International Journal of Molecular Sciences

27 pages, 3196 KiB

Open AccessReview

Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2

by Chloe J. Peach^1,2, Viviane W. Mignone^1,2,3, Maria Augusta Arruda^1,2,3

, Diana C. Alcobia^1,2, Stephen J. Hill^1,2, Laura E. Kilpatrick^1,2,* and Jeanette Woolard^1,2,*

¹ Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK

² Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, Midlands NG7 2UH, UK

³ CAPES-University of Nottingham Programme in Drug Discovery, Queen’s Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK

Int. J. Mol. Sci. 2018, 19(4), 1264; https://doi.org/10.3390/ijms19041264 - 23 Apr 2018

Cited by 377 | Viewed by 33132

Abstract

Vascular endothelial growth factor-A (VEGF-A) is a key mediator of angiogenesis, signalling via the class IV tyrosine kinase receptor family of VEGF Receptors (VEGFRs). Although VEGF-A ligands bind to both VEGFR1 and VEGFR2, they primarily signal via VEGFR2 leading to endothelial cell proliferation, [...] Read more.

Vascular endothelial growth factor-A (VEGF-A) is a key mediator of angiogenesis, signalling via the class IV tyrosine kinase receptor family of VEGF Receptors (VEGFRs). Although VEGF-A ligands bind to both VEGFR1 and VEGFR2, they primarily signal via VEGFR2 leading to endothelial cell proliferation, survival, migration and vascular permeability. Distinct VEGF-A isoforms result from alternative splicing of the Vegfa gene at exon 8, resulting in VEGF_xxxa or VEGF_xxxb isoforms. Alternative splicing events at exons 5–7, in addition to recently identified posttranslational read-through events, produce VEGF-A isoforms that differ in their bioavailability and interaction with the co-receptor Neuropilin-1. This review explores the molecular pharmacology of VEGF-A isoforms at VEGFR2 in respect to ligand binding and downstream signalling. To understand how VEGF-A isoforms have distinct signalling despite similar affinities for VEGFR2, this review re-evaluates the typical classification of these isoforms relative to the prototypical, “pro-angiogenic” VEGF₁₆₅a. We also examine the molecular mechanisms underpinning the regulation of VEGF-A isoform signalling and the importance of interactions with other membrane and extracellular matrix proteins. As approved therapeutics targeting the VEGF-A/VEGFR signalling axis largely lack long-term efficacy, understanding these isoform-specific mechanisms could aid future drug discovery efforts targeting VEGF receptor pharmacology. Full article

(This article belongs to the Special Issue Vascular Endothelial Growth Factor)

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18 pages, 797 KiB

Open AccessReview

ROS-Activated Ion Channels in Plants: Biophysical Characteristics, Physiological Functions and Molecular Nature

by Vadim Demidchik^1,2,3

¹ Department of Horticulture, School of Food Science and Engineering, Foshan University, Foshan 528000, China

² Department of Plant Cell Biology and Bioengineering, Biological Faculty, Belarusian State University, 4 Independence Avenue, 220030 Minsk, Belarus

³ Russian Academy of Sciences, Komarov Botanical Institute, 2 Professora Popova Street, 197376 St. Petersburg, Russia

Int. J. Mol. Sci. 2018, 19(4), 1263; https://doi.org/10.3390/ijms19041263 - 23 Apr 2018

Cited by 126 | Viewed by 9487

Abstract

Ion channels activated by reactive oxygen species (ROS) have been found in the plasma membrane of charophyte Nitella flixilis, dicotyledon Arabidopsis thaliana, Pyrus pyrifolia and Pisum sativum, and the monocotyledon Lilium longiflorum. Their activities have been reported in charophyte [...] Read more.

Ion channels activated by reactive oxygen species (ROS) have been found in the plasma membrane of charophyte Nitella flixilis, dicotyledon Arabidopsis thaliana, Pyrus pyrifolia and Pisum sativum, and the monocotyledon Lilium longiflorum. Their activities have been reported in charophyte giant internodes, root trichoblasts and atrichoblasts, pollen tubes, and guard cells. Hydrogen peroxide and hydroxyl radicals are major activating species for these channels. Plant ROS-activated ion channels include inwardly-rectifying, outwardly-rectifying, and voltage-independent groups. The inwardly-rectifying ROS-activated ion channels mediate Ca²⁺-influx for growth and development in roots and pollen tubes. The outwardly-rectifying group facilitates K⁺ efflux for the regulation of osmotic pressure in guard cells, induction of programmed cell death, and autophagy in roots. The voltage-independent group mediates both Ca²⁺ influx and K⁺ efflux. Most studies suggest that ROS-activated channels are non-selective cation channels. Single-channel studies revealed activation of 14.5-pS Ca²⁺ influx and 16-pS K⁺ efflux unitary conductances in response to ROS. The molecular nature of ROS-activated Ca²⁺ influx channels remains poorly understood, although annexins and cyclic nucleotide-gated channels have been proposed for this role. The ROS-activated K⁺ channels have recently been identified as products of Stellar K⁺ Outward Rectifier (SKOR) and Guard cell Outwardly Rectifying K⁺ channel (GORK) genes. Full article

(This article belongs to the Special Issue Plasma-Membrane Transport)

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17 pages, 5976 KiB

Open AccessArticle

Erythropoietin Intensifies the Proapoptotic Activity of LFM-A13 in Cells and in a Mouse Model of Colorectal Cancer

by Anna Tankiewicz-Kwedlo^1,*, Justyna Magdalena Hermanowicz^2,3, Krystyna Pawlak¹, Robert Czarnomysy⁴

, Krzysztof Bielawski⁴, Izabela Prokop⁵

and Dariusz Pawlak²

¹ Department of Monitored Pharmacotherapy, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland

² Department of Pharmacodynamics, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland

³ Department of Clinical Pharmacy, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland

⁴ Department of Synthesis and Technology of Drugs, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland

⁵ Department of Medicinal Chemistry, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland

Int. J. Mol. Sci. 2018, 19(4), 1262; https://doi.org/10.3390/ijms19041262 - 23 Apr 2018

Cited by 4 | Viewed by 4765

Abstract

The Bruton’s tyrosine kinase (BTK) inhibitor LFM-A13 has been widely employed as an antileukemic agent, but applications in solid cancer have been found recently. The compound promotes apoptosis, has an antiproliferative effect, and increases cancer cell sensitivity to chemotherapy drugs. We decided to [...] Read more.

The Bruton’s tyrosine kinase (BTK) inhibitor LFM-A13 has been widely employed as an antileukemic agent, but applications in solid cancer have been found recently. The compound promotes apoptosis, has an antiproliferative effect, and increases cancer cell sensitivity to chemotherapy drugs. We decided to assess the impact of the simultaneous use of erythropoietin (Epo) and LFM-A13 on signal transduction in colon DLD-1 and HT-29 cells, as well as in tumor xenografts. The induction of apoptosis by Epo and LFM-A-13 in the cells was confirmed by phosphatidylserine externalization, loss of mitochondrial membrane potential, and modulation of the expression of apoptotic protein BAX and antiapoptotic protein BCL-2 in colon adenocarcinoma cells. Nude mice were inoculated with adenocarcinoma cells and treated with Epo and LFM-A13 in order to evaluate the degree of tumor regression. The simultaneous use of Epo and LFM-A13 severely inhibited cell growth, activated apoptosis, and also inhibited tumor growth in xenografts. The addition of Epo to LFM-A13 intensified the antiproliferative effect of LFM-A13, confirmed by the loss of mitochondrial membrane potential and the accumulation of apoptotic colon cancer cells with externalized phosphatidylserine (PS). These preclinical results suggest that the combination of Epo and LFM-A13 has a high proapoptotic activity and should be tested in the clinic for the treatment of solid tumors such as colon cancer. Full article

(This article belongs to the Special Issue Tumor Targeting Therapy and Selective Killing 2018)

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12 pages, 3901 KiB

Open AccessArticle

Cytokine Expression and Macrophage Localization in Xenograft and Allograft Tumor Models Stimulated with Lipopolysaccharide

by Junko Masuda^1,*

, Tsukasa Shigehiro¹

, Takuma Matsumoto¹, Ayano Satoh¹

, Akifumi Mizutani¹, Chiho Umemura¹, Shoki Saito¹, Mayumi Kijihira², Eiji Takayama³, Akimasa Seno¹

, Hiroshi Murakami¹ and Masaharu Seno¹

¹ Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan

² Department of Applied Chemistry and Biotechnology, Faculty of Engineering, Okayama University, Okayama 700-8530, Japan

³ Department of Oral Biochemistry, School of Dentistry, Asahi University, Gifu 501-0223, Japan

Int. J. Mol. Sci. 2018, 19(4), 1261; https://doi.org/10.3390/ijms19041261 - 23 Apr 2018

Cited by 20 | Viewed by 8275

Abstract

T cell-deficient mice such as nude mice are often used to generate tumor xenograft for the development of anticancer agents. However, the functionality of the other immune cells including macrophages, dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs) in the xenograft are largely [...] Read more.

