[Characteristics and Source Apportionment of Atmospheric Fine Particles in Langfang in Autumn and Winter].

In this study, we report observations of various chemical species in PM2.5 samples that were collected between November 25, 2019 and March 31, 2020 in the northern, urban, and southern areas of Langfang, among which the concentrations of PM2.5 followed the order of southern>urban>northern. The abundance and chemical compositions of the particles in this study were temporally and spatially variable, with major contributions from organic matter (25.4%), nitrate (21.5%), sulfate (11.0%), ammonium (13.5%), and crustal matter (13.7%). The contributions of nitrate, sulfate, and ammonium were higher in the urban site compared with that in the southern and northern sites. On the contrary, organic matter and crustal matter exhibited much higher values in the southern and northern sites. In addition, the contributions of organic matter to the particle mass decreased from 27.3% to 23.0%, and the total contributions of sulfate, nitrate, and ammonium ions increased from 38.7% to 51.3% between clean and haze days, respectively. Source apportionment using positive matrix factorization showed five PM2.5 sources: secondary inorganic aerosol (41.9%), traffic emissions (19.9%), coal combustion (12.7%), industrial pollution (9.1%), and mineral dust (9.3%). The contributions of the first two factors followed the order of urban>northern>southern, whereas the contributions of the last three factors followed the order of southern>northern>urban. Further, the contributions of secondary inorganic aerosol, traffic emissions, and coal combustion were higher on haze days, whereas the contributions of industrial pollution and mineral dust were higher on clean days.

RING domain of zinc finger protein like 1 is essential for cell proliferation in endometrial cancer cell line RL95-2.

Endometrial cancer (EC) is the fourth most common cancer in women and exhibits increasing incidence and mortality. Some reports showed that the 5-year survival rate of EC was closely associated with the diagnosed stage. It is urgent to screen for sensitive and specific targets to improve early detection and EC therapy. In our study, we found that zinc finger protein like 1 (ZFPL1) was highly expressed in EC tissues and the EC cell line RL95-2, as detected via RT-qPCR and western blot analysis. Immunocytochemistry results showed that ZFPL1 was localized in the Golgi complex dependent on the C-terminal transmembrane domain. The MTT and EdU stains were employed to examine the effect of ZFPL1 on cell proliferation. We found that the silencing of ZFPL1 blocked cell proliferation and the expression of p-Akt308 and p-Akt473 but improved the protein level of PTEN. The overexpression of ZFPL1 and ZFPL1ΔTMD (deletion of the transmembrane domain) promoted cell proliferation and induced the expression of p-Akt308 and p-Akt473. However, the overexpression of ZFPL1ΔRING (deletion of the RING domain) caused loss of the function of ZFPL1 in cell proliferation and the PI3K/Akt pathway. In summary, ZFPL1 induced RL95-2 cell proliferation and was involved in PI3K/Akt pathway, suggesting the oncogenic role of ZFPL1 during EC development. Additionally, the RING domain was essential for the function of ZFPL1. These findings provided a new biomarker for EC diagnosis and therapy.

Pharmacological approaches promoting stem cell-based therapy following ischemic stroke insults.

Stroke can lead to long-term neurological deficits. Adult neurogenesis, the continuous generation of newborn neurons in distinct regions of the brain throughout life, has been considered as one of the appoaches to restore the neurological function following ischemic stroke. However, ischemia-induced spontaneous neurogenesis is not suffcient, thus cell-based therapy, including infusing exogenous stem cells or stimulating endogenous stem cells to help repair of injured brain, has been studied in numerous animal experiments and some pilot clinical trials. While the effects of cell-based therapy on neurological function during recovery remains unproven in randomized controlled trials, pharmacological agents have been administrated to assist the cell-based therapy. In this review, we summarized the limitations of ischemia-induced neurogenesis and stem-cell transplantation, as well as the potential proneuroregenerative effects of drugs that may enhance efficacy of cell-based therapies. Specifically, we discussed drugs that enhance proliferation, migration, differentiation, survival and function connectivity of newborn neurons, which may restore neurobehavioral function and improve outcomes in stroke patients.

Long non-coding RNAs in ischemic stroke.

