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Asthma is a chronic inflammatory disease characterized by airway hypersensitivity and remodeling. The current treatments provide only short-term benefits and may have undesirable side effects; thus, alternative or supplementary therapy is needed. Because intracellular calcium (Ca 2+ ) signaling plays an essential role in regulating the contractility and remodeling of airway smooth muscle cells, the targeting of Ca 2+ signaling is a potential therapeutic strategy for asthma. Houttuynia cordata is a traditional Chinese herb that is used to treat asthma due to its anti-allergic and anti-inflammatory properties. We hypothesized that H. cordata might modulate intracellular Ca 2+ signaling and could help relieve asthmatic airway remodeling. We found that the mRNA and protein levels of inositol trisphosphate receptors (IP 3 Rs) were elevated in interleukin-stimulated primary human bronchial smooth muscle cells and a house dust mite-sensitized model of asthma. The upregulation of IP 3 R expression enhanced intracellular Ca 2+ release upon stimulation and contributed to airway remodeling in asthma. Intriguingly, pretreatment with H. cordata essential oil rectified the disruption of Ca 2+ signaling, mitigated asthma development, and prevented airway narrowing. Furthermore, our analysis suggested that houttuynin/2-undecanone could be the bioactive component in H. cordata essential oil because we found similar IP 3 R suppression in response to the commercially available derivative sodium houttuyfonate. An in silico analysis showed that houttuynin, which downregulates IP 3 R expression, binds to the IP 3 binding domain of IP 3 R and may mediate a direct inhibitory effect. In summary, our findings suggest that H. cordata is a potential alternative treatment choice that may reduce asthma severity by targeting the dysregulation of Ca 2+ signaling., Competing Interests: Declaration of Competing Interest We confirm that all authors have read and approved the manuscript and have no potential conflicts of interest. We certify that this paper consists of original, unpublished work, which is not under consideration for publication elsewhere. We confirm that we have each made a substantial contribution to qualify for authorship and that we have approved the contents of the manuscript. We have disclosed all financial support for our work., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide pandemic with over 627 million cases and over 6.5 million deaths. It was reported that smoking-related chronic obstructive pulmonary disease (COPD) might be a crucial risk for COVID-19 patients to develop severe condition. As cigarette smoke (CS) is the major risk factor for COPD, we hypothesize that barrier dysfunction and an altered cytokine response in CS-exposed airway epithelial cells may contribute to increased SARS-CoV-2-induced immune response that may result in increased susceptibility to severe disease. The aim of this study was to evaluate the role of CS on SARS-CoV-2-induced immune and inflammatory responses, and epithelial barrier integrity leading to airway epithelial damage., Methods: Primary human airway epithelial cells were differentiated under air-liquid interface culture. Cells were then exposed to cigarette smoke medium (CSM) before infection with SARS-CoV-2 isolated from a local patient. The infection susceptibility, morphology, and the expression of genes related to host immune response, airway inflammation and damages were evaluated., Results: Cells pre-treated with CSM significantly caused higher replication of SARS-CoV-2 and more severe SARS-CoV-2-induced cellular morphological alteration. CSM exposure caused significant upregulation of long form angiotensin converting enzyme (ACE)2, a functional receptor for SARS-CoV-2 viral entry, transmembrane serine protease (TMPRSS)2 and TMPRSS4, which cleave the spike protein of SARS-CoV-2 to allow viral entry, leading to an aggravated immune response via inhibition of type I interferon pathway. In addition, CSM worsened SARS-CoV-2-induced airway epithelial cell damage, resulting in severe motile ciliary disorder, junctional disruption and mucus hypersecretion., Conclusion: Smoking led to dysregulation of host immune response and cell damage as seen in SARS-CoV-2-infected primary human airway epithelia. These findings may contribute to increased disease susceptibility with severe condition and provide a better understanding of the pathogenesis of SARS-CoV-2 infection in smokers., (© 2023. The Author(s).)

Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration in nigrostriatal and cortical brain regions associated with pathogenic α-synuclein (αSyn) aggregate/oligomer accumulation. LRRK2 hyperactivity is a disease-modifying therapeutic target in PD. However, LRRK2 inhibition may be associated with peripheral effects, albeit with unclear clinical consequences. Here, we significantly reduced αSyn oligomer accumulation in mouse striatum through long-term LRRK2 inhibition using GNE-7915 (specific brain-penetrant LRRK2 inhibitor) without causing adverse peripheral effects. GNE-7915 concentrations in wild-type (WT) mouse sera and brain samples reached a peak at 1 h, which gradually decreased over 24 h following a single subcutaneous (100 mg/kg) injection. The same dose in young WT and LRRK2 R1441G mutant mice significantly inhibited LRRK2 kinase activity (Thr73-Rab10 and Ser106-Rab12 phosphorylation) in the lung, which dissipated by 72 h post-injection. 14-month-old mutant mice injected with GNE-7915 twice weekly for 18 weeks (equivalent to ~13 human years) exhibited reduced striatal αSyn oligomer and cortical pSer129-αSyn levels, correlating with inhibition of LRRK2 hyperactivity in brain and lung to WT levels. No GNE-7915-treated mice showed increased mortality or morbidity. Unlike reports of abnormalities in lung and kidney at acute high doses of LRRK2 inhibitors, our GNE-7915-treated mice did not exhibit swollen lamellar bodies in type II pneumocytes or abnormal vacuolation in the kidney. Functional and histopathological assessments of lung, kidney and liver, including whole-body plethysmography, urinary albumin-creatinine ratio (ACR), serum alanine aminotransferase (ALT) and serum interleukin-6 (inflammatory marker) did not reveal abnormalities after long-term GNE-7915 treatment. Long-term inhibition of mutant LRRK2 hyper-kinase activity to physiological levels presents an efficacious and safe disease-modifying therapy to ameliorate synucleinopathy in PD., (© 2022. The Author(s).)

