SIRT3 facilitates mitochondrial structural repair and functional recovery in rats after ischemic stroke by promoting OPA1 expression and activity.

BACKGROUND: Optical atrophy 1 (OPA1), a protein accountable for mitochondrial fusion, facilitates the restoration of mitochondrial structure and function following cerebral ischemia/reperfusion (I/R) injury. The OPA1-conferred mitochondrial protection involves its expression and activity, which can be improved by SIRT3 in non-cerebral ischemia. Nevertheless, it remains obscure whether SIRT3 enhances the expression and activity of OPA1 after cerebral I/R injury. METHODS: Mature male Sprague Dawley rats were intracranially injected with adeno-associated viral-Sirtuin-3(AAV-SIRT3) and AAV-sh_OPA1, followed by a 90-min temporary blockage of the middle cerebral artery and subsequent restoration of blood flow. Cultured cortical neurons of rats were transfected with LV-SIRT3 or LV-sh_OPA1 before a 2-h oxygen-glucose deprivation and reoxygenation. The rats and neurons were subsequently treated with a selective OPA1 activity inhibitor (MYLS22). The interaction between SIRT3 and OPA1 was assessed by molecular dynamics simulation technology and co-immunoprecipitation. The expression, function, and specific protective mechanism of SIRT3 were examined by various analyses. RESULTS: SIRT3 interacted with OPA1 in the rat cerebral cortex before and after cerebral I/R. After cerebral I/R damage, SIRT3 upregulation increased the OPA1 expression, which enhanced deacetylation and OPA1 activity, thus alleviating cerebral infarct volume, neuronal apoptosis, oxidative pressure, and impairment in mitochondrial energy production; SIRT3 upregulation also improved neuromotor performance, repaired mitochondrial ultrastructure and membrane composition, and promoted the mitochondrial biogenesis. These neuroprotective effects were partly reversed by OPA1 expression interference and OPA1 activity inhibitor MYLS22. CONCLUSION: In rats, SIRT3 enhances the expression and activity of OPA1, facilitating the repair of mitochondrial structure and functional recovery following cerebral I/R injury. These findings highlight that regulating SIRT3 may be a promising therapeutic strategy for ischemic stroke.

SIRT1 restores mitochondrial structure and function in rats by activating SIRT3 after cerebral ischemia/reperfusion injury.

Mitochondrial dysfunction contributes to cerebral ischemia-reperfusion (CI/R) injury, which can be ameliorated by Sirtuin-3 (SIRT3). Under stress conditions, the SIRT3-promoted mitochondrial functional recovery depends on both its activity and expression. However, the approach to enhance SIRT3 activity after CI/R injury remains unelucidated. In this study, Sprague-Dawley (SD) rats were intracranially injected with either adeno-associated viral Sirtuin-1 (AAV-SIRT1) or AAV-sh_SIRT1 before undergoing transient middle cerebral artery occlusion (tMCAO). Primary cortical neurons were cultured and transfected with lentiviral SIRT1 (LV-SIRT1) and LV-sh_SIRT1 respectively before oxygen-glucose deprivation/reoxygenation (OGD/R). Afterwards, rats and neurons were respectively treated with a selective SIRT3 inhibitor, 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP). The expression, function, and related mechanism of SIRT1 were investigated by Western Blot, flow cytometry, immunofluorescence staining, etc. After CI/R injury, SIRT1 expression decreased in vivo and in vitro. The simulation and immune-analyses reported strong interaction between SIRT1 and SIRT3 in the cerebral mitochondria before and after CI/R. SIRT1 overexpression enhanced SIRT3 activity by increasing the deacetylation of SIRT3, which ameliorated CI/R-induced cerebral infarction, neuronal apoptosis, oxidative stress, neurological and motor dysfunction, and mitochondrial respiratory chain dysfunction, promoted mitochondrial biogenesis, and retained mitochondrial integrity and mitochondrial morphology. Meanwhile, SIRT1 overexpression alleviated OGD/R-induced neuronal death and mitochondrial bioenergetic deficits. These effects were reversed by AAV-sh_SIRT1 and the neuroprotective effects of SIRT1 were partially offset by 3-TYP. These results suggest that SIRT1 restores the structure and function of mitochondria by activating SIRT3, offering neuroprotection against CI/R injury, which signifies a potential approach for the clinical management of cerebral ischemia.

