International Journal of Molecular Sciences

35 pages, 2440 KiB

Open AccessReview

Rho GTPases in Intellectual Disability: From Genetics to Therapeutic Opportunities

by Valentina Zamboni¹, Rebecca Jones¹, Alessandro Umbach¹, Alessandra Ammoni¹, Maria Passafaro², Emilio Hirsch¹

and Giorgio R. Merlo^1,*

¹ Department Molecular Biotechnology and Health Science, University of Torino, Via Nizza 52, 10126 Turin, Italy

² National Research Council (CNR) Institute for Neuroscience, Via Luigi Vanvitelli, 32, I-20129 Milan, Italy

Int. J. Mol. Sci. 2018, 19(6), 1821; https://doi.org/10.3390/ijms19061821 - 20 Jun 2018

Cited by 64 | Viewed by 9738

Abstract

Rho-class small GTPases are implicated in basic cellular processes at nearly all brain developmental steps, from neurogenesis and migration to axon guidance and synaptic plasticity. GTPases are key signal transducing enzymes that link extracellular cues to the neuronal responses required for the construction [...] Read more.

Rho-class small GTPases are implicated in basic cellular processes at nearly all brain developmental steps, from neurogenesis and migration to axon guidance and synaptic plasticity. GTPases are key signal transducing enzymes that link extracellular cues to the neuronal responses required for the construction of neuronal networks, as well as for synaptic function and plasticity. Rho GTPases are highly regulated by a complex set of activating (GEFs) and inactivating (GAPs) partners, via protein:protein interactions (PPI). Misregulated RhoA, Rac1/Rac3 and cdc42 activity has been linked with intellectual disability (ID) and other neurodevelopmental conditions that comprise ID. All genetic evidences indicate that in these disorders the RhoA pathway is hyperactive while the Rac1 and cdc42 pathways are consistently hypoactive. Adopting cultured neurons for in vitro testing and specific animal models of ID for in vivo examination, the endophenotypes associated with these conditions are emerging and include altered neuronal networking, unbalanced excitation/inhibition and altered synaptic activity and plasticity. As we approach a clearer definition of these phenotype(s) and the role of hyper- and hypo-active GTPases in the construction of neuronal networks, there is an increasing possibility that selective inhibitors and activators might be designed via PPI, or identified by screening, that counteract the misregulation of small GTPases and result in alleviation of the cognitive condition. Here we review all knowledge in support of this possibility. Full article

(This article belongs to the Special Issue Small GTPases)

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13 pages, 3009 KiB

Open AccessArticle

Does the Automatic Measurement of Interleukin 6 Allow for Prediction of Complications during the First 48 h of Acute Pancreatitis?

by Witold Kolber¹, Paulina Dumnicka², Małgorzata Maraj³, Beata Kuśnierz-Cabala⁴, Piotr Ceranowicz^3,*

, Michał Pędziwiatr⁵

, Barbara Maziarz⁴, Małgorzata Mazur-Laskowska⁶, Marek Kuźniewski⁷, Mateusz Sporek⁸ and Jerzy Walocha⁸

¹ Department of Surgery, Complex of Health Care Centers in Wadowice, Karmelicka 5 St., 34-100 Wadowice, Poland

² Department of Medical Diagnostics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Krakow, Poland

³ Department of Physiology, Jagiellonian University Medical College, Grzegorzecka 16 St., 31-531 Krakow, Poland

⁴ Department of Diagnostics, Chair of Clinical Biochemistry, Jagiellonian University Medical College, Kopernika 15A St., 31-501 Krakow, Poland

⁵ 2nd Department of Surgery, Jagiellonian University Medical College, Kopernika 21 St., 31-501 Krakow, Poland

⁶ Diagnostics Department of University Hospital in Krakow, Kopernika 15B St., 31-501 Krakow, Poland

⁷ Department of Nephrology, Jagiellonian University Medical College, Kopernika 15 St., 31-501 Krakow, Poland

⁸ Department of Anatomy, Jagiellonian University Medical College, Kopernika 12 St., 31-034 Krakow, Poland

Int. J. Mol. Sci. 2018, 19(6), 1820; https://doi.org/10.3390/ijms19061820 - 20 Jun 2018

Cited by 23 | Viewed by 5605

Abstract

Acute pancreatitis (AP) in most patients takes a course of self-limiting local inflammation. However, up to 20% of patients develop severe AP (SAP), associated with systemic inflammation and/or pancreatic necrosis. Early prediction of SAP allows for the appropriate intensive treatment of severe cases, [...] Read more.

Acute pancreatitis (AP) in most patients takes a course of self-limiting local inflammation. However, up to 20% of patients develop severe AP (SAP), associated with systemic inflammation and/or pancreatic necrosis. Early prediction of SAP allows for the appropriate intensive treatment of severe cases, which reduces mortality. Serum interleukin-6 (IL-6) has been proposed as a biomarker to assist early diagnosis of SAP, however, most data come from studies utilizing IL-6 measurements with ELISA. Our aim was to verify the diagnostic usefulness of IL-6 for the prediction of SAP, organ failure, and need for intensive care in the course of AP using a fully automated assay. The study included 95 adult patients with AP of various severity (29 mild, 58 moderately-severe, 8 severe) admitted to a hospital within 24 h from the onset of symptoms. Serum IL-6 was measured using electochemiluminescence immunoassay in samples collected on admission and on the next day of hospital stay. On both days, patients with SAP presented the highest IL-6 levels. IL-6 correlated positively with other inflammatory markers (white blood cell and neutrophil counts, C-reactive protein, procalcitonin), the markers of renal injury (kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin), and the markers of endothelial dysfunction (angiopoietin-2, soluble fms-like tyrosine kinase-1). IL-6 on admission significantly predicted SAP, vital organ failure, and the need for intensive care or death, with areas under the receiver operating curve between 0.75 and 0.78, not significantly different from multi-variable prognostic scores. The fully automated assay allows for fast and repeatable measurements of serum IL-6, enabling wider clinical use of this valuable biomarker. Full article

(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders)

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14 pages, 2727 KiB

Open AccessArticle

Effect of Surfactant Type and Sonication Energy on the Electrical Conductivity Properties of Nanocellulose-CNT Nanocomposite Films

by Sanna Siljander^1,*, Pasi Keinänen¹

, Anna Räty¹, Karthik Ram Ramakrishnan¹, Sampo Tuukkanen²

, Vesa Kunnari³, Ali Harlin³, Jyrki Vuorinen¹

and Mikko Kanerva¹

¹ Laboratory of Materials Science, Tampere University of Technology, FI-33720 Tampere, Finland

² BioMediTech, Tampere University of Technology, FI-33720 Tampere, Finland

³ VTT Research Center, FI-02044 Espoo, Finland

Int. J. Mol. Sci. 2018, 19(6), 1819; https://doi.org/10.3390/ijms19061819 - 20 Jun 2018

Cited by 40 | Viewed by 6366

Abstract

We present a detailed study on the influence of sonication energy and surfactant type on the electrical conductivity of nanocellulose-carbon nanotube (NFC-CNT) nanocomposite films. The study was made using a minimum amount of processing steps, chemicals and materials, to optimize the conductivity properties [...] Read more.

We present a detailed study on the influence of sonication energy and surfactant type on the electrical conductivity of nanocellulose-carbon nanotube (NFC-CNT) nanocomposite films. The study was made using a minimum amount of processing steps, chemicals and materials, to optimize the conductivity properties of free-standing flexible nanocomposite films. In general, the NFC-CNT film preparation process is sensitive concerning the dispersing phase of CNTs into a solution with NFC. In our study, we used sonication to carry out the dispersing phase of processing in the presence of surfactant. In the final phase, the films were prepared from the dispersion using centrifugal cast molding. The solid films were analyzed regarding their electrical conductivity using a four-probe measuring technique. We also characterized how conductivity properties were enhanced when surfactant was removed from nanocomposite films; to our knowledge this has not been reported previously. The results of our study indicated that the optimization of the surfactant type clearly affected the formation of freestanding films. The effect of sonication energy was significant in terms of conductivity. Using a relatively low 16 wt. % concentration of multiwall carbon nanotubes we achieved the highest conductivity value of 8.4 S/cm for nanocellulose-CNT films ever published in the current literature. This was achieved by optimizing the surfactant type and sonication energy per dry mass. Additionally, to further increase the conductivity, we defined a preparation step to remove the used surfactant from the final nanocomposite structure. Full article

(This article belongs to the Special Issue Synthesis and Applications of Biopolymer Composites)

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12 pages, 3185 KiB

Open AccessReview

Possible Molecular Targets of Novel Ruthenium Complexes in Antiplatelet Therapy

by Thanasekaran Jayakumar^1,†, Chia-Yuan Hsu^1,2,†, Themmila Khamrang³, Chih-Hsuan Hsia¹, Chih-Wei Hsia¹, Manjunath Manubolu⁴ and Joen-Rong Sheu^1,5,*

¹ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan

² Department of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan

³ Department of Chemistry, North Eastern Hill University, Shillong 793022, India

⁴ Department of Evolution, Ecology and Organismal Biology, Ohio State University, Columbus, OH 43212, USA

⁵ Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan

^† These two authors contributed equally to this work.