Background: Improving mobility outcomes after hip fracture is key to recovery. Possible strategies include gait training, exercise and muscle stimulation. This is an update of a Cochrane Review last published in 2011., Objectives: To evaluate the effects (benefits and harms) of interventions aimed at improving mobility and physical functioning after hip fracture surgery in adults., Search Methods: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, trial registers and reference lists, to March 2021., Selection Criteria: All randomised or quasi-randomised trials assessing mobility strategies after hip fracture surgery. Eligible strategies aimed to improve mobility and included care programmes, exercise (gait, balance and functional training, resistance/strength training, endurance, flexibility, three-dimensional (3D) exercise and general physical activity) or muscle stimulation. Intervention was compared with usual care (in-hospital) or with usual care, no intervention, sham exercise or social visit (post-hospital)., Data Collection and Analysis: Members of the review author team independently selected trials for inclusion, assessed risk of bias and extracted data. We used standard methodological procedures expected by Cochrane. We used the assessment time point closest to four months for in-hospital studies, and the time point closest to the end of the intervention for post-hospital studies. Critical outcomes were mobility, walking speed, functioning, health-related quality of life, mortality, adverse effects and return to living at pre-fracture residence., Main Results: We included 40 randomised controlled trials (RCTs) with 4059 participants from 17 countries. On average, participants were 80 years old and 80% were women. The median number of study participants was 81 and all trials had unclear or high risk of bias for one or more domains. Most trials excluded people with cognitive impairment (70%), immobility and/or medical conditions affecting mobility (72%). In-hospital setting, mobility strategy versus control Eighteen trials (1433 participants) compared mobility strategies with control (usual care) in hospitals. Overall, such strategies may lead to a moderate, clinically-meaningful increase in mobility (standardised mean difference (SMD) 0.53, 95% confidence interval (CI) 0.10 to 0.96; 7 studies, 507 participants; low-certainty evidence) and a small, clinically meaningful improvement in walking speed (CI crosses zero so does not rule out a lack of effect (SMD 0.16, 95% CI -0.05 to 0.37; 6 studies, 360 participants; moderate-certainty evidence). Mobility strategies may make little or no difference to short-term (risk ratio (RR) 1.06, 95% CI 0.48 to 2.30; 6 studies, 489 participants; low-certainty evidence) or long-term mortality (RR 1.22, 95% CI 0.48 to 3.12; 2 studies, 133 participants; low-certainty evidence), adverse events measured by hospital re-admission (RR 0.70, 95% CI 0.44 to 1.11; 4 studies, 322 participants; low-certainty evidence), or return to pre-fracture residence (RR 1.07, 95% CI 0.73 to 1.56; 2 studies, 240 participants; low-certainty evidence). We are uncertain whether mobility strategies improve functioning or health-related quality of life as the certainty of evidence was very low. Gait, balance and functional training probably causes a moderate improvement in mobility (SMD 0.57, 95% CI 0.07 to 1.06; 6 studies, 463 participants; moderate-certainty evidence). There was little or no difference in effects on mobility for resistance training. No studies of other types of exercise or electrical stimulation reported mobility outcomes. Post-hospital setting, mobility strategy versus control Twenty-two trials (2626 participants) compared mobility strategies with control (usual care, no intervention, sham exercise or social visit) in the post-hospital setting. Mobility strategies lead to a small, clinically meaningful increase in mobility (SMD 0.32, 95% CI 0.11 to 0.54; 7 studies, 761 participants; high-certainty evidence) and a small, clinically meaningful improvement in walking speed compared to control (SMD 0.16, 95% CI 0.04 to 0.29; 14 studies, 1067 participants; high-certainty evidence). Mobility strategies lead to a small, non-clinically meaningful increase in functioning (SMD 0.23, 95% CI 0.10 to 0.36; 9 studies, 936 participants; high-certainty evidence), and probably lead to a slight increase in quality of life that may not be clinically meaningful (SMD 0.14, 95% CI -0.00 to 0.29; 10 studies, 785 participants; moderate-certainty evidence). Mobility strategies probably make little or no difference to short-term mortality (RR 1.01, 95% CI 0.49 to 2.06; 8 studies, 737 participants; moderate-certainty evidence). Mobility strategies may make little or no difference to long-term mortality (RR 0.73, 95% CI 0.39 to 1.37; 4 studies, 588 participants; low-certainty evidence) or adverse events measured by hospital re-admission (95% CI includes a large reduction and large increase, RR 0.86, 95% CI 0.52 to 1.42; 2 studies, 206 participants; low-certainty evidence). Training involving gait, balance and functional exercise leads to a small, clinically meaningful increase in mobility (SMD 0.20, 95% CI 0.05 to 0.36; 5 studies, 621 participants; high-certainty evidence), while training classified as being primarily resistance or strength exercise may lead to a clinically meaningful increase in mobility measured using distance walked in six minutes (mean difference (MD) 55.65, 95% CI 28.58 to 82.72; 3 studies, 198 participants; low-certainty evidence). Training involving multiple intervention components probably leads to a substantial, clinically meaningful increase in mobility (SMD 0.94, 95% CI 0.53 to 1.34; 2 studies, 104 participants; moderate-certainty evidence). We are uncertain of the effect of aerobic training on mobility (very low-certainty evidence). No studies of other types of exercise or electrical stimulation reported mobility outcomes., Authors' Conclusions: Interventions targeting improvement in mobility after hip fracture may cause clinically meaningful improvement in mobility and walking speed in hospital and post-hospital settings, compared with conventional care. Interventions that include training of gait, balance and functional tasks are particularly effective. There was little or no between-group difference in the number of adverse events reported. Future trials should include long-term follow-up and economic outcomes, determine the relative impact of different types of exercise and establish effectiveness in emerging economies., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Hip fracture is a major cause of morbidity and mortality in older people, and its impact on society is substantial. After surgery, people require rehabilitation to help them recover. Multidisciplinary rehabilitation is where rehabilitation is delivered by a multidisciplinary team, supervised by a geriatrician, rehabilitation physician or other appropriate physician. This is an update of a Cochrane Review first published in 2009., Objectives: To assess the effects of multidisciplinary rehabilitation, in either inpatient or ambulatory care settings, for older people with hip fracture., Search Methods: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, CENTRAL, MEDLINE and Embase (October 2020), and two trials registers (November 2019)., Selection Criteria: We included randomised and quasi-randomised trials of post-surgical care using multidisciplinary rehabilitation of older people (aged 65 years or over) with hip fracture. The primary outcome - 'poor outcome' - was a composite of mortality and decline in residential status at long-term (generally one year) follow-up. The other 'critical' outcomes were health-related quality of life, mortality, dependency in activities of daily living, mobility, and related pain., Data Collection and Analysis: Pairs of review authors independently performed study selection, assessed risk of bias and extracted data. We pooled data where appropriate and used GRADE for assessing the certainty of evidence for each outcome., Main Results: The 28 included trials involved 5351 older (mean ages ranged from 76.5 to 87 years), usually female, participants who had undergone hip fracture surgery. There was substantial clinical heterogeneity in the trial interventions and populations. Most trials had unclear or high risk of bias for one or more items, such as blinding-related performance and detection biases. We summarise the findings for three comparisons below. Inpatient rehabilitation: multidisciplinary rehabilitation versus 'usual care' Multidisciplinary rehabilitation was provided primarily in an inpatient setting in 20 trials. Multidisciplinary rehabilitation probably results in fewer cases of 'poor outcome' (death or deterioration in residential status, generally requiring institutional care) at 6 to 12 months' follow-up (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.80 to 0.98; 13 studies, 3036 participants; moderate-certainty evidence). Based on an illustrative risk of 347 people with hip fracture with poor outcome in 1000 people followed up between 6 and 12 months, this equates to 41 (95% CI 7 to 69) fewer people with poor outcome after multidisciplinary rehabilitation. Expressed in terms of numbers needed to treat for an additional harmful outcome (NNTH), 25 patients (95% CI 15 to 100) would need to be treated to avoid one 'poor outcome'. Subgroup analysis by type of multidisciplinary rehabilitation intervention showed no evidence of subgroup differences. Multidisciplinary rehabilitation may result in fewer deaths in hospital but the confidence interval does not exclude a small increase in the number of deaths (RR 0.77, 95% CI 0.58 to 1.04; 11 studies, 2455 participants; low-certainty evidence). A similar finding applies at 4 to 12 months' follow-up (RR 0.91, 95% CI 0.80 to 1.05; 18 studies, 3973 participants; low-certainty evidence). Multidisciplinary rehabilitation may result in fewer people with poorer mobility at 6 to 12 months' follow-up (RR 0.83, 95% CI 0.71 to 0.98; 5 studies, 1085 participants; low-certainty evidence). Due to very low-certainty evidence, we have little confidence in the findings for marginally better quality of life after multidisciplinary rehabilitation (1 study). The same applies to the mixed findings of some or no difference from multidisciplinary rehabilitation on dependence in activities of daily living at 1 to 4 months' follow-up (measured in various ways by 11 studies), or at 6 to 12 months' follow-up (13 studies). Long-term hip-related pain was not reported. Ambulatory setting: supported discharge and multidisciplinary home rehabilitation versus 'usual care' Three trials tested this comparison in 377 people mainly living at home. Due to very low-certainty evidence, we have very little confidence in the findings of little to no between-group difference in poor outcome (death or move to a higher level of care or inability to walk) at one year (3 studies); quality of life at one year (1 study); in mortality at 4 or 12 months (2 studies); in independence in personal activities of daily living (1 study); in moving permanently to a higher level of care (2 studies) or being unable to walk (2 studies). Long-term hip-related pain was not reported. One trial tested this comparison in 240 nursing home residents. There is low-certainty evidence that there may be no or minimal between-group differences at 12 months in 'poor outcome' defined as dead or unable to walk; or in mortality at 4 months or 12 months. Due to very low-certainty evidence, we have very little confidence in the findings of no between-group differences in dependency at 4 weeks or at 12 months, or in quality of life, inability to walk or pain at 12 months., Authors' Conclusions: In a hospital inpatient setting, there is moderate-certainty evidence that rehabilitation after hip fracture surgery, when delivered by a multidisciplinary team and supervised by an appropriate medical specialist, results in fewer cases of 'poor outcome' (death or deterioration in residential status). There is low-certainty evidence that multidisciplinary rehabilitation may result in fewer deaths in hospital and at 4 to 12 months; however, it may also result in slightly more. There is low-certainty evidence that multidisciplinary rehabilitation may reduce the numbers of people with poorer mobility at 12 months. No conclusions can be drawn on other outcomes, for which the evidence is of very low certainty. The generally very low-certainty evidence available for supported discharge and multidisciplinary home rehabilitation means that we are very uncertain whether the findings of little or no difference for all outcomes between the intervention and usual care is true. Given the prevalent clinical emphasis on early discharge, we suggest that research is best orientated towards early supported discharge and identifying the components of multidisciplinary inpatient rehabilitation to optimise patient recovery within hospital and the components of multidisciplinary rehabilitation, including social care, subsequent to hospital discharge., (Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Introduction: Immediate breast reconstruction offers cosmetic and psychological advantages post-mastectomy. There are various options of reconstruction, and this study aims to evaluate the associated complications., Patients and Methods: This is a single-center retrospective study analyzing data from January 1, 2008 to December 31, 2017 for immediate breast reconstruction procedures post-mastectomy performed at an academic breast unit. Procedures included expander and implant insertion, latissimus dorsi, pedicle transverse rectus abdominis musculocutaneous (TRAM), free TRAM, and deep inferior epigastric perforator. Complications and reoperative complications (defined as those requiring a reoperation within the first 30-day period), and associated risk factors were investigated using separate logistic regressions, and odds ratios (ORs) were calculated., Results: A total of 243 post-mastectomy immediate breast reconstruction procedures and complications rates were analyzed. The overall complication rate was 27.6%, comprised mainly of reconstruction-specific complications such as post-TRAM hernia or bulges, fat necrosis, and implant capsular contracture and leakage. The rate of reoperative complications was relatively low at 6.6%. The flap failure rate was similar between expander/implant reconstruction and autologous reconstruction methods at 3.3% and 5.6%, respectively (P = .60). Logistic regression identified significantly higher risks associated with diabetes mellitus (OR, 5.21; P = .022), obesity (OR, 5.80; P = .016), and free pedicle autologous reconstruction (OR, 3.975; P = .046) for reoperative complications., Conclusion: Different methods of immediate breast reconstruction post-mastectomy are feasible and safe. However, patient variables and procedure choice should be taken into consideration when counseling patients on reconstructive options, as they are strong predictors for postoperative complications., (Copyright © 2019. Published by Elsevier Inc.)

Flavonoids are polyphenolic compounds that are widely present in food and Chinese medicine. The aim of the present study was to identify the flavonoids with anti-inflammatory effects in the airway; and to determine the role of anti-oxidant and cyclic adenosine monophosphate (cAMP) in the anti-inflammatory effect. Human bronchial epithelial BEAS-2B cells were exposed to bacterial endotoxin lipopolysaccharide (LPS) in the absence or presence of different flavonoids, which are categorized according to their chemical structures in seven subclasses [anthocyanidins, chalcones, flavanes, flavanones, flavones, flavonols, isoflavones]. Among the 17 flavonoids tested, only apigenin (flavones), luteolin (flavones), daidzein (isoflavones) and genistein (isoflavones) reduced LPS-induced release of inflammatory cytokines/chemokines interleukin (IL)-6, IL-8 and monocyte chemoattractant protein-1 in BEAS-2B cells. Quercetin caused further increase in LPS-induced IL-6 and IL-8 levels. It alone significantly increased nuclear factor-kappa B (NF-κB) p65 activity and the cellular oxidative stress marker malondialdehyde (MDA) level in BEAS-2B cells. By contrast, apigenin and genistein reduced LPS-induced increases in nuclear NF-κB activity and MDA level. Apigenin and genistein, but not quercetin, increased the cAMP level in BEAS-2B cells, and the cell-permeable cAMP analogue, 8-Br-cAMP, inhibited LPS-induced increase of IL-8 level. These findings suggest that the presence of C5-OH, C7-OH, C2=C3 and C4=O functional groups in the flavonoids is associated with greater anti-inflammatory effect, while that of C3-OH or glycosylation group at the A-ring greatly decreased the anti-inflammatory effect. The anti-inflammatory effect of these flavonoids may be related to their anti-oxidant properties, and partly to their ability in increasing cAMP level., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Obstructive sleep apnoea (OSA) characterized by intermittent hypoxia (IH) is closely associated with cardiovascular diseases. IH confers cardiac injury via accelerating cardiomyocyte apoptosis, whereas the underlying mechanism has remained largely enigmatic. This study aimed to explore the potential mechanisms involved in the IH-induced cardiac damage performed with the IH-exposed cell and animal models and to investigate the protective effects of haemin, a potent haeme oxygenase-1 (HO-1) activator, on the cardiac injury induced by IH. Neonatal rat cardiomyocyte (NRC) was treated with or without haemin before IH exposure. Eighteen male Sprague-Dawley (SD) rats were randomized into three groups: control group, IH group (PBS, ip) and IH + haemin group (haemin, 4 mg/kg, ip). The cardiac function was determined by echocardiography. Mitochondrial fission was evaluated by Mitotracker staining. The mitochondrial dynamics-related proteins (mitochondrial fusion protein, Mfn2; mitochondrial fission protein, Drp1) were determined by Western blot. The apoptosis of cardiomyocytes and heart sections was examined by TUNEL. IH regulated mitochondrial dynamics-related proteins (decreased Mfn2 and increased Drp1 expressions, respectively), thereby leading to mitochondrial fragmentation and cell apoptosis in cardiomyocytes in vitro and in vivo, while haemin-induced HO-1 up-regulation attenuated IH-induced mitochondrial fragmentation and cell apoptosis. Moreover, IH resulted in left ventricular hypertrophy and impaired contractile function in vivo, while haemin ameliorated IH-induced cardiac dysfunction. This study demonstrates that pharmacological activation of HO-1 pathway protects against IH-induced cardiac dysfunction and myocardial fibrosis through the inhibition of mitochondrial fission and cell apoptosis., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Breast cancer is the most frequently diagnosed cancer and cause of cancer death in women worldwide. Current treatments often result in systematic toxicity and drug resistance. Combinational use of non-toxic phytochemicals with chemotherapeutic agents to enhance the efficacy and reduce toxicity would be one promising approach. In this study, bioactive proanthocyanidins from Uncaria rhynchophylla (UPAs) were isolated and their anti-breast cancer effects alone and in combination with 5- fluorouracil (5-FU) were investigated in MDA-MB-231 breast cancer cells. The results showed that UPAs significantly inhibited cell viability and migration ability in a dose-dependent manner. Moreover, UPAs induced apoptosis in a dose-dependent manner which was associated with increased cellular reactive oxygen species production, loss of mitochondrial membrane potential, increases of Bax/Bcl-2 ratio and levels of cleaved caspase 3. Treatments of the cells with UPAs resulted in an increase in G2/M cell cycle arrest. Cytotoxic effects of 5-FU against MDA-MB-231 cells were enhanced by UPAs. The combination treatment of UPAs and 5-FU for 48 h elicited a synergistic cytotoxic effect on MDA-MB-231 cells. Altogether, these data suggest that UPAs are potential therapeutic agents for breast cancer., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We present a silicon electro-optic transmitter consisting of a 28nm ultra-thin body and buried oxide fully depleted silicon-on-insulator (UTBB FD-SOI) CMOS driver flip-chip integrated onto a Mach-Zehnder modulator. The Mach-Zehnder silicon optical modulator was optimized to have a 3dB bandwidth of around 25 GHz at -1V bias and a 50 Ω impedance. The UTBB FD-SOI CMOS driver provided a large output voltage swing around 5 V pp to enable a high dynamic extinction ratio and a low device insertion loss. At 44 Gbps, the transmitter achieved a high extinction ratio of 6.4 dB at the modulator quadrature operation point. This result shows open eye diagrams at the highest bit rates and with the largest extinction ratios for silicon electro-optic transmitter using a CMOS driver.

Chronic obstructive pulmonary disease (COPD) is caused by the build-up of oxidative stress-induced damages due to cigarette smoking, but how monoamine oxidase (MAO)-B signaling is involved remains unclear. This study aims to establish the involvement of MAO-B signaling pathways in cigarette smoke medium (CSM)-induced oxidative stress and inflammation in human airway epithelial cells (AECs). CSM treatment increased MAO-B activity, ROS levels and IL-8 release in AECs. Pretreatment with MAO-B selective inhibitor selegiline reversed the CSM-induced changes in MAO-B activity, ROS levels and IL-8 release in a dose-dependent manner. Selegiline also reversed CSM-induced changes of anti-oxidant enzymes superoxide dismutase (SOD) and catalase (CAT) activities, GSH/GSSG ratio, as well expression of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1). The effects of selegiline are partially driven through the nuclear factor erythroid 2 related factor 2 (Nrf2) and cytosol translocation of its negative regulator, BTB and CNC homolog 1 (Bach1). Nevertheless, selegiline fully reversed the CSM-induced effects on IKK, cytoplasmic IκB expression, and nuclear translocation of nuclear factor-κB (NF-κB) p65 subunit. Our study demonstrated that in AECs, inhibition of MAO-B using selegiline reversed the CSM-induced oxidative stress and inflammation. These data may provide a novel strategy for therapy in COPD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Mesenchymal stem cells (MSCs) have emerged as a potential cell-based therapy for pulmonary emphysema in animal models. Our previous study demonstrated that human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) were superior over bone marrow-derived MSCs (BM-MSCs) in attenuating cigarette smoke (CS)-induced airspace enlargement possibly through mitochondrial transfer. This study further investigated the effects of iPSC-MSCs on inflammation, apoptosis, and proliferation in a CS-exposed rat model and examined the effects of the secreted paracrine factor from MSCs as another possible mechanism in an in vitro model of bronchial epithelial cells. Rats were exposed to 4% CS for 1 hr daily for 56 days. At days 29 and 43, human iPSC-MSCs or BM-MSCs were administered intravenously. We observed significant attenuation of CS-induced elevation of circulating 8-isoprostane and cytokine-induced neutrophil chemoattractant-1 after iPSC-MSC treatment. In line, a superior capacity of iPSC-MSCs was also observed in ameliorating CS-induced infiltration of macrophages and neutrophils and apoptosis/proliferation imbalance in lung sections over BM-MSCs. In support, the conditioned medium (CdM) from iPSC-MSCs ameliorated CS medium-induced apoptosis/proliferation imbalance of bronchial epithelial cells in vitro. Conditioned medium from iPSC-MSCs contained higher level of stem cell factor (SCF) than that from BM-MSCs. Deprivation of SCF from iPSC-MSC-derived CdM led to a reduction in anti-apoptotic and pro-proliferative capacity. Taken together, our data suggest that iPSC-MSCs may possess anti-apoptotic/pro-proliferative capacity in the in vivo and in vitro models of CS-induced airway cell injury partly through paracrine secretion of SCF., (© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Background: Older people with hip fractures are often malnourished at the time of fracture, and subsequently have poor food intake. This is an update of a Cochrane review first published in 2000, and previously updated in 2010., Objectives: To review the effects (benefits and harms) of nutritional interventions in older people recovering from hip fracture., Search Methods: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, CENTRAL, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, Embase, CAB Abstracts, CINAHL, trial registers and reference lists. The search was last run in November 2015., Selection Criteria: Randomised and quasi-randomised controlled trials of nutritional interventions for people aged over 65 years with hip fracture where the interventions were started within the first month after hip fracture., Data Collection and Analysis: Two review authors independently selected trials, extracted data and assessed risk of bias. Where possible, we pooled data for primary outcomes which were: all cause mortality; morbidity; postoperative complications (e.g. wound infections, pressure sores, deep venous thromboses, respiratory and urinary infections, cardiovascular events); and 'unfavourable outcome' defined as the number of trial participants who died plus the number of survivors with complications. We also pooled data for adverse events such as diarrhoea., Main Results: We included 41 trials involving 3881 participants. Outcome data were limited and risk of bias assessment showed that trials were often methodologically flawed, with less than half of trials at low risk of bias for allocation concealment, incomplete outcome data, or selective reporting of outcomes. The available evidence was judged of either low or very low quality indicating that we were uncertain or very uncertain about the estimates.Eighteen trials evaluated oral multinutrient feeds that provided non-protein energy, protein, vitamins and minerals. There was low-quality evidence that oral feeds had little effect on mortality (24/486 versus 31/481; risk ratio (RR) 0.81 favouring supplementation, 95% confidence interval (CI) 0.49 to 1.32; 15 trials). Thirteen trials evaluated the effect of oral multinutrient feeds on complications (e.g. pressure sore, infection, venous thrombosis, pulmonary embolism, confusion). There was low-quality evidence that the number of participants with complications may be reduced with oral multinutrient feeds (123/370 versus 157/367; RR 0.71, 95% CI 0.59 to 0.86; 11 trials). Based on very low-quality evidence from six studies (334 participants), oral supplements may result in lower numbers with 'unfavourable outcome' (death or complications): RR 0.67, 95% CI 0.51 to 0.89. There was very low-quality evidence for six studies (442 participants) that oral supplementation did not result in an increased incidence of vomiting and diarrhoea (RR 0.99, 95% CI 0.47 to 2.05).Only very low-quality evidence was available from the four trials examining nasogastric multinutrient feeding. Pooled data from three heterogeneous trials showed no evidence of an effect of supplementation on mortality (14/142 versus 14/138; RR 0.99, 95% CI 0.50 to 1.97). One trial (18 participants) found no difference in complications. None reported on unfavourable outcome. Nasogastric feeding was poorly tolerated. One study reported no cases of aspiration pneumonia.There is very low-quality evidence from one trial (57 participants, mainly men) of no evidence for an effect of tube feeding followed by oral supplementation on mortality or complications. Tube feeding, however, was poorly tolerated.There is very low-quality evidence from one trial (80 participants) that a combination of intravenous feeding and oral supplements may not affect mortality but could reduce complications. However, this expensive intervention is usually reserved for people with non-functioning gastrointestinal tracts, which is unlikely in this trial.Four trials tested increasing protein intake in an oral feed. These provided low-quality evidence for no clear effect of increased protein intake on mortality (30/181 versus 21/180; RR 1.42, 95% CI 0.85 to 2.37; 4 trials) or number of participants with complications but very low-quality and contradictory evidence of a reduction in unfavourable outcomes (66/113 versus 82/110; RR 0.78, 95% CI 0.65 to 0.95; 2 trials). There was no evidence of an effect on adverse events such as diarrhoea.Trials testing intravenous vitamin B1 and other water soluble vitamins, oral 1-alpha-hydroxycholecalciferol (vitamin D), high dose bolus vitamin D, different oral doses or sources of vitamin D, intravenous or oral iron, ornithine alpha-ketoglutarate versus an isonitrogenous peptide supplement, taurine versus placebo, and a supplement with vitamins, minerals and amino acids, provided low- or very low-quality evidence of no clear effect on mortality or complications, where reported.Based on low-quality evidence, one trial evaluating the use of dietetic assistants to help with feeding indicated that this intervention may reduce mortality (19/145 versus 36/157; RR 0.57, 95% CI 0.34 to 0.95) but not the number of participants with complications (79/130 versus 84/125)., Authors' Conclusions: There is low-quality evidence that oral multinutrient supplements started before or soon after surgery may prevent complications within the first 12 months after hip fracture, but that they have no clear effect on mortality. There is very low-quality evidence that oral supplements may reduce 'unfavourable outcome' (death or complications) and that they do not result in an increased incidence of vomiting and diarrhoea. Adequately sized randomised trials with robust methodology are required. In particular, the role of dietetic assistants, and peripheral venous feeding or nasogastric feeding in very malnourished people require further evaluation.