Multi-omics and tumor immune microenvironment characterization of a prognostic model based on aging-related genes in melanoma.

Melanoma is a common and fatal cutaneous malignancy with strong invasiveness and high mortality rate. Clinically, elderly melanoma patients tend to exhibit stronger invasion ability and poorer prognosis. Given the heterogeneity of tumors, we analyzed the prognosis and risk assessment of melanoma through aging-related genes rather than age stratification. FOXM1 and CCL4 were identified to be closely associated with melanoma prognosis. Single-cell transcriptome analysis showed that FOXM1 was significantly up-regulated in tumor cells, while CCL4 was markedly elevated in immune cells. A melanoma prognostic model was constructed based on the two independent prognostic factors. This model showed a high accuracy in predicting the mortality of melanoma patients over several years. The patients in low-risk group appeared to have more immune cell infiltration and better immune therapy efficacy. Cellular experiments showed that CCL4 could promote apoptosis of melanoma cells through immune cells, and apoptosis could regulate the expression of FOXM1. In addition, the results of the spatial transcriptome and immunohistochemistry suggested that CCL4 was highly expressed in macrophages and the expression of FOXM1 in melanoma cell was negatively correlated with immune cell infiltration, especially macrophages. Here, we established a novel prognostic model for melanoma, which showed promising predictive performance and may serve as a biomarker for the efficacy of immune checkpoint inhibition therapy in melanoma patients. In addition, we explored the function of two genes in the model in melanoma.

Identification of immune-related genes and integrated analysis of immune-cell infiltration in melanoma.

OBJECTIVE: This study was conducted to screen out immune-related genes in connection with the prognosis of melanoma, construct a prognosis model and explore the relevant mechanisms. METHODS AND MATERIALS: 1973 genes associated with immune system were derived from the Immport database, and RNA-seq data of melanoma and information of patients were searched from the Xena database. Cox univariate analysis, Lasso analysis and Cox multivariate analysis were used to screen out six genes to construct the model. Then the risk scores were estimated for patients based on our constructed prognosis model. Estimate was used to affirm that the model was about immune infiltration, and CIBERSORT was used to screen out immune cells associated with prognosis. TIDE was applied to predict the efficacy of immunotherapy. Finally, GSE65904 and GSE19234 were used to confirm the effectiveness of the model. RESULTS: ADCYAP1R1, GPI, NTS might cause poor prognosis while IFITM1, KIR2DL4, LIF were more likely conductive to prognosis of melanoma patients and a model of prognosis was constructed on the basis of these six genes. The effectiveness of the model has been proven by the ROC curve, and the miRNAs targeting the screened genes were found out, suggesting that the immune system might impact on the prognosis of melanoma by T cell CD8+, T cell CD4+ memory and NK cells. CONCLUSIONS: In this study, the screened six genes were associated with the prognosis of melanoma, which was conductive to clinical prognostic prediction and individualized treatment strategy.

Real-world Effectiveness of Azacitidine in Treatment-Naive Patients With Higher-risk Myelodysplastic Syndromes.

