The influence of uterine fibroids on adverse outcomes in pregnant women: a meta-analysis.

OBJECTIVE: The objective of the meta-analysis was to determine the influence of uterine fibroids on adverse outcomes, with specific emphasis on multiple or large (≥ 5 cm in diameter) fibroids. MATERIALS AND METHODS: We searched PubMed, Embase, Web of Science, ClinicalTrials.gov, China National Knowledge Infrastructure (CNKI), and SinoMed databases for eligible studies that investigated the influence of uterine fibroids on adverse outcomes in pregnancy. The pooled risk ratio (RR) of the variables was estimated with fixed effect or random effect models. RESULTS: Twenty-four studies with 237 509 participants were included. The pooled results showed that fibroids elevated the risk of adverse outcomes, including preterm birth, cesarean delivery, placenta previa, miscarriage, preterm premature rupture of membranes (PPROM), placental abruption, postpartum hemorrhage (PPH), fetal distress, malposition, intrauterine fetal death, low birth weight, breech presentation, and preeclampsia. However, after adjusting for the potential factors, negative effects were only seen for preterm birth, cesarean delivery, placenta previa, placental abruption, PPH, intrauterine fetal death, breech presentation, and preeclampsia. Subgroup analysis showed an association between larger fibroids and significantly elevated risks of breech presentation, PPH, and placenta previa in comparison with small fibroids. Multiple fibroids did not increase the risk of breech presentation, placental abruption, cesarean delivery, PPH, placenta previa, PPROM, preterm birth, and intrauterine growth restriction. Meta-regression analyses indicated that maternal age only affected the relationship between uterine fibroids and preterm birth, and BMI influenced the relationship between uterine fibroids and intrauterine fetal death. Other potential confounding factors had no impact on malposition, fetal distress, PPROM, miscarriage, placenta previa, placental abruption, and PPH. CONCLUSION: The presence of uterine fibroids poses increased risks of adverse pregnancy and obstetric outcomes. Fibroid size influenced the risk of breech presentation, PPH, and placenta previa, while fibroid numbers had no impact on the risk of these outcomes.

APC/C-regulated CPT1C promotes tumor progression by upregulating the energy supply and accelerating the G1/S transition.

BACKGROUND: In addition to functioning as a precise monitoring mechanism in cell cycle, the anaphase-promoting complex/cyclosome (APC/C) is reported to be involved in regulating multiple metabolic processes by facilitating the ubiquitin-mediated degradation of key enzymes. Fatty acid oxidation is a metabolic pathway utilized by tumor cells that is crucial for malignant progression; however, its association with APC/C remains to be explored. METHODS: Cell cycle synchronization, immunoblotting, and propidium iodide staining were performed to investigate the carnitine palmitoyltransferase 1 C (CPT1C) expression manner. Proximity ligation assay and co-immunoprecipitation were performed to detect interactions between CPT1C and APC/C. Flow cytometry, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium, inner salt (MTS) assays, cell-scratch assays, and transwell assays and xenograft transplantation assays were performed to investigate the role of CPT1C in tumor progression in vitro and in vivo. Immunohistochemistry was performed on tumor tissue microarray to evaluate the expression levels of CPT1C and explore its potential clinical value. RESULTS: We identified CPT1C as a novel APC/C substrate. CPT1C protein levels exhibited cell cycle-dependent fluctuations, peaking at the G1/S boundary. Elevated CPT1C accelerated the G1/S transition, facilitating tumor cell proliferation in vitro and in vivo. Furthermore, CPT1C enhanced fatty acid utilization, upregulated ATP levels, and decreased reactive oxygen species levels, thereby favoring cell survival in a harsh metabolic environment. Clinically, high CPT1C expression correlated with poor survival in patients with esophageal squamous cell carcinoma. CONCLUSIONS: Overall, our results revealed a novel interplay between fatty acid utilization and cell cycle machinery in tumor cells. Additionally, CPT1C promoted tumor cell proliferation and survival by augmenting cellular ATP levels and preserving redox homeostasis, particularly under metabolic stress. Therefore, CPT1C could be an independent prognostic indicator in esophageal squamous cell carcinoma.

Four-Dimensional Printing of Temperature-Responsive Liquid Crystal Elastomers with Programmable Shape-Changing Behavior.

Liquid crystal elastomers (LCEs) are polymer networks that exhibit anisotropic liquid crystalline properties while maintaining the properties of elastomers, presenting reversible high-speed and large-scale actuation in response to external stimuli. Herein, we formulated a non-toxic, low-temperature liquid crystal (LC) ink for temperature-controlled direct ink writing 3D printing. The rheological properties of the LC ink were verified under different temperatures given the phase transition temperature of 63 °C measured by the DSC test. Afterwards, the effects of printing speed, printing temperature, and actuation temperature on the actuation strain of printed LCEs structures were investigated within adjustable ranges. In addition, it was demonstrated that the printing direction can modulate the LCEs to exhibit different actuation behaviors. Finally, by sequentially conforming structures and programming the printing parameters, it showed the deformation behavior of a variety of complex structures. By integrating with 4D printing and digital device architectures, this unique reversible deformation property will help LCEs presented here apply to mechanical actuators, smart surfaces, micro-robots, etc.

Mechanism of Neural Regeneration Induced by Natural Product LY01 in the 5×FAD Mouse Model of Alzheimer's Disease.

Background: A sharp decline in neural regeneration in patients with Alzheimer's disease (AD) exacerbates the decline of cognition and memory. It is of great significance to screen for innovative drugs that promote endogenous neural regeneration. Cytisine N-methylene-(5,7,4'-trihydroxy)-isoflavone (LY01) is a new compound isolated from the Chinese herbal medicine Sophora alopecuroides with both isoflavone and alkaloid characteristic structures. Its pharmacological effects are worth studying. Objective: This study was designed to determine whether LY01 delays the cognitive and memory decline in the early stage of AD and whether this effect of LY01 is related to promoting neural regeneration. Methods: Eight-week-old 5×Familial Alzheimer's Disease (5×FAD) mice were used as disease models of early AD. Three doses of LY01 administered in two courses (2 and 5 weeks) of treatment were tested. Cognition, memory, and anxiety-like behaviors in mice were evaluated by the Morris water maze, fear conditioning, and open field experiments. Regeneration of neurons in the mouse hippocampus was observed using immunofluorescence staining. The effect of LY01 on cell regeneration was also demonstrated using a series of tests on primary cultured neurons, astrocytes, and neural stem cells (NSCs). In addition, flow cytometry and transcriptome sequencing were carried out to preliminarily explored the mechanisms. Results: We found that LY01 reduced the decline of cognition and memory in the early stage of 5×FAD mice. This effect was related to the proliferation of astrocytes, the proliferation and migration of NSCs, and increases in the number of new cells and neural precursor cells in the dentate gyrus area of 5×FAD mice. This phenomenon could be observed both in 2-week-old female and 5-week-old male LY01-treated 5×FAD mice. The neuronal regeneration induced by LY01 was related to the regulation of the extracellular matrix and associated receptors, and effects on the S phase of the cell cycle. Conclusion: LY01 increases the proliferation of NSCs and astrocytes and the number of neural precursor cells in the hippocampus, resulting in neural regeneration in 5×FAD mice by acting on the extracellular matrix and associated receptors and regulating the S phase of the cell cycle. This provides a new idea for the early intervention and treatment of AD.

The way of Qu-making significantly affected the volatile flavor compounds in Huangjiu (Chinese rice wine) during different brewing stages.

