Single-Cell Transcriptomic Analysis Reveals Dynamic Cellular Processes in Corneal Epithelium During Wound Healing in Cynomolgus Monkeys.

Purpose: Corneal wounding healing is critical for maintaining clear vision, however, a complete understanding of its dynamic regulatory mechanisms remains elusive. Here, we used single-cell RNA sequencing (scRNA-seq) to analyze the cellular activities and transcriptional changes of corneal limbal epithelial cells at different stages after wound healing in cynomolgus monkeys, which exhibit a closer transcriptomic similarity to humans. Methods: Corneal limbal tissues were collected during uninjured, 1-day and 3-day healing stages, dissociated into single cells, and subjected to scRNA-seq using the 10× Genomics platform. Cell types were clustered by graph-based visualization methods and unbiased computational analysis. Additionally, cell migration assays and immunofluorescent staining were performed on cultured human corneal epithelial cells. Results: We characterized nine cell clusters by scRNA-seq analysis of the cynomolgus monkey corneal epithelium. By comparing heterogeneous transcriptional changes in major cell types during corneal healing, we highlighted the importance of limbal epithelial cells (LEPCs) and basal epithelial cells (BEPCs) in extracellular matrix (ECM) formation and wound healing, as well as suprabasal epithelial cells (SEPCs) in epithelial differentiation during the healing processes. We further identified five different sub-clusters in LEPC, including the transit amplifying cell (TAC) sub-cluster that promotes early healing through the activation of thrombospondin-1 (THBS1) expression. Conclusions: Our study represents the first comprehensive exploration of the detailed transcriptome profile of individual corneal cells during the wound healing process in nonhuman primates. We demonstrate the intricate mechanisms involved in corneal healing and provide a promising avenue for potential therapies in corneal wound healing.

Cardioprotection of voluntary exercise against breast cancer-induced cardiac injury via STAT3.

Exercise is an effective way to alleviate breast cancer-induced cardiac injury to a certain extent. However, whether voluntary exercise (VE) activates cardiac signal transducer and activator of transcription 3 (STAT3) and the underlying mechanisms remain unclear. This study investigated the role of STAT3-microRNA(miRNA)-targeted protein axis in VE against breast cancer-induced cardiac injury.VE for 4 weeks not only improved cardiac function of transgenic breast cancer female mice [mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT +)] compared with littermate mice with no cancer (MMTV-PyMT -), but also increased myocardial STAT3 tyrosine 705 phosphorylation. Significantly more obvious cardiac fibrosis, smaller cardiomyocyte size, lower cell viability, and higher serum tumor necrosis factor (TNF)-α were shown in MMTV-PyMT + mice compared with MMTV-PyMT - mice, which were ameliorated by VE. However, VE did not influence the tumor growth. MiRNA sequencing identified that miR-181a-5p was upregulated and miR-130b-3p was downregulated in VE induced-cardioprotection. Myocardial injection of Adeno-associated virus serotype 9 driving STAT3 tyrosine 705 mutations abolished cardioprotective effects above. Myocardial STAT3 was identified as the transcription factor binding the promoters of pri-miR-181a (the precursor of miR-181a-5p) and HOX transcript antisense RNA (HOTAIR, sponged miR-130b-3p) in isolated cardiomyocytes. Furthermore, miR-181a-5p targeting PTEN and miR-130b-3p targeting Zinc finger and BTB domain containing protein 20 (Zbtb20) were proved in AC-16 cells. These findings indicated that VE protects against breast cancer-induced cardiac injury via activating STAT3 to promote miR-181a-5p targeting PTEN and to promote HOTAIR to sponge miR-130b-3p targeting Zbtb20, helping to develop new targets in exercise therapy for breast cancer-induced cardiac injury.

[Expert consensus on integrated traditional Chinese and western medicine diagnosis and treatment for osteoporotic fractures].

