International Journal of Molecular Sciences

15 pages, 3454 KiB

Open AccessArticle

Olmesartan Attenuates Kidney Fibrosis in a Murine Model of Alport Syndrome by Suppressing Tubular Expression of TGFβ

by Sang Heon Suh, Hong Sang Choi, Chang Seong Kim, In Jin Kim, Seong Kwon Ma, James W. Scholey, Soo Wan Kim and Eun Hui Bae

Int. J. Mol. Sci. 2019, 20(15), 3843; https://doi.org/10.3390/ijms20153843 - 06 Aug 2019

Cited by 14 | Viewed by 4125

Abstract

Despite the wide use of angiotensin II receptor blockers in the treatment of Alport syndrome (AS), the mechanism as to how angiotensin II receptor blockers prevent interstitial fibrosis remains unclear. Here, we report that treatment of olmesartan effectively targets the feedback loop between [...] Read more.

Despite the wide use of angiotensin II receptor blockers in the treatment of Alport syndrome (AS), the mechanism as to how angiotensin II receptor blockers prevent interstitial fibrosis remains unclear. Here, we report that treatment of olmesartan effectively targets the feedback loop between the renin–angiotensin system (RAS) and transforming growth factor β (TGFβ) signals in tubular epithelial cells and preserves renal angiotensin-converting enzyme 2 (ACE2) expression in the kidney of Col4a3^–/– mice, a murine model of experimental AS. Morphology analyses revealed amelioration of kidney fibrosis in Col4a3^–/– mice by olmesartan treatment. Upregulation of TGFβ and activation of its downstream in Col4a3^–/– mice were attenuated by olmesartan in Col4a3^–/– mice. Intriguingly, TGFβ expression was preferentially upregulated in damaged tubular epithelial cells in Col4a3^–/– mice. Concurrent upregulation of TNFα-converting enzyme and downregulation of ACE2 suggested RAS activation in Col4a3^–/– mice, which was prevented by olmesartan. Mechanistically, olmesartan suppressed TGFβ-induced RAS activation in tubular epithelial cells in vitro. Collectively, we concluded that olmesartan effectively suppresses the progression of tubulointerstitial fibrosis in AS by interrupting RAS-TGFβ feedback loop to counterbalance intrarenal RAS activation. Full article

(This article belongs to the Section Molecular Biology)

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32 pages, 910 KiB

Open AccessReview

Epigenetic Biomarkers in Colorectal Cancer Patients Receiving Adjuvant or Neoadjuvant Therapy: A Systematic Review of Epidemiological Studies

by Martina Barchitta, Andrea Maugeri, Giovanni Li Destri, Guido Basile and Antonella Agodi

Int. J. Mol. Sci. 2019, 20(15), 3842; https://doi.org/10.3390/ijms20153842 - 06 Aug 2019

Cited by 20 | Viewed by 4011

Abstract

Colorectal cancer (CRC) represents the third-most common cancer worldwide and one of the main challenges for public health. Despite great strides in the application of neoadjuvant and adjuvant therapies for rectal and colon cancer patients, each of these treatments is still associated with [...] Read more.

Colorectal cancer (CRC) represents the third-most common cancer worldwide and one of the main challenges for public health. Despite great strides in the application of neoadjuvant and adjuvant therapies for rectal and colon cancer patients, each of these treatments is still associated with certain adverse effects and different response rates. Thus, there is an urgent need for identifying novel potential biomarkers that might guide personalized treatments for specific subgroups of patients. However, until now, there are no biomarkers to predict the manifestation of adverse effects and the response to treatment in CRC patients. Herein, we provide a systematic review of epidemiological studies investigating epigenetic biomarkers in CRC patients receiving neoadjuvant or adjuvant therapy, and their potential role for the prediction of outcomes and response to treatment. With this aim in mind, we identified several epigenetic markers in CRC patients who received surgery with adjuvant or neoadjuvant therapy. However, none of them currently has the robustness to be translated into the clinical setting. Thus, more efforts and further large-size prospective studies and/or trials should be encouraged to develop epigenetic biomarker panels for personalized prevention and medicine in CRC cancer. Full article

(This article belongs to the Special Issue Molecular and Translational Research on Colorectal Cancer)

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30 pages, 3980 KiB

Open AccessReview

Role of Carbonic Anhydrases and Inhibitors in Acid–Base Physiology: Insights from Mathematical Modeling

by Rossana Occhipinti and Walter F. Boron

Int. J. Mol. Sci. 2019, 20(15), 3841; https://doi.org/10.3390/ijms20153841 - 06 Aug 2019

Cited by 50 | Viewed by 12555

Abstract

Carbonic anhydrases (CAs) catalyze a reaction fundamental for life: the bidirectional conversion of carbon dioxide (CO₂) and water (H₂O) into bicarbonate (HCO₃⁻) and protons (H⁺). These enzymes impact numerous physiological processes that occur within [...] Read more.