INTRODUCTION: Azacitidine (AZA) is an approved frontline therapy for higher-risk myelodysplastic syndromes (HR-MDS); however, poor survival denotes unmet needs to increase depth/duration of response (DOR). METHODS: This retrospective study with patient chart review evaluated AZA effectiveness in 382 treatment-naive patients with HR-MDS from a US electronic health record (EHR)-derived database. Responses were assessed using International Working Group (IWG) 2006 criteria; real-world equivalents were derived from EHRs. Primary endpoint was IWG 2006-based complete remission rate (CRR). Secondary endpoints were EHR-based CRR, IWG 2006- and EHR-based objective response rates (ORRs), duration of CR, DOR, progression-free survival, time-to-next-treatment, and overall survival (OS). RESULTS: Using IWG 2006 criteria, the CRR was 7.9% (n = 30); median duration of CR was 12.0 months (95% CI, 7.7-15.6). In poor cytogenetic risk (n = 101) and TP53 mutation (n = 46) subgroups, CRRs were 7.9% (n = 8) and 8.7% (n = 4), respectively. ORR was 62.8% (n = 240), including a hematologic improvement rate (HIR) of 46.9% (n = 179). Using EHR-based data, CRR was 3.7% (n = 14); median duration of CR was 13.5 months (95% CI, 4.5-21.5). ORR was 67.8% (n = 259), including an HIR of 29.3% (n = 112). Median follow-up was 12.9 months; median OS was 17.9 months (95% CI, 15.5-21.7). CONCLUSIONS: Consistent with other studies, CRRs and median OS with AZA in treatment-naive patients with HR-MDS were low in this large, real-world cohort. Novel agents/combinations are urgently needed to improve these outcomes in HR-MDS.

Risk factors for rehospitalization within 90 days in patients with total joint replacement: A meta-analysis.

BACKGROUND: The risk factors influencing the readmission within 90 days following total joint replacement (TJR) are complex and heterogeneous, and few systematic reviews to date have focused on this issue. METHODS: Web of Science, Embase, PubMed, and Chinese National Knowledge Infrastructure databases were searched from the inception dates to December 2022. Relevant, published studies were identified using the following keywords: risk factors, rehospitalization, total hip replacement, total knee replacement, total shoulder replacement, and total joint replacement. All relevant data were collected from the studies that meet the inclusion criteria. The methodological quality of the studies was assessed using the Newcastle-Ottawa Scale (NOS). RESULTS: Of 68,336 patients who underwent TJR, 1,269,415 (5.4%) were readmitted within 90 days. High American Society of Anesthesiologists (ASA) class (OR, 1.502; 95%CI:1.405-1.605; P < .001), heart failure (OR,1.494; 95%CI: 1.235-1.754; P < .001), diabetes (OR, 1.246; 95%CI:1.128-1.377; P < .001), liver disease (OR, 1.339; 95%CI:1.237-1.450; P < .001), drinking (OR, 1.114; 95%CI:1.041-1.192; P = .002), depression (OR, 1.294; 95%CI:1.223-1.396; P < .001), urinary tract infection (OR, 5.879; 95%CI: 5.119-6.753; P < .001), and deep vein thrombosis (OR, 10.007; 95%CI: 8.787-11.396; P < .001) showed statistically positive correlation with increased 90-day readmissions after TJR, but high blood pressure, smoking, and pneumonia had no significant association with readmission risk. CONCLUSION: The findings of this review and meta-analysis will aid clinicians as they seek to understand the risk factors for 90-day readmission following TJR. Clinicians should consider the identified key risk factors associated with unplanned readmissions and develop strategies to risk-stratify patients and provide dedicated interventions to reduce the rates of readmission and enhance the recovery process.

Effects of public reporting of prescription indicators on patient choices: evidence from propensity scores matching.

Background: Public reporting on health providers' performance (PRHPP) is increasingly used for empowering patients. This study aimed to test the effect of PRHPP using the theory of the consumer choice model. Methods: The study was conducted in 10 primary care institutions in Hubei province, China. Information related to the percentage of prescriptions requiring antibiotics, the percentage of prescriptions requiring injections, and average costs per prescription for each prescriber was calculated, ranked and displayed in a public place on a monthly basis. A questionnaire survey was undertaken on 302 patients 10 months after the initiation of the PRHPP, tapping into patient awareness, understanding, perceived value and use of the information in line with the theory of the consumer choice model. The fitness of data with the model was tested using structural equation modelling. The patients who were aware of the PRHPP were compared with those who were unaware of the PRHPP. The propensity score method (considering differences between the two groups of patients in age, gender, education, health and income) was used for estimating the effects of the PRHPP. Results: About 22% of respondents were aware of the PRHPP. Overall, the patients showed limited understanding, perceived value and use of the disclosed information. The data fit well into the consumer choice model. Awareness of the PRHPP was found to be associated with increased understanding of the antibiotic (p = 0.028) and injection prescribing indictors (p = 0.030). However, no significant differences in perceived value and use of the information (p > 0.097) were found between those who were aware and those who were unaware of the PRHPP. Conclusion: Although PRHPP may improve patient understanding of the prescribing performance indicators, its impacts on patient choices are limited due to low levels of perceived value and use of information from patients. Additional support is needed to enable patients to make informed choices using the PRHPP.

