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The Study on Regeneration Potential of Mouse Bone Marrow Cells for Paraquat-Induced Acute Kidney Injury in C57BL/6 Mice
No full text巴拉刈（Paraquat, PQ）又稱百草枯，其化學名為 1,1’-dimethyl-4,4’-bipyridylium dichloride，分子式為 C 12 H 14 C l2 N 2 ，屬於聯嘧啶（bypyridiniums）類的化合物，目前已超過一百三十個國家正式登記並使用，為全球使用最廣泛的除草劑之一。巴拉刈中毒大多由口服途徑引起，進入體內後，最早達到最高組織濃度的器官為腎臟，同時它也是最主要的排泄器官。若腎臟功能正常，在口服後6小時內約有百分之八十至九十的巴拉刈以原型型態從尿液中排出體外，在24小時內幾乎為百分之百會由腎臟排出。若腎功能不正常，則組織中(尤其是肺)的巴拉刈濃度將增高，且其濃度頂點將延到 15 至 20 小時之後。當巴拉刈進到腎臟細胞內後，隨即進行氧化還原循環(redox cycling)，消耗NADPH，產生大量的超氧化物 (superoxide anion, O 2.-)等自由基，導致腎臟的傷害。根據 2001 到 2002 年的統計資料指出，在台灣所有農藥中毒事件中，巴拉刈中毒佔了 18.9 %，造成的死亡率為 72.1 %。
過去文獻顯示，高劑量巴拉刈中毒後，會引發多重器官衰竭，其中包括急性腎損傷(acute kidney injury, AKI)，在 24 至 96 小時內出現的蛋白尿(proteinuria)、膿尿(pyuria)、氮血(azotemia)、血尿(hematuria)等較輕微症狀會出現，一旦出現寡尿或無尿，則代表更嚴重的急性腎小管壞死，也會發生腎絲球腎炎的情況。
傳統的治療方法包括洗胃(gastric lavage)、給予口服吸附劑如活性碳（active charcoal）、血液灌流(charcoal haemoperfusion)及糖質皮質固醇類(glucocorticoid)藥物治療，但這些治療往往無法有效提高存活率。急性腎損傷（AKI）目前仍然為高死亡率的疾病之一，主要是因為在臨床治療上有抗藥性的問題而造成治療無效的結果。因此在血管內移植骨髓間葉幹細胞（bone marrow mesenchymal stem cells,BM-MSCs）對於治療AKI是一種新穎且有希望的方法，過去已有研究利用BM-MSCs治療 AKI 模式小鼠，觀察到BM-MSCs會在受傷的腎臟上，修復腎小管及改善腎臟功能，且會分化成腎小管上皮細胞、腎小球系膜細胞（mesangial cells）及腎絲球上皮細胞。因此，本實驗利用雄鼠骨髓細胞對於巴拉刈中毒的雌鼠進行細胞處理，觀察是否能減少傷害並提高其存活率，接著探討其中的調節機制。
為了建立巴拉刈所造成的急性腎臟損傷，首先利用八週大雌性 C57BL/6小鼠以腹腔注射給予 55 mg/kg BW劑量的巴拉刈，使C57BL/6 小鼠腎功能指數與對照組相比有顯著上升的趨勢，隨著暴露巴拉刈後的天數增加，腎功能指數也有增加的趨勢。由組織切片中觀察到腎小管刷狀緣失去、細胞排列不規則且細胞因為毒性死亡而掉落，足細胞結構不完整及核掉落等現象。而在給予三次小鼠骨髓細胞
進行細胞治療後，可將C57BL/6小鼠存活率由20%提高至60%，但利用
dexamethasone (DEX)進行治療無法有效提升小鼠存活率。實驗結果也顯示細胞治療可改善巴拉刈對小鼠引起的腎臟組織傷害，並減少腎功能的破壞，且在處理後第六天可使腎功能恢復到與控制組相似，同時，可減少細胞凋亡及嗜中性白血球浸潤的現象。
綜合以上結論，實驗結果顯示在高劑量 55 mg/kg BW 巴拉刈處理後的 C57BL/6小鼠，以骨髓細胞進行細胞治療，恢復小鼠腎臟功能，減少腎臟傷害並且提高其存活率。而這樣的恢復的現象，或許是藉由骨髓細胞分泌出的細胞激素及生長因子作為免疫抑制的調節以改善巴拉刈對腎臟造成的傷害。本實驗是首先探討巴拉刈對腎臟足細胞造成傷害的研究。Paraquat(1,1’-dimethyl-4,4’-bipyridylium dichloride, PQ),a potent nephrotoxicant, belongs to the class of bipyridylium quaternary ammonium herbicides. Paraquat mainly excrete by kidney and undergoes a process of redox-cycling and finally leads to reactive oxygen species (ROS) production at the expense of NADPH. This alters the normal cell functions and causes kidney toxicity. Paraquat poisoning is the most common cause of fulminated and fatal herbicide intoxication. From 2001 to 2002, paraquat intoxication contributed to 18.9 % of all pesticide poisonings in Taiwan.
