Biomedicines最新文献

Aim and Background. This study aims to explore alternative diagnostic methods to assess thyroid function in patients unable to undergo blood tests for thyroid-stimulating hormones (TSH) and thyroxine (T4), such as individuals with trypanophobia, severe medical conditions, or coagulopathy. Considering the impact of thyroid dysfunction on mitochondrial metabolism and the essential role of proper mitochondrial function in ciliary motility, we postulate that assessing nasal ciliary function could serve as a surrogate diagnostic approach for thyroid dysfunction. Methods. This cross-sectional study was performed on individuals with no history of thyroid diseases. The primary endpoint was the diagnostic value of the nasal mucociliary (NMC) test using Iranica Picris (Asteraceae) aqueous extract in differentiating hypo- or hyperthyroidism cases from euthyroid cases. Results. 232 individuals were recruited (71% females, 86% euthyroid). Receiver operating characteristic (ROC) analysis showed a good diagnostic value for the NMC test in differentiating overt hypothyroidism (area under the ROC curve [AUROC] = 0.82, p = 0.004) and its fair value in diagnosing subclinical hyperthyroidism (AUROC = 0.78, p = 0.01) from the euthyroid condition. The NMC test had a significant positive correlation with TSH (r = 0.47, p < 0.001) and a significant negative correlation with T4 (r = -0.32, p < 0.001). The NMC rate was significantly different in distinct thyroid function groups (p < 0.001). Compared with euthyroid cases, the post-hoc analysis showed that the NMC test is significantly higher in overt hypothyroidism (15.06 vs. 21.07 min, p = 0.003) and significantly lower in subclinical hyperthyroidism (15.05 vs. 10.9 min, p = 0.02). Conclusions. The Iranica Picris-based NMC test might serve as a diagnostic method to distinguish overt hypothyroidism and subclinical hyperthyroidism.

Overexpression and aberrant activation of signal transducer and activator of transcription 3 (STAT3) contribute to tumorigenesis, drug resistance, and tumor-immune evasion, making it a potential cancer therapeutic target. BP1003 is a neutral liposome incorporated with a nuclease-resistant P-ethoxy antisense oligodeoxynucleotide (ASO) targeting the STAT3 mRNA. Its unique design enhances BP1003 stability, cellular uptake, and target affinity. BP1003 efficiently reduces STAT3 expression and enhances the sensitivity of breast cancer cells (HER2⁺, triple negative) and ovarian cancer cells (late stage, invasive ovarian cancer) to paclitaxel and 5-fluorouracil (5-FU) in both 2D and 3D cell cultures. Similarly, ex vivo and in vivo patient-derived models of pancreatic ductal adenocarcinoma (PDAC) show reduced tissue viability and tumor volume with BP1003 and gemcitabine combination treatments. In addition to directly affecting tumor cells, BP1003 can modulate the tumor microenvironment. Unlike M1 differentiation, monocyte differentiation into anti-inflammatory M2 macrophages is suppressed by BP1003, indicating its potential contribution to immunotherapy. The broad anti-tumor effect of BP1003 in numerous preclinical solid tumor models, such as breast, ovarian, and pancreatic cancer models shown in this work, makes it a promising cancer therapeutic.

Postural Orthostatic Tachycardia Syndrome (POTS) affects up to 1% of the US population, predominantly women, and is characterized by a complex, elusive etiology and heterogeneous phenotypes. This review delves into the intricate physiology and etiology of POTS, decoding the roles of the sinoatrial node, the autonomic nervous system, fluid dynamics, and the interplay between the immune and endocrine systems. It further examines key contributing factors such as dysautonomia, thoracic hypovolemia, autonomic neuropathies, sympathetic denervation, autoimmune responses, and associations with conditions such as small-fiber neuropathy and mast cell activation syndrome. Given the numerous mysteries surrounding POTS, we also cautiously bring attention to sinoatrial node and myocardial function, particularly in how the heart responds to stress despite exhibiting a normal cardiac phenotype at rest. The potential of genomic research in elucidating the underlying mechanisms of POTS is emphasized, suggesting this as a valuable approach that is likely to improve our understanding of the genetic underpinnings of POTS. The review introduces a tentative classification system for the etiological factors in POTS, which seeks to capture the condition's diverse aspects by categorizing various etiological factors and acknowledging co-occurring conditions. This classification, while aiming to enhance understanding and optimize treatment targets, is presented as a preliminary model needing further study and refinement. This review underscores the ongoing need for research to unravel the complexities of POTS and to develop targeted therapies that can improve patient outcomes.

