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Complement-mediated diseases can be treated using systemic inhibitors. However, complement components are abundant in circulation, affecting systemic inhibitors' exposure and efficacy. Furthermore, because of complement's essential role in immunity, systemic treatments raise infection risk in patients. To address these challenges, we developed antibody fusion proteins combining the alternative-pathway complement inhibitor factor H (fH1-5) with an anti-C3d monoclonal antibody (C3d-mAb-2fH). Because C3d is deposited at sites of complement activity, this molecule localizes to tissue complement while minimizing circulating complement engagement. These fusion proteins bind to deposited complement in diseased human skin sections and localize to activated complement in a primate skin injury model. We further explored the pharmacology of C3d-mAb-2fH proteins in rodent models with robust tissue complement activation. Doses of C3d-mAb-2fH >1 mg/kg achieved >75% tissue complement inhibition in mouse and rat injury models while avoiding circulating complement blockade. Glomerular-specific complement inhibition reduced proteinuria and preserved podocyte foot-process architecture in rat membranous nephropathy, indicating disease-modifying efficacy. These data indicate that targeting local tissue complement results in durable and efficacious complement blockade in skin and kidney while avoiding systemic inhibition, suggesting broad applicability of this approach in treating a range of complement-mediated diseases.
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Fator H do Complemento , Nefropatias , Humanos , Camundongos , Ratos , Animais , Fator H do Complemento/genética , Complemento C3d/metabolismo , Nefropatias/etiologia , Anticorpos , Ativação do ComplementoRESUMO
Complement alternative pathway (AP) dysregulation drives C3 glomerulopathy (C3G), a rare renal disorder characterized by glomerular C3 deposition and glomerular damage, for which no effective treatments are available. Blockade of complement C3 is emerging as a viable therapeutic option. In an earlier study we showed that SLN500, a small interfering RNA targeting liver C3 synthesis, was able to limit AP dysregulation and glomerular C3d deposits in mice with partial factor H (FH) deficiency (Cfh+/- mice). Here, we assessed the pharmacological effects of SLN501 - an optimized SLN500 version - in mice with complete FH deficiency (Cfh-/- mice) that exhibit a more severe C3G phenotype. SLN501 effectively prevented liver C3 synthesis, thus limiting AP dysregulation, glomerular C3d deposits and the development of ultrastructural alterations. These data provide firm evidence of the use of siRNA-mediated liver C3 gene silencing as a potential therapy for treating C3G patients with either partial or complete FH loss of function.
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Fator H do Complemento/deficiência , Glomerulonefrite Membranoproliferativa , Doenças da Deficiência Hereditária de Complemento , Nefropatias , Humanos , Animais , Camundongos , Complemento C3/genética , Complemento C3/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , Fator H do Complemento/genética , Fator H do Complemento/uso terapêutico , Glomerulonefrite Membranoproliferativa/genética , Glomerulonefrite Membranoproliferativa/tratamento farmacológico , Glomerulonefrite Membranoproliferativa/metabolismo , Via Alternativa do ComplementoRESUMO
Cannabigerol (CBG), a cannabinoid from Cannabis sativa L., recently attracted noteworthy attention for its dermatological applications, mainly due to its anti-inflammatory, antioxidant, and antimicrobial effectiveness similar to those of cannabidiol (CBD). In this work, based on results from studies of in vitro permeation through biomimetic membranes performed with CBG and CBD in the presence and in the absence of a randomly substituted methyl-ß-cyclodextrin (MßCD), a new CBG extemporaneous emulgel (oil-in-gel emulsion) formulation was developed by spray-drying. The powder (SDE) can be easily reconstituted with purified water, leading to a product with chemical-physical and technological characteristics that are comparable to those of the starting emulgels (E). Thermogravimetric analysis (TGA), attenuated total reflection-Fourier transformed infrared spectroscopy (ATR-FTIR), x-ray powder diffraction (XRPD), and high-performance liquid chromatography (HPLC) analyses demonstrated that the spray-drying treatment did not alter the chemical properties of CBG. This product can represent a metered-dosage form for the localized treatment of cutaneous afflictions such as acne and psoriasis.
