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1.
Nat Commun ; 12(1): 5214, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471131

RESUMO

Dyslipidemia and resulting lipotoxicity are pathologic signatures of metabolic syndrome and type 2 diabetes. Excess lipid causes cell dysfunction and induces cell death through pleiotropic mechanisms that link to oxidative stress. However, pathways that regulate the response to metabolic stress are not well understood. Herein, we show that disruption of the box H/ACA SNORA73 small nucleolar RNAs encoded within the small nucleolar RNA hosting gene 3 (Snhg3) causes resistance to lipid-induced cell death and general oxidative stress in cultured cells. This protection from metabolic stress is associated with broad reprogramming of oxidative metabolism that is dependent on the mammalian target of rapamycin signaling axis. Furthermore, we show that knockdown of SNORA73 in vivo protects against hepatic steatosis and lipid-induced oxidative stress and inflammation. Our findings demonstrate a role for SNORA73 in the regulation of metabolism and lipotoxicity.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Substâncias Protetoras/farmacologia , RNA Nucleolar Pequeno/metabolismo , Animais , Células CHO , Morte Celular/efeitos dos fármacos , Cricetulus , Diabetes Mellitus Tipo 2/metabolismo , Fígado Gorduroso/genética , Homeostase , Inflamação , Metabolismo dos Lipídeos , Lipídeos/farmacologia , Masculino , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , RNA Longo não Codificante , RNA Nucleolar Pequeno/genética , Transdução de Sinais/efeitos dos fármacos
2.
Oxid Med Cell Longev ; 2021: 7866992, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34497683

RESUMO

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is posing a great threat to the global economy and public health security. Together with the acknowledged angiotensin-converting enzyme 2, glucose-regulated protein 78, transferrin receptor, AXL, kidney injury molecule-1, and neuropilin 1 are also identified as potential receptors to mediate SARS-CoV-2 infection. Therefore, how to inhibit or delay the binding of SARS-CoV-2 with the abovementioned receptors is a key step for the prevention and treatment of COVID-19. As the third gasotransmitter, hydrogen sulfide (H2S) plays an important role in many physiological and pathophysiological processes. Recently, survivors were reported to have significantly higher H2S levels in COVID-19 patients, and mortality was significantly greater among patients with decreased H2S levels. Considering that the beneficial role of H2S against COVID-19 and COVID-19-induced comorbidities and multiorgan damage has been well-examined and reported in some excellent reviews, this review will discuss the recent findings on the potential receptors of SARS-CoV-2 and how H2S modulates the above receptors, in turn blocking SARS-CoV-2 entry into host cells.


Assuntos
Antivirais/farmacologia , Sulfeto de Hidrogênio/farmacologia , Receptores de Superfície Celular/metabolismo , SARS-CoV-2/metabolismo , Animais , Humanos , Especificidade de Órgãos/efeitos dos fármacos , Substâncias Protetoras/farmacologia , SARS-CoV-2/efeitos dos fármacos
3.
FASEB J ; 35(9): e21842, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34418159

RESUMO

Retinopathy of prematurity (ROP) remains one of the major causes of blindness in children worldwide. While current ROP treatments are mostly disruptive to reduce proliferative neovascularization by targeting the hypoxic phase, protection against early hyperoxia-induced retinal vascular loss represents an effective therapeutic window, but no such therapeutic strategy is available. Built upon our recent demonstration that the protection against oxygen-induced retinopathy by adenosine A2A receptor (A2A R) antagonists is most effective when administered at the hyperoxia (not hypoxic) phase, we here uncovered the cellular mechanism underlying the A2A R-mediated protection against early hyperoxia-induced retinal vascular loss by reversing the inhibition of cellular proliferation via possibly multiple signaling pathways. Specifically, we revealed two distinct stages of the hyperoxia phase with greater cellular proliferation and apoptosis activities and upregulation of adenosine signaling at postnatal 9 day (P9) but reduced cellular activities and adenosine-A2A R signaling at P12. Importantly, the A2A R-mediated protection at P9 was associated with the reversal of hyperoxia-induced inhibition of progenitor cells at the peripheral retina at P9 and of retinal endothelial proliferation at P9 and P12. The critical role of cellular proliferation in the hyperoxia-induced retinal vascular loss was validated by the increased avascular areas by siRNA knockdown of the multiple signaling molecules involved in modulation of cellular proliferation, including activin receptor-like kinase 1, DNA-binding protein inhibitor 1, and vascular endothelial growth factor-A.


Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Proliferação de Células/efeitos dos fármacos , Hiperóxia/metabolismo , Substâncias Protetoras/farmacologia , Receptor A2A de Adenosina/metabolismo , Neovascularização Retiniana , Vasos Retinianos/efeitos dos fármacos , Receptores de Activinas Tipo II/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteína 1 Inibidora de Diferenciação/metabolismo , Camundongos , Neovascularização Patológica , Oxigênio/efeitos adversos , Retina/citologia , Retina/efeitos dos fármacos , Retina/patologia , Vasos Retinianos/citologia , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Retinopatia da Prematuridade/metabolismo , Retinopatia da Prematuridade/patologia , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta2/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Int J Mol Sci ; 22(15)2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34360675

RESUMO

In recent decades, interest in natural compounds has increased exponentially due to their numerous beneficial properties in the treatment of various acute and chronic diseases. A group of plant derivatives with great scientific interest is terpenic compounds. Among the plants richest in terpenes, the genus Ferula L. is one of the most representative, and ferutinin, the most common sesquiterpene, is extracted from the leaves, rhizome, and roots of this plant. As reported in the scientific literature, ferutinin possesses antioxidant and anti-inflammatory properties, as well as valuable estrogenic properties. Neurodegenerative and demyelinating diseases are devastating conditions for which a definite cure has not yet been established. The mechanisms involved in these diseases are still poorly understood, and oxidative stress is considered to be both a key modulator and a common denominator. In the proposed experimental system, co-cultured human neurons (SH-SY5Y) and human oligodendrocytes (MO3.13) were treated with the pro-inflammatory agent lipopolysaccharide at a concentration of 1 µg/mL for 24 h or pretreated with ferutinin (33 nM) for 24 h and subsequently exposed to lipopolysaccharide 1 µg/mL for 24 h. Further studies would, however, be needed to establish whether this natural compound can be used as a support strategy in pathologies characterized by progressive inflammation and oxidative stress phenomena.


Assuntos
Benzoatos/farmacologia , Cicloeptanos/farmacologia , Inflamação/tratamento farmacológico , Lipopolissacarídeos/toxicidade , Neurônios/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Estresse Oxidativo , Sesquiterpenos/farmacologia , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular , Técnicas de Cocultura , Escherichia coli , Humanos , Inflamação/induzido quimicamente , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Substâncias Protetoras/farmacologia
5.
Nutrients ; 13(7)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34371836

RESUMO

Cardiometabolic disorders are among the leading causes of mortality in the human population. Dietary polyphenols exert beneficial effects on cardiometabolic health in humans. Molecular mechanisms, however, are not completely understood. Aiming to conduct in-depth integrative bioinformatic analyses to elucidate molecular mechanisms underlying the protective effects of polyphenols on cardiometabolic health, we first conducted a systematic literature search to identify human intervention studies with polyphenols that demonstrate improvement of cardiometabolic risk factors in parallel with significant nutrigenomic effects. Applying the predefined inclusion criteria, we identified 58 differentially expressed genes at mRNA level and 5 miRNAs, analyzed in peripheral blood cells with RT-PCR methods. Subsequent integrative bioinformatic analyses demonstrated that polyphenols modulate genes that are mainly involved in the processes such as inflammation, lipid metabolism, and endothelial function. We also identified 37 transcription factors that are involved in the regulation of polyphenol modulated genes, including RELA/NFKB1, STAT1, JUN, or SIRT1. Integrative bioinformatic analysis of mRNA and miRNA-target pathways demonstrated several common enriched pathways that include MAPK signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway, focal adhesion, or PPAR signaling pathway. These bioinformatic analyses represent a valuable source of information for the identification of molecular mechanisms underlying the beneficial health effects of polyphenols and potential target genes for future nutrigenetic studies.


Assuntos
Síndrome Metabólica/prevenção & controle , Fenômenos Fisiológicos da Nutrição/genética , Polifenóis/farmacologia , Substâncias Protetoras/farmacologia , Adulto , Fatores de Risco Cardiometabólico , Biologia Computacional , Feminino , Humanos , Masculino , Síndrome Metabólica/genética , MicroRNAs/sangue , Pessoa de Meia-Idade , Nutrigenômica , RNA Mensageiro/sangue , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética
6.
Oxid Med Cell Longev ; 2021: 9932099, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34457120

RESUMO

Oxidative stress, inflammation, and apoptosis are crucial in the pathogenesis of acute liver failure (ALF). 4-Octyl itaconate (OI) showed antioxidative and anti-inflammatory properties in many disease models. However, its role in lipopolysaccharide- (LPS-)/D-galactosamine- (D-GalN-) induced ALF is still not investigated. Here, we established an ALF murine model induced by LPS/D-GalN administration. And we found that OI improved survival rate in the murine ALF model. Our results also showed that OI alleviated LPS/D-GalN-induced hepatic histopathological injury and reduced the serum activities of alanine transaminase and aspartate transaminase. Moreover, OI reduced serum levels of proinflammatory cytokines such as monocyte chemotactic protein-1, tumor necrosis factors-α, and interlukin-6. Additionally, OI mitigated oxidative stress and alleviated lipid peroxidation in a murine model of ALF. This was evaluated by a reduction of thiobarbituric acid reactive substances (TBARS) in liver tissues. In addition, OI increased the ratio of reduced glutathione/oxidized glutathione and the activities of antioxidant enzymes including catalase and superoxide dismutase. Moreover, the apoptosis of hepatocytes in the liver was inhibited by OI. Furthermore, we found that OI inhibited LPS-induced nuclear translocation and activation of factor-kappa B (NF-κB) p65 in macrophages which could be inhibited by OI-induced activation of nuclear factor erythroid-2-related factor (Nrf2) signaling. Additionally, D-GalN-induced reactive oxygen species (ROS) generation and apoptosis in hepatocytes were inhibited by OI-induced activation of Nrf2 signaling. Therefore, the underlying mechanism for OI's protective effect in LPS/D-GalN-induced ALF may be associated with deactivation of NF-κB signaling in macrophages to reduce inflammation and inhibition of ROS-related hepatocyte apoptosis by activating Nrf2. In conclusion, OI showed a protective role in LPS/D-GalN-induced ALF by reducing inflammation, enhancing antioxidant capacity, and inhibiting cell apoptosis.


