Traumatic brain injury (TBI) leads to post-traumatic epilepsy (PTE); hence, both TBI and PTE share various similar molecular mechanisms. MicroRNA (miRNA) is a small noncoding RNA that acts as a gene-silencing molecule. Notably, the dysregulation of miRNAs in various neurological diseases, including TBI and epilepsy, has been reported in several studies. However, studies on commonly dysregulated miRNAs and the regulation of shared pathways in both TBI and epilepsy that can identify potential biomarkers of PTE are still lacking. This systematic review covers the peer-review publications of TBI and database studies of epilepsy-dysregulated miRNAs of clinical studies. For TBI, 290 research articles were identified after screening, and 12 provided data for dysregulated miRNAs in humans. The compiled data suggest that 85 and 222 miRNAs are consecutively dysregulated in TBI and epilepsy. In both, 10 miRNAs were found to be commonly dysregulated, implying that they are potentially dysregulated miRNAs for PTE. Furthermore, the targets and involvement of each putative miRNA in different pathways were identified and evaluated. Additionally, clusters of predicted miRNAs were analyzed. Each miRNA’s regulatory role was linked with apoptosis, inflammation, and cell cycle regulation pathways. Hence, these findings provide insight for future diagnostic biomarkers.
Brain damage caused by the metal accumulation may result in the permanent injuries including severe neurological disorders. Thus, the aim of this study was to determine the medicinal efficacy of broccoli extract in arsenic-induced brain poisoning. Twenty-eight female rats were classified into 4 groups; control, receiving sodium arsenate (As), As + broccoli extract (As + Bc), and (Bc). Then, the Elevated Plus-Maze and pathological-biochemical assessment of the brain tissue were performed. Moreover, the GC-MS was used to explore the quantity and quality of broccoli extract. The catalase had a significant decrease in the As group compared to that of the control group; As + Bc and Bc groups also showed a significant increase compared to that of the As group. Glutathione peroxidase was the lowest in the As group (1.84 ± 0.97) and the highest in the Bc group (5.51 ± 2.31). The Treatment significantly reduced pro-inflammatory cytokines in the As + Bc group. In addition, in terms of behavioral changes, the duration of presence in the open arm was reduced in the As group compared to that of the control group. Besides, the open arm duration increased significantly in the Bc group. Interestingly, there was a significant increase in estrogen and gonadotropin hormones in the Bc group compared to the other groups. Pathological findings showed that the condition of cortical neurons was improved and the surrounding space was reduced in As + Bc compared to that of the As group. In addition, more than 30% of the extract’s compounds are made up Phytol,1-isothiocyanate-4-[methylsulfinyl] butane, and γ-Sitosterol. Thereby, the broccoli extract with active substances was highly effective in enhancing the behavioral and pathological parameters switch in rats with arsenic-induced poisoned brains.
Neuroinflammation is a key pathological event triggering neurodegenerative process, resulting in neurologic sequelae. Curcumin (cur) has recently received increasing attention due to its anti-inflammatory properties. Therefore, we investigated the protective effects of curcumin on lipopolysaccharide (LPS)-induced memory impairments, long-term potentiation (LTP) deficiency, hippocampal inflammatory cytokines, and hippocampal neuronal loss in male rats. Rats were randomly divided into four groups as follows: (1) Vehicle; (2) cur; (3) LPS; and (4) cur/LPS. Following curcumin pretreatment (50 mg/kg, per oral via gavage, 14 consecutive days), animals received a single dose of LPS (1 mg/kg, intraperitoneally) or saline. Twenty-four hours after LPS/or saline administration, passive avoidance test (PAT), hippocampal LTP, inflammatory cytokines (TNFα, IL-1β), and neuronal loss were assessed in hippocampal tissue of rats. Our results indicated that pretreatment with curcumin in LPS-challenged rats attenuates memory impairment in PAT, which was accompanied by significant increase in the field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude. Hence, pretreatment with curcumin in LPS-treated rats decreased hippocampal concentration of tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β), as well as reduced neuronal loss in the hippocampal tissue. This study provide evidence that pretreatment with curcumin attenuates LPS-induced memory impairment and LTP deficiency, which may be partly related to the amelioration of inflammatory cytokines and neuronal loss in the hippocampal tissue.
Malnutrition and low dietary protein intake could be risk factors for developing peripheral and central hyperammonemia, especially in pediatrics. Both curcumin and resveratrol proved to be effective against several hepatic and cerebral injuries. They were reported to be beneficial in lowering circulating ammonia levels, yet both are known for their low bioavailability. The use of pharmaceutical nano-formulations as delivery systems for these two nutraceuticals could solve the aforementioned problem. Hence, the present study aimed to investigate the valuable outcome of using a combination of curcumin and resveratrol in a nanoemulsion formulation, to counteract protein-deficient diet (PDD)-induced hyperammonemia and the consequent complications in male albino rats. Results revealed that using a nanoemulsion containing both curcumin and resveratrol at a dose of (5 + 5 mg/kg) effectively reduced hepatic and brain ammonia levels, serum ALT and AST levels, hepatic and brain nitric oxide levels, oxidative DNA damage as well as disrupted cellular energy performance. In addition, there was a substantial increase in brain levels of monoamines, and a decrease in glutamate content. Therefore, it can be concluded that the use of combined curcumin and resveratrol nanoemulsion is an effective means of ameliorating the hepatic and cerebral adverse effects resulting from PDD-induced hyperammonemia in rats.
Vitamin D3 deficiency is associated with an increased risk of dementia. An association between vitamin D3 deficiency and subjective cognitive complaints in geriatric patients has been previously reported. This study aimed to evaluate the effects of two doses of vitamin D3 on spatial memory (using the Radial Maze) and cytokine levels [tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-10 (IL-10)] on 2-, 6-, 13-, 22-, and 31-month-old male Wistar rats. Animals were supplemented with vitamin D3 at doses of 42 IU/kg and 420 IU/kg for 21 days. A radial maze test was performed to evaluate spatial memory. After the behavioral test, the frontal cortex and hippocampus were dissected for enzyme immunoassay analyses to measure the cytokine levels (TNFα, IL-1β, IL-6, and IL-10). Our results showed that vitamin D3 supplementation reversed spatial memory impairment at the supplemented doses (42 and 420 IU/kg) in 6-, 13-, and 22-month-old animals and at a dose of 420 IU/kg in 31-month-old animals. The lower dose (42 IU/kg) regulates both pro- and anti-inflammatory cytokines mainly in the frontal cortex. Our results suggest that vitamin D3 has a modulatory action on pro- and anti-inflammatory cytokines, since older animals showed increased cytokine levels compared to 2-month-old animals, and that vitamin D3 may exert an immunomodulatory effect on aging.
Vagus nerve stimulation through the action of acetylcholine can modulate inflammatory responses and metabolism. α7 Nicotinic Acetylcholine Receptor (α7nAChR) is a key component in the biological functions of acetylcholine. To further explore the health benefits of vagus nerve stimulation, this study aimed to investigate whether α7nAChR agonists offer beneficial effects against poststroke inflammatory and metabolic changes and to identify the underlying mechanisms in a rat model of stroke established by permanent cerebral ischemia. We found evidence showing that pretreatment with α7nAChR agonist, GTS-21, improved poststroke brain infarction size, impaired motor coordination, brain apoptotic caspase 3 activation, dysregulated glucose metabolism, and glutathione reduction. In ischemic cortical tissues and gastrocnemius muscles with GTS-21 pretreatment, macrophages/microglia M1 polarization-associated Tumor Necrosis Factor-α (TNF-α) mRNA, Cluster of Differentiation 68 (CD68) protein, and Inducible Nitric Oxide Synthase (iNOS) protein expression were reduced, while expression of anti-inflammatory cytokine IL-4 mRNA, and levels of M2 polarization-associated CD163 mRNA and protein were increased. In the gastrocnemius muscles, stroke rats showed a reduction in both glutathione content and Akt Serine 473 phosphorylation, as well as an elevation in Insulin Receptor Substrate-1 Serine 307 phosphorylation and Dynamin-Related Protein 1 Serine 616 phosphorylation. GTS-21 reversed poststroke changes in the gastrocnemius muscles. Overall, our findings, provide further evidence supporting the neuroprotective benefits of α7nAChR agonists, and indicate that they may potentially exert anti-inflammatory and metabolic effects peripherally in the skeletal muscle in an acute ischemic stroke animal model.
