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关键词： AE   Adverse event   BCVA   Best corrected visual acuity   BID   Twice daily dosing   CI   Confidence interval   CFR   Code of Federal Regulations   DED   Dry eye disease   DEWS   Dry Eye Workshop   GCP   Good clinical practice   HCLE   Human corneal limbal epithelial   ICAM   Intercellular adhesion molecule   IL   Interleukin   IWRS   Interactive web based randomization system   logMAR   Logarithm of the minimum angle of resolution   IP   Investigationalproduct   IRB   Institutional review board   ITT   Intent-to-treat   LOCF   Last observation carried forward   LS   Least squares   MGD   Meibomian gland dysfunction   MMRM   Mixed model for repeated measures   MW   Molecular weight   NF-κB   Nuclear factor-kB   PP   Per protocol population   SANDE   Survey Assessment iN Dry Eye   SAE   Severe adverse event   SE   Standard error   SDP   Silk-derived protein   TBUT   Tear break-up time   TFOS   Tear Film and Ocular Society   TNF-α   Tumor necrosis factor alpha   VAS   Visual analog scale   VCAM   Vascular cell adhesion molecule  

摘要： center dot PURPOSE: In this study the safety and efficacy of silk- derived protein 4 (SDP-4), also known as amlisimod, , eye drops against a vehicle control formulation in patients with moderate to severe dry eye disease (DED) was assessed. SDP-4 is a novel, naturally derived, antiinflammatory wetting agent that enhances coating on the ocular surface. center dot DESIGN: Exploratory Phase 2, 12- and 8-week, serial cohort, multicenter, double-masked, randomized, vehicle- controlled study. center dot METHODS: In the first cohort (N = 305), patients were randomized 1:1:1:1 to SDP-4 (0.1%, 1%, 3% wt./wt.) or vehicle control and dosed 2 times per day (BID), while in the second cohort patients were randomized 1:1 with 1% wt./wt. SDP-4, the best performing formulation from the first cohort, or vehicle control BID (N = 151). Diagnosed DED patients were treated in the United States between April 2019 and May 2021. The first cohort of subjects had moderate to severe baseline symptoms, while the second cohort had moderate baseline symptoms to study the impact of baseline symptoms on SDP-4 performance. Key sign and symptom end points were mean change from baseline in TBUT and total SANDE score (0-100 visual analog scale) throughout the study. center dot RESULTS: SDP-4 (1%) significantly increased TBUT vs the vehicle control ( P < .05) at days 28 and 56 in the first cohort, and patient symptomatology from baseline was reduced by 46% based on subject reported SANDE VAS scores at day 84. Patients with more severe baseline DED symptoms experienced a significantly greater amount of relief than when compared to patients with moderate DED ( P < .05). All treatment groups were well tolerated with a 2.6% total discontinuation rate. center dot CONCLUSIONS: To the best of our knowledge, this was the first-in-human use of SDP-4 in a clinical trial. SDP- 4 is a first-in-class protein ingredient that offers a safe and multi-modal treatment approach for alleviating severe DED symptoms within a

关键词： Th1/Th2/Th17 cytokine   VL/HIV co-infection   Maranhao  

摘要： Visceral Leishmaniasis (VL) is an endemic disease in Latin America, and the clinical outcome worsens when a patient has HIV co-infection. In these patients, the immune response is complex and cytokines profile variable. We evaluate Th1/Th2/Th17 cytokine profile in VL/HIV patients from Brazilian high endemic area. In this crosssectional study, the serological cytokines production was compared with clinical and epidemiological traits of the VL/HIV, VL and HIV patients. VL/HIV patients are predominantly male (89.2 %) with relapses in 35.5 % of the cases. There is higher serum levels of IL-6 (p = 0.006) and IL-10 (p < 0.001) in VL/HIV patients. Furthermore, there is a moderate or strong positive correlation in the serum levels of IL-6 and TNF-alpha (Rho = 0.635, p < 0.001), IL-10 and IFN-gamma (Rho = 0.523, p < 0.001), IL-6 and IL-10 (Rho = 0.506, p < 0.001), IL-2 and IL-4 (Rho = 0.506, p < 0.001). Then, VL/HIV patients who died during VL treatment (p = 0.033), patients with oedema (p = 0.011), and patients with jaundice (p = 0.019) had statistically high levels of IL-6. In conclusion, VL/HIV patients have production or reduction of specific cytokines, highlights IL-6 and IL-10.

