Winter in the Ouchitas—A severe winter storm signature in Pinus echinata in the Ouachita Mountains of Oklahoma and Arkansas,USA

Each year severe winter storms (≈ice storms) damage trees throughout the southern USA. Arkansas and Oklahoma have a history of severe winter storms. To extend that history back beyond the reach of written records, a distinctive tree ring pattern or signature is needed. Storm-caused breakage, branch loss and bending stress provide that signature. We found a severe storm signature in shortleaf pine (Pinus echinata). We used three published site chronologies, a set of five new site chronologies from a growth-and-yield study conducted by Oklahoma State University and the unpublished Shortleaf Canyon chronology from a master’s thesis at the University of Arkansas. Our method is based on two ring width values for the first and second growing seasons after the storm standardized to the ring widths of the seven growing seasons after the storm. Concordance between storm years predicted by tree ring patterns and actual storm years was tested using Cohen’s Kappa. Concern about confounding of ice storm signals by droughts led us to test concordance between severe storms and drought in July, August and September; results were inconclusive but stand as a warning that these two phenomena cannot be distinguished with certainty in the tree ring record. Damaging severe storms occurred in about 2.8% of all years. Two out of three storms identified as “severe” produced glaze icing.     

Bone marrow-derived mesenchymal stem cells repair severe acute pancreatitis by secreting miR-181a-5p to target PTEN/Akt/TGF-β1 signaling

BackgroundSevere acute pancreatitis (SAP) is associated with high morbidity and mortality. Bone marrow mesenchymal stem cells (BMSCs) have shown obvious protective effect on SAP. However, little is known about the underlying mechanism. The objective of this study is to unravel the role and regulatory mechanism of miR-181a-5p in BMSCs-mediated pancreatic repair.MethodsBMSCs were isolated from Sprague-Dawley rats and characterized by flow cytometry and Oil Red O staining. Sodium taurocholate- and caerulein-induced models were used as SAP models in vivo and in vitro, respectively. Pancreatic injury were evaluated by H&E and histopathological analysis, as well as by measuring levels of amylase, lipase and cytokines. qRT-PCR and western blotting were performed to detect the level of miR-181a-5p and the protein levels of PTEN/Akt, respectively. ELISA was conducted to detect the levels of TNF-α, IL-1β, IL-6, angiopoietin, IL-4, IL-10 and TGF-β1. The apoptotic rate of AR42 J cells was quantitated by concurrent staining with Annexin-V-FITC and PI.ResultsBMSCs significantly attenuated pancreatic injury in SAP rats by reducing inflammatory infiltration and necrosis, and this effect was abolished by CXCR4 agonist AMD3100. ADM3100 exhibited more severe pancreatic injury and decreased miR-181a-5p levels in the pancreas and serum compared to SAP group. Overexpression of miR-181a-5p in BMSCs (BMSCs-miR-181a-5p) markedly potentiated the protective effect of BMSCs by reducing histological damage and levels of amylase and lipase. Moreover, BMSCs-miR-181a-5p dramatically reduced levels of angiopoietin, TNF-α, IL-1β and IL-6, but induced the levels of IL-4 and IL-10. In caerulein-treated AR42 J cells, co-culturing of BMSCs-miR-181a-5p alleviated caerulein-induced increase of amylase and lipase, and apoptosis via PTEN/Akt/TGF-β1 signaling.ConclusionBMSCs alleviate SAP and reduce inflammatory responses and apoptosis by secreting miR-181a-5p to target PTEN/Akt/TGF-β1 signaling. Hence, BMSCs-miR-181a-5p could serve as potential therapeutic target for SAP.     

Predictivity of an in vitro model for acute and chronic skin irritation (SkinEthic) applied to the testing of topical vehicles

An in vitro human reconstructed epidermis model (SkinEthic) used for screening acute and chronic skin irritation potential was validated against in vivo data from skin tolerability studies. The irritation potential of sodium lauryl sulfate (SLS), calcipotriol and trans-retinoic acid was investigated. The in vitro epidermis-like model consists of cultures of keratinocytes from human foreskin on a polycarbonate filter. The modulation of cell viability, the release and gene expression of proinflammatory cytokines, interleukins 1α and 8, and morphological changes were evaluated during 3 days as endpoints representative for an inflammatory reaction. The cumulative irritation potential of the topical products was evaluated in a human clinical study by visual scoring and biophysical measurement of inflammatory skin reaction after repeated 24 h applications over 3 weeks under Finn chamber patches. All topical products that were nonirritating in the human study were noncytotoxic and did not induce cytokine expression in the in vitro acute model (day 1 exposure). All irritating controls exhibited specific cell viability and cytokine patterns, which were predictive of the in vivo human data. The ranking of mild to moderate skin irritation potential was based on the lack of cytotoxicity and the presence of cytokine patterns including gene expression specific for each irritant, using the chronic in vitro model (up to 3 days exposure). The human reconstructed epidermis model SkinEthic was shown to be a reliable preclinical tool predicting the irritation potential of topical products. Moreover, it is a useful model in a two-step tiered strategy for screening acute and chronic irritation potential for the selection of vehicles for new topical drugs. This revised version was published online in July 2006 with corrections to the Cover Date.     

