Journal of Physiology and Pharmacology最新文献

The most reliable chronic endometritis diagnosis is based on immunohistochemistry plasma cell identification in endometrial samples. Our study aimed to compare multiple myeloma oncogene 1 (MUM1) and syndecan-1/CD138 immunohistochemistry staining for chronic endometritis diagnosis among patients with recurrent pregnancy loss. We evaluated the presence of endometrial stromal changes. Fifty-four patients with a history of at least two intrauterine pregnancy losses underwent diagnostic hysteroscopy in the follicular phase of the cycle with endometrial aspiration biopsy. In all 54 cases, three successive sections were cut from each paraffin-embedded tissue block for hematoxylin and eosin (H&E), CD138 and MUM1 staining. The goal was to evaluate the level of agreement between the MUM1 and CD138 results and plasma cell detection rate in assessing the endometrial stromal changes. The concordance analysis between CD138 and MUM1 immunohistochemistry staining showed consistent results in 43 of 54 (79.6%) cases. The level of agreement was moderate, based on a Kappa value of 0.60. MUM1 immunostaining was positive for CE in more cases than CD138 staining, and this difference was statistically significant, showing a higher sensitivity of MUM1 in plasma cell detection (p=0.01). Endometrial stromal changes were observed in the majority of cases - 49/54 (90%). Samples without stromal changes were consistently negative for plasma cells using both CD138 and MUM1 staining. We demonstrated that MUM1 staining, used in conjunction with assessing endometrial stromal changes, contributes to a more accurate and comprehensive diagnosis of chronic endometritis.

Withaferin A (WFA) is a natural compound separated from the medicinal plant Withania somnifera. As reported, it has the potential to safely cure rheumatoid arthritis (RA) in animal models. Nevertheless, the action mechanism of WFA in treating RA has not been completely illuminated. The study was to explore the action and mechanism of WFA on arthritic rats. First, a collagen-induced arthritis rat model was established. WFA administration alleviated inflammation and injury in arthritic rats. Subsequently, fibroblast synovial cells (FLS) of arthritic rats were separated and cell proliferation and apoptosis abilities were tested. It was found that WFA was available to repress FLS cell proliferation and accelerate apoptosis. MicroRNA-1297 was downregulated in RA patients. Clinical correlation analysis suggested that miR-1297 in the serum of RA patients was negatively associated with pro-inflammatory factors interleukin (IL)-6, IL-17, tumor necrosis factor (TNF)-α, and RA diagnostic indexes (RF, DAS28). In the meantime, miR-1297 had superior diagnostic value in differentiating RA patients from healthy people. Karyopherin α2 (KPNA2) was the downstream target of miR-1297, while miR-1297 negatively modulated KPNA2 expression. Importantly, WFA further restrained KPNA2 expression via elevating miR-1297 in functional rescue experiments, thereby treating inflammation and injury in arthritic rats and repressing FLS cell proliferation and activation. In short, WFA alleviated inflammation and joint damage in arthritic rats via elevating miR-1297 to target KPNA2.

We explored the involvement of orphan nuclear receptor 4 A1 (NR4A1) in myocardial fibrosis mediated by transforming growth factor-beta1 (TGF-β1) and its response to cytosporone B (Csn-B). We developed a diabetic cardiomyopathy mouse model by administering a high-fat diet in conjunction with a low-dose streptozotocin injection. Our analysis involved monitoring alterations in blood glucose and lipid levels, cardiac function and structure, as well as profibrotic factors such as α smooth muscle actin (α-SMA), collagen I, collagen III, TGF-β1, connective tissue growth factor, and fibronectin. These assessments were conducted using biochemical techniques, Doppler ultrasound, histopathology, and real-time quantitative polymerase chain reaction. Cardiac fibroblasts (CFs) were extracted from suckling mice and cultivated in a high-glucose medium to simulate diabetes-induced myocardial fibrosis in vitro. These CFs were then subjected to coculture experiments with TGF-β1 or Csn-B. The proliferation and migration of CFs were assessed using cell counting kit 8 (CCK-8) assays and Transwell assays, respectively. Western blotting and immunofluorescence assays were employed to evaluate the expression levels of NR4A1, p-NR4A1, and α-SMA in CFs treated with TGF-β1 after NR4A1 knockdown or Csn-B administration, respectively. In diabetic heart tissue, the expression of p-NR4A1 was notably elevated. Furthermore, CFs exhibited enhanced proliferative capabilities and increased p-NR4A1 expression following high glucose exposure. Interestingly, NR4A1 knockdown resulted in a significant increase in the expression of fibrosis-related proteins in CFs following treatment with TGF-β1. Moreover, our observations revealed a marked decrease in p-NR4A1 levels and a reduction in the expression of fibrosis-related proteins after Csn-B treatment. In diabetic mice treated with Csn-B, we noted diminished NR4A1 phosphorylation and a mitigation of myocardial fibrosis. We concluded that in the mouse model, Csn-B played a pivotal role in inhibiting diabetes-induced myocardial fibrosis by activating NR4A1.