T cell-deficient mice such as nude mice are often used to generate tumor xenograft for the development of anticancer agents. However, the functionality of the other immune cells including macrophages, dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs) in the xenograft are largely unknown. Macrophages and dendritic cells (DCs) acquire functionally distinct properties in response to various environmental stimuli; the interaction of these cells with MDSCs in tumor microenvironments regulates cancer progression. Nude mice are less likely to reject human cancer cells because of major histocompatibility complex (MHC) mismatches. The tumor microenvironment in a xenograft, comprising human and mouse cells, exhibits more complex bidirectional signaling and function than that of allograft. Here, we evaluated the differences of myeloid cells between them. Plasma interferon-γ and interleukin-18 concentrations in the xenograft tumor model after lipopolysaccharide (LPS) administration were significantly higher than those in the allograft tumor model. MHC class I, II, and CD80 expression levels were increased in CD11b⁺ and MDSC populations after LPS administration in the spleen of a xenograft tumor model but not in that of an allograft tumor model. Additionally, the number of CD80- and mannose receptor C type 1 (MRC1)-expressing cells was decreased upon LPS administration in the tumor of the xenograft tumor. These results suggest that functions of macrophages and DCs are sustained in the xenograft, whereas their functions in response to LPS were suppressed in the allograft. The findings will encourage the consideration of the effects of myeloid cells in the xenograft for drug development. Full article

(This article belongs to the Section Biochemistry)

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17 pages, 7774 KiB

Open AccessReview

The Role of PPAR and Its Cross-Talk with CAR and LXR in Obesity and Atherosclerosis

by Pengfei Xu^1,2

, Yonggong Zhai^1,2,* and Jing Wang^3,*

¹ Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China

² Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China

³ Department of Biology Science and Technology, Baotou Teacher’s College, Baotou 014030, China

Int. J. Mol. Sci. 2018, 19(4), 1260; https://doi.org/10.3390/ijms19041260 - 23 Apr 2018

Cited by 89 | Viewed by 14688

Abstract

The prevalence of obesity and atherosclerosis has substantially increased worldwide over the past several decades. Peroxisome proliferator-activated receptors (PPARs), as fatty acids sensors, have been therapeutic targets in several human lipid metabolic diseases, such as obesity, atherosclerosis, diabetes, hyperlipidaemia, and non-alcoholic fatty liver [...] Read more.

The prevalence of obesity and atherosclerosis has substantially increased worldwide over the past several decades. Peroxisome proliferator-activated receptors (PPARs), as fatty acids sensors, have been therapeutic targets in several human lipid metabolic diseases, such as obesity, atherosclerosis, diabetes, hyperlipidaemia, and non-alcoholic fatty liver disease. Constitutive androstane receptor (CAR) and liver X receptors (LXRs) were also reported as potential therapeutic targets for the treatment of obesity and atherosclerosis, respectively. Further clarification of the internal relationships between these three lipid metabolic nuclear receptors is necessary to enable drug discovery. In this review, we mainly summarized the cross-talk of PPARs-CAR in obesity and PPARs-LXRs in atherosclerosis. Full article

(This article belongs to the Special Issue PPARs in Cellular and Whole Body Energy Metabolism)

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17 pages, 2269 KiB

Open AccessReview

Clinicopathological Characteristics and Mutations Driving Development of Early Lung Adenocarcinoma: Tumor Initiation and Progression

by Kentaro Inamura

Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan

Int. J. Mol. Sci. 2018, 19(4), 1259; https://doi.org/10.3390/ijms19041259 - 23 Apr 2018

Cited by 117 | Viewed by 13258

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide, with lung adenocarcinoma representing the most common lung cancer subtype. Among all lung adenocarcinomas, the most prevalent subset develops via tumorigenesis and progression from atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), [...] Read more.

Lung cancer is the leading cause of cancer-related deaths worldwide, with lung adenocarcinoma representing the most common lung cancer subtype. Among all lung adenocarcinomas, the most prevalent subset develops via tumorigenesis and progression from atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), to minimally invasive adenocarcinoma (MIA), to overt invasive adenocarcinoma with a lepidic pattern. This stepwise development is supported by the clinicopathological and molecular characteristics of these tumors. In the 2015 World Health Organization classification, AAH and AIS are both defined as preinvasive lesions, whereas MIA is identified as an early invasive adenocarcinoma that is not expected to recur if removed completely. Recent studies have examined the molecular features of lung adenocarcinoma tumorigenesis and progression. EGFR-mutated adenocarcinoma frequently develops via the multistep progression. Oncogene-induced senescence appears to decrease the frequency of the multistep progression in KRAS- or BRAF-mutated adenocarcinoma, whose tumor evolution may be associated with epigenetic alterations and kinase-inactive mutations. This review summarizes the current knowledge of tumorigenesis and tumor progression in early lung adenocarcinoma, with special focus on its clinicopathological characteristics and their associations with driver mutations (EGFR, KRAS, and BRAF) as well as on its molecular pathogenesis and progression. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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17 pages, 3727 KiB

Open AccessArticle

Liu Jun Zi Tang—A Potential, Multi-Herbal Complementary Therapy for Chemotherapy-Induced Neurotoxicity

by Chun-Tang Chiou¹, Kaw-Chen Wang², Ying-Chen Yang³, Chuen-Lin Huang^4,5, Sien-Hung Yang⁶, Yao-Haur Kuo^1,7 and Nai-Kuei Huang^1,8,*

¹ National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei 11031, Taiwan

² Department of Neurology, Cardinal-Tien Hospital, New Taipei City 231, Taiwan

³ Department of Biotechnology and Animal Science, National Ilan University, Ilan 260, Taiwan

⁴ Medical Research Center, Cardinal Tien Hospital, Hsintien, New Taipei City 231, Taiwan

⁵ Graduate Institute of Physiology & Department of Physiology and Biophysics, National Defense Medical Center, Taipei 11031, Taiwan

⁶ School of Traditional Chinese Medicine, Chang Gung University, Taoyuan City 333, Taiwan

⁷ Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan

⁸ Ph.D. Program for Neural Regenerative Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan

Int. J. Mol. Sci. 2018, 19(4), 1258; https://doi.org/10.3390/ijms19041258 - 23 Apr 2018

Cited by 20 | Viewed by 6870

Abstract

Liu Jun Zi Tang (LJZT) has been used to treat functional dyspepsia and depression, suggesting its effects on gastrointestinal and neurological functions. LJZT is currently used as a complementary therapy to attenuate cisplatin-induced side effects, such as dyspepsia. However, its effect on chemotherapy-induced [...] Read more.

Liu Jun Zi Tang (LJZT) has been used to treat functional dyspepsia and depression, suggesting its effects on gastrointestinal and neurological functions. LJZT is currently used as a complementary therapy to attenuate cisplatin-induced side effects, such as dyspepsia. However, its effect on chemotherapy-induced neuropathic pain or neurotoxicity has rarely been studied. Thus, we explored potential mechanisms underlying LJZT protection against cisplatin-induced neurotoxicity. We observed that LJZT attenuated cisplatin-induced thermal hyperalgesia in mice and apoptosis in human neuroblastoma SH-SY5Y cells. Furthermore, it also attenuated cisplatin-induced cytosolic and mitochondrial free radical formation, reversed the cisplatin-induced decrease in mitochondrial membrane potential, and increased the release of mitochondrial pro-apoptotic factors. LJZT not only activated the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) promoter region, but also attenuated the cisplatin-induced reduction of PGC-1α expression. Silencing of the PGC-1α gene counteracted the protection of LJZT. Taken together, LJZT mediated, through anti-oxidative effect and mitochondrial function regulation, to prevent cisplatin-induced neurotoxicity. Full article

(This article belongs to the Special Issue Traditional Medicine – Unraveling Its Molecular Mechanism)

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18 pages, 4373 KiB

Open AccessArticle

Theoretical Studies Applied to the Evaluation of the DFPase Bioremediation Potential against Chemical Warfare Agents Intoxication

by Flávia V. Soares¹, Alexandre A. De Castro¹, Ander F. Pereira¹, Daniel H. S. Leal^1,2, Daiana T. Mancini¹, Ondrej Krejcar³

, Teodorico C. Ramalho^1,3

, Elaine F. F. Da Cunha¹ and Kamil Kuca^3,*

¹ Laboratory of Molecular Modeling, Chemistry Department, Federal University of Lavras, 37200-000 Lavras, MG, Brazil

² Department of Health Sciences, Federal University of Espírito Santo, 29932-540 São Mateus, ES, Brazil

³ Center for Basic and Applied Research, Faculty of Informatics and Management, University Hradec Kralove, 50003 Hradec Kralove, Czech Republic

Int. J. Mol. Sci. 2018, 19(4), 1257; https://doi.org/10.3390/ijms19041257 - 23 Apr 2018

Cited by 22 | Viewed by 5168

Abstract

Organophosphorus compounds (OP) are part of a group of compounds that may be hazardous to health. They are called neurotoxic agents because of their action on the nervous system, inhibiting the acetylcholinesterase (AChE) enzyme and resulting in a cholinergic crisis. Their high toxicity [...] Read more.

