RESUMO
Cornelian cherry (Cornus mas L.) fruits, abundant in iridoids and anthocyanins, are natural products with proven beneficial impacts on the functions of the cardiovascular system and the liver. This study aims to assess and compare whether and to what extent two different doses of resin-purified cornelian cherry extract (10 mg/kg b.w. or 50 mg/kg b.w.) applied in a cholesterol-rich diet rabbit model affect the levels of sterol regulatory element-binding protein 1c (SREBP-1c) and CCAAT/enhancer binding protein α (C/EBPα), and various liver X receptor-α (LXR-α), peroxisome proliferator-activated receptor-α (PPAR-α), and peroxisome proliferator-activated receptor-γ (PPAR-γ) target genes. Moreover, the aim is to evaluate the resistive index (RI) of common carotid arteries (CCAs) and aortas, and histopathological changes in CCAs. For this purpose, the levels of SREBP-1c, C/EBPα, ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette transporter G1 (ABCG1), fatty acid synthase (FAS), endothelial lipase (LIPG), carnitine palmitoyltransferase 1A (CPT1A), and adiponectin receptor 2 (AdipoR2) in liver tissue were measured. Also, the levels of lipoprotein lipase (LPL), visceral adipose tissue-derived serine protease inhibitor (Vaspin), and retinol-binding protein 4 (RBP4) in visceral adipose tissue were measured. The RI of CCAs and aortas, and histopathological changes in CCAs, were indicated. The oral administration of the cornelian cherry extract decreased the SREBP-1c and C/EBPα in both doses. The dose of 10 mg/kg b.w. increased ABCA1 and decreased FAS, CPT1A, and RBP4, and the dose of 50 mg/kg b.w. enhanced ABCG1 and AdipoR2. Mitigations in atheromatous changes in rabbits' CCAs were also observed. The obtained outcomes were compared to the results of our previous works. The beneficial results confirm that cornelian cherry fruit extract may constitute a potentially effective product in the prevention and treatment of obesity-related disorders.
Assuntos
Cornus , Lagomorpha , Extratos Vegetais , Animais , Coelhos , Antocianinas , Transportadores de Cassetes de Ligação de ATP , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Cornus/química , Dieta , Frutas/química , Fígado , Receptores X do Fígado/genética , Extratos Vegetais/farmacologia , PPAR alfa/genética , PPAR gama/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genéticaRESUMO
BACKGROUND: The coronavirus infectious disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has been a huge challenge, affecting directly or indirectly the human race worldwide. Many COVID-19-related risk factors have been identified. Various drugs, including proton pump inhibitors (PPIs), have been claimed to increase the risk of acquiring or affecting the outcome of COVID-19 prior to the availability of vaccines. The aim of this review was to summarize the uncertain role of PPI use on the SARS-CoV-2 infection and COVID-19 clinical course, including both some well-established and presumptive indications to these potent inhibitors of gastric acid secretion, before vaccinations against COVID-19 were implemented on a massive scale. SUMMARY: Although iatrogenic hypochlorhydria alters human microbiota and impairs the nonspecific innate immunity, increasing the likelihood of gastrointestinal and pulmonary infections, published data on the relationship between SARS-CoV-2 positivity and clinical manifestations of COVID-19 are quite inconclusive. On the contrary, the beneficial role of PPI use in the prevention of the upper gastrointestinal bleeding, particularly in at-risk patients receiving dual antiplatelet treatment and/or concomitant anticoagulation, constituting a significant proportion of COVID-19 patients, has been well-documented. Furthermore, PPIs have been marked as a potential antiviral remedy, just like many already existing repurposed drugs, that merit further studies in search of successful anti-CO-VID-19 pharmacotherapy. KEY MESSAGES: The controversial role of PPIs on the SARS-CoV-2 infection and COVID-19 severity propounded in the past should not prevent the use of these potent inhibitors of gastric acid secretion in well-established clinical indications.
