Perturbations in mitochondrial dynamics by p66Shc lead to renal tubular oxidative injury in human diabetic nephropathy
In this study, we observed changes in mitochondrial morphology and expression of associated proteins in tubules of patients with DN. We demonstrated mitochondrial fragmentation as an important pathogenic feature of tubular cell injury that is linked to oxidative stress and p66Shc up-regulation. In renal proximal tubular cells, alterations in mitochondrial dynamics and expression of fission-fusion proteins were observed under high glucose (HG) ambience, along with p66Shc Ser36 phosphorylation. Gene ablation of p66Shc alleviated HG-induced mitochondrial fragmentation, down-regulated Fis1 and reduced p66Shc-Fis1 binding, incr...
Source: Clinical Science - May 14, 2018 Category: Biomedical Science Authors: Zhan, M., Usman, I., Yu, J., Ruan, L., Bian, X., Yang, J., Yang, S., Sun, L., Kanwar, Y. S. Tags: PublishAheadOfPrint Source Type: research

Hyperfiltration in Ubiquitin C-Terminal Hydrolase L1-Deleted Mice
Neuronal ubiquitin C-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme that maintains intracellular ubiquitin pools and promotes axonal transport. Uchl1 deletion in mice leads to progressive axonal degeneration, affecting the dorsal root ganglion that harbours axons emanating to the kidney. Innervation is a crucial regulator of renal hemodynamics, though the contribution of neuronal UCHL1 to this is unclear. Immunofluorescence revealed significant neuronal UCHL1 expression in mouse kidney, including periglomerular axons. Glomerular filtration rate trended higher in 6-week-old Uchl1 -/- mice, and by twelve weeks of...
Source: Clinical Science - May 8, 2018 Category: Biomedical Science Authors: Boisvert, N. C., Holterman, C. E., Thibodeau, J.-F., Nasrallah, R., Kamto, E., Comin, C. H., da F. Costa, L., Carter, A., Hebert, R. L., Gutsol, A., Cron, G. O., Lacoste, B., Gray, D. A., Kennedy, C. R. Tags: PublishAheadOfPrint Source Type: research

PCSK9 inhibition with alirocumab reduces lipoprotein (a) levels in non-human primates by lowering apolipoprotein (a) production rate.
Therapeutic antibodies targeting PCSK9 (e.g. alirocumab) lower low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) [Lp(a)] levels in clinical trials. We recently showed that PCSK9 enhances apolipoprotein(a) [apo(a)] secretion from primary human hepatocytes but does not affect Lp(a) cellular uptake. Here we aimed to determine how PCSK9 neutralization modulates Lp(a) levels in vivo. Six non-human primates (NHP) were treated with alirocumab or a control antibody (IgG1) in a crossover protocol. After the lowering of lipids reached steady state, NHP received an intravenous injection of [2H3]-leucine, and blood sampl...
Source: Clinical Science - May 3, 2018 Category: Biomedical Science Authors: Croyal, M., Tran, T.-T.-T., Blanchard, R. H., Lebail, J.-C., Villard, E. F., Poirier, B., Aguesse, A., Billon-Crossouard, S., Ramin-Mangata, S., Blanchard, V., Nativel, B., Chemello, K., Khantalin, I., Thedrez, A., Janiak, P., Krempf, M., Boixel, C., Lamb Tags: PublishAheadOfPrint Source Type: research

Gremlin activates the Notch pathway linked to renal inflammation
In conclusion, Gremlin activates the Notch pathway in the kidney and this is linked to NF-kB-mediated inflammation, supporting the hypothesis that Notch inhibition could be a potential anti-inflammatory strategy for renal diseases. (Source: Clinical Science)
Source: Clinical Science - May 2, 2018 Category: Biomedical Science Authors: Lavoz, C., Poveda, J., Marquez-Exposito, L., Rayego-Mateos, S., Rodrigues-Diez, R. R., Ortiz, A., Egido, J., Mezzano, S., Ruiz-Ortega, M. Tags: PublishAheadOfPrint Source Type: research

Mindin deficiency in macrophages protects against foam cell formation and atherosclerosis by targeting LXR-{beta}
Conclusions -The present study demonstrated that mindin deficiency serves as a novel mediator that protects against foam cell formation and atherosclerosis by directly interacting with LXR-β. (Source: Clinical Science)
Source: Clinical Science - April 25, 2018 Category: Biomedical Science Authors: Zhang, C., Qin, J.-J., Gong, F.-H., Tong, J.-J., Cheng, W.-L., Wang, H., Zhang, Y., Zhu, X., She, Z.-G., Xia, H., Zhu, L.-H. Tags: PublishAheadOfPrint Source Type: research

Angiotensin-(1-7) reduces cardiac effects of thyroid hormone by GSK3B/NFATc3 signaling pathway
Patients with hyperthyroidism exhibit increased risk of development and progression of cardiac diseases. The activation of the Renin Angiotensin System (RAS) has been indirectly implicated in these cardiac effects observed in hyperthyroidism. Angiotensin-(1-7) (Ang-(1-7)) has previously been shown to counterbalance pathological effects of Angiotensin II (Ang II). The aim of this study was to investigate the effects of elevated circulating Ang-(1-7) levels on cardiac effects promoted by hyperthyroidism in a transgenic rat (TG) model that constitutively overexpress an Ang-(1-7)-producing fusion protein [TGR(A1-7)3292]. TG an...
Source: Clinical Science - April 23, 2018 Category: Biomedical Science Authors: Senger, N., Melo, M. B., Diniz, G. P., Campagnole-Santos, M. J., Souza dos Santos, R. A., Barreto-Chaves, M. L. M. Tags: PublishAheadOfPrint Source Type: research