Assuntos
Apoptose , Galactosamina/toxicidade , Inflamação/prevenção & controle , Lipopolissacarídeos/toxicidade , Falência Hepática Aguda/tratamento farmacológico , Estresse Oxidativo , Succinatos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/genética , NF-kappa B/metabolismo , Substâncias Protetoras/farmacologia , Transdução de Sinais
7.
Molecules ; 26(16)2021 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-34443306

RESUMO

This study aimed to evaluate and compare the effects of co-treatment with purified annatto oil (PAO) or its granules (GRA, Chronic®) with that of testosterone on the orchiectomy-induced osteoporosis in Wistar rats. After surgery, rats were treated from day 7 until day 45 with testosterone only (TES, 7 mg/kg, IM) or TES + PAO or GRA (200 mg/kg, p.o.). The following parameters were evaluated: food/water intake, weight, HDL, LDL, glucose, triglycerides (TG), total cholesterol (TC), alkaline phosphatase levels, blood phosphorus and calcium contents, femur weight, structure (through scanning electron microscopy), and calcium content (through atomic absorption spectrophotometry). Our results show that orchiectomy could significantly change the blood lipid profile and decrease bone integrity parameters. Testosterone reposition alone could improve some endpoints, including LDL, TC, bone weight, and bone calcium concentration. However, other parameters were not significantly improved. Co-treatment with PAO or GRA improved the blood lipid profile and bone integrity more significantly and improved some endpoints not affected by testosterone reposition alone (such as TG levels and trabeculae sizes). The results suggest that co-treatment with annatto products improved the blood lipid profile and the anti-osteoporosis effects of testosterone. Overall, GRA had better results than PAO.


Assuntos
Bixaceae/química , Carotenoides/química , Fêmur/efeitos dos fármacos , Lipídeos/sangue , Orquiectomia , Osteoporose/sangue , Osteoporose/etiologia , Extratos Vegetais/química , Óleos Vegetais/farmacologia , Testosterona/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Fêmur/ultraestrutura , Masculino , Substâncias Protetoras/farmacologia , Ratos Wistar
8.
Int J Mol Sci ; 22(16)2021 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-34445781

RESUMO

The prevalence of chronic kidney disease (CKD) is increasing worldwide, and a close association between acute kidney injury (AKI) and CKD has recently been identified. Black cumin (Nigella sativa) has been shown to be effective in treating various kidney diseases. Accumulating evidence shows that black cumin and its vital compound, thymoquinone (TQ), can protect against kidney injury caused by various xenobiotics, namely chemotherapeutic agents, heavy metals, pesticides, and other environmental chemicals. Black cumin can also protect the kidneys from ischemic shock. The mechanisms underlying the kidney protective potential of black cumin and TQ include antioxidation, anti-inflammation, anti-apoptosis, and antifibrosis which are manifested in their regulatory role in the antioxidant defense system, NF-κB signaling, caspase pathways, and TGF-ß signaling. In clinical trials, black seed oil was shown to normalize blood and urine parameters and improve disease outcomes in advanced CKD patients. While black cumin and its products have shown promising kidney protective effects, information on nanoparticle-guided targeted delivery into kidney is still lacking. Moreover, the clinical evidence on this natural product is not sufficient to recommend it to CKD patients. This review provides insightful information on the pharmacological benefits of black cumin and TQ against kidney damage.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Benzoquinonas/farmacologia , Rim/efeitos dos fármacos , Nigella sativa/química , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Humanos , Transdução de Sinais/efeitos dos fármacos
9.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443417

