Suppression of PRDX4 inhibits cell proliferation and invasion of ectopic endometrial stromal cells in endometriosis

Abstract

Oxidative stress (OS) has been proposed to play a role in the development of EMs. Peroxiredoxins are a family of antioxidant proteins that exhibit peroxidase activity in a thioredoxin-dependent manner, protecting cells against OS. The Western blotting results showed that the relative expression of PRDX4 was significantly increased in ectopic endometria compared with the normal endometria of EMs-free (p?<?.05). The H₂O₂ concentration was also significantly higher in the ectopic endometrium. PRDX4 siRNA was transfected into primary ectopic endometrial stromal cells (EESCs). The viability of the transfected EESCs was measured by CCK-8 assay, and the results showed significantly decreased cell viability. Furthermore, the apoptosis rate and ROS generation in flow cytometry assays were significantly increased after the knockdown of PRDX4 expression (p?<?.05). Scratch assays and transwell assays revealed that decreased expression of PRDX4 mediated by siRNA inhibited EESC migration and invasion. In conclusion, these findings indicate the potential role of PRDX4 in the development of EMs and PRDX4 as a possible therapeutic target for EMs treatment.     

An Environmental Scan of the National and Provincial Diagnostic Reference Levels in Canada for Common Adult Computed Tomography Scans

Several regulatory bodies have agreed that low-dose radiation used in medical imaging is a weak carcinogen that follows a linear, non-threshold model of cancer risk. While avoiding radiation is the best course of action to mitigate risk, computed tomography (CT) scans are often critical for diagnosis. In addition to the as low as reasonably achievable principle, a more concrete method of dose reduction for common CT imaging exams is the use of a diagnostic reference level (DRL). This paper examines Canada's national DRL values from the recent CT survey and compares it to published provincial DRLs as well as the DRLs in the United Kingdom and the United States of America for the 3 most common CT exams: head, chest, and abdomen/pelvis. Canada compares well on the international scale, but it should consider using more electronic dose monitoring solutions to create a culture of dose optimization.     

Investigation of non-linear Mate1-mediated efflux of trimethoprim in the mouse kidney as the mechanism underlying drug-drug interactions between trimethoprim and organic cations in the kidney

The purpose of this study was to elucidate the involvement of Mate1 in the tubular secretion of trimethoprim and saturation of Mate1-mediated efflux to address the mechanisms underlying the pharmacokinetic drug interactions with trimethoprim. Trimethoprim is a more potent inhibitor of MATE2-K than MATE1 with K_i values (μM) of 0.030–0.28 and 2.4–5.9, respectively. Trimethoprim is a substrate of human MATE1 and MATE2-K with K_m values of 2.3 ± 0.9 and 0.018 ± 0.004 μM, and mouse Mate1, but not human OCT2, mouse Oct1 and Oct2. Pyrimethamine significantly reduced the renal clearance (CL_R) of trimethoprim (mL/min/kg) from 40.0 ± 5.1 to 20.1 ± 3.7 (p < 0.05). Trimethoprim was given to mice at three infusion rates (150, 500, and 1500 nmol/min/kg). Together with an increase in the plasma concentrations of trimethoprim, the CL_R (mL/min/kg) of trimethoprim decreased to 25.9 ± 3.2, 13.5 ± 5.7, and 8.92 ± 1.50 at the respective rates. Trimethoprim decreased the CL_R of rhodamine 123 in an infusion rate-dependent manner: 11.5 ± 1.3 (control), 5.17 ± 1.55, 1.31 ± 0.50, and 0.532 ± 0.180. These results suggest that Mate1 mediates the tubular secretion of trimethoprim, and at therapeutic doses, MATEs-mediated efflux can be saturated, and thereby, cause drug interactions with other MATE substrates.     

A drug safety evaluation of mogamulizumab for the treatment of cutaneous T-Cell lymphoma

Introduction: Cutaneous T-cell lymphomas (CTCL) are rare non-Hodgkin lymphomas of skin-homing T-cells that initially or mainly manifest cutaneously. Treatment of CTCL is challenging given the disease states’ varying presentation and prognosis. Systemic treatment options often lack comparative evidence and have relatively low response rates and short duration of response. The recent Food and Drug Administration (FDA) approval of mogamulizumab in adult patients with relapsed or refractory (R/R) CTCL after at least one prior line of therapy provided a new treatment option to patients with advanced disease.

Areas covered: The authors discuss basic information about CTCL and mogamulizumab’s mechanism of action. Then, the authors discuss the agent’s efficacy. Finally, the authors evaluate the safety of mogamulizumab in comparison to other agents available in CTCL.

Expert opinion: Mogamulizumab has been shown to be an effective and well tolerated therapy for patients with relapsed and refractory MF/SS with excellent activity in the circulating component of the disease.     