Strategies to eliminate cervical cancer in China.

Cervical cancer is a widely distributed disease that is preventable and controllable through early intervention. The World Health Organization has identified three key measures, coverage populations and coverage targets to eliminate cervical cancer. The WHO and several countries have conducted model predictions to determine the optimal strategy and timing of cervical cancer elimination. However, specific implementation strategies need to be developed in the context of local conditions. China has a relatively high disease burden of cervical cancer but a low human papillomavirus vaccination rate and cervical cancer screening population coverage. The purpose of this paper is to review interventions and prediction studies for the elimination of cervical cancer and to analyze the problems, challenges and strategies for the elimination of cervical cancer in China.

A green synthesized medicine residue carbon-based iron composite for the removal of chromium (VI) and cadmium (II): Performance, kinetics and mechanism.

Nowadays, clean-up of heavy metals from wastewaters using waste residue carbon-based material has received increasing attention. In this work, a novel Chinese medicine residue carbon-based nano zero-valent iron composite (CM-nZVI) had been successfully prepared using the combined Chinese medicine residue, FeCl3 and green tea extract. Cr(VI) and/ or Cd(II) removal in water by the CM-nZVI were systematacially investigated with a series of batch experiments. The most relevant findings indicated the adsorption efficiecy and capacity of Cr(VI) by CM-nZVI were respecitvely nearly 98% and 26 mg/g under optimized reaction conditions. The negative influences of the cations on the Cr(VI) removal followed the order of Al3+ > Ca2+ > Mg2+ Na+ > K+, but the anions followed the order of HCO3- > PO43- > NO3- > Cl- > SO42-. Humic acid (HA) and ionic strength with high concentrations severely inhibited Cr(VI) removal. The Cr(VI) adsorption on CM-nZVI fitted well by the pseudo-second-order kinetic and Langmuir models. A monolayer endothermic chemisorption occurred on Cr(VI) adsorption over CM-nZVI, and Cr(VI) removal by CM-nZVI primarily involved in the absorption, reduction, precipitation and complexation processes. Both Cr(VI) and Cd(II) removals had been achieved by CM-nZVI at their low concentrations. This CM-nZVI showed a better reusability proprity for Cr(VI) and Cd(II) removal with the regeneration of CM-nZVI through simple pickling. The outcomes of this work show that CM-nZVI could be used an effective material for heavy metals removal from water.

Neuropilin-1 promotes mitochondrial structural repair and functional recovery in rats with cerebral ischemia.