Galectin-3 downregulates antioxidant peroxiredoxin-4 in human cardiac fibroblasts: a new pathway to induce cardiac damage?
Galectin-3 (Gal-3) is increased in heart failure (HF) and promotes cardiac fibrosis and inflammation. We investigated whether Gal-3 modulates oxidative stress in human cardiac fibroblasts, in experimental animal models and in human aortic stenosis (AS). Using proteomics and immunodetection approaches, we have identified that Gal-3 down-regulated the anti-oxidant peroxiredoxin-4 (Prx-4) in cardiac fibroblasts. In parallel, Gal-3 increased peroxide, nitrotyrosine, malondialdehyde and N-carboxymethyl-lysine levels and decreased total antioxidant capacity. Gal-3 decreased prohibitin-2 expression without modifying other mitocho...
Source: Clinical Science - April 19, 2018 Category: Biomedical Science Authors: Ibarrola, J., Arrieta, V., Sadaba, R., Martinez-Martinez, E., Garcia-Pena, A., Alvarez, V., Fernandez-Celis, A., Gainza, A., Santamaria, E., Fernandez-Irigoyen, J., Cachofeiro, V., Zalba, G., Fay, R., Rossignol, P., Lopez-Andres, N. Tags: PublishAheadOfPrint Source Type: research

Sodium bicarbonate loading limits tubular cast formation independent of glomerular injury and proteinuria in dahl salt-sensitive rats
Sodium bicarbonate (NaHCO3) slows the decline in kidney function in patients with chronic kidney disease (CKD), yet the mechanisms mediating this effect remain unclear. The Dahl salt-sensitive (SS) rat develops hypertension and progressive renal injury when fed a high salt diet; however, the effect of alkali loading on kidney injury has never been investigated in this model. We hypothesized that 'NaHCO3 protects from the development of renal injury in Dahl salt-sensitive rats via luminal alkalization which limits the formation of tubular casts, which are a prominent pathological feature in this model. To examine this hypot...
Source: Clinical Science - April 12, 2018 Category: Biomedical Science Authors: Ray, S. C., Patel, B., Irsik, D. L., Sun, J., Ocasio, H., Crislip, G. R., Jin, C. H., Chen, J. K., Baban, B., Polichnowski, A. J., O'Connor, P. M. Tags: PublishAheadOfPrint Source Type: research

Effects of dietary salt on gene and protein expression in brain tissue of a model of sporadic small vessel disease.
Conclusion: Salt exposure induced changes in gene and protein expression in an experimental model of SVD and its parent rat strain in multiple pathways involving components of the glio-vascular unit. Further studies in pertinent experimental models at different ages would help clarify the short and long-term effect of dietary salt in SVD. (Source: Clinical Science)
Source: Clinical Science - April 9, 2018 Category: Biomedical Science Authors: Bailey, E. L., McBride, M. W., McClure, J. D., Beattie, W., Graham, D., Dominiczak, A. F., Smith, C., Wardlaw, J. M. Tags: PublishAheadOfPrint Source Type: research

Impaired endocrine-metabolic homeostasis: underlying mechanism of its induction by unbalanced diet
Conclusions : OS may be actively involved in the mechanism by which unbalanced/unhealthy diets induce β-cell dysfunction. Since metabolic-endocrine dysfunctions recorded in HS rats resembled those measured in human pre-diabetes, knowledge of its molecular mechanism could help to develop appropriate strategies to prevent the progression of this metabolic state towards Type 2 Diabetes. (Source: Clinical Science)
Source: Clinical Science - April 6, 2018 Category: Biomedical Science Authors: Maiztegui, B., Roman, C. L., Gagliardino, J. J., Flores, L. E. Tags: PublishAheadOfPrint Source Type: research

Hypoxia-Inducible Factor Prolyl-Hydroxylase Inhibitor Roxadustat (FG-4592) Protects against Cisplatin-induced Acute Kidney Injury
Renal hypoxia occurs in acute kidney injury (AKI) of various etiologies. Activation of hypoxia-inducible transcription factor (HIF) has been identified as an important mechanism of cellular adaptation to low oxygen. Preconditional HIF activation protects against AKI, suggesting a new approach in AKI treatment. HIF is degraded under normoxic conditions mediated by oxygen-dependent hydroxylation of specific prolyl residues of the regulative α-subunits by HIF prolyl hydroxylases (PHD). FG-4592 is a novel, orally active small-molecule HIF PHD inhibitor for the treatment of anemia in patients with CKD. The current study a...
Source: Clinical Science - March 26, 2018 Category: Biomedical Science Authors: Yang, Y., Yu, X., Zhang, Y., Ding, G., Zhu, C., Huang, S., Jia, Z., Zhang, A. Tags: PublishAheadOfPrint Source Type: research

Cardiotrophin-1 attenuates experimental colitis in mice
In this study the role of endogenous CT-1 and the effect of exogenous CT-1 were evaluated in experimental ulcerative colitis. Colitis was induced in CT-1 knock-out and wild type mice by administration of dextran sodium sulphate (DSS) in the drinking water during 7 days. CT-1 knock-out mice showed higher colon damage and disease severity than wild type mice. In addition, CT-1 (200 µg/kg/day, iv) or vehicle (as control) were administered during 3 days to wild type, colitic mice, starting on day 4 after initiation of DSS. Disease activity index (DAI), inflammatory markers (TNF-α, INF, IL-17, IL-10, iNOS), colon da...
Source: Clinical Science - March 23, 2018 Category: Biomedical Science Authors: Prieto-Vicente, V., Sanchez-Garrido, A. I., Blanco-Gozalo, V., Arevalo, M., Garcia-Sanchez, E. M., Lopez-Montanes, D., Quiros, Y., Lopez-Hernandez, F. J., Rodriguez-Perez, A., Lopez-Novoa, J. M. Tags: PublishAheadOfPrint Source Type: research

