Investigating Potential Therapies to Decrease the Rate of Cystine Stone Growth in Slc3a1-/- Mice

Cystinuria is an autosomal recessive disorder characterized by a defective renal transporter involved in the reabsorption of cystine and other dibasic amino acids. This leads to an accumulation of cystine in the urine, resulting in cystine stones. The SLC3A1/SLC7A9 cystine transporter accounts for 90% of cystine reabsorption and mutations in this transporter result in the formation of cystine stones. For this study, micro-computed tomography (µCT) scanning was evaluated for its feasibility to track accurate volumetric measurements of in vivo cystine stone growth in the Slc3a1-/- cystinuric mouse model. Six pharmacological interventions – sulforaphane, methyl selenocysteine, homocysteine, tiopronin, TPEN and a zinc-supplemented diet– were also examined for their efficacy in reducing the rate of cystine stone growth. µCT analysis revealed stone growth proceeds linearly. Sulforaphane and TPEN supplementation resulted in a reduced rate of stone growth when compared to the respective vehicle controls; however, methyl selenocysteine and the zinc-supplemented diet displayed no effect on the rate or nature of stone formation. Homocysteine and tiopronin were shown to worsen stone growth rate. Sulforaphane and TPEN were effective interventions and our findings support both as a potential therapy for a cystinuric mouse model. A combination of treatments targeting the rate of cystine stone formation through similar agents appears to be a novel approach in further understanding cystine stone growth. Therapies that can manage the balance between these agents and adverse side effects provide an avenue to effectively treating cystinuria

Impact of pyriproxyfen on virus behavior: implications for pesticide-induced virulence and mechanism of transmission

Background More than 3 years since the last Zika virus (ZIKV) outbreak in Brazil, researchers are still deciphering the molecular mechanisms of neurovirulence and vertical transmission, as well as the best way to control spread of ZIKV, a flavivirus. The use of pesticides was the main strategy of mosquito control during the last ZIKV outbreak. Methods We used vesicular stomatitis virus (VSV) tagged with green fluorescent protein (GFP) as our prototypical virus to study the impact of insecticide pyriproxyfen (PPF). VZV-GFP infected and uninfected Jurkat, HeLa and trophoblast cells were treated with PPF and compared to untreated cells (control). Cell viability was determined by the MTT assay. Cell morphology, presence of extracellular vesicles (EVs), virus infection/GFP expression as well as active mitochondrial levels/localization were examined by confocal microscopy. Results PPF, which was used to control mosquito populations in Brazil prior to the ZIKV outbreak, enhances VSV replication and has cell membrane-altering properties in the presence of virus. PPF causes enhanced viral replication and formation of large EVs, loaded with virus as well as mitochondria. Treatment of trophoblasts or HeLa cells with increasing concentrations of PPF does not alter cell viability, however, it proportionately increases Jurkat cell viability. Increasing concentrations of PPF followed by VSV infection does not interfere with HeLa cell viability. Both Jurkats and trophoblasts show proportionately increased cell death with increased concentrations of PPF in the presence of virus. Conclusions We hypothesize that PPF disrupts the lipid microenvironment of mammalian cells, thereby interfering with pathways of viral replication. PPF lowers viability of trophoblasts and Jurkats in the presence of VSV, implying that the combination renders immune system impairment in infected individuals as well as enhanced vulnerability of fetuses towards viral vertical transmission. We hypothesize that similar viruses such as ZIKV may be vertically transmitted via EV-to-cell contact when exposed to PPF, thereby bypassing immune detection. The impact of pesticides on viral replication must be fully investigated before large scale use in future outbreaks of mosquito borne viruses

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Not AvailableHybrid breeding technology is one of the most feasible options to meet the future food challenges and sustainable agriculture. Genetic diversity studies determine the inherent potential of a cross for heterosis and frequency of desirable recombinants. Optimum parental diversity is required to obtain superior cross combinations in the further generations. Hence, the present study was conducted with 100 maintainer lines of rice hybrids using eighty SSR markers, out of which 16 were found to be polymorphic and 10 were monomorphic. Molecular diversity analysis revealed a total of five clusters at a similarity coefficient 0.73. Sixteen out of 80 markers were found to be polymorphic. The number of alleles per locus ranged from 2 to 8 with an average per locus of 4.5. The PIC values varied widely among SSR loci tested and ranged from a minimum 0.37 (JGT725.2) to maximum 0.76 (RM12424) with an average of 0.61. The highest similarity was observed between TCP 1128 and TCP 1145 whereas the most diverse genotypes were TCP726 and TCP816. The most diverse genotypes could be used as parents in the hybridization experiments.Not Availabl

α-Lipoic acid treatment prevents cystine urolithiasis in a mouse model of cystinuria

Excess urinary cystine can lead to painful stone formation. There is no current effective treatment, but here Pankaj Kapahi, Marshall Stoller and colleagues have found that α-lipoic acid can prevent or even reverse formation of these stones in a mouse model

α-Lipoic acid treatment prevents cystine urolithiasis in a mouse model of cystinuria

Excess urinary cystine can lead to painful stone formation. There is no current effective treatment, but here Pankaj Kapahi, Marshall Stoller and colleagues have found that α-lipoic acid can prevent or even reverse formation of these stones in a mouse model

α-Lipoic acid treatment prevents cystine urolithiasis in a mouse model of cystinuria

Cystinuria is an incompletely dominant disorder characterized by defective urinary cystine reabsorption that results in the formation of cystine-based urinary stones. Current treatment options are limited in their effectiveness at preventing stone recurrence and are often poorly tolerated. We report that the nutritional supplement α-lipoic acid inhibits cystine stone formation in the Slc3a1-/- mouse model of cystinuria by increasing the solubility of urinary cystine. These findings identify a novel therapeutic strategy for the clinical treatment of cystinuria