胃癌组织中多环芳烃水平变化及意义

目的 探讨多环芳烃(PAHs)在人胃癌发病过程中的作用.方法 采用固相萃取(SPE)-高效液相色谱(HPLC)法,测定人正常胃组织和胃癌组织中的5种多环芳烃(PAHs)类化合物.结果 胃癌组织中的芘和苯并(a)芘的水平显著高于正常胃组织,两组相比P<0.05;胃癌组织中二甲基萘和菲的水平近似,两者相比,P>0.05.结论 人胃组织对PAHs有很强的生物富集能力,PAHs与人胃癌的发生高度相关.     

Metabolic activation of polycyclic aromatic hydrocarbons by human colonic mucosa and Bacteroides fragilis

Abstract The Ames Salmonella mutagenicity assay has been used to assess the metabolic activation of the following polycyclic aromatic hydrocarbons by human colonic microsomes (S9) and a cell-free extract of Bacteroides fragilis (Bf): 2-aminoanthracene, 1-naphthylamine, 2-naphthylamine, 2-aminofluorene, 2-acetylaminofluorene, anthracene, benzo(a)pyrene, 3-methylcholanthrene, 7, 12-dimethylbenzanthracene, acridine, 9-aminoacridine and 3-methylindole.
2-Aminoanthracene and 2-aminofluorene were the only compounds activated. In both cases, activation was dose-dependent and 2-aminofluorene exhibited synergistic activation by S9+Bf, as has previously been demonstrated with 2-aminoanthracene.
The organospecific aliphatic colonic carcinogen, 1, 2-dimethylhydrazine was not activated in this system. Metabolic activation by S9+Bf is thus restricted to aromatic compounds with three rings and an amino group in position 2.
These findings are consistent with enzymic substrate specificity, and are compatible with an enzymic basis for activation of polycyclic aromatic hydrocarbons by B. fragilis , present in large concentrations in the colonic lumen, and colonic microsomes.     

Enhancement by growth hormone of phorbol diester-stimulated respiratory burst in human polymorphonuclear leukocytes

The oxidative metabolic burst of mononuclear and polymorphonuclear phagocytes can be stimulated to produce free oxygen radicals. Several substances can enhance this respiratory burst activity by a priming action: recently growth hormone (rat and porcine) was demonstrated to act as a priming agent on rat peritoneal and on porcine alveolar macrophages. In our study we wanted to verify whether also human GH had a similar priming action on homologous cells, in particular on polymorphonuclear leukocytes. To determine the oxidative activity of polymorphonuclear leukocytes, after stimulation with phorbol myristate acetate, a flow-cytometric assay was employed which registered the intracellular formation of highly fluorescent products as indicators for the intracellular formation of hydrogen peroxide. The incubation of phorbol myristate acetate-stimulated polymorphonuclear leukocytes with GH resulted in a time-dependent and dose-dependent increase in fluorescence, thus demonstrating that human GH enhances in vitro the oxidative metabolic burst of these cells. The action of GH appeared to be significant after 30 min of incubation, was maximal at 60 min, and decreased after 90 min. After one hour of incubation, the first significant variation of fluorescence appeared with GH at a concentration of 50 micrograms/l. The maximum effect was seen at 100 micrograms/l with no further increase. Specificity of GH action was demonstrated by the inhibition of its effect by the addition of monoclonal antibodies to GH.     

Correlation between atmospheric polycyclic aromatic hydrocarbons exposure and urinary hydroxyl metabolites of polycyclic aromatic hydrocarbons in elderly population in Tianjin

Objective To identify suitable hydroxyl polycyclic aromatic hydrocarbons(OH-PAHs) for co-evaluation of internal exposure level of PAHs by simultaneous determination of a variety of OH-PAHs in urine. Methods The 24-h individual particulate matter and morning urine     

Effect of phorbol myristate acetate on the oxidative metabolism of human polymorphonuclear leukocytes.

The addition of 0.1 mug/ml of phorbol myristate acetate (PMA) to a suspension of resting human neutrophils causes a marked stimulation of all aspects of cellular oxidative metabolism normally associated with phagocytosis. PMA induces a greatly increased rate of glucose oxidation via the hexose monophosphate shunt, increased production of superoxide anion and of hydrogen peroxide, increased cellular chemiluminescence, and increased iodination of protein material. The time course of hexose monophosphate shunt activation and of chemiluminescence are similar to those observed following phagocytosis of opsonized zymosan; the levels of activation achieved in all cases approximate those seen following phagocytosis. These phenomena are not simply reflections of altered cellular permeability, since PMA actually inhibits the uptake of radioactive 2-deoxyglucose and of uniformly labeled amino acids. The addition of PMA similarly inhibits the uptake of 14C-labeled bacteria, suggesting a competition between the effect of the chemical and the process of phagocytosis. These results suggest that PMA activates the cell in the same manner as does phagocytosis. This compound should provide a useful tool for elucidating the metabolic events underlying the phenomena of phagocytosis and bacterial killing by polymorphonuclear leukocytes.     

