Regulation Of Intracellular Pathways Research Articles

Patient-Specific iPSCs-Based Models of Neurodegenerative Diseases: Focus on Aberrant Calcium Signaling.

The development of cell reprogramming technologies became a breakthrough in the creation of new models of human diseases, including neurodegenerative pathologies. The iPSCs-based models allow for the studying of both hereditary and sporadic cases of pathologies and produce deep insight into the molecular mechanisms underlying neurodegeneration. The use of the cells most vulnerable to a particular pathology makes it possible to identify specific pathological mechanisms and greatly facilitates the task of selecting the most effective drugs. To date, a large number of studies on patient-specific models of neurodegenerative diseases has been accumulated. In this review, we focused on the alterations of such a ubiquitous and important intracellular regulatory pathway as calcium signaling. Here, we reviewed and analyzed the data obtained from iPSCs-based models of different neurodegenerative disorders that demonstrated aberrant calcium signaling.

The Role of Formyl Peptide Receptors in Neurological Diseases via Regulating Inflammation.

Formyl peptide receptors (FPRs) are a group of G protein-coupled cell surface receptors that play important roles in host defense and inflammation. Owing to the ubiquitous expression of FPRs throughout different cell types and since they interact with structurally diverse chemotactic agonists, they have a dual function in inflammatory processes, depending on binding with different ligands so that accelerate or inhibit key intracellular kinase-based regulatory pathways. Neuroinflammation is closely associated with the pathogenesis of neurodegenerative diseases, neurogenic tumors and cerebrovascular diseases. From recent studies, it is clear that FPRs are important biomarkers for neurological diseases as they regulate inflammatory responses by monitoring glial activation, accelerating neural differentiation, regulating angiogenesis, and controlling blood brain barrier (BBB) permeability, thereby affecting neurological disease progression. Given the complex mechanisms of neurological diseases and the difficulty of healing, we are eager to find new and effective therapeutic targets. Here, we review recent research about various mechanisms of the effects generated after FPR binding to different ligands, role of FPRs in neuroinflammation as well as the development and prognosis of neurological diseases. We summarize that the FPR family has dual inflammatory functional properties in central nervous system. Emphasizing that FPR2 acts as a key molecule that mediates the active resolution of inflammation, which binds with corresponding receptors to reduce the expression and activation of pro-inflammatory composition, govern the transport of immune cells to inflammatory tissues, and restore the integrity of the BBB. Concurrently, FPR1 is essentially related to angiogenesis, cell proliferation and neurogenesis. Thus, treatment with FPRs-modulation may be effective for neurological diseases.

Активація внутрішньоклітинних ферментних систем під впливом патогенетичних факторів канцерогенезу у хворих на цукровий діабет 2-го типу

Актуальність. У пацієнтів із цукровим діабетом (ЦД) доведено підвищений ризик онкологічних захворювань. Основними чинниками онкогенезу при ЦД визнано ожиріння, цитокіновий дисбаланс, гіпер­інсулінемію, гіперглікемію. Вказані розлади зумовлюють дисфункцію внутрішньоклітинних регуляторних сигнальних шляхів, основним з яких є шлях PI3K/Akt/mTOR. Мета. Дослідження ролі фосфорильованої Akt­протеїнкінази (фосфо­Akt) у процесах онкогенезу у пацієнтів із ЦД 2­го типу. Матеріали та методи. Обстежені 75 осіб. Хворі розподілені на групи: І — здорові, ІІ — пацієнти з ЦД 2­го типу, ІІІ — хворі на рак, IV — хворі на рак, що виник на тлі ЦД 2­го типу. Були залучені пацієнти з раком молочної залози (МЗ), ендометрія (РЕ), підшлункової залози та кишечника. Визначали рівень інсуліну, інсуліноподібного фактора росту 1 (IGF­1) та фосфо­Akt. Результати. Пацієнти ІІ і ІV груп мали декомпенсований ЦД із рівнем HbA1с > 8,0 %. Вірогідну гіперінсулінемію виявлено у хворих на ЦД ІІ та IV груп (p < 0,05), а підвищений рівень IGF­1 — в усіх групах дослідження (p < 0,05). Показники фосфо­Akt у пацієнтів ІІІ групи були підвищеними (p < 0,05), а в ІV групі — зниженими (p < 0,05). У ІІІ групі виявлено гіперінсулінемію у хворих на РЕ, МЗ і кишечника (p < 0,05) та підвищення рівня IGF­1 незалежно від локалізації (p < 0,05). У ІV групі підвищені рівні інсуліну та IGF­1 виявлені у хворих на рак МЗ та РЕ (p < 0,05). У жінок ІІІ групи, хворих на рак МЗ та РЕ, рівень IGF­1 був вищим від показників ІV групи (p < 0,05). У пацієнтів IV групи, які отримували монотерапію метформіном, рівень фосфо­Akt був вірогідно нижчим (p < 0,05). Виявлено прямий кореляційний зв’язок між фосфо­Akt та IGF­1 у пацієнтів ІІ групи (r = 0,50, p < 0,05) і між фосфо­Akt та інсуліном у ІІІ групі (r = 0,45, p < 0,05). Висновки. ГІ та IGF­1 є спільними патогенетичними факторами ЦД 2­го типу та онкологічних захворювань. Підвищений рівень фосфо­Akt може бути лабораторною ознакою онкоризику в здорових осіб. Поєднання ЦД 2­го типу та онкологічних захворювань зумовлює зниження рівня фосфо­Akt через конкурентну взаємодію внутрішньоклітинних сигнальних шляхів. Терапія метформіном сприяє зниженню рівня фосфо­Akt та може розглядатись як один із засобів протиракової профілактики.