Background: Chewing gum may enhance intestinal motility after surgery. This trial studied whether chewing gum could lead to a further reduction in ileus in patients who had a laparoscopic colorectal resection and followed an enhanced recovery programme., Methods: Patients undergoing laparoscopic colorectal resection were randomized to a control or intervention group. Patients in the control group received a standardized recovery programme. Patients in the intervention group were, in addition, given chewing gum three times daily from day 1 until discharge. Primary outcome measures were time to first flatus and first bowel motion. Time to feeling hungry and hospital stay were secondary outcome measures., Results: Forty-one patients were randomized into each group. Thirty-seven patients underwent rectal resection and 45 had a colonic resection. Time to passage of flatus was shorter (18 versus 34 h; P = 0·007), first bowel motion occurred earlier (19 versus 44 h; P = 0·001) and time to feeling hungry was earlier (16 versus 25 h; P = 0·001) in the intervention group. There was no difference in the duration of hospital stay (5 days in the intervention group versus 5·5 days in the control group). Subgroup analyses revealed that the benefits of chewing gum were clearer in patients who had a colonic resection, with a shorter time to first flatus (20 versus 35 h; P = 0·043), first bowel motion (19 versus 53 h; P = 0·014) and feeling hungry (14 versus 40 h; P = 0·001). No adverse events were attributed to chewing gum., Conclusion: Chewing gum is a simple intervention that speeds intestinal transit in patients managed with a recovery programme after laparoscopic colorectal resection., Registration Number: NCT02419586 (https://clinicaltrials.gov/)., (© 2016 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Compact power splitters designed ab initio using binary particle swarm optimization in a 2D mesh for a standard foundry silicon photonic platform are studied. Designs with a 4.8  μm×4.8  μm footprint composed of 200  nm×200  nm and 100  nm×100  nm cells are demonstrated. Despite not respecting design rules, the design with the smaller cells had lower insertion losses and broader bandwidth and showed consistent behavior across the wafer. Deviations between design and experiments point to the need for further investigations of the minimum feature dimensions.

Background: Improving vitamin D (25-OHD) status may be an important modifiable factor that could reduce disability severity, fall-rates and mortality associated after hip fracture surgery. Providing a loading-dose post-surgery may overcome limitations in adherence to daily supplementation., Method: In this randomized, double-blind, placebo-controlled trial, 218 adults, aged 65-years or older, requiring hip fracture surgery were assigned to receive a single loading-dose of cholecalciferol (250,000 IU vitamin-D3, the REVITAHIP - Replenishment of Vitamin D in Hip Fracture strategy) or placebo, both receiving daily vitamin-D(800 IU) and calcium (500 mg) for 26-weeks. Outcome measures were 2.4 m gait-velocity, falls, fractures, death (Week-4), 25-OHD levels, quality-of-life measure (EuroQoL) and mortality at weeks-2, 4 and 26., Results: Mean age of 218 participants was 83.9(7.2) years and 77.1 % were women. Baseline mean 25-OHD was 52.7(23.5)nmol/L, with higher levels at Week-2 (73 vs 66 nmol/L; p = .019) and Week-4 (83 vs 75 nmol/L; p = .030) in the Active-group, but not at Week-26. At week-4, there were no differences in 2.4 m gait-velocity (0.42 m/s vs 0.39 m/s, p = .490), fractures (2.7 % vs 2.8 %, p = .964) but Active participants reported less falls (6.3 % vs 21.1 %, χ(2) = 4.327; p = 0.024), with no significant reduction in deaths at week-4 (1 vs 3, p = 0.295), higher percentage reporting 'no pain or discomfort' (96.4 % vs 88.8 %, p = 0.037), and trended for higher EuroQoL-scores (p = 0.092) at week-26. One case of hypercalcemia at week-2 normalised by week-4., Conclusion: Among older people after hip fracture surgery, the REVITAHIP strategy is a safe and low cost method of improving vitamin-D levels, reducing falls and pain levels., Trial Registration: The protocol for this study is registered with the Australian New Zealand Clinical Trials Registry ANZCTRN ACTRN12610000392066 (Date of registration: 14/05/2010).

Aberrant release of adipocytokines from adipose tissues dysregulates cardiometabolic functions. The present study hypothesizes that chronic intermittent hypoxia (IH) present in obstructive sleep apnea leads to adipose tissue dysfunction, which in turn contributes to vascular pathogenesis. The effect of IH was evaluated in adipose depots and aortic tissues in lean rats in vivo. Furthermore, the cellular and molecular mechanisms underlying pathophysiological interactions between adipocytes and endothelial cells were investigated in vitro. The in vivo results showed that IH induced upregulation of IL-6 and monocyte chemoattractant protein-1 (MCP-1) in subcutaneous and periaortic adipose tissues and downregulated phosphorylation of endothelial nitric oxide synthase [eNOS (ser1177)] in the aorta with activation of Erk and p38 MAPK. In support, cultured adipocytes demonstrated IH-induced elevations of NADPH oxidase 4, phosphorylation of Erk, NF-κBp65, and inducible NOS (iNOS) and increased expression of IL-6 and MCP-1. Likewise, endothelial EA.hy926 (EA) cells exposed to IH showed eNOS (ser1177) and intracellular cGMP reduction, whereas MCP-1 and iNOS expression were upregulated. Treatment of EA cells with conditioned media derived from IH-exposed cultured adipocytes caused nuclear translocation of NF-κBp65 and elevation of MCP-1, which were prevented by addition of neutralizing IL-6 antibodies to the conditioned media. Recombinant IL-6 in addition to IH induced further MCP-1 release and iNOS protein expression in EA cells, which were prevented by pharmacological inhibition of Erk, p38, and NF-κB. These findings suggest that IH could induce adipose tissue inflammation, which may cross talk with endothelial cells via adipocyte-derived mediators such as IL-6, and promote NF-κB-dependent endothelial dysfunction., (Copyright © 2016 the American Physiological Society.)

Background: Endothelial dysfunction has been recognized to occur in the context of obstructive sleep apnea (OSA) or tobacco smoking. However, the deleterious effect on vascular function with concurrence of both conditions is largely unknown., Objective: To investigate whether the concurrence of OSA and smoking poses an additive detriment to endothelial dysfunction., Methods: Chinese men without a history of chronic medical illness were invited to complete a questionnaire including smoking pack-year exposure, polysomnography and peripheral arterial tonometry (PAT) for endothelial function. Serum 8-isoprostane, advanced oxidation protein products (AOPP) and monocyte chemo-attractant protein-1 (MCP-1) were measured., Results: 114 men were successfully enrolled. PAT ratio, adjusted for age and body mass index, correlated inversely with overall severity of OSA: apnea-hypopnea index (AHI), r = -0.160 (p = 0.092); oxygen desaturation index, r = -0.214 (p = 0.024); duration of oxygen saturation <90%, r = -0.219 (p = 0.020); and minimum oxygen saturation, r = 0.250 (p = 0.008). The PAT ratio decreased with increasing pack-year group (p = 0.018). It was lower with concurrent smoking history and moderate-severe OSA (AHI ≥15/h) compared to having one or neither factor (p = 0.011). Serum levels of 8-isoprostane and AOPP were positively related to severity of OSA, while MCP-1 correlated with smoking quantity. Multiple linear regression analyses showed that severity of intermittent hypoxia, MCP-1 and pack-year exposure were independent predictors of PAT ratio., Conclusion: While OSA, in particular intermittent hypoxemia, and tobacco smoking were independent risk factors, the concurrence of moderate-severe OSA and smoking was associated with the most severe impairment in endothelial function., (© 2016 S. Karger AG, Basel.)

