RELATIONSHIP OF CIGARETTE SMOKING TO BLOOD PRESSURE AND SERUM LIPIDS AND LIPOPROTEINS IN MEN

1. The relationship of cigarette smoking to blood pressure and serum lipids and lipoproteins was studied in 7608 men, ranging from 40 to 59 years of age. Analyses were performed separately for non-drinkers and drinkers. 2. After adjusting age and body mass index (BMI) in non-drinkers and age, BMI and alcohol intake in drinkers in forward stepwise multiple regression analysis, there was a dose-dependent negative relationship between cigarette smoking and diastolic blood pressure (DBP) and high density lipoprotein cholesterol (HDL-C), regardless of drinking habit. There was a dose-dependent positive relationship between cigarette smoking and the ratio of total cholesterol (TC) to HDL-C (TC:HDL-C) in non-drinkers, but not in drinkers. There was a dose-dependent negative relationship between cigarette smoking and TC and a positive relationship between cigarette smoking and triglycerides (TG) in drinkers, but not in non-drinkers. 3. After matching age and BMI in non-drinkers, subjects who smoked more than 30 cigarettes/day had significantly lower mean values of systolic blood pressure (SBP; 4.3%; P<0.05), DBP (3.0%;P<0.01) and HDL-C (15.5%;P<0.01) and higher mean values of TC:HDL-C (25.0%;P<0.01), TG (46.8%; P<0.01) and β-lipoprotein (12.0%; P<0.01) than non-smokers. In drinkers, after matching age, BMI, and alcohol intake, subjects who smoked more than 30 cigarettes/day had significantly lower mean values of SBP (2.8%; P<0.05), DBP (4.8%; P<0.01), HDL-C (17.3%; P<0.01) and TC (4.4%; P<0.01) and higher mean values of TC:HDL-C (15.4%; P<0.01) and TG (45.1%;P<0.01) than non-smokers. 4. Although the results are somewhat variable, the present study reveals that cigarette smoking is negatively associated with SBP and DBP and unfavourably associated with lipids and lipoproteins, regardless of drinking habit.     

THE MEASUREMENT OF PLASMA THROMBOXANE B2 AND THE EFFECT OF SMOKING

Plasma thromboxane B2 (TxB2) was measured by radioimmunoassay using an iodinated ligand following extraction and further purification by thin layer chromatography. Venous blood was sampled into a syringe containing the cyclooxygenase inhibitor meclofenamate. Normal levels, 15 pg/ml (s.d. = 8, n = 21), were lower than usually reported and measured values increased several fold over 20 min sampling from an indwelling needle. With appropriate sampling there was a statistically insignificant increase in plasma TxB2 after subjects smoked two cigarettes (n = 11). An average decrease occurred in a control group (n = 10) and the difference between groups was of borderline significance (P less than 0.05). Smoking did not change TxB2 production associated with platelet aggregation induced in vitro by collagen, whereas plasma adrenaline increased significantly. The results emphasize the importance of the technique of sampling and assay in the measurement of plasma TxB2.     

SHORT TERM VITAMIN E SUPPLEMENTATION HAS NO EFFECT ON PLATELET FUNCTION, PLASMA PHOSPHOLIPASE A2 AND LYSO-PAF IN MALE VOLUNTEERS

1. Based largely upon in vitro studies, vitamin E has been reported to inhibit phospholipase A2 activity, to alter phospholipid metabolism and reduce platelet aggregation. 2. The effect of dietary supplementation with D-alpha-tocopherol (1500 iu/day for 14 days) was studied in nine males, 41-63 years old, comparing active treatment with a preceding placebo period. 3. Despite an increase from 2.6 +/- 0.8 (s.d.) x 10(-5) mol/L to 6.0 +/- 1.8 10(-5) mol/L in plasma vitamin E there were no significant changes in the aggregation of diluted whole blood or platelet rich plasma to adenosine diphosphate (ADP) or collagen, in plasma phospholipase A2 activity or plasma lyso-platelet-activating factor (lyso-PAF) (bioassay after in vitro acetylation to PAF). 4. High dose vitamin E dietary supplementation had no effect on these phospholipid and platelet parameters.     