ViralLink: An integrated workflow to investigate the effect of SARS-CoV-2 on intracellular signalling and regulatory pathways.

The SARS-CoV-2 pandemic of 2020 has mobilised scientists around the globe to research all aspects of the coronavirus virus and its infection. For fruitful and rapid investigation of viral pathomechanisms, a collaborative and interdisciplinary approach is required. Therefore, we have developed ViralLink: a systems biology workflow which reconstructs and analyses networks representing the effect of viruses on intracellular signalling. These networks trace the flow of signal from intracellular viral proteins through their human binding proteins and downstream signalling pathways, ending with transcription factors regulating genes differentially expressed upon viral exposure. In this way, the workflow provides a mechanistic insight from previously identified knowledge of virally infected cells. By default, the workflow is set up to analyse the intracellular effects of SARS-CoV-2, requiring only transcriptomics counts data as input from the user: thus, encouraging and enabling rapid multidisciplinary research. However, the wide-ranging applicability and modularity of the workflow facilitates customisation of viral context, a priori interactions and analysis methods. Through a case study of SARS-CoV-2 infected bronchial/tracheal epithelial cells, we evidence the functionality of the workflow and its ability to identify key pathways and proteins in the cellular response to infection. The application of ViralLink to different viral infections in a context specific manner using different available transcriptomics datasets will uncover key mechanisms in viral pathogenesis.

Synthetic DNA for Cell-Surface Engineering.

The cell membrane is not only a physical barrier, but also a functional organelle that regulates the communication between a cell and its environment. The ability to functionalize the cell membrane with synthetic molecules or nanostructures would advance cellular functions beyond what evolution has provided. The aim of this Minireview is to introduce recent progress in using synthetic DNA and DNA-based nanostructures for cell-surface engineering. We first introduce chemical conjugation and physical binding methods for monovalent and polyvalent surface engineering. We then introduce the application of these methods for either the promotion or inhibition of cell-environment communication in numerous applications, including the promotion of cell-cell recognition, regulation of intracellular pathways, protection of therapeutic cells, and sensing of the intracellular and extracellular microenvironments. Lastly, we summarize current challenges existing in this area and potential solutions to solve these challenges.

Synthetic DNA for Cell‐Surface Engineering

AbstractThe cell membrane is not only a physical barrier, but also a functional organelle that regulates the communication between a cell and its environment. The ability to functionalize the cell membrane with synthetic molecules or nanostructures would advance cellular functions beyond what evolution has provided. The aim of this Minireview is to introduce recent progress in using synthetic DNA and DNA‐based nanostructures for cell‐surface engineering. We first introduce chemical conjugation and physical binding methods for monovalent and polyvalent surface engineering. We then introduce the application of these methods for either the promotion or inhibition of cell–environment communication in numerous applications, including the promotion of cell–cell recognition, regulation of intracellular pathways, protection of therapeutic cells, and sensing of the intracellular and extracellular microenvironments. Lastly, we summarize current challenges existing in this area and potential solutions to solve these challenges.

Interactions with PDZ proteins diversify voltage-gated calcium channel signaling.