OBJECTIVES: Available literature documents that ischemic stroke can disrupt the morphology and function of mitochondria and that the latter in other disease models can be preserved by neuropilin-1 (NRP-1) via oxidative stress suppression. However, whether NRP-1 can repair mitochondrial structure and promote functional recovery after cerebral ischemia is still unknown. This study tackled this very issue and explored the underlying mechanism. METHODS: Adeno-associated viral (AAV)-NRP-1 was stereotaxically inoculated into the cortex and ipsilateral striatum posterior of adult male Sprague-Dawley (SD) rats before a 90-min transient middle cerebral artery occlusion (tMCAO) and subsequent reperfusion. Lentivirus (LV)-NRP-1 was transfected into rat primary cortical neuronal cultures before a 2-h oxygen-glucose deprivation and reoxygenation (OGD/R) injury to neurons. The expression and function of NRP-1 and its specific protective mechanism were investigated by Western Blot, immunofluorescence staining, flow cytometry, magnetic resonance imaging, transmission electron microscopy, etc. The binding was detected by molecular docking and molecular dynamics simulation. RESULTS: Both in vitro and in vivo models of cerebral ischemia/reperfusion (I/R) injury presented a sharp increase in NRP-1 expression. The expression of AAV-NRP-1 markedly ameliorated the cerebral I/R-induced damage to the motor function and restored the mitochondrial morphology. The expression of LV-NRP-1 alleviated mitochondrial oxidative stress and bioenergetic deficits. AAV-NRP-1 and LV-NRP-1 treatments increased the wingless integration (Wnt)-associated signals and ß-catenin nuclear localization. The protective effects of NRP-1 were reversed by the administration of XAV-939. CONCLUSIONS: NRP-1 can produce neuroprotective effects against I/R injury to the brain by activating the Wnt/ß-catenin signaling pathway and promoting mitochondrial structural repair and functional recovery, which may serve as a promising candidate target in treating ischemic stroke.

Integration of bulk RNA sequencing and single-cell analysis reveals a global landscape of DNA damage response in the immune environment of Alzheimer's disease.

Background: We developed a novel system for quantifying DNA damage response (DDR) to help diagnose and predict the risk of Alzheimer's disease (AD). Methods: We thoroughly estimated the DDR patterns in AD patients Using 179 DDR regulators. Single-cell techniques were conducted to validate the DDR levels and intercellular communications in cognitively impaired patients. The consensus clustering algorithm was utilized to group 167 AD patients into diverse subgroups after a WGCNA approach was employed to discover DDR-related lncRNAs. The distinctions between the categories in terms of clinical characteristics, DDR levels, biological behaviors, and immunological characteristics were evaluated. For the purpose of choosing distinctive lncRNAs associated with DDR, four machine learning algorithms, including LASSO, SVM-RFE, RF, and XGBoost, were utilized. A risk model was established based on the characteristic lncRNAs. Results: The progression of AD was highly correlated with DDR levels. Single-cell studies confirmed that DDR activity was lower in cognitively impaired patients and was mainly enriched in T cells and B cells. DDR-related lncRNAs were discovered based on gene expression, and two different heterogeneous subtypes (C1 and C2) were identified. DDR C1 belonged to the non-immune phenotype, while DDR C2 was regarded as the immune phenotype. Based on various machine learning techniques, four distinctive lncRNAs associated with DDR, including FBXO30-DT, TBX2-AS1, ADAMTS9-AS2, and MEG3 were discovered. The 4-lncRNA based riskScore demonstrated acceptable efficacy in the diagnosis of AD and offered significant clinical advantages to AD patients. The riskScore ultimately divided AD patients into low- and high-risk categories. In comparison to the low-risk group, high-risk patients showed lower DDR activity, accompanied by higher levels of immune infiltration and immunological score. The prospective medications for the treatment of AD patients with low and high risk also included arachidonyltrifluoromethane and TTNPB, respectively. Conclusions: In conclusion, immunological microenvironment and disease progression in AD patients were significantly predicted by DDR-associated genes and lncRNAs. A theoretical underpinning for the individualized treatment of AD patients was provided by the suggested genetic subtypes and risk model based on DDR.

Treadmill exercise exerts a synergistic effect with bone marrow mesenchymal stem cell-derived exosomes on neuronal apoptosis and synaptic-axonal remodeling.

