Regenerative medicine aims to replenish damaged tissue. Boosting the capacity of intrinsic stem cells to proliferate is one key for successful regeneration. Adult zebrafish possess tissue resident stem and progenitor cells, which contribute to homeostatic growth and tissue regeneration. In the intact retina, Müller glia sporadically divide to generate fate restricted, proliferative precursors. Cell death reprograms Müller glia into stem cells that divide and produce multi-potent retinal progenitors. Using zebrafish, we evaluated the effect of taurine-conjugated bile acid, Tauroursodeoxycholic acid (TUDCA) on retinal regeneration. In the intact retina, treatment with TUDCA significantly promotes proliferation of the fate restricted precursors, but has no effect on Müller glia. Following constant light exposure, TUDCA attenuates photoreceptor death, indicating that TUDCA is neuroprotective. Following a stab wound, which initiates death of retinal neurons and reprogramming of Müller glia, treatment with TUDCA significantly increases the number of proliferating cells. In the intact retina, TUDCA-induced proliferation was accompanied by decreased expression of cell cycle inhibitors. These results suggest that TUDCA promotes proliferation of actively-cycling stem and progenitors, identifying TUDCA as a potential reagent to promote regeneration of retinal neurons.
Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic disorder, characterized by the fat accumulation in hepatocytes without significant alcohol assumption. In lipogenesis in hepatocytes, the tricarboxylic acid cycle citrate plays a crucial role as a carbon source. Citrate is transported into hepatocytes via Na+-coupled citrate transporter, NaCT. It has been demonstrated that knockdown of NaCT expression ameliorates diet-induced NAFLD in mice. In addition, NaCT expression in the liver has been reported to be induced in type 2 diabetic mice. Based on these findings, NaCT is considered to be involved in the high prevalence of NAFLD in patients with type 2 diabetes. On the other hand, it is still unclear for the expression level of NaCT under type 1 diabetic condition and its relationship to hepatic lipid accumulation. In this study, we investigated the gene and functional expression level of NaCT in streptozotocin (STZ)-induced type 1 diabetic mice. The mRNA and protein expression levels of NaCT in STZ-treated mice were gradually decreased after STZ treatment. On the other hand, the Na+-dependent citrate uptake activity in hepatocytes isolated from STZ-treated mice was not different from that isolated from non-treated mice. Nevertheless, the plasma triglyceride, cholesterol, and nonesterified fatty acid levels were much higher in STZ-treated mice. These results suggest that NaCT expression level is not closely related to the citrate uptake in hepatocytes under type 1 diabetic condition. In conclusion, unlike type 2 diabetes, NaCT may not be responsible for the pathogenesis of NAFLD in type 1 diabetes.
A decrease in renal function leads to the accumulation of various uremic toxins (UTs) which exert unfavorable physiological effects on the body. Indoxyl sulfate (IS), a tryptophan-derived UT, is known to closely associate with the progression of cognitive disorders (CD) including dementia, in addition to chronic kidney disease (CKD) and cardiovascular events. It is, therefore, important to assess blood IS levels in CKD patients with CD. In this study, we assayed serum IS levels in 37 residents who had been admitted to a geriatric health services facility with stage G3b to G5 CKD and evaluated the correlation between serum IS levels and estimated glomerular filtration rate (eGFR). Eighteen out of 37 residents were considered to suffer dementia. When plotting all serum IS levels against eGFR, a weak but significant correlation was observed with a regression coefficient (r) of -0.420. In the non-dementia group, the correlation between serum IS levels and eGFR became stronger (r = -0.720). However, no correlation was observed in the dementia group. At CKD stage G3b, mean serum IS level was higher in the dementia group than in the non-dementia group. These results suggest that eGFR becomes a good marker to predict serum IS level in the case of CKD patients without dementia, but not in those with dementia. Therefore, direct monitoring of serum IS level is essential to assess the onset and/or progression of dementia in the elderly, irrespective of CKD stages.
Cholesterol deficiency is believed to result in fragile plasma membranes. It remains unclear whether a reduction in the amounts of both mevalonate pyrophosphate decarboxylase (MPD), which is involved in cholesterol biosynthesis, and cholesterol content occurs in the cerebrum and brain stem (diencephalon and midbrain) in or near the sites of strokes in stroke-prone spontaneously hypertensive rats (SHRSP). In this study, we investigated whether a reduction in both the amounts of MPD and cholesterol content corresponded to the sites of strokes in the SHRSP brain. The results obtained suggested that a reduction in the amount of MPD was involved in the decrease observed in cholesterol content, and was also important as a risk factor for stroke in SHRSP because the reductions in cholesterol content and MPD protein levels were associated with the sites of strokes. The mechanism responsible for reducing MPD protein levels in the brains of SHRSP differed with each region.