RESUMEN
Polyphenols are natural compounds also contained in daily consumed foods that show their efficacy in different clinical fields. Both pre-clinical and clinical studies demonstrated that polyphenols may manage neuroinflammation and oxidative stress processes tightly connected to neurodegenerative diseases and mental disorders. Thus, a neuroinflammatory state may influence the neurotransmitters pathways, such as the noradrenergic, glutamatergic, serotoninergic, and, in particular, dopaminergic ones, whose impairment is strongly associated with attention deficit hyperactivity disorder (ADHD). Therefore, the aim of the present systematic review is to provide an overview of the clinical outcomes' changes following ADHD treatment with polyphenols alone and in combination with the traditional drugs. This review was conducted according to PRISMA guidelines and recorded on PROSPERO with the number CRD42023438491; PubMed, Scopus, and Web of Science were used as search-engines to lead our research until June 2023. The inclusion criteria were articles written in English, including clinical, placebo-controlled, and case-control trials. We excluded reviews, metanalyses, background articles, and papers published in other languages. To avoid any bias, Rayyan software (COPYRIGHT © 2022 RAYYAN) was used to organize the work and manage the literature review. After screening, 10 studies were included, with a total of 556 patients that met the established inclusion criteria. The data obtained from these studies showed that polyphenols rebalanced oxidative stress pathways through different mechanisms, are effective for the treatment of ADHD both alone and in combination with traditional drugs, and are able to reduce symptoms as well as the side effects related to the use of conventional therapies. Finally, a positive effect of using polyphenols for ADHD prevention could be hypothesized.
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Trastorno por Déficit de Atención con Hiperactividad , Polifenoles , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Humanos , Polifenoles/uso terapéutico , Polifenoles/farmacología , Estrés Oxidativo/efectos de los fármacos , Antioxidantes/uso terapéutico , Antioxidantes/farmacologíaRESUMEN
Neuroinflammation is an inflammatory response of the nervous tissue mediated by the production of cytokines, chemokines, and reactive oxygen species. Recent studies have shown that an upregulation of immunoproteasome is highly associated with various diseases and its inhibition attenuates neuroinflammation. In this context, the development of non-covalent immunoproteasome-selective inhibitors could represent a promising strategy for treating inflammatory diseases. Novel amide derivatives, KJ3 and KJ9, inhibit the ß5 subunit of immunoproteasome and were used to evaluate their possible anti-inflammatory effects in an in vitro model of TNF-α induced neuroinflammation. Differentiated SH-SY5Y and microglial cells were challenged with 10 ng/mL TNF-α for 24 h and treated with KJ3 (1 µM) and KJ9 (1 µM) for 24 h. The amide derivatives showed a significant reduction of oxidative stress and the inflammatory cascade triggered by TNF-α reducing p-ERK expression in treated cells. Moreover, the key action of these compounds on the immunoproteasome was further confirmed by halting the IkB-α phosphorylation and the consequent inhibition of NF-kB. As downstream targets, IL-1ß and IL-6 expression resulted also blunted by either KJ3 and KJ9. These preliminary results suggest that the effects of these two compounds during neuroinflammatory response relies on the reduced expression of pro-inflammatory targets.