Carbonic anhydrases (CAs) catalyze a reaction fundamental for life: the bidirectional conversion of carbon dioxide (CO₂) and water (H₂O) into bicarbonate (HCO₃⁻) and protons (H⁺). These enzymes impact numerous physiological processes that occur within and across the many compartments in the body. Within compartments, CAs promote rapid H⁺ buffering and thus the stability of pH-sensitive processes. Between compartments, CAs promote movements of H⁺, CO₂, HCO₃⁻, and related species. This traffic is central to respiration, digestion, and whole-body/cellular pH regulation. Here, we focus on the role of mathematical modeling in understanding how CA enhances buffering as well as gradients that drive fluxes of CO₂ and other solutes (facilitated diffusion). We also examine urinary acid secretion and the carriage of CO₂ by the respiratory system. We propose that the broad physiological impact of CAs stem from three fundamental actions: promoting H⁺ buffering, enhancing H⁺ exchange between buffer systems, and facilitating diffusion. Mathematical modeling can be a powerful tool for: (1) clarifying the complex interdependencies among reaction, diffusion, and protein-mediated components of physiological processes; (2) formulating hypotheses and making predictions to be tested in wet-lab experiments; and (3) inferring data that are impossible to measure. Full article

(This article belongs to the Special Issue Protease and Carbonic Anhydrase Inhibitors, II)

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25 pages, 4013 KiB

Open AccessArticle

The Development of Tetrazole Derivatives as Protein Arginine Methyltransferase I (PRMT I) Inhibitors

by Yutong Sun, Zhe Wang, Hao Yang, Xuanli Zhu, Han Wu, Lu Ma, Fang Xu, Wei Hong and Hao Wang

Int. J. Mol. Sci. 2019, 20(15), 3840; https://doi.org/10.3390/ijms20153840 - 06 Aug 2019

Cited by 9 | Viewed by 3926

Abstract

Protein arginine methyltransferase 1 (PRMT1) can catalyze protein arginine methylation by transferring the methyl group from S-adenosyl-L-methionine (SAM) to the guanidyl nitrogen atom of protein arginine, which influences a variety of biological processes. The dysregulation of PRMT1 is involved in a diverse [...] Read more.

Protein arginine methyltransferase 1 (PRMT1) can catalyze protein arginine methylation by transferring the methyl group from S-adenosyl-L-methionine (SAM) to the guanidyl nitrogen atom of protein arginine, which influences a variety of biological processes. The dysregulation of PRMT1 is involved in a diverse range of diseases, including cancer. Therefore, there is an urgent need to develop novel and potent PRMT1 inhibitors. In the current manuscript, a series of 1-substituted 1H-tetrazole derivatives were designed and synthesized by targeting at the substrate arginine-binding site on PRMT1, and five compounds demonstrated significant inhibitory effects against PRMT1. The most potent PRMT1 inhibitor, compound 9a, displayed non-competitive pattern with respect to either SAM or substrate arginine, and showed the strong selectivity to PRMT1 compared to PRMT5, which belongs to the type II PRMT family. It was observed that the compound 9a inhibited the functions of PRMT1 and relative factors within this pathway, and down-regulated the canonical Wnt/β-catenin signaling pathway. The binding of compound 9a to PRMT1 was carefully analyzed by using molecular dynamic simulations and binding free energy calculations. These studies demonstrate that 9a was a potent PRMT1 inhibitor, which could be used as lead compound for further drug discovery. Full article

(This article belongs to the Section Molecular Pharmacology)

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14 pages, 1988 KiB

Open AccessArticle

Tobacco Cutworm (Spodoptera Litura) Larvae Silenced in the NADPH-Cytochrome P450 Reductase Gene Show Increased Susceptibility to Phoxim

by Hong-Yi Ji, Christian Staehelin, Yan-Ping Jiang, Shi-Wei Liu, Zhi-Hui Ma, Yi-Juan Su, Jia-En Zhang and Rui-Long Wang

Int. J. Mol. Sci. 2019, 20(15), 3839; https://doi.org/10.3390/ijms20153839 - 06 Aug 2019

Cited by 11 | Viewed by 4059

Abstract

Nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P450 reductases (CPRs) function as redox partners of cytochrome P450 monooxygenases (P450s). CPRs and P450s in insects have been found to participate in insecticide resistance. However, the CPR of the moth Spodoptera litura has not been well characterized [...] Read more.

Nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P450 reductases (CPRs) function as redox partners of cytochrome P450 monooxygenases (P450s). CPRs and P450s in insects have been found to participate in insecticide resistance. However, the CPR of the moth Spodoptera litura has not been well characterized yet. Based on previously obtained transcriptome information, a full-length CPR cDNA of S. litura (SlCPR) was PCR-cloned. The deduced amino acid sequence contains domains and residues predicted to be essential for CPR function. Phylogenetic analysis with insect CPR amino acid sequences showed that SlCPR is closely related to CPRs of Lepidoptera. Quantitative reverse transcriptase PCR (RT-qPCR) was used to determine expression levels of SlCPR in different developmental stages and tissues of S. litura. SlCPR expression was strongest at the sixth-instar larvae stage and fifth-instar larvae showed highest expression in the midgut. Expression of SlCPR in the midgut and fat body was strongly upregulated when fifth-instar larvae were exposed to phoxim at LC₁₅ (4 μg/mL) and LC₅₀ (20 μg/mL) doses. RNA interference (RNAi) mediated silencing of SlCPR increased larval mortality by 34.6% (LC₁₅ dose) and 53.5% (LC₅₀ dose). Our results provide key information on the SlCPR gene and indicate that SlCPR expression levels in S. litura larvae influence their susceptibility to phoxim and possibly other insecticides. Full article