Stroke is one of the leading causes of mortality and disability worldwide. Uncovering the cellular and molecular pathophysiological processes in stroke have been a top priority. Long non-coding (lnc) RNAs play critical roles in different kinds of diseases. In recent years, a bulk of aberrantly expressed lncRNAs have been screened out in ischemic stroke patients or ischemia insulted animals using new technologies such as RNA-seq, deep sequencing, and microarrays. Nine specific lncRNAs, antisense non-coding RNA in the INK4 locus (ANRIL), metastasis-associate lung adenocarcinoma transcript 1 (MALAT1), N1LR, maternally expressed gene 3 (MEG3), H19, CaMK2D-associated transcript 1 (C2dat1), Fos downstream transcript (FosDT), small nucleolar RNA host gene 14 (SNHG14), and taurine-upregulated gene 1 (TUG1), were found increased in cerebral ischemic animals and/or oxygen-glucose deprived (OGD) cells. These lncRNAs were suggested to promote cell apoptosis, angiogenesis, inflammation, and cell death. Our Gene Ontology (GO) enrichment analysis predicted that MEG3, H19, and MALAT1 might also be related to functions such as neurogenesis, angiogenesis, and inflammation through mechanisms of gene regulation (DNA transcription, RNA folding, methylation, and gene imprinting). This knowledge may provide a better understanding of the functions and mechanisms of lncRNAs in ischemic stroke. Further elucidating the functions and mechanisms of these lncRNAs in biological systems under normal and pathological conditions may lead to opportunities for identifying biomarkers and novel therapeutic targets of ischemic stroke.

Meta-Analysis on the Association between Brain-Derived Neurotrophic Factor Polymorphism rs6265 and Ischemic Stroke, Poststroke Depression.

BACKGROUND: Ischemic stroke is a multifactorial neurologic injury that causes mortality and disability worldwide. Poststroke depression is the most important neuropsychiatric consequence of stroke. Brain-derived neurotrophic factor is a neurotrophin family member that plays key role in regulating neuron survival and differentiation. Studies found a polymorphism in brain-derived neurotrophic factor gene (rs6265) may associate with the ischemic stroke and poststroke depression risk. However, the results are inconclusive and inconsistent. METHODS: In the present meta-analysis, the database PubMed, Embase, Cochrane Central Register of Controlled Trials, CNKI, and Chinese Biomedical Literature Database were searched until July 9, 2017. RESULTS: Seven studies with 1287 cases and 1032 controls were included for the meta-analysis of ischemic stroke, and five studies with 272 cases and 503 controls were included for poststroke depression. The results indicated that the GG genotype of brain-derived neurotrophic factor is related to a significantly lower risk of ischemic stroke in the homozygous and dominant models (odds ratio = .57 and .80, respectively). No significant relation was found between rs6265 and poststroke depression. CONCLUSIONS: Thus, brain-derived neurotrophic factor rs6265 might be recommended as a predictor of susceptibility of ischemic stroke. However, the results of this meta-analysis should be interpreted with caution because of the heterogeneity between studies and low sample size. Further studies are needed to evaluate the associations between rs6265 and poststroke depression, especially in Caucasians, with large sample size.

Glibenclamide enhances the effects of delayed hypothermia after experimental stroke in rats.

In order to evaluate whether glibenclamide can extend the therapeutic window during which induced hypothermia can protect against stroke, we subjected adult male Sprague-Dawley rats to middle cerebral artery occlusion (MCAO). We first verified the protective effects of hypothermia induced at 0, 2, 4 or 6h after MCAO onset, and then we assessed the effects of the combination of glibenclamide and hypothermia at 6, 8 or 10h after MCAO onset. At 24h after MCAO, we assessed brain edema, infarct volume, modified neurological severity score, Evans Blue leakage and expression of Sulfonylurea receptor 1 (SUR1) protein and pro-inflammatory factors. No protective effects were observed when hypothermia was induced too long after MCAO. At 6h after MCAO onset, hypothermia alone failed to decrease cerebral edema and infarct volume, but the combination of glibenclamide and hypothermia decreased both. The combination also improved neurological outcome, ameliorated blood-brain barrier damage and decreased levels of COX-2, TNF-α and IL-1ß. These results suggest that glibenclamide enhances and extends the therapeutic effects of delayed hypothermia against ischemia stroke, potentially by ameliorating blood-brain barrier damage and declining levels of pro-inflammatory factors.

