Pharmacotherapeutic strategies for critical asthma syndrome: a look at the state of the art

ABSTRACT

Introduction

‘Critical Asthma Syndrome’ (CAS) is an umbrella term proposed to include several forms of asthma, responsible for acute and life-threatening exacerbations. CAS requires urgent and adequate supportive and pharmacological treatments to prevent serious outcomes.     

体外转染Cyclin A2基因对原代大鼠心肌细胞增殖的影响

目的探讨体外转染细胞周期素A2(Cyclin A2)基因对原代大鼠心肌细胞增殖的影响,为心脏再生提供细胞学依据。方法 SD乳鼠12只,分离、培养、鉴定原代乳鼠心肌细胞并分为3组,实验组:转染带有强化绿色荧光蛋白(GFP)和Cyclin A2基因的重组腺病毒(Ad-Cyclin A2-GFP);空病毒组:转染不含目的基因带有GFP的重组腺病毒(Ad-Null-GFP);阴性对照组:未做转染处理,仅加入等量的培养基。利用GFP示踪技术,评估原代心肌细胞转染效率;转染后的细胞继续体外培养3~5d,利用免疫荧光技术分别检测Cyclin A2、磷酸化组蛋白H3(H3P)、心肌肌钙蛋白-T(c Tn T)。结果 1.荧光GFP示踪表明原代心肌细胞的转染效率高达(97±0.74)%;2.免疫荧光标记显示,空病毒组和对照组结果相似;心肌细胞特异性标记蛋白c Tn T分布于细胞质,原代心肌细胞纯度高达(95±0.62)%;心肌细胞Cyclin A2主要在胞核内聚集,少数分布于细胞质。H3P为核蛋白在细胞核内分布。3.转染Cyclin A2后,实验组H3P阳性率明显高于空病毒组和对照组,差异具有统计学意义(P0.05);实验组可见大量多核细胞,以双核为主,伴少量3核细胞。结论腺病毒作为转染载体对原代心肌细胞有很好的侵染效率;Cyclin A2超表达促进原代心肌细胞形成双核。     

Tau Accumulation via Reduced Autophagy Mediates GGGGCC Repeat Expansion-Induced Neurodegeneration in Drosophila Model of ALS

Expansions of trinucleotide or hexanucleotide repeats lead to several neurodegenerative disorders, including Huntington disease [caused by expanded CAG repeats (CAGr) in the HTT gene], and amyotrophic lateral sclerosis [ALS, possibly caused by expanded GGGGCC repeats (G4C2r) in the C9ORF72 gene], of which the molecular mechanisms remain unclear. Here, we demonstrated that lowering the Drosophila homologue of tau protein (dtau) significantly rescued in vivo neurodegeneration, motor performance impairments, and the shortened life-span in Drosophila expressing expanded CAGr or expanded G4C2r. Expression of human tau (htau4R) restored the disease-related phenotypes that had been mitigated by the loss of dtau, suggesting an evolutionarily-conserved role of tau in neurodegeneration. We further revealed that G4C2r expression increased tau accumulation by inhibiting autophagosome–lysosome fusion, possibly due to lowering the level of BAG3, a regulator of autophagy and tau. Taken together, our results reveal a novel mechanism by which expanded G4C2r causes neurodegeneration via an evolutionarily-conserved mechanism. Our findings provide novel autophagy-related mechanistic insights into C9ORF72-ALS and possible entry points to disease treatment.Electronic supplementary materialThe online version of this article (10.1007/s12264-020-00518-2) contains supplementary material, which is available to authorized users.     

低密度脂蛋白在2型糖尿病骨质疏松中的作用研究进展

2型糖尿病及骨质疏松已成为我国最主要的慢性代谢性疾病。2型糖尿病常伴有血脂紊乱，常表现为低密度脂蛋白升高，而越来越多的研究表明血脂通过不同的方式影响骨代谢，其机制可能是通过抑制骨髓间充质干细胞成骨分化，通过RANK/RNAKL/OPG信号通路及炎症反应调节破骨细胞等方式调节骨代谢。     

Antidiabetic activity of Helicteres angustifolia root

Context The root of Helicteres angustifolia L. (Sterculiaceae) has been used as folk herbal drug to treat cancer, bacterial infections, inflammatory, and flu in China. However, there is no report on its antidiabetic activity.

Objective This study evaluates the antidiabetic activity of ethanol extract from H. angustifolia root.