The volatile flavor compounds of Huangjiu (Chinese rice wine) brewed from different raw materials were obviously different, but there were few studies on the volatile flavor compounds of Huangjiu brewed from different wheat Qu at different brewing stages. In this paper, headspace-solid phase microextraction combined with gas chromatography-mass spectrometry, combined with principal component analysis and sensory evaluation, was used to determine the volatile flavor compounds in Huangjiu brewed from wheat Qu made by hand and wheat Qu made by mechanical. The results showed that there were significant differences in the contents and types of volatile flavor substances in Huangjiu brewed from different wheat Qu at fermentation stages, and the prefermentation and postfermentation Huangjiu samples could be well distinguished from each other. Compared with the Huangjiu brewed from wheat Qu made by mechanical, the Huangjiu brewed from wheat Qu made by hand has stronger aroma and better taste.

Mitogen-activating protein kinase kinase kinase kinase-3, inhibited by Astragaloside IV through H3 lysine 4 monomethylation, promotes the progression of diabetic nephropathy by inducing apoptosis.

Astragaloside IV (AS-IV) is a bioactive saponin extracted from the Astragalus root and has been reported to exert a protective effect on diabetic nephropathy (DN). However, the underlying mechanism remains unclear. Herein, we found that AS-IV treatment alleviated DN symptoms in DN mice accompanied by reduced metabolic parameters (body weight, urine microalbumin and creatinine, creatinine clearance, and serum urea nitrogen and creatinine), pathological changes, and apoptosis. Epigenetic histone modifications are closely related to diabetes and its complications, including H3 lysine 4 monomethylation (H3K4me1, a promoter of gene transcription). A ChIP-seq assay was conducted to identify the genes regulated by H3K4me1 in DN mice after AS-IV treatment and followed by a Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. The results showed that there were 16 common genes targeted by H3K4me1 in normal and AS-IV-treated DN mice, 1148 genes were targeted by H3K4me1 only in DN mice. From the 1148 genes, we screened mitogen-activating protein kinase kinase kinase kinase-3 (MAP4K3) for the verification of gene expression and functional study. The results showed that MAP4K3 was significantly increased in DN mice and high glucose (HG)-treated NRK-52E cells, which was reversed by AS-IV. MAP4K3 silencing reduced the apoptosis of NRK-52E cells under HG condition, as evidenced by decreased cleaved caspase 3 and Bax (pro-apoptotic factors), and increased Bcl-2 and Bcl-xl (anti-apoptotic factors). Collectively, AS-IV may downregulate MAP4K3 expression by regulating H3K4me1 binding and further reducing apoptosis, which may be one of the potential mechanisms that AS-IV plays a protective effect on DN.

Large-scale preparation of a versatile bioinspired sponge with physic-mechanochemical robustness for multitasking separation.

Developing novel biomaterials integrating robustness and multitasking separation performance are of importance. However, those were limited in application due to the expensive, time-consuming and complex fabrication process. In this work, with the inspiration from high porosity and surface area of natural materials, the porous superhydrophobic melamine sponges (SMS) coated hydrophobic TiO2 and epoxy copolymer were fabricated via a facile, inexpensive, eco-friendly and large-scale strategy. The SMS showed excellent superhydrophobic property, and could well resist the harsh mechanical damage, chemical corrosion, extreme temperature, and irradiation of UV without losing antiwetting ability. Besides, it displayed selective oil absorbing ability, recyclability, and self-cleaning ability. Moreover, the SMS displayed superior multitasking performance for continuous oil/water separation, surfactant-stabilized O/W emulsions separation (separation efficiency above 99%), and bacterial/fungus containing filtration (filtration efficiency over 60% for S. aureus, 90% for E. coli and C. albicans). With the multifaceted features, the SMS is a promising sponge material for treatment of industry oily or bacterial/fungus-containing wastewater in practical application.

The sensory and flavor characteristics of Shaoxing Huangjiu (Chinese rice wine) were significantly influenced by micro-oxygen and electric field.