Interaction between human polymorphonuclear leukocytes and Streptococcus milleri group bacteria.

Because Streptococcus milleri group (SMG) bacteria--Streptococcus constellatus, Streptococcus intermedius, and Streptococcus anginosus--exhibit a striking propensity to cause abscesses, the interaction of these organisms with human polymorphonuclear leukocytes (PMNL) was examined. After incubation in pooled normal human serum, SMG stimulated less chemotaxis than did Staphylococcus aureus, in contrast to viridans streptococci, which caused greater chemotaxis than did S. aureus. PMNL ingested greater numbers of SMG and viridans streptococci than S. aureus but killed these organisms more slowly and less completely. Relative resistance to killing by PMNL is expected in organisms that cause abscesses, and inhibition of chemotaxis may contribute to pathogenicity, because delayed arrival of PMNL gives a head start to proliferating bacteria. This study helps explain the capacity of SMG to cause abscesses. It is unclear, however, why viridans streptococci, bacteria that rarely produce abscesses, share some of these same properties.     

Phagocytosis and killing of Brucella by human polymorphonuclear leukocytes

Although cellular immunity involving activated macrophages is important in resistance to Brucella, serum factors and polymorphonuclear leukocytes (PMNLs) play some role in the initial response to infection. The interaction between human PMNLs and virulent and attenuated strains of Brucella abortus and Brucella melitensis was studied by in vitro techniques. Virulent and attenuated strains of both species were rapidly phagocytosed after opsonization with normal human serum (NHS); nonopsonized bacteria were not phagocytosed. In contrast, NHS devoid of detectable antibodies was bactericidal for strains of B. abortus but not of B. melitensis. In addition, intracellular killing of ingested bacteria was shown for virulent B. abortus but not for B. melitensis. Ultrastructural studies revealed morphological alterations in about one-half of phagocytosed B. abortus and B. melitensis after incubation for 10 min; thereafter, nearly 100% of B. abortus showed some degree of degeneration, whereas B. melitensis remained intact during 120 min of observation.     

Kinetics of phagocytosis and bacterial killing by human polymorphonuclear leukocytes and monocytes.

The kinetics of phagocytosis and bacterial killing by normal human polymorphonuclear leukocytes (PMNLs) and by monocytes (MNs) were compared by use of [3H]thymidine-labeled Staphylococcus aureus, Escherichia coli, and Listeria monocytogenes. The rate of phagocytosis by PMNLs was approximately twice that by MNs for all three bacterial species. Although a marked difference was found in opsonic requirements for phagocytosis of S. aureus, E. coli, and L. monocytogenes, phagocytosis by PMNLs and MNs was mediated via the same serum factors. All three species were killed rapidly once they were associated with leukocytes; however, the rate of killing by MNs was slower than that of PMNLs. The slower rate of killing appeared to be secondary to slower ingestion of attached bacteria by MNs. Thus, PMNLs and MNs appear to possess receptors with specificity for the same bacterial opsonins; however, PMNLs are capable of more efficienct bacterial phagocytosis (attachment and ingestion) than are MNs.     

Inhalation exposure to ambient polycyclic aromatic hydrocarbons and lung cancer risk of Chinese population

An Euler atmospheric transport model (Canadian Model for Environmental Transport of Organochlorine Pesticides, CanMETOP) was applied and validated to estimate polycyclic aromatic hydrocarbon (PAH) ambient air concentrations at ground level in China based on a high-resolution emission inventory. The results were used to evaluate lung cancer risk for the Chinese population caused by inhalation exposure to PAHs. The uncertainties of the transport model, exposure, and risk analysis were assessed by using Monte Carlo simulation, taking into consideration the variation in PAH emission, aerosol and OH radical concentrations, dry deposition, respiration rate, and genetic susceptibility. The average benzo[a]pyrene equivalent concentration (B[a]P_eq) was 2.43 [≈1.29–4.50 as interquartile range (IR)] ng/m³. The population-weighted B[a]P_eq was 7.64 (IR, ≈4.05–14.1) ng/m³ because of the spatial overlap of the emissions and population density. It was estimated that 5.8% (IR, ≈2.0–11%) of China''s land area, where 30% (IR, ≈17–43%) of the population lives, exceeded the national ambient B[a]P_eq standard of 10 ng/m³. Taking into consideration the variation in exposure concentration, respiration rate, and susceptibility, the overall population attributable fraction (PAF) for lung cancer caused by inhalation exposure to PAHs was 1.6% (IR, ≈0.91–2.6%), corresponding to an excess annual lung cancer incidence rate of 0.65 × 10⁻⁵. Although the spatial variability was high, the lung cancer risk in eastern China was higher than in western China, and populations in major cities had a higher risk of lung cancer than rural areas. An extremely high PAF of >44% was estimated in isolated locations near small-scale coke oven operations.     