The Sigma-1 Receptor (Sigmar1) is a stress-activated chaperone and a promising target for pharmacological modulation due to its ability to induce multiple cellular responses. Yet, it is unknown how Sigmar1 is involved in cardiorenal syndrome type 4 (CRS4) in which renal damage results in cardiac dysfunction. This study explored the role of Sigmar1 and its ligands in a CRS4 model induced by unilateral ureteral obstruction (UUO) in male and female C57BL/6 mice. We evaluated renal and cardiac dysfunction markers, Sigmar1 expression, and cardiac remodeling through time (7, 12, and 21 days) and after chronically administering the Sigmar1 agonists PRE-084 (1 mg/kg/day) and SA4503 (1 mg/kg/day), and the antagonist haloperidol (2 mg/kg/day), for 21 days after UUO using colorimetric analysis, RT-qPCR, histology, immunohistochemistry, enzyme-linked immunosorbent assay, RNA-seq, and bioinformatics. We found that obstructive nephropathy induces Sigmar1 expression in the kidneys and heart, and that Sigmar1 stimulation with its agonists PRE-084 and SA4503 aggravates cardiac dysfunction and remodeling in both sexes. Still, their effects are significantly more potent in males. Our findings reveal essential differences associated with sex in the development of CRS4 and should be considered when contemplating Sigmar1 as a pharmacological target.

The number of adrenal incidentaloma (AI) cases has increased in the last few years due to the widespread use of imaging diagnostics. Management requires evaluation of the malignant nature and hormonal activity. The aim of the present study is to assess possible clinical abnormalities in 132 AI patients both at baseline and during follow-up (mean 48.6 ± 12.5 months). In all patients, demographic, anthropometric data, biochemical, metabolic and hormonal data, and 24-h ambulatory blood pressure monitoring were assessed. Mild autonomous cortisol secretions (MACS) were diagnosed in patients without signs and symptoms of overt Cushing's syndrome and post dexamethasone (DXM) plasma cortisol concentration > 50 nmol/L (>1.8 μg/dL). Patients with overnight DXM-1 mg test positive showed higher values of diastolic blood pressure, glycemia and uric acid levels compared to patients with negative DXM test at baseline. During follow-up, the potential development of MACS in patients with nonfunctional AI showed a prevalence of 29%, though the cardiovascular and metabolic alterations were less pronounced compared to those diagnosed with MACS at baseline. Therefore, follow-ups with AI patients are useful for observing changes in clinical features.

Background: The importance of identifying mortality biomarkers in chronic kidney disease (CKD), and especially in patients treated with hemodialysis (HD), has become evident. In addition to being a marker of tubulointerstitial injury, plasma kidney injury molecule-1 (KIM-1) has been mentioned in regard to HD patients as a risk marker for cardiovascular (CV) mortality and coronary artery calcification. The aim of this study was to assess the level of plasma KIM-1 as a marker of cardiovascular disease (CVD) and mortality in CKD5-HD patients (patients with CKD stage G5D treated with hemodialysis).

Methods: We conducted a prospective case-control study that included 63 CKD5-HD patients (HD for 1-5 years) followed up for 48 months and a control group consisting of 52 non-dialysis patients diagnosed with CKD stages G1-G5 (ND-CKD). All patients had a CVD baseline assessment including medical history, echocardiography, and electrocardiography (ECG). Circulating plasma KIM-1 levels were determined with single-molecule counting immunoassay technology using an enzyme-linked immunosorbent assay. We obtained the following parameters: serum creatinine and urea; the inflammation markers CRP (C-reactive protein) and IL-6 (interleukin-6); and the anemia markers complete blood count, serum ferritin, and transferrin saturation (TSAT).

Results: The mean plasma KIM-1 level was 403.8 ± 546.8 pg/mL, showing a statistically significant correlation with inflammation (CRP, R = 0.28, p = 0.02; IL-6, R = 0.36, p = 0.005) and with anemia (hematocrit, R = -0.5, p = -0.0316; hemoglobin (Hb), R = -0.5, p = 0.02). We found that patients with left ventricular hypertrophy (LVH) on echocardiography (59.7%) had significantly lower mean levels of plasma KIM-1 than patients from the control group (155.51 vs. 432.12 pg/mL; p = 0.026). Regarding the patients' follow-up, we assessed all-cause mortality as an endpoint. After 24 months of follow-up, we found a mortality rate of 22.23%, while after 48 months, the mortality rate was 50.73%. A plasma KIM-1 level < 82.98 pg/mL was significantly associated with decreased survival in hemodialysis patients (p < 0.001).