Voltage-gated Ca2+ (CaV ) channels are crucial for neuronal excitability and synaptic transmission upon depolarization. Their properties in vivo are modulated by their interaction with a variety of scaffolding proteins. Such interactions can influence the function and localization of CaV channels, as well as their coupling to intracellular second messengers and regulatory pathways, thus amplifying their signaling potential. Among these scaffolding proteins, a subset of PDZ (postsynaptic density-95, Drosophila discs-large, and zona occludens)-domain containing proteins play diverse roles in modulating CaV channel properties. At the presynaptic terminal, PDZ proteins enrich CaV channels in the active zone, enabling neurotransmitter release by maintaining a tight and vital link between channels and vesicles. In the postsynaptic density, these interactions are essential in regulating dendritic spine morphology and postsynaptic signaling cascades. In this review, we highlight the studies that demonstrate dynamic regulations of neuronal CaV channels by PDZ proteins. We discuss the role of PDZ proteins in controlling channel activity, regulating channel cell surface density, and influencing channel-mediated downstream signaling events. We highlight the importance of PDZ protein regulations of CaV channels and evaluate the link between this regulatory effect and human disease.

Plant-Derived Inhibitors of AHL-Mediated Quorum Sensing in Bacteria: Modes of Action.

Numerous gram-negative phytopathogenic and zoopathogenic bacteria utilise acylated homoserine lactone (AHL) in communication systems, referred to as quorum sensing (QS), for induction of virulence factors and biofilm development. This phenomenon positions AHL-mediated QS as an attractive target for anti-infective therapy. This review focused on the most significant groups of plant-derived QS inhibitors and well-studied individual compounds for which in silico, in vitro and in vivo studies provide substantial knowledge about their modes of anti-QS activity. The current data about sulfur-containing compounds, monoterpenes and monoterpenoids, phenylpropanoids, benzoic acid derivatives, diarylheptanoids, coumarins, flavonoids and tannins were summarized; their plant sources, anti-QS effects and bioactivity mechanisms have also been summarized and discussed. Three variants of plant-derived molecules anti-QS strategies are proposed: (i) specific, via binding with LuxI-type AHL synthases and/or LuxR-type AHL receptor proteins, which have been shown for terpenes (carvacrol and l-carvone), phenylpropanoids (cinnamaldehyde and eugenol), flavonoid quercetin and ellagitannins; (ii) non-specific, by affecting the QS-related intracellular regulatory pathways by lowering regulatory small RNA expression (sulphur-containing compounds ajoene and iberin) or c-di-GMP metabolism reduction (coumarin); and (iii) indirect, via alteration of metabolic pathways involved in QS-dependent processes (vanillic acid and curcumin).

Resveratrol reduces store-operated Ca2+ entry and enhances the apoptosis of fibroblast-like synoviocytes in adjuvant arthritis rats model via targeting ORAI1\u2013STIM1 complex

BackgroundResveratrol was reported to trigger the apoptosis of fibroblast-like synoviocytes in adjuvant arthritis rats but the subcellular mechanism remains unclear. Since ER stress, mitochondrial dysfunction and oxidative stress were involved in the effects of resveratrol with imbalance of calcium bio-transmission, store operated calcium entry (SOCE), a novel intracellular calcium regulatory pathway, may also participate in this process.ResultsIn the present study, Resveratrol was found to suppress ORAI1 expression of a dose dependent manner while have no evident effects on STIM1 expressive level. Besides, resveratrol had no effects on ATP or TG induced calcium depletion but present partly dose-dependent suppression of SOCE. On the one hand, microinjection of ORAI1 overexpressed vector in sick toe partly counteracted the therapeutic effects of resveratrol on adjuvant arthritis and serum inflammatory cytokine including IL-1, IL-6, IL-8, IL-10 and TNF-α. On the other hand, ORAI1 SiRNA injection provided slight relief to adjuvant arthritis in rats. In addition, ORAI1 overexpression partly diminished the alleviation of hemogram abnormality induced by adjuvant arthritis after resveratrol treatment while ORAI1 knockdown presented mild resveratrol-like effect on hemogram in rats model.ConclusionThese results indicated that resveratrol reduced store-operated Ca2+ entry and enhanced the apoptosis of fibroblast-like synoviocytes in adjuvant arthritis rats model via targeting ORAI1–STIM1 complex, providing a theoretical basis for ORAI1 targeted therapy in future treatment with resveratrol on rheumatoid arthritis.

