Does lithium attenuate the liver damage due to oxidative stress and liver glycogen depletion in experimental common bile duct obstruction?

In extrahepatic cholestasis, the molecular mechanisms of liver damage due to bile acid accumulation remain elusive. In this study, the activation of glutamatergic receptors was hypothesized to be responsible for bile acid-induced oxidative stress and liver damage. Recent evidence showed that lithium, as an N-methyl-d-aspartate receptor (NMDAR) GluN2B subunit inhibitor, may act on the glutamate/NMDAR signaling axis. Guinea pigs were assigned to four groups, as sham laparotomy (SL), bile duct ligated (BDL), lithium-treated SL (SL + Li) and lithium-treated BDL (BDL + Li) groups. Cholestasis-induced liver injury was evaluated by aspartate aminotransferase (AST), alanine transaminase (ALT), interleukin-6 (IL-6), tissue malondialdehyde (MDA), copper­zinc superoxide dismutase and reduced glutathione levels. The liability of glutamate/NMDAR signaling axis was clarified by glutamate levels in both plasma and liver samples, with the production of nitric oxide (NO), as well as with the serum calcium concentrations. Blood glucose, glucagon, insulin levels and glucose consumption rates, in addition to tissue glycogen were measured to evaluate the liver glucose-glycogen metabolism. A high liver damage index (AST/ALT) was calculated in BDL animals in comparison to SL group. In the BDL animals, lithium reduced plasma NO and glutamate in addition to tissue glutamate concentrations, while serum calcium increased. The antioxidant capacities and liver glycogen contents significantly increased, whereas blood glucose levels unchanged and tissue MDA levels decreased 3-fold in lithium-treated cholestatic animals. It was concluded that lithium largely protects the cholestatic hepatocyte from bile acid-mediated damage by blocking the NMDAR-GluN2B subunit.

Combined Toxicity of Metal Nanoparticles: Comparison of Individual and Mixture Particles Effect.

Toxicity of metal nanoparticles (NPs) are closely associated with increasing intracellular reactive oxygen species (ROS) and the levels of pro-inflammatory mediators. However, NP interactions and surface complexation reactions alter the original toxicity of individual NPs. To date, toxicity studies on NPs have mostly been focused on individual NPs instead of the combination of several species. It is expected that the amount of industrial and highway-acquired NPs released into the environment will further increase in the near future. This raises the possibility that various types of NPs could be found in the same medium, thereby, the adverse effects of each NP either could be potentiated, inhibited or remain unaffected by the presence of the other NPs. After uptake of NPs into the human body from various routes, protein kinases pathways mediate their toxicities. In this context, family of mitogen-activated protein kinases (MAPKs) is mostly efficient. Despite each NP activates almost the same metabolic pathways, the toxicity induced by a single type of NP is different than the case of co-exposure to the combined NPs. The scantiness of toxicological data on NPs combinations displays difficulties to determine, if there is any risk associated with exposure to combined nanomaterials. Currently, in addition to mathematical analysis (Response surface methodology; RSM), the quantitative-structure-activity relationship (QSAR) is used to estimate the toxicity of various metal oxide NPs based on their physicochemical properties and levels applied. In this chapter, it is discussed whether the coexistence of multiple metal NPs alter the original toxicity of individual NP. Additionally, in the part of "Toxicity of diesel emission/exhaust particles (DEP)", the known individual toxicity of metal NPs within the DEP is compared with the data regarding toxicity of total DEP mixture.

Aging and Protein Kinases.

Recently, aging has been tried to be explained with large numbers of theories, but none of them can elucidate the changes occurring in the aging process alone. A unified theory encompassing the mechanisms of genetic factors and repair systems in aging is becoming increasingly required. Almost 37 protein kinases contribute to all processes of aging and senescence. Furthermore, these kinases not only regulate the large number of metabolic pathways related to aging processes, but also control these pathways through 12 checkpoints. Thus, in this chapter, the metabolic targets of protein kinases signal transduction pathways were discussed in terms of the aging perspective under five headings, which are the indispensable stages of the aging process. Although the most popular classical aging theories have been stated as DNA damage theory, mitochondrial theory, free radical theory, and telomere theory, it was concluded that the aging process is controlled by protein kinases regardless of the different theories.