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13 pages, 972 KiB

Open AccessReview

Recent Progress in the Regeneration of Spinal Cord Injuries by Induced Pluripotent Stem Cells

by Maria Csobonyeiova, Stefan Polak, Radoslav Zamborsky and Lubos Danisovic

Int. J. Mol. Sci. 2019, 20(15), 3838; https://doi.org/10.3390/ijms20153838 - 06 Aug 2019

Cited by 33 | Viewed by 7487

Abstract

Regeneration of injuries occurring in the central nervous system, particularly spinal cord injuries (SCIs), is extremely difficult. The complex pathological events following a SCI often restrict regeneration of nervous tissue at the injury site and frequently lead to irreversible loss of motor and [...] Read more.

Regeneration of injuries occurring in the central nervous system, particularly spinal cord injuries (SCIs), is extremely difficult. The complex pathological events following a SCI often restrict regeneration of nervous tissue at the injury site and frequently lead to irreversible loss of motor and sensory function. Neural stem/progenitor cells (NSCs/NPCs) possess neuroregenerative and neuroprotective features, and transplantation of such cells into the site of damaged tissue is a promising stem cell-based therapy for SCI. However, NSC/NPCs have mostly been induced from embryonic stem cells or fetal tissue, leading to ethical concerns. The pioneering work of Yamanaka and colleagues gave rise to the technology to induce pluripotent stem cells (iPSCs) from somatic cells, overcoming these ethical issues. The advent of iPSCs technology has meant significant progress in the therapy of neurodegenerative disease and nerve tissue damage. A number of published studies have described the successful differentiation of NSCs/NPCs from iPSCs and their subsequent engraftment into SCI animal models, followed by functional recovery of injury. The aim of this present review is to summarize various iPSC- NPCs differentiation methods, SCI modelling, and the current status of possible iPSC- NPCs- based therapy of SCI. Full article

(This article belongs to the Special Issue Disease Modeling Using Human Induced Pluripotent Stem Cells 2.0)

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31 pages, 2209 KiB

Open AccessReview

Retrotransposons in Plant Genomes: Structure, Identification, and Classification through Bioinformatics and Machine Learning

by Simon Orozco-Arias, Gustavo Isaza and Romain Guyot

Int. J. Mol. Sci. 2019, 20(15), 3837; https://doi.org/10.3390/ijms20153837 - 06 Aug 2019

Cited by 48 | Viewed by 9772

Abstract

Transposable elements (TEs) are genomic units able to move within the genome of virtually all organisms. Due to their natural repetitive numbers and their high structural diversity, the identification and classification of TEs remain a challenge in sequenced genomes. Although TEs were initially [...] Read more.

Transposable elements (TEs) are genomic units able to move within the genome of virtually all organisms. Due to their natural repetitive numbers and their high structural diversity, the identification and classification of TEs remain a challenge in sequenced genomes. Although TEs were initially regarded as “junk DNA”, it has been demonstrated that they play key roles in chromosome structures, gene expression, and regulation, as well as adaptation and evolution. A highly reliable annotation of these elements is, therefore, crucial to better understand genome functions and their evolution. To date, much bioinformatics software has been developed to address TE detection and classification processes, but many problematic aspects remain, such as the reliability, precision, and speed of the analyses. Machine learning and deep learning are algorithms that can make automatic predictions and decisions in a wide variety of scientific applications. They have been tested in bioinformatics and, more specifically for TEs, classification with encouraging results. In this review, we will discuss important aspects of TEs, such as their structure, importance in the evolution and architecture of the host, and their current classifications and nomenclatures. We will also address current methods and their limitations in identifying and classifying TEs. Full article

(This article belongs to the Section Molecular Plant Sciences)

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14 pages, 1419 KiB

Open AccessArticle

A Hydroquinone-Based Derivative Elicits Apoptosis and Autophagy via Activating a ROS-Dependent Unfolded Protein Response in Human Glioblastoma

by Silvia Zappavigna, Alessia Maria Cossu, Marianna Abate, Gabriella Misso, Angela Lombardi, Michele Caraglia and Rosanna Filosa

Int. J. Mol. Sci. 2019, 20(15), 3836; https://doi.org/10.3390/ijms20153836 - 06 Aug 2019

Cited by 9 | Viewed by 4390

Abstract

5-Lipoxygenase (5-LO) has been reported to be highly expressed in brain tumors and to promote glioma cell proliferation. Therefore, we investigated the anticancer activity of the novel 5-LO inhibitor derivative 3-tridecyl-4,5-dimethoxybenzene-1,2-diol hydroquinone (EA-100C red) on glioblastoma (GBM) cell growth. Cell viability was evaluated [...] Read more.