RESUMO

Sambucus nigra flowers (elderflower) have been widely used in traditional medicine for the relief of early symptoms of common cold. Its chemical composition mainly consists of polyphenolic compounds such as flavonoids, hydroxycinnamic acids, and triterpenes. Although the antioxidant properties of polyphenols are well known, the aim of this study is to assess the antioxidant and protective potentials of Sambucus nigra flowers in the human neuroblastoma (SH-SY5Y) cell line using different in vitro approaches. The antioxidant capacity is first evaluated by the oxygen radical absorbance capacity (ORAC) and the free radical scavenging activity (DPPH) methods. Cell viability is assessed by the crystal violet method; furthermore, the intracellular ROS formation (DCFH-DA method) is determined, together with the effect on the cell antioxidant defenses: reduced glutathione (GSH) and antioxidant enzyme activities (GPx, GR). On the other hand, mTORC1 hyperactivation and autophagy blockage have been associated with an increase in the formation of protein aggregates, this promoting the transference and expansion of neurodegenerative diseases. Then, the ability of Sambucus nigra flowers in the regulation of mTORC1 signaling activity and the reduction in oxidative stress through the activation of autophagy/mitophagy flux is also examined. In this regard, search for different molecules with a potential inhibitory effect on mTORC1 activation could have multiple positive effects either in the molecular pathogenic events and/or in the progression of several diseases including neurodegenerative ones.


Assuntos
Técnicas de Cultura de Células , Degeneração Neural/tratamento farmacológico , Sambucus nigra/química , Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Compostos de Bifenilo/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Flores/química , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Degeneração Neural/patologia , Picratos/química , Extratos Vegetais/farmacologia , Polifenóis/farmacologia , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
Int J Mol Sci ; 22(15)2021 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-34361069

RESUMO

Postmenopausal osteoporosis is closely associated with excessive osteoclast formation and function, resulting in the loss of bone mass. Osteoclast-targeting agents have been developed to manage this disease. We examined the effects of ciclopirox on osteoclast differentiation and bone resorption in vitro and in vivo. Ciclopirox significantly inhibited osteoclast formation from primary murine bone marrow macrophages (BMMs) in response to receptor activator of nuclear factor kappa B ligand (RANKL), and the expression of genes associated with osteoclastogenesis and function was decreased. The formation of actin rings and resorption pits was suppressed by ciclopirox. Analysis of RANKL-mediated early signaling events in BMMs revealed that ciclopirox attenuates IκBα phosphorylation without affecting mitogen-activated protein kinase activation. Furthermore, the administration of ciclopirox suppressed osteoclast formation and bone loss in ovariectomy-induced osteoporosis in mice and reduced serum levels of osteocalcin and C-terminal telopeptide fragment of type I collagen C-terminus. These results indicate that ciclopirox exhibits antiosteoclastogenic activity both in vitro and in vivo and represents a new candidate compound for protection against osteoporosis and other osteoclast-related bone diseases.


Assuntos
Antifúngicos/farmacologia , Reabsorção Óssea/tratamento farmacológico , Ciclopirox/farmacologia , Osteoclastos/citologia , Osteogênese , Ovariectomia/efeitos adversos , Substâncias Protetoras/farmacologia , Animais , Reabsorção Óssea/etiologia , Reabsorção Óssea/patologia , Diferenciação Celular , Células Cultivadas , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoclastos/efeitos dos fármacos , Ligante RANK/genética , Ligante RANK/metabolismo
11.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360581

RESUMO

Ischemic stroke is the third leading cause of death in the world, which accounts for almost 12% of the total deaths worldwide. Despite decades of research, the available and effective pharmacotherapy is limited. Some evidence underlines the beneficial properties of hydrogen sulfide (H2S) donors, such as NaSH, in an animal model of brain ischemia and in in vitro research; however, these data are ambiguous. This study was undertaken to verify the neuroprotective activity of AP39, a slow-releasing mitochondria-targeted H2S delivery molecule. We administered AP39 for 7 days prior to ischemia onset, and the potential to induce brain tolerance to ischemia was verified. To do this, we used the rat model of 90-min middle cerebral artery occlusion (MCAO) and used LC-MS/MS, RT-PCR, LuminexTM assays, Western blot and immunofluorescent double-staining to determine the absolute H2S levels, inflammatory markers, neurotrophic factor signaling pathways and apoptosis marker in the ipsilateral frontal cortex, hippocampus and in the dorsal striatum 24 h after ischemia onset. AP39 (50 nmol/kg) reduced the infarct volume, neurological deficit and reduced the microglia marker (Iba1) expression. AP39 also exerted prominent anti-inflammatory activity in reducing the release of Il-1ß, Il-6 and TNFα in brain areas particularly affected by ischemia. Furthermore, AP39 enhanced the pro-survival pathways of neurotrophic factors BDNF-TrkB and NGF-TrkA and reduced the proapoptotic proNGF-p75NTR-sortilin pathway activity. These changes corresponded with reduced levels of cleaved caspase 3. Altogether, AP39 treatment induced adaptative changes within the brain and, by that, developed brain tolerance to ischemia.