关键词： crocin   diabetes   inflammatory markers   liver disease   losartan   Oxidative stress  

摘要： Background and Objectives AGEs, via RAGE, increase the development of hyperglycemia-induced liver damage, and blocking this axis is associated with a reduction in liver disease progression. The goal of this study was to determine how crocin and losartan influenced RAGE, TNF-alpha and TGF-beta gene expression in diabetic rats, as well as histological changes in liver tissue. Materials and Methods Diabetes was induced in 40 male Wistar rats using Streptozotocin (50 mg/kg, IP). There were five groups of rats: diabetic and healthy groups, diabetic rats given crocin (50 mg/kg), losartan (25 mg/kg) and both (crocin + Los). Serum glucose, ALT and AST levels were measured 4 weeks later. qPCR was used to examine the TNF-alpha, TGF-beta and RAGE gene expression in liver tissue. Results Crocin was found to be effective in lowering FBG in the diabetes group. The serum levels of ALT and AST decreased in all treated groups, but this decrease was significant in the crocin + Los group (p < 0.05). The relative expression of RAGE, TNF-alpha and TGF-beta genes was significantly higher in the diabetes group compared to the healthy group. The expression of these genes decreased in groups treated with crocin and Losartan compared to the diabetes group. The highest reduction in RAGE and TGF-beta gene expression was reported in those treated with crocin + Los. Histopathology results showed that the diabetes group had more bile ducts and necrosis than the healthy control group, which had no tissue changes. Hepatocyte degeneration, bile duct proliferation, inflammatory changes and hepatocyte necrosis were mild in the treated groups, but no hepatocyte necrosis was observed in the crocin + Los group. Conclusion Crocin may be a feasible therapeutic agent for treating diabetes and its symptoms when combined with pharmaceutical medications. Human research is still needed to reach clear conclusions.

关键词： Trachelospermi Caulis   Tracheloside   Lignan   Quantitative determination   Anti-rheumatoid arthritis effects  

摘要： A quantitative analysis method was established using high-performance liquid chromatography (HPLC) to simultaneously determine five lignans in the total lignan extract (TLE) from Trachelospermi Caulis at 280 nm, including nortracheloside, tracheloside, nortrachelogenin, trachelogenin, and arctigenin. The method demonstrated good linearity for each lignan within their respective ranges, with precision, stability, and repeatability meeting the criteria for quantitative analysis. Tracheloside, the most abundant compound in the TLE, effectively inhibited the release of inflammatory factors IL-6 and IL-17, and suppressed the migration MH7A cells in vitro. Furthermore, tracheloside reduced the production of key inflammatory factors, including COX-2, IL-6, IL-17, MMP2, MMP3, MMP9, JNK, p-JNK, p38, and p-p38 in TNF-alpha induced MH7A cells, thereby inhibiting the IL17/MAPK signaling pathway, and thus contributing to its anti-rheumatoid arthritis effects. This study represents the first report on the simultaneous quantification of five major lignans from Trachelospermi Caulis and the anti-inflammatory properties of tracheloside.

关键词： IL-22   Cattle   Mycobacterium bovis   Mammalian cells   Semi-stable expression   PEAKrapid  

摘要： Interleukin 22 is a member of the interleukin-10 superfamily of cytokines. This protein has a dual role as an inflammatory and anti-inflammatory molecule dependent on the context. IL-22 is produced mainly by immune cells and seems to have non-hematopoietic cells as its target. In this work, we report the production of bovine IL- 22 for the first time in a semi-stable expression system in mammalian cells. We showed that this recombinant IL- 22 possesses biological activity in bovine macrophages infected with Mycobacterium bovis and is easy to produce in large *** its role in the defence against infections, the IL-22 produced in this work has potential applications in scientific research as well as in immunotherapy to treat diseases in cattle

关键词： TNF receptor   Receptor-ligand interaction   Receptor-receptor interaction   Conformational dynamics   Conformational states   FRET biosensor   Drug discovery   Antibody   Small molecule   Peptide  

摘要： Tumor necrosis factor receptors (TNFR1 and TNFR2) play key roles in mediating inflammatory response and cell death signaling, which are associated with autoimmune disorders, neurodegenerative diseases, and cancers. The structure-function relationships of TNF receptors and their ligands determine the activation or inhibition of downstream signaling pathways. Available crystal structures have provided critical insights into the therapeutic targeting strategies of TNF receptors and their signaling networks. In this review, we discuss the potential of targeting receptor-ligand and receptor-receptor interactions in a competitive manner as well as perturbing receptor conformational dynamics through an allosteric mechanism to modulate TNF receptor signaling. We propose that conformational states of TNF receptors can act as a molecular switch in determining their functions and are important therapeutic targets. The knowledge of the structure-function relationships of TNF receptors can be applied to translational high-throughput drug screening and design of novel receptor-specific modulators with enhanced pharmacological properties.

