Search

Tumor cells can activate platelets, which in turn facilitate tumor cell survival and dissemination. Platelets inhibition or blocking platelet-tumor cell interactions has become a strategy to suppress tumor progression. In this study, we investigated the effect of ticagrelor, a new antiplatelet drug, on tumor cell proliferation and metastasis. Our results show that ticagrelor not only inhibits the proliferation, migration, and invasion of B16F10 and Lewis lung carcinoma cells but also induces platelet apoptosis. In addition, we find that apoptosis of the platelet cells is dose dependent. Further, the result of in-vivo experiments proved that ticagrelor treatment decreased the tumor metastasis. The results of this study demonstrate that ticagrelor may be a potential anti-tumor agent for tumor metastasis.

Novel carbon self-doped graphitic carbon nitride tube (denoted as C-CNT) was fabricated by the means of a facile in situ solvothermal method with melamine and glucose as precursor and additive, respectively. The C-CNT not only remained unique hexagonal tubular structure obtained from supramolecular self-assembly method, but also introduced aromatic carbon into CN framework under the glucose-assisted hydrothermal conditions. The as-prepared C-CNT exposed abundant nitrogen defects and dramatically improved the valid separation of photoexcited charge carriers, hence achieving excellent photocatalytic hydrogen evolution activity (32.3 μmol h−1, λ > 420 nm), which was up to 4.24 and 12-folds higher than pristine carbon nitride tube (CNT) and traditional bulk counterpart (BCN), respectively. Therefore, this work highlights an assisted hydrothermal approach to successfully prepare carbon-rich graphitic carbon nitride with hexagonal tubular structure.

Objective More than 2 billion women are experiencing menopause transition in China and some of them suffered from depression; while the risk factors of depression during menopause transition were still unclearin China. We aimed to investigate the risk factors in mid-life women in Southeast China. Method This study included 1748 Chinese women aged 40–65 years-old who visited gynecology outpatient department of Women’s hospital School of Medicine, Zhejiang University during 2010–2018. Demographic information was collected, and the modified Kupperman Menopausal Index (mKMI) and Hamilton Rating Scale for Depression were assessed. Circulating levels of sex hormones were tested. Ordinal logistic regression analysis was performed to identify risk factors for depression. Results The prevalence of depression symptoms was 47.43%. The majority of women had mild (38.56%) or moderate depressive symptoms (8.00%); only 0.86% had severe depressive symptoms. Compared with perimenopausal women, postmenopausal women had increased risks of more severe depression. The associations between menopausal syndromes and the intensity of depression were strongly positive (OR 6.69, 95% CI 5.39–8.29). Elder age, higher follicle stimulating hormone levels, lower estradiol levels, and fewer parity were positively related with the intensity of depression. Among postmenopausal women, underweight, mKMI > 14, earlier age at menopause, shorter reproductive period, and longer duration after menopause were risk factors for incresed intensity of depression. Conclusions The results demonstrated a high proportion of depression in women complaining of menopause. Menopausal symptoms were strongly related to the intensity of depression. In postmenopausal women, estrogen related events are associated with the intensity of depression. Gynecological endocrinologists in China should consider screening for depression in high-risk women.

It is widely accepted that tumor metastasis is the dominant factor leading to cancer-related death. Tumor metastasis is mediated by cell invasion, blood circulation and lymphatic circulation. Paclitaxel, as a common anti-tumor drug and a mitotic inhibitor, promotes microtubule assembly and inhibits microtubule depolymerization. In addition, ticagrelor, an anti-platelet drug, is used to treat acute coronary syndrome. An increasing numbers of studies have reported that platelets can facilitate tumor metastasis. Therefore, inhibiting the effects of platelets can serve as a novel therapeutic strategy for cancer. To explore the effect of anti-tumor and anti-platelet drugs on tumor progression, the murine melanoma cell line, B16F10, and Lewis Lung carcinoma (LLC) cells were treated with paclitaxel and/or ticagrelor. Interestingly, the results demonstrated that paclitaxel and ticagrelor could not only suppress the proliferation, migration and invasion of B16F10 and LLC cells, but they could also prevent tumor metastasis to the lungs. Furthermore, the inhibitory effect of paclitaxel and ticagrelor was more apparent when both drugs were used in combination. Collectively, the current study demonstrated that the combination of paclitaxel and ticagrelor could be considered as a potential anti-tumor therapy approach.

