International Journal of Molecular Sciences

14 pages, 1323 KiB

Open AccessArticle

Nutritional Strategies for the Individualized Treatment of Non-Alcoholic Fatty Liver Disease (NAFLD) Based on the Nutrient-Induced Insulin Output Ratio (NIOR)

by Ewa Stachowska^1,*

, Karina Ryterska¹, Dominika Maciejewska¹, Marcin Banaszczak¹, Piotr Milkiewicz^2,3, Małgorzata Milkiewicz⁴

, Izabela Gutowska¹

, Piotr Ossowski¹, Małgorzata Kaczorowska¹, Dominika Jamioł-Milc¹, Anna Sabinicz¹, Małgorzata Napierała⁵, Lidia Wądołowska⁶ and Joanna Raszeja-Wyszomirska³

¹ Department of Biochemistry and Human Nutrition, Pomeranian Medical University, Szczecin 71-460, Poland

² Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, Szczecin 70-111, Poland

³ Liver and Internal Medicine Unit, Department of General, Transplant and Liver Surgery of the Medical University of Warsaw, Warsaw 02-097, Poland

⁴ Department of Medical Biology, Pomeranian Medical University, Szczecin 70-111, Poland

⁵ Department of Diabetology and Internal Diseases Pomeranian Medical University, Szczecin 72-010, Poland

⁶ Department of Human Nutrition, University of Warmia and Mazury, Olsztyn 10-718, Poland

Int. J. Mol. Sci. 2016, 17(7), 1192; https://doi.org/10.3390/ijms17071192 - 22 Jul 2016

Cited by 24 | Viewed by 7414

Abstract

Nutrients play a fundamental role as regulators of the activity of enzymes involved in liver metabolism. In the general population, the action of nutrients may be affected by gene polymorphisms. Therefore, individualization of a diet for individuals with fatty liver seems to be [...] Read more.

Nutrients play a fundamental role as regulators of the activity of enzymes involved in liver metabolism. In the general population, the action of nutrients may be affected by gene polymorphisms. Therefore, individualization of a diet for individuals with fatty liver seems to be a fundamental step in nutritional strategies. In this study, we tested the nutrient-induced insulin output ratio (NIOR), which is used to identify the correlation between the variants of genes and insulin resistance. We enrolled 171 patients, Caucasian men (n = 104) and women (n = 67), diagnosed with non-alcoholic fatty liver disease (NAFLD). From the pool of genes sensitive to nutrient content, we selected genes characterized by a strong response to the NIOR. The polymorphisms included Adrenergic receptor (b3AR), Tumor necrosis factor (TNFα), Apolipoprotein C (Apo C III). Uncoupling Protein type I (UCP-1), Peroxisome proliferator activated receptor γ2 (PPAR-2) and Apolipoprotein E (APOEs). We performed three dietary interventions: a diet consistent with the results of genotyping (NIOR (+)); typical dietary recommendations for NAFLD (Cust (+)), and a diet opposite to the genotyping results (NIOR (−) and Cust (−)). We administered the diet for six months. The most beneficial changes were observed among fat-sensitive patients who were treated with the NIOR (+) diet. These changes included improvements in body mass and insulin sensitivity and normalization of blood lipids. In people sensitive to fat, the NIOR seems to be a useful tool for determining specific strategies for the treatment of NAFLD. Full article

(This article belongs to the Special Issue Non-Alcoholic Fatty Liver Disease Research 2016)

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14 pages, 2057 KiB

Open AccessArticle

Revisiting the Lamotrigine-Mediated Effect on Hippocampal GABAergic Transmission

by Yu-Yin Huang^1,2, Yu-Chao Liu², Cheng-Ta Lee³, Yen-Chu Lin³, Mong-Lien Wang⁴

, Yi-Ping Yang^1,5,6, Kaung-Yi Chang⁷ and Shih-Hwa Chiou^1,4,5,*

¹ Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan

² Department of Anesthesiology, Cheng Hsin General Hospital, Taipei 112, Taiwan

³ Institute of Neuroscience and Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan

⁴ Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan

⁵ Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan

⁶ Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 112, Taiwan

⁷ Department of Anesthesiology, Taipei Veterans General Hospital, Taipei 112, Taiwan

Int. J. Mol. Sci. 2016, 17(7), 1191; https://doi.org/10.3390/ijms17071191 - 22 Jul 2016

Cited by 14 | Viewed by 6213

Abstract

Lamotrigine (LTG) is generally considered as a voltage-gated sodium (Na_v) channel blocker. However, recent studies suggest that LTG can also serve as a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel enhancer and can increase the excitability of GABAergic interneurons (INs). Perisomatic inhibitory INs, [...] Read more.

Lamotrigine (LTG) is generally considered as a voltage-gated sodium (Na_v) channel blocker. However, recent studies suggest that LTG can also serve as a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel enhancer and can increase the excitability of GABAergic interneurons (INs). Perisomatic inhibitory INs, predominantly fast-spiking basket cells (BCs), powerfully inhibit granule cells (GCs) in the hippocampal dentate gyrus. Notably, BCs express abundant Na_v channels and HCN channels, both of which are able to support sustained action potential generation. Using whole-cell recording in rat hippocampal slices, we investigated the net LTG effect on BC output. We showed that bath application of LTG significantly decreased the amplitude of evoked compound inhibitory postsynaptic currents (IPSCs) in GCs. In contrast, simultaneous paired recordings from BCs to GCs showed that LTG had no effect on both the amplitude and the paired-pulse ratio of the unitary IPSCs, suggesting that LTG did not affect GABA release, though it suppressed cell excitability. In line with this, LTG decreased spontaneous IPSC (sIPSC) frequency, but not miniature IPSC frequency. When re-examining the LTG effect on GABAergic transmission in the cornus ammonis region 1 (CA1) area, we found that LTG markedly inhibits both the excitability of dendrite-targeting INs in the stratum oriens and the concurrent sIPSCs recorded on their targeting pyramidal cells (PCs) without significant hyperpolarization-activated current (I_h) enhancement. In summary, LTG has no effect on augmenting I_h in GABAergic INs and does not promote GABAergic inhibitory output. The antiepileptic effect of LTG is likely through Na_v channel inhibition and the suppression of global neuronal network activity. Full article

(This article belongs to the Section Biochemistry)

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10 pages, 1738 KiB

Open AccessArticle

Neuroprotective Effect of Salvianolic Acids against Cerebral Ischemia/Reperfusion Injury

by Shuai Hou¹

, Ming-Ming Zhao¹, Ping-Ping Shen¹, Xiu-Ping Liu², Yuan Sun³ and Jia-Chun Feng^1,*

¹ Department of Neurology and Neuroscience Center, the First Hospital of Jilin University, Changchun 130021, China

² Department of Neurology, the Center Hospital of Jilin City, Jilin 132000, China

³ Department of Neurology, Xuzhou Center Hospital, Xuzhou 221000, China

Int. J. Mol. Sci. 2016, 17(7), 1190; https://doi.org/10.3390/ijms17071190 - 22 Jul 2016

Cited by 64 | Viewed by 7004

Abstract

This study investigated the neuroprotective effect of salvianolic acids (SA) against ischemia/reperfusion (I/R) injury, and explored whether the neuroprotection was dependent on mitochondrial connexin43 (mtCx43) via the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. In vitro, we measured astrocyte apoptosis, mitochondrial membrane potential, and [...] Read more.

This study investigated the neuroprotective effect of salvianolic acids (SA) against ischemia/reperfusion (I/R) injury, and explored whether the neuroprotection was dependent on mitochondrial connexin43 (mtCx43) via the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. In vitro, we measured astrocyte apoptosis, mitochondrial membrane potential, and also evaluated the morphology of astrocyte mitochondria with transmission electron microscopy. In vivo, we determined the cerebral infarction volume and measured superoxide dismutase (SOD) activity and malondialdehyde (MDA) content. Additionally, mtCx43, p-mtCx43, AKT, and p-AKT levels were determined. In vitro, we found that I/R injury induced apoptosis, decreased cell mitochondrial membrane potential (MMP), and damaged mitochondrial morphology in astrocytes. In vivo, we found that I/R injury resulted in a large cerebral infarction, decreased SOD activity, and increased MDA expression. Additionally, I/R injury reduced both the p-mtCx43/mtCx43 and p-AKT/AKT ratios. We reported that both in vivo and in vitro, SA ameliorated the detrimental outcomes of the I/R. Interestingly, co-administering an inhibitor of the PI3K/AKT pathway blunted the effects of SA. SA represents a potential treatment option for cerebral infarction by up-regulating mtCx43 through the PI3K/AKT pathway. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2016)

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13 pages, 2051 KiB

Open AccessArticle

Orofacial Manifestations and Temporomandibular Disorders of Systemic Scleroderma: An Observational Study

by Vito Crincoli^1,*

, Laura Fatone¹, Margherita Fanelli²

, Rossana Patricia Rotolo¹, Angela Chialà³, Gianfranco Favia¹ and Giovanni Lapadula³

¹ Complex Operating Unit of Odontostomatology, Interdisciplinary Department of Medicine, “Aldo Moro” University of Bari., Piazza Giulio Cesare 11, 70124 Bari, Italy

² Complex Operating Unit of Nuclear Medicine—Medical Statistics, Interdisciplinary Department of Medicine, “Aldo Moro” University of Bari., Piazza Giulio Cesare 11, 70124 Bari, Italy

³ Complex Operating Unit of Rheumatology, Interdisciplinary Department of Medicine, “Aldo Moro” University of Bari., Piazza Giulio Cesare 11, 70124 Bari, Italy

Int. J. Mol. Sci. 2016, 17(7), 1189; https://doi.org/10.3390/ijms17071189 - 22 Jul 2016

Cited by 74 | Viewed by 17162

Abstract

Scleroderma is a disorder involving oral and facial tissues, with skin hardening, thin lips, deep wrinkles, xerostomia, tongue rigidity, and microstomia. The aim of this study was to investigate the prevalence of oral manifestations and temporomandibular disorders (TMD) in Systemic Sclerosis (SSc) patients [...] Read more.