We previously reported the involvement of serotonin (5-HT) metabolism in cigarette smoke-induced oxidative stress in rat lung in vivo. Here, we report cigarette smoke as a source of serotonin (5-HT) to the airways and aim at investigating the effects of 5-HT on oxidative stress and inflammation in human bronchial epithelial cells (BEAS-2B). A 5-HT analog was identified to be present in aqueous phase cigarette smoke using the LC-MS/MS approach, which was later confirmed by a 5-HT enzyme-linked immune assay (EIA). Furthermore, exposure to 5-HT caused a time-dependent elevation of intracellular ROS level, which was blocked in the presence of apocynin (a NOX inhibitor). In support, the immunoblot analysis indicated that there was an increase in the expression of NOX2 time-dependently. 5-HT-induced elevation of IL-8 at both mRNA and protein levels was observed, which was inhibited by TEMPOL (a free radical scavenger), and inhibitors for p38 MAPK (SB203580) and ERK (U0126), in line with the time-dependent phosphorylation of p38 MAPK and ERK. In conclusion, our findings suggest that 5-HT presented in bronchial epithelium of smokers may be involved in cigarette smoke-induced oxidative stress and inflammation via activation of p38 MAPK and ERK pathway after the formation of free radicals.

Cigarette smoke induces injury and neutrophilic inflammation in the airways of smokers. The stability and activity of inflammatory effectors, IL8 and neutrophil elastase (NE), can be prolonged by binding to airway heparan sulfate (HS)/syndecan-1, posing risk for developing chronic obstructive pulmonary disease(COPD). We hypothesize that antagonizing HS/syndecan-1 binding of the inflammatory effectors could reduce smoking-related neutrophil-mediated airway inflammation. Analysis of bronchoalveolar lavage fluid(BALF) of COPD patients found both total and unopposed NE levels to be significantly higher among smokers with COPD than non-COPD subjects. Similar NE burden was observed in smoke-exposed rats compared to sham air controls. We chose sulfated-maltoheptaose(SM), a heparin-mimetic, to antagonize HS/sydecan-1 binding of the inflammatory mediators in airway fluids and lung tissues of the smoke-exposed rat model. Airway treatment with SM resulted in displacement of CINC-1 and NE from complexation with bronchio-epithelial HS/syndecan-1, dissipating the chemokine gradient for neutrophil flux across to the bronchial lumen. Following SM displacement of NE from shed HS/syndecan-1 in bronchial fluids, NE became accessible to inhibition by α1-antitrypsin endogenous in test samples. The antagonistic actions of SM against syndecan-1 binding of NE and CINC-1 in smoke-exposed airways suggest new therapeutic opportunities for modulating airway inflammation in smokers with SM delivery.

Objective: To investigate the effect of chronic intermittent hypoxia (CIH) on inflammatory and pathological changes of the lung in an animal model as well as the protective effect of heme oxygenase-1 in this process., Methods: Twenty-four Male Sprague-Dawley rats were randomly divided into 4 groups: intermittent normoxia (IN) group, CIH group, IN+hemin injection (hemin) group and CIH+hemin injection (CIH+hemin) group. The CIH profiling was repetitive 4 min 10% O₂and 2 min 21% O₂for 8 hours per day for 6 weeks. Animals exposed to IN were kept in an identical chamber receiving intermittent air at the same flow rate. Hemin was intraperitoneally injected (4 mg/kg) to induced HO-1 expression, and other 2 groups only received an injection of same amount of saline. Western blot was utilized to detect the pulmonary HO-1 expression levels and ELISA was used to examine the pulmonary cytokine levels. H&E staining was used to investigate pathological changes of the lung., Results: CIH significantly induced HO-1 expression in the lung and hemin induced a synergistic increase of HO-1 expression. CIH exposure significantly increased pulmonary inflammatory cytokines levels, TNF-α [(2.20 ± 0.10) vs (1.80 ± 0.08) ng/ml], IL-6 [(0.87 ± 0.05) vs (0.52 ± 0.05) ng/ml], CINC-1 [(66 ± 6) vs (39 ± 5) pg/ml] and MCP-1 [(2.20 ± 0.09) vs (1.40 ± 0.10) ng/ml], accelerated cell apoptosis and induced pathological changes of the lung, while hemin could inhibit the elevation of cytokines [(TNF-α:(1.60 ± 0.20) ng/ml, IL-6: (0.60 ± 0.07) ng/ml, CINC-1: (45 ± 6) pg/ml, MCP-1: (1.80 ± 0.10) ng/ml, all P<0.05] and cell apoptosis, as well as reversing the structural injury of the lung under CIH condition., Conclusions: CIH leads to inflammatory stress, cell apoptosis and pathological changes within the lung, while HO-1 could inhibit inflammation and apoptosis, thereby reversing the pulmonary injury.

Background: This study aims to further elucidate the demographic and diabetes characteristics of diabetic patients in Australia who use complementary and alternative medicines (CAM)., Methods: This was a prospective, cross-sectional questionnaire-based study of 149 patients with diabetes attending a general endocrine clinic in a tertiary referral hospital in Sydney, Australia., Results: Thirty-seven patients (25%) stated they had used CAM therapies within the past 5 years. Vitamins (53%) were the most common CAM therapy used. A greater number of CAM nonusers reported calf pain whilst walking (21% vs. 9%, p=0.051), and HbA1c values were lower for CAM nonusers (7.7% vs. 8.1%, p=0.057). Amongst CAM users, a majority of patients (85%) did not consult with their specialist or general practitioner prior to starting CAM therapy., Conclusions: With the increasing burden of diabetes, health practitioners will need to be more vigilant and understanding of the potential impact of CAM use on diabetes management.

Background: Hypovitaminosis D is particularly common among older people with a proximal femoral (hip) fracture. There are currently no agreed strategies for vitamin D replenishment after hip fracture surgery. The REVITAHIP Study is a multisite, double-blinded randomized-controlled trial investigating the effects of an oral vitamin D loading dose on gait velocity after hip fracture surgery. We describe the baseline characteristics of participants, aiming to document hypovitaminosis D and its associations after hip fracture., Methods: Participants, over 65, recruited within 7 days following hip fracture surgery from 3 Australia hospitals, were randomly allocated to receive a loading dose of vitamin D3 (250,000IU) or placebo, followed by oral maintenance vitamin D3/calcium (800 IU/500 mg) and the usual hip fracture rehabilitation pathway. Demographic and clinical data were collected, including surgical procedure, pre-fracture functional status, Mini Mental State Examination (MMSE) score, serum 25-hydroxyvitamin D (25-OHD), Verbal Rating Scale (VRS) for pain, grip strength and gait velocity. The associations of baseline 25-OHD levels with demographic and clinical data were assessed using Pearson's correlation, ANOVA and regression analyses., Results: Two-hundred-and-eighteen people with hip fracture participated in the study. Mean age was 83.9+/-7.2 years, 77% were women and 82% lived in private homes. Fifty-six percent had a subcapital fracture. Mean comorbidity count was 3.13+/-2.0. Mean MMSE was 26.1+/-3.9. Forty-seven percent of participants had hypovitaminosis D (<50 nmol/L). Multivariate regression models demonstrated higher baseline vitamin D levels were significantly associated with higher premorbid Barthel index scores, lower post-operative VRS pain levels and use of vitamin D., Conclusion: This study cohort shared similar demographic characteristics and comorbidities with other cohorts of people with hip fracture, with the probable exception of less cognitive impairment. Hypovitaminosis D was not as prevalent as previously documented. Patients taking vitamin D supplements and with higher premorbid Barthel index, reflecting greater independence and activity, tended to have higher 25-OHD levels at baseline. Further, lower VRS pain ratings following surgery were associated with higher vitamin D levels. Such associations will need further investigation to determine causation. (ANZCTR number, ACTRN12610000392066)., Trial Registration: The protocol for this study is registered with the Australian New Zealand Clinical Trials Registry ANZCTRN ACTRN12610000392066.

Transplantation of mesenchymal stem cells (MSCs) holds great promise in the repair of cigarette smoke (CS)-induced lung damage in chronic obstructive pulmonary disease (COPD). Because CS leads to mitochondrial dysfunction, we aimed to investigate the potential benefit of mitochondrial transfer from human-induced pluripotent stem cell-derived MSCs (iPSC-MSCs) to CS-exposed airway epithelial cells in vitro and in vivo. Rats were exposed to 4% CS for 1 hour daily for 56 days. At Days 29 and, human iPSC-MSCs or adult bone marrow-derived MSCs (BM-MSCs) were administered intravenously to CS-exposed rats. CS-exposed rats exhibited severe alveolar destruction with a higher mean linear intercept (Lm) than sham air-exposed rats (P < 0.001) that was attenuated in the presence of iPSC-MSCs or BM-MSCs (P < 0.01). The attenuation of Lm value and the severity of fibrosis was greater in the iPSC-MSC-treated group than in the BM-MSC-treated group (P < 0.05). This might have contributed to the novel observation of mitochondrial transfer from MSCs to rat airway epithelial cells in lung sections exposed to CS. In vitro studies further revealed that transfer of mitochondria from iPSC-MSCs to bronchial epithelial cells (BEAS-2B) was more effective than from BM-MSCs, with preservation of adenosine triphosphate contents. This distinct mitochondrial transfer occurred via the formation of tunneling nanotubes. Inhibition of tunneling nanotube formation blocked mitochondrial transfer. Our findings indicate a higher mitochondrial transfer capacity of iPSC-MSCs than BM-MSCs to rescue CS-induced mitochondrial damage. iPSC-MSCs may thus hold promise for the development of cell therapy in COPD.

