Kidney Accumulation Research Articles

A CASE OF ACUTE KIDNEY INJURY CAUSED BY INTERSTITIAL NEPHRITIS COMPLICATED WITH DRESS SYNDROME

Objective: Drug reaction with eosinophilia with systemic symptoms (DRESS) syndrome is a life threatening hyperactivation of immune system by relevant drug use. Lethality accounts up to 10% of all patients. Herein, we present a successful treatment of a DRESS syndrome which complicated with end-stage renal disease, liver dysfunction, eosinophilia, congestive heart failure, skin rash and severe systemic symptoms. Design and method: Fifty-six- year-old Japanese woman was admitted to our hospital for the treatment of duodenal tumor by endoscopic submucosal dissection which accidentally caused perforation. She was treated by piperacillin tazobactam and acetoaminophen. Although the intraperitoneal abscess was cured, she had developed end-stage renal disease, liver dysfunction, eosinophilia, congestive heart failure, skin rash and severe systemic symptoms with high fever of 40 degrees Celcius and tachycardia. Plain CT scan showed kidney enlargement and gallium scintigraphy showed increased accumulation in the bilateral kidneys. eGFR declined to 12 ml/min/1.73m2 from the baseline of 75 and urine tubular makers were elevated. RegiSCAR score was six, and we diagnosed this case as DRESS syndrome. Drug-induced lymphocyte stimulation test turned out positive for both piperacillin tazobactam and acetoaminophen. Results: We decided to administer corticosteroids for the treatment of severe organ involvement. After 30 milligrams of intravenous prednisolone (0.6 mg/kg/day), the above symptoms subsided immediately without causing any adverse effects. The corticosteroids were tapered carefully because it is known that autoimmune disorders such as reactive arthritis, systemic lupus erythematosus and autoimmune hemolytic anemia could develop during the treatment course. The patient's renal function recovered to eGFR of 60 without induction of dialysis. After 12 months of treatment, the patient is free of corticosteroids without any relapse of DRESS syndrome. Conclusions: DRESS syndrome could be caused by a series of drugs, and could be a lethal disease. Immediate diagnosis and treatment are required for acceptable prognosis. Careful follow up should be made because of the relapses, reactivation of viruses such as cytomegaro virus and HHV-6, and autoimmune complications.

Reversal of Hepato-renal Impairment Induced by Meloxicam Paracetamol Toxicity in a Labrador Dog

An 8 years old male Labrador dog was referred to Small animal Medicine Referral Clinic, Veterinary Clinical complex, Veterinary College and Research Institute, Orathanadu for fever, anorexia, hematemesis and melenic stools. The dog on treatment with 2 ml of Meloxicam Paracetamol combination IM, along with Injection Oxytetracycline and fluid therapy for 3 days by locally and did not respond to treatment thus was referred. Clinical dullness, lethargy, respiratory distress, visible mucosal jaundice, ecchymosis on ventral abdomen was noticed. Physical examination revealed, halitosis, ulceration in the tip of the tongue, dehydration, pre scapular LN enlargement, distended abdomen, fluid thrill and splenomegaly. Hematology revealed anemia and thrombocytopenia. Biochemical analysis revealed Hyperbilirubinemia, Elevated BUN, Creatinine, AST, ALT, ALP and hypoalbuminemia. Abdominal ultrasound reveled splenomegaly, focal hyperechoic liver parenchyma, cortex echogenicity of right kidney and perirenal fluid accumulation. ECG revealed peaked T wave. Radiography revealed hepatosplenomegaly. Hemato-biochemical alteration was monitored before and after therapy. Animal was managed with fluid therapy, Acetylcysteine, Amino acid and supportives and the dog had an uneventful recovery.

Potential of three-step pretargeting radioimmunotherapy using biotinylated bevacizumab and succinylated streptavidin in triple-negative breast cancer xenograft.