Organophosphorus compounds (OP) are part of a group of compounds that may be hazardous to health. They are called neurotoxic agents because of their action on the nervous system, inhibiting the acetylcholinesterase (AChE) enzyme and resulting in a cholinergic crisis. Their high toxicity and rapid action lead to irreversible damage to the nervous system, drawing attention to developing new treatment methods. The diisopropyl fluorophosphatase (DFPase) enzyme has been considered as a potent biocatalyst for the hydrolysis of toxic OP and has potential for bioremediation of this kind of intoxication. In order to investigate the degradation process of the nerve agents Tabun, Cyclosarin and Soman through the wild-type DFPase, and taking into account their stereochemistry, theoretical studies were carried out. The intermolecular interaction energy and other parameters obtained from the molecular docking calculations were used to construct a data matrix, which were posteriorly treated by statistical analyzes of chemometrics, using the PCA (Principal Components Analysis) multivariate analysis. The analyzed parameters seem to be quite important for the reaction mechanisms simulation (QM/MM). Our findings showed that the wild-type DFPase enzyme is stereoselective in hydrolysis, showing promising results for the catalytic degradation of the neurotoxic agents under study, with the degradation mechanism performed through two proposed pathways. Full article

(This article belongs to the Special Issue Computational Studies of Structure-Dynamics-Function Relationships in Biomolecules)

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16 pages, 822 KiB

Open AccessReview

Ca²⁺ Regulation of TRP Ion Channels

by Raquibul Hasan¹

and Xuming Zhang^2,*

¹ Department of Pharmaceutical Sciences, College of Pharmacy Mercer University, Atlanta, GA 30341, USA

² School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK

Int. J. Mol. Sci. 2018, 19(4), 1256; https://doi.org/10.3390/ijms19041256 - 23 Apr 2018

Cited by 71 | Viewed by 7848

Abstract

Ca²⁺ signaling influences nearly every aspect of cellular life. Transient receptor potential (TRP) ion channels have emerged as cellular sensors for thermal, chemical and mechanical stimuli and are major contributors to Ca²⁺ signaling, playing an important role in diverse physiological and [...] Read more.

Ca²⁺ signaling influences nearly every aspect of cellular life. Transient receptor potential (TRP) ion channels have emerged as cellular sensors for thermal, chemical and mechanical stimuli and are major contributors to Ca²⁺ signaling, playing an important role in diverse physiological and pathological processes. Notably, TRP ion channels are also one of the major downstream targets of Ca²⁺ signaling initiated either from TRP channels themselves or from various other sources, such as G-protein coupled receptors, giving rise to feedback regulation. TRP channels therefore function like integrators of Ca²⁺ signaling. A growing body of research has demonstrated different modes of Ca²⁺-dependent regulation of TRP ion channels and the underlying mechanisms. However, the precise actions of Ca²⁺ in the modulation of TRP ion channels remain elusive. Advances in Ca²⁺ regulation of TRP channels are critical to our understanding of the diversified functions of TRP channels and complex Ca²⁺ signaling. Full article

(This article belongs to the Special Issue Calcium Binding Proteins)

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31 pages, 2344 KiB

Open AccessReview

Prostate Cancer Genomics: Recent Advances and the Prevailing Underrepresentation from Racial and Ethnic Minorities

by Shyh-Han Tan^*

, Gyorgy Petrovics and Shiv Srivastava

Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences and the Walter Reed National Military Medical Center, Rockville, MD 20852, USA

Int. J. Mol. Sci. 2018, 19(4), 1255; https://doi.org/10.3390/ijms19041255 - 22 Apr 2018

Cited by 56 | Viewed by 12167

Abstract

Prostate cancer (CaP) is the most commonly diagnosed non-cutaneous cancer and the second leading cause of male cancer deaths in the United States. Among African American (AA) men, CaP is the most prevalent malignancy, with disproportionately higher incidence and mortality rates. Even after [...] Read more.

Prostate cancer (CaP) is the most commonly diagnosed non-cutaneous cancer and the second leading cause of male cancer deaths in the United States. Among African American (AA) men, CaP is the most prevalent malignancy, with disproportionately higher incidence and mortality rates. Even after discounting the influence of socioeconomic factors, the effect of molecular and genetic factors on racial disparity of CaP is evident. Earlier studies on the molecular basis for CaP disparity have focused on the influence of heritable mutations and single-nucleotide polymorphisms (SNPs). Most CaP susceptibility alleles identified based on genome-wide association studies (GWAS) were common, low-penetrance variants. Germline CaP-associated mutations that are highly penetrant, such as those found in HOXB13 and BRCA2, are usually rare. More recently, genomic studies enabled by Next-Gen Sequencing (NGS) technologies have focused on the identification of somatic mutations that contribute to CaP tumorigenesis. These studies confirmed the high prevalence of ERG gene fusions and PTEN deletions among Caucasian Americans and identified novel somatic alterations in SPOP and FOXA1 genes in early stages of CaP. Individuals with African ancestry and other minorities are often underrepresented in these large-scale genomic studies, which are performed primarily using tumors from men of European ancestry. The insufficient number of specimens from AA men and other minority populations, together with the heterogeneity in the molecular etiology of CaP across populations, challenge the generalizability of findings from these projects. Efforts to close this gap by sequencing larger numbers of tumor specimens from more diverse populations, although still at an early stage, have discovered distinct genomic alterations. These research findings can have a direct impact on the diagnosis of CaP, the stratification of patients for treatment, and can help to address the disparity in incidence and mortality of CaP. This review examines the progress of understanding in CaP genetics and genomics and highlight the need to increase the representation from minority populations. Full article

(This article belongs to the Special Issue Molecular Research on Urology)

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16 pages, 1764 KiB

Open AccessArticle

Memory Function in Feeding Habit Transformation of Mandarin Fish (Siniperca chuatsi)

by Yaqi Dou, Shan He^*, Xu-Fang Liang^*, Wenjing Cai, Jie Wang, Linjie Shi and Jiao Li

College of Fisheries, Chinese Perch Research Center, Huazhong Agricultural University, No.1, Shizishan Street, Hongshan District, Wuhan, Hubei Province, 430070, China; Freshwater Aquaculture Collaborative Innovation Center of Hubei Province, Key Lab of Freshwater Animal Breeding, Ministry of Agriculture, Wuhan 430070, China

Int. J. Mol. Sci. 2018, 19(4), 1254; https://doi.org/10.3390/ijms19041254 - 22 Apr 2018

Cited by 23 | Viewed by 6833

Abstract

Mandarin fish refuse dead prey fish or artificial diets and can be trained to transform their inborn feeding habit. To investigate the effect of memory on feeding habit transformation, we compared the reaction time to dead prey fish and the success rate of [...] Read more.

Mandarin fish refuse dead prey fish or artificial diets and can be trained to transform their inborn feeding habit. To investigate the effect of memory on feeding habit transformation, we compared the reaction time to dead prey fish and the success rate of feeding habit transformation to dead prey fish with training of mandarin fish in the 1st experimental group (trained once) and the 2nd experimental group (trained twice). The mandarin fish in the 2nd group had higher success rate of feeding habit transformation (100%) than those in the 1st group (67%), and shorter reaction time to dead prey fish (<1 s) than those in the 1st group (>1 s). Gene expression of cAMP responsive element binding protein I (Creb I), brain-derived neurotrophic factor (Bdnf), CCAAT enhancer binding protein delta (C/EBPD), fos-related antigen 2 (Fra2), and proto-oncogenes c-fos (c-fos) involved in long-term memory formation were significantly increased in the 2nd group after repeated training, and taste 1 receptor member 1 (T1R1), involved in feeding habit formation, was significantly increased in brains of the 2nd group after repeated training. DNA methylation levels at five candidate CpG (cytosine–guanine) sites contained in the predicted CpG island in the 5′-flanking region of T1R1 were significantly decreased in brains of the 2nd group compared with that of the 1st group. These results indicated that the repeated training can improve the feeding habit transformation through the memory formation of accepting dead prey fish. DNA methylation of the T1R1 might be a regulatory factor for feeding habit transformation from live prey fish to dead prey fish in mandarin fish. Full article

(This article belongs to the Special Issue DNA Methylation)

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10 pages, 515 KiB

Open AccessArticle

Mesenchylmal Stem Cell Culture on Poly(N-isopropylacrylamide) Hydrogel with Repeated Thermo-Stimulation

by Aya Mizutani Akimoto^1,*,†

, Erika Hasuike Niitsu^2,†, Kenichi Nagase^3,‡

, Teruo Okano³, Hideko Kanazawa² and Ryo Yoshida^1,*

¹ Department of Materials Engineering, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo 113-8656, Japan

² Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato, Tokyo 105-8512, Japan

³ Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo 162-8666, Japan

^† These authors contributed equally to this work.

^‡ Present address: Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato, Tokyo 105-8512, Japan.

Int. J. Mol. Sci. 2018, 19(4), 1253; https://doi.org/10.3390/ijms19041253 - 21 Apr 2018

Cited by 29 | Viewed by 6303

Abstract

We prepared thermoresponsive hydrogels by mixing poly(N-isopropylacrylamide) (PNIPAAm) derivatives as the main chain components, octa-arm polyethylene glycol (PEG) as a crosslinker, and the Arg-Gly-Asp-Ser (RGDS) peptides as cell adhesion units. Human bone marrow-derived mesenchymal stem cells (hbmMSCs) were cultured on the [...] Read more.

