bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mesenchymal Stem Cells Ameliorate Uric Acid Induced Nephropathy in Rats
Authors: Li Lan , Cheng Dongqi , Yuan Yujia , Chen Younan , Cheng Jingqiu , Lu Yanrong 
Published: June 2021

BackgroundThe elevation of serum uric acid (UA) is positively correlated to the incidence and mortality of kidney diseases by evoked inflammation and epithelial‐mesenchymal transition (EMT) in renal tubular epithelial cells. Mesenchymal stem cells (MSCs) are able to facilitate immunomodulation and repair kidney injury in experimental models of acute or chronic kidney injury. Our study aims to investigate the effects of MSCs on kidney injury both in rats model of uric acid nephropathy and high uric acid‐treated renal tubular epithelial cells (NRK‐52E).MethodsIn vivo, rats were intragastric administrated with potassium oxonate (PO, 1500 mg/kg/day) plus adenine (Ad, 50 mg/kg/day) for 4 w to develop hyperuricemia. MSCs treatment (tail vain injection of MSCs 3×106 cells/rat) was conducted from the 2nd week for 2 times with one week interval. After 6 weeks, the kidney tissues were collected for further detections. In vitro, NRK‐52E cells were co‐cultured with or without MSCs in Transwell system. Cell cycle and apoptosis were analyzed by flow cytometry. The mRNA and protein expression of genes related to inflammation and fibrosis were detected by q‐PCR and WB.Results

MSCs alleviated kidney injury in rats of uric acid nephropathy. Compared with UA group, HE and Masson staining have shown that the histological abnormalities and fibrosis were significantly ameliorated after MSCs treatment. Moreover, the mRNA of FN, TNF‐α, TGF‐β and IL‐1β showed marked decrease in UA + MSCs group in comparison to UA group.
MSCs inhibited cellular damage in high uric acid‐treated NRK‐52E. Comparing with high uric acid group, MSCs co‐culture induced remarkable increase of cell proliferation index (62.61% vs. 54.55%), slight decreased of apoptosis rate (3.7% vs. 4.8%) and increased expression of anti‐apoptotic protein Bcl‐2. In respect of the expression of inflammation and fibrosis related protein, MSCs co‐culture slightly downregulated the expression of TNF‐α, α‐SMA and FN, while upregulated the expression of E‐cad, but no significant change was observed on VCAM‐1.
ConclusionDuring the development of hyperuricemia, MSCs effectively ameliorated inflammatory infiltration, suppressed the fibrosis progress trigged by inflammatory factors and fibrosis factor as TGF‐β, resulting in the improvement of high uric acid induced kidney lesion. MSCs exerted the protective role through increase of cell viability and proliferation, decrease of apoptosis and the expression of inflammatory factor TNF‐α, and increase the expression of E‐cad, which contributed to the suppression of interstitial transformation of renal tubular epithelial cells.Support or Funding InformationThis study was supported by the Program of National Natural Science Foundation of China (81370824), and the National Key Clinical Project.
Proximal Tubule Beta‐2 Adrenergic Receptor Is Responsible for Recovery of Renal Function Following Ischemia Reperfusion Injury
Authors: Cameron Robert Bruce , Simmons Epiphani , Miller Siennah , Gibbs Whitney , Schnellmann Rick 
Published: June 2021