Diet and inflammation: a link to metabolic and cardiovascular diseases.

Both epidemiological studies and intervention trials support an important role of diet in reducing the risk of a variety of chronic diseases, including cardiovascular disease, and overall mortality. We discuss available evidence indicating that the generation of a pro-inflammatory milieu might be one mechanism through which unhealthy diets are linked to metabolic and cardiovascular diseases. In practical terms, fully understanding the link between diet and inflammation holds the premise to elucidate the mechanisms by which dietary patterns improve cardiovascular health.     

Hydrogen peroxide production and killing of Staphylococcus aureus by human polymorphonuclear leukocytes.

The effects of bacterial neuraminidase on production of hydrogen peroxide (H2O2) and killing of Staphylococcus aureus by human polymorphonuclear leukocytes (PMN) were studied. The concentration of H2O2 was measured by the disappearance of scopoletin fluorescence in the presence of horseradish peroxidase. The results indicated that desialylation of human PMN inhibited the stimulation of H2O2 production during phagocytosis. It also markedly impaired the killing of S. aureus. Impaired killing of S. aureus by desialylated PMN was due to impaired intracellular killing rather than defective phagocytosis.     

Microbes: possible link between modern lifestyle transition and the rise of metabolic syndrome

The rapid decrease in infectious diseases globally has coincided with an increase in the prevalence of obesity and other components of metabolic syndrome. Insulin resistance is a common feature of metabolic syndrome and can be influenced by genetic and non‐genetic/environmental factors. The emergence of metabolic syndrome epidemics over only a few decades suggests a more prominent role of the latter. Changes in our environment and lifestyle have indeed paralleled the rise in metabolic syndrome. Gastrointestinal tract microbiota, the composition of which plays a significant role in host physiology, including metabolism and energy homeostasis, are distinctly different within the context of metabolic syndrome. Among humans, recent lifestyle‐related changes could be linked to changes in diversity and composition of ‘ancient’ microbiota. Given the co‐adaptation and co‐evolution of microbiota with the immune system over a long period of time, it is plausible that such lifestyle‐related microbiota changes could trigger aberrant immune responses, thereby predisposing an individual to a variety of diseases. Here, we review current evidence supporting a role for gut microbiota in the ongoing rise of metabolic syndrome. We conclude that population‐level shifts in microbiota can play a mediatory role between lifestyle factors and pathogenesis of insulin resistance and metabolic syndrome.     

Mutagenesis of the Ha-ras oncogene in mouse skin tumors induced by polycyclic aromatic hydrocarbons.

The importance of mutational activation of the Ha-ras protooncogene in polycyclic aromatic hydrocarbon-induced mouse skin tumors was investigated in a complete carcinogenesis model using repetitive applications of 7,12-dimethylbenz[a]anthracene (DMBA), or in an initiation-promotion model using a single application of dibenz[c,h]acridine (DB[c,h]ACR) or benzo[a]pyrene (B[a]BP) followed by chronic treatment with phorbol 12-myristate 13-acetate. DNA isolated from carcinomas induced by DMBA or DB[c,h]ACR, but not by B[a]P, efficiently transformed NIH 3T3 cells, and a high percentage of the transformed foci had an amplified Ha-ras gene. Restriction enzyme Southern blot analysis and DNA sequencing revealed that the amplified Ha-ras genes of the transformants had an A----T transversion in the second position of the 61st codon. The same mutation was also detected in primary tumor DNA in a high percentage of the DMBA- or DB[c,h]ACR-induced carcinomas. Identification of the mutation in NIH 3T3 cells transformed with DNA from DB[c,h]ACR-induced benign skin papillomas suggests that it is an early event in skin carcinogenesis. Thus, mutation of the 61st codon of the Ha-ras-1 gene appears to be a critical step in the formation of mouse skin tumors induced in both of the two models tested. Our analyses also delineate two other classes of hydrocarbon-induced carcinomas--namely, tumors whose DNAs efficiently transform 3T3 cells but do not contain mutated ras genes and tumors whose DNAs do not transform 3T3 cells.     