Assuntos
Isquemia Encefálica/prevenção & controle , Sulfeto de Hidrogênio/metabolismo , Infarto da Artéria Cerebral Média/complicações , Mitocôndrias/metabolismo , Compostos Organofosforados/farmacologia , Substâncias Protetoras/farmacologia , Tionas/farmacologia , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Sulfeto de Hidrogênio/análise , Masculino , Mitocôndrias/efeitos dos fármacos , Compostos Organofosforados/administração & dosagem , Substâncias Protetoras/administração & dosagem , Ratos , Ratos Sprague-Dawley , Tionas/administração & dosagem
12.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360588

RESUMO

Spinocerebellar ataxias are a family of fatal inherited diseases affecting the brain. Although specific mutated proteins are different, they may have a common pathogenetic mechanism, such as insufficient glutamate clearance. This function fails in reactive glia, leading to excitotoxicity and overactivation of NMDA receptors. Therefore, NMDA receptor blockers could be considered for the management of excitotoxicity. One such drug, memantine, currently used for the treatment of Alzheimer's disease, could potentially be used for the treatment of other forms of neurodegeneration, for example, spinocerebellar ataxias (SCA). We previously demonstrated close parallels between optogenetically induced cerebellar degeneration and SCA1. Here we induced reactive transformation of cerebellar Bergmann glia (BG) using this novel optogenetic approach and tested whether memantine could counteract changes in BG and Purkinje cell (PC) morphology and expression of the main glial glutamate transporter-excitatory amino acid transporter 1 (EAAT1). Reactive BG induced by chronic optogenetic stimulation presented increased GFAP immunoreactivity, increased thickness and decreased length of its processes. Oral memantine (~90 mg/kg/day for 4 days) prevented thickening of the processes (1.57 to 1.81 vs. 1.62 µm) and strongly antagonized light-induced reduction in their average length (186.0 to 150.8 vs. 171.9 µm). Memantine also prevented the loss of the key glial glutamate transporter EAAT1 on BG. Finally, memantine reduced the loss of PC (4.2 ± 0.2 to 3.2 ± 0.2 vs. 4.1 ± 0.3 cells per 100 µm of the PC layer). These results identify memantine as potential neuroprotective therapeutics for cerebellar ataxias.


Assuntos
Dopaminérgicos/farmacologia , Memantina/farmacologia , Doenças Neurodegenerativas/prevenção & controle , Neuroglia/efeitos dos fármacos , Optogenética/efeitos adversos , Substâncias Protetoras/farmacologia , Células de Purkinje/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Camundongos , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/patologia , Neuroglia/patologia , Células de Purkinje/patologia
13.
Spine (Phila Pa 1976) ; 46(15): E810-E816, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34228691

RESUMO

STUDY DESIGN: An in vivo model to study the effect of an injectable hyaluronic acid (HA) hydrogel following puncture-induced lumbar disc injury in rabbits. OBJECTIVES: The aim of this study was to determine the efficacy of an injectable HA hydrogel to maintain disc height and tissue hydration, promote structural repair, and attenuate inflammation and innervation in the lumbar discs. SUMMARY OF BACKGROUND DATA: Previously, we have demonstrated that HA hydrogel alleviated inflammation, innervation, and pain to promote disc repair. Nevertheless, the effect of an injectable HA hydrogel in the lumbar disc in a weight-bearing animal model was not performed. METHODS: We have adopted a surgically puncture-induced disc injury at lumbar levels in a rabbit model. The discs were grouped into sham, puncture with water injection, and puncture with HA hydrogel injection. Postoperatively, we measured changes in disc height using x-ray. We used magnetic resonance imaging to assess disc degeneration on tissue hydration after euthanasia. Post-mortem, we determined histological changes, innervation (PGP9.5) and inflammation (interleukin [IL]-6, IL-1ß, and tumor necrosis factor [TNF]-α) in the discs. RESULTS: We have demonstrated a significant reduction of disc height and T2/T1ρ mapping with histological evidence of degenerative discs, increase of innervation and inflammation in puncture-induced disc injury over time. In the HA hydrogel group, disc height was increased at weeks four and eight. A slight increase of T2 mapping, but significantly in T1ρ mapping, was observed in the HA hydrogel group at week 8. We observed homogenous NP distribution and organised AF lamellae at week eight and a slight reduced innervation score in the treatment group. HA hydrogel significantly downregulated IL-6 expression at day 1. This, however, was only slightly reduced for IL-1ß and TNF-α. CONCLUSION: An injectable HA hydrogel had the protective effects in suppressing the loss of disc height, promoting tissue hydration for structural repair, and attenuating inflammation and innervation to prevent further disc degeneration.Level of Evidence: N/A.