Pretargeting radioimmunotherapy (PRIT) is a promising approach that can reduce long-time retention of blood radioactivity and consequently reduce hematotoxicity. Among the PRIT strategies, the combination of biotin-conjugated mAb and radiolabeled streptavidin (StAv) is a simple and convenient method because of its ease of preparation. This study performed three-step (3-step) PRIT using the sequential injection of (1) biotinylated bevacizumab (Bt-BV), (2) avidin, and (3) radiolabeled StAv for the treatment of triple-negative breast cancer (TNBC). Four biodistribution studies were performed using 111In in tumor-bearing mice to optimize each step of our PRIT methods. Further, a therapeutic study was performed with optimized 3-step PRIT using 90Y-labeled StAv. Based on the biodistribution studies, the protein dose of Bt-BV and avidin was optimized to 100μg and 10 molar equivalent of BV, respectively. Succinylation of StAv significantly decreased the kidney accumulation level (with succinylation (6.96 ± 0.91) vs without succinylation (20.60 ± 1.47) at 1h after injection, p < 0.0001) with little effect on the tumor accumulation level. In the therapeutic study, tumor growth was significantly suppressed in treatment groups with optimized 3-step PRIT using 90Y-labeled succinylated StAv compared to that of the no-treatment group (p < 0.05). The 3-step PRIT strategy of this study achieved fast blood clearance and low kidney uptake with little effect on the tumor accumulation level, and a certain degree of therapeutic effect was consequently observed. These results indicated that the pretargeting treatment of the current study may be effective for human TNBC treatment.

Targeting Interstitial Myofibroblast-Expressed Integrin αvβ3 Alleviates Renal Fibrosis.

Renal fibrosis is the final manifestation of various chronic kidney diseases. Interstitial myofibroblasts, which are reported to highly express integrin αvβ3, are the effector cells in renal fibrogenesis. Since current therapies do not efficiently target these cells, there is no effective therapeutic method for preventing or mitigating the disease. Here, we modified sterically stable PEGylated liposomes with the pentapeptide cRGDfC (RGD-Lip), which has a high affinity for αvβ3, to specifically deliver drug to renal interstitial myofibroblasts. Our results showed that attaching cRGDfC to liposomes significantly increased their uptake by activated renal fibroblasts NRK-49F cells, and this effect was greatly abolished by adding excess-free cRGDfC or a knockdown of αvβ3. Systemic administration of RGD-Lip gave rise to significant accumulation in a fibrotic kidney, which is ascribed to the specific recognition with integrin αvβ3 on interstitial myofibroblasts. When loaded with celastrol, RGD-guided liposomes dramatically depressed the proliferation and activation of NRK-49F cells in vitro. Additionally, celastrol-loaded RGD-Lip markedly attenuated renal fibrosis, injury, and inflammation induced by unilateral ureteral obstruction (UUO) in mice, without inducing significant systemic toxicity. Thus, this liposomal system shows great promise for delivering therapeutic agents to interstitial myofibroblasts for renal fibrosis treatment with minimal side effects.

Biodegradable Nanodots: Biodegradable Self‐Assembled Ultrasmall Nanodots as Reactive Oxygen/Nitrogen Species Scavengers for Theranostic Application in Acute Kidney Injury (Small 8/2021)

In article number 2005113, Peng Huang and co-workers develop biodegradable self-assembled ultrasmall nanodots, which are composed of iron ion, gallic acid, and polyvinylpyrrolidone, as broad-spectrum reactive oxygen/nitrogen species scavengers (RONS) with preferential kidney accumulation and rapid excretion to alleviate both glycerinum- and cis-platinum-induced acute kidney injury in mice.

Artemisinin analogue SM934 protects against lupus-associated antiphospholipid syndrome via activation of Nrf2 and its targets.