We prepared thermoresponsive hydrogels by mixing poly(N-isopropylacrylamide) (PNIPAAm) derivatives as the main chain components, octa-arm polyethylene glycol (PEG) as a crosslinker, and the Arg-Gly-Asp-Ser (RGDS) peptides as cell adhesion units. Human bone marrow-derived mesenchymal stem cells (hbmMSCs) were cultured on the hydrogels. The PNIPAAm gel prepared by the post-crosslinking gelation method was revealed to be cytocompatible and showed temperature-dependent changes in mechanical properties. Repeated changes in the swelling ratio of the PNIPAAm gel affected the shape of the hbmMSCs. With respect to both cytocompatibility and reversibility of changes in mechanical properties, the PNIPAAm gel system could be potentially useful for the analysis of cell mechanobiology. Full article

(This article belongs to the Special Issue Smart Polymers for Biomedical Applications)

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13 pages, 5824 KiB

Open AccessArticle

SPAG17 Is Required for Male Germ Cell Differentiation and Fertility

by Elizabeth Kazarian¹, HyunYoung Son¹, Paulene Sapao¹

, Wei Li¹, Zhibing Zhang^1,2,†, Jerome F. Strauss III^1,2

and Maria E. Teves^1,*

¹ Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA 23298, USA

² Department of Biochemistry & Molecular Biology, Virginia Commonwealth University, Richmond, VA 23298, USA

^† Current address: Department of Physiology, Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48210, USA.

Int. J. Mol. Sci. 2018, 19(4), 1252; https://doi.org/10.3390/ijms19041252 - 21 Apr 2018

Cited by 42 | Viewed by 8952

Abstract

Spag17 encodes a protein present in the axoneme central pair complex of motile cilia and flagella. A mutation in this gene has been reported to be associated with infertility caused by defects in sperm motility. Here, we report that Spag17 knockout mice are [...] Read more.

Spag17 encodes a protein present in the axoneme central pair complex of motile cilia and flagella. A mutation in this gene has been reported to be associated with infertility caused by defects in sperm motility. Here, we report that Spag17 knockout mice are infertile because of a severe defect in spermatogenesis. The histological evaluation of testis sections from mutant mice revealed seminiferous tubules with spermatogenesis arrested at the spermatid stage and cell debris in the cauda epididymis. The few sperm collected from the cauda epididymis were immotile and displayed abnormal tail and head morphology. Immunofluorescence analysis of Spag17 knockout germ cells showed spermatids with abnormally long manchette structures and morphological defects in the head. Electron microscopy showed altered manchette microtubules, reduced chromatin condensation, irregular nuclear shape, and detached acrosomes. Additionally, the transport of proteins (Pcdp1 and IFT20) along the manchette microtubules was disrupted in the knockout elongating spermatids. Our results show for the first time that Spag17 is essential for normal manchette structure, protein transport, and formation of the sperm head and flagellum, in addition to its role in sperm motility. Full article

(This article belongs to the Section Biochemistry)

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17 pages, 2132 KiB

Open AccessReview

What Does This Mutation Mean? The Tools and Pitfalls of Variant Interpretation in Lymphoid Malignancies

by Yann Guillermin¹, Jonathan Lopez^2,3,4, Kaddour Chabane⁵

, Sandrine Hayette^3,5, Claire Bardel^6,7, Gilles Salles^3,4,8, Pierre Sujobert^3,4,5 and Sarah Huet^3,5,9,*

¹ Centre Léon Bérard, Service d’Hématologie Clinique, 69008 Lyon, France

² Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Laboratoire de Biochimie et Biologie moléculaire, 69495 Pierre-Bénite CEDEX, France

³ Cancer Research Center of Lyon, INSERM U1052 UMR CNRS 5286, Equipe labellisée LIGUE Contre le Cancer, 69008 Lyon, France

⁴ Université de Lyon, Université Lyon 1, Faculté de Médecine et de Maïeutique Lyon Sud Charles Mérieux, 69921 Oullins CEDEX, France

⁵ Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Laboratoire d’Hématologie, 69495 Pierre-Bénite CEDEX, France

⁶ Hospices Civils de Lyon, Service de Biostatistique—bioinformatique et plateforme de séquençage haut débit NGS-CHU Lyon, 69677 Bron CEDEX, France

⁷ Université de Lyon, Université Lyon 1, CNRS, Laboratoire de Biométrie et Biologie Evolutive UMR5558, équipe biostatistique-santé, F-69424 Lyon, France

⁸ Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Service d’Hématologie Clinique, 69495 Pierre-Bénite CEDEX, France

⁹ Université de Lyon, Université Lyon 1, Faculté de Pharmacie Rockefeller, 69373 Lyon CEDEX, France

Int. J. Mol. Sci. 2018, 19(4), 1251; https://doi.org/10.3390/ijms19041251 - 20 Apr 2018

Cited by 9 | Viewed by 5979

Abstract

High throughput sequencing (HTS) is increasingly important in determining cancer diagnoses, with subsequent prognostic and therapeutic implications. The biology of cancer is becoming increasingly deciphered and it is clear that therapy needs to be individually tailored. Whilst translational research plays an important role [...] Read more.

High throughput sequencing (HTS) is increasingly important in determining cancer diagnoses, with subsequent prognostic and therapeutic implications. The biology of cancer is becoming increasingly deciphered and it is clear that therapy needs to be individually tailored. Whilst translational research plays an important role in lymphoid malignancies, few guidelines exist to guide biologists and routine laboratories through this constantly evolving field. In this article, we review the challenges of interpreting HTS in lymphoid malignancies and provide a toolkit to interpret single nucleotide variants obtained from HTS. We define the pre-analytical issues such as sequencing DNA obtained from formalin-fixed and paraffin-embedded tissue (FFPE), the acquisition of germline DNA, or the bioinformatic pitfalls, the analytical issues encountered and how to manage them. We describe the main constitutional and cancer databases, their characteristics and limitations, with an emphasis on variant interpretation in lymphoid malignancies. Finally, we discuss the challenges of predictions that one can make using in silico or in vitro modelling, pharmacogenomic screening, and the limits of those prediction tools. This description of the current status in genomic interpretation highlights the need for new large databases and international collaboration in the lymphoma field. Full article

(This article belongs to the Special Issue Translational Diagnostics in Lymphoproliferative and Plasma Cell Disorders)

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22 pages, 1443 KiB

Open AccessArticle

In Vitro Identification of New Transcriptomic and miRNomic Profiles Associated with Pulmonary Fibrosis Induced by High Doses Everolimus: Looking for New Pathogenetic Markers and Therapeutic Targets

by Simona Granata¹

, Gloria Santoro¹

, Valentina Masola¹, Paola Tomei¹, Fabio Sallustio^2,3

, Paola Pontrelli²

, Matteo Accetturo², Nadia Antonucci¹

, Pierluigi Carratù⁴, Antonio Lupo¹ and Gianluigi Zaza^1,*

¹ Renal Unit, Department of Medicine, University of Verona, Piazzale Stefani 1, 37126 Verona, Italy

² Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy

³ Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy

⁴ Department of Respiratory Diseases, University of Bari “Aldo Moro”, Piazza Giulio Cesare 11, 70124 Bari, Italy

Int. J. Mol. Sci. 2018, 19(4), 1250; https://doi.org/10.3390/ijms19041250 - 20 Apr 2018

Cited by 9 | Viewed by 5005

Abstract

The administration of Everolimus (EVE), a mTOR inhibitor used in transplantation and cancer, is often associated with adverse effects including pulmonary fibrosis. Although the underlying mechanism is not fully clarified, this condition could be in part caused by epithelial to mesenchymal transition (EMT) [...] Read more.

The administration of Everolimus (EVE), a mTOR inhibitor used in transplantation and cancer, is often associated with adverse effects including pulmonary fibrosis. Although the underlying mechanism is not fully clarified, this condition could be in part caused by epithelial to mesenchymal transition (EMT) of airway cells. To improve our knowledge, primary bronchial epithelial cells (BE63/3) were treated with EVE (5 and 100 nM) for 24 h. EMT markers (α-SMA, vimentin, fibronectin) were measured by RT-PCR. Transepithelial resistance was measured by Millicell-ERS ohmmeter. mRNA and microRNA profiling were performed by Illumina and Agilent kit, respectively. Only high dose EVE increased EMT markers and reduced the transepithelial resistance of BE63/3. Bioinformatics showed 125 de-regulated genes that, according to enrichment analysis, were implicated in collagen synthesis/metabolism. Connective tissue growth factor (CTGF) was one of the higher up-regulated mRNA. Five nM EVE was ineffective on the pro-fibrotic machinery. Additionally, 3 miRNAs resulted hyper-expressed after 100 nM EVE and able to regulate 31 of the genes selected by the transcriptomic analysis (including CTGF). RT-PCR and western blot for MMP12 and CTGF validated high-throughput results. Our results revealed a complex biological network implicated in EVE-related pulmonary fibrosis and underlined new potential disease biomarkers and therapeutic targets. Full article

(This article belongs to the Special Issue mTOR in Human Diseases)

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13 pages, 1825 KiB

Open AccessArticle

Molecular Characterization and the Function of Argonaute3 in RNAi Pathway of Plutella xylostella

by Muhammad Salman Hameed^1,2,3,4, Zhengbing Wang⁵

, Liette Vasseur^1,6

and Guang Yang^1,2,3,4,*

¹ State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, College of Life Science, Fujian Agriculture and Forestry University, Fuzhou 350002, China

² Joint International Research Laboratory of Ecological Pest Control, Ministry of Education, Fuzhou 350002, China

³ Key Laboratory of Integrated Pest Management for Fujian-Taiwan Crops, Ministry of Agriculture, Fuzhou 350002, China

⁴ Key Laboratory of Green Pest Control (Fujian Agriculture and Forestry University), Fujian Province University, Fuzhou 350002, China

⁵ Key Laboratory of Natural Pesticides and Chemical Biology of the Ministry of Education, South China Agricultural University, Guangzhou 510642, China

⁶ Department of Biological Sciences, Brock University, 500 Glenridge Avenue, St. Catharines, ON L2S 3A1, Canada

Int. J. Mol. Sci. 2018, 19(4), 1249; https://doi.org/10.3390/ijms19041249 - 20 Apr 2018

Cited by 14 | Viewed by 4814

Abstract

Argonaute (Ago) protein family plays a key role in the RNA interference (RNAi) process in different insects including Lepidopteran. However, the role of Ago proteins in the RNAi pathway of Plutella xylostella is still unknown. We cloned an Argonaute3 gene in P. xylostella [...] Read more.

