ABSTRACT
Stroke is recognized as a leading cause of disability and mortality worldwide, posing a significant challenge, particularly in developing countries. The current study aimed to evaluate the neuroprotective effect of Ganoderic acid (GA) against focal ischemic stroke in rats. MATERIAL AND METHODS: Swiss Wistar rats were used for the current study. The rats were subjected to middle cerebral artery occlusion (MCAO) to simulate transient focal ischemia, followed by reperfusion. Various neurological parameters, including infarct size, neurological deficit score, brain water content, Evans blue leakage, nitric oxide (NO), inducible nitric oxide synthase (iNOS), lactate dehydrogenase (LDH), antioxidant levels, inflammatory cytokines, apoptosis markers, inflammatory parameters, and matrix metalloproteinases (MMP) levels, were estimated. Additionally, mRNA expressions were evaluated in the brain tissue. RESULTS: Dose dependently treatment of GA significantly (P < 0.001) suppressed the infarct size, neurological deflects score, brain water, evans blue leakage, NO, iNOS, LDH, C-X-C chemokine receptor type 4 (CXCR-4), monocyte chemoattractant protein-1 (MCP-1), S100 calcium-binding protein B (S-100ß) and K+-Cl- cotransporter 1 (KCC1) positive cells. GA altered the level of oxidative stress parameters like Total antioxidant capacity (T-AOC), 8-hydroxy-2'-deoxyguanosine (8-OhdG), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH), malonaldehyde (MDA); cytokines viz., tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-1ß, IL-6, IL-9, IL-10; inflammatory parameters such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), prostaglandin (PGE2), Nuclear factor kappa B (NF-κB); apoptosis parameters like B-cell leukemia/lymphoma 2 protein (Bcl-2), Bcl-2-associated protein x (Bax), Caspase-3; matrix metallopeptidase (MMP) parameters like MMP-2, MMP-3, and MMP-9, respectively. GA remarkably suppressed the mRNA expression of TRL-4, Syndecan-1, CSF, Aquaporin-1, OCT3, and RFX1. CONCLUSION: Ganoderic acid exhibited the protection against the cerebral ischemia reperfusion via multiple mechanism.
ABSTRACT
BACKGROUND: Acid phosphatase type 6 (ACP6) is a mitochondrial lipid phosphate phosphatase that played a role in regulating lipid metabolism and there is still blank in the clinico-pathological significance and functional roles of ACP6 in human cancers. No investigations have been conducted on ACP6 in hepatocellular carcinoma (HCC) up to date. METHODS: Herein, we appraised the clinico-pathological significance of ACP6 in HCC via organizing expression profiles from globally multi-center microarrays and RNA-seq datasets. The molecular basis of ACP6 in HCC was explored through multidimensional analysis. We also carried out in vitro and in vivo experiment on nude mice to investigate the effect of knocking down ACP6 expression on biological functions of HCC cells, and to evaluate the expression variance of ACP6 in xenograft of HCC tissues before and after the treatment of NC. RESULTS: ACP6 displayed significant overexpression in HCC samples (standard mean difference (SMD) = 0.69, 95% confidence interval (CI) = 0.56-0.83) and up-regulated ACP6 performed well in screening HCC samples from non-cancer liver samples. ACP6 expression was also remarkably correlated with clinical progression and worse overall survival of HCC patients. There were close links between ACP6 expression and immune cells including B cells, CD8 + T cells and naive CD4 + T cells. Co-expressed genes of ACP6 mainly participated in pathways including cytokine-cytokine receptor interaction, glucocorticoid receptor pathway and NABA proteoglycans. The proliferation and migration rate of HCC cells transfected with ACP6 siRNA was significantly suppressed compared with those transfected with negative control siRNA. ACP6 expression was significantly inhibited by nitidine chloride (NC) in xenograft HCC tissues. CONCLUSIONS: ACP6 expression may serve as novel clinical biomarker indicating the clinical development of HCC and ACP6 might be potential target of anti-cancer effect by NC in HCC.
