Advances in medical sciences最新文献

Recent events have raised concerns about the outbreak of a pandemic by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). An infection caused by a virus can provoke an inflammatory reaction, which can result in severe lung damage, failure of several organs, and death. The unique genetic makeup of each individual may be a component in the development of each of these responses. In this context, genetic variants of the genes linked to the invasion of the virus into the host's body can be analyzed. Various elements have a function in viral entry. ACE2 is used by SARS-CoV-2 as a receptor to enter the cell. TMPRSS2 is then responsible for cutting the virus into its components. In addition, lung damage occurs when there is an imbalance between ACE1 and ACE2. Another component that plays a significant role in virus penetration is called IFITM3, which is created as a reaction to interferon. This protein prevents viruses in the Coronaviridae family from entering cells.

This study aimed to analyze DNA polymorphisms in the ACE2, ACE1, TMPRSS2, and IFITM3 genes. Findings showed certain polymorphisms appear to be associated with the severity of the disease, including respiratory, coronary, and neurological disorders. The results also indicated that certain polymorphisms were protective against this virus. Varying populations have a different frequency of high-risk polymorphisms, so different treatment and preventative techniques must be implemented. Additional population studies should be conducted in this region to reduce the incidence of COVID-19-related morbidity and mortality.

Purpose

Myeloproliferative neoplasms (MPN) are a heterogeneous group of hematopoietic stem-cell diseases with excessive proliferation of one or more blood cell lines. In this study, we evaluated the effect of different oxygen concentrations on HIF-1α and NOS3 gene expression to determine the effect of the bone marrow microenvironment on JAK2V617F positive Philadelphia chromosome negative (Ph⁻) MPNs.

Patients and methods

Peripheral blood mononuclear cells (MNC) of 12 patients with Ph⁻ MPN were collected. The presence of JAK2V617F allele status was determined with allele-specific nested PCR analysis. MPN CD34⁺ and CD34^depleted populations were isolated from MNC by magnetic beads. Separate cell cultures of CD34^+/depleted populations were managed at different oxygen concentrations including anoxia (∼0%), hypoxia (∼3%), and normoxia (∼20%) conditions for 24 ​h. HIF-1α and NOS3 gene expression changes were examined in each population related to JAK2V617F status with real time RT-PCR.

Result

It was revealed that relative HIF-1α and NOS3 expressions were significantly increased in response to decreased oxygen concentration in all samples. Relative HIF-1α and NOS3 expressions were found to be higher especially in CD34⁺ and CD34^depleted populations carrying JAK2V617F mutations compared to MPN patients carrying wild-type JAK2.

Conclusion

JAK2V617F might have specific role in HIF-1α and NOS3 regulations with respect to low oxygen concentrations in Ph⁻ MPN. Further evaluations might reveal the effect of JAK2V617F on Ph⁻ MPN pathogenesis in bone marrow microenvironment.

Purpose

This study aimed to evaluate the role of Translationally Controlled Tumor Protein (TCTP) in breast cancer (BC) and investigate the effects of sertraline, a serotonin selective reuptake inhibitor (SSRI), on BC cells. The objective was to assess the potential of sertraline as a therapeutic agent in BC treatment by examining its ability to inhibit TCTP expression and exert antitumor effects.

Material and Methods

We utilized five different BC cell lines representing the molecular heterogeneity and distinct subtypes of BC, including luminal, normal-like, HER2-positive, and triple-negative BC. These subtypes play a crucial role in determining clinical treatment strategies and prognosis.

Results

The highest levels of TCTP were observed in triple-negative BC cell lines, known for their aggressive behavior. Sertraline treatment reduced TCTP expression in BC cell lines, significantly impacting cell viability, clonogenicity, and migration. Additionally, sertraline sensitized triple-negative BC cell lines to cytotoxic chemotherapeutic drugs (doxorubicin and cisplatin) suggesting its potential as an adjunctive therapy to enhance the chemotherapeutic response. Bioinformatic analysis of TCTP mRNA levels in TCGA BC data revealed a negative correlation between TCTP levels and patient survival, as well as between TCTP/tpt1 and Ki67. These findings contradict our data and previous studies indicating a correlation between TCTP protein levels and aggressiveness and poor prognosis in BC.

Conclusions

Sertraline shows a promise as a potential therapeutic option for BC, particularly in triple-negative BC. Its ability to inhibit TCTP expression, enhance chemotherapeutic response, highlights its potential clinical utility in BC treatment, specifically in triple-negative BC subtype.

Purpose

Interleukin (IL)-33 and its soluble receptor ST2 (sST2) play a crucial role in the immune response. sST2 has been approved by the Food and Drug Administration as a prognostic biomarker of mortality in chronic heart failure patients, however, the role of IL-33 and sST2 in atherosclerotic cardiovascular disease remains unclear. The aim of this study was to measure serum level of IL-33 and sST2 of patients at the onset of acute coronary syndrome (ACS) and 3 months after primary percutaneous revascularization.