Int. J. Mol. Sci. 2018, 19(6), 1818; https://doi.org/10.3390/ijms19061818 - 20 Jun 2018

Cited by 12 | Viewed by 4989

Abstract

In oncotherapy, ruthenium (Ru) complexes are reflected as potential alternatives for platinum compounds and have been proved as encouraging anticancer drugs with high efficacy and low side effects. Cardiovascular diseases (CVDs) are mutually considered as the number one killer globally, and thrombosis is [...] Read more.

In oncotherapy, ruthenium (Ru) complexes are reflected as potential alternatives for platinum compounds and have been proved as encouraging anticancer drugs with high efficacy and low side effects. Cardiovascular diseases (CVDs) are mutually considered as the number one killer globally, and thrombosis is liable for the majority of CVD-related deaths. Platelets, an anuclear and small circulating blood cell, play key roles in hemostasis by inhibiting unnecessary blood loss of vascular damage by making blood clot. Platelet activation also plays a role in cancer metastasis and progression. Nevertheless, abnormal activation of platelets results in thrombosis under pathological settings such as the rupture of atherosclerotic plaques. Thrombosis diminishes the blood supply to the heart and brain resulting in heart attacks and strokes, respectively. While currently used anti-platelet drugs such as aspirin and clopidogrel demonstrate efficacy in many patients, they exert undesirable side effects. Therefore, the development of effective therapeutic strategies for the prevention and treatment of thrombotic diseases is a demanding priority. Recently, precious metal drugs have conquered the subject of metal-based drugs, and several investigators have motivated their attention on the synthesis of various ruthenium (Ru) complexes due to their prospective therapeutic values. Similarly, our recent studies established that novel ruthenium-based compounds suppressed platelet aggregation via inhibiting several signaling cascades. Our study also described the structure antiplatelet-activity relationship (SAR) of three newly synthesized ruthenium-based compounds. This review summarizes the antiplatelet activity of newly synthesized ruthenium-based compounds with their potential molecular mechanisms. Full article

(This article belongs to the Special Issue Molecular Pharmacology and Pathology of Strokes)

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21 pages, 2754 KiB

Open AccessArticle

Studies of Microbiota Dynamics Reveals Association of “Candidatus Liberibacter Asiaticus” Infection with Citrus (Citrus sinensis) Decline in South of Iran

by Alessandro Passera¹, Hamidreza Alizadeh², Mehdi Azadvar³

, Fabio Quaglino¹

, Asma Alizadeh², Paola Casati¹

and Piero A. Bianco^1,*

¹ Department of Agricultural and Environmental Sciences, University of Milan, 20133 Milan, Italy

² Department of Plant Protection, Faculty of Agriculture, University of Jiroft, Jiroft 7867161167, Iran

³ Plant Protection Department, South Kerman Agricultural and Natural Resources Research and Education Center, Agricultural Research Education and Extension Organization, Jiroft 7867161167, Iran

Int. J. Mol. Sci. 2018, 19(6), 1817; https://doi.org/10.3390/ijms19061817 - 20 Jun 2018

Cited by 11 | Viewed by 4306

Abstract

Citrus Decline Disease was recently reported to affect several citrus species in Iran when grafted on a local rootstock variety, Bakraee. Preliminary studies found “Candidatus Phytoplasma aurantifoliae” and “Candidatus Liberibacter asiaticus” as putative etiological agents, but were not ultimately able to [...] Read more.

Citrus Decline Disease was recently reported to affect several citrus species in Iran when grafted on a local rootstock variety, Bakraee. Preliminary studies found “Candidatus Phytoplasma aurantifoliae” and “Candidatus Liberibacter asiaticus” as putative etiological agents, but were not ultimately able to determine which one, or if an association of both, were causing the disease. The current study has the aim of characterizing the microbiota of citrus plants that are either asymptomatic, showing early symptoms, or showing late symptoms through amplification of the V1–V3 region of 16S rRNA gene using an Illumina sequencer in order to (i) clarify the etiology of the disease, and (ii) describe the microbiota associated to different symptom stages. Our results suggest that liberibacter may be the main pathogen causing Citrus Decline Disease, but cannot rule out the possibility of phytoplasma being involved as well. The characterization of microbiota shows that the leaves show only two kinds of communities, either symptomatic or asymptomatic, while roots show clear distinction between early and late symptoms. These results could lead to the identification of bacteria that are related to successful plant defense response and, therefore, to immunity to the Citrus Decline Disease. Full article

(This article belongs to the Special Issue Plant Innate Immunity 2.0)

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14 pages, 557 KiB

Open AccessReview

Diabetic Retinopathy: Pathophysiology and Treatments

by Wei Wang and Amy C. Y. Lo^*

Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

Int. J. Mol. Sci. 2018, 19(6), 1816; https://doi.org/10.3390/ijms19061816 - 20 Jun 2018

Cited by 963 | Viewed by 48172

Abstract

Diabetic retinopathy (DR) is the most common complication of diabetes mellitus (DM). It has long been recognized as a microvascular disease. The diagnosis of DR relies on the detection of microvascular lesions. The treatment of DR remains challenging. The advent of anti-vascular endothelial [...] Read more.

Diabetic retinopathy (DR) is the most common complication of diabetes mellitus (DM). It has long been recognized as a microvascular disease. The diagnosis of DR relies on the detection of microvascular lesions. The treatment of DR remains challenging. The advent of anti-vascular endothelial growth factor (VEGF) therapy demonstrated remarkable clinical benefits in DR patients; however, the majority of patients failed to achieve clinically-significant visual improvement. Therefore, there is an urgent need for the development of new treatments. Laboratory and clinical evidence showed that in addition to microvascular changes, inflammation and retinal neurodegeneration may contribute to diabetic retinal damage in the early stages of DR. Further investigation of the underlying molecular mechanisms may provide targets for the development of new early interventions. Here, we present a review of the current understanding and new insights into pathophysiology in DR, as well as clinical treatments for DR patients. Recent laboratory findings and related clinical trials are also reviewed. Full article

(This article belongs to the Special Issue Retinal Diseases: Bridging Basic and Clinical Research)

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11 pages, 1792 KiB

Open AccessArticle

Exploring the Mechanism of Inhibition of Au Nanoparticles on the Aggregation of Amyloid-β(16-22) Peptides at the Atom Level by All-Atom Molecular Dynamics

by Menghua Song^1,2, Yunxiang Sun³, Yin Luo³, Yanyan Zhu¹, Yongsheng Liu¹ and Huiyu Li^1,3,*

¹ College of Mathematics and Physics, Shanghai University of Electric Power, Shanghai 200090, China

² College of Energy and Mechanical Engineering, Shanghai University of Electric Power, Shanghai 200090, China

³ State Key Laboratory of Surface Physics, Key Laboratory of Computational Physical Sciences (Ministry of Education), and Department of Physics, Fudan University, 220 Handan Road, Shanghai 200433, China

Int. J. Mol. Sci. 2018, 19(6), 1815; https://doi.org/10.3390/ijms19061815 - 20 Jun 2018

Cited by 45 | Viewed by 5912

Abstract

The abnormal self-assembly of the amyloid-β peptide into toxic β-rich aggregates can cause Alzheimer’s disease. Recently, it has been shown that small gold nanoparticles (AuNPs) inhibit Aβ aggregation and fibrillation by slowing down the nucleation process in experimental studies. However, the effects of [...] Read more.

The abnormal self-assembly of the amyloid-β peptide into toxic β-rich aggregates can cause Alzheimer’s disease. Recently, it has been shown that small gold nanoparticles (AuNPs) inhibit Aβ aggregation and fibrillation by slowing down the nucleation process in experimental studies. However, the effects of AuNPs on Aβ oligomeric structures are still unclear. In this study, we investigate the conformation of Aβ(16-22) tetramers/octamers in the absence and presence of AuNPs using extensive all-atom molecular-dynamics simulations in explicit solvent. Our studies demonstrate that the addition of AuNPs into Aβ(16-22) solution prevents β-sheet formation, and the inhibition depends on the concentration of Aβ(16-22) peptides. A detailed analysis of the Aβ(16-22)/Aβ(16-22)/water/AuNPs interactions reveals that AuNPs inhibit the β-sheet formation resulting from the same physical forces: hydrophobic interactions. Overall, our computational study provides evidence that AuNPs are likely to inhibit Aβ(16-22) and full-length Aβ fibrillation. Thus, this work provides theoretical insights into the development of inorganic nanoparticles as drug candidates for treatment of AD. Full article

(This article belongs to the Special Issue Translating Gold Nanoparticles to Diagnostics and Therapeutics)

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15 pages, 2699 KiB

Open AccessArticle

Yeast-Based Screen to Identify Natural Compounds with a Potential Therapeutic Effect in Hailey-Hailey Disease

by Graziella Ficociello^1,†, Azzurra Zonfrilli^2,†, Samantha Cialfi², Claudio Talora^2,* and Daniela Uccelletti^1,*

¹ Department of Biology and Biotechnology “C. Darwin”, Sapienza University of Rome, 00185 Rome, Italy

² Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy

^† These authors contribute equally to this paper.