Endothelial cell dysfunction plays an important role in cerebral ischemia-reperfusion (I/R) injury. LncRNA Peg13 is reported to be down-regulated in brain microvascular endothelial cells (BMVECs) induced by glucose-oxygen deprivation (OGD), but the mechanism of its involvement in I/R progression remains to be further explored. Here, mouse BMVECs (bEnd.3 cells) were treated with OGD / reoxygenation (OGD/R) to simulate I/R injury in vitro. Peg13 and Gli2 expression was decreased in OGD/R-treated bEnd.3 cells. And overexpression of Peg13 or Gli2 prevented OGD/R-induced reduction in cell migration and angiogenesis, as well as upregulation in cell apoptosis and oxidative stress levels. Mechanism exploration showed that Gli2 promoted the transcription of Peg13. And Peg13 repressed Yy1 transcription by binding to Ezh2 (a key subunit of PRC2 complex) and inducing the enrichment of H3K27me3 in Yy1 promoter region, thereby suppressing the transcriptional inhibition effect of Yy1 on Notch3 and promoting the expression of Notch3. Consistently, Notch3 overexpression hindered OGD/R-induced endothelium dysfunction. In addition, a brain I/R injury model was established using middle cerebral artery occlusion surgery. And lentivirus-mediated Gli2 and Peg13 overexpression vectors were injected into mice via the lateral ventricle one week before surgery. The results showed that overexpression of Peg13 or Gli2 alleviated I/R-induced neurological deficit, cerebral infarct and cerebral edema. And simultaneous overexpression of Peg13 and Gli2 showed a better protective effect than overexpression of Gli2 or Peg13 alone. In conclusion, Peg13 regulated by Gli2 inhibits Yy1 transcription in a PCR2 complex-dependent manner, and blocks the transcriptional repression of Notch3 by Yy1, thereby exerting neuroprotective effects on cerebral I/R injury.
Schizophrenia (SZ) is a devastating neurodevelopmental disease with an accelerated ageing feature. The criteria of metabolic disease firmly fit with those of schizophrenia. Disturbances in energy and mitochondria are at the core of complex pathology. Genetic and environmental interaction creates changes in redox, inflammation, and apoptosis. All the factors behind schizophrenia interact in a cycle where it is difficult to discriminate between the cause and the effect. New technology and advances in the multi-dispensary fields could break this cycle in the future.
Parkinson’s disease (PD) is a chronic, progressive, and second most prevalent neurological disorder affecting the motor system. It has been found that people suffering with inflammatory bowel disease (IBD) are at 22% more risk for PD. In the current study, we have established a molecular link between gut and brain. The microarray gene expression datasets of Homo sapiens were obtained from Gene Expression Omnibus Database. Major genes involved in gut-brain connection were found to be CXCR4, LRRK2, APOE, SNCA, IL6, HIF-1α, ABCA1 etc. The common biological pathways linking both the pathologies were found to be HIF-signaling, cytokines interactions, JAK-STAT pathway, cholesterol metabolism, apoptosis and CXCR4 signaling which modulates the synaptic function and neuronal survival in the mature brain. It is known that flavonoid-rich foods throughout life hold the potential to limit the inflammation, neurodegeneration and, to prevent the age-dependent cognitive impairment. Therefore, the potential receptor, CXCR4 was used further for docking with twenty-seven phytochemicals from 5 different classes of Flavonoids found in several dietary items. Docking studies of the top scoring compounds were compared with a known inhibitor (BPRCX807) of receptor CXCR4 (IC50 = 40.4 ± 8.0 nM). The study indicates that Flavan-3-ol families of flavonoids are the best fit and finest dietary supplements for improving brain health. Hence the food items like Pistachio nuts, hazelnuts, Green Tea, walnuts, etc. should be incorporated more in the diet of healthy people as well as in IBD and PD patients to prevent inflammation in gut and brain damage from oxidative stress.
Curcumin is a natural anti-inflammatory and antioxidant substance which plays a major role in reducing the amyloid plaques formation, which is the major cause of Alzheimer’s disease (AD). Consequently, a methodical approach was used to select the potential protein targets of curcumin in AD through network pharmacology. In this study, through integrative methods, AD targets of curcumin through SwissTargetPrediction database, STITCH database, BindingDB, PharmMapper, Therapeutic Target Database (TTD), Online Mendelian Inheritance in Man (OMIM) database were predicted followed by gene enrichment analysis, network construction, network topology, and docking studies. Gene ontology analysis facilitated identification of a list of possible AD targets of curcumin (74 targets genes). The correlation of the obtained targets with AD was analysed by using gene ontology (GO) pathway enrichment analyses and Kyoto Encyclopaedia of Genes and Genomes (KEGG). We have incorporated the applied network pharmacological approach to identify key genes. Furthermore, we have performed molecular docking for analysing the mechanism of curcumin. In order to validate the temporospatial expression of key genes in human central nervous system (CNS), we searched the Human Brain Transcriptome (HBT) dataset. We identified top five key genes namely, PPARγ, MAPK1, STAT3, KDR and APP. Further validated the expression profiling of these key genes in publicly available brain data expression profile databases. In context to a valuable addition in the treatment of AD, this study is concluded with novel insights into the therapeutic mechanisms of curcumin, will ease the treatment of AD with the clinical application of curcumin.
Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is one of the most common complications following carbon monoxide intoxication. Long noncoding RNAs (lncRNAs) exert critical functions in numerous neurological disorders. We intended to investigate the role of CRNDE in DEACMP. The DEACMP model in rats and the oxygen–glucose deprivation/reoxygenation (OGD/R) model in PC-12 cells were established. Brain and cell injuries were assessed with H&E staining, Nissl staining, TUNEL and CCK8 assays, respectively. Related proteins and RNAs were quantified with western blot and qRT-PCR. The N6-methyladenosine (m6A) level was determined using MeRIP-qPCR and immunofluorescence. Loss and gain function studies were performed to investigate the biological function of CRNDE. The potential mechanisms between each factor were explored using RNA immunoprecipitation, RNA-pull down and co-immunoprecipitation. CRNDE was increased in the hippocampal tissues of DEACMP rats and in OGD/R-treated PC-12 cells, which was positively correlated to m6A modification. Knockdown of CRNDE reduced cell damage and elevated UCHL5 and SMO expressions in OGD/R-treated PC-12 cells. hnRNPA1 was upregulated in DEACMP. In addition, inhibiting hnRNPA1 prevented apoptosis in PC-12 cells subjected to OGD/R. hnRNPA1 bound to CRNDE and remained in the nucleus, which inhibited UCHL5 expression through the formation of CRNDE-hnRNPA1-mRNA complex. UCHL5 could inhibit SMO ubiquitination and suppress PC-12 cell apoptosis during OGD/R. CRNDE silencing blocked brain injury in DEACMP, while knocking down UCHL5 reversed these effects. CRNDE interacted with hnRNPA1 to facilitate DEACMP via inhibition of UCHL5-mediated SMO deubiquitination. CRNDE might be a latent therapeutic target for treating DEACMP.