Assuntos
COVID-19 , Doenças Transmissíveis , Humanos , SARS-CoV-2 , Inibidores da Bomba de Prótons/efeitos adversos , Doenças Transmissíveis/induzido quimicamente , Doenças Transmissíveis/tratamento farmacológico , VacinaçãoRESUMO
Atherogenesis leads to the development of atherosclerosis, a progressive chronic disease characterized by subendothelial lipoprotein retention and endothelial impairment in the arterial wall. It develops mainly as a result of inflammation and also many other complex processes, which arise from, among others, oxidation and adhesion. Cornelian cherry (Cornus mas L.) fruits are abundant in iridoids and anthocyanins-compounds with potent antioxidant and anti-inflammatory activity. This study aimed to determine the effect of two different doses (10 mg and 50 mg per kg of body weight, respectively) of iridoid and anthocyanin-rich resin-purified Cornelian cherry extract on the markers that are important in the progress of inflammation, cell proliferation and adhesion, immune system cell infiltration, and atherosclerotic lesion development in a cholesterol-rich diet rabbit model. We used biobank blood and liver samples that were collected during the previous original experiment. We assessed the mRNA expression of MMP-1, MMP-9, IL-6, NOX, and VCAM-1 in the aorta, and the serum levels of VCAM-1, ICAM-1, CRP, PON-1, MCP-1, and PCT. The application of the Cornelian cherry extract at a dose of 50 mg/kg bw resulted in a significant reduction in MMP-1, IL-6, and NOX mRNA expression in the aorta and a decrease in VCAM-1, ICAM-1, PON-1, and PCT serum levels. The administration of a 10 mg/kg bw dose caused a significant decrease in serum ICAM-1, PON-1, and MCP-1. The results indicate the potential usefulness of the Cornelian cherry extract in the prevention or treatment of atherogenesis-related cardiovascular diseases, such as atherosclerosis or metabolic syndrome.
Assuntos
Aterosclerose , Colesterol na Dieta , Cornus , Dieta Aterogênica , Extratos Vegetais , Animais , Coelhos , Antocianinas/uso terapêutico , Aterosclerose/tratamento farmacológico , Frutas , Inflamação/tratamento farmacológico , Molécula 1 de Adesão Intercelular , Interleucina-6 , Iridoides/uso terapêutico , Metaloproteinase 1 da Matriz , Extratos Vegetais/uso terapêutico , RNA Mensageiro , Molécula 1 de Adesão de Célula VascularRESUMO
Schizophrenia is a severe mental disorder with a chronic, progressive course. The etiology of this condition is linked to the interactions of multiple genes and environmental factors. The earlier age of onset of schizophrenia, the higher frequency of negative symptoms in the clinical presentation, and the poorer response to antipsychotic treatment in men compared to women suggests the involvement of sex hormones in these processes. This article aims to draw attention to the possible relationship between testosterone and some clinical features in male schizophrenic patients and discuss the complex nature of these phenomena based on data from the literature. PubMed, Web of Science, and Google Scholar databases were searched to select the papers without limiting the time of the publications. Hormone levels in the body are regulated by many organs and systems, and take place through the neuroendocrine, hormonal, neural, and metabolic pathways. Sex hormones play an important role in the development and function of the organism. Besides their impact on secondary sex characteristics, they influence brain development and function, mood, and cognition. In men with schizophrenia, altered testosterone levels were noted. In many cases, evidence from available single studies gave contradictory results. However, it seems that the testosterone level in men affected by schizophrenia may differ depending on the phase of the disease, types of clinical symptoms, and administered therapy. The etiology of testosterone level disturbances may be very complex. Besides the impact of the illness (schizophrenia), stress, and antipsychotic drug-induced hyperprolactinemia, testosterone levels may be influenced by, i.a., obesity, substances of abuse (e.g., ethanol), or liver damage.
