Cadmium induces Wnt signaling to upregulate proliferation and survival genes in sub-confluent kidney proximal tubule cells

<p>Abstract</p> <p>Background</p> <p>The class 1 carcinogen cadmium (Cd²⁺) disrupts the E-cadherin/β-catenin complex of epithelial adherens junctions (AJs) and causes renal cancer. Deregulation of E-cadherin adhesion and changes in Wnt/β-catenin signaling are known to contribute to carcinogenesis.</p> <p>Results</p> <p>We investigated Wnt signaling after Cd²⁺-induced E-cadherin disruption in sub-confluent cultured kidney proximal tubule cells (PTC). Cd²⁺(25 μM, 3-9 h) caused nuclear translocation of β-catenin and triggered a Wnt response measured by TOPflash reporter assays. Cd²⁺reduced the interaction of β-catenin with AJ components (E-cadherin, α-catenin) and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (<it>c-Myc</it>, <it>cyclin D1 </it>and <it>ABCB1</it>) were up-regulated by Cd²⁺, electromobility shift assays showed increased TCF4 binding to <it>cyclin D1 </it>and <it>ABCB1 </it>promoter sequences with Cd²⁺. Overexpression of wild-type and mutant TCF4 confirmed Cd²⁺-induced Wnt signaling. Wnt signaling elicited by Cd²⁺was not observed in confluent non-proliferating cells, which showed increased E-cadherin expression. Overexpression of E-cadherin reduced Wnt signaling, PTC proliferation and Cd²⁺toxicity. Cd²⁺also induced reactive oxygen species dependent expression of the pro-apoptotic ER stress marker and Wnt suppressor CHOP/GADD153 which, however, did not abolish Wnt response and cell viability.</p> <p>Conclusions</p> <p>Cd²⁺induces Wnt signaling in PTC. Hence, Cd²⁺may facilitate carcinogenesis of PTC by promoting Wnt pathway-mediated proliferation and survival of pre-neoplastic cells.</p

Drosophila microRNAs 263a/b Confer Robustness during Development by Protecting Nascent Sense Organs from Apoptosis

microRNA-263a/b confer robustness to sense organ development by controlling expression of the pro-apoptotic gene hid during apoptotic tissue pruning in Drosophila

Assessment of the Role of Renal Organic Anion Transporters in Drug-Induced Nephrotoxicity

In the present review we have attempted to assess the involvement of the organic anion transporters OAT1, OAT2, OAT3, and OAT4, belonging to the SLC22 family of polyspecific carriers, in drug-induced renal damage in humans. We have focused on drugs with widely recognized nephrotoxic potential, which have previously been reported to interact with OAT family members, and whose underlying pathogenic mechanism suggests the participation of tubular transport. Thus, only compounds generally believed to cause kidney injury either by means of direct tubular toxicity or crystal nephropathy have been considered. For each drug, or class of agents, the evidence for actual transport mediated by individual OATs under in vivo conditions is discussed. We have then examined their role in the context of other carriers present in the renal proximal tubule sharing certain substrates with OATs, as these are critical determinants of the overall contribution of OAT-dependent transport to intracellular accumulation and transepithelial drug secretion, and thus the impact it may have in drug-induced nephrotoxicity

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice