International Journal of Molecular Sciences

21 pages, 38205 KiB

Open AccessArticle

The Peroxisome Proliferator-Activated Receptor α (PPARα) Agonist Pemafibrate Protects against Diet-Induced Obesity in Mice

by Masaya Araki¹, Yoshimi Nakagawa^1,2,*

, Asayo Oishi¹, Song-iee Han¹, Yunong Wang¹, Kae Kumagai¹, Hiroshi Ohno¹, Yuhei Mizunoe¹, Hitoshi Iwasaki¹, Motohiro Sekiya¹, Takashi Matsuzaka¹ and Hitoshi Shimano^1,2,3,4,*

¹ Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan

² International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan

³ Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan

⁴ Japan Agency for Medical Research and Development–Core Research for Evolutional Science and Technology (AMED-CREST), Chiyoda-ku, Tokyo 100-1004, Japan

Int. J. Mol. Sci. 2018, 19(7), 2148; https://doi.org/10.3390/ijms19072148 - 23 Jul 2018

Cited by 63 | Viewed by 9675

Abstract

Peroxisome proliferator-activated receptor α (PPARα) is a therapeutic target for hyperlipidemia. Pemafibrate (K-877) is a new selective PPARα modulator activating PPARα transcriptional activity. To determine the effects of pemafibrate on diet-induced obesity, wild-type mice were fed a high-fat diet (HFD) containing pemafibrate for [...] Read more.

Peroxisome proliferator-activated receptor α (PPARα) is a therapeutic target for hyperlipidemia. Pemafibrate (K-877) is a new selective PPARα modulator activating PPARα transcriptional activity. To determine the effects of pemafibrate on diet-induced obesity, wild-type mice were fed a high-fat diet (HFD) containing pemafibrate for 12 weeks. Like fenofibrate, pemafibrate significantly suppressed HFD-induced body weight gain; decreased plasma glucose, insulin and triglyceride (TG) levels; and increased plasma fibroblast growth factor 21 (FGF21). However, compared to the dose of fenofibrate, a relatively low dose of pemafibrate showed these effects. Pemafibrate activated PPARα transcriptional activity in the liver, increasing both hepatic expression and plasma levels of FGF21. Additionally, pemafibrate increased the expression of genes involved in thermogenesis and fatty acid oxidation, including Ucp1, Cidea and Cpt1b in inguinal adipose tissue (iWAT) and the mitochondrial marker Elovl3 in brown adipose tissue (BAT). Therefore, pemafibrate activates thermogenesis in iWAT and BAT by increasing plasma levels of FGF21. Additionally, pemafibrate induced the expression of Atgl and Hsl in epididymal white adipose tissue, leading to the activation of lipolysis. Taken together, pemafibrate suppresses diet-induced obesity in mice and improves their obesity-related metabolic abnormalities. We propose that pemafibrate may be useful for the suppression and improvement of obesity-induced metabolic abnormalities. Full article

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

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16 pages, 1240 KiB

Open AccessReview

Involvement of Melatonin in the Regulation of the Circadian System in Crayfish

by Leonor Mendoza-Vargas¹, Elizabeth Guarneros-Bañuelos², Armida Báez-Saldaña³

, Fabiola Galicia-Mendoza¹, Edgar Flores-Soto⁴, Beatriz Fuentes-Pardo⁵, Ramón Alvarado⁵, Marcela Valdés-Tovar⁶, Bettina Sommer⁷, Gloria Benítez-King⁶

and Héctor Solís-Chagoyán^6,*

¹ Departamento El Hombre y su Ambiente, Universidad Autónoma Metropolitana-Xochimilco (UAM-Xochimilco), 04960 Ciudad de México, Mexico

² Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, 11340 Ciudad de México, Mexico

³ Departamento de Biología Celular, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510 Ciudad de México, Mexico

⁴ Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510 Ciudad de México, Mexico

⁵ Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510 Ciudad de México, Mexico

⁶ Laboratorio de Neurofarmacología, Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz, 14370 Ciudad de México, Mexico

⁷ Departamento de Investigación en Hiperreactividad Bronquial, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, 14080 Ciudad de México, Mexico

Int. J. Mol. Sci. 2018, 19(7), 2147; https://doi.org/10.3390/ijms19072147 - 23 Jul 2018

Cited by 4 | Viewed by 5150

Abstract

Melatonin (MEL) is an ancient molecule, broadly distributed in nature from unicellular to multicellular species. MEL is an indoleamine that acts on a wide variety of cellular targets regulating different physiological functions. This review is focused on the role played by this molecule [...] Read more.

Melatonin (MEL) is an ancient molecule, broadly distributed in nature from unicellular to multicellular species. MEL is an indoleamine that acts on a wide variety of cellular targets regulating different physiological functions. This review is focused on the role played by this molecule in the regulation of the circadian rhythms in crayfish. In these species, information about internal and external time progression might be transmitted by the periodical release of MEL and other endocrine signals acting through the pacemaker. We describe documented and original evidence in support of this hypothesis that also suggests that the rhythmic release of MEL contributes to the reinforcement of the temporal organization of nocturnal or diurnal circadian oscillators. Finally, we discuss how MEL might coordinate functions that converge in the performance of complex behaviors, such as the agonistic responses to establish social dominance status in Procambarus clarkii and the burrowing behavior in the secondary digging crayfish P. acanthophorus. Full article

(This article belongs to the Special Issue Melatonin from an Antioxidant to a Classic Hormone or a Tissue Factor: Experimental and Clinical Aspects 2018)

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18 pages, 533 KiB

Open AccessReview

Cartilage Regeneration in Humans with Adipose Tissue-Derived Stem Cells and Adipose Stromal Vascular Fraction Cells: Updated Status

by Jaewoo Pak^1,†, Jung Hun Lee^2,†, Natalie Pak¹, Yoon Pak³, Kwang Seung Park², Jeong Ho Jeon², Byeong Chul Jeong² and Sang Hee Lee^2,*

¹ Mipro Medical Clinic, 32-3 Chungdamdong, Gangnamgu, Seoul 06068, Korea

² National Leading Research Laboratory, Department of Biological Sciences, Myongji University, 116 Myongjiro, Yongin, Gyeonggido 17058, Korea

³ First Medical Center, 11841 South St., Cerritos, CA 90703, USA

^† These two authors contributed equally to this work.

Int. J. Mol. Sci. 2018, 19(7), 2146; https://doi.org/10.3390/ijms19072146 - 23 Jul 2018

Cited by 75 | Viewed by 10942

Abstract

Adipose tissue-derived stem cells (ASCs) in the form of stromal vascular fraction (SVF) and cultured expansion have been applied in clinical settings in some countries to treat osteoarthritis (OA) of knees, one of the most common debilitating, incurable disorders. Since the first report [...] Read more.

Adipose tissue-derived stem cells (ASCs) in the form of stromal vascular fraction (SVF) and cultured expansion have been applied in clinical settings in some countries to treat osteoarthritis (OA) of knees, one of the most common debilitating, incurable disorders. Since the first report of successful cartilage-like tissue regeneration with autologous adipose SVF containing ASCs, there has been a gradual increase in the number of publications confirming such results. Thus far, most of the reports have been limited to treatments of OA of knees. Recently, successful applications of adipose SVF in treating OA of ankles and hips have been reported. In addition, several groups have reported modified methods of applying adipose SVF, such as combining bone marrow stimulation with adipose SVF or adding additional extracellular matrix (ECM) in treating OA. Here, we present an updated, systematic review of clinical effectiveness and safety in treating OA of knees, ankles, and one hip since 2016 using ASCs in the form of adipose SVF or in cultured expansion, along with a description and suggestion of potential biological mechanisms of cartilage regeneration. Full article

(This article belongs to the Special Issue Biological Basis of Musculoskeletal Regeneration)

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24 pages, 2914 KiB

Open AccessArticle

Early Transcriptomic Response to Phosphate Deprivation in Soybean Leaves as Revealed by RNA-Sequencing

by Houqing Zeng^1,*, Xiajun Zhang¹, Xin Zhang¹, Erxu Pi¹, Liang Xiao² and Yiyong Zhu^2,*

¹ College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China

² College of Resources and Environmental Sciences, Nanjing Agricultural University, Nanjing 210095, China

Int. J. Mol. Sci. 2018, 19(7), 2145; https://doi.org/10.3390/ijms19072145 - 23 Jul 2018

Cited by 23 | Viewed by 5868

Abstract

Low phosphate (Pi) availability is an important limiting factor affecting soybean production. However, the underlying molecular mechanisms responsible for low Pi stress response and tolerance remain largely unknown, especially for the early signaling events under low Pi stress. Here, a genome-wide transcriptomic analysis [...] Read more.

Low phosphate (Pi) availability is an important limiting factor affecting soybean production. However, the underlying molecular mechanisms responsible for low Pi stress response and tolerance remain largely unknown, especially for the early signaling events under low Pi stress. Here, a genome-wide transcriptomic analysis in soybean leaves treated with a short-term Pi-deprivation (24 h) was performed through high-throughput RNA sequencing (RNA-seq) technology. A total of 533 loci were found to be differentially expressed in response to Pi deprivation, including 36 mis-annotated loci and 32 novel loci. Among the differentially expressed genes (DEGs), 303 were induced and 230 were repressed by Pi deprivation. To validate the reliability of the RNA-seq data, 18 DEGs were randomly selected and analyzed by quantitative RT-PCR (reverse transcription polymerase chain reaction), which exhibited similar fold changes with RNA-seq. Enrichment analyses showed that 29 GO (Gene Ontology) terms and 8 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways were significantly enriched in the up-regulated DEGs and 25 GO terms and 16 KEGG pathways were significantly enriched in the down-regulated DEGs. Some DEGs potentially involved in Pi sensing and signaling were up-regulated by short-term Pi deprivation, including five SPX-containing genes. Some DEGs possibly associated with water and nutrient uptake, hormonal and calcium signaling, protein phosphorylation and dephosphorylation and cell wall modification were affected at the early stage of Pi deprivation. The cis-elements of PHO (phosphatase) element, PHO-like element and P responsive element were present more frequently in promoter regions of up-regulated DEGs compared to that of randomly-selected genes in the soybean genome. Our transcriptomic data showed an intricate network containing transporters, transcription factors, kinases and phosphatases, hormone and calcium signaling components is involved in plant responses to early Pi deprivation. Full article

(This article belongs to the Special Issue Ion Transporters and Abiotic Stress Tolerance in Plants)

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17 pages, 11365 KiB

Open AccessReview

Dynamic DNA Methylation in Plant Growth and Development

by Arthur Bartels^1,†, Qiang Han^1,†

, Pooja Nair^1,‡, Liam Stacey¹, Hannah Gaynier¹, Matthew Mosley¹, Qi Qing Huang¹, Jacob K. Pearson¹

, Tzung-Fu Hsieh^2,3, Yong-Qiang Charles An⁴ and Wenyan Xiao^1,*

¹ Department of Biology, Saint Louis University, St. Louis, MO 63103, USA

² Department of Plant and Microbial Biology, North Carolina State University, Raleigh, NC 27695, USA

³ Plants for Human Health Institute, North Carolina State University, North Carolina Research Campus, Kannapolis, NC 28081, USA

⁴ Plant Genetics Research Unit, Donald Danforth Plant Science Center, Midwest Area, Agricultural Research Service, US Department of Agriculture, St. Louis, MO 63132, USA

^† These authors contributed equally to this work.

^‡ Current address: School of Medicine, University of Missouri at Columbia, Columbia, MO 65203, USA.

Int. J. Mol. Sci. 2018, 19(7), 2144; https://doi.org/10.3390/ijms19072144 - 23 Jul 2018

Cited by 216 | Viewed by 14514

Abstract

DNA methylation is an epigenetic modification required for transposable element (TE) silencing, genome stability, and genomic imprinting. Although DNA methylation has been intensively studied, the dynamic nature of methylation among different species has just begun to be understood. Here we summarize the recent [...] Read more.

DNA methylation is an epigenetic modification required for transposable element (TE) silencing, genome stability, and genomic imprinting. Although DNA methylation has been intensively studied, the dynamic nature of methylation among different species has just begun to be understood. Here we summarize the recent progress in research on the wide variation of DNA methylation in different plants, organs, tissues, and cells; dynamic changes of methylation are also reported during plant growth and development as well as changes in response to environmental stresses. Overall DNA methylation is quite diverse among species, and it occurs in CG, CHG, and CHH (H = A, C, or T) contexts of genes and TEs in angiosperms. Moderately expressed genes are most likely methylated in gene bodies. Methylation levels decrease significantly just upstream of the transcription start site and around transcription termination sites; its levels in the promoter are inversely correlated with the expression of some genes in plants. Methylation can be altered by different environmental stimuli such as pathogens and abiotic stresses. It is likely that methylation existed in the common eukaryotic ancestor before fungi, plants and animals diverged during evolution. In summary, DNA methylation patterns in angiosperms are complex, dynamic, and an integral part of genome diversity after millions of years of evolution. Full article

(This article belongs to the Special Issue DNA Methylation)

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38 pages, 7731 KiB

Open AccessReview

A History of the Pharmacological Treatment of Bipolar Disorder

by Francisco López-Muñoz^1,2,3,4,*

, Winston W. Shen⁵, Pilar D’Ocon⁶, Alejandro Romero⁷

and Cecilio Álamo⁸

¹ Faculty of Health Sciences, University Camilo José Cela, C/Castillo de Alarcón 49, 28692 Villanueva de la Cañada, Madrid, Spain

² Neuropsychopharmacology Unit, Hospital 12 de Octubre Research Institute (i+12), Avda. Córdoba, s/n, 28041 Madrid, Spain

³ Portucalense Institute of Neuropsychology and Cognitive and Behavioural Neurosciences (INPP), Portucalense University, R. Dr. António Bernardino de Almeida 541, 4200-072 Porto, Portugal

⁴ Thematic Network for Cooperative Health Research (RETICS), Addictive Disorders Network, Health Institute Carlos III, MICINN and FEDER, 28029 Madrid, Spain

⁵ Departments of Psychiatry, Wan Fang Medical Center and School of Medicine, Taipei Medical University, 111 Hsin Long Road Section 3, Taipei 116, Taiwan

⁶ Department of Pharmacology, Faculty of Pharmacy, University of Valencia, Avda. Vicente Andrés, s/n, 46100 Burjassot, Valencia, Spain

⁷ Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Complutense University, Avda. Puerta de Hierro, s/n, 28040 Madrid, Spain

⁸ Department of Biomedical Sciences (Pharmacology Area), Faculty of Medicine and Health Sciences, University of Alcalá, Crta. de Madrid-Barcelona, Km. 33,600, 28871 Alcalá de Henares, Madrid, Spain

Int. J. Mol. Sci. 2018, 19(7), 2143; https://doi.org/10.3390/ijms19072143 - 23 Jul 2018

Cited by 90 | Viewed by 30701

Abstract

In this paper, the authors review the history of the pharmacological treatment of bipolar disorder, from the first nonspecific sedative agents introduced in the 19th and early 20th century, such as solanaceae alkaloids, bromides and barbiturates, to John Cade’s experiments with lithium and [...] Read more.

In this paper, the authors review the history of the pharmacological treatment of bipolar disorder, from the first nonspecific sedative agents introduced in the 19th and early 20th century, such as solanaceae alkaloids, bromides and barbiturates, to John Cade’s experiments with lithium and the beginning of the so-called “Psychopharmacological Revolution” in the 1950s. We also describe the clinical studies and development processes, enabling the therapeutic introduction of pharmacological agents currently available for the treatment of bipolar disorder in its different phases and manifestations. Those drugs include lithium salts, valproic acid, carbamazepine, new antiepileptic drugs, basically lamotrigine and atypical antipsychotic agents (olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, asenapine, cariprazine and lurasidone). Finally, the socio-sanitary implications derived from the clinical introduction of these drugs are also discussed. Full article

(This article belongs to the Special Issue Antidepressants and Mood Stabilizers: Novel Research Avenues and Recent Evidence-Based Clinical Insights)

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18 pages, 478 KiB

Open AccessReview

Colletotrichum higginsianum as a Model for Understanding Host–Pathogen Interactions: A Review

by Yaqin Yan¹

, Qinfeng Yuan¹, Jintian Tang¹, Junbin Huang¹, Tom Hsiang²

, Yangdou Wei³ and Lu Zheng^1,*

¹ The Key Lab of Plant Pathology of Hubei Province, Huazhong Agricultural University, Wuhan 430070, China

² School of Environmental Sciences, University of Guelph, Guelph, ON N1G 2W1, Canada

³ Department of Biology, University of Saskatchewan, Saskatoon, SK S7N 5E2, Canada

Int. J. Mol. Sci. 2018, 19(7), 2142; https://doi.org/10.3390/ijms19072142 - 23 Jul 2018

Cited by 60 | Viewed by 9362

Abstract

Colletotrichum higginsianum is a hemibiotrophic ascomycetous fungus that causes economically important anthracnose diseases on numerous monocot and dicot crops worldwide. As a model pathosystem, the Colletotrichum–Arabidopsis interaction has the significant advantage that both organisms can be manipulated genetically. The goal of this review [...] Read more.