In order to improve the high cost of equipment and difficult management caused by the natural aging of Chinese rice wine (Huangjiu), micro-oxygen (MO) and electric field (PEF) technology are used to accelerate the aging of Huangjiu. The results showed that micro-oxygen and electric field have a significant effect on the sensory characteristics and flavor characteristics of Huangjiu. Compared with the naturally aged Huangjiu, the flavor compounds of Huangjiu treated with micro-oxygen and electric field increase significantly. Based on principal component analysis, Huangjiu processed at 0.35 mg L/day or 0.5 mg L/day combined electric field exhibited similar flavor to the natural aged Huangjiu, which was highly associated with long-chain fatty acid ethyl esters (C13-C18). Moreover, partial least squares regression demonstrated that sensory attributes of cereal aroma and astringency were highlighted after aging time, while fruit aroma, continuation, and full body were dominant after micro-oxygen and electric field treatment. Micro-oxygen and electric field effectively enhanced the quality of Huangjiu, which could be applied in other alcoholic beverages.

Smart Bionic Surfaces with Switchable Wettability and Applications.

In order to satisfy the needs of different applications and more complex intelligent devices, smart control of surface wettability will be necessary and desirable, which gradually become a hot spot and focus in the field of interface wetting. Herein, we review interfacial wetting states related to switchable wettability on superwettable materials, including several classical wetting models and liquid adhesive behaviors based on the surface of natural creatures with special wettability. This review mainly focuses on the recent developments of the smart surfaces with switchable wettability and the corresponding regulatory mechanisms under external stimuli, which is mainly governed by the transformation of surface chemical composition and geometrical structures. Among that, various external stimuli such as physical stimulation (temperature, light, electric, magnetic, mechanical stress), chemical stimulation (pH, ion, solvent) and dual or multi-triggered stimulation have been sought out to realize the regulation of surface wettability. Moreover, we also summarize the applications of smart surfaces in different fields, such as oil/water separation, programmable transportation, anti-biofouling, detection and delivery, smart soft robotic etc. Furthermore, current limitations and future perspective in the development of smart wetting surfaces are also given. This review aims to offer deep insights into the recent developments and responsive mechanisms in smart biomimetic surfaces with switchable wettability under external various stimuli, so as to provide a guidance for the design of smart surfaces and expand the scope of both fundamental research and practical applications.

Astragaloside IV protects against diabetic nephropathy via activating eNOS in streptozotocin diabetes-induced rats.

BACKGROUND: Astragaloside IV (AS-IV) was reported to play a role in improving diabetic nephropathy (DN), however, the underlying mechanisms still remain unclear. The aim of the present study is to investigate whether AS-IV ameliorates DN via the regulation of endothelial nitric oxide synthase (eNOS). METHODS: DN model was induced in Sprague-Dawley (SD) male rats by intraperitoneal injection of 65 mg/kg streptozotocin (STZ). Rats in the AS-IV treatment group were orally gavaged with 5 mg/kg/day or 10 mg/kg/day AS-IV for eight consecutive weeks. Body weight, blood glucose, blood urea nitrogen (BUN), Serum creatinine (Scr), proteinuria and Glycosylated hemoglobin (HbA1c) levels were measured. Hematoxylin-Eosin (HE) and Periodic Acid-Schiff (PAS) staining were used to detect the renal pathology. The apoptosis status of glomerular cells was measured by TUNEL assay. The phosphorylation and acetylation of eNOS were detected by western blot. The effects of AS-IV on high-glucose (HG)-induced apoptosis and eNOS activity were also investigated in human renal glomerular endothelial cells (HRGECs) in vitro. RESULTS: Treatment with AS-IV apparently reduced DN symptoms in diabetic rats, as evidenced by reduced BUN, Scr, proteinuria, HbA1c levels and expanding mesangial matrix. AS-IV treatment also promoted the synthesis of nitric oxide (NO) in serum and renal tissues and ameliorated the phosphorylation of eNOS at Ser 1177 with decreased eNOS acetylation. Moreover, HG-induced dysfunction of HRGECs including increased cell permeability and apoptosis, impaired eNOS phosphorylation at Ser 1177, and decreased NO production, were all reversed by AS-IV treatment. CONCLUSIONS: These novel findings suggest that AS-IV ameliorates functional abnormalities of DN through inhibiting acetylation of eNOS and activating its phosphorylation at Ser 1177. AS-IV could be served as a potential therapeutic drug for DN.

