scholarly journals Histone acetyltransferase and Polo-like kinase 3 inhibitors prevent rat galactose-induced cataract

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Fumito Kanada ◽  
Yoshihiro Takamura ◽  
Seiji Miyake ◽  
Kazuma Kamata ◽  
Mayumi Inami ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Histone Acetyltransferase ◽  
Ex Vivo ◽  
Causative Factor ◽  
Mrna Levels ◽  
Cataract Formation ◽  
Diabetic Cataract ◽  
Novel Approach ◽  
Hat Inhibitor

AbstractDiabetic cataracts can occur at an early age, causing visual impairment or blindness. The detailed molecular mechanisms of diabetic cataract formation remain incompletely understood, and there is no well-documented prophylactic agent. Galactose-fed rats and ex vivo treatment of lenses with galactose are used as models of diabetic cataract. To assess the role of histone acetyltransferases, we conducted cataract prevention screening with known histone acetyltransferase (HAT) inhibitors. Ex vivo treatment with a HAT inhibitor strongly inhibited the formation of lens turbidity in high-galactose conditions, while addition of a histone deacetylase (HDAC) inhibitor aggravated turbidity. We conducted a microarray to identify genes differentially regulated by HATs and HDACs, leading to discovery of a novel cataract causative factor, Plk3. Plk3 mRNA levels correlated with the degree of turbidity, and Plk3 inhibition alleviated galactose-induced cataract formation. These findings indicate that epigenetically controlled Plk3 influences cataract formation. Our results demonstrate a novel approach for prevention of diabetic cataract using HAT and Plk3 inhibitors.

MO094SALT INFLUENCES UROMODULIN EXCRETION INDEPENDENT OF BLOOD PRESSURE

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Sheon Mary ◽  
Philipp Boder ◽  
Giacomo Rossitto ◽  
Lesley Graham ◽  
Kayley Scott ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endoplasmic Reticulum ◽  
Direct Effect ◽  
Ex Vivo ◽  
Mrna Levels ◽  
Salt Loading ◽  
Spontaneously Hypertensive ◽  
Risk Variants ◽  
Wistar Kyoto

Abstract Background and Aims Uromodulin (UMOD) is the most abundant renal protein secreted into urine by the thick ascending epithelial (TAL) cells of the loop of Henle. Genetic studies have demonstrated an association between UMOD risk variants and hypertension. Studies on UMOD overexpressing transgenic mice have shown that UMOD increases the tubular salt reabsorption via enhanced NKCC2 activity. We aimed to dissect the effect of salt-loading and blood pressure on the excretion of UMOD. Method Wistar-Kyoto (WKY) and stroke-prone spontaneously hypertensive (SHRSP) rats (n=8/sex/strain) were maintained on 1% NaCl for three weeks. Salt-loaded SHRSP were treated with nifedipine. Tubule isolation and ex vivo incubation with nifedipine were used to assess its direct effect on TAL. Results Urinary UMOD excretion was significantly reduced after salt loading in both strains (figure). In salt-loaded SHRSP, nifedipine treatment reduced blood pressure and urinary UMOD excretion. The reductions in urinary UMOD excretion were dissociated from unchanged kidney UMOD protein and mRNA levels, however, were associated with UMOD endoplasmic reticulum accumulation, thus suggesting secretion as a key regulatory step. Ex vivo experiments with TAL tubules showed that nifedipine did not have a direct effect on UMOD secretion. Conclusion Our data suggest a direct effect of salt on UMOD secretion independent of blood pressure and a potential role of endoplasmic reticulum stress on the control of UMOD secretion. The role of UMOD as a cardiovascular risk marker deserves mechanistic reappraisal and further investigations based on our findings.

scholarly journals Fetal hyperinsulinemia increases farnesylation of p21 Ras in fetal tissues

2001 ◽  
Vol 281 (2) ◽  
pp. E217-E223 ◽  
Author(s):  
Elizabeth Stephens ◽  
Patti J. Thureen ◽  
Marc L. Goalstone ◽  
Marianne S. Anderson ◽  
J. Wayne Leitner ◽  
...  
Keyword(s):  
Growth Factors ◽  
Molecular Mechanisms ◽  
Fetal Liver ◽  
White Blood Cells ◽  
Causative Factor ◽  
Ras Proteins ◽  
Direct Infusion ◽  
Fetal Tissues ◽  
P21 Ras