Thymidylate synthase (TYMS) is an important chemotherapeutic target in non-small cell lung cancer (NSCLC). Arsenic trioxide (ATO) has been shown to suppress TYMS in a colonic cancer model. We examined the effects of TYMS suppression by ATO in lung adenocarcinoma. A panel of 4 lung adenocarcinoma cell lines was used to determine the effects of ATO treatment on cell viability, TYMS expression (protein and mRNA), E2F1 protein expression and TYMS activity. TYMS knockdown and overexpression were performed. Tumor growth inhibition in vivo was studied using a nude mouse xenograft model. ATO showed antiproliferative effects with clinically achievable concentrations (around 1.1-6.9 µM) in 4 lung adenocarcinoma cell lines. Downregulation of TYMS protein and mRNA expression, reduced TYMS activity, and suppressed E2F1 expression were demonstrated in lung adenocarcinoma with ATO. Cell viability was reduced by 15-50% with TYMS knockdown. Overexpression of TYMS led to a 2.7-fold increase in IC50 value with ATO treatment in H358 cells, but not in H23 cells. Using a xenograft model with H358 cell line, relative tumor volume was reduced to 44% that of the control following 8 days of treatment with 7.5 mg/kg ATO, and associated with significant downregulation of TYMS protein expression. In conclusion, ATO has potent in vitro and in vivo activity in lung adenocarcinoma, and is partially mediated by transcriptional downregulation of TYMS.

Background: Vitamin D and related compounds have been used to prevent osteoporotic fractures in older people. This is the third update of a Cochrane review first published in 1996., Objectives: To determine the effects of vitamin D or related compounds, with or without calcium, for preventing fractures in post-menopausal women and older men., Search Methods: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (to December 2012), the Cochrane Central Register of Controlled Trials (2012, Issue 12), MEDLINE (1966 to November Week 3 2012), EMBASE (1980 to 2012 Week 50), CINAHL (1982 to December 2012), BIOSIS (1985 to 3 January 2013), Current Controlled Trials (December 2012) and reference lists of articles., Selection Criteria: Randomised or quasi-randomised trials that compared vitamin D or related compounds, alone or with calcium, against placebo, no intervention or calcium alone, and that reported fracture outcomes in older people. The primary outcome was hip fracture., Data Collection and Analysis: Two authors independently assessed trial risk of selection bias and aspects of methodological quality, and extracted data. Data were pooled, where possible, using the fixed-effect model, or the random-effects model when heterogeneity between studies appeared substantial., Main Results: We included 53 trials with a total of 91,791 participants. Thirty-one trials, with sample sizes ranging from 70 to 36,282 participants, examined vitamin D (including 25-hydroxy vitamin D) with or without calcium in the prevention of fractures in community, nursing home or hospital inpatient populations. Twelve of these 31 trials had participants with a mean or median age of 80 years or over.Another group of 22 smaller trials examined calcitriol or alfacalcidol (1-alphahydroxyvitamin D3), mostly with participants who had established osteoporosis. These trials were carried out in the setting of institutional referral clinics or hospitals.In the assessment of risk of bias for random sequence generation, 21 trials (40%) were deemed to be at low risk, 28 trials (53%) at unclear risk and four trials at high risk (8%). For allocation concealment, 22 trials were at low risk (42%), 29 trials were at unclear risk (55%) and two trials were at high risk (4%).There is high quality evidence that vitamin D alone, in the formats and doses tested, is unlikely to be effective in preventing hip fracture (11 trials, 27,693 participants; risk ratio (RR) 1.12, 95% confidence intervals (CI) 0.98 to 1.29) or any new fracture (15 trials, 28,271 participants; RR 1.03, 95% CI 0.96 to 1.11).There is high quality evidence that vitamin D plus calcium results in a small reduction in hip fracture risk (nine trials, 49,853 participants; RR 0.84, 95% confidence interval (CI) 0.74 to 0.96; P value 0.01). In low-risk populations (residents in the community: with an estimated eight hip fractures per 1000 per year), this equates to one fewer hip fracture per 1000 older adults per year (95% CI 0 to 2). In high risk populations (residents in institutions: with an estimated 54 hip fractures per 1000 per year), this equates to nine fewer hip fractures per 1000 older adults per year (95% CI 2 to 14). There is high quality evidence that vitamin D plus calcium is associated with a statistically significant reduction in incidence of new non-vertebral fractures. However, there is only moderate quality evidence of an absence of a statistically significant preventive effect on clinical vertebral fractures. There is high quality evidence that vitamin D plus calcium reduces the risk of any type of fracture (10 trials, 49,976 participants; RR 0.95, 95% CI 0.90 to 0.99).In terms of the results for adverse effects: mortality was not adversely affected by either vitamin D or vitamin D plus calcium supplementation (29 trials, 71,032 participants, RR 0.97, 95% CI 0.93 to 1.01). Hypercalcaemia, which was usually mild (2.6 to 2.8 mmol/L), was more common in people receiving vitamin D or an analogue, with or without calcium (21 trials, 17,124 participants, RR 2.28, 95% CI 1.57 to 3.31), especially for calcitriol (four trials, 988 participants, RR 4.41, 95% CI 2.14 to 9.09), than in people receiving placebo or control. There was also a small increased risk of gastrointestinal symptoms (15 trials, 47,761 participants, RR 1.04, 95% CI 1.00 to 1.08), especially for calcium plus vitamin D (four trials, 40,524 participants, RR 1.05, 95% CI 1.01 to 1.09), and a significant increase in renal disease (11 trials, 46,548 participants, RR 1.16, 95% CI 1.02 to 1.33). Other systematic reviews have found an increased association of myocardial infarction with supplemental calcium; and evidence of increased myocardial infarction and stroke, but decreased cancer, with supplemental calcium plus vitamin D, without an overall effect on mortality., Authors' Conclusions: Vitamin D alone is unlikely to prevent fractures in the doses and formulations tested so far in older people. Supplements of vitamin D and calcium may prevent hip or any type of fracture. There was a small but significant increase in gastrointestinal symptoms and renal disease associated with vitamin D and calcium. This review found that there was no increased risk of death from taking calcium and vitamin D.

Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH) during sleep, is increasingly recognized as an independent risk factor of cardiovascular diseases. OSA is associated with changes in the levels of circulating oxidative stress/inflammatory markers and dyslipidemia, supporting their mediating roles in cardiovascular pathogenesis. Our aims were to investigate the effect of IH on heart tissue using an IH-exposed rat model and to explore the potential mechanisms involved in the occurrence of cardiac damage. Male Sprague-Dawley rats were exposed to IH and intermittent normoxia as control and sacrificed after 2 or 4 weeks. IH for 4 weeks caused elevation in serum malondialdehyde and cytokine-induced neutrophil chemoattractant-1 and reduction in serum adiponectin levels. In contrast, cardiac oxidative stress and pro-inflammatory markers were suppressed while cardiac adiponectin and cholesterol levels were elevated after IH exposure for 4 weeks. In parallel, there was an increase in apoptosis in the heart of IH-exposed rats, demonstrated by elevations of Bax and cleaved caspase-3 protein and TUNEL staining. Cardiac damage was further evident with decreased arterial vessel and capillary densities, increased cardiac fibrosis, and the loss of troponin I. Our data demonstrated that IH exposure paradoxically caused systemic oxidative and inflammatory responses and cardioprotective responses, i.e., anti-oxidative and anti-inflammatory responses. Despite such a local compensatory protective mechanism, cardiac damage was observed that might be due to IH-induced cholesterol accumulation in the heart and caspase-dependent apoptosis.

Background: The objective of this study was to evaluate the evidence for different interventions in the preoperative, perioperative and post-operative care for people undergoing elective total hip (THR) and knee (TKR) replacement surgery., Method: A multidisciplinary working group comprising consumers, managers and clinicians from the areas of orthopaedics, rheumatology, aged care and rehabilitation evaluated randomized controlled trials (RCTs) and systematic reviews/meta-analyses concerning aspects of preoperative, perioperative and post-operative clinical care periods for THR/TKR through systematic searching of Medline, Embase, CENTRAL and the Cochrane Database of Systematic Reviews from May 2007 to April 2011. Multiple reviewers determined study eligibility and one or more members extracted primary study findings. The body of evidence were assessed and specific recommendations made according to NHMRC guidelines., Results: Twenty-five aspects were identified for review. Recommendations for 16 of 25 areas of care were made: impact of waiting, multidisciplinary preparation, preoperative exercise, smoking cessation, interventions for comorbid conditions, predictors of outcome, clinical pathways, implementation of a blood management programme, antibiotic prophylaxis, regional anaesthesia and analgesia, use of a tourniquet in knee replacement, venous thromboembolism prophylaxis, early post-operative cryotherapy, early mobilization and continuous passive motion. In the post-operative period, study heterogeneity across all aspects of care precluded specific recommendations., Conclusions: There was a deficiency in the quality of the evidence supporting key aspects of the continuum of care for primary THR/TKR surgery. Consequently, recommendations were limited. Prioritization and funding for research into areas likely to impact clinical practice and patient outcomes after elective joint replacement surgery are the next important steps., (© 2013 The Authors. ANZ Journal of Surgery © 2013 Royal Australasian College of Surgeons.)

