A glance at molecular mechanisms underlying cisplatin-induced nephrotoxicity and possible renoprotective strategies: a narrative review

Cisplatin is a platinum-based drug that is usually used for the treatment of many carcinomas. However, it comes with several devastating side effects, including nephrotoxicity. Cisplatin toxicity is a very complex process, which is exacerbated by the accumulation of cisplatin in renal tubular cells via passive diffusion and transporter-mediated processes. Once cisplatin enters these cells, it induces the formation of reactive oxygen species that cause cellular damage, including DNA damage, inflammation, and eventually cell death. On a small scale, these damages can be mitigated by cellular antioxidant defense mechanism. However, on a large scale, such as in chemotherapy, this defense mechanism may fail, resulting in nephrotoxicity. The current article reviews the molecular mechanisms underlying cisplatin-induced nephrotoxicity and possible renoprotective strategies to determine novel therapeutic interventions for alleviating this toxicity.

Download Full-text

Fibrinogen β–derived Bβ15-42 peptide protects against kidney ischemia/ reperfusion injury

Blood ◽

10.1182/blood-2011-02-338061 ◽

2011 ◽

Vol 118 (7) ◽

pp. 1934-1942 ◽

Cited By ~ 33

Author(s):

Aparna Krishnamoorthy ◽

Amrendra Kumar Ajay ◽

Dana Hoffmann ◽

Tae-Min Kim ◽

Victoria Ramirez ◽

...

Keyword(s):

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

High Sensitivity ◽

Kidney Damage ◽

Therapeutic Interventions ◽

Mrna Levels ◽

Renal Tubular Cells ◽

Renal Tubular ◽

Injury And Repair

AbstractIschemia/reperfusion (I/R) injury in the kidney is a major cause of acute kidney injury (AKI) in humans and is associated with significantly high mortality. To identify genes that modulate kidney injury and repair, we conducted genome-wide expression analysis in the rat kidneys after I/R and found that the mRNA levels of fibrinogen (Fg)α, Fgβ, and Fgγ chains significantly increase in the kidney and remain elevated throughout the regeneration process. Cellular characterization of Fgα and Fgγ chain immunoreactive proteins shows a predominant expression in renal tubular cells and the localization of immunoreactive Fgβ chain protein is primarily in the renal interstitium in healthy and regenerating kidney. We also show that urinary excretion of Fg is massively increased after kidney damage and is capable of distinguishing human patients with acute or chronic kidney injury (n = 25) from healthy volunteers (n = 25) with high sensitivity and specificity (area under the receiver operating characteristic of 0.98). Furthermore, we demonstrate that Fgβ-derived Bβ15-42 peptide administration protects mice from I/R-induced kidney injury by aiding in epithelial cell proliferation and tissue repair. Given that kidney regeneration is a major determinant of outcome for patients with kidney damage, these results provide new opportunities for the use of Fg in diagnosis, prevention, and therapeutic interventions in kidney disease.

Download Full-text

Wound healing and local neuroendocrine regulation in the injured liver

Expert Reviews in Molecular Medicine ◽

10.1017/s146239940800063x ◽

2008 ◽

Vol 10 ◽

Cited By ~ 11

Author(s):

Mohammad R. Ebrahimkhani ◽

Ahmed M. Elsharkawy ◽

Derek A. Mann

Keyword(s):

Wound Healing ◽

Molecular Mechanisms ◽

Cell Types ◽

Neuroendocrine System ◽

Therapeutic Interventions ◽

Antifibrotic Therapy ◽

Complex Process ◽

Wound Healing Response ◽

Fibrotic Scar ◽

Different Cell Types

The hepatic wound-healing response is a complex process involving many different cell types and factors. It leads to the formation of excessive matrix and a fibrotic scar, which ultimately disrupts proper functioning of the liver and establishes cirrhosis. Activated hepatic myofibroblasts, which are derived from cells such as hepatic stellate cells (HSCs), play a key role in this process. Upon chronic liver injury, there is an upregulation in the local neuroendocrine system and it has recently been demonstrated that activated HSCs express specific receptors and respond to different components of this system. Neuroendocrine factors and their receptors participate in a complex network that modulates liver inflammation and wound healing, and controls the development and progression of liver fibrosis. The first part of this review provides an overview of the molecular mechanisms governing hepatic wound healing. In the second section, we explore important components of the hepatic neuroendocrine system and their recently highlighted roles in HSC biology and hepatic fibrogenesis. We discuss the therapeutic interventions that are being developed for use in antifibrotic therapy.