RENAL HYPER-RESPONSIVENESS TO BLOOD VOLUME EXPANSION IN BRATTLEBORO RATS IS NOT RELATED TO PLASMA ANF IMMUNOREACTIVITY

1. Anaesthetized homozygous Brattleboro (DI) rats were used to study the renal response to iso-oncotic blood volume expansion. 2. With the same degree of hypervolaemia DI rats had exaggerated diuresis, natriuresis, and chloriuresis, but not kaliuresis, compared with heterozygous control rats. This increased excretion resulted in negative water balance by the end of the experiment in DI rats, whereas the controls showed restoration of normal balance. The control rats retained significant amounts of sodium and chloride, the Brattleboro rats, however, did not. 3. The lithium clearance method was used to localize the defect in sodium reabsorption. As judged from this method, there was a significantly lower sodium reabsorption in the proximal tubules as well as in the distal parts of the nephron of DI rats. 4. Plasma immunoreactivity of atrial natriuretic factor (ANF) was not different between groups before volume expansion. ANF levels rose and fell similarly in both groups during and after the iso-oncotic infusion. 5. Our results demonstrate that DI rats respond to acute hypervolaemia with an exaggerated diuresis and saluresis. The mechanism of the increased salt excretion may involve inhibition of sodium transport in the proximal tubules as well as in the distal parts of the nephron. These transport defects are not dependent on differing plasma ANF levels.     

WEB-2086 AND INDOMETHACIN DO NOT MODIFY BLOOD PRESSURE FALL ON UNCLIPPING HYPERTENSIVE RATS

1. Pretreatment with intravenous WEB-2086 (0.5 mg/ kg; an antagonist of the actions of platelet activating factor; PAF) with or without indomethacin (2 mg/ kg) failed to prevent or modify the fall in blood pressure following unclipping of the renal artery of anaesthetized two-kidney, one-clip hypertensive rats. 2. The same medications given to two other groups of rats 60 min after unclipping when the blood pressure had fallen to stable levels failed to reverse the fall. 3. Despite evidence that both prostanoids and PAF can be detected in increased amounts in renal venous blood after unclipping, they do not appear to mediate the reduction in blood pressure in this model of reversible hypertension.     

SPECTRAL ANALYSIS OF SYSTOLIC BLOOD PRESSURE AND HEART RATE OSCILLATIONS RELATED TO RESPIRATION

1. Non-invasive assessment of short-term systolic blood pressure (SBP) and heart rate (HR) variability was obtained with the plethysmographic finger blood pressure measurement device. Respiration was measured with a respiratory inductive plethysmograph, which was calibrated prior to each study. 2. The effects of breathing pattern on the respiratory (high frequency, HF) component of the SBP or HR spectrum were analysed by Fourier transform. 3. Our quantification of the changes in the HF (respiratory) peak of the HR or SBP spectrum with changes in tidal volume (Vt) and breathing frequency (BF) indicates that the modulus of this component may be predicted for any combination of depth and frequency of breathing. 4. The modulus of this HF component for the HR or SBP spectrum was linearly related to the respiratory sinus arrhythmia (RSA) or to the SBP oscillation related to respiration.     

依那普利与牛磺酸对肾性高血压大鼠血压、左室肥厚及血小板聚集率的影响

二肾一夹型高血压大鼠的血压,血小板聚集率及左心室与体重之比均高于正常对照组成。依那普利(enalapril)6mg·kg^-1·d^-1,牛磺酸(taurine)30mg·k^-1·d^-1均可降低肾性高血压大鼠的血压(降压幅度分别为39.2%和36.60%),抑制血小板聚集率和逆转左室肥厚,但与正常对照组仍有差异。两药合用后,其降压和抑制血小板聚集作用明显增强,与正常组无显著差异,逆转左室肥厚作用虽亦比单独用药作用明显,但左室重/体重仍高于正常组。     

EFFECT OF DIETARY FISH OILS ON THE FORMATION OF LEUKOTRIENE B4 AND B5, THROMBOXANE AND PLATELET ACTIVATING FACTOR BY RAT LEUKOCYTES

1. This study investigates the effect of dietary eicosapentaenoic acid (EPA), in the form of 'Max EPA' fish oil, on leukotriene B4 (LTB4) production in ionophore-stimulated rat leukocytes. Male Wistar rats (200-250 g) were fed for 3 weeks on a synthetic chow supplemented with either 10% by weight Max EPA oil or a coconut oil/safflower oil mixture. 2. The EPA-rich diet significantly increased the EPA content of leukocyte phospholipids and decreased the arachidonic acid level by 35% (P less than 0.001) compared with the control diet. 3. The concentration of leukotrienes in the ionophore (A23187) stimulated leukocytes was measured by reverse-phase HPLC using prostaglandin B2 as the internal standard. The EPA-supplemented diet caused a 50% decrease in LTB4 production (P less than 0.001) and a concomitant increase in the formation of the biologically less active LTB5 compared with the control diet. The amount of LTB4 and LTB5 produced by stimulated leukocytes closely resembled the changes in arachidonic acid and EPA content of leukocyte phospholipids. 4. Thromboxane B2 (TxB2) production in stimulated leukocytes from the EPA-fed animals was also decreased compared with the control group. 5. Although the formation of platelet activating factor by stimulated leukocytes was not altered by dietary treatment, the ability of an EPA-rich diet to decrease LTB4 and TxB2 production suggests that these diets may attenuate leukocyte activity and have useful anti-inflammatory effects.     