Argonaute (Ago) protein family plays a key role in the RNA interference (RNAi) process in different insects including Lepidopteran. However, the role of Ago proteins in the RNAi pathway of Plutella xylostella is still unknown. We cloned an Argonaute3 gene in P. xylostella (PxAgo3) with the complete coding sequence of 2832 bp. The encoded protein had 935 amino acids with an expected molecular weight of 108.9 kDa and an isoelectric point of 9.29. It contained a PAZ (PIWI/Argonaute/Zwile) domain and PIWI (P-element-induced whimpy testes) domain. PxAgo3 was classified into the Piwi subfamily of Ago proteins with a high similarity of 93.0% with Bombyx mori Ago3 (BmAgo3). The suppression of PxAgo3 by dsPxAgo3 was observed 3 h after treatment and was maintained until 24 h. Knockdown of PxAgo3 decreased the suppression level of PxActin by dsPxActin in P. xylostella cells, while overexpression of PxAgo3 increased the RNAi efficiency. Our results suggest that PxAgo3 play a key role in the double stranded RNA (dsRNA)-regulated RNAi pathway in P. xylostella. Full article

(This article belongs to the Special Issue Molecular Entomology of Insects of Economic Importance)

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13 pages, 2255 KiB

Open AccessArticle

Molecular Evolution and Expression Divergence of HMT Gene Family in Plants

by Man Zhao^1,*, Peng Chen¹, Wenyi Wang¹, Fengjie Yuan², Danhua Zhu², Zhao Wang¹ and Xiangxian Ying^1,*

¹ College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310014, China

² Institute of Crop Science, Zhejiang Academy of Agricultural Sciences, Hangzhou 310014, China

Int. J. Mol. Sci. 2018, 19(4), 1248; https://doi.org/10.3390/ijms19041248 - 20 Apr 2018

Cited by 12 | Viewed by 4876

Abstract

Homocysteine methyltransferase (HMT) converts homocysteine to methionine using S-methylmethionine (SMM) or S-adenosylmethionine (SAM) as methyl donors in organisms, playing an important role in supplying methionine for the growth and the development of plants. To better understand the functions of the HMT [...] Read more.

Homocysteine methyltransferase (HMT) converts homocysteine to methionine using S-methylmethionine (SMM) or S-adenosylmethionine (SAM) as methyl donors in organisms, playing an important role in supplying methionine for the growth and the development of plants. To better understand the functions of the HMT genes in plants, we conducted a wide evolution and expression analysis of these genes. Reconstruction of the phylogenetic relationship showed that the HMT gene family was divided into Class 1 and Class 2. In Class 1, HMTs were only found in seed plants, while Class 2 presented in all land plants, which hinted that the HMT genes might have diverged in seed plants. The analysis of gene structures and selection pressures showed that they were relatively conserved during evolution. However, type I functional divergence had been detected in the HMTs. Furthermore, the expression profiles of HMTs showed their distinct expression patterns in different tissues, in which some HMTs were widely expressed in various organs, whereas the others were highly expressed in some specific organs, such as seeds or leaves. Therefore, according to our results in the evolution, functional divergence, and expression, the HMT genes might have diverged during evolution. Further analysis in the expression patterns of AthHMTs with their methyl donors suggested that the diverged HMTs might be related to supply methionine for the development of plant seeds. Full article

(This article belongs to the Section Molecular Plant Sciences)

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16 pages, 2020 KiB

Open AccessArticle

Detrimental Effects of Helium Ion Irradiation on Cognitive Performance and Cortical Levels of MAP-2 in B6D2F1 Mice

by Jacob Raber^1,2,*

, Eileen Ruth S. Torres¹

, Tunde Akinyeke¹, Joanne Lee¹, Sydney J. Weber Boutros¹, Mitchell S. Turker³ and Amy Kronenberg⁴

¹ Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR 97239, USA

² Departments of Neurology and Radiation Medicine, Division of Neuroscience ONPRC, Oregon Health and Science University, Portland, OR 97239, USA

³ Oregon Institute of Occupational Health Sciences and Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97239, USA

⁴ Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA

Int. J. Mol. Sci. 2018, 19(4), 1247; https://doi.org/10.3390/ijms19041247 - 20 Apr 2018

Cited by 21 | Viewed by 4913

Abstract

The space radiation environment includes helium (⁴He) ions that may impact brain function. As little is known about the effects of exposures to ⁴He ions on the brain, we assessed the behavioral and cognitive performance of C57BL/6J × DBA2/J F1 [...] Read more.

The space radiation environment includes helium (⁴He) ions that may impact brain function. As little is known about the effects of exposures to ⁴He ions on the brain, we assessed the behavioral and cognitive performance of C57BL/6J × DBA2/J F1 (B6D2F1) mice three months following irradiation with ⁴He ions (250 MeV/n; linear energy transfer (LET) = 1.6 keV/μm; 0, 21, 42 or 168 cGy). Sham-irradiated mice and mice irradiated with 21 or 168 cGy showed novel object recognition, but mice irradiated with 42 cGy did not. In the passive avoidance test, mice received a slight foot shock in a dark compartment, and latency to re-enter that compartment was assessed 24 h later. Sham-irradiated mice and mice irradiated with 21 or 42 cGy showed a higher latency on Day 2 than Day 1, but the latency to enter the dark compartment in mice irradiated with 168 cGy was comparable on both days. ⁴He ion irradiation, at 42 and 168 cGy, reduced the levels of the dendritic marker microtubule-associated protein-2 (MAP-2) in the cortex. There was an effect of radiation on apolipoprotein E (apoE) levels in the hippocampus and cortex, with higher apoE levels in mice irradiated at 42 cGy than 168 cGy and a trend towards higher apoE levels in mice irradiated at 21 than 168 cGy. In addition, in the hippocampus, there was a trend towards a negative correlation between MAP-2 and apoE levels. While reduced levels of MAP-2 in the cortex might have contributed to the altered performance in the passive avoidance test, it does not seem sufficient to do so. The higher hippocampal and cortical apoE levels in mice irradiated at 42 than 168 cGy might have served as a compensatory protective response preserving their passive avoidance memory. Thus, there were no alterations in behavioral performance in the open filed or depressive-like behavior in the forced swim test, while cognitive impairments were seen in the object recognition and passive avoidance tests, but not in the contextual or cued fear conditioning tests. Taken together, the results indicate that some aspects of cognitive performance are altered in male mice exposed to ⁴He ions, but that the response is task-dependent. Furthermore, the sensitive doses can vary within each task in a non-linear fashion. This highlights the importance of assessing the cognitive and behavioral effects of charged particle exposure with a variety of assays and at multiple doses, given the possibility that lower doses may be more damaging due to the absence of induced compensatory mechanisms at higher doses. Full article

(This article belongs to the Special Issue Advances and Challenges in Biomolecular Radiation Research)

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15 pages, 615 KiB

Open AccessReview

Human Cancer and Platelet Interaction, a Potential Therapeutic Target

by Shike Wang¹, Zhenyu Li² and Ren Xu^1,3,*

¹ Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA

² Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, University of Kentucky, 741 South Limestone Street, Lexington, KY 40536, USA

³ Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, KY 40536, USA

Int. J. Mol. Sci. 2018, 19(4), 1246; https://doi.org/10.3390/ijms19041246 - 20 Apr 2018

Cited by 68 | Viewed by 8841

Abstract

Cancer patients experience a four-fold increase in thrombosis risk, indicating that cancer development and progression are associated with platelet activation. Xenograft experiments and transgenic mouse models further demonstrate that platelet activation and platelet-cancer cell interaction are crucial for cancer metastasis. Direct or indirect [...] Read more.

