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Presenilin-1 (PSEN1) is a crucial subunit within the γ-secretase complex and regulates β-amyloid (Aβ) production. Accumulated evidence indicates that n-butylidenephthalide (BP) acts effectively to reduce Aβ levels in neuronal cells that are derived from trisomy 21 (Ts21) induced pluripotent stem cells (iPSCs). However, the mechanism underlying this effect remains unclear. This article aims to investigate the possible mechanisms through which BP ameliorates the development of Alzheimer's disease (AD) and verify the effectiveness of BP through animal experiments. Results from RNA microarray analysis showed that BP treatment in Ts21 iPSC-derived neuronal cells reduced long noncoding RNA (lncRNA) CYP3A43-2 levels and increased microRNA (miR)-29b-2-5p levels. Bioinformatics tool prediction analysis, biotin-labeled miR-29b-2-5p pull-down assay, and dual-luciferase reporter assay confirmed a direct negative regulatory effect for miRNA29b-2-5p on lnc-RNA-CYP3A43-2 and PSEN1. Moreover, BP administration improved short-term memory and significantly reduced Aβ accumulation in the hippocampus and cortex of 3xTg-AD mice but failed in miR-29b-2-5p mutant mice generated by CRISP/Cas9 technology. In addition, analysis of brain samples from patients with AD showed a decrease in microRNA-29b-2-5p expression in the frontal cortex region. Our results provide evidence that the LncCYP3A43-2/miR29-2-5p/PSEN1 network might be involved in the molecular mechanisms underlying BP-induced Aβ reduction. [ABSTRACT FROM AUTHOR]

Background : The usage of machine vision technologies for image-based analysis and inspection is increasing. With the advent of the ability to process high-dimension data instantly, the possibilities of machine vision multiply exponentially. Robots now use this technology to assist in surgery. Objective: The aim of this study is to explore the efficacy of Surgical Navigation Robot NaoTrac (Brain Navi Biotechnology Co., Ltd.), which utilizes machine vision-inspired technology for patient registration and stereotactic external ventricular drainage (EVD) by the robotic arm. Methods: Preoperative and postoperative computed tomography (CT) scans were acquired for each case. The surgeons planned the targets and trajectories with the preoperative CT images. The postoperative CT images were utilized in the accuracy measurements. Results: All 14 cases had cerebrospinal fluid drained through the catheter. The NaoTrac placed the catheter into the frontal horn in one attempt in 13 cases and was able to drain CSF in 12 cases. Not a single case had any bleeding or intraoperative complications. The average time spent on the patient registration was 142.8 s. The mean target deviation was 1.68 mm, and the mean angular deviation was 1.99°, all within the accepted tolerance for minimal tissue damage. Conclusion: The results of this report demonstrate that machine vision-inspired patient registration is feasible and fast. NaoTrac has demonstrated its accuracy and safety in performing frameless catheter placement in 13 clinical cases. Other stereotactic neurosurgical operations such as stereotactic biopsy, depth electrode placement, deep brain stimulation electrode positioning, and neuroendoscopy may also be benefited from the assistance of NaoTrac. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase-3 (GSK-3) signaling has been shown to play a role in the regulation of nuclear factor erythroid-2-related factor 2 ( Nrf2 ), a master regulator of antioxidant genes, including heme oxygenase-1 ( HO-1 ). We assessed whether lithium, a GSK-3 inhibitor, attenuates cardiac sympathetic reinnervation after myocardial infarction, a status of high reactive oxygen species (ROS), by attenuating nerve growth factor (NGF) expression and whether Nrf2/HO-1 signaling is involved in the protection. Twenty-four hours after ligation of the left anterior descending artery, male Wistar rats were treated for 4 weeks. The postinfarction period was associated with increased oxidative–nitrosative stress, as measured by myocardial superoxide, nitrotyrosine, and dihydroethidium fluorescent staining. In concert, myocardial norepinephrine levels and immunohistochemical analysis of sympathetic nerve revealed a significant increase in innervation in vehicle-treated rats compared with sham-operated rats. Arrhythmic scores during programmed stimulation in the vehicle-treated rats were significantly higher than those in sham. This was paralleled by a significant upregulation of NGF protein and mRNA in the vehicle-treated rats, which was reduced after administration of LiCl. LiCl stimulated the nuclear translocation of Nrf2 and the transactivation of the Nrf2 target gene HO-1 . Inhibition of phosphoinositide 3-kinase by wortmannin reduced the increase in Nrf2 nucleus translocation and HO-1 expression compared with lithium alone. In addition, the lithium-attenuated NGF levels were reversed in the presence of the Nrf2 inhibitor trigonelline, HO-1 inhibitor SnPP, and peroxynitrite generator SIN-1, indicating the role of Nrf2/HO-1/ROS. In conclusion, lithium protects against ventricular arrhythmias by attenuating NGF-induced sympathetic innervation via antioxidant activation of the Nrf2/HO-1 axis. [ABSTRACT FROM AUTHOR]

We have demonstrated that long-term 17β-estradiol attenuated fibrosis after myocardial infarction, but recent evidence suggests that estrogen mediates more rapid cellular effects. RhoA has been shown to play a role in the control of myocardial fibrosis by regulating the actin-regulatory protein cofilin. We sought to elucidate whether RhoA activity regulates estradiol-induced fibrosis after infarction in ovariectomized female rats. Twenty-four hours after coronary ligation, female Wistar rats were randomized into control or estradiol treatment for 4 weeks starting from 2 weeks after bilateral ovariectomy. There were similar infarct sizes among the infarcted groups. Myocardial fibrosis was significantly reduced, as measured by hydroxyproline content, Sirius Red staining and actin polymerization after administering estradiol. Estradiol treatment was associated with RhoA/Rho kinase inhibition evidenced by increased phosphorylation of RhoA and decreased phosphorylation of downstream factors including cofilin. Administration of PPT, a specific ERα agonist, or a membrane impermeable estrogen-albumin construct also inhibited cofilin phosphorylation, suggesting that cofilin phosphorylation is achieved through the recruitment of a membrane ERα. The ERβ-selective agonist, DPN, did not alter cofilin phosphorylation levels, but the ER antagonist, ICI 182,780 increased cofilin phosphorylation levels. G-15 (an inhibitor of G-protein coupled estrogen receptor) did not affect the phosphorylation as compared with estradiol alone. The inhibitor of Rho kinase, Y-27632, attenuated cofilin phosphorylation levels, similar to the effect produced by estradiol. These results indicate that chronic use of estradiol after infarction attenuates cardiac fibrosis by inhibiting RhoA/ROCK/cofilin pathway, which is exerted through membrane ERα-mediated receptor mechanism. Key Message: [ABSTRACT FROM AUTHOR]

Cardiac remodeling was shown to be associated with reduced gap junction expression after myocardial infarction. A reduction in gap junctional proteins between myocytes may trigger ventricular arrhythmia. Therefore, we investigated whether N-acetylcysteine exerted antiarrhythmic effect by preserving connexin43 expression in postinfarcted rats, focusing on cAMP downstream molecules such as protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac). Male Wistar rats after ligating coronary artery were randomized to either vehicle, or N-acetylcysteine for 4 weeks starting 24 hours after operation. Infarct size was similar between two groups. Compared with vehicle, cAMP levels were increased by N-acetylcysteine treatment after infarction. Myocardial connexin43 expression was significantly decreased in vehicle-treated infarcted rats compared with sham operated rats. Attenuated connexin43 expression and function were blunted after administering N-acetylcysteine, assessed by immunofluorescent analysis, dye coupling, Western blotting, and real-time quantitative RT-PCR of connexin43. Arrhythmic scores during programmed stimulation in the N-acetylcysteine-treated rats were significantly lower than those treated with vehicle. In an ex vivo study, enhanced connexin43 levels afforded by N-acetylcysteine were partially blocked by either H-89 (a PKA inhibitor) or brefeldin A (an Epac-signaling inhibitor) and completely blocked when H-89 and brefeldin A were given in combination. Addition of either the PKA specific activator N6Bz or Epac specific activator 8-CPT did not have additional increased connexin43 levels compared with rats treated with lithium chloride alone. These findings suggest that N-acetylcysteine protects ventricular arrhythmias by attenuating reduced connexin43 expression and function via both PKA- and Epac-dependent pathways, which converge through the inactivation of glycogen synthase kinase-3β. [ABSTRACT FROM AUTHOR]