Osteoporotic fractures represent the most severe complications of osteoporosis,characterized by insidious onset,high mortality and disability rates,and a steadily increasing incidence,imposing a significant socioeconomic burden. Western medicine has advantages in diagnosis and surgical interventions,while traditional Chinese medicine excels in holistic management and the restoration of bodily equilibrium. The integration of both traditional Chinese medicine (TCM) and western medicine emerges as an effective therapeutic strategy for osteoporotic fractures. In order to propagate the concept of integrated diagnosis and treatment,foster the advancement of integrated medical techniques for osteoporotic fractures,and establish standardized and normative protocols for disease prevention,diagnosis,and treatment,a consensus expert group,led by Geriatric Branch of Chinese Geriatrics Society,the Young Osteoporosis Group of Orthopedics Branch of Chinese Medical Association,Osteoporosis Group of Orthopedics Branch of Chinese Physician Association,and Osteoporosis Professional Committee of the Shanghai Society of Integrated Traditional Chinese and Western Medicine,was established. This group engaged in deliberations and formulated the "Expert Consensus on Integrated Traditional Chinese and Western Medicine Diagnosis and Treatment of Osteoporotic Fractures" elucidating the concept of integrated medicine and offering recommendations in the domains of prevention,diagnosis,and treatment,with the aspiration of ameliorating the prognosis of osteoporotic fractures and enhancing the quality of life for these patients.

Comprehensive analysis of distal-less homeobox family gene expression in colon cancer.

BACKGROUND: The distal-less homeobox (DLX) gene family plays an important role in the development of several tumors. However, the expression pattern, prognostic and diagnostic value, possible regulatory mechanisms, and the relationship between DLX family genes and immune infiltration in colon cancer have not been systematically reported. AIM: We aimed to comprehensively analyze the biological role of the DLX gene family in the pathogenesis of colon cancer. METHODS: Colon cancer tissue and normal colon tissue samples were collected from the Cancer Genome Atlas and Gene Expression Omnibus databases. Wilcoxon rank sum test and t-test were used to assess DLX gene family expression between colon cancer tissue and unpaired normal colon tissue. cBioPortal was used to analyze DLX gene family variants. R software was used to analyze DLX gene expression in colon cancer and the relationship between DLX gene family expression and clinical features and correlation heat map. The survival package and Cox regression module were used to assess the prognostic value of the DLX gene family. The pROC package was used to analyze the diagnostic value of the DLX gene family. R software was used to analyze the possible regulatory mechanisms of DLX gene family members and related genes. The GSVA package was used to analyze the relationship between the DLX gene family and immune infiltration. The ggplot2, the survminer package, and the clusterProfiler package were used for visualization. RESULTS: DLX1/2/3/4/5 were significantly aberrantly expressed in colon cancer patients. The expression of DLX genes were associated with M stage, pathologic stage, primary therapy outcome, residual tumor, lymphatic invasion, T stage, N stage, age, perineural invasion, and history of colon polyps. DLX5 was independently correlated with the prognosis of colon cancer in multivariate analysis. DLX1/2/3/4/5/6 were involved in the development and progression of colon cancer by participating in immune infiltration and associated pathways, including the Hippo signaling pathway, the Wnt signaling pathway, several signaling pathways regulating the pluripotency of stem cells, and Staphylococcus aureus infection. CONCLUSION: The results of this study suggest a possible role for the DLX gene family as potential diagnostic or prognostic biomarkers and therapeutic targets in colon cancer.

Integrative Single-Cell RNA-Seq and ATAC-Seq Analysis of Mouse Corneal Epithelial Cells.