Colletotrichum higginsianum is a hemibiotrophic ascomycetous fungus that causes economically important anthracnose diseases on numerous monocot and dicot crops worldwide. As a model pathosystem, the Colletotrichum–Arabidopsis interaction has the significant advantage that both organisms can be manipulated genetically. The goal of this review is to provide an overview of the system and to point out recent significant studies that update our understanding of the pathogenesis of C. higginsianum and resistance mechanisms of Arabidopsis against this hemibiotrophic fungus. The genome sequence of C. higginsianum has provided insights into how genome structure and pathogen genetic variability has been shaped by transposable elements, and allows systematic approaches to longstanding areas of investigation, including infection structure differentiation and fungal–plant interactions. The Arabidopsis-Colletotrichum pathosystem provides an integrated system, with extensive information on the host plant and availability of genomes for both partners, to illustrate many of the important concepts governing fungal–plant interactions, and to serve as an excellent starting point for broad perspectives into issues in plant pathology. Full article

(This article belongs to the Special Issue Plant–Fungal Interactions)

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16 pages, 352 KiB

Open AccessArticle

Assembly Mechanism for Aggregation of Amyloid Fibrils

by Lingyun Zhang

Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China

Int. J. Mol. Sci. 2018, 19(7), 2141; https://doi.org/10.3390/ijms19072141 - 23 Jul 2018

Cited by 3 | Viewed by 3819

Abstract

The assembly mechanism for aggregation of amyloid fibril is important and fundamental for any quantitative and physical descriptions because it needs to have a deep understanding of both molecular and statistical physics. A theoretical model with three states including coil, helix and sheet [...] Read more.

The assembly mechanism for aggregation of amyloid fibril is important and fundamental for any quantitative and physical descriptions because it needs to have a deep understanding of both molecular and statistical physics. A theoretical model with three states including coil, helix and sheet is presented to describe the amyloid formation. The corresponding general mathematical expression of N molecule systems are derived, including the partition function and thermodynamic quantities. We study the equilibrium properties of the system in the solution and find that three molecules have the extreme value of free energy. The denaturant effect on molecular assemble is also discussed. Furthermore, we apply the kinetic theories to take account of the nucleation and growth of the amyloid in the solution. It has been shown that our theoretical results can be compared with experimental results. Full article

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

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16 pages, 5392 KiB

Open AccessArticle

Effects and Mechanism of Nano-Copper Exposure on Hepatic Cytochrome P450 Enzymes in Rats

by Huaqiao Tang¹, Min Xu¹, Fei Shi¹, Gang Ye¹, Cheng Lv¹, Jie Luo^1,2, Ling Zhao¹ and Yinglun Li^1,*

¹ Department of Pharmacy, School of Animal Medicine, Sichuan Agricultural University, Chengdu 611130, China

² School of Medicine, Tongren Polytechnic College, Guizhou 554300, China

Int. J. Mol. Sci. 2018, 19(7), 2140; https://doi.org/10.3390/ijms19072140 - 23 Jul 2018

Cited by 62 | Viewed by 6045

Abstract

Although nano-copper is currently used extensively, the adverse effects on liver cytochrome P450 (CYP450) enzymes after oral exposure are not clear. In this study, we determined the effects and mechanisms of action of nano- and micro-copper on the expression and activity of CYP450 [...] Read more.

Although nano-copper is currently used extensively, the adverse effects on liver cytochrome P450 (CYP450) enzymes after oral exposure are not clear. In this study, we determined the effects and mechanisms of action of nano- and micro-copper on the expression and activity of CYP450 enzymes in rat liver. Rats were orally exposed to micro-copper (400 mg/kg), Cu ion (100 mg/kg), or nano-copper (100, 200 and 400 mg/kg) daily for seven consecutive days. Histopathological, inflammatory and oxidative stress were measured in the livers of all rats. The mRNA levels and activity of CYP450 enzymes, as well as the mRNA levels of select nuclear receptors, were determined. Exposure to nano-copper (400 mg/kg) induced significant oxidative stress and inflammation relative to the controls, indicated by increased levels of interleukin (IL)-2, IL-6, interferon (IFN)-γ, macrophage inflammatory protein (MIP-1), total antioxidant capacity (T-AOC), malondialdehyde (MDA), inducible nitric oxide synthase (iNOS) and nitric oxide (NO) after exposure. The levels of mRNA expression of pregnane X receptor (PXR), constitutive androstane receptor (CAR) and aryl hydrocarbon receptor (AHR) were significantly decreased in 400 mg/kg nano-copper treated rats. Nano-copper activated the expression of the NF-kappa B (NF-κB), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription (STAT)3 signaling pathways. Nano-copper decreased the mRNA expression and activity of CYP 1A2, 2C11, 2D6, 2E1 and 3A4 in a dose-dependent manner. The adverse effects of micro-copper are less severe than those of nano-copper on the CYP450 enzymes of rats after oral exposure. Ingestion of large amounts of nano-copper in animals severely affects the drug metabolism of the liver by inhibiting the expression of various CYP450 enzymes, which increases the risk of drug-drug interactions in animals. Full article

(This article belongs to the Section Molecular Toxicology)

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13 pages, 1098 KiB

Open AccessReview

The Role of Na/K-ATPase Signaling in Oxidative Stress Related to Aging: Implications in Obesity and Cardiovascular Disease

by David E. Bartlett^1,†, Richard B. Miller^1,†, Scott Thiesfeldt^1,†, Hari Vishal Lakhani^1,†, Joseph I. Shapiro¹ and Komal Sodhi^2,*

¹ Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA

² Department of Surgery and Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2018, 19(7), 2139; https://doi.org/10.3390/ijms19072139 - 23 Jul 2018

Cited by 44 | Viewed by 6411

Abstract

Aging has been associated with a series of pathophysiological processes causing general decline in the overall health of the afflicted population. The cumulative line of evidence suggests an important role of oxidative stress in the development and progression of the aging process and [...] Read more.

Aging has been associated with a series of pathophysiological processes causing general decline in the overall health of the afflicted population. The cumulative line of evidence suggests an important role of oxidative stress in the development and progression of the aging process and metabolic abnormalities, exacerbating adipocyte dysfunction, cardiovascular diseases, and associated complications at the same time. In recent years, robust have established the implication of Na/K-ATPase signaling in causing oxidative stress and alterations in cellular mechanisms, in addition to its distinct pumping function. Understanding the underlying molecular mechanisms and exploring the possible sources of pro-oxidants may allow for developing therapeutic targets in these processes and formulate novel intervention strategies for patients susceptible to aging and associated complications, such as obesity and cardiovascular disease. The attenuation of oxidative stress with targeted treatment options can improve patient outcomes and significantly reduce economic burden. Full article

(This article belongs to the Special Issue The 20th Anniversary of the Discovery of the Scaffolding Function of the Sodium Pump by Dr. Zijian Xie)

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13 pages, 2453 KiB

Open AccessArticle

Involvement of Endocytosis in the Transdermal Penetration Mechanism of Ketoprofen Nanoparticles

by Noriaki Nagai^1,*, Fumihiko Ogata¹, Miyu Ishii¹, Yuya Fukuoka¹, Hiroko Otake¹, Yosuke Nakazawa² and Naohito Kawasaki¹

¹ Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka, Osaka 577-8502, Japan

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

Int. J. Mol. Sci. 2018, 19(7), 2138; https://doi.org/10.3390/ijms19072138 - 23 Jul 2018

Cited by 35 | Viewed by 6790

Abstract

We previously designed a novel transdermal formulation containing ketoprofen solid nanoparticles (KET-NPs formulation), and showed that the skin penetration from the KET-NPs formulation was higher than that of a transdermal formulation containing ketoprofen microparticles (KET-MPs formulation). However, the precise mechanism for the skin [...] Read more.

We previously designed a novel transdermal formulation containing ketoprofen solid nanoparticles (KET-NPs formulation), and showed that the skin penetration from the KET-NPs formulation was higher than that of a transdermal formulation containing ketoprofen microparticles (KET-MPs formulation). However, the precise mechanism for the skin penetration from the KET-NPs formulation was not clear. In this study we investigated whether energy-dependent endocytosis relates to the transdermal delivery from a 1.5% KET-NPs formulation. Transdermal formulations were prepared by a bead mill method using additives including methylcellulose and carbopol 934. The mean particle size of the ketoprofen nanoparticles was 98.3 nm. Four inhibitors of endocytosis dissolved in 0.5% DMSO (54 μM nystatin, a caveolae-mediated endocytosis inhibitor; 40 μM dynasore, a clathrin-mediated endocytosis inhibitor; 2 μM rottlerin, a macropinocytosis inhibitor; 10 μM cytochalasin D, a phagocytosis inhibitor) were used in this study. In the transdermal penetration study using a Franz diffusion cell, skin penetration through rat skin treated with cytochalasin D was similar to the control (DMSO) group. In contrast to the results for cytochalasin D, skin penetration from the KET-NPs formulation was significantly decreased by treatment with nystatin, dynasore or rottlerin with penetrated ketoprofen concentration-time curves (AUC) values 65%, 69% and 73% of control, respectively. Furthermore, multi-treatment with all three inhibitors (nystatin, dynasore and rottlerin) strongly suppressed the skin penetration from the KET-NPs formulation with an AUC value 13.4% that of the control. In conclusion, we found that caveolae-mediated endocytosis, clathrin-mediated endocytosis and macropinocytosis are all related to the skin penetration from the KET-NPs formulation. These findings provide significant information for the design of nanomedicines in transdermal formulations. Full article

(This article belongs to the Special Issue Bioactive Nanoparticles)

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18 pages, 1821 KiB

Open AccessArticle

Binding of Organometallic Ruthenium Anticancer Complexes to DNA: Thermodynamic Base and Sequence Selectivity

by Suyan Liu^1,2, Aihua Liang¹, Kui Wu^2,3,*

, Wenjuan Zeng^2,4, Qun Luo^2,4 and Fuyi Wang^2,4,*

¹ Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China

² Beijing National Laboratory for Molecular Sciences, National Centre for Mass Spectrometry in Beijing, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, CAS Research/Education Centre for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China

³ School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan 430081, China

⁴ University of Chinese Academy of Sciences, Beijing 100049, China

Int. J. Mol. Sci. 2018, 19(7), 2137; https://doi.org/10.3390/ijms19072137 - 23 Jul 2018

Cited by 12 | Viewed by 5205

Abstract

Organometallic ruthenium(II) complexes [(η⁶-arene)Ru(en)Cl][PF₆] (arene = benzene (1), p-cymene (2), indane (3), and biphenyl (4); en = ethylenediamine) are promising anticancer drug candidates both in vitro and in vivo. In [...] Read more.