Assuntos
Antipsicóticos , Esquizofrenia , Humanos , Masculino , Feminino , Esquizofrenia/tratamento farmacológico , Eixo Hipotalâmico-Hipofisário-Gonadal , Prolactina , Antipsicóticos/efeitos adversos , Hormônios Esteroides Gonadais , Testosterona/uso terapêuticoRESUMO
Given that one of the crucial events in the pathogenesis of inflammatory bowel disease is the loss of homeostasis between Th17 and Treg cells, targeting the specific molecules of the Th17/Treg axis developmental pathway is a promising strategy for inflammatory bowel disease prevention and treatment. The current study aimed to assess the impact of cornelian cherry (Cornus mas L.) extract, rich in iridoids and polyphenols known for their potential anti-inflammatory activity, at two doses (20 or 100 mg/kg) on the crucial factors for Th17/Treg cell differentiation in the course of experimental colitis and compare this action with that of sulfasalazine. This study was conducted on the biobank colon tissue samples collected during the previous original experiment, in which colitis in rats was induced by trinitrobenzenesulfonic acid (TNBS). The levels of IL-6, RORγt, total STAT3, p-STAT3, and Foxp3 were determined by ELISA. The expression of PIAS3 mRNA was quantified by qPCR. Cornelian cherry extract at a dose of 100 mg/kg counteracted the TNBS-induced elevation of IL-6, RORγt, and p-STAT3 levels and a decrease in Foxp3 level and PIAS3 mRNA expression, while given concomitantly with sulfasalazine was more effective than sulfasalazine alone in reversing the TNBS-induced changes in IL-6, RORγt, total STAT3, p-STAT3, Foxp3 levels, and PIAS3 mRNA expression. The beneficial effect of cornelian cherry extract on experimental colitis may be due to its immunomodulatory activity reflected by the influence on factors regulating the Th17/Treg axis.
Assuntos
Colite , Cornus , Doenças Inflamatórias Intestinais , Ratos , Animais , Linfócitos T Reguladores , Ácido Trinitrobenzenossulfônico/efeitos adversos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Interleucina-6/farmacologia , Sulfassalazina/farmacologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Células Th17 , Modelos Animais de DoençasRESUMO
Along with the increase in life expectancy in the populations of developed and developing countries resulting from better access and improved health care, the number of patients with dementia, including Alzheimer's disease (AD), is growing. The disease was first diagnosed and described at the beginning of the 20th century. However, to this day, there is no effective causal therapy, and symptomatic treatment often improves patients' quality of life only for a short time. The current pharmacological therapies are based mainly on the oldest hypotheses of the disease-cholinergic (drugs affecting the cholinergic system are available), the hypothesis of amyloid-ß aggregation (an anti-amyloid drug was conditionally approved by the FDA in 2020), and one drug is an N-methyl-D-aspartate receptor (NMDAR) antagonist (memantine). Hypotheses about AD pathogenesis focus on the nervous system and the brain. As research progresses, it has become known that AD can be caused by diseases that have been experienced over the course of a lifetime, which could also affect other organs. In this review, we focus on the potential association of AD with the digestive system, primarily the gut microbiota. The role of diet quality in preventing and alleviating Alzheimer's disease is also discussed. The problem of neuroinflammation, which may be the result of microbiota disorders, is also described. An important aspect of the work is the chapter on the treatment strategies for changing the microbiota, potentially protecting against the disease and alleviating its course in the initial stages.
Assuntos
Doença de Alzheimer , Eixo Encéfalo-Intestino , Microbiota , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Colinérgicos/uso terapêutico , Humanos , Memantina , Qualidade de Vida , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
The pharmacotherapy of inflammatory bowel disease (IBD) is still not fully effective and safe. Attempts to search for new IBD drugs remain an incessant research aim. One of the novel approaches is targeting the developmental pathway molecules and effector cytokines of Th17/Treg axis. This study aimed to elucidate the impact of new pyrrolo[3,4-d]pyridazinone derivatives, compounds 7b, 10b, or 13b, on the course of experimental colitis in rats and to assess whether these new compounds may influence Th17/Treg axis. Rats were pretreated with studied compounds intragastrically before intrarectal administration of 2,4,6-trinitrobenzenesulfonic acid used for colitis induction. Body weight loss, disease activity index, colon index, and colon tissue damage were analyzed to evaluate the severity of colitis. The colonic levels of RORγt, STAT3, CCR6, Foxp3, IL-6, IL-10, IL-17, TNF-α, IL-23, and PGE2 were assessed. Pretreatment with compounds 7b and 13b alleviated the severity of colitis and concomitantly counteracted the increased levels of RORγt, STAT3, CCR6, IL-6, IL-17, IL-23, TNF-α, and PGE2. The beneficial effect of compounds 7b and 13b may be due to the decrease in the levels of Th17-specific transcription factors and cytokines. The studied compounds might therefore constitute a promising therapeutic strategy in Th17/Treg imbalance-driven inflammatory conditions such as IBD.
