Treatment with analogues of the SERCA-inhibitor Thapsigargin is a promising new approach for a wide variety of cancer entities. However, our previous studies on various tumor cells suggested resistance of SEC62 over-expr...Treatment with analogues of the SERCA-inhibitor Thapsigargin is a promising new approach for a wide variety of cancer entities. However, our previous studies on various tumor cells suggested resistance of SEC62 over-expressing tumors to this treatment. Therefore, we proposed the novel concept that e.g. lung-, prostate-, and thyroid-cancer patients should be tested for SEC62 over-expression, and developed a novel therapeutic strategy for a combinatorial treatment of SEC62 over-expressing tumors. The latter was based on the observations that treatment of SEC62 over-expressing tumor cells with SEC62-targeting siRNAs showed less resistance to Thapsigargin as well as a reduction in migratory potential and that the siRNA effects can be mimicked by the Calmodulin antagonist Trifluoperazine. Therefore, the combinatorial treatment of SEC62 over-expressing tumors was proposed to involve Thapsigargin and Trifluoperazine. Here, we addressed the impact of Thapsigargin and Trifluoperazine in separate and combined treatments of heterotopic tumors, induced by inoculation of human hypopharyngeal squamous cell carcinoma (FaDu)-cells into the mouse flank. Seeding of the tumor cells and/or their growth rate were significantly reduced by all three treatments, suggesting Trifluoperazine is a small molecule to be considered for future therapeutic strategies for patients, suffering from Sec62-overproducing tumors.
Among Human immunodeficiency virus (HIV) infected individuals, around two-thirds of patients present with neuroAIDS, where HIV-associated neurocognitive disorders (HAND), and HIV-associated dementia (HAD) are the most pr...Among Human immunodeficiency virus (HIV) infected individuals, around two-thirds of patients present with neuroAIDS, where HIV-associated neurocognitive disorders (HAND), and HIV-associated dementia (HAD) are the most prevailing neurological complications. The neuropathology of neuroAIDS can be characterized by the presence of HIV infected macrophages and microglia in the brain, with the formation of multinucleated giant cells. Global predominant subtypes of HIV-1 clade B and C infections influence the differential effect of immune and neuronal dysfunctions, leading to clade-specific clinical variation in neuroAIDS patient cohorts. Highly active antiretroviral therapy (HAART) enhances the survival rate among AIDS patients, but due to the inability to cross the Blood-Brain-Barrier (BBB), incidence of neuroAIDS during disease progression may be envisaged. The complex structure of blood-brain-barrier, and poor pharmacokinetic profile coupled with weak bio-distribution of antiretroviral drugs, are the principle barriers for the treatment of neuroAIDS. In the combined antiretroviral therapy (cART) era, the frequency of HAD has decreased; however the incidence of asymptomatic neurocognitive impairment (ANI) and minor neurocognitive disorder (MND) remains consistent. Therefore, several effective novel nanotechnology based therapeutic approaches have been developed to improve the availability of antiretroviral drugs in the brain for the management of neuroAIDS.
One of the major causes of cardiac cell death during myocardial ischemia is the oversecretion of protease enzymes surrounding the ischemic tissue. Therefore, inhibition of the protease activity could be an alternative st...One of the major causes of cardiac cell death during myocardial ischemia is the oversecretion of protease enzymes surrounding the ischemic tissue. Therefore, inhibition of the protease activity could be an alternative strategy for preventing the expansion of the injured area. In the present study, we investigated the effects of Secretory Leukocyte Protease Inhibitor (SLPI), by means of overexpression and treatment of recombinant human SLPI (rhSLPI) in an in vitro model. Rat cardiac myoblast (H9c2) cells overexpressing rhSLPI were generated by gene delivery using pCMV2-SLPI-HA plasmid. The rhSLPI-H9c2 cells, mock transfected cells, and wild-type (WT) control were subjected to simulated ischemia/reperfusion (sI/R). Moreover, the treatment of rhSLPI in H9c2 cells was also performed under sI/R conditions. The results showed that overexpression of rhSLPI in H9c2 cells significantly reduced sI/R-induced cell death and injury, intracellular ROS level, and increased Akt phosphorylation, when compared to WT and mock transfection (p <0.05). Treatment of rhSLPI prior to sI/R reduced cardiac cell death and injury, and intra-cellular ROS level. In addition, 400 ng/ml rhSLPI treatment, prior to sI, significantly inhibited p38 MAPK phosphorylation and rhSLPI at 400-1000 ng/ml could increase Akt phosphorylation.