Tortoiseshell and deer antler gelatin has been used to treat bone diseases in Chinese society. A pepsin-digested gelatin peptide with osteoblast-proliferation-stimulating properties was identified via LC-MS/MS. The resulting pentapeptide, TSKYR, was presumably subjected to further degradation into TSKY, TSK, and YR fragments in the small intestine. The above four peptides were chemically synthesized. Treatment of tripeptide TSK can lead to a significant 30- and 50-fold increase in the mineralized nodule area and density in osteoblast cells and a 47.5% increase in the number of chondrocyte cells. The calcium content in tortoiseshell was relatively higher than in human soft tissue. The synergistic effects of calcium ions and the peptides were observed for changes in osteoblast proliferation and differentiation. Moreover, these peptides can enhance the expression of RUNX2, OCN, FGFR2, and FRFR3 genes in osteoblasts, and aggrecan and collagen type II in chondrocyte (patent pending). [ABSTRACT FROM AUTHOR]

Abstract: Urocortin (UCN) is a member of the corticotropin-releasing hormone (CRH) family of neuropeptides that regulates stress responses. Although UCN is principally expressed in dopaminergic neurons in rat substantia nigra (SN), the function of UCN in modulating dopaminergic neuronal survival remains unclear. Using primary mesencephalic cultures, we demonstrated that dopaminergic neurons underwent spontaneous cell death when their age increased in culture. Treatment of mesencephalic cultures with UCN markedly prolonged the survival of dopaminergic neurons, whereas neutralization of UCN with anti-UCN antibody accelerated dopaminergic neurons degeneration. UCN increased intracellular cAMP levels followed by phosphorylating glycogen synthase kinase-3β (GSK-3β) on Ser9. Moreover, UCN directly inhibited the histone deacetylase (HDAC) activity and induced a robust increase in histone H3 acetylation levels. Using pharmacological approaches, we further demonstrated that inhibition of GSK-3β and HDAC contributes to UCN-mediated neuroprotection. These results suggest that dopaminergic neurons-derived UCN might be involved in an autocrine protective signaling mechanism. [Copyright &y& Elsevier]

Secretoneurin (SN), a neuropeptide derived from secretogranin II, promotes neurite outgrowth of immature cerebellar granule cells. SN also aids in the growth and repair of neuronal tissue, although the precise mechanisms underlying the promotion of brain tissue neuroprotection and plasticity by SN are not understood. Here, in a rat model of stroke and in ischemic human brain tissue, SN was markedly upregulated in both neurons and endothelial cells. SN-mediated neuroprotection rescued primary cortical cell cultures from oxygen/glucose deprivation. SN also induced expression of the antiapoptotic proteins Bcl-2 and Bcl-xL through the Jak2/Stat3 pathway and inhibited apoptosis by blocking caspase-3 activation. In addition, rats with occluded right middle cerebral arteries showed less cerebral infarction, improved motor performance, and increased brain metabolic activity following i.v. administration of SN. Furthermore, SN injection enhanced stem cell targeting to the injured brain in mice and promoted the formation of new blood vessels to increase local cortical blood flow in the ischemic hemisphere. Both in vitro and in vivo, SN not only promoted neuroprotection, but also enhanced neurogenesis and angiogenesis. Our results demonstrate that SN acts directly on neurons after hypoxia and ischemic insult to further their survival by activating the Jak2/Stat3 pathway. [ABSTRACT FROM AUTHOR]

Abstract: Granulocyte colony-stimulating factor (G-CSF) is known to have various functions such as induction of survival, proliferation and differentiation of hematopoietic cells. Recently, this factor has also been shown to exhibit neuroprotective effects in rat ischemic brain. In the present study, we first demonstrated that both G-CSF and G-CSF receptor were expressed in dopaminergic neurons in the adult substantia nigra and mesencephalic cultures, suggesting that G-CSF might exert its neuroprotective effects in dopaminergic neurons. Pretreatment with G-CSF protected dopaminergic neurons from 6-hydroxydopamine (6-OHDA)-induced neurotoxicity. Investigation of the underlying mechanisms showed that the extracellular-regulated kinase (ERK), but not Janus kinase/signal transducer(s) and activator(s) of transcription (JAK/STAT), was activated following G-CSF treatment. Moreover, G-CSF also increased phosphorylation of Bad, and restored 6-OHDA-induced decrease in Bcl-xL level. The 6-OHDA-caused caspase-3 activation in dopaminergic neurons was inhibited by G-CSF. Inhibition of ERK abrogated G-CSF-mediated Bad phosphorylation, Bcl-xL expression, activated caspase-3 reduction, and the protection of dopaminergic neurons. Taken together, G-CSF prevents dopaminergic neurons from 6-OHDA-induced toxicity via ERK pathway followed by inhibiting the apoptosis-execution process. These results suggest that G-CSF might have a therapeutic potential in Parkinson''s disease. [Copyright &y& Elsevier]

Abstract: The aim of this study was to assess whether the GAITRite gait analysis system an effective tool in evaluating parkinsonian bradykinesia. In their best ON and worst OFF states, 13 parkinsonian patients were asked to perform walking trail at their fastest velocity, and to submit to traditional timed tests. Significant correlations existed between OFF–ON improvement in gait parameters and in UPDRS III score () except cadence. Among the gait parameters, stride length is the most effective indicator of timed test and UPDRS III score improvements. The GAITRite system is an efficient, yet effective device in evaluating parkinsonian bradykinesia and can be used as a substitute for the traditional timed test. [Copyright &y& Elsevier]

Abstract: We previously demonstrated that the crude acetone extract of Bupleurum scorzonerifolium (BS-AE) 60μg/ml has anti-proliferation activity and apoptotic effects on A549 non-small cell lung cancer (NSCLC). A novel lignan, isochaihulactone (4-benzo[1,3]dioxol-5-ylmethyl-3(3,4,5-trimethoxyl-benzylidene)-dihydro-furan-2-one), was isolated from BS-AE and identified from spectral evidence (1H NMR, 13C NMR, IR, and MS) and by comparison with authentic synthetic standards. Isochaihulactone was cytotoxic (IC50 =10–50μM) in a variety of human tumor cell lines. In in vitro and in vivo microtubule assembly assays, it inhibited tubulin polymerization in a concentration-dependent manner. As determined by flow cytometry, isochaihulactone caused G2/M phase arrest and apoptosis in a time- and concentration-dependent manner. G2/M arrest was correlated with increased p21/WAF1 levels, downregulation of the checkpoint proteins cyclin B1/cdc2 and mobility shift of cdc25C. Moreover, isochaihulactone (30 and 50mg/kg) inhibited the growth of non-small cell lung carcinoma A549 xenograft in nude mice. These findings indicate isochaihulactone is a promising new antimitotic anticancer compound with potential for clinical application in the future. [Copyright &y& Elsevier]

Abstract: Early Onset Parkinson''s Disease (EOPD) is characterized by selective degeneration of nigrostriatal dopaminergic neurons and a marked response to levodopa. However, at present, few methods are available as diagnostic tools for EOPD except for 18F-DOPA PET. In addition, little is known about the correlation between clinical severity, neuroimaging grading and genetic susceptibility. In the present study, 99mTc-TRODAT-1 SPECT and brain MRI were used to identify 30 cases of non-familial EOPD from a Chinese cohort of 230. All 30 PD patients had an age of onset of less than 55 years (mean age at onset, 41.5±9.3 years). Each of the 30 EOPD cases was sub-classified into one of five stages based on the 99mTc-TRODAT-1 SPECT findings. In the early stages of PD (stages 1 and 2), a lower uptake of 99mTc-TRODAT-1 in the putamen was found, while uptake in the caudate nucleus was normal. In the latter stages (stages 3, 4, 5), 24 patients revealed a diffuse and uniform loss of 99mTc-TRODAT-1 uptake in the putamen and the caudate nucleus. Further, in conventional genetic studies of the 30 patients, six novel mutations were found in the Parkin gene, and these included five heterozygous point mutations (C441R, Q311H, V258M, C212G, and S193I) and one homozygous deletion (exon 10-12). Known polymorphisms (Ser167Asn, Val380Leu) were also found in a number of patients. However, gene dosage analysis did not reveal any compound heterozygous mutations in these 30 patients using quantitative duplex PCR. This is the first study to examine EOPD patients of Chinese ethnic background (not exhibiting a definite familial trait), to offer a complete genetic analysis of the Parkin gene, and to correlate clinical stages of the disease with dopamine re-uptake. [Copyright &y& Elsevier]

