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1.
EXCLI J ; 23: 491-508, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38741725

RESUMO

Alzheimer's disease remains an issue of great controversy due to its pathology. It is characterized by cognitive impairments and neuropsychiatric symptoms. The FDA approved medications for this disease, can only mitigate the symptoms. One reason for the lack of effective medications is the inaccessibility of the brain which is encompassed by the blood-brain barrier, making intranasal (IN) route of administration potentially advantageous. Male Wistar rats underwent stereotaxic surgery to induce an Alzheimer's disease model via intracerebroventricular (ICV) streptozotocin injection, and Carbamylated Erythropoietin-Fc (CEPO-FC), a derivative of Erythropoietin without its harmful characteristics, was administered intranasally for ten consecutive days. Cognition performance for memory and attention was assessed using the Novel Object Recognition Test and the Object-Based Attention Test respectively. Depression like behavior was evaluated using the Forced Swim Test. Western blotting was done on the extracted hippocampus to quantify STIM proteins. Calbindin, PSD-95, Neuroplastin, Synaptophysin and GAP-43 genes were assessed by Realtime PCR. Behavioral tests demonstrated that IN CEPO-FC could halt cognition deficits and molecular investigations showed that, STIM proteins were decreased in Alzheimer's model, and increased after IN CEPO-FC treatment. Calbindin and PSD-95 were downregulated in our disease model and upregulated when treated with IN CEPO-FC. While Neuroplastin, and GAP-43 expressions remained unchanged. This study suggests that IN CEPO-FC in low doses could be promising for improving cognition and synaptic plasticity deficits in Alzheimer's disease and since IN route of administration is a convenient way, choosing IN CEPO-FC for clinical trial might worth consideration. See also the graphical abstract(Fig. 1).

2.
Genome Med ; 16(1): 46, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38584274

RESUMO

BACKGROUND: Genome sequencing of large biobanks from under-represented ancestries provides a valuable resource for the interrogation of Mendelian disease burden at world population level, complementing small-scale familial studies. METHODS: Here, we interrogate 6045 whole genomes from Qatar-a Middle Eastern population with high consanguinity and understudied mutational burden-enrolled at the national Biobank and phenotyped for 58 clinically-relevant quantitative traits. We examine a curated set of 2648 Mendelian genes from 20 panels, annotating known and novel pathogenic variants and assessing their penetrance and impact on the measured traits. RESULTS: We find that 62.5% of participants are carriers of at least 1 known pathogenic variant relating to recessive conditions, with homozygosity observed in 1 in 150 subjects (0.6%) for which Peninsular Arabs are particularly enriched versus other ancestries (5.8-fold). On average, 52.3 loss-of-function variants were found per genome, 6.5 of which affect a known Mendelian gene. Several variants annotated in ClinVar/HGMD as pathogenic appeared at intermediate frequencies in this cohort (1-3%), highlighting Arab founder effect, while others have exceedingly high frequencies (> 5%) prompting reconsideration as benign. Furthermore, cumulative gene burden analysis revealed 56 genes having gene carrier frequency > 1/50, including 5 ACMG Tier 3 panel genes which would be candidates for adding to newborn screening in the country. Additionally, leveraging 58 biobank traits, we systematically assess the impact of novel/rare variants on phenotypes and discover 39 candidate large-effect variants associating with extreme quantitative traits. Furthermore, through rare variant burden testing, we discover 13 genes with high mutational load, including 5 with impact on traits relevant to disease conditions, including metabolic disorder and type 2 diabetes, consistent with the high prevalence of these conditions in the region. CONCLUSIONS: This study on the first phase of the growing Qatar Genome Program cohort provides a comprehensive resource from a Middle Eastern population to understand the global mutational burden in Mendelian genes and their impact on traits in seemingly healthy individuals in high consanguinity settings.


