The inflammatory response plays essential roles in the pathological process and prognosis of Parkinson's disease (PD). This research investigated the predictive value of the neutrophil to ...high-density lipoprotein ratio (NHR), neutrophil to lymphocyte ratio (NLR), and monocyte to high-density lipoprotein ratio (MHR) for PD.
Patients with PD (n = 98) were divided into three groups according to disease duration: < 6 years (n = 55), 6-10 years (n = 29) and > 10 years (n = 14). Based on the classification system of Hoehn and Yahr, grades 1 ~ 2.5 were considered early-stage PD (n = 44), and grades 3 ~ 5 were considered advanced-stage PD (n = 54). In addition, healthy subjects (n = 98) matched to the above PD patients in the same period were selected as the control group. Differences in the NHR, NLR, MHR and other indicators among the groups were evaluated.
Smoking, drinking, the neutrophil count and the NHR and NLR were remarkably greater and hypertension, index of body mass, the lymphocyte count, and the levels of cholesterol in total, triglycerides, lipoprotein cholesterol with low density and uric acid were sharply lower in the PD group compared with in the control group. Analysis of multifactor logistic regression indicated that the NHR (odds ratio (adjusted OR) = 1.576, 95% CI: 1.053 ~ 2.358, P = 0.027) and NLR (adjusted OR = 1.734, 95% CI: 1.046 ~ 2.876, P = 0.033) were factors of risk for PD, while the MHR was not significantly correlated with PD. The areas under the receiver operating characteristic (ROC) curve (AUCs) for the prediction of PD by the NHR and NLR were 0.654 (95% CI: 0.583 ~ 0.721, P = 0.0001) and 0.69 (95% CI: 0.62 ~ 0.754, P < 0.0001), respectively, and the optimal cutoff values were 1.848 × 10
/mmol and 2.62 × 10
/mmol. Spearman's correlation analysis indicated that the NHR was correlated with the disease duration significantly negatively and that the MHR was positively correlated with disease severity.
In summary, the NHR not only has strong predictive value for PD but is also closely related to disease duration. The NHR may be a better prediction for the long-period clinical results in PD patients than the MHR and NLR.
Clinical medical reserach center project of Qinghai Province (2017-SF-L1).
Memantine is a non-competitive antagonist of glutamatergic NMDA receptor that is mainly used in the treatment of Alzheimer's disease. The excitatory toxicity mediated by glutamate via glutamatergic ...receptor signals is considered to be one of the mechanisms mediating neuronal injury and cognitive impairment after exposure to a hypoxic environment at a high altitude. Therefore, in this study, we hypothesized that inhibiting glutamate signaling using memantine could alleviate neuronal injury and cognitive impairment in rats exposed to chronic hypoxia.
we made animal models in the natural environment of the Qinghai-Tibet Plateau at an altitude of 4300 m, and used animal behavior, morphology, molecular biology and other methods to evaluate the impact of chronic hypoxia exposure on cognitive function and the neuroprotective effect of Memantine.
Our results showed that the expression of NMDA receptors increased, while the expression of AMPA receptors decreased, after 4 weeks of chronic hypoxia exposure. Concomitantly, apoptotic neuronal cell death in the hippocampus and frontal cortex was significantly increased, along with levels of oxidative stress, whereas innate ability to inhibit free radicals decreased. Moreover, after 8 weeks of hypoxia exposure, learning, memory, and space exploration abilities were significantly decreased. Notably, after treatment with memantine, apoptotic neuronal cell death, oxidative stress, and free radical levels decreased, and the cognitive function of the animals improved.
Present study shows that chronic hypoxia can produce the excitatory toxicity leading to neural injury and cognitive impairment that can be suppressed with memantine treatment by inhibiting excitatory toxicity.
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•The mechanism of cognitive impairment induced by chronic hypoxic exposure is unclear.•Here, we showed that apoptotic neuronal cell death in the hippocampus and frontal cortex was significantly increased, along with levels of oxidative stress, whereas innate ability to inhibit free radicals decreased.•Notably, after treatment with memantine, apoptotic neuronal cell death, oxidative stress, and free radical levels decreased, and the cognitive function of the animals improved.•Together, our study shows that chronic hypobaric hypoxic environmental exposure can produce excitatory toxicity leading to neural injury and cognitive impairment that can be suppressed with memantine treatment by inhibiting excitatory toxicity.