Kidney is a major target organ in both antiphospholipid syndrome (APS) and systemic lupus erythematosus (SLE). The etiology of antiphospholipid syndrome nephropathy associated lupus nephritis (APSN-LN) is intricate and remains largely unrevealed. We proposed in present work, that generation of antiphospholipid antibodies (aPLs), especially those directed towards the oxidized neoepitopes, are largely linked with the redox status along with disease progression. Moreover, we observed that compromised antioxidative capacity coincided with turbulence of inflammatory cytokine profile in the kidney of male NZW×BXSB F1 mice suffered from APSN-LN. SM934 is an artemisinin derivative that has been proved to have potent immunosuppressive properties. In current study, we elaborated the therapeutic benefits of SM934 in male NZW×BXSB F1 mice, a murine model develops syndrome resembled human APS associated with SLE, for the first time. SM934 treatment comprehensively impeded autoantibodies production, inflammatory cytokine accumulation and excessive oxidative stress in kidney. Among others, we interpreted in present work that both anti-inflammatory and antioxidative effects of SM934 is closely correlated with the enhancement of Nrf2 signaling and expression of its targets. Collectively, our finding confirmed that therapeutic strategy simultaneously exerting antioxidant and anti-inflammatory efficacy provide a novel feasible remedy for treating APSN-LN.

Fibrillar pharmacology of functionalized nanocellulose

Cellulose nanocrystals (CNC) are linear organic nanomaterials derived from an abundant naturally occurring biopolymer resource. Strategic modification of the primary and secondary hydroxyl groups on the CNC introduces amine and iodine group substitution, respectively. The amine groups (0.285 mmol of amine per gram of functionalized CNC (fCNC)) are further reacted with radiometal loaded-chelates or fluorescent dyes as tracers to evaluate the pharmacokinetic profile of the fCNC in vivo. In this way, these nanoscale macromolecules can be covalently functionalized and yield water-soluble and biocompatible fibrillar nanoplatforms for gene, drug and radionuclide delivery in vivo. Transmission electron microscopy of fCNC reveals a length of 162.4 ± 16.3 nm, diameter of 11.2 ± 1.52 nm and aspect ratio of 16.4 ± 1.94 per particle (mean ± SEM) and is confirmed using atomic force microscopy. Size exclusion chromatography of macromolecular fCNC describes a fibrillar molecular behavior as evidenced by retention times typical of late eluting small molecules and functionalized carbon nanotubes. In vivo, greater than 50% of intravenously injected radiolabeled fCNC is excreted in the urine within 1 h post administration and is consistent with the pharmacological profile observed for other rigid, high aspect ratio macromolecules. Tissue distribution of fCNC shows accumulation in kidneys, liver, and spleen (14.6 ± 6.0; 6.1 ± 2.6; and 7.7 ± 1.4% of the injected activity per gram of tissue, respectively) at 72 h post-administration. Confocal fluorescence microscopy reveals cell-specific accumulation in these target tissue sinks. In summary, our findings suggest that functionalized nanocellulose can be used as a potential drug delivery platform for the kidneys.

An investigation of calcium carbonate core-shell particles for incorporation of 225Ac and sequester of daughter radionuclides: in vitro and in vivo studies

Alpha therapy provides an outstanding prospect in the treatment of recalcitrant and micrometastatic cancers. However, side effects on the normal tissues and organs (especially, kidneys) due to the release of daughter isotopes from α-emitters remain a bottleneck. In this work, calcium carbonate core-shell particles of different sizes were considered as isotope carriers for encapsulation of 225Ac (highly powerful alpha-emitter that generates 4 net alpha particle isotopes in a short decay chain) in order to achieve in vitro and in vivo retention of 225Ac and its daughter isotopes. According to the in vitro studies, the developed calcium carbonate core-shell particles were able to retain 225Ac and its daughter isotopes (221Fr and 213Bi) exhibited good stability in biological media and dose-dependent biocompatibility (over 30 d). The SPECT imaging demonstrated the size-dependent distribution of 225Ac-doped core-shell particles. Further, in vivo studies confirmed the high retention efficiency of calcium carbonate core-shell particles, which was demonstrated in normal Wistar rats (up to 10 d). Interestingly, the radioactivity accumulation in kidney and urine was significantly less for encapsulated 225Ac than in case of non-encapsulated form of 225Ac (225Ac conjugated with albumin), indicating the absence of radioisotope leakage from the developed particles. Thus, our study validates the application of 225Ac-doped core-shell particles to sequester α-emitter (225Ac) and its decay products in order to reduce their systemic toxicity during alpha therapy.