Protein Kinases Signaling in Pancreatic Beta-cells Death and Type 2 Diabetes.

Type 2 diabetes (T2D) is a worldwide serious public health problem. Insulin resistance and ß-cell failure are the two major components of T2D pathology. In addition to defective endoplasmic reticulum (ER) stress signaling due to glucolipotoxicity, ß-cell dysfunction or ß-cell death initiates the deleterious vicious cycle observed in T2D. Although the primary cause is still unknown, overnutrition that contributes to the induction of the state of low-grade inflammation, and the activation of various protein kinases-related metabolic pathways are main factors leading to T2D. In this chapter following subjects, which have critical checkpoints regarding ß-cell fate and protein kinases pathways are discussed; hyperglycemia-induced ß-cell failure, chronic accumulation of unfolded protein in ß-cells, the effect of intracellular reactive oxygen species (ROS) signaling to insulin secretion, excessive saturated free fatty acid-induced ß-cell apoptosis, mitophagy dysfunction, proinflammatory responses and insulin resistance, and the reprogramming of ß-cell for differentiation or dedifferentiation in T2D. There is much debate about selecting proposed therapeutic strategies to maintain or enhance optimal ß-cell viability for adequate insulin secretion in T2D. However, in order to achieve an effective solution in the treatment of T2D, more intensive clinical trials are required on newer therapeutic options based on protein kinases signaling pathways.

The Connection Between Cell Fate and Telomere.

Abolition of telomerase activity results in telomere shortening, a process that eventually destabilizes the ends of chromosomes, leading to genomic instability and cell growth arrest or death. Telomere shortening leads to the attainment of the "Hayflick limit", and the transition of cells to state of senescence. If senescence is bypassed, cells undergo crisis through loss of checkpoints. This process causes massive cell death concomitant with further telomere shortening and spontaneous telomere fusions. In functional telomere of mammalian cells, DNA contains double-stranded tandem repeats of TTAGGG. The Shelterin complex, which is composed of six different proteins, is required for the regulation of telomere length and stability in cells. Telomere protection by telomeric repeat binding protein 2 (TRF2) is dependent on DNA damage response (DDR) inhibition via formation of T-loop structures. Many protein kinases contribute to the DDR activated cell cycle checkpoint pathways, and prevent DNA replication until damaged DNA is repaired. Thereby, the connection between cell fate and telomere length-associated telomerase activity is regulated by multiple protein kinase activities. Contrarily, inactivation of DNA damage checkpoint protein kinases in senescent cells can restore cell-cycle progression into S phase. Therefore, telomere-initiated senescence is a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres. In this review, in addition to the above mentioned, the choice of main repair pathways, which comprise non-homologous end joining and homologous recombination in telomere uncapping telomere dysfunctions, are discussed.

Indoleamine 2,3-Dioxygenase Activity-Induced Acceleration of Tumor Growth, and Protein Kinases-Related Novel Therapeutics Regimens.