Purpose: Corneal epithelial homeostasis is maintained by coordinated gene expression across distinct cell populations, but the gene regulatory programs underlying this cellular diversity remain to be characterized. Here we applied single-cell multi-omics analysis to delineate the gene regulatory profile of mouse corneal epithelial cells under normal homeostasis. Methods: Single cells isolated from the cornea epithelium (with marginal conjunctiva) of adult mice were subjected to scRNA-seq and scATAC-seq using the 10×Genomics platform. Cell types were clustered by the graph-based visualization method uniform manifold approximation and projection and unbiased computational informatics analysis. The scRNA-seq and scATAC-seq datasets were integrated following the integration pipeline described in ArchR and Seurat. Results: We characterized diverse corneal epithelial cell types based on gene expression signatures and chromatin accessibility. We found that cell type-specific accessibility regions were mainly located at distal regions, suggesting essential roles of distal regulatory elements in determining corneal epithelial cell diversity. Trajectory analyses revealed a continuum of cell state transition and higher coordination between transcription factor (TF) motif accessibility and gene expression during corneal epithelial cell differentiation. By integrating transcriptomic and chromatin accessibility analysis, we identified cell type-specific and shared gene regulation programs. We also uncovered critical TFs driving corneal epithelial cell differentiation, such as nuclear factor I (NFI) family members, Rarg, Elf3. We found that nuclear factor-κB (NF-κB) family members were positive TFs in limbal cells and some superficial cells, but they were involved in regulating distinct biological processes. Conclusions: Our study presents a comprehensive gene regulatory landscape of mouse cornea epithelial cells, and provides valuable foundations for future investigation of corneal epithelial homeostasis in the context of cornea pathologies and regenerative medicine.

[Effect of HumicAcid-Heavy Metals on the Nitrogen Removal Performance of ANAMMOX Bacteria and Its Kinetic Analysis].

The effects of two typical heavy metal ions[Cu(Ⅱ) and Ni(Ⅱ)] and humic acid on ANAMMOX nitrogen removal (SAA) were studied through batch experiments, and the kinetic model was analyzed. At the same time, the effects of humic acid-heavy metal on ANAMMOX nitrogen removal were discussed. The results showed that ANAMMOX was promoted when ρ[Cu(Ⅱ)] and ρ[Ni(Ⅱ)] were 3 mg·L-1, and SAA was increased by 8.64% and 7.78%, respectively; ANAMMOX was inhibited when the ρ[Cu(Ⅱ)] and ρ[Ni(Ⅱ)] were 20 mg·L-1 and 5 mg·L-1, respectively, and the inhibition effect was more significant with the increase in heavy metal ion concentration. The index fitting showed that the IC50 of Cu(Ⅱ) and Ni(Ⅱ) on ANAMMOX were 29.67 mg·L-1 and 28.75 mg·L-1, respectively. SAA was increased by 7.37% when the ρ(humic acid) was 1 mg·L-1, and the inhibition rate reached 36.80% when the humic acid concentration was 40 mg·L-1. The linear fitting showed that the IC50 of humic acid on ANAMMOX was 58.36 mg·L-1. The modified Michaelis-Menten model could better describe the inhibitory kinetic behavior of heavy metals and humic acid on ANAMMOX. The model fitting showed that the complete inhibition concentrations (I*) of Cu(Ⅱ), Ni(Ⅱ), and humic acid on ANAMMOX were 49.59, 74.46, and 84.27 mg·L-1, respectively. An appropriate amount of humic acid was beneficial to improve the inhibition of heavy metals on ANAMMOX bacteria activity, and excessive humic acid would cause inhibition on ANAMMOX bacteria again.

[Application of Methylprednisolone Sodium Succinate Combined with Tropisetron in Prevention of Nausea and Vomiting under Microvascular Decompression of Hemifacial Spasm].

Objective To evaluate the effect of methylprednisolone sodium succinate combined with tropisetron on postoperative nausea and vomiting(PONV)under microvascular decompression of hemifacial spasm.Methods From January to June 2019,485 patients undergoing microvascular decompression for facial spasm at Department of Neurosurgery,Peking University People's Hospital were randomly assigned into two groups with random number table method.For group A(n=242),2 ml saline was administrated by intravenous drip before induction and 5 mg tropisetron after operation.For group B(n=243),40 mg methylprednisolone sodium succinate was administrated by intravenous drip before induction and 5 mg tropisetron after operation.The anesthesia time,operation time,and incidence of PONV in 0-24 h and 24-48 h were recorded for the comparison of the remedial treatment rate of nausea and vomiting between the two groups.Results There was no significant difference in age,gender,smoking history,body mass index value,American Society of Anesthesiologists score,medical history,surgical side,PONV history,operation time or anesthesia time between the two groups(all P > 0.05).The incidence of PONV in group A was 35.5% and 18.2% during 0-24 h and 24-48 h,respectively,which was significantly higher than that(18.5%,χ 2=7.331,P=0.007;8.2%,χ 2=4.364,P=0.037)in group B.The application rate of antiemetic drugs in group A was 15.2% and 8.7% during 0-24 h and 24-48 h,respectively,which was significantly higher than that(5.3%,χ 2=5.327,P=0.021;2.0%,χ 2=4.432,P=0.035)in group B.Conclusion The combination of methylprednisolone sodium succinate and tropisetron can effectively prevent PONV under microvascular decompression of hemifacial spasm,with the performance superior to single drug treatment.