Subject(s)
Acid Phosphatase , Carcinoma, Hepatocellular , Liver Neoplasms , Animals , Humans , Mice , Acid Phosphatase/genetics , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Mice, Nude , RNA, Small InterferingABSTRACT
BACKGROUND Hepatocellular carcinoma (HCC) causes a heavy disease burden worldwide. Cell division cycle 45 (Cdc45) and its encoding gene (CDC45) have been studied for a long time, but their expression patterns and roles in liver carcinogenesis and advanced HCC deterioration are still incompletely understood. This study integrated tissue microarray and bioinformatics analyses to explore the expression and clinical value of CDC45 and Cdc45 in HCC. MATERIAL AND METHODS In HCC, the expression and relationships with clinic-pathological parameters of CDC45 and Cdc45 were investigated by integrating the RNA-sequencing data, downloaded from The Cancer Genome Atlas and Oncomine databases, and tissue microarray with immunohistochemistry staining. Co-expressed genes and genetic alterations of CDC45 separately obtained from Oncomine and cBioPortal databases were identified to shed light on the potential mechanisms of CDC45 in HCC. RESULTS CDC45 and Cdc45 were both overexpressed in HCC tissues, and the CDC45 level progressively increased from stage I to III. The survival outcomes of the group with high CDC45 expression were significantly worse compared with the group with low expression. Amplification and deep deletion were 2 major significant alteration types in HCC patients, and the outcomes were worse in patients with altered versus unaltered CDC45. NUDT1, E2F1, CCNE2, MCM5, and CENPM were identified as the most significantly co-expressed genes. CONCLUSIONS CDC45 and Cdc45 were both upregulated in HCC, and increased expression levels and genetic alternations of CDC45 were correlated with worse prognosis in HCC patients. CDC45 may promote HCC by co-expressing with NUDT1, E2F1, CCNE2, MCM5, and CENPM.
Subject(s)
Carcinoma, Hepatocellular/genetics , Cell Cycle Proteins/genetics , Biomarkers, Tumor/genetics , Cell Cycle Proteins/metabolism , Computational Biology/methods , Gene Expression , Gene Expression Profiling/methods , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/genetics , Prognosis , Sequence Analysis, RNA , TranscriptomeABSTRACT
BACKGROUND: Polyphenols extracted from plants are usually highly unstable and rapidly transformed into various reaction products during food and drug processing, thus limiting their applications. To improve the stability and solubility of polyphenols from the leaves of Chinese star anise (Illicium verum Hook. f.), and hence to expand their application to food and medicine, the extracted anise leaf polyphenols (ALPs) were microencapsulated using ß-cyclodextrin (ß-CD) and cyclodextrin-based metal-organic frameworks (ß-CD-MOFs). RESULTS: The optimum inclusion rate of ALP/ß-CD-MOFs was 97.80% at a core-wall ratio of 1:10. Meanwhile, the stabilities, solubilities and antioxidant activities of the polyphenols before and after inclusion were compared. The results showed both the stabilities and solubilities of ALP/ß-CD-MOFs were significantly improved compared with those of ALPs and ALP/ß-CD, suggesting the potential of ß-CD-MOFs as newer and better carriers than ß-CD for polyphenols in food industry applications. The free radical (including superoxide, hydroxyl and DPPH radicals) scavenging activities were also improved by microencapsulation. Superoxide radical scavenging reaction also showed slow-release property of ALP/ß-CD-MOFs. The formation of the inclusion complex was further confirmed using Fourier transform infrared spectral characterization. CONCLUSIONS: Microencapsulation with ß-CD-MOFs could expand the application scope of ALPs, and it is more effective than encapsulation with ß-CD. This is important for a better understanding and application of this useful traditional Chinese plant. As a new material with high efficiency and edibility, ß-CD-MOFs are not limited to the chemical field, but also have potential in new areas of food, medicine and healthcare products. © 2020 Society of Chemical Industry.
Subject(s)
Antioxidants/chemistry , Illicium/chemistry , Metal-Organic Frameworks/chemistry , Plant Extracts/chemistry , Polyphenols/chemistry , beta-Cyclodextrins/chemistry , Plant Leaves/chemistryABSTRACT
The aim of this study was to investigate the inhibitory effect of regulation of miR-122-MAP3K2 signal pathway on the hepatitis B cells. We detected the content of MAP3K2 from patients with HBV blood serum samples and analyzed the correlation between content of MAP3K2 and copies of HBV-DNA. Wound healing and Transwell assays were used to detect the function of cells from control group (wild type) and observer group (overexpresses miR-122). Secretion levels of HBsAg and MAP3K2 in the supernatant and level of MAP3K2 in cells were detected by ELISA and western blot, respectively. The results showed that there was a positive correlation between the copies of HBV-DNA and MAP3K2 in serum. In the assays involving detection of the number of HBV-DNA copies, the supernatant levels of HBsAg and MAP3K2, and the level of MAP3K2 in the cells, the rate of increase of these indicators significantly slowed as culture time. In conclusion, overexpression of miR-122 could inhibit the migration of hepatoblastoma cells; however, following transfection with miR-122, DNA synthesis and the secretion of HBsAg were inhibited. Overexpression of miR-122 can also downregulate MAP3K2. Consequently, we concluded that regulating the miR-122-MAP3K2 signaling pathway exerts an inhibitory effect in hepatitis B cells.
