There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

The important life-supporting role of hydrogen sulfide (H2S) has evolved from bacteria to plants, invertebrates, vertebrates, and finally to mammals. Over the centuries, however, H2S had only been known for its toxicity and environmental hazard. Physiological importance of H2S has been appreciated for about a decade. It started by the discovery of endogenous H2S production in mammalian cells and gained momentum by typifying this gasotransmitter with a variety of physiological functions. The H2S-catalyzing enzymes are differentially expressed in cardiovascular, neuronal, immune, renal, respiratory, gastrointestinal, reproductive, liver, and endocrine systems and affect the functions of these systems through the production of H2S. The physiological functions of H2S are mediated by different molecular targets, such as different ion channels and signaling proteins. Alternations of H2S metabolism lead to an array of pathological disturbances in the form of hypertension, atherosclerosis, heart failure, diabetes...

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Physiological Implications of Hydrogen Sulfide: A Whiff Exploration That Blossomed

https://www.kidney-international.org/article/S0085-2538(15)53124-4/pdf

Cisplatin nephrotoxicity: Mechanisms and renoprotective strategies

Cisplatin is a widely used and highly effective cancer chemotherapeutic agent. One of the limiting side effects of cisplatin use is nephrotoxicity. Research over the past 10 years has uncovered many of the cellular mechanisms which underlie cisplatin-induced renal cell death. It has also become apparent that inflammation provoked by injury to renal epithelial cells serves to amplify kidney injury and dysfunction in vivo. This review summarizes recent advances in our understanding of cisplatin nephrotoxicity and discusses how these advances might lead to more effective prevention.

Mechanisms of Cisplatin nephrotoxicity.

Extensive research within the last decade has revealed that most chronic illnesses such as cancer, cardiovascular and pulmonary diseases, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple cell signaling pathways that have been linked to inflammation. Thus mono-targeted therapies developed for the last two decades for these diseases have proven to be unsafe, ineffective and expensive. Although fruits and vegetables are regarded to have therapeutic potential against chronic illnesses, neither their active component nor the mechanism of action is well understood. Resveratrol (trans-3, 5, 4'-trihydroxystilbene), a component of grapes, berries, peanuts and other traditional medicines, is one such polyphenol that has been shown to mediate its effects through modulation of many different pathways. This stilbene has been shown to bind to numerous cell-signaling molecules such as multi drug resistance protein, topoisomerase II, aromatase, DNA polymerase, estrogen receptors, tubulin and F1-ATPase. Resveratrol has also been shown to activate various transcription factor (e.g; NFkappaB, STAT3, HIF-1alpha, beta-catenin and PPAR-gamma), suppress the expression of antiapoptotic gene products (e.g; Bcl-2, Bcl-X(L), XIAP and survivin), inhibit protein kinases (e.g; src, PI3K, JNK, and AKT), induce antioxidant enzymes (e,g; catalase, superoxide dismutase and hemoxygenase-1), suppress the expression of inflammatory biomarkers (e.g., TNF, COX-2, iNOS, and CRP), inhibit the expression of angiogenic and metastatic gene products (e.g., MMPs, VEGF, cathepsin D, and ICAM-1), and modulate cell cycle regulatory genes (e.g., p53, Rb, PTEN, cyclins and CDKs). Numerous animal studies have demonstrated that this polyphenol holds promise against numerous age-associated diseases including cancer, diabetes, Alzheimer, cardiovascular and pulmonary diseases. In view of these studies, resveratrol's prospects for use in the clinics are rapidly accelerating. Efforts are also underway to improve its activity in vivo through structural modification and reformulation. Our review describes various targets of resveratrol and their therapeutic potential.

Resveratrol: a multitargeted agent for age-associated chronic diseases.

The effects of oral glutamine on cisplatin-induced nephrotoxicity in rats

Cisplatin is an antitumor drug widely used in the treatment of many malignant tumors. However, the most common adverse effect, nephrotoxicity, limits the use of this drug in many cancer patients. Resveratrol is a phytoalexin that presents highly efficient protection in experimental nephrotoxicity models. This study evaluated the effect of resveratrol on cisplatin-induced kidney damage. Male Wistar rats were treated with resveratrol (25 mg/kg b.w., i.p.) before the administration of cisplatin (5 mg/kg b.w., i.p.) and killed 2 or 5 days later. Blood and urine samples were collected and the kidneys were removed. Rats from the cisplatin group showed acute tubular cell necrosis and increased immunostaining for ED1 (macrophages/monocytes) and T-lymphocytes in the renal cortex and outer medulla when compared with the control group. These alterations were less intense in animals pre-treated with resveratrol. Moreover, indicators of renal injury such as increased serum creatinine levels, urinary volume and urinary protein caused by the administration of cisplatin, were also significantly reduced with resveratrol. Increased lipid peroxidation and glutathione depletion in tissue were attenuated by resveratrol. In conclusion, resveratrol attenuated the cisplatin-induced structural and functional renal changes by reducing free radicals and inhibiting inflammatory cell infiltrates.

Resveratrol attenuates cisplatin-induced nephrotoxicity in rats

http://if-pan.krakow.pl/pjp/pdf/2006/4_526.pdf

Comparative study of multiple dosage of quercetin against cisplatin- induced nephrotoxicity and oxidative stress in rat kidneys

Background. Cisplatin therapy is effective against many tumours, however, the nephrotoxicity of this drug is a dose-limiting factor. Apoptosis and necrosis of tubular cells and inflammatory events contribute to the cisplatin-induced nephrotoxicity. Cisplatin promotes increased production of reactive oxygen species, which can activate c-jun N-terminal kinase (JNK) that is a mediator of apoptosis and can lead to increased expression of proinflammatory mediators that could intensify the cytotoxic effects of cisplatin. In this study, we evaluated the effect that SP600125, a selective inhibitor of phosphorylated JNK (p-JNK), has on the renal damage caused by cisplatin use. Methods. A total of 33 male Wistar rats received SP600125 (15 mg/kg/day, s.c., diluted in polyethylene glycol) for 4 days. At 24 h after the first dose, those 33 rats, plus an additional 30, were injected with cisplatin (5 mg/kg, i.p.). In addition, 18 control rats were injected with saline, and 12 rats with polyethylene glycol. At 2 and 5 days after saline or cisplatin injection, blood and urine samples were collected for measurement of creatinine, sodium and potassium, and the kidneys removed for histological, immunohistochemical and Western blot studies. Results. Cisplatin-treated rats presented higher plasma creatinine, as well as greater immunostaining for ED1 (macrophages/monocytes), p-JNK, apoptotic cells, and tubular cell necrosis in the renal cortices and outer medullae. The increase of p-JNK expression was also confirmed by Western blot analysis. All of these alterations were attenuated by treatment with SP600125. Conclusion. The protective effect of SP600125 on cisplatin-induced renal damage seems to be related to the reduction in the apoptotic cell death and to the restriction of renal inflammation.

Heloísa Della Coletta Francescato

Papers

The effects of oral glutamine on cisplatin-induced nephrotoxicity in rats

Resveratrol attenuates cisplatin-induced nephrotoxicity in rats

Comparative study of multiple dosage of quercetin against cisplatin- induced nephrotoxicity and oxidative stress in rat kidneys

Effect of JNK inhibition on cisplatin-induced renal damage

Parthenolide reduces cisplatin-induced renal damage