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Topic Review
Sphingosine 1-phosphate
The breakdown of the endothelial cell (EC) barrier contributes significantly to sepsis mortality. Sphingosine 1-phosphate (S1P) is one of the most effective EC barrier-stabilizing signaling molecules. Stabilization is mainly transduced via the S1P receptor type 1 (S1PR1). Here, we demonstrate that S1P was autonomously produced by ECs. S1P secretion was significantly higher in primary human umbilical vein endothelial cells (HUVEC) compared to the endothelial cell line EA.hy926. Constitutive barrier stability of HUVEC, but not EA.hy926, was significantly compromised by the S1PR1 antagonist W146 and by the anti-S1P antibody Sphingomab. HUVEC and EA.hy926 differed in the expression of the S1P-transporter Spns2, which allowed HUVEC, but not EA.hy926, to secrete S1P into the extracellular space. Spns2 deficient mice showed increased serum albumin leakage in bronchoalveolar lavage fluid (BALF). Lung ECs isolated from Spns2 deficient mice revealed increased leakage of fluorescein isothiocyanate (FITC) labeled dextran and decreased resistance in electric cell-substrate impedance sensing (ECIS) measurements. Spns2 was down-regulated in HUVEC after stimulation with pro-inflammatory cytokines and lipopolysaccharides (LPS), which contributed to destabilization of the EC barrier. Our work suggests a new mechanism for barrier integrity maintenance. Secretion of S1P by EC via Spns2 contributed to constitutive EC barrier maintenance, which was disrupted under inflammatory conditions via the down-regulation of the S1P-transporter Spns2.
  • 1.4K
  • 30 Oct 2020
Topic Review
Mechanisms of α-Syn Aggregation In Vitro
The aggregation of proteins into amyloid fibers is linked to more than forty still incurable cellular and neurodegenerative diseases such as Parkinson’s disease (PD), multiple system atrophy, Alzheimer’s disease and type 2 diabetes, among others. The process of amyloid formation is a main feature of cell degeneration and disease pathogenesis. Despite being methodologically challenging, a complete understanding of the molecular mechanism of aggregation, especially in the early stages, is essential to find new biological targets for innovative therapies. Here, chemical and biophysical methodologies that provided insights on Alpha-synuclein aggregation that would help to investigate other less-known aggregation-prone peptides and proteins were presented.
  • 1.4K
  • 03 Jan 2023
Topic Review
CIDE Proteins in Human Health
Cell death-Inducing DNA Fragmentation Factor Alpha (DFFA)-like Effector (CIDE) proteins have emerged as lipid droplet-associated proteins that regulate fat metabolism. There are three members in the CIDE protein family—CIDEA, CIDEB, and CIDEC (also known as fat-specific protein 27 (FSP27)). CIDEA and FSP27 are primarily expressed in adipose tissue, while CIDEB is expressed in the liver. Originally, based upon their homology with DNA fragmentation factors, these proteins were identified as apoptotic proteins. However, recent studies have changed the perception of these proteins, redefining them as regulators of lipid droplet dynamics and fat metabolism, which contribute to a healthy metabolic phenotype in humans. Despite various studies in humans and gene-targeting studies in mice, the physiological roles of CIDE proteins remains elusive.
  • 1.4K
  • 07 Jun 2022
Topic Review
Targeted Cytokine Delivery for Cancer Treatment
Anti-tumor properties of several cytokines have already been investigated in multiple experiments and clinical trials. However, those studies evidenced substantial toxicities, even at low cytokine doses, and the lack of tumor specificity. These factors significantly limit clinical applications. Due to their high specificity and affinity, tumor-specific monoclonal antibodies or their antigen-binding fragments are capable of delivering fused cytokines to tumors and, therefore, of decreasing the number and severity of side effects, as well as of enhancing the therapeutic index. Targeted cytokine-mediated activation of the immune cells may trigger massive cytokine production at the disease site, making the local environmental conditions more favorable for local immune system cell functioning.
  • 1.4K
  • 10 Feb 2023
Topic Review
Anti-Cancer Peptides as Immunomodulatory Agents
The usage of peptide-based drugs to combat cancer is gaining significance in the pharmaceutical industry. The collateral damage caused to normal cells due to the use of chemotherapy, radiotherapy, etc. has given an impetus to the search for alternative methods of cancer treatment.
  • 1.4K
  • 23 Dec 2022
Topic Review
Lysosomes Support DNA Replication
Lysosomes, acidic, membrane-bound organelles, are not only the core of the cellular recycling machinery, but they also serve as signaling hubs regulating various metabolic pathways. Lysosomes maintain energy homeostasis and provide pivotal substrates for anabolic processes, such as DNA replication. Every time the cell divides, its genome needs to be correctly duplicated; therefore, DNA replication requires rigorous regulation. Challenges that negatively affect DNA synthesis, such as nucleotide imbalance, result in replication stress with severe consequences for genome integrity. The lysosomal complex mTORC1 is directly involved in the synthesis of purines and pyrimidines to support DNA replication.