Int. J. Mol. Sci. 2018, 19(6), 1814; https://doi.org/10.3390/ijms19061814 - 20 Jun 2018

Cited by 6 | Viewed by 5562

Abstract

The term orthodisease defines human disorders in which the pathogenic gene has orthologs in model organism genomes. Yeasts have been instrumental for gaining insights into the molecular basis of many human disorders, particularly those resulting from impaired cellular metabolism. We and others have [...] Read more.

The term orthodisease defines human disorders in which the pathogenic gene has orthologs in model organism genomes. Yeasts have been instrumental for gaining insights into the molecular basis of many human disorders, particularly those resulting from impaired cellular metabolism. We and others have used yeasts as a model system to study the molecular basis of Hailey-Hailey disease (HHD), a human blistering skin disorder caused by haploinsufficiency of the gene ATP2C1 the orthologous of the yeast gene PMR1. We observed that K. lactis cells defective for PMR1 gene share several biological similarities with HHD derived keratinocytes. Based on the conservation of ATP2C1/PMR1 function from yeast to human, here we used a yeast-based assay to screen for molecules able to influence the pleiotropy associated with PMR1 deletion. We identified six compounds, Kaempferol, Indirubin, Lappaconite, Cyclocytidine, Azomycin and Nalidixic Acid that induced different major shape phenotypes in K. lactis. These include mitochondrial and the cell-wall morphology-related phenotypes. Interestingly, a secondary assay in mammalian cells confirmed activity for Kaempferol. Indeed, this compound was also active on human keratinocytes depleted of ATP2C1 function by siRNA-treatment used as an in-vitro model of HHD. We found that Kaempferol was a potent NRF2 regulator, strongly inducing its expression and its downstream target NQO1. In addition, Kaempferol could decrease oxidative stress of ATP2C1 defective keratinocytes, characterized by reduced NRF2-expression. Our results indicated that the activation of these pathways might provide protection to the HHD-skin cells. As oxidative stress plays pivotal roles in promoting the skin lesions of Hailey-Hailey, the NRF2 pathway could be a viable therapeutic target for HHD. Full article

(This article belongs to the Special Issue Rare Diseases: Molecular Mechanisms and Therapeutic Strategies)

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24 pages, 988 KiB

Open AccessReview

Lead (Pb) Exposure Enhances Expression of Factors Associated with Inflammation

by Emilia Metryka¹

, Karina Chibowska¹, Izabela Gutowska²

, Anna Falkowska¹, Patrycja Kupnicka¹, Katarzyna Barczak³

, Dariusz Chlubek¹

and Irena Baranowska-Bosiacka^1,*

¹ Department of Biochemistry and Medical Chemistry, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland

² Department of Biochemistry and Human Nutrition, Pomeranian Medical University, Broniewskiego 24, 71-460 Szczecin, Poland

³ Department of Conservative Dentistry and Endodontics, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111 Szczecin, Poland

Int. J. Mol. Sci. 2018, 19(6), 1813; https://doi.org/10.3390/ijms19061813 - 20 Jun 2018

Cited by 167 | Viewed by 9702

Abstract

The human immune system is constantly exposed to xenobiotics and pathogens from the environment. Although the mechanisms underlying their influence have already been at least partially recognized, the effects of some factors, such as lead (Pb), still need to be clarified. The results [...] Read more.

The human immune system is constantly exposed to xenobiotics and pathogens from the environment. Although the mechanisms underlying their influence have already been at least partially recognized, the effects of some factors, such as lead (Pb), still need to be clarified. The results of many studies indicate that Pb has a negative effect on the immune system, and in our review, we summarize the most recent evidence that Pb can promote inflammatory response. We also discuss possible molecular and biochemical mechanisms of its proinflammatory action, including the influence of Pb on cytokine metabolism (interleukins IL-2, IL-4, IL-8, IL-1b, IL-6), interferon gamma (IFNγ), and tumor necrosis factor alpha (TNF-α); the activity and expression of enzymes involved in the inflammatory process (cyclooxygenases); and the effect on selected acute phase proteins: C-reactive protein (CRP), haptoglobin, and ceruloplasmin. We also discuss the influence of Pb on the immune system cells (T and B lymphocytes, macrophages, Langerhans cells) and the secretion of IgA, IgE, IgG, histamine, and endothelin. Full article

(This article belongs to the Section Molecular Toxicology)

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25 pages, 720 KiB

Open AccessReview

Anti-Inflammatory Effects of Resveratrol: Mechanistic Insights

by Diego De Sá Coutinho¹, Maria Talita Pacheco¹, Rudimar Luiz Frozza^2,* and Andressa Bernardi^1,*

¹ Laboratory of Inflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21040-360, Brazil

² Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro 21040-360, Brazil

Int. J. Mol. Sci. 2018, 19(6), 1812; https://doi.org/10.3390/ijms19061812 - 20 Jun 2018

Cited by 220 | Viewed by 13636

Abstract

Inflammation is the principal response invoked by the body to address injuries. Despite inflammation constituting a crucial component of tissue repair, it is well known that unchecked or chronic inflammation becomes deleterious, leading to progressive tissue damage. Studies over the past years focused [...] Read more.

Inflammation is the principal response invoked by the body to address injuries. Despite inflammation constituting a crucial component of tissue repair, it is well known that unchecked or chronic inflammation becomes deleterious, leading to progressive tissue damage. Studies over the past years focused on foods rich in polyphenols with anti-inflammatory and immunomodulatory properties, since inflammation was recognized to play a central role in several diseases. In this review, we discuss the beneficial effects of resveratrol, the most widely investigated polyphenol, on cancer and neurodegenerative, respiratory, metabolic, and cardiovascular diseases. We highlight how resveratrol, despite its unfavorable pharmacokinetics, can modulate the inflammatory pathways underlying those diseases, and we identify future opportunities for the evaluation of its clinical feasibility. Full article

(This article belongs to the Special Issue Natural Anti-Inflammatory Agents 2018)

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13 pages, 1557 KiB

Open AccessReview

Role of Membrane Cholesterol Levels in Activation of Lyn upon Cell Detachment

by Takao Morinaga^1,2,*, Noritaka Yamaguchi², Yuji Nakayama³, Masatoshi Tagawa^1,4 and Naoto Yamaguchi²

¹ Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan

² Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan

³ Department of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan

⁴ Department of Molecular Biology and Oncology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan

Int. J. Mol. Sci. 2018, 19(6), 1811; https://doi.org/10.3390/ijms19061811 - 19 Jun 2018

Cited by 6 | Viewed by 6168

Abstract

Cholesterol, a major component of the plasma membrane, determines the physical
properties of biological membranes and plays a critical role in the assembly of membrane
microdomains. Enrichment or deprivation of membrane cholesterol affects the activities of many
signaling molecules at the plasma membrane. [...] Read more.

Cholesterol, a major component of the plasma membrane, determines the physical
properties of biological membranes and plays a critical role in the assembly of membrane
microdomains. Enrichment or deprivation of membrane cholesterol affects the activities of many
signaling molecules at the plasma membrane. Cell detachment changes the structure of the plasma
membrane and influences the localizations of lipids, including cholesterol. Recent studies showed
that cell detachment changes the activities of a variety of signaling molecules. We previously reported
that the localization and the function of the Src-family kinase Lyn are critically regulated by its
membrane anchorage through lipid modifications. More recently, we found that the localization and
the activity of Lyn were changed upon cell detachment, although the manners of which vary between
cell types. In this review, we highlight the changes in the localization of Lyn and a role of cholesterol
in the regulation of Lyn’s activation following cell detachment.
Full article

(This article belongs to the Special Issue Cholesterol and Lipoprotein Metabolism)

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13 pages, 1643 KiB

Open AccessArticle

Differential Expression and Pathway Analysis in Drug-Resistant Triple-Negative Breast Cancer Cell Lines Using RNASeq Analysis

by Safa Shaheen¹, Febin Fawaz¹, Shaheen Shah¹

and Dietrich Büsselberg^2,*

¹ Genomics Central, Thrissur 680125, India

² Weill Cornell Medicine, Qatar Foundation-Education City, P.O. Box 24144, Doha, Qatar

Int. J. Mol. Sci. 2018, 19(6), 1810; https://doi.org/10.3390/ijms19061810 - 19 Jun 2018

Cited by 25 | Viewed by 10049

Abstract

Triple-negative breast cancer (TNBC) is among the most notorious types of breast cancer, the treatment of which does not give consistent results due to the absence of the three receptors (estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 [...] Read more.