Background:Glutamate excitotoxicity caused by dysfunctional glutamate transporters plays an important role in the pathogenesis of Parkinson’s disease (PD); however, the mechanisms that underlie the regulation of glutamate transporters in PD are still not fully elucidated. MicroRNAs have been reported to play key roles in regulating the translation of glutamate-transporter mRNA. Methods: We established model of PD 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice in vivo and 1-methyl-4-phenylpyridinium (MPP+) treated astrocyte in vitro. Stereotaxic injection of shRNA in mouse, and miRNA inhibitor/mimic, or antagonist/agonist treated the cell model, Behavioral experiments, glutamic acid uptake, transport activity of synaptosomes, underlying mechanisms and the impact on neuronal survival were assessed.Results We demonstrated that short-hairpin RNA-mediated knockdown of miR-30a-5p ameliorated motor deficits and pathological changes like astrogliosis and reactive microgliosis in a mouse model of PD. Western blotting and immunofluorescent labeling revealed that miR-30a-5p suppressed the expression and function of GLT-1 in MPTP-treated mice and specifically in astrocytes treated with (cell model of PD). Conclusion Both in vitro and in vivo, we found that miR-30a-5p knockdown promoted glutamate uptake and increased GLT-1 expression by hindering GLT-1 ubiquitination and subsequent degradation in a PKCα-dependent manner. Therefore, miR-30a-5p represents a potential therapeutic target for the treatment of PD.

Objective . To compare the metabolic profile of women with spontaneous premature ovarian insufficiency (POI) with that of age-matched healthy controls. Study design . A cross-sectional case-control study was conducted using 1:1 matching by age. Women below the age of 40 with spontaneous POI who did not receive any medication (n = 303) and age-matched healthy women (n = 303) were included in this study. Main outcome measures . Metabolic profiles, including serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), glucose, uric acid, urea and creatinine, were compared between women with POI and controls. For women with POI, factors associated with the metabolic profile were analyzed. Results . Women with POI were more likely to exhibit increased serum levels of TG (β, 0.155; 95% CI, 0.086, 0.223) and glucose (0.067; 0.052, 0.083), decreased levels of HDL-C (-0.087; -0.123, -0.051), LDL-C (-0.047; -0.091, -0.003) and uric acid (-0.053; -0.090, -0.015), and impaired kidney function (urea [0.070; 0.033, 0.107]; creatinine [0.277; 0.256, 0.299]; eGFR [-0.234; -0.252, -0.216]) compared with controls after adjusting for age and BMI. BMI, parity, gravidity, FSH and E2 levels were independent factors associated with the metabolic profile of women with POI. Conclusion . Women with POI exhibited abnormalities in lipid metabolism, glucose metabolism, and a decrease in kidney function. In women with POI, early detection and lifelong management of metabolic abnormalities are needed.

The aim of this study was to investigate the association between a relatively high HbA1c level within the normal range and the risk of adverse pregnancy outcomes. This retrospective cohort study was conducted between March 2018 and March 2019 at Women’s Hospital, School of Medicine, Zhejiang University. Multiple logistic regression models after adjusting for plausible confounders were implemented to assess the relationships between the level of HbA1c and adverse pregnancy outcomes. A total of 8585 women were included in our study. The rates of preterm birth, macrosomia and preeclampsia were 4.4% (380/8585), 5.3% (457/8585) and 1.7% (149/8585), respectively. After adjusting for potential confounding variables, an HbA1c range of 5.5–5.9% (37–41 mmol/mol) remained significantly associated with an increased risk of preterm delivery (a-OR 2.27; 95% CI, 1.50–3.43), macrosomia (a-OR 1.97; 95% CI, 1.32–2.94) and preeclampsia (a-OR 3.70; 95% CI, 2.07–6.60). GDM-negative pregnant women with an HbA1c level in the range of 5.5–5.9% (37–41 mmol/mol) had an increased risk of preterm delivery (a-OR 2.84; 95% CI, 1.71–4.71) and preeclampsia (a-OR 3.82; 95% CI, 1.81–8.04). However, GDM-positive pregnant women had an increased risk of macrosomia (a-OR 2.12; 95% CI, 1.13–3.97) and preeclampsia (a-OR 2.62; 95% CI, 1.01–6.81). A higher HbA1c level within the normal range is an independent risk factor for preterm delivery and preeclampsia, especially among GDM-negative women. Therefore, relevant medical staff should enhance the awareness of risk and prevention to strengthen pregnancy monitoring.

