scholarly journals Risedronate Attenuates Podocyte Injury in Phosphate Transporter-Overexpressing Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-10
Author(s):  
Yohei Asada ◽  
Takeshi Takayanagi ◽  
Tsukasa Kawakami ◽  
Eisuke Tomatsu ◽  
Atsushi Masuda ◽  
...  

Osteoporosis patients with chronic kidney disease (CKD) are becoming common in our superaging society. Renal dysfunction causes phosphorus accumulation in the circulating plasma and leads to the development of CKD-mineral bone disorder (MBD). We have previously reported that type III Pi transporter-overexpressing transgenic (Pit-1 TG) rats manifest phosphate (Pi)-dependent podocyte injury. In the present study, we explored the effect of risedronate on Pi-induced podocyte injury in vivo. Pit-1 TG rats and wild-type rats at 5 weeks old were divided into a risedronate-treated group and an untreated group. We subcutaneously administered 5 μg/kg body weight of risedronate or saline twice a week during the experimental period. Risedronate did not alter serum creatinine levels at 5, 8, and 12 weeks of age. However, electron microscopy images showed that thickening of the glomerular basement membrane was improved in the risedronate treatment group. Furthermore, immunostaining for podocyte injury markers revealed that both desmin- and connexin43-positive areas were smaller in the risedronate-treated group than in the untreated group, suggesting that bisphosphonates could rescue Pi-induced podocyte injury. In conclusion, our findings suggest that risedronate could maintain glomerular barrier function by rescuing Pi-induced podocyte injury.

Author(s):  
Janet Herrada ◽  
Ahmed Gamal ◽  
Lisa Long ◽  
Sonia P. Sanchez ◽  
Thomas S. McCormick ◽  
...  

Antifungal activity of AmBisome against Candida auris was determined in vitro and in vivo. AmBisome showed MIC50 and MIC90 values of 1 and 2 μg/mL, respectively. Unlike conventional amphotericin B, significant in vivo efficacy was observed in the AmBisome 7.5 mg/kg -treated group in survival and reduction of kidney tissue fungal burden compared to the untreated group. Our data shows that AmBisome shows significant antifungal activity against C. auris in vitro as well as in vivo.


2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Seyedmojtaba Seyedmousavi ◽  
Johan W. Mouton ◽  
Willem J. G. Melchers ◽  
Paul E. Verweij

ABSTRACT Using an immunocompetent murine model of invasive aspergillosis (IA), we previously reported that the efficacy of liposomal amphotericin B (L-AmB) (Ambisome) is not hampered by the presence of azole resistance mutations in Aspergillus fumigatus (S. Seyedmousavi, W. J. G. Melchers, J. W. Mouton, and P. E. Verweij, Antimicrob Agents Chemother 57:1866–1871, 2013, https://doi.org/10.1128/AAC.02226-12 ). We here investigated the role of immune suppression, i.e., neutropenia and steroid treatment, in L-AmB efficacy in mice infected with wild-type (WT) A. fumigatus and with azole-resistant A. fumigatus harboring a TR34/L98H mutation in the cyp-51A gene. Survival of treated animals at day 14 in both immunosuppressed models was significantly better than that of nontreated controls. A dose-response relationship was observed that was independent of the azole-resistant mechanism and the immunosuppression method used. In the neutropenic model, 100% survival was reached at an L-AmB dose of 16 mg/kg of body weight for the WT strain and the TR34/L98H isolate. In the steroid-treated group, 90.9% survival and 100% survival were achieved for the WT isolate and the TR34/L98H isolate with an L-AmB dose of 16 mg/kg, respectively. The 50% effective dose (ED50) was 1.40 mg/kg (95% confidence interval [CI], 0.66 to 3.00 mg/kg) for the WT isolate and 1.92 mg/kg (95% CI, 0.60 to 6.17 mg/kg) for the TR34/L98H isolate in the neutropenic model and was 2.40 mg/kg (95% CI, 1.93 to 2.97 mg/kg) for the WT isolate and 2.56 mg/kg (95% CI, 1.43 to 4.56 mg/kg) for the TR34/L98H isolate in the steroid-treated group. Overall, there were no significant differences between the two different immunosuppressed conditions in the efficacy of L-AmB against the wild-type and azole-resistant isolates (P > 0.9). However, the required L-AmB exposure was significantly higher than that seen in the immunocompetent model.