Diagnosis and treatment of an elderly patient with 2019-nCoV pneumonia and acute exacerbation of chronic obstructive pulmonary disease in Gansu Province: A case report.

BACKGROUND: In December 2019, the first patient with 2019-novel coronavirus (2019-nCoV) was reported in Wuhan, China, and the disease spread rapidly across the country and surrounding countries within 2 mo. As of February 29, 2020, a total of 91 confirmed cases had been reported in Gansu Province. This case report of the diagnosis and treatment of an elderly patient with 2019-nCoV pneumonia complicated by acute exacerbation of chronic obstructive pulmonary disease in Gansu Province aims to provide a better reference for the treatment of patients in the future. CASE SUMMARY: The patient, a 94-year-old female, lived in Maiji District of Tianshui, Gansu Province, China. On January 30, 2020, she was admitted to the Fourth People's Hospital of Tianshui after 9 d of close contact with a patient with 2019-nCoV pneumonia. She was subsequently admitted to Gansu Provincial Hospital of Traditional Chinese Medicine for isolation and transferred to Tianshui Gansu Provincial Hospital of Infectious Diseases on February 3, 2020 for treatment. Upon initial examination, her body temperature was 36.7 °C , pulse was 80, breathing was 20, and blood pressure was 130/80 mmHg. She was conscious with normal development and normal nutrition. The pharynx was not red, and bilateral tonsils were not red and swollen. The lungs sounded slightly coarse with no dry or wet rales. The first symptoms were cough and fatigue on 2 February. The patient was hospitalized for 12 d. After active treatment, she was discharged on February 14 with a good prognosis. CONCLUSION: A history of exposure to the affected area or patient is a major cause of 2019-nCoV infection, and population clustering is a high risk factor for transmission. Patients may not necessarily have respiratory system symptoms as the only clinical manifestation but may also have concomitant or first onset digestive symptoms. Attention should be paid to the prevention and treatment of multiple organ dysfunction syndrome. Nucleic acid testing is extremely important and needs to be repeated several times. Laboratory and auxiliary examination indicators during the first week of admission are extremely important. It is feasible to carry out dynamic and continuous index monitoring, which can predict and guide the prevention and treatment of multiple organ dysfunction and the prognosis of the disease.

Flavor Components Comparison between the Neck Meat of Donkey, Swine, Bovine, and Sheep.

Donkey in China is well known for its draft purpose and transportation; however, donkey meat has attracted more and more consumers in recent years, yet it lacks sufficient information on its flavor components compared to other main meats. Therefore, in this study, volatile flavor compounds in neck meat of donkey, swine, bovine, and sheep were classified by electronic nose, then confirmed and quantified by gas chromatography-mass spectrometry. High-performance liquid chromatography (HPLC) and gas chromatography were used to quantify free fatty acid, amino acid, and flavor nucleotide. A total of 73 volatile compounds were identified, and aldehydes were identified as the characteristic flavor compounds in neck meat of donkey, bovine, swine and sheep in proportion of 76.39%, 46.62%, 31.64%, and 35.83%, respectively. Particularly, hexanal was the most abundant volatile flavor. Compared with other neck meat, much higher unsaturated free fatty acids were present in donkeys. Furthermore, neck meat of donkeys showed essential amino acid with highest content. Thus, special flavor and nutrition in donkey neck meat make it probably a candidate for consumers in other regions besides Asia.

[Clinical Application of New Antiepileptic Drugs].

Epilepsy has high incidence and complex etiologies,and its treatment remains challenging.For around 70% of people with epilepsy,seizures can be controlled after proper antiepileptic treatment.The availability of some new antiepileptic drugs in recent years has offered new options for epileptic patients.A solid knowledge on the pharmacokinetics,efficacy,and tolerability profiles of these new antiepileptic drugs will help to provide safe,proper,reasonable,and standardized treatment for patients.