Assuntos
Diabetes Mellitus Tipo 2 , Recém-Nascido , Humanos , Bancos de Espécimes Biológicos , Frequência do Gene , Fenótipo , Homozigoto
3.
Mol Neurobiol ; 2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38368286

RESUMO

Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by memory impairment and a progressive decline in cognitive function. Mitochondrial dysfunction has been identified as an important contributor to the development of AD, leading to oxidative stress and energy deficits within the brain. While current treatments for AD aim to alleviate symptoms, there is an urgent need to target the underlying mechanisms. The emerging field of mitotherapy, which involves the transplantation of healthy mitochondria into damaged cells, has gained substantial attention and has shown promising results. However, research in the context of AD remains limited, necessitating further investigations. In this review, we summarize the mitochondrial pathways that contribute to the progression of AD. Additionally, we discuss mitochondrial transfer among brain cells and mitotherapy, with a focus on different administration routes, various sources of mitochondria, and potential modifications to enhance transplantation efficacy. Finally, we review the limited available evidence regarding the immune system's response to mitochondrial transplantation in damaged brain regions.

4.
Cancer Metastasis Rev ; 43(1): 261-292, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38169011

RESUMO

Plasticity of phenotypic traits refers to an organism's ability to change in response to environmental stimuli. As a result, the response may alter an organism's physiological state, morphology, behavior, and phenotype. Phenotypic plasticity in cancer cells describes the considerable ability of cancer cells to transform phenotypes through non-genetic molecular signaling activities that promote therapy evasion and tumor metastasis via amplifying cancer heterogeneity. As a result of metastable phenotypic state transitions, cancer cells can tolerate chemotherapy or develop transient adaptive resistance. Therefore, new findings have paved the road in identifying factors and agents that inhibit or suppress phenotypic plasticity. It has also investigated novel multitargeted agents that may promise new effective strategies in cancer treatment. Despite the efficiency of conventional chemotherapeutic agents, drug toxicity, development of resistance, and high-cost limit their use in cancer therapy. Recent research has shown that small molecules derived from natural sources are capable of suppressing cancer by focusing on the plasticity of phenotypic responses. This systematic, comprehensive, and critical review analyzes the current state of knowledge regarding the ability of phytocompounds to target phenotypic plasticity at both preclinical and clinical levels. Current challenges/pitfalls, limitations, and future perspectives are also discussed.


Assuntos
Transição Epitelial-Mesenquimal , Neoplasias , Humanos , Transição Epitelial-Mesenquimal/fisiologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Transdução de Sinais , Adaptação Fisiológica , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico
5.
Behav Brain Res ; 452: 114585, 2023 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-37467964

RESUMO

Parkinson's disease (PD) is a progressive and debilitating neurodegenerative disorder associated with motor and non-motor complaints. Dysregulation of neurotrophic factors and related signaling cascades have been reported to be common events in PD which is accompanied by dopaminergic (DA) neuron demise. However, the restoration of neurotrophic factors has several limitations. Bis-(N-monosuccinyl-L-methionyl-L-serine) heptamethylenediamide (BHME) is a dipeptide mimetic of brain-derived neurotrophic factor (BDNF) with reported anti-oxidant and neuroprotective effects in several experimental models. The current study has investigated the effect of BHME on 6-hydroxydopamine (6-OHDA)-caused motor anomalies in Wistar rats. In this regard, rats were treated daily with BHME (0.1 or 1 mg/kg) 1 h after 6-OHDA-caused damage until the twelfth day. Afterwards, motor behavior and DA neuron survival were evaluated via behavioral tests and immunohistochemistry (IHC) staining, respectively. Moreover, the activity of Akt, mitogen-activated protein kinases (MAPKs) family, and Bax/Bcl-2 ratio were evaluated by Western blotting. Our results indicated that BHME prevents motor dysfunction and DA cell death following 6-OHDA injection, and this improvement was in parallel with an enhancement in Akt activity, decrement of P38 phosphorylation, along with a reduction in Bax/Bcl-2 ratio. In conclusion, our findings indicated that BHME, as a mimetic of BDNF, can be considered for further research and is a promising therapeutic agent for PD therapy.


Assuntos
Fármacos Neuroprotetores , Doença de Parkinson , Ratos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Oxidopamina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Dipeptídeos/farmacologia , Dipeptídeos/metabolismo , Dipeptídeos/uso terapêutico , Proteína X Associada a bcl-2/metabolismo , Ratos Wistar , Apoptose , Neurônios Dopaminérgicos , Fármacos Neuroprotetores/uso terapêutico , Substância Negra/metabolismo
6.
Naunyn Schmiedebergs Arch Pharmacol ; 396(11): 3075-3086, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37145127