Subject(s)
B-Lymphocytes/metabolism , Hepatitis B virus/genetics , Hepatitis B/metabolism , MAP Kinase Kinase Kinases/metabolism , MicroRNAs/metabolism , Signal Transduction/genetics , Blotting, Western , DNA, Viral/genetics , Enzyme-Linked Immunosorbent Assay , Hepatitis B/pathology , Humans , MAP Kinase Kinase Kinase 2 , MAP Kinase Kinase Kinases/genetics , MicroRNAs/genetics , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
BACKGROUND miR-490-3p could play vital roles in multiple cancers. However, the role of miR-490-3p in hepatocellular carcinoma (HCC) remains uncertain. In this study, we sought to explore the underlying role of miR-490-3p in HCC. MATERIAL AND METHODS In this study, we explored the clinical role of miR-490-3p in HCC via quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and The Cancer Genome Atlas (TCGA) database. Then, a meta-analysis was performed to evaluate the expression trend and diagnostic value of miR-490-3p in HCC. Furthermore, 12 miRNA prediction algorithms were applied to predict the potential target genes of miR-490-3p. The differentially expressed genes in HCC in the Gene Expression Profiling Interactive Analysis (GEPIA) database were also selected. Additionally, bioinformatics analyses were utilized to investigate the possible functions and pathways of the target genes. RESULTS miR-490-3p was clearly down-regulated in HCC based on RT-qPCR (P=0.002). Consistent with the results of RT-qPCR, miR-490 was more highly expressed in normal liver tissue than in HCC (P<0.001). Additionally, the meta-analysis confirmed the results from RT-qPCR and TCGA. Furthermore, based on the prediction algorithms and GEPIA, a total of 113 genes were selected. According to the bioinformatics analyses, we found that the most remarkably enriched functional terms included protein transport, poly(A) RNA binding, and intracellular organelle part. Additionally, the miR-490-3p target genes were significantly related to the pathways in cancer. CONCLUSIONS We found that miR-490-3p is down-regulated in HCC and is related to genes that have potential tumoral functions. However, the exact mechanism should be confirmed by functional experiments.
Subject(s)
Carcinoma, Hepatocellular/genetics , Liver Neoplasms/genetics , MicroRNAs/genetics , Down-Regulation/genetics , Gene Expression Regulation, Neoplastic/genetics , Humans , MicroRNAs/analysis , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction/methods , Reverse TranscriptionABSTRACT
OBJECTIVE: To investigate whether electro-acupuncture can serve as a method of inducing brain ischaemic tolerance (BIT) by encouraging the expression of glutamate transporter-1 (GLT-1) and suppressing the release of glutamate (Glu). METHODS: Sprague-Dawley (SD) rats were divided into sham, ischaemia and EA groups. EA was performed on dazhui and baihui acupoints and the rat cerebral ischaemia model was achieved by occluding the middle cerebral artery (MCA) for 2 hours, followed by reperfusion. Dialysate was collected from the striatum in vivo to detect the concentration of Glu and the expression of Glutamate Transporter-1 (GLT-1) was examined. The changes of neurological deficit scores were evaluated at 24 hours after reperfusion, while the infarct volumes of brains were then measured with 2,3,5-triphenyltetrazolium chloride (TTC) staining. RESULTS: Compared with the ischaemia group, the concentration of Glu decreased and the expression of GLT-1 increased at most of the detective time points in the EA group; the neurological deficit scores were lower and the infarct volumes were smaller in the EA group. CONCLUSION: EA can up-regulate the expression of GLT-1 and inhibit the excessive release of Glu in the striatum in the process of subsequent ischaemic-reperfusion brain injury, which may be one of the mechanisms of inducing BIT and, thus, be neuroprotective for early ischaemic brain injury.