Abstract: We previously demonstrated that the crude acetone extract of Bupleurum scorzonerifolium (AE-BS) 60 μg/ml has anti-proliferation activity and apoptosis effects to A549 human lung cancer cells. They can also cause tumor cell arrest in G2/M phase. To better understand its target protein in A549 cell, two-dimensional electrophoresis and liquid chromatography-tandem mass spectrometry were applied. The modification of keratin 8 was identified. By immunoblot, the expression of phosphorylated keratin 8 at Ser-73 was increased from 2.0 to 3.0-fold after AE-BS treatment 24 to 48 hr respectively as compared with untreated A549 control cells. Furthermore, the A549 cells were pretreated with 50 μM PD98059, a specific inhibitor of the upstream regulator of ERK1/2, or with the p38 kinase inhibitor 20 μM SB203580 or JNK inhibitor 20 μM SP600125 for 30 min, followed by 24 h of incubation with AE-BS, PD98059 can inhibit K8-Ser-73 hyperphosphorylation and prevented cell apoptosis which was induced by AE-BS significantly. By immunoblot, AE-BS also can induce ERK 1/2 phosphorylation. In conclusion, our data indicate that the AE-BS induced tumor apoptosis in A549 cells was related to ERK 1/2 activation. The molecular mechanism of hyperphosphorylation of K8 on Ser-73 was associated with ERK 1/2 activation rather than JNK and p38 kinase. The apoptosis induced by AE-BS may be related to K8 phosphorylation. [Copyright &y& Elsevier]

Neuregulin-1 (NRG-1) is expressed throughout the immature and adult central nervous system and it has been demonstrated to influence the migration of a variety of cell types in developing brain. Elevated levels of NRG-1 transcript are found in the adult brain after injury, leading to the suggestion that NRG-1 is involved in the physiological response to neuronal injury. Here, we report our findings that rats pre-treated with NRG-1 protein, undergoing cerebral ischemia 30 min later, had increased motor performance and less cerebral infarction than untreated rats. In the cortex of NRG-1 treated rats, ischemia induced a decrease in caspase-3 immunoreactivity and a reduction in the density of cells positive for terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end-labeling. Improvement in behavioral assays was also found in animals treated with NRG-1. Pre-treatment with NRG-1 did not alter cerebral blood flow or other physiological parameters. NRG-1 reduced ischemia/reperfusion injury, indicating that it may act as an endogenous neuroprotective factor against stroke. Therefore, NRG-1 may represent a target for the development of new treatments for stroke. [Copyright &y& Elsevier]

Obesity is one of the world's largest health problems, and 3-N-butylphthalide (NBP), a bioactive compound in celery, has been used in dieting and weight management programs. In this study, NBP prevented high-fat-diet-induced weight gain, reduced the food efficiency ratio, altered the blood biochemical profile, and reduced the obesity-related index. NBP reduced adiposity, white fat depots, liver weight, and hepatic steatosis in obese mice. NBP ameliorated the diabetic state by decreasing glucose levels and improving glucose and insulin tolerance. NBP increased uncoupling protein-1 expression in white adipose tissue and upregulated thermogenesis by enhancing mitochondrial respiration. NBP inhibited white adipocyte development by prohibiting lipid accumulation in human adipose-derived stem cells. NBP increased free fatty acid uptake and the oxygen consumption rate in beige adipocytes. Our results suggest that NBP could be used as functional natural supplement against obesity and its associated disorders. [ABSTRACT FROM AUTHOR]

The most effective drug, doxorubicin (DOX), is widely used worldwide for clinical application as an anticancer drug. DOX‐induced cytotoxicity is characterized by mitochondrial dysfunction. There is no alternative treatment against DOX‐induced cardiac damage despite intensive research in the present decades. Ohwia caudata has emerged as a potential herbal remedy that prevents from DOX‐induced cytotoxicity owing to its pharmacological action of sustaining mitochondrial dynamics by attenuating oxidative stress and inducing cellular longevity. However, its underlying mechanisms are unknown. The novel treatment provided here depends on new evidence from DOX‐treated H9c2 cells, which significantly enhanced insulin‐like growth factor (IGF) II receptor (IGF‐IIR) pathways that activated calcineurin and phosphorylated dynamin‐related protein 1 (p‐Drp1) at ser616 (p‐Drp1[ser616]); cells undergo apoptosis due to these factors, which translocate to mitochondria and disrupt their function and integrity, and in terms of herbal medicine treatment, which significantly blocked these phenomena. Thus, our findings indicate that maintaining integrity of mitochondria is an essential element in lowering DOX‐induced cytotoxicity, which further emphasizes that our herbal medicine can successfully block IGF‐IIR pathways and could potentially act as an alternative mechanism in terms of cardioprotective against doxorubicin. [ABSTRACT FROM AUTHOR]

This article discusses a study on gene editing in Salvia miltiorrhiza, a plant used in Eastern medicine to treat cardiovascular diseases. The researchers developed a protoplast regeneration system for S. miltiorrhiza using CRISPR/Cas9 gene editing technology. They targeted seven transcription factor genes involved in the production of bioactive compounds in the plant. The study demonstrated high-efficiency gene editing and the regeneration of knockout plants, which could potentially enhance the contents of active compounds in medicinal plants. [Extracted from the article]

The discovery of brown fat in adult humans has led to increased research of the thermogenic function of this tissue in various metabolic diseases. In addition, high levels of brown fat have been correlated with lower body mass index values. Therefore, increasing brown fat mass and/or activity through methods such as the browning of white fat is considered a promising strategy to prevent and treat obesity-associated diseases. Cell-based approaches using mesenchymal stromal cells and brown adipose tissue (BAT) have been utilized to directly increase BAT mass/activity through cell and tissue implantation into animals. In addition, recent studies evaluating the transplantation of human embryonic stem cells and induced pluripotent stem (iPS) cells have shown promising results in terms of positive metabolic function. In this comprehensive review, we provide a summary of the research over the past 10 years with regard to stem cell therapy and brown fat tissue transplantation for the effective treatment of metabolic syndrome. Recent advancements in stem cell methods have allowed for the production of brown adipocytes from human iPS cells, which represent an unlimited source of cellular material with which to study adipocyte development. In addition, this process is expected to be used to further explore drug- and cell-based therapies to treat obesity-related metabolic complications. [ABSTRACT FROM AUTHOR]

Rostral intralaminar thalamic deep brain stimulation (ILN-DBS) has been shown to enhance attention and cognition through neuronal activation and brain plasticity. We examined whether rostral ILN-DBS can also attenuate memory deficits and impaired synaptic plasticity and protect glutamatergic transmission in the rat intraventricular β-amyloid (Aβ) infusion model of Alzheimer's disease (AD). Spatial memory was tested in the Morris water maze (MWM), while structural synaptic plasticity and glutamatergic transmission strength were estimated by measuring dendritic spine densities in dye-injected neurons and tissue expression levels of postsynaptic density protein 95 (PSD-95) in medial prefrontal cortex (mPFC) and hippocampus. All these assessments were compared among the naïve control rats, AD rats, and AD rats with ILN-DBS. We found that a single rostral ILN-DBS treatment significantly improved MWM performance and reversed PSD-95 expression reductions in the mPFC and hippocampal region of Aβ-infused rats. In addition, ILN-DBS preserved dendritic spine densities on mPFC and hippocampal pyramidal neurons. In fact, MWM performance, PSD-95 expression levels, and dendritic spine densities did not differ between naïve control and rostral ILN-DBS treatment groups, indicating near complete amelioration of Aβ-induced spatial memory impairments and dendritic regression. These findings suggest that the ILN is critical for modulating glutamatergic transmission, neural plasticity, and spatial memory functions through widespread effects on distributed brain regions. Further, these findings provide a rationale for examining the therapeutic efficacy of ILN-DBS in AD patients. [ABSTRACT FROM AUTHOR]

Background: Hormonal fluctuations may trigger the onset of bipolar disorder. We designed a longitudinal follow-up study to evaluate the association between hysterectomies and bipolar disorder risk.Methods: We conducted a large retrospective cohort study using Taiwan's National Health Insurance Research Database. A total of 4,337 women aged 30 to 50 years who underwent the hysterectomy during 2000-2013 were selected and 17,348 patients without hysterectomy were selected for comparison (1:4 match). Poisson regression analysis was used to calculate the incidence rate ratio (IRR) and 95% confidence interval (CI).Results: During the follow-up of 7.93 years, 20 participants with hysterectomy and 28 without hysterectomy developed bipolar disorder. Receiving hysterectomy was associated with the risk of developing bipolar disorder (adjusted IRR = 2.80; 95% CI = 2.54-3.09). Women with hysterectomy had a higher risk of bipolar disorder in follow-up durations of <1 year (adjusted IRR = 2.18 with 95% CI = 1.94-1.45) and ≥1 year (adjusted IRR = 2.85 with 95% CI = 2.58-3.15). Endometriosis and Premarin use increased bipolar disorder incidence in the hysterectomy group (adjusted IRR = 3.17 [95% CI = 2.83-3.56] and 4.22 [95% CI = 3.71-4.80], respectively).Conclusion: This study concluded that women with hysterectomy have an increased risk of bipolar disorder. Endometriosis and hormone therapy may add to the risk of bipolar disorder after hysterectomy. Knowledge about how surgical or natural hormonal withdrawal influences mood is fundamental and emphasizes the importance of coordinated psychiatric and gynecological care. [ABSTRACT FROM AUTHOR]