Regulation of RhoB Gene Expression during Tumorigenesis and Aging Process and Its Potential Applications in These Processes.

RhoB, a member of the Ras homolog gene family and GTPase, regulates intracellular signaling pathways by interfacing with epidermal growth factor receptor (EGFR), Ras, and phosphatidylinositol 3-kinase (PI3K)/Akt to modulate responses in cellular structure and function. Notably, the EGFR, Ras, and PI3K/Akt pathways can lead to downregulation of RhoB, while simultaneously being associated with an increased propensity for tumorigenesis. Functionally, RhoB, part of the Rho GTPase family, regulates intracellular signaling pathways by interfacing with EGFR, RAS, and PI3K/Akt/mammalian target of rapamycin (mTOR), and MYC pathways to modulate responses in cellular structure and function. Notably, the EGFR, Ras, and PI3K/Akt pathways can lead to downregulation of RhoB, while simultaneously being associated with an increased propensity for tumorigenesis. RHOB expression has a complex regulatory backdrop consisting of multiple histone deacetyltransferase (HDACs 1 and 6) and microRNA (miR-19a, -21, and -223)-mediated mechanisms of modifying expression. The interwoven nature of RhoB’s regulatory impact and cellular roles in regulating intracellular vesicle trafficking, cell motion, and the cell cycle lays the foundation for analyzing the link between loss of RhoB and tumorigenesis within the context of age-related decline in RhoB. RhoB appears to play a tissue-specific role in tumorigenesis, as such, uncovering and appreciating the potential for restoration of RHOB expression as a mechanism for cancer prevention or therapeutics serves as a practical application. An in-depth assessment of RhoB will serve as a springboard for investigating and characterizing this key component of numerous intracellular messaging and regulatory pathways that may hold the connection between aging and tumorigenesis.

Recent Advances in the Characterization of Skeletal Muscle and Whole-Body Protein Responses to Dietary Protein and Exercise during Negative Energy Balance.

In a review published in 2012, we concluded that higher-protein diets preserve muscle mass during energy deficit via stimulated mammalian target of rapamycin complex 1 signaling, coincident increased muscle protein synthesis (PS), inhibited ubiquitin-mediated proteolysis, and suppressed muscle protein breakdown (PB). Since then, there have been significant advances in understanding the fundamental effects of higher-protein diets, with or without exercise training, on muscle and whole-body protein homeostasis during negative energy balance. Therefore, an update on the evolution of this field of research is warranted to better inform recommendations on best practices for healthy weight loss and muscle preservation. We will review the most recent studies examining the effects of higher-protein diets and negative energy balance on body composition, muscle PS, muscle PB, associated intracellular regulatory pathway activities, and whole-body protein homeostasis. In addition to critically analyzing contemporary findings, knowledge gaps and opportunities for continued research will be identified. Overall, the newest research confirms that consuming higher-protein diets, particularly when coupled with resistance exercise, preserves muscle mass and maintains whole-body protein homeostasis during moderate energy deficits (i.e., normal weight loss). However, these newer findings also indicate that as the magnitude of energy deficit increases, the efficacy of higher-protein diets for mitigating losses of fat-free mass is diminished. Further, recent results suggest that alterations in muscle PS, more so than muscle PB, may be primarily responsible for changes in muscle mass that occur in response to negative energy balance.

Immunotopological Analysis of the Treponema denticola Major Surface Protein (Msp).