5-Lipoxygenase (5-LO) has been reported to be highly expressed in brain tumors and to promote glioma cell proliferation. Therefore, we investigated the anticancer activity of the novel 5-LO inhibitor derivative 3-tridecyl-4,5-dimethoxybenzene-1,2-diol hydroquinone (EA-100C red) on glioblastoma (GBM) cell growth. Cell viability was evaluated by MTT assay. The effects of the compound on apoptosis, oxidative stress and autophagy were assessed by flow cytometry (FACS). The mode of action was confirmed by Taqman apoptosis array, Real Time qPCR, confocal microscopy analysis and the western blotting technique. Our results showed that EA-100C Red had a higher anti-proliferative effect on LN229 as compared to U87MG cells. The compound induced a significant increase of apoptosis and autophagy and up-regulated pro-apoptotic genes (Bcl3, BNIP3L, and NFKBIA) in both GBM cell lines. In this light, we studied the effects of EA-100C red on the expression of CHOP and XBP1, that are implicated in ER-stress-mediated cell death. In summary, our findings revealed that EA-100C red induced ER stress-mediated apoptosis associated to autophagy in GBM cells through CHOP and Beclin1 up-regulation and activation of caspases 3, 9, JNK and NF-kappaB pathway. On these bases, EA-100C red could represent a promising compound for anti-cancer treatment. Full article

(This article belongs to the Special Issue Apoptosis and Autophagy: The Double Edge in Cancer Development and Progression and in Other Human Diseases 2.0)

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20 pages, 9657 KiB

Open AccessArticle

Biological Response to Macroporous Chitosan-Agarose Bone Scaffolds Comprising Mg- and Zn-Doped Nano-Hydroxyapatite

by Paulina Kazimierczak, Joanna Kolmas and Agata Przekora

Int. J. Mol. Sci. 2019, 20(15), 3835; https://doi.org/10.3390/ijms20153835 - 06 Aug 2019

Cited by 35 | Viewed by 4843

Abstract

Modification of implantable scaffolds with magnesium and zinc for improvement of bone regeneration is a growing trend in the engineering of biomaterials. The aim of this study was to synthesize nano-hydroxyapatite substituted with magnesium (Mg²⁺) (HA-Mg) and zinc (Zn²⁺) [...] Read more.

Modification of implantable scaffolds with magnesium and zinc for improvement of bone regeneration is a growing trend in the engineering of biomaterials. The aim of this study was to synthesize nano-hydroxyapatite substituted with magnesium (Mg²⁺) (HA-Mg) and zinc (Zn²⁺) (HA-Zn) ions in order to fabricate chitosan-agarose-hydroxyapatite (HA) scaffolds (chit/aga/HA) with improved biocompatibility. Fabricated biomaterials containing Mg²⁺ or Zn²⁺ were tested using osteoblasts and mesenchymal stem cells to determine the effect of incorporated metal ions on cell adhesion, spreading, proliferation, and osteogenic differentiation. The study was conducted in direct contact with the scaffolds (cells were seeded onto the biomaterials) and using fluid extracts of the materials. It demonstrated that incorporation of Mg²⁺ ions into chit/aga/HA structure increased spreading of the osteoblasts, promoted cell proliferation on the scaffold surface, and enhanced osteocalcin production by mesenchymal stem cells. Although biomaterial containing Zn²⁺ did not improve cell proliferation, it did enhance type I collagen production by mesenchymal stem cells and extracellular matrix mineralization as compared to cells cultured in a polystyrene well. Nevertheless, scaffolds made of pure HA gave better results than material with Zn²⁺. Results of the experiments clearly showed that modification of the chit/aga/HA scaffold with Zn²⁺ did not have any positive impact on cell behavior, whereas, incorporation of Mg²⁺ ions into its structure may significantly improve biocompatibility of the resultant material, increasing its potential in biomedical applications. Full article

(This article belongs to the Special Issue Molecular and Tissue Engineering Approaches in Musculoskeletal Regenerative Medicine)

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14 pages, 1187 KiB

Open AccessReview

Sequence and Evolutionary Features for the Alternatively Spliced Exons of Eukaryotic Genes

by Shi-Yi Chen, Cao Li, Xianbo Jia and Song-Jia Lai

Int. J. Mol. Sci. 2019, 20(15), 3834; https://doi.org/10.3390/ijms20153834 - 06 Aug 2019

Cited by 11 | Viewed by 4706

Abstract

Alternative splicing of pre-mRNAs is a crucial mechanism for maintaining protein diversity in eukaryotes without requiring a considerable increase of genes in the number. Due to rapid advances in high-throughput sequencing technologies and computational algorithms, it is anticipated that alternative splicing events will [...] Read more.