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Neuroblastoma , Enfermedades Neuroinflamatorias , Humanos , Factor de Necrosis Tumoral alfa/metabolismo , Neuroblastoma/metabolismo , Transducción de Señal , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , FN-kappa B/metabolismo , Microglía/metabolismo , Lipopolisacáridos/farmacologíaRESUMEN
Cardiac fibrosis is a common pathological feature of different cardiovascular diseases, characterized by the aberrant deposition of extracellular matrix (ECM) proteins in the cardiac interstitium, myofibroblast differentiation and increased fibrillar collagen deposition stimulated by transforming growth factor (TGF)-ß activation. Biglycan (BGN), a small leucine-rich proteoglycan (SLRPG) integrated within the ECM, plays a key role in matrix assembly and the phenotypic control of cardiac fibroblasts. Moreover, BGN is critically involved in pathological cardiac remodeling through TGF-ß binding, thus causing myofibroblast differentiation and proliferation. Adenosine receptors (ARs), and in particular A2AR, may play a key role in stimulating fibrotic damage through collagen production/deposition, as a consequence of cyclic AMP (cAMP) and AKT activation. For this reason, A2AR modulation could be a useful tool to manage cardiac fibrosis in order to reduce fibrotic scar deposition in heart tissue. Therefore, the aim of the present study was to investigate the possible crosstalk between A2AR and BGN modulation in an in vitro model of TGF-ß-induced fibrosis. Immortalized human cardiac fibroblasts (IM-HCF) were stimulated with TGF-ß at the concentration of 10 ng/mL for 24 h to induce a fibrotic phenotype. After applying the TGF-ß stimulus, cells were treated with two different A2AR antagonists, Istradefylline and ZM241385, for an additional 24 h, at the concentration of 10 µM and 1 µM, respectively. Both A2AR antagonists were able to regulate the oxidative stress induced by TGF-ß through intracellular reactive oxygen species (ROS) reduction in IM-HCFs. Moreover, collagen1a1, MMPs 3/9, BGN, caspase-1 and IL-1ß gene expression was markedly decreased following A2AR antagonist treatment in TGF-ß-challenged human fibroblasts. The results obtained for collagen1a1, SMAD3, α-SMA and BGN were also confirmed when protein expression was evaluated; phospho-Akt protein levels were also reduced following Istradefylline and ZM241385 use, thus suggesting that collagen production involves AKT recruited by the A2AR. These results suggest that A2AR modulation might be an effective therapeutic option to reduce the fibrotic processes involved in heart pathological remodeling.
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Fibroblastos , Proteínas Proto-Oncogénicas c-akt , Humanos , Biglicano/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fibroblastos/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Colágeno/metabolismo , Fibrosis , Adenosina/farmacología , Adenosina/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Células CultivadasRESUMEN
Cadmium (Cd) is a transition heavy metal that is able to accumulate in the central nervous system and may induce cell death through reactive oxygen species (ROS)-mediated mechanisms and inactivating the antioxidant processes, becoming an important risk factor for neurodegenerative diseases. The antioxidant effects of cannabinoid receptor modulation have been extensively described, and, in particular, ß-Caryophyllene (BCP), a plant-derived cannabinoid 2 receptor (CB2R) agonist, not only showed significant antioxidant properties but also anti-inflammatory, analgesic, and neuroprotective effects. Therefore, the aim of the present study was to evaluate BCP effects in a model of Cd-induced toxicity in the neuroblastoma SH-SY5Y cell line used to reproduce Cd intoxication in humans. SH-SY5Y cells were pre-treated with BCP (25, 50, and 100 µM) for 24 h. The day after, cells were challenged with cadmium chloride (CdCl2; 10 µM) for 24 h to induce neuronal toxicity. CdCl2 increased ROS accumulation, and BCP treatment significantly reduced ROS production at concentrations of 50 and 100 µM. In addition, CdCl2 significantly decreased the protein level of nuclear factor erythroid 2-related factor 2 (Nrf2) compared to unstimulated cells; the treatment with BCP at a concentration of 50 µM markedly increased Nrf2 expression, thus confirming the BCP anti-oxidant effect. Moreover, BCP treatment preserved cells from death, regulated the apoptosis pathway, and showed a significant anti-inflammatory effect, thus reducing the pro-inflammatory cytokines increased by the CdCl2 challenge. The results indicated that BCP preserved neuronal damage induced by Cd and might represent a future candidate for protection in neurotoxic conditions.