Scleroderma is a disorder involving oral and facial tissues, with skin hardening, thin lips, deep wrinkles, xerostomia, tongue rigidity, and microstomia. The aim of this study was to investigate the prevalence of oral manifestations and temporomandibular disorders (TMD) in Systemic Sclerosis (SSc) patients compared with healthy people. Eighty patients (6 men, 74 women) fulfilling ACR/EULAR SSc Criteria were enrolled. A randomly selected group of 80 patients, matched by sex and age served as control group. The examination for TMD signs and symptoms was based on the standardized Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) through a questionnaire and clinical examination. SSc patients complained more frequently (78.8%) of oral symptoms (Xerostomia, dysgeusia, dysphagia and stomatodynia) than controls (28.7%) (χ² = 40.23 p = 0.001). TMD symptoms (muscle pain on chewing, difficulty in mouth opening, headaches) were complained by 92.5% of SSc patients and by 76.2% of controls (χ² = 8.012 p = 0.005). At the clinical examination, 85% of SSc patients showed restricted opening versus 20.0% of controls (χ² = 67.77 p = 0.001), 81.2% of SSc showed reduced right lateral excursion versus 50% of controls (χ² = 17.316 p = 0.001); 73.8% of SSc showed limited left lateral excursion versus 53.8% of controls (χ² = 6.924 p = 0.009); and 73.8% of SSc had narrow protrusion versus 56.2% of controls (χ² = 5.385 p = 0.02). Full article

(This article belongs to the Special Issue Inflammatory Skin Conditions)

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12 pages, 3762 KiB

Open AccessArticle

High Expression of XRCC6 Promotes Human Osteosarcoma Cell Proliferation through the β-Catenin/Wnt Signaling Pathway and Is Associated with Poor Prognosis

by Bin Zhu^1,†, Dongdong Cheng^1,†, Shijie Li¹, Shumin Zhou²

and Qingcheng Yang^1,*

¹ Department of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600, Yishan Road, Shanghai 200233, China

² Institute of Orthopedics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, No. 600, Yishan Road, Shanghai 200233, China

^† These authors contribute equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1188; https://doi.org/10.3390/ijms17071188 - 22 Jul 2016

Cited by 18 | Viewed by 7913

Abstract

Increasing evidences show that XRCC6 (X-ray repair complementing defective repair in Chinese hamster cells 6) was upregulated and involved in tumor growth in several tumor types. However, the correlation of XRCC6 and human osteosarcoma (OS) is still unknown. This study was conducted with [...] Read more.

Increasing evidences show that XRCC6 (X-ray repair complementing defective repair in Chinese hamster cells 6) was upregulated and involved in tumor growth in several tumor types. However, the correlation of XRCC6 and human osteosarcoma (OS) is still unknown. This study was conducted with the aim to reveal the expression and biological function of XRCC6 in OS and elucidate the potential mechanism. The mRNA expression level of XRCC6 was measured in osteosarcoma cells and OS samples by quantitative transcription-PCR (qRT-PCR). The expression of XRCC6 protein was measured using Western blot and immunohistochemical staining in osteosarcoma cell lines and patient samples. Cell Counting Kit 8 (CCK8), colony-forming and cell cycle assays were used to test cell survival capacity. We found that XRCC6 was overexpressed in OS cells and OS samples compared with the adjacent non-tumorous samples. High expression of XRCC6 was correlated with clinical stage and tumor size in OS. Reduced expression of XRCC6 inhibits OS cell proliferation through G2/M phase arrest. Most importantly, further experiments demonstrated that XRCC6 might regulate OS growth through the β-catenin/Wnt signaling pathway. In conclusion, these findings indicate that XRCC6 exerts tumor-promoting effects for OS through β-catenin/Wnt signaling pathway. XRCC6 may serve as a novel therapeutic target for OS patients. Full article

(This article belongs to the Special Issue Molecular Classification of Human Cancer: Diagnosis and Treatment 2016)

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15 pages, 1627 KiB

Open AccessReview

Non-Invasive Methods to Monitor Mechanisms of Resistance to Tyrosine Kinase Inhibitors in Non-Small-Cell Lung Cancer: Where Do We Stand?

by Paola Ulivi

Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy

Int. J. Mol. Sci. 2016, 17(7), 1186; https://doi.org/10.3390/ijms17071186 - 22 Jul 2016

Cited by 20 | Viewed by 6616

Abstract

The induction of resistance mechanisms represents an important problem for the targeted therapy of patients with non-small-cell lung cancer (NSCLC). The best-known resistance mechanism induced during treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is EGFR T790M mutation for which specific [...] Read more.

The induction of resistance mechanisms represents an important problem for the targeted therapy of patients with non-small-cell lung cancer (NSCLC). The best-known resistance mechanism induced during treatment with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is EGFR T790M mutation for which specific drugs are have been developed. However, other molecular alterations have also been reported as induced resistance mechanisms to EGFR-TKIs. Similarly, there is growing evidence of acquired resistance mechanisms to anaplastic lymphoma kinase (ALK)-TKI treatment. A better understanding of these acquired resistance mechanisms is essential in clinical practice as patients could be treated with specific drugs that are active against the induced alterations. The use of free circulating tumor nucleic acids or circulating tumor cells (CTCs) enables resistance mechanisms to be characterized in a non-invasive manner and reduces the need for tumor re-biopsy. This review discusses the main resistance mechanisms to TKIs and provides a comprehensive overview of innovative strategies to evaluate known resistance mechanisms in free circulating nucleic acids or CTCs and potential future orientations for these non-invasive approaches. Full article

(This article belongs to the Special Issue Liquid Biopsy for Clinical Application)

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13 pages, 1839 KiB

Open AccessArticle

Mutant LRP6 Impairs Endothelial Cell Functions Associated with Familial Normolipidemic Coronary Artery Disease

by Jian Guo¹

, Yang Li¹, Yi-Hong Ren², Zhijun Sun², Jie Dong¹, Han Yan¹, Yujun Xu³, Dao Wen Wang³, Gu-Yan Zheng¹, Jie Du⁴ and Xiao-Li Tian^1,5,*

¹ Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing 100871, China

² Department of Cardiovascular, PLA General Hospital, Beijing 100853, China

³ The Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China

⁴ Beijing Anzhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Beijing Institute of Heart, Lung & Blood Vessel Disease, Beijing 100029, China

⁵ Department of Human Population Genetics, Human Aging Research Institute and School of Life Science, Nanchang University, Nanchang 330031, China

Int. J. Mol. Sci. 2016, 17(7), 1173; https://doi.org/10.3390/ijms17071173 - 22 Jul 2016

Cited by 13 | Viewed by 5792

Abstract

Mutations in the genes low-density lipoprotein (LDL) receptor-related protein-6 (LRP6) and myocyte enhancer factor 2A (MEF2A) were reported in families with coronary artery disease (CAD). We intend to determine the mutational spectrum of these genes among hyperlipidemic and normolipidemic [...] Read more.

