Search

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and invasive type of pancreatic cancer (PCa) and is expected to be the second most common cause of cancer-associated deaths. The high mortality rate is due to the asymptomatic progression of the clinical features until the advanced stages of the disease and the limited effectiveness of the current therapeutics. Aberrant expression of several microRNAs (miRs/miRNAs) has been related to PDAC progression and thus they could be potential early diagnostic, prognostic, and/or therapeutic predictors for PDAC. miRs are small (18 to 24 nucleotides long) non-coding RNAs, which regulate the expression of key genes by targeting their 3′-untranslated mRNA region. Increased evidence has also suggested that the chemoresistance of PDAC cells is associated with metabolic alterations. Metabolic stress and the dysfunctionality of systems to compensate for the altered metabolic status of PDAC cells is the foundation for cellular damage. Current data have implicated multiple systems as hallmarks of PDAC development, such as glutamine redox imbalance, oxidative stress, and mitochondrial dysfunction. Hence, both the aberrant expression of miRs and dysregulation in metabolism can have unfavorable effects in several biological processes, such as apoptosis, cell proliferation, growth, survival, stress response, angiogenesis, chemoresistance, invasion, and migration. Therefore, due to these dismal statistics, it is crucial to develop beneficial therapeutic strategies based on an improved understanding of the biology of both miRs and metabolic mediators. This review focuses on miR-mediated pathways and therapeutic resistance mechanisms in PDAC and evaluates the impact of metabolic alterations in the progression of PDAC.

Aim: The aim of our study is to the evaluation of melatonin (MLT) and Momordica charantia (MC) combination on PC-3 and HT-29 cancer lines and to address the question of where or not MLT increases MC antitumor effect in the PC-3 and HT-29 cancer lines. Material and Method: The PC-3 and HT-29 cell lines were grown in a manufacturer-specified culture medium. Cisplatin, MLT, increasing concentrations of MC, 40 μg/ml MLT + increasing concentrations MC were applied to PC-3 and HT-29 cell lines for 72 hours. 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) cell viability, Total Antioxidant Capacity (TAC), Total Oxidant Status (TOS), Cellular Migration (Wound Healing test), and Lactate Dehydrogenase (LDH) tests were done 72 hours after drug administration.Results: The combination of MLT 40 μg/ml + MC 100 µg/ml reduced cell viability in both PC-3 and HT-29 cells. Besides, TAC and TOS levels showed a correlation with LDH and MTT assays and were found to be statistically significant (P, Amaç: Çalışmamızın amacı, PC-3 ve HT-29 kanser hatlarında melatonin (MLT) ve Momordica charantia (MC) kombinasyonunun değerlendirilmesi ve MLT'nin PC-3 ve HT-29 kanser hatlarında MC antitümör etkisini nerede artırdığı sorusunu ele almaktır. Gereç ve yöntem: PC-3 ve HT-29 hücre çizgileri, üreticinin belirlediği bir kültür ortamında büyütüldü. Sisplatin, MLT, artan MC konsantrasyonları, MLT 40 μg / ml + artan konsantrasyonlar MC, PC-3 ve HT-29 hücre hatlarına 72 saat süreyle uygulandı. 3- (4,5-Dimetiltiyazol-2-Yl) -2,5-Difeniltetrazolyum Bromür (MTT) hücre canlılığı, Toplam Antioksidan Kapasitesi (TAC), Toplam Oksidan Durumu (TOS), Hücresel Göç (Yara İyileştirme testi) ve Laktat Dehidrojenaz (LDH) testleri, ilaç uygulamasından 72 saat sonra yapıldı.Bulgular: MLT 40 ug / ml + MC 100 ug / ml kombinasyonu, hem PC-3 hem de HT-29 hücrelerinde hücre canlılığını azalttı. Ayrıca TAC ve TOS seviyeleri LDH ve MTT testleri ile korelasyon gösterdi ve istatistiksel olarak anlamlı bulundu (P

Glutamate, one of the most important excitatory neurotransmitters, acts as a signal transducer in peripheral tissues and endocrine cells. Excessive glutamate secretion has been shown to cause excitotoxicity and neurodegenerative disease. Cerebrolysin is a mixture of enzymatically treated peptides derived from pig brain including neurotrophic factors, like brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and ciliary neurotrophic factor (CNTF). The present study investigated the protective effects of cerebrolysin on glutamate transporters (EAAT 1, EAAT 2) and cytokines (IL-1β and IL-10) activity in glutamate-mediated neurotoxicity. Primary cortex neuron culture was exposed to glutamate and successively treated with various cerebrolysin concentrations for 24 and 48 h. Our data showed that cerebrolysin primarily protects neurons by decreasing glutamate concentration in the synaptic cleft. In addition, Cerebrolysin can decrease oxidative stress and neuron cell damage by increasing antioxidant activity and decreasing inflammation cytokine levels.

