Acute kidney injury (AKI) is a complex disorder for which currently there is no accepted definition. Having a uniform standard for diagnosing and classifying AKI would enhance our ability to manage these patients. Future clinical and translational research in AKI will require collaborative networks of investigators drawn from various disciplines, dissemination of information via multidisciplinary joint conferences and publications, and improved translation of knowledge from pre-clinical research. We describe an initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI. Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a two day conference in Amsterdam, The Netherlands, in September 2005 and were assigned to one of three workgroups. Each group's discussions formed the basis for draft recommendations that were later refined and improved during discussion with the larger group. Dissenting opinions were also noted. The final draft recommendations were circulated to all participants and subsequently agreed upon as the consensus recommendations for this report. Participating societies endorsed the recommendations and agreed to help disseminate the results. The term AKI is proposed to represent the entire spectrum of acute renal failure. Diagnostic criteria for AKI are proposed based on acute alterations in serum creatinine or urine output. A staging system for AKI which reflects quantitative changes in serum creatinine and urine output has been developed. We describe the formation of a multidisciplinary collaborative network focused on AKI. We have proposed uniform standards for diagnosing and classifying AKI which will need to be validated in future studies. The Acute Kidney Injury Network offers a mechanism for proceeding with efforts to improve patient outcomes.

Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury

Reactive oxygen species

The kidney requires a large number of mitochondria to remove waste from the blood and regulate fluid and electrolyte balance. Mitochondria provide the energy to drive these important functions and can adapt to different metabolic conditions through a number of signalling pathways (for example, mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways) that activate the transcriptional co-activator peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α), and by balancing mitochondrial dynamics and energetics to maintain mitochondrial homeostasis. Mitochondrial dysfunction leads to a decrease in ATP production, alterations in cellular functions and structure, and the loss of renal function. Persistent mitochondrial dysfunction has a role in the early stages and progression of renal diseases, such as acute kidney injury (AKI) and diabetic nephropathy, as it disrupts mitochondrial homeostasis and thus normal kidney function. Improving mitochondrial homeostasis and function has the potential to restore renal function, and administering compounds that stimulate mitochondrial biogenesis can restore mitochondrial and renal function in mouse models of AKI and diabetes mellitus. Furthermore, inhibiting the fission protein dynamin 1-like protein (DRP1) might ameliorate ischaemic renal injury by blocking mitochondrial fission.

Mitochondrial energetics in the kidney

Much work has been carried out in recent years on the beneficial effect of phenolic compounds which act as natural antioxidants and help to neutralize free radicals. We analysed the antioxidant activity of the rutin (quercetin-3-rhamnosyl glucoside) using different assays including: total antioxidant activity and reducing power, hydroxyl radical scavenging assay, superoxide radical scavenging assay, 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging assay and lipid peroxidation assay which uses egg yolk as the lipid-rich source. Total antioxidant capacity was determined by the assay based on the decrease in absorbance of β-carotene by the sample. Rutin exhibited strong DPPH radical scavenging activity. At the concentration of 0.05 mg/ml, ascorbic acid (Vc), butylated hydroxytoluene (BHT) and rutin showed 92.8%, 58.8%, and 90.4% inhibition, respectively. In addition, rutin had effective inhibition of lipid peroxidation. Those various antioxidant activities were compared to standard antioxidants such as BHT and Vc.

In vitro antioxidant properties of rutin

The accumulation of knowledge associated with cancer biology continues to progress at a phenomenal rate; the electronic availability of research papers and news items makes access to new discoveries almost instantaneous. International meetings present opportunities to share scientific knowledge and develop collaborations, as well as fuelling competition between groups, to drive research forward. As a primary researcher or graduate student, the ability to adapt research projects to take advantage of new technological and scientific developments in the field of cancer biology requires a broad knowledge of subjects outside the primary areas of research. Similarly, an undergraduate or newcomer to the field must initially familiarise themselves with established principles before facing the daunting task of processing the vast amount of specialised knowledge available. The editors of The Molecular Biology of Cancer have identified the need for a book that assimilates critical aspects of cancer biology into a single resource to function as a reference tool and teaching aid applicable to both students and researchers alike.

The book is divided into 18 chapters and a glossary. Each chapter is authored by experts in the field and is prefaced by a list of the key points covered in that section. The chapters are organised according to a common format; of particular note is the arrangement of the bibliographies at the end of each chapter where references are grouped according to the concepts discussed. This format facilitates navigation of the information presented in each section, allowing the book to be used as a reference tool. This is ideal for established cancer biologists requiring clarity of specific subjects as well as those using the book to learn topics from first principles. It is in catering to this dual audience that the book is particularly strong.

The Introduction presents cancer as a genetic disease that requires the acquisition of the classical ‘hallmarks' by cancer cells to promote tumour development. Basic concepts are clearly presented in this chapter that would be redundant to an established cancer biologist but invaluable to a newcomer to the field and of great importance in the context of the book as a teaching resource. Chapter 2 considers the clinical features of lung, breast and prostate cancer and determines the context in which the molecular biology described in the subsequent chapters should be considered; namely, in terms of disease manifestation.

The interplay between the environment and genetic lesions associated with cancer is considered in Chapter 3; the book then focuses on the molecular basis of the cellular processes relevant to the cancer cell. The mechanisms fundamental to the normal cell cycle and DNA replication are described in Chapter 4; Chapters 6, 7 and 10 discuss the role of oncogenes, tumour suppressor genes and genetic instability, respectively. Chapter 11 describes the role of epigenetic factors in gene expression and the influence of post-translational modifications on protein expression. There is, however, comparatively little discussion of the role of signal transduction in cancer development. The vast nature of this field makes consideration of every pathway impossible in this context but a more thorough overview could be achieved if a whole chapter were devoted to this topic. The RAS – MAPK pathway and PI3K – Akt pathway are highlighted as examples of critical signalling modules in cell growth as part of Chapter 5 but could be included on their own. This is especially relevant given the potential of signalling pathway components as drug targets.