Organometallic ruthenium(II) complexes [(η⁶-arene)Ru(en)Cl][PF₆] (arene = benzene (1), p-cymene (2), indane (3), and biphenyl (4); en = ethylenediamine) are promising anticancer drug candidates both in vitro and in vivo. In this paper, the interactions between ruthenium(II) complexes and 15-mer single- and double-stranded oligodeoxynucleotides (ODNs) were thermodynamically investigated using high performance liquid chromatography (HPLC) and electrospray ionization mass spectroscopy (ESI-MS). All of the complexes bind preferentially to G₈ on the single strand 5′-CTCTCTT₇G₈T₉CTTCTC-3′ (I), with complex 4 containing the most hydrophobic ligand as the most reactive one. To the analogs of I (changing T₇ and/or T₉ to A and/or C), complex 4 shows a decreasing affinity to the G₈ site in the following order: -AG₈T- (K: 5.74 × 10⁴ M⁻¹) > -CG₈C- > -TG₈A- > -AG₈A- > -AG₈C- > -TG₈T- (I) ≈ -CG₈A- (K: 2.81 × 10⁴ M⁻¹). In the complementary strand of I, the G bases in the middle region are favored for ruthenation over guanine (G) bases in the end of oligodeoxynucleotides (ODNs). These results indicate that both the flanking bases (or base sequences) and the arene ligands play important roles in determining the binding preference, and the base- and sequence-selectivity, of ruthenium complex in binding to the ODNs. Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA)

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9 pages, 1114 KiB

Open AccessArticle

Development of Convenient System for Detecting Yeast Cell Stress, Including That of Amyloid Beta

by Yen Nhi Luu and Ian Macreadie^*

School of Science, RMIT University, Bundoora, VIC 3083, Australia

Int. J. Mol. Sci. 2018, 19(7), 2136; https://doi.org/10.3390/ijms19072136 - 23 Jul 2018

Cited by 10 | Viewed by 4614

Abstract

(1) Background: As a model eukaryote, the study of stress responses in yeast can be employed for studying human health and disease, and the effects of various drugs that may impact health. “Reporting” of stress in yeast has frequently utilised enzymes like β-galactosidase [...] Read more.

(1) Background: As a model eukaryote, the study of stress responses in yeast can be employed for studying human health and disease, and the effects of various drugs that may impact health. “Reporting” of stress in yeast has frequently utilised enzymes like β-galactosidase that require laborious assays for quantitative results. The use of a stress reporter that can be measured quantitatively and with high sensitivity in living cells in a multi-well plate reader is a more desirable approach; (2) Methods: A multi-copy yeast-Escherichia coli shuttle plasmid containing the HSP42 promoter upstream of the mCherry reporter, along with the URA3 selectable marker was constructed and tested; (3) Results: Under certain stress conditions inducing the heat shock response, transformants containing the plasmid produced red fluorescence that could be readily quantitated in a microtitre plate reader. Stresses that produced red fluorescence included exposure to heat shock, copper ions, oligomeric amyloid beta (Aβ₄₂) and fibrillar Aβ₄₂; (4) Conclusions: Being able to conveniently and quantitatively monitor stresses in whole live populations of yeast offers great opportunities to screen compounds and conditions that cause stress, as well as conditions that alleviate stress. While freshly prepared oligomeric amyloid beta has previously been shown to exhibit high toxicity, fibrils have been generally considered to be non-toxic or of low toxicity. In this study, fibrillar amyloid beta has also been shown to induce stress. Full article

(This article belongs to the Special Issue Molecular Mechanism of Alzheimer's Disease)

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9 pages, 3924 KiB

Open AccessArticle

In Planta Preliminary Screening of ER Glycoprotein Folding Quality Control (ERQC) Modulators

by Lucia Marti¹, Andrea Lia¹, Ida-Barbara Reca¹, Pietro Roversi^2,3,*

, Angelo Santino^1,*

and Nicole Zitzmann^2,*

¹ Institute of Sciences of Food Production, C.N.R. Unit of Lecce, via Monteroni, I-73100 Lecce, Italy

² Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK

³ Leicester Institute of Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Henry Wellcome Building, Lancaster Road, Leicester LE1 7RH, UK

Int. J. Mol. Sci. 2018, 19(7), 2135; https://doi.org/10.3390/ijms19072135 - 23 Jul 2018

Cited by 6 | Viewed by 4684

Abstract

Small molecule modulators of the Endoplasmic Reticulum glycoprotein folding quality control (ERQC) machinery have broad-spectrum antiviral activity against a number of enveloped viruses and have the potential to rescue secretion of misfolded but active glycoproteins in rare diseases. In vivo assays of candidate [...] Read more.

Small molecule modulators of the Endoplasmic Reticulum glycoprotein folding quality control (ERQC) machinery have broad-spectrum antiviral activity against a number of enveloped viruses and have the potential to rescue secretion of misfolded but active glycoproteins in rare diseases. In vivo assays of candidate inhibitors in mammals are expensive and cannot be afforded at the preliminary stages of drug development programs. The strong conservation of the ERQC machinery across eukaryotes makes transgenic plants an attractive system for low-cost, easy and fast proof-of-concept screening of candidate ERQC inhibitors. The Arabidopsis thaliana immune response is mediated by glycoproteins, the folding of which is controlled by ERQC. We have used the plant response to bacterial peptides as a means of assaying an ERQC inhibitor in vivo. We show that the treatment of the plant with the iminosugar NB-DNJ, which is a known ER α-glucosidase inhibitor in mammals, influences the immune response of the plant to the bacterial peptide elf18 but not to the flagellin-derived flg22 peptide. In the NB-DNJ-treated plant, the responses to elf18 and flg22 treatments closely follow the ones observed for the ER α-glucosidase II impaired plant, At psl5-1. We propose Arabidopsis thaliana as a promising platform for the development of low-cost proof-of-concept in vivo ERQC modulation. Full article

(This article belongs to the Special Issue Glycosylation and Glycoproteins 2017)

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11 pages, 2651 KiB

Open AccessCommunication

Intrinsic Oncogenic Function of Intracellular Connexin26 Protein in Head and Neck Squamous Cell Carcinoma Cells

by Nobuko Iikawa^1,2, Yohei Yamamoto¹, Yohei Kawasaki², Aki Nishijima-Matsunobu¹, Maya Suzuki¹, Takechiyo Yamada² and Yasufumi Omori^1,*

¹ Department of Molecular and Tumour Pathology, Akita University Graduate School of Medicine, Akita 010-8543, Japan

² Department of Otorhinolaryngology and Head-and-Neck Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan

Int. J. Mol. Sci. 2018, 19(7), 2134; https://doi.org/10.3390/ijms19072134 - 23 Jul 2018

Cited by 8 | Viewed by 4258

Abstract

It has long been known that the gap junction is down-regulated in many tumours. One of the downregulation mechanisms is the translocation of connexin, a gap junction protein, from cell membrane into cytoplasm, nucleus, or Golgi apparatus. Interestingly, as tumours progress and reinforce [...] Read more.