Download Full-text

Accuracy mechanism of eukaryotic ribosome translocation

Nature ◽

10.1038/s41586-021-04131-9 ◽

2021 ◽

Author(s):

Muminjon Djumagulov ◽

Natalia Demeshkina ◽

Lasse Jenner ◽

Alexey Rozov ◽

Marat Yusupov ◽

...

Keyword(s):

Messenger Rna ◽

Large Scale ◽

Molecular Mechanisms ◽

Elongation Factor ◽

80S Ribosome ◽

Reading Frame ◽

Transfer Rnas ◽

Elongation Factor 2 ◽

Complex Process ◽

Translation Accuracy

AbstractTranslation of the genetic code into proteins is realized through repetitions of synchronous translocation of messenger RNA (mRNA) and transfer RNAs (tRNA) through the ribosome. In eukaryotes translocation is ensured by elongation factor 2 (eEF2), which catalyses the process and actively contributes to its accuracy1. Although numerous studies point to critical roles for both the conserved eukaryotic posttranslational modification diphthamide in eEF2 and tRNA modifications in supporting the accuracy of translocation, detailed molecular mechanisms describing their specific functions are poorly understood. Here we report a high-resolution X-ray structure of the eukaryotic 80S ribosome in a translocation-intermediate state containing mRNA, naturally modified eEF2 and tRNAs. The crystal structure reveals a network of stabilization of codon–anticodon interactions involving diphthamide1 and the hypermodified nucleoside wybutosine at position 37 of phenylalanine tRNA, which is also known to enhance translation accuracy2. The model demonstrates how the decoding centre releases a codon–anticodon duplex, allowing its movement on the ribosome, and emphasizes the function of eEF2 as a ‘pawl’ defining the directionality of translocation3. This model suggests how eukaryote-specific elements of the 80S ribosome, eEF2 and tRNAs undergo large-scale molecular reorganizations to ensure maintenance of the mRNA reading frame during the complex process of translocation.

Download Full-text

RA-map: building a state-of-the-art interactive knowledge base for rheumatoid arthritis

Database ◽

10.1093/database/baaa017 ◽

2020 ◽

Vol 2020 ◽

Cited By ~ 4

Author(s):

Vidisha Singh ◽

George D Kalliolias ◽

Marek Ostaszewski ◽

Maëva Veyssiere ◽

Eleftherios Pilalis ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Knowledge Base ◽

Large Scale ◽

Molecular Mechanisms ◽

State Of The Art ◽

Underlying Disease ◽

Small Scale ◽

Map Building ◽

Scientific Publications ◽

Molecular Map

Abstract Rheumatoid arthritis (RA) is a progressive, inflammatory autoimmune disease of unknown aetiology. The complex mechanism of aetiopathogenesis, progress and chronicity of the disease involves genetic, epigenetic and environmental factors. To understand the molecular mechanisms underlying disease phenotypes, one has to place implicated factors in their functional context. However, integration and organization of such data in a systematic manner remains a challenging task. Molecular maps are widely used in biology to provide a useful and intuitive way of depicting a variety of biological processes and disease mechanisms. Recent large-scale collaborative efforts such as the Disease Maps Project demonstrate the utility of such maps as versatile tools to organize and formalize disease-specific knowledge in a comprehensive way, both human and machine-readable. We present a systematic effort to construct a fully annotated, expert validated, state-of-the-art knowledge base for RA in the form of a molecular map. The RA map illustrates molecular and signalling pathways implicated in the disease. Signal transduction is depicted from receptors to the nucleus using the Systems Biology Graphical Notation (SBGN) standard representation. High-quality manual curation, use of only human-specific studies and focus on small-scale experiments aim to limit false positives in the map. The state-of-the-art molecular map for RA, using information from 353 peer-reviewed scientific publications, comprises 506 species, 446 reactions and 8 phenotypes. The species in the map are classified to 303 proteins, 61 complexes, 106 genes, 106 RNA entities, 2 ions and 7 simple molecules. The RA map is available online at ramap.elixir-luxembourg.org as an open-access knowledge base allowing for easy navigation and search of molecular pathways implicated in the disease. Furthermore, the RA map can serve as a template for omics data visualization.

