This review summarizes the latest advances in knowledge on the effects of flavonoids on renal function in health and disease. Flavonoids have antihypertensive, antidiabetic, and antiinflammatory effects, among other therapeutic activities. Many of them also exert renoprotective actions that may be of interest in diseases such as glomerulonephritis, diabetic nephropathy, and chemically-induced kidney insufficiency. They affect several renal factors that promote diuresis and natriuresis, which may contribute to their well-known antihypertensive effect. Flavonoids prevent or attenuate the renal injury associated with arterial hypertension, both by decreasing blood pressure and by acting directly on the renal parenchyma. These outcomes derive from their interference with multiple signaling pathways known to produce renal injury and are independent of their blood pressure-lowering effects. Oral administration of flavonoids prevents or ameliorates adverse effects on the kidney of elevated fructose consumption, high fat diet, and types I and 2 diabetes. These compounds attenuate the hyperglycemia-disrupted renal endothelial barrier function, urinary microalbumin excretion, and glomerular hyperfiltration that results from a reduction of podocyte injury, a determinant factor for albuminuria in diabetic nephropathy. Several flavonoids have shown renal protective effects against many nephrotoxic agents that frequently cause acute kidney injury (AKI) or chronic kidney disease (CKD), such as LPS, gentamycin, alcohol, nicotine, lead or cadmium. Flavonoids also improve cisplatin- or methotrexate-induced renal damage, demonstrating important actions in chemotherapy, anticancer and renoprotective effects. A beneficial prophylactic effect of flavonoids has been also observed against AKI induced by surgical procedures such as ischemia/reperfusion (I/R) or cardiopulmonary bypass. In several murine models of CKD, impaired kidney function was significantly improved by the administration of flavonoids from different sources, alone or in combination with stem cells. In humans, cocoa flavanols were found to have vasculoprotective effects in patients on hemodialysis. Moreover, flavonoids develop antitumor activity against renal carcinoma cells with no toxic effects on normal cells, suggesting a potential therapeutic role in patients with renal carcinoma.

In regenerative dentistry, stem cell-based therapy often requires a scaffold to deliver cells and/or growth factors to the injured site. Graphene oxide (GO) and silk fibroin (SF) are promising biomaterials for tissue engineering as they are both non toxic and promote cell proliferation. On the other hand, periodontal ligament stem cells (PDLSCs) are mesenchymal stem cells readily accessible with a promising use in cell therapy. The purpose of this study was to investigate the effects of composite films of GO, SF and GO combined with fibroin in the mesenchymal phenotype, viability, adhesion and proliferation rate of PDLSCs. PDLSCs obtained from healthy extracted teeth were cultured on GO, SF or combination of GO and SF films up to 10 days. Adhesion level of PDSCs on the different biomaterials were evaluated after 12 h of culture, whereas proliferation rate of cells was assessed using the MTT assay. Level of apoptosis was determined using Annexin-V and 7-AAD and mesenchymal markers expression of PDLSCs were analyzed by flow cytometry. At day 7 of culture, MTT experiments showed a high rate of proliferation of PDLSCs growing on GO films compared to the other tested biomaterials, although it was slightly lower than in plastic (control). However PDLSCs growing in fibroin or GO plus fibroin films showed a discrete proliferation. Importantly, at day 10 of culture it was observed a significant increase in PDLSCs proliferation rate in GO films compared to plastic (P < 0.05), as well as in GO plus fibroin compared to fibroin alone (P < 0.001). Flow cytometry analysis showed that culture of PDLSCs in fibroin, GO or GO plus fibroin films did not significantly alter the level of expression of the mesenchymal markers CD73, CD90 or CD105 up to 168 h, being the cell viability in GO even better than obtained in plastic. Our findings suggest that the combination of human dental stem cells/fibroin/GO based-bioengineered constructs have strong potential for their therapeutic use in regenerative dentistry.

Background: we have evaluated the antihypertensive effect of several flavonoid extracts in a rat model of arterial hypertension caused by chronic administration (6 weeks) of the nitric oxide synthesis inhibitor, L-NAME. Methods: Sprague Dawley rats received L-NAME alone or L-NAME plus flavonoid-rich vegetal extracts (Lemon, Grapefruit + Bitter Orange, and Cocoa) or purified flavonoids (Apigenin and Diosmin) for 6 weeks. Results: L-NAME treatment resulted in a marked elevation of blood pressure, and treatment with Apigenin, Lemon Extract, and Grapefruit + Bitter Orange extracts significantly reduced the elevated blood pressure of these animals. Apigenin and some of these flavonoids also ameliorated nitric oxide-dependent and -independent aortic vasodilation and elevated nitrite urinary excretion. End-organ abnormalities such as cardiac infarcts, hyaline arteriopathy and fibrinoid necrosis in coronary arteries and aorta were improved by these treatments, reducing the end-organ vascular damage. Conclusions: the flavonoids included in this study, specially apigenin, may be used as functional food ingredients with potential therapeutic benefit in arterial hypertension.