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Peritubular capillary rarefaction is a recurrent aspect of progressive nephropathies. We previously found that peritubular capillary density was reduced in BTBR ob/ob mice with type 2 diabetic nephropathy. In this model, we searched for abnormalities in the ultrastructure of peritubular capillaries, with a specific focus on the endothelial glycocalyx, and evaluated the impact of treatment with an angiotensin-converting enzyme inhibitor (ACEi). Mice were intracardially perfused with lanthanum to visualise the glycocalyx. Transmission electron microscopy analysis revealed endothelial cell abnormalities and basement membrane thickening in the peritubular capillaries of BTBR ob/ob mice compared to wild-type mice. Remodelling and focal loss of glycocalyx was observed in lanthanum-stained diabetic kidneys, associated with a reduction in glycocalyx components, including sialic acids, as detected through specific lectins. ACEi treatment preserved the endothelial glycocalyx and attenuated the ultrastructural abnormalities of peritubular capillaries. In diabetic mice, peritubular capillary damage was associated with an enhanced tubular expression of heparanase, which degrades heparan sulfate residues of the glycocalyx. Heparanase was also detected in renal interstitial macrophages that expressed tumor necrosis factor-α. All these abnormalities were mitigated by ACEi. Our findings suggest that, in experimental diabetic nephropathy, preserving the endothelial glycocalyx is important in order to protect peritubular capillaries from damage and loss.
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Diabetes Mellitus Experimental , Nefropatias Diabéticas , Camundongos , Animais , Nefropatias Diabéticas/metabolismo , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/metabolismo , Diabetes Mellitus Experimental/metabolismo , Capilares/patologia , Glicocálix/metabolismo , Lantânio , Rim/patologia , Camundongos EndogâmicosRESUMO
Diabetes mellitus and alterations in thyroid hormone (TH) signaling are closely linked. Though the role of TH signaling in cell differentiation and growth is well known, it remains unclear whether its alterations contribute to the pathobiology of diabetic cells. Here, we aim to investigate whether the administration of exogenous T3 can counteract the cellular remodeling that occurs in diabetic cardiomyocytes, podocytes, and pancreatic beta cells. Treating diabetic rats with T3 prevents dedifferentiation, pathological growth, and ultrastructural alterations in podocytes and cardiomyocytes. In vitro, T3 reverses glucose-induced growth in human podocytes and cardiomyocytes, restores cardiomyocyte cytoarchitecture, and reverses pathological alterations in kidney and cardiac organoids. Finally, T3 treatment counteracts glucose-induced transdifferentiation, cell growth, and loss in pancreatic beta cells through TH receptor alpha1 activation. Our studies indicate that TH signaling activation substantially counteracts diabetes-induced pathological remodeling, and provide a potential therapeutic approach for the treatment of diabetes and its complications.
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Uncontrolled activation of the alternative pathway (AP) of complement, due to genetic and/or acquired defects, plays a primary pathogenetic role in C3 glomerulopathy (C3G), a rare and heterogeneous disease characterised by predominant C3 fragment deposition within the glomerulus, as well as glomerular damage. There are currently no approved disease-specific treatments for C3G, but new drugs that directly counteract AP dysregulation, targeting components of the pathway, have opened promising new perspectives for managing the disease. Complement factor B (FB), which is primarily synthesised by hepatocytes, is a key component of the AP, as it drives the central amplification loop of the complement system. In this study we used a GalNAc (N-Acetylgalactosamine)-conjugated siRNA to selectively target and suppress liver FB expression in two mouse models characterised by the complete (Cfh-/- mice) or partial (Cfh+/-) loss of function of complement factor H (FH). Homozygous deletion of FH induced a severe C3G phenotype, with strong dysregulation of the AP of complement, glomerular C3 deposition and almost complete C3 consumption. Mice with a heterozygous deletion of FH had intermediate C3 levels and exhibited slower disease progression, resembling human C3G more closely. Here we showed that FB siRNA treatment did not improve serum C3 levels, nor limit glomerular C3 deposition in Cfh-/- mice, while it did normalise circulating C3 levels, reduce glomerular C3 deposits, and limit mesangial electron-dense deposits in Cfh+/- mice. The present data provide important insights into the potential benefits and limitations of FB-targeted inhibition strategies and suggest RNA interference-mediated FB silencing in the liver as a possible therapeutic approach for treating C3G patients with FH haploinsufficiency.