The long-term use of proton pump inhibitors (PPIs) has been shown to increase the risk of cardiovascular mortality, however the molecular mechanisms are unknown. Superoxide has been implicated in the regulation of nerve growth factor (NGF), a mediator of sympathetic innervation. The purpose of this study was to determine whether PPIs increase ventricular arrhythmias through magnesium-mediated superoxide production in infarcted rats. Male Wistar rats were randomly assigned to receive vehicle, omeprazole, omeprazole + magnesium sulfate, or famotidine treatment for 4 weeks starting 24 hours after the induction of myocardial infarction by ligating the coronary artery. Increased myocardial superoxide and nitrotyrosine levels were noted post-infarction, in addition to a significant upregulation of NGF expression on mRNA and protein levels. Sympathetic hyperinnervation after infarction was confirmed by measuring myocardial norepinephrine and immunofluorescent analysis. Compared with the vehicle, omeprazole-treated infarcted rats had significantly reduced myocardial magnesium content, increased oxidant production, and increased sympathetic innervation, which in turn increased ventricular arrhythmias. These effects were prevented by the coadministration of magnesium sulfate. In an in vivo study, an omeprazole-induced increase in NGF was associated with a superoxide pathway, which was further confirmed by an ex vivo study showing the attenuation of NGF levels after coadministration of the superoxide scavenger Tiron. Magnesium sulfate did not further attenuate NGF levels compared with omeprazole + Tiron. Our results indicate that the long-term administration of PPIs was associated with reduced tissue magnesium content and increased myocardial superoxide production, which exacerbated ventricular arrhythmias after infarction. Magnesium may be a potential target for PPI-related arrhythmias after infarction. [ABSTRACT FROM AUTHOR]

Metabolic-associated fatty liver disease (MAFLD) is a global concern, often undetected until reaching an advanced stage. Palmitic acid (PA) is a type of fatty acid that increases and leads to liver apoptosis in MAFLD. However, there is currently no approved therapy or compound for MAFLD. Recently, branched fatty acid esters of hydroxy fatty acids (FAHFAs), a group of bioactive lipids, have emerged as promising agents to treat associated metabolic diseases. This study utilizes one type of FAHFA, oleic acid ester of 9-hydroxystearic acid (9-OAHSA), to treat PA-induced lipoapoptosis in an in vitro MAFLD model using rat hepatocytes and a high-fat high-cholesterol high-fructose (HFHCHFruc) diet in Syrian hamsters. The results indicate that 9-OAHSA rescues hepatocytes from PA-induced apoptosis and attenuates lipoapoptosis and dyslipidemia in Syrian hamsters. Additionally, 9-OAHSA decreases the generation of mitochondrial reactive oxygen species (mito-ROS) and stabilizes the mitochondrial membrane potential in hepatocytes. The study also demonstrates that the effect of 9-OAHSA on mito-ROS generation is at least partially mediated by PKC-δ signaling. These findings suggest that 9-OAHSA shows promise as a therapy for MAFLD. • 9-OAHSA has potential protective effect against liver apoptosis by preserving mitochondrial function and stability. • PKCδ downregulation is involved in the elevation of mitochondrial ROS levels in fatty liver model. • 9-OAHSA prevents dyslipidemia and maintains body weight induced by high-fat high-cholesterol high-fructose diet. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is a primary brain tumor of unknown etiology. It is extremely aggressive, incurable and has a short average survival time for patients. Therefore, understanding the precise molecular mechanisms of this diseases is essential to establish effective treatments. In this study, we cloned and sequenced a splice variant of the hydroxysteroid 11-β dehydrogenase 1 like gene (HSD11B1L) and named it HSD11B1L-181. HSD11 B1L-181 was specifically expressed only in GBM cells. Overexpression of this variant can significantly promote the proliferation, migration and invasion of GBM cells. Knockdown of HSD11B1L-181 expression inhibited the oncogenic potential of GBM cells. Furthermore, we identified the direct interaction of parkin with HSD11B1L-181 by screening the GBM cDNA expression library via yeast two-hybrid. Parkin is an RBR E3 ubiquitin ligase whose mutations are associated with tumorigenesis. Small interfering RNA treatment of parkin enhanced the proliferative, migratory and invasive abilities of GBM. Finally, we found that the alkaloid peiminine from the bulbs of Fritillaria thunbergii Miq blocks the interaction between HSD11B1L-181 and parkin, thereby lessening carcinogenesis of GBM. We further confirmed the potential of peiminine to prevent GBM in cellular, ectopic and orthotopic xenograft mouse models. Taken together, these findings not only provide insight into GBM, but also present an opportunity for future GBM treatment. [ABSTRACT FROM AUTHOR]

Introduction: The current standard surgical treatment for cerebrospinal fluid diversion is a ventriculoperitoneal shunt (VPS) implantation. Lumboperitoneal shunts (LPS) are an alternative treatment for communicating hydrocephalus. Prior studies comparing these two included a limited number of participants. Methods: We performed a meta‐analysis determined the treatment failure, complications and effectiveness of lumboperitoneal shunt for communicating hydrocephalus. We reviewed studies with clinical and imaging diagnoses of communicating hydrocephalus, all causes and subtypes of communicating hydrocephalus, and studies that analyzed the primary and secondary outcomes listed below. We included randomized controlled trials (RCTs), non‐RCTs and retrospective studies. We performed the meta‐analysis in R, using a random‐effects model and reporting 95% confidence intervals. Results: Data from 25 studies, including 3654 patients, were analyzed. The total complication rates were 12.98% (188/1448) for lumboperitoneal shunt and 23.80% (398/1672) for ventriculoperitoneal shunt. The odds ratio for lumboperitoneal shunt versus ventriculoperitoneal shunt complication rates was 0.29 (95% CI 0.19 to 0.45, p < 0.0001), and the I2 was 72%. The shunt obstruction/malfunction rate was 3.99% (48/1204) for lumboperitoneal shunt and 8.31% (115/1384) for ventriculoperitoneal shunt (Odds ratio 0.54, 95% CI 0.37 to 0.79, p = 0.002, I2 = 0%). Based on the Modified Rankin Scale score, there were no differences in effectiveness between lumboperitoneal shunt and ventriculoperitoneal shunt. Nevertheless, lumboperitoneal shunt improved radiological outcomes. Conclusions: This analysis demonstrated that lumboperitoneal shunt is a safe and equally effective choice for treating communicating hydrocephalus. More studies are needed to confirm the safety of lumboperitoneal shunt. [ABSTRACT FROM AUTHOR]

During myocardial infarction, infiltrated macrophages have pivotal roles in cardiac remodeling and delayed M1 toward M2 macrophage phenotype transition is considered one of the major factors for adverse ventricular remodeling. We investigated whether dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, attenuates cardiac fibrosis via regulating macrophage phenotype by a reactive oxygen and nitrogen species (RONS)/STAT3-dependent pathway in postinfarcted rats. Normoglycemic male Wistar rats were subjected to coronary ligation and then randomized to either saline, dapagliflozin (a specific SGLT2 inhibitor), phlorizin (a nonspecific SGLT1/2 inhibitor), dapagliflozin + S3I-201 (a STAT3 inhibitor), or phlorizin + S3I-201 for 4 weeks. There were similar infarct sizes among the infarcted groups at the acute and chronic stages of infarction. At day 3 after infarction, post-infarction was associated with increased levels of superoxide and nitrotyrosine, which can be inhibited by administering either dapagliflozin or phlorizin. SGLT2 inhibitors significantly increased STAT3 activity, STAT3 nuclear translocation, myocardial IL-10 levels and the percentage of M2 macrophage infiltration. At day 28 after infarction, SGLT2 inhibitors were associated with attenuated myofibroblast infiltration and cardiac fibrosis. Although phlorizin decreased myofibroblast infiltration, the effect of dapagliflozin on attenuated myofibroblast infiltration was significantly higher than phlorizin. The effects of SGLT2 inhibitors on cardiac fibrosis were nullified by adding S3I-201. Furthermore, the effects of dapagliflozin on STAT3 activity and myocardial IL-10 levels can be reversed by 3-morpholinosydnonimine, a peroxynitrite generator. Taken together, these observations provide a novel mechanism of SGLT2 inhibitors-mediated M2 polarization through a RONS-dependent STAT3-mediated pathway and selective SGLT2 inhibitors are more effective in attenuating myofibroblast infiltration during postinfarction remodeling. [ABSTRACT FROM AUTHOR]