Cancer patients experience a four-fold increase in thrombosis risk, indicating that cancer development and progression are associated with platelet activation. Xenograft experiments and transgenic mouse models further demonstrate that platelet activation and platelet-cancer cell interaction are crucial for cancer metastasis. Direct or indirect interaction of platelets induces cancer cell plasticity and enhances survival and extravasation of circulating cancer cells during dissemination. In vivo and in vitro experiments also demonstrate that cancer cells induce platelet aggregation, suggesting that platelet-cancer interaction is bidirectional. Therefore, understanding how platelets crosstalk with cancer cells may identify potential strategies to inhibit cancer metastasis and to reduce cancer-related thrombosis. Here, we discuss the potential function of platelets in regulating cancer progression and summarize the factors and signaling pathways that mediate the cancer cell-platelet interaction. Full article

(This article belongs to the Special Issue Extracellular Matrix in Development and Disease)

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20 pages, 6074 KiB

Open AccessReview

NF-κB-Mediated Inflammation in the Pathogenesis of Intracranial Aneurysm and Subarachnoid Hemorrhage. Does Autophagy Play a Role?

by Elzbieta Pawlowska¹

, Joanna Szczepanska², Karol Wisniewski³, Paulina Tokarz⁴, Dariusz J. Jaskólski³

and Janusz Blasiak^4,*

¹ Department of Orthodontics, Medical University of Lodz, 92-216 Lodz, Poland

² Department of Pediatric Dentistry, Medical University of Lodz, 92-216 Lodz, Poland

³ Department of Neurosurgery and Neurooncology, Medical University of Lodz, Barlicki University Hospital, Kopcinskiego 22, 90-153 Lodz, Poland

⁴ Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, 90-236 Lodz, Poland

Int. J. Mol. Sci. 2018, 19(4), 1245; https://doi.org/10.3390/ijms19041245 - 19 Apr 2018

Cited by 65 | Viewed by 7593

Abstract

The rupture of saccular intracranial aneurysms (IA) is the commonest cause of non-traumatic subarachnoid hemorrhage (SAH)—the most serious form of stroke with a high mortality rate. Aneurysm walls are usually characterized by an active inflammatory response, and NF-κB (nuclear factor kappa-light-chain-enhancer of activated [...] Read more.

The rupture of saccular intracranial aneurysms (IA) is the commonest cause of non-traumatic subarachnoid hemorrhage (SAH)—the most serious form of stroke with a high mortality rate. Aneurysm walls are usually characterized by an active inflammatory response, and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) has been identified as the main transcription factor regulating the induction of inflammation-related genes in IA lesions. This transcription factor has also been related to IA rupture and resulting SAH. We and others have shown that autophagy interacts with inflammation in many diseases, but there is no information of such interplay in IA. Moreover, NF-κB, which is a pivotal factor controlling inflammation, is regulated by autophagy-related proteins, and autophagy is regulated by NF-κB signaling. It was also shown that autophagy mediates the normal functioning of vessels, so its disturbance can be associated with vessel-related disorders. Early brain injury, delayed brain injury, and associated cerebral vasospasm are among the most serious consequences of IA rupture and are associated with impaired function of the autophagy–lysosomal system. Further studies on the role of the interplay between autophagy and NF-κB-mediated inflammation in IA can help to better understand IA pathogenesis and to identify IA patients with an increased SAH risk. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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24 pages, 41100 KiB

Open AccessArticle

Molecular Modeling Studies on Carbazole Carboxamide Based BTK Inhibitors Using Docking and Structure-Based 3D-QSAR

by Rui Li¹, Yongli Du^1,*, Zhipei Gao¹ and Jingkang Shen²

¹ School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology (Shandong Academy of Sciences), 3501 Daxue Road, Jinan 250353, China

² State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China

Int. J. Mol. Sci. 2018, 19(4), 1244; https://doi.org/10.3390/ijms19041244 - 19 Apr 2018

Cited by 8 | Viewed by 5454

Abstract

Rheumatoid arthritis (RA) is the second common rheumatic immune disease with chronic, invasive inflammatory characteristics. Non-steroidal anti-inflammatory drugs (NSAIDs), slow-acting anti-rheumatic drugs (SAARDs), or glucocorticoid drugs can improve RA patients’ symptoms, but fail to cure. Broton’s tyrosine kinase (BTK) inhibitors have been proven [...] Read more.

Rheumatoid arthritis (RA) is the second common rheumatic immune disease with chronic, invasive inflammatory characteristics. Non-steroidal anti-inflammatory drugs (NSAIDs), slow-acting anti-rheumatic drugs (SAARDs), or glucocorticoid drugs can improve RA patients’ symptoms, but fail to cure. Broton’s tyrosine kinase (BTK) inhibitors have been proven to be an efficacious target against autoimmune indications and B-cell malignancies. Among the current 11 clinical drugs, only BMS-986142, classified as a carbazole derivative, is used for treating RA. To design novel and highly potent carbazole inhibitors, molecular docking and three dimensional quantitative structure–activity relationship (3D-QSAR) were applied to explore a dataset of 132 new carbazole carboxamide derivatives. The established comparative molecular field analysis (CoMFA) (q² = 0.761, r² = 0.933) and comparative molecular similarity indices analysis (CoMSIA) (q² = 0.891, r² = 0.988) models obtained high predictive and satisfactory values. CoMFA/CoMSIA contour maps demonstrated that bulky substitutions and hydrogen-bond donors were preferred at R₁ and 1-position, respectively, and introducing hydrophilic substitutions at R₁ and R₄ was important for improving BTK inhibitory activities. These results will contribute to the design of novel and highly potent BTK inhibitors. Full article

(This article belongs to the Special Issue Computational Studies of Structure-Dynamics-Function Relationships in Biomolecules)

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19 pages, 6719 KiB

Open AccessArticle

4-Hydroxypiperidines and Their Flexible 3-(Amino)propyloxy Analogues as Non-Imidazole Histamine H₃ Receptor Antagonist: Further Structure–Activity Relationship Exploration and In Vitro and In Vivo Pharmacological Evaluation

by Beata Olszewska^1,*, Anna Stasiak², Daniel McNaught Flores³, Wiesława Agnieszka Fogel², Rob Leurs³ and Krzysztof Walczyński^1,*

¹ Department of Synthesis and Technology of Drugs, Medical University of Lodz, Muszyńskiego Street 1, 90-145 Łódź, Poland

² Department of Hormone Biochemistry, Medical University of Lodz, Żeligowskiego Street 7/9, 90-752 Łódź, Poland

³ Amsterdam Institute of Molecules, Medicines & Systems, Division of Medicinal Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands

Int. J. Mol. Sci. 2018, 19(4), 1243; https://doi.org/10.3390/ijms19041243 - 19 Apr 2018

Cited by 6 | Viewed by 4842

Abstract

Presynaptic histamine H₃ receptors (H₃R) act as auto- or heteroreceptors controlling, respectively, the release of histamine and of other neurotransmitters in the central nervous system (CNS). The extracellular levels of several neurotransmitters are enhanced by H₃R antagonists, and [...] Read more.

Presynaptic histamine H₃ receptors (H₃R) act as auto- or heteroreceptors controlling, respectively, the release of histamine and of other neurotransmitters in the central nervous system (CNS). The extracellular levels of several neurotransmitters are enhanced by H₃R antagonists, and there is a great interest for potent, brain-penetrating H₃ receptor antagonists/inverse agonists to compensate for the neurotransmitter deficits present in various neurological disorders. We have shown that 1-[(benzylfuran-2-yl)methyl]piperidinyl-4-oxyl- and benzyl- derivatives of N-propylpentan-1-amines exhibit high in vitro potencies toward the guinea pig H₃ receptor (jejunum), with pA₂ = 8.47 and 7.79, respectively (the reference compound used was thioperamide with pA₂ = 8.67). Furthermore, following the replacement of 4-hydroxypiperidine with a 3-(methylamino)propyloxy chain, the pA₂ value for the first group decreased, whereas it increased for the second group. Here, we present data on the impact of elongating the aliphatic chain between the nitrogen of 4-hydroxypiperidine or 3-(methylamino)propan-1-ol and the lipophilic residue. Additionally, the most active compound in this series of non-imidazole H₃ receptor antagonists/inverse agonists, i.e., ADS-003, was evaluated for its affinity to the recombinant rat and human histamine H₃ receptors transiently expressed in HEK-293T cells. It was shown that ADS-003, given parenterally for 5 days, reduced the food intake of rats, as well as changed histamine and noradrenaline concentrations in the rats’ brain in a manner and degree similar to the reference H₃ antagonist Ciproxifan. Full article

(This article belongs to the Section Molecular Toxicology)

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18 pages, 2070 KiB

Open AccessArticle

Proteomic Identification of the Galectin-1-Involved Molecular Pathways in Urinary Bladder Urothelial Carcinoma

by Chien-Feng Li^1,2,3

, Kun-Hung Shen⁴, Lan-Hsiang Chien⁵, Cheng-Hao Huang^1,†, Ting-Feng Wu^1,* and Hong-Lin He²

¹ Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan 710, Taiwan

² Departments of Pathology, Chi Mei Medical Center, Tainan 710, Taiwan

³ National Institute of Cancer Research, National Health Research Institutes, Miaoli 350, Taiwan

⁴ Department of Urology, Chi Mei Medical Center, Tainan 710, Taiwan

⁵ Department of Medical Research, Chi Mei Medical Center, Tainan 710, Taiwan

^† Current address: Nan Pao Resins Chemical Company Ltd., Tainan 710, Taiwan.

Int. J. Mol. Sci. 2018, 19(4), 1242; https://doi.org/10.3390/ijms19041242 - 19 Apr 2018

Cited by 8 | Viewed by 4492

Abstract

Among various heterogeneous types of bladder tumors, urothelial carcinoma is the most prevalent lesion. Some of the urinary bladder urothelial carcinomas (UBUCs) develop local recurrence and may cause distal invasion. Galectin-1 de-regulation significantly affects cell transformation, cell proliferation, angiogenesis, and cell invasiveness. In [...] Read more.

