulation of these genes' expression. Methods. The control U87MG glioblastoma cells (transfected by an empty vector) and ERN1 knockdown cells with inhibited ERN1 endoribonuclease and protein kinase (dnERN1) were used. Hypoxia was induced at normoxic conditions with dimethyloxalylglycine (0.5 mM for 4 h). RNA was extracted and reverse transcribed. The expression levels of EGLN1, HSPA5, DDIT4, PA2G4, XIAP, and MTOR genes were studied by real-time qPCR and normalized to ACTB mRNA. Results. It was established that hypoxia increases the expression level of EGLN1, HSPA5, DDIT4, and XIAP in glioblastoma cells with native ERN1. However, the expression levels of two other stress-dependent genes (PA2G4 and MTOR) were reduced in these glioblastoma cells under hypoxia. Furthermore, inhibition of ERN1 enzymatic activity attenuated the effects of hypoxia on the expression of most of the genes studied in glioblastoma cells, while XIAP gene expression was dramatically increased. Conclusion. The results of this study showed that hypoxia differentially affects the expression of genes related to endoplasmic reticulum stress in glioblastoma cells and is dependent on ERN1 activity. This reflected the ERN1-mediated reprogramming of hypoxic regulation of gene expression.
Objectives. Atherosclerosis contributes to higher mortality and morbidity in people with diabetes. Preventing future complications largely depends on the early detection of imminent atherosclerosis. This study aimed to explore the relationship between the subclinical atherosclerosis measured by carotid intima-media thickness (CIMT), ankle-brachial index (ABI), and circulating levels of adipocyte fatty acid-binding protein (AFABP) in individuals with type 2 diabetes mellitus (T2DM). Methods. A total of 80 participants evenly divided into two groups: 40 newly diagnosed patients with T2DM and 40 healthy controls. Patients with T2DM had no prior history or clinical signs of macrovascular complications, such as coronary artery disease, cerebrovascular stroke or peripheral artery disease. Serum total cholesterol, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), and glycated hemoglobin (HbA1c) were measured. Plasma AFABP levels were determined using a human enzyme-linked immunosorbent assay (ELISA) kit. ABI was assessed using a sphygmomanometer with a cuff that fits the limb's circumference and a portable Doppler device. Doppler ultrasound of the carotid artery was used to measure CIMT. Results. In patients with T2DM, circulating AFABP levels were significantly higher than those in healthy subjects (p=0.007). Multivariate regression analysis indicated that AFABP is the only independent factor influencing the maximum CIMT (β=0.004, 95% CI: 0.001-0.007, p=0.017). Conclusion. Plasma AFABP level could serve as a biomarker for early diagnosis of atherosclerosis in patients with T2DM.
Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease of the central nervous system characterized by inflammation, reactive gliosis, and progressive neuroaxonal damage resulting in heterogeneous clinical and histopathological manifestations. As MS often leads to disability at a young age, it represents a substantial socio-economic burden in developed countries. The etiopathogenesis of MS is multifactorial and incompletely understood, involving genetic, immunologic, and environmental factors. Recent research highlights immune responses to Epstein-Barr virus, blood-brain barrier disruption, microbiome-gut-brain axis alterations, oxidative damage, and mitochondrial dysfunction. Studying patients with newly diagnosed MS without significant comorbidities provides insight into early disease mechanisms before disability development or long-term treatment effects. This mini-review focuses on early vascular and metabolic alterations that may contribute to MS, including lipoprotein subfractions as markers of incipient atherosclerosis, endothelial dysfunction as an initiating vascular event, and autonomic nervous system imbalance during disease progression. It also addresses insulin sensitivity as a key metabolic factor alongside chronic inflammation and oxidative damage as interconnected mechanisms driving tissue injury. Metabolic changes reflecting neuronal impairment, mitochondrial dysfunction, and astroglial activation are detectable in both lesional and normal-appearing white matter in early stages. Reduced antioxidant capacity supports a role of oxidative damage in MS pathogenesis. Accelerated vascular aging, independent of traditional cardiovascular risk factors, may progress from endothelial dysfunction to structural atherosclerotic changes. Subtle alterations in lipoprotein profiles further suggest an increased risk of atherosclerosis, potentially influenced by inflammatory activity and oxidative damage, with possible sex-specific differences. Autonomic dysfunction appears to develop secondary to disease progression rather than as a primary driver of pathogenesis.