It has long been known that the gap junction is down-regulated in many tumours. One of the downregulation mechanisms is the translocation of connexin, a gap junction protein, from cell membrane into cytoplasm, nucleus, or Golgi apparatus. Interestingly, as tumours progress and reinforce their malignant phenotype, the amount of aberrantly-localised connexin increases in different malignant tumours including oesophageal squamous cell carcinoma, thus suggesting that such an aberrantly-localised connexin should be oncogenic, although gap junctional connexins are often tumour-suppressive. To define the dual roles of connexin in head and neck squamous cell carcinoma (HNSCC), we introduced the wild-type connexin26 (wtCx26) or the mutant Cx26 (icCx26) gene, the product of which carries the amino acid sequence AKKFF, an endoplasmic reticulum-Golgi retention signal, at the C-terminus and is not sorted to cell membrane, into the human FaDu hypopharyngeal cancer cell line that had severely impaired the expression of connexin during carcinogenesis. wtCx26 protein was trafficked to the cell membrane and formed gap junction, which successfully exerted cell-cell communication. On the other hand, the icCx26 protein was co-localised with a Golgi marker, as revealed by immunofluorescence, and thus was retained on the way to the cell membrane. While the forced expression of wtCx26 suppressed both cell proliferation in vitro and tumorigenicity in mice in vivo, icCx26 significantly enhanced both cell proliferation and tumorigenicity compared with the mock control clones, indicating that an excessive accumulation of connexin protein in intracellular domains should be involved in cancer progression and that restoration of proper subcellular sorting of connexin might be a therapeutic strategy to control HNSCC. Full article

(This article belongs to the Special Issue Interplay of Connexins and Pannexins in Tissue Function and Disease)

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14 pages, 2255 KiB

Open AccessArticle

Neuroglobin Regulates Wnt/β-Catenin and NFκB Signaling Pathway through Dvl1

by Yu Xun^1,†

, Zhen Li^1,†, Yingxin Tang^1,†, Manjun Yang¹, Shengwen Long¹, Pan Shu¹, Jiabing Li¹, Ye Xiao¹, Fen Tang¹, Chenxi Wei¹, Ning Liu^1,2,* and Shuanglin Xiang^1,*

¹ Key Laboratory of Protein Chemistry and Development Biology of State Education Ministry of China, College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China

² College of Medicine, Hunan Normal University, Changsha 410013, Hunan, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2018, 19(7), 2133; https://doi.org/10.3390/ijms19072133 - 23 Jul 2018

Cited by 10 | Viewed by 4733

Abstract

Neuroglobin is an endogenous neuroprotective protein, but the underlying neuroprotective mechanisms remain to be elucidated. Our previous yeast two-hybrid screening study identified that Dishevelled-1, a key hub protein of Wnt/β-Catenin signaling, is an interaction partner of Neuroglobin. In this study, we further examined [...] Read more.

Neuroglobin is an endogenous neuroprotective protein, but the underlying neuroprotective mechanisms remain to be elucidated. Our previous yeast two-hybrid screening study identified that Dishevelled-1, a key hub protein of Wnt/β-Catenin signaling, is an interaction partner of Neuroglobin. In this study, we further examined the role of Neuroglobin in regulating Dishevelled-1 and the downstream Wnt/β-Catenin and NFκB signaling pathway. We found that Neuroglobin directly interacts with Dishevelled-1 by co-immunoprecipitation, and the two proteins are co-localized in both cytoplasma and nucleus of SK-N-SH cells. Moreover, the ectopic expression of Neuroglobin promotes the degradation of exogenous and endogenous Dishevelled-1 through the proteasomal degradation pathway. Furthermore, our results showed that Neuroglobin significantly inhibits the luciferase activity of Topflash reporter and the expression of β-Catenin mediated by Dishevelled-1 in SK-N-SH cells. In addition, we also documented that Neuroglobin enhances TNF-α-induced NFκB activation via down-regulating Dishevelled-1. Finally, 3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide (MTT) assays showed that Neuroglobin is an important neuroprotectant that protects SK-N-SH cells from TNF-α-induced decrease in cell viability. Taken together, these findings demonstrated that Neuroglobin functions as an important modulator of the Wnt/β-Catenin and NFκB signaling pathway through regulating Dishevelled-1. Full article

(This article belongs to the Section Biochemistry)

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17 pages, 2595 KiB

Open AccessArticle

Identification of Two Auxin-Regulated Potassium Transporters Involved in Seed Maturation

by Rubén Tenorio-Berrío^1,†, Marta-Marina Pérez-Alonso^1,†, Jesús Vicente-Carbajosa¹

, Leticia Martín-Torres¹, Ingo Dreyer^1,2

and Stephan Pollmann^1,*

¹ Centro de Biotecnología y Genómica de Plantas, Instituto Nacional de Investigación y Tecnología Agraria y Alimentación (INIA), Universidad Politécnica de Madrid (UPM), 28223 Pozuelo de Alarcón, Spain

² Centro de Bioinformática y Simulación Molecular (CBSM), Universidad de Talca, 2 Norte 685, 3460000 Talca, Chile

^† Those authors contributed equally to the work.

Int. J. Mol. Sci. 2018, 19(7), 2132; https://doi.org/10.3390/ijms19072132 - 22 Jul 2018

Cited by 22 | Viewed by 6752

Abstract

The seed is the most important plant reproductive unit responsible for the evolutionary success of flowering plants. Aside from its essential function in the sexual reproduction of plants, the seed also represents the most economically important agricultural product worldwide, providing energy, nutrients, and [...] Read more.

The seed is the most important plant reproductive unit responsible for the evolutionary success of flowering plants. Aside from its essential function in the sexual reproduction of plants, the seed also represents the most economically important agricultural product worldwide, providing energy, nutrients, and raw materials for human nutrition, livestock feed, and countless manufactured goods. Hence, improvements in seed quality or size are highly valuable, due to their economic potential in agriculture. Recently, the importance of indolic compounds in regulating these traits has been reported for Arabidopsis thaliana. The transcriptional and physiological mechanisms involved, however, remain largely undisclosed. Potassium transporters have been suggested as possible mediators of embryo cell size, controlling turgor pressure during seed maturation. In addition, it has been demonstrated that the expression of K⁺ transporters is effectively regulated by auxin. Here, we provide evidence for the identification of two Arabidopsis K⁺ transporters, HAK/KT12 (At1g60160) and KUP4 (At4g23640), that are likely to be implicated in determining seed size during seed maturation and, at the same time, show a differential regulation by indole-3-acetic acid and indole-3-acetamide. Full article

(This article belongs to the Special Issue Phytohormones and Their Crosstalk during Plant Growth, Development and Environmental Stress Adaptation)

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16 pages, 4009 KiB

Open AccessArticle

Genome-Wide Identification and Characterization of CIPK Family and Analysis Responses to Various Stresses in Apple (Malus domestica)

by Lili Niu^1,†, Biying Dong^2,†, Zhihua Song², Dong Meng^2,3,*

and Yujie Fu^1,2,3,*

¹ Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin 150040, China

² The College of Forestry, Beijing Forestry University, Beijing 100083, China

³ Beijing Advanced Innovation Center for Tree Breeding by Molecular Design, Beijing Forestry University, Beijing 100083, China

^† These authors contributed equally to the work.

Int. J. Mol. Sci. 2018, 19(7), 2131; https://doi.org/10.3390/ijms19072131 - 22 Jul 2018

Cited by 37 | Viewed by 6073

Abstract

In the CIPK family, the CBL-interacting protein kinases have shown crucial roles in hormone signaling transduction, and response to abiotic stress in plant developmental processes. The CIPK family is characterized by conserved NAF/FISL (Asn-Ala-Phe) and PPI (protein-phosphatase interaction) domains in the C-terminus. However, [...] Read more.

In the CIPK family, the CBL-interacting protein kinases have shown crucial roles in hormone signaling transduction, and response to abiotic stress in plant developmental processes. The CIPK family is characterized by conserved NAF/FISL (Asn-Ala-Phe) and PPI (protein-phosphatase interaction) domains in the C-terminus. However, little data has been reported about the CIPK family in apple. A total of 34 MdCIPK genes were identified from the apple genome in this study and were later divided into two groups according to the CIPK domains, characterized by gene structure and chromosomal distribution, and then mapped onto 17 chromosomes. All MdCIPK genes were expressed in the four apple tissues (leaf, root, flower, and fruit). In addition, the MdCIPK gene expression profile showed that five members among them revealed enhanced expression during the pollen tube growth stages. The MdCIPK4 was the most expressive during the entire fruit development stages. Under stress conditions 21 MdCIPK genes transcript levels were up-regulated in response to fungal and salt treatments. This suggested the possible features of these genes’ response to stresses in apples. Our findings provide a new insight about the roles of CIPK genes in apples, which could contribute to the cloning and functional analysis of CIPK genes in the future. Full article

(This article belongs to the Special Issue Ion Transporters and Abiotic Stress Tolerance in Plants)

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15 pages, 3103 KiB

Open AccessArticle

High-Content Screening of a Taiwanese Indigenous Plant Extract Library Identifies Syzygium simile leaf Extract as an Inhibitor of Fatty Acid Uptake

by Chia-Hung Yen^1,2,3,4,*

, Hsun-Shuo Chang^1,2,5, Tsai-Hsun Yang¹, Sheng-Fan Wang^2,4

, Ho-Cheng Wu¹, Yu-Chang Chen⁵, Kai-Jay Lin¹ and Sheena Wang¹

¹ Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan

² Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung 80708, Taiwan

³ Research Center for Natural Products & Drug Development, Kaohsiung Medical University, Kaohsiung 80708, Taiwan