Indoxyl sulfates are uremic indolic toxins known to participate in the pathogenesis of cardiovascular diseases during chronic kidney disease in humans and some animal species. However, nothing is known about the indoxyl sulfate effect on the thyroid gland which is especially responsible for the general organism metabolism. This study determines the morpho-functional status of the thyroid gland after exposure to indoxyl sulfate (10, 25, and 50 mM) with the use of an ex vivo system and rabbit (n=10) as an experimental model thyroid gland histology, immunoexpression of thyrotropin receptor (TSHR), and concentrations of thyroxine (T4) and triiodothyronine (T3) were evaluated. Statistical analyses were performed using one-way analysis of the variance (ANOVA) followed by Tukey's post hoc comparison test. Minor alterations in thyroid tissue structure e.g. very rare exfoliated epithelial cells, condensed colloid fluid, or slight loosening of the epithelium were found. In addition, modulated dose dependent-expression of TSHR (p<0.01, p<0.001) together with a decreased level of T4 and T3 (p<0.001, p<0.01) exception of an increased level of T4 after the middle dose of indoxyl sulfate were revealed. We report here, for the first time, that indoxyl sulfate affects the thyroid gland mainly at the molecular level. The rabbit thyroid gland ex vivo system seems to be suitable for further studies on the thyroid gland in health and disease. However, the effect of TSH-TSHR signaling at ultrastructural, and epigenetic levels needs supplementary appraisal.

The prevalence of diabetic retinopathy (DR) is high among individuals with diabetes. Curcumin (CUR) has been suggested as a possible treatment for this condition. This study aimed to investigate the impact of CUR on pro-inflammatory cytokines, oxidative stress markers, and vascular endothelial growth factor (VEGF) in an experimental model of DR. The study used Spontaneously Diabetic Torii (SDT) rats and divided them into groups to receive various CUR doses (10, 50, 100 mg/kg/day) or distilled water for four weeks. Non-diabetic Sprague-Dawley (SD) rats were used as a control group. Pro-inflammatory cytokines (interleukin (IL)-1, IL-6, tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ)) (by ELISA), oxidative stress markers (superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GPX), catalase (CAT)), and VEGF expression (by RT-PCR) and content (by Western-blot and immunostaining) were assessed as outcome measures. The study found that diabetic rats who received varying doses of CUR showed a decrease in pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1), oxidative stress markers (SOD, MDA, GPX, CAT), and VEGF expression and content in the vitreous. The decrease in these markers was dose-dependent and significantly different from diabetic rats who did not receive CUR (p<0.01). However, there was no significant difference in the vitreous level of IL-6 between the groups (p=0.35). The study concluded that CUR has the potential to alleviate inflammation and oxidative stress induced by diabetes in the vitreous microenvironment of rats. CUR also reduced the increase in VEGF levels in the vitreous of diabetic rats. These findings suggest that CUR could be a viable therapeutic option for the treatment of DR.

Paeonol (2-hydroxy-4-methoxyphenylacetophenone) is a natural phenolic component isolated from the root bark of peony with multiple pharmacological activities and has been proven to have anti-cancer effects. The objective of this study is to investigate the influence mechanism of paeonol on the proliferatory and apoptotic activities of ovarian cancer (OC) cells by modulating the transforming growth factor beta (TGF-β)/Smad3 pathway. The SKOV3 cells were pretreated with various concentrations of paeonol (0, 25, 50, 100, 200, 400 μg/mL) for 48 hours to determine the optimal experimental concentration of paeonol. Following this, the TGF-β overexpression vector was constructed and transfected into the SKOV3 cells. The assessment of cell proliferation, invasion, and migration was conducted through MTT, colony formation, flow cytometry, transwell, and wound-healing experiments. The detection of TGF-β/Smad3 pathway-related proteins and apoptosis-related proteins (B-cell lymphoma (Bcl-2) Bcl-2-associated X protein (Bax)) was performed using Western blot analysis. Paeonol exhibited a significant inhibitory effect on SKOV3 cell viability when administered at concentrations ranging from 50-400 μg/mL, with an IC₅₀ value of 200 μg/mL. Within the concentration range of 50 to 200 μg/mL, paeonol exhibited a dose-dependent effect on the progression of SKOV3 cells, including a reduction in the anti-apoptotic protein Bcl-2, an increase in the pro-apoptotic protein Bax (P<0.05), inhibition of cell migration and invasion (P<0.05), and promotion of cell apoptosis (P<0.05), particularly at a concentration of 200 μg/mL. These effects were found to be more pronounced. The aforementioned effects of paeonol can be ascribed to its inhibition of the TGFβ/Smad3 pathway, according to a mechanistic viewpoint. It is noteworthy that the inhibitory impact of paeonol on SKOV3 cell progression is counteracted by the elevation of TGF-β levels following overexpression. We conclude that paeonol exerts regulatory effects on the TGF-β/Smad3 pathway, leading to the inhibition of proliferation, migration, and invasion of OC cells, thereby attenuating malignant behavior of cancer cells.