Assuntos
Colite , Doenças Inflamatórias Intestinais , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Doenças Inflamatórias Intestinais/tratamento farmacológico , Interleucina-17/metabolismo , Interleucina-23/metabolismo , Interleucina-6/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Oxidiazóis , Prostaglandinas E/efeitos adversos , Ratos , Fator de Transcrição STAT3/metabolismo , Linfócitos T Reguladores/metabolismo , Células Th17/metabolismo , Ácido Trinitrobenzenossulfônico/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
(1) Background: A novel bioreactor platform of neuronal cell cultures using low-magnitude, low-frequency (LMLF) vibrational stimulation was designed to discover vibration influence and mimic the dynamic environment of the in vivo state. To better understand the impact of 40 Hz and 100 Hz vibration on cell differentiation, we join biotechnology and advanced medical technology to design the nano-vibration system. The influence of vibration on the development of nervous tissue on the selected cell line SH-SY5Y (experimental research model in Alzheimer's and Parkinson's) was investigated. (2) Methods: The vibration stimulation of cell differentiation and elongation of their neuritis were monitored. We measured how vibrations affect the morphology and differentiation of nerve cells in vitro. (3) Results: The highest average length of neurites was observed in response to the 40 Hz vibration on the collagen surface in the differentiating medium, but cells response did not increase with vibration frequency. Also, vibrations at a frequency of 40 Hz or 100 Hz did not affect the average density of neurites. 100 Hz vibration increased the neurites density significantly with time for cultures on collagen and non-collagen surfaces. The exposure of neuronal cells to 40 Hz and 100 Hz vibration enhanced cell differentiation. The 40 Hz vibration has the best impact on neuronal-like cell growth and differentiation. (4) Conclusions: The data demonstrated that exposure to neuronal cells to 40 Hz and 100 Hz vibration enhanced cell differentiation and proliferation. This positive impact of vibration can be used in tissue engineering and regenerative medicine. It is planned to optimize the processes and study its molecular mechanisms concerning carrying out the research.
Assuntos
Neurônios , Vibração , Ciclo Celular , Diferenciação Celular , Proliferação de CélulasRESUMO
In this study, we investigated the influence of long-term administration of stiripentol on sex hormones and semen quality in young Wistar rats. Investigated animals received for 6 months either stiripentol or saline solution. After one month, stiripentol increased temporarily serum level of testosterone (p < 0.05) and FSH (p < 0.01). However, after 6 months levels of testosterone, FSH, LH, prolactin and SHBG were comparable in both groups. After 6 months, semen analysis did not reveal differences in sperm concentration, total sperm count and sperm motility between groups. However, stiripentol increased the rate of head defect (p < 0.001) and midpiece abnormalities (p < 0.05). Flow cytometry revealed higher percentage of live cells without lipid peroxidation (p < 0.00001) and higher percentage of live spermatozoa with intact acrosomes (p < 0.000001) in rats receiving stiripentol. There was no significant difference between groups in sperm mitochondrial activity and DNA fragmentation index. However, percentage of high DNA stainability cells was increased in stiripentol group (p < 0.001). The data showed that stiripentol does not cause obvious disturbances in young rat's semen. Detected changes in semen morphology and chromatin structure need further explanation, and their influence on rat's fertility should be evaluated.
Assuntos
Análise do Sêmen , Motilidade dos Espermatozoides , Animais , Anticonvulsivantes , Dioxolanos , Hormônio Foliculoestimulante , Humanos , Masculino , Ratos , Ratos Wistar , Sêmen , Contagem de Espermatozoides , Espermatozoides , TestosteronaRESUMO
Nutrition determines our health, both directly and indirectly. Consumed foods affect the functioning of individual organs as well as entire systems, e.g., the cardiovascular system. There are many different diets, but universal guidelines for proper nutrition are provided in the WHO healthy eating pyramid. According to the latest version, plant products should form the basis of our diet. Many groups of plant compounds with a beneficial effect on human health have been described. Such groups include anthocyanins and iridoids, for which it has been proven that their consumption may lead to, inter alia, antioxidant, cholesterol and lipid-lowering, anti-obesity and anti-diabetic effects. Transcription factors directly affect a number of parameters of cell functions and cellular metabolism. In the context of lipid and cholesterol metabolism, five particularly important transcription factors can be distinguished: liver X receptor (LXR), peroxisome proliferator-activated receptor-α (PPAR-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), CCAAT/enhancer binding protein α (C/EBPα) and sterol regulatory element-binding protein 1c (SREBP-1c). Both anthocyanins and iridoids may alter the expression of these transcription factors. The aim of this review is to collect and systematize knowledge about the impact of anthocyanins and iridoids on transcription factors crucial for lipid and cholesterol homeostasis.