Human pluripotent stem cell (hPSC)-derived motor neurons (MNs) act as models for motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS) or spinal muscular atrophy. However, the MN differentiation efficiency and viability following cryopreservation require further development for application in large-scale studies and drug screening. Here, we developed a robust protocol to convert hPSCs into MN cryopreservation stocks (hPSCs were converted into >92% motor neural progenitors and >91% MNs). Near-mature MNs were cryopreserved at a high thawing survival rate and 89% MN marker expression on day 32. Moreover, these MNs exhibited classical electrophysiological properties and neuromuscular junction (NMJ) formation ability within only 4–6 days after thawing. To apply this platform as an MND model, MN stocks were generated from SOD1G85R, SOD1G85G isogenic control, and sporadic ALS hPSC lines. The thawed ALS MNs expressed ALS-specific cytopathies, including SOD1 protein aggregation and TDP-43 redistribution. Thus, a stable and robust protocol was developed to generate ready-to-use cryopreserved MNs without further neuronal maturation processes for application in MND mechanistic studies, NMJ model establishment, and large-scale drug screening. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal disease in which motor neurons gradually degenerate. The mutation of the C9orf72 gene is the main genetic cause of ALS (C9-ALS). One of its specific pathological features is the production of proline-arginine (PR) dipeptide repeat protein (DPR). In this study, we developed a PR-DPR (PR50)-expressing human HMC3 microglial cell model. We found that PR50 mainly aggregates into spots in the nucleus and induces significant NLRP3 inflammasome activity. Moreover, mouse NSC-34 motor neuron cells treated with a conditional medium of PR50-expressing HMC3 cells (PR-CM) caused cell damage and apoptosis activity. However, R50-expressing HMC cells treated with MCC950 (an NLRP3 inhibitor) reversed this result. Furthermore, we identified complement component 1 q subcomponent-binding protein (C1QBP) as one of the interaction partners of PR50. The downregulation of C1QBP in HMC3 cells induces NLRP3 inflammasome activity similar to PR50 expression. Finally, we found that syringin can block the interaction between PR50 and C1QBP, and effectively reduce the PR50-induced NLRP3 inflammasome activity in HMC3 cells. This improves the apoptosis of NSC-34 cells caused by PR-CM. This study is the first to link PR50, C1QBP, and NLRP3 inflammasome activity in microglia and develop potential therapeutic strategies for syringin intervention in C9-ALS. [ABSTRACT FROM AUTHOR]

Simple Summary: BCAS1-SV1, a novel splice variant of BCAS1, promotes the proliferation and migration of glioblastoma cells by directly binding to and inhibiting the tumor suppressor function of β-arrestin 2. Maackiain blocks the specific interaction of BCAS1-SV1 with β-arrestin 2 and shows potential application as a therapeutic for glioblastoma. Brain-enriched myelin-associated protein 1 (BCAS1) is frequently highly expressed in human cancer, but its detailed function is unclear. Here, we identified a novel splice variant of the BCAS1 gene in glioblastoma multiforme (GBM) named BCAS1-SV1. The expression of BCAS1-SV1 was weak in heathy brain cells but high in GBM cell lines. The overexpression of BCAS1-SV1 significantly increased the proliferation and migration of GBM cells, whereas the RNA-interference-mediated knockdown of BCAS1-SV1 reduced proliferation and migration. Moreover, using a yeast-two hybrid assay, immunoprecipitation, and immunofluorescence staining, we confirmed that β-arrestin 2 is an interaction partner of BCAS1-SV1 but not BCAS1. The downregulation of β-arrestin 2 directly enhanced the malignancy of GBM and abrogated the effects of BCAS1-SV1 on GBM cells. Finally, we used a yeast two-hybrid-based growth assay to identify that maackiain (MK) is a potential inhibitor of the interaction between BCAS1-SV1 and β-arrestin 2. MK treatment lessened the proliferation and migration of GBM cells and prolonged the lifespan of tumor-bearing mice in subcutaneous xenograft and intracranial U87-luc xenograft models. This study provides the first evidence that the gain-of-function BCAS1-SV1 splice variant promotes the development of GBM by suppressing the β-arrestin 2 pathway and opens up a new therapeutic perspective in GBM. [ABSTRACT FROM AUTHOR]

Background. The role of inherent tumor heterogeneity and an immunosuppressive microenvironment in therapeutic resistance has been determined to be of importance for the better management of glioblastoma multiforme (GBM). Some studies have suggested that combined drugs with divergent mechanisms may be promising in treating recurrent GBM. Methods. Intracranial sustained (Z)-n-butylidenephthalide [(Z)-BP] delivery through Cerebraca Wafers (CWs) to eliminate unresectable brain tumors was combined with the administration of temozolomide (TMZ), pembrolizumab, and cytokine-induced killer (CIK) cells for treating a patient with recurrent glioblastoma. Neurological adverse events and wound healing delay were monitored for estimating tolerance and efficacy. Response Assessment in Neuro-Oncology criteria were applied to evaluate progression-free survival (PFS); further, the molecular characteristics of GBM tissues were analyzed, and the underlying mechanism was investigated using primary culture. Results. Intracerebral (Z)-BP in residual tumors could not only inhibit cancer stem cells but also increase interferon gamma levels in serum, which then led to the regression of GBM and an immune-responsive microenvironment. Targeting receptor tyrosine kinases, including Axl and epidermal growth factor receptor (EGFR), and inhibiting the mechanistic target of rapamycin (mTOR) through (Z)-BP were determined to synergize CIK cells in the presence of pembrolizumab and TMZ in recurrent GBM. Therefore, this well-tolerated regimen could simultaneously block multiple cancer pathways, which allowed extended PFS and improved quality of life for 22 months. Conclusion. Given the several unique functions of (Z)-BP, greater sensitivity of chemotherapy and the synergism of pembrolizumab and CIK cells could have affected the excellent prognosis seen in this patient with recurrent GBM. [ABSTRACT FROM AUTHOR]

Acupuncture has been applied as a complementary therapy in stroke survivors worldwide and approved to be beneficial to stroke recovery. However, there is little medical evidence regarding the association between acupuncture and the risk of poststroke comorbidities. We reviewed big data studies from the Taiwan National Health Insurance Research Database to investigate the risk of poststroke comorbidities after acupuncture treatment in a real-world situation. Ten English (PubMed, Embase, Medline, Cochrane, Alt HealthWatch, CINAHL, Health Source, PsycINFO, PsycARTICLES, and Psychology and Behavioral Sciences Collection) and two Chinese (AiritiLibray and Visualizing Health Data) electronic databases were searched from inception until December 2020 for nationalized cohort studies comparing the effects of acupuncture treatment with a nonacupuncture control group among stroke patients. Eight nationalized cohort studies were included. Six of eight studies showed a moderate overall risk of bias, while two studies showed a serious overall risk of bias. Included studies have investigated the effect of acupuncture in reducing the risk of seven medical conditions after stroke, including stroke recurrence, new-onset acute myocardial infarction (AMI), pneumonia, dementia, epilepsy, urinary tract infection (UTI), and depression. The meta-analysis showed clinically significant reductions in the risk of poststroke comorbidities in the acupuncture group compared to the nonacupuncture group (HR, 0.776; 95% CI, 0.719–0.838; p < 0.0001). In this systematic review and meta-analysis of nationalized cohort studies, acupuncture showed clinically relevant benefits in reducing the incidence of poststroke comorbidities, such as stroke recurrence, new-onset acute myocardial infarction (AMI), pneumonia, dementia, epilepsy, and UTI. [ABSTRACT FROM AUTHOR]

Thermogenesis (non-exercise activity) in brown adipose tissue (BAT) promotes energy expenditure because of its higher number of mitochondria than white adipose tissue (WAT). The main function of thermogenesis in BAT can counteract obesity through the dissipation of calories as heat. N-butylidenephthalide (BP) is a natural derivative from Angelica sinensis , a Chinese herb that has been used for thousands of years. In this report, we demonstrated that BP improved the metabolic profiles of mice with high fat diet-induced obesity (DIO) by preventing weight gain, improving serum blood parameters, enhancing energy expenditure, stimulating white fat browning, and reversing hepatic steatosis. Further investigations demonstrated that BP administration upregulated the mRNA expression of beige (CD137, TMEM26) and brown fat selected genes (UCP1, PRDM16, PGC-1α, PPARγ) in white adipose tissues. In vitro studies, BP treatment increased multilocular lipid droplet levels, induced β-adrenergic receptor (cAMP/PKA) and AMP-activated protein kinase (AMPK) signaling (AMPK/acetyl-CoA carboxylase/SIRT1), and increased oxygen consumption in murine differentiated beige adipocytes, and the effects of BP were blocked by an AMPK inhibitor. BP promoted the interaction of AMPK with PGC-1α in beige adipocytes. Our findings provide novel insights into the application of BP in regulating energy metabolism and suggest its utility for clinical use in the treatment of obesity and related diseases. • BP administratoion reduces high-fat diet (HFD)-induced obesity in mice. • BP administration ameliorates high-fat diet (HFD)-induced metabolic profiles and improves insulin sensitivity in mice. • BP administration increases energy expenditure and cold tolerance via thermogenesis. • BP-treated mice display reduced adiposity and increased fat browning characteristics in sWAT and iBAT. • BP treatment regulated thermogenic markers through cAMP/PKA/AMPK pathway in differentiated adipocytes. [ABSTRACT FROM AUTHOR]