were only small nonsignificant changes in SO animals. ThereRecent work indicates that nitric oxide (NO) plays an imfore, these results indicate that the expression, activity and portant role in the systemic and renal alterations of cirrhosis.production of NO in kidneys, glomeruli, and mononuclear In the present study, we have evaluated whether the inducible lymphocyte cells is elevated in BDL rats, and this is partly NO synthase (iNOS) isoform participates in the enhanced because of a plasma-derived substance(s), which stimulates renal and systemic NO production of a rat model of cirrhosis.iNOS formation. The amelioration of the arterial hypotension In vitro and in vivo experiments were performed in rats suband the associated reduced excretory levels of these cirrhotic jected to chronic bile duct ligation (BDL) and in sham-operanimals by aminoguanidine further support the involvement ated (SO) animals. Plasma nitrite (3.1 { 0.1 mmol/L in SO of the inducible NO synthase isoform in the renal alterations and 6.6 { 0.2 mmol/L in BDL), glomerular nitrite production observed in BDL animals. (HEPATOLOGY 1997;26:268-276.) (6.4 { 0.1 vs. 9.8 { 0.1 nmol/24h/7,000 glomeruli, respectively), and mononuclear lymphocyte cells nitrite production During the last years, it has become increasingly clear that (0.3 { 0.04 vs. 0.6 { 0.12 nmol/10 6 cells, respectively) nitric oxide (NO) plays an important role as a mediator of were all significantly higher in BDL than in SO. Moreover, the systemic and renal alterations of liver cirrhosis. 1 Recent mononuclear lymphocytes and glomeruli from BDL rats studies have revealed that rats with experimentally induced showed an increased expression of macrophage-type iNOS, cirrhosis show an increased endothelium-dependent renal detected by Western blot. Kidneys from BDL animals also vasodilation, 2 as well as an increased renal sensitivity to NO showed an increased calcium-independent NO synthase activinhibition. [3][4][5] Moreover, NO inhibition results in a reduction ity, compared with those from SO rats. Constitutive endotheof the hyperdynamic circulation 3,6-7 and produces beneficial lial-type NO synthase expression in glomeruli or the activity effects on renal excretory function. 4,5,8 However, to the best of calcium-dependent NO synthase in whole kidney did not of our knowledge, no direct demonstration of increased renal show differences between BDL and SO rats. In cultured mesproduction of NO in experimental or clinical cirrhosis has angial cells from normal rats, the addition of plasma from been published. Moreover, the type of NO synthase (NOS) BDL but not of plasma from SO significantly stimulated (35%) isoforms involved and the mechanisms responsible for their nitrite production and increased the expression of macroactivation are not completely established. 9-13phage-type iNOS. In addition, administration of aminoguaIn the present study, we have evaluated whether the inducnidine (AG), a preferential iNOS inhibitor, elevated dose-deible NOS isoform participates in the enhanced renal a...

Background The treatment of extensive and/or chronic skin wounds is a widespread and costly public health problem. Mesenchymal stem cells (MSCs) have been proposed as a potential cell therapy for inducing wound healing in different clinical settings, alone or in combination with biosynthetic scaffolds. Among them, silk fibroin (SF) seeded with MSCs has been shown to have increased efficacy in skin wound healing experimental models. Methods In this report, we investigated the wound healing effects of electrospun SF scaffolds cellularized with human Wharton’s jelly MSCs (Wj-MSCs-SF) using a murine excisional wound splinting model. Results Immunohistopathological examination after transplant confirmed the presence of infiltrated human fibroblast-like CD90-positive cells in the dermis of the Wj-MSCs-SF-treated group, yielding neoangiogenesis, decreased inflammatory infiltrate and myofibroblast proliferation, less collagen matrix production, and complete epidermal regeneration. Conclusions These findings indicate that Wj-MSCs transplanted in the wound bed on a silk fibroin scaffold contribute to the generation of a well-organized and vascularized granulation tissue, enhance reepithelization of the wound, and reduce the formation of fibrotic scar tissue, highlighting the potential therapeutic effects of Wj-MSC-based tissue engineering approaches to non-healing wound treatment. Electronic supplementary material The online version of this article (10.1186/s13287-019-1229-6) contains supplementary material, which is available to authorized users.

Nitric oxide (NO) is a vasodilator substance controlling renal papillary blood flow (PBF) in the rat. In this study we have evaluated the role of AT1 angiotensin II receptors as modulators of the whole kidney and papillary vasoconstrictor effects induced by the acute or chronic inhibition of NO synthesis. Experiments have been performed in anesthetized, euvolemic Munich-Wistar rats prepared for the study of renal blood flow (RBF) and PBF. In normal rats, acute administration of the NO synthesis inhibitor N ω-nitro-l-arginine methyl ester (l-NAME) increased mean arterial pressure (MAP) and decreased RBF and PBF. Either acute or chronic treatment with the AT1 receptor blocker losartan did not modify the decreases in RBF or PBF secondary to l-NAME. In animals made hypertensive by chronic inhibition of NO, basal MAP was higher, whereas RBF and PBF were lower than in the controls. In these animals, acute or chronic administration of losartan decreased MAP and increased both RBF and PBF significantly. These results indicate that, under normal conditions, the decreases in RBF or PBF induced by the acute inhibition of NO synthesis are not modulated by AT1-receptor stimulation. However, the arterial hypertension, renal vasoconstriction, and reduced PBF present in chronic NO-deficient hypertensive rats is partially due to the effects of angiotensin II, via stimulation of AT1-receptors.