One of the neuropathological hallmarks of Alzheimer's disease (AD) is accumulation and deposition of amyloid-beta (Aβ1-42) plaques in the hippocampus. Recently, microRNAs (miRNAs), have been demonstrated to play an essential role in AD. We have previously demonstrated that miR-132-3p exerts neuroprotection via regulating histone deacetylase 3 (HDAC3) in a mouse model of AD. In the present study, we further unveiled neuroprotective roles of miR-132-3p in transgenic amyloid precursor protein/presenilin 1 (APP/PS1) mice compared with those in age-matched wild-type C57BL/6 mice. Lentiviral-mediated inhibition or overexpression of miR-132-3p in the hippocampus of APP/PS1 mice was used to explore the contributions of hippocampal miR-132-3p in spatial memory, amyloid burden, apoptosis, and the number of hippocampal cells in a mouse model of AD. Overexpression of hippocampal miR-132-3p ameliorated spatial memory deficits in the Morris water maze, reduced both Aβ1-42 accumulation and apoptosis, and promoted the numbers of hippocampal cells in the brains of APP/PS1 mice. Furthermore, trichostatin A (TSA) promoted the expression of miR-132-3p in Aβ1-42-burdened neurons while increasing the expression levels of synaptic proteins. Taken together, our results suggest that miR-132-3p may represent a promising therapeutic target for the treatment of AD.

Background. Gestational diabetes mellitus (GDM) is a type of glucose intolerance disorder that first occurs during women’s pregnancy. The main diagnostic method for GDM is based on the midpregnancy oral glucose tolerance test. The rise of metabolomics has expanded the opportunity to better identify early diagnostic biomarkers and explore possible pathogenesis. Methods. We collected blood serum from 34 GDM patients and 34 normal controls for a LC-MS-based metabolomics study. Results. 184 metabolites were increased and 86 metabolites were decreased in the positive ion mode, and 65 metabolites were increased and 71 were decreased in the negative ion mode. Also, it was found that the unsaturated fatty acid metabolism was disordered in GDM. Ten metabolites with the most significant differences were selected for follow-up studies. Since the diagnostic specificity and sensitivity of a single differential metabolite are not definitive, we combined these metabolites to prepare a ROC curve. We found a set of metabolite combination with the highest sensitivity and specificity, which included eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, arachidonic acid, citric acid, α-ketoglutaric acid, and genistein. The area under the curves (AUC) value of those metabolites was 0.984 between the GDM and control group. Conclusions. Our results provide a direction for the mechanism of GDM research and demonstrate the feasibility of developing a diagnostic test that can distinguish between GDM and normal controls clearly. Our findings were helpful to develop novel biomarkers for precision or personalized diagnosis for GDM. In addition, we provide a critical insight into the pathological and biological mechanisms for GDM.

Parkinson's disease (PD) is a common neurodegenerative disease that is characterized by pathological dopaminergic (DA) neuronal death and α-synuclein aggregation. Glutamate excitotoxicity is a well-established pathogenesis of PD that involves dysfunctional expression of glutamate transporters. Glutamate transporter-1 (GLT-1) is mainly responsible for clearance of glutamate at synapses, including DA synapses. However, the role of GLT-1 in the aberrant synaptic transmission in PD remains elusive. In the present study, we generated small-interfering RNAs (siRNAs) to knockdown GLT-1 expression in primary astrocytes, and we report that siRNA knockdown of astrocytic GLT-1 decreased postsynaptic density-95 (PSD-95) expression in neuron-astrocyte cocultures in vitro. Using adeno-associated viruses (AAVs) targeting GLT-1 short-hairpin RNA (shRNA) sequences with a glial fibrillary acidic protein (GFAP) promoter, we abolished astrocytic GLT-1 expression in the substantia nigra pars compacta (SNpc) of mice. We found that GLT-1 deficiency in the SNpc induced parkinsonian phenotypes in terms of progressive motor deficits and nigral DA neuronal death in mice. We also found that there were reactive astrocytes and microglia in the SNpc upon GLT-1 knockdown. Furthermore, we used RNA sequencing to determine altered gene expression patterns upon GLT-1 knockdown in the SNpc, which revealed that disrupted calcium signaling pathways may be responsible for GLT-1 deficiency-mediated DA neuronal death in the SNpc. Taken together, our findings provide evidence for a novel role of GLT-1 in parkinsonian phenotypes in mice, which may contribute to further elucidation of the mechanisms of PD pathogenesis.

