Current understandings and perspectives on non-cancer health effects of benzene: A global concern

Objective

Benzene, as a volatile organic compound, is known as one of the main air pollutants in the environment. The aim of this review is to summarize all available evidences on non-cancerous health effects of benzene providing an overview of possible association of exposure to benzene with human chronic diseases, specially, in those regions of the world where benzene concentration is being poorly monitored.

Methodology

A bibliographic search of scientific databases including PubMed, Google Scholar, and Scirus was conducted with key words of “benzene toxic health effects”, “environmental volatile organic compounds”, “diabetes mellitus and environmental pollutants”, “breast cancer and environmental pollution”, “prevalence of lung cancer”, and “diabetes prevalence”. More than 300 peer reviewed papers were examined. Experimental and epidemiologic studies reporting health effects of benzene and volatile organic compounds were included in the study.

Results

Epidemiologic and experimental studies suggest that benzene exposure can lead to numerous non-cancerous health effects associated with functional aberration of vital systems in the body like reproductive, immune, nervous, endocrine, cardiovascular, and respiratory.

Conclusion

Chronic diseases have become a health burden of global dimension with special emphasis in regions with poor monitoring over contents of benzene in petrochemicals. Benzene is a well known carcinogen of blood and its components, but the concern of benzene exposure is more than carcinogenicity of blood components and should be evaluated in both epidemiologic and experimental studies. Aspect of interactions and mechanism of toxicity in relation to human general health problems especially endocrine disturbances with particular reference to diabetes, breast and lung cancers should be followed up.     

Nitidine chloride induces apoptosis and inhibits tumor cell proliferation via suppressing ERK signaling pathway in renal cancer

Nitidine chloride (NC), a natural bioactive alkaloid derived from Zanthoxylum nitidum (Roxb) DC, has been shown to have inhibitory effects on various tumors. However, whether NC could exert anti-cancer activity and the underlying mechanisms have not been elucidated in renal cancer cells. In this study, we demonstrated the growth inhibitory and pro-apoptotic effects of NC on renal cancer cells both in vitro and in vivo. With cell viability and flow cytometric apoptosis assays, we found that NC potently suppressed the growth of 786-O and A498 cells in a time- and dose- dependent manner. Consistently, the xenograft model performed in nude mice exhibited reduced tumor growth with NC treatment. Mechanically, we presented that NC significantly decreased phosphorylation of ERK and Akt, accompanied by up-regulation of P53, Bax, cleavage caspase-3 and cleavage PARP, downregulation of Bcl-2, caspase-3 and PARP. Furthermore, a specific MEK inhibitor, PD98059, could potentiate the pro-apoptotic effects of NC, which indicated that NC might trigger apoptosis in renal cancer cells partly via inhibition of ERK activity. Taken together, our results imply that NC could be developed as a potential anticancer agent to renal cancer and worthy of further studies.     

Lysophosphatidic acid-induced IL-8 secretion involves MSK1 and MSK2 mediated activation of CREB1 in human fibroblast-like synoviocytes

Lysophosphatidic acid (LPA) is a pleiotropic lipid mediator that promotes motility, survival, and the synthesis of chemokines/cytokines such as interleukin-8 (IL-8) and interleukin-6 by human fibroblast-like synoviocytes from patients with rheumatoid arthritis (RAFLS). In those cells LPA was reported to induce IL-8 secretion through activation of various signaling pathways including p38 mitogen-activated protein kinase (p38 MAPK), p42/44 MAPK, and Rho kinase. In addition to those pathways we report that mitogen- and stress-activated protein kinases (MSKs) known to be activated downstream of the ERK1/2 and p38 MAPK cascades and CREB are phosphorylated in response to LPA. The silencing of MSKs with small-interfering RNAs and the pharmacological inhibitor of MSKs SB747651A shows a role for both MSK1 and MSK2 in LPA-mediated phosphorylation of CREB at Ser-133 and secretion of IL-8 and MCP-1. Whereas CREB inhibitors have off target effects and increased LPA-mediated IL-8 secretion, the silencing of CREB1 with short hairpin RNA significantly reduced LPA-induced chemokine production in RAFLS. Taken together the data clearly suggest that MSK1 and MSK2 are the major CREB kinases in RAFLS stimulated with LPA and that phosphorylation of CREB1 at Ser-133 downstream of MSKs plays a significant role in chemokine production.     

Protein kinase C isoforms in atherosclerosis: Pro- or anti-inflammatory?