Download Full-text

Mechanistic Understanding of the Engineered Nanomaterial-Induced Toxicity on Kidney

Journal of Nanomaterials ◽

10.1155/2019/2954853 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Haiyang Zhao ◽

Luxin Li ◽

Huilu Zhan ◽

Yanhui Chu ◽

Bingbing Sun

Keyword(s):

Adverse Effects ◽

Molecular Mechanisms ◽

Basilar Membrane ◽

Rapid Development ◽

Health And Safety ◽

Whole Body ◽

Renal Tubular Cells ◽

Engineered Nanomaterial ◽

Renal Tubular ◽

Exogenous Substances

With the rapid development of nanotechnology, engineered nanomaterials (ENMs) have been applied in many fields, such as food industry, biomedicine, and so on. However, the study on the health and safety implications of ENMs is still insufficient. Previous studies have shown that nanoparticles under acute or chronic exposure could be transported and accumulated in various organs and tissues, resulting in adverse effects or systemic toxicity. Among these, the kidney is one of the main organs that exposed ENMs will target through different routes. One of the important functions of the kidney is to discharge metabolic wastes and exogenous substances from the blood circulation of the whole body. During ENM exposure, the kidney may become vulnerable to toxicity. Studies have suggested that nanoparticles exposed to the kidney could provoke glomerular swelling, basilar membrane thickening, degeneration, and necrosis of renal tubular cells. These adverse effects of nanoparticles on the kidney may be related to their induced oxidative stress, inflammation, autophagy, DNA damage, and ER stress. This review aims to examine current studies on ENM-induced nephrotoxicity, with the focus on elucidating the potential molecular mechanisms of nanoparticle-induced toxicity on the kidney, which will further facilitate the safer design of ENMs and their applications.

Download Full-text

α-Tocopherol induces calnexin in renal tubular cells: Another protective mechanism against free radical-induced cellular damage

Archives of Biochemistry and Biophysics ◽

10.1016/j.abb.2006.07.002 ◽

2006 ◽

Vol 453 (2) ◽

pp. 168-178 ◽

Cited By ~ 5

Author(s):

Wen-Hua Lee ◽

Shinya Akatsuka ◽

Tomoyuki Shirase ◽

Khokon Kumar Dutta ◽

Li Jiang ◽

...

Keyword(s):

Free Radical ◽

Cellular Damage ◽

Protective Mechanism ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Renal Tubular

Download Full-text

The Perspective of Dysregulated LncRNAs in Alzheimer's Disease: A Systematic Scoping Review

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.709568 ◽

2021 ◽

Vol 13 ◽

Author(s):

Mohammad Reza Asadi ◽

Mehdi Hassani ◽

Shiva Kiani ◽

Hani Sabaie ◽

Marziyeh Sadat Moslehian ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Scoping Review ◽

Large Scale ◽

Molecular Mechanisms ◽

Small Scale ◽

Regulatory Pathways ◽

Therapeutic Goals ◽

Molecular Therapeutic

LncRNAs act as part of non-coding RNAs at high levels of complex and stimulatory configurations in basic molecular mechanisms. Their extensive regulatory activity in the CNS continues on a small scale, from the functions of synapses to large-scale neurodevelopment and cognitive functions, aging, and can be seen in both health and disease situations. One of the vast consequences of the pathological role of dysregulated lncRNAs in the CNS due to their role in a network of regulatory pathways can be manifested in Alzheimer's as a neurodegenerative disease. The disease is characterized by two main hallmarks: amyloid plaques due to the accumulation of β-amyloid components and neurofibrillary tangles (NFT) resulting from the accumulation of phosphorylated tau. Numerous studies in humans, animal models, and various cell lines have revealed the role of lncRNAs in the pathogenesis of Alzheimer's disease. This scoping review was performed with a six-step strategy and based on the Prisma guideline by systematically searching the publications of seven databases. Out of 1,591 records, 69 articles were utterly aligned with the specified inclusion criteria and were summarized in the relevant table. Most of the studies were devoted to BACE1-AS, NEAT1, MALAT1, and SNHG1 lncRNAs, respectively, and about one-third of the studies investigated a unique lncRNA. About 56% of the studies reported up-regulation, and 7% reported down-regulation of lncRNAs expressions. Overall, this study was conducted to investigate the association between lncRNAs and Alzheimer's disease to make a reputable source for further studies and find more molecular therapeutic goals for this disease.

Download Full-text

StoneMod: a database for kidney stone modulatory proteins with experimental evidence

Scientific Reports ◽

10.1038/s41598-020-71730-3 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Supatcha Sassanarakkit ◽

Paleerath Peerapen ◽

Visith Thongboonkerd

Keyword(s):