In the present study, we have characterized the renal response to inhibition of endogenous nitric oxide (NO) synthesis [intravenous NG-nitro-L-arginine methyl ester (L-NAME) for 3 h] in anesthetized cirrhotic rats, with (ASC) and without (CIR) ascites, at doses that do not change blood pressure (BP). Administration of L-NAME induced opposite effects on water (UV) and sodium (UNaV) excretion in cirrhotic and control animals. Infusion of 1 microgram.kg-1.min-1 of L-NAME in CIR (n = 5) decreased renal plasma flow (RPF) at the end of the 3-h period, whereas UV, UNaV, and glomerular filtration rate (GFR) were unaltered. In contrast, infusion of L-NAME at 10 micrograms.kg-1.min-1 in six more CIR increased UV and UNaV significantly by the 1st h, without changes in BP or GFR, and these parameters remained elevated throughout the experiment. Infusion of 1 microgram.kg-1.min-1 in ASC (n = 6) did not change BP or GFR but significantly enhanced UV and UNaV after the 1st h. These effects were prevented by pretreatment with L-arginine (0.1 mg.kg-1.min-1) in another group of ASC infused with 1 microgram.kg-1.min-1 of L-NAME. These results indicate that, in ASC and CIR cirrhotic rats, inhibition of NO synthesis at nonpressor does improves renal excretion of sodium and water via a decrease in tubular reabsorption. NO is an important mediator of the renal excretory and hemodynamic alterations of experimental liver cirrhosis.

The mechanisms mediating the hyporesponsiveness to vasoconstrictors in portal hypertension are not completely established. In the present study, we evaluated the role of cyclic guanosine monophosphate (cGMP) and potassium channels as contributors to the pressor hyporesponsiveness to methoxamine (MTX) of the mesenteric vascular bed of portal vein-ligated (PVL) hypertensive rats. In basal conditions, and compared with sham-operated control rat (SHAM) vessels, PVL preparations showed a blunted pressor response (maximum: 39.3 ؎ 6.1 vs. 94.5 ؎ 8.9 mm Hg), which increased by pretreatment with methylene blue (MB), a guanylate cyclase inhibitor (118.7 ؎ 8.9 vs. 152.0 ؎ 10.0, respectively), and even more with the nitric oxide (NO) synthesis inhibitor N -nitro-L-arginine (NNA) (159.9 ؎ 7.4 vs. 194.1 ؎ 5.7, respectively), suggesting that NO acts through cGMP-dependent and independent mechanisms. In all cases, however, the pressor responses of PVL vessels were lower than those of SHAM. Pretreatment of the vessels with the potassium channel inhibitors, tetraethylammonium (TEA), glibenclamide (GLB), or charybdotoxin (CHX), did not improve the reduced pressor responses of the PVL rats. However, when the preparations were simultaneously pretreated with MB and TEA or with NNA and TEA, the pressor responses were potentiated with respect to groups treated with MB or NNA alone, and the differences between PVL and SHAM vessels were completely corrected. These data suggest that both NO and potassium channels mediate the vascular hyporesponsiveness to methoxamine of the PVL mesenteric vasculature. Our results also disclose that NO blunts the pressor response of the PVL vessels by a dual mechanism of action, through activation of potassium channels and through the formation of cGMP. Finally, the NO-independent component mediated by potassium channels can be only seen when the main cGMP-NO component is inactivated. In conclusion, both cGMP and potassium channels mediate the vascular hyporesponsiveness to MTX of the mesenteric bed of portal hypertensive rats. (HEPATOLOGY 1998;27:900-905.)The mesenteric vasculature in portal hypertensive states is an important contributor to the systemic arterial vasodilation, one of the most important features of the hyperdynamic circulation present in liver diseases. 1,2 One of the abnormalities that accompanies the splanchnic and peripheral vasodilation in liver diseases, the hyporesponsiveness to vasoconstrictors, has been related to elevated levels of vasodilator substances interacting at a postreceptor level. [3][4][5][6] Although many studies point to nitric oxide (NO) as an important mediator of such alteration, 7-12 the role and identity of all these vasodilator substances is not completely established. 13,14 Recent data have demonstrated that this abnormal mesenteric vascular response is completely eliminated, in two different experimental models, by removal of the endothelium, 15,16 but not by blockade of NO synthesis. 13,15 Other studies have also suggested that NO is only partly involved in t...