关键词： Pulmonary arterial hypertension (PAH)   IL-34   Inflammation   Biomarkers   Right Ventricular Dysfunction  

摘要： Background: Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary artery pressure with significant morbidity and mortality. Inflammatory processes are crucial in PAH pathogenesis, with inflammatory cells and mediators present early in disease progression. IL-34 involvement in inflammatory pathways suggests that IL-34 could be an important player in the progression of PAH, influencing both pulmonary pressures and vascular changes. Objective: The purpose of this study was to investigate the correlation between IL-34 levels and pulmonary arterial hypertension (PAH), aiming to enhance the understanding of the molecular mechanisms underlying PAH and explore IL-34's potential as a biomarker. Methods: Consecutive PAH patients diagnosed via right-heart catheterization at Malatya Turgut Ozal E & gbreve;itim ve Ara & scedil;t & imath;rma Hastanesi (Dec 2022 - Apr 2024) were enrolled. Patients were classified into low-risk and high-risk groups based on comprehensive risk assessments that included clinical parameters, hemodynamic measurements and biomarkers, in-line with ESC/ERS guidelines. Serum IL-34, hs-CRP, and NT-proBNP levels were measured and compared with those of healthy controls. Echocardiographic assessments and statistical analyses, including ROC analysis, were conducted to evaluate biomarker significance and predictive capabilities. Results: The mean age of low-risk and high-risk PAH patients was 42 +/- 7.2 years and 45 +/- 5.5 years, respectively. The mean age of the control group was 40 +/- 6.4 years. Males comprised 54.29 % of the low-risk group, 56 % of the high-risk group, and 53.3 % of the control group. IL-34 and hs-CRP levels were significantly elevated in PAH patients compared to controls. IL-34 correlated positively with systolic pulmonary artery pressure, RA area, and NT-proBNP levels. Multivariate analysis revealed that IL-34 and hs-CRP were independent predictors of PAH. IL-34 levels>29.8 pg/mL predicted PAH with 78 % sensitivit

关键词： 白细胞介素(IL)-17A   非小细胞肺癌   IL-8   破骨细胞分化  

摘要： 目的 研究肺癌A549细胞来源的白细胞介素(IL)-17A对破骨细胞分化的作用及分子机制。方法 利用慢病毒基因干扰技术建立低表达IL-17A的A549细胞(A549-si)。将A549细胞与破骨细胞前体细胞共培养，观察A549-si对破骨细胞分化的影响；荧光定量聚合酶链反应(qPCR)检测A549-si对破骨细胞分化相关基因和IL-8 mRNA表达的影响；酶联免疫吸附试验(ELISA)检测A549-si对IL-8蛋白表达的影响；将IL-8抗体作用于A549细胞与破骨细胞共培养模型，观察IL-8抗体能否减弱A549细胞对破骨细胞分化的促进作用。结果 A549细胞与破骨细胞前体细胞共培养可以明显促进破骨细胞分化，A549-si能够明显抑制A549细胞对破骨细胞分化的促进作用并明显抑制破骨细胞分化相关基因表达(P<0.05);A549-si能够明显抑制A549细胞IL-8 mRNA表达和水平(P<0.05);IL-8抗体能够明显逆转A549细胞对破骨细胞分化的促进作用(P<0.05)。结论 A549细胞来源的IL-17A通过促进IL-8表达促进破骨细胞分化。

关键词： 华支睾吸虫   分泌代谢产物   白介素17A   肝纤维化  

摘要： 目的 探讨华支睾吸虫感染刺激胆管上皮细胞产生IL-17A激活HSC导致肝纤维化的机制。方法 从流行区获取华支睾吸虫感染的患者血清，ELISA法检测IL-17A的表达。人工消化麦穗鱼，分离华支睾吸虫囊蚴，分别灌胃感染新西兰大白兔和BALB/c小鼠，无菌分离小鼠肝脏和血清。ELISA法、Western blot和免疫组化法检测小鼠血清和肝脏中IL-17A的表达；ESP刺激人胆管癌细胞RBE,分别应用qRT-PCR和Western blot检测RBE细胞IL-17A的表达。收集RBE细胞培养上清加入LX-2细胞培养体系，qRT-PCR和Western blot检测LX-2细胞的α-SMA和Collagen-I的表达。结果 华支睾吸虫感染患者血清IL-17A水平显著高于健康体检者(t=6.536,P<0.01)。被感染的小鼠血清和肝脏中IL-17A的表达水平显著高于正常对照组(t=12.98,P<0.01;t=4.155,P<0.05)。免疫组化结果显示，感染小鼠的肝胆管上皮中IL-17A表达量增多(t=10.80,P<0.01)。ESP刺激后，RBE细胞的IL-17A表达水平显著升高(均P<0.01)。RBE细胞培养上清加入LX-2细胞培养体系后，α-SMA和Collagen-I的表达水平显著高于对照组(均P<0.01)。结论 华支睾吸虫可以刺激胆管上皮细胞产生IL-17A,进一步促进炎症并激活HSC产生胶原沉积，从而促进肝纤维化的进展。