Apoptosis delimits platelet life span in the circulation and leads to storage lesion, which severely limits the shelf life of stored platelets. Moreover, accumulating evidence indicates that platelet apoptosis provoked by various pathological stimuli results in thrombocytopenia in many common diseases. However, little is known about how platelet apoptosis is initiated or regulated. Here, we show that PKA activity is markedly reduced in platelets aged in vitro, stored platelets, and platelets from patients with immune thrombocytopenia (ITP), diabetes, and bacterial infections. Inhibition or genetic ablation of PKA provoked intrinsic programmed platelet apoptosis in vitro and rapid platelet clearance in vivo. PKA inhibition resulted in dephosphorylation of the proapoptotic protein BAD at Ser155, resulting in sequestration of prosurvival protein BCL-XL in mitochondria and subsequent apoptosis. Notably, PKA activation protected platelets from apoptosis induced by storage or pathological stimuli and elevated peripheral platelet levels in normal mice and in a murine model of ITP. Therefore, these findings identify PKA as a homeostatic regulator of platelet apoptosis that determines platelet life span and survival. Furthermore, these results suggest that regulation of PKA activity represents a promising strategy for extending platelet shelf life and has profound implications for the treatment of platelet number-related diseases and disorders.

Glutamate is an essential excitatory neurotransmitter that regulates brain functions, and its activity is tightly regulated by glutamate transporters. Excess glutamate in the synaptic cleft and dysfunction of excitatory amino acid transporters have been shown to be involved in development of Alzheimer's disease, but the precise regulatory mechanism is poorly understood. Using a D-[3H]-aspartic acid uptake assay, we found that Aβ1-42 oligomers impaired glutamate uptake in astrocytes and neurons. In astrocytes, this process was accompanied by reduced expression of GLT-1 and GLAST as detected by Western blot and immunocytofluorescence. However, mRNA levels of EAATs detected by qPCR in astrocytes and neurons were not altered, which suggests that this process is post-translational. Co-localization analysis using immunocytofluorescence showed that ubiquitylation of GLT-1 significantly increased. Therefore, we hypothesized that Aβ1-42 oligomers-induced endocytosis of astrocytic GLT-1 may be involved in ubiquitylation. In addition, Aβ1-42 oligomers enhanced secretion of IL-1β, TNF-α, and IL-6 into culture supernatant, which may be correlated with an inflammatory response and altered EAATs expression or function in Alzheimer's disease. These findings support the idea that dysregulation of the glutamatergic system may play a significant role in pathogenesis of Alzheimer's disease. Furthermore, enhancing expression or function of EAATs in astrocytes and neurons might be a new therapeutic approach in treatment of Alzheimer's disease.

Parkinson's disease (PD) features the degeneration and death of dopamine neurons in the substantia nigra pars compacta and the formation of Lewy bodies that contain α-synuclein. Among the numerous PD etiologies, glutamate excitotoxicity is a research hot spot, and glutamate transporters play key roles in this theory. It has been shown that the expression of the glutamate transporter is regulated by microRNAs. In this study, we found that the levels of expression and function of glutamate transporter type 1 (GLT-1) were significantly reduced and miR-543-3p was upregulated during the development of PD. Furthermore, our results indicated that GLT-1 plays an important role in the pathomechanism of PD. We found that miR-543-3p can suppress the expression and function of GLT-1 in MPP+-treated astrocytes and MPTP-treated mice. Inhibition of miR-543-3p can rescue the expression and function of GLT-1 and relieve dyskinesia in the PD model, which suggests that inhibition of miR-543-3p could serve as a potential therapeutic target for PD.