Low dose of caffeine enhances the efficacy of antidepressants in major depressive disorder and the underlying neural substrates.

SCOPE: Caffeine is one of the most frequently used psychoactive substances ingested mainly via beverage or food products. Major depressive disorder is a serious and devastating psychiatric disorder. Emerging evidence indicates that caffeine enhances the antidepressant-like activity of common antidepressant drugs in rodents. However, whether joint administration of low dose of caffeine enhances the antidepressant actions in depressed patients remains unclear. METHODS AND RESULTS: A total of 95 male inpatients were assigned to three groups and were asked to take either caffeine (60, 120 mg) or placebo (soymilk powder) daily for 4 wk on the basis of their current antidepressant medications. Results showed that chronic supplementation with low dose of caffeine (60 mg) produced rapid antidepressant action by reduction of depressive scores. Furthermore, low dose of caffeine improved cognitive performance in depressed patients. However, caffeine did not affect sleep as measured by overnight polysomnography. Moreover, chronic caffeine consumption elicited inhibition of hypothalamic-pituitary-adrenal axis activation by normalization of salivary cortisol induced by Trier social stress test. CONCLUSIONS: These findings indicated the potential benefits of further implications of supplementary administration of caffeine to reverse the development of depression and enhance the outcome of antidepressants treatment in major depressive disorder.

Chymase activities and survival in endotoxin-induced human chymase transgenic mice.

We examined the effects of overexpressed human chymase on survival and activity in lipopolysaccharide (LPS)-treated mice. Human chymase transgenic (Tg) and wild-type C57BL/6 (WT) mice were treated with LPS (0.03, 0.1 and 0.3 mg/day; intraperitoneal) for 2 weeks. Treatment with 0.03 mg LPS did not affect survival in either WT or Tg mice. WT mice were not affected by 0.1 mg/day of LPS, whereas 25% of Tg mice died. Survival of mice treated with 0.3 mg/day of LPS was 87.5% and 0% in WT and Tg, respectively. LPS-induced increases in chymase activity in the heart and skin were significantly greater in Tg than WT mice. These data suggest a possible contribution of human chymase activation to LPS-induced mortality.

Add-on aliskiren elicits stronger renoprotection than high-dose valsartan in type 2 diabetic KKAy mice that do not respond to low-dose valsartan.

We hypothesized that aliskiren provides renoprotection in diabetic animals that did not receive sufficient renoprotection by AT1-receptor antagonist treatment. Type 2 diabetic KKAy mice were treated with group 1: vehicle or group 2: valsartan (15 mg/kg per day) from 12 to 16 weeks of age. The mice were subsequently divided into 4 groups and treated with the following combinations of drugs for another 6 weeks: 1: group 1 kept receiving vehicle, 2: group 2 continuously received 15 mg/kg per day of valsartan (Val-Val15), 3: group 2 received 50 mg/kg per day of valsartan (Val-Val50), 4: group 2 continuously received 15 mg/kg per day of valsartan with 25 mg/kg per day of aliskiren (Val-Val+Ali). Aliskiren exerted significant anti-albuminuric effects, whereas valsartan failed to ameliorate the albuminuria in the first four weeks. Surprisingly, the increasing dosage of valsartan in the Val-Val50 group showed non-significant tendencies to attenuate the albuminuria compared with vehicle infusion. Val-Val+Ali significantly suppressed the development of albuminuria and podocyte injury. Val-Val50 and Val-Val+Ali showed similar suppression of angiotensin II contents in the kidney of KKAy mice. In conclusion, the anti-albuminuric effect that was observed in the type 2 diabetic mice showing no anti-albuminuric effect by valsartan can be attributed to the add-on aliskiren.