Even though the role of fetal hyperinsulinemia in the pathogenesis of fetal macrosomia in patients with overt diabetes and gestational diabetes mellitus seems plausible, the molecular mechanisms of action of hyperinsulinemia remain largely enigmatic. Recent indications that hyperinsulinemia “primes” various tissues to the mitogenic influence of growth factors by increasing the pool of prenylated Ras proteins prompted us to investigate the effect of fetal hyperinsulinemia on the activitiy of farnesyltransferase (FTase) and the amounts of farnesylated p21 Ras in fetal tissues in the ovine experimental model. Induction of fetal hyperinsulinemia by direct infusion of insulin into the fetus and by either fetal or maternal infusions of glucose resulted in significant increases in the activity of FTase and the amounts of farnesylated p21 Ras in fetal liver, skeletal muscle, fat, and white blood cells. An additional infusion of somatostatin into hyperglycemic fetuses blocked fetal hyperinsulinemia and completely prevented these increases, specifying insulin as the causative factor. We conclude that the ability of fetal hyperinsulinemia to increase the size of the pool of farnesylated p21 Ras may prime fetal tissues to the action of other growth factors and thereby constitute one mechanism by which fetal hyperinsulinemia could induce macrosomia in diabetic pregnancies.

scholarly journals Cellular Distribution, Regulated Expression, and Functional Role of the Anorexigenic Peptide, NUCB2/Nesfatin-1, in the Testis

Endocrinology ◽  
2012 ◽  
Vol 153 (4) ◽  
pp. 1959-1971 ◽  
Author(s):  
D. García-Galiano ◽  
R. Pineda ◽  
T. Ilhan ◽  
J. M. Castellano ◽  
F. Ruiz-Pino ◽  
...  
Keyword(s):  
Leydig Cell ◽  
Functional Role ◽  
Energy Homeostasis ◽  
Ex Vivo ◽  
Whole Body ◽  
Mrna Levels ◽  
Gonadal Function ◽  
Human Choriogonadotropin ◽  
Puberty Onset

Nesfatin-1, product of the precursor NEFA/nucleobindin2 (NUCB2), was initially identified as anorectic hypothalamic neuropeptide, acting in a leptin-independent manner. In addition to its central role in the control of energy homeostasis, evidence has mounted recently that nesfatin-1 is also produced in peripheral metabolic tissues, such as pancreas, adipose, and gut. Moreover, nesfatin-1 has been shown to participate in the control of body functions gated by whole-body energy homeostasis, including puberty onset. Yet, whether, as is the case for other metabolic neuropeptides, NUCB2/nesfatin-1 participates in the direct control of gonadal function remains unexplored. We document here for the first time the expression of NUCB2 mRNA in rat, mouse, and human testes, where NUCB2/nesfatin-1 protein was identified in interstitial mature Leydig cells. Yet in rats, NUCB2/nesfatin-1 became expressed in Sertoli cells upon Leydig cell elimination and was also detected in Leydig cell progenitors. Although NUCB2 mRNA levels did not overtly change in rat testis during pubertal maturation and after short-term fasting, NUCB2/nesfatin-1 content significantly increased along the puberty-to-adult transition and was markedly suppressed after fasting. In addition, testicular NUCB2/nesfatin-1 expression was up-regulated by pituitary LH, because hypophysectomy decreased, whereas human choriogonadotropin (super-agonist of LH receptors) replacement enhanced, NUCB2/nesfatin-1 mRNA and peptide levels. Finally, nesfatin-1 increased human choriogonadotropin-stimulated testosterone secretion by rat testicular explants ex vivo. Our data are the first to disclose the presence and functional role of NUCB2/nesfatin-1 in the testis, where its expression is regulated by developmental, metabolic, and hormonal cues as well as by Leydig cell-derived factors. Our observations expand the reproductive dimension of nesfatin-1, which may operate directly at the testicular level to link energy homeostasis, puberty onset, and gonadal function.

scholarly journals Role of Insulin Receptor Substrate-1 Serine 307 Phosphorylation and Adiponectin in Adipose Tissue Insulin Resistance in Late Pregnancy

Endocrinology ◽  
2007 ◽  
Vol 148 (12) ◽  
pp. 5933-5942 ◽  
Author(s):  
Julio Sevillano ◽  
Javier de Castro ◽  
Carlos Bocos ◽  
Emilio Herrera ◽  
M. Pilar Ramos
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Late Pregnancy ◽  
Serine Phosphorylation ◽  
Pregnant Rats

