Signal Transduction Molecules Research Articles

Recent advances of using personal glucose meter as a biosensor readout for non-glucose targets.

Personal glucose meter (PGM) has become the most successful biosensor in past decades due to its advantages of small size, convenient operation, and low cost. To take advantage of many years of research and development of PGMs, new signal transduction methods has been developed to expand the PGM from simple monitoring blood glucose to detection of numerous non-glucose targets. This review summarizes recent advance of PGM-based biosensors for non-glucose targets including signal transduction, signal amplification and target molecule recognition and analysis. Current challenges and future directions are also discussed. PGM can be used as biosensor readout to detect various non-glucose targets from metal ion, small molecule to protein and even living organisms such as bacteria and other pathogens by using different signal transduction elements such as invertase and amylase, and different signal amplification methods such as nanomaterials, nucleic acid reaction, liposome encapsulation, hydrogel trapping, DNAzyme amplification and biotin-streptavidin reaction.

Molecular Characterization of MyD88 in Anodonta woodiana and Its Involvement in the Innate Immune Response to Bacterial Infection.

Myeloid differentiation factor 88 (MyD88) is a key adapter molecule in Toll-like receptor signal transduction that triggers downstream immune cascades involved in the host defense response to exogenous pathogens. However, the function of MyD88s in mollusks, especially in freshwater shellfish, remains poorly understood. In this study, a novel freshwater shellfish MyD88 (denoted AwMyD88) was characterized from Anodonta woodiana. The present AwMyD88 protein consists of 474 amino acids and contains a conserved a typical death domain (DD) and a conservative Toll/IL-1R (TIR) domain with three typical boxes. Quantitative real-time PCR (qRT-PCR) analysis showed that AwMyD88 was broadly expressed in all the examined tissues, and the highest expression level was observed in hemocytes of A. woodiana. When challenged with Aeromonas hydrophila and lipopolysaccharide (LPS), the mRNA expression levels of AwMyD88 were significantly induced in hemocytes of A. woodiana in vivo and in vitro. In addition, in vivo injection experiments revealed that MyD88 signaling pathway genes showed strong responsiveness to A. hydrophila challenge, and their expression levels were significantly upregulated in hemocytes. Knockdown of AwMyD88 reduced the transcript levels of immune related transcription factors (AwNF-κB and AwAP-1) and effectors (AwTNF, AwLYZ, AwDefense and AwAIF) during A. hydrophila infection. Moreover, subcellular localization analysis indicated that AwMyD88 was mainly localized to the cytoplasm in HEK293T cells. Finally, luciferase reporter assays revealed that AwMyD88 associates with AwTLR to activate the NF-κB and AP-1 signaling pathways in HEK293T cells. These results suggested that AwMyD88 might be involved in the host defense response to bacterial challenge, providing new insight into the immune function of the MyD88 signaling pathway in freshwater shellfish.

Lipid Metabolism and Cancer.

Lipid metabolism is involved in the regulation of numerous cellular processes, such as cell growth, proliferation, differentiation, survival, apoptosis, inflammation, movement, membrane homeostasis, chemotherapy response, and drug resistance. Reprogramming of lipid metabolism is a typical feature of malignant tumors. In a variety of cancers, fat uptake, storage and fat production are up-regulated, which in turn promotes the rapid growth, invasion, and migration of tumors. This paper systematically summarizes the key signal transduction pathways and molecules of lipid metabolism regulating tumors, and the role of lipid metabolism in programmed cell death. In conclusion, understanding the potential molecular mechanism of lipid metabolism and the functions of different lipid molecules may facilitate elucidating the mechanisms underlying the occurrence of cancer in order to discover new potential targets for the development of effective antitumor drugs.

A Molecular Landscape of Mouse Hippocampal Neuromodulation.