Indoleamine 2,3-dioxygenase (IDO) is overexpressed in response to interferon-gamma (IFN-γ). IDO-mediated degradation of tryptophan (Trp) along the kynurenine (Kyn) pathway by immune cells is associated with the anti-microbial, and anti-tumor defense mechanisms. In contrast, IDO is constitutively expressed by various tumors and creates an immunosuppressive microenvironment around the tumor tissue both by depletion of the essential amino acid Trp and by formation of Kyn, which is immunosuppressive metabolite of Trp. IDO may activate its own expression in human cancer cells via an autocrine aryl hydrocarbon receptor (AhR)- interleukin 6 (IL-6)-signal transducer and activator of transcription 3 (STAT3) signaling loop. Although IDO is not a unique marker, in many clinical trials serum IDO activity is suggested to be an important parameter in the pathogenesis of cancer development and growth. Measuring IDO activity in serum seems to be an indicator of cancer growth rate, however, it is controversial whether this approach can be used as a reliable guide in cancer patients treated with IDO inhibitors. Thus, IDO immunostaining is strongly recommended for the identification of higher IDO producing tumors, and IDO inhibitors should be included in post-operative complementary therapy in IDO positive cancer cases only. Novel therapies that target the IDO pathway cover checkpoint protein kinases related combination regimens. Currently, multi-modal therapies combining IDO inhibitors and checkpoint kinase blockers in addition to T regulatory (Treg) cell-modifying treatments seem promising.

N-Methyl-D-Aspartate Receptor Signaling-Protein Kinases Crosstalk in Cerebral Ischemia.

Although stroke is very often the cause of death worldwide, the burden of ischemic and hemorrhagic stroke varies between regions and over time regarding differences in prognosis, prevalence of risk factors, and treatment strategies. Excitotoxicity, oxidative stress, dysfunction of the blood-brain barrier, neuroinflammation, and lysosomal membrane permeabilization, sequentially lead to the progressive death of neurons. In this process, protein kinases-related checkpoints tightly regulate N-methyl-D-aspartate (NMDA) receptor signaling pathways. One of the major hallmarks of cerebral ischemia is excitotoxicity, characterized by overactivation of glutamate receptors leading to intracellular Ca2+ overload and ultimately neuronal death. Thus, reduced expression of postsynaptic density-95 protein and increased protein S-nitrosylation in neurons is responsible for neuronal vulnerability in cerebral ischemia. In this chapter death-associated protein kinases, cyclin-dependent kinase 5, endoplasmic reticulum stress-induced protein kinases, hyperhomocysteinemia-related NMDA receptor overactivation, ephrin-B-dependent amplification of NMDA-evoked neuronal excitotoxicity and lysosomocentric hypothesis have been discussed.Consequently, ample evidences have demonstrated that enhancing extrasynaptic NMDA receptor activity triggers cell death after stroke. In this context, considering the dual roles of NMDA receptors in both promoting neuronal survival and mediating neuronal damage, selective augmentation of NR2A-containing NMDA receptor activation in the presence of NR2B antagonist may constitute a promising therapy for stroke.

Alzheimer's Disease and Protein Kinases.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and accounts for more than 60-80% of all cases of dementia. Loss of pyramidal neurons, extracellular amyloid beta (Abeta) accumulated senile plaques, and neurofibrillary tangles that contain hyperphosphorylated tau constitute the main pathological alterations in AD.Synaptic dysfunction and extrasynaptic N-methyl-D-aspartate receptor (NMDAR) hyperactivation contributes to excitotoxicity in patients with AD. Amyloid precursor protein (APP) and Abeta promoted neurodegeneration develop through the activation of protein kinase signaling cascade in AD. Furthermore, ultimate neuronal death in AD is under control of protein kinases-related signaling pathways. In this chapter, critical check-points within the cross-talk between neuron and protein kinases have been defined regarding the initiation and progression of AD. In this context, amyloid cascade hypothesis, neuroinflammation, oxidative stress, granulovacuolar degeneration, loss of Wnt signaling, Abeta-related synaptic alterations, prolonged calcium ions overload and NMDAR-related synaptotoxicity, damage signals hypothesis and type-3 diabetes are discussed briefly.In addition to clinical perspective of AD pathology, recommendations that might be effective in the treatment of AD patients have been reviewed.