Alternative splicing of pre-mRNAs is a crucial mechanism for maintaining protein diversity in eukaryotes without requiring a considerable increase of genes in the number. Due to rapid advances in high-throughput sequencing technologies and computational algorithms, it is anticipated that alternative splicing events will be more intensively studied to address different kinds of biological questions. The occurrences of alternative splicing mean that all exons could be classified to be either constitutively or alternatively spliced depending on whether they are virtually included into all mature mRNAs. From an evolutionary point of view, therefore, the alternatively spliced exons would have been associated with distinctive biological characteristics in comparison with constitutively spliced exons. In this paper, we first outline the representative types of alternative splicing events and exon classification, and then review sequence and evolutionary features for the alternatively spliced exons. The main purpose is to facilitate understanding of the biological implications of alternative splicing in eukaryotes. This knowledge is also helpful to establish computational approaches for predicting the splicing pattern of exons. Full article

(This article belongs to the Section Molecular Informatics)

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14 pages, 5165 KiB

Open AccessReview

Current Knowledge of the Potential Links between Inflammation and Prostate Cancer

by Tommaso Cai, Raffaella Santi, Irene Tamanini, Ilaria Camilla Galli, Gianpaolo Perletti, Truls E. Bjerklund Johansen and Gabriella Nesi

Int. J. Mol. Sci. 2019, 20(15), 3833; https://doi.org/10.3390/ijms20153833 - 06 Aug 2019

Cited by 64 | Viewed by 6551

Abstract

Inflammation is inherent in prostatic diseases and it is now accepted that it may facilitate cellular proliferation in both benign and malignant conditions. The strong relationship between prostatic inflammation and pathogenesis of benign prostatic hyperplasia (BPH) is supported by epidemiologic, histopathologic and molecular [...] Read more.

Inflammation is inherent in prostatic diseases and it is now accepted that it may facilitate cellular proliferation in both benign and malignant conditions. The strong relationship between prostatic inflammation and pathogenesis of benign prostatic hyperplasia (BPH) is supported by epidemiologic, histopathologic and molecular evidence. Contrariwise, the role of inflammation in prostate carcinogenesis is still controversial, although current data indicate that the inflammatory microenvironment can regulate prostate cancer (PCa) growth and progression. Knowledge of the complex molecular landscape associated with chronic inflammation in the context of PCa may lead to the introduction and optimization of novel targeted therapies. In this perspective, evaluation of the inflammatory component in prostate specimens could be included in routine pathology reports. Full article

(This article belongs to the Special Issue Inflammation and Cancer 2018)

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29 pages, 2498 KiB

Open AccessReview

A Narrative Role of Vitamin D and Its Receptor: With Current Evidence on the Gastric Tissues

by Shaima Sirajudeen, Iltaf Shah and Asma Al Menhali

Int. J. Mol. Sci. 2019, 20(15), 3832; https://doi.org/10.3390/ijms20153832 - 05 Aug 2019

Cited by 65 | Viewed by 14074

Abstract

Vitamin D is a major steroid hormone that is gaining attention as a therapeutic molecule. Due to the general awareness of its importance for the overall well-being, vitamin D deficiency (VDD) is now recognized as a major health issue. The main reason for [...] Read more.

Vitamin D is a major steroid hormone that is gaining attention as a therapeutic molecule. Due to the general awareness of its importance for the overall well-being, vitamin D deficiency (VDD) is now recognized as a major health issue. The main reason for VDD is minimal exposure to sunlight. The vitamin D receptor (VDR) is a member of the steroid hormone receptors that induces a cascade of cell signaling to maintain healthy Ca²⁺ levels that serve to regulate several biological functions. However, the roles of vitamin D and its metabolism in maintaining gastric homeostasis have not yet been completely elucidated. Currently, there is a need to increase the vitamin D status in individuals worldwide as it has been shown to improve musculoskeletal health and reduce the risk of chronic illnesses, including some cancers, autoimmune and infectious diseases, type 2 diabetes mellitus, neurocognitive disorders, and general mortality. The role of vitamin D in gastric homeostasis is crucial and unexplored. This review attempts to elucidate the central role of vitamin D in preserving and maintaining the overall health and homeostasis of the stomach tissue. Full article

(This article belongs to the Special Issue Vitamin D and Its Analogues 2019: New Insights on Biological Effects and Therapeutic Uses)

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11 pages, 1237 KiB

Open AccessReview

The Activation Status of the TGF-β Transducer Smad2 Is Associated with a Reduced Survival in Gastrointestinal Cancers: A Systematic Review and Meta-Analysis

by Ilaria Girolami, Nicola Veronese, Lee Smith, Maria G. Caruso, Rosa Reddavide, Gioacchino Leandro, Jacopo Demurtas and Alessia Nottegar

Int. J. Mol. Sci. 2019, 20(15), 3831; https://doi.org/10.3390/ijms20153831 - 05 Aug 2019

Cited by 6 | Viewed by 6132

Abstract

Aberrant function of Smad2, a crucial member of transforming growth factor beta (TGF-β) signaling, is associated with the development of malignancies, particularly in the gastrointestinal district. However, little is known about its possible prognostic role in such tumor types. With the first meta-analysis [...] Read more.