Genome-wide CRISPR Screens Reveal Host Factors Critical for SARS-CoV-2 Infection

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Effects of esculetin on lipopolysaccharide (LPS)-induced acute lung injury via regulation of RhoA/Rho Kinase/NF-кB pathways in vivo and in vitro

The purpose of the present study was to investigate the protective effect of esculetin (ES) in lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the lung epithelial A549 cells. Mice were intragastrically administered with ES (20 and 40 mg/kg) 1 h prior to LPS challenge. ES pretreatment at doses of 20 and 40 mg/kg effectively attenuated LPS-induced lung histopathological change, myeloperoxidase or MPO activity, inflammatory cells infiltration, pulmonary wet-to-dry weight ratio, and the generation of pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in vivo and in vitro. Furthermore, we demonstrated that ES blocked the activation of NF-кB and RhoA/Rho kinase pathways in LPS-induced mice and A549 cells. The results suggested that ES exhibited protective effect on ALI and might attribute partly to the inhibition of NF-кB and RhoA/Rho kinase pathways in vivo and in vitro.     

Vitamin D Receptor Controls Cell Stemness in Acute Myeloid Leukemia and in Normal Bone Marrow

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Two-hit wonders: The expanding universe of multitargeting epigenetic agents

Multitargeting involves the application of molecules that are deliberately intended to bind to two or more unrelated cellular targets with high affinity. In epigenetic chemical biology and drug discovery, the rational design of multitargeting agents has evolved to a sophisticated level, and there are now five examples that have reached clinical trials. This review covers recent developments in the field and future prospects.     

肠内营养支持联合益生菌促进重症急性胰腺炎患者恢复的临床机制研究

目的阐述益生菌联合肠内营养支持对改善重症急性胰腺炎患者肠道微生态以及粘膜屏障功能的临床应用价值。方法选取我院收治的100例重症急性胰腺炎患者作为研究对象,随机分为观察组和对照组,各50例。观察组患者接受益生菌制剂联合肠内营养,对照组患者仅接受肠内营养,持续2周。比较两组患者的血浆生化指标、胃肠道功能、肠粘膜屏障功能、并发症发生率、病死率及住院时间。收集两组患者的粪便,检测菌群变化。结果在治疗第7 d,观察组患者的白细胞数和血浆生化指标明显低于对照组。治疗第14 d,观察组生化检测指标均明显低于对照组。胃肠道功能评分方面,治疗第7、14 d,观察组评分均较对照组明显降低；治疗第7 d、14 d,两组患者血浆MDA、ET、CRP水平和尿L/M均出现明显下降,观察组较对照组下降更明显；观察组的总体并发症发生率及住院时间与对照组比较,具有统计学差异。实时荧光定量PCR结果显示,经过14 d治疗后观察组患者大肠埃希菌、肺炎克雷伯菌的数量明显低于对照组。对照组病人双歧杆菌和乳酸菌数量明显高于对照组。结论肠内营养治疗联合益生菌有利于促进重症急性胰腺炎肠道功能的恢复,值得在临床上应用推广。     

The role of interleukin-18 in pancreatitis and pancreatic cancer

Originally described as an interferon (IFN)-γ-inducing factor, interleukin (IL)-18 has been reported to be involved in Th1 and Th2 immune responses, as well as in activation of NK cells and macrophages. There is convincing evidence that IL-18 plays an important role in various pathologies (i.e. inflammatory diseases, cancer, chronic obstructive pulmonary disease, Crohn's disease and others). Recently, IL-18 has also been shown to execute specific effects in pancreatic diseases, including acute and chronic pancreatitis, as well as pancreatic cancer. The aim of this study was to give a profound review of recent data on the role of IL-18 and its potential as a therapeutic target in pancreatic diseases. The existing data on this topic are in part controversial and will be discussed in detail. Future studies should aim to confirm and clarify the role of IL-18 in pancreatic diseases and unravel their molecular mechanisms.