温阳祛风活血法治疗早期糖尿病周围血管病变的临床研究

目的：观察温阳祛风活血法治疗早期糖尿病周围血管病变的临床疗效。方法将120例早期糖尿病周围血管病变患者随机分为治疗组60例、对照组60例。治疗过程中脱落2例。2组均采取控制血糖、血压等基础治疗。治疗组加用口服祛风活血中药汤剂、外用温阳活血中药汤剂。对照组加服己酮可可碱肠溶片。观察2组临床疗效,2组踝肱指数（ ABI）及足背动脉血流量。结果治疗组59例中,显效11例（18．6％）,有效37例（62．7％）,无效11例（18．6％）,总有效率为81.4％;对照组59例中,显效9例（15．3％）,有效28例（47．5％）,无效22例（37．3％）,总有效率为62．7％。经Ridit分析,U＝－2．198,P＝0．039,P＜0．05,说明治疗组临床疗效优于对照组。2组ABI治疗后较本组治疗前均增加（P＜0．05）,治疗组前后差值较对照组增加明显（P＜0．01）,治疗组优于对照组。足背动脉血流量治疗组治疗后较本组治疗前增加（P＜0．01）,对照组治疗前后差异无统计学意义（P＞0．05）,治疗组前后差值较对照组增加明显（P＜0．01）,治疗组优于对照组。结论温阳祛风活血法内外同治,对早期糖尿病周围血管病变有较好的临床疗效。     

ALTERED BLOOD PRESSURE, RENAL TUBULAR FUNCTION AND LEVELS OF CIRCULATING INHIBITORS OF Na-K-ATPase IN MATURE SHR EXPOSED TO LOW SALT DIET IN THE PERINATAL PERIOD

1. It has been shown previously that low salt diet, confined to the perinatal period only, reduces blood pressure (BP) and sodium retention in spontaneously hypertensive rat (SHR) offspring at maturity when compared with those given high salt diet. 2. In this study it is shown that such high salt diets are associated with an increased level of circulating Na-K-ATPase inhibitor (CINK) activity. 3. Animals given perinatal high salt diet have a significantly greater tubular reabsorptive capacity when compared with those given low salt diet. 4. The finding of a high level of circulating Na-K-ATPase inhibitory material in the face of increased renal tubular capacity and blood pressure suggests that while this inhibitory material may play a role in the elevated blood pressure of animals given high salt diet, it cannot cause the elevated rate of fluid reabsorption.     

SIRT4 inhibits cigarette smoke extracts-induced mononuclear cell adhesion to human pulmonary microvascular endothelial cells via regulating NF-κB activity

Cigarette smoking is an important risk factor for chronic obstructive pulmonary disease (COPD), yet its pathogenic mechanisms are not yet fully understood. Endothelial dysfunction is known to be involved in the pathogenesis of COPD. A detailed understanding of the mechanism involved in its progression would have a substantial impact on the optimization and development of treatment strategies. Here, we report that the expression of SIRT4, a mitochondrial sirtuin, is markedly down-regulated in cigarette smoke extract (CSE)-treated human pulmonary microvascular endothelial cells (HPMECs). Overexpression of SIRT4 significantly inhibits CSE-induced mononuclear cell adhesion to HPMECs. Consistently, we found that overexpression of SIRT4 attenuates the induction of vascular cell adhesion molecule 1 (VCAM-1) and E-selectin. Importantly, SIRT4 was found to negatively regulate CSE-induced NF-κB activation via inhibiting the degradation of IκBα. Moreover, we also found that proinflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6, the downstream target genes of NF-κB, are also inhibited by overexpression of SIRT4. These results suggest that SIRT4 protects HPMECs exposed to CSE stress via a mechanism that may involve the NF-κB pathway. Strategies based on the enhancement of SIRT4 may prove to be beneficial in the treatment of cigarette smoking caused COPD.     