Among various heterogeneous types of bladder tumors, urothelial carcinoma is the most prevalent lesion. Some of the urinary bladder urothelial carcinomas (UBUCs) develop local recurrence and may cause distal invasion. Galectin-1 de-regulation significantly affects cell transformation, cell proliferation, angiogenesis, and cell invasiveness. In continuation of our previous investigation on the role of galectin-1 in UBUC tumorigenesis, in this study, proteomics strategies were implemented in order to find more galectin-1-associated signaling pathways. The results of this study showed that galectin-1 knockdown could induce 15 down-regulated proteins and two up-regulated proteins in T24 cells. These de-regulated proteins might participate in lipid/amino acid/energy metabolism, cytoskeleton, cell proliferation, cell-cell interaction, cell apoptosis, metastasis, and protein degradation. The aforementioned dys-regulated proteins were confirmed by western immunoblotting. Proteomics results were further translated to prognostic markers by analyses of biopsy samples. Results of cohort studies demonstrated that over-expressions of glutamine synthetase, alcohol dehydrogenase (NADP⁺), fatty acid binding protein 4, and toll interacting protein in clinical specimens were all significantly associated with galectin-1 up-regulation. Univariate analyses showed that de-regulations of glutamine synthetase and fatty acid binding protein 4 in clinical samples were respectively linked to disease-specific survival and metastasis-free survival. Full article

(This article belongs to the Special Issue Galectins in Cancer and Translational Medicine)

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14 pages, 3877 KiB

Open AccessReview

HIV Vaccination: A Roadmap among Advancements and Concerns

by Maria Trovato^1,2,*, Luciana D’Apice²

, Antonella Prisco³

and Piergiuseppe De Berardinis²

¹ INSERM u1016, Institut Cochin, 27 Rue du Faubourg Saint Jacques, 75014 Paris, France

² Institute of Protein Biochemistry, C.N.R., Via Pietro Castellino 111, 80131 Naples, Italy

³ Institute of Genetics and Biophysics A. Buzzati-Traverso, C.N.R., Via Pietro Castellino 111, 80131 Naples, Italy

Int. J. Mol. Sci. 2018, 19(4), 1241; https://doi.org/10.3390/ijms19041241 - 19 Apr 2018

Cited by 32 | Viewed by 8101

Abstract

Since the identification of the Human Immunodeficiency Virus type 1 (HIV-1) as the etiologic agent of AIDS (Acquired Immunodeficiency Syndrome), many efforts have been made to stop the AIDS pandemic. A major success of medical research has been the development of the highly [...] Read more.

Since the identification of the Human Immunodeficiency Virus type 1 (HIV-1) as the etiologic agent of AIDS (Acquired Immunodeficiency Syndrome), many efforts have been made to stop the AIDS pandemic. A major success of medical research has been the development of the highly active antiretroviral therapy and its availability to an increasing number of people worldwide, with a considerable effect on survival. However, a safe and effective vaccine able to prevent and eradicate the HIV pandemic is still lacking. Clinical trials and preclinical proof-of-concept studies in nonhuman primate (NHP) models have provided insights into potential correlates of protection against the HIV-1 infection, which include broadly neutralizing antibodies (bnAbs), non-neutralizing antibodies targeting the variable loops 1 and 2 (V1V2) regions of the HIV-1 envelope (Env), polyfunctional antibody, and Env-specific T-cell responses. In this review, we provide a brief overview of different HIV-1 vaccine approaches and discuss the current understanding of the cellular and humoral correlates of HIV-1 immunity. Full article

(This article belongs to the Special Issue New Advances in Human Vaccine)

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13 pages, 7367 KiB

Open AccessArticle

Activation of ER Stress-Dependent miR-216b Has a Critical Role in Salvia miltiorrhiza Ethanol-Extract-Induced Apoptosis in U266 and U937 Cells

by Changmin Kim^1,†, Hyo-Sook Song^2,†, Hojung Park^1,† and Bonglee Kim^1,*

¹ Department of Pathology, College of Korean Medicine, Graduate School, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Korea

² Department of Science in Korean Medicine, College of Korean Medicine, Graduate School, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2018, 19(4), 1240; https://doi.org/10.3390/ijms19041240 - 19 Apr 2018

Cited by 25 | Viewed by 9101

Abstract

Although Salvia miltiorrhiza has been reported to have anti-cancer mechanisms, such as caspase activation, cell cycle arrest, an anti-angiogenesis effect, and Bcl-2 family regulation, its underlying mechanism of endoplasmic reticulum (ER) stress-mediated apoptosis has never been demonstrated. Thus, in this current study, ER [...] Read more.

Although Salvia miltiorrhiza has been reported to have anti-cancer mechanisms, such as caspase activation, cell cycle arrest, an anti-angiogenesis effect, and Bcl-2 family regulation, its underlying mechanism of endoplasmic reticulum (ER) stress-mediated apoptosis has never been demonstrated. Thus, in this current study, ER stress-related apoptosis via miR-216b of the ethanol extract of Salvia miltiorrhiza (SM) is elucidated for the first time. SM treatment inhibited the viability of U266 and U937 cells in a concentration-dependent manner. However, SM-exposed Raw264.7 cells were intact compared to U266 or U937 cells. Treatment with SM significantly elevated the generation of reactive oxygen species (ROS). The anti-proliferative effect of SM was reversed by pretreatment with the ROS scavenger, N-acetyl-l-cysteine (NAC), compared to cells treated only with SM. Also, SM treatment increased the ER stress by elevation of phosphorylated activating transcription factor 4 (p-ATF4), phosphorylated eukaryotic Initiation Factor 2 (p-eIF2), and phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (p-PERK) expression. Caspase-3 and Poly (ADP-ribose) polymerase (PARP) were cleaved and CCAAT-enhancer-binding protein homologous protein (CHOP) was activated by SM treatment. PARP cleavage and CHOP activation were attenuated by NAC pretreatment. Furthermore, SM increased the tumor suppressor, miR-216b, and suppressed its target, c-Jun. miR-216b inhibitor attenuated the apoptotic effect of SM. Taken together, SM treatment induced apoptosis through regulation of miR-216b and ROS/ER stress pathways. SM could be a potential drug for treatment of multiple myeloma and myeloid leukemia. Full article

(This article belongs to the Special Issue Traditional Medicine – Unraveling Its Molecular Mechanism)

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14 pages, 15646 KiB

Open AccessArticle

Telomerase Inhibition by a New Synthetic Derivative of the Aporphine Alkaloid Boldine

by Sakineh Kazemi Noureini^1,*

, Mitra Kheirabadi^1,*, Fatima Masoumi^1,†, Farve Khosrogerdi^1,†, Younes Zarei^1,†, Cristian Suárez-Rozas²

, Julio Salas-Norambuena² and Bruce Kennedy Cassels^2,*

¹ Department of Biology, Faculty of Sciences, Hakim Sabzevari University, Sabzevar 9617976487, Iran

² Department of Chemistry, Faculty of Sciences, University of Chile, Santiago 1058, Chile

^† These authors had equal contributions in this study.

Int. J. Mol. Sci. 2018, 19(4), 1239; https://doi.org/10.3390/ijms19041239 - 19 Apr 2018

Cited by 16 | Viewed by 5708

Abstract

Telomerase, the enzyme responsible for cell immortality, is an important target in anti-cancer drug discovery. Boldine, an abundant aporphine alkaloid of Peumus boldus, is known to inhibit telomerase at non-toxic concentrations. Cytotoxicity of N-benzylsecoboldine hydrochloride (BSB), a synthetic derivative of boldine, [...] Read more.

Telomerase, the enzyme responsible for cell immortality, is an important target in anti-cancer drug discovery. Boldine, an abundant aporphine alkaloid of Peumus boldus, is known to inhibit telomerase at non-toxic concentrations. Cytotoxicity of N-benzylsecoboldine hydrochloride (BSB), a synthetic derivative of boldine, was determined using the MTT method in MCF7 and MDA-MB231 cells. Aliquots of cell lysates were incubated with various concentrations of BSB in qTRAP (quantitative telomere repeat amplification protocol)-ligand experiments before substrate elongation by telomerase or amplification by hot-start Taq polymerase. The crystal structure of TERT, the catalytic subunit of telomerase from Tribolium castaneum, was used for docking and molecular dynamics analysis. The qTRAP-ligand data gave an IC₅₀ value of about 0.17 ± 0.1 µM for BSB, roughly 400 times stronger than boldine, while the LD₅₀ in the cytotoxicity assays were 12.5 and 21.88 µM, respectively, in cells treated for 48 h. Although both compounds interacted well with the active site, MD analysis suggests a second binding site with which BSB interacts via two hydrogen bonds, much more strongly than boldine. Theoretical analyses also evaluated the IC₅₀ for BSB as submicromolar. BSB, with greater hydrophobicity and flexibility than boldine, represents a promising structure to inhibit telomerase at non-toxic concentrations. Full article

(This article belongs to the Special Issue Role of Telomeres and Telomerase in Cancer and Aging)

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11 pages, 3748 KiB

Open AccessArticle

PIN7 Auxin Carrier Has a Preferential Role in Terminating Radial Root Expansion in Arabidopsis thaliana

by Michel Ruiz Rosquete^†, Sascha Waidmann and Jürgen Kleine-Vehn^*

¹ Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences (BOKU), Vienna 1190, Austria

^† Current address: Department of Plant Sciences, University of California, Davis, CA 95616, USA.