Assuntos
Ácido Hialurônico , Hidrogéis , Disco Intervertebral , Substâncias Protetoras , Animais , Modelos Animais de Doenças , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/farmacologia , Hidrogéis/administração & dosagem , Hidrogéis/farmacologia , Disco Intervertebral/diagnóstico por imagem , Disco Intervertebral/efeitos dos fármacos , Disco Intervertebral/lesões , Imageamento por Ressonância Magnética , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/farmacologia , Coelhos
14.
Ulus Travma Acil Cerrahi Derg ; 27(4): 389-394, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34212999

RESUMO

BACKGROUND: The free oxygen radicals formed with reperfusion following intestinal ischaemia are extremely toxic for the cells. Glutathione peroxidase, an important enzyme that prevents the formation of reactive oxygen species, requires selenium as a co-factor. This study aims to demonstrate the effects of selenium administration on reducing ischaemia-reperfusion damage. METHODS: In this study, 28 male Wistar rats were separated into four groups. To Groups 3 and 4, sodium selenite at the dose of 10 µg/kg/day was administered intraperitoneally for five days. In Groups 1 and 3, laparotomy was applied, and in Groups 2 and 4, following laparotomy, ischaemia was created by clamping the superior mesenteric artery for 45 mins, then reperfusion was provided for 90 mins. Blood, liver and ileum samples were taken from all the animals for examination of malondialdehyde. For examination of bacterial translocation, liver, spleen and mesenteric lymph node tissue samples were taken. A sample taken from the ileum was examined histopathologically. RESULTS: There was determined to be significantly more bacterial translocation in the mesenteric lymph nodes of the ischaemia-reperfusion group (p<0.05). In the histopathological evaluation, the score in the ischaemia-reperfusion group was significantly higher than the scores in the other groups (p<0.05). Elevated serum, liver and ileum malondialdehyde levels in the ischaemia-reperfusion group were significantly higher than those in the other groups (p<0.05). CONCLUSION: Selenium was seen to have decreased serum and tissue malondialdehyde levels and increased the histopathological damage developing in the intestines with ischaemia-reperfusion and thereby increased bacterial translocation.


Assuntos
Translocação Bacteriana/efeitos dos fármacos , Isquemia Mesentérica , Traumatismo por Reperfusão , Selênio/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Substâncias Protetoras/farmacologia , Ratos , Ratos Wistar
15.
Ulus Travma Acil Cerrahi Derg ; 27(4): 402-409, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34213002

RESUMO

BACKGROUND: The increase in free oxygen radicals and proinflammatory cytokines in the ischemia-reperfusion injury caused by acute mesenteric ischemia are the key responsibilities of intestinal histopathological alterations. It has been reported that Ficus carica and its various parts contain antioxidant and anti-inflammatory compounds recently. Thus, in the present study, we aimed to investigate how Ficus carica seed oil affects intestinal ischemia-reperfusion injury in a rat model. METHODS: In this study, 50 male Wistar albino rats were randomly divided into five equal groups. Negative control (NC), sham-operated (Sham), ischemia and reperfusion (IR), 3 ml/kg/day Ficus carica seed oil (FC3), 6 ml/kg/day Ficus carica seed oil (FC6). IR, FC3 and FC6 groups underwent ischemia and reperfusion procedure for 45+120 min. Only abdominal midline laparotomy was performed in the Sham group for 165 minutes. RESULTS: Tissue levels of TNFα and IL-1ß, which were proinflammatory cytokines, were significantly reduced in the FC6 group than the IR group (p<0.05). In FC3 and FC6 groups, the tissue MPO and MDA enzyme levels were significantly lower than the IR group, but there was a significantly greater decrease in the FC6 group than the FC3 group (p<0.05). SOD and CAT enzymes and reduced glutathione levels of FC3 and FC6 groups were significantly lower than IR group (p<0.05); however, there was no statistically significant difference between the FC3 and FC6 groups. FC3 and FC6 groups were histopathologically graded statistically lower than the IR group, and the FC6 group showed a significant decrease than the FC3 group (p<0.05). CONCLUSION: Oral administration of fig seed oil may reverse biochemical and histopathological findings resulting from ischemia-reperfusion injury in an experimental model of acute mesenteric ischemia in rats, probably because of its antioxidant and anti-inflammatory compounds.


Assuntos
Isquemia Mesentérica , Óleos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão , Animais , Masculino , Ratos , Ratos Wistar , Sementes/química
16.
Ulus Travma Acil Cerrahi Derg ; 27(4): 381-388, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34213003

RESUMO

BACKGROUND: Ischemia-reperfusion injury (IRI) is cellular damage that emerges from re-oxygenation of a hypoxic organ. In the present study, we aimed to examine the effects of a combination of levosimendan, an inotropic agent, and N-Acetylcysteine, the precursor of antioxidants and glutathione, in an experimental liver IRI model. METHODS: In this study, 38 rats were randomly divided into five groups. Before the ischemia, study arms were given physiological saline solution, N-Acetylcysteine (NAS), levosimendan or a combination of NAS+levosimendan in a predetermined amount and duration, and the infusion was continued until the end of this study. The hepatic pedicle was occluded using an atraumatic vein clamp, and 60 minutes of ischemia was achieved. The clamp was then opened and 60 minutes of reperfusion was ensured. Liver tissue samples were obtained after sacrifice, and tissue malondialdehyde (MDA) and myeloperoxidase (MPO) levels were determined. Serum Tumor Necrosis Factor (TNF)-α, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and MPO levels of blood samples were also measured. RESULTS: Among the histopathological changes in the liver tissue after IRI, differences between groups were statistically significant in the injury scoring system based on congestion, vacuolization and necrosis levels. Histopathological injury score, plasma MPO, AST, ALT, tissue MPO and tissue MDA values were statistically significantly lower in the treatment groups, prominently in the levosimendan and NAS combination group concerning liver histopathological damage. CONCLUSION: The use of a levosimendan plus NAS combination in liver IRI markedly suppressed inflammation and oxidative stress and significantly reduced liver ischemia-reperfusion injury and can be recommended for decreasing IRI instead of single agent use of levosimendan or NAS.