Triple-negative breast cancer (TNBC) is among the most notorious types of breast cancer, the treatment of which does not give consistent results due to the absence of the three receptors (estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) as well as high amount of molecular variability. Drug resistance also contributes to treatment unresponsiveness. We studied differentially expressed genes, their biological roles, as well as pathways from RNA-Seq datasets of two different TNBC drug-resistant cell lines of Basal B subtype SUM159 and MDA-MB-231 treated with drugs JQ1 and Dexamethasone, respectively, to elucidate the mechanism of drug resistance. RNA sequencing(RNA-Seq) data analysis was done using edgeR which is an efficient program for determining the most significant Differentially Expressed Genes (DEGs), Gene Ontology (GO) terms, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. iPathway analysis was further used to obtain validated results using analysis that takes into consideration type, function, and interactions of genes in the pathway. The significant similarities and differences throw light into the molecular heterogeneity of TNBC, giving clues into the aspects that can be focused to overcome drug resistance. From this study, cytokine-cytokine receptor interaction pathway appeared to be a key factor in TNBC drug resistance. Full article

(This article belongs to the Special Issue New Strategies to Overcome Resistance to Chemotherapy and Immune System in Cancer)

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13 pages, 2899 KiB

Open AccessArticle

Diethyl Blechnic, a Novel Natural Product Isolated from Salvia miltiorrhiza Bunge, Inhibits Doxorubicin-Induced Apoptosis by Inhibiting ROS and Activating JNK1/2

by Jie Yu¹, Hongwei Gao¹, Chuanhong Wu¹, Qiong-Ming Xu², Jin-Jian Lu¹

and Xiuping Chen^1,*

¹ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau China

² College of Pharmaceutical Science, Soochow University, Suzhou 215123, China

Int. J. Mol. Sci. 2018, 19(6), 1809; https://doi.org/10.3390/ijms19061809 - 19 Jun 2018

Cited by 19 | Viewed by 4801

Abstract

Doxorubicin (DOX) is a widely used antineoplastic agent in clinics. However, its clinical application is largely limited by its cardiotoxicity. Diethyl blechnic (DB) is a novel compound isolated from Salvia miltiorrhiza Bunge. Here, we study the effect of DB on DOX-induced cardiotoxicity and [...] Read more.

Doxorubicin (DOX) is a widely used antineoplastic agent in clinics. However, its clinical application is largely limited by its cardiotoxicity. Diethyl blechnic (DB) is a novel compound isolated from Salvia miltiorrhiza Bunge. Here, we study the effect of DB on DOX-induced cardiotoxicity and its underlying mechanisms. Cellular viability was tested by 3-[-4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and protein level was evaluated by Western blotting. 5,5’,6,6’-tetrachloro-1,1’,3,3’-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) staining was performed to determine the mitochondrial membrane potential (MMP). Hoechst 33342 staining and TUNEL staining was performed to test the apoptosis. Reactive oxygen species (ROS) generation was investigated by using flow cytometry. DB significantly inhibited DOX-induced apoptosis in H9c2 cells and primary cultured cardiomyocytes. Moreover, DB decreased cell apoptotic morphological changes and reversed the mitochondrial membrane potential induced by DOX. Meanwhile, pre-treatment with DB increased the expression levels of B-cell lymphoma 2 (Bcl-2), B-cell lymphoma-extra-large (Bcl-xl), and survivin and reduced the expression levels of Bcl-2-associated X protein (Bax), p-p53, cytochrome c (cyt c), and cleaved-caspase 3, 7, 8, 9 in the protein levels in DOX-treated H9c2 cells. Furthermore, DB suppressed ROS generation. The DB-mediated protective effects were accompanied by increased c-Jun N-terminal kinase1/2 (JNK1/2) expression. In addition, SP600125, the inhibitor of JNK1/2, abolished the protective effect of DB. We concluded that DB protected cardiomyocytes against DOX-induced cytotoxicity by inhibiting ROS and activating the JNK1/2 pathway. Therefore, DB is a promising candidate as a cardioprotective agent against DOX-induced cardiotoxicity. Full article

(This article belongs to the Special Issue Free Radicals and Oxidants in Pathogenesis)

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25 pages, 3259 KiB

Open AccessArticle

Co-Expression Network Analysis of AMPK and Autophagy Gene Products during Adipocyte Differentiation

by Mahmoud Ahmed¹

, Jin Seok Hwang¹, Trang Huyen Lai¹

, Sahib Zada¹, Huynh Quoc Nguyen¹, Trang Min Pham¹, Miyong Yun² and Deok Ryong Kim^1,*

¹ Department of Biochemistry and Convergence Medical Sciences and Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 527-27, Korea

² Department of Bioindustry and Bioresource Engineering, College of Life Sciences, Sejong University, Seoul 05006, Korea

Int. J. Mol. Sci. 2018, 19(6), 1808; https://doi.org/10.3390/ijms19061808 - 19 Jun 2018

Cited by 8 | Viewed by 6377

Abstract

Autophagy is involved in the development and differentiation of many cell types. It is essential for the pre-adipocytes to respond to the differentiation stimuli and may contribute to reorganizing the intracellulum to adapt the morphological and metabolic demands. Although AMPK, an energy sensor, [...] Read more.

Autophagy is involved in the development and differentiation of many cell types. It is essential for the pre-adipocytes to respond to the differentiation stimuli and may contribute to reorganizing the intracellulum to adapt the morphological and metabolic demands. Although AMPK, an energy sensor, has been associated with autophagy in several cellular processes, how it connects to autophagy during the adipocyte differentiation remains to be investigated. Here, we studied the interaction between AMPK and autophagy gene products at the mRNA level during adipocyte differentiation using public-access datasets. We used the weighted-gene co-expression analysis to detect and validate multiple interconnected modules of co-expressed genes in a dataset of MDI-induced 3T3-L1 pre-adipocytes. These modules were found to be highly correlated with the differentiation course of the adipocytes. Several novel interactions between AMPK and autophagy gene products were identified. Together, it is possible that AMPK-autophagy interaction is temporally and locally modulated in response to the differentiation stimuli. Full article

(This article belongs to the Special Issue AMP-Activated Protein Kinase Signalling)

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21 pages, 4835 KiB

Open AccessArticle

Collagen as Coating Material for 45S5 Bioactive Glass-Based Scaffolds for Bone Tissue Engineering

by Jasmin Hum^* and Aldo R. Boccaccini^*

Institute of Biomaterials, Department of Materials Science and Engineering, University of Erlangen-Nuremberg, Cauerstrasse 6, 91058 Erlangen, Germany

Int. J. Mol. Sci. 2018, 19(6), 1807; https://doi.org/10.3390/ijms19061807 - 19 Jun 2018

Cited by 59 | Viewed by 8930

Abstract

Highly porous 45S5 bioactive glass-based scaffolds were fabricated by the foam replica technique and coated with collagen by a novel method. After an initial cleaning step of the bioactive glass surface to expose reactive –OH groups, samples were surface functionalized by (3-aminopropyl)triethoxysilane (APTS). [...] Read more.

Highly porous 45S5 bioactive glass-based scaffolds were fabricated by the foam replica technique and coated with collagen by a novel method. After an initial cleaning step of the bioactive glass surface to expose reactive –OH groups, samples were surface functionalized by (3-aminopropyl)triethoxysilane (APTS). Functionalized scaffolds were immersed in a collagen solution, left for gelling at 37 °C, and dried at room temperature. The collagen coating was further stabilized by crosslinking with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysuccinimide (NHS). Applying this coating method, a layer thickness of a few micrometers was obtained without affecting the overall scaffold macroporosity. In addition, values of compressive strength were enhanced by a factor of five, increasing from 0.04 ± 0.02 MPa for uncoated scaffolds to 0.18 ± 0.03 MPa for crosslinked collagen-coated scaffolds. The composite material developed in this study exhibited positive cell (MG-63) viability as well as suitable cell attachment and proliferation on the surface. The combination of bioactivity, mechanical competence, and cellular response makes this novel scaffold system attractive for bone tissue engineering. Full article

(This article belongs to the Special Issue Novel Biomaterials for Tissue Engineering 2018)

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21 pages, 6664 KiB

Open AccessArticle

5-Azacitidine Induces Cell Death in a Tissue Culture of Brachypodium distachyon

by Alexander Betekhtin^1,*

, Anna Milewska-Hendel², Lukasz Chajec³, Magdalena Rojek¹, Katarzyna Nowak⁴, Jolanta Kwasniewska¹

, Elzbieta Wolny¹, Ewa Kurczynska²

and Robert Hasterok¹

¹ Department of Plant Anatomy and Cytology, Faculty of Biology and Environmental Protection, University of Silesia in Katowice, 40-032 Katowice, Poland

² Department of Cell Biology, Faculty of Biology and Environmental Protection, University of Silesia in Katowice, 40-032 Katowice, Poland

³ Department of Animal Histology and Embryology, Faculty of Biology and Environmental Protection, University of Silesia in Katowice, 40-032 Katowice, Poland

⁴ Department of Genetics, Faculty of Biology and Environmental Protection, University of Silesia in Katowice, 40-032 Katowice, Poland

Int. J. Mol. Sci. 2018, 19(6), 1806; https://doi.org/10.3390/ijms19061806 - 19 Jun 2018

Cited by 19 | Viewed by 6259

Abstract

Morphological and histological observations revealed that, at a concentration of 50 µM, 5-azacitidine (5-azaC) totally inhibited the induction of embryogenic masses (EM), while the cultivation of explants (zygotic embryos; ZEs) in the presence of 5 µM of 5-azaC led to the formation of [...] Read more.

