An update on the efficacy of non-steroidal anti-inflammatory drugs in Alzheimer's disease

Several epidemiological studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD), especially for patients carrying one or more ?4 allele of the apolipoprotein E. The biological mechanism of this protection is not completely understood and may involve inhibition of COX activity, inhibition of β-amyloid_1-42 (Aβ42) production and aggregation, inhibition of β-secretase activity, activation of PPAR-γ or stimulation of neurotrophin synthesis. Unfortunately, long-term, placebo-controlled clinical trials with both non-selective and COX-2 selective NSAIDs in AD patients produced negative results. A secondary prevention study with rofecoxib in patients with mild cognitive impairment and a primary prevention study with naproxen and celecoxib in elderly subjects with a family history of AD were also negative. All these failures have diminished the hope that NSAIDs could be beneficial in the treatment of AD. It is hypothesized that the chronic use of NSAIDs may be beneficial only in the normal brain by inhibiting the production of Aβ42. Once the Aβ deposition process has started, NSAIDs are no longer effective and may even be detrimental because of their inhibiting activity on activated microglia of the AD brain, which mediates Aβ clearance and activates compensatory hippocampal neurogenesis.     

Therapeutic potential of Notch inhibition in T-cell acute lymphoblastic leukemia: rationale,caveats and promises

T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy that presents with poor prognosis. Treatment relies on the application of aggressive therapies that produce deleterious side-effects, justifying the quest for novel, more efficient and selective molecular targeting agents. Mutations leading to abnormal Notch-1 activity are present in more than half of the T-ALL patients, underscoring the potential therapeutic relevance of targeting Notch-1 inhibition and further reinforcing the need to better comprehend the mechanisms by which Notch-1 drives T cell leukemogenesis. Clinical application of γ-secretase inhibitors to block Notch signaling in T-ALL revealed new challenges that involve improvement of the therapeutic benefit and reduction of intestinal toxicity. Here, we review the latest advances in the development and use of Notch antagonists and summarize the current knowledge on Notch function in T-ALL to understand how it may translate into novel therapeutic strategies that increment the efficiency of Notch inhibition.     

A Novel GAP460 Biopolymer for Use as a Carrier in Drug-Delivery Applications

We synthesized a new non-toxic biopolymer (GAP460) containing γ,L-glutamic acid and aspartate (Asp). Conjugates of GAP460 and cisplatin exhibited a drug-carrying capacity of nearly 40%, 3-times higher than γ-PGA and dramatically decreasing the amount of biopolymer required for high-dose delivery. Treatment with GAP460-cisplatin conjugate (PACC) not only effectively inhibited tumor growth in nude mice, but also resulted in extended survival and lower nephrotoxicity, suggesting that GAP460 could be used as an effective carrier for drug delivery and that PACC may have potential therapeutic applications in the clinical treatment of cancer.     

Identification of biomarkers for essential hypertension based on metabolomics

AimEssential hypertension (EH) is one of the most important public health problems worldwide. However, the pathogenesis of EH is unclear and early diagnostic methods are lacking. Metabolomics demonstrates great potential for biomarker discovery and the mechanistic exploration of metabolic diseases.Data synthesisThis review included human and animal metabolomics studies related to EH in the PubMed and Web of Science databases between February 1996 and May 2020. The study designs, EH standards, and reported metabolic biomarkers were systematically examined and compared. The pathway analysis was conducted through the online software MetaboAnalyst 4.0.Twenty-two human studies and fifteen animal studies were included in this systematic review. There were many frequently reported biomarkers with consistent trends (e.g., pyruvate, lactic acid, valine, and tryptophan) in human and animal studies, and thus had potential as biomarkers of EH. In addition, several shared metabolic pathways, including alanine, aspartate, and glutamate metabolism, aminoacyl-tRNA biosynthesis, and arginine biosynthesis, were identified in human and animal metabolomics studies. These biomarkers and pathways, closely related to insulin resistance, the inflammatory state, and impaired nitric oxide production, were demonstrated to contribute to EH development.ConclusionsThis study summarized valuable metabolic biomarkers and pathways that could offer opportunities for the early diagnosis or prediction of EH and the discovery of the metabolic mechanisms of EH.     