Atherosclerosis is a pathologic condition caused by chronic inflammation in response to lipid deposition in the arterial wall. There are many known contributing factors such as long-term abnormal glucose levels, smoking, hypertension, and hyperlipidemia. Under the influence of such factors, immune and non-immune effectors cells are activated and participate during the progression of atherosclerosis. Protein kinase C (PKC) family isoforms are key players in the signal transduction pathways of cellular activation and have been associated with several aspects of the atherosclerotic vascular disease. This review article summarizes the current knowledge of PKC isoforms functions during atherogenesis, and addresses differential roles and disputable observations of PKC isoforms. Among PKC isoforms, both PKCβ and PKCδ are the most attractive and potential therapeutic targets. This commentary discusses in detail the outcomes and current status of clinical trials on PKCβ and PKCδ inhibitors in atherosclerosis-associated disorders like diabetes and myocardial infarction. The risk and benefit of these inhibitors for clinical purposes will be also discussed. This review summarizes what is already being done and what else needs to be done in further targeting PKC isoforms, especially PKCβ and PKCδ, for therapy of atherosclerosis and atherosclerosis-associated vasculopathies in the future.     

The effects of water immersion and restraint stress on the expressions of apelin,apelin receptor (APJR) and apoptosis rate in the rat heart

Apelin has been identified as an endogenous ligand of the orphan G-protein-coupled apelin receptor (APJR). These receptors are widely expressed in the central nervous system and periphery and play a role in the regulation of fluid and glucose homeostasis, feeding behavior, vessel formation, cell proliferation and immunity. We aimed to investigate whether water immersion and restraint stress have effects on apelin and APJR expression and apoptosis in heart tissue of male Wistar rats. The cardiac tissues were obtained from control, water immersion and restraint stress (WIRS) and apelin antagonist (F13A) + WIRS groups of rats and embedded in paraffin wax. Immunohistochemical staining methods were used to localize apelin, APJR and TUNEL immunopositive cells. H-SCORE was used for semi-quantitative determinations. Apelin protein levels were determined by Western blot in the cardiac tissues and plasma corticosteroid levels were measured by enzyme immunoassay (EIA). Apelin immunolocalization was found especially in endothelial cells and mast cells and faintly in cardiomyocytes, APJR immunostaining was shown in endothelial cells and cardiomyocytes, and TUNEL reaction was observed in endothelial cells and in some fibroblasts. Apelin expression was significantly increased in the WIRS and F13A + WIRS groups compared to the control group. The APJR reaction was similar in all groups. The number of TUNEL-positive cells was significantly higher in the F13A + WIRS group than that of the control group. Our study showed that WIRS for 6 h increased plasma corticosterone levels and cardiac apelin expression in rats. The increased levels of apelin inhibited stress-induced apoptosis in heart. These results may be important for the therapeutic approach to a variety of stress-related heart disease.     

Antioxidant marine algae phlorotannins and radioprotection: A review of experimental evidence

Radiation has been widely used for cancer therapy in human medicine. However, the side effects of radiation are problematic and can limit its application. Radiation generates reactive oxygen species, leading to cell death via multiple signaling pathways. The blocking of certain signaling cascades using antioxidants represents a compensatory therapy of radiation-induced tissue injury. Although synthetic chemicals have been investigated in recent decades, anti-oxidants from natural resources have been searched for continuously. Among them, phlorotannins from marine algae, including Ecklonia cava, have been shown to protect cells from radiation-induced injury as well as oxidative stress. In the present review, the radioprotective capacity of phlorotannins derived from marine algae and the mechanisms involved are discussed.     

The effect of pharmacological PI3Kγ inhibitor on eotaxin-induced human eosinophil functions

BackgroundAsthma is characterized by chronic inflammation caused by activation of immune cells including Th2 lymphocytes and eosinophils. Phosphoinositide 3-kinase (PI3K) γ deficient asthmatic mice did not develop lung eosinophilia, although the detailed mechanisms are not well known. A CC chemokine eotaxin (CCL11) plays a prominent role in developing eosinophilic inflammation through CCR3. In this study, we tested the roles of PI3Kγ in eotaxin-induced eosinophil functions using a pharmacological inhibitor.MethodHuman peripheral blood eosinophils were isolated by CD16-negative selection method. The effect of AS605240, synthetic PI3Kγ inhibitor on eotaxin-induced adhesion, chemotaxis, and degranulation were studied using intracellular adhesion molecule-1 (ICAM-1)-coated plates, Boyden chamber system, ELISA for eosinophil-derived neurotoxin (EDN) levels in the culture supernatant, respectively. CCR3 expression levels and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation were assessed by flowcytometry. Involvement of PI3Kγ in spontaneous apoptosis was studied using flowcytometry.ResultsAlthough AS605240 did not affect the eosinophil spontaneous apoptosis, eotaxin-induced chemotaxis, adhesion to ICAM-1 coated plate, and EDN release were inhibited by AS605240. AS605240 also inhibited the eotaxin-induced ERK1/2 phosphorylation without down-regulation of surface CCR3 expression.ConclusionThese results indicate that PI3Kγ inhibitor attenuates eotaxin-induced eosinophil functions by suppressing the downstream signaling of CCR3 without significant cytotoxicity. PI3Kγ plays an important role in the development of eosinophilic inflammation and blockade of PI3Kγ might be a therapeutic strategy for treatment of eosinophil-related diseases including asthma.