ABSTRACT
Background/Aims@#Tacrolimus has been used as an immunosuppressive agent in organ transplantation. Despite the therapeutic benefits, tacrolimus’s use is limited due to its nephrotoxicity. To reduce tacrolimus nephrotoxicity, effective humanized experimental models may be helpful. Here, we modeled tacrolimus nephrotoxicity using kidney organoids derived from human inducible pluripotent stem cells (iPSCs) in vitro. @*Methods@#Kidney organoids were differentiated from the CMC11 iPSC cell line, re-seeded in 96-well plates, and treated with tacrolimus at doses of 0, 30, or 60 μM for 24 hours. This in vitro model was compared to a mouse model of tacrolimus nephrotoxicity and the associated mechanisms were investigated. @*Results@#The size of the kidney organoids and cell viability decreased in dose-dependent manners after treatment with tacrolimus. The number of tubular cells decreased with a loss of polarity, similar to the effects seen in mouse tacrolimus nephrotoxicity. Ultrastructural analysis showed numerous vacuoles in the proximal tubular cells of the kidney organoids treated with tacrolimus. Tacrolimus treatment induced oxidative stress and mitochondrial dysfunction, and autophagic activity was enhanced in the kidney organoids. Rapamycin, an autophagy inducer, accelerated cell death in the kidney organoid model of tacrolimus nephrotoxicity, which was attenuated by treatment with 3-methyladenine, an autophagy inhibitor. These findings indicate that the augmentation of autophagy by rapamycin treatment accelerated tacrolimus nephrotoxicity. @*Conclusions@#Our data suggest that human kidney organoids are an effective in vitro model of tacrolimus nephrotoxicity and that autophagy plays a critical role in tacrolimus nephrotoxicity.
ABSTRACT
Background/Aims@#Coenzyme Q10 (CoQ10), is a promising antioxidant; however, low bioavailability owing to lipid-solubility is a limiting factor. We developed water-soluble CoQ10 (CoQ10-W) and compared its effects with conventional lipid-soluble CoQ10 (CoQ10-L) in an experimental model of chronic tacrolimus (Tac) nephropathy. @*Methods@#CoQ10-W was developed from a glycyrrhizic-carnitine mixed layer CoQ10 micelle based on acyltransferases. Chronic nephropathy was induced in rats with 28-day Tac treatment; they were concomitantly treated with CoQ10-L or CoQ10-W. CoQ10 level in plasma and kidney were measured using liquid chromatography–mass spectrometry. CoQ10-W and CoQ10-L effects on Tac-induced nephropathy were assessed in terms of renal function, histopathology, oxidative stress, and apoptotic cell death. Their effects on cell viability and reactive oxygen species (ROS) production were assessed in cultured proximal tubular cells, human kidney 2 (HK-2) cells. @*Results@#The plasma CoQ10 level was significantly higher in the CoQ10-W group than in the CoQ10-L group. Tac treatment caused renal dysfunction, typical pathologic lesions, and oxidative stress markers. Serum creatinine was restored in the Tac + CoQ10-L or CoQ10-W groups compared with that in the Tac group. CoQ10-W administration reduced oxidative stress and apoptosis markers. Mitochondrial ultrastructure assessment revealed that the addition of CoQ10-L or CoQ10-W with Tac increased mitochondrial size and number than Tac treatment alone. In vitro investigations revealed that both CoQ10-L and CoQ10-W improved cell viability and reduced ROS production in the Tac-induced HK-2 cell injury. @*Conclusions@#CoQ10-W has a better therapeutic effect in Tac-induced renal injury than conventional CoQ10-L, possibly associated with improved CoQ10 bioavailability
ABSTRACT
Background/Aims@#Coenzyme Q10 (CoQ10), is a promising antioxidant; however, low bioavailability owing to lipid-solubility is a limiting factor. We developed water-soluble CoQ10 (CoQ10-W) and compared its effects with conventional lipid-soluble CoQ10 (CoQ10-L) in an experimental model of chronic tacrolimus (Tac) nephropathy. @*Methods@#CoQ10-W was developed from a glycyrrhizic-carnitine mixed layer CoQ10 micelle based on acyltransferases. Chronic nephropathy was induced in rats with 28-day Tac treatment; they were concomitantly treated with CoQ10-L or CoQ10-W. CoQ10 level in plasma and kidney were measured using liquid chromatography–mass spectrometry. CoQ10-W and CoQ10-L effects on Tac-induced nephropathy were assessed in terms of renal function, histopathology, oxidative stress, and apoptotic cell death. Their effects on cell viability and reactive oxygen species (ROS) production were assessed in cultured proximal tubular cells, human kidney 2 (HK-2) cells. @*Results@#The plasma CoQ10 level was significantly higher in the CoQ10-W group than in the CoQ10-L group. Tac treatment caused renal dysfunction, typical pathologic lesions, and oxidative stress markers. Serum creatinine was restored in the Tac + CoQ10-L or CoQ10-W groups compared with that in the Tac group. CoQ10-W administration reduced oxidative stress and apoptosis markers. Mitochondrial ultrastructure assessment revealed that the addition of CoQ10-L or CoQ10-W with Tac increased mitochondrial size and number than Tac treatment alone. In vitro investigations revealed that both CoQ10-L and CoQ10-W improved cell viability and reduced ROS production in the Tac-induced HK-2 cell injury. @*Conclusions@#CoQ10-W has a better therapeutic effect in Tac-induced renal injury than conventional CoQ10-L, possibly associated with improved CoQ10 bioavailability