Aberrant function of Smad2, a crucial member of transforming growth factor beta (TGF-β) signaling, is associated with the development of malignancies, particularly in the gastrointestinal district. However, little is known about its possible prognostic role in such tumor types. With the first meta-analysis on this topic, we demonstrated that the lack of the activated form of Smad2 (phosphor-Smad2 or pSmad2), which was meant to be the C-terminally phosphorylated form, showed a statistically significant association with an increased risk of all-cause mortality in patients with gastrointestinal cancers (RR, 1.58; 95% CI, 1.05–2.37, p = 0.029, I² = 84%), also after having adjusted for potential confounders (RR, 1.65; 95% CI, 1.24–2.18; p < 0.001; I² = 4%). This finding highlights the importance of the TGF-β signaling in this type of cancer. In this line, further studies are needed to explore more in depth this important molecular pathway, focusing also on potential therapeutic strategies based on its effectors or molecular targets. Full article

(This article belongs to the Special Issue TGF-Beta Super Family Signaling 2.0)

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18 pages, 2419 KiB

Open AccessReview

Biochemistry of Copper Site Assembly in Heme-Copper Oxidases: A Theme with Variations

by María-Eugenia Llases, Marcos N. Morgada and Alejandro J. Vila

Int. J. Mol. Sci. 2019, 20(15), 3830; https://doi.org/10.3390/ijms20153830 - 05 Aug 2019

Cited by 14 | Viewed by 4488

Abstract

Copper is an essential cofactor for aerobic respiration, since it is required as a redox cofactor in Cytochrome c Oxidase (COX). This ancient and highly conserved enzymatic complex from the family of heme-copper oxidase possesses two copper sites: Cu_A and Cu_B [...] Read more.

Copper is an essential cofactor for aerobic respiration, since it is required as a redox cofactor in Cytochrome c Oxidase (COX). This ancient and highly conserved enzymatic complex from the family of heme-copper oxidase possesses two copper sites: Cu_A and Cu_B. Biosynthesis of the oxidase is a complex, stepwise process that requires a high number of assembly factors. In this review, we summarize the state-of-the-art in the assembly of COX, with special emphasis in the assembly of copper sites. Assembly of the Cu_A site is better understood, being at the same time highly variable among organisms. We also discuss the current challenges that prevent the full comprehension of the mechanisms of assembly and the pending issues in the field. Full article

(This article belongs to the Special Issue Copper in Biology: Maturation of Copper Proteins and Copper Homeostasis)

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14 pages, 4432 KiB

Open AccessArticle

High-Fat Feeding in Time-Dependent Manner Affects Metabolic Routes Leading to Nervonic Acid Synthesis in NAFLD

by Karolina Konstantynowicz-Nowicka, Klaudia Berk, Adrian Chabowski, Irena Kasacka, Patrycja Bielawiec, Bartłomiej Łukaszuk and Ewa Harasim-Symbor

Int. J. Mol. Sci. 2019, 20(15), 3829; https://doi.org/10.3390/ijms20153829 - 05 Aug 2019

Cited by 14 | Viewed by 3543

Abstract

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver. The disturbances in the fatty acid composition of stored lipids are more important than the lipid species itself, which may influence the overall effect caused by these molecules. Thus, [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver. The disturbances in the fatty acid composition of stored lipids are more important than the lipid species itself, which may influence the overall effect caused by these molecules. Thus, uncovering time-dependent changes in the fatty acid composition of accumulated lipid fractions after a high fat diet seems to be a new marker of NAFLD occurrence. The experiments were conducted on high fat fed Wistar rats. The blood and liver samples were collected at the end of each experimental week and used to assess the content of lipid fractions and their fatty acid composition by gas liquid chromatography. The expression of proteins from lipid metabolism pathways and of fatty acid exporting proteins were detected by Western blotting. In the same high fat feeding period, decreased de novo lipogenesis, increased β-oxidation and lipid efflux were demonstrated. The observed effects may be the first liver protective mechanisms against lipotoxicity. Nevertheless, such effects were still not sufficient to prevent the liver from proinflammatory lipid accumulation. Moreover, the changes in liver metabolic pathways caused the plasma nervonic acid concentration in sphingomyelin to decrease simultaneously with NAFLD development, which may be a steatosis occurrence prognostic marker. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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26 pages, 2736 KiB

Open AccessArticle

Comparative Analysis of two Sugarcane Ancestors Saccharum officinarum and S. spontaneum based on Complete Chloroplast Genome Sequences and Photosynthetic Ability in Cold Stress

by Fu Xu, Lilian He, Shiwu Gao, Yachun Su, Fusheng Li and Liping Xu

Int. J. Mol. Sci. 2019, 20(15), 3828; https://doi.org/10.3390/ijms20153828 - 05 Aug 2019

Cited by 16 | Viewed by 4518

Abstract

Polyploid Saccharum with complex genomes hindered the progress of sugarcane improvement, while their chloroplast genomes are much smaller and simpler. Chloroplast (cp), the vital organelle, is the site of plant photosynthesis, which also evolves other functions, such as tolerance to environmental stresses. In [...] Read more.