Subject(s)
Acupuncture Therapy/methods , Brain Ischemia/pathology , Electroacupuncture , Excitatory Amino Acid Transporter 2/metabolism , Glutamates/metabolism , Animals , Disease Models, Animal , Rats , Rats, Sprague-Dawley , Up-RegulationABSTRACT
Bone marrow mesenchymal stem cells (BMSCs) inhibit immune cell responsiveness, and especially of T lymphocytes. We showed that BMSCs markedly inhibited the proliferation and cytokine production by CD8(+) T cells by a cell-to-cell contact phenomenon and secretion of soluble factors. BMSCs down-regulate the expression of natural killer group 2, member D protein (NKG2D) receptors on CD8(+) T cells when co-cultured with them. Moreover, CD8(+) T cells that express low levels of NKG2D had impaired proliferation after triggering by a mitogen. The major histocompatibility complex (MHC) class I chain-related (MIC) A/B molecule, which is a typical ligand for NKG2D, was expressed on BMSCs, and caused dampening of cell proliferation. Monoclonal antibody blocking experiments targeted to MIC A/B impaired CD8(+) T cell function, as evaluated by proliferation and cytokine production. In addition, the production of prostaglandin E2 (PGE2 ), indoleamine 2, 3-dioxygenase (IDO) and transforming growth factor (TGF)-ß1 were increased when BMSCs were co-cultured with CD8(+) T cells. The addition of specific inhibitors against PGE2 , IDO and TGF-ß partially restored the proliferation of CD8(+) T cells. Our results suggest that BMSCs suppress CD8(+) T cell-mediated activation by suppressing NKG2D expression and secretion of PGE2, IDO and TGF-ß. Our observations further confirm the feasibility of BMSCs as a potential adoptive cellular therapy in immune-mediated diseases such as graft-versus-host disease (GVHD).
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Dinoprostone/biosynthesis , Indoleamine-Pyrrole 2,3,-Dioxygenase/biosynthesis , Lymphocyte Activation , Mesenchymal Stem Cells/physiology , NK Cell Lectin-Like Receptor Subfamily K/physiology , Transforming Growth Factor beta/biosynthesis , Cell Communication , Cells, Cultured , Granzymes/biosynthesis , Histocompatibility Antigens Class I/physiology , Humans , Interferon-gamma/biosynthesis , Interleukin-2/biosynthesisABSTRACT
We investigated the efficacy of motor imagery-based Brain Computer Interface (MI-based BCI) training for eight stroke patients with severe upper extremity paralysis using longitudinal clinical assessments. The results were compared with those of a control group (n = 7) that only received FES (Functional Electrical Stimulation) treatment besides conventional therapies. During rehabilitation training, changes in the motor function of the upper extremity and in the neurophysiologic electroencephalographic (EEG) were observed for two groups. After 8 weeks of training, a significant improvement in the motor function of the upper extremity for the BCI group was confirmed (p < 0.05 for ARAT), simultaneously with the activation of bilateral cerebral hemispheres. Additionally, event-related desynchronization (ERD) of the affected sensorimotor cortexes (SMCs) was significantly enhanced when compared to the pretraining course, which was only observed in the BCI group (p < 0.05). Furthermore, the activation of affected SMC and parietal lobe were determined to contribute to motor function recovery (p < 0.05). In brief, our findings demonstrate that MI-based BCI training can enhance the motor function of the upper extremity for stroke patients by inducing the optimal cerebral motor functional reorganization.
Subject(s)
Brain-Computer Interfaces/statistics & numerical data , Electric Stimulation Therapy/methods , Neuronal Plasticity/physiology , Paralysis/rehabilitation , Sensorimotor Cortex/physiopathology , Stroke Rehabilitation , Upper Extremity/pathology , Aged , Electroencephalography , Female , Humans , Imagination/physiology , Longitudinal Studies , Male , Middle Aged , Motor Activity/physiology , Paralysis/etiology , Stroke/complications , Treatment OutcomeABSTRACT
BACKGROUND: Electroacupuncture (EA) is a promising rehabilitation treatment for upper-limb motor recovery in stroke patients. However, the neurophysiological mechanisms underlying its clinical efficacy remain unclear. This study aimed to explore the immediate modulatory effects of EA on brain network functional connectivity and topological properties. METHODS: The randomized, single-blinded, self-controlled two-period crossover trial was conducted among 52 patients with subacute subcortical stroke. These patients were randomly allocated to receive either EA as the initial intervention or sham electroacupuncture (SEA) as the initial intervention. After a washout period of 24 hours, participants underwent the alternate intervention (SEA or EA). Resting state electroencephalography signals were recorded synchronously throughout both phases of the intervention. The functional connectivity (FC) of the parietofrontal network and small-world (SW) property indices of the whole-brain network were compared across the entire course of the two interventions. RESULTS: The results demonstrated that EA significantly altered ipsilesional parietofrontal network connectivity in the alpha and beta bands (alpha: Fâ =â 5.05, Pâ =â .011; beta: Fâ =â 3.295, Pâ =â .047), whereas no significant changes were observed in the SEA group. When comparing between groups, EA significantly downregulated ipsilesional parietofrontal network connectivity in both the alpha and beta bands during stimulation (alpha: tâ =â -1.998, Pâ =â .049; beta: tâ =â -2.342, Pâ =â .022). Significant differences were also observed in the main effects of time and the groupâ ×â time interaction for the SW index (time: Fâ =â 5.516, Pâ =â .026; groupâ ×â time: Fâ =â 6.892, Pâ =â .01). In terms of between-group comparisons, the EA group exhibited a significantly higher SW index than the SEA group at the post-stimulation stage (tâ =â 2.379, Pâ =â .018). CONCLUSION: These findings suggest that EA downregulates ipsilesional parietofrontal network connectivity and enhances SW properties, providing a potential neurophysiological mechanism for facilitating motor performance in stroke patients.