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Glomerulonefrite Membranoproliferativa , Nefropatias , Humanos , Animais , Camundongos , Fator B do Complemento/genética , Fator B do Complemento/metabolismo , Complemento C3 , Homozigoto , Deleção de Sequência , Fator H do Complemento/genética , Fígado/metabolismo , Via Alternativa do Complemento/genética , Glomerulonefrite Membranoproliferativa/genética , Glomerulonefrite Membranoproliferativa/terapia , Glomerulonefrite Membranoproliferativa/metabolismoRESUMO
The spike protein of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can interact with endothelial cells. However, no studies demonstrated the direct effect of the spike protein subunit 1 (S1) in inducing lung vascular damage and the potential mechanisms contributing to lung injury. Here, we found that S1 injection in mice transgenic for human angiotensin converting enzyme 2 (ACE2) induced early loss of lung endothelial thromboresistance at 3 days, as revealed by thrombomodulin loss and von Willebrand factor (vWF) increase. In parallel, vascular and epithelial C3 deposits and enhanced C3a receptor (C3aR) expression were observed. These changes preceded diffuse alveolar damage and lung vascular fibrin(ogen)/platelets aggregates at 7 days, as well as inflammatory cell recruitment and fibrosis. Treatment with C3aR antagonist (C3aRa) inhibited lung C3 accumulation and C3a/C3aR activation, limiting vascular thrombo-inflammation and fibrosis. Our study demonstrates that S1 triggers vascular dysfunction and activates complement system, instrumental to lung thrombo-inflammatory injury. By extension, our data indicate C3aRa as a valuable therapeutic strategy to limit S1-dependent lung pathology.
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Complemento C3a , Células Endoteliais , Receptores de Complemento , Glicoproteína da Espícula de Coronavírus , SARS-CoV-2 , Células Endoteliais/citologia , Células Endoteliais/virologia , Pulmão/patologia , Pulmão/virologia , Complemento C3a/metabolismo , Receptores de Complemento/metabolismo , Fibrose , Camundongos Transgênicos , Humanos , Animais , Camundongos , COVID-19 , InflamaçãoRESUMO
Strawberries and raspberries are susceptible to physiological and biological damage. Due to the consumer concern about using pesticides to control fruit rot, recent attention has been drawn to essential oils. Microbiological activity evaluations of different concentrations of tested EOs (cinnamon, clove, bergamot, rosemary and lemon; 10% DMSO-PBS solution was used as a diluent) against fruit rot fungal strains and a fruit-born human pathogen (Escherichia coli) indicated that the highest inhibition halos was found for pure cinnamon and clove oils; according to GC-MS analysis, these activities were due to the high level of the bioactive compounds cinnamaldehyde (54.5%) in cinnamon oil and eugenol (83%) in clove oil. Moreover, thermogravimetric evaluation showed they were thermally stable, with temperature peak of 232.0 °C for cinnamon and 200.6/234.9 °C for clove oils. Antibacterial activity evaluations of all tested EOs at concentrations from 5-50% (v/v) revealed a concentration of 10% (v/v) to be the minimum inhibitory concentration and minimum bactericidal concentration. The physicochemical analysis of fruits in an in vivo assay indicated that used filter papers doped with 10% (v/v) of cinnamon oil (stuck into the lids of plastic containers) were able to increase the total polyphenols and antioxidant activity in strawberries after four days, with it being easier to preserve strawberries than raspberries.
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BACKGROUND: Home parenteral nutrition (HPN) is the standard treatment for patients with chronic intestinal failure (CIF). Mortality and weaning rates of these patients differ widely among cohorts; however, these outcomes were often considered independent-rather than competing-events, leading to an upward bias of the retrieved estimates. OBJECTIVES: The aim of this retrospective cohort study was to evaluate, evaluating through a competing risk analysis, the rates and predictors of mortality and weaning in CIF patients from an Italian referral center. METHODS: All adult patients with CIF receiving > 3 mo HPN from 1985 until 2016 were enrolled. Clinical information was collected from the database of the Intestinal Failure Unit of Torino, Italy. Patients were stratified according to the presence or not of short bowel syndrome (SBS). RESULTS: The cumulative incidences of death and weaning were 27.3% and 32.3% and 39.0% and 33.7% at 5 and 10 y from HPN initiation, respectively. At multivariable competing risk analyses, mortality was predicted by age (sub-distribution hazard ratio [SHR] = 1.65 per 10-y increase; 95% CI, 1.35-2.01), type 3 SBS (SHR = 0.38; 0.15-0.94), small bowel length ≥ 100 cm (SHR = 0.42; 0.22-0.83), and reconstructive surgery (SHR = 0.11; 0.02-0.64) in SBS patients, and by age (SHR = 1.38 per 10-y increase; 1.16-1.64) and presence of stoma (SHR = 0.30; 0.12-0.78) in non-SBS patients. In the same model, weaning was predicted by type 3 SBS (SHR = 6.86; 3.10-15.16), small bowel length ≥ 100 cm (SHR = 3.54; 1.99-6.30), and reconstructive surgery (SHR = 2.86; 1.44-5.71) in SBS patients, and by age (SHR = 0.79 per 10-y increase; 0.66-0.94) and presence of stoma (SHR = 2.64; 1.38-5.07) in non-SBS patients. CONCLUSIONS: Surgical procedures strongly affected mortality and weaning risk in CIF patients.