MicroRNA-27-3p regulates TLR2/4-dependent mouse alveolar macrophage activation by targeting PPAR{gamma}
Activation of alveolar macrophages (AMs) and the release of cytokines play critical roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, little is known about the mechanisms of AM activation. miRNAs have recently emerged as key regulators of inflammation and as mediators of macrophage activation and polarization. We identified potential miRNAs related to AM activation using miRNA microarray analysis, which showed that miR-27-3p expression was up-regulated in AMs&nb...
Source: Clinical Science - March 23, 2018 Category: Biomedical Science Authors: Wang, D., He, S., Liu, B., Liu, C. Tags: PublishAheadOfPrint Source Type: research

CTRP3 attenuates high-fat diet-induced male reproductive dysfunction in mice
Recent studies have suggested a role for abdominal obesity in male infertility. Previous studies have found that cell apoptosis exerts an important role in obesity-related male infertility. C1q/TNF-related protein 3 (CTRP3), a paralog of adiponectin, has been proposed to exert anti-apoptotic effects and to attenuate diabetes-related cardiac injuries. However, the role of CTRP3 in high-fat diet (HFD)-induced spermatogenic impairment remains unclear. In the present study, we fed male mice a HFD for 24 weeks to induce obesity. The expression of CTRP3 was decreased by HFD feeding. Supplementation with the recombinant human glo...
Source: Clinical Science - March 23, 2018 Category: Biomedical Science Authors: Mu, Y., Yin, T.-l., Yin, L., Hu, X., Yang, J. Tags: PublishAheadOfPrint Source Type: research

Identification of protein phosphatase involvement in the AT2-receptor induced activation of endothelial nitric oxide synthase
The angiotensin AT2 receptor (AT2R) promotes vasodilation by nitric oxide (NO) release from endothelial cells. However, the mechanisms underlying the AT2R-induced stimulation of endothelial NO synthase (eNOS) is still not completely understood. Therefore, we investigated whether in addition to the known AT2R-mediated phosphorylation of eNOS at Ser1177, activation of phosphatases and dephosphorylation of eNOS at Tyr657 and Thr495 are also involved. Human Aortic Endothelial Cells (HAEC) were stimulated with the AT2R-agonist C21 (1µM) in the presence or absence of either PD123319 (10µM; AT2R-antagonist), L-NAME (1...
Source: Clinical Science - March 14, 2018 Category: Biomedical Science Authors: Peluso, A. A., Bertelsen, J. B., Andersen, K., Mortensen, T. P., Hansen, P. B., Sumners, C., Bader, M., Santos, R. A., Steckelings, U. M. Tags: PublishAheadOfPrint Source Type: research

Metformin inhibits inflammatory signals in the gut by controlling AMPK and p38 MAP kinase activation
Metformin, a hypoglycemic drug used for treatment of type 2 diabetes, regulates also inflammatory pathways. By using several models of intestinal inflammation, we examined whether metformin exerts anti-inflammatory effects and investigated the basic mechanism by which metformin blocks pathologic signals. Colitic mice given metformin exhibited less colonic inflammation and increased expression of active AMP-activated protein kinase, a mediator of the metabolic effects of metformin, in both epithelial and lamina propria compartments. Pharmacological inhibition of AMP-activated protein kinase reduced but did not prevent metfo...
Source: Clinical Science - March 14, 2018 Category: Biomedical Science Authors: Di Fusco, D., Dinallo, V., Monteleone, I., Laudisi, F., Marafini, I., Franze, E., Di Grazia, A., Dwairi, R., Colantoni, A., Ortenzi, A., Stolfi, C., Monteleone, G. Tags: PublishAheadOfPrint Source Type: research

A77 1726 (Leflunomide) blocks and reverses cardiac hypertrophy and fibrosis in mice
In conclusion, A77 1726 attenuated cardiac hypertrophy and cardiac fibrosis via inhibiting FYN/AKT signaling pathway. (Source: Clinical Science)
Source: Clinical Science - March 14, 2018 Category: Biomedical Science Authors: Ma, Z.-G., Zhang, X., Yuan, Y.-P., Jin, Y.-G., Li, N., Kong, C.-Y., Song, P., Tang, Q.-Z. Tags: PublishAheadOfPrint Source Type: research

High level of C-type natriuretic peptide induced by hyperandrogen-mediated anovulation in polycystic ovary syndrome mice
Polycystic ovary syndrome (PCOS), which is characterized by hyperandrogenism, is a complex endocrinopathy that affects the fertility of 9%-18% of reproductive-age women. However, the exact mechanism of PCOS, especially hyperandrogen-induced anovulation, is largely unknown to date. Physiologically, the natriuretic peptide type C/natriuretic peptide receptor 2 (CNP/NPR2) system is essential for sustaining oocyte meiotic arrest until the preovulatory luteinizing hormone (LH) surge. We therefore hypothesized that the CNP/NPR2 system is also involved in PCOS and contributes to arresting oocyte meiosis and ovulation. Here, based...
Source: Clinical Science - March 13, 2018 Category: Biomedical Science Authors: Wang, X., Wang, H., Liu, W., Zhang, Z., Zhang, Y., Zhang, W., Chen, Z., Xia, G., Wang, C. Tags: PublishAheadOfPrint Source Type: research

Prader-Willi region non-protein coding RNA 1 suppressed gastric cancer growth as a competing endogenous RNA of microRNA-425-5p
Gastric cancer (GC) is one of a major global health problem especially in Asia. Nowadays, long non-coding RNA has gained significantly attention in the current research climate such as carcinogenesis. This research desired to explore the mechanism of Prader-Willi region non-protein coding RNA 1 (PWRN1) on regulating GC process. Differentially expressed lncRNAs in GC tissues were screened out through microarray analysis. The RNA and protein expression level was detected by qRT-PCR and western blot. Cell proliferation, apoptosis rate, metastasis abilities were respectively determined by CCK8, flow cytometry, wound healing an...
Source: Clinical Science - March 13, 2018 Category: Biomedical Science Authors: Chen, Z., Ju, H., Yu, S., Zhao, T., Jing, X., Li, P., Jia, J., Li, N., Tan, B., Li, Y. Tags: PublishAheadOfPrint Source Type: research

