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.

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.

Can iron, zinc, copper and selenium status be a prognostic determinant in COVID-19 patients?

In severe COVID-19, the levels of iron (Fe), copper (Cu), zinc (Zn) and selenium (Se), do not only regulate host immune responses, but modify the viral genome, as well. While low serum Fe concentration is an independent risk factor for the increased death rate, Zn controls oxidative stress, synthesis of inflammatory cytokines and viral replication. Therefore, Zn deficiency associates with a worse prognosis. Although Cu exposure inactivates the viral genome and exhibits spike protein dispersal, increase in Cu/Zn due to high serum Cu levels, are correlated with enhanced risk of infections. Se levels are significantly higher in surviving COVID-19 patients. Meanwhile, both Zn and Se suppress the replication of SARS-CoV-2. Since the balance between the deficiency and oversupply of these metals due to a reciprocal relationship, has decisive effect on the prognosis of the SARS-CoV-2 infection, monitoring their concentrations may facilitate improved outcomes for patients suffering from COVID-19.

Current opinion in neurological manifestations of SARS-CoV-2 infection.

Neurological symptoms occur in approximately one-third of hospitalized patients with coronavirus disease 2019 (COVID-19). Among these symptoms, hypoxic encephalopathy develops in one-fifth of severe cases, while ischemic strokes due to thrombotic complications are common in one-third of COVID-19 intensive care patients. Brain involvement of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is eventuated by several routes, including hematogenous spread, transsynaptic entry through infected neurons, olfactory nerve, ocular epithelium, vascular endothelium, and impaired blood-brain barrier. Besides the high angiotensin-converting enzyme-2 (ACE2) binding affinity, and FURIN preactivation, SARS-CoV-2 maintains efficient neuronal entry while evading immune surveillance by using basigin and neuropilin-1 receptors. However, the neurological manifestations and their pathogenic mechanisms are still debated in COVID-19 patients.

The effect of environmental diesel exhaust pollution on SARS-CoV-2 infection: The mechanism of pulmonary ground glass opacity.

Diesel exhaust particles (DEP) are the major components of atmospheric particulate matter (PM) and chronic exposure is recognized to enhance respiratory system complications. Although the spread of SARS-CoV-2 was found to be associated with the PMs, the mechanism by which exposure to DEP increases the risk of SARS-CoV-2 infection is still under discussion. However, diesel fine PM (dPM) elevate the probability of SARS-CoV-2 infection, as it coincides with the increase in the number of ACE2 receptors. Expression of ACE2 and its colocalized activator, transmembrane protease serine 2 (TMPRSS2) facilitate the entry of SARS-CoV-2 into the alveolar epithelial cells exposed to dPM. Thus, the coexistence of PM and SARS-CoV-2 in the environment augments inflammation and exacerbates lung damage. Increased TGF-ß1 expression due to DEP accompanies the proliferation of the extracellular matrix. In this case, "multifocal ground-glass opacity" (GGO) in a CT scan is an indication of a cytokine storm and severe pneumonia in COVID-19.

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.

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.

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.

The effect of environmental Bisphenol A exposure on breast cancer associated with obesity.

Bisphenol A (BPA) is a widely used endocrine disrupter. Its environmental exposure is a causative factor of cell aging via decreasing telomerase activity, thus leading to shortening of telomere length. Epidemiological studies confirm positive associations between BPA exposure and the incidence of obesity and type 2 diabetes (T2DM). Increased urinary BPA levels in obese females are both significantly correlated with shorter relative telomere length and T2DM. BPA is a critically effective endocrine disrupter leading to poor prognosis via the obesity-inflammation-aromatase axis in breast cancer. Environmental BPA exposure contributes to the progression of both estrogen dependent and triple negative breast cancers. BPA is a positive regulator of human telomerase reverse transcriptase (hTERT) and it increases the expression of hTERT mRNA in breast cancer cells. BPA exposure can lead to tamoxifen resistance. Among patients treated with chemotherapy, those with persistent high telomerase activity due to BPA are at higher risk of death.

The effect of environmental pollution on immune evasion checkpoints of SARS-CoV-2.

Many diverse strategies allow and facilitate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to evade antiviral innate immune mechanisms. Although the type I interferon (IFN) system has a critical role in restricting the dissemination of viral infection, suppression of IFN receptor signals by SARS-CoV-2 constitutes a checkpoint that plays an important role in the immune escape of the virus. Environmental pollution not only facilitates SARS-CoV-2 infection but also increases infection-associated fatality risk, which arises due to Systemic Aryl hydrocarbon Receptor (AhR) Activation Syndrome. The intracellular accumulation of endogenous kynurenic acid due to overexpression of the indoleamine 2,3-dioxygenase (IDO) by AhR activation induces AhR-interleukin-6 (IL-6)-signal transducers and activators of the transcription 3 (STAT3) signaling pathway. The AhR-IDO1-Kynurenine pathway is an important checkpoint, which leads to fatal consequences in SARS-CoV-2 infection and immune evasion in the context of Treg/Th17 imbalance and cytokine storm.

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.

Dual function of sialic acid in gastrointestinal SARS-CoV-2 infection.

