Inactivation of Tsc2 in Abcg2 Lineage Derived Cells Drives the Appearance of Polycystic Lesions and Fibrosis in the Adult Kidney.

Inactivation of Tsc2 in Abcg2 Lineage Derived Cells Drives the Appearance of Polycystic Lesions and Fibrosis in the Adult Kidney. Am J Physiol Renal Physiol. 2019 Aug 28;: Authors: Gewin L, Summers ME, Harral JW, Gaskill CF, Nlandu Khodo S, Neelisetty S, Sullivan TM, Hopp K, Reese JJ, Klemm DJ, Kon V, Ess KC, Shi W, Majka SM Abstract Tuberous sclerosis complex 2, or Tuberin, is a pivotal regulator of the mechanistic target of rapamycin (mTOR) signaling pathway that controls cell survival, proliferation, growth and migration. Loss of Tsc2 function manifests in organ specific consequences, the mechanisms of which remain incompletely understood. Recent single cell analysis of kidney identified Abcg2 expression in renal proximal tubules of adult mice as well as a novel cell population. The impact in adult kidney of Tsc2 knockdown in the ATP binding cassette G2 (Abcg2) expressing lineage has not been evaluated. We engineered an inducible system in which expression of truncated Tsc2, lacking exons 36-37 with an intact 3 prime region and Pkd1, is driven by Abcg2. Here we demonstrate that selective expression of Tsc2fl36-37in the Abcg2pos lineage drives recombination in proximal tubule epithelial and rare perivascular mesenchymal cells which results in progressive proximal tubule injury, impaired kidney function, the formation of cystic lesions, and fibrosis in adult mice. These data illustrate the critical importance of Tsc2 function in the Abcg2 expressing pro...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research

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García-Peñas JJ Abstract It is estimated that about 70 million people all over the world suffer from epilepsy, half of which are children, in whom the prevalence is around 0.5 to 0.8%. Although there are several therapies, the treatment of epilepsy is based mainly on drugs, which, depending on the year of coming onto the market are classified as first, second, or third generation. In this article, a description is presented on the main characteristics of the latest generation of anti-epileptic drugs (lacosamide, eslicarbazepine acetate, brivaracetam, perampanel, retigabine, everolimus and cannabidiol...
Source: Anales de Pediatria - Category: Pediatrics Authors: Tags: An Pediatr (Barc) Source Type: research
Source: Frontiers in Neurology - Category: Neurology Source Type: research
Resistance exercise ‐induced skeletal muscle protein synthesis does not occur during a severe fasting. AbstractResistance exercise (RE) activates the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway and increases muscle protein synthesis. Severe fasting induces 5 ′ adenosine monophosphate‐activated protein kinase (AMPK), which attenuates mTORC1 activation. However, the effect of RE on the response of mTORC1 signaling proteins after a period of severe fasting is unclear. We investigated the effect of RE on rat skeletal muscle protein metabolism after a pe riod of severe fasting. We hypothesized...
Source: Physiological Reports - Category: Physiology Authors: Tags: Original Research Source Type: research
Tuberous sclerosis complex (TSC) is characterized by tumor development in the brain, heart, kidney, and lungs. In TSC tumors, loss of the TSC1/TSC2 protein complex leads to activation of mTORC1 with downstream effects on anabolism and cell growth. Because mTORC1 activation enhances mRNA transcription, we hypothesized that aberrant mTORC1 activation might confer TSC-null cell dependence on transcriptional regulation. We demonstrate that TSC1- or TSC2-null cells, in contrast to their wild-type counterparts, are sensitive to pharmacological inhibition of CDK7. Mechanistic studies revealed that CDK7 inhibition markedly reduces...
Source: The Journal of Experimental Medicine - Category: Internal Medicine Authors: Tags: Solid Tumors Articles Source Type: research
This study aims to develop an inhaled formulation of rapamycin solid lipid nanoparticles (Rapa-SLNs) to avoid first-pass metabolism, increase in-vivo half-life and facilitate entry into the lymphatic system through the lungs. Rapa-SLNs were manufactured using a hot evaporation technique and freeze-dried overnight with 5% (w/v) mannitol and before being assessed further for particle characteristics and in vitro aerosol performance and release. The formulation's ability to penetrate through bronchial epithelial layer was evaluated using a Calu-3 cell model, while its ability to interfere with the LAM intracellular cascade wa...
Source: European Journal of Pharmaceutical Sciences - Category: Drugs & Pharmacology Authors: Tags: Eur J Pharm Sci Source Type: research
NPRL3 (nitrogen permease regulator-like 3), NPRL2, and DEPDC5 (disheveled, Egl-10, and pleckstrin (DEP) domain-containing 5) form the GATOR1 complex (GTPase-activating protein (GAP) activity toward RAG complex 1) [1]. GATOR1 is in the mammalian target of rapamycin (mTOR) pathway and negatively regulates it (Fig. 1) [2]. Mutations in DEPDC5, NPRL2, and NPRL3 are associated with focal epilepsy and cortical malformations [2,3]. Treatment with a mTOR inhibitor reduces seizures in patients with tuberous sclerosis complex, a known mTORopathy [4].
Source: Seizure: European Journal of Epilepsy - Category: Neurology Authors: Tags: Clinical letter Source Type: research
Hepatic angiomyolipomas (HAMLs) are rare mesenchymal neoplasms, which have highly variable imaging appearances, often leading to misdiagnosis. They belong to the family of perivascular epithelioid cell neoplasms (PEComas). HAMLs have a wide spectrum of imaging appearances due to variable amounts of smooth muscle cells, adipose tissue, and blood vessels in their makeup. Although typically sporadic, they are also associated with tuberous sclerosis. Sporadic lesions tend to be solitary whilst patients with tuberous sclerosis often have multiple HAMLs invariably accompanied by renal AMLs.
Source: Clinical Radiology - Category: Radiology Authors: Tags: Pictorial Review Source Type: research
Conclusion: Epileptogenic tubers presented much more diffusive connectivity with other tubers and perituberal cortexes than any other connectivity relationships across propagating tubers, and the peripheral region of epileptogenic tubers presented the greatest connectivity with propagating tubers and perituberal cortexes. CCEP can be an effective tool in epileptogenic tuber localization in patients with TSC.
Source: Frontiers in Neurology - Category: Neurology Source Type: research
Authors: Woodford MR, Hughes M, Sager RA, Backe SJ, Baker-Williams AJ, Bratslavsky MS, Jacob JM, Shapiro O, Wong M, Bratslavsky G, Bourboulia D, Mollapour M Abstract The molecular chaperone Heat shock protein 90 (Hsp90) is essential for the folding, stability, and activity of several drivers of oncogenesis. Hsp90 inhibitors are currently under clinical evaluation for cancer treatment, however their efficacy is limited by lack of biomarkers to optimize patient selection. We have recently identified the tumor suppressor tuberous sclerosis complex 1 (Tsc1) as a new co-chaperone of Hsp90 that affects Hsp90 binding to i...
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
Mutations in TSC1 or TSC2 gene cause tuberous sclerosis complex (TSC), an autosomal dominant disorder characterized by the formation of non-malignant hamartomas in multiple vital organs. TSC1 and TSC2 gene produc...
Source: BMC Medical Genetics - Category: Genetics & Stem Cells Authors: Tags: Research article Source Type: research
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