Morphological and histological observations revealed that, at a concentration of 50 µM, 5-azacitidine (5-azaC) totally inhibited the induction of embryogenic masses (EM), while the cultivation of explants (zygotic embryos; ZEs) in the presence of 5 µM of 5-azaC led to the formation of a callus with EM in 10% of the cases. Transmission electron microscopy (TEM) analyzes revealed the presence of the morphological and ultrastructural features that are typical for the vacuolar type of cell death in the callus cells that were treated. A TUNEL assay confirmed the presence of DNA double-strand breaks for the callus cells that had been treated with both 5 and 50 µM 5-azaC concentrations. Analysis of the gene expression of selected cell death markers demonstrated a reduced expression of metacaspase, protein executer 1 (EX1), and thioredoxin (TRX) in the callus cells that had been treated compared to the control culture. The strongest increase in the gene activity was characteristic for glutathione S-transferase (GST). Our studies also included an analysis of the distribution of some arabinogalactan proteins (AGPs) and extensin epitopes, which can be used as markers of cells that are undergoing death in a Brachypodium distachyon tissue culture. Full article

(This article belongs to the Section Molecular Plant Sciences)

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17 pages, 2320 KiB

Open AccessArticle

Inter-Individual Variability in Acute Toxicity of R-Pulegone and R-Menthofuran in Human Liver Slices and Their Influence on miRNA Expression Changes in Comparison to Acetaminophen

by Tomáš Zárybnický¹

, Petra Matoušková¹

, Bibiána Lancošová¹, Zdeněk Šubrt^2,3, Lenka Skálová¹ and Iva Boušová^1,*

¹ Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, 500 05 Hradec Králové, Czech Republic

² Department of Surgery, Faculty of Medicine in Hradec Králové, Charles University, 500 05 Hradec Králové, Czech Republic

³ Department of Surgery, University Hospital Hradec Králové, 500 05 Hradec Králové, Czech Republic

Int. J. Mol. Sci. 2018, 19(6), 1805; https://doi.org/10.3390/ijms19061805 - 19 Jun 2018

Cited by 19 | Viewed by 5142

Abstract

Monoterpenes R-pulegone (PUL) and R-menthofuran (MF), abundant in the Lamiaceae family, are frequently used in herb and food products. Although their hepatotoxicity was shown in rodent species, information about their effects in human liver has been limited. The aim of our study was [...] Read more.

Monoterpenes R-pulegone (PUL) and R-menthofuran (MF), abundant in the Lamiaceae family, are frequently used in herb and food products. Although their hepatotoxicity was shown in rodent species, information about their effects in human liver has been limited. The aim of our study was to test the effects of PUL, MF and acetaminophen (APAP, as a reference compound) on cell viability and microRNA (miRNA) expression in human precision-cut liver slices. Slices from five patients were used to follow up on the inter-individual variability. PUL was toxic in all liver samples (the half-maximal effective concentration was 4.0 µg/mg of tissue), while MF and surprisingly APAP only in two and three liver samples, respectively. PUL also changed miRNA expression more significantly than MF and APAP. The most pronounced effect was a marked decrease of miR-155-5p expression caused by PUL even in non-toxic concentrations in all five liver samples. Our results showed that PUL is much more toxic than MF and APAP in human liver and that miR-155-5p could be a good marker of PUL early hepatotoxicity. Marked inter-individual variabilities in all our results demonstrate the high probability of significant differences in the hepatotoxicity of tested compounds among people. Full article

(This article belongs to the Special Issue Hepatotoxicity: Molecular Mechanisms and Pathophysiology)

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20 pages, 1415 KiB

Open AccessReview

The Type 3 Deiodinase: Epigenetic Control of Brain Thyroid Hormone Action and Neurological Function

by Arturo Hernandez^1,2,3,*

and J. Patrizia Stohn¹

¹ Center for Molecular Medicine, Maine Medical Center Research Institute, Maine Medical Center, Scarborough, ME 04074, USA

² Graduate School for Biomedical Science and Engineering, University of Maine, Orono, ME 04469, USA

³ Department of Medicine, Tufts University School of Medicine, Boston, MA 02111, USA

Int. J. Mol. Sci. 2018, 19(6), 1804; https://doi.org/10.3390/ijms19061804 - 19 Jun 2018

Cited by 34 | Viewed by 10973

Abstract

Thyroid hormones (THs) influence multiple processes in the developing and adult central nervous system, and their local availability needs to be maintained at levels that are tailored to the requirements of their biological targets. The local complement of TH transporters, deiodinase enzymes, and [...] Read more.

Thyroid hormones (THs) influence multiple processes in the developing and adult central nervous system, and their local availability needs to be maintained at levels that are tailored to the requirements of their biological targets. The local complement of TH transporters, deiodinase enzymes, and receptors is critical to ensure specific levels of TH action in neural cells. The type 3 iodothyronine deiodinase (DIO3) inactivates THs and is highly present in the developing and adult brain, where it limits their availability and action. DIO3 deficiency in mice results in a host of neurodevelopmental and behavioral abnormalities, demonstrating the deleterious effects of TH excess, and revealing the critical role of DIO3 in the regulation of TH action in the brain. The fact the Dio3 is an imprinted gene and that its allelic expression pattern varies across brain regions and during development introduces an additional level of control to deliver specific levels of hormone action in the central nervous system (CNS). The sensitive epigenetic nature of the mechanisms controlling the genomic imprinting of Dio3 renders brain TH action particularly susceptible to disruption due to exogenous treatments and environmental exposures, with potential implications for the etiology of human neurodevelopmental disorders. Full article

(This article belongs to the Special Issue Epigenetics of Neurodevelopmental Disorders)

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14 pages, 1127 KiB

Open AccessReview

STAT3 in Tumor-Associated Myeloid Cells: Multitasking to Disrupt Immunity

by Yu-Lin Su, Shuvomoy Banerjee, Seok Voon White and Marcin Kortylewski^*

Department of Immuno-Oncology, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Duarte, 91010 CA, USA

Int. J. Mol. Sci. 2018, 19(6), 1803; https://doi.org/10.3390/ijms19061803 - 19 Jun 2018

Cited by 87 | Viewed by 8972

Abstract

Myeloid immune cells, such as dendritic cells, monocytes, and macrophages, play a central role in the generation of immune responses and thus are often either disabled or even hijacked by tumors. These new tolerogenic activities of tumor-associated myeloid cells are controlled by an [...] Read more.

Myeloid immune cells, such as dendritic cells, monocytes, and macrophages, play a central role in the generation of immune responses and thus are often either disabled or even hijacked by tumors. These new tolerogenic activities of tumor-associated myeloid cells are controlled by an oncogenic transcription factor, signal transducer and activator of transcription 3 (STAT3). STAT3 multitasks to ensure tumors escape immune detection by impairing antigen presentation and reducing production of immunostimulatory molecules while augmenting the release of tolerogenic mediators, thereby reducing innate and adaptive antitumor immunity. Tumor-associated myeloid cells and STAT3 signaling in this compartment are now commonly recognized as an attractive cellular target for improving efficacy of standard therapies and immunotherapies. Hereby, we review the importance and functional complexity of STAT3 signaling in this immune cell compartment as well as potential strategies for cancer therapy. Full article

(This article belongs to the Special Issue Advances in Biological Functions of STAT3)

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17 pages, 2358 KiB

Open AccessArticle

Structure–Activity Relationship of Piplartine and Synthetic Analogues against Schistosoma mansoni and Cytotoxicity to Mammalian Cells

by Yuri Campelo^1,2,3, Alicia Ombredane⁴, Andreanne G. Vasconcelos⁵, Lucas Albuquerque⁶, Daniel C. Moreira⁵

, Alexandra Plácido⁷, Jefferson Rocha²

, Harold Hilarion Fokoue⁸, Lydia Yamaguchi⁹, Ana Mafud¹⁰

, Yvonne P. Mascarenhas¹⁰, Cristina Delerue-Matos⁷

, Tatiana Borges⁶, Graziella A. Joanitti⁴, Daniel D.R. Arcanjo¹¹

, Massuo J. Kato⁹, Selma A. S. Kuckelhaus⁵, Marcos P. N. Silva¹², Josué De Moraes¹² and José Roberto S. A. Leite^1,5,*