RESUMO

Spinal cord edema is a quick-onset phenomenon with long-term effects. This complication is associated with inflammatory responses, as well as poor motor function. No effective treatment has been developed against spinal edema, which urges the need to provide novel therapies. Astaxanthin (AST) is a fat-soluble carotenoid with anti-inflammatory effects and a promising candidate for treating neurological disorders. This study aimed to investigate the underlying mechanism of AST on the inhibition of spinal cord edema, astrocyte activation, and reduction of inflammatory responsesin a rat compression spinal cord injury (SCI) model. Male rats underwent laminectomy at thoracic 8-9, and the SCI model was induced using an aneurysm clip. After SCI, rats received dimethyl sulfoxide or AST via intrathecal injection. The effects of AST were examined on the motor function, spinal cord edema, integrity of blood-spinal cord barrier (BSCB), and expression of high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), glial fibrillary acidic protein (GFAP), and aquaporin-4 (AQP4), and matrix metallopeptidase- 9 (MMP-9) post-SCI. We showed that AST potentially improved the recovery of motor function and inhibited the spinal cord edema via maintaining the integrity of BSCB, reducing the expression of HMGB1, TLR4, and NF-κB, MMP-9 as well as downregulation of astrocyte activation (GFAP) and AQP4 expression. AST improves motor function and reduces edema and inflammatory responses in the spinal tissue. These effects are mediated by suppression of the HMGB1/TLR4/NF-κB signaling pathway, suppressing post-SCI astrocyte activation, and decreasing AQP4 and MMP-9 expression.


Assuntos
Antioxidantes , Astrócitos , Proteína HMGB1 , Traumatismos da Medula Espinal , Animais , Masculino , Ratos , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Edema/tratamento farmacológico , Edema/metabolismo , Proteína HMGB1/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , NF-kappa B/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Medula Espinal/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Receptor 4 Toll-Like/metabolismo , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Modelos Animais de Doenças , Injeções Espinhais
7.
Clin Nutr ESPEN ; 54: 227-238, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36963867

RESUMO

BACKGROUND AND AIM: Several studies have been conducted to evaluate the effect of N-acetylecysteine (NAC) supplementation on antioxidant status, while no dose-response meta-analysis summarized the efficacy of NAC supplementation. METHODS: The systematic search of literatures was conducted on Scopus, PubMed, Embase, Web of Science electronic databases. Controlled clinical trials investigating the effects of NAC on antioxidant biomarkers were included in the current meta-analysis. Random-effect model was used to perform meta-analysis. Heterogeneity was examined using I2 index. Subgroup analysis was carried out to find the possible sources of heterogeneity. Dose-response analysis was performed to find the non-linear relationships between effect size and independent variables. RESULTS: Overall, 26 eligible studies were included in the review. NAC supplementation significantly increased TAC (SMD = 0.77 µmol/L; 95% CI: 0.38, 1.16; p < 0.001), GSH (SMD = 0.80 nmol/ml; 95% CI:0.25, 1.34; p = 0.004) and CAT (SMD = -0.57 IU/L; 95% CI:-1.13, -0.02; p = 0.042) levels. However, no significant improving effect was observed in terms of GR (SMD = 0.25 IU/g; 95% CI:-0.14, 0.63; p = 0.210), SOD (SMD = 0.14 U/ml; 95% CI:-0.20, 0.49; p = 0.414) and GPx (SMD = 0.19 IU/g; 95% CI:-0.48, 0.86; p = 0.576) levels. Furthermore, dose-response analysis show that NAC supplementation in participants with mean age up to 30 years had more robust effect on increasing GSH levels. CONCLUSION: We found a significant effect of NAC supplementation on TAC, GSH, CAT in adults. Overall, NAC could be considered as a potent agent in enhancing antioxidant capacity.


Assuntos
Antioxidantes , Suplementos Nutricionais , Antioxidantes/farmacologia , Estresse Oxidativo , Biomarcadores/metabolismo
8.
Brief Funct Genomics ; 22(2): 143-160, 2023 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-36722043