Seafood consumption is highly demanding due to the important source of protein it contains, as well as being rich in omega-3 fatty acids. However, the adulteration of seafood is an alarming issue worldwide, including Ind...Seafood consumption is highly demanding due to the important source of protein it contains, as well as being rich in omega-3 fatty acids. However, the adulteration of seafood is an alarming issue worldwide, including India. This study deals with edible crabs from seafood shops on the Odisha state coast in eastern India. The generated DNA barcode sequences successfully identified most of the studied brachyuran crab species by similarity search results in global databases. The species were also delimited by significant genetic divergence and Neighbour-Joining phylogeny. Additionally, the study detected the contamination of unknown organisms in the commercialized crab recipes from seafood shops. The DNA based species detection of brachyuran crab may be useful to resolve many ambiguities in species identification and monitoring of commercialized seafood concerning food safety.
The microtubule-associated protein Tau plays a crucial role in stabilizing neuronal microtubules. In Tauopathies, Tau loses its ability to bind microtubules, detach from them and forms intracellular aggregates. Increasin...The microtubule-associated protein Tau plays a crucial role in stabilizing neuronal microtubules. In Tauopathies, Tau loses its ability to bind microtubules, detach from them and forms intracellular aggregates. Increasing evidence in recent years supports the notion that Tau pathology spreading throughout the brain in AD and other Tauopathies is the consequence of the propagation of specific Tau species along neuroanatomically connected brain regions in a so-called "prion-like" manner. A number of steps are assumed to be involved in this process, including secretion, cellular uptake, transcellular transfer and/or seeding, although the precise mechanisms underlying propagation of Tau pathology are not fully understood yet. This review summarizes recent evidence on the nature of the specific Tau species that are propagated and the different mechanisms of Tau pathology spreading.
The crucial role of water in amyloid-β(Aβ) fibril proteins is evaluated in several ways including the water's thermodynamic and kinetic solvation effects. As regards the water's character, its hindered-rotation barriers...The crucial role of water in amyloid-β(Aβ) fibril proteins is evaluated in several ways including the water's thermodynamic and kinetic solvation effects. As regards the water's character, its hindered-rotation barriers are also considered. The following protein molecules considered here are: the Aβ40 (PDB ID: 2LMN), Aβ42 (PDB ID: 5KK3 and 2NAO) and the double-layered Aβ17-42 fibril. We discuss: (i) extracellular Aβ40 and Aβ42 fibril monomers exhibit an ambivalent propensity to transform into a helical form toward the N-term region and a β-strand-like form near the C-terminal; (ii) interfacial water molecules play a crucial role in protein-protein interactions, as molecular dynamics simulations have shown a significant impact on the protein-protein binding; (iii) it is shown that the spontaneous dimerization process of the Aβ42 fibril protein in water occurs via a two-step nucleation-accommodation mechanism; (iv) MD simulations of the double-layered Aβ17-42 fibril model show that the C↔C interface appears more energetically favorable than the N↔N interface due to large hydrophobic contacts; (v) the water's role in the HET-s prion and in the Aβ fibrillar aggregates; (vi) it was found that the monomer-oligomer equilibrium spontaneously dissociates into stable monomeric species when they are incubated up to 3 μm for a longer time (>1 week) in a physiological buffer.
MicroRNAs (miRNAs) are single-stranded RNAs of 18-25 nucleotides that regulate gene expression at the post-transcriptional level. They are involved in many physiological and pathological processes, including cell prolife...MicroRNAs (miRNAs) are single-stranded RNAs of 18-25 nucleotides that regulate gene expression at the post-transcriptional level. They are involved in many physiological and pathological processes, including cell proliferation, apoptosis, development and carcinogenesis. Because of the central role of miRNAs in the regulation of gene expression, their expression needs to be tightly controlled. Here, we summarize the different mechanisms of epigenetic regulation of miRNAs, with a particular focus on DNA methylation and histone modification.