This paper describes the synthesis of enamino carbonyl compounds by the copper(i)-catalyzed coupling of acceptor-substituted diazo compounds and tertiary thioamides. We plan to use this method to synthesize indolizidine (-)-237D analogs to find α6-selective antismoking agents. Therefore, we also performed

Methylmercury (MeHg) is a globally relevant environmental neurotoxic pollutant. Recent evidence from the Faroe Islands and Seychelles cohort studies suggest that maternal exposure to MeHg via consumption of contaminated fish and seafood results in transplacental exposure of the fetus to MeHg, seriously affecting fetal neurodevelopment. In birth cohorts, with mercury exposure below the existing tolerable weekly intake (1.3 μg/kg b.w., European Food Safety Authority) MeHg exposure associations to adverse neurodevelopmental effects have been observed. However, there are inconsistencies between studies, attributing confounding factors as the primary source of data variability. We summarize current knowledge of MeHg-mediated effects during nervous system development. Major molecular targets are thiols and selenols and, in particular, selenoenzymes, resulting in exacerbated oxidative stress–related damage. Generation of reactive oxygen species (ROS) is an underlying trigger for apoptosis. Low levels of MeHg can induce apoptotic death in cerebellar neurons, and MeHg can induce endoplasmic reticulum stress, disrupt calcium homeostasis, and cause mitochondrial disruption. At a cellular level, the effects of MeHg exposure involve the dysfunction of a myriad of neurodevelopment and neurobehavioral functions.

Humans are exposed to multiple chemicals on a daily basis instead of to just a single chemical, yet the majority of existing toxicity data comes from single-chemical exposure. Multiple factors must be considered such as the route, concentration, duration, and the timing of exposure when determining toxicity to the organism. The need for adequate model systems (in vivo, in vitro, in silico and mathematical) is paramount for better understanding of chemical mixture toxicity. Currently, shortcomings plague each model system as investigators struggle to find the appropriate balance of rigor, reproducibility and appropriateness in mixture toxicity studies. Significant questions exist when comparing single-to mixture-chemical toxicity concerning additivity, synergism, potentiation, or antagonism. Dose/concentration relevance is a major consideration and should be subthreshold for better accuracy in toxicity assessment. Previous work was limited by the technology and methodology of the time, but recent advances have resulted in significant progress in the study of mixture toxicology. Novel technologies have added insight to data obtained from in vivo studies for predictive toxicity testing. These include new in vitro models: omics-related tools, organs-on-a-chip and 3D cell culture, and in silico methods. Taken together, all these modern methodologies improve the understanding of the multiple toxicity pathways associated with adverse outcomes (e.g., adverse outcome pathways), thus allowing investigators to better predict risks linked to exposure to chemical mixtures. As technology and knowledge advance, our ability to harness and integrate separate streams of evidence regarding outcomes associated with chemical mixture exposure improves. As many national and international organizations are currently stressing, studies on chemical mixture toxicity are of primary importance., The research was partly supported by the Ministry of Education, Science and Technological Development of Serbia (Project III 46009), the Special Research Account of University of Crete (ELKE No 3550, No 3963, No 4920) and the University of Crete Spin- Off ToxPlus S.A., the Oklahoma State University Center for Health Science Pilot Grant Program (#1-54333), Ministry of Research and Innovation in Romania: Program 1—The Improvement of the National System of Research and Development, Subprogram 1.2—Institutional Excellence—Projects of Excellence Funding in RDI, Contract No. 7PFE/16.10.2018.