2006 ◽  
Vol 105 (Supplement) ◽  
pp. 208-213 ◽  
Author(s):  
Desheng Xu ◽  
Qiang Jia ◽  
Yanhe Li ◽  
Chunsheng Kang ◽  
Peiyu Pu

ObjectThe authors sought to study the combined potential of wild-type p53 gene transfer and Gamma Knife surgery (GKS) for the treatment of glioblastomas multiforme. Modification of the radiation response in C6 glioma cells in vitro and in vivo by the wild-type p53 gene was investigated.MethodsStable expression of wild-type p53 in C6 cells was achieved by transduction of the cells with adenoviral p53. Two days later, some cells were treated with GKS. Forty-eight hours after irradiation, the comparative survival rate was assessed by monotetrazolium (MTT) assays. Treated and control C6 glioma cells (4 × 103 per well) were plated into a 96-well plate in octuplicate and tested every 24 hours. Meanwhile, immunohistopathological examination of proliferating cell nuclear antigen (PCNA) and terminal deoxynucleotidyl transferase—mediated deoxyuridine triphosphate (TUNEL) assays were performed. The MTT assays indicated the p53, GKS, and combined treated cells proliferated at a significantly lower rate than those of the control group (p < 0.01, Days 2–6) and the positive fraction of PCNA in p53-treated group and GKS-treated group was 70.18 ± 3.61 and 50.71 ± 2.61, respectively, whereas the percentage in the combined group was 30.68 ± 1.49 (p < 0.01).Fifty-six male Sprague–Dawley rats were anesthetized and inoculated with 106 cultured C6 glioma cells into the cerebrum. Forty-eight hours after transduction with adenoviral p53, some rats underwent GKS. A margin dose of 15 Gy was delivered to the 50% isodose line. Two days later, six rats in each group were killed. Their brains were removed and paraffin-embedded section were prepared for immunohistopathological examination and TUNEL assays. The remaining rats were observed for the duration of the survival period. The survival curve indicated that a modest but significant enhancement of survival duration was seen in the p53-treated or GKS alone groups, whereas a more marked and highly significant enhancement of survival duration was achieved when these two treatment modalities were combined. When PCNA expression was downregulated, apoptotic cells become obvious after TUNEL staining.Conclusions The findings of this study suggest that p53-based gene therapy in combination with GKS may be superior to single-modality treatment of C6 glioma.


2020 ◽  
Vol 34 (6) ◽  
pp. 823-834
Author(s):  
Min Park ◽  
Takanori Nishimura ◽  
Carlos D. Baeza-Garza ◽  
Stuart T. Caldwell ◽  
Pamela Boon Li Pun ◽  
...  

Abstract Purpose HFpEF (heart failure with preserved ejection fraction) is a major consequence of diabetic cardiomyopathy with no effective treatments. Here, we have characterized Akita mice as a preclinical model of HFpEF and used it to confirm the therapeutic efficacy of the mitochondria-targeted dicarbonyl scavenger, MitoGamide. Methods and Results A longitudinal echocardiographic analysis confirmed that Akita mice develop diastolic dysfunction with reduced E peak velocity, E/A ratio and extended isovolumetric relaxation time (IVRT), while the systolic function remains comparable with wild-type mice. The myocardium of Akita mice had a decreased ATP/ADP ratio, elevated mitochondrial oxidative stress and increased organelle density, compared with that of wild-type mice. MitoGamide, a mitochondria-targeted 1,2-dicarbonyl scavenger, exhibited good stability in vivo, uptake into cells and mitochondria and reactivity with dicarbonyls. Treatment of Akita mice with MitoGamide for 12 weeks significantly improved the E/A ratio compared with the vehicle-treated group. Conclusion Our work confirms that the Akita mouse model of diabetes replicates key clinical features of diabetic HFpEF, including cardiac and mitochondrial dysfunction. Furthermore, in this independent study, MitoGamide treatment improved diastolic function in Akita mice.


Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 827
Author(s):  
Matan Soll ◽  
Hagit Goldshtein ◽  
Ron Rotkopf ◽  
Niva Russek-Blum ◽  
Zeev Gross