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet count which can cause fatal hemorrhage. ITP patients with antiplatelet glycoprotein (GP) Ib-IX autoantibodies appear refractory to conventional treatments, and the mechanism remains elusive. Here we show that the platelets undergo apoptosis in ITP patients with anti-GPIbα autoantibodies. Consistent with these findings, the anti-GPIbα monoclonal antibodies AN51 and SZ2 induce platelet apoptosis in vitro. We demonstrate that anti-GPIbα antibody binding activates Akt, which elicits platelet apoptosis through activation of phosphodiesterase (PDE3A) and PDE3A-mediated PKA inhibition. Genetic ablation or chemical inhibition of Akt or blocking of Akt signaling abolishes anti-GPIbα antibody-induced platelet apoptosis. We further demonstrate that the antibody-bound platelets are removed in vivo through an apoptosis-dependent manner. Phosphatidylserine (PS) exposure on apoptotic platelets results in phagocytosis of platelets by macrophages in the liver. Notably, inhibition or genetic ablation of Akt or Akt-regulated apoptotic signaling or blockage of PS exposure protects the platelets from clearance. Therefore, our findings reveal pathogenic mechanisms of ITP with anti-GPIbα autoantibodies and, more importantly, suggest therapeutic strategies for thrombocytopenia caused by autoantibodies or other pathogenic factors.

As the most common cause of progressive cognitive decline in humans, Alzheimer’s disease (AD) has been intensively studied, but the mechanisms underlying its profound synaptic dysfunction remain unclear. Here we confirm that exposing wild-type mice to an enriched environment (EE) facilitates signaling in the hippocampus that promotes long-term potentiation (LTP). Exposing the hippocampus of mice kept in standard housing to soluble Aβ oligomers impairs LTP, but EE can fully prevent this. Mechanistically, the key molecular features of the EE benefit are an upregulation of miRNA-132 and an inhibition of histone deacetylase (HDAC) signaling. Specifically, soluble Aβ oligomers decreased miR-132 expression and increased HDAC3 levels in cultured primary neurons. Further, we provide evidence that HDAC3 is a direct target of miR-132. Overexpressing miR-132 or injecting an HDAC3 inhibitor into mice in standard housing mimics the benefits of EE in enhancing hippocampal LTP and preventing hippocampal impairment by Aβ oligomers in vivo. We conclude that EE enhances hippocampal synaptic plasticity by upregulating miRNA-132 and reducing HDAC3 signaling in a way that counteracts the synaptotoxicity of human Aβ oligomers. Our findings provide a rationale for prolonged exposure to cognitive novelty and/or epigenetic modulation to lessen the progressive effects of Aβ accumulation during human brain aging.

Evidence suggests that oxidative stress is involved in the pathogenesis of Parkinson disease (PD). Simvastatin has been suggested to protect against oxidative stress in several diseases. However, the molecular mechanisms by which simvastatin protects against neuropathology and oxidative damage in PD are poorly elucidated. In this study, we aimed to investigate the potential neuroprotective effects of simvastatin owing to its anti-oxidative properties in 6-hydroxydopamine (6-OHDA)-treated SH-SY5Y cells and mice. The results of 2′,7′-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence and CCK-8 assay demonstrated that simvastatin reduced intracellular reactive oxygen species (ROS) levels and reversed apoptosis in 6-OHDA-treated SH-SY5Y cells. Mechanistic studies revealed that 6-OHDA-induced activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase/p38 mitogen-activated protein kinase (MAPK) pathway was inhibited and nuclear factor-κB (NF-κB) nuclear transcription decreased in SH-SY5Y cells after simvastatin treatment. Enhanced expression levels of superoxide dismutase (SOD), heme oxygenase-1 (HO-1), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and glutamate-cysteine ligase modifier subunit (GCLM) were observed after simvastatin treatment in 6-OHDA-treated SH-SY5Y cells. In vivo studies revealed that administration of simvastatin by gavage decreased limb-use asymmetry and apomorphine-induced rotations in 6-OHDA-lesioned mice. Simvastatin increased dopaminergic neurons and reduced protein tyrosine nitration and gliosis in the midbrain of PD mice. An inhibitory effect on activation of the NADPH oxidase/p38 MAPK was observed, and increased antioxidant protein expression in the midbrain were seen in the simvastatin plus 6-OHDA group compared with the 6-OHDA-lesioned group. Taken together, these results demonstrate that simvastatin might inhibit the activation of NADPH oxidase/p38 MAPK pathway, enhance antioxidant protein expression and protect against oxidative stress, thereby providing a novel antioxidant mechanism that has therapeutic validity.