Studies showed that high doses of paraquat lead to multiple organ failure such as lung, kidney, liver and so on. Kidney has the most highest concentration compare to the other organs at any detection time. Paraquat-induced acute kidney injury (AKI) caused proteinuria, pyuria, azotemia, uremia and other minor symptoms within 24-96 hours and this can be used as a predict marker of AKI. Despite severe tubular necrosis, paraquat may also cause glomerular damage and eventually lead to glomerulonephritis.
The conventional clinical therapies for the patients of fulminant paraquat poisoning are ineffective. On the other hand, AKI patients remain high mortality after clinical treatment due to drug-resistance. Recently, bone marrow mesenchymal stem cells(BM-MSCs) have been reported to have the ability to repair injured kidney and improve survival rate of mice. Therefore, this study aim to evaluate the treatment efficacy of mouse bone marrow cells（mBMCs）on mice with acute kidney paraquat poisoning.
In animal model,to mimic AKI, 8 weeks female C57BL/6 mice were intraperitoneally administered with 55 mg/kg BW paraquat. Histopathologically, kidneys showed tubular brush border lost, irregular cell arrangement and inflammatory cells infiltration. Furthermore, kidney functions evaluation also revealed significant differences in BUN, SCr, urine total protein and urine Cr compared to the control group. After three times co-treatment with mBMCs, paraquat-induced AKI mice showed an increased survival rate from 20% to 60%. One time treatment with mBMCs or
dexamethasone, however, did not elevate the survival rate of mice. Histopathologically, three times mBMCs co-treatment repaired the injury caused by paraquat and the structure of renal tubular and podocytes seemed to be similar as control group. Renal functions study also suggested that three times mBMCs co-treatment would restore the physiological functions of kidney and results showed that there was no differences between treatment group and control group on Day 6.
As a conclusion, the results of this study demonstrated that mBMCs co-treatment could decrease kidney damage,repair kidney functions and increase the survivalrate of mice with acute kidney paraquat poisoning. Besides, this is also the first study to evaluate the damage of podocytes that caused by paraquat
Activation of ubiquitin-proteasome pathway is involved in skeletal muscle wasting in a rat model with biliary cirrhosis: potential role of TNF-α
No full textUnfractionated bone marrow cells attenuate paraquat-induced glomerular injury and acute renal failure by modulating the inflammatory response
No full textThe aim of this study was to evaluate the efficacy of unfractionated bone marrow cells (BMCs) in attenuating acute kidney injury (AKI) induced by paraquat (PQ) in a mouse model. PQ (55 mg/kg BW) was intraperitoneally injected into C57BL/6 female mice to induce AKI, including renal function failure, glomerular damage and renal tubule injury. Glomerular podocytes were the first target damaged by PQ, which led to glomerular injury. Upon immunofluorescence staining, podocytes depletion was validated and accompanied by increased urinary podocin levels, measured on days 1 and 6. A total of 5.4 x 10(6) BMCs obtained from the same strain of male mice were injected into AKI mice through the tail vein at 3, 24, and 48 hours after PQ administration. As a result, renal function increased, tubular and glomerular injury were ameliorated, podocytes loss improved, and recipient mortality decreased. In addition, BMCs co-treatment decreased the extent of neutrophil infiltration and modulated the inflammatory response by shifting from pro-inflammatory Th1 to an anti-inflammatory Th2 profile, where IL-1 beta, TNF-alpha, IL-6 and IFN-gamma levels declined and IL-10 and IL-4 levels increased. The present study provides a platform to investigate PQ-induced AKI and repeated BMCs injection represents an efficient therapeutic strategy
Stimulated resistin expression in white adipose of rats with bile duct ligation-induced liver cirrhosis: relationship to cirrhotic hyperinsulinemia and increased tumor necrosis factor-alpha
No full textResistin, an adipose-derived polypeptide hormone, is proposed as a candidate of insulin resistance, although its roles in inhibiting adipogenesis & in inflammation have also been suggested. Liver cirrhosis is characterized by elevated circulating proinflammatory cytokines, including tumor necrosis factor- (TNF-), hyperinsulinemia & insulin resistance. The study aimed to examine resistin expression & its association with insulin & TNF- in a cirrhotic rat model using bile duct ligation (BDL). The BDL-induced cirrhotic rats showed significantly lower fat mass, insulin sensitivity & elevated plasma insulin & TNF- compared to sham animals. In addition, epididymal TNF- & resistin mRNA & protein levels were higher in cirrhotic rats. In normal control rats, in vivo insulin infusion & ex vivo administration of TNF- to cultured fat pads increased resistin gene expression significantly. These results implied that hyperinsulinemia & increased TNF- levels might upregulate adipose resistin gene in BDL-induced liver cirrhosis. Further study is necessary to document the role of resistin in metabolic abnormalities of liver cirrhosis
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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