Iron homeostasis is altered in response to hypoxia and hypothermic preconditioning in brain glial cells

Background/aim: Altered iron metabolism is one of the pathophysiological mechanisms occurring during hypoxic injuries in the central nervous system. Proper homeostasis of cellular iron is regulated by iron import, storage, and export proteins that prevent excess iron overload or iron starvation in cells. Therapeutic hypothermia is an approved treatment for hypoxic ischemia in newborns, but the underlying molecular mechanism is still unknown. We studied the effects of hypoxia, preceded with preconditioning, on the iron homeostasis of glial cells, known as a major actor in the inflammatory process during perinatal brain injury. Materials and methods: Primary microglia and astrocytes in culture were exposed to 12 h of hypoxia with or without mild hypothermic preconditioning. The mRNA expression was assessed using qPCR. Iron accumulation was visualized via modified Perl's histochemistry. Cytokine levels in cell cultures were measured using ELISA. Results: Hypothermic preconditioning enhanced microglial viability, which previously was decreased in both cell types due to hypoxia. Hypoxia increased iron accumulation in the mixed glial cells and in ferritin expression in both microglia and astrocytes. Hypotermic preconditioning decreased the elevated ferritin-light chain expression significantly in microglia. Iron importer proteins, DMT1 and TfR1, both increased their mRNA expression after hypoxia, and hypothermic preconditioning continued to support the elevation of DMT1 in both glial cell types. Ferroportin expression increased as a survival factor of the glial cell following hypoxia. Hypothermic preconditioning supported this increase in both cell types and was especially significant in astrocytes. IL-10 levels were prominently increased in cell culture after hypothermic preconditioning. Conclusion: The data suggest that hypothermic preconditioning affects cellular iron homeostasis by regulating the storage and transfer proteins of iron. Regulation of the cellular iron traffic may prevent glial cells from experiencing the detrimental effects of hypoxia-related inflammation.

The blood-brain barrier and beyond: Nano-based neuropharmacology and the role of extracellular matrix.

Restrained drug delivery due to the blood-brain barrier (BBB) considerably limits options for the treatment of brain pathologies. The utilization of nanoparticulate (NP) carriers has been proposed as a solution. The development strategies need to address the important hurdle of NP passage across the BBB as well as the altered cellular up-take due to the pathophysiological changes of the damaged or diseased tissue as well as immunological and toxicological aspects of nanomedicine penetration. This review therefore scopes to: 1) outline the state-of-the art knowledge on BBB passage, 2) address the significant influence of pathological conditions on nanoparticulate drug delivery, and, 3) highlight the largely neglected role of the extracellular matrix (ECM). Interactions of the nanosystem with biological barriers, cells and ECM in the milieu of brain pathologies are critically discussed in order to present a holistic overview of the advances and pits of nanomedicine applications in brain disease.

Chemical-induced contact allergy: from mechanistic understanding to risk prevention.

Chemical allergens are small molecules able to form a sensitizing complex once they bound to proteins. One of the most frequent manifestations of chemical allergy is contact hypersensitivity, which can have serious impact on quality of life. Allergic contact dermatitis is a predominantly CD8 + T cell-mediated immune disease, resulting in erythema and eczema. Chemical allergy is of considerable importance to the toxicologist, who has the responsibility of identifying and characterizing the allergenic potential of chemicals, and estimating the risk they pose to human health. This review aimed at exploring the phenomena of chemical-induced contact allergy starting from a mechanistic understanding, immunoregulatory mechanisms, passing through the potency of contract allergen until the hazard identification, pointing out the in vitro models for assessing contact allergen-induced cell activation and the risk prevention.

Basophil mediated pro-allergic inflammation in vehicle-emitted particles exposure.