Mutations in the genes low-density lipoprotein (LDL) receptor-related protein-6 (LRP6) and myocyte enhancer factor 2A (MEF2A) were reported in families with coronary artery disease (CAD). We intend to determine the mutational spectrum of these genes among hyperlipidemic and normolipidemic CAD families. Forty probands with early-onset CAD were recruited from 19 hyperlipidemic and 21 normolipidemic Chinese families. We sequenced all exons and intron-exon boundaries of LRP6 and MEF2A, and found a novel heterozygous variant in LRP6 from a proband with normolipidemic CAD. This variant led to a substitution of histidine to tyrosine (Y418H) in an evolutionarily conserved domain YWTD in exon 6 and was not found in 1025 unrelated healthy individuals. Co-segregated with CAD in the affected family, LRP6_Y418H significantly debilitated the Wnt3a-associated signaling pathway, suppressed endothelial cell proliferation and migration, and decreased anti-apoptotic ability. However, it exhibited no influences on low-density lipoprotein cholesterol uptake. Thus, mutation Y418H in LRP6 likely contributes to normolipidemic familial CAD via impairing endothelial cell functions and weakening the Wnt3a signaling pathway. Full article

(This article belongs to the Special Issue Atherosclerosis and Vascular Imaging 2016)

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17 pages, 5353 KiB

Open AccessArticle

De Novo Assembly and Characterization of the Transcriptome of Grasshopper Shirakiacris shirakii

by Zhongying Qiu¹, Fei Liu^1,2, Huimeng Lu³, Hao Yuan¹, Qin Zhang¹ and Yuan Huang^1,*

¹ College of Life Sciences, Shaanxi Normal University, Xi’an 710062, China

² College of Life Sciences and Food Engineering, Shaanxi Xueqian Normal University, Xi’an 710061, China

³ Key Laboratory for Space Bioscience & Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, China

Int. J. Mol. Sci. 2016, 17(7), 1110; https://doi.org/10.3390/ijms17071110 - 22 Jul 2016

Cited by 10 | Viewed by 6039

Abstract

Background: The grasshopper Shirakiacris shirakii is an important agricultural pest and feeds mainly on gramineous plants, thereby causing economic damage to a wide range of crops. However, genomic information on this species is extremely limited thus far, and transcriptome data relevant to insecticide [...] Read more.

Background: The grasshopper Shirakiacris shirakii is an important agricultural pest and feeds mainly on gramineous plants, thereby causing economic damage to a wide range of crops. However, genomic information on this species is extremely limited thus far, and transcriptome data relevant to insecticide resistance and pest control are also not available. Methods: The transcriptome of S. shirakii was sequenced using the Illumina HiSeq platform, and we de novo assembled the transcriptome. Results: Its sequencing produced a total of 105,408,878 clean reads, and the de novo assembly revealed 74,657 unigenes with an average length of 680 bp and N50 of 1057 bp. A total of 28,173 unigenes were annotated for the NCBI non-redundant protein sequences (Nr), NCBI non-redundant nucleotide sequences (Nt), a manually-annotated and reviewed protein sequence database (Swiss-Prot), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Based on the Nr annotation results, we manually identified 79 unigenes encoding cytochrome P450 monooxygenases (P450s), 36 unigenes encoding carboxylesterases (CarEs) and 36 unigenes encoding glutathione S-transferases (GSTs) in S. shirakii. Core RNAi components relevant to miroRNA, siRNA and piRNA pathways, including Pasha, Loquacious, Argonaute-1, Argonaute-2, Argonaute-3, Zucchini, Aubergine, enhanced RNAi-1 and Piwi, were expressed in S. shirakii. We also identified five unigenes that were homologous to the Sid-1 gene. In addition, the analysis of differential gene expressions revealed that a total of 19,764 unigenes were up-regulated and 4185 unigenes were down-regulated in larvae. In total, we predicted 7504 simple sequence repeats (SSRs) from 74,657 unigenes. Conclusions: The comprehensive de novo transcriptomic data of S. shirakii will offer a series of valuable molecular resources for better studying insecticide resistance, RNAi and molecular marker discovery in the transcriptome. Full article

(This article belongs to the Section Biochemistry)

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9 pages, 2420 KiB

Open AccessArticle

Prolonged Starvation Causes Up-Regulation of AQP1 in Adipose Tissue Capillaries of AQP7 Knock-Out Mice

by Mariusz T. Skowronski^1,*

, Agnieszka Skowronska², Aleksandra Rojek³, Michal K. Oklinski³ and Søren Nielsen³

¹ Department of Animal Physiology, University of Warmia and Mazury in Olsztyn, Olsztyn 10-752, Poland

² Department of Human Physiology, University of Warmia and Mazury in Olsztyn, Olsztyn 10-752, Poland

³ Department of Health Science and Technology, Aalborg University, Aalborg 9220, Denmark

Int. J. Mol. Sci. 2016, 17(7), 1101; https://doi.org/10.3390/ijms17071101 - 22 Jul 2016

Cited by 10 | Viewed by 5859

Abstract

Aquaporins (AQPs) are membrane proteins involved in the regulation of cellular transport and the balance of water and glycerol and cell volume in the white adipose tissue (WAT). In our previous study, we found the co-expression of the AQP1 water channel and AQP7 [...] Read more.

Aquaporins (AQPs) are membrane proteins involved in the regulation of cellular transport and the balance of water and glycerol and cell volume in the white adipose tissue (WAT). In our previous study, we found the co-expression of the AQP1 water channel and AQP7 in the mouse WAT. In our present study, we aimed to find out whether prolonged starvation influences the AQP1 expression of AQP7 knock-out mice (AQP7 KO) in the WAT. To resolve this hypothesis, immunoperoxidase, immunoblot and immunogold microscopy were used. AQP1 expression was found with the use of immunohistochemistry and was confirmed by immunogold microscopy in the vessels of mouse WAT of all studied groups. Semi-quantitative immunoblot and quantitative immunogold microscopy showed a significant increase (by 2.5- to 3-fold) in the abundance of AQP1 protein expression in WAT in the 72 h starved AQP7 KO mice as compared to AQP7+/+ (p < 0.05) and AQP7−/− (p < 0.01) controls, respectively. In conclusion, the AQP1 water channel located in the vessels of WAT is up-regulated in response to prolonged starvation in the WAT of AQP7 KO mice. The present data suggest that an interaction of different AQP isoforms is required for maintaining proper water homeostasis within the mice WAT. Full article

(This article belongs to the Special Issue Aquaporin)

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10 pages, 991 KiB

Open AccessReview

The Clinical Value of High-Intensity Signals on the Coronary Atherosclerotic Plaques: Noncontrast T1-Weighted Magnetic Resonance Imaging

by Shoichi Ehara^*, Kenji Matsumoto and Kenei Shimada

Department of Cardiovascular Medicine, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan

Int. J. Mol. Sci. 2016, 17(7), 1187; https://doi.org/10.3390/ijms17071187 - 21 Jul 2016

Cited by 6 | Viewed by 5460

Abstract

Over the past several decades, significant progress has been made in the pathohistological assessment of vulnerable plaques and in invasive intravascular imaging techniques. However, the assessment of plaque morphology by invasive modalities is of limited value for the detection of subclinical coronary atherosclerosis [...] Read more.

Over the past several decades, significant progress has been made in the pathohistological assessment of vulnerable plaques and in invasive intravascular imaging techniques. However, the assessment of plaque morphology by invasive modalities is of limited value for the detection of subclinical coronary atherosclerosis and the subsequent prediction or prevention of acute cardiovascular events. Recently, magnetic resonance (MR) imaging technology has reached a sufficient level of spatial resolution, which allowed the plaque visualization of large and static arteries such as the carotids and aorta. However, coronary wall imaging by MR is still challenging due to the small size of coronary arteries, cardiac and respiratory motion, and the low contrast-to-noise ratio between the coronary artery wall and the surrounding structures. Following the introduction of carotid plaque imaging with noncontrast T1-weighted imaging (T1WI), some investigators have reported that coronary artery high-intensity signals on T1WI are associated with vulnerable plaque morphology and an increased risk of future cardiac events. Although there are several limitations and issues that need to be resolved, this novel MR technique for coronary plaque imaging could influence treatment strategies for atherothrombotic disease and may be useful for understanding the pathophysiological mechanisms of atherothrombotic plaque formation. Full article

(This article belongs to the Special Issue Atherosclerosis and Vascular Imaging 2016)

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10 pages, 701 KiB

Open AccessArticle

Assessment of Dextran Antigenicity of Intravenous Iron Preparations with Enzyme-Linked Immunosorbent Assay (ELISA)

by Susann Neiser¹, Taija S. Koskenkorva², Katrin Schwarz¹, Maria Wilhelm¹ and Susanna Burckhardt^2,*

¹ Chemical and Preclinical Research and Development, Vifor International Ltd., 9014 St. Gallen, Switzerland

² Global Medical Affairs, Vifor Pharma Ltd., 8152 Glattbrugg, Switzerland

Int. J. Mol. Sci. 2016, 17(7), 1185; https://doi.org/10.3390/ijms17071185 - 21 Jul 2016

Cited by 21 | Viewed by 8909

Abstract

Intravenous iron preparations are typically classified as non-dextran-based or dextran/dextran-based complexes. The carbohydrate shell for each of these preparations is unique and is key in determining the various physicochemical properties, the metabolic pathway, and the immunogenicity of the iron-carbohydrate complex. As intravenous dextran [...] Read more.