Acute kidney injury (AKI) is the transient loss of renal function following an insult, such as nephrotoxicant exposure, sepsis, or ischemia. Numerous cell types play a role in the pathogenesis of AKI, including immune, endothelial, and renal proximal tubule cells. Our laboratory demonstrated that the beta‐2 adrenergic receptor (ADRB2) agonist formoterol accelerates the recovery of renal and mitochondrial function in mice following ischemia‐reperfusion injury (IRI). However, the cell type(s) responsible for this recovery remains unknown. To assess the role of renal proximal tubule cells in formoterol‐induced recovery of renal function, we generated a proximal tubule‐specific knockout of the ADRB2 receptor (γGT‐Cre: ADRB2Flox/Flox). Compared to controls (ADRB2Flox/Flox), renal cortical mRNA expression of the ADRB2 receptor was decreased 90% in γGT‐Cre:ADRB2Flox/Flox mice. These mice were subjected to renal IRI, followed by once daily dosing with 0.3 mg/kg formoterol or vehicle beginning at 24 h and euthanasia at 144 h. At 24 h following IRI, ADRB2Flox/Flox and γGT‐Cre: ADRB2Flox/Flox mice had a similar loss of renal function as measured by serum creatinine (0.89 mg/dL and 0.86 mg/dL, respectively). At 144 h following IRI, both ADRB2Flox/Flox and γGT‐Cre:ADRB2Flox/Flox mice treated with vehicle exhibited a modest but incomplete recovery of renal function as measured by serum creatinine (0.43 mg/dL and 0.46 mg/dL, respectively). These mice had similarly suppressed renal cortical mRNA and protein expression of markers of mitochondrial homeostasis such as NDUFB8, COX1, ATPSβ, and Mfn2. Following treatment with formoterol, ADRB2Flox/Flox mice exhibited accelerated recovery of renal function as measured by serum creatinine (0.20 mg/dL) with associated rescue of mitochondrial markers in the renal cortex. In contrast, formoterol did not enhance the recovery of renal function as measured by serum creatinine (0.39 mg/dL) or mitochondrial markers in γGT‐Cre:ADRB2Flox/Flox mice subjected to IRI. These data reveal that formoterol‐induced ADRB2 receptor activation on proximal tubule cells induces mitochondrial biogenesis and restores renal function following AKI.Support or Funding InformationR.B.C. is supported by F30 DK104550 and T32 GM008716 (National Institutes of Health). W.S.G. is supported by T32 DK083262. R.G.S. is supported by R01 GM084147 (National Institutes of Health) and 1BX000851 (Department of Veterans Affairs).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Short‐ and Long‐term Effects of Phenytoin Exposure on the Liver Proteome of Neonatal and Adult Mice Using SWATH‐MS Technology
Authors: Shi Jian , Piekos Stephanie C. , Chen Liming , Jing Xinyue , Zhong Xiao‐Bo , Zhu Hao‐Jie 
Published: June 2021

Phenytoin, a drug listed on the World Health Organization's Model List of Essential Medicines, has been widely used for the treatment of seizures and several other indications. However, it has a narrow therapeutic index and some severe side effects, such as drug‐induced liver diseases. In addition, phenytoin is a well‐known inducer of several drug‐metabolizing enzymes and transporters expressed in the liver, which could lead to severe drug‐drug interactions. In the present study, a newly developed untargeted proteomics approach, sequential window acquisition of all theoretical mass spectra (SWATH), was utilized to investigate the short‐ and long‐term effects of phenytoin exposure on the liver proteome of neonatal and adult mice. A total of 1,780 protein groups were identified in the liver microsomes prepared from neonatal and adult mice. Markedly different liver proteome profiles were observed between newborn (day 5) and adult mice (day 60). Administration of phenytoin exhibited a greater short‐term impact on the liver proteome in neonates than that in adults, in which hepatic expression levels of 214 protein groups were significantly altered in newborn mice relative to 88 protein groups in adult mice at 24 h following an intraperitoneal injection of phenytoin (100 mg/kg). Furthermore, relative to vehicle control, phenytoin treatment resulted in significant changes of the expressions of 50 protein groups in the liver at age day 60 after the mice received a single intraperitoneal injection of phenytoin (100 mg/kg) at age day 5. Taken together, our study provides an insight into the effect of phenytoin treatment on the liver proteome, which might lead to a better understanding of the phenytoin‐induced hepatotoxicity and drug‐drug interactions.Support or Funding InformationThis study was supported by National Institutes of Health National Institute of General Medical Sciences [R01GM‐118367] (Xiao‐Bo Zhong).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Generation of an Adult Hyperbilirubinemia Model in Liver‐specific Humanized UGT1A1*6 Mice
Authors: Mennillo Elvira , Maruo Yoshihiro , Nguyen Nghia , Thérien Ariane , Chen Shujuan , Barbier Olivier , Tukey Robert H. 
Published: June 2021