Assuntos
Antocianinas/farmacologia , Colesterol/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Homeostase , Iridoides/farmacologia , Lipídeos/análise , Fatores de Transcrição/metabolismo , Animais , Humanos , Metabolismo dos Lipídeos , Fatores de Transcrição/genéticaRESUMO
(1) Background: Melanoma is an aggressive neoplasm derived from melanocyte precursors with a high metastatic potential. Responses to chemotherapy and immunotherapy for melanoma remain weak, underlining the urgent need to develop new therapeutic strategies for the treatment of melanoma. (2) Methods: The viability of NHDF and A375 cell cultures after the administration of the tested isoxazole derivatives was assessed after 24-h and 48-h incubation periods with the test compounds in the MTT test. ROS and NO scavenging analyses, a glycoprotein-P activity analysis, a migration assay, a test of apoptosis, and a multiple-criteria decision analysis were also performed. (3) Results: All compounds that were tested resulted in a slower migration of melanoma neoplastic cells. The mechanism of the antitumor activity of the tested compounds was confirmed-i.e., the pro-apoptotic activity of the compounds in A375 cell cultures. Compound O7K qualified for further research. (4) Conclusions: All the tested compounds inhibited the formation of melanoma metastases and demonstrated the ability to reduce the risk of developing drug resistance in the tumor. The MCDA results showed that O7K showed the strongest antitumor activity.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Isoxazóis/química , Antineoplásicos/química , Antioxidantes/química , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Glicoproteínas/metabolismo , Humanos , Isoxazóis/farmacologia , Melanoma/metabolismo , Melanoma/patologia , Espécies Reativas de Oxigênio/química , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
Hydroxyapatite has been used in medicine for many years as a biomaterial or a cover for other biomaterials in orthopedics and dentistry. This study characterized the physicochemical properties (structure, particle size and morphology, surface properties) of Li+- and Li+/Eu3+-doped nanohydroxyapatite obtained using the wet chemistry method. The potential regenerative properties against neurite damage in cultures of neuron-like cells (SH-SY5Y and PC12 after differentiation) were also studied. The effect of nanohydroxyapatite (nHAp) on the induction of repair processes in cell cultures was assessed in tests of metabolic activity, the level of free oxygen radicals and nitric oxide, and the average length of neurites. The study showed that nanohydroxyapatite influences the increase in mitochondrial activity, which is correlated with the increase in the length of neurites. It has been shown that the doping of nanohydroxyapatite with Eu3+ ions enhances the antioxidant properties of the tested nanohydroxyapatite. These basic studies indicate its potential application in the treatment of neurite damage. These studies should be continued in primary neuronal cultures and then with in vivo models.
Assuntos
Materiais Biocompatíveis/farmacologia , Durapatita/farmacologia , Nanopartículas/administração & dosagem , Regeneração Nervosa , Neuroblastoma/tratamento farmacológico , Nervos Periféricos/citologia , Animais , Humanos , Técnicas In Vitro , Nanopartículas/química , Neuroblastoma/patologia , Células PC12 , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/patologia , Ratos , Propriedades de Superfície , Células Tumorais CultivadasRESUMO
Molecular mechanisms underlying the beneficial effect of sitagliptin repurposed for hepatic ischemia-reperfusion injury (IRI) are poorly understood. We aimed to evaluate the impact of IRI and sitagliptin on the hepatic profile of eicosanoids (LC-MS/MS) and expression/concentration (RTqPCR/ELISA) of GLP-1/GLP-1R, SDF-1α/CXCR4 and VIP/VPAC1, VPAC2, and PAC1 in 36 rats. Animals were divided into four groups and subjected to ischemia (60 min) and reperfusion (24 h) with or without pretreatment with sitagliptin (5 mg/kg) (IR and SIR) or sham-operated with or without sitagliptin pretreatment (controls and sitagliptin). PGI2, PGE2, and 13,14-dihydro-PGE1 were significantly upregulated in IR but not SIR, while sitagliptin upregulated PGD2 and 15-deoxy-12,14-PGJ2. IR and sitagliptin non-significantly upregulated GLP-1 while Glp1r expression was borderline detectable. VIP concentration and Vpac2 expression were downregulated in IR but not SIR, while Vpac1 was significantly downregulated solely in SIR. IRI upregulated both CXCR4 expression and concentration, and sitagliptin pretreatment abrogated receptor overexpression and downregulated Sdf1. In conclusion, hepatic IRI is accompanied by an elevation in proinflammatory prostanoids and overexpression of CXCR4, combined with downregulation of VIP/VPAC2. Beneficial effects of sitagliptin during hepatic IRI might be mediated by drug-induced normalization of proinflammatory prostanoids and upregulation of PGD2 and by concomitant downregulation of SDF-1α/CXCR4 and reinstating VIP/VCAP2 signaling.