Subject(s)
Electroacupuncture , Stroke , Humans , Electroacupuncture/methods , Cross-Over Studies , Stroke/therapy , Brain , ElectroencephalographyABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Dingxian Pill (DXP), a famous traditional Chinese medicine prescription, and has been widely proven to have positive therapeutic effects on "Xianzheng" (the name of epilepsy in ancient China). However, the anti-epileptic molecular mechanisms of DXP are not yet fully understood and remain to be further investigated. AIM OF THE STUDY: To elucidate the molecular mechanism of DXP's improvement in epileptic neuronal loss, damage and apoptosis by regulating TNF-α/TNFR1 signaling pathway. MATERIALS AND METHODS: Sixty Kunming mice were randomly divided in 6 groups: control group (equal volume of normal saline), model group (180 mg kg-1 pilocarpine hydrochloride - used to establish the epilepsy animal model), carbamazepine group (30 mg kg-1), and low, medium, and high-dose Dingxian Pill groups (4.08, 8.16, and 16.32 g kg-1, respectively - oral administration once daily for 2 weeks). Successful establishment of the epileptic mouse model was monitored with electroencephalography. Pathological changes in hippocampal tissue were analyzed with hematoxylin-eosin staining. Hippocampal neuronal apoptosis was analyzed with TUNEL staining. TNF-α, TNFR1, TRADD, FADD, and caspase-8 mRNA and protein expression levels in hippocampal tissue were analyzed with real-time quantitative polymerase chain reaction, immunohistochemistry, and Western blot, respectively. Cleaved caspase-8 protein levels in hippocampal tissue were measured with immunohistochemistry and Western blot. RESULTS: Compared to control, the model group showed an increase in continuous epileptic discharge waves on EEG, a damaged hippocampal neuron morphological structure, increased hippocampal neuronal apoptosis, and significantly increased TNF-α, TNFR1, TRADD, FADD, and caspase-8 mRNA and protein levels, and increased caspase-8 cleavage (P < 0.05). Compared to the model group, the carbamazepine group as well as the low-, medium-, and high-dose Dingxian Pill groups showed decreased epileptic discharges on EEG, an obvious hippocampal neuron morphological structure restoration, varying degrees of attenuated hippocampal neuronal apoptosis, and significantly decreased TNF-α, TNFR1, TRADD, FADD, and caspase-8 mRNA and protein levels as well as decreased caspase-8 cleavage (P < 0.05). CONCLUSIONS: Dingxian Pill exerts an anti-epileptic effect through inhibition of TNF-α/TNFR1 signaling pathway-mediated apoptosis in hippocampal neurons.
Subject(s)
Anticonvulsants , Apoptosis , Drugs, Chinese Herbal , Epilepsy , Hippocampus , Neurons , Receptors, Tumor Necrosis Factor, Type I , Signal Transduction , Tumor Necrosis Factor-alpha , Animals , Receptors, Tumor Necrosis Factor, Type I/metabolism , Apoptosis/drug effects , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/pathology , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/metabolism , Epilepsy/drug therapy , Drugs, Chinese Herbal/pharmacology , Male , Neurons/drug effects , Neurons/pathology , Neurons/metabolism , Mice , Anticonvulsants/pharmacology , Pilocarpine/toxicity , Disease Models, Animal , Animals, Outbred StrainsABSTRACT
BACKGROUND: Predicting motor recovery in stroke patients is essential for effective rehabilitation planning and goal setting. However, intervention-specific biomarkers for such predictions are limited. This study investigates the potential of electroacupuncture (EA) - induced brain network connectivity as a prognostic biomarker for upper limb motor recovery in stroke. METHODS: A randomized crossover and prospective observational study was conducted involving 40 stroke patients within 30 days of onset. Patients underwent both EA and sham electroacupuncture (SEA) interventions. Simultaneously, resting electroencephalography signals were recorded to assess brain response. Patients' motor function was monitored for 3 months and categorized into Poor and proportional (Prop) recovery groups. The correlations between the targeted brain network of parietofrontal (PF) functional connectivity (FC) during the different courses of the 2 EA interventions and partial least squares regression models were constructed to predict upper limb motor recovery. RESULTS: Before the EA intervention, only ipsilesional PF network FC in the beta band correlated with motor recovery (râ =â -0.37, Pâ =â .041). Post-EA intervention, significant correlations with motor recovery were found in the beta band of the contralesional PF network FC (râ =â -0.43, Pâ =â .018) and the delta and theta bands of the ipsilesional PF network FC (delta: râ =â -0.59, Pâ =â .0004; theta: râ =â -0.45, Pâ =â .0157). No significant correlations were observed for the SEA intervention (all Pâ >â .05). Specifically, the delta band ipsilesional PF network FC after EA stimulation significantly differed between Poor and Prop groups (tâ =â 3.474, Pâ =â .002, Cohen's dâ =â 1.287, Poorâ >â Prop). Moreover, the partial least squares regression model fitted after EA stimulation exhibited high explanatory power (R2 = 0.613), predictive value (Q2â =â 0.547), and the lowest root mean square error (RMSEâ =â 0.192) for predicting upper limb proportional recovery compared to SEA. CONCLUSION: EA-induced PF network FC holds potential as a robust prognostic biomarker for upper limb motor recovery, providing valuable insights for clinical decision-making.