Aims: The effects of subthalamic nucleus (STN)‐deep brain stimulation (DBS) on brain topological metrics, functional connectivity (FC), and white matter integrity were studied in levodopa‐treated Parkinson's disease (PD) patients before and after DBS. Methods: Clinical assessment, resting‐state functional MRI (rs‐fMRI), and diffusion tensor imaging (DTI) were performed pre‐ and post‐DBS in 15 PD patients, using a within‐subject design. The rs‐fMRI identified brain network topological metric and FC changes using graph‐theory‐ and seed‐based methods. White matter integrity was determined by DTI and tract‐based spatial statistics. Results: Unified Parkinson's Disease Rating Scale III (UPDRS‐ III) scores were significantly improved by 35.3% (p < 0.01) after DBS in PD patients, compared with pre‐DBS patients without medication. Post‐DBS PD patients showed a significant decrease in the graph‐theory‐based degree and cost in the middle temporal gyrus and temporo‐occipital part‐Right. Changes in FC were seen in four brain regions, and a decrease in white matter integrity was seen in the left anterior corona radiata. The topological metrics changes were correlated with Beck Depression Inventory II (BDI‐II) and the FC changes with UPDRS‐III scores. Conclusion: STN‐DBS modulated graph‐theoretical metrics, FC, and white matter integrity. Brain connectivity changes observed with multi‐modal imaging were also associated with postoperative clinical improvement. These findings suggest that the effects of STN‐DBS are caused by brain network alterations. [ABSTRACT FROM AUTHOR]

Cognitive impairment is a serious side effect of post-myocardial infarction (MI) course. We have recently demonstrated that human adipose-derived stem cells (hADSCs) ameliorated myocardial injury after MI by attenuating reactive oxygen species (ROS) levels. Here, we studied whether the beneficial effects of intramyocardial hADSC transplantation can extend to the brain and how they may attenuate cognitive dysfunction via modulating ROS after MI. After coronary ligation, male Wistar rats were randomized via an intramyocardial route to receive either vehicle, hADSC transplantation (1 × 106 cells), or the combination of hADSCs and 3-Morpholinosydnonimine (SIN-1, a peroxynitrite donor). Whether hADSCs migrated into the hippocampus was assessed by using human-specific primers in qPCR reactions. Passive avoidance test was used to assess cognitive performance. Postinfarction was associated with increased oxidative stress in the myocardium, circulation, and hippocampus. This was coupled with decreased numbers of dendritic spines as well as a significant downregulation of synaptic plasticity consisting of synaptophysin and PSD95. Step-through latency during passive avoidance test was impaired in vehicle-treated rats after MI. Intramyocardial hADSC injection exerted therapeutic benefits in improving cardiac function and cognitive impairment. None of hADSCs was detected in rat's hippocampus at the 3rd day after intramyocardial injection. The beneficial effects of hADSCs on MI-induced histological and cognitive changes were abolished after adding SIN-1. MI-induced ROS attacked the hippocampus to induce neurodegeneration, resulting in cognitive deficit. The remotely intramyocardial administration of hADSCs has the capacity of improved synaptic neuroplasticity in the hippocampus mediated by ROS, not the cell engraftment, after MI. Key messages: Human adipose-derived stem cells (hADSCs) ameliorated injury after myocardial infarction by attenuating reactive oxygen species (ROS) levels. Intramyocardial administration of hADSCs remotely exerted therapeutic benefits in improving cognitive impairment after myocardial infarction. The improved synaptic neuroplasticity in the hippocampus was mediated by hADSC-inhibiting ROS, not by the stem cell engraftment. [ABSTRACT FROM AUTHOR]

Background: This study aimed to evaluate fetal adverse outcomes of laparoscopy and laparotomy in pregnant women to determine the safety of these surgical approaches.Methods: This was a retrospective nationwide case-control study of women who became pregnant for the first time between 2000 and 2012 in Taiwan. The case (with adverse fetal outcomes) and control groups comprised 208,604 and 417,124 participants, respectively. Participants who underwent appendectomy, cholecystectomy, ovarian cystectomy, or myomectomy were treated with either laparoscopy or laparotomy. A conditional logistic regression model was used to calculate the odds ratios (ORs) for adverse fetal outcomes.Results: The laparotomy and laparoscopy groups comprised 632 and 536 patients, respectively. Women who underwent laparoscopy had a significantly higher risk of adverse fetal outcomes (adjusted OR [AOR] = 2.33; 95% CI 1.66-2.99) than those who underwent laparotomy. Adverse fetal outcomes were found to be significantly associated with laparoscopy among women aged 20-39 years (AOR = 2.30; 95% CI 1.70-3.31). Regarding surgical indication, unlike laparotomy, laparoscopic cholecystectomy and appendectomy were not associated with adverse fetal outcomes. However, laparoscopic myomectomy and ovarian surgeries were associated with a higher incidence of adverse fetal outcomes than the laparotomy group (AOR = 2.29 [95% CI 1.57-3.35, p < 0.0001] and AOR = 2.52 [95% CI 1.58-4.04, p = 0.0001], respectively).Conclusions: Pregnant women who underwent laparoscopic surgery experienced significantly more adverse fetal outcomes than those who underwent laparotomy. Therefore, pregnant women undergoing either laparotomy or laparoscopy should be informed of the risk of adverse fetal outcomes. [ABSTRACT FROM AUTHOR]

A retrospective, single-centre, non-randomized study in the management of symptomatic middle cerebral artery (MCA) total occlusion disease to evaluate extracranial-intracranial (EC-IC) bypass as an intervention for patients with atherosclerotic MCA total occlusion, ischemic symptoms (transient ischemic attacks [TIAs]) or poor cerebral haemodynamics who had not responded well to maximal medical treatment was reported. Twenty-three patients were included in the study with the criteria of: having ischemic syndrome, for example, TIA; being associated with atherosclerotic MCA total occlusion disease (compatible with radiological assessment); being failed to respond to optimal medical therapy (e.g. antiplatelet therapy), indicating a repeat TIA or ischemic stroke attack was noted during maximal medical therapy; having poor cerebral perfusion on CT imaging; and having regional cerebrovascular reactivity (rCVR) of <20% when acetazolamide challenge was undergone. Patients had acute ischemic stroke or other major medical co-morbidities were excluded. No patient experienced any recurrent ischemic stroke during a mean follow-up period of 26.5 months except one patient suffered of immediate post-operative ischemic stroke because of the temporal vessel being clipped too long and the hypotension caused by anaesthesia. Post-operative follow-up imaging, which included MRI (MR angiography) and four-vessel digital subtraction angiography revealed a 100% patency of superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis. No significant differences between observation periods (baseline status: 5.46 ± 5.13/85 ± 15; 0.5 month after surgery: 5.18 ± 5.29/85.91 ± 15.46 and 3 months after surgery: 5.09 ± 4.75/85.36 ± 12.27) were found for the neurological evaluations of NIHSS and Barthel Index (both expressed in mean ± SD) in all of the 23 patients. The annual risk of recurrent stroke was 0% after EC-IC bypass. However, studies with a larger scale are warranted to further confirm the effectiveness of EC-IC bypass. [ABSTRACT FROM AUTHOR]

Objective: To investigate the inter-relationship among diabetes, urinary tract infection (UTI), and urinary tract calculi (UTC). Methods: This study used Taiwan''s National Health Insurance claims data of ambulatory care visits and hospitalizations. A total of 12,257 newly diagnosed diabetes cases in 2000-2002 and 96,781 controls were followed to the end of 2007. The person-year approach with Poisson assumption was used to estimate the incidence density (ID) of UTC by diabetic status. Relative risk of UTC in relation to diabetes and UTI were estimated from Cox proportional hazard model with adjustment for sociodemographic variables and comorbidities. Results: Over nearly 8 years of follow-up, 8.9% of diabetes and 7.2% of control subjects sought ambulatory care or were hospitalized for UTC, representing the ID of 14.4 and 11.4 per 1000 person-years, respectively. The multivariate analysis indicated that UTC risk was independently associated with diabetes (hazard ratio 1.18, 95% CI 1.10-1.27) and UTI (HR 1.68, 95% CI 1.60-1.76). The hazard ratio of UTC in relation to diabetes in men and women without UTI was 1.24 and 1.26, respectively. Diabetes may further increase the rate of UTC in women with UTI, with an hazard ratio increased from 1.79-2.12. Such additive effect by diabetes in men with UTI was only marginal (HR 1.68 vs 1.67). Conclusion: This cohort study provides epidemiologic support for the causal association between diabetes and UTC, which is independent of UTI. In addition, female patients with UTI accompanied by diabetes tended to be associated with a greater rate of UTC. [ABSTRACT FROM AUTHOR]