Arachidonate metabolism by human polymorphonuclear leukocytes stimulated by N-formyl-Met-Leu-Phe or complement component C5a is independent of phospholipase activation.

Release of arachidonic acid by the membrane phospholipase and metabolism by the 5-lipoxygenase pathway was examined in human polymorphonuclear leukocytes (PMNs). The 5-lipoxygenase pathway is activated when PMNs are given arachidonic acid in ethanol and there is extensive metabolism to 5-hydroxyicosatetraenoic acid (5-HETE) and leukotriene B4 (LTB4). This activation event was shown to be altered by the ethanol because resting PMNs given arachidonic acid with bovine serum albumin fail to metabolize arachidonic acid. However, cells activated by the inflammatory agents N-formyl-Met-Leu-Phe (fMLF) or complement component C5a recruit the 5-lipoxygenase to metabolize exogenous arachidonic acid to 5-HETE and LTB4. When PMNs were incubated with arachidonic acid-bovine serum albumin and challenged with fMLF or C5a (des-Arg-C5a) they produced 49-75 pmol of LTB4 and 310-440 pmol of 5-HETE per 10(7) cells. PMNs stimulated by fMLF or C5a (des-Arg-C5a) do not induce membrane phospholipases to mobilize endogenous arachidonic acid and neither 5-HETE nor LTB4 is formed. In contrast, PMN stimulation by the ionophore A23187 activates both the membrane phospholipase and the 5-lipoxygenase to produce 5-HETE and LTB4 from endogenous arachidonic acid. Our results indicate that the lipoxygenase pathway is inoperative in resting PMNs but can be recruited by chemotactic factors to act on arachidonate from extracellular sources. It was previously believed that formation of 5-HETE and LTB4 by the PMN depends solely on phospholipase to mobilize endogenous arachidonic acid. The results reported here refute this concept and indicate that the role of phospholipase activation in PMN may be overestimated. Therefore, subsequent involvement of lipoxygenase products in mediating stimulation of PMN by inflammatory factors (e.g., as in aggregation and chemotaxis) remains in question unless an exogenous source of arachidonate can be identified.     

Effect of cyanide on NADPH oxidation by granules from human polymorphonuclear leukocytes.

Cyanide has been shown to stimulate both oxygen uptake and hexose monophosphate shunt activity in phagocytizing human polymorphonuclear leukocytes. It also stimulates the oxidation of NADPH by a particulate fraction derived from phagocytizing cells. This stimulation of NADPH oxidase is not observed in the presence of exogenous Mn2+. Studies with purified enzymes have shown that CN- also stimulates NADPH oxidation by horseradish peroxidase or lactoperoxidase, suggesting that the respiratory burst might be initiated by activation of a peroxidase-like enzyme in the human polymorphonuclear leukocyte. Based on studies of others, however, it does not appear as though the enzyme is identical to myeloperoxidase. The mechanism of the CN- stimulation appears to involve an oxidatic chain reaction, since it stimulates markedly NADPH oxidation in the presence of an artificial superoxide-generating system.     

JNKs, insulin resistance and inflammation: A possible link between NAFLD and coronary artery disease

The incidence of obesity has dramatically increased in recent years.Consequently,obesity and associated disorders such as nonalcoholic fatty liver disease constitute a serious problem.Therefore,the contribution of adipose tissue to metabolic homeostasis has become a focus of interest.In this review,we discuss the latest discoveries that support the role of lipids in nonalcoholic fatty liver disease.We describe the common mechanisms(cJun aminoterminal kinases,endoplasmic reticulum stress,unfolded protein res...     

Methicillin-resistant strains of Staphylococcus aureus: relation between expression of resistance and phagocytosis by polymorphonuclear leukocytes.

Virulent strains of staphylococci are known to resist phagocytic destruction better than avirulent strains. In this context, in vitro elimination by human polymorphonuclear leukocytes of eight methicillin-resistant strains of Staphylococcus aureus of unknown virulence was studied. After incubation for 1, 3, 5, or 24 hr in a modified phagocytic assay, the methicillin-resistant strains survived as well as other virulent but methicillin-sensitive strains of S. aureus. Highly resistant subpopulations were obtained from three parent strains, and a methicillin-sensitive revertant subpopulation from one resistant parent strain. All subpopulations were eliminated to the same extent as were the moderately resistant parent strains. When the phagocytic assay was performed in the presence of 25 microgram of methicillin/ml, only the methicillin-sensitive strains and the sensitive subpopulation derived from one resistant parent strain were eliminated after incubation for 24 hr. These in vitro data are further evidence against the use of methicillin in infections due to these organisms.