Bilirubin is metabolized in liver by UDP‐glucuronosyltransferase 1A1 (UGT1A1). Genetic polymorphisms associated with the UGT1A1 gene are commonly known to be responsible for increased levels of total serum bilirubin (TSB). Variants in the UGT1A1 gene promoter as well as Single Nucleotide Polymorphisms (SNPs) at both promoter and exons can result in UGT1A1 deficiency and impairment of bilirubin conjugation, leading to an icterus condition (jaundice) or hereditary unconjugated hyperbilirubinemia. Gilbert Syndrome (GS) is a common heritable condition of adult hyperbilirubinemia affecting over 10% of the population. The most common polymorphisms are the TA‐insertion in the TATA box (TA7) sequence in the promoter region of the UGT1A1 gene. In addition, a SNP at nucleotide 211G>A (G71R) in exon 1 of the UGT1A1*6 gene confers adult hyperbilirubinemia or GS. To examine the contribution of the UGT1A1*6 gene (R71) towards adult hyperbilirubinemia, a UGT1A1*6 and a UGT1A1*1 (G71) cDNA was expressed specifically in the liver of Ugt1−/− mice. Adult humanized UGT1A1*6 mice (h1A1*6HEP mice) expressed an icteric condition compared to normal TSB levels in h1A1*1HEP mice. Differences in TSB levels between h1A1*1HEP and h1A1*6HEP mice was reflected in expression levels of liver UGT1A1. The elevated TSB levels in h1A1*6HEP mice was consistent with the h1A1*6HEP mice being leaner than h1A1*1HEP mice, linking elevated TSB levels and its antioxidant potential with reduced body fat. Functional studies using liver extracts confirmed that the Km for 7‐ethyl‐10‐hydroxy‐camptothecin (SN‐38) and bilirubin glucuronidation was similar for UGT1A1*1 and UGT1A1*6, while there was a significant decrease in the Vmax associated with UGT1A1*6. The reduced Vmax is associated with reduced liver UGT1A1*6 expression and elevated TSB levels. Reduced expression of UGT1A1*6 may explain in part the contribution of elevated TSB levels in GS.Support or Funding InformationUSPHS grants GM086713 and ES010337 and grant PJT‐148611This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Engineered CaS clusters to limit breast cancer cell growth and proliferation selectively
Authors: Castro Miguel , Suarez Edu , Rivera Daniel , Adorno Wilmer , Munoz Kevin 
Published: June 2021

The pH is a major difference between normal and cancer cells. Thermodynamic calculations indicate that CaS has limited dissociation in slightly basic pH, like the one found in normal cells, but dissociates easily into H2S and Ca2+ in the acidic pH found in cancer cell environments. We have studied the effect of CaS – in the size range of a few A to about 1 nm‐ in the cell cycle of breast cancer and normal fibroblasts. A single dose of CaS nanoclusters does not affect the survival and growth rate of normal fibroblasts but inhibits the proliferation rate of carcinoma cells in vitro. Human carcinoma cells treated with the CaS nanocluster dispersion exhibited a decreased ability to properly enter the cell cycle marked by a decrease in cell concentration in G0/G1 phase at 24‐ hours post treatment and then an increase in cells held in the SubG1 and G0/G1 phases up to 72‐hours post treatment. Apoptosis and necrotic channels were found to play significant roles in the death of human carcinoma exposed to the CaS nanoclusters. In contrast, any effect on normal fibroblasts appeared to be short lived and non‐detrimental. Passive uptake and intracellular pH levels of carcinoma cells are proposed to result in the observed selectivity of CaS to inhibit cancer cell proliferation with no significant effect on normal fibroblast cells. The results encourage further research with other cell lines in vitro as well as in vivo to translate this nanotechnology into clinical use.Support or Funding InformationNIH RISE #R25GM096955NIH RISE 5R25GM088023‐02This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The hydrogel‐encapsulated T0901317 reduces atherosclerosis without effect on lipogenesis in apoE deficient mice
Authors: Li Qi 
Published: June 2021