Insulin resistance is a hallmark of late pregnancy both in human and rat. Adipose tissue is one of the tissues that most actively contributes to this reduced insulin sensitivity. The aim of the present study was to characterize the molecular mechanisms of insulin resistance in adipose tissue at late pregnancy. To this end, we analyzed the insulin signaling cascade in lumbar adipose tissue of nonpregnant and pregnant (d 20) rats both under basal and insulin-stimulated conditions. We found that the levels of relevant signaling proteins, such as insulin receptor (IR), IR substrate-1 (IRS-1), phosphatidylinositol 3-kinase, 3-phosphoinositide-dependent kinase-1, ERK1/2, and phosphatase and tensin homolog (PTEN) did not change at late pregnancy. However, insulin-stimulated tyrosine phosphorylation of both IR and IRS-1 were significantly decreased, coincident with decreased IRS-1/p85 association and impaired phosphorylation of AKR mouse thymoma viral protooncogene (Akt) and ERK1/2. This impaired activation of IRS-1 occurred together with an increase of IRS-1 phosphorylation at serine 307 and a decrease in adiponectin levels. To corroborate the role of IRS-1 in adipose tissue insulin resistance during pregnancy, we treated pregnant rats with the antidiabetic drug englitazone. Englitazone improved glucose tolerance, and this pharmacological reversal of insulin resistance was paralleled by an increase of adiponectin levels in adipose tissue as well as by a reduction of IRS-1 serine phosphorylation. Furthermore, the impaired insulin-stimulated tyrosine phosphorylation of IRS-1 in adipose tissue of pregnant animals could be restored ex vivo by treating isolated adipocytes with adiponectin. Together, our findings support a role for adiponectin and serine phosphorylation of IRS-1 in the modulation of insulin resistance in adipose tissue at late pregnancy.

scholarly journals Hepcidin links gluco-toxicity to pancreatic beta cell dysfunction by inhibiting Pdx-1 expression

2017 ◽  
Vol 6 (3) ◽  
pp. 121-128 ◽  
Author(s):  
Xuhua Mao ◽  
Hucheng Chen ◽  
Junmin Tang ◽  
Liangliang Wang ◽  
Tingting Shu
Keyword(s):  
High Glucose ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Pancreatic Beta Cell ◽  
Mrna Levels ◽  
Β Cell ◽  
Min6 Cells ◽  
Hepcidin Expression ◽  
Insulin Synthesis

Objective Gluco-toxicity is a term used to convey the detrimental effect of hyperglycemia on β-cell function through impaired insulin synthesis. Although it is known that the expression and activity of several key insulin transcription regulators is inhibited, other molecular mechanisms that mediate gluco-toxicity are poorly defined. Our objective was to explore the role of hepcidin in β-cell gluco-toxicity. Design We first confirmed that high glucose levels inhibited hepcidin expression in the mouse insulinoma cell line, MIN6. The downregulation of hepcidin decreased Pdx-1 expression, which reduced insulin synthesis. Methods MIN6 cells were exposed to high glucose concentrations (33.3 mmol/L). Glucose-stimulated insulin secretion (GSIS) and serum hepcidin levels were measured by ELISA. The mRNA levels of insulin1, insulin2, Pdx-1 and hepcidin were measured by real-time polymerase chain reaction. Western blot analysis was used to detect the changes in PDX-1 expression. Transient overexpression with hepcidin was used to reverse the downregulation of Pdx-1 and insulin synthesis induced by gluco-toxicity. Results Exposure of MIN6 cells to high glucose significantly decreased GSIS and inhibited insulin synthesis as well as Pdx-1 transcriptional activity and expression at both the mRNA and protein levels. High glucose also decreased hepcidin expression and secretion. Hepcidin overexpression in MIN6 cells partially reversed the gluco-toxicity-induced downregulation of Pdx-1 and insulin expression and improved GSIS. The restoration of insulin synthesis by transfection of a hepcidin overexpression plasmid confirmed the role of hepcidin in mediating the gluco-toxic inhibition of insulin synthesis. Conclusions Our observations suggest that hepcidin is associated with gluco-toxicity-reduced pancreatic β-cell insulin synthesis in type 2 diabetes by inhibiting Pdx-1 expression.

scholarly journals Diabetic cataract formation: potential role of glycosylation of lens crystallins.