Recent analysis concerning the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)- angiotensin converting enzyme (ACE) receptor interaction in enterocytes, the definition of gut-lung axis, as well as the molecular basis of sialic acid-related dual recognition concept in gastrointestinal SARS-CoV-2 infection, have brought a new perspective to potential therapeutic targets. In this review evolving research and clinical data on gastrointestinal SARS-CoV-2 infection are discussed in the context of viral fusion and entry mechanisms, focusing on the different triggers used by coronaviruses. Furthermore, it is emphasized that the viral spike protein is prevented from binding gangliosides, which are composed of a glycosphingolipid with one or more sialic acids, in the presence of chloroquine or hydroxychloroquine. In gastrointestinal SARS-CoV-2 infection the efficiency of these repositioned drugs is debated.

Two important controversial risk factors in SARS-CoV-2 infection: Obesity and smoking.

The effects of obesity and smoking in the coronavirus disease 2019 (COVID-19) pandemic remain controversial. Angiotensin converting enzyme 2 (ACE2), a component of the renin-angiotensin system (RAS), is the human cell receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. ACE2 expression increases on lung alveolar epithelial cells and adipose tissue due to obesity, smoking and air pollution. A significant relationship exists between air pollution and SARS-CoV-2 infection, as more severe COVID-19 symptoms occur in smokers; comorbid conditions due to obesity or excess ectopic fat accumulation as underlying risk factors for severe COVID-19 strongly encourage the virus/ACE2 receptor-ligand interaction concept. Indeed, obesity, air pollution and smoking associated risk factors share underlying pathophysiologies that are related to the Renin-Angiotensin-System in SARS-CoV-2 infection. The aim of this review is to emphasize the mechanism of receptor-ligand interaction and its impact on the enhanced risk of death due to SARS-CoV-2 infection.

Nanoantibiotics: A Novel Rational Approach to Antibiotic Resistant Infections.

BACKGROUND: The main drawbacks for using conventional antimicrobial agents are the development of multiple drug resistance due to the use of high concentrations of antibiotics for extended periods. This vicious cycle often generates complications of persistent infections, and intolerable antibiotic toxicity. The problem is that while all new discovered antimicrobials are effective and promising, they remain as only short-term solutions to the overall challenge of drug-resistant bacteria. OBJECTIVE: Recently, nanoantibiotics (nAbts) have been of tremendous interest in overcoming the drug resistance developed by several pathogenic microorganisms against most of the commonly used antibiotics. Compared with free antibiotic at the same concentration, drug delivered via a nanoparticle carrier has a much more prominent inhibitory effect on bacterial growth, and drug toxicity, along with prolonged drug release. Additionally, multiple drugs or antimicrobials can be packaged within the same smart polymer which can be designed with stimuli-responsive linkers. These stimuli-responsive nAbts open up the possibility of creating multipurpose and targeted antimicrobials. Biofilm formation still remains the leading cause of conventional antibiotic treatment failure. In contrast to conventional antibiotics nAbts easily penetrate into the biofilm, and selectively target biofilm matrix constituents through the introduction of bacteria specific ligands. In this context, various nanoparticles can be stabilized and functionalized with conventional antibiotics. These composites have a largely enhanced bactericidal efficiency compared to the free antibiotic. CONCLUSION: Nanoparticle-based carriers deliver antibiotics with better biofilm penetration and lower toxicity, thus combating bacterial resistance. However, the successful adaptation of nanoformulations to clinical practice involves a detailed assessment of their safety profiles and potential immunotoxicity.

Nanoparticles and neurotoxicity: Dual response of glutamatergic receptors.

Although the use of nanoparticles for neuro-diagnostic and neurotherapeutic purposes provides superior benefits than the conventional approaches, it may be potentially toxic in central nervous system. In this respect, nanotechnological research focuses on nanoneurotoxicity-nanoneurosafety concepts. Despite these efforts, nanoparticles (NPs) may cause neurotoxicity, neuroinflammation, and neurodegeneration by penetrating the brain-olfactory route and blood-brain barrier (BBB). Indeed, due to their unique structures nanomaterials can easily cross biological barriers, thus avoid drug delivery problems. Despite the advancement of nanotechnology for designing therapeutic agents, toxicity of these nanomaterials is still a concern. Activation of neurons by astrocytic glutamate is a result of NPs-mediated astrocyte-neuron crosstalk. Increased extracellular glutamate levels due to enhanced synthesis and reduced reuptake may induce neuronal damage by abnormal activation of extrasynaptic N-methyl d-aspartate receptor (NMDAR) subunits. NMDAR is the key factor that mediates the disturbances in intracellular calcium homeostasis, mitochondrial dysfunction and generation of reactive oxygen species in NPs exposed neurons. While some NPs cause neuronal death by inducing NMDARs, others may be neurotoxic through the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors or protect the neurons via blocking NMDARs. However, mechanisms of dual effects of NPs, neurotoxicity or neuroprotection are not precisely known. Some NPs present neuroprotective effect either by selectively inhibiting extrasynaptic subunit of NMDARs or by attenuating oxidative stress. NPs-related proinflammatory activation of microglia contributes to the dysfunction and cytotoxicity in neurons. Therefore, investigation of the interaction of NPs with the neuronal signaling molecules and neuronal receptors is necessary for the better understanding of the neurotoxicity or neurosafety of nanomaterials.