METTL14-regulated PI3K/Akt signaling pathway via PTEN affects HDAC5-mediated epithelial\u2013mesenchymal transition of renal tubular cells in diabetic kidney disease

Histone deacetylase 5 (HDAC5) belongs to class II HDAC subfamily and is reported to be increased in the kidneys of diabetic patients and animals. However, little is known about its function and the exact mechanism in diabetic kidney disease (DKD). Here, we found that HDAC5 was located in renal glomeruli and tubular cells, and significantly upregulated in diabetic mice and UUO mice, especially in renal tubular cells and interstitium. Knockdown of HDAC5 ameliorated high glucose-induced epithelial–mesenchymal transition (EMT) of HK2 cells, indicated in the increased E-cadherin and decreased α-SMA, via the downregulation of TGF-β1. Furthermore, HDAC5 expression was regulated by PI3K/Akt signaling pathway and inhibition of PI3K/Akt pathway by LY294002 treatment or Akt phosphorylation mutation reduced HDAC5 and TGF-β1 expression in vitro high glucose-cultured HK2 cells. Again, high glucose stimulation downregulated total m6A RNA methylation level of HK2 cells. Then, m6A demethylase inhibitor MA2 treatment decreased Akt phosphorylation, HDAC5, and TGF-β1 expression in high glucose-cultured HK2 cells. In addition, m6A modification-associated methylase METTL3 and METTL14 were decreased by high glucose at the levels of mRNA and protein. METTL14 not METTL3 overexpression led to PI3K/Akt pathway inactivation in high glucose-treated HK2 cells by enhancing PTEN, followed by HDAC5 and TGF-β1 expression downregulation. Finally, in vivo HDACs inhibitor TSA treatment alleviated extracellular matrix accumulation in kidneys of diabetic mice, accompanied with HDAC5, TGF-β1, and α-SMA expression downregulation. These above data suggest that METTL14-regulated PI3K/Akt signaling pathway via PTEN affected HDAC5-mediated EMT of renal tubular cells in diabetic kidney disease.

The controversial role of glucose in the diabetic kidney.

The kidneys play an important role in maintaining glucose homeostasis being the main mechanisms, the gluconeogenesis, renal glucose consumption and glucose reabsorption in the proximal tubules. In this review, we present the main research into the role of glycogen—the stored form of glucose, and how it accumulates in the cells, providing new information on the link between diabetes and diabetic kidney disease. In the last 10 years, research under the scope of renal insulin handling, glucose transport in the proximal tubules, renal gluconeogenesis and renal insulin resistance, made possible to relate the roles of glucose and glycogen in the kidney with other several organs, like the liver. On the one hand, insulin positively regulates kidney uptake and degradation, and there is probably a specific action and resistance to insulin at the renal site. Moreover, insulin regulates the bioavailability of the sodium-glucose co-transporters—SGLT2 inhibitor, and inhibits renal gluconeogenesis. Only the liver and kidneys can supply glucose to the circulation through the process of gluconeogenesis, which involves the synthesis of glucose again from non-glycemic substrates; and the decomposition of stored glycogen. In the mind of nephrologists, diabetologists and scientists, glucose metabolism in the kidney is the focus, with the relevant success of inhibitors in reducing kidney and cardiovascular diseases in individuals with diabetes. However, these new data led to the intriguing paradigm that many of the beneficial effects on the renal and cardiovascular system appear to be independent of the systemic glucose-lowering actions of these agents. The goal of this work puts in context a highly relevant research area for renal glucose metabolism, of glycogen accumulation and metabolism in the diabetic kidney.