Smoking-cessation drugs bind many off-target nicotinic acetylcholine receptors (nAChRs) and cause severe side effects if they are based on nicotine. New drugs that bind only those receptors, such as α6β2* nAChR, implicated in nicotine addiction would avoid the off-target binding. Indolizidine (-)-237D (IND (-)-237D), a bicyclic alkaloid, has been shown to block α6β2* containing nAChRs and functionally inhibit the nicotine-evoked dopamine release. To improve the affinity of indolizidine (-)-237D for α6β2*, we built a library of 2226 analogs. We screened virtually the library against a homology model of α6β2 nAChR that we derived from the recent crystal structure of α4β2 nAChR. We also screened the crystal structure of α4β2 nAChR as a control on specificity. We ranked the compounds based on their predicted free energy of binding. We selected the top eight compounds bound in their best pose and subjected the complexes to 100 ns molecular dynamics simulations to assess the stability of the complexes. All eight analogs formed stable complexes for the duration of the simulations. The results from this work highlight nine distinct analogs of IND (-)-237D with high affinity towards α6β2* nAChR. These leads can be synthesized and tested in in vitro and in vivo studies as lead candidates for drugs to treat nicotine addiction.

As our understanding of changes to the neurological system has improved, it has become clear that patients who have contracted human immunodeficiency virus type 1 (HIV-1) can potentially suffer from a cascade of neurological issues, including neuropathy, dementia, and declining cognitive function. The progression from mild to severe symptoms tends to affect motor function, followed by cognitive changes. Central nervous system deficits that are observed as the disease progresses have been reported as most severe in later-stage HIV infection. Examining the full spectrum of neuronal damage, generalized cortical atrophy is a common hallmark, resulting in the death of multiple classes of neurons. With antiretroviral therapy (ART), we can partially control disease progression, slowing the onset of the most severe symptoms such as, reducing viral load in the brain, and developing HIV-associated dementia (HAD). HAD is a severe and debilitating outcome from HIV-related neuropathologies. HIV neurotoxicity can be direct (action directly on the neuron) or indirect (actions off-site that affect normal neuronal function). There are two critical HIV-associated proteins, Tat and gp120, which bear responsibility for many of the neuropathologies associated with HAD and HIV-associated neurocognitive disorder (HAND). A cascade of systems is involved in HIV-related neurotoxicity, and determining a critical point where therapeutic strategies can be employed is of the utmost importance. This review will provide an overview of the existing hypotheses on HIV-neurotoxicity and the potential for the development of therapeutics to aid in the treatment of HIV-related nervous system dysfunction.

Recent research has helped clarify the role of cadmium (Cd) in various pathological states. We have demonstrated Cd involvement in pancreatic cancer, as well as the bioaccumulation of Cd in the pancreas. Bioaccumulation and increased toxicity suggest that Cd may also be involved in other pancreas-mediated diseases, like diabetes. Cd falls into the category of “hyperglycemic” metals, i.e., metals that increase blood glucose levels, which could be due to increased gluconeogenesis, damage to β-cells leading to reduced insulin production, or insulin resistance at target tissue resulting in a lack of glucose uptake. This review addresses the current evidence for the role of Cd, leading to insulin resistance from human, animal, and in vitro studies. Available data have shown that Cd may affect normal insulin function through multiple pathways. There is evidence that Cd exposure results in the perturbation of the enzymes and modulatory proteins involved in insulin signal transduction at the target tissue and mutations of the insulin receptor. Cd, through well-described mechanisms of oxidative stress, inflammation, and mitochondrial damage, may also alter insulin production in β-cells. More work is necessary to elucidate the mechanisms associated with Cd-mediated insulin resistance.

Tauopathies are a disease group characterized by either pathological accumulation or release of fragments of hyperphosphorylated tau proteins originating from the central nervous system. The tau hypotheses of Parkinson’s and Alzheimer’s diseases contain a clinically diverse spectrum of tauopathies. Studies of case records of various tauopathies may reveal clinical phenotype characteristics of the disease. In addition, improved understanding of different tauopathies would disclose environmental factors, such as xenobiotics and trace metals, that can precipitate or modify the progression of the disorder. Important for diagnostics and monitoring of these disorders is a further development of adequate biomarkers, including refined neuroimaging, or proteomics. Our goal is to provide an in-depth review of the current literature regarding the pathophysiological roles of tau proteins and the pathogenic factors leading to various tauopathies, with the perspective of future advances in potential therapeutic strategies. This research was partially funded by the Innlandet Hospital Trust, Norway, and by the Oklahoma State University Center for Health Sciences Seed/Pilot Grant Program, grant number 154357.