RESUMO

Neurodegenerative diseases (NDDs) are on the rise in the world. Therefore, it is a critical issue to reveal the precise pathophysiological mechanisms and novel therapeutic strategies to deal with such conditions. Passing through different mechanisms, non-coding RNAs (ncRNAs) play a pivotal role in NDDs through various mechanisms, by changing the expression of some genes, interference with protein translation and alterations in some signaling pathways. It urges the need to introduce novel strategies and therapeutic agents with multi-targeting potentials. Phytochemicals are hopeful antioxidants and anti-inflammatory agents with promising modulatory roles on dysregulated signaling pathways and protein translation during NDDs. In this study, the role of ncRNAs (e.g. lncRNAs, miRNA, siRNAs and piRNAs) was highlighted in NDDs. This study also aimed to investigate the role of phytochemicals (phenolic compounds, alkaloids, terpenoids and sulfur compounds) in the modulation of ncRNAs during NDDs such as Alzheimer's disease, Parkinson's disease, epilepsy, depression and amyotrophic lateral sclerosis.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , RNA não Traduzido/genética , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico
9.
Cell Genom ; 3(1): 100218, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36777185

RESUMO

Natural human knockouts of genes associated with desirable outcomes, such as PCSK9 with low levels of LDL-cholesterol, can lead to the discovery of new drug targets and treatments. Rare loss-of-function variants are more likely to be found in the homozygous state in consanguineous populations, and deep molecular phenotyping of blood samples from homozygous carriers can help to discriminate between silent and functional variants. Here, we combined whole-genome sequencing with proteomics and metabolomics for 2,935 individuals from the Qatar Biobank (QBB) to evaluate the power of this approach for finding genes of clinical and pharmaceutical interest. As proof-of-concept, we identified a homozygous carrier of a very rare PCSK9 variant with extremely low circulating PCSK9 levels and low LDL. Our study demonstrates that the chances of finding such variants are about 168 times higher in QBB compared with GnomAD and emphasizes the potential of consanguineous populations for drug discovery.

10.
Behav Pharmacol ; 33(7): 505-512, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36148838

RESUMO

Astaxanthin (AST) is a lipid-soluble carotenoid with antioxidant and anti-inflammatory properties. Previous reports demonstrated the promising effects of AST on spinal cord injury (SCI)-induced inflammation and sensory-motor dysfunction. Macrophage migration inhibitory factor (MIF), as a cytokine, plays a critical role in the inflammatory phase of SCI. The aim of this study was to evaluate the effects of AST on post-SCI levels of MIF in serum and spinal cord. The possible correlation between MIF and mechanical pain threshold was also assessed. Adult male rats were subjected to a severe compression spinal injury and 30 min later were treated with AST (Intrathecal, 2 nmol) or vehicle. Neuropathic pain was assessed by von Frey filaments before the surgery, and then on days 7, 14, 21, and 28 post-SCI. Western blot and ELISA were used to measure the serum level and spinal expression of MIF following SCI in the same time points. AST treatment significantly attenuated the SCI-induced dysregulations in the serum levels and tissue expression of MIF. A negative correlation was observed between mechanical pain threshold and serum MIF level (r = -0.5463, P < 0.001), as well as mechanical pain threshold and spinal level of MIF (r = -0.9562; P < 0.001). AST ameliorates SCI-induced sensory dysfunction, probably through inhibiting MIF-regulated inflammatory pathways.


Assuntos
Fatores Inibidores da Migração de Macrófagos , Traumatismos da Medula Espinal , Animais , Antioxidantes/farmacologia , Lipídeos , Fatores Inibidores da Migração de Macrófagos/metabolismo , Fatores Inibidores da Migração de Macrófagos/farmacologia , Masculino , Ratos , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/metabolismo , Xantofilas/metabolismo , Xantofilas/farmacologia
11.
BMC Genom Data ; 23(1): 73, 2022 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-36131251