To 1) investigate the morphological brain-tissue changes in patients with dialysis- and non-dialysis-dependent chronic kidney disease (CKD); 2) analyze the effects of CKD on whole-brain cortical thickness, cortical volume, surface area, and surface curvature; and 3) analyze the correlation of these changes with clinical and biochemical indices. This study included normal controls (NCs, n = 34) and patients with CKD who were divided into dialysis (dialysis-dependent chronic kidney disease [DD-CKD], n = 26) and non-dialysis (non-dialysis patients who underwent cranial magnetic resonance imaging scans [NDD-CKD], n = 26) groups. Cortical thickness, volume, surface area, and surface curvature in each group were calculated using FreeSurfer software. Brain morphological indicators with statistical differences were correlated with clinical and biochemical indicators. Patients with CKD exhibited a significant and widespread decrease in cortical thickness and volume compared with NCs. Among the brain regions associated with higher neural activity, patients with CKD exhibited more significant morphological changes in the paracentral gyrus, transverse temporal gyrus, and lateral occipital cortex than in other brain regions. Cortical thickness and volume in patients with CKD correlated with blood pressure, lipid, hemoglobin, creatinine, and urea nitrogen levels. The extent of brain atrophy was further increased in the DD-CKD group compared with that in the NDD-CKD group. Patients with CKD potentially exhibit a certain degree of structural brain-tissue imaging changes, with morphological changes more pronounced in patients with DD-CKD, suggesting that blood urea nitrogen and dialysis may be influential factors in brain morphological changes in patients with CKD.
Estrogen receptor alpha (ERα) is a transcription factor activated by estrogenic hormones to regulate gene expression in certain organs, including the brain. In the brain, estrogen signaling pathways are central for maintaining cognitive functions. Herein, we review the neuroprotective effects of estrogens mediated by ERα. The estrogen/ERα pathways are affected by the reduction of estrogens in menopause, and this event may be a risk factor for neurodegeneration associated with Alzheimer’s disease in women. Thus, developing a better understanding of estrogen/ERα signaling may be critical for defining new biomarkers and potential therapeutic targets for Alzheimer’s disease in women.
The brain requires a large amount of energy. Its function can be altered when energy demand exceeds supply or during metabolic disturbances such as diabetes mellitus. Diabetes, a chronic disease with a high incidence worldwide, is characterized by high glucose levels (hyperglycemia); however, hypoglycemic states may also occur due to insulin treatment or poor control of the disease. These alterations in glucose levels affect the brain and could cause epileptic seizures and status epilepticus. In addition, it is known that oxidative stress states emerge as diabetes progresses, contributing to the development of diseases secondary to diabetes, including retinopathy, nephropathy, cardiovascular alterations, and alterations in the central nervous system, such as epileptic seizures. Seizures are a complex of transient signs and symptoms resulting from abnormal, simultaneous, and excessive activity of a population of neurons, and they can be both a cause and a consequence of oxidative stress. This review aims to outline studies linking diabetes mellitus and seizures to oxidative stress, a condition that may be relevant to the development of severe seizures in diabetes mellitus patients.
Hormonal imbalance may be an important factor in the severity of multiple sclerosis (MS) disease. In this context, hormone therapy has been shown to have immunoregulatory potential in various experimental approaches. There is increasing evidence of potentially beneficial effects of thyroid, melatonin, and sex hormones in MS models. These hormones may ameliorate the neurological impairment through immunoregulatory and neuroprotective effects, as well as by reducing oxidative stress. Expanding our knowledge of hormone therapy may be an effective step toward identifying additional molecular/cellular pathways in MS disease. In this review, we discuss the role of several important hormones in MS pathogenesis in terms of their effects on immunoregulatory aspects and neuroprotection.
Neurobehavioral deficits have been severally reported as a comorbid outcome in inflammatory bowel diseases (IBDs). This study evaluated neurological changes in the experimental model of IBDs, as well potential protective effects of methyl jasmonate (MJ). The study used the acetic acid model of colitis and thereafter delayed the healing process by the administration of indomethacin (Indo) (2 mg/kg, SC). Thirty male Wistar rats (120-160 g) were divided into 5 groups (n = 6). Control, Colitis, Colitis + Indo, MJ (50 mg/kg, IP) + Colitis and MJ + Colitis + Indo. Colitis was induced by intrarectal administration of 2 mL, 4% acetic acid. Neurobehavioral studies were carried out to assess memory function, depression, and anxiety on day 7 of post-colitis induction. Animals were thereafter sacrificed to collect the brain tissues for routine histology, immunoreactivity of GFAP and IBA-1, and biochemical assays. Neurobehavioral tests showed anxiety, depression, and memory deficits, especially in the Colitis + Indo group which were accompanied by increased IBA-1 and GFAP count. MJ reversed these effects and reduced GFAP count in the hippocampus and amygdala as well as IBA-1 count in the hippocampus, amygdala, and cortex. Histological observations of these areas showed no significant histopathological changes across all groups. GPx and CAT levels were significantly reduced, while MPO was significantly increased in colitis and Colitis+indo groups when compared with control, which was attenuated in groups administered with MJ. These findings tuggest that MJ possesses neuroprotective, anti-oxidant, and neuron-regeneration properties. Therefore, it could be considered as a potential treatment for behavioral deficits associated with ulcerative colitis.
Memory deficit has been reported as one of the complications of diabetes. Fermented seeds of Pentaclethra Macrophylla (P. macrophylla) have been used in folklore for the management of metabolic diseases. The research aims to evaluate the impact of diets with the inclusion of the fermented seed of P. macrophylla on memory deficit in diabetic rats and its underlying mechanisms. Before the induction, the rats were subjected to training sessions. Thereafter, streptozotocin (50 mg/kg body weight) was administered to the trained rats via intraperitoneal (i.p). 72 hours after, the rats blood glucose level was checked, rats with blood glucose level greater than 250 mg/dl were selected for the memory index evaluation study. The induced rats were randomly distributed into groups: Normal rats (group 1), untreated diabetic rat (Group 2), acarbose treated diabetic rats (group 3); diabetic rats placed on diet supplemented with fermented seed of P. macrophylla (10 & 20% inclusion) were allotted to group 4 & 5. Then, evaluation of memory retention capacity was performed on the day 14 of the experiment. Thereafter, experimental rats were sacrificed, tissue of interest (brain) was excised, homogenized and homogenates were used for biochemical analysis. The cholinergic, angiotensin-1-converting enzyme (ACE), arginase activity and biomarkers for oxidative stress were significantly altered in untreated diabetic rats when compared with non-diabetes rats. Also, the memory capacity of the diabetic rats was significantly reduced when compared with the non-diabetes rats. Meanwhile, diabetic rats placed on diet with fermented seeds of P. macrophylla (10 & 20% inclusion) exhibited significantly higher memory capacity, lower activity of cholinergic, ACE, arginase activity in relation to untreated diabetic rats while the antioxidant status of the brain was enhanced. Nevertheless, fermented seeds of P. macrophylla ameliorated memory deficit in STZ induced diabetes rats. This gave credence to P. macrophylla nutraceutical potential as claimed in folk medicine.
Diabetes-related cognitive impairment has been shown in diverse epidemiological investigations and lab-based studies, although the underlying pathological mechanisms remain unclear. Unbalanced protein homeostasis may contribute to cognitive decline by inducing abnormal protein aggregation in the diabetic brain. This study aimed to determine possible changes in the proteasome, which is an important pathway involved in abnormal protein degradation. To this end, we examined potential alterations of proteasomal subunits and hydrolytic activity in the brain of diabetic rats fed with high-fat diet combined with small doses of streptozotocin (STZ). Furthermore, lactacystin were used to inhibit proteasomal activity in vivo and typical Alzheimer’s disease (AD)-like pathologies were detected, including amyloid-beta, tau phosphorylation, and oxidative protein changes. Our results showed that proteasomal activity increased in the brains of diabetic rats compared to age-matched control rats. After proteasome inhibition, the levels of tau phosphorylation and protein oxidative modification significantly increased; however, no changes were detected in the pathway involved in amyloid production. These results indicated that changes in protein homeostasis balance in diabetes play a role in some typical AD-like changes, especially in oxidative protein degradation, providing evidence that prevention of diabetes-induced protein imbalance may be a potential therapeutic target.
