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Objective Chronic obstructive pulmonary disease (COPD) can be prevented and treated, although presenting with persistent airflow restriction; the airflow restriction caused by COPD is mostly progressive. In recent years, more attention has been paid to the home-based pulmonary rehabilitation (PR) and its influence on COPD. Exercise training is the basic constituent of PR. However, it is not clear which exercise trainings are the ideal ways to deliver home-based PR. Methods In this review, we focus on the effect of home-based exercise training on patients with COPD. We searched literature, which was necessarily required to be randomized controlled trails (RCTs) from the establishment of the four respective databases (Medline, PubMed, Web of Science, and China National Knowledge Infrastructure) from January 2008 to January 2018. We used the Cochrane collaborative “risk of bias” tool to assess the quality of evidence. A total of 21 trials (1694 participants) were included. Through the analysis of the literature, we find that a simple, low-cost, and low-intensity family-based lung-rehabilitation plan to adapt to the real life may lead to the improvement of the ability to exercise, the reduction of the difficulty in breathing, and the improvement of carrying out daily activities. Results In the exercise training of home-based PR, lower limb exercise (LLE) training demonstrated a more perceptible effect in improving the quality of life of patients with COPD. At the same time, the combination of LLE training, breathing training, and upper limb exercise training is more obvious than the simple LLE training. In addition, home-based low-intensity aerobic training may sometimes be no less than the outpatient or center intervention to improve dyspnea, health status, and exercise tolerance. In conclusion, the simple and easy home-based PR exercise program is useful. Long-term home-based PR may require an enhanced need for maintenance. Conclusions A simple, low-cost, and low-intensity high blood pressure response (HBPR) plan to adapt to the real life may lead to an augmentation in the ability to exercise, a reduction of the difficulty in breathing, and an improvement in carrying out day-to-day activities. HBPR strategies can benefit patients (elderly patients with COPD at home) in the long term.

Objectives: Cigarette smoke, a strong risk factor for cardiovascular diseases, upregulates contractile endothelin (ET) receptors in coronary arteries. The present study examined the effects of second hand cigarette smoke exposure on the contractile endothelin receptors and the role of the MEK1/2 pathway in rat coronary arteries. Design: Rats were exposed to secondhand smoke (SHS) for 8 weeks followed by intraperitoneal injection of a MEK1/2 inhibitor, U0126 daily for another 4 weeks. Contractile responses of isolated coronary arteries were recorded by a sensitive wire myograph. The receptor protein expression levels were examined by Western blotting. Results: The results showed that SHS in vivo caused increased expression of ET receptors ETA and ETB, and that the MEK1/2 blocker U0126 significantly reversed SHS exposure-increased ETA-mediated contractile responses and protein levels. Similar alterations were observed in ETB receptors. U0126 showed dose-dependent effects on SHS-induced response on contractile property and protein levels of the ETB receptor. However, only the higher dose U0126 (15 mg/kg) had inhibitory effects on the ETA receptor. Conclusions: Taken together, our data show that SHS increases contractile ET receptors and MEK1/2 pathway inhibitor offsets SHS exposure-induced ETA and ETB receptor upregulation in rat coronary arteries.

Oxidative stress induced by long-term cyclosporine A (CsA) administration is a major cause of chronic nephrotoxicity, which is characterized by tubular atrophy, tubular cell apoptosis, and interstitial fibrosis in the progression of organ transplantation. Although hydrogen-rich water (HRW) has been used to prevent various oxidative stress-related diseases, its underlying mechanisms remain unclear. This study investigated the effects of HRW on CsA-induced nephrotoxicity and its potential mechanisms. After administration of CsA (25 mg/kg/day), rats were treated with or without HRW (12 mL/kg) for 4 weeks. Renal function and vascular activity were investigated. Histological changes in kidney tissues were analyzed using Masson's trichrome and terminal deoxynucleotidyl transferase dUTP nick-end labeling stains. Oxidative stress markers and the activation of the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway were also measured. We found that CsA increased the levels of reactive oxygen species (ROS) and malonaldehyde (MDA), but it reduced glutathione (GSH) and superoxide dismutase (SOD) levels. Such alterations induced vascular dysfunction, tubular atrophy, interstitial fibrosis, and tubular apoptosis. This was evident secondary to an increase in urinary protein, serum creatinine, and blood urea nitrogen, ultimately leading to renal dysfunction. Conversely, HRW decreased levels of ROS and MDA while increasing the activity of GSH and SOD. This was accompanied by an improvement in vascular and renal function. Moreover, HRW significantly decreased the level of Keap1 and increased the expression of Nrf2, NADPH dehydrogenase quinone 1, and heme oxygenase 1. In conclusion, HRW restored the balance of redox status, suppressed oxidative stress damage, and improved kidney function induced by CsA via activation of the Keap1/Nrf2 signaling pathway.