Assuntos
Acetilcisteína/farmacologia , Hepatopatias/metabolismo , Fígado , Traumatismo por Reperfusão/metabolismo , Simendana/farmacologia , Animais , Fígado/efeitos dos fármacos , Fígado/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Ratos
17.
Mol Med Rep ; 23(5)2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34240225

RESUMO

Tracheal stenosis following injury cannot be effectively treated. The current study compared the protective effects of different anti­inflammatory drugs on tracheal stenosis and investigated their possible mechanisms. Rabbit tracheal stenosis models following injury were constructed and confirmed using hematoxylin and eosin (H&E) staining. A total of 30 rabbits were divided into the control (CON), penicillin (PEN), erythromycin (ERY), budesonide (BUD) and PEN + ERY + BUD groups (n=6). Stenotic tracheal tissue, serum and bronchoalveolar lavage fluid (BALF) were collected 10 days after continuous treatment. Pathological changes in the tracheas were observed by H&E staining. Histone deacetylase 2 (HDAC2) expression in tracheal tissues was detected by immunofluorescence. Immunohistochemistry was performed to detect collagen I (Col­I) and collagen III (Col­III) levels in tracheal tissues. Transforming growth factor ß1 (TGF­ß1), vascular endothelial growth factor (VEGF) and interleukin 8 (IL­8) levels in serum and BALF samples were determined using ELISA kits. Western blotting detected HDAC2, IL­8, TGF­ß1 and VEGF levels in tracheal tissues. H&E staining demonstrated that tracheal epithelial hyperplasia and fibroblast proliferation in the ERY and PEN + ERY + BUD groups markedly improved compared with the CON group. Furthermore, in tracheal tissues, HDAC2 expression was significantly increased and IL­8, TGF­ß1, VEGF, Col­I and Col­III levels were significantly decreased in the ERY and PEN + ERY + BUD groups compared with the CON group. Additionally, the results for the PEN + ERY + BUD were more significant compared with the ERY group. In serum and BALF samples, IL­8, TGF­ß1 and VEGF levels in the ERY and PEN + ERY + BUD groups were significantly lower compared with the CON group, with the results of the PEN + ERY + BUD group being more significant compared with the ERY group. There were no significant differences between the PEN, BUD and CON groups. ERY inhibited tracheal granulation tissue proliferation and improved tracheal stenosis following injury and synergistic effects with PEN and BUD further enhanced these protective effects. The mechanism may involve HDAC2 upregulation and inhibition of local airway and systemic inflammatory responses.


Assuntos
Anti-Inflamatórios/uso terapêutico , Budesonida/uso terapêutico , Eritromicina/uso terapêutico , Penicilinas/uso terapêutico , Substâncias Protetoras/uso terapêutico , Estenose Traqueal/metabolismo , Estenose Traqueal/prevenção & controle , Animais , Anti-Inflamatórios/farmacologia , Líquido da Lavagem Broncoalveolar/química , Budesonida/farmacologia , Colágeno/metabolismo , Modelos Animais de Doenças , Eritromicina/farmacologia , Tecido de Granulação/efeitos dos fármacos , Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismo , Hiperplasia/tratamento farmacológico , Hiperplasia/metabolismo , Interleucina-8/sangue , Interleucina-8/metabolismo , Penicilinas/farmacologia , Substâncias Protetoras/farmacologia , Coelhos , Traqueia/lesões , Traqueia/patologia , Estenose Traqueal/etiologia , Estenose Traqueal/patologia , Fator de Crescimento Transformador beta1/sangue , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
Biomolecules ; 11(7)2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209255

RESUMO

Various environmental stimuli, including oxidative stress, could lead to granulosa cell (GC) death through mitophagy. Recently, it was reported that melatonin (MEL) has a significant effect on GC survival during oxidative damage. Here, we found that MEL inhibited oxidative stress-induced mitophagy to promote GC survival. The loss of cell viability upon H2O2 exposure was significantly restored after MEL treatment. Concomitantly, MEL inhibited the activation of mitophagy during oxidative stress. Notably, blocking mitophagy repressed GC death caused by oxidative stress. However, MEL cannot further restore viability of cells treated with mitophagy inhibitor. Moreover, PTEN-induced putative kinase 1 (PINK1), a mitochondrial serine/threonine-protein kinase, was inhibited by MEL during oxidative stress. As a result, the E3 ligase Parkin failed to translocate to mitochondria, leading to impaired mitochondria clearance. Using RNAi to knock down PINK1 expression, we further verified the role of the MEL-PINK1-Parkin (MPP) pathway in maintaining GC survival by suppressing mitophagy. Our findings not only clarify the protective mechanisms of MEL against oxidative damage in GCs, but also extend the understanding about how circadian rhythms might influence follicles development in the ovary. These findings reveal a new mechanism of melatonin in defense against oxidative damage to GCs by repressing mitophagy, which may be a potential therapeutic target for anovulatory disorders.