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Neuroblastoma , Sesquiterpenos , Humanos , Cadmio/toxicidad , Sesquiterpenos/farmacología , Receptor Cannabinoide CB2 , Especies Reactivas de Oxígeno/metabolismo , Antioxidantes/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Antiinflamatorios no Esteroideos , Línea Celular TumoralRESUMEN
Many natural substances commonly found in healthy diets have been studied for their potential to reduce male infertility associated with varicocele. A positive role of selenium (Se) or lycopene alone was demonstrated in experimental varicocele, while no data are available on their association. One group of male Sprague-Dawley rats was sham operated and daily treated with Se (3 mg/kg, i.p.), lycopene (1 mg/kg, i.p.), or their association. A second group underwent surgery to induce varicocele. Sham and half of the varicocele animals were sacrificed after twenty-eight days, while the residual animals were treated for one more month and then sacrificed. In varicocele animals, testosterone levels and testes weight were reduced, Hypoxia Inducible Factor-1α (HIF-1α) expression was absent in the tubules and increased in Leydig cells, caspare-3 was increased, seminiferous epithelium showed evident structural changes, and many apoptotic germ cells were demonstrated with TUNEL assay. The treatment with lycopene or Se alone significantly increased testis weight and testosterone levels, reduced apoptosis and caspase-3 expression, improved the tubular organization, decreased HIF-1α positivity of Leydig cells, and restored its tubular positivity. Lycopene or Se association showed a better influence on all biochemical and morphological parameters. Therefore, the nutraceutical association of lycopene plus Se might be considered a possible therapeutic tool, together with surgery, in the treatment of male infertility. However, long-term experimental and clinical studies are necessary to evaluate sperm quantity and quality.
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Infertilidad Masculina , Selenio , Varicocele , Masculino , Ratas , Animales , Humanos , Ratas Sprague-Dawley , Selenio/farmacología , Licopeno/farmacología , Varicocele/tratamiento farmacológico , Semen , Suplementos Dietéticos , Infertilidad Masculina/tratamiento farmacológico , Infertilidad Masculina/etiología , TestosteronaRESUMEN
Experimental and clinical studies have suggested that several neurological disorders are associated with the occurrence of central nervous system neuroinflammation. Metaxalone is an FDA-approved muscle relaxant that has been reported to inhibit monoamine oxidase A (MAO-A). The aim of this study was to investigate whether metaxalone might exert antioxidant and anti-inflammatory effects in HMC3 microglial cells. An inflammatory phenotype was induced in HMC3 microglial cells through stimulation with interleukin-1ß (IL-1ß). Control cells and IL-1ß-stimulated cells were subsequently treated with metaxalone (10, 20, and 40 µM) for six hours. IL-1ß stimulated the release of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), but reduced the anti-inflammatory cytokine interleukin-13 (IL-13). The upstream signal consisted of an increased priming of nuclear factor-kB (NF-kB), blunted peroxisome proliferator-activated receptor gamma (PPARγ), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression. IL-1ß also augmented MAO-A expression/activity and malondialdehyde levels and decreased Nrf2 mRNA expression and protein levels. Metaxalone decreased MAO-A activity and expression, reduced NF-kB, TNF-α, and IL-6, enhanced IL-13, and also increased PPARγ, PGC-1α, and Nrf2 expression. The present experimental study suggests that metaxalone has potential for the treatment of several neurological disorders associated with neuroinflammation.
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Inflamación/tratamiento farmacológico , Interleucina-1beta/metabolismo , Microglía/efectos de los fármacos , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Oxazolidinonas/farmacología , Antiinflamatorios , Línea Celular , Humanos , Inflamación/metabolismo , Interleucina-13/metabolismo , Interleucina-6/metabolismo , Microglía/metabolismo , PPAR gamma/metabolismo , Fenotipo , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The antibiotic doxorubicin is often used as an anti-neoplastic drug; however, many patients showed very unpleasant side-effects. Previous studies have demonstrated that dietary substances such as Aloe arborescens, Annona muricata, Morinda citrifolia, Beta rubra, Scutellaria baicalensis, and Vaccinium myrtillus may have anti-oxidant, anti-proliferative, and anti-inflammatory effects. The purpose of this study was to investigate the protective effects of a mixture of these components in an experimental model of doxorubicin toxicity. Rats (n = 30) received doxorubicin (5 mg/kg/day) for 4 weeks and were randomized to receive the dietary mixture 2 hours following the first doxorubicin injection and until the end of the experiment. Animals were killed following 4 weeks, and blood, liver, and heart were collected for further analysis. The dietary supplement improved the depressed body weight and food consumption induced by DOX. In addition, the nutraceutical mixture reduced oxidative stress, ameliorated the morphological score, and preserved liver and heart structure, demonstrating a protective effect. These data show for the first time that the mixture of Aloe arborescens, Annona muricata, Morinda citrifolia, Beta rubra, Scutellaria baicalensis, and Vaccinium myrtillus may be useful to reduce the side effects following treatment with doxorubicin, and might ameliorate the quality of life of patients following chemotherapy.