Synthesis,in vivo and in silico evaluation of novel 2,3-dihydroquinazolin-4(1H)-one derivatives as potential anticonvulsant agents

In light of the pharmacophoric structural requirements for achieving anticonvulsant activity, a series of N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)benzamide (4a-g) and N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)-2-phenylacetamide (4h-n) derivatives were synthesized in two steps starting from the reaction of N-methyl isatoic anhydride with the appropriate hydrazide and followed by condensation with the appropriate aldehyde. The anticonvulsant activities of the synthesized compounds were evaluated according to the anticonvulsant drug development (ADD) programme protocol. Among the synthesized compounds, 4n showed promising activity in both the maximal electroshock (MES) and pentylenetetrazole (PTZ) tests with median effective dose (ED₅₀) values of 40.7 and 6 mg/kg, respectively. The six most promising derivatives, 4b , 4a , 4c , 4f , 4j , and 4i , showed very low ED₅₀ values in the PTZ test (3.1, 4.96, 8.68, 9.89, 12, and 13.53 mg/kg, respectively). All the tested compounds showed no to low neurotoxicity in the rotarod test with a wide therapeutic index. Docking studies of compound 4n suggested that GABA_A binding could be the mechanism of action of these derivatives. The in silico drug likeliness parameters indicated that none of the designed compounds violate Lipinski's rule of five and that they are able to cross the blood–brain barrier.

Functional beta-cells derived from umbilical cord blood mesenchymal stem cells for curing rats with streptozotocin-induced diabetes mellitus

INTRODUCTIONThis study aimed to investigate the therapeutic response to injected human umbilical cord blood mesenchymal stem cells (UCBMSCs) among albino rats with streptozotocin (STZ)-induced diabetes mellitus.METHODSControl group (GI; n = 25) rats were fed with standard rat diet. Rats with STZ-induced diabetes mellitus without (GII; n = 25) and with (GIII; n = 25) differentiated human UCBMSCs implantation were the test groups. Rats were sacrificed in Week 11 following implantation. Liver biopsies were sectioned and stained in order to highlight both the presence and function of impregnated cells in the liver tissue.RESULTSHaematoxylin and eosin-stained sections in GI and GII rats showed normal liver architecture while GIII rats showed presence of cell clusters inside the liver tissue and around the central veins. Cell clusters with blue cytoplasm were present in sections in GIII rats but absent in GI and GII rats, indicating the presence of injected differentiated human UCBMSCs. The anti-human insulin immunostaining of GIII rats showed clusters of cells within the liver parenchyma and around central veins, indicating that these cells were active and secreting insulin.CONCLUSIONUCBMSCs are proficient in differentiating into insulin-producing cells in vivo under specific conditions and, when transplanted into the liver of albino rats with STZ-induced diabetes mellitus, were able to secrete insulin and partially control the status of diabetes mellitus in rats.     

Serum retinol-binding protein 4 is associated with insulin resistance in patients with early and untreated rheumatoid arthritis

ObjectiveRetinol-binding protein 4 (RBP4), systemic inflammation and insulin resistance (IR) are linked, yet the determinants of RBP4 and its impact on IR in rheumatoid arthritis (RA) are incompletely understood. The aim of this study was to explore the prevalence of IR in RA and investigate whether the serum levels of RBP4 were associated with IR in patients with RA.MethodsIn this study, 403 individuals with newly diagnosed and untreated RA were consecutively recruited. We calculated the Disease Activity Score assessed using 28-joint counts for swelling and tenderness (DAS28). Levels of serum RBP4, interleukin-6 (IL-6) and tumor necrosis factor (TNF) α were tested. IR was defined as Homeostasis model assessment for insulin resistance (HOMA-IR) index greater than or equal 2.40.ResultsIn those 403 patients, 68 (16.9%) were male and the median age was 43 years (IQR: 36–52). There was an evidently positive correlation between increased serum levels of RBP4 and increasing severity of RA (DAS28) (r = 0.403, P < 0.001). Furthermore, a modest positive correlation between levels of serum RBP4 and HOMA-IR score (r = 0.251; P < 0.0001) was found. Eighty-five patients (21.1%) in patients with RA were defined as IR (HOMA-IR ≥ 2.40), which was significantly higher than in normal cases (4.7%). In the patients with IR, serum levels of RBP4 were higher when compared with those in patients free-IR P < 0.001. The IR distribution across the quartiles of RBP4 ranged between 5.0% (first quartile) to 39.0% (fourth quartile), P for trend < 0.001. For each 1unit increase of RBP4, the unadjusted and adjusted risk of IR increased by 8% (OR: 1.08; 95% CI: 1.05–1.11, P < 0.001) and 5% (1.05; 1.02–1.09, P = 0.001), respectively. When RBP4 was added to the model containing established significant risk factors, AUROC (standard error) was increased from 0.768 (0.025) to 0.807(0.021). A significant difference in the AUC between the established risk factors alone and the addition of RBP4 was observed (difference, 0.039[0.004]; P = 0.02).ConclusionElevated serum levels of RBP4 were associated with increased risk of IR and might be useful in identifying RA at risk for IR and/or impaired glucose tolerance for early prevention strategies, especially in obese and women patients     