⁴ Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan

⁵ School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan

Int. J. Mol. Sci. 2018, 19(7), 2130; https://doi.org/10.3390/ijms19072130 - 22 Jul 2018

Cited by 15 | Viewed by 5751

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease in the recent decades in both developed and developing countries, and is predicted to be the major etiology for liver transplantation in the next decade. Thus, pharmacological strategies to treat NAFLD [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease in the recent decades in both developed and developing countries, and is predicted to be the major etiology for liver transplantation in the next decade. Thus, pharmacological strategies to treat NAFLD are urgently needed. Natural products are considered an excellent source for drug discovery. By utilizing an image-based high-throughput screening with a library containing 3000 Taiwanese indigenous plant extracts, we discovered that the extract of Syzygium simile leaves (SSLE) has an anti-lipid droplet (LD) accumulation effect in hepatic cell lines. Analyses of the expression profile of genes involved in lipid metabolism revealed that SSLE suppressed the mRNA expression of CD36, fatty acid translocase. In agreement with this observation, we showed that SSLE inhibited CD36 protein expression and fatty acid uptake and has only limited effects on pre-formed LDs. Moreover, SSLE reduced LD accumulation and CD36 expression in enterocyte and macrophage cell lines. In conclusion, our findings suggest that SSLE could serve as a potential source for the discovery of novel therapeutic modalities for NAFLD and that the suppression of CD36 expression and fatty acid uptake could contribute to the lipid-lowering effect of SSLE. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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17 pages, 3331 KiB

Open AccessArticle

Succinate Accumulation Is Associated with a Shift of Mitochondrial Respiratory Control and HIF-1α Upregulation in PTEN Negative Prostate Cancer Cells

by Anja Weber¹

, Helmut Klocker¹, Herbert Oberacher², Erich Gnaiger^3,4

, Hannes Neuwirt⁵, Natalie Sampson¹

and Iris E. Eder^1,*

¹ Department of Urology, Medical University of Innsbruck, 6020 Innsbruck, Austria

² Institute of Legal Medicine and Core Facility Metabolomics, Medical University of Innsbruck, 6020 Innsbruck, Austria

³ D. Swarovski Research Lab, Department of Visceral, Transplant Thoracic Surgery, Medical University of Innsbruck, 6020 Innsbruck, Austria

⁴ Oroboros Instruments, 6020 Innsbruck, Austria

⁵ Department of Internal Medicine IV-Nephrology and Hypertension, Medical University of Innsbruck, 6020 Innsbruck, Austria

Int. J. Mol. Sci. 2018, 19(7), 2129; https://doi.org/10.3390/ijms19072129 - 21 Jul 2018

Cited by 25 | Viewed by 6372

Abstract

The idea of using metabolic aberrations as targets for diagnosis or therapeutic intervention has recently gained increasing interest. In a previous study, our group discovered intriguing differences in the oxidative mitochondrial respiration capacity of benign and prostate cancer (PCa) cells. In particular, we [...] Read more.

The idea of using metabolic aberrations as targets for diagnosis or therapeutic intervention has recently gained increasing interest. In a previous study, our group discovered intriguing differences in the oxidative mitochondrial respiration capacity of benign and prostate cancer (PCa) cells. In particular, we found that PCa cells had a higher total respiratory activity than benign cells. Moreover, PCa cells showed a substantial shift towards succinate-supported mitochondrial respiration compared to benign cells, indicating a re-programming of respiratory control. This study aimed to investigate the role of succinate and its main plasma membrane transporter NaDC3 (sodium-dependent dicarboxylate transporter member 3) in PCa cells and to determine whether targeting succinate metabolism can be potentially used to inhibit PCa cell growth. Using high-resolution respirometry analysis, we observed that ROUTINE respiration in viable cells and succinate-supported respiration in permeabilized cells was higher in cells lacking the tumor suppressor phosphatase and tensin-homolog deleted on chromosome 10 (PTEN), which is frequently lost in PCa. In addition, loss of PTEN was associated with increased intracellular succinate accumulation and higher expression of NaDC3. However, siRNA-mediated knockdown of NaDC3 only moderately influenced succinate metabolism and did not affect PCa cell growth. By contrast, mersalyl acid—a broad acting inhibitor of dicarboxylic acid carriers—strongly interfered with intracellular succinate levels and resulted in reduced numbers of PCa cells. These findings suggest that blocking NaDC3 alone is insufficient to intervene with altered succinate metabolism associated with PCa. In conclusion, our data provide evidence that loss of PTEN is associated with increased succinate accumulation and enhanced succinate-supported respiration, which cannot be overcome by inhibiting the succinate transporter NaDC3 alone. Full article

(This article belongs to the Special Issue Hormones-Dependent Cancers: New Aspects on Biochemistry and Molecular Pathology)

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12 pages, 3752 KiB

Open AccessArticle

Comparison of the Anion Inhibition Profiles of the α-CA Isoforms (SpiCA1, SpiCA2 and SpiCA3) from the Scleractinian Coral Stylophora pistillata

by Sonia Del Prete¹, Silvia Bua²

, Didier Zoccola³

, Fatmah A.S. Alasmary⁴

, Zeid AlOthman⁴, Linah S. Alqahtani^4,5, Nathalie Techer³, Claudiu T. Supuran²

, Sylvie Tambutté^3,* and Clemente Capasso^1,*

¹ Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 111, 80131 Napoli, Italy

² Dipartimento Neurofarba, Università degli Studi di Firenze, Sezione di Scienze Farmaceutiche e Nutraceutiche, Via U. Schiff 6, Sesto Fiorentino, 50019 Florence, Italy

³ Department of Marine Biology, Centre Scientifique de Monaco, 8 Quai Antoine 1, 98000 Monaco, Monaco

⁴ Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia

⁵ Department of Chemistry, King Faisal University, Alahsa 31982, Saudi Arabia

Int. J. Mol. Sci. 2018, 19(7), 2128; https://doi.org/10.3390/ijms19072128 - 21 Jul 2018

Cited by 11 | Viewed by 4474

Abstract

Carbonic anhydrases (CAs, EC 4.2.1.1) are widespread metalloenzymes used by living organisms to accelerate the CO₂ hydration/dehydration reaction at rates dramatically high compared to the uncatalyzed reaction. These enzymes have different isoforms and homologues and can be found in the form of [...] Read more.

Carbonic anhydrases (CAs, EC 4.2.1.1) are widespread metalloenzymes used by living organisms to accelerate the CO₂ hydration/dehydration reaction at rates dramatically high compared to the uncatalyzed reaction. These enzymes have different isoforms and homologues and can be found in the form of cytoplasmic, secreted or membrane-bound proteins. CAs play a role in numerous physiological processes including biomineralization and symbiosis, as is the case in reef-building corals. Previously, molecular and biochemical data have been obtained at the molecular level in the branching coral Stylophora pistillata for two coral isoforms which differ significantly in their catalytic activity and susceptibility to inhibition with anions and sulfonamides. More recently it has been determined that the genome of S. pistillata encodes for 16 CAs. Here, we cloned, expressed, purified and characterized a novel α-CA, named SpiCA3, which is cytoplasmic and ubiquitously expressed in all the cell layers including the calcifying cells. SpiCA3 is the most effective CA among the coral isoforms investigated and the most efficient catalyst known up to date in Metazoa. We also investigated the inhibition profiles of SpiCA3 and compared it with those obtained for the two other isoforms in the presence of inorganic anions and other small molecules known to interfere with metalloenzymes. These results suggest that S. pistillata has adapted its CA isoforms to achieve the physiological functions in different physicochemical microenvironments. Full article

(This article belongs to the Special Issue Protease and Carbonic Anhydrase Inhibitors and Their Roles in Pathological Processes)

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20 pages, 683 KiB

Open AccessReview

Understanding the Role of Dysfunctional and Healthy Mitochondria in Stroke Pathology and Its Treatment

by Hung Nguyen¹, Sydney Zarriello¹, Mira Rajani¹, Julian Tuazon¹, Eleonora Napoli^2,* and Cesar V. Borlongan^1,*

¹ College of Medicine, University of South Florida Morsani, Tampa, FL 33612, USA

² Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA

Int. J. Mol. Sci. 2018, 19(7), 2127; https://doi.org/10.3390/ijms19072127 - 21 Jul 2018

Cited by 24 | Viewed by 7242

Abstract

Stroke remains a major cause of death and disability in the United States and around the world. Solid safety and efficacy profiles of novel stroke therapeutics have been generated in the laboratory, but most failed in clinical trials. Investigations into the pathology and [...] Read more.