Despite of the fact that engine manufacturers develop a new technology to reduce exhaust emissions, insufficient attention given to particulate emissions. However, diesel exhaust particles are a major source of air-borne pollution, contain vast amount of polycyclic aromatic hydrocarbons (PAHs) and may have deleterious effects on the immune system, resulting in the induction and enhancement of pro-allergic processes. In the current study, vehicle emitted particles (VEP) from 2 different types of cars (diesel - D and gasoline - G) and locomotive (L) were collected. Overall, 129 four-week-old, male SPF-class Kunming mice were subcutaneously instilled with either low dose 100, 250 or high dose, 500mg/kg VEP and 15 mice were assigned as control group. The systemic toxicity was evaluated and alterations in the percentages of the CD3, CD4, CD8, CD16, CD25 expressing cells, basophils, eosinophils and neutrophils were determined. Basophil percentages were inversely associated with the PAH content of the VEPs, however basophil sensitization was more important than cell count in VEP exposure. Thus, the effects of VEP-PAHs emerge with the activation of basophils in an allergen independent fashion. Despite the increased percentage of CD4+ T cells, a sharp decrease in basophil counts at 500mg/kg of VEP indicates a decreased inhibitory effect of CD16+ monocytes on the proliferation of CD4+ T cell and suppressed polarization into a Th2 phenotype. Therefore, although the restrictions for vehicles emissions differ between countries, follow up studies and strict regulations are needed.

Mechanistic understanding of nanoparticles' interactions with extracellular matrix: the cell and immune system.

Extracellular matrix (ECM) is an extraordinarily complex and unique meshwork composed of structural proteins and glycosaminoglycans. The ECM provides essential physical scaffolding for the cellular constituents, as well as contributes to crucial biochemical signaling. Importantly, ECM is an indispensable part of all biological barriers and substantially modulates the interchange of the nanotechnology products through these barriers. The interactions of the ECM with nanoparticles (NPs) depend on the morphological characteristics of intercellular matrix and on the physical characteristics of the NPs and may be either deleterious or beneficial. Importantly, an altered expression of ECM molecules ultimately affects all biological processes including inflammation. This review critically discusses the specific behavior of NPs that are within the ECM domain, and passing through the biological barriers. Furthermore, regenerative and toxicological aspects of nanomaterials are debated in terms of the immune cells-NPs interactions.

Protein bio-corona: critical issue in immune nanotoxicology.

With the expansion of the nanomedicine field, the knowledge focusing on the behavior of nanoparticles in the biological milieu has rapidly escalated. Upon introduction to a complex biological system, nanomaterials dynamically interact with all the encountered biomolecules and form the protein "bio-corona." The decoration with these surface biomolecules endows nanoparticles with new properties. The present review will address updates of the protein bio-corona characteristics as influenced by nanoparticle's physicochemical properties and by the particularities of the encountered biological milieu. Undeniably, bio-corona generation influences the efficacy of the nanodrug and guides the actions of innate and adaptive immunity. Exploiting the dynamic process of protein bio-corona development in combination with the new engineered horizons of drugs linked to nanoparticles could lead to innovative functional nanotherapies. Therefore, bio-medical nanotechnologies should focus on the interactions of nanoparticles with the immune system for both safety and efficacy reasons.

What Is Lipotoxicity?

Enlarged fat cells in obese adipose tissue diminish capacity to store fat and are resistant to the anti-lipolytic effect of insulin. Insulin resistance (IR)-associated S-nitrosylation of insulin-signaling proteins increases in obesity. In accordance with the inhibition of insulin-mediated anti-lipolytic action, plasma free fatty acid (FFA) levels increase. Additionally, endoplasmic reticulum stress stimuli induce lipolysis by activating cyclic adenosine monophosphate/Protein kinase A (cAMP/PKA) and extracellular signal-regulated kinase ½ (ERK1/2) signaling in adipocytes. Failure of packaging of excess lipid into lipid droplets causes chronic elevation of circulating fatty acids, which can reach to toxic levels within non-adipose tissues. Deleterious effects of lipid accumulation in non-adipose tissues are known as lipotoxicity. In fact, triglycerides may also serve a storage function for long-chain non-esterified fatty acids and their products such as ceramides and diacylglycerols (DAGs). Thus, excess DAG, ceramide and saturated fatty acids in obesity can induce chronic inflammation and have harmful effect on multiple organs and systems. In this context, chronic adipose tissue inflammation, mitochondrial dysfunction and IR have been discussed within the scope of lipotoxicity.