Adaptive neuronal circuit function requires a continual adjustment of synaptic network parameters known as “neuromodulation.” This process is now understood to be based primarily on the binding of myriad secreted “modulatory” ligands such as dopamine, serotonin and the neuropeptides to G protein-coupled receptors (GPCRs) that, in turn, regulate the function of the ion channels that establish synaptic weights and membrane excitability. Many of the basic molecular mechanisms of neuromodulation are now known, but the organization of neuromodulation at a network level is still an enigma. New single-cell RNA sequencing data and transcriptomic neurotaxonomies now offer bright new lights to shine on this critical “dark matter” of neuroscience. Here we leverage these advances to explore the cell-type-specific expression of genes encoding GPCRs, modulatory ligands, ion channels and intervening signal transduction molecules in mouse hippocampus area CA1, with the goal of revealing broad outlines of this well-studied brain structure’s neuromodulatory network architecture.

Structure of NAD+ consuming Acinetobacter baumannii TIR domain.

Abstract Toll-like and Interleukin-1/18 receptor (TIR) resistance proteins have been identified across biology to function as important multimodal signal transduction and immune regulatory molecules. Select TIR domain containing proteins identified in both eukaryotic and prokaryotic species have also been found to have NAD+ hydrolase activity in bacteria, plants and in mammalian cells. We report the crystal structure of the Acinetobacter baumannii Toll-Interleukin-1 receptor resistance domain protein (AbTIR) determined to a resolution of 2.8 Å, confirm its enzymatic function in NAD+ hydrolysis and map its interaction with NAD+ using HDX-MS. Additionally, we have developed a novel assay for measuring AbTIR’s enzymatic activity in live bacteria using label-free quantitative two-photon fluorescence lifetime (FLT) imaging microscopy (2p-FLIM). These studies provide new insight into TIR protein mechanisms and their varying roles across biology. Supported by R01 AI-082299, R21 CA191726-01

The Role of Adipocyte‐derived Extracellular Vesicles in Diabetes‐associated Endothelial Dysfunction

The development of diabetes (T2D) is strongly associated with obesity, and both are well‐established risk factors for cardiovascular disease. Endothelial dysfunction is an early event in developing vascular complications in obese diabetic (OB‐T2D) adults. Therefore, our long‐term goal is to identify endothelial dysfunction mechanisms in this population, mainly those related to the multifaceted crosstalk between dysfunctional adipocytes and endothelial cells. Our recent findings revealed that ex vivocultured human adipose tissues (AT) release extracellular vesicles (EVs) that are efficiently captured by endothelial cells. These EVs are lipid‐enclosed structures that carry bioactive cargos and are considered vital mediators of intercellular communication. Adipocyte‐derived EVs (adiposomes) mediate signaling between cell types within the AT and circulate in the blood to communicate signals to remote cells and tissues. The purpose of this study is to investigate the role of adiposomes in communicating the unhealthy milieu of dysfunctional AT to endothelial cells in OB‐T2D. Altered lipid metabolism and enhanced ceramide synthesis in OB‐T2D induce adiposome production. Under hyperglycemia, ceramides could be glycosylated into glycosphingolipids (GSLs), selectively packed in adiposomes to be cleared away from adipocytes. We hypothesize that the AT from OB‐T2D patients creates excess GSL‐rich adiposomes, which are incorporated into endothelial cells causing alterations in endothelial cell properties and function. To test this hypothesis, AT samples were collected from OB‐T2D and non‐OB subjects (n=10, each). Nanoparticle analysis and confocal microscopy were used to analyze these adiposomes, and mass spectrometry and Western blotting techniques were used to examine their content. Adiposome uptake, lipid fusion, and changes in endothelial membrane structure and signaling pathways were also assessed following adiposome incubation with microvascular endothelial cells. Our data showed that in comparison to non‐obese controls, adiposomes isolated from OB‐T2D adipose tissues contained higher levels of GSLs. When added to cultured endothelial cells, GSL‐rich adiposomes tended to accumulate in an endothelial structure known as caveolae. These caveolae cover more than 50% of the endothelial cell surface and serve to concentrate signal transduction molecules such as endothelial nitric oxide synthase (eNOS) and others involved in angiogenesis, transcytosis, and permeability. According to our findings, the phosphorylation of the key caveolar protein caveolin‐1 by GSL‐rich adiposomes caused caveolar fission from the endothelial cell surface. This effect was mediated via an activation of Src kinase, as it was inhibited by the Src kinase inhibitor, PP2. These molecular events were accompanied by reductions in endothelial nitric oxide synthase (eNOS) activation and nitric oxide production, disturbances in endothelial gap junction, and increased permeability. Accordingly, we conclude that dysfunctional AT in OB‐T2D patients produce GSL‐loaded adiposomes that fuse with endothelial cells and activate the Src kinase pathway resulting in caveolar fission and endothelial cell dysfunction.