Interleukin-3 stimulates matrix metalloproteinase 12 production from macrophages promoting thoracic aortic aneurysm/dissection
In this study, 3-aminopropionitrile (BAPN) treatment was used to induce TAAD mouse model. Through transcriptome analysis, we found the expression levels of genes associated with interleukin-3 (IL-3) signaling pathway were upregulated during TAAD development in mouse, which were validated by real-time PCR. IL-3 positive cells were increased in TAAD mouse aortas, especially for smooth muscle cells (SMCs). IL-3 deficiency reduced BAPN-induced TAAD formation. We then examined the matrix metalloproteinases (MMPs) expression during TAAD formation in both wild-type and IL-3 deficient mice, showing that MMP12 were significantly do...
Source: Clinical Science - March 9, 2018 Category: Biomedical Science Authors: Liu, C., Zhang, C., Jia, L., Chen, B., Liu, L., Sun, J., Zhang, W., You, B., Li, Y., Li, P., Du, J. Tags: PublishAheadOfPrint Source Type: research

Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in patients with high blood pressure
Recent evidence indicates a link between gut pathology and microbiome with hypertension in animal models. However, whether this association exists in humans is unknown. Thus, our objectives in this study were to test the hypotheses that high blood pressure patients have distinct gut microbiomes and that gut epithelial barrier function markers and microbiome composition could predict systolic blood pressure. Fecal samples, analyzed by shotgun metagenomics, displayed taxonomic and functional changes, including altered butyrate production between patients with high blood pressure and reference subjects. Significant increases ...
Source: Clinical Science - March 5, 2018 Category: Biomedical Science Authors: Kim, S., Goel, R., Kumar, A., Qi, Y., Lobaton, G., Hosaka, K., Mohammed, M., Handberg, E. M., Richards, E. M., Pepine, C. J., Raizada, M. K. Tags: PublishAheadOfPrint Source Type: research

TLR2 and TLR4 Play Opposite Role in Autophagy associated with Cisplatin-Induced Acute Kidney Injury
Acute kidney injury (AKI) is considered an inflammatory disease in which Toll-like receptors (TLRs) signaling pathways play an important role. The activation of TLRs results in production of several inflammatory cytokines leading to further renal damage. In contrast, TLRs are key players on autophagy induction, which is associated with a protective function on cisplatin-induced AKI. Hence, this study aimed evaluate the specific participation of TLR2 and TLR4 molecules on development of cisplatin-induced AKI. Complementarily, we also investigated the link between TLRs and HO-1, a promisor cytoprotective molecule. Firstly, w...
Source: Clinical Science - March 2, 2018 Category: Biomedical Science Authors: Andrade-Silva, M., Cenedeze, M. A., Perandini, L. A., Felizardo, R. J. F., Watanabe, I. M., Agudelo, J. S. H., Castoldi, A., Goncalves, G. M., Origassa, C. S. T., Semedo, P., Hiyane, M. I., Neto, O. F., Malheiros, D. M. A. C., Reis, M. A., Fujihara, C. K. Tags: PublishAheadOfPrint Source Type: research

Protective Effects of the Angiotensin II AT2 Receptor Agonist Compound 21 in Ischemic Stroke: A Nose-to-Brain Delivery Approach
Significant neuroprotective effects of angiotensin II type 2 (AT2) receptor agonists in ischemic stroke have been previously demonstrated in multiple studies.  However, the routes of agonist application used in these pre-clinical studies, direct intracerebroventricular and systemic administration, are unsuitable for translation to humans; in the latter case because AT2 receptor agonists are blood brain barrier (BBB) impermeable. To circumvent this problem, in the current study we utilized the nose-to-brain (N2B) route of administration to bypass the blood brain barrier and deliver the selective AT2 receptor agonist Co...
Source: Clinical Science - March 2, 2018 Category: Biomedical Science Authors: Bennion, D. M., Jones, C. H., Dang, A. N., Isenberg, J. D., Graham, J. T., Lindblad, L., Domenig, O., Waters, M. F., Poglitsch, M., Sumners, C., Steckelings, U. M. Tags: PublishAheadOfPrint Source Type: research

Cardiac-specific inducible over-expression of human Plasma Membrane Ca2+ ATPase 4b is cardioprotective and improves survival in mice following ischemic injury.
Conclusions: Cardiac PMCA4b regulates nNOS activity, cardiac mass and contractility, such that PMCA4b overexpression preserves cardiac function following IRI, heightens cardiac performance and limits infarct progression, cardiac hypertrophy and HF, even when induced late post-MI. These data identify PMCA4b as a novel therapeutic target for IRI and HF. (Source: Clinical Science)
Source: Clinical Science - February 27, 2018 Category: Biomedical Science Authors: Sadi, A. M., Afroze, T., Siraj, M. A., Momen, A., White-Dzuro, C., Zarrin-Khat, D., Handa, S., Ban, K., Kabir, M. G., Trivieri, M. G., Gros, R., Backx, P., Husain, M. Tags: PublishAheadOfPrint Source Type: research