Subject(s)
Electroacupuncture , Stroke , Humans , Stroke/therapy , Brain , Electroencephalography , Upper ExtremityABSTRACT
DNA sensors play crucial roles in inflammation and have been indicated to be involved in antitumor or tumorigenesis, while it is still unclear whether DNA sensors have potential roles in the prognosis and immunotherapy of hepatocellular carcinoma (HCC). Herein, The Cancer Genome Atlas and Gene Expression Omnibus databases were used to analyze RNA sequencing data and clinical information. A total of 14 DNA sensors were collected and performed consensus clustering to determine their molecular mechanisms in HCC. Two distinct molecular subtypes (Clusters C1 and C2) were identified and were associated with different overall survival (OS). Immune subtype analysis revealed that C1 was mainly characterized by inflammation, while C2 was characterized by lymphocyte depletion. Immune scoring and immunomodulatory function analysis confirmed the different immune microenvironment of C1 and C2. Notably, significant differences in "Hot Tumor" Immunophenotype were observed between the two subtypes. Moreover, the prognostic model based on DNA sensors is capable of effectively predicting the OS of HCC patients. Besides, the chemotherapeutic drug analysis showed the different sensitivity of two subtypes. Taken together, our study shows that the proposed DNA sensors were a reliable signature to predict the prognosis and immunotherapy response with potential application in the clinical decision and treatment of HCC.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/genetics , Prognosis , DNA , Inflammation , Tumor MicroenvironmentABSTRACT
Pre-ischemic treadmill training exerts cerebral protection in the prevention of cerebral ischemia by alleviating neurotoxicity induced by excessive glutamate release following ischemic stroke. However, the underlying mechanism of this process remains unclear. Cerebral ischemia-reperfusion injury was observed in a rat model after 2 weeks of pre-ischemic treadmill training. Cerebrospinal fluid was collected using the microdialysis sampling method, and the concentration of glutamate was determined every 40 min from the beginning of ischemia to 4 h after reperfusion with high-performance liquid chromatography (HPLC)-fluorescence detection. At 3, 12, 24, and 48 h after ischemia, the expression of the glutamate transporter-1 (GLT-1) protein in brain tissues was determined by Western blot respectively. The effect of pre-ischemic treadmill training on glutamate concentration and GLT-1 expression after cerebral ischemia in rats along with changes in neurobehavioral score and cerebral infarct volume after 24 h ischemia yields critical information necessary to understand the protection mechanism exhibited by pre-ischemic treadmill training. The results demonstrated that pre-ischemic treadmill training up-regulates GLT-1 expression, decreases extracellular glutamate concentration, reduces cerebral infarct volume, and improves neurobehavioral score. Pre-ischemic treadmill training is likely to induce neuroprotection after cerebral ischemia by regulating GLT-1 expression, which results in re-uptake of excessive glutamate.