Stroke remains a major cause of death and disability in the United States and around the world. Solid safety and efficacy profiles of novel stroke therapeutics have been generated in the laboratory, but most failed in clinical trials. Investigations into the pathology and treatment of the disease remain a key research endeavor in advancing scientific understanding and clinical applications. In particular, cell-based regenerative medicine, specifically stem cell transplantation, may hold promise as a stroke therapy, because grafted cells and their components may recapitulate the growth and function of the neurovascular unit, which arguably represents the alpha and omega of stroke brain pathology and recovery. Recent evidence has implicated mitochondria, organelles with a central role in energy metabolism and stress response, in stroke progression. Recognizing that stem cells offer a source of healthy mitochondria—one that is potentially transferrable into ischemic cells—may provide a new therapeutic tool. To this end, deciphering cellular and molecular processes underlying dysfunctional mitochondria may reveal innovative strategies for stroke therapy. Here, we review recent studies capturing the intimate participation of mitochondrial impairment in stroke pathology, and showcase promising methods of healthy mitochondria transfer into ischemic cells to critically evaluate the potential of mitochondria-based stem cell therapy for stroke patients. Full article

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

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19 pages, 3885 KiB

Open AccessReview

“Sweet Flavonoids”: Glycosidase-Catalyzed Modifications

by Kristýna Slámová, Jana Kapešová and Kateřina Valentová^*

Laboratory of Biotransformation, Institute of Microbiology, Czech Academy of Sciences, Vídeňská 1083, CZ-14220 Prague 4, Czech Republic

Int. J. Mol. Sci. 2018, 19(7), 2126; https://doi.org/10.3390/ijms19072126 - 21 Jul 2018

Cited by 162 | Viewed by 11042

Abstract

Natural flavonoids, especially in their glycosylated forms, are the most abundant phenolic compounds found in plants, fruit, and vegetables. They exhibit a large variety of beneficial physiological effects, which makes them generally interesting in a broad spectrum of scientific areas. In this review, [...] Read more.

Natural flavonoids, especially in their glycosylated forms, are the most abundant phenolic compounds found in plants, fruit, and vegetables. They exhibit a large variety of beneficial physiological effects, which makes them generally interesting in a broad spectrum of scientific areas. In this review, we focus on recent advances in the modifications of the glycosidic parts of various flavonoids employing glycosidases, covering both selective trimming of the sugar moieties and glycosylation of flavonoid aglycones by natural and mutant glycosidases. Glycosylation of flavonoids strongly enhances their water solubility and thus increases their bioavailability. Antioxidant and most biological activities are usually less pronounced in glycosides, but some specific bioactivities are enhanced. The presence of l-rhamnose (6-deoxy-α-l-mannopyranose) in rhamnosides, rutinosides (rutin, hesperidin) and neohesperidosides (naringin) plays an important role in properties of flavonoid glycosides, which can be considered as “pro-drugs”. The natural hydrolytic activity of glycosidases is widely employed in biotechnological deglycosylation processes producing respective aglycones or partially deglycosylated flavonoids. Moreover, deglycosylation is quite commonly used in the food industry aiming at the improvement of sensoric properties of beverages such as debittering of citrus juices or enhancement of wine aromas. Therefore, natural and mutant glycosidases are excellent tools for modifications of flavonoid glycosides. Full article

(This article belongs to the Special Issue Molecular Transformations of Natural Products)

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19 pages, 1960 KiB

Open AccessReview

TGF-β Signaling-Related Genes and Thoracic Aortic Aneurysms and Dissections

by Norifumi Takeda^*

, Hironori Hara, Takayuki Fujiwara

, Tsubasa Kanaya, Sonoko Maemura and Issei Komuro

Department of Cardiovascular Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

Int. J. Mol. Sci. 2018, 19(7), 2125; https://doi.org/10.3390/ijms19072125 - 21 Jul 2018

Cited by 109 | Viewed by 15482

Abstract

Transforming growth factor-β (TGF)-β signaling plays a crucial role in the development and maintenance of various organs, including the vasculature. Accordingly, the mutations in TGF-β signaling pathway-related genes cause heritable disorders of the connective tissue, such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), [...] Read more.

Transforming growth factor-β (TGF)-β signaling plays a crucial role in the development and maintenance of various organs, including the vasculature. Accordingly, the mutations in TGF-β signaling pathway-related genes cause heritable disorders of the connective tissue, such as Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and Shprintzen-Goldberg syndrome (SGS), and these syndromes may affect skeletal, ocular, pulmonary, and cardiovascular systems. Aortic root aneurysms are common problems that can result in aortic dissection or rupture, which is the leading cause of sudden death in the natural history of MFS and LDS, and recent improvements in surgical treatment have improved life expectancy. However, there is currently no genotype-specific medical treatment. Accumulating evidence suggest that not only structural weakness of connective tissue but also increased TGF-β signaling contributes to the complicated pathogenesis of aortic aneurysm formation, but a comprehensive understanding of governing molecular mechanisms remains lacking. Inhibition of angiotensin II receptor signaling and endothelial dysfunction have gained attention as a possible MFS treatment strategy, but interactions with TGF-β signaling remain elusive. Heterozygous loss-of-function mutations in TGF-β receptors 1 and 2 (TGFBR1 and TGFBR2) cause LDS, but TGF-β signaling is activated in the aorta (referred to as the TGF-β paradox) by mechanisms yet to be elucidated. In this review, we present and discuss the current understanding of molecular mechanisms responsible for aortopathies of MFS and related disorders. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling)

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16 pages, 3597 KiB

Open AccessReview

PPARs and Metabolic Disorders Associated with Challenged Adipose Tissue Plasticity

by Patricia Corrales^1,*, Antonio Vidal-Puig^2,3 and Gema Medina-Gómez^1,*

¹ Área de Bioquímica y Biología Molecular, Departamento de Ciencias Básicas de la Salud, Facultad de Ciencias de la Salud, Universidad Rey Juan Carlos, Avda. de Atenas s/n. Alcorcón, 28922 Madrid, Spain

² Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge, Cambridge CB2 0QQ, UK

³ Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK

Int. J. Mol. Sci. 2018, 19(7), 2124; https://doi.org/10.3390/ijms19072124 - 21 Jul 2018

Cited by 144 | Viewed by 9713

Abstract

Peroxisome proliferator-activated receptors (PPARs) are members of a family of nuclear hormone receptors that exert their transcriptional control on genes harboring PPAR-responsive regulatory elements (PPRE) in partnership with retinoid X receptors (RXR). The activation of PPARs coordinated by specific coactivators/repressors regulate networks of [...] Read more.

Peroxisome proliferator-activated receptors (PPARs) are members of a family of nuclear hormone receptors that exert their transcriptional control on genes harboring PPAR-responsive regulatory elements (PPRE) in partnership with retinoid X receptors (RXR). The activation of PPARs coordinated by specific coactivators/repressors regulate networks of genes controlling diverse homeostatic processes involving inflammation, adipogenesis, lipid metabolism, glucose homeostasis, and insulin resistance. Defects in PPARs have been linked to lipodystrophy, obesity, and insulin resistance as a result of the impairment of adipose tissue expandability and functionality. PPARs can act as lipid sensors, and when optimally activated, can rewire many of the metabolic pathways typically disrupted in obesity leading to an improvement of metabolic homeostasis. PPARs also contribute to the homeostasis of adipose tissue under challenging physiological circumstances, such as pregnancy and aging. Given their potential pathogenic role and their therapeutic potential, the benefits of PPARs activation should not only be considered relevant in the context of energy balance-associated pathologies and insulin resistance but also as potential relevant targets in the context of diabetic pregnancy and changes in body composition and metabolic stress associated with aging. Here, we review the rationale for the optimization of PPAR activation under these conditions. Full article

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

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11 pages, 4071 KiB

Open AccessArticle

Characterization of a Long Non-Coding RNA, the Antisense RNA of Na/K-ATPase α1 in Human Kidney Cells

by Xiaoming Fan¹, Usman M. Ashraf², Christopher A. Drummond^1,3

, Huilin Shi¹, Xiaolu Zhang¹, Sivarajan Kumarasamy² and Jiang Tian^1,*

¹ Department of Medicine, University of Toledo, Toledo, OH 43614, USA

² Department of Physiology and Pharmacology, Center for Hypertension and Personalized Medicine, University of Toledo, Toledo, OH 43614, USA

³ MPI Research, Mattawan, MI 49071, USA

Int. J. Mol. Sci. 2018, 19(7), 2123; https://doi.org/10.3390/ijms19072123 - 21 Jul 2018

Cited by 3 | Viewed by 4399

Abstract

Non-coding RNAs are important regulators of protein-coding genes. The current study characterized an antisense long non-coding RNA, ATP1A1-AS1, which is located on the opposite strand of the Na/K-ATPase α1 gene. Our results show that four splice variants are expressed in human adult [...] Read more.