ABSTRACT
Neuron-glial antigen-2 (NG2) glia undergo proliferation and morphological changes following brain insults. Here, we show that NG2 glia is activated in a characteristic time- and layer-specific manner in the ischemia-vulnerable CA1 region of the rat hippocampus. Resting NG2 glia of the pyramidal cell layer (somatic region) shared morphological features with those of the neighboring dendritic stratum radiatum. During the postischemic period, reactive NG2 glia of the pyramidal cell layer exhibited shortened, scarcely branched processes, while those of the stratum radiatum had multiple branching processes with their arborization being almost indiscernible 7~14 days after reperfusion. Immunoelectron microscopy demonstrated that NG2 immunoreactivity was specifically associated with the plasma membrane and the adjacent extracellular matrix of NG2 glia in the stratum radiatum at 14 days. NG2 glia also exhibited differences in their numbers and proliferation profiles in the two examined hippocampal strata after ischemia. In addition, induced NG2 expression in activated microglia/macrophages exhibited a characteristic strata-dependent pattern in the ischemic CA1 hippocampus. NG2 induction was prominent in macrophage-like phenotypes which were predominantly localized in the pyramidal cell layer, compared with activated stellate microglial cells in the stratum radiatum. Thus, our data demonstrate that activation of NG2 glia and the induction of NG2 expression in activated microglia/macrophages occur in a distinct time- and layer-specific manner in the ischemic CA1 hippocampus. These characteristic profiles of reactive NG2 glia could be secondary to the degeneration processes occurring in the cell bodies or dendritic domains of hippocampal CA1 pyramidal neurons after ischemic insults.
ABSTRACT
The retina is a highly specialised part of the brain responsible for visual processing. It is well-laminated; three layers containing five different types of neurons are compartmentalised by two synaptic layers. Among the retinal layers, the inner nuclear layer (INL) is composed of horizontal, bipolar, and amacrine cell types. Bipolar cells form one sublayer in the distal half of the IPL, while amacrine cells form another sublayer in the proximal half, without any border-like structure. Here, we report that a plexiform layer-like structure exists temporarily in the border between the bipolar and amacrine sublayers in the INL in the rat retina during retinal development. This transient intermediate plexiform layer (TIPL) appeared at postnatal day (PD) 7 and then disappeared around PD 12. Most apoptotic cells in the INL were found near the TIPL. These results suggest that the TIPL may contribute to the formation of sublayers and the cell number limit in the INL.
Subject(s)
Animals , Rats , Amacrine Cells , Apoptosis , Brain , Cell Count , Neurons , Retina , RetinaldehydeABSTRACT
No abstract available.
Subject(s)
Cyclosporine , Eczema , Hand , Retrospective Studies , Treatment OutcomeABSTRACT
Basosquamous carcinoma is a rare epithelial neoplasm, mostly occurring on the head and neck area. There are few reports of basosquamous carcinoma on the finger. Here, the authors experienced treatment of basosquamous carcinoma on the finger in a radiologist. Treatment was successful by the wide excision and the cross-finger flap operation with a split-thickness skin graft and K-wire fixation. The rare finger basosquamous carcinoma case in our study is likely to be linked with radiation. Considering of the high reliance of C-arm during hand surgeries, we think that the hand of the surgeons should be more strictly protected.
Subject(s)
Carcinoma, Basosquamous , Fingers , Hand , Head , Neck , Neoplasms, Glandular and Epithelial , Radiation Exposure , Skin , Surgeons , TransplantsABSTRACT
Some retinal neurons, including intrinsically photosensitive retinal ganglion cells have their dendrites stratified in sublamina a of the inner plexiform (IPL), the OFF sublayer, but paradoxically show light-driven ON electrophysiological responses. In order to understand the mechanism on this paradoxical response, by using immunoelectron microscopy with a specific antibody against calbindin, we examined the synaptic connections of the calbindin-immunoreactive ON cone bipolar cell of the rabbit retina, which is thought to make the ribbon synapse in sublamina a of the IPL. The ribbon synapses in sublamina a by calbindin-immunoreactive ON cone bipolar cells were mainly found at the border between the inner nuclear layer and the IPL. Interestingly, the output targets at these ribbon synapses turned out as monads, and multiple synaptic ribbons were engaged in each synapse. These findings were different from those at the conventional ribbon synapse formed by calbindin-immunoreactive ON cone bipolar axon terminals. Thus, these findings may be the characteristics of the calbindin-immunoreactive ON cone bipolar ribbon synapse in sublamina a and can be used to classify the synapse in the retinal circuit research.