Assuntos
Hepatopatias/tratamento farmacológico , Prostaglandinas/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Fosfato de Sitagliptina/administração & dosagem , Animais , Quimiocina CXCL12/genética , Cromatografia Líquida , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatopatias/etiologia , Ratos , Receptores CXCR4/genética , Receptores Tipo II de Peptídeo Intestinal Vasoativo/genética , Traumatismo por Reperfusão/complicações , Transdução de Sinais/efeitos dos fármacos , Fosfato de Sitagliptina/farmacologia , Espectrometria de Massas em Tandem , Peptídeo Intestinal Vasoativo/genéticaRESUMO
Bone structure abnormalities are increasingly observed in patients chronically treated with antiepileptic drugs (AEDs). The majority of the available data concern older conventional AEDs, while the amount of information regarding newer AEDs, including stiripentol, is limited. The aim of the study was to assess the effect of stiripentol on bones. For 24 weeks, male Wistar rats, received 0.9% sodium chloride (control group) or stiripentol (200 mg/kg/day) (STP group). In the 16th week of the study, we detected lower serum PINP levels in the STP group compared to the control group. In the 24th week, a statistically significant lower 1,25-dihydroxyvitamin D3 level, higher inorganic phosphate level and higher neutrophil gelatinase-associated lipocalin (NGAL) levels in serum were found in the STP group compared to the control. Micro X-ray computed tomography of the tibias demonstrated lower bone volume fraction, lower trabecular thickness, higher trabecular pattern factor and a higher structure model index in the stiripentol group. Considering the results of this experiment on rats which suggests that long-term administration of stiripentol may impair the cancellous bone microarchitecture, further prospective human studies seem to be justified. However, monitoring plasma vitamin D, calcium, inorganic phosphate and kidney function in patients on long-term stiripentol therapy may be suggested.
Assuntos
Anticonvulsivantes/efeitos adversos , Osso e Ossos/efeitos dos fármacos , Dioxolanos/efeitos adversos , Animais , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/diagnóstico por imagem , Masculino , Distribuição Aleatória , Ratos Wistar , Microtomografia por Raio-XRESUMO
Despite the availability of the current drug arsenal for pain management, there is still a clinical need to identify new, more effective, and safer analgesics. Based on our earlier study, newly synthesized 1,3,4-oxadiazole derivatives of pyrrolo[3,4-d]pyridazinone, especially 10b and 13b, seem to be promising as potential analgesics. The current study was designed to investigate whether novel derivatives attenuate nociceptive response in animals subjected to thermal or chemical noxious stimulus, and to compare this effect to reference drugs. The antinociceptive effect of novel compounds was studied using the tail-flick and formalin test. Pretreatment with novel compounds at all studied doses increased the latency time in the tail-flick test and decreased the licking time during the early phase of the formalin test. New derivatives given at the medium and high doses also reduced the late phase of the formalin test. The achieved results indicate that new derivatives dose-dependently attenuate nociceptive response in both models of pain and exert a lack of gastrotoxicity. Both studied compounds act more efficiently than indomethacin, but not morphine. Compound 13b at the high dose exerts the greatest antinociceptive effect. It may be due to the reduction of nociceptor sensitization via prostaglandin E2 and myeloperoxidase levels decrease.