Alterations in Placental Long Chain Polyunsaturated Fatty Acid Metabolism in Human Intrauterine Growth Restriction
Fatty acids (FA) are critical for fetal brain development and are transferred across the placenta by membrane-bound FA transport proteins (FATP), translocases (FAT/CD36) and cytosolic binding proteins (FABP). The cytosolic protein perilipin-2 aids in neutral lipid storage within lipid droplets. Decreased placental nutrient transport is believed to contribute to intrauterine growth restriction (IUGR); however, IUGR placental lipid transport and metabolism are poorly understood. We hypothesized protein expression of FATPs, FABPs, and perilipin-2 in human placenta is decreased and placental lipid content and incorporation int...
Source: Clinical Science - February 20, 2018 Category: Biomedical Science Authors: Chassen, S. S., Ferchaud-Roucher, V., Gupta, M. B., Jansson, T., Powell, T. L. Tags: PublishAheadOfPrint Source Type: research

Extrahepatic angiogenesis hinders recovery of portal hypertension and collaterals in rats with cirrhosis resolution
In conclusion, cirrhosis resolution attenuates but not completely normalizes portal hypertension because of persistently high splanchnic inflow and angiogenesis. In clinical setting, vascular complications such as varices could persist after cirrhosis resolution and further investigation to define the follow-up and treatment strategies is anticipated. (Source: Clinical Science)
Source: Clinical Science - February 15, 2018 Category: Biomedical Science Authors: Hsu, S.-J., Tsai, M.-H., Chang, C.-C., Hsieh, Y.-H., Huang, H.-C., Lee, F.-Y., Chuang, C.-L., Hou, M.-C., Lee, S.-D. Tags: PublishAheadOfPrint Source Type: research

Quantification of hepatic perfusion and hepatocyte function with dynamic gadoxetic acid-enhanced MR imaging in patients with chronic liver disease
The purpose of this study was to develop and perform initial validation of dynamic MR imaging enhanced with gadoxetic acid as hepatobiliary contrast agent to quantify hepatic perfusion and hepatocyte function in patients with chronic liver disease. Free-breathing, dynamic gadoxetic acid-enhanced MR imaging was performed at 3.0 T using a three-dimensional time-resolved angiography sequence with stochastic trajectories during 38 minutes. A dual-input three-compartment model was developed to derive hepatic perfusion and hepatocyte function parameters. Method feasibility was assessed in 23 patients with biopsy-proven chronic l...
Source: Clinical Science - February 12, 2018 Category: Biomedical Science Authors: Leporq, B., Daire, J.-L., Pastor, C. M., Deltenre, P., Sempoux, C., Schmidt, S., Van Beers, B. E. Tags: PublishAheadOfPrint Source Type: research

Urinary levels of sirtuin-1 associated with disease activity in lupus nephritis
Identifying new markers of disease flares in lupus nephritis (LN) that facilitate patient stratification and prognosis is important. Therefore, the aim of this study was to analyze whether urinary SIRT1 expression was altered in LN and whether SIRT1 values in urine could be valuable biomarker of disease activity. In a cohort study, urinary pellets from 40 patients diagnosed with systemic lupus erythematosus (SLE) were analyzed. Clinical measures of lupus activity were assessed. The expression of SIRT1 was quantified by quantitative PCR (qRT-PCR) and immunoblot, then compared between patients with active lupus nephritis, in...
Source: Clinical Science - February 12, 2018 Category: Biomedical Science Authors: Olivares, D., Perez-Hernandez, J., Forner, M. J., Perez-Soriano, C., Tormos, M. C., Saez, G. T., Chaves, F. J., Redon, J., Cortes, R. Tags: PublishAheadOfPrint Source Type: research

Short-term early exposure to thirdhand cigarette smoke increases lung cancer incidence in mice
Exposure to thirdhand smoke (THS) is a recently described health concern that arises in many indoor environments. However, the carcinogenic potential of THS, a critical consideration in risk assessment, remains untested. Here we investigated the effects of short-term early exposure to THS on lung carcinogenesis in A/J mice. Forty weeks after THS exposure from 4 to-7 weeks of age, the mice had increased incidence of lung adenocarcinoma, tumor size and multiplicity, compared to controls. In vitro studies using cultured human lung cancer cells showed that THS exposure induced DNA double-strand breaks and increased cell prolif...
Source: Clinical Science - February 12, 2018 Category: Biomedical Science Authors: Hang, B., Wang, Y., Huang, Y., Wang, P., Langley, S. A., Bi, L., Sarker, A. H., Schick, S. F., Havel, C., Jacob, P., Benowitz, N., Destaillats, H., Tang, X., Xia, Y., Jen, K.-Y., Gundel, L. A., Mao, J.-H., Snijders, A. Tags: PublishAheadOfPrint Source Type: research

Long-term diet-induced hypertension in rats is associated with reduced expression and function of small artery SKCa, IKCa, and Kir2.1 channels
Conclusions: Reduced expression and function of SKCa, IKCa and Kir2.1 channels is associated with elevated blood pressure in rats fed a long-term high fat/high fructose diet. Rats fed a 28-week high fat/high fructose diet provide a relevant model of diet-induced hypertension. (Source: Clinical Science)
Source: Clinical Science - February 7, 2018 Category: Biomedical Science Authors: Gradel, A. K. J., Salomonsson, M., Sorensen, C. M., Holstein-Rathlou, N.-H., Jensen, L. J. Tags: PublishAheadOfPrint Source Type: research

The Angiotensin Type 2 Receptor In Human Adrenocortical Zona Glomerulosa And In Aldosterone-Producing Adenoma: Low Expression And No Functional Role
The angiotensin II type 2 receptor (AT2R) and the angiotensin-(1-7) receptor (MasR) play a cardiovascular protective role by counter-regulating angiotensin II type 1 receptor (AT1R)-mediated effects, but whether this involves blunting of adrenocortical hormone secretion is unknown. We investigated the presence of AT1R, AT2R and MasR in aldosterone-producing adenoma (APA), a condition featuring hyperaldosteronism, and in APA-adjacent tissue. The effect of C21, an AT2R agonist, on CYP11B1 (cortisol synthase) and CYP11B2 (aldosterone synthase) gene expression in NCI-H295R and HAC15 cell lines, and in APA and APA-adjacent tiss...
Source: Clinical Science - February 7, 2018 Category: Biomedical Science Authors: Vanderriele, P. E., Caroccia, B., Seccia, T. M., Piazza, M., Lenzini, L., Torresan, F., Iacobone, M., Unger, T., Rossi, G. P. Tags: PublishAheadOfPrint Source Type: research