  • 1.4K
  • 25 May 2021
Topic Review
Aging Stress Response
Aging induces several stress response pathways to counterbalance detrimental changes associated with this process. These pathways include nutrient signaling, proteostasis, mitochondrial quality control and DNA damage response. At the cellular level, these pathways are controlled by evolutionarily conserved signaling molecules, such as 5'AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor 1 (IGF-1) and sirtuins, including SIRT1. Peroxisome proliferation-activated receptor coactivator 1 alpha (PGC-1α), encoded by the PPARGC1A gene, playing an important role in antioxidant defense and mitochondrial biogenesis, may interact with these molecules influencing lifespan and general fitness. Perturbation in the aging stress response may lead to aging-related disorders, including age-related macular degeneration (AMD), the main reason for vision loss in the elderly. This is supported by studies showing an important role of disturbances in mitochondrial metabolism, DDR and autophagy in AMD pathogenesis. In addition, disturbed expression of PGC-1α was shown to associate with AMD. Therefore, the aging stress response may be critical for AMD pathogenesis, and further studies are needed to precisely determine mechanisms underlying its role in AMD.
  • 1.4K
  • 28 Sep 2021
Topic Review
Ion Channels of Nociception
Acute pain plays the vital role protecting our health whereas chronic and pathological pain are debilitating conditions.  However molecular mechanisms of pain which are the keys for pain relief remain largely unaddressed. Nevertheless, new molecular actors with important roles in pain mechanisms are being characterized, such as the mechanosensitive Piezo ion channels. This study presents modern trends and promising advances in the field of molecular mechanisms of pain. 
  • 1.4K
  • 24 Mar 2021
Topic Review
Coenzyme Q
Coenzyme Q (CoQ), ubiquinone or 2,3-dimethoxy-5-methyl-6-polyprenyl-1,4-benzoquinone is a two-part molecule composed of a benzoquinone ring, which has redox active sites, and a long polyisoprenoid lipid chain that positions the molecule in the mid-plane of a membrane bilayer. It is an essential endogenously synthesized molecule that links different metabolic pathways to mitochondrial energy production thanks to its location in the mitochondrial inner membrane and its redox capacity, which also provide it with the capability to work as an antioxidant. 
  • 1.4K
  • 26 Aug 2021
Topic Review
Anti-Obesity Properties of Polyphenols
The prevalence of obesity has steadily increased around the world over the past three decades. Polyphenols can be considered nutraceuticals and food supplements recommended for different syndromes. Polyphenols are a class of naturally occurring phytochemicals, some of which have been shown to modulate the physiological and molecular pathways involved in energy metabolism. Polyphenols could act in the stimulation of β-oxidation, in the inhibition of the differentiation of adipocytes, in counteracting oxidative stress, etc.
  • 1.4K
  • 26 Sep 2022
Topic Review
Decoding CD271 in melanoma
The evolution of melanoma, the most aggressive type of skin cancer, is triggered bydriver mutations that are acquired in the coding regions of particularly BRAF (rat fibrosarcomaserine/threonine kinase, isoform B) or NRAS (neuroblastoma-type ras sarcoma virus) in melanocytes.Although driver mutations strongly determine tumor progression, additional factors are likelyrequired and prerequisite for melanoma formation. Melanocytes are formed during vertebratedevelopment in a well-controlled di erentiation process of multipotent neural crest stem cells(NCSCs). However, mechanisms determining the properties of melanocytes and melanoma cellsare still not well understood. The nerve growth factor receptor CD271 is likewise expressed inmelanocytes, melanoma cells and NCSCs and programs the maintenance of a stem-like and migratoryphenotype via a comprehensive network of associated genes. Moreover, CD271 regulates phenotypeswitching, a process that enables the rapid and reversible conversion of proliferative into invasive ornon-stem-like states into stem-like states by yet largely unknown mechanisms. Here, we summarizecurrent findings about CD271-associated mechanisms in melanoma cells and illustrate the role ofCD271 for melanoma cell migration and metastasis, phenotype-switching, resistance to therapeuticinterventions, and the maintenance of an NCSC-like state.
  • 1.4K
  • 28 Oct 2020
Topic Review
Base Excision Repair Mechanisms
Base excision repair (BER) corrects forms of oxidative, deamination, alkylation, and abasic single-base damage that appear to have minimal effects on the helix. Since its discovery in 1974, the field has grown in several facets: mechanisms, biology and physiology, understanding deficiencies and human disease, and using BER genes as potential inhibitory targets to develop therapeutics.