Experimental Evidence ◽

Kidney Stone ◽

Molecular Mechanisms ◽

Stone Formation ◽

Stone Disease ◽

Depth Information ◽

Renal Tubular Cells ◽

Human Protein Atlas ◽

Renal Tubular ◽

User Friendly

Abstract Better understanding of molecular mechanisms for kidney stone formation is required to improve management of kidney stone disease with better therapeutic outcome. Recent kidney stone research has indicated critical roles of a group of proteins, namely ‘stone modulators’, in promotion or inhibition of the stone formation. Nevertheless, such information is currently dispersed and difficult to obtain. Herein, we present the kidney stone modulator database (StoneMod), which is a curated resource by obtaining necessary information of such stone modulatory proteins, which can act as stone promoters or inhibitors, with experimental evidence from previously published studies. Currently, the StoneMod database contains 10, 16, 13, 8 modulatory proteins that affect calcium oxalate crystallization, crystal growth, crystal aggregation, and crystal adhesion on renal tubular cells, respectively. Informative details of each modulatory protein and PubMed links to the published articles are provided. Additionally, hyperlinks to other protein/gene databases (e.g., UniProtKB, Swiss-Prot, Human Protein Atlas, PeptideAtlas, and Ensembl) are made available for the users to obtain additional in-depth information of each protein. Moreover, this database provides a user-friendly web interface, in which the users can freely access to the information and/or submit their data to deposit or update. Database URL:https://www.stonemod.org.

Download Full-text

A Brief Study of Nephrotoxicity and Nephroprotective Agents

Indian Journal of Pharmaceutical and Biological Research ◽

10.30750/ijpbr.8.1.2 ◽

2020 ◽

Vol 8 (01) ◽

pp. 09-13 ◽

Cited By ~ 1

Author(s):

Shamna . ◽

Jasteena Jose ◽

Shijikumar . ◽

Riyaz Ahmed

Keyword(s):

Serum Creatinine ◽

Blood Urea Nitrogen ◽

Renal Damage ◽

Early Stage ◽

Therapeutic Interventions ◽

Test Evaluation ◽

Urea Nitrogen ◽

Renal Tubular Cells ◽

Sensitivity And Selectivity ◽

Renal Tubular

A kidney is particularly prone to the action of nephrotoxins because it receives 25% of the cardiac output. The presence of the metabolic processes in the renal tubular cells, nephrotoxins can release toxic components and induce damage. Nephrotoxicity can be diagnosed through a simple blood test. Evaluation of nephrotoxicity through blood tests includes the measurements of blood urea nitrogen (BUN), the concentration of serum creatinine, glomerular filtration rate and creatinine clearance. The majority of cases of renal disease remain unnoticed unless they progress to advance stages when conventional therapeutic interventions are usually not sufficient to cure them completely. In this review, the study attempted to identify biomarkers that are more sensitive than the established markers and that are more indicative of pre-renal damage. Research is also focused on identifying biomarkers that can indicate the nature of the mechanisms involved. Nephrotoxicity assays such as measurement of the concentration of serum creatinine or blood urea nitrogen (BUN) do not have the sensitivity and selectivity required to determine nephrotoxicity in an early stage. Recently identified biomarkers described in this review may provide useful information to diagnose nephrotoxicity earlier and more selectively.

Download Full-text

Loss of Function of von Hippel-Lindau Trigger Lipocalin 2-Dependent Inflammatory Responses in Cultured and Primary Renal Tubular Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/5571638 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Chan-Yen Kuo ◽

Valeria Chiu ◽

Po-Chun Hsieh ◽

Tien Hsu ◽

Ting-Yun Lin

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Responses ◽

Conditional Knockout ◽

Dependent Manner ◽

Lipocalin 2 ◽

Loss Of Function ◽

Von Hippel Lindau ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Renal Tubular

Previous studies have shown that mutations in the tumor suppressor gene von Hippel-Lindau (VHL) can result in the overproduction of reactive oxygen species (ROS) and chronic inflammation and are a significant predisposing factor for the development of clear-cell renal cell carcinoma (ccRCC). To study VHL’s role in ccRCC formation, we previously developed a novel conditional knockout mouse model that mimicked the features of kidney inflammation and fibrosis that lead to cyst formation and hyperplasia. However, due to VHL’s complex cellular functions, the mechanism of this phenomenon remains unclear. Here, we used the HK-2 cells and mouse primary renal tubule cells (mRTCs) carrying VHL mutations as models to study the effects and underlying molecular mechanisms of ROS accumulation. We also studied the role of lipocalin 2 (LCN2) in regulating macrophage recruitment by HK-2 cells. We measured the level of ROS in HK-2 cells in the presence or absence of LCN2 knockdown and found that the VHL mutation caused ROS overproduction, but an LCN2 knockdown could attenuate the process. VHL was also found to mediate the in vitro and in vivo expression and secretion of LCN2. Thus, VHL likely affects ROS production in an LCN2-dependent manner. Our findings also suggest that LCN2 sensitizes the inflammatory response of HK-2 cells and the chemotactic abilities of macrophage RAW264.7 cells. By demonstrating that the loss of function of von Hippel-Lindau triggers lipocalin 2-dependent inflammatory responses in cultured and primary renal tubular cells, our results offer novel insights into a potential therapeutic approach for interfering with the development of ccRCC.

Download Full-text