Introduction: Small cell lung cancer (SCLC) carries high mortality despite standard chemotherapy. Arsenic trioxide (ATO) has demonstrated clinical efficacy in leukemia and in vitro activity in various solid tumors. This study was conducted to determine the in vitro and in vivo combination effects of ATO and chemotherapy in SCLC., Materials and Methods: The in vitro model consisted of 5 SCLC cell lines (H187, H526, H69, H841 and DMS79) and the anti-proliferative effects of ATO, cisplatin, etoposide or combinations thereof were measured. Synergism was determined by calculation of the combination index (CI) according to Chou and Talalay. Assays for apoptosis, intracellular glutathione (GSH) content, and mitochondrial membrane depolarization (MMD) were performed. Arsenic content was measured by inductively coupled plasma-mass spectrometry. Expression level of MRP1, MRP2 and pH2AX was detected by Western blot while cellular pH2AX level was monitored by immunofluorescent staining. An in vivo xenograft model in nude mice was established with a H841 cell line to test the effects of drug combinations., Results: All 5 SCLC cell lines were sensitive to ATO, with IC(50) values (48 h) 1.6-8 μM. Synergistic or additive effects were obtained by combining cisplatin with ATO in all 5 cell lines. Combination of etoposide with ATO resulted in antagonistic or barely additive effects. Apoptotic assays and pH2AX immunofluorescent staining corroborated the synergistic combination of ATO and cisplatin. In addition, the ATO/cisplatin combination enhanced MMD, depleted GSH, downregulated MRP2 and elevated intracellular ATO content compared with either ATO or cisplatin alone. In vivo combination of ATO and cisplatin also demonstrated synergism in the H841 xenograft model., Conclusions: There was clinically relevant in vitro activity of ATO in a panel of 5 SCLC cell lines. Significant synergism was demonstrated with the ATO/cisplatin combination, while antagonism was noted with the ATO/etoposide combination in both in vitro and in vivo models., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Erlotinib is a commonly used tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC). Autophagy is a catabolic process in response to stress and deprivation of nutrients. This study aims to investigate whether autophagy confers acquired resistance to erlotinib treatment in NSCLC., Methods: Four NSCLC cell lines (HCC827, HCC4006, H358 and H1975) with different epidermal growth factor receptor (EGFR) mutation status (exon 19 deletion, exon 19 deletion, wild-type and L858R/T790M respectively) were selected. MTT assay, crystal violet staining and Annexin-V assay were performed to determine cell viability and apoptosis. Autophagic proteins were detected by Western blot. Acidic vesicular organelle (AVO) formation was determined by acridine orange staining. Autophagy inhibitor (chloroquine) and RNA interference were used to demonstrate the biological effect of erlotinib-induced autophagy., Results: In line with EGFR mutation status, it was shown that both HCC827 and HCC4006 cells were sensitive to erlotinib, while H358 and H1975 cell lines were resistant. Erlotinib treatment at clinically relevant concentrations induced autophagy (increased LC3II expression, Atg-5/Atg12 conjugation, formation of AVO and p62 degradation) in sensitive NSCLC cell lines, via p53 nuclear translocation, AMPK activation and mTOR suppression. Addition of chloroquine, as an autophagy inhibitor, enhanced erlotinib sensitivity in sensitive cells. Similarly, silencing of Atg5 or Beclin-1 significantly increased sensitivity to erlotinib in both sensitive cell lines. In contrast, there was no induction of autophagy in resistant H358 and H1975 cell lines upon erlotinib exposure., Conclusions: Erlotinib can induce both apoptosis and autophagy in sensitive NSCLC cell lines with activating EGFR mutation (exon 19 del). Inhibition of autophagy can further enhance sensitivity to erlotinib in EGFR-mutated NSCLC, suggesting that autophagy may serve as a protective mechanism., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Obstructive sleep apnea (OSA) is independently associated with endothelial dysfunction, which may be perpetuated by alteration in endothelial repair capacity. Our study evaluates changes in endothelial progenitor cell (EPC) profile in relation to OSA and the role of advanced glycation end-products (AGE) in this relationship., Methods: Consecutive Chinese adults undergoing sleep studies, who had no medical illnesses or regular medications, were enrolled. Subjects with morbid obesity or grossly elevated lipoprotein levels were excluded from analysis. Circulating EPC was measured with flow cytometry analysis., Results: Seventy-two subjects, 64 % with OSA defined by apnea-hypopnea index (AHI) ≥ 5, were analyzed. CD34+ cell counts were positively correlated with oxygen desaturation index (ODI) (r = 0.250, p = 0.041) and duration of oxygen desaturation <90 % (T90) (r = 0.261, p = 0.033) and negatively with minimal oxygen saturation (r = -0.247, p = 0.044) after adjusting for age, glucose, body weight, and smoking status. AGE was positively correlated with indices of OSA severity (AHI, r = 0.249, p = 0.042; ODI, r = 0.244, p = 0.047; T90, r = 0.243, p = 0.047; minimal oxygen saturation, r = -0.251, p = 0.041) and negatively with CD133+ cells (r = -0.281, p = 0.021). On stepwise multiple linear regression analysis, minimal oxygen saturation (p = 0.013) and CD133+ cell counts (p = 0.029) were found to be significant determinants of AGE level (R(2) = 0.147)., Conclusions: Nocturnal hypoxemia in OSA subjects was associated with increase in endothelial cells (CD34+) which may promote vascular repair. Accumulation of AGE in OSA may lead to diminution in early EPC (CD133+) and endothelial repair capacity over time, thus contributing to vascular pathogenesis.

Oxidative stress has been implicated in the pathogenesis of asthma. We aimed at investigating the biomarkers of oxidative stress, inflammation, and tissue damage in patients with asthma in acute exacerbation and remission. We recruited 18 asthmatics admitted to hospital with acute exacerbation and 18 healthy nonsmoking controls matched for age. We evaluated plasma levels of 8-isoprostane, C-reactive protein (CRP) and total matrix metalloproteinase- (MMP-) 9 by ELISA, and MMP-9 activity by zymographic analysis. Plasma levels of 8-isoprostane and CRP were significantly elevated in acute exacerbation and decreased in remission but remained significantly higher compared to healthy controls. The activities of pro-MMP-9 were also significantly higher in acute exacerbation and decreased in remission but remained significantly higher compared to healthy controls in parallel to plasma levels of total MMP-9. These data suggest that overproduction of MMP-9 along with highly elevated levels of oxidative stress and inflammation is implicated in asthma exacerbation and that measurements of these biomarkers can be a valid index in its management.

Intermittent hypoxia (IH) is a hallmark feature in obstructive sleep apnea (OSA) which is increasingly recognized as an independent risk factor for atherosclerosis. Oxidative stress, inflammation, and cell apoptosis are major pathological events initiating or accelerating atherogenesis. This study addressed whether IH would affect these proatherogenic factors in endothelial cells and the mechanistic pathways involved. EA.hy926 cells were exposed to intermittent normoxia or IH for different numbers of cycles (32, 64, or 96). IH exposure time-dependently raised cellular GSSG/GSH ratio, increased production of IL-6 and IL-8, and accelerated cell apoptosis and death, concurrent with activation of NF-κB and inhibition of Nrf2/HO-1 pathways. At 64 cycles, inhibition of NF-κB attenuated IH-induced cellular oxidative stress and accumulation of inflammatory cytokines in cell culture medium but aggravated IH-induced cell apoptosis, while stimulation of HO-1 suppressed IH-induced cellular oxidative stress and cell apoptosis without affecting accumulation of inflammatory cytokines in cell culture medium. We demonstrated that early stage of exposure to IH-induced oxidative and inflammatory stresses leading to acceleration of cell apoptosis via NF-κB and Nrf2/HO-1 pathways in endothelial cells, suggesting the potential mechanisms for IH-induced vascular pathogenesis, in resemblance to OSA.

Recently, we have reported the dysregulation of circulating serotonin (5-hydroxytryptamine, 5-HT) homeostasis in patients with chronic obstructive pulmonary disease (COPD). An increase in metabolism of 5-HT has been reported to induce oxidative stress via monoamine oxidase (MAO)-dependent pathway. The present study aimed at investigating the effect of cigarette smoke exposure on the systemic circulation and local airway 5-HT levels as well as MAO-mediated oxidative pathway using a cigarette smoke-exposed rat model. Male Sprague-Dawley rats (150-200 g) were exposed to either sham air or 4% (v/v, smoke/air) cigarette smoke for 1 hour daily for 56 consecutive days. Sera, bronchoalveolar larvage (BAL) and lung tissues were collected 24 hours after the last exposure. We found a significant reduction in the reduced glutathione (rGSH) and an elevation in advanced oxidation protein products (AOPP), a protein oxidation marker, in the lung of cigarette smoke-exposed group (p < 0.05). A significant increase in 5-HT was found in serum (p < 0.05), but not in the BAL or lung, after cigarette smoke exposure. MAO-A activity was significantly elevated in the lung of cigarette smoke-exposed group (p < 0.05). Furthermore, increased superoxide anion levels were found in lung homogenates of cigarette smoke-exposed rats after incubation with 5-HT (p < 0.05), which was positively associated with the increase in MAO-A activity (r = 0.639, p < 0.05). Our findings supported the presence of GSH disruption and protein oxidation in the lung after cigarette smoke exposure. The metabolism of 5-HT by MAO-A in the lung enhanced cigarette smoke-induced superoxides, which might contribute to the pathogenesis of COPD.