  • 1.4K
  • 26 Sep 2023
Topic Review
Potential Biochemical Properties and Genetics of C-Reactive Protein
C-Reactive Protein (CRP) is supposed to be an accredited benchmark for physicians, to reveal or rule out inflammation, and multifarious scientific endeavors have been made so as to detect the direct pleiotropic functions of this protein. The use of CRP as the most important and critical immunochemical marker of several medical conditions, including infections such as sepsis, physiological organ diseases, various autoimmune disorders, malignancies and other health conditions, has become widely popular.
  • 1.4K
  • 14 Nov 2023
Topic Review
Insights into HP1a-Chromatin Interactions
     Understanding the packaging of DNA into chromatin is essential for the study of gene expression regulatory mechanisms. Heterochromatin establishment and maintenance dynamics have emerged as key features involved in genome stability, cellular growth, and disease. The heterochromatin protein HP1a is the most extensively studied factor that has both establishment and heterochromatin maintenance activities. This protein has two primary domains, namely the chromoshadow and the chromodomain, separated by a hinge region. Several works have taken place over the years, taking the challenge of defining HP1a partners using diverse experimental approaches. We revised and assemble on explaining these interactions and the potential complexes and subcomplexes associated formed with this essential protein. Characterization of these complexes will allow us to clearly understand the consequences of HP1a interactions in heterochromatin in maintenance, heterochromatin dynamics, and the direct relationship of heterochromatin with gene regulation.
  • 1.4K
  • 03 Apr 2021
Topic Review
Cardiac Autonomic Neuropathy
Cardiac autonomic neuropathy (CAN) is one of the earliest manifestations of type 2 diabetes (T2D). It constitutes the major cause of silent cardiovascular events in patients without overt cardiac disease. The high prevalence of CAN in patients newly diagnosed with T2D suggests that its pathophysiology is rooted in an earlier stage of metabolic derangement, possibly being prediabetes.
  • 1.4K
  • 11 Dec 2020
Topic Review
Biochemistry of Antioxidants and Their Mode of Action
Antioxidants are a class of a multitude of chemical substances clearly associated with large health benefits and lower risks of various age-related diseases.
  • 1.4K
  • 11 Apr 2023
Topic Review
Multivariate Analysis
Multivariate analysis (MA) is becoming a fundamental tool for processing in an efficient way the large amount of data collected in X-ray diffraction experiments. Multi-wedge data collections can increase the data quality in case of tiny protein crystals; in situ or operando setups allow investi-gating changes on powder samples occurring during repeated fast measurements; pump and probe experiments at X-ray free-electron laser (XFEL) sources supply structural characterization of fast photo-excitation processes. In all these cases, MA can facilitate the extraction of relevant in-formation hidden in data, disclosing the possibility of automatic data processing even in absence of a priori structural knowledge.
  • 1.4K
  • 12 Jan 2021
Topic Review
CRISPR/Cas in Research of Telomeres
Telomeres are highly specialized nucleoprotein complexes that play a critical role in cell senescence and aging. Each chromosomal end must be “capped” with a critical amount of telomere repeats to prevent DNA repair pathways from being activated. As a result of the clustered regularly interspaced short palindromic repeats (CRISPR)-associated system’s (Cas) method, targeted genetic studies are now underway to change telomerase, the genes that govern it as well as telomeres.
  • 1.4K
  • 24 Mar 2022
Topic Review
α-Syn Structure, Aggregation, and Degradation in Parkinson’s Disease
Parkinson’s disease (PD) is a progressive neurodegenerative disorder. The classical behavioral defects of PD patients involve motor symptoms such as bradykinesia, tremor, and rigidity, as well as non-motor symptoms such as anosmia, depression, and cognitive impairment. Pathologically, the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN) and the accumulation of α-synuclein (α-syn)-composed Lewy bodies (LBs) and Lewy neurites (LNs) are key hallmarks.
  • 1.4K
  • 01 Dec 2022
Topic Review
Signal Transduction by VIP and PACAP Receptors
Homeostasis of the human immune system is regulated by many cellular components, including two neuropeptides, VIP and PACAP, primary stimuli for three class B G protein-coupled receptors, VPAC1, VPAC2, and PAC1. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) regulate intestinal motility and secretion and influence the functioning of the endocrine and immune systems. Inhibition of VIP and PACAP receptors is an emerging concept for new pharmacotherapies for chronic inflammation and cancer, while activation of their receptors provides neuroprotection. Major molecular switches of VPAC1, VPAC2, and PAC1 may act as triggers for receptor activation and compare them with similar non-covalent interactions changing upon activation that were observed for other GPCRs. Interhelical interactions in VIP and PACAP receptors that are important for agonist binding and/or activation provide a molecular basis for the design of novel selective drugs demonstrating anti-inflammatory, anti-cancer, and neuroprotective effects. As to the genetic variants of VIP, PACAP, and their receptors on signalling mediated by endogenous agonists, this sequence diversity resulting from gene splicing has a significant impact on agonist selectivity and potency as well as on the signalling properties of VIP and PACAP receptors. 
  • 1.4K
  • 28 Mar 2022
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