Treponema denticola, one of several recognized periodontal pathogens, is a model organism for studying Treponema physiology and host-microbe interactions. Its major surface protein Msp (or MOSP) comprises an oligomeric outer membrane-associated complex that binds fibronectin, has cytotoxic pore-forming activity, and disrupts several intracellular responses. There are two hypotheses regarding native Msp structure and membrane topology. One hypothesis predicts that the entire Msp protein forms a β-barrel structure similar to that of well-studied outer membrane porins of Gram-negative bacteria. The second hypothesis predicts a bipartite Msp with distinct and separate periplasmic N-terminal and porin-like β-barrel C-terminal domains. The bipartite model, based on bioinformatic analysis of the orthologous Treponema pallidum Tpr proteins, is supported largely by studies of recombinant TprC and Msp polypeptides. The present study reports immunological studies in both T. denticola and Escherichia coli backgrounds to identify a prominent Msp surface epitope (residues 229 to 251 in ATCC 35405) in a domain that differs between strains with otherwise highly conserved Msps. These results were then used to evaluate a series of in silico structural models of representative T. denticola Msps. The data presented here are consistent with a model of Msp as a large-diameter β-barrel porin. This work adds to the knowledge regarding the diverse Msp-like proteins in oral treponemes and may contribute to an understanding of the evolutionary and potential functional relationships between Msps of oral Treponema and the orthologous group of Tpr proteins of T. pallidum.IMPORTANCETreponema denticola is among a small subset of the oral microbiota contributing to severe periodontal disease. Due to its relative genetic tractability, T. denticola is a model organism for studying Treponema physiology and host-microbe interactions. T. denticola Msp is a highly expressed outer membrane-associated oligomeric protein that binds fibronectin, has cytotoxic pore-forming activity, and disrupts intracellular regulatory pathways. It shares homology with the orthologous group of T. pallidum Tpr proteins, one of which is implicated in T. pallidum in vivo antigenic variation. The outer membrane topologies of both Msp and the Tpr family proteins are unresolved, with conflicting reports on protein domain localization and function. In this study, we combined empirical immunological data derived both from diverse T. denticola strains and from recombinant Msp expression in E. coli with in silico predictive structural modeling of T. denticola Msp membrane topology, to move toward resolution of this important issue in Treponema biology.

Constrained α-Helical Peptides as Inhibitors of Protein-Protein and Protein-DNA Interactions.

Intracellular regulatory pathways are replete with protein-protein and protein-DNA interactions, offering attractive targets for therapeutic interventions. So far, most drugs are targeted toward enzymes and extracellular receptors. Protein-protein and protein-DNA interactions have long been considered as “undruggable”. Protein-DNA interactions, in particular, present a difficult challenge due to the repetitive nature of the B-DNA. Recent studies have provided several breakthroughs; however, a design methodology for these classes of inhibitors is still at its infancy. A dominant motif of these macromolecular interactions is an α-helix, raising possibilities that an appropriate conformationally-constrained α-helical peptide may specifically disrupt these interactions. Several methods for conformationally constraining peptides to the α-helical conformation have been developed, including stapling, covalent surrogates of hydrogen bonds and incorporation of unnatural amino acids that restrict the conformational space of the peptide. We will discuss these methods and several case studies where constrained α-helices have been used as building blocks for appropriate molecules. Unlike small molecules, the delivery of these short peptides to their targets is not straightforward as they may possess unfavorable cell penetration and ADME properties. Several methods have been developed in recent times to overcome some of these problems. We will discuss these issues and the prospects of this class of molecules as drugs.

Mechanical perspective on chemotaxis

Cell motion in response to external chemical cues (chemotaxis) is a fundamental step in many physiological and pathological phenomena. The ability of cells to move onto two-dimensional flat substrates requires the activation of numerous intracellular mechanical and chemical mechanisms to achieve cell polarization and dynamic assembly and reorganization of the actin network. In this work we aim to bridge the gap between the mathematical models focusing on the mechanics of cell motion and the one describing the final motion of the cell in response to the external chemical field. We thus develop a one-dimensional continuous model representing cell migration, taking into account the mechanical stress inside the cell, the intracellular signaling molecules triggered by external factors, such as an external chemical field, and the actin dynamics during polymerization and depolymerization. The proposed model is solved numerically to simulate cell behavior during biologically relevant conditions and to study different mechanisms of conversion of the external field onto the intracellular chemical messenger, here called the polymerizing factor. The model is able to reproduce the transitions from the nonmigrating to the migrating regime, possibly triggered by the external chemotactic gradient, which is amplified by the internal chemical dynamics. More complex migratory behaviors can be described, as well, by including intracellular regulatory pathways of the polymerizing factor. Thus, the proposed model, even though kept as simple as possible, provides an interesting insight onto possible mathematical laws defining cell migratory velocity inside external chemical field gradients.

Transglutaminase type 2 in the regulation of proteostasis

The maintenance of protein homeostasis (proteostasis) is a fundamental aspect of cell physiology that is essential for the survival of organisms under a variety of environmental and/or intracellular stress conditions. Acute and/or persistent stress exceeding the capacity of the intracellular homeostatic systems results in protein aggregation and/or damaged organelles that leads to pathological cellular states often resulting in cell death. These events are continuously suppressed by a complex macromolecular machinery that uses different intracellular pathways to maintain the proteome integrity in the various subcellular compartments ensuring a healthy cellular life span. Recent findings have highlighted the role of the multifunctional enzyme type 2 transglutaminase (TG2) as a key player in the regulation of intracellular pathways, such as autophagy/mitophagy, exosomes formation and chaperones function, which form the basis of proteostasis regulation under conditions of cellular stress. Here, we review the role of TG2 in these stress response pathways and how its various enzymatic activities might contributes to the proteostasis control.

