Translational research : the journal of laboratory and clinical medicine
-
The prevalence of chronic kidney disease (CKD) in the worldwide population is currently estimated between 11% and 13%. Adequate renal clearance is compromised in these patients and the accumulation of a large number of uremic retention solutes results in an irreversible worsening of renal function which can lead to end stage renal disease (ESRD). Approximately three million ESRD patients currently receive renal replacement therapies (RRTs), such as hemodialysis, which only partially restore kidney function, as they are only efficient in removing mainly small, unbound solutes from the circulation while leaving larger and protein-bound uremic toxins (PBUTs) untouched. ⋯ In this review, we address several strategies currently being explored toward reducing PBUT concentrations, including clinical and medical approaches, therapeutic techniques, and recent developments in RRT technology. These include preservation of renal function, limitation of colon derived PBUTs, oral sorbents, adsorbent RRT technology, and use of albumin displacers. Despite the promising results of the different approaches to promote enhanced removal of a small percentage of the more than 30 identified PBUTs, on their own, none of them provide a treatment with the required efficiency, safety and cost-effectiveness to prevent CKD-related complications and decrease mortality and morbidity in ESRD.
-
Iron plays a key role in secondary neuronal injury after intracerebral hemorrhage (ICH), and hepcidin is able to reduce brain iron in iron-overloaded rats by down-regulating iron transport proteins including ferroportin 1 and transferrin receptor 1. These led us to hypothesize that hepcidin might reduce iron-mediated neurotoxicity by inhibiting iron accumulation in ICH brain. ⋯ The findings collectively showed that hepcidin could effectively attenuate iron-mediated secondary neuronal injury after ICH in rats. This naturally existing protein can potentially be developed into a therapeutic drug for the treatment of ICH patients.
-
Abundant intraperitoneal (IP) accumulation of extracellular mucus in patients with appendiceal mucinous carcinoma peritonei (MCP) causes compressive organ dysfunction and prevents delivery of chemotherapeutic drugs to cancer cells. We hypothesized that reducing extracellular mucus would decrease tumor-related symptoms and improve chemotherapeutic effect in patient-derived models of MCP. Mucolysis was achieved using a combination of bromelain (BRO) and N-acetylcysteine (NAC). ⋯ Conversion of solid mucinous tumors into mucinous ascites decreases tumor bulk and allows for minimally invasive drainage of liquified tumors. Lysis of extracellular mucus removes the protective mucinous coating surrounding cancer cells and improves chemotherapeutic drug delivery/efficacy in cancer cells. Our data provide a preclinical rationale for the clinical evaluation of BRO + NAC as a therapeutic strategy for MCP.
-
Sulfonylureas, widely used as hypoglycemic agents in adults with type 2 diabetes, have neuroprotective effects in preclinical models of central nervous system injury, and in children with neuropsychomotor impairments linked to neonatal diabetes secondary to ATP-sensitive potassium channel mutations. In the human and rodent retina, we show that the glibenclamide-activated channel sulfonylurea receptor 1 (SUR1) is expressed in the retina and enriched in the macula; we also show that it colocalizes with the potassium channel Kir6.2, and with the cation channel transporter TRPM4. ⋯ The glibenclamide effects include the transcriptional regulation of antioxidant and neuroprotective genes. Ocular glibenclamide could be repurposed for diabetic retinopathy.