Adipocyte-Macrophage Cross-Talk in Obesity.

Obesity is characterized by the chronic low-grade activation of the innate immune system. In this respect, macrophage-elicited metabolic inflammation and adipocyte-macrophage interaction has a primary importance in obesity. Large amounts of macrophages are accumulated by different mechanisms in obese adipose tissue. Hypertrophic adipocyte-derived chemotactic monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2) pathway also promotes more macrophage accumulation into the obese adipose tissue. However, increased local extracellular lipid concentrations is a final mechanism for adipose tissue macrophage accumulation. A paracrine loop involving free fatty acids and tumor necrosis factor-alpha (TNF-alpha) between adipocytes and macrophages establishes a vicious cycle that aggravates inflammatory changes in the adipose tissue. Adipocyte-specific caspase-1 and production of interleukin-1beta (IL-1beta) by macrophages; both adipocyte and macrophage induction by toll like receptor-4 (TLR4) through nuclear factor-kappaB (NF-kappaB) activation; free fatty acid-induced and TLR-mediated activation of c-Jun N-terminal kinase (JNK)-related pro-inflammatory pathways in CD11c+ immune cells; are effective in macrophage accumulation and in the development of adipose tissue inflammation. Old adipocytes are removed by macrophages through trogocytosis or sending an "eat me" signal. The obesity-induced changes in adipose tissue macrophage numbers are mainly due to increases in the triple-positive CD11b+ F4/80+ CD11c+ adipose tissue macrophage subpopulation. The ratio of M1-to-M2 macrophages is increased in obesity. Furthermore, hypoxia along with higher concentrations of free fatty acids exacerbates macrophage-mediated inflammation in obesity. The metabolic status of adipocytes is a major determinant of macrophage inflammatory output. Macrophage/adipocyte fatty-acid-binding proteins act at the interface of metabolic and inflammatory pathways. Both macrophages and adipocytes are the sites for active lipid metabolism and signaling.

MicroRNA and Adipogenesis.

In obesity, the process of adipogenesis largely determines the number of adipocytes in body fat depots. Adipogenesis is regulated by several adipocyte-selective microRNAs (miRNAs) and transcription factors that modulate adipocyte proliferation and differentiation. However, some miRNAs block expression of master regulators of adipogenesis. Additionally, specific miRNAs have been implicated in adipocyte differentiation and mature adipocyte functions. While, each miRNA targets multiple mRNAs, which may coordinate or antagonize each other's functions, several miRNAs are dysregulated in other tissues during obesity-related comorbidities. In this respect, development of lipid droplets, macrophage accumulation, macrophage polarization, tumor necrosis factor receptor-associated factor 6 activity, lipolysis, lipotoxicity and insulin resistance are effectively controlled by miRNAs.

The Interactions Between Kynurenine, Folate, Methionine and Pteridine Pathways in Obesity.