Different aspects of bacterial and fungal siderophore biotechnological applications will be discussed. Areas of application presented include, but are not limited to agriculture, medicine, pharmacology, bioremediation, b...Different aspects of bacterial and fungal siderophore biotechnological applications will be discussed. Areas of application presented include, but are not limited to agriculture, medicine, pharmacology, bioremediation, biodegradation and food industry. In agriculture-related applications, siderophores could be employed to enhance plant growth due to their uptake by rhizobia. Siderophores hindered the presence of plant pathogens in biocontrol strategies. Bioremediation studies on siderophores discuss mostly the mobilization of heavy metals and radionuclides; the emulsifying effects of siderophore-producing microorganisms in oil-contaminated environments are also presented. The different applications found in literature based in medicine and pharmacological approaches range from iron overload to drug delivery systems and, more recently, vaccines. Additional research should be done in siderophore production and their metabolic relevance to have a deeper understanding for future biotechnological advances.
Amphibian metamorphosis has historically attracted a good deal of scientific attention owing to its dramatic nature and easy observability. However, the genetic mechanisms of amphibian metamorphosis have not been thoroug...Amphibian metamorphosis has historically attracted a good deal of scientific attention owing to its dramatic nature and easy observability. However, the genetic mechanisms of amphibian metamorphosis have not been thoroughly examined using modern techniques such as gene cloning, DNA sequencing, polymerase chain reaction or genomic editing. Here, we review the current state of knowledge regarding molecular mechanisms underlying tadpole tail resorption.
Biomol Concepts
· 2017 Sep · PMID 28841567
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Cell-penetrating peptides (CPPs) have long held great promise for the manipulation of living cells for therapeutic and research purposes. They allow a wide array of biomolecules from large, oligomeric proteins to nucleic...Cell-penetrating peptides (CPPs) have long held great promise for the manipulation of living cells for therapeutic and research purposes. They allow a wide array of biomolecules from large, oligomeric proteins to nucleic acids and small molecules to rapidly and efficiently traverse cytoplasmic membranes. With few exceptions, if a molecule can be associated with a CPP, it can be delivered into a cell. However, a growing realization in the field is that CPP-cargo fusions largely remain trapped in endosomes and are eventually targeted for degradation or recycling rather than released into the cytoplasm or trafficked to a desired subcellular destination. This 'endosomal escape problem' has confounded efforts to develop CPP-based delivery methods for drugs, enzymes, plasmids, etc. This review provides a brief history of CPP research and discusses current issues in the field with a primary focus on the endosomal escape problem, for which several promising potential solutions have been developed. Are we on the verge of developing technologies to deliver therapeutics such as siRNA, CRISPR/Cas complexes and others that are currently failing because of an inability to get into cells, or are we just chasing after another promising but unworkable technology? We make the case for optimism.
Protein kinase C (PKC) comprises a family of lipid-sensitive enzymes that have been involved in a broad range of cellular functions. PKC-α is a member of classical PKC with ubiquitous expression and different cellular lo...Protein kinase C (PKC) comprises a family of lipid-sensitive enzymes that have been involved in a broad range of cellular functions. PKC-α is a member of classical PKC with ubiquitous expression and different cellular localization. This unique PKC isoform is activated by various signals which evoke lipid hydrolysis, after activation it interacts with various adapter proteins and is localized to specific cellular compartments where it is devised to work. The universal expression and activation by various stimuli make it a perfect player in uncountable cellular functions including differentiation, proliferation, apoptosis, cellular transformation, motility, adhesion and so on. However, these functions are not intrinsic properties of PKC-α, but depend on cell types and conditions. The activities of PKC-α are managed by the various pharmacological activators/inhibitors and antisense oligonucleotides. The aim of this review is to elaborate the structural feature, and provide an insight into the mechanism of PKC-α activation and regulation of its key biological functions in different cellular compartments to develop an effective pharmacological approach to regulate the PKC-α signal array.