Aim Hydrogen sulphide (H2S) exhibits a dual modulation of isolated artery tension. This study investigated the vasoconstrictive effect of sulphur sodium hydride (NaHS), a donor of gaseous H2S, on rat coronary artery. Methods The contractile response of isolated arteries was recorded using a wire myograph. Fluo-3/AM was used to load vascular smooth muscle, and intracellular calcium was determined using confocal laser microscopy. The protein expression of Rho kinase was examined using Western blot. Results NaHS induced concentration-dependent contractions of rat coronary artery, and the contraction reached approx. 65% of 60 mm KCl-induced contraction. The NaHS-induced contraction was elevated following the removal of endothelium or the use of the nitric oxide synthase inhibitor L-NAME. The cyclooxygenase inhibitor indomethacin reduced NaHS-induced contraction. The Rho kinase inhibitor Y-27632 significantly attenuated NaHS-induced vasoconstriction. Furthermore, NaHS elevated the protein expression of Rho kinase. NaHS-induced contraction was completely abolished in a Ca2+-free solution and suppressed by the Ca2+ influx blocker nifedipine (100 nm). NaHS also significantly increased the change rate of Ca2+ fluorescence intensity. However, treatment with a Cl−/HCO3− exchanger blocker, K+ channel blockers, the mitogen-activated protein kinase inhibitor U-0126 or cyclic adenosine monophosphate did not affect contraction. Species-dependent differences in NaHS-induced vasoconstriction were observed because these effects were only modest in dog coronary artery and absent in rabbit coronary artery. Conclusions NaHS induces the contraction of rat coronary artery, which is dependent on the activation of Ca2+ influx. Rho kinase likely participates in the vasoconstriction.

Published data on the association between the myeloperoxidase (MPO) G-463A polymorphism and coronary artery disease (CAD) are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis on this topic was performed. PubMed, EMBASE and Chinese national knowledge infrastructure were searched for studies regarding the association between the MPO G-463A polymorphism and CAD. A logistic regression analysis was used to estimate the genetic effect and the possible genetic model of action. Summary odds ratios (ORs) with their corresponding 95% confidence intervals (CIs) were calculated. There was strong evidence for an association between the MPO G-463A polymorphism and CAD. The genetic model of action was most likely to be co-dominant. Overall, the data showed that AA and GA genotypes were significantly associated with reduced risk of CAD (AA vs. GG: OR = 0.37, 95% CI = 0.17–0.78; GA vs. GG: OR = 0.73, 95% CI = 0.57–0.92). In subgroup analyses by study population and sources of controls, statistically significant results were observed in the Chinese population (AA vs. GG: OR = 0.21, 95% CI = 0.10–0.43; GA vs. GG: OR = 0.57, 95% CI =0.44–0.74) and in hospital-based control studies (AA vs. GG: OR = 0.20, 95% CI = 0.10–0.39; GA vs. GG: OR = 0.61, 95% CI = 0.48–0.77). This meta-analysis suggests that the MPO G-463A variant genotypes may be associated with decreased risk of CAD. However, given the limited number of studies and the potential biases, the influence of this polymorphism on CAD risk needs further investigation.

Vitamin K1 injection induces severe dose-related anaphylactoid reactions and overdose for the treatment of vitamin K deficiency. We aimed to find an optimal and small dose of vitamin K1 injection to treat vitamin K deficiency and avoid anaphylactoid reactions in animal. Rats were administered a vitamin K-deficient diet and gentamicin to establish vitamin K deficiency model. Behaviour tests were performed in beagle dogs to observe anaphylactoid reactions. The results showed an increased protein induced by vitamin K absence or antagonist II (PIVKA-II) levels, a prolonging of prothrombin time (PT) and activated partial thromboplastin time (APTT) and a decrease in vitamin K-dependent coagulation factor (F) II, VII, IX and X activities in the model group. In vitamin K1 0.01 mg/kg group, the liver vitamin K1 levels increased fivefold and the liver vitamin K2 levels increased to the normal amount. Coagulation markers PT, APTT, FVII and FIX activities returned to normal. Both in the 0.1 and 1.0 mg/kg vitamin K1 groups, coagulation functions completely returned to normal. Moreover, the amount of liver vitamin K1 was 40 (0.1 mg/kg) or 100 (1.0 mg/kg) times as in normal. Vitamin K2 was about 4 (0.1 mg/kg) or 5 (1.0 mg/kg) times as the normal amount. There was no obvious anaphylactoid symptom in dogs with the dose of 0.03 mg/kg, which is equivalent to the dose of 0.01 mg/kg in rats. These results demonstrated that a small dose of vitamin K1 is effective to improve vitamin K deficiency and to prevent anaphylactoid reactions, simultaneously.