Blood glucose level and survival in streptozotocin-treated human chymase transgenic mice.

A growing body of evidence suggests the potential role of chymase in organ injury in diabetes. We investigated blood glucose levels and survival in transgenic mice carrying the human chymase gene (Tg). Intraperitoneal injections of streptozotocin (STZ) (200, 100, 75 and 50 mg/kg in total, i.p.) were given to uninephrectomized Tg mice and wild-type C57BL/6 (BL) mice. Before STZ injection, the Tg mice had significantly lower body weights and slightly higher systolic blood pressure as compared with the BL mice. STZ-treated Tg mice showed significantly higher postprandial blood glucose levels as compared with the STZ-treated BL mice. The survival prevalence of STZ-treated Tg mice was zero, whereas BL mice showed a value of 40% until 42 days. STZ (100, 75 or 50 mg/kg, i.p.)-treated Tg mice also showed a similar pattern as compared with the STZ-treated BL mice. These data suggest that human chymase contributes to blood glucose levels and mortality during the progression of diabetes.

Aldosterone/Mineralocorticoid receptor stimulation induces cellular senescence in the kidney.

Recent studies demonstrated a possible role of aldosterone in mediating cell senescence. Thus, the aim of this study was to investigate whether aldosterone induces cell senescence in the kidney and whether aldosterone-induced renal senescence affects the development of renal injury. Aldosterone infusion (0.75 µg/h) into rats for 5 weeks caused hypertension and increased urinary excretion rates of proteins and N-acetyl-ß-D-glucosaminidase. Aldosterone induced senescence-like changes in the kidney, exhibited by increased expression of the senescence-associated ß-galactosidase, overexpression of p53 and cyclin-dependent kinase inhibitor (p21), and decreased expression of SIRT1. These changes were abolished by eplerenone (100 mg/kg/d), a mineralocorticoid receptor (MR) antagonist, but unaffected by hydralazine (80 mg/liter in drinking water). Furthermore, aldosterone induced similar changes in senescence-associated ß-galactosidase, p21, and SIRT1 expression in cultured human proximal tubular cells, which were normalized by an antioxidant, N-acetyl L-cysteine, or gene silencing of MR. Aldosterone significantly delayed wound healing and reduced the number of proliferating human proximal tubular cells, while gene silencing of p21 diminished the effects, suggesting impaired recovery from tubular damage. These findings indicate that aldosterone induces renal senescence in proximal tubular cells via the MR and p21-dependent pathway, which may be involved in aldosterone-induced renal injury.

Cilnidipine suppresses podocyte injury and proteinuria in metabolic syndrome rats: possible involvement of N-type calcium channel in podocyte.

OBJECTIVES: Clinical studies have indicated the beneficial effect of an L/N-type calcium channel blocker (CCB), cilnidipine, on the progression of proteinuria in hypertensive patients compared with an L-type CCB, amlodipine. In the present study, we examined the effects of cilnidipine and amlodipine on the renal injury in spontaneously hypertensive rat/ND mcr-cp (SHR/ND) and their underlying mechanism. METHODS AND RESULTS: SHR/ND were treated with vehicle (nU10), cilnidipine [33 mg/kg per day, orally (p.o.); nU11] or amlodipine (20 mg/kg per day, p.o.; nU9) for 20 weeks. SHR/ND developed proteinuria in an age-dependent manner. Cilnidipine suppressed the proteinuria greater than amlodipine did. The immunohistochemical analysis showed that N-type calcium channel and Wilm's tumor factor, a marker of podocyte, were co-expressed. SHR/ND had significantly greater desmin staining, an indicator of podocyte injury, with lower podocin and nephrin expression in the glomeruli than Wistar-Kyoto rat or SHR. Cilnidipine significantly prevented the increase in desmin staining and restored the glomerular podocin and nephrin expression compared with amlodipine. Cilnidipine also prevented the increase in renal angiotensin II content, the expression and membrane translocation of NADPH oxidase subunits and dihydroethidium staining in SHR/ND. In contrast, amlodipine failed to change these renal parameters. CONCLUSION: These data suggest that cilnidipine suppressed the development of proteinuria greater than amlodipine possibly through inhibiting N-type calcium channel-dependent podocyte injury in SHR/ND.