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Antibióticos Antineoplásicos/toxicidad , Cardiotoxicidad/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Suplementos Dietéticos , Doxorrubicina/toxicidad , Extractos Vegetales/farmacología , Aloe/química , Animales , Annona/química , Cardiotoxicidad/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Masculino , Morinda/química , Extractos Vegetales/administración & dosificación , Ratas , Ratas Sprague-Dawley , Scutellaria baicalensis/química , Vaccinium myrtillus/químicaRESUMEN
Traumatic brain injury (TBI) represents an important problem of global health. The damage related to TBI is first due to the direct injury and then to a secondary phase in which neuroinflammation plays a key role. NLRP3 inflammasome is a component of the innate immune response and different diseases, such as neurodegenerative diseases, are characterized by NLRP3 activation. This review aims to describe NLRP3 inflammasome and the consequences related to its activation following TBI. NLRP3, caspase-1, IL-1ß, and IL-18 are significantly upregulated after TBI, therefore, the use of nonspecific, but mostly specific NLRP3 inhibitors is useful to ameliorate the damage post-TBI characterized by neuroinflammation. Moreover, NLRP3 and the molecules associated with its activation may be considered as biomarkers and predictive factors for other neurodegenerative diseases consequent to TBI. Complications such as continuous stimuli or viral infections, such as the SARS-CoV-2 infection, may worsen the prognosis of TBI, altering the immune response and increasing the neuroinflammatory processes related to NLRP3, whose activation occurs both in TBI and in SARS-CoV-2 infection. This review points out the role of NLRP3 in TBI and highlights the hypothesis that NLRP3 may be considered as a potential therapeutic target for the management of neuroinflammation in TBI.
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Betacoronavirus/inmunología , Lesiones Traumáticas del Encéfalo/fisiopatología , Infecciones por Coronavirus/complicaciones , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Neumonía Viral/complicaciones , Biomarcadores/metabolismo , Lesiones Traumáticas del Encéfalo/diagnóstico , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , COVID-19 , Humanos , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Pandemias , Pronóstico , Piroptosis , SARS-CoV-2RESUMEN
Nuclear factor-κB (NF-κB) plays a central role in psoriasis and canonical Wnt/ß-catenin pathway blunts the immune-mediated inflammatory cascade in psoriasis. Adenosine A2A receptor activation blocks NF-κB and boosts the Wnt/ß-catenin signaling. PDRN (Polydeoxyribonucleotide) is a biologic agonist of the A2A receptor and its effects were studied in an experimental model of psoriasis. Psoriasis-like lesions were induced by a daily application of imiquimod (IMQ) on the shaved back skin of mice for 7 days. Animals were randomly assigned to the following groups: Sham psoriasis challenged with Vaseline; IMQ animals challenged with imiquimod; and IMQ animals treated with PDRN (8 mg/kg/ip). An additional arm of IMQ animals was treated with PDRN plus istradefylline (KW6002; 25 mg/kg/ip) as an A2A antagonist. PDRN restored a normal skin architecture, whereas istradefylline abrogated PDRN positive effects, thus pointing out the mechanistic role of the A2A receptor. PDRN decreased pro-inflammatory cytokines, prompted Wnt signaling, reduced IL-2 and increased IL-10. PDRN also reverted the LPS repressed Wnt-1/ß-catenin in human keratinocytes and these effects were abolished by ZM241385, an A2A receptor antagonist. Finally, PDRN reduced CD3+ cells in superficial psoriatic dermis. PDRN anti-psoriasis potential may be linked to a "dual mode" of action: NF-κB inhibition and Wnt/ß-catenin stimulation.