Abstract: There was increasing evidence suggesting that angiotensin I-converting enzyme may play an important role in the pathogenesis of PD. Our former study has shown that angiotensin I-converting enzyme gene (ACE) may confer a susceptibility for the risk of Parkinson''s disease (PD). Meanwhile, recent studies have emphasized that genetic factors may involve in the occurrence of the adverse effects of chronic l-dopa therapy in PD patients. This study was designed to assess whether genetic polymorphism of the ACE could be a predictor of l-dopa-induced adverse effects in PD. There were 251 patients included in this study and their mean age at onset of disease was 63.3±11.4 years. The duration of disease and the treatment with l-dopa was 6.3±5.1 and 5.0±4.3 years, respectively. The frequency of the homozygote ACE-II genotype of the ACE in PD patients with l-dopa-induced psychosis was significantly higher than that in PD patients without the adverse effect (63.3% vs 43.0%; χ 2 =6.347, OR=1.435, 95%CI=1.105–1.864, p =0.012). However, the ACE polymorphism was not associated with the risk to develop dyskinesia or motor fluctuation induced by l-dopa. Furthermore, a logistic regression analysis confirmed that the ACE-II genotype was an independent risk factor for l-dopa-induced psychosis in PD patients (OR=2.542, p =0.012). In conclusion, results of the study showed that ACE-II genotype might confer a primary predictor for the occurrence of psychosis in l-dopa-treated PD. [Copyright &y& Elsevier]

Abstract: Nan-Chai-Hu, the root of Bupleurum scorzonerifolium, is a traditional Chinese herb used in treatment of liver diseases such as hepatitis and cirrhosis. We recently reported that the acetone extract of B. scorzonerifolium (BS-AE) could inhibit proliferation and induce apoptosis in A549 human lung cancer cells. We further examined its anti-proliferative mechanisms and in vivo anticancer effect. Our results showed that BS-AE had the ability to cause cell cycle arrest in G2/M phase, inducing tubulin polymerization, and activating caspase-3 and -9 in A549 cells. BS-AE-induced apoptosis could be blocked by the broad caspase inhibitor z-VAD-fmk in majority. The result of in vivo study showed that BS-AE could suppress growth in A549 subcutaneous xenograft tumors. These results indicate that BS-AE exerts antiproliferative effects on A549 cells in vitro and in vivo, and prompted us to further evaluate and elucidate the chemical composition profile of BS-AE. [Copyright &y& Elsevier]

The association between bladder antimuscarinic use and dementia development is unclear. We used data from the Taiwan National Health Insurance Research Database to determine the association between the exposure dose and duration of bladder antimuscarinics and the subsequent dementia risk. We enrolled participants aged 55 years or more and defined a dementia cohort (International Classification of Diseases, Ninth Revision, Clinical Modification codes 290, 294.1, and 331.0). We used a propensity score matching method, and randomly enrolled two controls without dementia. We evaluated dementia risk with respect to the exposure dose and duration of treatment with seven bladder antimuscarinics (oxybutynin, propiverine, tolterodine, solifenacin, trospium, darifenacin, and fesoterodine) used for at least 1 year before the index date, after adjusting for age, sex, comorbidities, and medications. The dementia risk was 2.46-fold (95% confidence interval: 2.22–2.73) higher in Taiwanese patients who used bladder antimuscarinics for ≥ 1 year than in those who were not exposed to this treatment. The risk proportionally increased with increasing doses of antimuscarinics for less than 4 years. Taiwanese patients aged 55 years or more on bladder antimuscarinics exhibited a higher risk of dementia. Additional studies in other countries are required to determine whether this result is valid worldwide. [ABSTRACT FROM AUTHOR]

Exosome therapy is a novel trend in regeneration medicine. However, identifying a suitable biomarker that can associate the therapeutic efficacy of exosomes with SCA3/MJD is essential. In this study, parental cells were preconditioned with butylidenephthalide (Bdph) for exosome preparation to evaluate the therapeutic effect of SCA3/MJD. The therapeutic agent hsa-miRNA-6780–5p was enriched up to 98-fold in exosomes derived from butylidenephthalide (Bdph)-preconditioned human olfactory ensheathing cells (hOECs) compared with that in naïve hOECs exosomes. The particle sizes of exosomes derived from naïve hOECs and those derived from hOECs preconditioned with Bdph were approximately 113.0 ± 3.5 nm and 128.9 ± 0.7 nm, respectively. A liposome system was used to demonstrate the role of hsa-miRNA-6780–5p, wherein hsa-miRNA-6780–5p was found to enhance autophagy and inhibit the expression of spinocerebellar ataxia type 3 (SCA3) disease proteins with the polyglutamine (polyQ) tract. Exosomes with enriched hsa-miRNA-6780–5p were further applied to HEK-293–84Q cells, leading to decreased expression of polyQ and increased autophagy. The results were reversed when 3MA, an autophagy inhibitor, was added to the cells treated with hsa-miRNA-6780–5p-enriched exosomes, indicating that the decreased polyQ expression was modulated via autophagy. SCA3 mice showed improved motor coordination behavior when they intracranially received exosomes enriched with hsa-miRNA-6780–5p. SCA3 mouse cerebellar tissues treated with hsa-miRNA-6780–5p-enriched exosomes showed decreased expression of polyQ and increased expression of LC3II/I, an autophagy marker. In conclusion, our findings can serve as a basis for developing an alternative therapeutic strategy for SCA3 disease treatment using miRNA-enriched exosomes derived from chemically preconditioned cells. [Display omitted] [ABSTRACT FROM AUTHOR]

Aim: This study investigated the risk of osteoporosis or bone fractures (vertebrae, hip and others) in hysterectomized women in Taiwan. Materials and methods: This is a retrospective population-based cohort study from 2000 to 2013. Women aged ≥30 years who underwent hysterectomy between 2000 and 2012 were included in this study. The comparison group was randomly selected from the database with a 1:4 matching with age and index year. Incidence rate and hazard ratios of osteoporosis and bone fracture between hysterectomized women and the comparison group were calculated. Cox proportional hazard regressions were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: We identified 9,189 hysterectomized women and 33,942 age-matched women without a hysterectomy. All women were followed for a median time of about 7 years. The adjusted hazard ratio (aHR) of subsequent osteoporosis or bone fracture was higher in the hysterectomy women (2.26, 95% confidence interval [CI] = 2.09–2.44) than in the comparison group. In the subgroup analysis, oophorectomy and estrogen therapy increase the risk of osteoporosis or fracture in both groups. Regarding the fracture site, the aHR of vertebral fracture (4.92, 95% CI = 3.78–6.40) was higher in the hysterectomized women than in the comparison group. As follow-up time increasing, the aHR of vertebral fracture in hysterectomized women were 4.33 (95% CI = 2.99–6.28), 3.89 (95% CI = 2.60–5.82) and 5.42 (95% CI = 2.66–11.01) for <5, 5–9 and ≥9 years of follow-up, respectively. Conclusions: In conclusion, we found that hysterectomized women might be associated with increased risks of developing osteoporosis or bone fracture. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) is a progressive motor disease with no broadly effective treatment. However, most current therapies are based on symptoms rather than the underlying disease mechanisms. In this review, we describe potential therapeutic strategies based on known pathological biomarkers and related pathogenic processes. The three major conclusions from the current studies are summarized as follows: (i) for the drugs currently being tested in clinical trials; a weak connection was observed between drugs and SCA3/MJD biomarkers. The only two exceptions are the drugs suppressing glutamate-induced calcium influx and chemical chaperon. (ii) For most of the drugs that have been tested in animal studies, there is a direct association with pathological biomarkers. We further found that many drugs are associated with inducing autophagy, which is supported by the evidence of deficient autophagy biomarkers in SCA3/MJD, and that there may be more promising therapeutics. (iii) Some reported biomarkers lack relatively targeted drugs. Low glucose utilization, altered amino acid metabolism, and deficient insulin signaling are all implicated in SCA3/MJD, but there have been few studies on treatment strategies targeting these abnormalities. Therapeutic strategies targeting multiple pathological SCA3/MJD biomarkers may effectively block disease progression and preserve neurological function. [ABSTRACT FROM AUTHOR]