Conclusions: In patients treated with hemodialysis, low levels of plasma KIM-1 were associated with cardiovascular changes and an increased risk of mortality. Plasma KIM-1 levels were significantly higher in HD patients compared to ND-CKD patients.

Peripheral insulin resistance (IR) is a well-documented, independent risk factor for the development of type 2 diabetes, cardiovascular disease, cancer and cellular senescence. Recently, the brain has also been identified as an insulin-responsive region, where insulin acts as regulator of the brain metabolism. Despite the clear link between IR and the brain, the exact mechanisms underlying this relationship remain unclear. Therapeutic intervention in patients showing symptoms of neurodegenerative diseases has produced little or no results. It has been demonstrated that insulin resistance plays a significant role in the pathogenesis of neurodegenerative diseases, particularly cognitive decline. Peripheral and brain IR may represent a modifiable state that could be used to prevent major brain disorders. In this review, we will analyse the scientific literature supporting IR as a risk factor for Alzheimer's disease and suggest some therapeutic strategies to provide a new proposal for the prevention of brain IR and its consequences.

Background: Age plays a primary role in the development of age-related macular degeneration (AMD). Telomere length (TL) is one of the most relevant biomarkers of aging. In our study, we aimed to determine the association of TL with T lymphocytes, B lymphocytes, NK cells or monocytes with different forms of AMD.

Methods: Our study included 62 patients with AMD: geographic atrophy (GA), neovascular AMD (NVAMD) with and without macular atrophy and 22 healthy controls. Each leukocyte subtype was isolated from peripheral blood by immunomagnetic separation, and the DNA was purified. The TL in the genomic DNA was determined using qPCR by amplifying the telomere region with specific oligonucleotide primers and normalizing to the control gene. Statistical analysis was performed using R version 4.5.1.

Results: We observed a statistically significant increase in TL in the T cells between the control and NVAMD groups but not for the GA group. The B cells and monocytes showed a significant decrease in TL in all AMD groups. The TL in the NK cells did not decrease in any of the AMD groups.

Conclusions: The TL in the monocytes had the strongest association with AMD. It reflects a person's "telomeric status" and may become a diagnostic hallmark of these degenerative processes.

Experimental animal studies of hypoxic-ischemic injury of the hippocampus of pigs are limited due to the unprecise definition of hippocampal subfields, cornu ammonis 1 to 4, compared to humans. Given that the pig model closely mirrors human physiology and serves as an important model for critical care research, a more precise description is necessary to draw valid conclusions applicable to human diseases. In our study, we were able to precisely define the CA2 and its adjacent regions in a domestic pig model by arginine vasopressin receptor 1B (AVPR1B) and calbindin-D28K like (CaBP-Li) expression patterns. Our findings demonstrate that the histoarchitecture of the porcine cornu ammonis subfields closely resembles that of the human hippocampus. Notably, we identified unusually strong neuronal damage in regions of the pig hippocampus following global ischemia, which are typically not susceptible to hypoxic-ischemic damage in humans.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a public health concern due to infections with new SARS-CoV-2 variants. Therefore, finding effective preventive and therapeutic treatments against all SARS-CoV-2 variants is of great interest. In this study, we examined the capacity of eucalyptus essential oil (EEO) and eucalyptol (EOL) to prevent SARS-CoV-2 infection, using as a model SARS-CoV-2 Spike pseudotyped lentivirus (SARS-CoV-2 pseudovirus) and 293T cells transfected with human angiotensin-converting enzyme 2 (hACE2-293T cells). First, we determined the cytotoxicity of EEO and EOL using the MTT colorimetric assay, selecting non-cytotoxic concentrations ≤ 0.1% (v/v) for further analysis. Subsequently, we evaluated the capacity of EEO and EOL in cell cultures to preclude infection of hACE2-293T cells by SARS-CoV-2 pseudovirus, using a luciferase-based assay. We found that EEO and EOL significantly reduced SARS-CoV-2 pseudovirus infection, obtaining IC₅₀ values of 0.00895% and 0.0042% (v/v), respectively. Likewise, EEO and EOL also reduced infection by vesicular stomatitis virus (VSV) pseudovirus, although higher concentrations were required. Hence, EEO and EOL may be able to inhibit SARS-CoV-2 infection, at least partially, through a Spike-independent pathway, supporting the implementation of aromatherapy with these agents as a cost-effective antiviral measure.