Intravenous iron preparations are typically classified as non-dextran-based or dextran/dextran-based complexes. The carbohydrate shell for each of these preparations is unique and is key in determining the various physicochemical properties, the metabolic pathway, and the immunogenicity of the iron-carbohydrate complex. As intravenous dextran can cause severe, antibody-mediated dextran-induced anaphylactic reactions (DIAR), the purpose of this study was to explore the potential of various intravenous iron preparations, non-dextran-based or dextran/dextran-based, to induce these reactions. An IgG-isotype mouse monoclonal anti-dextran antibody (5E7H3) and an enzyme-linked immunosorbent assay (ELISA) were developed to investigate the dextran antigenicity of low molecular weight iron dextran, ferumoxytol, iron isomaltoside 1000, ferric gluconate, iron sucrose and ferric carboxymaltose, as well as isomaltoside 1000, the isolated carbohydrate component of iron isomaltoside 1000. Low molecular weight iron dextran, as well as dextran-based ferumoxytol and iron isomaltoside 1000, reacted with 5E7H3, whereas ferric carboxymaltose, iron sucrose, sodium ferric gluconate, and isolated isomaltoside 1000 did not. Consistent results were obtained with reverse single radial immunodiffusion assay. The results strongly support the hypothesis that, while the carbohydrate alone (isomaltoside 1000) does not form immune complexes with anti-dextran antibodies, iron isomaltoside 1000 complex reacts with anti-dextran antibodies by forming multivalent immune complexes. Moreover, non-dextran based preparations, such as iron sucrose and ferric carboxymaltose, do not react with anti-dextran antibodies. This assay allows to assess the theoretical possibility of a substance to induce antibody-mediated DIARs. Nevertheless, as this is only one possible mechanism that may cause a hypersensitivity reaction, a broader set of assays will be required to get an understanding of the mechanisms that may lead to intravenous iron-induced hypersensitivity reactions. Full article

(This article belongs to the Special Issue Recent Advances in Metal Based Drugs)

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10 pages, 408 KiB

Open AccessArticle

Psychopathological Variables and Sleep Quality in Psoriatic Patients

by Maria Luca¹

, Antonina Luca²

, Maria Letizia Musumeci³, Federica Fiorentini³, Giuseppe Micali³ and Carmela Calandra^1,*

¹ Psychiatry Unit, Department of Medical and Surgical Sciences and Advanced Technologies, University Hospital Policlinico-Vittorio Emanuele, Santa Sofia Street 78, Catania, 95100 Sicily, Italy

² Department of Medical and Surgical Sciences and Advanced Technologies, University Hospital Policlinico-Vittorio Emanuele, Santa Sofia Street 78, Catania, 95100 Sicily, Italy

³ Dermatology Clinic, University of Catania, University Hospital Policlinico-Vittorio Emanuele, Santa Sofia Street 78, Catania, 95100 Sicily, Italy

Int. J. Mol. Sci. 2016, 17(7), 1184; https://doi.org/10.3390/ijms17071184 - 21 Jul 2016

Cited by 18 | Viewed by 6019

Abstract

Psoriasis is an inflammatory disease frequently associated with psychiatric disturbances and sleep disorders. The aim of the study was to assess the prevalence of depression, interaction anxiety, audience anxiety, and sleep quality in psoriatic patients. One hundred and two psoriatic patients were enrolled [...] Read more.

Psoriasis is an inflammatory disease frequently associated with psychiatric disturbances and sleep disorders. The aim of the study was to assess the prevalence of depression, interaction anxiety, audience anxiety, and sleep quality in psoriatic patients. One hundred and two psoriatic patients were enrolled and underwent the following questionnaires: Zung Self-Rating Depression Scale (SDS), Interaction Anxiousness Scale (IAS), Audience Anxiousness Scale (AAS), Pittsburgh Sleep Quality Index (PSQI). The severity of skin lesions was assessed by Psoriasis Area Severity Index (PASI). The presence of a link between clinical variables and with demographic data has been investigated. Psoriasis was linked to depression, interaction and audience anxiety, as well as to poor sleep quality; 37.5% of patients were depressed, 46.1% scored above 37 at the IAS, 47.1% scored above 33 at the AAS. Thirty-nine subjects (38.2%) presented a PSQI ≥ 5. An association between interaction anxiety and lower limbs psoriasis-related erythema as well as between PSQI and head psoriasis-related erythema was found, particularly among male patients. Hence, psoriatic patients should be assessed from a holistic point of view, in order to identify associated disorders that could benefit from targeted treatments. Full article

(This article belongs to the Special Issue Sleep, Circadian Rhythm and Skin)

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11 pages, 3220 KiB

Open AccessArticle

The Effects of Aquaporin-1 in Pulmonary Edema Induced by Fat Embolism Syndrome

by Yiwei Zhang^†, Kun Tian^†, Yan Wang, Rong Zhang, Jiawei Shang, Wei Jiang and Aizhong Wang^*

¹ Department of Anesthesiology, the Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai 200233, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1183; https://doi.org/10.3390/ijms17071183 - 21 Jul 2016

Cited by 19 | Viewed by 6613

Abstract

This study was designed to investigate the role of aquaporin1 (AQP1) in the pathologic process of pulmonary edema induced by fat embolism syndrome (FES) and the effects of a free fatty acid (FFA) mixture on AQP1 expression in pulmonary microvascular endothelial cells (PMVECs). [...] Read more.

This study was designed to investigate the role of aquaporin1 (AQP1) in the pathologic process of pulmonary edema induced by fat embolism syndrome (FES) and the effects of a free fatty acid (FFA) mixture on AQP1 expression in pulmonary microvascular endothelial cells (PMVECs). In vivo, edema was more serious in FES mice compared with the control group. The expression of AQP1 and the wet-to-dry lung weight ratio (W/D) in the FES group were significantly increased compared with the control group. At the same time, inhibition of AQP1 decreased the pathological damage resulting from pulmonary edema. Then we performed a study in vitro to investigate whether AQP1 was induced by FFA release in FES. The mRNA and protein level of AQP1 were increased by FFAs in a dose- and time-dependent manner in PMVECs. In addition, the up-regulation of AQP1 was blocked by the inhibitor of p38 kinase, implicating the p38 MAPK pathway as involved in the FFA-induced AQP1 up-regulation in PMVECs. Our results demonstrate that AQP1 may play important roles in pulmonary edema induced by FES and can be regarded as a new therapy target for treatment of pulmonary edema induced by FES. Full article

(This article belongs to the Special Issue Aquaporin)

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13 pages, 8410 KiB

Open AccessArticle

High Morphologic Plasticity of Microglia/Macrophages Following Experimental Intracerebral Hemorrhage in Rats

by Shu-Sheng Yang^1,2,†, Li Lin^1,3,†, Yue Liu^4,5, Jie Wang⁵, Jiang Chu¹, Teng Zhang¹, Lin-Na Ning¹, Yan Shi¹, Ying-Yan Fang¹, Peng Zeng¹, Jian-Zhi Wang¹, Ming-Yi Qiu^2,* and Qing Tian^1,*

¹ Department of Pathology and Pathophysiology, School of Basic Medicine; Institute for Brain Research, Huazhong University of Science and Technology, Hangkong Road 13#, Wuhan 430030, China

² Department of Shang-Han, Clinical College of Traditional Chinese Medicine, Hubei University of Traditional Chinese Medicine, Tan-Hua-Lin Road 1, Wuhan 430061, China

³ Laboratory of Medical Molecular and Cellular Biology, School of Basic Medicine, Hubei University of Traditional Chinese Medicine, Wuhan 430065, China

⁴ Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, China

⁵ Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1181; https://doi.org/10.3390/ijms17071181 - 21 Jul 2016

Cited by 18 | Viewed by 7183

Abstract

As current efforts have limited effects on the clinical outcome of intracerebral hemorrhage (ICH), the mechanisms including microglia/macrophages that involved inflammation need further investigation. Here, 0.4 units of collagenase VII were injected into the left caudate putamen (CPu) to duplicate ICH rat models. [...] Read more.

As current efforts have limited effects on the clinical outcome of intracerebral hemorrhage (ICH), the mechanisms including microglia/macrophages that involved inflammation need further investigation. Here, 0.4 units of collagenase VII were injected into the left caudate putamen (CPu) to duplicate ICH rat models. In the brains of ICH rats, microglia/macrophages, the nearest cells to the hemorrhagic center, were observed as ameboid and Prussian-blue positive. Furthermore, the ameboid microglia/macrophages were differentiation (CD) 68 and interleukin-1β (IL-1β) positive, and neither CD206 nor chitinase3-like 3 (Ym1) positive, suggesting their strong abilities of phagocytosis and secretion of IL-1β. According to the distance to the hemorrhagic center, we selected four areas—I, II, III, and IV—to analyze the morphology of microglia/macrophages. The processes decreased successively from region I to region IV. Microglia/macrophages in region IV had no processes. The processes in region I were radially distributed, however, they showed obvious directivity towards the hemorrhagic center in regions II and III. Region III had the largest density of compactly arrayed microglia/macrophages. All these in vivo results present the high morphologic plasticity of microglia/macrophages and their functions in the pathogenesis of ICHs. Full article

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

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19 pages, 573 KiB

Open AccessArticle

Aluminum Toxicity-Induced Alterations of Leaf Proteome in Two Citrus Species Differing in Aluminum Tolerance

by Huan Li^1,2, Lin-Tong Yang^1,2, Yi-Ping Qi³, Peng Guo^1,2, Yi-Bin Lu^1,2 and Li-Song Chen^1,2,4,*

¹ Institute of Plant Nutritional Physiology and Molecular Biology, College of Resources and Environment, Fujian Agriculture and Forestry University, Fuzhou 350002, China

² Fujian Provincial Key Laboratory of Soil Environmental Health and Regulation, College of Resources and Environment, Fujian Agriculture and Forestry University, Fuzhou 350002, China

³ Institute of Materia Medica, Fujian Academy of Medical Sciences, Fuzhou 350001, China

⁴ The Higher Educational Key Laboratory of Fujian Province for Soil Ecosystem Health and Regulation, Fujian Agriculture and Forestry University, Fuzhou 350002, China

Int. J. Mol. Sci. 2016, 17(7), 1180; https://doi.org/10.3390/ijms17071180 - 21 Jul 2016

Cited by 44 | Viewed by 7619

Abstract

Seedlings of aluminum-tolerant ‘Xuegan’ (Citrus sinensis) and Al-intolerant ‘sour pummelo’ (Citrus grandis) were fertigated for 18 weeks with nutrient solution containing 0 and 1.2 mM AlCl₃·6H₂O. Al toxicity-induced inhibition of photosynthesis and the decrease of [...] Read more.