Materials and methods The promoting effect of H. angustifolia root ethanol extract (25, 50, and 100 μg/mL) on glucose uptake was evaluated using HepG2 cell, differentiated C2C12 myotubes, and differentiated 3T3-L1 adipocytes. The antidiabetic activity of the extract was assessed in vivo using STZ-induced diabetic rats by orally administration of the extract (200 and 400?mg/kg b.w.) once per day for 28 d. Blood glucose, TG, TC, TP, HDL-C, UA, BUN, AST, ALT, insulin, and HOMA-IR were analyzed.

Results The results showed that the extract increased glucose uptake in C2C12 myotubes and 3T3-L1 adipocytes with an IC₅₀ value of 79.95 and 135.96 μg/mL, respectively. And about 12%, 19%, and 10% (p < 0.05) in HepG2 cells when compared with the control at the concentration of 25, 50, and 100 μg/mL, respectively. After 28 days’ treatment with the extract, significant reduction was observed in blood glucose, HOMA-IR, TC, TG, UA, BUN, AST, and ALT levels, while the levels of TP and HDL cholesterol increased.

Discussion and conclusion These results suggest that H. angustifolia root ethanol extract possess potent antidiabetic activity, which is the first report on antidiabetic activity of this plant.     

Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes

Autoimmune thyroid diseases (AITD) and Type 1 diabetes (T1D) frequently occur in the same individual pointing to a strong shared genetic susceptibility. Indeed, the co-occurrence of T1D and AITD in the same individual is classified as a variant of the autoimmune polyglandular syndrome type 3 (designated APS3v). Our aim was to identify new genes and mechanisms causing the co-occurrence of T1D + AITD (APS3v) in the same individual using a genome-wide approach. For our discovery set we analyzed 346 Caucasian APS3v patients and 727 gender and ethnicity matched healthy controls. Genotyping was performed using the Illumina Human660W-Quad.v1. The replication set included 185 APS3v patients and 340 controls. Association analyses were performed using the PLINK program, and pathway analyses were performed using the MAGENTA software. We identified multiple signals within the HLA region and conditioning studies suggested that a few of them contributed independently to the strong association of the HLA locus with APS3v. Outside the HLA region, variants in GPR103, a gene not suggested by previous studies of APS3v, T1D, or AITD, showed genome-wide significance (p < 5 × 10⁻⁸). In addition, a locus on 1p13 containing the PTPN22 gene showed genome-wide significant associations. Pathway analysis demonstrated that cell cycle, B-cell development, CD40, and CTLA-4 signaling were the major pathways contributing to the pathogenesis of APS3v. These findings suggest that complex mechanisms involving T-cell and B-cell pathways are involved in the strong genetic association between AITD and T1D.     

Dissecting the biological heterogeneity of HER2-positive breast cancer

HER2-positive (HER2+) breast cancer (BC) is a heterogenous and multifaceted disease, with interesting therapeutic implications. First, all intrinsic molecular subtypes can be identified in HER2+ tumors, with the HER2-enriched being the most frequent. Such subtypes do not differ much from their counterparts in HER2-negative disease, apart for the high expression of genes in/near the HER2 amplicon on chromosome 17. Intrinsic subtyping, along with the quantification of ERBB2 mRNA levels, is associated with higher rates of pathologic complete response across neoadjuvant trials of dual HER2 blockade and might help select patients for de-escalation and escalation treatment strategies. Secondly, HER2+ tumors have a broad range of DNA alterations. ERBB2 mutations and alterations in the PI3K/Akt/mTOR pathway are among the most frequent and might predict benefit from potent pan-HER, PI3K and mTOR inhibitors. Moreover, HER2+ tumors are usually infiltrated by lymphocytes. These tumor infiltrating-lymphocytes (TILs) predict response to neoadjuvant anti-HER2-based treatment and exert a prognostic role. PD-L1, detected in ∼42 % of HER2+ BC, might also be useful to define patients responding to novel anti-PD1/PD-L1 immunotherapies. New multiparametric clinicopathologic and genomic tools accounting for this complexity, such as HER2DX, are under development to define more tailored treatment approaches. Finally, HER2-targeted antibody-drug conjugates (ADC) such as trastuzumab deruxtecan might be active in tumors with low expression of HER2. Overall, there is a need to molecularly characterize and develop novel targeted therapies for HER2+ disease.