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons. To date, the etiology of the disease is still unclear, with evidence of reactive oxygen species, mitochondrial dysfunction, iron homeostasis perturbation, protein misfolding and protein aggregation as key players in the pathology of the disease. Twenty percent of familial ALS and two percent of sporadic ALS instances are due to a mutation in Cu/Zn superoxide dismutase (SOD1). Sporadic and familial ALS affects the same neurons with similar pathology; therefore, the underlying hypothesis is that therapies effective in mutant SOD1 models could be translated to sporadic ALS. Corrole metal complexes have lately been identified as strong and potent catalytic antioxidants with beneficial effects in oxidative stress-related diseases such as Parkinson’s disease, Alzheimer’s disease, atherosclerosis, diabetes and its complications. One of the most promising candidates is the iron complex of an amphiphilic corrole, 1-Fe. In this study we used the SOD1 G93R mutant zebrafish ALS model to assess whether 1-Fe, as a potent catalytic antioxidant, displays any therapeutic merits in vivo. Our results show that 1-Fe caused a substantial increase in mutant zebrafish locomotor activity (up to 30%), bringing the locomotive abilities of the mutant treated group close to that of the wild type untreated group (50% more than the mutated untreated group). Furthermore, 1-Fe did not affect WT larvae locomotor activity, suggesting that 1-Fe enhances locomotor ability by targeting mechanisms underlying SOD1 ALS specifically. These results may pave the way for future development of 1-Fe as a viable treatment for ALS.


2020 ◽  
Author(s):  
Zhi Chen ◽  
Qing Zhou ◽  
Cong Liu ◽  
Yiping Zeng ◽  
Shaolong Yuan

Abstract Background: Diabetic nephropathy (DN) is a progressive disease, the main pathogeny of which is podocyte injury inducing glomerular filtration barrier and proteinuria. The occurrence and development of DN could be partly attributed to the reactive oxygen species (ROS) generated by mitochondria. However, researches on how mitochondrial dysfunction (MtD) ultimately causes DNA damage is poor.Methods: We generated streptozotocin (STZ)-induced diabetic mice with wild-type(C57BL/6J) or Klotho deficiency mice (KL+/-) and treated podocytes with high glucose (HG) to investigated the function of Klotho on HG-induced podocyte injury in vivo and in vitro.Results: The absence of Klotho aggravated diabetic phenotypes indicated by podocyte injury accompanied by elevated urea albumin creatinine ratio (UACR), creatinine, urea nitrogen. Then, Klotho deficiency could significantly aggravate DNA damage by increasing 8-OHdG and reducing OGG1. Finally, Klotho deficiency may promote MtD to promote 8-OHdG-induced podocyte injury.Conclusions: Klotho deficiency may promote diabetes-induced podocytic MtD and aggravate 8-OHdG-induced DNA damage by affecting OOG1.


2021 ◽  
Vol 41 (3) ◽  
pp. 192-213
Author(s):  
M.O Otu ◽  
I.A Lawal ◽  
D George ◽  
M Abubakar ◽  
A.A Sekoni ◽  
...  

A study to determine the anticoccidial efficacy of Khaya senegalensis in relation to oocyst shedding by broilers experimentally infected with Eimeria tenella was conducted. The development of drug- resistant field strains of Eimeria species has prompted the exploitation of alternative methods for controlling coccidiosis and there is an increasing use of medicinal plants as alternatives to orthodox medicine. Fresh leaves of Khaya senegalensis (KS) were collected dried under shade and the extract prepared using the maceration method in 70% methanol. The dried crude extract was partitioned into petroleum ether, chloroform, n-butanol and aqueous portions, dried with phytochemical analysis conducted on them. One hundred and twenty birds reared under standard management practice were divided into six groups (A, B, C, D, E and F). All the groups except group F (uninfected untreated group) were infected at four weeks old with sporulated Eimeria tenella oocysts (1.0 x 105 sporulated oocysts / ml / bird) obtained locally from the intestinal scrapings of experimentally infected broilers. Groups A, B and C were given calculated three dose levels of 11mg/kg, 33mg/kg, 99mg/kg respectively of the prepared n-butanol methanol extract twice daily for 5 days, group D was given Amprolium while E and F were each given 0.2ml water. Faecal samples were collected daily for 4 weeks into clean well labelled polythene bags and analysed in the laboratory for oocyst count using the McMaster counting chamber and were expressed as oocysts count per gramme of faeces. The birds were observed for pathological lesions grossly and histopathologically and the survival rates were determined. Data collected were analysed using analysis of variance and chi square. Results from the Phytochemical studies showed the presence of phenolic compounds in Khaya senegalensis. Post-infection faecal examination revealed oocyst load of +++ in all the infected pens (A-E) on the 6th day. Comparison of the groups with time showed statistical significance (P˂0.05). High mean oocyst production (A; 156060 ± 67020, B; 261590 ± 144310, C; 211620 ± 114280, D; 276930 ± 233650 and E; 159230 ± 100970) among the infected groups one week post infection as well as irregular oocyst production were observed in the course of this study. The higher mean oocysts count obtained in the infected untreated group (1748849 ± 40869) than the extract treated groups in the first week post treatment indicated that the extract had some inhibitory effects on oocyst production. This however, was dose dependent. Among the extract treated group, the 99mg/kg had lower mean oocyst production 2 weeks post treatment (9720 ± 3180) and this was comparable to the group treated with normal dose of the conventional drug Amprolium (8600 ± 40). This was therefore seen as the effective dose. Grossly, the extract had a beneficial effect in alleviating the damages to the caecal epithelium of the infected treated groups compared to the shrunken caeca of the infected untreated groups. The survival percentage was higher in the treated groups compared to the infected un treated group (55%) though Amprolium was more efficacious in the in vivo study with the highest survival rate of 90%. The histopathological lesions observed in the infected birds in this study were consistent with those associated with E tenella infection in which the parasite induced very severe lesions including severe villous atrophy and fusion. The anticoccidial efficacy of Khaya senegalensis promises greater areas for research as it relates to drug development and it is recommended that Khaya senegalensis should be exploited further for its anticoccidial properties using other parts of the plant. Key words: Broiler chickens, Eimeria tenella, oocyst production, Khaya senegalensis, in vivo