Objectives
Sequelae of stroke were mainly caused by neuronal injury. Oxygen is a key factor affecting the microenvironment of neural stem cells (NSCs), and oxygen levels are used to promote NSC ...neurogenesis. In this study, effects of intermittent hypoxic preconditioning (HPC) on neurogenesis were investigated in a rat model of middle cerebral artery occlusion (MCAO).
Methods
SD rats were used to establish the MCAO model. Nissl staining and Golgi staining were used to confirm the neuronal injury status in the MCAO model. Immunofluorescence, transmission electron microscopy, Western blot, and qPCR were used to observe the effects of HPC on neurogenesis. At the same time, the hypothesis that HPC could affect proliferation, apoptosis, differentiation, and migration of NSC was verified in vitro.
Results
Hypoxic preconditioning significantly ameliorated the neuronal injury induced by MCAO. Compared with MCAO group, the dendrites, Edu+/SOX2+, Edu+/DCX+, Edu+/NeuN+, Edu+/GFAP+, and Edu+/Tubulin+ positive cells in the HPC + MCAO group exhibited significantly difference. Similarly, axonal and other neuronal injuries in the HPC + MCAO group were also ameliorated. In the in vitro experiments, mild HPC significantly enhanced the viability of NSCs, promoted the migration of differentiated cells, and reduced apoptosis.
Conclusions
Our results showed that HPC significantly promotes neurogenesis after MCAO and ameliorates neuronal injury.
1. HPC alleviated the nerve injury of MCAO; 2. HPC promoted neurogenesis; 3. HPC affects proliferation and apoptosis of NSCs.
Moderate hypobaric hypoxia induces cerebral ischemic tolerance. We investigated the optimal method for applying hypobaric hypoxia preconditioning at 5,000 m to ischemic brain tissue and combined it ...with proteomics to determine the mechanisms underlying this effect.
Male SD rats were randomly grouped as S (sham,
= 20), M (middle cerebral artery occlusion MCAO,
= 28), H2M (intermittent hypobaric hypoxia preconditioned MCAO group, 2 h/day, 10 days,
= 20), H6M (intermittent hypobaric hypoxia preconditioned MCAO group, 6 h/day, 10 days,
= 28), and HpM (persistent hypobaric hypoxia preconditioned MCAO group, 10 days,
= 28). The permanent MCAO model was established based on the Zea Longa method. Infarction was assessed with the modified neurological severity score (mNSS) and 2,3,5-triphenyl tetrazolium chloride staining. The total protein expression of the neuron-specific nuclear protein (NeuN), cysteinyl aspartate specific proteinase 3 (caspase-3), cleaved-caspase-3, and interleukin 6 (IL-6) was determined using western blotting. We assessed the peri-infarct cortex's ultrastructural changes. A label-free proteomic study and western blot verification were performed on the most effective preconditioned group.
The H6M group showed a lower infarct volume (
= 0.0005), lower mNSS score (
= 0.0009) than the M group. The H2M showed a lower level of IL-6 (
= 0.0213) than the M group. The caspase-3 level decreased in the H2M (
= 0.0002), H6M (
= 0.0025), and HpM groups (
= 0.0054) compared with that in the M group. Cleaved-caspase-3 expression decreased in the H2M (
= 0.0011), H6M (
< 0.0001), and HpM groups (
< 0.0001) compared with that in the M group. The neurons' ultrastructure and the blood-brain barrier in the peri-infarct tissue improved in the H2M and H6M groups. Immunofluorescence revealed increased NeuN-positive cells in the peri-infarct tissue in the H6M group (
= 0.0003, H6M vs. M). Protein expression of Chmp1a, Arpc5, and Hspa2 factors related to endocytosis were upregulated in the H6M compared with those of the M group (
< 0.05 for all) on western blot verification of label-free proteomics.
Intermittent hypobaric hypoxia preconditioning exerts a neuroprotective effect in a rat stroke model. Persistent hypobaric hypoxia stimulation exhibited no significant neuroprotective effect. Intermittent hypoxic preconditioning for 6 h/day for 10 days upregulates key proteins in clathrin-dependent endocytosis of neurons in the cortex.