Ceroid lipofuscinosis type 3 (CLN3) is an autosomal recessive, neurodegenerative metabolic disease. Typical clinical symptoms include progressive visual loss, epilepsy of unknown etiology and dementia. Presence of lipofuscin deposits with typical pattern of ‘fingerprints’ and vacuolized lymphocytes suggest the diagnosis of CLN3. Cause of CLN3 are mutations in the CLN3 gene, among which the most frequently found is the large deletion 1.02 kb spreading on exons 7 and 8. We present 4 patients from 2 families, in whom the deterioration of visual quality and acuity was observed as first clinical sign, when they were a few years old and it was successively accompanied by symptoms of neurologic deterioration (like generalized convulsions with consciousness impairment). In all patients the 1.02 kb deletion in the CLN3 gene was detected in homo- or heterozygosity with other CLN3 pathogenic variant. Ultrastructural studies revealed abnormal structures corresponding to ‘fingerprint’ profiles (FPPs) in conjunctival endothelial cells. It should be emphasized that in patients with blindness of unknown cause the diagnosis of ceroid lipofuscinosis should be considered and in older children—especially CLN3. The facility of the analysis for the presence of 1.02 kb deletion and economic costs are a solid argument for intensive use of this test in the diagnostic procedure of CLN3.
Parkinson’s disease (PD) is a neurodegenerative disease characterized by the pathological loss of nigrostriatal dopaminergic neurons, which causes an insufficient release of dopamine (DA) and then induces motor and nonmotor symptoms. Hyperoside (HYP) is a lignan component with anti-inflammatory, antioxidant, and neuroprotective effects. In this study, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active neurotoxic metabolite 1-methyl-4-phenylpyridinium ion (MPP+) were used to induce dopaminergic neurodegeneration. The results showed that HYP (100 µg/mL) reduced MPTP-mediated cytotoxicity of SH-SY5Y cells in vitro, and HYP [25 mg/(kg d)] alleviated MPTP-induced motor symptoms in vivo. HYP treatment reduced the contents of nitric oxide (NO), H2O2, and malondialdehyde (MDA), as well as the mitochondrial damage of dopaminergic neurons, both in vitro and in vivo. Meanwhile, HYP treatment elevated the levels of neurotrophic factors such as glial cell line–derived neurotrophic factor, brain-derived neurotrophic factor, and recombinant cerebral dopamine neurotrophic factor in vivo, but not in vitro. Finally, Akt signaling was activated after the administration of HYP in MPP+/MPTP-induced dopaminergic neurodegeneration. However, the blockage of the Akt pathway with Akt inhibitor did not abolish the neuroprotective effect of HYP on DA neurons. These results showed that HYP protected the dopaminergic neurons from the MPP+- and MPTP-induced injuries, which did not rely on the Akt pathway.
Microglial activation is a key event in neuroinflammation, which, in turn, is a central process in neurological disorders. In this study, we investigated the protective effects of D-beta-hydroxybutyrate (BHB) against microglial activation in lipopolysaccharide (LPS)-treated mice and BV-2 cells. The effects of BHB in mice were assessed using behavioral testing, morphological analysis and immunofluorescence labeling for the microglial marker ionizing calcium-binding adaptor molecule 1 (IBA-1) and the inflammatory cytokine interleukin-6 (IL-6) in the hippocampus. Moreover, we examined the levels of the inflammatory IL-6 and tumor necrosis factor-α (TNF-α), as well as those of the neuroprotective brain-derived neurotrophic factor (BDNF) and transforming growth factor-β (TGF-β) in the brain. In addition, we examined the effects of BHB on IL-6, TNF-α, BDNF, TGF-β, reactive oxygen species (ROS) level and cell viability in LPS-stimulated BV-2 cells. BHB treatments attenuated behavioral abnormalities, reduced the number of IBA-1-positive cells and the intensity of IL-6 fluorescence in the hippocampus, with amelioration of microglia morphological changes in the LPS-treated mice. Furthermore, BHB inhibited IL-6 and TNF-α generation, but promoted BDNF and TGF-β production in the brain of LPS-treated mice. In vitro, BHB inhibited IL-6 and TNF-α generation, increased BDNF and TGF-β production, reduced ROS level, ameliorated morphological changes and elevated cell viability of LPS-stimulated BV-2 cells. Together, our findings suggest that BHB exerts protective effects against microglial activation in vitro and in vivo, thereby reducing neuroinflammation.
Hepatic encephalopathy (HE), a subtype of delirium, is common in cirrhosis and associated with poor outcomes. Yet, objective bedside screening tools for HE are lacking. We examined the relationship between an established screening tool for delirium, Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) and short-term outcomes while comparing its performance with previously established measures of cognitive function such as West Haven criteria (WHC). Prospectively enrolled adults with cirrhosis who completed the CAM-ICU from 6/2014–6/2018 were followed for 90 days. Blinded provider-assigned West Haven Criteria (WHC) and other measures of cognitive function were collected. Logistic regression was used to test associations between CAM-ICU status and outcomes. Mortality prediction by CAM-ICU status was assessed using Area under the Receiver Operating Characteristics curves (AUROC). Of 469 participants, 11% were CAM-ICU( +), 55% were male and 94% were White. Most patients were Childs-Pugh class C (59%). CAM-ICU had excellent agreement with WHC (Kappa = 0.79). CAM-ICU( +) participants had similar demographic features to those CAM-ICU(-), but had higher MELD (25 vs. 19, p < 0.0001), were more often admitted to the ICU (28% vs. 7%, p < 0.0001), and were more likely to be admitted for HE and infection. CAM-ICU( +) participants had higher mortality (inpatient:37% vs. 3%, 30-day:51% vs. 11%, 90-day:63% vs. 23%, p < 0.001). CAM-ICU status predicted mortality with AUROC of 0.85, 0.82 and 0.77 for inpatient, 30-day and 90-day mortality, respectively. CAM-ICU easily screens for delirium/HE, has excellent agreement with WHC, and identifies a hospitalized cirrhosis cohort with high short-term mortality.
Oxidative stress (OS) is well established as a major event in Alzheimer’s disease (AD) pathology. One of the mostly-researched classes of antioxidants to manage with overwhelming OS include flavonoids. This study was aimed to investigate the protective effect of A. congolensis extract (HEEAC) on AlCl3-mediated AD-like OS and assess the contribution of its antioxidant flavonoid contents. Female Wistar (250–300 g) rats received orally 50 mg/Kg bw of AlCl3, followed one hour later by doses (150 or 300 mg/kg) of HEEAC or vitamin E at 100 mg/kg daily for eight consecutive weeks. OS related biomarkers were evaluated at the end of treatment. To assess the contribution of flavonoid contents to its activity, HEEAC was fractioned using solvent of varying polarities. Flavonoid-rich extracts obtained were tested for their antioxidant capacity. AlCl3 administration significantly lowered antioxidant enzymes (catalase, glutathione peroxidase) and aconitase levels, reduced total thiol and thiol protein levels and increased lipid peroxidation and protein oxidation levels in brain. When co-administrated with HEEAC at 150 mg/kg, all of these OS related biomarkers were significantly moderated. The efficacity of the extract was significantly higher than vitamin E. Flavonoid-rich fractions extracted mainly n-butanol fraction show strong antioxidant activity, which can be considered as the major antioxidant fraction of this plant. HEEAC protect brain cells against oxidative damage induced by AlCl3, specifically through the strong antioxidant property of its n-butanol flavonoid-rich fraction, which may be a promising agent for preventing oxidative damage in AD.