Assuntos
Analgésicos/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Nociceptividade/efeitos dos fármacos , Dor Nociceptiva/tratamento farmacológico , Oxidiazóis/química , Piridazinas/química , Pirróis/química , Analgésicos/química , Animais , Dinoprostona/metabolismo , Mucosa Gástrica/patologia , Masculino , Dor Nociceptiva/metabolismo , Dor Nociceptiva/patologia , Medição da Dor , Peroxidase/metabolismo , Ratos , Ratos WistarRESUMO
BACKGROUND: Inflammatory bowel disease (IBD) [including Crohn's disease (CD) and ulcerative colitis (UC)] constitutes an important clinical problem. The pathogenesis of IBD remains unclear. It is believed that immune dysfunction, inflammatory mediators and oxidative damage play crucial roles in development of IBD. The condition is clinically associated with symptoms ranging from mild to severe during relapses, depending on the affected segment of the gastrointestinal tract. Bloody diarrhea with mucus, abdominal pain, weight loss and anemia are initial symptoms of both CD and UC. Differences between diseases become more evident in time, along with the development of intestinal and extraintestinal complications. Mangiferin (1,3,6,7-tetrahydroxyxanthone-C-2-ß-D-glucoside), a natural polyphenol in plants, exerts antioxidant and anti-inflammatory effects making it an interesting option for the treatment of inflammatory pathologies associated with oxidative stress in humans, such as IBD. PURPOSE: The aim of the current study was to elucidate the impact of mangiferin on colon tissues in 2,4,6-trinitrobenzensulfonic acid (TNBS)-induced colitis in rats. METHODS: Mangiferin was obtained from Belamcanda chinensis rhizomes by a multistage process. Groups of rats were pre-treated with 10, 30 or 100 mg/kg of mangiferin, or with distilled water administered intragastrically for 16 days. An ethanol solution of TNBS or saline was given rectally on the day 15 of the experiment. The experiment was terminated on the day 17. The colon was removed, cleaned, weighed and examined macro- and microscopically. Determination of tumor necrosis factor α (TNF-α), interleukin 17 (IL-17), malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity were performed spectrophotometrically in homogenates of colon tissues. RESULTS: Rats in the TNBS group developed symptoms of colitis, including: body weight loss, colon mass index increase and damage of intestinal tissues with concomitant increase in TNF-α, IL-17, MDA levels and decreased SOD activity. In non-TNBS-treated rats mangiferin did not cause any changes of studied parameters. Pre-treatment with mangiferin exerted a protective effect, reducing the intensity of damage caused by TNBS. Mangiferin at the doses of 30 and 100 mg/kg reduced the macro- and microscopic damage score and the MDA level in colon tissues. Only at the dose of 100 mg/kg, mangiferin decreased TNF-α and IL-17 concentrations, and SOD activity in colon tissues. CONCLUSION: Mangiferin attenuates inflammatory changes of colon tissues in experimental, TNBS-induced colitis in rats. Protective effect exerted by mangiferin depends primarily on its anti-inflammatory activity and secondarily on its antioxidant properties.
Assuntos
Colite/tratamento farmacológico , Iridaceae/química , Extratos Vegetais/farmacologia , Xantonas/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Colite/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: The aim of this study was to assess the influence of propranolol, nebivolol, and carvedilol on intraocular pressure and blood flow in vessels of rabbit's (New Zealand White) eyeball. METHODS: The study was carried out on New Zealand white rabbits. Intraocular pressure was measured with the applanation tonometer Möller-Wedel and Icare; blood flow was measured with Doppler Laser Blood Flow Monitor MBD3. RESULTS: Following a single administration into a conjunctival sac, all drugs decreased intraocular pressure. Iris blood flow was decreased following administration of propranol, but increased by nebivolol and carvedilol. After single and repeated oral administration of nebivolol and carvedilol an IOP decrease was demonstrated, but with no effect of all applied doses on iris or retina/choroid blood flow. CONCLUSION: Studies performed on an animal model indicate that it is possible to reduce the intraocular pressure and increase ocular blood flow in humans, following topical administration of carvedilol and nebivolol. Confirmation of those results in clinical trials may lead to development of a new anti-glaucoma treatment. Further clinical studies of long-term nebivolol and carvedilol are recommended. They are necessary for evaluation of usefulness of those drugs for selected groups of patients, for example those with glaucoma and arterial hypertension.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Anti-Hipertensivos/farmacologia , Benzopiranos/farmacologia , Carbazóis/farmacologia , Etanolaminas/farmacologia , Pressão Intraocular/efeitos dos fármacos , Iris/irrigação sanguínea , Propanolaminas/farmacologia , Administração Oral , Administração Tópica , Antagonistas de Receptores Adrenérgicos beta 1/administração & dosagem , Animais , Anti-Hipertensivos/administração & dosagem , Benzopiranos/administração & dosagem , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Carbazóis/administração & dosagem , Carvedilol , Etanolaminas/administração & dosagem , Feminino , Masculino , Nebivolol , Soluções Oftálmicas , Propanolaminas/administração & dosagem , Propranolol/administração & dosagem , Propranolol/farmacologia , Coelhos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Tonometria OcularRESUMO