¹ Núcleo de Pesquisa em Biodiversidade e Biotecnologia, Biotec, Universidade Federal do Piauí, UFPI, Parnaíba-PI, 64202-020 Brazil

² Programa de Pós-Graduação em Biotecnologia, RENORBIO, Ponto focal Universidade Federal do Piauí, UFPI, Teresina, PI, 64049-550, Brazil

³ Instituto de Educação Superior do Vale do Parnaíba, FAHESP/IESVAP, Parnaíba-PI, 64212-790, Brazil

⁴ Laboratório de Nanobiotecnologia, Instituto de Biologia, Campus Darcy Ribeiro, Universidade de Brasília, UnB, Brasília-DF 70910-900, Brazil

⁵ Área de Morfologia, Faculdade de Medicina, Universidade de Brasília, UnB, Brasília-DF 70910-900, Brazil

⁶ Laboratorio de Imunologia, Faculdade de Medicina, Universidade de Brasília, UnB, Brasília-DF 70910-900, Brazil

⁷ LAQV/REQUIMTE, GRAQ, Instituto Superior de Engenha do Porto, ISEP, Porto 4200-072, Portugal

⁸ Laboratório de Avaliação e Síntese de Substâncias Bioativas, Universidade Federal do Rio de Janeiro, CCS, Cidade Universitária, Rio de Janeiro-RJ 21941-902, Brasil

⁹ Instituto de Química, Universidade de São Paulo, São Paulo-SP 01005-010, Brazil

¹⁰ Instituto de Física de São Carlos, Universidade de São Paulo-SP 01005-010, Brazil

¹¹ Núcleo de Pesquisas em Plantas Medicinais, NPPM, Universidade Federal do Piauí, UFPI, Parnaíba-PI 64202-020, Brazil

¹² Núcleo de Pesquisa em Doenças Negligenciadas, Universidade de Guarulhos, Guarulhos-SP 07023-070, Brazil

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Int. J. Mol. Sci. 2018, 19(6), 1802; https://doi.org/10.3390/ijms19061802 - 19 Jun 2018

Cited by 16 | Viewed by 5309

Abstract

Schistosomiasis, caused by helminth flatworms of the genus Schistosoma, is an infectious disease mainly associated with poverty that affects millions of people worldwide. Since treatment for this disease relies only on the use of praziquantel, there is an urgent need to identify [...] Read more.

Schistosomiasis, caused by helminth flatworms of the genus Schistosoma, is an infectious disease mainly associated with poverty that affects millions of people worldwide. Since treatment for this disease relies only on the use of praziquantel, there is an urgent need to identify new antischistosomal drugs. Piplartine is an amide alkaloid found in several Piper species (Piperaceae) that exhibits antischistosomal properties. The aim of this study was to evaluate the structure–function relationship between piplartine and its five synthetic analogues (19A, 1G, 1M, 14B and 6B) against Schistosoma mansoni adult worms, as well as its cytotoxicity to mammalian cells using murine fibroblast (NIH-3T3) and BALB/cN macrophage (J774A.1) cell lines. In addition, density functional theory calculations and in silico analysis were used to predict physicochemical and toxicity parameters. Bioassays revealed that piplartine is active against S. mansoni at low concentrations (5–10 µM), but its analogues did not. In contrast, based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays, piplartine exhibited toxicity in mammalian cells at 785 µM, while its analogues 19A and 6B did not reduce cell viability at the same concentrations. This study demonstrated that piplartine analogues showed less activity against S. mansoni but presented lower toxicity than piplartine. Full article

(This article belongs to the Section Biochemistry)

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15 pages, 666 KiB

Open AccessReview

Role of Human Macrophage Polarization in Inflammation during Infectious Diseases

by Chiraz Atri^1,2,3

, Fatma Z. Guerfali^1,2

and Dhafer Laouini^1,2,*

¹ Institut Pasteur de Tunis, LR11IPT02, Laboratory of Transmission, Control and Immunobiology of Infections (LTCII), Tunis-Belvédère 1002, Tunisia

² Université Tunis El Manar, Tunis 1068, Tunisia

³ Faculté des Sciences de Bizerte, Université de Carthage, 7021 Jarzouna, Tunisia

Int. J. Mol. Sci. 2018, 19(6), 1801; https://doi.org/10.3390/ijms19061801 - 19 Jun 2018

Cited by 1000 | Viewed by 38498

Abstract

Experimental models have often been at the origin of immunological paradigms such as the M1/M2 dichotomy following macrophage polarization. However, this clear dichotomy in animal models is not as obvious in humans, and the separating line between M1-like and M2-like macrophages is rather [...] Read more.

Experimental models have often been at the origin of immunological paradigms such as the M1/M2 dichotomy following macrophage polarization. However, this clear dichotomy in animal models is not as obvious in humans, and the separating line between M1-like and M2-like macrophages is rather represented by a continuum, where boundaries are still unclear. Indeed, human infectious diseases, are characterized by either a back and forth or often a mixed profile between the pro-inflammatory microenvironment (dominated by interleukin (IL)-1β, IL-6, IL-12, IL-23 and Tumor Necrosis Factor (TNF)-α cytokines) and tissue injury driven by classically activated macrophages (M1-like) and wound healing driven by alternatively activated macrophages (M2-like) in an anti-inflammatory environment (dominated by IL-10, Transforming growth factor (TGF)-β, chemokine ligand (CCL)1, CCL2, CCL17, CCL18, and CCL22). This review brews the complexity of the situation during infectious diseases by stressing on this continuum between M1-like and M2-like extremes. We first discuss the basic biology of macrophage polarization, function, and role in the inflammatory process and its resolution. Secondly, we discuss the relevance of the macrophage polarization continuum during infectious and neglected diseases, and the possibility to interfere with such activation states as a promising therapeutic strategy in the treatment of such diseases. Full article

(This article belongs to the Special Issue Macrophages in Inflammation)

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15 pages, 2793 KiB

Open AccessArticle

MK-0677, a Ghrelin Agonist, Alleviates Amyloid Beta-Related Pathology in 5XFAD Mice, an Animal Model of Alzheimer’s Disease

by Yu-on Jeong¹, Soo Jung Shin¹, Jun Yong Park¹, Bo Kyeong Ku¹, Ji Soo Song¹, Jwa-Jin Kim^2,3, Seong Gak Jeon^1,*, Sang Min Lee^4,5,* and Minho Moon^1,5,*

¹ Department of Biochemistry, College of Medicine, Konyang University, Daejeon 35365, Korea

² Department of Biomedical Science, Jungwon University, Geosan, Chungbuk 28024, Korea

³ Department of Nephrology, School of Medicine, Chungnam National University, Daejeon 35015, Korea

⁴ Department of Psychiatry, Konyang University College of Medicine, Konyang University Hospital, Daejeon 35365, Korea

⁵ Myunggok Medical Research Institute, Konyang University, Daejeon 35365, Korea

Int. J. Mol. Sci. 2018, 19(6), 1800; https://doi.org/10.3390/ijms19061800 - 18 Jun 2018

Cited by 37 | Viewed by 11302

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive deficits, neuroinflammation, and neuronal death. The primary pathogenic cause is believed to be the accumulation of pathogenic amyloid beta (Aβ) assemblies in the brain. Ghrelin, which is a peptide hormone predominantly secreted [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive deficits, neuroinflammation, and neuronal death. The primary pathogenic cause is believed to be the accumulation of pathogenic amyloid beta (Aβ) assemblies in the brain. Ghrelin, which is a peptide hormone predominantly secreted from the stomach, is an endogenous ligand for the growth hormone secretagogue-receptor type 1a (GHS-R1a). MK-0677 is a ghrelin agonist that potently stimulates the GHS-R1a ghrelin receptor. Interestingly, previous studies have shown that ghrelin improves cognitive impairments and attenuates neuronal death and neuroinflammation in several neurological disorders. However, it is unknown whether MK-0677 can affect Aβ accumulation or Aβ-mediated pathology in the brains of patients with AD. Therefore, we examined the effects of MK-0677 administration on AD-related pathology in 5XFAD mice, an Aβ-overexpressing transgenic mouse model of AD. MK-0677 was intraperitoneally administered to three-month-old 5XFAD mice. To visualize Aβ accumulation, neuroinflammation, and neurodegeneration, thioflavin-S staining and immunostaining with antibodies against Aβ (4G8), ionized calcium-binding adaptor molecule 1 (Iba-1), glial fibrillary acidic protein (GFAP), neuronal nuclear antigen (NeuN), and synaptophysin were conducted in the neocortex of 5XFAD and wild-type mice, and to evaluate changes of phosphorylated cyclic adenosine monophosphate (cAMP) response element binding protein (pCREB) levels, immunostaining with antibody against pCREB was performed in dentate gyrus of the hippocampus of 5XFAD and wild-type mice. The histological analyses indicated that MK-0677-treated 5XFAD mice showed reduced Aβ deposition, gliosis, and neuronal and synaptic loss in the deep cortical layers, and inhibited the decrement of pCREB levels in dentate gyrus of the hippocampus compared to vehicle-treated 5XFAD mice. Our results showed that activation of the ghrelin receptor with MK-0677 inhibited the Aβ burden, neuroinflammation, and neurodegeneration, which suggested that MK-0677 might have potential as a treatment of the early phase of AD. Full article