Autophagy, switched by the AMPK/mTOR signaling, has been revealed to contribute greatly to traumatic brain injury (TBI). Electroacupuncture (EA) is a promising therapeutic method for TBI, however, the underlying mechanism is still unclear. Herein, we hypothesize that the therapeutic effect of EA on TBI is associated with its inhibition on AMPK/mTOR-mediated autophagy. Sprague-Dawley rats were randomly divided into three groups: sham, TBI, and TBI + EA. TBI model was established by using an electronic controlled cortical impactor. Rats were treated with EA at 12 h after modeling, 15 min daily for 14 consecutive days. EA was applied at the acupuncture points Quchi (LI 11), Hegu (LI4), Baihui (GV20), Guanyuan (CV4), Zusanli (ST36) and Yongquan (KI1), using dense-sparse wave, at frequencies of 1 Hz, and an amplitude of 1 mA. After 3, 7 and 14 days of modeling, the modified neurological severity scale (mNSS), rota rod system, and Morris Water Maze (MWM) test showed that EA treatment promoted neurological function recovery in TBI rats. Moreover, EA treatment alleviated brain edema, pathological damage, neuronal apoptosis in TBI rats. EA improved abnormal ultrastructure, including abnormal mitochondrial morphology and increased autophagosomes, in the brain neurons of TBI rats, as measured by transmission electron microscopy, and the concentration of adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP). Western blot and immunohistochemistry (IHC) assays were performed to measure the protein levels of interleukin 10 (IL-10), autophagy-related proteins and key proteins in the AMPK/mTOR signaling pathway. EA treatment increased IL-10 production, inhibited the AMPK/mTOR signaling, and inhibited excessive autophagy in TBI rats. Additionally, AMPK inhibitor Compound C treatment had similar effects to EA. Both AMPK agonist AICAR and IL-10 neutralizing antibody treatments reversed the effects of EA on the related protein levels of autophagy and the AMPK/mTOR signaling pathway, and abolished the protective effects of EA on TBI rats. In conclusion, EA treatment promoted neurological function recovery and alleviated pathological damage and neuronal apoptosis in TBI rats through inhibiting excessive autophagy via increasing IL-10 production and blocking the AMPK/mTOR signaling pathway.
Parkinson’s disease (PD) is an age-related neurodegenerative disease. Long non-coding RNA urothelial carcinoma-associated 1 (UCA1) is involved in the pathogenesis of PD. However, the pathogenesis of PD regulated by UCA1 has not been fully explained. We used 1-Methyl-4-phenylpyridinium (MPP+)-induced SK-N-SH cells for functional analysis. Expression levels of UCA1, microRNA (miR)-671-5p, and KPNA4 (karyopherin subunit alpha 4) mRNA were detected using quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability and apoptosis were analyzed using MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) or flow cytometry assays. Some protein levels were measured by western blotting. The levels of pro-inflammatory cytokines were tested by ELISA (enzyme-linked immunosorbent assay). The levels of LDH (lactate dehydrogenase), MDA (malondialdehyde), and SOD (superoxide dismutase) were measured using corresponding kits. The relationship between UCA1 or KPNA4 and miR-671-5p was verified by dual-luciferase reporter assay and/or RNA immunoprecipitation (RIP) assay. MPP+ induced UCA1 expression in SK-N-SH cells in a concentration-dependent manner or time-dependent manner. UCA1 knockdown reduced MPP+-induced apoptosis, inflammation, and oxidative stress in SK-N-SH cells. MiR-671-5p was downregulated while KPNA4 was upregulated in MPP+-treated SK-N-SH cells. UCA1 sponged miR-671-5p to regulate KPNA4 expression. MiR-671-5p inhibition counteracted UCA1 knockdown-mediated influence on apoptosis, inflammation, and oxidative stress of MPP+-induced SK-N-SH cells. KPNA4 overexpression offset the inhibitory influence of miR-671-5p mimic on apoptosis, inflammation, and oxidative stress of MPP+-treated SK-N-SH cells. UCA1 inhibition reduced MPP+-induced neuronal damage through the miR-671-5p/KPNA4 pathway in SK-N-SH cells, providing a novel mechanism to understand the pathogenesis of PD.
Hepatic Encephalopathy (HE) is a critically important complication of chronic liver disease and portal hypertension, but especially in early covert stages remains underdiagnosed and a common cause of hospitalization and morbidity. Defined by often subtle neuropsychiatric changes, significant cognitive deficits have been extensively described. While traditional methods of assessment remain underutilized in practice and subject to significant confounding with other diseases, mobile technology has emerged as a potential future tool to provide simple and dynamic cognitive assessments. This review discusses the proliferation of cognitive assessment tools, describing possible applications in encephalopathy and the challenges such an implementation may face. There are significant potential advantages to assessing cognition in real time in order to aid early detection and intervention and provide a more realistic measurement of real-world function. Despite this, there are issues with reliability, privacy, applicability and more which must be addressed prior to wide proliferation and acceptance for clinical use. Regardless, the rapid uptake of mobile technology in healthcare is likely to have significant implications for the future management of encephalopathy and liver disease at large.
L-Cysteine (L-Cys) is a semi-essential amino acid. It serves as a substrate for enzyme cystathionine-β-synthase in the central nervous system (CNS). L-Cys showed various antioxidant characteristics. Though, studies on the effect of free L-Cys administration to evaluate the CNS functioning is very limited. Therefore, we assessed the effects of L-Cys on corticosterone (CORT) induced oxidative stress, behavioral deficits and memory impairment in male rats. L-Cys (150 mg/kg/ml) administered to vehicle and CORT (20 mg/kg/ml) treated rats orally for 28 days. Behavioral activities were conducted after treatment period. Subsequently, rats were sacrificed, blood and brain were removed. Hippocampus was isolated from brain and then hippocampus and plasma were collected for oxidative, biochemical and neurochemical analysis. Results showed that repeated treatment of L-Cys produced antidepressant, anxiolytic and memory-improving effects which may be ascribed to the enhanced antioxidant profile, normalized cholinergic, serotonergic neurotransmission in brain (hippocampus) following CORT administration. Increased plasma CORT by CORT administration was also normalized by L-Cys. The current study concluded that administration of free L-Cys improved the behavioral, biochemical, neurochemical and redox status of CNS. Hence, L-Cys could be protective therapeutic modulator against stress induced neurological ailments.
The altered expression of microRNA (miRNA) has been implicated in glioma. Here, the current study aimed to clarify the oncogenic effects of miR-19b-3p on cellular processes of glioma and to elucidate the underlying mechanism associated with SOCS3 and the JAK-STAT signaling pathway. Differentially expressed genes related to glioma were initially identified via microarray analysis. Twenty-five glioma patients were selected for clinical data collection, while additional 12 patients with traumatic brain injuries were selected as controls. Cell senescence was assessed by β-galactosidase staining, proliferation by MTT assay and apoptosis by flow cytometry following gain- and/or loss-of-function of miR-19b-3p or SOCS3. Glioma xenograft mouse model was developed through subcutaneous injection to nude mice to provide evidence in vivo. The glioma patients exhibited overexpressed miR-19b-3p and poorly-expressed SOCS3. SOCS3 was identified as a target gene of miR-19b-3p through dual-luciferase reporter gene assay. miR-19b-3p repressed SOCS3 expression and activated the JAK-STAT signaling pathway. Furthermore, miR-19b-3p inhibition promoted apoptosis and senescence, and suppressed cell proliferation through inactivation of the JAK-STAT signaling pathway and up-regulation of SOCS3. The reported regulatory axis was validated in nude mice as evidenced by suppressed tumor growth. Taken together, this study demonstrates that miR-19b-3p facilitates glioma progression via activation of the JAK-STAT signaling pathway by targeting SOCS3, highlighting a novel therapeutic target for glioma treatment.
Alpiniae Oxyphyliae Fructus (AOF) (yizhi) is a frequently medicated Chinese herb for Alzheimer disease (AD) treatment. The present study investigated the components and potential mechanisms of AOF through network pharmacology analysis and molecular docking. The results showed that AOF contains at least 20 active ingredients and involves 184 target genes. A total of 301 AD-related genes were obtained from the DisGeNET, GeneCards, GEO, OMIM, and Alzheimer Disease: Genes databases. A total of 41 key targets were identified from the topology analysis of the AOF-AD target network. These key targets are involved in 105 signal pathways, such as the PI3K-Akt, HIF-1, and MAPK pathways, and can regulate gene transcription, cell death, cell proliferation, drug response, and protein phosphorylation. AOF’s active ingredients, Chrysin, Isocyperol, Izalpinin, Linolenic acid, CHEMBL489541, Oxyphyllenone A, Oxyphyllenone B, and Oxyphyllol C, show high affinity to targets, including PPARG, ESR1, and AKT1. These findings provide a new basis for AOF application and anti-AD study.