Seedlings of aluminum-tolerant ‘Xuegan’ (Citrus sinensis) and Al-intolerant ‘sour pummelo’ (Citrus grandis) were fertigated for 18 weeks with nutrient solution containing 0 and 1.2 mM AlCl₃·6H₂O. Al toxicity-induced inhibition of photosynthesis and the decrease of total soluble protein only occurred in C. grandis leaves, demonstrating that C. sinensis had higher Al tolerance than C. grandis. Using isobaric tags for relative and absolute quantification (iTRAQ), we obtained more Al toxicity-responsive proteins from C. sinensis than from C. grandis leaves, which might be responsible for the higher Al tolerance of C. sinensis. The following aspects might contribute to the Al tolerance of C. sinensis: (a) better maintenance of photosynthesis and energy balance via inducing photosynthesis and energy-related proteins; (b) less increased requirement for the detoxification of reactive oxygen species and other toxic compounds, such as aldehydes, and great improvement of the total ability of detoxification; and (c) upregulation of low-phosphorus-responsive proteins. Al toxicity-responsive proteins related to RNA regulation, protein metabolism, cellular transport and signal transduction might also play key roles in the higher Al tolerance of C. sinensis. We present the global picture of Al toxicity-induced alterations of protein profiles in citrus leaves, and identify some new Al toxicity-responsive proteins related to various biological processes. Our results provide some novel clues about plant Al tolerance. Full article

(This article belongs to the Special Issue Plant Proteomic Research)

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29 pages, 991 KiB

Open AccessReview

Matrix Metalloproteinases in Non-Neoplastic Disorders

by Akinori Tokito and Michihisa Jougasaki^*

Institute for Clinical Research, National Hospital Organization Kagoshima Medical Center, 8-1 Shiroyama-cho, Kagoshima 892-0853, Japan

Int. J. Mol. Sci. 2016, 17(7), 1178; https://doi.org/10.3390/ijms17071178 - 21 Jul 2016

Cited by 71 | Viewed by 13292

Abstract

The matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. There are at least 23 members of MMPs ever reported in human, and they and their substrates are widely expressed in many tissues. Recent growing evidence has established that MMP not [...] Read more.

The matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases belonging to the metzincin superfamily. There are at least 23 members of MMPs ever reported in human, and they and their substrates are widely expressed in many tissues. Recent growing evidence has established that MMP not only can degrade a variety of components of extracellular matrix, but also can cleave and activate various non-matrix proteins, including cytokines, chemokines and growth factors, contributing to both physiological and pathological processes. In normal conditions, MMP expression and activity are tightly regulated via interactions between their activators and inhibitors. Imbalance among these factors, however, results in dysregulated MMP activity, which causes tissue destruction and functional alteration or local inflammation, leading to the development of diverse diseases, such as cardiovascular disease, arthritis, neurodegenerative disease, as well as cancer. This article focuses on the accumulated evidence supporting a wide range of roles of MMPs in various non-neoplastic diseases and provides an outlook on the therapeutic potential of inhibiting MMP action. Full article

(This article belongs to the Special Issue Metalloproteins)

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33 pages, 6466 KiB

Open AccessReview

Molecular Approaches to Genetically Improve the Accumulation of Health-Promoting Secondary Metabolites in Staple Crops—A Case Study: The Lipoxygenase-B1 Genes and Regulation of the Carotenoid Content in Pasta Products

by Grazia M. Borrelli

and Daniela Trono^*

Consiglio per la Ricerca in Agricoltura e l’Analisi dell’Economia Agraria, Centro di Ricerca per la Cerealicoltura, S.S. 673 Km 25,200, 71122 Foggia, Italy

Int. J. Mol. Sci. 2016, 17(7), 1177; https://doi.org/10.3390/ijms17071177 - 21 Jul 2016

Cited by 27 | Viewed by 8729

Abstract

Secondary metabolites, also known as phytochemicals, represent a large subset of plant molecules that include compounds with health-promoting effects. Indeed, a number of epidemiological studies have shown that, when taken regularly and in adequate amounts, these molecules can have long-term beneficial effects on [...] Read more.

Secondary metabolites, also known as phytochemicals, represent a large subset of plant molecules that include compounds with health-promoting effects. Indeed, a number of epidemiological studies have shown that, when taken regularly and in adequate amounts, these molecules can have long-term beneficial effects on human health, through reduction of the incidence of degenerative diseases, such as cardiovascular diseases, obesity, diabetes, and cancer. As the dietary intake of these phytochemicals is often inadequate, various strategies are in use to improve their content in staple crops, and the end-products thereof. One of the most effective strategies is crop improvement through genetic approaches, as this is the only way to generate new cultivars in which the high accumulation of a given phytochemical is stably fixed. Efforts to genetically improve quality traits are rapidly evolving, from classical breeding to molecular-assisted approaches; these require sound understanding of the molecular bases underlying the traits, to identify the genes/alleles that control them. This can be achieved through global analysis of the metabolic pathway responsible for phytochemical accumulation, to identify the link between phytochemical content and the activities of key enzymes that regulate the metabolic pathway, and between the key enzymes and their encoding genes/alleles. Once these have been identified, they can be used as markers for selection of new improved genotypes through biotechnological approaches. This review provides an overview of the major health-promoting properties shown to be associated with the dietary intake of phytochemicals, and describes how molecular approaches provide means for improving the health quality of edible crops. Finally, a case study is illustrated, of the identification in durum wheat of the Lipoxygenase-B1 genes that control the final carotenoid content in semolina-based foods, such as pasta products. Full article

(This article belongs to the Section Molecular Plant Sciences)

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13 pages, 6795 KiB

Open AccessArticle

Protective Effect of Salicornia europaea Extracts on High Salt Intake-Induced Vascular Dysfunction and Hypertension

by Nisha Panth^1,†

, Sin-Hee Park^1,2,†, Hyun Jung Kim¹, Deuk-Hoi Kim³ and Min-Ho Oak^1,*

¹ College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Muan-gun, Jeonnam 58554, Korea

² UMR CNRS 7213, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, Illkirch 67401, France

³ Research Center, Phyto Corporation, Seoul 08826, Korea

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1176; https://doi.org/10.3390/ijms17071176 - 21 Jul 2016

Cited by 35 | Viewed by 8825

Abstract

High salt intake causes and aggravates arterial hypertension and vascular dysfunction. We investigated the effect of Salicornia europaea extracts (SE) on vascular function and blood pressure. SE constituents were analyzed using high performance liquid chromatography, and SE’s effect on vascular function was evaluated [...] Read more.

High salt intake causes and aggravates arterial hypertension and vascular dysfunction. We investigated the effect of Salicornia europaea extracts (SE) on vascular function and blood pressure. SE constituents were analyzed using high performance liquid chromatography, and SE’s effect on vascular function was evaluated in isolated porcine coronary arteries. SE’s vascular protective effect was also evaluated in vivo using normotensive and spontaneous hypertensive rats (SHRs). SE mainly contained sodium chloride (55.6%), 5-(hydroxymethyl)furfural, p-coumaric acid, and trans-ferulic acid. High sodium (160 mmol/L) induced vascular dysfunction; however, SE containing the same quantity of sodium did not cause vascular dysfunction. Among the compounds in SE, trans-ferulic acid accounts for the vascular protective effect. Normotensive rats fed a high-salt diet showed significantly increased systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP), which decreased significantly in the SE-treated groups. In SHRs, high edible salt intake significantly increased SBP, DBP, and MAP, but SE intake was associated with a significantly lower MAP. Thus, SE did not induce vascular dysfunction, and trans-ferulic acid might be at least partly responsible for the vasoprotective effect of SE. Taken together, SE could be used as an alternative to purified salt to prevent and ameliorate hypertension. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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20 pages, 2205 KiB

Open AccessReview

Developments in Methods for Measuring the Intestinal Absorption of Nanoparticle-Bound Drugs

by Wei Liu^1,2,†, Hao Pan^3,†, Caiyun Zhang²

, Liling Zhao², Ruixia Zhao², Yongtao Zhu² and Weisan Pan^1,*

¹ Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China

² Department of Pharmaceutics, School of Pharmacy, Zhengzhou University, 100 Science Avenue, Zhengzhou 450001, China

³ School of Pharmacy, Queen’s University Belfast, Belfast BT7 1NN, UK

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1171; https://doi.org/10.3390/ijms17071171 - 21 Jul 2016

Cited by 57 | Viewed by 13333

Abstract

With the rapid development of nanotechnology, novel drug delivery systems comprising orally administered nanoparticles (NPs) have been paid increasing attention in recent years. The bioavailability of orally administered drugs has significant influence on drug efficacy and therapeutic dosage, and it is therefore imperative [...] Read more.