Patients and methods

Forty patients were divided into ST segment elevation myocardial infarction (STEMI) group, non-ST segment elevation myocardial infarction (NSTEMI) and unstable angina (UA) group. IL-33 and sST2 level were measured with ELISA. Additionally, IL-33 expression in peripheral blood mononuclear cells (PBMCs), was evaluated.

Results

All ACS patients had a significantly lower level of sST2 3 months after ACS as compared to the baseline (p ​< ​0.039). The STEMI patients had higher serum levels of IL-33 at the moment of ACS as compared to 3 months after the event, with an average decrease of 17.87 ​pg/ml (p ​< ​0.007). Conversely, sST2 serum levels were still high after 3 months following an ACS in STEMI patients. ROC curve demonstrated that increased IL-33 serum level could be STEMI predictor.

Conclusions

The assessment of the baseline and dynamics of changes in IL-33 and sST2 concentrations in patients with ACS may be important for the diagnostic process and may help in understanding of how the immune mechanisms work at the moment of an ACS event.

Purpose

The normal healthy valve is devoid of inflammatory cells, however background of aortic stenosis (AS) may include inflammatory processes. Moreover, the link between hyperparathyroidism and heart failure is postulated. Simple whole blood analysis with indices is a beneficial tool in cardiovascular diseases’ assessment. The purpose of the study was to evaluate correlation between parathyroid hormone (PTH) and simple blood parameters in severe AS.

Material and methods

The study included 62 patients with severe AS. Patients with inflammatory or autoimmune co-morbidities were excluded. Blood samples were collected, and clinical and demographic data were analyzed.

Results

The final study group comprised 55 patients (31 females, 56.4%; mean age 77.13 (SD 6.76)). In 23 patients (41.8%), PTH concentration was markedly increased. The study group was divided into two subgroups according to the PTH concentration. Patients from both groups did not differ significantly in terms of age and co-morbidities. PTH concentration correlated positively with monocyte-lymphocyte ratio (MLR) (p ​= ​0.008, Spearman rho 0.356) and platelet-lymphocyte ratio (PLR) (p ​= ​0.047, Spearman rho 0.269), creatinine level (p ​= ​0.001, Spearman rho 0.425) and glomerular filtration rate (GFR-MDRD) (p ​= ​0.009, Spearman rho −0.349).

The multivariable logistic regression with backward analysis revealed MLR (p ​= ​0.029) and GFR (p ​= ​0.028) as independent significant predictors of abnormal PTH values.

The receiver operator characteristics (ROC) curve was performed for the model of MLR and GFR-MDRD (AUC ​= ​0.777), yielding the sensitivity of 60.9% and specificity of 90.6%.

Conclusions

PTH concentration correlates with monocyte-to-lymphocyte and platelet-to-lymphocyte ratios in calcified AS.

Purpose

Dipeptidyl peptidase 4 (DPP₄) inactivates a range of bioactive peptides. The cleavage of insulinotropic peptides and glucagon-like peptide 1 (GLP₁) by DPP₄ directly influences glucose homeostasis. This study aimed to describe the mode of interaction between sitagliptin (an antidiabetic drug) and human DPP₄ using in silico approaches.

Materials and methods

Docking studies were conducted using AutoDock Vina, 2D and 3D schematic drawings were obtained using PoseView and PLIP servers, and the DPP₄-sitagliptin complex was visualized with Pymol software.

Results

The best affinity energy to form the DPP₄-sitagliptin complex was E-value ​= ​- 8.1 ​kcal ​mol⁻¹, as indicated by docking simulations. This result suggests a strong interaction. According to our observations, hydrophobic interactions involving the amino acids residues Tyr⁶⁶³ and Val⁷¹², hydrogen bonds (Glu²⁰³, Glu²⁰⁴, Tyr⁶⁶³, and Tyr⁶⁶⁷), π-Stacking interactions (Phe³⁵⁵ and Tyr⁶⁶⁷), and halogenic bonds (Arg¹²³, Glu²⁰⁴, and Arg³⁵⁶) were prevalent in the DPP₄-sitagliptin complex. Root Mean Square Deviation prediction also demonstrated that the global structure of the human DPP₄ did not have a significant change in its topology, even after the formation of the DPP₄-sitagliptin complex.

Conclusion

The stable interaction between the sitagliptin ligand and the DPP₄ enzyme was demonstrated through molecular docking simulations. The findings presented in this work enhance the understanding of the physicochemical properties of the sitagliptin interaction site, supporting the design of more efficient gliptin-like iDPP₄ inhibitors.

Purpose

For many years, statins have been the most commonly used drugs in cholesterol-lowering therapy. In addition to these therapeutic effects, statins exhibit other, pleiotropic effects that can be beneficial, but also harmful to cells and tissues. The aim of this research was to determine and compare the pleiotropic effects of structurally different statins: atorvastatin, simvastatin and rosuvastatin at different concentrations on hepatocellular carcinoma (HepG2) cells.

Materials and methods

The MTT assay was used to determine the cytotoxic effects of statins. The influence of statins on the production of reactive oxygen species (ROS) was determined by measuring fluorescent response of 2,7-dichlorofluorescein diacetate (DCFH-DA). The effect of statins on glucose production and excretion was determined with glucose production assay.