2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Andrey V. Cybulsky ◽  
Chris R. J. Kennedy

Focal segmental glomerulosclerosis (FSGS) is an important cause of proteinuria and nephrotic syndrome in humans. The pathogenesis of FSGS may be associated with glomerular visceral epithelial cell (GEC; podocyte) injury, leading to apoptosis, detachment, and “podocytopenia”, followed by glomerulosclerosis. Mutations in α-actinin-4 are associated with FSGS in humans. In cultured GECs, α-actinin-4 mediates adhesion and cytoskeletal dynamics. FSGS-associated α-actinin-4 mutants show increased binding to actin filaments, compared with the wild-type protein. Expression of an α-actinin-4 mutant in mouse podocytes in vivo resulted in proteinuric FSGS. GECs that express mutant α-actinin-4 show defective spreading and motility, and such abnormalities could alter the mechanical properties of the podocyte, contribute to cytoskeletal disruption, and lead to injury. The potential for mutant α-actinin-4 to injure podocytes is also suggested by the characteristics of this mutant protein to form microaggregates, undergo ubiquitination, impair the ubiquitin-proteasome system, enhance endoplasmic reticulum stress, and exacerbate apoptosis.


2016 ◽  
Vol 220 (1) ◽  
pp. 167-173 ◽  
Author(s):  
F. Siegerist ◽  
W. Zhou ◽  
K. Endlich ◽  
N. Endlich

2018 ◽  
Vol 16 (1) ◽  
pp. 49-55 ◽  
Author(s):  
J. Stenzel ◽  
C. Rühlmann ◽  
T. Lindner ◽  
S. Polei ◽  
S. Teipel ◽  
...  

Background: Positron-emission-tomography (PET) using 18F labeled florbetaben allows noninvasive in vivo-assessment of amyloid-beta (Aβ), a pathological hallmark of Alzheimer’s disease (AD). In preclinical research, [<sup>18</sup>F]-florbetaben-PET has already been used to test the amyloid-lowering potential of new drugs, both in humans and in transgenic models of cerebral amyloidosis. The aim of this study was to characterize the spatial pattern of cerebral uptake of [<sup>18</sup>F]-florbetaben in the APPswe/ PS1dE9 mouse model of AD in comparison to histologically determined number and size of cerebral Aβ plaques. Methods: Both, APPswe/PS1dE9 and wild type mice at an age of 12 months were investigated by smallanimal PET/CT after intravenous injection of [<sup>18</sup>F]-florbetaben. High-resolution magnetic resonance imaging data were used for quantification of the PET data by volume of interest analysis. The standardized uptake values (SUVs) of [<sup>18</sup>F]-florbetaben in vivo as well as post mortem cerebral Aβ plaque load in cortex, hippocampus and cerebellum were analyzed. Results: Visual inspection and SUVs revealed an increased cerebral uptake of [<sup>18</sup>F]-florbetaben in APPswe/ PS1dE9 mice compared with wild type mice especially in the cortex, the hippocampus and the cerebellum. However, SUV ratios (SUVRs) relative to cerebellum revealed only significant differences in the hippocampus between the APPswe/PS1dE9 and wild type mice but not in cortex; this differential effect may reflect the lower plaque area in the cortex than in the hippocampus as found in the histological analysis. Conclusion: The findings suggest that histopathological characteristics of Aβ plaque size and spatial distribution can be depicted in vivo using [<sup>18</sup>F]-florbetaben in the APPswe/PS1dE9 mouse model.


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