Assuntos
Células da Granulosa/metabolismo , Melatonina/farmacologia , Mitofagia/fisiologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Feminino , Células da Granulosa/fisiologia , Peróxido de Hidrogênio/farmacologia , Masculino , Melatonina/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias/metabolismo , Mitofagia/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Substâncias Protetoras/farmacologia , Proteínas Quinases/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
19.
J Photochem Photobiol B ; 221: 112246, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34243023

RESUMO

Photo-oxidative skin damage is mainly caused by the UV-A radiation of the sun. Synthetic sunscreens used to counter this acts mostly on the superficial skin layer and possess serious side effects. P-coumaric acid (PCA) is a UV-A protective plant phenolic having quick diffusion and distribution in superficial skin layers limiting its application as herbal sunscreen. The present study was designed to formulate an optimized phospholipid complex of PCA (PCAPC) through response surface methodology to enhance its skin permeation to deeper skin layers providing protection against photo-oxidative stress. PCAPC was characterized by FT-IR, DTA, PXRD, TEM, zeta potential etc. PCAPC was then incorporated into a gel formulation (PCAPC-GE) to facilitate its transdermal delivery. Physicochemical properties of the gel were assessed by pH, homogeneity, rheology, spreadability etc. In-vitro SPF and UVA-PF of the gel was evaluated and compared with conventional gel (PCA-GE). Ex-vivo skin permeation flux, permeability coefficient, skin deposition and dermatokinetic analysis were carried out to measure the rate and level of skin permeation. This was accompanied by in-vivo evaluation of PCAPC-GE and PCA-GE in the experimental rat model by measuring the various oxidative stress markers such as superoxide dismutase, catalase etc. PCAPC-GE provided high SPF and UVA-PF value compared to PCA-GE. The physicochemical parameters were suitable for transdermal application. PCAPC-GE enhanced the permeation rate of PCA by almost 6 fold compared to PCA-GE. Besides, a significant reduction of UV-A induced oxidative stress biomarkers were observed for PCAPC-GE. Thus, the PCAPC-GE may be an effective alternative of synthetic sunscreens due to its enhanced permeation and protection against UVA-induced oxidative stress.


Assuntos
Ácidos Cumáricos/química , Géis/química , Estresse Oxidativo/efeitos dos fármacos , Fosfolipídeos/química , Substâncias Protetoras/farmacologia , Raios Ultravioleta , Animais , Estabilidade de Medicamentos , Masculino , Estresse Oxidativo/efeitos da radiação , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , Permeabilidade/efeitos da radiação , Substâncias Protetoras/química , Substâncias Protetoras/metabolismo , Ratos , Ratos Wistar , Reologia , Pele/efeitos dos fármacos , Pele/metabolismo , Pele/efeitos da radiação , Solubilidade , Fator de Proteção Solar , Temperatura de Transição
20.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299209

RESUMO

Misfolded amyloid beta (Aß) peptides aggregate and form neurotoxic oligomers. Membrane and mitochondrial damages, calcium dysregulation, oxidative stress, and fibril deposits are among the possible mechanisms of Aß cytotoxicity. Galantamine (GAL) prevents apoptosis induced by Aß mainly through the ability to stimulate allosterically the α7 nAChRs and to regulate the calcium cytosolic concentration. Here, we examined the cytoprotective effects of two GAL derivatives, namely compounds 4b and 8, against Aß cytotoxicity on the human neuroblastoma cell line SH-SY5Y. The protective effects were tested at simultaneous administration, pre-incubation and post-incubation, with Aß. GAL and curcumin (CU) were used in the study as reference compounds. It was found that 4b protects cells in a similar mode as GAL, while compound 8 and CU potentiate the toxic effects of Aß. Allosteric stimulation of α7 nAChRs is suggested as a possible mechanism of the cytoprotectivity of 4b. These and previous findings characterize 4b as a prospective non-toxic multi-target agent against neurodegenerative disorders with inhibitory activity on acetylcholinesterase, antioxidant, and cytoprotective properties.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Antioxidantes/farmacologia , Inibidores da Colinesterase/farmacologia , Curcumina/química , Galantamina/química , Neuroblastoma/tratamento farmacológico , Substâncias Protetoras/farmacologia , Acetilcolinesterase/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antioxidantes/química , Inibidores da Colinesterase/química , Curcumina/farmacologia , Citoproteção , Galantamina/farmacologia , Humanos , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Substâncias Protetoras/química , Células Tumorais Cultivadas
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