Tumour necrosis factor receptor-associated factor 3 (TRAF3) is a member of the TRAF adaptor protein family, which exerts different effects on the cell depending on the receptor to which it binds and the cell type in whic...Tumour necrosis factor receptor-associated factor 3 (TRAF3) is a member of the TRAF adaptor protein family, which exerts different effects on the cell depending on the receptor to which it binds and the cell type in which it is expressed. TRAF3 is a major regulator of the innate immune response. To perform its functions properly, TRAF3 is transcriptionally and epigenetically regulated. At the transcriptional level, TRAF3 expression has been associated with neurological and cardiovascular diseases including stroke, among other pathologies. Epigenetic modifications of TRAF3 have been observed at the histone and DNA levels. It has been observed that acetylation of TRAF3, as well as other NF-κβ target genes, is associated with cardiac hypertrophy. Furthermore, TRAF3 methylation has been associated with vascular recurrence after ischemic stroke in patients treated with clopidogrel. In this overview, we summarise the most interesting studies related to transcriptional and epigenetic regulation of TRAF3 focusing on those studies performed in neurological and cardiovascular diseases.
The benefits of breastfeeding over formula feed are widely appreciated. However, for many mothers breastfeeding is not possible, highlighting the need for a significant improvement in the contents of formula feed. In thi...The benefits of breastfeeding over formula feed are widely appreciated. However, for many mothers breastfeeding is not possible, highlighting the need for a significant improvement in the contents of formula feed. In this article, the overlooked role of melatonin and the melatonergic pathways in breast milk and in the regulation of wider breast milk components are reviewed. There is a growing appreciation that the benefits of breastfeeding are mediated by its effects in the infant gut, with consequences for the development of the gut-brain axis and the immune system. The melatonergic pathways are intimately associated with highly researched processes in the gut, gut microbiome and gut-brain axis. As the melatonergic pathways are dependent on the levels of serotonin availability as a necessary precursor, decreased melatonin is linked to depression and depression-associated disorders. The association of breastfeeding and the gut-brain axis with a host of medical conditions may be mediated by their regulation of processes that modulate depression susceptibility. The biological underpinnings of depression include increased levels of pro-inflammatory cytokines, oxidative stress, kynurenine pathway activity and dysregulation of the hypothalamic-pituitary adrenal axis, all of which can decrease melatonergic pathway activity. The inclusion of the melatonergic pathways in the biological interactions of breast milk and gut development has significant theoretical and treatment implications, as well as being important to the prevention of a host of infant-, child- and adult-onset medical conditions.
Protein folding and assembly into macromolecule complexes within the living cell are complex processes requiring intimate coordination. The biogenesis of complex iron sulfur molybdoenzymes (CISM) requires use of a system...Protein folding and assembly into macromolecule complexes within the living cell are complex processes requiring intimate coordination. The biogenesis of complex iron sulfur molybdoenzymes (CISM) requires use of a system specific chaperone - a redox enzyme maturation protein (REMP) - to help mediate final folding and assembly. The CISM dimethyl sulfoxide (DMSO) reductase is a bacterial oxidoreductase that utilizes DMSO as a final electron acceptor for anaerobic respiration. The REMP DmsD strongly interacts with DMSO reductase to facilitate folding, cofactor-insertion, subunit assembly and targeting of the multi-subunit enzyme prior to membrane translocation and final assembly and maturation into a bioenergetic catalytic unit. In this article, we discuss the biogenesis of DMSO reductase as an example of the participant network for bacterial CISM maturation pathways.
Selenium is an essential trace element due to its incorporation into selenoproteins with important biological functions. However, at high doses it is toxic. Selenium toxicity is generally attributed to the induction of o...Selenium is an essential trace element due to its incorporation into selenoproteins with important biological functions. However, at high doses it is toxic. Selenium toxicity is generally attributed to the induction of oxidative stress. However, it has become apparent that the mode of action of seleno-compounds varies, depending on its chemical form and speciation. Recent studies in various eukaryotic systems, in particular the model organism Saccharomyces cerevisiae, provide new insights on the cytotoxic mechanisms of selenomethionine and selenocysteine. This review first summarizes current knowledge on reactive oxygen species (ROS)-induced genotoxicity of inorganic selenium species. Then, we discuss recent advances on our understanding of the molecular mechanisms of selenocysteine and selenomethionine cytotoxicity. We present evidences indicating that both oxidative stress and ROS-independent mechanisms contribute to selenoamino acids cytotoxicity. These latter mechanisms include disruption of protein homeostasis by selenocysteine misincorporation in proteins and/or reaction of selenols with protein thiols.
