Overview of CF lung pathophysiology

Defects of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein affect the homeostasis of chloride, bicarbonate, sodium, and water in the airway surface liquid, influencing the mucus composition and viscosity, which induces a severe condition of infection and inflammation along the whole life of CF patients. The introduction of CFTR modulators, novel drugs directly intervening to rescue the function of CFTR protein, opens a new era of experimental research. The review summarizes the most recent advancements to understand the characteristics of the infective and inflammatory pathology of CF lungs.     

Synthesis and docking studies of N-(5-(alkylthio)-1,3,4-oxadiazol-2-yl)methyl)benzamide analogues as potential alkaline phosphatase inhibitors

A series of N-(5-(alkylthio)-1,3,4-oxadiazol-2-yl)methyl)benzamides 6a–i were synthesized as alkaline phosphatase inhibitors. The intermediate 5-substituted 1,3,4-oxadiazole-2-thione 4 was synthesized starting with hippuric acid. Hippuric acid in the first step was converted into corresponding methyl ester 2 which upon reaction with hydrazine hydrate furnished the formation of hydrazide 3 . The hippuric acid hydrazide was then cyclized into 5-substituted 1,3,4-oxadiazole-2-thione 4 . The intermediate 4 was then reacted with alkyl or aryl halides 5a–5i to afford the title compounds N-(5-(methylthio)-1,3,4-oxadiazol-2-yl)methyl)benzamides 6a–i . The bioassay results showed that compounds 6a–i exhibited good to excellent alkaline phosphatase inhibitory activity. The most potent activity was exhibited by the compound 6i having IC₅₀ value 0.420 μM, whereas IC₅₀ value of standard (KH₂PO₄) was 2.80 μM. Molecular docking studies was performed against alkaline phosphatase enzyme (PDBID 1EW2) to check binding affinity of the synthesized compounds 6a–i against target protein. The docking results showed that three compounds 6c , 6e , and 6i have maximum binding interactions with binding energy values of −8 kcal/mol. The compound 6i displayed the interactions of oxadiazole ring nitrogen with amino acid His265 having a binding distance 2.13 Ǻ. It was concluded from our results that synthesized compounds, especially compound 6i may serve as lead structure to design more potent inhibitors of human alkaline phosphatase.     

血液透析对患者血清碱性磷酸酶、骨硬化蛋白与骨代谢的影响

目的血液透析对患者血清碱性磷酸酶(ALP)、骨硬化蛋白(SOST)与骨代谢等指标的影响。方法选取本院2016年1月至2019年1月期间收治的血液透析患者116例为研究对象纳入观察组,另选同期在本院进行体检的50例健康受试者为对照组。采用酶联免疫吸附试验法对两组患者入院时的ALP、SOST、骨代谢指标:血清骨钙素(OC)、β胶原蛋白(β-CTX)、I型前胶原氨基末端前肽(PINP)指标水平,并进行组间对比。对观察组患者进行维持性的血液透析治疗,并检测比较在患者透析治疗前、透析治疗1、6、12个月的各项指标水平。采用Pearson检验对观察组患者的ALP、SOST与骨代谢指标的相关性进行分析。结果与对照组比较,观察组患者血液透析治疗前ALP、SOST、OC、β-CTX、PINP等指标均低于对照组受试者各项指标水平,组间比较差异有统计学意义(P<0.05)。观察组患者中随着透析治疗时间的延长,患者的ALP、SOST、OC、β-CTX、PINP等指标水平均明显上升,各时间点间比较差异有统计学意义(P<0.05)。经Pearson检验分析,血液透析患者的ALP、SOST与骨代谢指标OC、β-CTX、PINP呈正相关性。结论血液透析患体内的ALP、SOST、骨代谢指标均呈现异常降低,经持续性血液透析治疗患者的ALP、SOST、骨代谢指标均有改善,且ALP、SOST与骨代谢指标OC、β-CTX、PINP呈正相关性。     

加味温经汤联合阿仑膦酸钠片治疗肾阳亏虚型绝经后骨质疏松症临床研究

目的:观察加味温经汤联合阿仑膦酸钠片治疗肾阳亏虚型绝经后骨质疏松症(PMOP)的临床疗效。方法:选取150例肾阳亏虚型PMOP患者,按随机数字表法分为对照组和观察组各75例。对照组给予口服阿仑膦酸钠片治疗,观察组在对照组基础上加服加味温经汤,2组均治疗6个月。对比2组总体疗效、治疗前后碱性磷酸酶(ALP),血钙(Ca)、磷(P),雌二醇(E2),促卵泡雌素(FSH),促黄体生成素(LH)水平,记录治疗过程中不良反应发生情况。结果:观察组总有效率96.0%,对照组总有效率80.0%,2组比较,差异有统计学意义(P<0.05)。治疗后,2组ALP水平均较治疗前降低(P<0.05),血Ca含量均较治疗前增加(P<0.05);观察组ALP水平低于对照组(P<0.05),血Ca含量高于对照组(P<0.05)。治疗后,2组E2水平均较治疗前升高,FSH及LH水平均较治疗前降低,差异均有统计学意义(P<0.05);观察组E2水平高于对照组,差异有统计学意义(P<0.05)。2组血常规异常、肝肾功能异常、消化道症状、皮肤过敏发生率比较,差异均无统计学意义(P>0.05)。结论:加味温经汤治疗肾阳亏虚型PMOP,能有效改善患者的临床症状和性激素水平,用药安全性高。     