This narrative review provides an overview of scientific studies on dietary supplements that may affect circulating testosterone (T) levels to explore which substances are scientifically proven to increase T concentration. We also review the scientific literature for their potential mechanisms and laboratory test changes triggered by their use. Based on the analysis of existing data on substances used to increase endogenous T levels, especially double-blind placebo-controlled randomized clinical trials, we selected 2 herbal extracts with the best documented positive effects on T levels, Withania somnifera root and root extracts/leaves and seed extracts of Trigonella foenum-graecum. Although these substances have different postulated mechanisms of action, both significantly increase T levels in men. Withania somnifera may inhibit the effects of cortisol and prolactin on the hypothalamic-pituitary-gonadal axis and directly affect the hypothalamus. Trigonella foenum-graecum seeds contain the active substance diosgenin, which is a precursor for sex hormone synthesis in gonads.
RESUMO
Background: One factor that may negatively impact male reproductive health is the illegal use of testosterone and anabolic-androgenic steroids. This study aimed to evaluate the prevalence of testosterone use in recreational athletes, as well as factors associated with its use, and to determine the profile of a person using testosterone. Methods: A cross-sectional analysis of data from an anonymous, online questionnaire of men recruited from gyms, randomly selected in Wroclaw, Poland, has been performed. The minimal sample size was evaluated with the univariate logistic regression model. The association between testosterone use and other factors was also evaluated with the univariate logistic regression model. Results: A total of 35% of respondents used testosterone. The main purposes of testosterone use were the improvement of training effects and the improvement of body shape. The respondents most likely to use testosterone and other anabolic-androgenic steroids were men aged 26-35, whose earnings were at the level of the middle class or higher, who were married, had children, had training experience of at least 6 months, exercised at least once a week, took part in weightlifting competitions, were managers in a corporation or enterprise, or were self-employed. Most of the people using testosterone had self-treated side effects. Conclusions: The profile of the person most likely to use testosterone corresponds to the characteristics of men in optimal socio-demographic conditions for reproduction. These results indicate that this is a significant social problem that may impact male reproductive health.
RESUMO
Many studies have proven the involvement of the RhoA/ROCK pathway in autoimmune and cardiovascular diseases and the beneficial effects of its downregulation. Here, we examined whether the effect of simvastatin on experimental autoimmune myocarditis (EAM) may be through targeting the Ras homolog family member A/Rho-associated coiled-coil containing kinases (RhoA/ROCK) pathway and whether previously shown downregulation of metalloproteinase 9 (MMP-9) could be associated with MLC phosphorylation. Two doses of simvastatin were administered to experimental rats with autoimmune myocarditis by gastric gavage for 3 weeks, at the stage of development of the inflammatory process. Immunohistochemical staining for RhoA and ROCK1 was evaluated semi-quantitatively with H-score. The RhoA staining showed no significant differences in expression between the groups, but the ROCK1 expression was significantly upregulated in the hearts of the EAM group and was not downregulated by simvastatin. The Western blotting analysis of the last downstream product of the RhoA/ROCK axis, phosphorylated myosin light chain (phospho-MYL9), revealed that protein content increased in EAM hearts and it was prevented by the highest dose of simvastatin. Our findings suggest that the RhoA/ROCK pathway is upregulated in EAM, and simvastatin in EAM settings inhibits the RhoA/ROCK pathway at the stage of phosphorylation of myosin light chains and provides a new insight into the molecular pathology of autoimmune myocarditis.