ObjectiveActivation of liver X receptor (LXR) by ligand induces macrophage ATP‐binding cassette transporter A1 and G1 (ABCA1/ABCG1) expression to enhance cholesterol efflux, thereby inhibiting formation of foam cells and development of atherosclerosis. However, LXR activation in hepatocytes induces fatty acid synthesis, which leads to development of fatty liver by an LXR ligand, such as T0901317. Targeting macrophage LXR selectively can avoid the adverse effects of LXR ligand on the liver. A hydrogel can be taken up by monocytes or macrophages, but not by hepatocytes. In this study, we treated apoE deficient mice with a hydrogel‐encapsulated T0901317, and determined whether the hydrogel‐encapsulated T0901317 can inhibit atherosclerosis while eliminating LXR‐induced fatty liver. We also attempted to disclose the involved molecular mechanisms.Approach and ResultsApoE−/− mice randomly in three groups received the following treatment for 16 weeks. Group 1 (control group): mice were fed high‐fat diet (HFD); Group 2 (TF group): mice were fed HFD containing T0901317; Group 3 (THI group): mice were fed HFD while subcutaneously injected the hydrogel‐encapsulated T0901317 once every 3 days. At the end of experiment, we found that compared with control group, en face lesions were decreased by ~37.4 and ~33.17% by TF and THI, respectively. In the fibrous cap of aortic wall, the smooth muscle cell/collagen content was increased while necrotic cores, macrophages accumulation and inflammation were decreased by TF and THI. The inhibition of foam cell formation by TF and THI was attributed by LXR‐induced ABCA1/ABCG1 expression. Interestingly, compared with severe liver steatosis induced by TF, THI totally blocked T0901317‐induced fatty liver. Meanwhile, levels of serum total cholesterol, triglyceride and ALT/ALP, and liver triglyceride accumulation induced by LXR were also decreased by THI. Mechanistically, we determined that the hydrogel‐encapsulated T0901317 was taken up by monocyte/macrophages via a receptor‐mediated endocytosis, and the drug‐loaded macrophages were recruited to the lesion areas. Therefore, hepatic LXR and LXR‐targeted genes expression, such as SREBP1, ACC1 and FASN, were not activated by T0901317. As a result, hydrogel‐encapsulated T0901317 eliminated LXR ligand‐induced fatty liver.ConclusionsOur study demonstrates that the hydrogel‐encapsulated T0901317 can reduce atherosclerosis while eliminate T0901317‐induced fatty liver, indicating the hydrogel‐encapsulated LXR ligand might be a novel therapy for atherosclerosis treatment.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Knockout of Sphingosine Kinase 1 Attenuates Kidney Damage in DOCA‐salt Mice
Authors: Lyu Bingqing , Wang Weili , Li Pin‐Lan , Li Ningjun 
Published: June 2021

Sphingosine‐1‐phosphate (S1P) is a bioactive sphingolipid metabolite. S1P is produced from phosphorylation of sphingosine catalyzed by sphingosine kinases (SphK). SphK1/S1P signaling pathway is implicated in the progression of chronic kidney disease. We recently showed that knockout (KO) of SphK1 attenuated renal interstitial fibrosis in unilateral ureteral obstruction model. However, the role of SphK1/S1P pathway in the renal injury in hypertension has not yet been reported. The aim of this study was to test the hypothesis that SphK1/S1P signaling pathway mediates the kidney damage in DOCA‐salt hypertensive mice. Male wild type C57BL6 mice and Sphk1 KO mice were unilaterally nephrectomized and received a subcutaneous silicone strip containing 50 mg of deoxycorticosterone acetate (DOCA) and 1% NaCl drinking water. At the 7th week, blood pressure was measured, 24h urine collected, and kidney tissues harvested. Four groups were studied: wild type control (WT‐C), wild type DOCA (WT‐DOCA), knockout control (KO‐C) and knockout DOCA (KO‐DOCA). There was no difference in DOCA‐salt‐induced hypertension between WT and KO mice (mean arterial pressure: 135.4 ± 6.1 mmHg vs. 130.4 ± 4.7 mmHg in WT‐DOCA and KO‐DOCA mice). The urine albumin was increased in two DOCA‐salt groups and that the KO‐DOCA group showed significantly lower urine albumin than WT‐DOCA mice (0.43 ± 0.09 mg/kg/24h in WT‐C, 19.36 ± 4.84 in WT‐DOCA, 0.52 ± 0.21 in KO‐C and 3.16 ± 0.74 in KO‐DOCA, P<0.05 for WT‐DOCA vs. KO‐DOCA). The glomerulosclerosis indices were significantly lower in KO‐DOCA than WT‐DOCA in kidney tissue slides with PAS staining (0.62 ± 0.12 in WT‐C, 1.93± 0.13 in WT‐DOCA, 0.43 ± 0.05 in KO‐C, and 1.31 ± 0.11 in KO‐DOCA, p<0.05 for WT‐DOCA vs. KO‐DOCA). The protein levels of α‐smooth muscle actin (α‐SMA) in kidney tissues were upregulated in both DOCA‐salt groups but were significant lower in KO‐DOCA group than in WT‐DOCA group. The relative protein levels of α‐SMA were 1.0 ± 0.1 in WT‐C, 3.97 ± 0.55 in WT‐DOCA, 1.12 ± 0.15 in KO‐C, and 1.61 ± 0.24 in KO‐DOCA (P<0.05 for WT‐DOCA vs. KO‐DOCA). These results suggest that Sphk1/S1P signaling pathway mediates kidney damage in DOCA‐salt hypertensive mice independent of blood pressure. Manipulating Sphk1/S1P signaling pathway may be used as a therapeutic strategy in kidney damage associated with hypertension. (Supported by NIH grant DK107991 to NL and DK54927 to PL)Support or Funding InformationNIH grant DK107991 to NL and DK54927 to PLThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Femoral artery ligation impairs skeletal muscle force production in C57Bl/6J mice
Authors: Nickell Courtney Elizabeth , Cardinal Trevor Ryan 
Published: June 2021