HORDB a comprehensive database of peptide hormones

Peptide hormones (also known as hormone peptides and polypeptide hormones) are hormones composed of peptides and are signal transduction molecules produced by a class of multicellular organisms. It plays an important role in the physiological and behavioral regulation of animals and humans as well as in the growth of plants. In order to promote the research on peptide hormones, we constructed HORDB database. The database currently has a total of 6024 entries, including 5729 peptide hormones, 40 peptide drugs and 255 marketed pharmaceutical preparations information. Each entry provided comprehensive information related to the peptide, including general information, sequence, activity, structure, physical information and literature information. We also added information on IC50, EC50, ED50, target, and whether or not the blood-brain barrier was crossed to the activity information note. In addition, HORDB integrates search and sequence analysis to facilitate user browsing and data analysis. We believe that the peptide hormones information collected by HORDB will promote the design and discovery of peptide hormones, All data are hosted and available in figshare https://doi.org/10.6084/m9.figshare.c.5522241.

A Review of the Synthesis of Nitric Oxide Donor and Donor Derivatives with Pharmacological Activities.

Endogenous nitric oxide (NO) is an important effector molecule and signal transduction molecule, which participates in the regulation of multiple functions in organisms, involving various a variety of physiological and pathological processes, especially playing a very important role in the cardiovascular, immune, and nervous systems. NO is a gaseous substance with a short half-life in the body and is unstable in aqueous solutions. Therefore, many researchers focus on the release and activity of NO donors and their derivatives. However, NO donors can release free NO or NO analogues under physiological conditions to meet the human need. NO donors can be coupled with the corresponding active basic nucleus, so that they have the biological activity derived from both the basic nucleus and the NO donors, thus performing better bioactivity. This paper reviewed the routes of synthesis and advance activities of NO donor derivatives.

Potential Anti-allergic Effects of Bibenzyl Derivatives from Liverworts, Radula perrottetii.

The liverwort Radula perrottetii contains various bibenzyl derivatives which are known to possess various biological activities, such as anti-inflammatory effects. Mast cells (MC) play crucial roles in allergic and inflammatory diseases; thus, inhibition of MC activation is pivotal for the treatment of allergic and inflammatory disorders. We investigated the effects of perrottetin D (perD), isolated from Radula perrottetii, and perD diacetate (Ac-perD) on antigen-induced activation of MCs. Bone marrow-derived MCs (BMMCs) were generated from C57BL/6 mice. The degranulation ratio, histamine release, and the interleukin (IL)-4 and leukotriene B4 productions on antigen-triggered BMMC were investigated. Additionally, the effects of the bibenzyls on binding of IgE to FcεRI were observed by flow cytometry, and signal transduction proteins was examined by Western blot. Furthermore, binding of the bibenzyls to the Fyn kinase domain was calculated. At 10 µM, perD decreased the degranulation ratio (p < 0.01), whereas 10 µM Ac-perD down-regulated IL-4 production (p < 0.05) in addition to decreasing the degranulation ratio (p < 0.01). Both compounds tended to decrease histamine release at a concentration of 10 µM. Although 10 µM perD reduced only Syk phosphorylation, 10 µM Ac-perD diminished phosphorylation of Syk, Gab2, PLC-γ, and p38. PerD appeared to selectively bind Fyn, whereas Ac-perD appeared to act as a weak but broad-spectrum inhibitor of kinases, including Fyn. In conclusion, perD and Ac-perD suppressed the phosphorylation of signal transduction molecules downstream of the FcεRI and consequently inhibited degranulation, and/or IL-4 production. These may be beneficial potential lead compounds for the development of novel anti-allergic and anti-inflammatory drugs.

Scallop IKK1 Responds to Bacterial and Virus-Related Pathogen Stimulation and Interacts With MyD88 Adaptor of Toll-Like Receptor Pathway Signaling.