Cyclic stretch-induced Crp3 sensitizes vascular smooth muscle cells to apoptosis during vein arterialization remodeling
Vein graft failure limits the long-term patency of the saphenous vein used as a conduit for coronary artery bypass graft. Early graft adaptation involves some degree of intima hyperplasia to sustain the hemodynamic stress, but the progress to occlusion in some veins remains unclear. We have demonstrated that stretch-induced up-regulation of cysteine and glycine-rich protein 3 (Crp3) in rat jugular vein and human saphenous vein in response to arterialization. Here, we developed a Crp3-KO rat to investigate the role of Crp3 in vascular remodeling. After 28 days jugular vein arterialization, the intima layer was 3-fold thicke...
Source: Clinical Science - February 2, 2018 Category: Biomedical Science Authors: Campos, L. C. G., Ribeiro-Silva, J. C., Menegon, A. S., Barauna, V. G., Miyakawa, A. A., Krieger, J. E. Tags: PublishAheadOfPrint Source Type: research

Metformin attenuates effects of cyclophilin A on macrophages, reduces lipid uptake and secretion of cytokines by repressing decreased AMPK activity
Growing evidence implicates cyclophilin A secreted by vascular wall cells and monocytes as a key mediator in atherosclerosis. Cyclophilin A in addition to its proliferative effects, during hyperglycaemic conditions, increases lipid uptake in macrophages by increasing scavenger receptors on the cell's surface. It also promotes macrophage migration across endothelial cells and conversion of macrophages to foam cells. Given the known effects of metformin in reducing vascular complications of diabetes, we investigated the effect of metformin on cyclophilin A action in macrophages. Using an ex vivo  model of cultured macro...
Source: Clinical Science - January 30, 2018 Category: Biomedical Science Authors: Ramachandran, S., Anandan, V., Kutty, V. R., Mullasari, A., Pillai, M. R., Kartha, C. C. Tags: PublishAheadOfPrint Source Type: research

Elevated Vasopressin in Pregnant Mice Induces T Helper Subset Alterations Consistent with Human Preeclampsia
The pathogenesis of preeclampsia, a hypertensive disorder of pregnancy, involves imbalanced T helper (TH) cell populations and resultant changes in pro- and anti-inflammatory cytokine release. Elevated copeptin (an inert biomarker of arginine vasopressin (AVP)), secretion precedes the development of symptoms in preeclampsia in humans, and infusion of AVP proximal to and throughout gestation is sufficient to initiate cardiovascular and renal phenotypes of preeclampsia in wild-type C57BL/6J mice. We hypothesize that AVP infusion in wild-type mice is sufficient to induce the immune changes observed in human preeclampsia. AVP ...
Source: Clinical Science - January 25, 2018 Category: Biomedical Science Authors: Scroggins, S. M., Santillan, D. A., Lund, J. M., Sandgren, J. A., Krotz, L. K., Hamilton, W. S., Devor, E. J., Davis, H. A., Pierce, G. L., Gibson-Corley, K. N., Sigmund, C. D., Grobe, J. L., Santillan, M. K. Tags: PublishAheadOfPrint Source Type: research

Gene delivery of medium chain acyl-coenzyme A dehydrogenase (MCAD) induces physiological cardiac hypertrophy and protects against pathological remodelling
We previously showed that medium chain acyl-coenzyme A dehydrogenase (MCAD, key regulator of fatty acid oxidation) is positively modulated in the heart by the cardioprotective kinase, phosphoinositide 3-kinase [PI3K(p110α)]. Disturbances in cardiac metabolism are a feature of heart failure patients, and targeting metabolic defects is considered a potential therapeutic approach. The specific role of MCAD in the adult heart is unknown. To examine the role of MCAD in the heart and to assess the therapeutic potential of increasing MCAD in the failing heart, we developed a gene therapy tool using recombinant adeno-associa...
Source: Clinical Science - January 22, 2018 Category: Biomedical Science Authors: Bernardo, B. C., Weeks, K. L., Pongsukwechkul, T., Gao, X., Kiriazis, H., Cemerlang, N., Boey, E. J., Tham, Y. K., Johnson, C. J., Qian, H., Du, X.-J., Gregorevic, P., McMullen, J. R. Tags: PublishAheadOfPrint Source Type: research

Blockade of histone deacetylase 6 protects against cisplatin-induced acute kidney injury
In this study, we utilized a murine model of cisplatin-induced acute kidney injury (AKI) and a highly selective inhibitor of HDAC6, tubastatin A (TA), to assess the role of HDAC6 in nephrotoxicity and its associated mechanisms. Cisplatin-induced AKI was accompanied by increased expression and activation of HDAC6; blocking HDAC6 with TA lessened renal dysfunction, attenuated renal pathological changes, reduced expression of neutrophil gelatinase-associated lipocalin and Kim-1, and decreased tubular cell apoptosis. In cultured human epithelial cells, TA or HDAC6 siRNA treatment also inhibited cisplatin-induced apoptosis. Mec...
Source: Clinical Science - January 22, 2018 Category: Biomedical Science Authors: Tang, J., Shi, Y., Liu, N., Xu, L., Zang, X., Li, P., Zhang, J., Zheng, X., Qiu, A., Zhuang, S. Tags: PublishAheadOfPrint Source Type: research