Inflammatory and fibrosis infiltration in synovium associated with the progression in developmental dysplasia of the hip.

Developmental dysplasia of the hip (DDH) is a common musculoskeletal disorder characterized by progressive joint soreness and limited mobility. The aim of the present study was to investigate the pathological changes and inflammatory infiltration in the hypertrophic synovium of the hip joint associated with the progression of DDH. Synovial biopsies in the hip joint are obtained from patients with moderate DDH and severe DDH during surgery. These biopsies are processed for histological and immunohistochemical (IHC) analysis and investigation of the pathological processes in a synovium, including types of inflammatory cell infiltration, synovial angiogenesis and fibrosis, neuron endings and neuropeptide invasion. Correlation analysis was performed between the mean optical density (MOD) of each antibody, and Harris hip score (HHS) and visual analogue score (VAS) using the Spearman correlation test. Chronic inflammation in the synovium was observed via the positive IHC staining of inflammatory cells, such as T cells, B cells, macrophages and leukocytes. Excessive staining of vimentin and α smooth muscle actin in the synovium of severe DDH represented significant fibrosis and angiogenesis. These targets were also significantly correlated with HHS in severe DDH. The MOD levels of CD68 (indicators of macrophage) indicated apparent correlations with HHS and VAS in patients with severe DDH. The labels of nerve fibers and pain transmission indicators were as follows: Neurofilament­200 and substance P. Calcitonin gene­related peptide was upregulated in the synovium of severe DDH in contrast to that in the synovium of moderate DDH. The MOD levels of NF­200, SP and CGRP were correlated with VAS in severe DDH. The pathology of DDH includes chronic inflammatory cell infiltration corresponding with nerve fibers and fibroblastic proliferation, which might contribute to arthritis progression and joint soreness in DDH.

Dissociating nNOS (Neuronal NO Synthase)-CAPON (Carboxy-Terminal Postsynaptic Density-95/Discs Large/Zona Occludens-1 Ligand of nNOS) Interaction Promotes Functional Recovery After Stroke via Enhanced Structural Neuroplasticity.

Background and Purpose- Stroke is a major public health concern worldwide. Although clinical treatments have improved in the acute period after stroke, long-term therapeutics remain limited to physical rehabilitation in the delayed phase. This study is aimed to determine whether nNOS (neuronal NO synthase)-CAPON (carboxy-terminal postsynaptic density-95/discs large/zona occludens-1 ligand of nNOS) interaction may serve as a new therapeutic target in the delayed phase for stroke recovery. Methods- Photothrombotic stroke and transient middle cerebral artery occlusion were induced in mice. Adeno-associated virus (AAV)-cytomegalovirus (CMV)-CAPON-125C-GFP (green fluorescent protein)-3Flag and the other 2 drugs (Tat-CAPON-12C and ZLc-002) were microinjected into the peri-infarct cortex immediately and 4 to 10 days after photothrombotic stroke, respectively. ZLc-002 was also systemically injected 4 to 10 days after transient middle cerebral artery occlusion. Grid-walking task and cylinder task were conducted to assess motor function. Western blotting, immunohistochemistry, Golgi staining, and electrophysiology recordings were performed to uncover the mechanisms. Results- Stroke increased nNOS-CAPON association in the peri-infarct cortex in the delayed period. Inhibiting the ischemia-induced nNOS-CAPON association substantially decreased the number of foot faults in the grid-walking task and forelimb asymmetry in the cylinder task, suggesting the promotion of functional recovery from stroke. Moreover, dissociating nNOS-CAPON significantly facilitated dendritic remodeling and synaptic transmission, indicated by increased dendritic spine density, dendritic branching, and length and miniature excitatory postsynaptic current frequency but did not affect stroke-elicited neuronal loss, infarct size, or cerebral edema, suggesting that nNOS-CAPON interaction may function via regulating structural neuroplasticity, rather than neuroprotection. Furthermore, ZLc-002 reversed the transient middle cerebral artery occlusion-induced impairment of motor function. Conclusions- Our results reveal that nNOS-CAPON coupling can serve as a novel pharmacological target for functional restoration after stroke.