IKK proteins are key signaling molecules in the innate immune system of animals, and act downstream of pattern recognition receptors. However, research on IKKs in invertebrates, especially marine mollusks, remains scarce. In this study, we cloned CfIKK1 gene from the Zhikong scallop (Chlamys farreri) and studied its function and the signaling it mediates. The open reading frame of CfIKK1 was 2190 bp and encoded 729 amino acids. Phylogenetic analysis showed that CfIKK1 belonged to the invertebrate IKKα/IKKβ family. Quantitative real-time PCR analysis revealed the ubiquitous expression of CfIKK1 mRNA in all scallop tissues and challenge with lipopolysaccharide, peptidoglycan, or poly(I:C) significantly upregulated the expression of CfIKK1. Co-immunoprecipitation assays confirmed the interaction of CfIKK1 with scallop MyD88 (Myeloid differentiation actor 88, the key adaptor of the TLR signaling pathway) via its N-terminal kinase domain. Additionally, CfIKK1 protein could form homodimers and even oligomers, with N-terminal kinase domain and C-terminal scaffold dimerization domain playing key roles in this process. Finally, the results of RNAi experiments showed that when the scallop IKK1 gene was suppressed, the expression of IRF genes also decreased significantly. In conclusion, CfIKK1 could respond to PAMPs challenge and interact with MyD88 protein of scallop TLR signaling, with the formation of CfIKK1 dimers or oligomers. At the same time, the results of RNAi experiments revealed the close regulatory relationship between IKK1 and IRF genes of scallop. Therefore, as a key signal transduction molecule and immune activity regulator, CfIKK1 plays important roles in the innate immune system of scallops.

SAGE: Novel Therapy to Reduce Inflammation in a Naturally Occurring-Dog Model of Periodontal Disease.

ObjectiveTo determine the effect of a semi-synthetic-glycosaminoglycan Ether (SAGE) as a universal therapeutic benefit to reduce periodontal inflammation and alveolar bone loss in naturally occurring-beagle-dog model of periodontal disease as a surrogate for human non-risk associated natural periodontitis.MethodsSix adult female dogs with generalized periodontitis were distributed into two groups: control and SAGE treatment (n=3/group). After a 1-hour full-mouth scaling and root planning (SRP) at baseline, control or SAGE treatment (50mg/mL) bioadhesive gel formulation was locally applied for 12 weeks. Various clinical periodontal measurements (probing depth, CAL) were measured at different time periods (baseline, 4, 8 and 12 weeks), and gingival crevicular fluid (GCF), blood samples and gingival tissue biopsies (12 week) were analyzed for inflammatory mediators, collagenases and cell-signaling molecules. Standardized radiographs were taken at baseline and 12week period.ResultsSAGE treatment significantly reduced gingival inflammation (GCF flow), pocket depth (PD), and clinical attachment loss (CAL) compared to control. SAGE also considerably reduced alveolar bone loss and reduced MMP-9, IL-6, CRP levels in gingival tissue, GCF and plasma. Cell-signaling molecules in the inflammatory cascade system TLR-2, TLR-4, p38 MAPK, ERK1/2 and NF-kB responded to SAGE in a pattern consistent with reductions at the active phase of the inflammatory process and collagenolysis.ConclusionIn the beagle dog model of periodontitis, local SAGE administration significantly attenuated clinical measures of periodontitis, pro-inflammatory cytokines, MMPs, and signal transduction molecules. All our studies, using in vitro and in vivo models, support the therapeutic potential of SAGE as an innovative adjunct to SRP in the treatment of chronic periodontal disease.

