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The l-arginine (l-Arg)/nitric oxide/cyclic GMP/potassium channel (KATP) pathway and opioid receptors are known to play critical roles in pain perception and the antinociceptive effects of various compounds. While there is evidence suggesting that the analgesic effects of rutin may involve nitric oxide modulation, the direct link between rutin and the l-Arg/nitric oxide/cyclic GMP/KATP pathway in the context of pain modulation requires further investigation. The antinociceptive effect of rutin was studied in male NMRI mice using the formalin test. To investigate the role of the l-Arg/nitric oxide/cyclic GMP/KATP pathway and opioid receptors, the mice were pretreated intraperitoneally with different substances. These substances included l-Arg (a precursor of nitric oxide), S-nitroso-N-acetylpenicillamine (SNAP, a nitric oxide donor), N(gamma)-nitro-l-arginine methyl ester (L-NAME, an inhibitor of nitric oxide synthase), sildenafil (an inhibitor of phosphodiesterase enzyme), glibenclamide (a KATP channel blocker), and naloxone (an opioid receptor antagonist). All pretreatments were administered 20 min before the administration of the most effective dose of rutin. Based on our investigation, it was found that rutin exhibited a dose-dependent antinociceptive effect. The administration of SNAP enhanced the analgesic effects of rutin during both the initial and secondary phases. Moreover, L-NAME, naloxone, and glibenclamide reduced the analgesic effects of rutin in both the primary and secondary phases. In conclusion, rutin holds significant value as a flavonoid with analgesic properties, and its analgesic effect is directly mediated through the nitric oxide/cyclic GMP/KATP channel pathway.
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Background: Considering the complex pathological mechanisms behind spinal cord injury (SCI) and the adverse effects of present non-approved drugs against SCI, new studies are needed to introduce novel multi-target active ingredients with higher efficacy and lower side effects. Polydatin (PLD) is a naturally occurring stilbenoid glucoside recognized for its antioxidative and anti-inflammatory properties. This study aimed to assess the effects of PLD on sensory-motor function following SCI in rats. Methods: Following laminectomy and clip compression injury at the thoracic 8 (T8)-T9 level of the spinal cord, rats were randomly assigned to five groups: Sham, SCI, and three groups receiving different doses of PLD treatment (1, 2, and 3 mg/kg). Over 4 weeks, behavioral tests were done such as von Frey, acetone drop, hot plate, Basso-Beattie-Bresnahan, and inclined plane test. At the end of the study, changes in catalase and glutathione activity, nitrite level, activity of matrix metalloproteinase 2 (MMP2) and MMP9 as well as spinal tissue remyelination/neurogenesis, were evaluated. Results: The results revealed that PLD treatment significantly improved the behavioral performance of the animals starting from the first week after SCI. Additionally, PLD increased catalase, and glutathione levels, and MMP2 activity while reduced serum nitrite levels and MMP9. These positive effects were accompanied by a reduction in the size of the lesion and preservation of neuronal count. Conclusion: In conclusion, PLD showed neuroprotective effects in SCI rats by employing anti-inflammatory and antioxidant effects, through which improve sensory and motor function.
ABSTRACT
Spinal cord injury (SCI) is a common neurological disease worldwide, often resulting in a substantial decrease in quality of life, disability, and in severe cases, even death. Unfortunately, there is currently no effective treatment for this disease. Nevertheless, current basic and clinical evidence suggests that vitamins, with their antioxidant properties and biological functions, may play a valuable role in improving the quality of life for individuals with SCI. They can promote overall health and facilitate the healing process. In this review, we discuss the mechanisms and therapeutic potential of vitamins in the treatment of SCI.
Subject(s)
Spinal Cord Injuries , Vitamins , Spinal Cord Injuries/drug therapy , Humans , Vitamins/therapeutic use , Vitamins/pharmacology , Animals , Antioxidants/therapeutic use , Antioxidants/pharmacologyABSTRACT
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).
ABSTRACT
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.
Subject(s)
Diabetes Mellitus, Type 2 , Infant, Newborn , Humans , Biological Specimen Banks , Gene Frequency , Phenotype , HomozygoteABSTRACT
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.