Int. J. Mol. Sci. 2018, 19(4), 1238; https://doi.org/10.3390/ijms19041238 - 19 Apr 2018

Cited by 43 | Viewed by 8353

Abstract

Directional growth of lateral roots is critical for radial expansion and soil coverage. Despite its importance, almost nothing is known about its molecular determinants. Initially, young lateral roots (LRs) grow away from the parental root, maintaining the angle acquired shortly after emergence. A [...] Read more.

Directional growth of lateral roots is critical for radial expansion and soil coverage. Despite its importance, almost nothing is known about its molecular determinants. Initially, young lateral roots (LRs) grow away from the parental root, maintaining the angle acquired shortly after emergence. A second downwards bending response to gravity terminates the so-called plateau phase and thereby limits radial root expansion. Here, we show that the exit from the plateau phase correlates with an increase in auxin signalling at the tip of the LRs. Moreover, the increase in auxin levels induces the termination of the plateau phase, which requires PIN-FORMED (PIN) auxin efflux carriers. Our data suggests that the developmental increase in auxin triggers the preferential derepression of PIN7 in gravity-sensing columella cells. The subsequent polarization of PIN7 heralds the bending towards gravity and, hence, the exit from the plateau phase. This developmental framework reveals the distinct roles of PIN auxin efflux carriers in controlling the radial growth of root systems. Full article

(This article belongs to the Special Issue Auxin)

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26 pages, 434 KiB

Open AccessReview

Calcium and Nuclear Signaling in Prostate Cancer

by Ivan V. Maly and Wilma A. Hofmann^*

Department of Physiology and Biophysics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 955 Main Street, Buffalo, NY 14203, USA

Int. J. Mol. Sci. 2018, 19(4), 1237; https://doi.org/10.3390/ijms19041237 - 19 Apr 2018

Cited by 24 | Viewed by 7358

Abstract

Recently, there have been a number of developments in the fields of calcium and nuclear signaling that point to new avenues for a more effective diagnosis and treatment of prostate cancer. An example is the discovery of new classes of molecules involved in [...] Read more.

Recently, there have been a number of developments in the fields of calcium and nuclear signaling that point to new avenues for a more effective diagnosis and treatment of prostate cancer. An example is the discovery of new classes of molecules involved in calcium-regulated nuclear import and nuclear calcium signaling, from the G protein-coupled receptor (GPCR) and myosin families. This review surveys the new state of the calcium and nuclear signaling fields with the aim of identifying the unifying themes that hold out promise in the context of the problems presented by prostate cancer. Genomic perturbations, kinase cascades, developmental pathways, and channels and transporters are covered, with an emphasis on nuclear transport and functions. Special attention is paid to the molecular mechanisms behind prostate cancer progression to the malignant forms and the unfavorable response to anti-androgen treatment. The survey leads to some new hypotheses that connect heretofore disparate results and may present a translational interest. Full article

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

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17 pages, 3120 KiB

Open AccessArticle

CD9 and CD81 Interactions and Their Structural Modelling in Sperm Prior to Fertilization

by Michaela Frolikova¹, Pavla Manaskova-Postlerova^1,2, Jiri Cerny³

, Jana Jankovicova⁴

, Ondrej Simonik^1,2

, Alzbeta Pohlova^1,5, Petra Secova⁴, Jana Antalikova⁴

and Katerina Dvorakova-Hortova^1,6,*

¹ Group of Reproductive Biology, Institute of Biotechnology, Czech Academy of Sciences, v.v.i., BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic

² Department of Veterinary Sciences, Faculty of Agrobiology, Food and Natural Resources, University of Life Sciences Prague, Kamycka 129, 165 00 Prague, Czech Republic

³ Laboratory of Structural Bioinformatics of Proteins, Institute of Biotechnology Czech Academy of Sciences, v.v.i., BIOCEV, Prumyslova 595, 252 50 Vestec, Czech Republic

⁴ Laboratory of Reproductive Physiology, Institute of Animal Biochemistry and Genetics Centre of Biosciences Slovak Academy of Sciences, Dubravska Cesta 9, 845 05 Bratislava, Slovakia

⁵ Department of Biochemistry, Faculty of Science, Charles University, Hlavova 2030/8, 128 43 Prague, Czech Republic

⁶ Department of Zoology, Faculty of Science, Charles University, Vinicna 7, 128 44 Prague, Czech Republic

Int. J. Mol. Sci. 2018, 19(4), 1236; https://doi.org/10.3390/ijms19041236 - 19 Apr 2018

Cited by 38 | Viewed by 9285

Abstract

Proteins CD9 and CD81 are members of the tetraspanin superfamily and were detected in mammalian sperm, where they are suspected to form an active tetraspanin web and to participate in sperm–egg membrane fusion. The importance of these two proteins during the early stages [...] Read more.

Proteins CD9 and CD81 are members of the tetraspanin superfamily and were detected in mammalian sperm, where they are suspected to form an active tetraspanin web and to participate in sperm–egg membrane fusion. The importance of these two proteins during the early stages of fertilization is supported by the complete sterility of CD9/CD81 double null female mice. In this study, the putative mechanism of CD9/CD81 involvement in tetraspanin web formation in sperm and its activity prior to fertilization was addressed. Confocal microscopy and colocalization assay was used to determine a mutual CD9/CD81 localization visualised in detail by super-resolution microscopy, and their interaction was address by co-immunoprecipitation. The species-specific traits in CD9 and CD81 distribution during sperm maturation were compared between mice and humans. A mutual position of CD9/CD81 is shown in human spermatozoa in the acrosomal cap, however in mice, CD9 and CD81 occupy a distinct area. During the acrosome reaction in human sperm, only CD9 is relocated, compared to the relocation of both proteins in mice. The structural modelling of CD9 and CD81 homologous and possibly heterologous network formation was used to propose their lateral Cis as well as Trans interactions within the sperm membrane and during sperm–egg membrane fusion. Full article

(This article belongs to the Special Issue Membrane Fusion)

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18 pages, 2432 KiB

Open AccessArticle

Identification of the Candidate Proteins Related to Oleic Acid Accumulation during Peanut (Arachis hypogaea L.) Seed Development through Comparative Proteome Analysis

by Hao Liu^1,†, Haifen Li^1,†, Jianzhong Gu², Li Deng², Li Ren², Yanbin Hong¹, Qing Lu¹, Xiaoping Chen^1,* and Xuanqiang Liang^1,*

¹ Crops Research Institute, Guangdong Academy of Agricultural Sciences, South China Peanut Sub-Center of National Center of Oilseed Crops Improvement, Guangdong Provincial Key Laboratory of Crop Genetic Improvement, Guangzhou 510640, China

² Peanut Research Institute, Kaifeng Academy of Agricultural Sciences, Kaifeng 475004, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2018, 19(4), 1235; https://doi.org/10.3390/ijms19041235 - 18 Apr 2018

Cited by 32 | Viewed by 5401

Abstract

Peanuts (Arachis hypogaea L.) are an important oilseed crop, containing high contents of protein and fatty acids (FA). The major components of FA found in peanut oil are unsaturated FAs, including oleic acid (OA, C18:1) and linoleic acid (LOA, C18:2). Moreover, the [...] Read more.

Peanuts (Arachis hypogaea L.) are an important oilseed crop, containing high contents of protein and fatty acids (FA). The major components of FA found in peanut oil are unsaturated FAs, including oleic acid (OA, C18:1) and linoleic acid (LOA, C18:2). Moreover, the high content of OA in peanut oil is beneficial for human health and long-term storage due to its antioxidant activity. However, the dynamic changes in proteomics related to OA accumulation during seed development still remain largely unexplored. In the present study, a comparative proteome analysis based on iTRAQ (isobaric Tags for Relative and Absolute Quantification) was performed to identify the critical candidate factors involved in OA formation. A total of 389 differentially expressed proteins (DEPs) were identified between high-oleate cultivar Kainong176 and low-oleate cultivar Kainong70. Among these DEPs, 201 and 188 proteins were upregulated and downregulated, respectively. In addition, these DEPs were categorized into biosynthesis pathways of unsaturated FAs at the early stage during the high-oleic peanut seed development, and several DEPs involved in lipid oxidation pathway were found at the stage of seed maturation. Meanwhile, 28 DEPs were sporadically distributed in distinct stages of seed formation, and their molecular functions were directly correlated to FA biosynthesis and degradation. Fortunately, the expression of FAB2 (stearoyl-acyl carrier protein desaturase), the rate-limiting enzyme in the upstream biosynthesis process of OA, was significantly increased in the early stage and then decreased in the late stage of seed development in the high-oleate cultivar Kainong176. Furthermore, real-time PCR verified the expression pattern of FAB2 at the mRNA level, which was consistent with its protein abundance. However, opposite results were found for the low-oleate cultivar Kainong70. Overall, the comparative proteome analysis provided valuable insight into the molecular dynamics of OA accumulation during peanut seed development. Full article

(This article belongs to the Section Molecular Plant Sciences)

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