BEZ235 reduction of cisplatin resistance on wild-type EGFR non-small cell lung cancer cells

Cisplatin, as a first-line chemotherapy drug for advanced wild-type epidermal growth factor receptor (wtEGFR) non-small cell lung cancer (NSCLC), often loses effectiveness because of acquired drug resistance. We found that ataxia-telangiectasia mutated (ATM), ataxia-telangiectasia and Rad3-related (ATR) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) of DNA repair kinases and signal transduction molecules, protein kinase B (AKT)/target mammalian target of rapamycin (mTOR), were significantly phosphorylated in cisplatin-resistant wtEGFR NSCLC cell lines (H358R and A549R) than in their parental cells. Also, BEZ235 (dual phosphatidylinositol-3-kinase (PI3K)/mTOR inhibitor) significantly decreased the phosphorylation levels of these kinases/proteins, as detected by Western blot analysis. In H358R and A549R cells, the results of indirect immunofluorescence, single-cell gel electrophoresis, flow cytometry, methylthiazolyldiphenyl-tetrazolium bromide, clone formation assay, and scratch healing experiment showed that BEZ235 enhanced cisplatin-induced DNA damage and cell apoptosis, and effectively inhibited cellular proliferation/migration when combined with cisplatin. The data indicated that the abnormal activation of ATM/ATR/DNA-PKcs kinases and AKT/mTOR pathway might induce wtEGFR NSCLC cell resistance to cisplatin. The effects of the combination of BEZ235 and cisplatin suggested that BEZ235 should be considered as a combination therapy for patients with cisplatin-resistant wtEGFR NSCLC.

Ras guanine nucleotide-releasing protein-4 promotes renal inflammatory injury in type 2 diabetes mellitus

IntroductionRas guanine nucleotide-releasing protein-4 (RasGRP4) is an activator of Ras protein, which plays significant roles in both the inflammatory response and immune activation. This study determined the role of RasGRP4 in diabetic kidney disease (DKD) progression. MethodsCRISPR/Cas9 technology was used to establish RasGRP4 knockout (KO) mice. Diabetes was induced by a high-fat diet combined with five consecutive daily intraperitoneal injections of streptozotocin (60 mg/kg) in C57BL/6J wild-type (WT) mice and RasGRP4 KO mice. Hematoxylin and eosin, periodic acid-Schiff, and Masson's trichrome staining were used to observe the histology of pathological injury. Immunohistochemical staining was used to analyze inflammatory cell infiltration. Quantitative PCR and Western blotting were used to detect the expression of inflammatory mediators and the activation of signaling pathways in renal tissues. In vitro cell co-culture experiments were performed to explore the interactions between peripheral blood mononuclear cells (PBMCs) and glomerular endothelial cells (GEnCs). ResultsRasGRP4 KO mice developed less severe diabetic kidney injury compared to WT mice, exhibiting lower proteinuria, reduced CD3+ T lymphocyte and F4/80+ macrophage infiltration, less inflammatory mediator expression including interleukin 6, tumor necrosis alpha, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, and lower expression levels of critical signal transduction molecules in the NLR family pyrin domain-containing 3 inflammasome and mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NF-κB) signaling pathways in the diabetic kidney. In vitro experiments showed that the adhesion function of PBMCs of RasGRP4 KO mice was reduced compared to that of WT mice. Moreover, the expression of adhesion molecules and critical signal transduction molecules in the NLRP3 inflammasome and MAPK/NF-κB signaling pathways in GEnCs was stimulated by the supernatant of PBMCs, which were derived from RasGRP4 KO mice treated with high glucose and were also significantly reduced compared to those derived from WT mice. ConclusionRasGRP4 promotes the inflammatory injury mediated by PBMCs in diabetes, probably by regulating the interaction between PBMCs and GEnCs and further activating the NLRP3 inflammasome and MAPK/NF-κB signaling pathways.

SIRT1: A Key Player in Male Reproduction.

Reproduction is the way to immortality for an individual, and it is essential to the continuation of the species. Sirtuins are involved in cellular homeostasis, energy metabolism, apoptosis, age-related problems, and sexual reproduction. Sirtuin 1 (SIRT1) belongs to the sirtuin family of deacetylases, and it is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase. It removes the acetyl group from a variety of substrates. SIRT1 regulates endocrine/metabolic, reproductive, and placental development by deacetylating histone, different transcription factors, and signal transduction molecules in a variety of cellular processes. It also plays a very important role in the synthesis and secretion of sex hormones via regulating the hypothalamus-pituitary-gonadal (HPG) axis. Moreover, SIRT1 participates in several key stages of spermatogenesis and sperm maturation. The current review will give a thorough overview of SIRT1’s functions in male reproductive processes, thus paving the way for more research on restorative techniques and their uses in reproductive medicine.