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Imiquimod/efectos adversos , FN-kappa B/metabolismo , Polidesoxirribonucleótidos/farmacología , Psoriasis/tratamiento farmacológico , Psoriasis/metabolismo , Vía de Señalización Wnt/efectos de los fármacos , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Queratinocitos/metabolismo , Queratinocitos/patología , Ratones , Ratones Endogámicos BALB C , Psoriasis/inducido químicamente , Psoriasis/patología , Receptor de Adenosina A2A/metabolismo , Piel/metabolismo , Piel/patología , beta Catenina/metabolismoRESUMEN
Diabetes is characterized by poor wound healing which currently lacks an efficacious treatment. The innate repair receptor (IRR) is a master regulator of tissue protection and repair which is expressed as a response injury or metabolic stress, including in diabetes. Activation of the IRR might provide benefit for diabetic wound healing. A specific IRR agonist cibinetide was administered in an incisional wound healing model performed mice with genetic diabetes (db+/db+) and compared to the normal wild-type. Animals were treated daily with cibinetide (30µg/kg/s.c.) or vehicle and euthanized 3, 7, and 14days after the injury to quantitate vascular endothelial growth factor (VEGF), malondialdehyde (MAL), phospho-Akt (pAkt), phospho e-NOS (p-eNOS), and nitrite/nitrate content within the wound. Additional evaluations included quantification of skin histological change, angiogenesis, scar strength, and time to complete wound closure. Throughout the wound healing process diabetic animals treated with vehicle exhibited increased wound MAL with reduced VEGF, pAkt, peNOS and nitrite/nitrate, all associated with poor re-epitheliziation, angiogenesis, and wound breaking strength. Cibenitide administration significantly improved these abnormalities. The results suggest that cibinetide-mediated IRR activation may represent an interesting strategy to treat diabetes-associated wound healing.
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Subunidad beta Común de los Receptores de Citocinas/metabolismo , Diabetes Mellitus Experimental/genética , Oligopéptidos/farmacología , Receptores de Eritropoyetina/metabolismo , Cicatrización de Heridas/efectos de los fármacos , Animales , Femenino , Malondialdehído/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neovascularización Fisiológica , Óxido Nítrico Sintasa de Tipo III/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Resistencia a la Tracción , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
This paper describes the design, synthesis, and biological evaluation of 2-thioxoimidazolidin-4-one derivatives as inhibitors of proteasome and immunoproteasome, potential targets for the treatment of hematological malignancies. In particular, we focused our efforts on the design of noncovalent inhibitors, which might be a promising therapeutic option potentially devoid of drawbacks and side-effects related to irreversible inhibition. Among all the synthesized compounds, we identified a panel of active inhibitors with Ki values towards one or two chymotrypsin-like activities of proteasome (ß5c) and immunoproteasome (ß5i and ß1i subunits) in the low micromolar range. Docking studies suggested a unique binding mode of the molecules in the catalytic site of immunoproteasome proteolytic subunits.
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Imidazolidinas/farmacología , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Imidazolidinas/síntesis química , Imidazolidinas/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteasoma/síntesis química , Inhibidores de Proteasoma/química , Relación Estructura-ActividadRESUMEN
The oral administration is probably the most used and largely applicable method, even if absorption across the intestinal epithelium is a limiting factor that can invalidate the achievement of a therapy. The aim of this study was to assess the steady state bioavailability of very low molecular weight hyaluronic acid (vLMW-HA) and its distribution in different districts of mice. Adult female C57BL6/J mice (n = 26) were divided in three groups and orally treated for 7 days with: saline solution (SHAM-HA), high dose of vLMW-HA (5 kDa; 500 mg/kg/day; HD-vLMW-HA), and low dose of vLMW-HA (5 kDa; 100 mg/kg/day; LD-vLMW-HA). HA content was quantified in plasma, skin, bladder, gut, rectum, vagina, and eyes with ELISA assay at the end of treatment. HA level significantly increased after treatment with HD-vLMW-HA in all analyzed tissues and plasma. Therefore, vLMW-HA easy absorption and distribution after the oral intake opens new possibilities for future biomedical applications.