Aim Bitter taste is sensed by the bitter taste receptor (TAS2R), which is mainly expressed in the tongue as well as in extra-oral organs, such as the gastrointestinal tract, respiratory tract, brain, heart and testis. This study aimed to investigate whether TAS2R is expressed in the mesenteric, cerebral and omental arteries. Main methods The expression levels of TAS2R mRNA and protein were determined by reverse-transcription polymerase chain reaction and Western blotting, respectively. The location of TAS2R was determined by immunofluorescence imaging. TAS2R agonists were used in a sensitive myograph to study the function of TAS2R in arteries. Key findings The mRNA of rat TAS2Rs, including rTAS2R39, rTAS2R40, rTAS2R108, rTAS2R114, rTAS2R130, rTAS2R137, and rTAS2R140, was expressed in rat mesenteric and cerebral arteries, but rTAS2R114 was not expressed in the cerebral arteries. The mRNA of human TAS2Rs, including hTAS2R3, hTAS2R4, hTAS2R7, hTAS2R10, hTAS2R14, hTAS2R39 and hTAS2R40, was expressed in human omental arteries. The TAS2R7 protein was expressed in rat mesenteric and cerebral arteries, as well as in human omental arteries. Immunofluorescence imaging confirmed that TAS2R7 was located in vascular smooth muscle cells and endothelial cells. The TAS2R agonists, chloroquine and quinine relaxed rat mesenteric arteries and cerebral arteries and human omental arteries in a concentration-dependent manner. Significance TAS2R is expressed in the arteries of systemic circulation, including rat mesenteric and cerebral arteries and human omental arteries. This study provides evidence that TAS2R do exist in the arteries and may be involved in the mediation of vessel functions.

Hydrogen sulfide (H2S), traditionally known for its toxic effects, is now involved in regulating vascular tone. Here we investigated the vasoconstrictive effect of H2S on cerebral artery and the underlying mechanism. Sodium hydrosulfide (NaHS), a donor of H2S, concentration-dependently induced vasoconstriction on basilar artery, which was enhanced in the presence of isoprenaline, a β-adrenoceptor agonist or forskolin, an adenylyl cyclase activator. Administration of NaHS attenuated the vasorelaxant effects of isoprenaline or forskolin. Meanwhile, the NaHS-induced vasoconstriction was diminished in the presence of 8B-cAMP, an analog of cAMP, but was not affected by Bay K-8644, a selective L-type Ca(2+) channel agonist. These results could be explained by the revised effects of NaHS on isoprenaline-induced cAMP elevation and forskolin-stimulated adenylyl cyclase activity. Additionally, NaHS-induced vasoconstriction was enhanced by removing the endothelium or in the presence of L-NAME, an inhibitor of nitric oxide synthase. L-NAME only partially attenuated the effect of NaHS which was given together with forskolin on the pre-contracted artery. In conclusion, H2S induces vasoconstriction of cerebral artery via, at least in part, cAMP/adenylyl cyclase pathway.