负载IL-4及BMP-2的氧化石墨烯-羧甲基壳聚糖凝胶对骨免疫和骨修复的早期影响研究

目ݨ4;探讨负载 IL-4 48c; BMP-2 ݨ4;氧化石墨烯（graphene oxide，GO）-羧甲基壳聚糖（carboxymethyl chitosan，CMC）凝胶诱导巨噬细胞 M2 型分化及对 BMSCs 成骨分化ݨ4;影4cd;。方法取 CMC、GO 制备混408;溶液40e;，分别添加 PBS、IL-4、BMP-2 或 IL-4+BMP-2，在�4ea4;ࠅ4;R42;�4f5c;用�4e0b;制备单纯或负载�4e0d;40c;因子ݨ4; GO-CMC 凝胶支架；取单纯 GO-CMC 凝胶表征观m4b;，包括大�4f53;、扫描电镜及傅里叶变换红外438;收Q49;谱�4eea;（Fourier transform infrared spectroscopy，FTIR）检m4b;，�4ee5;单纯 CMC 凝胶�4f5c;�4e3a;对照；取负载�4e0d;40c;因子ݨ4; GO-CMC 凝胶ˆ4c;�4f53;外缓释实验。取 4～5 468;৸4; SPF 级 SD 雌性大鼠分离培养巨噬细胞，分别�4e0e;单纯�4ee5;及负载�4e0d;40c;因子ݨ4; GO-CMC 凝胶培养，24 h 40e;ˆ4c; CD206 Q4d;疫荧Q49;检m4b;巨噬细胞分化情况；取第 3 �4ee3;大鼠 BMSCs 分别�4e0e;单纯�4ee5;及负载�4e0d;40c;因子ݨ4; GO-CMC 凝胶成骨诱导培养，10 d 40e;ˆ4c; ALP 染色观m4b;早期成骨，21 d ˆ4c;茜素红染色观m4b;晚期成骨。结果大�4f53;观察 GO-CMC 凝胶448;棕色、S4a;透明状；扫描电镜观察示，GO-CMC 凝胶ֵ4;׸4;及ֵ4;壁厚度�4e0e;单纯 CMC 凝胶相�4f3c;，�4f46;内壁粗糙度增加；FTIR 检m4b;显示 CMC 发生聚408;形成凝胶。�4f53;外缓释实验示 3 种负载�4e0d;40c;因子ݨ4; GO-CMC 凝胶缓释性能相�4f3c;，W47;448;线性缓慢释放因子。CD206 Q4d;疫荧Q49;检m4b;示 GO-CMC 凝胶可诱导巨噬细胞 M2 型分化，ALP 及茜素红染色示 GO-CMC 凝胶可诱导 BMSCs 成骨分化；其�4e2d;负载 IL-4+BMP-2 ݨ4; GO-CMC 凝胶�4f5c;用最显457;（P<0.05）。 结论负载 IL-4 48c; BMP-2 ݨ4; GO-CMC 凝胶可诱导巨噬细胞 M2 型分化，增强 BMSCs 成骨分化能力，�4e3a;40e;期骨缺损�4fee;复及骨Q4d;疫调节ށ4;究提�4f9b;�4e86;新ݨ4;策略。     

臀部筋膜脂肪瓣修复坐骨结节和大转子复发性窦道型压疮

目ݨ4;总结臀部{4b;膜脂肪4e3;�4fee;复坐骨结节、大转子复发性窦道型压疮ݨ4;e48;果。方法2018 ק4; 2 月ȁ4;2019 ק4; 6 月，收治 12 �4f8b; 13 ֐4;长期截瘫�4f34;坐骨结节、大转子复发性窦道型压疮患者。其�4e2d;男 10 �4f8b; 11 ֐4;，女 2 �4f8b; 2 ֐4;；ק4;৸4; 46～56 岁，平W47; 51 岁。截瘫 10～20 ק4;，平W47; 13 ק4;；b40;有患者W47;有压疮b4b;术史，术40e; 3 �4e2a;月～12 ק4;复发。其�4e2d;坐骨结节֐4;压疮 11 �4f8b;，坐骨结节408;并大转子֐4;压疮 1 �4f8b;。创面清创、切०4;窦道P47;性滑液囊，采用单�4fa7;或双�4fa7;臀部{4b;膜脂肪4e3;填塞窦道，术区�4e00;期缝408;闭408;切口。结果术40e; 13 ֐4;压疮切口W47;Ⅰ期愈408;，\40;部无红肿、渗液，术40e; 14 d 拆线出院。术40e;\40;部平坦，外观406;想。术40e;患者W47;获随访，随访时य़4; 8～24 �4e2a;月，平W47; 14 �4e2a;月。随访期य़4;压疮W47;无复发。结论臀部脂肪߬4;织�4e30;富，利用{4b;膜脂肪4e3;�4fee;复坐骨结节、大转子复发性窦道型压疮设计、4cd;�4f5c;简�4fbf;，�4e34;床e48;果良好。