Lithium Chloride Promotes Milk Protein and Fat Synthesis in Bovine Mammary Epithelial Cells via HIF-1α and β-Catenin Signaling Pathways.

Lithium is one of the trace elements with many physiological properties, such as being anti-cancer, anti-viral, and anti-inflammatory. However, little is known about its effect on milk synthesis during lactation. Therefore, we selected different concentrations (5mM, 10mM, and 20mM) of lithium chloride (LiCl) and assessed the effect of LiCl on bovine mammary epithelial (MAC-T) cells that underwent 4days of differentiation induction. Moreover, we analyzed the effect of LiCl on the expression of genes related to milk fat and milk protein synthesis. Herein, LiCl (5-20mM) significantly increased the expression of β-casein, promoted mRNA expression and phosphorylated protein expression of the signal transduction molecule and activator of transcription 5β (STAT5-β), and inhibited mRNA and protein expression of suppressor of cytokine signaling 2 (SOCS2). In contrast, 5 and 10mM LiCl significantly inhibited expression of SOCS3. LiCl at concentration of 5-20mM enhanced phosphorylation level of mTOR protein; at 10mM and 20mM, LiCl significantly promoted expression and phosphorylation of downstream ribosomal protein S6 kinase beta-1 (S6K1) protein. Considering milk fat synthesis, mRNA expression of acetyl CoA carboxylase (ACC) and lipoprotein lipase (LPL) genes was considerably increased in the presence of LiCl (5-20mM). Additionally, increased protein expression levels of stearoyl-CoA desaturase (SCD), peroxisome proliferator-activated receptor-γ (PPARγ), and sterol regulatory element-binding protein 1 (SREBP1) were observed at all LiCl concentrations tested. Subsequently, LiCl (5-20mM) significantly promoted protein expression and phosphorylation of β-catenin, while 10mM and 20mM of LiCl significantly promoted protein expression of hypoxia-inducible factor-1α (HIF-1α). Collectively, it has been shown that 10mM LiCl can effectively activate HIF-1α, β-catenin, and β-catenin downstream signaling pathways. Conversely, at 10mM, LiCl inhibited SOCS2 and SOCS3 protein expression through JAK2/STAT5, mTOR, and SREBP1 signaling pathways, improving synthesis of milk protein and fat. Therefore, LiCl can be used as a potential nutrient to regulate milk synthesis in dairy cows.

Blocking TNF signaling may save lives in COVID-19 infection.

Global vaccination effort and better understanding of treatment strategies provided a ray of hope for improvement in COVID-19 pandemic, however, in many countries, the disease continues to collect its death toll. The major pathogenic mechanism behind severe cases associated with high mortality is the burst of pro-inflammatory cytokines TNF, IL-6, IFNγ and others, resulting in multiple organ failure. Although the exact contribution of each cytokine is not clear, we provide an evidence that the central mediator of cytokine storm and its devastating consequences may be TNF. This cytokine is known to be involved in activated blood clotting, lung damage, insulin resistance, heart failure, and other conditions. A number of currently available pharmaceutical agents such as monoclonal antibodies and soluble TNF receptors can effectively prevent TNF from binding to its receptor(s). Other drugs are known to block NFkB, the major signal transducer molecule used in TNF signaling, or to block kinases involved in downstream activation cascades. Some of these medicines have already been selected for clinical trials, but more work is needed. A simple, rapid, and inexpensive method of directly monitoring TNF levels may be a valuable tool for a timely selection of COVID-19 patients for anti-TNF therapy.

Pillars and Gaps of S-Nitrosylation-Dependent Epigenetic Regulation in Physiology and Cancer.