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Ácido Hialurónico , Piel , Ratones , Femenino , Animales , Ácido Hialurónico/uso terapéutico , Peso Molecular , Distribución Tisular , Administración OralRESUMEN
Bone remodeling is a process that involves osteoblasts, osteoclasts, and osteocytes, and different intracellular signaling, such as the canonical Wnt/ß-catenin pathway. Dysregulations of this pathway may also occur during secondary osteoporosis, as in the case of glucocorticoid-induced osteoporosis (GIO), which accelerates osteoblast and osteocyte apoptosis by reducing bone formation, osteoblast differentiation and function, accelerates in turn osteoblast, and osteocyte apoptosis. Genistein is a soy-derived nutrient belonging to the class of isoflavones that reduces bone loss in osteopenic menopausal women, inhibiting bone resorption; however, genistein may also favor bone formation. The aim of this study was to investigate whether estrogen receptor stimulation by genistein might promote osteoblast and osteocyte function during glucocorticoid challenge. Primary osteoblasts, collected from C57BL6/J mice, and MLO-A5 osteocyte cell line were used to reproduce an in vitro model of GIO by adding dexamethasone (1 µM) for 24 h. Cells were then treated with genistein for 24 h and quantitative Polymerase Chain Reaction (qPCR) and western blot were performed to study whether genistein activated the Wnt/ß-catenin pathway. Dexamethasone challenge reduced bone formation in primary osteoblasts and bone mineralization in osteocytes; moreover, canonical Wnt/ß-catenin pathway was reduced following incubation with dexamethasone in both osteoblasts and osteocytes. Genistein reverted these changes and this effect was mediated by both estrogen receptors α and ß. These data suggest that genistein could induce bone remodeling through Wnt/ß-catenin pathway activation.
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Genisteína , Isoflavonas , Osteoporosis , Animales , Ratones , beta Catenina/genética , beta Catenina/metabolismo , Diferenciación Celular , Dexametasona/farmacología , Genisteína/farmacología , Glucocorticoides , Isoflavonas/farmacología , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteocitos/efectos de los fármacos , Osteocitos/metabolismo , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismo , Vía de Señalización Wnt/efectos de los fármacos , Glycine max/químicaRESUMEN
Hypovolemic shock is a circulatory failure, due to a loss in the effective circulating blood volume, that causes tissue hypoperfusion and hypoxia. This condition stimulates reactive oxygen species (ROS) and pro-inflammatory cytokine production in different organs and also in the central nervous system (CNS). Levosimendan, a cardioprotective inodilator, and dobutamine, a ß1-adrenergic agonist, are commonly used for the treatment of hypovolemic shock, thanks to their anti-inflammatory and antioxidant effects. For this reason, we aimed at investigating levosimendan and dobutamine's neuroprotective effects in an "in vitro" model of lipopolysaccharide (LPS)-induced neuroinflammation. Human microglial cells (HMC3) were challenged with LPS (0.1 µg/mL) to induce an inflammatory phenotype and then treated with levosimendan (10 µM) or dobutamine (50 µM) for 24 h. Levosimendan and dobutamine significantly reduced the ROS levels and markedly increased Nrf2 and HO-1 protein expression in LPS-challenged cells. Levosimendan and dobutamine also decreased p-NF-κB expression and turned off the NLRP3 inflammasome together with its downstream signals, caspase-1 and IL-1ß. Moreover, a reduction in TNF-α and IL-6 expression and an increase in IL-10 levels in LPS-stimulated HMC3 cells was observed following treatment. In conclusion, levosimendan and dobutamine attenuated LPS-induced neuroinflammation through NF-κB pathway inhibition and NLRP3 inflammasome activation via Nrf2/HO-1 signalling, suggesting that these drugs could represent a promising therapeutic approach for the treatment of neuroinflammation consequent to hypovolemic shock.