Contribution of chymase-dependent angiotensin II formation to the progression of tubulointerstitial fibrosis in obstructed kidneys in hamsters.

Recent studies indicate a role of chymase in the regulation of angiotensin II (AngII) formation in cardiovascular and renal tissues. We investigated a possible contribution of chymase to AngII formation and to renal fibrosis in unilateral ureteral obstruction (UUO). Eight-week-old Syrian hamsters were subjected to UUO and treated with vehicle, the specific chymase inhibitor (CI) 4-[1-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1H-benzimidazol-2-ylsulfanyl]-butyric acid (50 mg/kg, twice a day, p.o.), or the selective AT(1)-receptor blocker olmesartan (10 mg/kg per day, p.o.) for 14 days. UUO-induced renal interstitial fibrosis was associated with increases in renal mRNA levels of alpha-smooth muscle actin (SMA), type I collagen, and transforming growth factor (TGF)-beta. The UUO hamsters showed markedly higher AngII contents and increased AT(1)-receptor mRNA level in the obstructed kidney than sham-operated ones. In contrast, angiotensin-converting enzyme (ACE) protein expression was significantly lower in UUO hamsters. In UUO hamsters, treatment with CI or olmesartan significantly decreased AngII levels in renal tissue and mRNA levels of alpha-SMA, type I collagen, and TGF-beta and ameliorated tubulointerstitial injury. On the other hand, neither CI nor olmesartan changed systolic blood pressure, renal ACE, and AT(1)-receptor protein levels. These data suggest that chymase-dependent intrarenal AngII formation contributes to the pathogenesis of interstitial fibrosis in obstructed kidneys of hamsters.

Inhibitory effects of a dihydropyridine calcium channel blocker on renal injury in aldosterone-infused rats.

OBJECTIVES: Recent in-vitro studies demonstrated that dihydropyridine calcium channel blockers have direct mineralocorticoid receptor antagonistic activity. The present study was conducted to examine the effects of a dihydropyridine calcium channel blocker, azelnidipine, on aldosterone-induced oxidative stress and renal injury. METHODS AND RESULTS: Uninephrectomized rats subjected to 6 weeks treatment with aldosterone (0.75 microg/h, subcutaneous) and 1% NaCl (in drinking water) showed higher systolic blood pressure (SBP), urinary excretion of protein (UproteinV), glomerular cell proliferation and renal interstitial fibrosis than vehicle (2% ethanol)-infused rats. Aldosterone-induced renal injury was associated with increased renal cortical content of thiobarbituric acid-reactive substances (TBARS), NAD(P)H oxidase complex formation and mRNA expression of NAD(P)H oxidase membrane components (p22 and gp91). Administration of azelnidipine [3 mg/kg per day, orally (p.o.)] markedly attenuated the aldosterone-induced increases in SBP, UproteinV, renal cortical tissues TBARS content, NAD(P)H oxidase complex formation, mRNA levels of p22 and gp91, and morphological changes. In aldosterone-infused rats, treatment with a nonspecific vasodilator, hydralazine (5 mg/kg per day in drinking water) resulted in a reduction in SBP similar to azelnidipine; however, it did not affect any renal parameters. Treatment with azelnidipine suppressed aldosterone/mineralocorticoid receptor-dependent but not mineralocorticoid receptor-independent superoxide production in cultured rat mesangial cells. CONCLUSION: These data suggest that dihydropyridine calcium channel blockers may elicit marked amelioration of aldosterone-induced renal injury through their inhibitory effects on NAD(P)H oxidase-dependent oxidative stress.