Miousse IR, Tobacyk J, Melnyk S
… +5 more, James SJ, Cheema AK, Boerma M, Hauer-Jensen M, Koturbash I
Biomol Concepts
· 2017 May · PMID 28574375
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Ionizing radiation (IR) is a ubiquitous component of our environment and an important tool in research and medical treatment. At the same time, IR is a potent genotoxic and epigenotoxic stressor, exposure to which may le...Ionizing radiation (IR) is a ubiquitous component of our environment and an important tool in research and medical treatment. At the same time, IR is a potent genotoxic and epigenotoxic stressor, exposure to which may lead to negative health outcomes. While the genotoxocity is well described and characterized, the epigenetic effects of exposure to IR and their mechanisms remain under-investigated. In this conceptual review, we propose the IR-induced changes to one-carbon metabolism as prerequisites to alterations in the cellular epigenome. We also provide evidence from both experimental and clinical studies describing the interactions between IR and one-carbon metabolism. We further discuss the potential for the manipulation of the one-carbon metabolism in clinical applications for the purpose of normal tissue protection and for increasing the radiosensitivity of cancerous cells.
Classical all α-helical globins are present in all living organisms and are ordered in three lineages: (i) flavohemoglobins and single domain globins, (ii) protoglobins and globin coupled sensors and (iii) truncated hemo...Classical all α-helical globins are present in all living organisms and are ordered in three lineages: (i) flavohemoglobins and single domain globins, (ii) protoglobins and globin coupled sensors and (iii) truncated hemoglobins, displaying the 3/3 or the 2/2 all α-helical fold. However, over the last two decades, all β-barrel and mixed α-helical-β-barrel heme-proteins displaying heme-based functional properties (e.g. ligand binding, transport and sensing) closely similar to those of all α-helical globins have been reported. Monomeric nitrophorins (NPs) and α1-microglobulin (α1-m), belonging to the lipocalin superfamily and nitrobindins (Nbs) represent prototypical heme-proteins displaying the all β-barrel and mixed α-helical-β-barrel folds. NPs are confined to the Reduviidae and Cimicidae families of Heteroptera, whereas α1-m and Nbs constitute heme-protein families spanning bacteria to Homo sapiens. The structural organization and the reactivity of the stable ferric solvent-exposed heme-Fe atom suggest that NPs and Nbs are devoted to NO transport, storage and sensing, whereas Hs-α1-m participates in heme metabolism. Here, the structural and functional properties of NPs and Nbs are reviewed in parallel with those of sperm whale myoglobin, which is generally taken as the prototype of monomeric globins.
MicroRNAs (miRNAs) are non-coding small RNAs that are master regulators of genic expression and consequently of many cellular processes. But their expression is often deregulated in human tumors leading to cancer develop...MicroRNAs (miRNAs) are non-coding small RNAs that are master regulators of genic expression and consequently of many cellular processes. But their expression is often deregulated in human tumors leading to cancer development. Recently miRNAs were discovered in body fluids (serum, plasma and others) and their levels have often been reported to be altered in patients. Circulating miRNAs became one of the most promising biomarkers in oncology for early diagnosis, prognosis and therapeutic response prediction. Here we describe the origins and roles of miRNAs, and summarize the most recent studies focusing on their usefulness as cancer biomarkers in lung, breast, colon, prostate, ovary cancers and melanoma. Lastly, we describe the main methodologies related to miRNA detection, which should be standardized for their use in clinical practice.
Vascular calcification represents the deposition of calcium phosphate salts in the tunica media of the vascular wall. It occurs during aging but is accelerated and pronounced in patients with diabetes mellitus, chronic k...Vascular calcification represents the deposition of calcium phosphate salts in the tunica media of the vascular wall. It occurs during aging but is accelerated and pronounced in patients with diabetes mellitus, chronic kidney disease (CKD) and established cardiovascular disease. Due to the loss of elasticity of the vessel wall, vascular calcification might result in left ventricular hypertrophy and compromise coronary perfusion. Accordingly, several studies showed that vascular calcification is associated with increased risk for cardiovascular morbidity and mortality. Accumulating data suggest that microRNAs (miRs) play an important role in vascular calcification. A variety of miRs have been implicated in the development of vascular calcification, whereas others appear to play a protective role. Accordingly, miRs might represent promising targets for the prevention of vascular calcification and its adverse cardiovascular sequelae. However, given the complexity of regulation of this process and the multitude of miRs involved, more research is needed to identify the optimal candidate miRs for targeting.