(This article belongs to the Special Issue Amyloid Fibrils and Methods for Their Study)

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16 pages, 4737 KiB

Open AccessArticle

STIM1 Knockout Enhances PDGF-Mediated Ca²⁺ Signaling through Upregulation of the PDGFR–PLCγ–STIM2 Cascade

by Tzu-Yu Huang¹, Yi-Hsin Lin¹, Heng-Ai Chang², Tzu-Ying Yeh¹, Ya-Han Chang¹, Yi-Fan Chen², Ying-Chi Chen¹, Chun-Chun Li³ and Wen-Tai Chiu^1,2,*

¹ Department of Biomedical Engineering, National Cheng Kung University, Tainan 701, Taiwan

² Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan

³ Department of Life Sciences, National Cheng Kung University, Tainan 701, Taiwan

Int. J. Mol. Sci. 2018, 19(6), 1799; https://doi.org/10.3390/ijms19061799 - 18 Jun 2018

Cited by 11 | Viewed by 5352

Abstract

Platelet-derived growth factor (PDGF) has mitogenic and chemotactic effects on fibroblasts. An increase in intracellular Ca²⁺ is one of the first events that occurs following the stimulation of PDGF receptors (PDGFRs). PDGF activates Ca²⁺ elevation by activating the phospholipase C gamma [...] Read more.

Platelet-derived growth factor (PDGF) has mitogenic and chemotactic effects on fibroblasts. An increase in intracellular Ca²⁺ is one of the first events that occurs following the stimulation of PDGF receptors (PDGFRs). PDGF activates Ca²⁺ elevation by activating the phospholipase C gamma (PLCγ)-signaling pathway, resulting in ER Ca²⁺ release. Store-operated Ca²⁺ entry (SOCE) is the major form of extracellular Ca²⁺ influx following depletion of ER Ca²⁺ stores and stromal interaction molecule 1 (STIM1) is a key molecule in the regulation of SOCE. In this study, wild-type and STIM1 knockout mouse embryonic fibroblasts (MEF) cells were used to investigate the role of STIM1 in PDGF-induced Ca²⁺ oscillation and its functions in MEF cells. The unexpected findings suggest that STIM1 knockout enhances PDGFR–PLCγ–STIM2 signaling, which in turn increases PDGF-BB-induced Ca²⁺ elevation. Enhanced expressions of PDGFRs and PLCγ in STIM1 knockout cells induce Ca²⁺ release from the ER store through PLCγ–IP3 signaling. Moreover, STIM2 replaces STIM1 to act as the major ER Ca²⁺ sensor in activating SOCE. However, activation of PDGFRs also activate Akt, ERK, and JNK to regulate cellular functions, such as cell migration. These results suggest that alternative switchable pathways can be observed in cells, which act downstream of the growth factors that regulate Ca²⁺ signaling. Full article

(This article belongs to the Special Issue Calcium Signaling in Human Health and Diseases)

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18 pages, 3795 KiB

Open AccessArticle

Regulation and Function of TMEM16F in Renal Podocytes

by Laura K. Schenk¹

, Jiraporn Ousingsawat², Boris V. Skryabin³

, Rainer Schreiber^2,†, Hermann Pavenstädt^1,† and Karl Kunzelmann^2,*,†

¹ Department of Nephrology, Hypertension and Rheumatology, University Hospital Muenster, 48149 Muenster, Germany

² Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany

³ Transgenic Animal and Genetic Engineering Models (TRAM), Department of Medicine, Westfälischen, Wilhelms–Universität Münster, 48149 Münster, Germany

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2018, 19(6), 1798; https://doi.org/10.3390/ijms19061798 - 18 Jun 2018

Cited by 6 | Viewed by 5326

Abstract

The Ca²⁺-activated phospholipid scramblase and ion channel TMEM16F is expressed in podocytes of renal glomeruli. Podocytes are specialized cells that form interdigitating foot processes as an essential component of the glomerular filter. These cells, which participate in generation of the primary [...] Read more.

The Ca²⁺-activated phospholipid scramblase and ion channel TMEM16F is expressed in podocytes of renal glomeruli. Podocytes are specialized cells that form interdigitating foot processes as an essential component of the glomerular filter. These cells, which participate in generation of the primary urine, are often affected during primary glomerular diseases, such as glomerulonephritis and secondary hypertensive or diabetic nephropathy, which always leads to proteinuria. Because the function of podocytes is known to be controlled by intracellular Ca²⁺ signaling, it is important to know about the role of Ca²⁺-activated TMEM16F in these cells. To that end, we generated an inducible TMEM16F knockdown in the podocyte cell line AB8, and produced a conditional mouse model with knockout of TMEM16F in podocytes and renal epithelial cells of the nephron. We found that knockdown of TMEM16F did not produce proteinuria or any obvious phenotypic changes. Knockdown of TMEM16F affected cell death of tubular epithelial cells but not of glomerular podocytes when analyzed in TUNEL assays. Surprisingly, and in contrast to other cell types, TMEM16F did not control intracellular Ca²⁺ signaling and was not responsible for Ca²⁺-activated whole cell currents in podocytes. TMEM16F levels in podocytes were enhanced after inhibition of the endolysosomal pathway and after treatment with angiotensin II. Renal knockout of TMEM16F did not compromise renal morphology and serum electrolytes. Taken together, in contrast to other cell types, such as platelets, bone cells, and immune cells, TMEM16F shows little effect on basal properties of podocytes and does not appear to be essential for renal function. Full article

(This article belongs to the Special Issue Ion Transporters and Channels in Physiology and Pathophysiology)

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29 pages, 5040 KiB

Open AccessReview

Role of MicroRNAs in Renal Parenchymal Diseases—A New Dimension

by Saeed Kamran Shaffi^1,*

, David Galas², Alton Etheridge² and Christos Argyropoulos¹

¹ Department of Internal Medicine, Division of Nephrology, University of New Mexico, Albuquerque, NM 87131, USA

² Pacific Northwest Research Institute, Seattle, WA 98122, USA

Int. J. Mol. Sci. 2018, 19(6), 1797; https://doi.org/10.3390/ijms19061797 - 17 Jun 2018

Cited by 23 | Viewed by 5492

Abstract

Since their discovery in 1993, numerous microRNAs (miRNAs) have been identified in humans and other eukaryotic organisms, and their role as key regulators of gene expression is still being elucidated. It is now known that miRNAs not only play a central role in [...] Read more.

Since their discovery in 1993, numerous microRNAs (miRNAs) have been identified in humans and other eukaryotic organisms, and their role as key regulators of gene expression is still being elucidated. It is now known that miRNAs not only play a central role in the processes that ensure normal development and physiology, but they are often dysregulated in various diseases. In this review, we present an overview of the role of miRNAs in normal renal development and physiology, in maladaptive renal repair after injury, and in the pathogenesis of renal parenchymal diseases. In addition, we describe methods used for their detection and their potential as therapeutic targets. Continued research on renal miRNAs will undoubtedly improve our understanding of diseases affecting the kidneys and may also lead to new therapeutic agents. Full article

(This article belongs to the Special Issue The Role of MicroRNAs in Human Diseases)

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26 pages, 37748 KiB

Open AccessReview

Bioengineering Approaches for Bladder Regeneration

by Ángel Serrano-Aroca^1,*

, César David Vera-Donoso² and Victoria Moreno-Manzano^3,*

¹ Faculty of Veterinary and Experimental Sciences, Universidad Católica de Valencia San Vicente Mártir, 46001 Valencia, Spain

² Department of Urology, La Fe University and Polytechnic Hospital and Health Research Institute, Hospital La Fe, 46026 Valencia, Spain

³ Neuronal Regeneration Lab, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain

Int. J. Mol. Sci. 2018, 19(6), 1796; https://doi.org/10.3390/ijms19061796 - 17 Jun 2018

Cited by 72 | Viewed by 11464

Abstract

Current clinical strategies for bladder reconstruction or substitution are associated to serious problems. Therefore, new alternative approaches are becoming more and more necessary. The purpose of this work is to review the state of the art of the current bioengineering advances and obstacles [...] Read more.