The early life experiences have an important impact on the development of the brain and behavior and early life adversities (ELA) may affect several biological systems including the hypothalamic-pituitary-adrenal (HPA) axis, neurotransmitter and immune signaling systems, and microbiota composition. Dysregulation of these systems may result in an altered stress reactivity in both early life and the adulthood periods leading to maladaptive responses to the environmental stimuli. The activation of certain neuropeptides, including oxytocin, stimulation of the HPA axis, and increased glucocorticoid levels, may also play an important role in the early adaptive processes. In terms of brain maturation, ELA can directly or indirectly elicit structural changes in neurite growth, neurogenesis, neuronal connectivities, and signaling processes, which may contribute to the production of the long-term behavioral changes associated with an increased risk of the neuropsychiatric disorders' development in later periods of the life. In this review, we summarize the effect of ELA on the HPA axis function, stress-related hormonal balance, immune responses, and the gut microbiome indicating how these changes may affect the brain function and behavior in the early stages of the life and adulthood. We also provide insight into animal studies revealing the responses of corticotropin-releasing hormone, urocortins, and corticosterone in various neural circuits in response to ELA evoked by maternal separation and limited bedding paradigms.
The endocannabinoid system (ECS), comprising cannabinoid receptors, endogenous lipid ligands, and enzymes that regulate their synthesis and degradation, has emerged as an important modulator of neuroendocrine regulation. This review summarises current evidence on the role of endocannabinoid signalling in hypothalamic-pituitary neuroendocrine circuits, with particular focus on the hypothalamic-pituitary-adrenocortical, gonadal, thyroid, and somatotropic axes, as well as prolactin and posterior pituitary hormones regulation. Available data indicate that endocannabinoid signalling predominantly influences neuroendocrine function by modulating synaptic transmission within hypothalamic circuits. Acting mainly as retrograde messengers at presynaptic CB1 receptors, endocannabinoids regulate excitatory and inhibitory inputs to neurosecretory neurons and thus shape endocrine output in a context-dependent manner. Among the systems discussed, the hypothalamic-pituitary-adrenocortical axis is the best characterised, with relatively well-defined links between glucocorticoid feedback and rapid endocannabinoid-mediated suppression of synaptic input to corticotropin-releasing hormone neurons. In other neuroendocrine systems, evidence supports a predominantly modulatory, often inhibitory, role for endocannabinoid signalling, although the underlying cellular processes remain less well-defined and are largely based on preclinical studies. Interactions with glucocorticoids, gonadal steroids and neuropeptidergic pathways further underscore the integrative nature of ECS signalling. Overall, the ECS should be viewed not as a primary endocrine driver, but as a dynamic regulatory network that fine-tunes the translation of neural activity into hormonal responses.
Objective. The BAG cochaperone 1 (BAG1) binds to oncogene BCL2 and markedly enhances its anti-apoptotic effects. This cochaperone represents a link between growth factor receptors and anti-apoptotic mechanisms mediated by endoplasmic reticulum stress. BAG1 interacts with the glucocorticoid receptor and modulates its transcription activity. As a cochaperone for several HSP70 proteins, it participates in control of protein folding. The present study aims to investigate the regulation of the BAG1 mRNA expression in U87MG glioblastoma cells by hypoxia and glucose or glutamine deprivation, depending on the inhibition of ERN1 (endoplasmic reticulum to nucleus signaling 1) with the intent to reveal the role of ERN1 signaling in the regulation of this gene expression and function in oncogenesis. Methods. The U87MG glioblastoma cells (transfected by an empty vector; control) and cells with inhibited ERN1 endoribonuclease and protein kinase (dnERN1) or only ERN1 endoribonuclease (dnrERN1) were used. Silencing of ERN1 and XBP1 mRNAs for suppression of ERN1 function was also used. A hypoxic condition was created by dimethyloxalylglycine (4 h). DMEM medium without glucose or glutamine was used for glucose and glutamine deprivation (16 h). The expression level of the BAG1 mRNA was studied by real-time qPCR and normalized to the beta-actin mRNA. Results. Inhibition of the endoribonuclease activity of ERN1 significantly decreased BAG1 mRNA expression. However, a lesser suppression of this mRNA expression was observed in dnERN1 cells (with inhibited ERN1 endoribonuclease and protein kinase) indicating the involvement of protein kinase in controlling BAG1 expression. The silencing of ERN1 and XBP1 mRNAs also reduced the expression of BAG1 mRNA demonstrating the involvement of XBP1s in this regulation. The expression of the BAG1 gene was resistant to glutamine deprivation and upregulated in response to glucose deprivation in control glioblastoma cells. However, the inhibition of ERN1 increased the sensitivity of BAG1 gene expression to both glucose and glutamine deprivation. Furthermore, the expression of the BAG1 gene was increased under hypoxia in control U87MG cells; however, a greater induction was observed in dnERN1 cells. Conclusion. The results of this study demonstrated that ERN1 inhibition reduces BAG1 mRNA expression through the endoribonuclease activity of ERN1 and that protein kinase activity counteracts endoribonuclease in regulating the expression of BAG1 mRNA. Moreover, ERN1 inhibition also enhances the sensitivity of BAG1 mRNA expression to nutrient supply and hypoxia resulting in reduced resistance of glioblastoma cells.