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Enteropatias , Insuficiência Intestinal , Nutrição Parenteral no Domicílio , Adulto , Humanos , Estudos Retrospectivos , Desmame , Nutrição Parenteral no Domicílio/métodos , Enteropatias/terapia , Enteropatias/etiologia , Doença CrônicaRESUMO
The suitability of chickpea, red lentil and green pea for the production of extruded products (i.e., snacks and pasta) was studied. Besides starch and technological properties, the impact of processing on some bioactive compounds was evaluated. The best results were obtained for lentil: the snacks showed the lowest porosity (21 %), the highest average pore radius (18.8 µm), and high expansion (section area: 310 mm2; inner area: 114 mm2), while pasta exhibited low cooking loss (5.7 g 100 g-1) and high firmness (924 N). Extrusion-cooking reduced the soluble phenolic acid content (-45 %) and flavonoids (-41 %), but increased the cell-wall bound phenolic acids and antioxidant activity. The different pulses did not lead to a marked difference in the antioxidant activity of the extruded products, although the lentil maintained the highest flavonoid content after both processes.
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Farinha , Lens (Planta) , Farinha/análise , Antioxidantes/análise , Fenóis/análise , Culinária/métodos , Lens (Planta)/metabolismo , Triticum/metabolismo , FlavonoidesRESUMO
This study investigated the impact of seed coats from peas (PC) and chickpeas (CC) (at 15 % and 30 % levels) on rice-based co-extruded snacks. Using PC and CC reduced the content of soluble (29 %) and cell-wall bound phenolic acids (21 %), but it enhanced the amount and the profile of flavonoids of rice-based snacks (up to 16 times with PC), resulting in significantly higher antioxidant activity (134 %). Snacks with 15 % CC showed a higher section area (about 335 versus 191 mm2) and a lower average pore radius (20.1 versus 23.9 mm) than PC-snacks; however, such features did not affect either texture or porosity. At 30 % level, PC resulted in a more porous structure (porosity: 73.1 versus 66.7 %) with smaller pores (17.2 versus 27.3 mm) and high firmness (55.9 versus 40.1 N). Consumers' acceptability evaluation revealed that samples containing pulse seed coat were comparable and preferred to the control (i.e., 100 % polished rice).
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Cicer , Oryza , Cicer/química , Oryza/química , Pisum sativum/química , Fenóis/metabolismo , Sementes , LanchesRESUMO
Anthocyanins are widespread and biologically active water-soluble phenolic pigments responsible for a wide range of vivid colours, from red (acidic conditions) to purplish blue (basic conditions), present in fruits, vegetables, and coloured grains. The pigments' stability and colours are influenced mainly by pH but also by structure, temperature, and light. The colour-stabilizing mechanisms of plants are determined by inter- and intramolecular co-pigmentation and metal complexation, driven by van der Waals, π-π stacking, hydrogen bonding, and metal-ligand interactions. This group of flavonoids is well-known to have potent anti-inflammatory and antioxidant effects, which explains the biological effects associated with them. Therefore, this review provides an overview of the role of anthocyanins as natural colorants, showing they are less harmful than conventional colorants, with several technological potential applications in different industrial fields, namely in the textile and food industries, as well as in the development of photosensitizers for dye-sensitized solar cells, as new photosensitizers in photodynamic therapy, pharmaceuticals, and in the cosmetic industry, mainly on the formulation of skin care formulations, sunscreen filters, nail colorants, skin & hair cleansing products, amongst others. In addition, we will unveil some of the latest studies about the health benefits of anthocyanins, mainly focusing on the protection against the most prevalent human diseases mediated by oxidative stress, namely cardiovascular and neurodegenerative diseases, cancer, and diabetes. The contribution of anthocyanins to visual health is also very relevant and will be briefly explored.