Uranium inhibits mammalian mitochondrial cytochrome c oxidase and ATP synthase.

As an emerging pollutant, uranium poses serious concerns to ecological and human health. The kidney has been established as a major deposition site and the most sensitive target organ for uranium poisoning, and the underlying toxicological mechanisms have been associated with oxidative stress and mitochondrial respiration. However, the identities of key molecular targets in uranium-induced toxicity remain elusive. In this study, we comprehensively evaluated the invitro effects of uranium on ten critical enzymes in the mitochondrial respiration pathway and discovered that respiratory chain complex IV (cytochrome c oxidase) and complex V (ATP synthase) were strongly inhibited. The inhibitory effects were validated with mitochondria from human renal proximal tubule cells-the most affected renal site in uranium poisoning. The IC50 values (around 1mg/L) are physiologically relevant, as they are comparable to known kidney accumulation levels in uranium poisoning. In addition, these inhibitory effects could explain the well-documented uranium-induced reactive oxygen species generation and mitochondrial alterations. In conclusion, cytochrome c oxidase and ATP synthase are possibly key molecular targets underlying the toxic effects of uranium.

Understanding the role of colon-specific microparticles based on retrograded starch/pectin in the delivery of chitosan nanoparticles along the gastrointestinal tract

The encapsulation of nanoparticles within microparticles designed for specific delivery to the colon is a relevant strategy to avoid premature degradation or release of nanoparticles during their passage through the stomach and upper gastrointestinal tract (GIT), allowing the targeted delivery of chemotherapeutics to the colon after oral administration. Here, we designed an oral multiparticulate system to achieve targeted release in the colon. In this sense, chitosan nanoparticles (CS NPs) encapsulated with 5-fluorouracil (5-FU) and incorporated into retrograded starch and pectin (RS/P) microparticles were developed and their in vivo distribution along the mouse GIT after oral administration was monitored using multispectral optical imaging. In vitro release studies revealed that the encapsulation of CS NPs into RS/P microparticles promoted greater control of 5-FU release rates, with a significant reduction (53%) in acid media that might replicate that found in the stomach following oral administration. The evaluation of the in vivo biodistribution of the CS NPs in mice showed a faster clearance in the distribution pattern along the mouse GIT, i.e., a shorter transit time of CS NPs compared to CS NPs-loaded RS/P microparticles. Additionally, CS NPs alone showed non-specific absorption into the blood-stream with associated kidney accumulation, while for the CS NPs-loaded RS/P microparticles no significant accumulation was observed in blood or major clearance organs. This suggests the specific degradability of RS/P by the colon microbiota appears to have been decisive in the higher protection of the CS NPs along the GIT until release in the colon, preventing unwanted absorption into the bloodstream and major organs following oral administration. Our findings represent a proof of concept for the use of RS/P microparticles as potential carriers for delivering drug-loaded nanoparticles to the colon and this work will contribute to the development of oral-systems for colorectal cancer therapy.

Preclinical comparison of four [18F, natGa]rhPSMA-7 isomers: influence of the stereoconfiguration on pharmacokinetics