With the rapid development of nanotechnology, novel drug delivery systems comprising orally administered nanoparticles (NPs) have been paid increasing attention in recent years. The bioavailability of orally administered drugs has significant influence on drug efficacy and therapeutic dosage, and it is therefore imperative that the intestinal absorption of oral NPs be investigated. This review examines the various literature on the oral absorption of polymeric NPs, and provides an overview of the intestinal absorption models that have been developed for the study of oral nanoparticles. Three major categories of models including a total of eight measurement methods are described in detail (in vitro: dialysis bag, rat gut sac, Ussing chamber, cell culture model; in situ: intestinal perfusion, intestinal loops, intestinal vascular cannulation; in vivo: the blood/urine drug concentration method), and the advantages and disadvantages of each method are contrasted and elucidated. In general, in vitro and in situ methods are relatively convenient but lack accuracy, while the in vivo method is troublesome but can provide a true reflection of drug absorption in vivo. This review summarizes the development of intestinal absorption experiments in recent years and provides a reference for the systematic study of the intestinal absorption of nanoparticle-bound drugs. Full article

(This article belongs to the Section Materials Science)

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12 pages, 5042 KiB

Open AccessArticle

Enhancement of Anti-Hypoxic Activity and Differentiation of Cardiac Stem Cells by Supernatant Fluids from Cultured Macrophages that Phagocytized Dead Mesenchymal Stem Cells

by Liang Liu^1,†

, Xian Jin^2,†, Zhong’e Zhou² and Chengxing Shen^1,*

¹ Department of Cardiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, China

² Department of Cardiology, Central Hospital of Minhang District, 170 Xinsong Road, Shanghai 201199, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1175; https://doi.org/10.3390/ijms17071175 - 20 Jul 2016

Cited by 1 | Viewed by 5433

Abstract

Background: Most mesenchymal stem cells (MSCs) die shortly after transplantation into a myocardial infarcted area. Dead MSCs (dMSCs) are phagocytized by macrophages (pMΦ) in vivo and in vitro; however, the effects of pMΦ on cardiac stem cells (CSCs) remain unknown. Methods: MSCs, CSCs, [...] Read more.

Background: Most mesenchymal stem cells (MSCs) die shortly after transplantation into a myocardial infarcted area. Dead MSCs (dMSCs) are phagocytized by macrophages (pMΦ) in vivo and in vitro; however, the effects of pMΦ on cardiac stem cells (CSCs) remain unknown. Methods: MSCs, CSCs, and macrophages were obtained from bone marrow, hearts, and peritoneal cavity of mice, respectively. dMSCs were harvested after hypoxia for 24 h, and incubated with macrophages (2:1) for another 2 days with or without lipopolysaccharide (LPS, 50 ng/mL) and sorted by flow cytometry to obtain pMΦ. Viability and apoptosis of CSCs were respectively evaluated with the cell counting kit-8 (CCk-8) assay and Annexin V-PE/7-AAD staining at 0, 6, 12, and 24 h of culture with supernatant fluids from macrophages (MΦ), LPS-stimulated macrophages (LPS-pMΦ), pMΦ, and MSCs. GATA-4 and c-TnI expression was measured by flow cytometry on the seventh day. Expression of inflammation and growth factors was assessed by real-time polymerase chain reaction (RT-PCR) in MΦ, LPS-pMΦ, and pMΦ cells. Results: pMΦ expressed higher levels of interleukin-10 (IL-10) and transforming growth factor-β (TGF-β)and lower levels of tumor necrosis factor-α(TNF-α)and IL-6 than LPS-pMΦ, higher levels of growth factors and of GATA-4 and c-TnI at the 7th day, which were similar to those in MSCs. CSCs cultured with supernatant fluids of pMΦ exhibited higher proliferative, anti-hypoxic, and differentiation activities. Conclusion: The supernatant fluids of macrophages that had phagocytized dead MSCs encouraged changes in phenotype and growth factor expression, enhanced proliferation, differentiation, and anti-hypoxic activity of CSCs, which is relevant to understanding the persistent therapeutic effect of MSCs after their massive demise upon transplantation in myocardial infarction. Furthermore, some miRNAs or proteins which were extracted from the supernatant fluids may give us a new insight into the treatment of myocardial infarction in the future. Full article

(This article belongs to the Section Biochemistry)

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16 pages, 3811 KiB

Open AccessArticle

La Autoantigen Induces Ribosome Binding Protein 1 (RRBP1) Expression through Internal Ribosome Entry Site (IRES)-Mediated Translation during Cellular Stress Condition

by Wenqing Gao^†, Qi Li^†, Ruiyu Zhu^* and Jian Jin^*

¹ Laboratory of Molecular Pharmacology, School of Pharmaceutical Sciences, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1174; https://doi.org/10.3390/ijms17071174 - 20 Jul 2016

Cited by 18 | Viewed by 7017

Abstract

The function of ribosome binding protein 1 (RRBP1) is regulating the transportation and secretion of some intracellular proteins in mammalian cells. Transcription of RRBP1 is induced by various cytokines. However, few studies focused on the process of RRPB1 mRNA translation. The RRBP1 mRNA [...] Read more.

The function of ribosome binding protein 1 (RRBP1) is regulating the transportation and secretion of some intracellular proteins in mammalian cells. Transcription of RRBP1 is induced by various cytokines. However, few studies focused on the process of RRPB1 mRNA translation. The RRBP1 mRNA has a long 5′ untranslated region that potentially formed a stable secondary structure. In this study, we show that the 5′ UTR of RRBP1 mRNA contains an internal ribosome entry site (IRES). Moreover, the RRBP1 expression is induced by chemotherapeutic drug paclitaxel or adriamycin in human hepatocellular carcinoma cells and accompanied with the increased expression of La autoantigen (La), which binds to RRBP1 IRES element and facilitates translation initiation. Interestingly, we found IRES-mediated RRBP1 translation is also activated during serum-starvation condition which can induce cytoplasmic localization of La. After mapping the entire RRBP1 5′ UTR, we determine the core IRES activity is located between nt-237 and -58. Furthermore, two apical GARR loops within the functional RRBP1 IRES elements may be important for La binding. These results strongly suggest an important role for IRES-dependent translation of RRBP1 mRNA in hepatocellular carcinoma cells during cellular stress conditions. Full article

(This article belongs to the Special Issue Post-Transcriptional Gene Regulation by Ribonucleoprotein Complexes)

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10 pages, 3299 KiB

Open AccessReview

Aquaporins in the Colon as a New Therapeutic Target in Diarrhea and Constipation

by Nobutomo Ikarashi^*,†, Risako Kon^† and Kiyoshi Sugiyama

¹ Department of Clinical Pharmacokinetics, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan

^† These authors contributed equally to this work.

Int. J. Mol. Sci. 2016, 17(7), 1172; https://doi.org/10.3390/ijms17071172 - 20 Jul 2016

Cited by 122 | Viewed by 10985

Abstract

Aquaporins (AQPs) play important roles in the water transport system in the human body. There are currently 13 types of AQP, AQP0 through AQP12, which are expressed in various organs. Many members of the AQP family are expressed in the intestinal tract. AQP3 [...] Read more.

Aquaporins (AQPs) play important roles in the water transport system in the human body. There are currently 13 types of AQP, AQP0 through AQP12, which are expressed in various organs. Many members of the AQP family are expressed in the intestinal tract. AQP3 is predominantly expressed in the colon, ultimately controlling the water transport. Recently, it was clarified that several laxatives exhibit a laxative effect by changing the AQP3 expression level in the colon. In addition, it was revealed that morphine causes severe constipation by increasing the AQP3 expression level in the colon. These findings have shown that AQP3 is one of the most important functional molecules in water transport in the colon. This review will focus on the physiological and pathological roles of AQP3 in the colon, and discuss clinical applications of colon AQP3. Full article

(This article belongs to the Special Issue Aquaporin)

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13 pages, 3029 KiB

Open AccessArticle

Structural Analysis of Hand Drawn Bumblebee Bombus terrestris Silk

by Andrea L. Woodhead¹, Tara D. Sutherland²

and Jeffrey S. Church^1,*

¹ CSIRO Manufacturing, Pigdons Road, Waurn Ponds, VIC 3216, Australia

² CSIRO Food and Nutrition, Clunies Ross Street, Black Mountain, ACT 2601, Australia

Int. J. Mol. Sci. 2016, 17(7), 1170; https://doi.org/10.3390/ijms17071170 - 20 Jul 2016

Cited by 5 | Viewed by 6091

Abstract

Bombus terrestris, commonly known as the buff-tailed bumblebee, is native to Europe, parts of Africa and Asia. It is commercially bred for use as a pollinator of greenhouse crops. Larvae pupate within a silken cocoon that they construct from proteins produced in [...] Read more.