Non-coding RNAs are important regulators of protein-coding genes. The current study characterized an antisense long non-coding RNA, ATP1A1-AS1, which is located on the opposite strand of the Na/K-ATPase α1 gene. Our results show that four splice variants are expressed in human adult kidney cells (HK2 cells) and embryonic kidney cells (HEK293 cells). These variants can be detected in both cytosol and nuclear fractions. We also found that the inhibition of DNA methylation has a differential effect on the expression of ATP1A1-AS1 and its sense gene. To investigate the physiological role of this antisense gene, we overexpressed the ATP1A1-AS1 transcripts, and examined their effect on Na/K-ATPase expression and related signaling function in human kidney cells. The results showed that overexpression of the ATP1A1-AS1-203 transcript in HK2 cells reduced the Na/K-ATPase α1 (ATP1A1) gene expression by approximately 20% (p < 0.05), while reducing the Na/K-ATPase α1 protein synthesis by approximately 22% (p < 0.05). Importantly, overexpression of the antisense RNA transcript attenuated ouabain-induced Src activation in HK2 cells. It also inhibited the cell proliferation and potentiated ouabain-induced cell death. These results demonstrate that the ATP1A1-AS1 gene is a moderate negative regulator of Na/K-ATPase α1, and can modulate Na/K-ATPase-related signaling pathways in human kidney cells. Full article

(This article belongs to the Special Issue The 20th Anniversary of the Discovery of the Scaffolding Function of the Sodium Pump by Dr. Zijian Xie)

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17 pages, 2372 KiB

Open AccessReview

The Making of Hematopoiesis: Developmental Ancestry and Environmental Nurture

by Geoffrey Brown^1,*, Rhodri Ceredig² and Panagiotis Tsapogas³

¹ Institute of Clinical Sciences, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

² Discipline of Physiology, College of Medicine & Nursing Health Science, National University of Ireland, Galway, Ireland

³ Developmental and Molecular Immunology, Department of Biomedicine, University of Basel, 4058 Basel, Switzerland

Int. J. Mol. Sci. 2018, 19(7), 2122; https://doi.org/10.3390/ijms19072122 - 21 Jul 2018

Cited by 11 | Viewed by 5887

Abstract

Evidence from studies of the behaviour of stem and progenitor cells and of the influence of cytokines on their fate determination, has recently led to a revised view of the process by which hematopoietic stem cells and their progeny give rise to the [...] Read more.

Evidence from studies of the behaviour of stem and progenitor cells and of the influence of cytokines on their fate determination, has recently led to a revised view of the process by which hematopoietic stem cells and their progeny give rise to the many different types of blood and immune cells. The new scenario abandons the classical view of a rigidly demarcated lineage tree and replaces it with a much more continuum-like view of the spectrum of fate options open to hematopoietic stem cells and their progeny. This is in contrast to previous lineage diagrams, which envisaged stem cells progressing stepwise through a series of fairly-precisely described intermediate progenitors in order to close down alternative developmental options. Instead, stem and progenitor cells retain some capacity to step sideways and adopt alternative, closely related, fates, even after they have “made a lineage choice.” The stem and progenitor cells are more inherently versatile than previously thought and perhaps sensitive to lineage guidance by environmental cues. Here we examine the evidence that supports these views and reconsider the meaning of cell lineages in the context of a continuum model of stem cell fate determination and environmental modulation. Full article

(This article belongs to the Special Issue Cell Lineage Choice During Haematopoiesis: A Commemorative Issue in Honor of Professor Antonius Rolink)

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14 pages, 2087 KiB

Open AccessReview

Functions of Rhotekin, an Effector of Rho GTPase, and Its Binding Partners in Mammals

by Hidenori Ito¹, Rika Morishita¹ and Koh-ichi Nagata^1,2,*

¹ Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kamiya, Kasugai 480-0392, Japan

² Department of Neurochemistry, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan

Int. J. Mol. Sci. 2018, 19(7), 2121; https://doi.org/10.3390/ijms19072121 - 20 Jul 2018

Cited by 22 | Viewed by 7346

Abstract

Rhotekin is an effector protein for small GTPase Rho. This protein consists of a Rho binding domain (RBD), a pleckstrin homology (PH) domain, two proline-rich regions and a C-terminal PDZ (PSD-95, Discs-large, and ZO-1)-binding motif. We, and other groups, have identified various binding [...] Read more.

Rhotekin is an effector protein for small GTPase Rho. This protein consists of a Rho binding domain (RBD), a pleckstrin homology (PH) domain, two proline-rich regions and a C-terminal PDZ (PSD-95, Discs-large, and ZO-1)-binding motif. We, and other groups, have identified various binding partners for Rhotekin and carried out biochemical and cell biological characterization. However, the physiological functions of Rhotekin, per se, are as of yet largely unknown. In this review, we summarize known features of Rhotekin and its binding partners in neuronal tissues and cancer cells. Full article

(This article belongs to the Special Issue Small GTPases)

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25 pages, 1748 KiB

Open AccessReview

Non-Coding RNAs in Endometrial Physiopathology

by Alessandro La Ferlita¹, Rosalia Battaglia¹, Francesca Andronico¹, Salvatore Caruso², Antonio Cianci², Michele Purrello¹ and Cinzia Di Pietro^1,*

¹ Department of Biomedical and Biotechnological Sciences, Biology and Genetics Section G. Sichel, University of Catania, 95123 Catania, Italy

² Department of General Surgery and Medical Surgical Specialties, University of Catania, 95123 Catania, Italy

Int. J. Mol. Sci. 2018, 19(7), 2120; https://doi.org/10.3390/ijms19072120 - 20 Jul 2018

Cited by 84 | Viewed by 9687

Abstract

The Human Genome Project led to the discovery that about 80% of our DNA is transcribed in RNA molecules. Only 2% of the human genome is translated into proteins, the rest mostly produces molecules called non-coding RNAs, which are a heterogeneous class of [...] Read more.

The Human Genome Project led to the discovery that about 80% of our DNA is transcribed in RNA molecules. Only 2% of the human genome is translated into proteins, the rest mostly produces molecules called non-coding RNAs, which are a heterogeneous class of RNAs involved in different steps of gene regulation. They have been classified, according to their length, into small non-coding RNAs and long non-coding RNAs, or to their function, into housekeeping non-coding RNAs and regulatory non-coding RNAs. Their involvement has been widely demonstrated in all cellular processes, as well as their dysregulation in human pathologies. In this review, we discuss the function of non-coding RNAs in endometrial physiology, analysing their involvement in embryo implantation. Moreover, we explore their role in endometrial pathologies such as endometrial cancer, endometriosis and chronic endometritis. Full article

(This article belongs to the Special Issue Molecular Research of Endometrial Pathophysiology)

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11 pages, 1245 KiB

Open AccessReview

Vitamins D: Relationship between Structure and Biological Activity

by Andrzej Kutner¹ and Geoffrey Brown^2,*

¹ Pharmaceutical Research Institute, 8 Rydygiera, Warsaw 01-793, Poland

² Institute of Clinical Sciences, Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK

Int. J. Mol. Sci. 2018, 19(7), 2119; https://doi.org/10.3390/ijms19072119 - 20 Jul 2018

Cited by 22 | Viewed by 7426

Abstract

The most active metabolite of vitamin D is 1α,25-dihydroxyvitamin D₃, which is a central regulator of mineral homeostasis: excessive administration leads to hypercalcemia. Additionally, 1α,25-dihydroxyvitamin D₃ is important to decision-making by cells, driving many cell types to growth arrest, differentiate [...] Read more.

The most active metabolite of vitamin D is 1α,25-dihydroxyvitamin D₃, which is a central regulator of mineral homeostasis: excessive administration leads to hypercalcemia. Additionally, 1α,25-dihydroxyvitamin D₃ is important to decision-making by cells, driving many cell types to growth arrest, differentiate and undergo apoptosis. 1α,25-Dihydroxyvitamin D₃ regulates gene transcription by binding to a single known receptor, the vitamin D receptor. Rapid intracellular signals are also elicited in vitro by 1α,25-dihydroxyvitamin D₃ that are independent of transcription. There are many aspects of the multiple actions of 1α,25-dihydroxyvitamin D₃ that we do not fully understand. These include how a single receptor and provoked rapid events relate to the different actions of 1α,25-dihydroxyvitamin D₃, its calcemic action per se, and whether a large number of genes are activated directly, via the vitamin D receptor, or indirectly. A strategy to resolving these issues has been to generate synthetic analogues of 1α,25-dihydroxyvitamin D₃: Some of these separate the anti-proliferative and calcemic actions of the parent hormone. Crystallography is important to understanding how differences between 1α,25-dihydroxyvitamin D₃- and analogue-provoked structural changes to the vitamin D receptor may underlie their different activity profiles. Current crystallographic resolution has not revealed such information. Studies of our new analogues have revealed the importance of the A-ring adopting the chair β-conformation upon interaction with the vitamin D receptor to receptor-affinity and biological activity. Vitamin D analogues are useful probes to providing a better understanding of the physiology of vitamin D. Full article

(This article belongs to the Special Issue Cell Lineage Choice During Haematopoiesis: A Commemorative Issue in Honor of Professor Antonius Rolink)

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Int. J. Mol. Sci., Volume 19, Issue 7 (July 2018) – 327 articles

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