At times, the complex nature of the mechanisms and theories discussed necessitates detailed descriptions resulting in large blocks of text. However, large, monochrome figures clearly summarise these descriptions or are used in place of them where possible. Additional colour plates illustrate signalling pathways and clinical images that would be unclear in black and white. Information that is relevant to the chapter but would be incongruous in the main text, such as highlights of key experiments, is presented in additional text boxes. Tables are also used to present lists of information, such as protein classifications, in an organised format that would not be possible in the main text. The conclusion of each chapter summarises the topics covered and suggests questions that still remain in the field.

Chapters 15, 16 and 17 address the issues of cancer diagnosis, treatment and patient care and set the book apart from a general molecular biology reference by considering the clinical implications of understanding this subject. Chapter 17 is especially poignant in its highly informative discussion of the management of the palliative care of cancer patients. The title of the book does not imply that these topics would be included; however, it is information I feel is essential to complete the comprehensive reference guide that the editors aimed to produce. The development of therapies specifically targeting the molecules responsible for the transformed phenotype demands a detailed understanding of the mechanisms behind normal cellular processes. This knowledge should not be gained at the expense of an appreciation of the impact that bench-based research has on the patient in hospital. An awareness of the human implications of gaps in our understanding of cancer development should drive research.

The pace of cancer research means that the latest knowledge of highly specialised concepts is essential but, equally, the cross talk between different subject areas means a solid understanding is essential to take advantage of the plethora of new data available. Essentially, The Molecular Biology of Cancer is a book that can be used as an introduction to the subject as well as a platform on which to assimilate new information in the context of established principles. This book is applicable to both graduate and undergraduate students and, in the context of a research laboratory, this book would be an excellent resource as a reference guide for scientists at all levels.

/pdf/the-molecular-biology-of-cancer-44o8a7nt3s.pdf

The Molecular Biology of Cancer

Arsenic is an environmental pollutant and its contamination in the drinking water is considered as a serious worldwide environmental health threat. The chronic arsenic exposure is a cause of immense health distress as it accounts for the increased risk of various disorders such as cardiovascular abnormalities, diabetes mellitus, neurotoxicity, and nephrotoxicity. In addition, the exposure to arsenic has been suggested to affect the liver function and to induce hepatotoxicity. Moreover, few studies demonstrated the induction of carcinogenicity especially cancer of the skin, bladder, and lungs after the chronic exposure to arsenic. The present review addresses diverse mechanisms involved in the pathogenesis of arsenic-induced toxicity and end-organ damage.

Mechanisms pertaining to arsenic toxicity

http://if-pan.krakow.pl/pjp/pdf/2012/1_31.pdf

Animal models of acute renal failure

/pdf/mycobacterial-antigen-driven-activation-of-cd14-cd16-5c6kzvkysl.pdf

Mycobacterial antigen driven activation of CD14++ CD16-monocytes is a predictor of tuberculosis-associated immune reconstitution inflammatory syndrome

Rodent models of heart failure.

We investigated the involvement of peroxisome proliferator activated receptor-γ (PPAR-γ)/endothelial nitric oxide synthase (eNOS) pathway in estradiol mediated protection against ischemia reperfusion (I/R)-induced acute kidney injury (AKI) in rats To induce AKI, rats underwent 40 min of bilateral renal ischemia followed by 24 h of reperfusion I/R-induced kidney damage was quantified by measuring serum creatinine, creatinine clearance, urea nitrogen, uric acid, potassium, fractional excretion of sodium, microproteinuria, and renal oxidative stress (thiobarbituric acid reactive substances, superoxide anion generation, and reduced glutathione) Hematoxylin eosin stain demonstrated renal histology, while renal expression of apoptotic markers (Bcl-2, Bax), PPAR-γ and eNOS were quantified by immunohistochemistry Estradiol (1 mg/kg, ip) was administered 30 min before I/R in rats In separate groups, PPAR-γ antagonist, BADGE (30 mg/kg, ip), and NOS inhibitor, l-NAME (20 mg/kg, ip) were administered prior to estradiol treatment, which was followed by I/R in rats I/R caused significant renal damage as demonstrated by biochemical (serum/urine), renal oxidative stress and histological changes alongwith increased expression of Bax and decreased levels of Bcl-2, PPAR-γ and eNOS, which were prevented by estradiol Pre-treatment with BADGE and l-NAME abolished estradiol mediated renoprotection Notably, I/R + estradiol + BADGE group revealed decreased expression of PPAR-γ and eNOS in renal tissues In I/R + estradiol + l-NAME group, eNOS expression was reduced while PPAR-γ levels remained unchanged These results suggest that estradiol modulates PPAR-γ which consequently regulates eNOS expression in rat kidneys We conclude that estradiol protects against I/R-induced AKI through PPAR-γ stimulated eNOS activation in rats

Amrit Pal Singh

Papers

Mechanisms pertaining to arsenic toxicity

Animal models of acute renal failure

Mycobacterial antigen driven activation of CD14++ CD16-monocytes is a predictor of tuberculosis-associated immune reconstitution inflammatory syndrome

Rodent models of heart failure.

Estradiol attenuates ischemia reperfusion-induced acute kidney injury through PPAR-γ stimulated eNOS activation in rats