We aim to evaluate breast cancer risk relating to PPIs usage in women with peptic ulcer. From 2000 to 2013, incidence rates of breast cancer were compared between the two cohorts (with or without PPIs). Each study cohort consisted of 4838 women. The incidence density rate of breast cancer in the PPI cohort was 0.29 that in the comparison cohort (10.0 vs 31.6 per 10 000 person‐years), with an adjusted HR (hazard ratio) of 0.32 (95% CI = 0.20‐0.49) for the PPI cohort. In conclusion, the medication of PPIs is associated with reduced breast cancer risk for women with gastric ulcer. [ABSTRACT FROM AUTHOR]

• NanoCsA provided sustained release of CsA in vitro for 6 weeks. • Transplantation of NanoCsA/iPSCs improved locomotor activity in 6-OHDA –lesioned rats. • Transplantation of NanoCsA/iPSCs increased human Stem121 and TH immunoreactivity in lesioned striatum. • Systemic application of CsA or co-grafting of NanoCsA with iPSCs increased teratoma formation. • Co-grafting of NanoCsA reduces immunorejection of human iPSCs xenograft in a 6-hydroxydopamine rat model of PD. Increasing evidence has supported that transplantation of human stem cells induces neuroprotective and reparative effects in animal models of Parkinson's disease (PD). However, without systemic immunosuppressive therapy, most of these grafted cells are rejected by the hosts. Long term and systemic injection of cyclosporine-A (CsA) is required to maintain the survival of grafted cells. The purpose this study is to examine a new treatment strategy to suppress the immunorejection by locally co-grafting of polylactic/glycolic acid nanoparticles containing CsA (NanoCsA) with differentiated human induced pluripotent stem cells (iPSCs). In the in vitro media, NanoCsA provided sustained release of CsA for >6 weeks. The differentiated human iPSCs were co-grafted with NanoCsA or NanoVeh (nanoparticle without CsA) to the striatum of unilaterally 6-hydroxydopamine -lesioned rats. NanoCsA/iPSCs co-graft significantly improved locomotor activity compared to NanoVeh/iPSCs co-grafts or iPSC grafts + sytemic CsA at 1 month after transplantation. Brain tissues were collected for measurements of tyrosine hydroxylase (TH) and human marker Stem121 immunoreactivity. Cografting with NanoCsA/iPSCs, compared to NanoVeh/iPSCs, significantly increased TH and Stem121 immunoreactivity as well as tumor formation in the lesioned striatum. Taken together, our study supports that NanoCsA provides long-lasting CsA release and reduces immunorejection of human iPSCs xenograft in a 6-hydroxydopamine rat model of PD. [ABSTRACT FROM AUTHOR]

Study Question: Is polycystic ovarian syndrome (PCOS) in women associated with the increasing incidence of depression in an East Asian population?Summary Answer: Younger PCOS patients (aged 15-29 years), but not middle-aged patients, have an increased risk of depression in Taiwan.What Is Known Already: During reproductive age, 6-10% of women have PCOS. Among them, ~40% experience depression, mostly at young ages.Study Design, Size, Duration: This is a retrospective population-based cohort study analysing depression risk in Taiwanese women using data from a nationwide database containing 1998-2013 data of nearly 1 million people.Participants/materials, Setting, Methods: We included 15- to 50-year-old women newly diagnosed with PCOS during 1998-2013 from the Taiwan National Health Insurance Research Database as the PCOS cohort (n = 7684) and then randomly matched them 4 : 1 by sex, age and index year with women without PCOS as the comparison cohort (n = 30 736). We used multivariable Cox proportional hazard regression analysis to determine the association between PCOS and depression risk [hazard ratio (HR) with 95% confidence interval (CI)].Main Results and the Role Of Chance: The incidence of depression was higher in the PCOS group than in the comparison group (6.67 vs. 4.82 per 1000 person-years; adjusted HR = 1.28, 95% CI = 1.12-1.46). PCOS patients aged 15-29 years had a significantly higher depression risk (adjusted HR = 1.39, 95% CI = 1.18-1.65); no such significant association was noted among patients aged 30-39 years and 40-50 years.Limitations, Reasons For Caution: A history of malignancy, which may increase depression, could not be obtained for our study patients. Moreover, we could not obtain a family history of depression, a relevant risk factor for depression. Finally, the database has no records of body mass index, which may influence depression outcome.Wider Implications Of the Findings: In Taiwan, younger PCOS patients (15-29 years), but not the middle-aged patients, have an increased risk of depression. Our findings provide vital information to patients, clinicians, the Taiwan Government and other developing Asian countries to improve the PCOS treatment strategies in the future. Routine screening for depression in PCOS patients may be implemented into the health practice.Study Funding/competing Interest(s): This study was supported in part by the Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW108-TDU-B-212-133 004), China Medical University Hospital, Academia Sinica Stroke Biosignature Project (BM10701010021), MOST Clinical Trial Consortium for Stroke (MOST 107-2321-B-039 -004-), Tseng-Lien Lin Foundation, Taichung, Taiwan and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. No competing interest existed.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Background: The current study evaluated whether the risk of developing thyroid cancer in Asian women was associated with infertility and the use of fertility drugs. Methods: The authors conducted a large, retrospective cohort study using Taiwan's National Health Insurance Research Database. From the insurance claims data, a total of 13,356 women aged 20 to 49 years who were diagnosed with infertility from 2000 through 2013 were included in the infertile group, and 53,424 women without a history of infertility were selected as fertile comparisons and were frequency matched by age and year of diagnosis. Both groups were followed up to 2013 to calculate incident thyroid cancer. Poisson regression analysis was used to estimate the incidence rate ratio (IRR). Results: The incidence of thyroid cancer was 1.9‐fold greater in the infertile group compared with the comparison group (2.85 vs 1.53 per 10,000 person‐years), with an adjusted IRR of 1.80 (95% confidence interval [95% CI], 1.70‐1.92) for the infertile group. Higher cancer incidence was demonstrated for the infertile group after 7 years of follow‐up, with an adjusted IRR of 4.39 (95% CI, 4.03‐4.78) compared with the comparison group. Among infertile women, those who had taken the fertility drug clomiphene were found to have a reduced incidence of thyroid cancer compared with those who were treated without the drug (2.69 vs 3.42 per 10,000 person‐years), with an adjusted IRR of 0.86 (95% CI, 0.75‐0.99). However, the cancer incidence in infertile women being treated with clomiphene was nearly 6‐fold greater than that in fertile women taking the drug. Conclusions: The results of the current study provide evidence that women with infertility are at an increased risk of developing thyroid cancer. In the current study, the incidence of thyroid cancer is found to be 1.9‐fold greater in women in the infertile group compared with women in the comparison group (2.85 vs 1.53 per 10,000 person‐years). A higher cancer incidence is noted for the infertile group after 7 years of follow‐up, with an adjusted hazard ratio of 4.39 (95% confidence interval, 4.03‐4.78) compared with the comparison group. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Annually, 48,000 people die from pancreatic ductal adenocarcinoma (PDAC), ranking it the fourth among cancer-related deaths in the United States. Currently, anti-cancer drugs are not effective against PDAC, and only extends survival by 3 months. Aberrant DNA methylation has been shown to play an important role during carcinogenesis in PDAC, with approximately 80% of tumor overexpressing the DNA methyltransferase 1 (DNMT1) protein. In the present study, we used DNMTs as a screening platform to find a new DNMT inhibitor, n-butylidenephthalide (n-BP), which is identified from a Chinese herbal drug. n-BP could inhibit DNMT1 expression in both dose-dependent and time-dependent manner. It also displays an effect in suppressing growth of PDAC cells and inducing cell cycle arrest at G0/G1 phase leading apoptosis. Growth suppression can be restored by the overexpression of DNMT1 in PDAC cells. Furthermore, we found n-BP-mediated DNMT1 suppression influenced the protein stability rather than changing the RNA expression. Through microarray studies, we found that the patched domain contained 4 (PTCHD4) is the potential downstream gene of DNMT1. Following silencing of PTCHD4 expression by siRNA, n-BP decreased tumor growth inhibition. Finally, in vivo , two animal models were used to evaluate the efficacy and survival after n-BP treatment by interstitial control release polymer delivery. The results show that n-BP could effectively inhibit PDAC tumor volume growth and extend animal survival. In summary, n-BP may inhibit the growth of human PDAC cells though reducing DNMT1 and increasing the expression of PTCHD4 both in vitro and in vivo. [ABSTRACT FROM AUTHOR]