IntroductionRadiohybrid (rh) ligands, a novel class of prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals, can be labeled either with [18F]fluorine via isotopic exchange or with radiometals (such as [68Ga]Gallium, [177Lu]Lutetium, [225Ac]Actinium). Among these, [18F, natGa]rhPSMA-7 has recently entered clinical assessment.AimSince [18F, natGa]rhPSMA-7 is composed of four stereoisomers ([18F, natGa]rhPSMA-7.1, -7.2, -7.3 and -7.4), we initiated a preclinical selection process to identify the isomer with the most favorable pharmacokinetics for further clinical investigation.MethodsA synthetic protocol for enantiopure [19F, natGa]rhPSMA-7 isomers has been developed. The comparative evaluation of the four isomers comprised human serum albumin binding, lipophilicity, IC50, internalization and classical biodistribution studies and competition experiments in LNCaP tumor-bearing CB-17 SCID mice. In addition, a radio high-performance liquid chromatography-based method was developed allowing quantitative, intraindividual comparison of [18F, natGa]rhPSMA-7.1 to -7.4 in LNCaP tumor-bearing mice.ResultsCell studies revealed high PSMA affinity and internalization for [18/19F, natGa]rhPSMA-7.2, -7.3 and -7.4, whereas [18/19F, natGa]rhPSMA-7.1 showed approximately twofold lower values. Although the biodistribution profile obtained was typical of PSMA inhibitors, it did not allow for selection of a lead candidate for clinical studies. Thus, an intraindividual comparison of all four isomers in LNCaP tumor-bearing mice was carried out by injection of a diastereomeric mixture, followed by analysis of the differential uptake and excretion pattern of each isomer. Based on its high tumor accumulation and low uptake in blood, liver and kidneys, [18F, natGa]rhPSMA-7.3 was identified as the preferred isomer and transferred into clinical studies.Conclusion[18F, natGa]rhPSMA-7.3 has been selected as a lead compound for clinical development of a [18F]rhPSMA-based candidate. The intraindividual differential uptake and excretion analysis in vivo allowed for an accurate comparison and assessment of radiopharmaceuticals.

Evaluation of 99mTc-CN5DG as a broad-spectrum SPECT probe for tumor imaging

Previously, we reported a [99mTc(ǀ)]+ labeled d-glucoamine derivative (99mTc-CN5DG) and evaluated it as a tumor imaging agent in mice bearing A549 tumor xenografts. In this paper, 99mTc-CN5DG was further studied in U87 MG (human glioma cells), HCT-116 (human colon cancer cells), PANC-1 (human pancreatic cancer cells) and TE-1 (human esophageal cancer cells) tumor xenografts models to verify its potential application for imaging of different kinds of tumors. The biodistribution data showed that 99mTc-CN5DG had a similar biodistribution pattern in four tumor models at 2 h post-injection with high accumulation in tumors and kidneys. The tumor/muscle ratios (from 4.08 ± 0.42 to 9.63 ± 3.53) and tumor/blood ratios (from 17.18 ± 7.40 to 53.17 ± 16.16) of 99mTc-CN5DG in four tumor models were high. All four kinds of tumors could be clearly seen on their corresponding SPECT/CT images. Pharmacokinetic study in healthy CD-1 mice demonstrated that 99mTc-CN5DG cleared fast from blood (2 min, 12.97 ± 0.88%ID/g; 60 min, 0.33 ± 0.06%ID/g) and the blood distribution, elimination half-life was 5.81 min and 21.16 min, respectively. No abnormality was observed through the abnormal toxicity study. All of the above results demonstrated that 99mTc-CN5DG could be a broad-spectrum SPECT probe for tumor imaging and its further clinical application is warranted.

In Vivo Evaluation and Dosimetry Estimate for a High Affinity Affibody PET Tracer Targeting PD-L1