Mineralocorticoid receptor blockade and calcium channel blockade have different renoprotective effects on glomerular and interstitial injury in rats.

We hypothesized that combination treatment with the mineralocorticoid receptor antagonist eplerenone and the calcium channel blocker amlodipine elicits better renoprotective effects than monotherapy with either drug, via different mechanisms in Dahl salt-sensitive (DS) hypertensive rats. DS rats were fed a high-salt diet (4% NaCl) for 10 wk and were treated with vehicle (n = 12), eplerenone (50 mg x kg(-1) x day(-1), p.o., n = 12), amlodipine (3 mg x kg(-1) x day(-1), p.o., n = 12), or eplerenone plus amlodipine (n = 12) after 2 wk of salt feeding. Vehicle-treated DS rats developed proteinuria, which was attenuated by eplerenone or amlodipine. Interestingly, eplerenone attenuated the glomerulosclerosis and podocyte injury, but amlodipine did not. Conversely, treatment with amlodipine markedly improved interstitial fibrosis, while the effect of eplerenone was minimal. Combination treatment markedly improved proteinuria, glomerulosclerosis, podocyte injury, and interstitial fibrosis in DS rats. Renal hypoxia estimated by pimonidazole, vascular endothelial growth factor expression, and density of peritubular endothelial cells was exacerbated by salt feeding. Amlodipine, either as monotherapy or in combination, ameliorated the renal hypoxia, whereas eplerenone treatment had no effect. In conclusion, both eplerenone and amlodipine attenuated renal injuries in high salt-fed DS rats, but the targets for renoprotection differed between these two drugs, with eplerenone predominantly acting on glomeruli and amlodipine acting on interstitium. The combination of eplerenone and amlodipine improved renal injury more effectively than either monotherapy in high salt-fed DS rats, presumably by achieving their own renoprotective effects.

Effects of adrenomedullin on cardiac oxidative stress and collagen accumulation in aldosterone-dependent malignant hypertensive rats.

We examined the effects of adrenomedullin on cardiac oxidative stress and collagen accumulation in aldosterone-dependent malignant hypertensive rats. Spontaneously hypertensive rats (SHRs) were treated with one of the following combinations for 4 weeks: tap water and vehicle [0.5% ethanol, subcutaneously (s.c.), n = 5], 1% NaCl in drinking water and vehicle (n = 8), 1% NaCl and aldosterone (0.75 microg/h s.c., n = 8), and 1% NaCl, aldosterone, and adrenomedullin (1.3 microg/kg/h s.c., n = 8). Systolic blood pressure (SBP) and left ventricular (LV) weight were higher in aldosterone-treated SHRs than vehicle- or vehicle/1% NaCl-treated SHRs. Thiobarbituric acid reactive substances (TBARS) levels and NADPH oxidase activity in LV tissues of aldosterone-treated SHRs were also higher than those of vehicle- or vehicle/1% NaCl-treated SHRs, and these changes were associated with increases in LV mRNA levels of p22phox, gp91phox, fibronectin, collagen types I and III, as well as collagen content. Treatment with adrenomedullin did not alter SBP or LV weight but attenuated aldosterone-induced increases in TBARS levels, NADPH oxidase activity, and mRNA levels of p22phox, gp91phox, fibronectin, collagen types I and III, as well as collagen content in LV tissues. These data suggest that NADPH oxidase-mediated reactive oxygen species production is involved in the pathogenesis of cardiac collagen accumulation in aldosterone-dependent malignant hypertensive rats and that the cardioprotective effects of adrenomedullin are mediated through the suppression of this pathway.