五加减正气散化裁对溃疡性结肠炎大鼠干扰素-γ的影响

目的:讨论五加减正气散化裁对溃疡结肠炎(UC)大鼠血中的干扰素-γ(INF-γ)的影响。方法:实验动物分成4组,分别为空白组、模型组、西药组和中药组,采用乙酸诱导法造模,观察大鼠结肠黏膜病理变化,用ELISA法检测大鼠血中INF-γ的水平。结果:空白组大鼠血中INF-γ和结肠黏膜无变化,模型组的大鼠血中INF-γ和结肠黏膜变化明显,西药组与中药组大鼠血中INF-γ和结肠黏膜无明显变化。西药组、中药组与空白组间差异无统计学意义;模型组与空白组比较,大鼠血清中INF-γ显著升高,结肠黏膜充血、水肿、糜烂并有溃疡形成,两者之间差异有统计学意义(P<0.05);模型组与西药组、中药组间大鼠血清中INF-γ显著升高,结肠黏膜充血、水肿、糜烂并有溃疡形成,差异有统计学意义(P<0.05)。结论:五加减正气散化裁能干预实验性UC大鼠血中的INF-γ的活性,对UC大鼠结肠溃疡面有修复和保护作用。     

4种宫内节育器使用36个月效果观察

目的:比较4种宫内节育器(IUD)的使用效果.方法:对分别放置4种IUD的3 000例育龄妇女随访36个月,对比观察其的使用效果、副反应等.结果:放置吉妮致美IUD 1 200例、爱母功能性IUD 1 000例、母体乐铜375IUD 400例、活性γ型IUD 400例,4种IUD 3年带器妊娠率分别为1.54/百妇女年、4.49/百妇女年、1.92/百妇女年、3.53/百妇女年,差异有统计学意义(P＜0.05)；脱落率分别为4.07/百妇女年、5.36/百妇女年、4.80/百妇女年、5.62/百妇女年,差异有统计学意义(P＜0.05)；在疼痛和出血副反应发生率方面,以母体乐铜375 IUD较高.结论:吉妮致美IUD避孕效果较好,副作用少,值得临床应用.     

非抗菌疗法在泛耐药菌珠所致老年重症肺部感染疾病治疗中的可行性研究

目的：探讨非抗生素治疗手段在泛耐药菌珠所致老年重症肺部感染疾病治疗中的可行性。方法选取2010年4月－2012年9月机械通气患者81例，根据治疗方案不同将患者分为A组36例及B组45例。 A组治疗措施主要为应用胸腺肽类药物、丙种球蛋白免疫调节剂和血必净，每天进行1～2次的气管镜吸引及灌洗等。 B组在A组的基础上继续给予经验性抗生素治疗。比较2组APACHEⅡ评分、白细胞数、体温及耐药性。结果 A组患者致病菌的耐药性由原来的100．0％广泛耐药特性降至55．2％，而B组患者致病菌耐药性未见明显改变；而白细胞含量经过非抗生素处理干预治疗后的A组白细胞数量有所下降，且与治疗前比较差异有统计学意义（P＜0．05）。治疗1个月，A组死亡2例，病死率为5．6％，而B组死亡10例，病死率为22．2％，差异有统计学意义（P＜0．01）。结论非抗生素治疗可使患者致病菌耐药性下降，降低病死率，具有可行性。     

dNK derived IFN-γ mediates VSMC migration and apoptosis via the induction of LncRNA MEG3: A role in uterovascular transformation

IntroductionAppropriate spiral artery remodeling is critical for successful fetal development and pregnancy outcomes. The vascular smooth muscle cell (VSMC) loss and separation, involving cell apoptosis and migration, plays an important role in this process. Decidual natural killer cells (dNK)-derived interferon gamma (IFN-γ), a key regulator of uterine arterial remodeling, can facilitate separation of VSMC layers, however, the specific mechanisms of it action are unknown. Long non-coding RNA MEG3 functions as tumor suppressor by regulating apoptosis and migration. Moreover, IFN-γ has been shown to influence cell vitality through regulating MEG3 expression. However, the functional role of dNK derived IFN-γ and MEG3 on VSMC viability, as well as the relationship between IFN-γ and MEG3 in VSMCs, has not been completely elaborated.MethodsThe up-regulation strategies and reagent treatment were employed to detect the effects of MEG3 and dNK/IFN-γ on VSMC proliferation, apoptosis and migration. At the same time, MEG3, p53 and matrix metalloproteinase 2 (MMP-2) expressions were investigated.Results: dNK/IFN-γ treatment led to up-regulation of MEG3 expression in VSMCs. Both MEG3 over-expression and dNK/IFN-γ treatment inhibited VSMC proliferation, stimulated VSMC migration and resulted in a small but significant induction of VSMC apoptosis, as well as promoted p53 and MMP-2 expression in VSMCs.DiscussionMEG3 is regulated by dNK-derived IFN-γ and regulates VSMC migration and apoptosis. Therefore, it may be an important positive regulator in VSMC loss from the maternal uterine spiral arteries during vascular transformation.