There is a growing body of evidence that various pesticides and heavy metals are carcinogenic. If not directly, there is also evidence that shows that these compounds can participate in carcinogenesis in a passive or permissive role, facilitating other compounds from inducing tumor formation. Little evidence is available to aid in understanding the toxicity of metal-pesticide mixtures. In many instances, exposure to subclinical, or subtoxic, levels would be asymptomatic under a single-chemical exposure. But, we do not know how these compounds would act together. A synergistic or potentiating response could be highly possible. By chemically interacting with the environment, as well as each other, metal pesticide mixtures may yield unpredictable toxicity. Because we are not exposed to a single xenobiotic at a time, the importance of studying the toxicity of mixtures has never been more critical.

Nickel compounds are Group 1 carcinogens and possibly cancer-causing in the pancreas. We examined the toxicity of nickel in both 2-D and 3-D pancreatic cell cultures, to determine the LD50 for organic and inorganic nickel in normal and cancerous cells. Assays with cadmium chloride were performed to be a comparison to potential nickel-induced toxicity. Cells were exposed to twelve concentrations of NiCl2 or Ni-(Ac)2 for 48h (2-D), or six concentrations for 48 hours (3-D). There was a significant (P=0.0016) difference between HPNE and AsPC-1 LD50values after cadmium exposure, at 69.9 μM and 29.2 μM, respectively. Neither form of nickel exhibited toxicity in 2-D or 3-D cultures, but after 48h, changes in spheroid morphology were observed. The inability of Ni to reduce viable cell numbers suggests a toxic mechanism that differs from cadmium, also a Group 1 carcinogen. The cell microenvironment was not a factor in nickel toxicity with no changes in viable cells in either 2-D or 3-D cultures. These studies only examined cytotoxicity, and not genotoxicity, a potential mechanism of nickel carcinogenicity. Alterations in DNA function or the expression of apoptotic proteins/processes would take longer to manifest. Current work focuses on cellular changes following extended nickel exposure. Uloga nikla, toksičnog metala, u nastanku karcinoma pankreasa još uvek nije u potpunosti ispitana. Cilj rada je da ispita toksičnost nikla (Ni) u 2-D i 3-D kulturi ćelija pankreasa, kako bi se utvrdila LD50 vrednost za organski i neorganski nikl u normalnim i tumorskim ćelijama. Ispitivanja su izvršena i sa kadmijumom (Cd), metalom čija je uloga u nastanku karcinoma pankreasa potvrđena u prethodnim istraživanjima, a u svrhu poređenja sa potencijalnom toksičnošću izazvanom Ni. Ćelije su bile tretirane sa 12 različitih koncentracija NiCl2 ili Ni-(Ac)2 tokom 48h (2-D), odnosno sa šest različitih koncentracija tokom 48 sati (3-D). Nijedan oblik Ni nije ispoljio toksičnost u 2-D ili 3-D kulturama, ali nakon 48h primećene su promene u sferoidnoj morfologiji. Nemogućnost Ni da smanji broj vijabilnih ćelija sugeriše mehanizam karcinogeneze različit od mehanizma koji ispoljava Cd. Ipak, da bi se uočile izmene u funkciji DNK ili izražavanju apoptotičkih proteina/procesa potrebno je duže vremena, pa su dalja istraživanja upravo fokusirana na ćelijske promene nakon produžene izloženosti nikla.

Pancreatic cancer (PC) is insidious with a high mortality rate due to the lack of symptomology prior to diagnosis. Mitochondrial involvement in PC development is becoming accepted, and exposure to cadmium (Cd) is suspected of being a risk factor for the development of PC; however, the mechanisms involved remain unclear. In this study, we examined the role of Cd as a mitochondrial toxicant and whether alterations in mitochondrial function may be an underlying cause for the development of PC. In this study, cadmium chloride (CdCl2)-mediated toxicity in hTERT-HPNE and AsPC-1 pancreatic cell lines was determined by MTT assay. We also investigated the release of LDH and the generation of free radicals. Mitochondrial toxicity assays were performed in media containing glucose (25 mM) or galactose (10 mM) and following exposure to CdCl2 (0-100 μM) followed by MTT assay. For the confirmation of mitochondrial toxicity, we measured the release of ATP following exposure to CdCl2. Initial experiments confirmed that exposure to CdCl2 did not reduce the viability of either cell line until a concentration of >10 μM was used. Non-linear analysis of the response curves revealed lethal concentration 50% (LC50) values for CdCl2 in the HPNE cells of 77 μM compared to 42 μM in the AsPC-1 cells (P tumor cells). Therefore, the findings of this study indicate that the mitochondria may be a site of action for cadmium in promoting tumor development.