RESUMO

BACKGROUND: Describing how genetic history shapes the pattern of medically relevant variants could improve the understanding of how specific loci interact with each other and affect diseases and traits prevalence. The Qatari population is characterized by a complex history of admixture and substructure, and the study of its population genomic features would provide valuable insights into the genetic landscape of functional variants. Here, we analyzed the genomic variation of 186 newly-genotyped healthy individuals from the Qatari peninsula. RESULTS: We discovered an intricate genetic structure using ancestry related analyses. In particular, the presence of three different clusters, Cluster 1, Cluster 2 and Cluster 3 (with Near Eastern, South Asian and African ancestry, respectively), was detected with an additional fourth one (Cluster 4) with East Asian ancestry. These subpopulations show differences in the distribution of runs of homozygosity (ROH) and admixture events in the past, ranging from 40 to 5 generations ago. This complex genetic history led to a peculiar pattern of functional markers under positive selection, differentiated in shared signals and private signals. Interestingly we found several signatures of shared selection on SNPs in the FADS2 gene, hinting at a possible common evolutionary link to dietary intake. Among the private signals, we found enrichment for markers associated with HDL and LDL for Cluster 1(Near Eastern ancestry) and Cluster 3 (South Asian ancestry) and height and blood traits for Cluster 2 (African ancestry). The differences in genetic history among these populations also resulted in the different frequency distribution of putative loss of function variants. For example, homozygous carriers for rs2884737, a variant linked to an anticoagulant drug (warfarin) response, are mainly represented by individuals with predominant Bedouin ancestry (risk allele frequency G at 0.48). CONCLUSIONS: We provided a detailed catalogue of the different ancestral pattern in the Qatari population highlighting differences and similarities in the distribution of selected variants and putative loss of functions. Finally, these results would provide useful guidance for assessing genetic risk factors linked to consanguinity and genetic ancestry.


Assuntos
Genética Populacional , Varfarina , Anticoagulantes , Consanguinidade , Homozigoto , Humanos
12.
Transl Neurosci ; 13(1): 218-223, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-35990554

RESUMO

Background: A specific biological vulnerability underlies suicidal behavior. Recent findings have suggested a possible role of inflammation and neuroaxonal injury. However, the relationship between inflammation and clinical symptoms in this disorder is still unclear. The objective of this study is applying novel blood markers of neuroaxonal integrity such as neurofilament light chain (NfL) and comparing the results with the healthy control subjects. Methods: In this cross-sectional study patients with suicide attempts were evaluated. The serum concentration of NfL on admission was measured by enzyme-linked immunosorbent assays. Results: A total of 50 patients with a suicide attempts and 35 healthy controls were included in the study. The levels of NfL in attempted suicide patients were significantly higher in comparison with healthy controls (40.52 ± 33.54 vs 13.73 ± 5.11, P < 0.001). A significant association between serum levels of NfL and risk factors for suicide was not found. Conclusion: These findings indicate that axonal damage may be an underlying neuropathological component of suicide attempt patients, although no correlation was observed with clinical features. This line of work could lead to new horizons in understanding the neurobiology of suicidal attempts and the development of better management strategies for these patients.

13.
Korean J Pain ; 35(3): 291-302, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35768984

RESUMO

Background: Spinal cord injury (SCI) is one of the most debilitating disorders throughout the world, causing persistent sensory-motor dysfunction, with no effective treatment. Oxidative stress and inflammatory responses play key roles in the secondary phase of SCI. Naringenin (NAR) is a natural flavonoid with known anti-inflammatory and antioxidative properties. This study aims at evaluating the effects of intrathecal NAR administration on sensory-motor disability after SCI. Methods: Animals underwent a severe compression injury using an aneurysm clip. About 30 minutes after surgery, NAR was injected intrathecally at the doses of 5, 10, and 15 mM in 20 µL volumes. For the assessment of neuropathic pain and locomotor function, acetone drop, hot plate, inclined plane, and Basso, Beattie, Bresnahan tests were carried out weekly till day 28 post-SCI. Effects of NAR on matrix metalloproteinase (MMP)-2 and MMP-9 activity was appraised by gelatin zymography. Also, histopathological analyses and serum levels of glutathione (GSH), catalase and nitrite were measured in different groups. Results: NAR reduced neuropathic pain, improved locomotor function, and also attenuated SCI-induced weight loss weekly till day 28 post-SCI. Zymography analysis showed that NAR suppressed MMP-9 activity, whereas it increased that of MMP-2, indicating its anti-neuroinflammatory effects. Also, intrathecal NAR modified oxidative stress related markers GSH, catalase, and nitrite levels. Besides, the neuroprotective effect of NAR was corroborated through increased survival of sensory and motor neurons after SCI. Conclusions: These results suggest intrathecal NAR as a promising candidate for medical therapeutics for SCI-induced sensory and motor dysfunction.