Memory deficiency is a common non-motor symptom of Parkinson's disease (PD), and conventionally, α-synuclein is considered to be an important biomarker for both motor and cognitive characteristics attributed to PD. However, the role of physiological α-synuclein in cognitive impairment remains undetermined. Ginsenoside Rb1 has been shown to protect dopaminergic neurons (DA) from death and inhibit α-synuclein fibrillation and toxicity in vitro. Our recent study also revealed that ginsenoside Rb1 ameliorates motor deficits and prevents DA neuron death via upregulating glutamate transporter GLT-1 in the 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Whether Rb1 can improve memory deficiency and the underlying mechanism is still unknown. In this study, we found that Rb1 can prevent the spatial learning and memory deficits, increase long-term potentiation (LTP) and hippocampal glutamatergic transmission, and protect hippocampal neurons from death in the MPTP mouse model. The underlying neuroprotective mechanism involves Rb1 improving hippocampal CA3 α-synuclein expression, restoring the glutamate in the CA3-schaffer collateral-CA1 pathway, and sequentially increasing postsynaptic density-95 (PSD-95) expression. Thus, we provide evidence that Rb1 modulates memory function, synaptic plasticity, and excitatory transmission via the trans-synaptic α-synuclein/PSD-95 pathway. Our findings suggest that Rb1 may serve as a functional drug in treating the memory deficiency in PD. Funding Statement: This project was supported by the National Natural Science Foundation of China (Nos. 81870991 and U1603281 to SQ, No. 81704130 to YZ), the Natural Science Foundation of Fujian Province of China (No. 2017J05139 to YZ), the Natural Science Foundation of Guangdong Province of China (No. 2017A030310643 to YZ), and the China Postdoctoral Science Foundation (No. 2016M590598 to YZ). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: All experiments were conducted according to the National Institute of Health guidelines on the care and use of animals (NIH Publications No. 8023, revised 1978) and approved by the Institutional Animal Care and Use Committee of Guangzhou Medical University.

Docosahexaenoic acid (DHA), a derivative of ω3- polyunsaturated fatty acids present in fish oil, is well known to have anticancer activity on colon cancer cells, but the molecular and cellular mechanisms remain to be further clarified. In this study, anti-cancer effects of DHA on colon cancer cells were observed in a nude mouse HCT-15 xenograft model. And then, the different genes expression and signal pathways involved in this process were screened and identified using cDNA microarray analysis. Results of genes expression profiles indicated a reprogramming pattern of previously known and unknown genes and transcription factors associated with the action of DHA on colon cancer cells. And several genes related to tumor growth and metastasis including COX2, HIF-1α, VEGF-A, COMP, MMP-1, MMP-9, SCP2, SDC3, which were down-regulated by DHA, were further confirmed in HCT-15 cell line using RT-PCR method. In summary, our data might provide novel information for anti-cancer mechanism of DHA in colon cancer model.

DNA polymerase iota (Polι) can repair several types of DNA damage but has extremely low fidelity. Previous studies have shown an aberrantly elevated Polι expression in human esophageal squamous cell cancer tissues. However, there were few reports describing the role of Polι in esophageal cancer progression. Based on Real-time PCR assay, we found Polι expression was up-regulated in esophageal cancer tissues compared to adjacent normal tissues and overexpression of Polι was correlated to lymph node metastasis. Clonogenic assay and transwell chamber assay showed that overexpression of Polι had higher clongenic capability and invasive tendency in human esophageal squamous cell cancer cells. Expression of cyclin D1, an important cell cycle regulator, was found to be associated with that of Polι in tissue samples and cancer cells as analyzed by real-time PCR, immunohistochemistry, Western blotting and immunofluorescence assay. Flow cytometry analysis further showed that cell cycle distribution was altered in Polι overexpressing cells. These results indicated that expression of Polι correlates significantly with tumor proliferation and invasion. We conclude that Polι is involved in the degree of aggressiveness of human esophageal squamous cell cancer.