Rapamycin activates TGF receptor independently of its ligand: implications for endothelial dysfunction
In conclusion, we provide evidence that rapamycin activates TGF receptor independent of its ligand TGFb, in concert with promotion of PAI-1 expression and changes in endothelial phenotype. These undesirable effects, the prothrombogenic state and activation of EndMT, are SMAD2-dependent and independent of the therapeutic rapamycin-induced cell proliferation arrest. (Source: Clinical Science)
Source: Clinical Science - January 17, 2018 Category: Biomedical Science Authors: Miyakawa, A. A., Girao-Silva, T., Krieger, J. E., Edelman, E. R. Tags: PublishAheadOfPrint Source Type: research

The VEGFA165b isoform is dysregulated in senescent endothelial cells and may be associated with prevalent and incident coronary heart disease
Coronary heart disease (CHD) is a leading cause of morbidity in the over 65s; over 40% of all deaths are due to this condition. The association between increasing age and CHD is well-documented; the accumulation of senescent cells in cardiac and vascular tissues may represent one factor underpinning this observation. We aimed to identify senescence-related expression changes in primary human senescent cardiomyocytes and endothelial cells and to relate transcript expression in peripheral blood leucocytes to prevalent and incident CHD in the InCHIANTI study of aging. We quantified splicing factor expression and splicing patt...
Source: Clinical Science - January 12, 2018 Category: Biomedical Science Authors: Latorre, E., Pilling, L. C., Lee, B. P., Bandinelli, S., Melzer, D., Ferrucci, L., Harries, L. W. Tags: PublishAheadOfPrint Source Type: research

Non-uniform relationship between salt status and aldosterone activity in patients with chronic kidney disease
Discussion: We demonstrate dysregulation of aldosterone in CKD in response to salt loading with intravenous saline, but not to dietary salt modification. (Source: Clinical Science)
Source: Clinical Science - January 10, 2018 Category: Biomedical Science Authors: Taylor, A. H. M., Rankin, A. J., McQuarrie, E. P., Freel, E. M., Homer, N. Z. M., Andrew, R., Jardine, A. G., Mark, P. B. Tags: PublishAheadOfPrint Source Type: research

Impaired contraction of blood clots as a novel prothrombotic mechanism in systemic lupus erythematosus
In conclusion, autoantibodies in SLE can affect platelet contractility, resulting in reduced ability of clots and thrombi to shrink in volume, which increases vessel obstruction and may aggravate the course and outcomes of thrombotic complications in SLE. (Source: Clinical Science)
Source: Clinical Science - January 2, 2018 Category: Biomedical Science Authors: Le Minh, G., Peshkova, A. D., Andrianova, I. A., Sibgatullin, T. B., Maksudova, A. N., Weisel, J. W., Litvinov, R. Tags: PublishAheadOfPrint Source Type: research

Independent and combined effects of airway remodelling and allergy on airway responsiveness
This study investigated the separate and combined effects of increased airway smooth muscle (ASM) layer thickness and allergy on airway hyperresponsiveness. We integrated a protocol of ovalbumin (OVA)-induced allergy into a non-inflammatory mouse model of ASM remodelling induced by conditional and airway-specific expression of TGF-α in Egr-1 deficient transgenic mice, which produced thickening of the ASM layer following ingestion of doxycycline. Mice were sensitised to OVA and assigned to one of four treatment groups: Allergy - normal chow diet and OVA challenge; Remodelling - doxycycline in chow and saline challenge...
Source: Clinical Science - December 21, 2017 Category: Biomedical Science Authors: Wang, K. C., Le Cras, T. D., Larcombe, A. N., Zosky, G. R., Elliot, J. G., James, A. L., Noble, P. B. Tags: PublishAheadOfPrint Source Type: research

Functional Blocking of Ninjurin1 as a Strategy for Protecting Endothelial Cells in Diabetes Mellitus
Ongoing efforts to remove pathological inflammatory stimuli are crucial for the protection of endothelial cells in diabetes. Nerve injury-induced protein 1 (Ninj1) is an adhesion molecule that not only contributes to inflammation but also regulates the apoptosis of endothelial cells. In the present study, Ninj1 was found highly expressed in endothelial cells in type 2 diabetic mice and increased in high-glucose (HG) cultured HUVECs. Furthermore, we found that Ninj1 levels are up-regulated in endothelial cells in clinical specimens of diabetic patients when compared with non-diabetic tissues, indicating a biological correla...
Source: Clinical Science - December 20, 2017 Category: Biomedical Science Authors: Wang, X., Qin, J., Zhang, X., Peng, Z., Ye, K., Wu, X., Yang, X., Shi, H., Zhao, Z., Guo, X., Liu, X., Yin, M., Lu, X. Tags: PublishAheadOfPrint Source Type: research

Fetal growth restriction in mice modifies postnatal airway responsiveness in an age and sex-dependent manner
Epidemiological studies demonstrate an association between intrauterine growth restriction (IUGR) and asthma, however the underlying mechanism is unknown. We investigated the impact of maternal hypoxia-induced IUGR on airway responsiveness in male and female mice during juvenility and adulthood. Pregnant BALB/c mice were housed under hypoxic conditions for gestational days 11-17.5 and then returned to normoxic conditions for the remainder of pregnancy. A control group were housed under normoxic conditions throughout pregnancy. Offspring were studied at 2 weeks (juveniles) and 8 weeks (adults), where lung volume was assesse...
Source: Clinical Science - December 20, 2017 Category: Biomedical Science Authors: Wang, K. C. W., Larcombe, A. N., Berry, L. J., Morton, J. S., Davidge, S. T., James, A. L., Noble, P. B. Tags: PublishAheadOfPrint Source Type: research