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Antocianinas , Cosméticos , Humanos , Antocianinas/química , Frutas/química , Verduras/química , Pigmentação , Preparações Farmacêuticas/análiseRESUMO
A reduced nephron number at birth, due to critical gestational conditions, including maternal malnutrition, is associated with the risk of developing hypertension and chronic kidney disease in adulthood. No interventions are currently available to augment nephron number. We have recently shown that sirtuin 3 (SIRT3) has an important role in dictating proper nephron endowment. The present study explored whether SIRT3 stimulation, by means of supplementation with nicotinamide riboside (NR), a precursor of the SIRT3 co-substrate nicotinamide adenine dinucleotide (NAD+), was able to improve nephron number in a murine model of a low protein (LP) diet. Our findings show that reduced nephron number in newborn mice (day 1) born to mothers fed a LP diet was associated with impaired renal SIRT3 expression, which was restored through supplementation with NR. Glomerular podocyte density, as well as the rarefaction of renal capillaries, also improved through NR administration. In mechanistic terms, the restoration of SIRT3 expression through NR was mediated by the induction of proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α). Moreover, NR restored SIRT3 activity, as shown by the reduction of the acetylation of optic atrophy 1 (OPA1) and superoxide dismutase 2 (SOD2), which resulted in improved mitochondrial morphology and protection against oxidative damage in mice born to mothers fed the LP diet. Our results provide evidence that it is feasible to prevent nephron mass shortage at birth through SIRT3 boosting during nephrogenesis, thus providing a therapeutic option to possibly limit the long-term sequelae of reduced nephron number in adulthood.
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Sirtuína 3 , Camundongos , Animais , Sirtuína 3/metabolismo , NAD , Dieta com Restrição de Proteínas , PPAR gama , Néfrons/metabolismo , Suplementos NutricionaisRESUMO
Sirtuin 3 (SIRT3) is the primary mitochondrial deacetylase that controls the antioxidant pathway and energy metabolism. We previously found that renal Sirt3 expression and activity were reduced in mice with type 2 diabetic nephropathy associated with oxidative stress and mitochondrial abnormalities and that a specific SIRT3 activator improved renal damage. SIRT3 is modulated by diet, and to assess whether Sirt3 deficiency aggravates mitochondrial damage and accelerates kidney disease in response to nutrient overloads, wild-type (WT) and Sirt3-/- mice were fed a high-fat-diet (HFD) or standard diet for 8 months. Sirt3-/- mice on HFD exhibited earlier and more severe albuminuria compared to WT mice, accompanied by podocyte dysfunction and glomerular capillary rarefaction. Mesangial matrix expansion, tubular vacuolization and inflammation, associated with enhanced lipid accumulation, were more evident in Sirt3-/- mice. After HFD, kidneys from Sirt3-/- mice showed more oxidative stress than WT mice, mitochondria ultrastructural damage in tubular cells, and a reduction in mitochondrial mass and energy production. Our data demonstrate that Sirt3 deficiency renders mice more prone to developing oxidative stress and mitochondrial abnormalities in response to HFD, resulting in more severe kidney diseases, and this suggests that mitochondria protection may be a method to prevent HFD-induced renal injury.
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Nefropatias Diabéticas , Sirtuína 3/metabolismo , Animais , Antioxidantes/metabolismo , Dieta Hiperlipídica , Camundongos , Camundongos Knockout , Estresse Oxidativo , Sirtuína 3/genéticaRESUMO
Shiga toxin (Stx)-producing Escherichia coli is the predominant offending agent of post-diarrheal hemolytic uremic syndrome (HUS), a rare disorder of microvascular thrombosis and acute kidney injury possibly leading to long-term renal sequelae. We previously showed that C3a has a critical role in the development of glomerular damage in experimental HUS. Based on the evidence that activation of C3a/C3a receptor (C3aR) signaling induces mitochondrial dysregulation and cell injury, here we investigated whether C3a caused podocyte and tubular injury through induction of mitochondrial dysfunction in a mouse model of HUS. Mice coinjected with Stx2/LPS exhibited glomerular podocyte and tubular C3 deposits and C3aR overexpression associated with cell damage, which were limited by C3aR antagonist treatment. C3a promoted renal injury by affecting mitochondrial wellness as demonstrated by data showing that C3aR blockade reduced mitochondrial ultrastructural abnormalities and preserved mitochondrial mass and energy production. In cultured podocytes and tubular cells, C3a caused altered mitochondrial fragmentation and distribution, and reduced anti-oxidant SOD2 activity. Stx2 potentiated the responsiveness of renal cells to the detrimental effects of C3a through increased C3aR protein expression. These results indicate that C3aR may represent a novel target in Stx-associated HUS for the preservation of renal cell integrity through the maintenance of mitochondrial function.