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The meat of snails can be considered a high-quality food for the human diet and demand is already increasing across Europe. Due to the bioaccumulation of trace elements in their tissues, land snails can be a significant tool also for environmental pollution evaluation. In this study, 28 mineral elements (Ag, Al, As, B, Ba, Be, Bi, Cd, Co, Cr, Cu, Fe, Hg, K, Li, Na, Mg, Mn, Mo, Ni, Pb, Sb, Se, Sr, Ti, Tl, V, Zn) in both the edible part and the shell of edible land snails commercially available in Southern Italy belonging to Cernuella virgata, Helix aperta, Theba pisana species were investigated by ICP-MS and direct mercury analyser. The concentration of trace elements was variable among the samples. The variability demonstrates the close connection among the type of snail, the geographical origin, and the habitat in which the species grows. The edible part of the snails analysed in this study was found to be a good source of macro-nutrients. Toxic elements were detected in some samples, especially in shells; nevertheless, the values fell within the safety limits. Further investigations and monitoring of mineral contents in edible land snails are suggested both for human health and environmental pollution evaluation.
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In the original publication [...].
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Cardiac fibrosis is a pathological process characterized by an excessive deposition of extracellular matrix (ECM) and an increased production of fibrillar collagen in the cardiac interstitium, mainly caused by the activation of cardiac fibroblasts and their transition into myofibroblasts. Oxidative stress is deeply implicated in the pathogenesis of cardiac fibrosis both directly and via its involvement in the tumor growth factor ß1 (TGF-ß1) signaling. Ellagic acid (EA) and punicic acid (PA) are the main components of the Punica granatum L (pomegranate) fruit and seed oil respectively, whose antioxidant, anti-inflammatory and anti-fibrotic effects have been previously described. Therefore, the aim of this study was to investigate the effects of EA or PA or EA+PA in an in vitro model of cardiac fibrosis. Immortalized Human Cardiac Fibroblasts (IM-HCF) were stimulated with 10 ng/ml of TGF-ß1 for 24 h to induce a fibrotic damage. Cells were then treated with EA (1 µM), PA (1 µM) or EA+PA for additional 24 h. Both EA and PA reduced the pro-fibrotic proteins expressions and the intracellular reactive oxygen species (ROS) accumulation. The anti-oxidant activity was also observed by Nrf2 activation with the consequent TGF-ß1-Smad2/3-MMP2/9 and Wnt/ß-catenin signaling inhibition, thus reducing collagen production. EA and PA significantly inhibit NF-κB pathway and, consequently, TNF-α, IL-1ß and IL-6 levels: the greater effect was observed when EA and PA were used in combination. These results suggest that EA, PA and in particular EA+PA might be effective in reducing fibrosis through their antioxidant and anti-inflammatory properties by the modulation of different molecular pathways.
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Antioxidantes , Factor de Crecimiento Transformador beta1 , Humanos , Factor de Crecimiento Transformador beta1/metabolismo , Fibrosis , Antiinflamatorios , Ácido ElágicoRESUMEN
Glucocorticoid-induced osteoporosis (GIO) complicates the clinical management of patients subjected to long-term glucocorticoid use. This study explored the effects of genistein on bone loss in a randomized double-blind alendronate-controlled trial in postmenopausal women with GIO. 200 postmenopausal women (taking at least 5 mg of prednisone equivalents) since 3 months, or more, and expected to continue for at least other 12 months, were randomized to receive genistein (54 mg/day daily) or alendronate (70 mg once a week) for 24 months. Both groups received also Calcium and Vitamin D3 supplementation. Median bone mineral density (BMD) at the antero-posterior lumbar spine significantly increased from 0.75 g/cm2 at baseline to 0.77 g/cm2 at 1 year and 0.79 g/cm2 at 2 years in alendronate-treated patients and from 0.77 g/cm2 at baseline to 0.79 g/cm2 at 12 months and to 0.80 g/cm2 at 24 months in genistein recipients. No difference was observed between the two treatments. Median BMD at the femoral neck increased from 0.67 g/cm2 at baseline to 0.68 g/cm2 at 1 year and 0.69 g/cm2 at 2 years in alendronate-treated patients and from 0.68 g/cm2 at baseline to 0.70 g/cm2 at 12 months and to 0.71 g/cm2 at 24 months in genistein recipients. No difference was observed between alendronate and genistein groups in BMD. Regarding bone markers genistein and alendronate statistically decreased c-terminal telopeptide, while osteocalcin, bone-ALP, and sclerostin showed greater changes in genistein treated patients. This randomized clinical trial suggests that genistein aglycone represents an additional therapeutic option for patients with GIO.