1978 ◽  
Vol 75 (6) ◽  
pp. 2918-2922 ◽  
Author(s):  
V. J. Stevens ◽  
C. A. Rouzer ◽  
V. M. Monnier ◽  
A. Cerami
Keyword(s):  
Potential Role ◽  
Cataract Formation ◽  
Lens Crystallins ◽  
Diabetic Cataract ◽  
Formation Potential

scholarly journals Salt loading decreases urinary excretion and increases intracellular accumulation of uromodulin in stroke-prone spontaneously hypertensive rats.

2021 ◽  
Author(s):  
Sheon Mary ◽  
Philipp Boder ◽  
Giacomo Rossitto ◽  
Lesley Graham ◽  
Kayley Scott ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Spontaneously Hypertensive Rats ◽  
Ex Vivo ◽  
Chronic Hypertension ◽  
Thick Ascending Limb ◽  
Mrna Levels ◽  
Hypertensive Rats ◽  
Salt Loading ◽  
Spontaneously Hypertensive

Uromodulin (UMOD) is the most abundant renal protein secreted into urine by the thick ascending limb (TAL) epithelial cells of the loop of Henle. Genetic studies have demonstrated an association between UMOD risk variants and hypertension. We aimed to dissect the role of dietary salt in renal UMOD excretion in normotension and chronic hypertension. Normotensive Wistar-Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) (n=8/sex/strain) were maintained on 1% NaCl for three weeks. A subset of salt-loaded SHRSP was treated with nifedipine. Salt-loading in SHRSP increased blood pressure (ΔSBP 35 ± 5 mmHg, p<0.0001) and kidney injury markers such as KIM-1 (fold change, FC 3.4; p=0.003), NGAL (FC, 2.0; p=0.012) and proteinuria. After salt-loading there was a reduction in urinary UMOD excretion in WKY and SHRSP by 26% and 55% respectively, compared to baseline. Nifedipine treatment reduced blood pressure in SHRSP, however, did not prevent salt-induced reduction in urinary UMOD excretion. In all experiments, changes in urinary UMOD excretion were dissociated from kidney UMOD protein and mRNA levels. Colocalization and ex-vivo studies showed that salt-loading increased intracellular UMOD retention in both WKY and SHRSP. Our study provides novel insights into the interplay between salt, UMOD, and blood pressure. The role of UMOD as a cardiovascular risk marker deserves mechanistic reappraisal and further investigations based on our findings.

scholarly journals Rational cotargeting of HDAC6 and BET proteins yields synergistic antimyeloma activity

2019 ◽  
Vol 3 (8) ◽  
pp. 1318-1329 ◽  
Author(s):  
Jennifer S. Carew ◽  
Claudia M. Espitia ◽  
Weiguo Zhao ◽  
Valeria Visconte ◽  
Faiz Anwer ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Family Members ◽  
Apoptosis Induction ◽  
Histone Deacetylase 6 ◽  
Novel Approach ◽  
Bet Inhibitors ◽  
Hdac6 Inhibitor ◽  
Bet Protein

Abstract Inhibition of bromodomain and extra terminal (BET) protein family members, including BRD4, decreases the expression of c-MYC and other key oncogenic factors and also significantly induces histone deacetylase 6 (HDAC6) expression. On the basis of the role of HDAC6 in malignant pathogenesis, we hypothesized that rational cotargeting of HDAC6 and BET family proteins may represent a novel approach that yields synergistic antimyeloma activity. We used genetic and pharmacologic approaches to selectively impair HDAC6 and BET function and evaluated the consequential impact on myeloma pathogenesis. These studies identified HDAC6 upregulation as an efficacy reducing mechanism for BET inhibitors because antagonizing HDAC6 activity synergistically enhanced the activity of JQ1 in a panel of multiple myeloma (MM) cell lines and primary CD138+ cells obtained from patients with MM. The synergy of this therapeutic combination was linked to significant reductions in c-MYC expression and increases in apoptosis induction. Administration of the clinical HDAC6 inhibitor ricolinostat was very well tolerated and significantly augmented the in vivo antimyeloma activity of JQ1. Ex vivo pharmacodynamic analyses demonstrated that the combination of JQ1 and ricolinostat led to significantly lower MM cell proliferation and increased apoptosis and diminished expression of c-MYC and BCL-2. These data demonstrate that cotargeting of HDAC6 and BET family members is a novel and clinically actionable approach to augment the efficacy of both classes of agents that warrants further investigation.