Notch1 contributes to TNF-α-induced proliferation and migration of airway smooth muscle cells through regulation of the Hes1/PTEN axis

Notch1 has been implicated in asthma pathogenesis. However, the function of Notch1 in regulating airway smooth muscle (ASM) cell proliferation and migration during airway remodeling of asthma remains unknown. Using an in vitro model induced by tumor necrosis factor (TNF)-α, we reported in this study that Notch1 participated in TNF-α-induced proliferation and migration of ASM cells. Our results demonstrated that Notch1 expression was significantly upregulated in ASM cells exposed to TNF-α. Notch1 inhibition significantly repressed TNF-α-induced ASM cell proliferation and migration, while Notch1 overexpression promoted the opposite effect. Moreover, Notch1 inhibition downregulated the expression of Notch-1 intracellular domain (NICD) and Hes1, while upregulated PTEN expression in TNF-α-exposed cells. Notably, Hes1 overexpression partially reversed the Notch1-inhibition-mediated inhibitory effect on TNF-α-induced ASM cell proliferation and migration. In addition, the promoting effect of Notch1 inhibition on PTEN expression was markedly abrogated by Hes1 overexpression. Overall, these findings demonstrated that Notch1 inhibition repressed TNF-α-induced ASM cell proliferation and migration by modulating the Hes1/PTEN signaling axis, a finding that highlights the involvement of Notch1/Hes1/PTEN in regulating airway remodeling of asthma.     

Comparison of Salivary and Serum Alkaline Phosphates Level and Lactate Dehydrogenase Levels in Patients with Tobacco Related Oral Lesions with Healthy Subjects - A Step Towards Early Diagnosis

Aim: To evaluate and compare salivary and serum levels of Alkaline Phosphates and Lactate Dehydrogenase in patients without the habit of tobacco, in patients with the habit of tobacco, in patients with benign oral lesions and in patients with oral premalignant lesions and oral malignant lesions. Material and Methodology: This study was comprised of 500 subjects, Group I: 100 healthy individuals without the habit of tobacco usage formed the control group. Group II: 100 patients with the habit of tobacco/ smoking consumption without any oral lesion. Group III: 100 patients with benign oral lesions. Group IV: 100 patients having the history of tobacco consumption and having apparent precancerous lesions like leukoplakia, erythroplakia. Group V:100  patients having frank oral cancer. The grade of dysplasia in these patients was statically correlated with the levels of serum and salivary ALP and LDH. Results: This study revealed that there was high expression of both serum and salivary ALP and LDH  in group IV and Group V as compared with the other groups and mean difference showed a statistically significant p value of less than 0.01. This study revealed that the in group V, the highest level of serum and salivary ALP was found in those patients who were reported with poorly differentiated oral cancer. Conclusion: Both Alkaline phosphates and Lactate dehydrogenase could be considered a sensitive markers for the detection of dysplasia with already existing precancancerous and cancerous lesions.     

Comparative Analysis of Safety and Efficacy of Transarterial Chemoembolization for the Treatment of Hepatocellular Carcinoma in Patients with and without Pre-Existing Transjugular Intrahepatic Portosystemic Shunts

PurposeTo compare the safety and efficacy of transarterial chemoembolization for hepatocellular carcinoma (HCC) in patients with and without transjugular intrahepatic portosystemic shunts (TIPS).Materials and MethodsThis single-institution study included a retrospective review of 50 patients who underwent transarterial chemoembolization for HCC between January 2010 and April 2017. Twenty-five patients had preexisting TIPS, and 25 patients were selected to control for age, sex, and target tumor size. Baseline median Model for End-Stage Liver Disease (MELD; 13 TIPS, 9 control; P < .001) and albumin-bilirubin (ALBI; 3 TIPS, 2 control; P < .001) differed between groups. Safety was assessed on the basis of Common Terminology Criteria for Adverse Events (CTCAE) and change in MELD and ALBI grade assessed between 3 and 6 months. Efficacy was assessed by tumor response and time to progression (TTP).ResultsThere was 1 severe adverse event (CTCAE grade >2) in the TIPS group. There was no difference in the change in MELD or ALBI grade. Although there was no difference in tumor response (P = .19), more patients achieved a complete response in the control group (19/25, 76%) than in the TIPS group (13/25, 52%). There was no difference in TTP (P = .82). At 1 year, 2 patients in the control group and 3 patients in the TIPS group received a liver transplant. Seven patients died in the TIPS group.ConclusionsTransarterial chemoembolization is as safe and effective in patients with TIPS as in patients without TIPS, despite worse baseline liver function. Severe adverse events are rare and may be transient.