Cigarette smoking, a major stroke risk factor, upregulates endothelin receptors in cerebral arteries. The present study examined the effects of MEK1/2 pathway inhibition on cigarette smoke exposure-induced ET receptor upregulation. Rats were exposed to the secondhand smoke (SHS) for 8weeks followed by intraperitoneal injection of MEK1/2 inhibitor, U0126 for another 4weeks. The urine cotinine levels were assessed with high-performance liquid chromatography. Contractile responses of isolated cerebral arteries were recorded by a sensitive wire myograph. The mRNA and protein expression levels of receptor and MEK/ERK1/2 pathway molecules were examined by real-time PCR and Western blotting, respectively. Cerebral artery receptor localization was determined with immunohistochemistry. The results showed the urine cotinine levels from SHS exposure group were significantly higher than those from the fresh group. In addition, the MEK1/2 inhibitor, U0126 significantly reduced SHS exposure-increased ETA receptor mRNA and protein levels as well as contractile responses mediated by ETA receptors. The immunoreactivity of increased ETA receptor expression was primarily cytoplasmic in smooth muscle cells. In contrast, ETB receptor was noted in endothelial cells. However, the SHS-induced decrease in endothelium-dependent relaxation was unchanged after U0126 treatment. Furthermore, SHS increased the phosphorylation of MEK1/2 and ERK1/2 protein in cerebral arteries. By using U0126 could inhibit the phosphorylated ERK1/2 protein but not MEK1/2. Taken together, our data show that treatment with MEK1/2 pathway inhibitor offsets SHS exposure-induced ETA receptor upregulation in rat cerebral arteries.

Summary The main vitamin K-deficient model, minidose warfarin, is different from the pathological mechanism of vitamin K deficiency, which is a shortage of vitamin K. The objective of this study was to establish a new method of vitamin K-deficient model combining a vitamin K-deficient diet with the intragastrical administration of gentamicin in rats. The clotting was assayed by an automated coagulation analyser. The plasma PIVKA-II was assayed by ELISA. The vitamin K status was detected by an HPLC-fluorescence system. In the diet- and gentamicin-induced vitamin K-deficient 14-day group, the rats had undetected vitamin K1 and vitamin K2 in the liver and a prolonged APTT. In the 21-day group, there was also a prolonged PT and a decrease of the FIX activities. In the 28-day group, the undetected vitamin K1 and vitamin K2, the prolonged PT and APTT, and the decrease of the FII, FVII, FIX, and FX activities prompted the suggestion that there were serious deficiencies of vitamin K and vitamin K-dependent coagulation in rats. It is suggested that the diet- and gentamicin-induced vitamin K-deficient 14-day or 21-day model can be used for studies related to the status of vitamin K. The vitamin K-deficient 28-day model can be applied to research involving both the status of vitamin K and of vitamin K-dependent coagulation. In conclusion, the combination of a vitamin K-deficient diet with the administration of gentamicin results in a useful model of vitamin K-deficieny.

Objectives Formononetin, a phytoestrogen, can improve arterial endothelial cell function by upregulating endothelial nitric oxide synthase (eNOS). The estrogen receptor plays an important role in the regulation of eNOS. This study investigated the hypothesis that formononetin upregulates eNOS through estrogen receptors and MAPK pathways. Methods The rat superior mesenteric arteries were cultured with formononetin or formononetin plus inhibitors for 24 h. The isometric tension of the arteries was measured using a myograph system. The mRNA and protein expression levels of eNOS were determined by real-time PCR and immunohistochemistry, respectively. Key findings Acetylcholine (ACh) relaxed the mesenteric arteries precontracted with 5-hydroxytryptamine. This relaxation could be enhanced by formononetin. The removal of endothelium or incubation with l-NAME (a NOS inhibitor) completely abolished the formononetin-enhanced relaxation induced by ACh, suggesting that the formononetin-enhanced vasodilatation is dependent on endothelium and NO pathway. The estrogen receptor inhibitor ICI 182780 attenuated the formononetin-enhanced vasodilatation induced by ACh, suggesting that the formononetin-enhanced arterial relaxation is mediated by the estrogen receptor. Formononetin increased the mRNA and protein expression levels of eNOS. ICI 182780, U0126 (an ERK1/2 inhibitor) and SP600125 (a JNK inhibitor) prevented the increases in arterial relaxation and eNOS levels. Conclusions Formononetin upregulates eNOS expression in mesenteric arteries via estrogen receptors, ERK1/2 and JNK pathways.

The aim of the present study was to determine the optimal initial tension, i.e. initial stretch for rat coronary artery when using the multi-wire myograph system. We used the normalization procedure to mimic physiological conditions and to stretch the coronary arterial segments to normalized internal circumference (IC1). It is determined the internal circumference when the vessel relaxed under a transmural pressure of 100 mm Hg (IC100), and the IC1 is calculated by multiplying the IC100 by a factor k. The impact of different factor k on the initial stretch and agonist-induced tension of coronary arteries were investigated. The results showed that the maximal agonist-induced tension was achieved at the factor k value of 0.90 and the initial stretch tension was given 1.16±0.04 mN/mm. The most appropriate factor k value was 0.90-0.95 and the most appropriate initial tension was 1.16-1.52 mN/mm. The equilibration time of the coronary artery segments should be at least 1.0 h. In the same optimal initial tension, the agonist-induced tension increased as equilibration time lengthened.