Our recent study has indicated that Chinese green tea (Lung Chen), in which epigallocatechin-3-gallate (EGCG) accounts for 60% of catechins, protected cigarette smoke-induced lung injury. We now hypothesized that Lung Chen tea may also have potential effect on lung oxidative stress and proteases/anti-proteases in a smoking rat model. Sprague-Dawley rats were exposed to either sham air (SA) or 4% cigarette smoke (CS) plus 2% Lung Chen tea or water by oral gavage. Serine proteases, matrix metalloproteinases (MMPs) and their respective endogenous inhibitors were determined in bronchoalveolar lavage (BAL) and lung tissues by gelatin/casein zymography and biochemical assays. Green tea consumption significantly decreased CS-induced elevation of lung lipid peroxidation marker, malondialdehyde (MDA), and CS-induced up-regulation of neutrophil elastase (NE) concentration and activity along with that of α(1)-antitrypsin (α(1)-AT) and secretory leukoproteinase inhibitor (SLPI) in BAL and lung. In parallel, significant elevation of MMP-12 activity was found in BAL and lung of the CS-exposed group, which returned to the levels of SA-exposed group after green tea consumption but not CS-induced reduction of tissue inhibitor of metalloproteinase (TIMP)-1 activity, which was not reversed by green tea consumption. Taken together, our data supported the presence of local oxidative stress and protease/anti-protease imbalance in the airways after CS exposure, which might be alleviated by green tea consumption through its biological antioxidant activity.

The author group has previously established an in vivo subchronic cigarette smoke (CS) exposure rat model, in which the systemic oxidative burden as well as the modulation of local anti-oxidative enzymes in the lung has been demonstrated. Oxidative stress has been shown to induce pro-inflammatory cytokine release, including interleukin (IL)-6 in the airways. In this study, we aimed to investigate the changes in IL-6 production, as well as the oxidative/anti-oxidative responses in the cerebral cortex using the same in vivo model. IL-6 was determined by RT-PCR and western-blot analysis. Local oxidative and anti-oxidative responses were determined by measuring cerebral cortical malondialdehyde (MDA) and advanced oxidation protein product (AOPP) levels, superoxide dismutase (SOD) and catalase activities, and the reduced to oxidized glutathione (GSH/GSSG) ratio. Nitrite level was measured by fluorescent spectrophotometry. Our results demonstrated a significant increase in both IL-6 mRNA and protein levels. Reductions of SOD activity and manganese (Mn)SOD protein level were observed together with the increased level of superoxide measured by chemiluminescent signal, after 56 days of CS exposure. There were no significant changes in the cerebral cortical levels of MDA, AOPP, catalase activity, and the GSH/GSSG ratio. Nitrite level was significantly reduced, together with the decreased protein level of nNOS in the cerebral cortex, after 56 days of CS exposure. Our results suggest that exposure to CS induces IL-6 expression in the cerebral cortex, which is not mediated by the oxidative/anti-oxidative imbalance.

Green tea (from the plant Camellia sinensis), a beverage whose consumption started 5000 years ago in China, has important biological and pharmacological properties. The beneficial effects of green tea have been attributed to the presence of phenolic compounds that are powerful anti-oxidants and free iron scavengers. Of all the catechins found in green tea, namely (-)-epicatechin-3-gallate, (-)-epigallocatechin, (-)-epicatechin and (-)-epigallocatechin-3-gallate (EGCG), EGCG is the most abundant and powerful. It is widely believed that green tea may protect against death from all causes, especially cardiovascular diseases (coronary heart disease and stroke) owing to the presence of catechins associated with green tea consumption. Other health benefits include various types of cancer chemoprevention, weight loss and protective effects against neurodegenerative diseases (Alzheimer's disease and Parkinson's disease). Thus far, numerous pharmacological activities regulating disease-specific molecular targets have been reported in vitro for EGCG concentrations in the micromolar range, which are physiologically irrelevant. Although most of the studies have shown benefits with two to three cups of green tea per day, the optimal dose has not yet been established to enable any solid conclusions to be drawn regarding the various health benefits of green tea or its constituents in humans. With Phase I trials providing information on the safety profile and pharmacokinetics of EGCG, the window of opportunity is wider to undertake well-controlled long-term human studies to enable a full understanding of the protective effects of green tea catechins on various parameters in different settings., (© 2012 The Author Clinical and Experimental Pharmacology and Physiology © 2012 Blackwell Publishing Asia Pty Ltd.)

OSA is increasingly recognized as a major health problem in developed countries. Obesity is the most common risk factor in OSA and hence, the prevalence of OSA is undoubtedly rising given the epidemic of obesity. Recent data also suggest that OSA is highly associated with the metabolic syndrome, and it is postulated that OSA contributes to cardiometabolic dysfunction, and subsequently vasculopathy. Current evidence regarding the magnitude of impact on ultimate cardiovascular morbidity or mortality attributable to OSA-induced metabolic dysregulation is scarce. Given the known pathophysiological triggers of intermittent hypoxia and sleep fragmentation in OSA, the potential mechanisms of OSA-obesity-metabolic syndrome interaction involve sympathetic activation, oxidative stress, inflammation and neurohumoral changes. There is accumulating evidence from human and animal/cell models of intermittent hypoxia to map out these mechanistic pathways. In spite of support for an independent role of OSA in the contribution towards metabolic dysfunction, a healthy diet and appropriate lifestyle modifications towards better control of metabolic function are equally important as CPAP treatment in the holistic management of OSA., (© 2011 The Authors. Respirology © 2011 Asian Pacific Society of Respirology.)

Cigarette smoking is a major risk factor in chronic obstructive pulmonary disease (COPD) with chronic airway inflammation as a key feature. Blockade of serotonin receptor 2A (5-HTR(2A)) with ketanserin has been found to improve lung function in COPD patients. Furthermore, ketanserin has been shown to possess anti-inflammatory properties in vivo. In this study, we investigated the antioxidative and anti-inflammatory properties of ketanserin and its underlying mechanism of action on cigarette smoke-induced interleukin (IL)-8 release in vitro. Primary normal human bronchial epithelial cells and human bronchial epithelial cell line (BEAS-2B) were treated with or without ketanserin prior to exposure to cigarette smoke medium (CSM). Exposure to CSM caused elevation of both mRNA and release of IL-8 with increased phosphorylation of p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2). Consistently, CSM-induced IL-8 release was blocked by SB203580, U0126, or MEK1 small interfering RNA (siRNA) but not SP600125. On the other hand, CSM caused a dose-dependent decrease in the ratio of reduced glutathione to oxidized glutathione (rGSH/GSSG) together with an increased translocation of Nrf2 to the nucleus demonstrated by Western blot analysis. Knock down of Nrf2 by siRNA completely blocked CSM-induced IL-8 release. Ketanserin suppressed CSM-induced IL-8 release by inhibiting p38, ERK1/2 MAPK, and Nrf2 signaling pathways and partially inhibited CSM-induced reduction of rGSH/GSSG ratio. Our data demonstrated the novel antioxidative and anti-inflammatory role of ketanserin via the Nrf2 signaling pathway in CSM-exposed human bronchial epithelial cells. This may open up new perspectives in the development of novel therapeutic targets in the treatment of cigarette smoke-related COPD.

Cigarette smoking has been proposed as a major risk factor for aging-related pathological changes and Alzheimer's disease (AD). To date, little is known for how smoking can predispose our brains to dementia or cognitive impairment. This study aimed to investigate the cigarette smoke-induced pathological changes in brains. Male Sprague-Dawley (SD) rats were exposed to either sham air or 4% cigarette smoke 1 hour per day for 8 weeks in a ventilated smoking chamber to mimic the situation of chronic passive smoking. We found that the levels of oxidative stress were significantly increased in the hippocampus of the smoking group. Smoking also affected the synapse through reducing the expression of pre-synaptic proteins including synaptophysin and synapsin-1, while there were no changes in the expression of postsynaptic protein PSD95. Decreased levels of acetylated-tubulin and increased levels of phosphorylated-tau at 231, 205 and 404 epitopes were also observed in the hippocampus of the smoking rats. These results suggested that axonal transport machinery might be impaired, and the stability of cytoskeleton might be affected by smoking. Moreover, smoking affected amyloid precursor protein (APP) processing by increasing the production of sAPPβ and accumulation of β-amyloid peptide in the CA3 and dentate gyrus region. In summary, our data suggested that chronic cigarette smoking could induce synaptic changes and other neuropathological alterations. These changes might serve as evidence of early phases of neurodegeneration and may explain why smoking can predispose brains to AD and dementia.

Background: Cigarette smoking is a major risk factor in the development of age-related chronic obstructive pulmonary disease (COPD). The serotonin transporter (SERT) gene polymorphism has been reported to be associated with COPD, and the degree of cigarette smoking has been shown to be a significant mediator in this relationship. The interrelation between circulating serotonin (5-hydroxytyptamine, 5-HT), cigarette smoking and COPD is however largely unknown. The current study aimed at investigating the mediation effects of plasma 5-HT on cigarette smoking-induced COPD and the relation between plasma 5-HT levels and age., Methods: The association between plasma 5-HT, age and COPD was analyzed in a total of 62 COPD patients (ever-smokers) and 117 control subjects (healthy non-smokers and ever-smokers). Plasma 5-HT levels were measured by enzyme-linked immuno assay (EIA)., Results: The elevated plasma 5-HT levels were significantly associated with increased odds for COPD (OR = 1.221, 95% CI = 1.123 to 1.319, p<0.0001). The effect remained significant after being adjusted for age and pack-years smoked (OR = 1.271, 95% CI = 1.134 to 1.408, p = 0.0003). Furthermore, plasma 5-HT was found to mediate the relation between pack-years smoked and COPD. A positive correlation (r = 0.303, p = 0.017) was found between plasma 5-HT levels and age in COPD, but not in the control subjects (r = -0.149, p = 0.108)., Conclusion: Our results suggest that cigarette smoke-induced COPD is partially mediated by the plasma levels of 5-HT, and that these become elevated with increased age in COPD. The elevated plasma 5-HT levels in COPD might contribute to the pathogenesis of this disease.