Cadmium induces ovarian granulosa cell damage by activating PERK-eIF2α-ATF4 through endoplasmic reticulum stress.

This study aimed to investigate whether cadmium induces ovarian granulosa cell damage by activating protein kinase R-like endoplasmic reticulum kinase (PERK)-eIF2α-ATF4 through endoplasmic reticulum (ER) stress and to elucidate the underlying regulation mechanism. Two models of cadmium exposure were established. In one model, ovarian granulosa cells isolated from 21-day-old female Sprague Dawley rats were cultured in vitro for 36 h and exposed to CdCl2 (0, 5, 10, and 20 µM), and in another model, a human ovarian granulosa tumor cell line (COV434) was used to construct the binding immunoglobulin protein (BIP)-knockdown cell line sh-BIP and exposed to 0 and 20 µM CdCl2. After exposure to cadmium for 12 h, the expression mRNA and protein levels of BIP, p-PERK, and p-eIF2α were determined in the two models. miRNAs related to BIP were also detected in granulosa cells after cadmium exposure. We found that mRNA and protein levels of all factors were upregulated in each cadmium-dose group, except for BIP mRNA expression in the 5 µM Cd group. The BIP gene was knocked down in COV434 cells before exposure to cadmium. All factors were upregulated in COV434 cells exposed to Cd, and the expression of the p-eIF2α protein was downregulated in sh-BIP cells exposed to Cd. In addition, no differences in BIP-related miRNAs were detected in cadmium-exposed rat ovarian granulosa cells versus the control group. Cadmium induces ovarian granulosa cell damage by inducing ER stress.

Correction: An efficient and recyclable ionic diphosphine-based Ir-catalyst for hydroaminomethylation of olefins with H2O as the hydrogen source.

Correction for 'An efficient and recyclable ionic diphosphine-based Ir-catalyst for hydroaminomethylation of olefins with H2O as the hydrogen source' by Huan Liu et al., Chem. Commun., 2018, 54, 7979-7982.

An efficient and recyclable ionic diphosphine-based Ir-catalyst for hydroaminomethylation of olefins with H2O as the hydrogen source.

Hydroaminomethylation of olefins with H2O as the hydrogen source was accomplished over an Ir-catalyst with the involvement of an ionic diphosphine (L6). The use of H2O as the hydrogen source could completely inhibit the hydrogenation of olefins. The π-accepting ability and improved stability of L6 endowed the corresponding Ir-catalyst with high activity and good longevity for recycling uses.

The Orally Active Noncompetitive AMPAR Antagonist Perampanel Attenuates Focal Cerebral Ischemia Injury in Rats.

Inhibition of ionotropic glutamate receptors (iGluRs) is a potential target of therapy for ischemic stroke. Perampanel is a potent noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor (AMPAR) antagonist with good oral bioavailability and favorable pharmacokinetic properties. Here, we investigated the potential protective effects of perampanel against focal cerebral ischemia in a middle cerebral artery occlusion (MCAO) model in rats. Oral administration with perampanel significantly reduced MCAO-induced brain edema, brain infarct volume, and neuronal apoptosis. These protective effects were associated with improved functional outcomes, as measured by foot-fault test, adhesive removal test, and modified neurological severity score (mNSS) test. Importantly, perampanel was effective even when the administration was delayed to 1 h after reperfusion. The results of enzyme-linked immunosorbent assay (ELISA) showed that perampanel significantly decreased the expression of pro-inflammatory cytokines IL-1ß and TNF-α, whereas it increased the levels of anti-inflammatory cytokines IL-10 and TGF-ß1 after MCAO. In addition, perampanel treatment markedly decreased the expression of inducible nitric oxide synthase (iNOS) and neuronal nitric oxide synthase (nNOS), and also inhibited nitric oxide (NO) generation in MCAO-injured rats at 24 and 72 h after reperfusion. In conclusion, this study demonstrated that the orally active AMPAR antagonist perampanel protects against experimental ischemic stroke via regulating inflammatory cytokines and NOS pathways.