Current clinical strategies for bladder reconstruction or substitution are associated to serious problems. Therefore, new alternative approaches are becoming more and more necessary. The purpose of this work is to review the state of the art of the current bioengineering advances and obstacles reported in bladder regeneration. Tissue bladder engineering requires an ideal engineered bladder scaffold composed of a biocompatible material suitable to sustain the mechanical forces necessary for bladder filling and emptying. In addition, an engineered bladder needs to reconstruct a compliant muscular wall and a highly specialized urothelium, well-orchestrated under control of autonomic and sensory innervations. Bioreactors play a very important role allowing cell growth and specialization into a tissue-engineered vascular construct within a physiological environment. Bioprinting technology is rapidly progressing, achieving the generation of custom-made structural supports using an increasing number of different polymers as ink with a high capacity of reproducibility. Although many promising results have been achieved, few of them have been tested with clinical success. This lack of satisfactory applications is a good reason to discourage researchers in this field and explains, somehow, the limited high-impact scientific production in this area during the last decade, emphasizing that still much more progress is required before bioengineered bladders become a commonplace in the clinical setting. Full article

(This article belongs to the Special Issue Cell Colonization in Scaffolds)

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38 pages, 4933 KiB

Open AccessReview

Shining Light on Chitosan: A Review on the Usage of Chitosan for Photonics and Nanomaterials Research

by Sreekar B. Marpu^* and Erin N. Benton

Department of Chemistry, University of North Texas, Denton, TX 76203, USA

Int. J. Mol. Sci. 2018, 19(6), 1795; https://doi.org/10.3390/ijms19061795 - 17 Jun 2018

Cited by 60 | Viewed by 9186

Abstract

Chitosan (CS) is a natural polymer derived from chitin that has found its usage both in research and commercial applications due to its unique solubility and chemical and biological attributes. The biocompatibility and biodegradability of CS have helped researchers identify its utility in [...] Read more.

Chitosan (CS) is a natural polymer derived from chitin that has found its usage both in research and commercial applications due to its unique solubility and chemical and biological attributes. The biocompatibility and biodegradability of CS have helped researchers identify its utility in the delivery of therapeutic agents, tissue engineering, wound healing, and more. Industrial applications include cosmetic and personal care products, wastewater treatment, and corrosion protection, to name a few. Many researchers have published numerous reviews outlining the physical and chemical properties of CS, as well as its use for many of the above-mentioned applications. Recently, the cationic polyelectrolyte nature of CS was found to be advantageous for stabilizing fascinating photonic materials including plasmonic nanoparticles (e.g., gold and silver), semiconductor nanoparticles (e.g., zinc oxide, cadmium sulfide), fluorescent organic dyes (e.g., fluorescein isothiocyanate (FITC)), luminescent transitional and lanthanide complexes (e.g., Au(I) and Ru(II), and Eu(III)). These photonic systems have been extensively investigated for their usage in antimicrobial, wound healing, diagnostics, sensing, and imaging applications. Highlighted in this review are the different works involving some of the above-mentioned molecular-nano systems that are prepared or stabilized using the CS polymer. The advantages and the role of the CS for synthesizing and stabilizing the above-mentioned optically active materials have been illustrated. Full article

(This article belongs to the Special Issue Chitins 2018)

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13 pages, 1639 KiB

Open AccessReview

Scorpins in the DNA Damage Response

by Dario Palmieri, Anna Tessari and Vincenzo Coppola^*

Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University and James Comprehensive Cancer Center, Columbus, OH 43210, USA

Int. J. Mol. Sci. 2018, 19(6), 1794; https://doi.org/10.3390/ijms19061794 - 17 Jun 2018

Cited by 10 | Viewed by 5401

Abstract

The DNA Damage Response (DDR) is a complex signaling network that comes into play when cells experience genotoxic stress. Upon DNA damage, cellular signaling pathways are rewired to slow down cell cycle progression and allow recovery. However, when the damage is beyond repair, [...] Read more.

The DNA Damage Response (DDR) is a complex signaling network that comes into play when cells experience genotoxic stress. Upon DNA damage, cellular signaling pathways are rewired to slow down cell cycle progression and allow recovery. However, when the damage is beyond repair, cells activate complex and still not fully understood mechanisms, leading to a complete proliferative arrest or cell death. Several conventional and novel anti-neoplastic treatments rely on causing DNA damage or on the inhibition of the DDR in cancer cells. However, the identification of molecular determinants directing cancer cells toward recovery or death upon DNA damage is still far from complete, and it is object of intense investigation. SPRY-containing RAN binding Proteins (Scorpins) RANBP9 and RANBP10 are evolutionarily conserved and ubiquitously expressed proteins whose biological functions are still debated. RANBP9 has been previously implicated in cell proliferation, survival, apoptosis and migration. Recent studies also showed that RANBP9 is involved in the Ataxia Telangiectasia Mutated (ATM) signaling upon DNA damage. Accordingly, cells lacking RANBP9 show increased sensitivity to genotoxic treatment. Although there is no published evidence, extensive protein similarities suggest that RANBP10 might have partially overlapping functions with RANBP9. Like RANBP9, RANBP10 bears sites putative target of PIK-kinases and high throughput studies found RANBP10 to be phosphorylated following genotoxic stress. Therefore, this second Scorpin might be another overlooked player of the DDR alone or in combination with RANBP9. This review focuses on the relatively unknown role played by RANBP9 and RANBP10 in responding to genotoxic stress. Full article

(This article belongs to the Special Issue Alterations to Signalling Pathways in Cancer Cells 2018)

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14 pages, 1022 KiB

Open AccessReview

Epigenomic Control of Thermogenic Adipocyte Differentiation and Function

by Xu Peng^1,†, Qiongyi Zhang^1,2,†, Cheng Liao³, Weiping Han² and Feng Xu^1,4,*

¹ Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Singapore 138673, Singapore

² Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, 11 Biopolis Way, Singapore 138667, Singapore

³ Department of Preclinical Development, Translation Medicine and External Research, Jiangsu Hengrui Medicine Co., Ltd., 778 Dongfang Road, Shanghai 200085, China

⁴ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore 117596, Singapore

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2018, 19(6), 1793; https://doi.org/10.3390/ijms19061793 - 17 Jun 2018

Cited by 14 | Viewed by 6213

Abstract

Obesity and its associated metabolic disorders are spreading at a fast pace throughout the world; thus, effective therapeutic approaches are necessary to combat this epidemic. Obesity develops when there is a greater caloric intake than energy expenditure. Promoting energy expenditure has recently attracted [...] Read more.

Obesity and its associated metabolic disorders are spreading at a fast pace throughout the world; thus, effective therapeutic approaches are necessary to combat this epidemic. Obesity develops when there is a greater caloric intake than energy expenditure. Promoting energy expenditure has recently attracted much attention as a promising approach for the management of body weight. Thermogenic adipocytes are capable of burning fat to dissipate chemical energy into heat, thereby enhancing energy expenditure. After the recent re-discovery of thermogenic adipocytes in adult humans, much effort has focused on understanding the molecular mechanisms, especially the epigenetic mechanisms, which regulate thermogenic adipocyte development and function. A number of chromatin signatures, such as histone modifications, DNA methylation, chromatin accessibilities, and interactions, have been profiled at the genome level and analyzed in various murine and human thermogenic fat cell systems. Moreover, writers and erasers, as well as readers of the epigenome are also investigated using genomic tools in thermogenic adipocytes. In this review, we summarize and discuss the recent advance in these studies and highlight the insights gained into the epigenomic regulation of thermogenic program as well as the pathogenesis of human metabolic diseases. Full article

(This article belongs to the Special Issue Transcriptional Regulation in Lipid Metabolism)

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16 pages, 1644 KiB

Open AccessReview

The Expensive-Tissue Hypothesis in Vertebrates: Gut Microbiota Effect, a Review

by Chun Hua Huang^1,2, Xin Yu^1,2 and Wen Bo Liao^1,2,*

¹ Key Laboratory of Southwest China Wildlife Resources Conservation (Ministry of Education), China West Normal University, Nanchong 637009, Sichuan, China

² Institute of Eco-adaptation in Amphibians and Reptiles, China West Normal University, Nanchong 637009, Sichuan, China

Int. J. Mol. Sci. 2018, 19(6), 1792; https://doi.org/10.3390/ijms19061792 - 17 Jun 2018

Cited by 23 | Viewed by 9497

Abstract

The gut microbiota is integral to an organism’s digestive structure and has been shown to play an important role in producing substrates for gluconeogenesis and energy production, vasodilator, and gut motility. Numerous studies have demonstrated that variation in diet types is associated with [...] Read more.

The gut microbiota is integral to an organism’s digestive structure and has been shown to play an important role in producing substrates for gluconeogenesis and energy production, vasodilator, and gut motility. Numerous studies have demonstrated that variation in diet types is associated with the abundance and diversity of the gut microbiota, a relationship that plays a significant role in nutrient absorption and affects gut size. The Expensive-Tissue Hypothesis states (ETH) that the metabolic requirement of relatively large brains is offset by a corresponding reduction of the other tissues, such as gut size. However, how the trade-off between gut size and brain size in vertebrates is associated with the gut microbiota through metabolic requirements still remains unexplored. Here, we review research relating to and discuss the potential influence of gut microbiota on the ETH. Full article

(This article belongs to the Special Issue The (Microbiota)–Gut–Brain Axis: Hype or Revolution?)

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Int. J. Mol. Sci., Volume 19, Issue 6 (June 2018) – 276 articles

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