Treadmill exercise and mesenchymal stem cell transplantation are both practical and effective methods for the treatment of cerebral ischemia. However, whether there is a synergistic effect between the two remains unclear. In this study, we established rat models of ischemia/reperfusion injury by occlusion of the middle cerebral artery for 2 hours and reperfusion for 24 hours. Rat models were perfused with bone marrow mesenchymal stem cell-derived exosomes (MSC-exos) via the tail vein and underwent 14 successive days of treadmill exercise. Neurological assessment, histopathology, and immunohistochemistry results revealed decreased neuronal apoptosis and cerebral infarct volume, evident synaptic formation and axonal regeneration, and remarkably recovered neurological function in rats subjected to treadmill exercise and MSC-exos treatment. These effects were superior to those in rats subjected to treadmill exercise or MSC-exos treatment alone. Mechanistically, further investigation revealed that the activation of JNK1/c-Jun signaling pathways regulated neuronal apoptosis and synaptic-axonal remodeling. These findings suggest that treadmill exercise may exhibit a synergistic effect with MSC-exos treatment, which may be related to activation of the JNK1/c-Jun signaling pathway. This study provides novel theoretical evidence for the clinical application of treadmill exercise combined with MSC-exos treatment for ischemic cerebrovascular disease.

Identification of immune microenvironment subtypes and signature genes for Alzheimer's disease diagnosis and risk prediction based on explainable machine learning.

Background: Using interpretable machine learning, we sought to define the immune microenvironment subtypes and distinctive genes in AD. Methods: ssGSEA, LASSO regression, and WGCNA algorithms were used to evaluate immune state in AD patients. To predict the fate of AD and identify distinctive genes, six machine learning algorithms were developed. The output of machine learning models was interpreted using the SHAP and LIME algorithms. For external validation, four separate GEO databases were used. We estimated the subgroups of the immunological microenvironment using unsupervised clustering. Further research was done on the variations in immunological microenvironment, enhanced functions and pathways, and therapeutic medicines between these subtypes. Finally, the expression of characteristic genes was verified using the AlzData and pan-cancer databases and RT-PCR analysis. Results: It was determined that AD is connected to changes in the immunological microenvironment. WGCNA revealed 31 potential immune genes, of which the greenyellow and blue modules were shown to be most associated with infiltrated immune cells. In the testing set, the XGBoost algorithm had the best performance with an AUC of 0.86 and a P-R value of 0.83. Following the screening of the testing set by machine learning algorithms and the verification of independent datasets, five genes (CXCR4, PPP3R1, HSP90AB1, CXCL10, and S100A12) that were closely associated with AD pathological biomarkers and allowed for the accurate prediction of AD progression were found to be immune microenvironment-related genes. The feature gene-based nomogram may provide clinical advantages to patients. Two immune microenvironment subgroups for AD patients were identified, subtype2 was linked to a metabolic phenotype, subtype1 belonged to the immune-active kind. MK-866 and arachidonyltrifluoromethane were identified as the top treatment agents for subtypes 1 and 2, respectively. These five distinguishing genes were found to be intimately linked to the development of the disease, according to the Alzdata database, pan-cancer research, and RT-PCR analysis. Conclusion: The hub genes associated with the immune microenvironment that are most strongly associated with the progression of pathology in AD are CXCR4, PPP3R1, HSP90AB1, CXCL10, and S100A12. The hypothesized molecular subgroups might offer novel perceptions for individualized AD treatment.

Role of lipocalin-2 in surgery-induced cognitive decline in mice: a signal from neuron to microglia.

BACKGROUND: Perioperative neurocognitive disorders (PNDs) are common complications observed among surgical patients. Accumulating evidence suggests that neuroinflammation is one of the major contributors to the development of PNDs, but the underlying mechanisms remain unclear. METHODS: qPCR and ELISA analysis were used for detecting LCN2 and cytokine levels. cx3cr1CreER/-:: R26iDTR/- crossed mouse line was used for microglia depletion; intracranial injection of recombinant LCN2 (rLCN2) and adeno-associated viruses (AAV)-mediated shRNA silencing approaches were used for gain and loss of function, respectively. Combing with in vitro microglia cell culture, we have studied the role of LCN2 in surgery-induced cognitive decline in mice. RESULTS: We revealed that Lcn2 mRNA and protein levels were greatly increased in mouse hippocampal neurons after surgery. This surgery-induced elevation of LCN2 was independent of the presence of microglia. Gain of function by intracranial injection of rLCN2 protein into hippocampus disrupted fear memory in naive mice without surgery. Conversely, silencing LCN2 in hippocampus by AAV-shRNA protected mice from surgery-induced microglia morphological changes, neuroinflammation and cognitive decline. In vitro, application of rLCN2 protein induced the expression of several pro-inflammatory cytokines in both BV-2 and primary microglia culture. CONCLUSIONS: These data suggest LCN2 acts as a signal from neuron to induce proinflammatory microglia, which contributes to surgery-induced neuroinflammation and cognitive decline in mice.