Objective. Phosphoenolpyruvate carboxykinase (PCK) catalyzes the conversion of oxaloacetate to phosphoenolpyruvate and regulates pyruvate metabolism and gluconeogenesis in response to glucocorticoid and insulin stimuli. Mitochondrial isoform of this enzyme (PCK2) is overexpressed in glioblastoma cells and participates in metabolic reprogramming and cell proliferation. This study aims to examine the impact of ERN1 (endoplasmic reticulum to nucleus signaling 1) inhibition on PCK2 expression and sensitivity to glucose and glutamine deprivation to determine the role of ERN1 signaling in the regulating its expression in glioblastoma cells. Methods. The glioblastoma cell line U87MG and two genetically modified variants of these cells were used. These were glioblastoma cell sublines with suppressed endoribonuclease and protein kinase activities of ERN1 (dnERN1) or only ERN1 endoribonuclease (dnrERN1), and control cells transfected with an empty vector. The suppression of ERN1 function by silencing of ERN1 and XBP1 mRNAs was also used. Hypoxia was generated using the HIF1A prolyl hydroxylase inhibitor dimethyloxalylglycine. For glucose and glutamine deprivation, DMEM medium without glucose or glutamine was used. The expression level of the PCK2 mRNA was analyzed by real-time qPCR and normalized to the beta-actin mRNA. Results. It has been demonstrated that PCK2 mRNA expression is significantly decreased in dnERN1 glioblastoma cells. Similar suppression of this mRNA expression was also observed in cells with only the endoribonuclease activity of ERN1 inhibited, indicating that this enzymatic activity is involved in the regulation of PCK2 expression. The silencing of ERN1 and XBP1 mRNAs also induced similar changes in PCK2 mRNA expression, possibly mediated by XBP1s. The expression of PCK2 was enhanced under glutamine deprivation in control glioblastoma cells, but inhibition of ERN1 activity strongly increased this effect. Upregulated PCK2 expression was also observed in control glioblastoma cells under glucose deprivation. However, the inhibition of ERN1 activity strongly increased the sensitivity of this gene expression to glucose deprivation. Furthermore, PCK2 mRNA expression was resistant to hypoxic conditions in cells with native ERN1. At the same time, in glioblastoma cells with inhibited ERN1 activity, a strong induction of PCK2 expression was observed. Conclusion. The results of this study demonstrated that ERN1 inhibition reduces PCK2 mRNA expression through the ERN1 endoribonuclease activity. This mRNA expression is upregulated under glutamine and glucose deprivation. Moreover, ERN1 inhibition strongly enhanced the sensitivity of PCK2 mRNA expression to glucose and glutamine deprivation as well as to hypoxia.