Asunto(s)
Conservadores de la Densidad Ósea , Osteoporosis Posmenopáusica , Osteoporosis , Humanos , Femenino , Alendronato/uso terapéutico , Glucocorticoides/farmacología , Genisteína/farmacología , Genisteína/uso terapéutico , Conservadores de la Densidad Ósea/farmacología , Conservadores de la Densidad Ósea/uso terapéutico , Osteoporosis/inducido químicamente , Osteoporosis/tratamiento farmacológico , Densidad Ósea , Osteoporosis Posmenopáusica/inducido químicamente , Osteoporosis Posmenopáusica/tratamiento farmacológico , Método Doble CiegoRESUMEN
Activation of peroxisome proliferator-activated receptors (PPARs) not only regulates multiple metabolic pathways, but mediates various biological effects related to inflammation and oxidative stress. We investigated the effects of four new PPAR ligands containing a fibrate scaffold-the PPAR agonists (1a (αEC50 1.0 µM) and 1b (γEC50 0.012 µM)) and antagonists (2a (αIC50 6.5 µM) and 2b (αIC50 0.98 µM, with a weak antagonist activity on γ isoform))-on proinflammatory and oxidative stress biomarkers. The PPAR ligands 1a-b and 2a-b (0.1-10 µM) were tested on isolated liver specimens treated with lipopolysaccharide (LPS), and the levels of lactate dehydrogenase (LDH), prostaglandin (PG) E2, and 8-iso-PGF2α were measured. The effects of these compounds on the gene expression of the adipose tissue markers of browning, PPARα, and PPARγ, in white adipocytes, were evaluated as well. We found a significant reduction in LPS-induced LDH, PGE2, and 8-iso-PGF2α levels after 1a treatment. On the other hand, 1b decreased LPS-induced LDH activity. Compared to the control, 1a stimulated uncoupling protein 1 (UCP1), PR-(PRD1-BF1-RIZ1 homologous) domain containing 16 (PRDM16), deiodinase type II (DIO2), and PPARα and PPARγ gene expression, in 3T3-L1 cells. Similarly, 1b increased UCP1, DIO2, and PPARγ gene expression. 2a-b caused a reduction in the gene expression of UCP1, PRDM16, and DIO2 when tested at 10 µM. In addition, 2a-b significantly decreased PPARα gene expression. A significant reduction in PPARγ gene expression was also found after 2b treatment. The novel PPARα agonist 1a might be a promising lead compound and represents a valuable pharmacological tool for further assessment. The PPARγ agonist 1b could play a minor role in the regulation of inflammatory pathways.
RESUMEN
Lycopene is a carotenoid found in tomatoes that has potent antioxidant activity. The Mediterranean diet is particularly rich in lycopene, which has well-known beneficial effects on cardiovascular health. We tested the effects of lycopene extract in a group of 20 ApoE knockout mice, fed with a high fat western diet for 14 weeks. Starting from week 3 and up to week 14, the mice were randomly divided into two groups that received lycopene (n = 10) by oral suspension every day at the human equivalent dose of 60 mg/day (0.246 mg/mouse/day), or the vehicle solution (n = 10). The lycopene administration reduced triglycerides and cholesterol blood levels starting from week 6 and continuing through to the end of the experiment (p < 0.001). This reduction was mediated by an enhanced liver expression of PPAR-α and AMPK-α and reduced SREBP levels (p < 0.0001). As a histological red-out, the extent of atherosclerotic plaques and the intima−media thickness in the aorta were significantly reduced by lycopene. In this context, lycopene augmented the Nrf-2 positivity staining in the endothelium, thereby confirming that its antioxidant activity was mediated by this nuclear factor. The positive results obtained in this pre-clinical model further support the use of lycopene extracts to reduce atherosclerosis.