Subject(s)
Brain Injuries/prevention & control , Brain Ischemia/prevention & control , Excitatory Amino Acid Transporter 2/metabolism , Exercise Therapy/methods , Glutamates/metabolism , Infarction, Middle Cerebral Artery/prevention & control , Neuroprotective Agents , Animals , Blotting, Western , Brain Injuries/metabolism , Brain Ischemia/metabolism , Exercise Therapy/instrumentation , Infarction, Middle Cerebral Artery/metabolism , Male , Microdialysis , Rats , Rats, Sprague-DawleyABSTRACT
Liver cancer is one of the most common malignant tumors in the world and metastasis is the leading cause of death associated with liver cancer. Hypoxia is a common feature of solid tumors and enhances malignant character of cancer cells. However, the exact mechanisms involved in hypoxia-driven liver cancer progression and metastasis have not been well clarified so far. The aim of this study was to investigate the contribution of long non-coding RNA (lncRNA) in hypoxia promoting liver cancer progression. We screened and revealed LINC00839 as a novel hypoxia-responsive lncRNA in liver cancer. LINC00839 expression was up-regulated in liver cancer tissues and cell lines, and the patients with high LINC00839 expression had shortened overall survival. LINC00839 further overexpressed under hypoxia and promoted liver cancer cell proliferation, migration, and invasion. Mechanistically, LINC00839 bound multiple proteins that were primarily associated with the metabolism and RNA transport, and positively regulated the expression of Formin-like protein 2 (FMNL2). LINC00839 could promote hypoxia-mediated liver cancer progression, suggesting it may be a clinically valuable biomarker and serve as a molecular target for the diagnosis, prognosis, and therapy of liver cancer.
Subject(s)
Liver Neoplasms , MicroRNAs , RNA, Long Noncoding , Humans , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Cell Line, Tumor , Liver Neoplasms/pathology , Cell Proliferation/genetics , Hypoxia/genetics , Hypoxia/metabolism , Gene Expression Regulation, Neoplastic , Cell Movement/genetics , MicroRNAs/genetics , ForminsABSTRACT
Long non-coding RNAs (lncRNAs) as important regulators of gene expression also have critical functions in immune regulation. This study identified lncRNA modulators of immune-related pathways as biomarkers for hepatocellular carcinoma (HCC). The profile of lncRNA regulation in immune pathways in HCC was comprehensively mapped. To determine lncRNAs with immunomodulatory functions specific to HCC, the enrichment of lncRNAs in a collection of 17 immune functions was calculated applying gene set enrichment analysis (GSEA). Unsupervised clustering of samples were performed in the R package ConsensusClusterPlus to analyze subtype survival and immunological characteristics. The enrichment of 3,134 lncRNA-immune pathway pairs in both diseased and normal samples showed a total of 1,984 immunoregulatory functional lncRNAs specific to HCC only. In addition, 18 immune-related lncRNAs were disordered in HCC and were significantly associated with immune cell infiltration. Functional enrichment analysis indicated that the 18 dysregulated immune lncRNAs were enriched in cytokines, cytokine receptors, TGFb family members, TNF family members, and TNF family member receptor pathways. Two molecular subtypes of hepatocellular carcinoma were identified based on 18 dysregulated immune lncRNAs. Immunological profiling showed that subtype 1 samples with higher levels of cytokine response had a better survival, but subtype 2 samples with higher levels of tumor proliferation had poorer survival. This study identified 18 HCC-specific dysregulated immune lncRNAs and two HCC molecular subtypes with significant prognostic differences and immune characteristics. The current findings help understand the function of lncRNAs and promote the identification of immunotherapy targets.
ABSTRACT
Hepatocellular carcinoma (HCC) is a rapidly developing digestive tract carcinoma. The prognosis of patients and side effects caused by clinical treatment should be better improved. Nonnegative matrix factorization (NMF) clustering was performed using 109 homologous recombination deficiency (HRD)-related of HCC genes from The Cancer Genome Atlas (TCGA) database. Limma was applied to analyze subtype differences. Immune scores and clinical characteristics of different subtypes were compared. An HRD signature were built with least absolute shrinkage operator (LASSO) and multivariate Cox analysis. Performance of the signature system was then assessed by Kaplan-Meier curves and receiver operating characteristic (ROC) curves. We identified two molecular subtypes (C1 and C2), with C2 showing a significantly better prognosis than C1. C1 contained 3623 differentially expressed genes. A 4-gene prognostic signature for HCC was established, and showed a high predicting accuracy in validation sets, entire TCGA data set, HCCDB18 and GSE14520 queues. Moreover, the risk score was validated as an independent prognostic marker for HCC. Our research identified two molecular subtypes of HCC, and proposed a novel scoring system for evaluating the prognosis of HCC in clinical practice.