Glutamate transporters play a key role in glutamate clearance and protect the central nervous system from glutamate excitotoxicity. Dysfunctional glutamate transporters contribute to the pathogenesis of Parkinson’s disease (PD); however, the mechanisms that underlie the regulation of glutamate transporters in PD are still not well characterized. Here we report that Nedd4-2 mediates the ubiquitination of glutamate transporters in 1-methyl-4- phenylpyridinium (MPP+)-treated astrocytes and in the midbrain of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-constructed PD model mice. Nedd4-2-mediated ubiquitination induces abnormal glutamate transporter trafficking between the membrane and cytoplasm and consequently decreases the expression and function of glutamate transporters in the membrane. Conversely, Nedd4-2 knockdown decreases glutamate transporter ubiquitination, promotes glutamate uptake and increases glutamate transporter expression in vitro and in vivo. We report for the first time that Nedd4-2 knockdown ameliorates movement disorders in PD mice and increases tyrosine hydroxylase expression in the midbrain and striatum of PD mice; Nedd4-2 knockdown also attenuates astrogliosis and reactive microgliosis in the MPTP model that may be associated with glutamate excitotoxicity. Furthermore, the SGK/PKC pathway is regulated downstream of Nedd4-2 in MPTP-treated mice. These findings indicate that Nedd4-2 may serve as a potential therapeutic target for the treatment of PD.

Objective Radiation-induced skin injury remains a serious concern for radiation therapy. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, has been reported to have potential antioxidant and anti-apoptotic properties. However, the role of HO-1 in radiation-induced skin damage remains unclear. This study aims to elucidate the effects of HO-1 on radiation-induced skin injury in rats. Methods A control adenovirus (Ad-EGFP) and a recombinant adenovirus (Ad-HO1-EGFP) were constructed. Rats were irradiated to the buttock skin with a single dose of 45 Gy followed by a subcutaneous injection of PBS, 5 × 109 genomic copies of Ad-EGFP or Ad-HO1-EGFP (n = 8). After treatment, the skin MDA concentration, SOD activity and apoptosis were measured. The expression of antioxidant and pro-apoptotic genes was determined by RT-PCR and real-time PCR. Skin reactions were measured at regular intervals using the semi-quantitative skin injury score. Results Subcutaneous injection of Ad-HO1-EGFP infected both epidermal and dermal cells and could spread to the surrounding regions. Radiation exposure upregulated the transcription of the antioxidant enzyme genes, including SOD-1, GPx2 and endogenous HO-1. HO-1 overexpression decreased lipid peroxidation and inhibited the induction of ROS scavenging proteins. Moreover, HO-1 exerted an anti-apoptotic effect by suppressing FAS and FASL expression. Subcutaneous injection of Ad-HO1-EGFP demonstrated significant improvement in radiation-induced skin injury. Conclusions The present study provides evidences for the protective role of HO-1 in alleviating radiation-induced skin damage in rats, which is helpful for the development of therapy for radiation-induced skin injury.

Purpose: Exposure to radiation provokes cellular responses, which are likely regulated by gene expression networks. MicroRNAs are small non-coding RNAs, which regulate gene expression by promoting mRNA degradation or inhibiting protein translation. The expression patterns of both mRNA and miRNA during the radiation-induced lung injury (RILI) remain less characterized and the role of miRNAs in the regulation of this process has not been studied. The present study sought to evaluate miRNA and mRNA expression profiles in the rat lung after irradiation. Methods and materials: Male Wistar rats were subjected to single dose irradiation with 20 Gy using 6 MV x-rays to the right lung. (A dose rate of 5 Gy/min was applied). Rats were sacrificed at 3, 12 and 26 weeks after irradiation, and morphological changes in the lung were examined by haematoxylin and eosin. The miRNA and mRNA expression profiles were evaluated by microarrays and followed by quantitative RT-PCR analysis. Results: A cDNA microarray analysis found 2183 transcripts being up-regulated and 2917 transcripts down-regulated (P ≤ 0.05, ≥2.0 fold change) in the lung tissues after irradiation. Likewise, a miRNAs microarray analysis indicated 15 miRNA species being up-regulated and 8 down-regulated (P ≤ 0.05). Subsequent bioinformatics anal -yses of the differentially expressed mRNA and miRNAs revealed that alterations in mRNA expression following irradiation were negatively correlated with miRNAs expression. Conclusions: Our results provide evidence indicating that irradiation induces alterations of mRNA and miRNA expression in rat lung and that there is a negative correlation of mRNA and miRNA expression levels after irradiation. These findings significantly advance our understanding of the regulatory mechanisms underlying the pathophysiology of radiation-induced lung injury. In summary, RILI does not develop gradually in a linear process. In fact, different cell types interact via cytokines in a very complex network. Furthermore, this study suggests that microRNAs may serve an important role in the pathogenesis of RILI and that understanding their role in RILI may have a significant effect on patient management and diagnosis in the future.