Background: Cadmium and lead are widespread and non-biodegradable pollutants of great concern to human health. In real life scenarios, we are exposed to mixtures of chemicals rather than single chemicals, and it is therefore of paramount importance to assess their toxicity. In this study, we investigated the toxicity of Cd and Pb alone and as a mixture in an animal model of acute exposure. Methods: Experimental groups received a single treatment of aqueous solution of Cd-chloride (15 and 30 mg/kg body weight (b.w.) and Pb-acetate (150 mg/kg b.w.), while the mixture group received 15 mg Cd/kg b.w. and 150 mg Pb/kg b.w. Toxic effects of individual metals and their mixture were investigated on hematological and biochemical parameters, and the redox status in the plasma, liver, and kidneys of treated Wistar rats. Results: Tissue-specific changes were recorded in various parameters of oxidative damage, while the accumulation of metals in tissues accompanied the disturbances of both hematological and biochemical parameters. It was observed that the level of toxic metals in tissues had a different distribution pattern after mixture and single exposure. Conclusions: Comprehensive observations suggest that exposure to Cd and Pb mixtures produces more pronounced effects compared to the response observed after exposure to single metal solutions. However, further research is needed to confirm toxicokinetic or toxicodynamic interactions between these two toxic metals in the organisms.

Humans are exposed to a significant number of chemicals that are suspected to produce disturbances in hormone homeostasis. Hence, in recent decades, there has been a growing interest in endocrine disruptive chemicals. One of the alleged thyroid disrupting substances is cadmium (Cd), a ubiquitous toxic metal shown to act as a thyroid disruptor and carcinogen in both animals and humans. Multiple PubMed searches with core keywords were performed to identify and evaluate appropriate studies which revealed literature suggesting evidence for the link between exposure to Cd and histological and metabolic changes in the thyroid gland. Furthermore, Cd influence on thyroid homeostasis at the peripheral level has also been hypothesized. Both in vivo and in vitro studies revealed that a Cd exposure at environmentally relevant concentrations results in biphasic Cd dose-thyroid response relationships. Development of thyroid tumors following exposure to Cd has been studied mainly using in vitro methodologies. In the thyroid, Cd has been shown to activate or stimulate the activity of various factors, leading to increased cell proliferation and a reduction in normal apoptotic activity. Evidence establishing the association between Cd and thyroid disruption remains ambiguous, with further studies needed to elucidate the issue and improve our understanding of Cd-mediated effects on the thyroid gland.

The nuclear factor erythroid 2-related factor 2 (NRF2)–Kelch-like ECH-associated protein 1 (KEAP1) regulatory pathway plays an essential role in protecting cells and tissues from oxidative, electrophilic, and xenobiotic stress. By controlling the transactivation of over 500 cytoprotective genes, the NRF2 transcription factor has been implicated in the physiopathology of several human diseases, including cancer. In this respect, accumulating evidence indicates that NRF2 can act as a double-edged sword, being able to mediate tumor suppressive or pro-oncogenic functions, depending on the specific biological context of its activation. Thus, a better understanding of the mechanisms that control NRF2 functions and the most appropriate context of its activation is a prerequisite for the development of effective therapeutic strategies based on NRF2 modulation. In line of principle, the controlled activation of NRF2 might reduce the risk of cancer initiation and development in normal cells by scavenging reactive-oxygen species (ROS) and by preventing genomic instability through decreased DNA damage. In contrast however, already transformed cells with constitutive or prolonged activation of NRF2 signaling might represent a major clinical hurdle and exhibit an aggressive phenotype characterized by therapy resistance and unfavorable prognosis, requiring the use of NRF2 inhibitors. In this review, we will focus on the dual roles of the NRF2-KEAP1 pathway in cancer promotion and inhibition, describing the mechanisms of its activation and potential therapeutic strategies based on the use of context-specific modulation of NRF2.