Objective. The obesity is associated with profound disturbances in appetite-regulating and metabolic hormones including ghrelin, leptin, adiponectin, resistin, and insulin. Bariatric arterial embolization (BEA) has recently emerged as a minimally invasive alternative to established bariatric procedures. However, comparative endocrine evidence remains limited. The aim of the study was to assess postoperative changes in key metabolic and appetite-regulating hormones following laparoscopic sleeve gastrectomy (LSG), laparoscopic gastric plication (LGP), and bariatric embolization of the gastric arteries (BEA). Methods. A total of 76 patients with obesity (BMI >35 kg/m²) were assigned to LSG (n=32), LGP (n=37), or BEA (n=7). Serum concentrations of total ghrelin, leptin, adiponectin, resistin, insulin, and HbA1c were measured preoperatively 3 and 6 months after intervention using standardized ELISA assays. Statistical significance was set at p<0.05. Results. All procedures resulted in significant improvements in hormonal and metabolic profiles within 6 months. Total ghrelin decreased by 55.6% after LGP, 69.7% after LSG, and 74.5% after BEA at 6 months (all p<0.001). Leptin significantly declined, while adiponectin increased in all groups with the most pronounced early (3-month) rise after BEA (+36.1%, p=0.033). Resistin, insulin, and HbA1c progressively decreased across all interventions indicating improved insulin sensitivity. Overall, BEA demonstrated the strongest early hormonal response, whereas long-term (6-month) effects were comparable across procedures. Conclusion. Laparoscopic gastric plication, sleeve gastrectomy, and bariatric embolization provide substantial improvements in appetite-regulating and metabolic hormones in patients with obesity. BEA shows a particularly favorable early endocrine profile supporting its potential as a minimally invasive metabolic intervention.
Objective. Thyroid dysfunction is associated with metabolic disturbances and an increased risk of atherosclerosis. This cross-sectional study investigated the relationships between the triglyceride-glucose index (TyG index), complement C5, lipoprotein(a) (Lp(a)), and carotid intima-media thickness (cIMT). Methods. Clinical data were collected, blood samples analyzed, and cIMT measured using high-resolution ultrasound in 54 participants with thyroid dysfunction (27 with hypothyroidism and 27 with hyperthyroidism). Results. The study found a significant positive correlation between the TyG index and cIMT in both hypothyroid and hyperthyroid patients. Complement C5 levels were also positively correlated with cIMT. No significant association was found between Lp(a) and cIMT. Discussion. These findings highlight the complex interplay between thyroid dysfunction, metabolic dysregulation, and vascular health emphasizing the need for comprehensive cardiovascular risk assessment and management in patients with thyroid disorders.
Objective. Metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) share a chronic low-grade inflammatory milieu driven by adiposity. C-X-C motif chemokine ligand 1 (CXCL1) has been linked to insulin resistance and endothelial dysfunction, but its diagnostic relevance remains unclear. Methods. Our study employed a cross-sectional design and enrolled 104 adults: 52 newly diagnosed treatment-naive T2DM patients and 52 normoglycemic controls matched for age and sex. Serum CXCL1, high-sensitivity C-reactive protein (hs-CRP), and metabolic parameters were measured. Logistic regression models to discriminate MS and T2DM status were constructed (base model: age, sex, BMI) and then expanded by adding hs-CRP, CXCL1, or both. Model performance was assessed for discrimination (AUC), calibration (Integrated Calibration Index [ICI], Expected Calibration Error [ECE]), and clinical utility (decision curve analysis, DCA) in accordance with TRIPOD 2024. Results. CXCL1 correlated with BMI (r=0.33, q=0.004) and hs-CRP (r=0.29, q=0.021), but not glycemic indices. For MS, CXCL1 marginally improved the base model (ΔAUC=+0.003, p=0.81); for T2DM, ΔAUC=+0.007 (p=0.60). hs-CRP performed better (AUC=0.744 for T2DM; 0.743 for MS) and the combined panel achieved the highest discrimination (AUC=0.769 and 0.745, respectively). Conclusions. CXCL1 reflects adiposity-related inflammation but provides only minimal incremental discrimination for metabolic syndrome and T2DM beyond conventional markers such as age, sex, BMI, and hs-CRP. The combined hs-CRP+CXCL1 panel achieved the best overall statistical performance, although its clinical utility remains limited. These findings emphasize the need for integrated multi-marker approaches rather than single-biomarker screening in metabolic risk assessment.
Objective. Recently, multicomponent quality-of-life indicators have become increasingly important in monitoring the health status of patients with hypertension and evaluating the effectiveness of treatment. Improving patient quality of life is considered one of the key objectives of the medical intervention. Methods. To assess the quality of life of patients with, we used the standardized SF-36 (Short Form-36 Health Survey) questionnaire, which allows to explicitly examine the respondent physical and psycho-emotional status. Results. We analyzed the association between polymorphisms of endothelial nitric oxide (NO) synthase (eNOS) (NOS3, T786C) and angiotensin II receptor type 1 (AGTR1, A1166C) genes and quality of life. Patients with polymorphisms associated with lower intravascular pressure had lower baseline QoL scores, particularly on the "physical functioning" and "general health" scales (p<0.05). Patients with heterozygous or homozygous "unfavorable" genotypes (AGTR1_CC, NOS3_CC) have significantly lower total indicators of both physical and psycho-emotional health compared to patients with "better" genotypes (AA, TT) and the control group. Conclusion. Patients with polymorphisms that cause reduced bioavailability of NO or excessive activation of AGRT1 show a significant deterioration in quality of life on all key SF-36 scales. This indicates the significant role of genetic factors in shaping the subjective perception of health in patients with arterial hypertension.
