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Background Photosensitisation is a clinical condition occurring in both humans and animals that causes significant injury to affected individuals. In livestock, outbreaks of photosensitisation caused by ingestion of toxic plants are relatively common and can be associated with significant economic loss. Objectives The agents that are most commonly implicated in outbreaks of photosensitisation have not been formally investigated on a global scale. To address this question, a systematic review of the literature was undertaken to determine the most common causative agents implicated in outbreaks of photosensitisation in livestock in Australia and globally, as well as the prevalence and morbidity of such outbreaks. Methods A systematic database search was conducted to identify peer-reviewed case reports of photosensitisation in livestock published worldwide between 1900 and April 2018. Only case reports with a full abstract in English were included. Non peer-reviewed reports from Australia were also investigated. Case reports were then sorted by plant and animal species, type of photosensitisation by diagnosis, location, morbidity and mortality rate and tabulated for further analysis. Results One hundred and sixty-six reports qualified for inclusion in this study. Outbreaks were reported in 20 countries. Australia (20), Brazil (20) and the United States (11) showed the highest number of peer-reviewed photosensitisation case reports from this analysis. Hepatogenous (Type III) photosensitisation was the most frequently reported diagnosis (68.5%) and resulted in higher morbidity. Panicum spp., Brachiaria spp. and Tribulus terrestris were identified as the most common causes of hepatogenous photosensitisation globally. Conclusions Hepatogenous photosensitisation in livestock represents a significant risk to livestock production, particularly in Australia, Brazil, and the United States. Management of toxic pastures and common pasture weeds may reduce the economic impact of photosensitisation both at a national and global level.

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Autosomal dominant polycystic kidney disease (ADpKD) is one of the most common inherited monogenic disorders, characterized by a progressive decline in kidney function due in part to the formation of fluid-filled cysts. While there is one FDA-approved therapy, it is associated with potential adverse effects, and all other clinical interventions are largely supportive. Insights into the cellular pathways underlying ADpKD have revealed striking similarities to cancer. Moreover, several drugs originally developed for cancer have shown to ameliorate cyst formation and disease progression in animal models of ADpKD. these observations prompted us to develop a high-throughput screening platform of cancer drugs in a quest to repurpose them for ADPKD. We screened ~8,000 compounds, including compounds with oncological annotations, as well as FDA-approved drugs, and identified 155 that reduced the viability of Pkd1-null mouse kidney cells with minimal effects on wild-type cells. We found that 109 of these compounds also reduced in vitro cyst growth of Pkd1-null cells cultured in a 3D matrix. Moreover, the result of the cyst assay identified therapeutically relevant compounds, including agents that interfere with tubulin dynamics and reduced cyst growth without affecting cell viability. Because it is known that several ADpKD therapies with promising outcomes in animal models failed to be translated to human disease, our platform also incorporated the evaluation of compounds in a panel of primary ADPKD and normal human kidney (NHK) epithelial cells. Although we observed differences in compound response amongst ADPKD and NHK cell preparation, we identified 18 compounds that preferentially affected the viability of most ADPKD cells with minimal effects on NHK cells. Our study identifies attractive candidates for future efficacy studies in advanced pre-clinical models of ADPKD. Autosomal dominant polycystic kidney disease (ADPKD) has a prevalence of 1 in 500-1,000 individuals and is the most common inherited kidney disease, accounting for 6-9% of patients on renal replacement therapy. ADPKD is caused mainly by mutations in PKD1 and to a lesser extent in PKD2, GANAB and DNAJB11 genes. The disease is characterized by a progressive decline in kidney function due to the formation of fluid-filled cysts as well as activation of inflammatory and proliferative pathways, typically leading to end-stage renal disease by the fifth or sixth decade of life 1. Although cyst formation in the kidneys is the hallmark of ADPKD, other epithelial organs including the liver and pancreas are also commonly affected 2,3. With the 2018 FDA approval of Tolvaptan, a vasopressin V 2-receptor antagonist, there is now one therapy available to slow disease progression; however, the drug was only approved for patients at risk of rapid disease progression due to its potential side effects. Nevertheless, most interventions focus on alleviating disease-related symptoms.

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BackgroundLingguizhugan decoction (LGZG), an ancient Chinese herbal formula, has been used to treat cardiovascular diseases in eastern Asia. We investigated whether LGZG has protective activity and the mechanism underlying its effect in an animal model of heart failure (HF).MethodsA rat model of HF was established by administering eight intraperitoneal injections of doxorubicin (DOX) (cumulative dose of 16 mg/kg) over a 4-week period. Subsequently, LGZG at 5, 10, and 15 mL/kg/d was administered to the rats intragastrically once daily for 4 weeks. The body weight, heart weight index (HWI), heart weight/tibia length ratio (HW/TL), and serum BNP level were investigated to assess the effect of LGZG on HF. Echocardiography was performed to investigate cardiac function, and H&E staining to visualize myocardial morphology. Myocardial ultrastructure and T-tubule-sarcoplasmic reticulum (TT-SR) junctions were observed by transmission electron microscopy. The JP-2 protein level was determined by Western blotting. The mRNA level of CACNA1S and RyR2 and the microRNA-24 (miR-24) level were assayed by quantitative RT-PCR.ResultsFour weeks after DOX treatment, rats developed cardiac damage and exhibited a significantly increased BNP level compared with the control rats (169.6 ± 29.6 pg/mL versus 80.1 ± 9.8 pg/mL, P < 0.001). Conversely, LGZG, especially at the highest dose, markedly reduced the BNP level (93.8 ± 17.9 pg/mL, P < 0.001). Rats treated with DOX developed cardiac dysfunction, characterized by a strong decrease in left ventricular ejection fraction compared with the control (58.5 ± 8.7% versus 88.7 ± 4.0%; P < 0.001). Digoxin and LGZG improved cardiac dysfunction (79.6 ± 6.1%, 69.2 ± 2.5%, respectively) and preserved the left ventricular ejection fraction (77.9 ± 5.1, and 80.5 ± 4.9, respectively, P < 0.01). LGZG also improved the LVEDD, LVESD, and FS and eliminated ventricular hypertrophy, as indicated by decreased HWI and HW/TL ratio. LGZG attenuated morphological abnormalities and mitochondrial damage in the myocardium. In addition, a high dose of LGZG significantly downregulated the expression of miR-24 compared with that in DOX-treated rats (fold change 1.4 versus 3.4, P < 0.001), but upregulated the expression of JP-2 and antagonized DOX-induced T-tubule TT-SR microstructural remodeling. These activities improved periodic Ca2+ transients and cell contraction, which may underly the beneficial effect of LGZG on HF.ConclusionsLGZG exerted beneficial effects on DOX-induced HF in rats, which were mediated in part by improved TT-SR microstructural remodeling.

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