Neuroinflammation plays an essential role in the pathogenesis of Alzheimer’s disease. The preventive effect of physical exercise on attenuating neuroinflammation has not been completely defined. Levisticum officinale is known as a medicinal plant with antioxidant and anti-inflammatory properties. The current study was designed to investigate the neuroprotective impacts of treadmill running and Levisticum officinale on lipopolysaccharide (LPS)-induced learning and memory impairments and neuroinflammation in rats. Male Wistar rats ran on a treadmill and/or were pretreated with Levisticum officinale extract at a dose of 100 mg/kg for a week. Then, rats received intraperitoneal injection of LPS at a dose of 1 mg/kg. Treadmill running and/or treatment of extract lasted three more weeks. Behavioral, molecular, biochemical and immunohistochemical assessments were carried out after the end of the experiment. LPS administration resulted in spatial learning and memory impairments along with increased mRNA expression of interleukin-6 and malondialdehyde levels, as well as decreased superoxide dismutase activity and neurogenesis in the hippocampus. Moreover, treadmill running for four weeks, alone and in combination with Levisticum officinale extract attenuated spatial learning and memory deficits, decreased the mRNA expression of interleukin-6 and malondialdehyde levels, and enhanced superoxide dismutase activity and neurogenesis in the hippocampus. In conclusion, the advantageous effects of running exercise and Levisticum officinale extract on LPS-induced memory impairments are possibly due to the antioxidant and anti-inflammatory activity and enhancing neurogenesis.
Ischemic stroke is one of major causes of disability. In the pathological process of ischemic stroke, the up-regulation of Ras homolog gene family, member A (RhoA) and its downstream effector, Ras homolog gene family (Rho)-associated coiled coil-containing kinase (ROCK), contribute to the neuroinflammation, blood-brain barrier (BBB) dysfunction, neuronal apoptosis, axon growth inhibition and astrogliosis. Accumulating evidences have revealed that hydrogen sulphide (H2S) could reduce brain injury in animal model of ischemic stroke via inhibiting the RhoA/ROCK pathway. Recently, noncoding RNAs (ncRNAs) such as circular RNAs (circRNAs), long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) have attracted much attention because of their essential role in adjusting gene expression both in physiological and pathological conditions. Numerous studies have uncovered the role of RhoA/ROCK pathway and ncRNAs in ischemic stroke. In this review, we focused on the role of H2S, RhoA/ROCK pathway and ncRNAs in ischemic stroke and aimed to reveal new strategies for preventing and treating this devastating disease.
Sleep deprivation (SD) is prevalent throughout the world, which has negative effects on cognitive abilities, and causing mood alterations. 8-O-acetyl shanzhiside methylester (8-OaS), a chief component in Lamiophlomis rotata (L. rotata) Kudo, possesses potent neuroprotective properties and analgesic effects. Here, we evaluated the alleviative effects of 8-OaS on memory impairment and anxiety in mice subjected to SD (for 72-h). Our results demonstrated that 8-OaS (0.2, 2, 20 mg/kg) administration dose-dependently ameliorated behavioral abnormalities in SD mice, accompanied with restored synaptic plasticity and reduced shrinkage and loss of hippocampal neurons. 8-OaS reduced the inflammatory response and oxidative stress injury in hippocampus caused by SD, which may be related to inhibition of NLRP3 inflammasome-mediated inflammatory process and activation of the Nrf2/HO-1 pathway. SD also led to increases in the expressions of TLR-4/MyD88, active NF-κB, pro-IL-1β, TNFα and MDA, as well as a decrease in the level of SOD in mice hippocampus, which were reversed by 8-OaS administration. Moreover, our molecular docking analyses showed that 8-OaS also has good affinity for NLRP3 and Nrf2 signaling pathways. These results suggested that 8-OaS could be used as a novel herbal medicine for the treatment of sleep loss and for use as a structural base for developing new drugs.
Microglia are resident immune cells in the brain and are closely associated with central nervous system inflammation and neurodegenerative diseases. It is known that mammalian target of rapamycin (mTOR) pathway plays an important role in the polarization of microglia. Castor1 has been identified as the cytosolic arginine sensor for the mTOR complex 1 (mTORC1) pathway, but the role of Castor1 in microglial polarization is still unknown. The purpose of this study was to explore the regulatory effect of Castor1 on microglial polarization and the underlying mechanism. The results demonstrated that Castor1 expression was significantly decreased in lipopolysaccharides (LPS) and interferon (IFN)-γ treated microglia. Castor1 overexpression inhibited the microglia M1 polarization by reducing the expression of M1 related markers. However, the expression of M2-related genes was promoted when Castor1 was overexpressed in IL-4 treated microglia. Mechanistically, Castor1 overexpression inhibited the activation of mTOR signaling pathway. In addition, after treatment with the mTOR activator MHY1485, the inhibitory effect of Castor1 overexpression on M1 polarization was attenuated, indicating that the regulation effects of Castor1 on M1 polarization was dependent on its inhibition of mTOR pathway. We propose that Castor1-mTOR signaling pathway could be considered as a potential target for treatment and intervention of central nervous system-related diseases by regulating microglia polarization.
Alterations in the apoptosis pathway have been linked to changes in serotonin levels seen in autistic patients. Cc2d1a is a repressor of the HTR1A gene involved in the serotonin pathway. The hippocampus and hypothalamus of Cc2d1a ± mice were analyzed for the expression of apoptosis markers (caspase 3, 8 and 9). Gender differences were observed in the expression levels of the three caspases consistent with some altered activity in the open-field assay. The number of apoptotic cells was significantly increased. We concluded that apoptotic pathways are only partially affected in the pathogenesis of the Cc2d1a heterozygous mouse model.
A) Apoptosis is suppressed because the cell does not receive a death signal, or the receptor cannot activate the caspase 8 pathway despite the death signal. B) Since Caspase 8 and Caspase 3 expression is downregulated in our mouse model, the mechanism of apoptosis is not activated.
The globus pallidus has emerged as a crucial node in the basal ganglia motor control circuit under both healthy and parkinsonian states. Previous studies have shown that angiotensin II (Ang II) and angiotensin subtype 1 receptor (AT1R) are closely related to Parkinson’s disease (PD). Recent morphological study revealed the expression of AT1R in the globus pallidus of mice. To investigate the functions of Ang II/AT1R on the globus pallidus neurons of both normal and parkinsonian rats, electrophysiological recordings and behavioral tests were performed in the present study. Electrophysiological recordings showed that exogenous and endogenous Ang II mainly excited the globus pallidus neurons through AT1R. Behavioral tests further demonstrated that unilateral microinjection of Ang II into the globus pallidus induced significantly contralateral-biased swing in elevated body swing test (EBST), and bilateral microinjection of Ang II into the globus pallidus alleviated catalepsy and akinesia caused by haloperidol. AT1R was involved in Ang II-induced behavioral effects. Immunostaining showed that AT1R was expressed in the globus pallidus of rats. On the basis of the present findings, we concluded that pallidal Ang II/AT1R alleviated parkinsonian motor deficits through activating globus pallidus neurons, which will provide a rationale for further investigations into the potential of Ang II in the treatment of motor disorders originating from the basal ganglia.