Objective. Multiple endocrine neoplasia type 1 (MEN1) is a very rare genetic disorder characterized by an autosomal dominant inheritance. We aim through this case series to delineate the wide spectrum of its clinical features. Methods. In the present study, we report the clinical and genetic findings of four siblings affected by this disorder. DNA was extracted from patients' blood leukocytes using a phenol-chloroform method and assessed for purity with a NanoDrop spectrophotometer. Ten exons of the MEN1 gene were amplified by PCR, verified by gel electrophoresis, and sequenced using Big Dye Terminator chemistry followed by capillary electrophoresis. The sequences were than analyzed with CHROMAS and compared to reference sequences. As for the variant, interpretation and pathogenicity were assessed using Ensembl, ClinVar, dbSNP, gnomAD, Alamut Visual, and VARSOME. Results. We highlight the wide range of phenotypes encompassing primary hyperparathyroidism, macroprolactinoma, lipomas, papillary thyroid carcinoma, ectopic thyroid, multinodular goiter, and bilateral adrenal nodules observed in this family contrasting with the same pathogenic frameshift mutation. We also pinpoint to a second mutation detected in two of the siblings while discussing its pathogenicity. Finally, we provide an overview of the clinical manifestations of MEN1 and its genetic background. Conclusion. This research sets the stage to further investigate the molecular mechanisms underlying the novel nonsense mutation. Additionally, it incites other research to explore the frequency of this mutation in other populations and finally to conduct functional studies.
Objective. Despite the advances in diabetes management, there is still a high prevalence of poor glycemic control worldwide. This study aimed to determine the prevalence and predictors of poor glycemic control among patients with type 2 diabetes mellitus (T2DM) attending the outpatient clinic at Alexandria Main University Hospital (AMUH) Egypt. Methods. This cross-sectional study was conducted on 290 patients with T2DM. Data were collected on sociodemographic factors, medical history, comorbidities, lifestyle behaviors, medication adherence, and biochemical measures. Statistical analyses including correlation and regression models were used to explore the relationships between various factors and glycemic control. Results. The study revealed that 82.8% of participants had uncontrolled diabetes. Poor glycemic control was significantly associated with older age, lower education, rural residence, unemployment, and lower income. Additionally, patients with uncontrolled diabetes had higher rates of hypertension, dyslipidemia, ischemic heart disease, and diabetic peripheral neuropathy. Better physical activity and dietary adherence were linked to improved glycemic control, while medication adherence was significantly lower in the uncontrolled group. Among the significant predictors, physical activity (ORs=116.6-575.8) was the strongest predictor of improved diabetes control. Moreover, medication adherence (OR=4.098) and higher education (OR=8.354) were strongly associated with better diabetes control. Conclusions. Socioeconomic factors, lifestyle behaviors, and medication adherence are key predictors of glycemic control in T2DM patients. Physical activity, medication adherence, and higher education were the strongest predictors of better glycemic control. Addressing these factors through targeted interventions, particularly in rural areas, is crucial for improving diabetes management and reducing the related complications.