In vivo imaging of programmed death ligand 1 (PD-L1) during immunotherapy could potentially monitor changing PD-L1 expression and PD-L1 expression heterogeneity within and across tumors. Some protein constructs can be used for same-day positron emission tomography (PET) imaging. Previously, we evaluated the PD-L1-targeting Affibody molecule [18F]AlF-NOTA-ZPD-L1_1 as a PET tracer in a mouse tumor model of human PD-L1 expression. In this study, we evaluated the affinity-matured Affibody molecule ZPD-L1_4, to determine if improved affinity for PD-L1 resulted in increased in vivo targeting of PD-L1. ZPD-L1_4 was conjugated with NOTA and radiolabeled with either [18F]AlF or 68Ga. [18F]AlF-NOTA-ZPD-L1_4 and [68Ga]NOTA-ZPD-L1_4 were evaluated in immunocompromised mice with LOX (PD-L1+) and SUDHL6 (PD-L1-) tumors with PET and ex vivo biodistribution measurements. In addition, whole-body PET studies were performed in rhesus monkeys to predict human biodistribution in a model with tracer binding to endogenous PD-L1, and to calculate absorbed radiation doses. Ex vivo biodistribution measurements showed that both tracers had > 25 fold higher accumulation in LOX tumors than SUDHL6 ([18F]AlF-NOTA-ZPD-L1_4: LOX: 8.7 ± 0.7 %ID/g (N = 4) SUDHL6: 0.2 ± 0.01 %ID/g (N = 6), [68Ga]NOTA-ZPD-L1_4: LOX: 15.8 ± 1.0 %ID/g (N = 6) SUDHL6: 0.6 ± 0.1 %ID/g (N = 6)), considerably higher than ZPD-L1_1. In rhesus monkeys, both PET tracers showed fast clearance through kidneys and low background signal in the liver ([18F]AlF-NOTA-ZPD-L1_4: 1.26 ± 0.13 SUV, [68Ga]NOTA-ZPD-L1_4: 1.11 ± 0.06 SUV). PD-L1-expressing lymph nodes were visible in PET images, indicating in vivo PD-L1 targeting. Dosimetry estimates suggest that both PET tracers can be used for repeated clinical studies, although high kidney accumulation may limit allowable radioactive doses. [18F]AlF-NOTA-ZPD-L1_4 and [68Ga]NOTA-ZPD-L1_4 are promising candidates for same-day clinical PD-L1 PET imaging, warranting clinical evaluation. The ability to use either [18F] or [68Ga] may expand access to clinical sites.

Tetrahedral framework nucleic acids act as antioxidants in acute kidney injury treatment

Antioxidants play an early intervention role in the pathogenesis of kidney injury by alleviating oxidative damage to the injured kidney. The development of safe and effective reactive oxygen species (ROS) scavengers for acute kidney injury (AKI) treatment is still worth exploring. Here, we presented tetrahedral framework nucleic acids (tFNAs) as a therapeutic drug for the treatment of rhabdomyolysis (RM)-AKI. tFNAs exhibited protective effects of cells mainly by relieving oxidative stress and inhibiting apoptosis. The features of tFNAs greatly facilitated kidney enrichment and decreased kidney injuries after injection in AKI models. Our findings showed that tFNAs constituted a novel class of antioxidative nanomaterials for AKI treatment with excellent antioxidant efficiency, superior structure stability, preferential kidney accumulation and good biocompatibility.

E4orf1, an Adeno-viral protein, attenuates renal lipid accumulation in high fat fed mice: A novel approach to reduce a key risk factor for chronic kidney disease

Obesity and hyperlipidemia are independent risk factors of chronic kidney disease (CKD). In mice, diet induced obesity accelerates lipogenesis, lipid accumulation, and injury in kidneys. Expression of adenoviral protein, E4orf1, improves glucose clearance and reduces endogenous insulin secretion to glucose challenge in mice. Therefore, in this pilot study, we examined, if enhanced glycemic control in HFD fed E4orf1 transgenic (E4orf1-Tg) mice, will reduce renal lipogenesis and lipid accumulation. In two separate experiments, E4orf1-Tg mice were fed 60% (kcal) high-fat diet (HFD) supplemented with doxycycline for 10-weeks or 20-weeks along with wild-type (C57BL6/J) or E4orf1-non-transgenic (E4orf1-non-Tg) control mice, respectively. Protein expression of Fatty Acid Synthase (FAS) and Acetyl-CoA Carboxylase (ACC), accumulation of triglyceride (TG) along with mRNA levels of lipid metabolism and injury markers were determined in kidneys. Renal expression of FAS and ACC, and TG content was significantly reduced in E4orf1-Tg mice compared to controls. E4orf1-Tg mice show significant increase in genes involved in mitochondrial fatty acid oxidation and oxidative stress compared to wild-type mice after 10-weeks of HFD. However, mice exposed to 20-weeks of HFD, show no difference in gene expression. E4orf1 expression reduces lipid synthesis and accumulation in kidneys despite HFD, which may be due to attenuation of hyperinsulinemia by E4orf1.