Evaluation of cytotoxicity of different tobacco product preparations

Acute exposure to cigarette smoke or its components triggers diverse cellular effects, including cytotoxicity. However, available data regarding the potential cytotoxic effects of smokeless tobacco (ST) extracts lack consensus. Here, we investigated the relative biological effects of 2S3 reference ST, and whether ST elicits differential cellular/molecular responses compared to combustible tobacco product preparations (TPPs) prepared from 3R4F cigarettes. Total particulate matter (TPM) and whole smoke conditioned medium (WS-CM) were employed as combustible TPPs, while the ST extract was used as non-combustible TPP. HL60, THP1 cells and human PBMCs were used to examine the effects of TPPs in short-term cell culture. Corresponding EC₅₀ values, normalized for nicotine content of the TPPs, suggest that combustible TPPs induced higher cytotoxicity as follows: WS-CM ? TPM ? ST extract > nicotine. While all three TPPs induced detectable levels of DNA damage and IL8 secretion, the combustible TPPs were significantly more potent than the ST preparation. The major PBMC subsets showed differential cytotoxicity to combustible TPPs as follows: CD4 > CD8 > monocytes > NK cells. These findings suggest that, relative cytotoxic and other cell biological effects of TPPs are dose-dependent, and that ST extract is the least cytotoxic TPP tested in this study.     

Neutrophils: Cinderella of innate immune system

Neutrophils are the first line of innate immune defense against infectious diseases. However, since their discovery by Elie Metchnikoff, they have always been considered tissue-destructive cells responsible for inflammatory tissue damage occurring during acute infections. Now, extensive research in the field of neutrophil cell biology and their role skewing the immune response in various infections or inflammatory disorders revealed their importance in the regulation of immune response. Along with releasing various antimicrobial molecules, neutrophils also release neutrophil extracellular traps (NETs) for the containment of infection and inflammation. Activated neutrophils provide signals for the activation and maturation of macrophages as well as dendritic cells. Neutrophils are also involved in the regulation of T-cell immune response against various pathogens and tumor antigens. Thus, the present review is intended to highlight the emerging role of neutrophils in the regulation of both innate and adaptive immunity during acute infectious or inflammatory conditions.     

Salvianolic acid B protects human endothelial progenitor cells against oxidative stress-mediated dysfunction by modulating Akt/mTOR/4EBP1, p38 MAPK/ATF2, and ERK1/2 signaling pathways

The vascular endothelium is specifically sensitive to oxidative stress, and this is one of the mechanisms that causes widespread endothelial dysfunction in most cardiovascular diseases and disorders. Protection against reactive oxygen species (ROS)-mediated oxidative damage via antioxidant mechanisms is essential for tissue maintenance and shows therapeutic potential for patients suffering from cardiovascular and metabolic disorders. Salvianolic acid B (SalB), a natural bioactive component known from Traditional Chinese Medicine, has been reported to exert cellular protection in various types of cells. However, the underlying mechanisms involved are not fully understood. Here, we showed that SalB significantly promoted the migratory and tube formation abilities of human bone marrow derived-endothelial progenitor cells (BM-EPCs) in vitro, and substantially abrogated hydrogen peroxide (H₂O₂)-induced cell damage. SalB down-regulated Nox4 and eNOS, as well as nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase expression upon H₂O₂ induction that in turn prevents oxidative-induced endothelial dysfunction. Moreover, SalB suppressed the Bax/Bcl-xL ratio and caspase-3 activation after H₂O₂ induction. Furthermore, our results provide mechanistic evidence that activation of the mTOR/p70S6K/4EBP1 pathways is required for both SalB-mediated angiogenic and protective effects against oxidative stress-induced cell injury in BM-EPCs. Suppression of MKK3/6-p38 MAPK-ATF2 and ERK1/2 signaling pathways by SalB significantly protected BM-EPCs against cell injury caused by oxidative stress via reduction of intracellular ROS levels and apoptosis. Taken together, by providing a mechanistic insight into the modulation of redox states in BM-EPCs by SalB, we suggest that SalB has a strong potential of being a new proangiogenic and cytoprotective therapeutic agent with applications in the field of endothelial injury-mediated vascular diseases.     

Evaluating the role of Toll-like receptors in diseases of the central nervous system

A key part of the innate immune system is a network of pattern recognition receptors (PRRs) and their associated intracellular signalling pathways. Toll-like receptors (TLRs) are one such group of PRRs that detect pathogen associated molecular patterns (PAMPs). Activation of the TLRs with their respective agonists results in the activation of intracellular signalling pathways leading to the expression of proinflammatory mediators and anti-microbial effector molecules. Activation of the innate immune system through TLRs also triggers the adaptive immune response, resulting in a comprehensive immune program to eradicate invading pathogens. It is now known that immune surveillance and inflammatory responses occur in the central nervous system (CNS). Furthermore it is becoming increasingly clear that TLRs have a role in such CNS responses and are also implicated in the pathogenesis of a number of conditions in the CNS, such as Alzheimer's, stroke and multiple sclerosis. This is likely due to the generation of endogenous TLR agonists in these conditions which amplifies a detrimental neurotoxic inflammatory response. However TLRs in some situations can be neuroprotective, if triggered in a favourable context. This review aims to examine the recent literature on TLRs in the CNS thus demonstrating their importance in a range of infectious and non-infectious diseases of the brain.