Subject(s)
Alzheimer Disease , Mitochondria , Humans , Alzheimer Disease/immunology , Alzheimer Disease/therapy , Alzheimer Disease/pathology , Mitochondria/metabolism , Animals , Brain/pathology , Brain/immunology , Brain/metabolism , Immunity , Biological TransportABSTRACT
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.
Subject(s)
Epithelial-Mesenchymal Transition , Neoplasms , Humans , Epithelial-Mesenchymal Transition/physiology , Neoplasms/drug therapy , Neoplasms/pathology , Signal Transduction , Adaptation, Physiological , Phytochemicals/pharmacology , Phytochemicals/therapeutic useABSTRACT
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.
Subject(s)
Neuroprotective Agents , Parkinson Disease , Rats , Animals , Brain-Derived Neurotrophic Factor/metabolism , Oxidopamine/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Mitogen-Activated Protein Kinases/metabolism , Dipeptides/pharmacology , Dipeptides/metabolism , Dipeptides/therapeutic use , bcl-2-Associated X Protein/metabolism , Rats, Wistar , Apoptosis , Dopaminergic Neurons , Neuroprotective Agents/therapeutic use , Substantia Nigra/metabolismABSTRACT
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.
Subject(s)
Antioxidants , Astrocytes , HMGB1 Protein , Spinal Cord Injuries , Animals , Male , Rats , Astrocytes/drug effects , Astrocytes/metabolism , Edema/drug therapy , Edema/metabolism , HMGB1 Protein/metabolism , Matrix Metalloproteinase 9/metabolism , NF-kappa B/metabolism , Rats, Sprague-Dawley , Signal Transduction , Spinal Cord/drug effects , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/metabolism , Toll-Like Receptor 4/metabolism , Antioxidants/administration & dosage , Antioxidants/pharmacology , Antioxidants/therapeutic use , Disease Models, Animal , Injections, SpinalABSTRACT
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.
Subject(s)
Antioxidants , Dietary Supplements , Antioxidants/pharmacology , Oxidative Stress , Biomarkers/metabolismABSTRACT
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.
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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.
Subject(s)
Alzheimer Disease , Neurodegenerative Diseases , Parkinson Disease , Humans , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Parkinson Disease/drug therapy , Parkinson Disease/genetics , Parkinson Disease/metabolism , RNA, Untranslated/genetics , Phytochemicals/pharmacology , Phytochemicals/therapeutic useABSTRACT
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.
Subject(s)
Genetics, Population , Warfarin , Anticoagulants , Consanguinity , Homozygote , HumansABSTRACT
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.
Subject(s)
Macrophage Migration-Inhibitory Factors , Spinal Cord Injuries , Animals , Antioxidants/pharmacology , Lipids , Macrophage Migration-Inhibitory Factors/metabolism , Macrophage Migration-Inhibitory Factors/pharmacology , Male , Rats , Spinal Cord/metabolism , Spinal Cord Injuries/drug therapy , Spinal Cord Injuries/metabolism , Xanthophylls/metabolism , Xanthophylls/pharmacologyABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Dimethyl Sulfoxide , Spinal Cord Injuries , Animals , Antioxidants/metabolism , Antioxidants/pharmacology , Antioxidants/therapeutic use , Apoptosis , Autophagy , Beclin-1/metabolism , Dimethyl Sulfoxide/pharmacology , Glutathione Peroxidase/metabolism , Oxidative Stress , Proto-Oncogene Proteins c-bcl-2/metabolism , Rats , Rats, Sprague-Dawley , Spinal Cord/metabolism , Spinal Cord Injuries/metabolism , Superoxide Dismutase/metabolism , Xanthophylls , bcl-2-Associated X Protein/metabolismABSTRACT
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.
Subject(s)
Genome, Human , Genomics , Consanguinity , Genetics, Population , Genome, Human/genetics , Genomics/methods , Humans , Middle East , Qatar/epidemiologyABSTRACT
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.
Subject(s)
Inflammation/drug therapy , Neurodegenerative Diseases/drug therapy , Neuroprotective Agents/therapeutic use , Oxidative Stress/drug effects , Polyphenols/therapeutic use , Spinal Cord Injuries/drug therapy , Animals , Humans , Mice , Neuroprotective Agents/pharmacology , Polyphenols/pharmacologyABSTRACT
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.