14.
Neurochem Res ; 47(7): 2043-2051, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35435619

RESUMO

The effects of astaxanthin (AST) were evaluated on oxidative mediators, neuronal apoptosis, and autophagy in functional motor recovery after spinal cord injury (SCI). Rats were divided into three groups of sham, SCI + DMSO (dimethyl sulfoxide), and SCI + AST. Rats in the sham group only underwent a laminectomy at thoracic 8-9. While, the SCI + DMSO and SCI + AST groups had a compression SCI with an aneurysm clip. Then, this groups received an intrathecal (i.t.) injection of 5% DMSO and AST (10 µl of 0.005 mg/kg), respectively. The rat motor functions were assessed weekly until the 28th day using a combined behavioral score (CBS). Total antioxidant capacity (TAC), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GPx) were measured in spinal tissue to evaluate oxidative stress-related parameters. Besides, autophagy-related proteins (P62, LC3B, and Beclin1) and apoptosis-associated proteins (Bax and Bcl2) were determined using western blotting on the 1st and 7th days after surgery. Hematoxylin-eosin and Fluoro-Jade B staining were performed to detect the histological alterations and neuronal degeneration. As the result, treatment with AST potentially attenuated rat CBS scores (p < 0.001) towards a better motor performance. AST significantly reduced the spinal level of oxidative stress by increasing TAC, SOD, and GPx, while decreasing MDA (p < 0.001). Furthermore, AST treatment remarkably upregulated expression of LC3B (p < 0.001), and Beclin1 (p < 0.05) in the spinal cord, but downregulated P62 (p < 0.05) and the Bax/Bcl2 ratio (p < 0.001). Consequently, AST reduced SCI-induced histological alterations and neuronal degeneration (p < 0.001). In conclusion, AST can improve motor function after SCI by reducing oxidative stress/apoptosis and increasing neuronal autophagy.


Assuntos
Dimetil Sulfóxido , Traumatismos da Medula Espinal , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Apoptose , Autofagia , Proteína Beclina-1/metabolismo , Dimetil Sulfóxido/farmacologia , Glutationa Peroxidase/metabolismo , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/metabolismo , Superóxido Dismutase/metabolismo , Xantofilas , Proteína X Associada a bcl-2/metabolismo
15.
Hum Mutat ; 43(4): 499-510, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35112413

RESUMO

Despite recent biomedical breakthroughs and large genomic studies growing momentum, the Middle Eastern population, home to over 400 million people, is underrepresented in the human genome variation databases. Here we describe insights from Phase 1 of the Qatar Genome Program with whole genome sequenced 6047 individuals from Qatar. We identified more than 88 million variants of which 24 million are novel and 23 million are singletons. Consistent with the high consanguinity and founder effects in the region, we found that several rare deleterious variants were more common in the Qatari population while others seem to provide protection against diseases and have shaped the genetic architecture of adaptive phenotypes. These results highlight the value of our data as a resource to advance genetic studies in the Arab and neighboring Middle Eastern populations and will significantly boost the current efforts to improve our understanding of global patterns of human variations, human history, and genetic contributions to health and diseases in diverse populations.


Assuntos
Genoma Humano , Genômica , Consanguinidade , Genética Populacional , Genoma Humano/genética , Genômica/métodos , Humanos , Oriente Médio , Catar/epidemiologia
16.
Oxid Med Cell Longev ; 2022: 8100195, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35035667

RESUMO

Despite the progression in targeting the complex pathophysiological mechanisms of neurodegenerative diseases (NDDs) and spinal cord injury (SCI), there is a lack of effective treatments. Moreover, conventional therapies suffer from associated side effects and low efficacy, raising the need for finding potential alternative therapies. In this regard, a comprehensive review was done regarding revealing the main neurological dysregulated pathways and providing alternative therapeutic agents following SCI. From the mechanistic point, oxidative stress and inflammatory pathways are major upstream orchestras of cross-linked dysregulated pathways (e.g., apoptosis, autophagy, and extrinsic mechanisms) following SCI. It urges the need for developing multitarget therapies against SCI complications. Polyphenols, as plant-derived secondary metabolites, have the potential of being introduced as alternative therapeutic agents to pave the way for treating SCI. Such secondary metabolites presented modulatory effects on neuronal oxidative stress, neuroinflammatory, and extrinsic axonal dysregulated pathways in the onset and progression of SCI. In the present review, the potential role of phenolic compounds as critical phytochemicals has also been revealed in regulating upstream dysregulated oxidative stress/inflammatory signaling mediators and extrinsic mechanisms of axonal regeneration after SCI in preclinical and clinical studies. Additionally, the coadministration of polyphenols and stem cells has shown a promising strategy for improving post-SCI complications.