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Síndrome Hemolítico-Urêmica , Podócitos , Receptores de Complemento , Toxina Shiga II , Animais , Síndrome Hemolítico-Urêmica/etiologia , Síndrome Hemolítico-Urêmica/metabolismo , Glomérulos Renais , Camundongos , Mitocôndrias/metabolismo , Podócitos/metabolismo , Receptores de Complemento/metabolismo , Toxina Shiga II/farmacologiaRESUMO
Alternative pathway complement dysregulation with abnormal glomerular C3 deposits and glomerular damage is a key mechanism of pathology in C3 glomerulopathy (C3G). No disease-specific treatments are currently available for C3G. Therapeutics inhibiting complement are emerging as a potential strategy for the treatment of C3G. In this study, we investigated the effects of N-acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) targeting the C3 component of complement that inhibits liver C3 expression in the C3G model of mice with heterozygous deficiency of factor H (Cfh +/- mice). We showed a duration of action for GalNAc-conjugated C3 siRNA in reducing the liver C3 gene expression in Cfh +/- mice that were dosed s.c. once a month for up to 7 mo. C3 siRNA limited fluid-phase alternative pathway activation, reducing circulating C3 fragmentation and activation of factor B. Treatment with GalNAc-conjugated C3 siRNA reduced glomerular C3d deposits in Cfh +/- mice to levels similar to those of wild-type mice. Ultrastructural analysis further revealed the efficacy of the C3 siRNA in slowing the formation of mesangial and subendothelial electron-dense deposits. The present data indicate that RNA interference-mediated C3 silencing in the liver may be a relevant therapeutic strategy for treating patients with C3G associated with the haploinsufficiency of complement factor H.
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Glomerulonefrite Membranoproliferativa , Nefropatias , Animais , Complemento C3/genética , Complemento C3/metabolismo , Fator B do Complemento/metabolismo , Fator H do Complemento/genética , Via Alternativa do Complemento/genética , Glomerulonefrite Membranoproliferativa/patologia , Humanos , Camundongos , RNA Interferente Pequeno/genéticaRESUMO
In addition to having blood glucose-lowering effects, inhibitors of sodium glucose cotransporter 2 (SGLT2) afford renoprotection in diabetes. We sought to investigate which components of the glomerular filtration barrier could be involved in the antiproteinuric and renoprotective effects of SGLT2 inhibition in diabetes. BTBR (black and tan, brachyuric) ob/ob mice that develop a type 2 diabetic nephropathy received a standard diet with or without empagliflozin for 10 weeks, starting at 8 weeks of age, when animals had developed albuminuria. Empagliflozin caused marked decreases in blood glucose levels and albuminuria but did not correct glomerular hyperfiltration. The protective effect of empagliflozin against albuminuria was not due to a reduction in podocyte damage as empagliflozin did not affect the larger podocyte filtration slit pore size nor the defective expression of nephrin and nestin. Empagliflozin did not reduce the thickening of the glomerular basement membrane. In BTBR ob/ob mice, the most profound abnormality seen using electron microscopy was in the endothelial aspect of the glomerular capillary, with significant loss of endothelial fenestrations. Remarkably, empagliflozin ameliorated the subverted microvascular endothelial ultrastructure. Caveolae and bridging diaphragms between adjacent endothelial fenestrae were seen in diabetic mice and associated with increased expression of caveolin-1 and the appearance of PV-1. These endothelial abnormalities were limited by the SGLT2 inhibitor. Although no expression of SGLT2 was found in glomerular endothelial cells, SGLT2 was expressed in the podocytes of diabetic mice. VEGF-A, which is a known stimulus for endothelial caveolin-1 and PV-1, was increased in podocytes of BTBR ob/ob mice and normalized by SGLT2 inhibitor treatment. Thus, empagliflozin's protective effect on the glomerular endothelium of diabetic mice could be due to a limitation of the paracrine signaling of podocyte-derived VEGF-A that resulted in a reduction of the abnormal endothelial caveolin-1 and PV-1, with the consequent preservation of glomerular endothelial function and permeability. © 2022 The Pathological Society of Great Britain and Ireland.