This study was designed to explore cryptanshinone (CPT) extract of Salvia miltiorrhiza stimulating pediatric acute myeloid leukemia (AML) stem cell (LSC) apoptosis and anti-inflammatory mechanism via accelerating microRNA (miR)-211-5p to restrain Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway activation. Obtaining blood samples from pediatric acute myeloid leukemia patients and healthy volunteers and detecting miR-211-5p and JAK2 were performed. Purchase of the human AML cell line KG1a was conducted, and sorting of KG1a cells was to gain LSC. Test of miR-211-5p and JAK2, the phosphorylation of JAK2/STAT3 was implemented. Pretreatment of LSCs was with CPT. Variation of miR-211-5p and JAK2 in LSCs was via plasmid transfection to explore their actions in cell advancement with apoptosis and inflammation. Identification of the targeting of miR-211-5p with JAK2 was implemented. In results: MiR-211-5p was declined in endometrial cancer, while JAK2 was elevated; CPT was available to boost LSC apoptosis and restrain the inflammation; elevated miR-211-5p or repressive JAK2 was available to strengthen the acceleration of CPT on LSCs apoptosis and the repression of inflammation; MiR-211-5p targeted JAK2; augmented JAK2 was available to turn around the action of elevated miR-211-5p. We conclude that CPT extract of Salvia miltiorrhiza stimulated pediatric LSC apoptosis and restrained the inflammation via accelerating microRNA (miR)-211-5p to suppress JAK2/STAT3 pathway activation.

Dyxin is a LIM-domain containing transcriptional regulator protein shown to play a role in a hypertrophic response in the heart. Here, the effect of adenoviral dyxin overexpression was studied on cardiac function and gene expression in the normal heart and in angiotensin II (Ang II)-induced hypertension in rats. The adenovirus-mediated intramyocardial gene transfer of dyxin (1.5x10⁹ infectious units/animal) was performed into the left ventricle (LV) of Sprague-Dawley rats with and without the Ang II (33 μg/kg/h) infusion, administered via osmotic minipumps for 1 and 2 weeks. Echocardiography was used to assess the structural and functional changes. Dyxin expression and localization in the heart was analyzed with quantitative RT-PCR and immunohistochemistry, respectively. In the normal rat heart, the adenoviral overexpression of dyxin did not alter LV function in normal hearts as assessed by echocardiography. Dyxin was found to be localized in the cardiomyocytes as shown by the immunohistochemical staining. In Ang II-induced hypertrophy, echocardiographic data revealed a significant increase in the posterior wall diameter both in systole (21%, P<0.05) and diastole (21%, P<0.01) as well as in the diameter of the interventricular septum in systole (19%, P<0.05) in the dyxin-injected group compared with the LacZ-injected animals after two weeks of Ang II infusion. Interestingly, a significant decrease in the levels of both atrial natriuretic peptide (ANP) mRNA (55%, P<0.01) and B-type natriuretic peptide (BNP) mRNA (68%, P<0.05) was observed in the dyxin-injected group compared with the LacZ control group after one week of Ang II infusion. These results indicate that dyxin overexpression was deteriorative against pressure overload by inducing structural changes in the LV in rats. Interestingly, simultaneous adenoviral overexpression of dyxin suppressed the Ang II-induced changes of ANP and BNP genes suggesting that dyxin might have a role as a regulator of the cardiac hypertrophic gene program.

The radial artery (RA) access is currently the gold standard to perform cardiovascular interventions. One of the more common limitations is radial artery spasm which is an often complication interrupting the procedure. Common risk factors associated with spasm include female gender, periprocedural anxiety, multiple puncture attempts, distal radial access, diabetes, hypertension, and smoking. The mechanism of spasm is complex and includes calmodulin and rho-kinase pathways leading to the smooth muscle contraction. Proper hydration, anxiety management, and adequate local anesthesia should be applied to decrease the risk of spasms. Radial cocktail is often used to prevent spasm. Its composition differs between catheterization laboratories and the effect is attributed either to the verapamil or nitroglycerin, with contradictory results of different studies. Balbay maneuver is also an effective mean of prevention. Hydrophilic-coated devices can be used both to avoid spasms or reverse them. Radial angiography can be used to differentiate spasm from a tortuosity and choose proper method of management. Fasudil, a Rho-kinase inhibitor, has been reported as a pharmacological method to prevent spasm and reverse radial artery spasm.

Orexins A (OXA) and B (OXB) (hypocretin 1 and 2) are neuropeptides produced in the brain and peripheral tissues. Biological activities of orexins are mediated through activation of two G-protein coupled receptors termed as orexin 1 receptor (OX1R) and orexin 2 receptor (OX1R). Orexin system (OXA, OXB, OX1R, OX2R) was implicated in controlling sleep, energy expenditure, appetite, reproduction as well as metabolism and energy homeostasis. In this review, we summarize the current knowledge regarding the role of the orexin system in controlling porcine physiology. Particularly, we review and discuss evidence indicating that in pig and other living organisms, orexins and their receptors modulate the energy homeostasis, reproduction as well as functions of peripheral tissues including the pancreas, adrenal glands, gastro-intestinal tract and adipose tissue.