Assuntos
Inflamação/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Polifenóis/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Humanos , Camundongos , Fármacos Neuroprotetores/farmacologia , Polifenóis/farmacologia
17.
Crit Rev Food Sci Nutr ; 62(31): 8589-8645, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34096420

RESUMO

Edible flowers are attracting special therapeutic attention and their administration is on the rise. Edible flowers play pivotal modulatory roles on oxidative stress and related interconnected apoptotic/inflammatory pathways toward the treatment of cancer. In this review, we highlighted the phytochemical content and therapeutic applications of edible flowers, as well as their modulatory potential on the oxidative stress pathways and apoptotic/inflammatory mediators, resulting in anticancer effects. Edible flowers are promising sources of phytochemicals (e.g., phenolic compounds, carotenoids, terpenoids) with several therapeutic effects. They possess anti-inflammatory, anti-diabetic, anti-microbial, anti-depressant, anxiolytic, anti-obesity, cardioprotective, and neuroprotective effects. Edible flowers potentially modulate oxidative stress by targeting erythroid nuclear transcription factor-2/extracellular signal-regulated kinase/mitogen-activated protein kinase (Nrf2/ERK/MAPK), reactive oxygen species (ROS), nitric oxide (NO), malondialdehyde (MDA) and antioxidant response elements (AREs). As the interconnected pathways to oxidative stress, inflammatory mediators, including tumor necrosis factor (TNF)-α, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interleukins (ILs) as well as apoptotic pathways such as Bcl-2-associated X protein (Bax), Bcl-2, caspase and cytochrome C are critical targets of edible flowers in combating cancer. In this regard, edible flowers could play promising anticancer effects by targeting oxidative stress and downstream dysregulated pathways.


Assuntos
Antioxidantes , Estresse Oxidativo , Antioxidantes/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Mediadores da Inflamação/metabolismo , Flores , Apoptose , Inflamação/tratamento farmacológico
18.
Neurologist ; 27(4): 168-172, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34855658

RESUMO

BACKGROUND: Perihematomal edema (PHE) following primary intracranial hemorrhages (ICHs) affects the patient outcome. Also, serum biomarkers such as S100 calcium-binding protein B (S100B) and glial fibrillary acidic protein (GFAP) have been associated with ICHs outcome. We aimed to investigate the association between these biomarkers and PHE in ICH patients. METHODS: In this cross-sectional study, patients with primary ICH between January 2020 and August 2020 were evaluated. All participants underwent spiral brain computed tomography scans upon admission, and 48 to 72 hours later and quantification of initial hematoma volume was performed. Serum level of matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF), GFAP, and S100B on admission were measured by enzyme-linked immunosorbent assays. Acute clinical outcome was assessed by the modified-Rankin scale, National Institute of Health Stroke Scale (NIHSS), and ICH score. RESULTS: Thirty-seven ICH patients (21 patients with a favorable outcome and 16 unfavorable) were studied. Compared with survival patients, nonsurvivor patients showed a higher serum level of MMP-9, VEGF, GFAP, and S100B ( P <0.05). Scores of absolute PHE, edema expansion distance, and PHE growth rate in the nonsurvivor group were higher than the survivors ( P <0.001). The regression model revealed that MMP-9, VEGF, ICH score, and hematoma volume were associated with the PHE growth rate. S100B and ICH score were associated with edema expansion distance. CONCLUSIONS: Our data showed that the serum level of molecular biomarkers was associated with higher PHE volume and PHE scores were higher in nonsurvival patients, suggesting it may have a pathogenic role in developing PHE after ICH.


Assuntos
Edema Encefálico , Metaloproteinase 9 da Matriz , Biomarcadores , Encéfalo/patologia , Edema Encefálico/diagnóstico por imagem , Edema Encefálico/etiologia , Hemorragia Cerebral/complicações , Hemorragia Cerebral/diagnóstico por imagem , Estudos Transversais , Edema/complicações , Hematoma/complicações , Hematoma/patologia , Humanos , Hemorragias Intracranianas/complicações , Hemorragias Intracranianas/diagnóstico por imagem , Metaloproteinase 9 da Matriz/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
19.
Behav Pharmacol ; 32(7): 590-598, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34483246