BackgroundIL-10 knockout (KO) mice can be protected against experimental autoimmune encephalomyelitis (EAE) with low-dose estrogen (E2) treatment similar to wild type (WT) mice, indicating that IL-10 is not required for E2-induced EAE protection. Our previous study demonstrated that E2 treatment induced an increase in programmed death ligands 1 (PD-L1) and 2 (PD-L2) on monocytes and macrophages in the periphery and within the CNS. In this study, we selectively inhibited the function of PD-L1 and PD-L2 to evaluate their critical role in maintaining E2-induced protection against EAE in IL-10-KO mice.Methods
This study used female IL-10 KO mice pre-treated with either E2 or sham pellets seven days prior to induction of EAE and subsequently treated with Vehicle or antibodies to PD-L1, PD-L2 or respective isotype controls. Mice were scored daily for EAE severity over 21 days post-EAE induction. Cells from the spleen and brain were evaluated by flow cytometry.ResultsDifferences in EAE severity were assessed in E2 and sham pre-treated IL-10-KO mice treated with α-PD-L1 or α-PD-L2 antibodies over the course of disease compared to treatment with Vehicle or isotype control antibodies. The results revealed real-time development of severe EAE in E2-pre-treated IL-10-KO mice treated with α-PD-L1 but not α-PD-L2 antibodies, mediated in part by increased percentages of activated CD74+CD11b+ myeloid cells in spleen and brain as well as splenic B-cells, T-cells and CD73+ cells.Conclusion
These results demonstrate unequivocally that PD-L1 but not PD-L2 was required to retain the inhibitory effects of E2 on clinical EAE scores in female IL-10-KO mice and further implicate the emergence of the MIF/CD74 axis as a contributing pathogenic mechanism.
Glioma is a common tumor in the brain. CircRNA hsa_circ_0030018, also termed as hsa_circPOSTN_001 (circ_POSTN), is reported to exert a promoting influence on the development of glioma. Our study intends to deeply explore its regulation mechanism of circ_POSTN. Expression of circ_POSTN, microRNA-433-3p (miR-433-3p) and Secreted protein acidic and rich in cysteine (SPARC) was detected by qRT-PCR or western blot assay. The function of circ_POSTN was analyzed by loss-of-function experiments. The targeting relationship between miR-433-3p and circ_POSTN or SPARC was predicted by bioinformatics analysis and validated by dual-luciferase reporter assay. Xenograft modeling was employed to validate the function of circ_POSTN in glioma in vivo. circ_POSTN and SPARC were upregulated while miR-433-3p was downregulated in glioma tissues and cells. Both circ_POSTN and SPARC knockdown inhibited clonogenicity, migration, and promoted apoptosis of glioma cells. Circ_POSTN sponged miR-433-3p to regulate SPARC expression. Gain of SPARC largely attenuated circ_POSTN knockdown or miR-433-3p overexpression-mediated effects on glioma cell clonogenicity, migration, and apoptosis. Furthermore, silencing of circ_POSTN decreased xenograft tumor growth in vivo. Inhibition of circ_POSTN repressed glioma development, at least in part, via regulating the miR-433-3p/SPARC axis, providing evidence for circ_POSTN as a potential therapeutic target for glioma.
Niemann-Pick C disease (NPC) is an autosomal recessive genetic disorder resulting from mutation in one of two cholesterol transport genes: NPC1 or NPC2, causing accumulation of unesterified cholesterol, together with glycosphingolipids, within the endosomal/lysosomal compartment of cells. The result is a severe disease in both multiple peripheral organs and the central nervous system, causing neurodegeneration and early death. However, the pathophysiological mechanisms of NPC1 remain poorly understood. Recent studies have shown that the primary lysosomal defect found in fibroblasts from NPC1 patients is accompanied by a deregulation of mitochondrial organization and function. There is currently no cure for NPC1, but recently the potential of β-cyclodextrin (β-CD) for the treatment of the disease was discovered, which resulted in the redistribution of cholesterol from subcellular compartments to the circulation and increased longevity in an animal model of NPC1. Considering the above, the present work evaluated the in vitro therapeutic potential of β-CD to reduce cholesterol in fibroblasts from NPC1 patients. β-CD was used in its free and nanoparticulate form. We also evaluated the β-CD potential to restore mitochondrial functions, as well as the beneficial combined effects of treatment with antioxidants N-Acetylcysteine (NAC) and Coenzyme Q10 (CoQ10). Besides, we evaluated oxidative and nitrative stress parameters in NPC1 patients. We showed that oxidative and nitrative stress could contribute to the pathophysiology of NPC1, as the levels of lipoperoxidation and the nitrite and nitrate levels were increased in these patients when compared to healthy individuals, as well as DNA damage. The nanoparticles containing β-CD reduced the cholesterol accumulated in the NPC1 fibroblasts. This result was potentiated by the concomitant use of the nanoparticles with the antioxidants NAC and CoQ10 compared to those presented by healthy individuals cells ́. In addition, treatments combining β-CD nanoparticles and antioxidants could reduce mitochondrial oxidative stress, demonstrating advantages compared to free β-CD. The results obtained are promising regarding the combined use of β-CD loaded nanoparticles and antioxidants in the treatment of NPC1 disease.
The effect of Celastrol on cerebral ischemia-reperfusion remains unknown. The study aims to explore the role of circular RNA DLGAP4 (circDLGAP4) in cerebral ischemia-reperfusion and the underlying mechanism. Ischemia-reperfusion (I/R) injury of human brain microvascular endothelial cells (HBMECs) was induced by oxygen-glucose deprivation and reoxygenation (OGD/R). Reverse transcription quantitative real-time PCR (RT-qPCR) and western blotting analysis were performed to detect the expression of circDLGAP4, microRNA-6085 (miR-6085), growth differentiation factor 11 (GDF11), B-cell lymphoma-2 (BCL2) and BCL2-associated x protein (BAX). Cell viability, proliferation, and apoptosis were analyzed by cell counting kit-8, 5-Ethynyl-2’-deoxyuridine and flow cytometry analysis. Oxidative stress was analyzed by evaluating the levels of Malondialdehyde (MDA) and Reactive Oxygen Species (ROS) and the activity of Superoxide Dismutase (SOD). The associations among circDLGAP4, miR-6085 and GDF11 were identified by dual-luciferase reporter, RNA immunoprecipitation (RIP) and RNA pull-down assays. Celastrol reduced OGD/R-induced inhibition of circDLGAP4 expression in HBMECs. Celastrol treatment protected HBMECs from OGD/R-induced cell proliferation inhibition and apoptosis and oxidative stress promotion; however, circDLGAP4 depletion attenuated these effects. CircDLGAP4 acted as a sponge for miR-6085, and miR-6085 mimics restored circDLGAP4-mediated effects in OGD/R-stimulated HBMECs. In addition, GDF11 was identified as a targte of miR-6085, and participated in the regulation of miR-6085 to OGD/R-induced HBMEC damage. Further, circDLGAP4 absence inhibited GDF11 expression by interacting with miR-6085 under Celastrol treatment. Celastrol ameliorated OGD/R-induced HBMEC apoptosis and oxidative stress by circDLGAP4/miR-6085/GDF11 pathway, supporting the use of Celastrol as a therapeutic agent for cerebral infarction.
Transjugular intrahepatic portosystemic shunt (TIPS) has been used since more than 25 years to treat some of the complications of portal hypertension, especially variceal bleeding and ascites refractory to conventional therapy. TIPS establishes a communication between the portal and hepatic veins, inducing the blood to shift from the splanchnic circulation into the systemic vascular bed with the aim of decompressing the portal venous system, and avoids the major complications of portal hypertension. However, the shunt of the portal blood into the systemic circulation is the cause of one of the major complications of the procedure: the post-TIPS hepatic encephalopathy (HE). To date, few pharmacological treatment has been proven effective to prevent this complication and thus, the identification of patients at high risk of post-TIPS hepatic encephalopathy and the patients’ carefully selection is the only way to prevent this frequent complication.
Parkinson’s disease (PD) is slowly developing neurodegenerative disorder associated with gradual decline in cerebration and laboriousness to perform routine piece of work. PD imposed a social burden on society through higher medical cost and by loss of social productivity in current era. The available treatment options are expensive and associated with serious adverse effect after long term use. Therefore, there is a critical clinical need to develop alternative pharmacotherapies from natural sources to prevent and cure the pathological hall marks of PD with minimal cost. Our study aimed to scrutinize the antiparkinsonian potential of curcuminoids-rich extract and its binary and ternary inclusion complexes. In healthy rats, 1 mg/kg haloperidol daily intraperitoneally, for 3 weeks was used to provoke Parkinsonism like symptoms except control group. Curcuminoids rich extract, binary and ternary inclusion complexes formulations 15–30 mg/kg, L-dopa and carbidopa (100 + 25 mg/kg) were orally administered on each day for 3 weeks. Biochemical, histopathological and RT-qPCR analyses were conducted after neurobehavioral observations. Findings of current study indicated that all curcuminoids formulations markedly mitigated the behavioral abnormalities, recovered the level of antioxidant enzymes, acetylcholinesterase inhibitory activity and neurotransmitters. Histological analysis revealed that curcuminoids supplements stabilized the neuronal loss, pigmentation and Lewy bodies’ formation. The mRNA expressions of neuro-inflammatory and specific PD pathological biomarkers were downregulated by treatment with curcuminoids formulations. Therefore, it is suggested that these curcuminoids rich extract, binary and ternary supplements should be considered as promising therapeutic agents in development of modern anti-Parkinson’s disease medications.