Subject(s)
Biomarkers, Tumor , Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/mortality , Homologous Recombination , Liver Neoplasms/etiology , Liver Neoplasms/mortality , Transcriptome , Aged , Aged, 80 and over , Carcinoma, Hepatocellular/diagnosis , Computational Biology/methods , Disease Susceptibility , Female , Gene Expression Profiling/methods , Gene Ontology , Humans , Kaplan-Meier Estimate , Liver Neoplasms/diagnosis , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Male , Middle Aged , Neoplasm Grading , Neoplasm Staging , Prognosis , ROC Curve , Risk AssessmentABSTRACT
Capsanthin is the major natural carotenoid pigment in red chili pepper possessing important bioactivity. Its conventional determination method is high performance liquid chromatography (HPLC) with complex and tedious sample pretreatment. In this study, synchronous front-face fluorescence spectroscopy (FFFS) was applied for the fast and non-invasive detection of free capsanthin in chili powders. Although capsanthin was only weak fluorescent in solution state, it showed strong fluorescence in two separated regions in front-face geometry which could also be clearly observed in chili powders. The mechanisms of these emissions are revealed to be aggregation-induced emission (AIE) and J-aggregate formation (JAF). The free capsanthin in 85 chili powder samples were determined by HPLC as in the range of 0.6-3.0 mg/g. The total synchronous FFFS spectra of these samples were scanned. Simple first-order models were built by partial least square regression (PLSR), and were validated by 5-fold cross-validation and external validation. The coefficients of determination (R2) were higher than 0.9, and the root mean square errors (RMSE) were less than 0.2 mg/g. The relative error of prediction (REP) was 9.9%, and the residual predictive deviation (RPD) was 3.7. The method was applied for the estimation of free capsanthin in several real-world samples with satisfactory analytical results. The average relative error to HPLC reference values was -11.8%.
Subject(s)
Capsicum , Carotenoids , Powders , Spectrometry, Fluorescence , XanthophyllsABSTRACT
Temporal lobe epilepsy (TLE) is a chronic disease of the nervous system, associated with increased proliferation in the hippocampus. Urothcarcinoma associated 1 (UCA1) is a long long non-coding RNA that was shown to regulate proliferation and differentiation of neural progenitors in vitro. We hypothesised that TLE-associated abnormal proliferation is a consequence of the downregulation of UCA1. This hypothesis was tested in mice with kainic acid (KA)-induced seizures, and then the potential mechanism was explored in vitro and in vivo. Result showed that the expression of UCA1 and Secreted Frizzled Related Protein 1 (SFRP1) were significantly reduced in hippocampal tissues of epileptic mice, while miR-375 was increased compared with the control group. Pearson correlation analysis showed that UCA1 was positively correlated with SFRP1, while miR-375 was negatively correlated with UCA1 and SFRP1. Besides, UCA1 was overexpressed in mice and the overexpression of UCA1 significantly reversed the abnormal proliferation of hippocampal neurons in epilepsy mice. In vitro Luciferase assay showed that UCA1 and Sfrp1 are both the targets of miR-375, and UCA1 promotes the expression of Sfrp1 by competitively adsorbing miR-375, thereby inhibiting the activation of the WNT/ß-catenin pathway. The inactivation of the WNT/ß-catenin pathway prevented the abnormal proliferation of neural progenitors in the epileptic hippocampus. In conclusion, our findings provide a theoretical basis for the clinical application of UCA1.
Subject(s)
Epilepsy/genetics , Hippocampus/drug effects , Membrane Proteins/metabolism , MicroRNAs/metabolism , Neurogenesis/drug effects , RNA, Long Noncoding/genetics , Wnt Signaling Pathway/drug effects , Animals , Cell Proliferation/genetics , Epilepsy/metabolism , Genetic Vectors/pharmacology , HEK293 Cells , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Kainic Acid/adverse effects , Male , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , MicroRNAs/genetics , Neurogenesis/genetics , Wnt Signaling Pathway/geneticsABSTRACT
BACKGROUND: Stroke is one of the most common disorders among the elderly. A practical problem in stroke rehabilitation systems is that how to separate motor imagery patterns from electroencephalographic (EEG) recordings. There is a sharp decline in performance of these systems when classical algorithms, such as Common Spatial Pattern (CSP), are directly applied on stroke patients. NEW METHOD: We propose a tensor-based scheme to detect motor imagery EEG patterns in spatial-spectral-temporal domain directly from multidimensional EEG constructed by wavelet transform method. Discriminative motor imagery EEG patterns are obtained by Fisher score strategy. Furthermore, the most contributed channel groups and frequency bands are selected from these patterns and utilized as prior knowledge for the following motor imagery tasks. RESULTS: We evaluate our scheme based on EEG datasets recorded from stroke patients. The results show that our method outperforms five other traditional methods in both online and offline recognition performance. COMPARISON WITH EXISTING METHODS: Unlike the existing methods, motor imagery EEG patterns in spatial-spectral-temporal domain are simultaneously obtained by our method, preserving the structural information of the multi-channel time-varying EEG. CONCLUSIONS: Our scheme is encouraged to be transferred to some other practical rehabilitation applications for its better performance.