This study aims to evaluate the risk and benefit profiles of panitumumab-based therapy (PBT) in patients with metastatic colorectal cancer (mCRC). Relevant randomized controlled trials were identified by searching PubMed, Medline, EMBASE and Cochrane Library. Data on progression-free survival (PFS), overall survival (OS), all grade and severe (grade ≥3) adverse events were extracted and pooled to calculate hazard ratios (HRs) and risk ratios (RRs) with 95 % confidence intervals (CIs). Number needed to treat (NNT) for PFS and number needed to harm (NNH) for significantly changed toxicities were calculated. A total of 4,155 patients were included in the analysis. PBT significantly improved PFS (HRrandom = 0.66, 95 % CI = 0.45–0.95) but not OS (HRfixed = 0.93, 95 % CI = 0.83–1.04) when used in the subsequent-line setting. The effect on PFS was more evident in patients with wild-type KRAS (HRrandom = 0.64, 95 % CI = 0.47–0.87) and the NNT for PFS is 11 to 23at 1 year. PBT did not benefit patients when used in the first-line setting. In addition, PBT significantly increased the risk of skin toxicity, infections, diarrhea, dehydration, mucositis, hypokalemia, fatigue, hypomagnesemia, pulmonary embolism and paronychia. The NNHs for skin toxicity, diarrhea, infection, hypokalemia and mucositis are less than 23. In conclusion, when used in the subsequent-line setting, PBT can improve the disease progression, especially in mCRC patients with wild-type KRAS. Regarding the adverse events associated with the PBT, close monitoring and necessary preparations are recommended during the therapy.

The severe adverse reaction to vitamin K1 injection is always remarkable and is thought to result from anaphylaxis. Paradoxically, however, some patients administered vitamin K1 injection for the first time have adverse reactions. Using beagle dogs, the present study tested the hypothesis that the response to vitamin K1 is an anaphylactoid reaction. The results showed that serious anaphylaxis-like symptoms appeared in beagle dogs after the administration of vitamin K1 injection for the first time. The plasma histamine concentration increased, and blood pressure decreased sharply. After sensitization, dogs were challenged with vitamin K1 injection and displayed the same degree of symptoms as prior to sensitization. However, when the vitamin K1 injection-sensitized dogs were challenged with a vitamin K1-fat emulsion without solubilizers such asTween-80, the abnormal reactions did not occur. Furthermore, there was no significant change in the plasma immunoglobulin E concentration after vitamin K1 challenge. Following treatment with vitamin K1 injection, the release of histamine and β-hexosaminidase by rat basophilic leukemia-2H3 cells as well as the rate of apoptosis increased. The Tween-80 group displayed results similar to those observed following vitamin K1 injection in vivo. However, the dogs in the vitamin K1-fat emulsion group did not display any abnormal behavior or significant change in plasma histamine. Additionally, degranulation and apoptosis did not occur in rat basophilic leukemia-2H3 cells. Our results indicate that the adverse reaction induced by vitamin K1 injection is an anaphylactoid reaction, not anaphylaxis. Vitamin K1 injection induces the release of inflammatory factors via a non-IgE-mediated immune pathway, for which the trigger may be the solubilizer.

The objective of the study was to assess the association between tea consumption and endometrial cancer.Studies were identified by searching PubMed and EMBASE databases and screening the references of retrieved articles. The summary relative risk (RR) with 95% confidence interval (CI) was calculated.The combined RR for ever drinkers vs non/lowest drinkers was 0.85 (95% CI, 0.77-0.94). Compared with non/lowest drinkers, the summary RR was 0.88 (95% CI, 0.78-0.98) for low to moderate drinkers and 0.75 (95% CI, 0.64-0.88) for high drinkers. An increase in tea intake of 2 cups/day was associated with a 25% decreased risk of endometrial cancer. In subgroup analyses, tea consumption was significantly associated with reduced endometrial cancer risk in Asian studies and studies using interviewing techniques. Furthermore, the protective effect of green tea on endometrial cancer seemed more evident than that of black tea.Findings from this metaanalysis suggest that tea consumption may reduce the risk of endometrial cancer. Because of the limited number of studies, further prospective studies are needed to explore the protective effect of tea on endometrial cancer.