Objective. Involvement of various endocrine disruptors (EDs) in pathophysiology of reproductive system disorders has been suggested previously. The studies have shown adverse effects of the individual substances, however, in the real-life situation, numerous chemicals enter the organism on a daily basis. This points to the importance of examination of the combined effects of exogenous chemicals on biological systems, including reproductive system. The ovaries are a target of different EDs, which may impact the processes within the ovarian follicles. The aim of the present study was to examine the effects of binary or ternary mixtures combining selected nonpersistent disruptors: bisphenol A (BPA), BPA-dimethacrylate (BPADM), benzyl butyl phthalate (BBP), 4-chloro-3-methylphenol (CMP), or alkylphenols (4-octylphenol, OP; 4-nonylphenol, NP; and tert-octylphenol, TOP) on ovarian follicular cell functions. Methods. Porcine oocyte-cumulus complexes (OCCs) and granulosa cells (GCs) were treated with the tested ED mixtures (BPA+BBP, CMP+BBP, BPA+BPADM, BPA+BBP+CMP, and OP+NP+TOP) in a wide concentration range from 10-10 to 10-4 M. Follicle-stimulating hormone (FSH)-induced cumulus expansion was assessed after 24 h of culture according to a subjective scoring system. After 44-h treatment, oocyte nuclear maturation was evaluated. Basal and FSHstimulated progesterone production by OCCs and GCs was measured by commercial radioimmunoassay after 44 h and 72 h of the culture, respectively. One-way ANOVA and Bonferroni post-test were used for statistical analysis of data. Results. The results obtained showed that the lower concentrations of ED mixtures (10-10- 10-6 M) did not exert significant changes, while the highest concentration (10-4 M) significantly inhibited cumulus expansion, oocyte meiotic maturation, and progesterone production by OCCs and GCs. Moreover, the inhibitory effects of ED mixtures seem to be more profound than the effects caused by the individual substances. Conclusion. The experimental approach of testing mixtures should provide a more comprehensive view on the effects of the ubiquitous EDs on various cell types of the reproductive organs.
Objective. Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a rare, but potentially life-threatening cause of Cushing's syndrome. Its clinical recognition may be delayed, especially when classical features of hypercortisolism are absent. We present two cases, in which hypokalemic metabolic alkalosis was the initial and main clinical clue leading to the diagnosis of neuroendocrine carcinoma with ectopic ACTH production. Case 1. The first case was a 71-year-old woman admitted with progressive weakness, gait disturbance, and uncontrolled hypertension. Laboratory tests revealed severe hypokalemia and metabolic alkalosis. Endocrine evaluation showed markedly elevated urinary free cortisol and plasma ACTH, with absent suppression on low-dose dexamethasone testing. Colonoscopy for anemia revealed a rectal mass and histopathology confirmed poorly differentiated neuroendocrine carcinoma. Imaging demonstrated widespread metastases. Despite supportive treatment, she died of multi-organ failure during hospitalization. Case 2. The second case was a 67-year-old woman presenting with fatigue, weakness, and weight loss. Laboratory findings included hypokalemia, metabolic alkalosis, renal dysfunction, and elevated liver enzymes. Hormonal studies again confirmed ACTH-dependent Cushing's syndrome without suppression on dexamethasone testing. Imaging revealed a right hilar lung mass and bronchoscopy with biopsy confirmed small-cell neuroendocrine carcinoma. PET-CT showed disseminated metastases. Although chemotherapy was initiated, she developed rapid progression and died shortly thereafter. Conclusion. These cases highlight that severe hypokalemic metabolic alkalosis may represent the primary manifestation of ectopic ACTH syndrome even in the absence of overt Cushingoid features. Recognition of this biochemical pattern should prompt consideration of neuroendocrine tumors allowing earlier diagnosis and timely therapeutic intervention in this aggressive condition.
Head and neck tumors are common in Slovakia. Although the number of tumors associated with smoking and alcohol is decreasing, the number of tumors associated with human papilloma-virus increases. Radiotherapy plays an important role in their treatment. The thyroid gland, due to its oneself location, is predisposed to the development of post-radiation dysfunction. Nowadays, there are methods able to reduce this risk and also available new options for treatment and dispensary care for these patients. The aim of this work is to analyze the incidence and pathophysiological mechanisms of post-radiation hypothyroidism in patients with head and neck tumors, to highlight the risk factors associated with radiotherapy and evaluation of prevention possibilities and treatments, and an overview of modern therapeutic approaches. Special attention is devoted to the importance of a multidisciplinary approach and the need for a long-term patient monitoring as well as the assessment of thyroid function as an integral part of a comprehensive oncological care.