Structured RNAs encode native conformations that are more stable than the vast ensembles of alternative conformations, but how this specificity is evolved is incompletely understood. Here we show ...that a variant of the Tetrahymena group I intron ribozyme that was generated previously by in vitro selection for enhanced thermostability also displays modestly enhanced specificity against a stable misfolded structure that is globally similar to the native state, despite the absence of selective pressure to increase the energy gap between these structures. The enhanced specificity for native folding arises from mutations in two nucleotides that are close together in space in the native structure, and additional experiments show that these two mutations do not affect the stability of the misfolded conformation relative to the largely unstructured transition state ensemble for interconversion between the native and misfolded conformers. Thus, they selectively stabilize the native state, presumably by strengthening a local tertiary contact network that cannot form in the misfolded conformation. The stabilization is larger in the presence of the peripheral element P5abc, suggesting that cooperative tertiary structure formation plays a key role in the enhanced stability. The increased specificity in the absence of explicit selection suggests that the large energy gap in the wild-type RNA may have arisen analogously, a consequence of selective pressure for stability of the functional structure. More generally, the structural rigidity and intricate networks of contacts in structured RNAs may allow them to evolve substantial structural specificity without explicit negative selection, even against closely related alternative structures.
To investigate the protective role of immune response gene 1 (IRG1) and exogenous itaconate in autoimmune hepatitis (AIH) and elucidate the underlying mechanisms. Wild-type and IRG1
AIH mouse models ...were established, and samples of liver tissue and ocular blood were collected from each group of mice to assess the effects of IRG1/itaconate on the expression of pro- and anti-inflammatory cytokines. The levels of liver enzymes and related inflammatory factors were determined using enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction (PCR). Liver histomorphology was detected through hematoxylin and eosin staining and then scored for liver injury, and the infiltration levels of tissue-resident memory T (TRM) cells and related molecules in the liver tissue were detected through immunofluorescence staining in vitro. RNA sequencing and gene enrichment analysis were conducted to identify the corresponding molecules and pathways, and lentiviral transfection was used to generate TRM cell lines with IRG1, Jak3, Stat3, and p53 knockdown. Real-time quantitative PCR and western blot were performed to detect the expression levels of relevant mRNAs and proteins in the liver tissue and cells. The percentage of apoptotic cells was determined using flow cytometry. IRG1/itaconate effectively reduced the release of pro-inflammatory cytokines and the pathological damage to liver tissue, thereby maintaining normal liver function. At the same time, IRG1/itaconate inhibited the JAK3/STAT3 signaling pathway, regulated the expression of related downstream proteins, and inhibited the proliferation and promoted the apoptosis of CD69
CD103
CD8
TRM cells. For the first time, P53 was found to act as a downstream molecule of the JAK3/STAT3 pathway and was regulated by IRG1/itaconate to promote the apoptosis of CD8
TRM cells. IRG1/itaconate can alleviate concanavalin A-induced autoimmune hepatitis in mice by inhibiting the proliferation and promoting the apoptosis of CD69
CD103
CD8
TRM cells via the JAK3/STAT3/P53 pathway.