Rhodiola and salidroside in the treatment of metabolic disorders

2019 ◽  
Vol 19 (19) ◽  
pp. 1611-1626 ◽  
Author(s):  
Xiang-Li Bai ◽  
Xiu-Ling Deng ◽  
Guang-Jie Wu ◽  
Wen-Jing Li ◽  
Si Jin
Keyword(s):  
Metabolic Disorders ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Ex Vivo ◽  
Treatment Strategies ◽  
Ampk Signaling ◽  
Beneficial Effects

Over the past three decades, the knowledge gained about the mechanisms that underpin the potential use of Rhodiola in stress- and ageing-associated disorders has increased, and provided a universal framework for studies that focused on the use of Rhodiola in preventing or curing metabolic diseases. Of particular interest is the emerging role of Rhodiola in the maintenance of energy homeostasis. Moreover, over the last two decades, great efforts have been undertaken to unravel the underlying mechanisms of action of Rhodiola in the treatment of metabolic disorders. Extracts of Rhodiola and salidroside, the most abundant active compound in Rhodiola, are suggested to provide a beneficial effect in mental, behavioral, and metabolic disorders. Both in vivo and ex vivo studies, Rhodiola extracts and salidroside ameliorate metabolic disorders when administered acutely or prior to experimental injury. The mechanism involved includes multi-target effects by modulating various synergistic pathways that control oxidative stress, inflammation, mitochondria, autophagy, and cell death, as well as AMPK signaling that is associated with possible beneficial effects on metabolic disorders. However, evidence-based data supporting the effectiveness of Rhodiola or salidroside in treating metabolic disorders is limited. Therefore, a comprehensive review of available trials showing putative treatment strategies of metabolic disorders that include both clinical effective perspectives and fundamental molecular mechanisms is warranted. This review highlights studies that focus on the potential role of Rhodiola extracts and salidroside in type 2 diabetes and atherosclerosis, the two most common metabolic diseases.

scholarly journals A regulatory role of LPCAT1 in the synthesis of inflammatory lipids, PAF and LPC, in the retina of diabetic mice

2009 ◽  
Vol 297 (6) ◽  
pp. E1276-E1282 ◽  
Author(s):  
Long Cheng ◽  
Xiao Han ◽  
Yuguang Shi
Keyword(s):  
Diabetic Retinopathy ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Regulatory Role ◽  
Mrna Levels ◽  
Diabetic Mice ◽  
Acyltransferase Activity ◽  
Onset Of Diabetes ◽  
Anti Inflammatory

Platelet-activating factor (PAF) and lysophosphatidylcholine (LPC) are potent inflammatory lipids. Elevated levels of PAF and LPC are associated with the onset of diabetic retinopathy and neurodegeneration. However, the molecular mechanisms underlying such defects remain elusive. LPCAT1 is a newly reported lysophospholipid acyltransferase implicated in the anti-inflammatory response by its role in conversion of LPC to PC. Intriguingly, the LPCAT1 enzyme also catalyzes the synthesis of PAF from lyso-PAF with use of acetyl-CoA as a substrate. The present studies investigated regulatory roles of LPCAT1 in the synthesis of inflammatory lipids during the onset of diabetes. Our work shows that LPCAT1 plays an important role in the inactivation of PAF by catalyzing the synthesis of alkyl-PC, an inactivated form of PAF with use of acyl-CoA and lyso-PAF as substrates. In support of a role of LPCAT1 in anti-inflammatory responses in diabetic retinopathy, LPCAT1 is most abundantly expressed in the retina. Moreover, LPCAT1 mRNA levels and acyltransferase activity toward lyso-PAF and LPC were significantly downregulated in retina and brain tissues in response to the onset of diabetes in Ins2 Akita and db/db mice, mouse models of type 1 and type 2 diabetes, respectively. Conversely, treatment of db/db mice with rosiglitazone, an antidiabetes compound, significantly upregulated LPCAT1 mRNA levels concurrently with increased acyltransferase activity in the retina and brain. Collectively, these findings identified a novel regulatory role of LPCAT1 in catalyzing the inactivation of inflammatory lipids in the retina of diabetic mice.

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