Objective. The study aims to evaluate the severity of endogenous intoxication and characterize morpho-functional liver changes during experimental acute generalized peritonitis (AGP) in diabetic rats. Methods. Fifty-six adult male Wistar rats were used, including 8 controls and 48 males with experimental pathology. Diabetes mellitus was induced by an intraperitoneal (i.p.) injection of streptozotocin (60 mg/kg). On day 14, AGP was induced by i.p. injection of a 10% filtered fecal suspension. Endogenous intoxication was assessed by measuring hydrophilic and hydrophobic molecular products in the blood. Liver function was evaluated by serum aminotransferase activity, total protein, and protein fractions. Histological analysis of liver tissue was performed using standard hematoxylin-eosin staining. Results. A progressive increase in endogenous intoxication was observed peaking on day 7. This was marked by a significant elevation in middle molecular weight molecule (MMWM) concentrations at wavelengths of 254 nm and 280 nm by 103.0% (p<0.001) and 340.0% (p<0.001), respectively. The erythrocyte intoxication index (EII) increased by 148.8% (p<0.001) compared to controls. Concurrently, aminotransferase activity increased, while serum total protein and albumin levels decreased. Histologically, inflammatory infiltration and vascular congestion were evident on day 1 progressing to hepatocellular dystrophy and necrosis by day 3. By day 7, signs of hepatic failure were present including disruption of trabecular architecture, hydropic degeneration, intra-cellular cholestasis, and portal tract expansion due to vascular hyperemia. Conclusions. Experimental acute generalized peritonitis in diabetic rats resulted in a pronounced endogenous intoxication accompanied by progressive morpho-functional liver damage culminating in hepatic insufficiency by day 7.
Objective. Symptoms of thyroid defects involve sleep disorders, gain or loss of weight, tremors of hand, constipation, dry skin, bradycardia, diarrhea, irregular menses, and hot or cold tolerance. Workers in different professions face different situations that can lead to stress. This study aimed to examine the association between shift work (office or irregular) and thyroid function indicators, interleukin-37 (IL-37) levels, and development of chronic diseases (cardiovascular, diabetes). Methods. The current study comprised three groups: 1) office staff, 2) irregular staff (comprising different jobs), and 3) controls (not working subjects). Eighty-five subjects, aged 30-55 years, were included in the study. Body mass index (BMI) was calculated for each participant. Venous blood was collected and serum levels of triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), and thyroid peroxidase (TPO) were determined by electrochemiluminescence (ECL) analysis using an automatic immunochemical analyzer Cobas E 411 (Roche Diagnostics, Germany). Serum IL-37 levels were measured using ELISA kit. Results. Serum T3 (p<0.01) and T4 (p<0.001) levels were significantly decreased in both office and irregular shift work groups compared to the controls. The mean T3 levels were higher in subjects with irregular shift work (1.162±0.11 ng/mL) compared to subjects with office shift work (1.14±0.12 ng/mL). Significantly increased TSH and TPO serum levels (p<0.01) were found in both the irregular shift work and office shift work groups compared to the control group. Similarly, IL37 levels were significantly increased in office shift work (294.8±21.05 ng/mL) and irregular shift work subjects (278.0±16.22 ng/mL) (p<0.001) compared to controls (56.5±0.28 ng/mL). Cardiac disease (p<0.01), hypertension (p<0.001), and diabetes (p<0.001) showed significant differences between subjects with office shift work, irregular shift work, and the control group. Conclusion. Elevated levels of IL-37 and TSH in shift workers may serve as biomarkers of the impact of shift work and the workplace on the immunological and hormonal status of employees.
Objective. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) play a role in management of type 2 diabetes (T2D) and obesity by promoting glycemic control and weight reduction. Beyond these benefits, GLP-1 RAs have demonstrated positive effects on cardiovascular, renal, and neurological health, with emerging evidence supporting their therapeutic potential in conditions such as chronic kidney disease, asthma, obstructive sleep apnea, Parkinson's disease, and Alzheimer's disease. However, their widespread clinical use is often hindered by gastrointestinal side effects including nausea, anorexia, vomiting, and diarrhea that limit adherence and dose titration. Effective management of these adverse effects is essential to optimize treatment outcomes and maintain long-term therapy. Case report. A 72-year-old woman with a history of cognitive impairment, T2D, atrial fibrillation, obesity, and mood disorders presented with persistent gastrointestinal symptoms while receiving semaglutide. Dose escalation was restricted due to severe nausea, vomiting, and diarrhea, which markedly affected her quality of life. To manage these symptoms, mirtazapine was initiated. Following its introduction, the patient reported significant improvement in gastrointestinal tolerance enabling continued semaglutide therapy and successful dose advancement. Additional benefits included enhanced mood, better sleep, and overall well-being. No adverse effects related to mirtazapine were observed throughout the treatment. Conclusion. This case suggests that mirtazapine may be beneficial in mitigating GLP-1 RA-induced gastrointestinal side effects, thereby improving adherence and therapeutic efficacy. Further research is needed to evaluate the safety, mechanism, and generalizability of this approach in broader clinical practice.