The aim was to investigate the association between plasma levels of cellular adhesion molecules (CAMs) and risk factors, subtypes, severity and short-term mortality of acute ischemic stroke (IS), and to identify a panel of biomarkers to predict short-term mortality after IS. The prospective study evaluated 132 IS patients within 24 h of their hospital admission. The baseline IS severity was assessed using the National Institutes Health Stroke Scale (NIHSS) and categorized as mild (NIHSS < 5), moderate (NIHSS 5–14) and severe (NIHSS ≥ 15). After three-month follow-up, the disability was assessed using the modified Rankin Scale (mRS); moreover, the patients were classified as survivors and non-survivors. Baseline inflammatory and anti-inflammatory cytokines and soluble CAMs were evaluated. Twenty-nine (21.9%) IS patients were non-survivors and showed higher NIHSS and soluble vascular cellular adhesion molecule 1 (sVCAM-1) than the survivors. The sVCAM-1 levels positively correlated with age, homocysteine, severity, and disability. The model #3 combining sVCAM-1 and NIHSS showed better results to predict short-term mortality with an area under the curve receiving operating characteristics (AUC/ROC) of 0.8841 [95% confidence interval (CI): 0.795–0.941] than the models with sVCAM-1 and NIHSS alone, with positive predictive value of 68.0%, negative predictive value of 91.3%, and accuracy of 86.5%. In conclusion, the combined model with baseline severity of IS and sVCAM-1 levels can early predict the prognosis of IS patients who may benefit with therapeutic measures of personalized therapy that taken into account these biomarkers. Moreover, this result suggests that VCAM-1 might be a potential target for the therapeutic strategies in IS.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by both motor and non-motor features. The current treatment regimen for PD are dopamine enhancers which have been reported to worsen the disease prognosis after long term treatment, thus, the need for better treatment options. This study sought to investigate the protective action of Double Stem Cell® (DSC), a blend of stem cells extracts from Swiss apples (Malus Domestica) and Burgundy grapes (Vitis vinifera) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism in mice and genetic model of PD in Drosophila melanogaster. Male albino mice were pretreated with MPTP (4 × 20 mg/kg, i.p., two hourly in 8 h), twelve hours before administration of DSC (8, 40, or 200 mg/kg, p.o.). Thereafter, behavioural, biochemical and immunohistochemical assays were carried out. The impact of vehicle or DSC supplementation on α-synuclein aggregation was evaluated in Drosophila melanogaster using the UAS-Gal4 system, female DDC-Gal4 flies were crossed with male UAS-α-synuclein, the progenies were examined for fecundity, locomotion, memory, and lifespan. MPTP-induced motor deficits in open field test (OFT), working memory impairment (Y-maze test (YMT)) and muscle incoordination (rotarod test) were ameliorated by DSC (8, 40 or 200 mg/kg) through dose-dependent and significant improvements in motor, cognitive and motor coordination. Moreso, MPTP exposure caused significant increase in lipid peroxidation and decrease in antioxidant enzymes activities (glutathione, catalase and superoxide dismutase) in the midbrain which were attenuated by DSC. MPTP-induced expression of microglia (iba-1), astrocytes (glia fibrillary acidic protein; GFAP) as well as degeneration of dopamine neurons (tyrosine hydroxylase positive neurons) in the substantia nigra (SN) were reversed by DSC. Supplementation of flies feed with graded concentration of DSC (0.8, 4 or 20 mg/ml) did not affect fecundity but improved climbing activity and lifespan. Findings from this study showed that Double Stem Cell improved motor and cognitive functions in both mice and Drosophila through attenuation of neurotoxin-induced oxidative stress and neuroinflammation.
Spontaneous portosystemic shunts (SPSS) are an often neglected cause of hepatic encephalopathy associated with cirrhosis. Nowadays, SPSS are considered as radiological biomarkers of clinically significant portal hypertension rather than the previous dogmatic perceived decompressive vessels. SPSS are not rare as they can be diagnosed in over 60% of the patients with cirrhosis by mere contrast-enhanced CT. Moreover, they are clinically relevant since they impact on all portal hypertensive related complications, in particular medically refractory HE, and represent an independent predictor of decompensation and mortality in cirrhosis, irrespective of the type of SPSS. Taken together, these elements warrant strategies to target these shunts directly which is currently is achieved via interventional radiology embolization. In this review, we discuss why it makes sense to tackle SPSS, how to do it and what it takes to do it right based on aggregated literature.
Treatment of epilepsy remains a major problem as some epileptic patients do not respond to the current therapeutics. Transient receptor potential ankyrin 1 (TRPA1) belongs to the TRP channels and has diverse physiological functions in the body. Considering its physiological properties, we aimed to evaluate its role in two experimental models of epilepsy, including pentylenetetrazol (PTZ)-induced acute seizure and PTZ-evoked kindling. Furthermore, the TRPA1 protein levels were assessed in the cerebral cortex, hippocampus, and cerebellum after seizure induction. Three groups of Wistar rats received acute intraperitoneal injection of pentylenetetrazol (PTZ, 85 mg/kg). The groups received intraventricular injections of vehicle (dimethyl sulfoxide, Tween 80, and sterile 0.9% saline), valproate (30 µg/rat), or HC030031 (TRPA1 antagonist, 14 µg/rat) before PTZ injection. In the PTZ-induced kindling model, PTZ was administrated 35 mg/kg every other day for 24 days. PTZ gradually provoked seizure-related behaviors. After experiments, the TRPA1 levels in the brain were assessed using western blot. The results showed that HC030031 reduced the median of seizure scores and S5 duration while increasing S2 and S5 latencies in acute and kindling models. The anticonvulsant effect of HC030031 was comparable with valproate as a standard anticonvulsant drug. Furthermore, induction of seizure, either acute or kindling, enhanced TRPA1 levels in the cerebral cortex, hippocampus, and cerebellum that were prevented by HC030031 or valproate administration. The results of this study showed that HC030031 as a TRPA1 receptor antagonist promoted a significant anticonvulsant effect comparable with valproate. Both drugs prevented TRPA1 upregulation during seizures. These findings imply that TRPA1 is a potential target in treating epilepsy.
In this review article, we aimed to discuss intricate roles of SD in modulating depression in preclinical and clinical studies. Decades of research have shown the inconsistent effects of SD on depression, focusing on SD duration. However, inconsistent role of SD seems to be more complicated, and SD duration cannot be the only one factor. Regarding this issue, we chose some important factors involved in the effects of SD on cognitive functions and mood including brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), serotonin, cortisol, and tumor necrosis factor-alpha (TNF-α). It was concluded that SD has a wide-range of inconsistent effects on BDNF, VEGF, serotonin, and cortisol levels. It was noted that BDNF diurnal rhythm is significantly involved in the modulatory role of SD in depression. Furthermore, the important role of VEGF in blood–brain barrier permeability which is involved in modulating depression was discussed. It was also noted that there is a negative correlation between cortisol and BDNF that modulates depression. Eventually, it was concluded that TNF-α regulates sleep/wake cycle and is involved in the vulnerability to cognitive and behavioral impairments following SD. TNF-α also increases the permeability of the blood–brain barrier which is accompanied by depressive behavior. In sum, it was suggested that future studies should focus on these mechanisms/factors to better investigate the reasons behind intricate roles of SD in modulating depression.