Negative inotropic effects of diadenosine tetraphosphate are mediated by protein kinase C and phosphodiesterases stimulation in the rat heart

Extracellular diadenosine polyphosphates (ApnA) are recently considered as an endogenous signaling compounds with transmitter-like activity which present in numerous tissues, including heart. It has been demonstrated previously that extracellular ApnA cause alteration of the heart functioning via purine receptors in different mammalian species. Nevertheless, principal intracellular pathways which underlie ApnA action in the heart remain unknown. In the present study the role of the P2Y-associated intracellular regulatory pathway in the mediation of diadenosine tetraphosphate (Ap4A) effects in the rat heart has been investigated for the first time.Extracellular Ap4A caused significant decreasing of the ventricular inotropy. Ap4A evoked reduction of the left ventricle contractility in the isolated Langendorff-perfused rat hearts, decreasing of the Ca2+ transients in the enzymatically isolated ventricular cardiomyocytes and induced shortening of action potentials in the ventricle multicellular preparations. The inhibitory effects of Ap4A in the rat heart were significantly attenuated by protein kinase C (PKC) inhibitor chelerythrine but these effects were not affected by NO-synthase inhibitor L-NAME and guanylyl cyclase (sGC) inhibitor ODQ. In addition, substantial attenuation of Ap4A-caused negative inotropy in the left ventricle was produced by nonselective phsophodiesterase (PDE) inhibitor IBMX, while PDE type 2 inhibitor EHNA was ineffective.In conclusion, our results allow suggesting that Ap4A-induced inhibitory effects in the rat heart are mediated by PKC, but not by NO/sGC/PKG-related signaling pathway. In addition, PDE stimulation may contribute to Ap4A-caused inhibition of the rat heart contractility.

Structural basis of Zn(II) induced metal detoxification and antibiotic resistance by histidine kinase CzcS in Pseudomonas aeruginosa.

Pseudomonas aeruginosa (P. aeruginosa) is a major opportunistic human pathogen, causing serious nosocomial infections among immunocompromised patients by multi-determinant virulence and high antibiotic resistance. The CzcR-CzcS signal transduction system in P. aeruginosa is primarily involved in metal detoxification and antibiotic resistance through co-regulating cross-resistance between Zn(II) and carbapenem antibiotics. Although the intracellular regulatory pathway is well-established, the mechanism by which extracellular sensor domain of histidine kinase (HK) CzcS responds to Zn(II) stimulus to trigger downstream signal transduction remains unclear. Here we determined the crystal structure of the CzcS sensor domain (CzcS SD) in complex with Zn(II) at 1.7 Å resolution. This is the first three-dimensional structural view of Zn(II)-sensor domain of the two-component system (TCS). The CzcS SD is of α/β-fold in nature, and it senses the Zn(II) stimulus at micromole level in a tetrahedral geometry through its symmetry-related residues (His55 and Asp60) on the dimer interface. Though the CzcS SD resembles the PhoQ-DcuS-CitA (PDC) superfamily member, it interacts with the effector in a novel domain with the N-terminal α-helices rather than the conserved β-sheets pocket. The dimerization of the N-terminal H1 and H1’ α-helices is of primary importance for the activity of HK CzcS. This study provides preliminary insight into the molecular mechanism of Zn(II) sensing and signaling transduction by the HK CzcS, which will be beneficial to understand how the pathogen P. aeruginosa resists to high levels of heavy metals and antimicrobial agents.

Impairment of the Intrinsic Capability of Th1 Polarization in Irradiated Mice: A Close Look at the Imbalanced Th1/Th2 Response after Irradiation.