Polyploid Saccharum with complex genomes hindered the progress of sugarcane improvement, while their chloroplast genomes are much smaller and simpler. Chloroplast (cp), the vital organelle, is the site of plant photosynthesis, which also evolves other functions, such as tolerance to environmental stresses. In this study, the cp genome of two sugarcane ancestors Saccharum officinarum and S. spontaneum were sequenced, and genome comparative analysis between these two species was carried out, together with the photosynthetic ability. The length is 141,187 bp for S. officinarum and that is 7 bp longer than S. spontaneum, with the same GC content (38.44%) and annotated gene number (134), 13 with introns among them. There is a typical tetrad structure, including LSC, SSC, IRb and IRa. Of them, LSC and IRa/IRb are 18 bp longer and 6 bp shorter than those in S. spontaneum (83,047 bp and 22,795 bp), respectively, while the size of SSC is same (12,544 bp). Five genes exhibit contraction and expansion at the IR junctions, but only one gene ndhF with 29 bp expansion at the border of IRb/SSC. Nucleotide diversity (Pi) based on sliding window analysis showed that the single copy and noncoding regions were more divergent than IR- and coding regions, and the variant hotspots trnG-trnM, psbM-petN, trnR-rps14, ndhC-trnV and petA-psbJ in the LSC and trnL-ccsA in the SSC regions were detected, and petA-psbJ with the highest divergent value of 0.01500. Genetic distances of 65 protein genes vary from 0.00000 to 0.00288 between two species, and the selective pressure on them indicated that only petB was subjected to positive selection, while more genes including rpoC2, rps3, ccsA, ndhA, ndhA, psbI, atpH and psaC were subjected to purifying or very strong purifying selection. There are larger number of codons in S. spontaneum than that in S. officinarum, while both species have obvious codon preference and the codons with highest-(AUG) and lowest frequency (AUA) are same. Whilst, the most abundant amino acid is leucine in both S. officinarum and S. spontaneum, with number of 2175 (10.88% of total) and 2228 (10.90% of total) codons, respectively, and the lowest number is cysteine, with only 221 (1.105%) and 224 (1.096%), respectively. Protein collinearity analysis showed the high collinearity though several divergences were present in cp genomes, and identification of simple sequence repeats (SSRs) were included in this study. In addition, in order to compare cold tolerance and explore the expanding function of this environmental stress, the chlorophyll relative content (SPAD) and chlorophyll fluorescence Fv/Fm were measured. The significantly higher SPAD were observed in S. spontaneum than those in S. officinarum, no matter what the control conditions, exposure to low temperature or during recovery, and so was for Fv/Fm under exposure to low temperature, together with higher level of SPAD in S. spontaneum in each measurement. Aforementioned results suggest much stronger photosynthetic ability and cold tolerance in S. spontaneum. Our findings build a foundation to investigate the biological mechanism of two sugarcane ancestor chloroplasts and retrieve reliable molecular resources for phylogenetic and evolutionary studies, and will be conducive to genetic improvement of photosynthetic ability and cold resistance in modern sugarcane. Full article

(This article belongs to the Section Molecular Plant Sciences)

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32 pages, 794 KiB

Open AccessReview

Current Strategies to Enhance Adipose Stem Cell Function: An Update

by Yoojin Seo, Tae-Hoon Shin and Hyung-Sik Kim

Int. J. Mol. Sci. 2019, 20(15), 3827; https://doi.org/10.3390/ijms20153827 - 05 Aug 2019

Cited by 96 | Viewed by 9309

Abstract

Mesenchymal stem cells (MSCs) emerged as a promising therapeutic tool targeting a variety of inflammatory disorders due to their multiple remarkable properties, such as superior immunomodulatory function and tissue-regenerative capacity. Although bone marrow (BM) is a dominant source for adult MSCs, increasing evidence [...] Read more.

Mesenchymal stem cells (MSCs) emerged as a promising therapeutic tool targeting a variety of inflammatory disorders due to their multiple remarkable properties, such as superior immunomodulatory function and tissue-regenerative capacity. Although bone marrow (BM) is a dominant source for adult MSCs, increasing evidence suggests that adipose tissue-derived stem cells (ASCs), which can be easily obtained at a relatively high yield, have potent therapeutic advantages comparable with BM-MSCs. Despite its outstanding benefits in pre-clinical settings, the practical efficacy of ASCs remains controversial since clinical trials with ASC application often resulted in unsatisfactory outcomes. To overcome this challenge, scientists established several strategies to generate highly functional ASCs beyond the naïve cells, including (1) pre-conditioning of ASCs with various stimulants such as inflammatory agents, (2) genetic manipulation of ASCs and (3) modification of culture conditions with three-dimensional (3D) aggregate formation and hypoxic culture. Also, exosomes and other extracellular vesicles secreted from ASCs can be applied directly to recapitulate the beneficial performance of ASCs. This review summarizes the current strategies to improve the therapeutic features of ASCs for successful clinical implementation. Full article