Background The inflammatory response plays essential roles in the pathological process and prognosis of Parkinson's disease (PD). This research investigated the predictive value of the neutrophil to ...high-density lipoprotein ratio (NHR), neutrophil to lymphocyte ratio (NLR), and monocyte to high-density lipoprotein ratio (MHR) for PD. Methods Patients with PD (n = 98) were divided into three groups according to disease duration: < 6 years (n = 55), 6-10 years (n = 29) and > 10 years (n = 14). Based on the classification system of Hoehn and Yahr, grades 1 ~ 2.5 were considered early-stage PD (n = 44), and grades 3 ~ 5 were considered advanced-stage PD (n = 54). In addition, healthy subjects (n = 98) matched to the above PD patients in the same period were selected as the control group. Differences in the NHR, NLR, MHR and other indicators among the groups were evaluated. Results Smoking, drinking, the neutrophil count and the NHR and NLR were remarkably greater and hypertension, index of body mass, the lymphocyte count, and the levels of cholesterol in total, triglycerides, lipoprotein cholesterol with low density and uric acid were sharply lower in the PD group compared with in the control group. Analysis of multifactor logistic regression indicated that the NHR (odds ratio (adjusted OR) = 1.576, 95% CI: 1.053 ~ 2.358, P = 0.027) and NLR (adjusted OR = 1.734, 95% CI: 1.046 ~ 2.876, P = 0.033) were factors of risk for PD, while the MHR was not significantly correlated with PD. The areas under the receiver operating characteristic (ROC) curve (AUCs) for the prediction of PD by the NHR and NLR were 0.654 (95% CI: 0.583 ~ 0.721, P = 0.0001) and 0.69 (95% CI: 0.62 ~ 0.754, P < 0.0001), respectively, and the optimal cutoff values were 1.848 x 10.sup.9/mmol and 2.62 x 10.sup.9/mmol. Spearman's correlation analysis indicated that the NHR was correlated with the disease duration significantly negatively and that the MHR was positively correlated with disease severity. Conclusions In summary, the NHR not only has strong predictive value for PD but is also closely related to disease duration. The NHR may be a better prediction for the long-period clinical results in PD patients than the MHR and NLR. Trial registration Clinical medical reserach center project of Qinghai Province (2017-SF-L1). Keywords: Parkinson's disease, Neutrophil to ratio of lipoprotein with high density, Ratio of neutrophil to lymphocyte, Monocyte to high-density lipoprotein ratio, Disease duration, Severity
Despite the ubiquitous nature of misfolded intermediates in RNA folding, little is known about their physical properties or the folding transitions that allow them to continue folding productively. ...Folding of the
Tetrahymena group I ribozyme includes sequential accumulation of two intermediates, termed I
trap and misfolded (M). Here, we probe the structure and folding transition of I
trap and compare them to those of M. Hydroxyl radical and dimethyl sulfate footprinting show that both I
trap and M are extensively structured and crudely resemble the native RNA. However, regions of the core P3–P8 domain are more exposed to solvent in I
trap than in M. I
trap rearranges to continue folding nearly 1000-fold faster than M, and urea accelerates folding of I
trap much less than M. Thus, the rate-limiting transition from I
trap requires a smaller increase in exposed surface. Mutations that disrupt peripheral tertiary contacts give large and nearly uniform increases in re-folding of M, whereas the same mutations give at most modest increases in folding from I
trap. Intriguingly, mutations within the peripheral element P5abc give 5- to 10-fold accelerations in escape from I
trap, whereas ablation of P13, which lies on the opposite surface in the native structure, near the P3–P8 domain, has no effect. Thus, the unfolding required from I
trap appears to be local, whereas the unfolding of M appears to be global. Further, the modest effects from several mutations suggest that there are multiple pathways for escape from I
trap and that escape is aided by loosening nearby native structural constraints, presumably to facilitate local movements of nucleotides or segments that have not formed native contacts. Overall, these and prior results suggest a model in which the global architecture and peripheral interactions of the RNA are achieved relatively early in folding. Multiple folding and re-folding events occur on the predominant pathway to the native state, with increasing native core interactions and cooperativity as folding progresses.
Despite the importance of 3D structure to understand the myriad functions of RNAs in cells, most RNA molecules remain out of reach of crystallographic and NMR methods. However, certain structural ...information such as base pairing and some tertiary contacts can be determined readily for many RNAs by bioinformatics or relatively low cost experiments. Further, because RNA structure is highly modular, it is possible to deduce local 3D structure from the solved structures of evolutionarily related RNAs or even unrelated RNAs that share the same module. RNABuilder is a software package that generates model RNA structures by treating the kinematics and forces at separate, multiple levels of resolution. Kinematically, bonds in bases, certain stretches of residues, and some entire molecules are rigid while other bonds remain flexible. Forces act on the rigid bases and selected individual atoms. Here we use RNABuilder to predict the structure of the 200-nucleotide Azoarcus group I intron by homology modeling against fragments of the distantly-related Twort and Tetrahymena group I introns and by incorporating base pairing forces where necessary. In the absence of any information from the solved Azoarcus intron crystal structure, the model accurately depicts the global topology, secondary and tertiary connections, and gives an overall RMSD value of 4.6 A relative to the crystal structure. The accuracy of the model is even higher in the intron core (RMSD = 3.5 A), whereas deviations are modestly larger for peripheral regions that differ more substantially between the different introns. These results lay the groundwork for using this approach for larger and more diverse group I introns, as well for still larger RNAs and RNA-protein complexes such as group II introns and the ribosomal subunits.
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