Dual {alpha}v{beta}3 And {alpha}v{beta}5 Blockade Attenuates Fibrotic And Vascular Alterations In A Murine Model Of Systemic Sclerosis
Systemic sclerosis (SSc) is a connective tissue disorder characterized by fibroblast activation and fibrosis of the skin and internal organs. Alterations in cell-integrin interaction are sufficient to initiate pro-fibrotic processes. SSc fibroblasts express both αvβ3 and αvβ5 integrins and their activation induces myofibroblasts differentiation. The aim of this study was to evaluate the effect of the anb3 and anb5 inhibitor, cilengitide, on the development of vascular and fibrotic changes in the chronic oxidant stress murine model of systemic sclerosis. SSc was induced in BALB/c mice by daily s.c. inj...
Source: Clinical Science - December 13, 2017 Category: Biomedical Science Authors: Bagnato, G., Irrera, N., Pizzino, G., Santoro, D., Roberts, W. N., Bagnato, G., Pallio, G., Vaccaro, M., Squadrito, F., Saitta, A., Altavilla, D., Bitto, A. Tags: PublishAheadOfPrint Source Type: research

Intracranial pulsatility in patients with cerebral small vessel disease: a systematic review
In conclusion, most studies support a cross-sectional association between higher pulsatility in large intracranial arteries and SVD. Future studies should minimise bias, adjust for potential confounders, include pulsatility in veins and CSF, and examine longitudinal relationship between pulsatility and SVD. Agreement on reliable measures of intracranial pulsatility would be helpful. (Source: Clinical Science)
Source: Clinical Science - December 11, 2017 Category: Biomedical Science Authors: Shi, Y., Thrippleton, M. J., Marshall, I., Wardlaw, J. M. Tags: PublishAheadOfPrint Source Type: research

Sex-dependent differences in inflammatory responses during liver regeneration in a murine model of acute liver injury
A sexual dimorphism in liver inflammation and repair was previously demonstrated. Its cellular dissection in the course of acute liver injury (ALI) was explored. BALB/c mice were treated with carbon tetrachloride (CCl4) by intraperitoneal injection and sacrificed after 3, 5 and 8 days. Histological and hepatic cell population analyses were performed. The correlation between androgen receptor (AR) expression and liver recruited inflammatory cells was investigated by treatment with the AR antagonist flutamide. Additionally, patients with a diagnosis of Drug Induced Liver Injury (DILI) were included in the study, with a parti...
Source: Clinical Science - December 11, 2017 Category: Biomedical Science Authors: Bizzaro, D., Crescenzi, M., Di Liddo, R., Arcidiacono, D., Cappon, A., Bertalot, T., Amodio, V., Tasso, A., Stefani, A., Bertazzo, V., Germani, G., Frasson, C., Basso, G., Parnigotto, P., Alison, M. R., Burra, P., Conconi, M. T., Russo, F. P. Tags: PublishAheadOfPrint Source Type: research

Targeted disruption of the KCNJ5 gene in the female mouse lowers aldosterone levels
Aldosterone is released from adrenal zona glomerulosa cells and plays an important role in Na and K homeostasis. Mutations in the human KCNJ5 gene encoding the GIRK4 potassium channel cause abnormal aldosterone secretion and hypertension. To better understand the role of wild-type (WT) GIRK4 in regulating aldosterone release we have looked at aldosterone secretion in a Kcnj5 knock-out (KO) mouse.  We found that female, but not male, KO mice have reduced aldosterone levels compared to WT female controls, but higher levels of aldosterone after Ang-II stimulation. These differences could not be explained by sex-differenc...
Source: Clinical Science - December 8, 2017 Category: Biomedical Science Authors: Hardege, I., Long, L., Al Maskari, R., Figg, N., O'Shaughnessy, K. M. Tags: PublishAheadOfPrint Source Type: research

Endoplasmic reticulum stress/autophagy pathway is involved in diabetes-induced neuronal apoptosis and cognitive decline in mice
Diabetes mellitus is a significant global public health problem depicting a rising prevalence worldwide. As a serious complication of diabetes, diabetes-associated cognitive decline is attracting increasing attention. However, the underlying mechanisms are yet to be fully determined. Both endoplasmic reticulum (ER) stress and autophagy have been reported to modulate neuronal su...
Source: Clinical Science - December 6, 2017 Category: Biomedical Science Authors: Kong, F.-J., Ma, L.-L., Guo, J.-J., Xu, L.-H., Li, Y., Qu, S. Tags: PublishAheadOfPrint Source Type: research

A critical evaluation of the anabolic response after bolus or continuous feeding in COPD and healthy older adults
After bolus and continuous enteral feeding of the same protein, different digestion and absorption kinetics and anabolic responses are observed. Establishing which mode of feeding has the highest anabolic potential in patients with chronic obstructive pulmonary disease (COPD) may aid in the prevention of muscle wasting, but an important confounding factor is the duration of assessments after bolus feeding. We hypothesized that the anabolic response to bolus and continuous feeding in COPD patients is comparable when methodological issues are addressed. Twenty-one older adults (12 patients with stage II-IV COPD and 9 healthy...
Source: Clinical Science - November 29, 2017 Category: Biomedical Science Authors: Jonker, R., Deutz, N. E., Harrykissoon, R., Zachria, A. J., Veley, E. A., Engelen, M. P. Tags: PublishAheadOfPrint Source Type: research

Therapeutic Effect of a Novel Wnt Pathway Inhibitor on Cardiac Regeneration after Myocardial Infarction
In conclusion, porcupine inhibitor CGX1321 reduces MI injury by limiting fibrosis and promoting regeneration. It promotes cardiomyocyte proliferation by stimulating cell cycle regulating genes with a Hippo/YAP independent pathway. (Source: Clinical Science)
Source: Clinical Science - November 26, 2017 Category: Biomedical Science Authors: Yang, D., Fu, W., Li, L., Xia, X., Liao, Q., Yue, R., Chen, H., Chen, X., An, S., Zeng, C., Wang, W. E. Tags: PublishAheadOfPrint Source Type: research