RESUMO

As a promising flavonoid, naringenin has shown potential anti-inflammatory and antioxidant properties mainly in inflammatory pain models by oral administration. Therefore, we investigated the antinociceptive activity of this compound by intraperitoneally (i.p.) administration, as well as, associated mechanism of action considering the involvement of L-arginine/nitric oxide (NO)/cyclic GMP (cGMP)/potassium channel (KATP) pathway and opioid receptors. The antinociceptive effect of naringenin was evaluated in male NMRI mice using formalin test at early and late phases. To assess the involvement of L-arginine/NO/cGMP/KATP pathway and opioid receptors, mice were pretreated i.p. with L-arginine (NO precursor), S-nitroso-N-acetylpenicillamine (SNAP, NO donor), N(gamma)-nitro-L-arginine methyl ester (L-NAME, inhibitor of nitric oxide synthase), sildenafil (inhibitor of phosphodiesterase enzyme), glibenclamide (KATP channel blocker) and naloxone (an opioid receptor antagonist), respectively 20 min before administration of the most effective dose of naringenin. Naringenin showed a dose-dependent antinociceptive effect at both early and late phases of the formalin test. The dose of 100 mg/kg of naringenin was identified as the most effective dose and selected for further experiments. Our mechanistic evaluations showed that L-arginine, SNAP and sildenafil could enhance the antinociceptive effects of naringenin, revealing the critical role of NO and cGMP during its antinociceptive effect. On the other hand, glibenclamide and naloxone could mitigate the antinociceptive potential of naringenin at both phases of formalin test, which confirmed the associated role of KATP channels and opioid receptors. In conclusion, naringenin could be a promising antinociceptive agent acting through opioid receptors and L-arginine/NO/cGMP/KATP channel pathway.


Assuntos
Arginina , Flavanonas/farmacologia , Canais KATP , Óxido Nítrico/metabolismo , S-Nitroso-N-Acetilpenicilamina/farmacologia , Citrato de Sildenafila/farmacologia , Analgésicos/farmacologia , Animais , Arginina/metabolismo , Arginina/farmacologia , GMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Antagonistas de Estrogênios/farmacologia , Flavonoides/farmacologia , Infusões Parenterais , Canais KATP/antagonistas & inibidores , Canais KATP/metabolismo , Masculino , Camundongos , NG-Nitroarginina Metil Éster/farmacologia , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Behav Pharmacol ; 32(8): 607-614, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34561366

RESUMO

One of the main functions of the sensory system in our body is to maintain somatosensory homeostasis. Recent reports have led to a significant advance in our understanding of pain signaling mechanisms; however, the exact mechanisms of pain transmission have remained unclear. There is an urgent need to reveal the precise signaling mediators of pain to provide alternative therapeutic agents with more efficacy and fewer side effects. Accordingly, although the anti-inflammatory, antioxidative and anti-neuropathic effects of astaxanthin (AST) have been previously highlighted, its peripheral antinociceptive mechanisms are not fully understood. In this line, considering the engagement of l-arginine/nitric oxide (NO)/cyclic GMP (cGMP)/potassium channel (KATP) signaling pathway in the antinociceptive responses, the present study evaluated its associated role in the antinociceptive activity of AST. Male mice were intraperitoneally (i.p.) injected with l-arginine (100 mg/kg), SNAP (1 mg/kg), L-NAME (30 mg/kg), sildenafil (5 mg/kg), and glibenclamide (10 mg/kg) alone and prior to the most effective dose of AST. Following AST administration, intraplantarly (i.pl) injection of formalin was done, and pain responses were evaluated in mice during the primary (acute) and secondary (inflammatory) phases of formalin test. The results highlighted that 10 mg/kg i.p. dose of AST showed the greatest antinociceptive effect. Besides, while L-NAME and glibenclamide reduced the antinociceptive effect of AST, it was significantly increased by l-arginine, SNAP and sildenafil during both the primary and secondary phases of formalin test. These data suggest that the antinociceptive activity of AST is passing through the l-arginine/NO/cGMP/KATP pathway.


Assuntos
Analgésicos/farmacologia , Dor/tratamento farmacológico , Analgésicos/administração & dosagem , Animais , Arginina/metabolismo , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Glibureto/farmacologia , Canais KATP/metabolismo , Masculino , Camundongos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Citrato de Sildenafila/farmacologia , Xantofilas/administração & dosagem , Xantofilas/farmacologia
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