Opening a New Time Window for Treatment of Stroke by Targeting HDAC2.

Narrow therapeutic window limits treatments with thrombolysis and neuroprotection for most stroke patients. Widening therapeutic window remains a critical challenge. Understanding the key mechanisms underlying the pathophysiological events in the peri-infarct area where secondary injury coexists with neuroplasticity over days to weeks may offer an opportunity for expanding the therapeutic window. Here we show that ischemia-induced histone deacetylase 2 (HDAC2) upregulation from 5 to 7 d after stroke plays a crucial role. In this window phase, suppressing HDAC2 in the peri-infarct cortex of rodents by HDAC inhibitors, knockdown or knock-out of Hdac2 promoted recovery of motor function from stroke via epigenetically enhancing cells survival and neuroplasticity of surviving neurons as well as reducing neuroinflammation, whereas overexpressing HDAC2 worsened stroke-induced functional impairment of both WT and Hdac2 conditional knock-out mice. More importantly, inhibiting other isoforms of HDACs had no effect. Thus, the intervention by precisely targeting HDAC2 in this window phase is a novel strategy for the functional recovery of stroke survivors.SIGNIFICANCE STATEMENT Narrow time window phase impedes current therapies for stroke patients. Understanding the key mechanisms underlying secondary injury may open a new window for pharmacological interventions to promote recovery from stroke. Our study indicates that ischemia-induced histone deacetylase 2 upregulation from 5 to 7 d after stroke mediates the secondary functional loss by reducing survival and neuroplasticity of peri-infarct neurons as well as augmenting neuroinflammation. Thus, precisely targeting histone deacetylase 2 in the window phase provides a novel therapeutic strategy for stroke recovery.

ZL006 promotes migration and differentiation of transplanted neural stem cells in male rats after stroke.

New strategies must be developed to resolve the problems of stroke treatment. In recent years, stem cell-based therapy after stroke has come into the public and academic lens. Previously we have shown that uncoupling neuronal nitric oxide synthase (nNOS) from the postsynaptic density protein-95 (PSD-95) by ZL006, a small molecular compound, can ameliorate ischemic damage and promote neuronal differentiation of endogenous neural stem cells (NSCs) in focal cerebral ischemic male rats. In this study, we transplanted exogenous NSCs into the ipsilateral hemisphere of male rats in combination with ZL006 treatment after ischemic stroke. We show that ZL006 treatment facilitates the migration of transplanted NSCs into the ischemia-injured area and promotes neuronal differentiation of these cells, which is not due to a direct effect of ZL006 on exogenous NSCs but is associated with increased phosphorylation of cAMP response element-binding protein (CREB) in neurons and favorable microenvironment. Moreover, improved functional outcome in the ZL006-treated group was also found. Taken together, our data indicate that ZL006, uncoupling nNOS-PSD-95 in neurons, positively regulates the fate of transplanted NSCs and benefits the functional outcome after stroke in male rats.

Knockdown of Angiopoietin-Like Protein 2 Inhibits Proliferation and Invasion in Glioma Cells via Suppressing the ERK/MAPK Signaling Pathway.

Angiopoietin-like protein 2 (ANGPTL2), a member of the glycoprotein family, is mainly secreted by adipose tissues under normal conditions. Recently, ANGPTL2 has been found to be upregulated in some types of cancers and is considered to be a tumor promoter. However, the functional significance of ANGPTL2 in glioma has not yet been elucidated. In this study, we investigated the specific role of ANGPTL2 in glioma. The results showed that ANGPTL2 was highly expressed in glioma tissues and cell lines. Knockdown of ANGPTL2 reduced the proliferative and invasive abilities of glioma cells. Moreover, the tumorigenesis assay showed that ANGPTL2 knockdown inhibited glioma tumor growth in vivo. We also found that ANGPTL2 knockdown decreased the protein levels of p-ERK1/2 in glioma cells and thus blocked the activity of the ERK/MAPK signaling pathway. Taken together, our study provided the first evidence that ANGPTL2 played an oncogenic role in glioma development and might be considered as a new therapeutic target for glioma treatment.