Nitric oxide (NO) is a diffusible signaling molecule produced by three isoforms of nitric oxide synthase, which release NO during the metabolism of the amino acid arginine. NO participates in pathophysiological responses of many different tissues, inducing concentration-dependent effect. Indeed, while low NO levels generally have protective effects, higher NO concentrations induce cytotoxic/cytostatic actions. In recent years, evidences have been accumulated unveiling S-nitrosylation as a major NO-dependent post-translational mechanism ruling gene expression. S-nitrosylation is a reversible, highly regulated phenomenon in which NO reacts with one or few specific cysteine residues of target proteins generating S-nitrosothiols. By inducing this chemical modification, NO might exert epigenetic regulation through direct effects on both DNA and histones as well as through indirect actions affecting the functions of transcription factors and transcriptional co-regulators. In this light, S-nitrosylation may also impact on cancer cell gene expression programs. Indeed, it affects different cell pathways and functions ranging from the impairment of DNA damage repair to the modulation of the activity of signal transduction molecules, oncogenes, tumor suppressors, and chromatin remodelers. Nitrosylation is therefore a versatile tool by which NO might control gene expression programs in health and disease.

Functional studies on neuropeptides and receptors in model animal &amp;lt;italic&amp;gt;Aplysia&amp;lt;/italic&amp;gt;

<p indent="0mm">Neuropeptides are widely distributed in the central nervous system and the endocrine system. As signaling transduction molecules between cells, neuropeptides play important roles in regulating a variety of physiological processes, such as behavioral control, temperature regulation, energy balance, circadian rhythm. In this paper, we primarily review the discoveries and functions of neuropeptides that are released by neuronal elements in behavior-generating neural circuits in the central nervous system. Due to the complexity of neural circuits, it has been highly challenging to study all or most of the neuropeptides and their functions in a specific system in vertebrates. Consequently, many invertebrates have been used as model animals to discover novel neuropeptides and their receptors, and to study the functions of these neuropeptides and receptors. We describe the basic characteristics, modes of actions, and research approaches, particularly the progress of neuropeptide research in the experimentally-advantageous mollusc <italic>Aplysia</italic>. We highlight the diversity of neuropeptide/receptor signaling systems and the challenges in studying them. We believe that the findings in invertebrates will provide novel insights for the research on the functions and mechanisms of neuropeptides in vertebrates, including mammals.

Molecular Bases of Human Malformation Syndromes Involving the SHH Pathway: GLIA/R Balance and Cardinal Phenotypes

Human hereditary malformation syndromes are caused by mutations in the genes of the signal transduction molecules involved in fetal development. Among them, the Sonic hedgehog (SHH) signaling pathway is the most important, and many syndromes result from its disruption. In this review, we summarize the molecular mechanisms and role in embryonic morphogenesis of the SHH pathway, then classify the phenotype of each malformation syndrome associated with mutations of major molecules in the pathway. The output of the SHH pathway is shown as GLI activity, which is generated by SHH in a concentration-dependent manner, i.e., the sum of activating form of GLI (GLIA) and repressive form of GLI (GLIR). Which gene is mutated and whether the mutation is loss-of-function or gain-of-function determine in which concentration range of SHH the imbalance occurs. In human malformation syndromes, too much or too little GLI activity produces symmetric phenotypes affecting brain size, craniofacial (midface) dysmorphism, and orientation of polydactyly with respect to the axis of the limb. The symptoms of each syndrome can be explained by the GLIA/R balance model.

An Overview of Glycosylation and its Impact on Cardiovascular Health and Disease.

The cardiovascular system is a complex and well-organized system in which glycosylation plays a vital role. The heart and vascular wall cells are constituted by an array of specific receptors; most of them are N- glycosylated and mucin-type O-glycosylated. There are also intracellular signaling pathways regulated by different post-translational modifications, including O-GlcNAcylation, which promote adequate responses to extracellular stimuli and signaling transduction. Herein, we provide an overview of N-glycosylation and O-glycosylation, including O-GlcNAcylation, and their role at different levels such as reception of signal, signal transduction, and exogenous molecules or agonists, which stimulate the heart and vascular wall cells with effects in different conditions, like the physiological status, ischemia/reperfusion, exercise, or during low-grade inflammation in diabetes and aging. Furthermore, mutations of glycosyltransferases and receptors are associated with development of cardiovascular diseases. The knowledge on glycosylation and its effects could be considered biochemical markers and might be useful as a therapeutic tool to control cardiovascular diseases.