Results

The obtained results confirmed that all tested statins exhibit cytotoxic effects, increase the production of ROS as well as the production and excretion of glucose from HepG2 cells. It was observed that all the mentioned effects are more pronounced with lipophilic statins, atorvastatin and simvastatin compared to hydrophilic rosuvastatin.

Conclusion

The less pronounced pleiotropic effects of rosuvastatin on HepG2 cells are probably due to differences in structure and solubility compared to atorvastatin and simvastatin. Transporter-dependent and a slower influx of rosuvastatin into cells compared to the tested lipophilic statins probably lead to a weaker accumulation of rosuvastatin in HepG2 cells, which results in less pronounced pleiotropic effects compared to lipophilic atorvastatin and simvastatin.

Purpose

The measurement of biomarkers in exhaled breath condensate (EBC) offers a non-invasive way to assess airway disease and can be easily done in a clinical setting among patients with cystic fibrosis (CF). The role of oxidative and nitrosative stress in the complex pathophysiology of CF is widely accepted and biomarkers of oxidative and nitrosative stress can be measured in the serum and EBC. To our knowledge, this is the first study to assess markers of nitrosative stress in EBC and serum, collected simultaneously from the CF patients.

Patients and methods

Paired EBC and serum samples were collected from 36 stable patients with CF and 14 healthy controls. Markers of nitrosative stress ‒ 3-nitrotyrosine and nitrate/nitrite were measured in the EBC and serum using an enzyme-linked immunosorbent assay.

Results

We found no differences in 3-nitrotyrosine and nitrate/nitrite in the EBC of patients with CF as compared to healthy controls (125.37 ​± ​3.29 vs. 126.24 ​± ​2.21 ​nmol/L, p ​= ​0.218; 12.66 ​± ​7.23 vs. 8.79 ​± ​4.83 ​μmol/L, p ​= ​0.133, respectively). Furthermore, 3-nitrotyrosine and nitrate/nitrite were significantly higher in the serum of patients with CF as compared to the healthy controls (0.13 ​± ​0.02 vs. 0.11 ​± ​0.01 ​nmol/mg protein, p ​= ​0.003; 70.78 ​± ​22.55 vs. 53.08 ​± ​8.5 ​μmol/L, p ​= ​0.009, respectively). No correlations were found between the markers determined in the EBC and serum.

Conclusions

The results of the EBC nitrosative stress biomarkers should be interpreted with caution, especially in patients with stable disease, as the EBC values may be independent on levels of circulating markers that are elevated in the serum of patients with stable CF.

Purpose

Recent studies, conducted mainly on the rodent model, have demonstrated that regulatory pathway in the skin provided by glycosaminoglycans, nuclear factor of activated T cells 5 (NFAT5), vascular endothelial growth factor C (VEGF-C) and process of lymphangiogenesis may play an important role in extrarenal regulation of sodium (Na⁺) balance, body water volume, and blood pressure. We aimed to investigate the concentrations and relations among the main factors of this pathway in human skin to confirm that this regulatory axis also exists in humans.

Patients and methods

Skin specimens from patients diagnosed with arterial hypertension and from control group were histologically and molecularly examined.

Results

The primary hypertensive and control groups did not differ in Na⁺ ​concentrations in the skin. However, the patients with hypertension and higher skin Na⁺ concentration had significantly greater density of skin lymphatic vessels. Higher skin Na⁺concentration was associated with higher skin water content. In turn, skin water content correlated with factors associated with lymphangiogenesis, i.e. NFAT5, VEGF-C, and podoplanin (PDPN) mRNA expression in the skin. The strong mutual pairwise correlations of the expressions of NFAT5, VEGF-C, vascular endothelial growth factor D (VEGF-D) and PDPN mRNA were noted in the skin in all of the studied groups.

Conclusions

Our study confirms that skin interstitium and the lymphatic system may be important players in the pathophysiology of arterial hypertension in humans. Based on the results of our study and existing literature in this field, we propose the hypothetical model which might explain the phenomenon of salt-sensitivity.

Cancer cell migration and metastasis are the biggest problems in the treatment of cancer patients. The most aggressive breast cancer (BC) is the triple-negative type. Therefore, effective therapeutic targets that limit cell migration are sought. One such target may be fascin, as its overexpression is characteristic to triple-negative breast cancer. The high level of fascin enables the formation of protrusion and thus promotes the invasion of cancer cells. Fascin also shows co-localization or functional relationships with other proteins. These are proteins involved in the epithelial-mesenchymal transition process, vimentin, cadherins, β-catenin, and matrix metalloproteinases 2/9 (MMP-2/9). Fascin is also involved in many signaling pathways protein kinase C-δ (PKCδ), Wnt/β-catenin, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and phosphatidylinositol 3-kinase (PI3K)-Akt. Therefore, in this article, we review currently available in vitro studies and compare them with The Cancer Genome Atlas (TCGA) data analysis of BC patients to demonstrate the role of fascin in the migration and invasion of cancer cells.