Obesity activates both innate and adaptive immune responses in adipose tissue. Elevated levels of eosinophils with depression of monocyte and neutrophil indicate the deficiencies in the immune system of morbidly obese individuals. Actually, adipose tissue macrophages are functional antigen-presenting cells that promote the proliferation of interferon-gamma (IFN-gamma)-producing CD4+ T cells in adipose tissue of obese subjects. Eventually, diet-induced obesity is associated with the loss of tissue homeostasis and development of type 1 inflammatory responses in visceral adipose tissue. Activity of inducible indoleamine 2,3-dioxygenase-1 (IDO-1) plays a major role under pro-inflammatory, IFN-gamma dominated settings. One of the two rate-limiting enzymes which can metabolize tryptophan to kynurenine is IDO-1. Tumor necrosis factor-alpha (TNF-alpha) correlates with IDO-1 in adipose compartments. Actually, IDO-1-mediated tryptophan catabolism due to chronic immune activation is the cause of reduced tryptophan plasma levels and be considered as the driving force for food intake in morbidly obese patients. Thus, decrease in plasma tryptophan levels and subsequent reduction in serotonin (5-HT) production provokes satiety dysregulation that leads to increased caloric uptake and obesity. However, after bariatric surgery, weight reduction does not lead to normalization of IDO-1 activity. Furthermore, there is a connection between arginine and tryptophan metabolic pathways in the generation of reactive nitrogen intermediates. Hence, abdominal obesity is associated with vascular endothelial dysfunction and reduced nitric oxide (NO) availability. IFN-gamma-induced activation of the inducible nitric oxide synthase (iNOS) and dissociation of endothelial adenosine monophosphate activated protein kinase (AMPK)- phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt)- endothelial NO synthase (eNOS) pathway enhances oxidative stress production secondary to high-fat diet. Thus, reduced endothelial NO availability correlates with the increase in plasma non-esterified fatty acids and triglycerides levels. Additionally, in obese patients, folate-deficiency leads to hyperhomocysteinemia. Folic acid confers protection against hyperhomocysteinemia-induced oxidative stress.

Could 8-oxoguanine DNA glycosylase 1 Ser326Cys polymorphism be a biomarker of susceptibility in cancer?

Biomarkers are key molecular or cellular events that give an indication whether there is a threat for disease, whether a disease already exists, or how such disease may develop in an individual case. The discovery of polymorphisms in genes that function in the metabolism of chemicals and in DNA repair has demonstrated the importance of understanding the phenomenon of genetic susceptibility in a population. Polymorphisms in DNA repair genes as an important component of the individual susceptibility to the development of cancer and various hereditary diseases have been commonly studied, since these genes have critical roles in maintaining genome integrity. Furthermore, the evaluation of cancer risk depends on the level of exposure to carcinogenic factors as well as on the genetic codes of the individual. This approach is supported by studies that present positive association between these polymorphic genes and cancers. Although 8-oxoguanine DNA glycosylase 1 (OGG1) is one of the promising biomarker candidates of cancer susceptibility, there are also some controversial results. Epidemiological studies show that the OGG1 might be a biomarker of susceptibility for various cancers; however, the small sample size and difference in the eligibility criteria for inclusion of subjects and sources might limit the studies to demonstrate the association between the OGG1 Ser326Cys polymorphism and the risk of cancer. Thus, meta-analyses may provide more valuable and reliable data to demonstrate the potential of OGG1 Ser326Cys DNA repair enzyme polymorphisms that could be the biomarkers of susceptibility of cancer. Our aim in this review is to compile published studies, including some controversial results on the association between the OGG1 Ser326Cys polymorphism and the risk of cancer.

Effects of co-selection of antibiotic-resistance and metal-resistance genes on antibiotic-resistance potency of environmental bacteria and related ecological risk factors.

The inadequate elimination of micropollutants in wastewater treatment plants (WWTP), cause to increase in the incidence of antibiotic resistant bacterial strains. Growth of microbial pathogens in WWTP is one of the serious public health problems. The widespread and simultaneous emergence of antibiotic resistance genes (ARGs) and heavy metal resistance genes (HMRGs) in the environment with heavy metals create persistent and selective pressure for co-selection of both genes on environmental microorganisms. Co-localization of ARGs and HMRGs on the same horizontal mobile genetic elements (MGEs) allows the spreading of numerous antibiotic-resistant strains of bacteria in aquatic and terrestrial environment. The biofilm formation and colonization potential of environmental bacteria leads to the co-selection of multi-antibiotic resistance and multi-metal tolerance. Horizontal gene transfer (HGT), co-localization of both ARGs and HMRGs on the same MGEs, and the shared resistomes are important bacteria-associated ecological risks factors, which reduce the effectiveness of antibiotics against bacterial infections.