Bombus terrestris, commonly known as the buff-tailed bumblebee, is native to Europe, parts of Africa and Asia. It is commercially bred for use as a pollinator of greenhouse crops. Larvae pupate within a silken cocoon that they construct from proteins produced in modified salivary glands. The amino acid composition and protein structure of hand drawn B. terrestris, silk fibres was investigated through the use of micro-Raman spectroscopy. Spectra were obtained from single fibres drawn from the larvae salivary gland at a rate of 0.14 cm/s. Raman spectroscopy enabled the identification of poly(alanine), poly(alanine-glycine), phenylalanine, tryptophan, and methionine, which is consistent with the results of amino acid analysis. The dominant protein conformation was found to be coiled coil (73%) while the β-sheet content of 10% is, as expected, lower than those reported for hornets and ants. Polarized Raman spectra revealed that the coiled coils were highly aligned along the fibre axis while the β-sheet and random coil components had their peptide carbonyl groups roughly perpendicular to the fibre axis. The protein orientation distribution is compared to those of other natural and recombinant silks. A structural model for the B. terrestris silk fibre is proposed based on these results. Full article

(This article belongs to the Special Issue Silk-Based Materials: From Production to Characterization)

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13 pages, 400 KiB

Open AccessReview

Immune Checkpoint Inhibitors: A New Opportunity in the Treatment of Ovarian Cancer?

by Gloria Mittica^1,2,†, Sofia Genta^1,2,†, Massimo Aglietta^1,2 and Giorgio Valabrega^1,2,*

¹ Candiolo Cancer Institute-FPO-IRCCS, Candiolo, Turin 10060, Italy

² Department of Oncology, University of Torino, Turin 10060, Italy

^† These authors contributed equally to the work.

Int. J. Mol. Sci. 2016, 17(7), 1169; https://doi.org/10.3390/ijms17071169 - 20 Jul 2016

Cited by 52 | Viewed by 8834

Abstract

Epithelial ovarian cancer (EOC) is the leading cause of death for gynecological cancer. The standard treatment for advanced stage is the combination of optimal debulking surgery and platinum-based chemotherapy. Nevertheless, recurrence is frequent (around 70%) and prognosis is globally poor. New therapeutic agents [...] Read more.

Epithelial ovarian cancer (EOC) is the leading cause of death for gynecological cancer. The standard treatment for advanced stage is the combination of optimal debulking surgery and platinum-based chemotherapy. Nevertheless, recurrence is frequent (around 70%) and prognosis is globally poor. New therapeutic agents are needed to improve survival. Since EOC is strongly immunogenic, immune checkpoint inhibitors are under evaluation for their capacity to contrast the “turn off” signals expressed by the tumor to escape the immune system and usually responsible for self-tolerance maintenance. This article reviews the literature on anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies in EOC and highlights their possible lines of development. Further studies are needed to better define the prognostic role of the immune checkpoint inhibitors, to identify predictors of response and the optimal clinical setting in EOC. Full article

(This article belongs to the Special Issue Cancer Immunology with a Focus on Understudied Cancers as Targets for Immunotherapy)

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7 pages, 959 KiB

Open AccessCommunication

Inflammaging and Frailty Status Do Not Result in an Increased Extracellular Vesicle Concentration in Circulation

by Ainhoa Alberro¹

, Matías Sáenz-Cuesta^1,2, Maider Muñoz-Culla^1,2, Maider Mateo-Abad³, Esperanza Gonzalez⁴, Estefania Carrasco-Garcia⁵, Marcos J. Araúzo-Bravo^6,7

, Ander Matheu^5,7, Itziar Vergara^3,8 and David Otaegui^1,2,*

¹ Multiple Sclerosis Unit, Biodonostia Health Research Institute—Donostia University Hospital, San Sebastian 20014, Spain

² Spanish Network of Multiple Sclerosis, Barcelona 08028, Spain

³ Primary Care Research Unit-Gipuzkoa, Osakidetza, Biodonostia Health Research Institute, San Sebastian 20014, Spain

⁴ Metabolomics Unit, CIC bioGUNE, CIBERehd, Technology Park of Bizkaia, Derio, Bizkaia 48980, Spain

⁵ Cellular Oncology Group, Biodonostia Health Research Institute, San Sebastian 20014, Spain

⁶ Computational Biology and Systems Biomedicine Group, Biodonostia Health Research Institute, San Sebastian 20014, Spain

⁷ IKERBASQUE, Basque Foundation for Science, Bilbao 48015, Spain

⁸ Health Services Research on Chronic Patients Network (REDISSEC), Bilbao 48013, Spain

Int. J. Mol. Sci. 2016, 17(7), 1168; https://doi.org/10.3390/ijms17071168 - 20 Jul 2016

Cited by 25 | Viewed by 5925

Abstract

In the last decades extracellular vesicles (EVs) have emerged as key players for intercellular communication. In the case of inflammation, several studies have reported that EV levels are increased in circulation during inflammatory episodes. Based on this, we investigated whether aging results in [...] Read more.

In the last decades extracellular vesicles (EVs) have emerged as key players for intercellular communication. In the case of inflammation, several studies have reported that EV levels are increased in circulation during inflammatory episodes. Based on this, we investigated whether aging results in elevated EV number, as a basal proinflammatory status termed “inflammaging” has been described in aged individuals. Moreover, we also hypothesized that frailty and dependence conditions of the elderly could affect EV concentration in plasma. Results showed that inflammaging, frailty or dependence status do not result in EV increase, at least in the total number of EVs in circulation. These results open a new perspective for investigating the role of EVs in human aging and in the inflammaging process. Full article

(This article belongs to the Special Issue Focus on Extracellular Vesicles)

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25 pages, 1893 KiB

Open AccessReview

Clinical Metabolomics: The New Metabolic Window for Inborn Errors of Metabolism Investigations in the Post-Genomic Era

by Abdellah Tebani^1,2,3

, Lenaig Abily-Donval^2,4, Carlos Afonso³, Stéphane Marret^2,4 and Soumeya Bekri^1,2,*

¹ Department of Metabolic Biochemistry, Rouen University Hospital, Rouen 76031, France

² Normandie Univ, UNIROUEN, INSERM, CHU Rouen, IRIB, Laboratoire NeoVasc ERI28, Rouen 76000, France

³ Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA, Rouen 76000, France

⁴ Department of Neonatal Pediatrics and Intensive Care, Rouen University Hospital, Rouen 76031, France

Int. J. Mol. Sci. 2016, 17(7), 1167; https://doi.org/10.3390/ijms17071167 - 20 Jul 2016

Cited by 100 | Viewed by 13417

Abstract

Inborn errors of metabolism (IEM) represent a group of about 500 rare genetic diseases with an overall estimated incidence of 1/2500. The diversity of metabolic pathways involved explains the difficulties in establishing their diagnosis. However, early diagnosis is usually mandatory for successful treatment. [...] Read more.

Inborn errors of metabolism (IEM) represent a group of about 500 rare genetic diseases with an overall estimated incidence of 1/2500. The diversity of metabolic pathways involved explains the difficulties in establishing their diagnosis. However, early diagnosis is usually mandatory for successful treatment. Given the considerable clinical overlap between some inborn errors, biochemical and molecular tests are crucial in making a diagnosis. Conventional biological diagnosis procedures are based on a time-consuming series of sequential and segmented biochemical tests. The rise of “omic” technologies offers holistic views of the basic molecules that build a biological system at different levels. Metabolomics is the most recent “omic” technology based on biochemical characterization of metabolites and their changes related to genetic and environmental factors. This review addresses the principles underlying metabolomics technologies that allow them to comprehensively assess an individual biochemical profile and their reported applications for IEM investigations in the precision medicine era. Full article

(This article belongs to the Special Issue Metabolomic Technologies in Medicine)

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15 pages, 9951 KiB

Open AccessArticle

Leptin Receptor Metabolism Disorder in Primary Chondrocytes from Adolescent Idiopathic Scoliosis Girls

by Yun-Jia Wang

, Hong-Gui Yu, Zhen-Hai Zhou, Qiang Guo, Long-Jie Wang and Hong-Qi Zhang^*

Department of Spine Surgery, Xiangya Hospital, Central South University, No. 87, Xiangya Road, Changsha 410008, China

Int. J. Mol. Sci. 2016, 17(7), 1160; https://doi.org/10.3390/ijms17071160 - 20 Jul 2016

Cited by 30 | Viewed by 5648

Abstract

To investigate the underlying mechanisms of low metabolic activity of primary chondrocytes obtained from girls with adolescent idiopathic scoliosis (AIS); AIS is a spine-deforming disease that often occurs in girls. AIS is associated with a lower bone mass than that of healthy individuals [...] Read more.