Shape stable poly(vinyl alcohol) hydrogels with immobilized metal hexacyanoferrates for cesium removal from waters.

The metal hexacyanoferrates with transition metal ions to replace ferric ions in the face center cubic structure of Prussian blue (PB) crystals are candidate adsorbents for radioactive cesium ions in waters. This study for the first time synthesized the shape stable poly(vinyl alcohol) (PVA) hydrogels with immobilized metal hexacynoferrate (PB analogue) that can be stored at dry and can efficiently adsorb cesium ions from waters after rewetting. A total of eight PB analogue particles in two families M3[Fe(III)(CN)6]2 (MFe(III)) or M4[Fe(II)(CN)6]2 (MFe(II)) with M=Zn, Ni, Cu, or Co were synthesized and were immobilized in the PVA hydrogels following boric acid and sulfate crosslinking. The produced PVA-PB analogue hydrogels are all stable in shape after dry and rewet, and the rewet hydrogels can adsorb cesium ions from waters at much higher rates. As predicted by the diffusion-reaction model, the apparent reaction constants for cesium ion adsorption are 4.2×10-4 1/s, 3.4×10-4 1/s, 3.9×10-4 1/s, 4.1×10-4 1/s, 4.1×10-4 1/s, 3.8×10-4 1/s, 1.1×10-3 1/s, and 9.6×10-4 1/s, for ZnFe(III), ZnFe(II), NiFe(III), NiFe(II), CuFe(III), CuFe(II), CoFe(III), and CoFe(II), respectively. The corresponding maximum adsorption capacities based on Langmuir isotherm model at 25 °C are 232.6 mg/g, 389.0 mg/g, 193.9 mg/g, 256.8 mg/g, 388.2 mg/g, 395.1 mg/g, 297.3 mg/g, and 391.2 mg/g, respectively. The use of PVA-CoFe(III) is the candidate for enhanced Cs removal from waters comparing the use of other PB analogues as adsorbent.

Bone marrow-derived mesenchymal stem cells improve post-ischemia neurological function in rats via the PI3K/AKT/GSK-3ß/CRMP-2 pathway.

BACKGROUND: Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) is a potential therapy for cerebral ischemia. However, the underlying protective mechanism remains undetermined. Here, we tested the hypothesis that transplantation of BMSCs via intravenous injection can alleviate neurological functional deficits through activating PI3K/AKT signaling pathway after cerebral ischemia in rats. METHODS: A cerebral ischemic rat model was established by the 2 h middle cerebral artery occlusion (MCAO). Twenty-four hours later, BMSCs (1 × 106 in 1 ml PBS) from SD rats were injected into the tail vein. Neurological function was evaluated by modified neurological severity score (mNSS) and modified adhesive removal test before and on d1, d3, d7, d10 and d14 after MCAO. Protein expressions of AKT, GSK-3ß, CRMP-2 and GAP-43 were detected by Western-bolt. NF-200 was detected by immunofluorescence. RESULTS: BMSCs transplantation did not only significantly improve the mNSS score and the adhesive-removal somatosensory test after MCAO, but also increase the density of NF-200 and the expression of p-AKT, pGSK-3ß and GAP-43, while decrease the expression of pCRMP-2. Meanwhile, these effects can be suppressed by LY294002, a specific inhibitor of PI3K/AKT. CONCLUSION: These data suggest that transplantation of BMSCs could promote axon growth and neurological deficit recovery after MCAO, which was associated with activation of PI3K/AKT /GSK-3ß/CRMP-2 signaling pathway.