Sex-specific accumulation of silver nanoparticles in rat kidneys is not ovarian hormone regulated but elimination limited

Preferential Ag deposition in female kidneys has been reported in subacute and subchronic oral gavage and inhalation studies of various sizes of silver nanoparticles (AgNPs). In these in vivo animal studies, female kidneys were shown to accumulate 3–4 times more silver than male kidneys. The current 28-day oral gavage study of AgNPs administered to ovariectomized female rats investigated the effect of sex-dependent hormones. Ovariectomized rats were allowed to recover for 14 days, then AgNPs (60 nm) were administered by gavage for 28 days based on 500 mg/kg body weight. After this subacute oral exposure, the rats were sacrificed and the Ag content in the kidneys was measured using an atomic absorption spectrophotometer. No statistically significant difference was noted in the Ag content in the kidneys among the AgNP administered, AgNP administered sham, and AgNP administered ovariectomized rats, although the female kidneys showed a statistically significant higher accumulation of Ag than the male kidneys. Reanalysis of the clearance of Ag accumulated in the kidneys showed 2 different phases; fast (T1/210.4 days) and slow (T1/2 61.9 days) for males, while the clearance of females showed (T1/2 20.8 days) and slow (T1/2 154 days). The higher accumulation of Ag in female kidneys is due to slower clearance of Ag in female kidneys than those of males. Therefore, the current results indicate that the preferential silver accumulation in female kidneys is not regulated by ovarian hormones, but by elimination rate differences between males and females.

Cellulose nanocrystals: a multimodal tool to enhance the targeted drug delivery against bone disorders.

Aim: We investigated the use of cellulose nanocrystals (CNCs) as drug nanocarriers combining an anti-osteoporotic agent, alendronate (ALN), and an anti-cancer drug, doxorubicin (DOX). Materials & methods: CNC physicochemical characterization, in vivo imaging coupled with histology andin vitro uptake and toxicity assays were carried out. Results:In vivo CNC-ALN did not modify bone tropism and lung penetration, whereas its liver and kidneyaccumulation wasslightly higher compared with CNCs alone. In vitro studies showed that CNC-ALN did not impair ALN's effect on osteoclasts, whereasCNC-DOX confirmed the therapeutic potential against bone metastatic cancer cells. Conclusions: This study provides robust proofof the potential of CNCs as easy, flexible and specific carriers to deliver compounds to the bone.

Myricetin derivative-rich fraction from Syzygium malaccense prevents high-fat diet-induced obesity, glucose intolerance and oxidative stress in C57BL/6J mice

Aim A high-fat diet (HFD) can lead to obesity and related metabolic disorders. This study evaluated the preventive efficacy of myricetin derivative-rich fraction (MD) from Syzygium malaccense leaf extract against HFD-induced obesity, hyperglycaemia, and oxidative stress in C57BL/6J mice. Methods HFD-fed mice were administered MD (50 mg/kg, 100 mg/kg, and 150 mg/kg) or 2 mg/kg metformin (positive control) orally for 16 weeks. Normal diet and HFD-fed control groups received normal saline. Results MD dose of 50 mg/kg was better than 100 mg/kg and 150 mg/kg in significantly reducing weight-gain, glucose intolerance, insulin resistance, lipid accumulation in liver and kidney, and improving the serum lipid profile. Lowered protein carbonyls and lipid hydroperoxides in urine and tissue homogenates and elevated reduced glutathione, ferric reducing antioxidant power (FRAP), and Trolox equivalent antioxidant capacity (TEAC) levels in tissue homogenates indicated amelioration of oxidative stress. Conclusion MD has therapeutic value in the prevention and management of obesity, hyperglycaemia, and oxidative stress.