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Diabetes Mellitus Experimental , Nefropatias Diabéticas , Inibidores do Transportador 2 de Sódio-Glicose , Albuminúria/tratamento farmacológico , Albuminúria/patologia , Albuminúria/prevenção & controle , Animais , Compostos Benzidrílicos , Glicemia/metabolismo , Caveolina 1/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/prevenção & controle , Células Endoteliais/metabolismo , Feminino , Membrana Basal Glomerular/metabolismo , Glucosídeos , Humanos , Masculino , Camundongos , Transdução de Sinais , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
For centuries, wine has had a fundamental role in the culture and habits of different civilizations. Amongst numerous wine types that involve specific winemaking processes, fortified wines possess an added value and are greatly honored worldwide. This review comprises the description of the most important characteristics of the main worldwide fortified wines-Madeira, Port, Sherry, Muscat, and Vermouth-structured in three parts. The first part briefly describes the chemistry of wine flavor, the origin of typical aroma (primary, secondary and tertiary), and the influencing parameters during the winemaking process. The second part describes some specificities of worldwide fortified wine, highlighting the volatile composition with particular emphasis on aroma compounds. The third part reports the volatile composition of the most important fortified wines, including the principal characteristics, vinification process, the evolution of volatile organic compounds (VOCs) during the aging processes, and the most important odor descriptors. Given the worldwide popularity and the economic relevance of fortified wines, much research should be done to better understand accurately the reactions and mechanisms that occur in different stages of winemaking, mainly during the oxidative and thermal aging.
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The consumption of black rice has grown in recent years due to its particular organoleptic properties and high content of antioxidant polyphenols, which make it a sort of natural functional food. However, heat treatment applied during cooking can influence the content and the composition of antioxidant components, particularly anthocyanins, the main compounds of black rice, responsible for its color. The aim of this work was to evaluate the impact of different cooking techniques (boiling, microwaves oven, under pressure pot and risotto preparation) on the chemical and nutritional composition of the Italian Artemide black rice. Different cooking methods had significant and different impact on rice composition. Proximate composition was not affected by cooking, except for moisture, which increased, and fiber content, which decreased. Total polyphenols, total anthocyanin content, and antioxidant capacity were reduced; moreover, anthocyanins and phenolic acids determined by HPLC-DAD generally decreased, with the only exception of protocatechuic acid. The risotto preparation was the most useful cooking technique to preserve anthocyanins and antioxidant activity. Our results demonstrated the importance to study cooking methods and to evaluate their impact on rice characteristics, in order to preserve its nutritional and beneficial properties.
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OBJECTIVE: CER-001 is an HDL mimetic that has been tested in different pathological conditions, but never with LCAT deficiency. This study was designed to investigate whether the absence of LCAT affects the catabolic fate of CER-001, and to evaluate the effects of CER-001 on kidney disease associated with LCAT deficiency. METHODS: Lcat-/- and wild-type mice received CER-001 (2.5, 5, 10â¯mg/kg) intravenously for 2â¯weeks. The plasma lipid/ lipoprotein profile and HDL subclasses were analyzed. In a second set of experiments, Lcat-/- mice were injected with LpX to induce renal disease and treated with CER-001 and then the plasma lipid profile, lipid accumulation in the kidney, albuminuria and glomerular podocyte markers were evaluated. RESULTS: In Lcat-/- mice a decrease in total cholesterol and triglycerides, and an increase in HDL-c was observed after CER-001 treatment. While in wild-type mice CER-001 entered the classical HDL remodeling pathway, in the absence of LCAT it disappeared from the plasma shortly after injection and ended up in the kidney. In a mouse model of renal disease in LCAT deficiency, treatment with CER-001 at 10â¯mg/kg for one month had beneficial effects not only on the lipid profile, but also on renal disease, by limiting albuminuria and podocyte dysfunction. CONCLUSIONS: Treatment with CER-001 ameliorates the dyslipidemia typically associated with LCAT deficiency and more importantly limits renal damage in a mouse model of renal disease in LCAT deficiency. The present results provide a rationale for using CER-001 in FLD patients.