Hypothermia followed by rapid rewarming exacerbates ischemia-induced brain injury and augments inflammatory response in rats.

Hypothermia followed by slow rewarming is neuroprotective for ischemic stroke. However, slow rewarming causes patients' longer stay in intensive care unit and increases the risk of hypothermic complications. Hypothermia followed by rapid rewarming (HTRR) is more convenient; but it exacerbates intracranial hypertension for patients with massive hemispheric infarcts. The present study aims to investigate in detail how HTRR exacerbates ischemic brain injury and what are underlying mechanisms. Rats subjected to transient focal ischemia by middle cerebral artery occlusion were treated with normothermia or hypothermia followed by rapid rewarming. Neurological outcome, neuronal injury, blood-brain barrier integrity and expressions of inflammatory cytokines were observed. Results showed that HTRR at a rate of 3 °C/20 min increased both neurological deficit score and Longa score, enhanced the loss of neurons and the plasma level of neuron-specific enolase. Rapid rewarmed rats also displayed increased Evans blue dye extravasation, matrix metalloproteinase 9 level and tight junction impairment. Meanwhile, interleukin-1ß, -6, tumor necrosis factor α and cyclooxygenase-2 were markedly elevated in rapid rewarmed rats. Anti-inflammatory agent minocycline suppressed HTRR-induced elevation of inflammatory cytokines and improved neurological outcome. These results indicated that HTRR significantly impaired neurovascular unit and augmented proinflammatory response in stroke.

Prolonged hypothermia exposure diminishes neuroprotection for severe ischemic-hypoxic primary neurons.

This study aimed to identify optimal mild hypothermic (MH) condition that would provide the best protection for neuronal cells undergoing severe ischemia and hypoxia. We also sought to determine if longer exposure to mild hypothermia would confer greater protection to severe ischemia and hypoxia in these cells. We designed a primary neuronal cell model for severe glucose and oxygen deprivation/reoxygenation (OGD/R) to simulate the hypoxic-ischemic condition of patients with severe stroke, trauma, or hypoxic-ischemic encephalopathy. We evaluated the viability of these neurons following 3 h of OGD/R and variable MH conditions including different temperatures and durations of OGD/R exposure. We further explored the effects of the optimal MH condition on several parts which are associated with mitochondrial apoptosis pathway: intracellular calcium, reactive oxygen species (ROS), and mitochondrial transmembrane potential (MTP). The results of this study showed that the apoptosis proportion (AP) and cell viability proportion (CVP) after OGD/R significantly varied depending on which MH condition cells were exposed to (p < 0.001). Further, our findings showed that prolonged MH reduced the neuroprotection to AP and CVP. We also determined that the optimal MH conditions (34 °C for 4.5 h) reduced intracellular calcium, ROS, and recovered MTP. These findings indicate that there is an optimal MH treatment strategy for severely hypoxia-ischemic neurons, prolonged duration might diminish the neuroprotection, and that MH treatment likely initiates neuroprotection by inhibiting the mitochondrial apoptosis pathway.

Combination of mild hypothermia with neuroprotectants has greater neuroprotective effects during oxygen-glucose deprivation and reoxygenation-mediated neuronal injury.

Co-treatment of neuroprotective reagents may improve the therapeutic efficacy of hypothermia in protecting neurons during ischemic stroke. This study aimed to find promising drugs that enhance the neuroprotective effect of mild hypothermia (MH). 26 candidate drugs were selected based on different targets. Primary cultured cortical neurons were exposed to oxygen-glucose deprivation and reoxygenation (OGD/R) to induce neuronal damage, followed by either single treatment (a drug or MH) or a combination of a drug and MH. Results showed that, compared with single treatment, combination of MH with brain derived neurotrophic factor, glibenclamide, dizocilpine, human urinary kallidinogenase or neuroglobin displayed higher proportion of neuronal cell viability. The latter three drugs also caused less apoptosis rate in combined treatment. Furthermore, co-treatment of those three drugs and MH decreased the level of reactive oxygen species (ROS) and intracellular calcium accumulation, as well as stabilized mitochondrial membrane potential (MMP), indicating the combined neuroprotective effects are probably via inhibiting mitochondrial apoptosis pathway. Taken together, the study suggests that combined treatment with hypothermia and certain neuroprotective reagents provide a better protection against OGD/R-induced neuronal injury.