Candidate reference genes for quantitative gene expression analysis in Lagerstroemia indica.

Quantitative gene expression analysis by qPCR requires reference genes for normalization. Lagerstroemia indica (crape myrtle) is a popular ornamental plant in the world, but suitable endogenous reference genes are lacking. To find suitable reference genes, we evaluated the stabilities of nine candidate genes in six experimental data sets: six different tissues, three leaf colors, nine flower colors, and under three abiotic stresses (salt, drought, cold) using four statistical algorithms. A target gene LiMYB56 (homolog of Arabidopsis MYB56) was used to verify the authenticity and accuracy of the candidate reference genes. The results showed that the combination of two stably expressed reference genes, rather than a single reference gene, improved the accuracy of the qPCR. LiEF1α-2 + LiEF1α-3 was best for the tissue, salt treatment, and drought treatment sets; LiEF1α-2 + LiEF1α-1 was optimal for leaf color; LiEF1α-2 + LiACT7 was optimal for cold treatment; and LiUBC + LiEF1α-1 was best for the flower color set. Notably, LiEF1α-2 had high expression stability in all six experimental sets, implying it may be a good reference gene for expression studies in L. indica. Our results will facilitate future gene expression studies in L. indica.

Inhibiting Caspase-12 Mediated Inflammasome Activation protects against Oxygen-Glucose Deprivation Injury in Primary Astrocytes.

Stroke is one of the leading causes of death worldwide. Accumulating evidence suggests that NLRP3 inflammasome activation plays an important role in ischemic stroke injury. However, the existence of the NLRP3 inflammasome in astrocytes remains controversial. In this study, we demonstrated the presence of the NLRP3 inflammasome in primary mouse astrocytes and investigated the role of caspase-12 in NLRP3 inflammasome activation and cell injury in an in vitro astrocyte oxygen-glucose deprivation (OGD) model. Astrocytes exposed to 2, 3, and 4 h of OGD exhibited increased cell injury and apoptosis, and the protein levels of caspase-12, cleaved caspase-3, NLRP3 inflammasome components, and IL-1ß were also significantly elevated. Interestingly, pretreatment with the caspase-12-specific inhibitor Z-ATAD-FMK attenuated cell injury and apoptosis and decreased the levels of NLRP3, caspase-1, IL-1ß, and cleaved caspase-3 in the OGD group. In conclusion, Z-ATAD-FMK protected astrocytes against OGD-induced cell death and inhibited NLPR3-inflammasome activation. Our results indicate that caspase-12 and its potential regulation of NLRP3 inflammasome activation might be a promising target for treatment of ischemic stroke.

Novel Targets for Stroke Therapy: Special Focus on TRPC Channels and TRPC6.

Stroke remains a leading cause of death, disability, and medical care burden worldwide. However, transformation from laboratory findings toward effective pharmacological interventions for clinical stroke has been unsatisfactory. Novel evidence has been gained on the underlying mechanisms and therapeutic potential related to the transient receptor potential (TRP) channels in several disorders. The TRP superfamily consists of a diverse group of Ca2+ permeable non-selective cation channels. In particular, the members of TRP subfamilies, TRP canonical (TRPC) channels and TRPC6, have been found in different cell types in the whole body and have high levels of expression in the central nervous system (CNS). Notably, the TRPCs and TRPC6 channel have been implicated in neurite outgrowth and neuronal survival during normal development and in a range of CNS pathological conditions. Recent studies have shown that suppression of TRPC6 channel degradation prevents ischemic neuronal cell death in experimental stroke. Accumulating evidence supports the important functions of TRPC6 in brain ischemia. We have highlighted some crucial advancement that points toward an important involvement of TRPCs and TRPC6 in ischemic stroke. This review will make an overview of the TRP and TRPC channels due to their roles as targets for clinical trials and CNS disorders. Besides, the primary goal is to discuss and update the critical role of TRPC6 channels in stroke and provide a promising target for stroke prevention and therapy.