To investigate the underlying mechanisms of low metabolic activity of primary chondrocytes obtained from girls with adolescent idiopathic scoliosis (AIS); AIS is a spine-deforming disease that often occurs in girls. AIS is associated with a lower bone mass than that of healthy individuals and osteopenia. Leptin was shown to play an important role in bone growth. It can also regulate the function of chondrocytes. Changes in leptin and Ob-R levels in AIS patients have been reported in several studies. The underlying mechanisms between the dysfunction of peripheral leptin signaling and abnormal chondrocytes remain unclear; The following parameters were evaluated in AIS patients and the control groups: total serum leptin levels; Ob-R expression in the plasma membrane of primary chondrocytes; JAK2 and STAT3 phosphorylation status. Then, we inhibited the lysosome and proteasome and knocked down clathrin heavy chain (CHC) expression in primary chondrocytes isolated from girls with AIS and evaluated Ob-R expression. We investigated the effects of leptin combined with a lysosome inhibitor or CHC knockdown in primary chondrocytes obtained from AIS patients; Compared with the controls, AIS patients showed similar total serum leptin levels, reduced JAK2 and STAT3 phosphorylation, and decreased cartilage matrix synthesis in the facet joint. Lower metabolic activity and lower membrane expression of Ob-R were observed in primary chondrocytes from the AIS group than in the controls. Lysosome inhibition increased the total Ob-R content but had no effect on the membrane expression of Ob-R or leptin’s effects on AIS primary chondrocytes. CHC knockdown upregulated the membrane Ob-R levels and enhanced leptin’s effects on AIS primary chondrocytes; The underlying mechanism of chondrocytes that are hyposensitive to leptin in some girls with AIS is low plasma membrane Ob-R expression that results from an imbalance between the rate of receptor endocytosis and the insertion of newly synthesized receptors into the membrane. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)

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9 pages, 759 KiB

Open AccessReview

Angiotensin A/Alamandine/MrgD Axis: Another Clue to Understanding Cardiovascular Pathophysiology

by Jaroslav Hrenak^1,2

, Ludovit Paulis^1,3

and Fedor Simko^1,4,5,*

¹ Institute of Pathophysiology, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia

² 1st Clinic of Medicine, Donauisar Klinikum, 944 69 Deggendorf, Germany

³ Institute of Normal and Pathological Physiology, Slovak Academy of Sciences, 814 38 Bratislava, Slovakia

⁴ 3rd Clinic of Medicine, Faculty of Medicine, Comenius University, 833 05 Bratislava, Slovakia

⁵ Institute of Experimental Endocrinology, BMC, Slovak Academy of Sciences, 814 38 Bratislava, Slovakia

Int. J. Mol. Sci. 2016, 17(7), 1098; https://doi.org/10.3390/ijms17071098 - 20 Jul 2016

Cited by 81 | Viewed by 10381

Abstract

The renin-angiotensin system (RAS) plays a crucial role in cardiovascular regulations and its modulation is a challenging target for the vast majority of cardioprotective strategies. However, many biological effects of these drugs cannot be explained by the known mode of action. Our comprehension [...] Read more.

The renin-angiotensin system (RAS) plays a crucial role in cardiovascular regulations and its modulation is a challenging target for the vast majority of cardioprotective strategies. However, many biological effects of these drugs cannot be explained by the known mode of action. Our comprehension of the RAS is thus far from complete. The RAS represents an ingenious system of “checks and balances”. It incorporates vasoconstrictive, pro-proliferative, and pro-inflammatory compounds on one hand and molecules with opposing action on the other hand. The list of these molecules is still not definitive because new biological properties can be achieved by minor alteration of the molecular structure. The angiotensin A/alamandine-MrgD cascade associates the deleterious and protective branches of the RAS. Its identification provided a novel clue to the understanding of the RAS. Angiotensin A (Ang A) is positioned at the “crossroad” in this system since it either elicits direct vasoconstrictive and pro-proliferative actions or it is further metabolized to alamandine, triggering opposing effects. Alamandine, the central molecule of this cascade, can be generated both from the “deleterious” Ang A as well as from the “protective” angiotensin 1–7. This pathway modulates peripheral and central blood pressure regulation and cardiovascular remodeling. Further research will elucidate its interactions in cardiovascular pathophysiology and its possible therapeutic implications. Full article

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

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9 pages, 1642 KiB

Open AccessArticle

Tissue-Specific Effects of Vitamin E Supplementation

by Eugene Jansen^1,*, Dale Viezeliene², Piet Beekhof¹, Eric Gremmer¹ and Leonid Ivanov²

¹ Centre for Health Protection, National Institute for Public Health and the Environment, PO Box 1, 3720 BA Bilthoven, The Netherlands

² Biochemistry Department, Medical Academy, Lithuanian University of Health Sciences, Eiveniu 4, LT-50009 Kaunas, Lithuania

Int. J. Mol. Sci. 2016, 17(7), 1166; https://doi.org/10.3390/ijms17071166 - 19 Jul 2016

Cited by 10 | Viewed by 6206

Abstract

A multivitamin and mineral supplementation study of 6 weeks was conducted with male and female mice. The control group received a standard dose of vitamins and minerals of 1× the Recommended Daily Intake (RDI), whereas a second group received 3× RDI. A third [...] Read more.

A multivitamin and mineral supplementation study of 6 weeks was conducted with male and female mice. The control group received a standard dose of vitamins and minerals of 1× the Recommended Daily Intake (RDI), whereas a second group received 3× RDI. A third group received a high dose of vitamin E (25× RDI), close to the upper limit of toxicity (UL), but still recommended and considered to be harmless and beneficial. The high dose of vitamin E caused a number of beneficial, but also adverse effects. Different biomarkers of tissue toxicity, oxidative stress related processes and inflammation were determined. These biomarkers did not change in plasma and erythrocytes to a large extent. In the liver of male mice, some beneficial effects were observed by a lower concentration of several biomarkers of inflammation. However, in the kidney of male mice, a number of biomarkers increased substantially with the higher dose of vitamin E, indicating tissue toxicity and an increased level of inflammation. Since this dose of vitamin E, which is lower than the UL, cause some adverse effects, even after a short exposure period, further studies are required to reconsider the UL for vitamin E. Full article

(This article belongs to the Special Issue Tocopherols and Tocotrienols: Metabolism and Properties)

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18 pages, 816 KiB

Open AccessReview

Senescence in Human Mesenchymal Stem Cells: Functional Changes and Implications in Stem Cell-Based Therapy

by Valentina Turinetto^*

, Emanuela Vitale and Claudia Giachino

Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Turin, Italy

Int. J. Mol. Sci. 2016, 17(7), 1164; https://doi.org/10.3390/ijms17071164 - 19 Jul 2016

Cited by 388 | Viewed by 21255

Abstract

Regenerative medicine is extensively interested in developing cell therapies using mesenchymal stem cells (MSCs), with applications to several aging-associated diseases. For successful therapies, a substantial number of cells are needed, requiring extensive ex vivo cell expansion. However, MSC proliferation is limited and it [...] Read more.

Regenerative medicine is extensively interested in developing cell therapies using mesenchymal stem cells (MSCs), with applications to several aging-associated diseases. For successful therapies, a substantial number of cells are needed, requiring extensive ex vivo cell expansion. However, MSC proliferation is limited and it is quite likely that long-term culture evokes continuous changes in MSCs. Therefore, a substantial proportion of cells may undergo senescence. In the present review, we will first present the phenotypic characterization of senescent human MSCs (hMSCs) and their possible consequent functional alterations. The accumulation of oxidative stress and dysregulation of key differentiation regulatory factors determine decreased differentiation potential of senescent hMSCs. Senescent hMSCs also show a marked impairment in their migratory and homing ability. Finally, many factors present in the secretome of senescent hMSCs are able to exacerbate the inflammatory response at a systemic level, decreasing the immune modulation activity of hMSCs and promoting either proliferation or migration of cancer cells. Considering the deleterious effects that these changes could evoke, it would appear of primary importance to monitor the occurrence of senescent phenotype in clinically expanded hMSCs and to evaluate possible ways to prevent in vitro MSC senescence. An updated critical presentation of the possible strategies for in vitro senescence monitoring and prevention constitutes the second part of this review. Understanding the mechanisms that drive toward hMSC growth arrest and evaluating how to counteract these for preserving a functional stem cell pool is of fundamental importance for the development of efficient cell-based therapeutic approaches. Full article

(This article belongs to the Special Issue DNA Damage and Repair in Degenerative Diseases 2016)

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Int. J. Mol. Sci., Volume 17, Issue 7 (July 2016) – 200 articles

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