Two major CD4+ T-helper (Th) lineages are Th1 and Th2, and well balanced Th1/Th2 responses are essential for immune function. In previously published studies, it was reported that radiation induces a Th1/Th2 immune imbalance toward a Th2-dominant direction, and this imbalance may contribute to postirradiation immune dysfunction. The polarization of Th cells is driven by the cytokine milieu and controlled by intracellular regulatory pathways that respond to cytokine signaling. It is widely accepted that radiation induces cytokine aberration, however, the precise alterations of cytokines in various tissue environments have been difficult to evaluate. In addition, the effects of radiation on the intrinsic functions of Th cells remain uncharacterized. Therefore, how radiation affects Th1/Th2 balance remains somewhat unclear. To address this, we investigated the changes in the polarization capability of Th cells by isolating them from mice previously exposed to radiation and assessing the cells in an established in vitro Th polarization system. Our novel results demonstrate that prior exposure to radiation led to the persistent aberration of the inherent capability of Th cells to differentiate into Th1 and Th2 lineages. The parallel changes in expression of Th1-specific master transcription factors and the key genes in metabolic reprograming indicated that radiation affects the core components in Th1 polarization. While Th1 differentiation was impaired after irradiation, little adverse effect was observed in Th2 differentiation; both of these findings contribute to the known phenotypes of Th1/Th2 imbalance caused by radiation.

Naturally occurring compounds acting as potent anti-metastatic agents and their suppressing effects on Hedgehog and WNT/β-catenin signalling pathways.

Despite numerous remarkable achievements in the field of anti-cancer therapy, tumour relapse and metastasis still remain major obstacles in improvement of overall cancer survival, which may be at least partially owing to epithelial-mesenchymal transition (EMT). Multiple signalling pathways have been identified in EMT; however, it appears that the role of the Hedgehog and WNT/β-catenin pathways are more prominent than others. These are well-known preserved intracellular regulatory pathways of different cellular functions including proliferation, survival, adhesion and differentiation. Over the last few decades, several naturally occurring compounds have been identified to significantly obstruct several intermediates in Hedgehog and WNT/β-catenin signalling, eventually resulting in suppression of signal transduction. This article highlights the current state of knowledge associated with Hedgehog and WNT/β-catenin, their involvement in metastasis through EMT processes and introduction of the most potent naturally occurring agents with capability of suppressing them, eventually overcoming tumour relapse, invasion and metastasis.

Abstract 809: Dietary iron intake, genetic variants in microRNA related iron regulatory pathway genes, and the risk of non-small cell lung cancer

Abstract As an essential nutrient that facilitates DNA synthesis, cell proliferation and metabolism, iron is involved in carcinogenesis. While epidemiological studies suggest a J-shaped model for the relationship of serum iron level and cancer risk with both too low and too high levels associated with increased cancer risks, the effect of genetic variants related to intracellular iron regulatory pathway and dietary iron intake on non-small cell lung cancer (NSCLC) risk is little known. In this study, we evaluated a panel of miRNA related genetic variants in iron regulatory pathway genes on the risk of NSCLC. In discovery phrase, 157 miRNA related single nucleotide polymorphisms (SNPs) from 81 genes of iron regulatory pathway were genotyped in 1656 NSCLC cases and 1486 healthy controls. Eight SNPs in 6 genes were significantly associated with risk of NSCLC. A SNP in 3’ UTR of Iron-Responsive Element Binding Protein 2 (IREB2) gene at 15q25 region was subsequently replicated in dbGaP lung cancer GWAS dataset. Combining all subjects (7,352 cases, 7,296 controls), the overall P-value was 4.9 × 10−9 (Odds ratio (OR) = 0.86). eQTL analysis showed that the SNP on IREB2 alters IREB2 gene expression (P = 3.0 × 10−11). The SNP is predicted to alter a miR-29 binding site on IREB2 gene and indeed the expression of miR-29 is inversely correlated with IREB2 expression in tumor tissues. We then determined the expression of serum miR-29a in 150 early-stage NSCLC patients and 172 healthy controls and found that miR-29a was significantly associated with higher risk of cancer (OR = 1.78, P = 0.03). By analyzing dietary intake information of the discovery population, iron intake was significantly associated with risk of NSCLC in logistic regression analysis and there was also evidence of a synergistic interaction with between the SNP and iron intake in modulating NSCLC risk (P for interaction = 0.01). Taken together, SNPs at miRNA binding sites of iron regulatory pathway genes and dietary iron intake may modify risk of NSCLC individually and jointly. Citation Format: Liren Zhang, Yuanquing Ye, Huakang Tu, Michelle A.t. Hildebrandt, John V. Heymach, Jack A. Roth, Jian Gu, Xifeng Wu. Dietary iron intake, genetic variants in microRNA related iron regulatory pathway genes, and the risk of non-small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 809.