Patients diagnosed with Peripheral Arterial Occlusive Disease (PAOD), generally caused by atherosclerotic plaque accumulation in conduit arteries, typically experience intermittent claudication, which is characterized by pain during exercise in the lower extremities due to ischemia. Perfusion distal to occluded arteries can be maintained through enlargement of natural bypass collaterals by arteriogenesis. Unfortunately, clinical trials of arteriogenesis‐ and angiogenesis‐stimulating therapies have been unsuccessful, despite clear efficacy in animal models. This may be at least partially explained by the differences in endpoints in animal models and human patients. For example, the most common assessment of ischemic revascularization in animal models is hindpaw perfusion while the most clinical endpoint is pain‐free walking distance, which depends both on vascular supply and skeletal muscle function. However, it is unclear how occlusion affects skeletal muscle performance in animal models. To better understand the natural history of the tissue response following arterial occlusion, it is necessary to determine the impact of occlusion on skeletal muscle performance using precise and quantitative methods.Therefore, we developed a muscle force production protocol following distal femoral artery ligation (FAL). Specifically, following ligation between the epigastric and popliteal branches, we measured force production in the triceps surae, i.e. gastrocnemius and soleus, in response to single, tetanic, and fatiguing stimulations in male C57Bl/6J mice. Pilot studies indicated that force production was not different between unoperated right and left hindlimbs, with maximum twitch forces of 398.6 ± 80.5mN and 389.2 ± 41.8mN, respectively, and maximum tetanic forces of 1420.7 ± 271.4mN and 1361.7 ± 246.5mN, respectively. Following protocol development, we investigated whether forces produced at day‐7 following FAL were consistently lower than those produced by a sham‐operated hindlimb. As expected, maximum twitch force was reduced in the operated hindlimb as compared to the contralateral sham operated hindlimb, 458.95 ± 28.02 mN and 504.08 ± 28.12 mN in the operated and sham hindlimbs, respectively. Similarly, maximum tetanic force production was also reduced in the operated hindlimb, 1583.8 ± 218.2 mN, as compared to 1990.7 ± 270.7 mN in the sham. Having determined that force production is impaired at day‐7 following FAL, future studies may include characterizing the time course of force production recovery and/or investigating if force production in ligated hindlimbs can be rescued with myoblast cell transplantation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
FPR2/ALX is a therapeutic target for the resolution of thrombo‐inflammation
Authors: Gavins Felicity Nicola Emma 
Published: June 2021

Patients with Sickle Cell Disease (SCD) are more susceptible to thrombotic events, in which leukocytes, platelets and erythrocytes have all been implicated in the pathogenesis. However, the underlying mechanisms promoting a pro‐coagulant and pro‐thrombotic phenotype in SCD (especially in the brain) are still unknown. The causes for the SCD phenotype may relate to a well‐established link between thrombosis and inflammation i.e. inflammation can beget local thrombosis, and thrombosis can amplify inflammation. Accumulating data linking inflammation and thrombosis supports the hypothesis that anti‐inflammatory therapies may limit thrombosis and that anti‐thrombotic therapies may reduce vascular inflammation. One such target is the anti‐inflammatory and pro‐resolving endogenous mediator Annexin A1 (AnxA1) and its interaction with the Formyl Peptide Receptor (FPR) family. In humans three FPRs (FPR1, FPR2, and FPR3) regulate innate inflammatory responses. Their function has been most extensively investigated in the context of leukocyte recruitment and activation, where FPRs promote cell motility (chemotaxis) and microbicidal respiratory burst. Here we have tested the effect of targeting the AnxA1‐Fpr2/ALX pathway as a therapeutic strategy for SCD with a special focus on thrombo‐inflammation. In conclusion, our novel results demonstrate the importance of the AnxaA1/FPR2 system in effecting the resolution of SCD associated cerebral thrombo‐inflammation and may therefore provide a novel anti‐thrombo‐inflammatory therapeutic target.Support or Funding InformationNIH/NHLBI (HL125572‐01A1)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.