(This article belongs to the Special Issue Adipose Stem Cells 2019)

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13 pages, 1358 KiB

Open AccessReview

Periodontal Therapy for Improving Lipid Profiles in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis

by Siddharth Garde, Rahena Akhter, Mai Anh Nguyen, Clara K. Chow and Joerg Eberhard

Int. J. Mol. Sci. 2019, 20(15), 3826; https://doi.org/10.3390/ijms20153826 - 05 Aug 2019

Cited by 14 | Viewed by 4139

Abstract

Periodontitis is a chronic inflammatory disorder often seen in patients with diabetes mellitus (DM). Individuals with diabetes are at a greater risk of developing cardiovascular complications and this may be related, in part, to lipid abnormalities observed in these individuals. The objective of [...] Read more.

Periodontitis is a chronic inflammatory disorder often seen in patients with diabetes mellitus (DM). Individuals with diabetes are at a greater risk of developing cardiovascular complications and this may be related, in part, to lipid abnormalities observed in these individuals. The objective of this systematic review is to compile the current scientific evidence of the effects of periodontal treatment on lipid profiles in patients with type 2 diabetes mellitus. Through a systematic search using MEDLINE, EMBASE, PubMed, and Web of Science, 313 articles were identified. Of these, seven clinical trials which met all inclusion criteria were chosen for analysis. Between baseline and 3-month follow-up, there was a statistically significant reduction in the levels of total cholesterol (mean differences (MD) −0.47 mmol/L (95% confidence interval (CI), −0.75, −0.18, p = 0.001)), triglycerides (MD −0.20 mmol/L (95% CI −0.24, −0.16, p < 0.00001)) favouring the intervention arm, and a statistically significant reduction in levels of high density lipoprotein (HDL) (MD 0.06 mmol/L (95% CI 0.03, 0.08, p < 0.00001)) favouring the control arm. No significant differences were observed between baseline and 6-month follow-up levels for any lipid analysed. The heterogeneity between studies was high. This review foreshadows a potential benefit of periodontal therapy for lipid profiles in patients suffering from type 2 DM, however, well designed clinical trials using lipid profiles as primary outcome measures are warranted. Full article

(This article belongs to the Special Issue Oral Inflammations and Systemic Diseases)

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25 pages, 329 KiB

Open AccessReview

Liquid Biopsy as a Tool for Differentiation of Leiomyomas and Sarcomas of Corpus Uteri

by Dana Dvorská, Henrieta Škovierová, Dušan Braný, Erika Halašová and Zuzana Danková

Int. J. Mol. Sci. 2019, 20(15), 3825; https://doi.org/10.3390/ijms20153825 - 05 Aug 2019

Cited by 9 | Viewed by 3729

Abstract

Utilization of liquid biopsy in the management of cancerous diseases is becoming more attractive. This method can overcome typical limitations of tissue biopsies, especially invasiveness, no repeatability, and the inability to monitor responses to medication during treatment as well as condition during follow-up. [...] Read more.

Utilization of liquid biopsy in the management of cancerous diseases is becoming more attractive. This method can overcome typical limitations of tissue biopsies, especially invasiveness, no repeatability, and the inability to monitor responses to medication during treatment as well as condition during follow-up. Liquid biopsy also provides greater possibility of early prediction of cancer presence. Corpus uteri mesenchymal tumors are comprised of benign variants, which are mostly leiomyomas, but also a heterogenous group of malignant sarcomas. Pre-surgical differentiation between these tumors is very difficult and the final description of tumor characteristics usually requires excision and histological examination. The leiomyomas and malignant leiomyosarcomas are especially difficult to distinguish and can, therefore, be easily misdiagnosed. Because of the very aggressive character of sarcomas, liquid biopsy based on early diagnosis and differentiation of these tumors would be extremely helpful. Moreover, after excision of the tumor, liquid biopsy can contribute to an increased knowledge of sarcoma behavior at the molecular level, especially on the formation of metastases which is still not well understood. In this review, we summarize the most important knowledge of mesenchymal uterine tumors, the possibilities and benefits of liquid biopsy utilization, the types of molecules and cells that can be analyzed with this approach, and the possibility of their isolation and capture. Finally, we review the typical abnormalities of leiomyomas and sarcomas that can be searched and analyzed in liquid biopsy samples with the final aim to pre-surgically differentiate between benign and malignant mesenchymal tumors. Full article

(This article belongs to the Special Issue Cell-Free Nucleic Acids)

21 pages, 1478 KiB

Open AccessReview

The Autophagy Status of Cancer Stem Cells in Gliobastoma Multiforme: From Cancer Promotion to Therapeutic Strategies

by Larisa Ryskalin, Anderson Gaglione, Fiona Limanaqi, Francesca Biagioni, Pietro Familiari, Alessandro Frati, Vincenzo Esposito and Francesco Fornai

Int. J. Mol. Sci. 2019, 20(15), 3824; https://doi.org/10.3390/ijms20153824 - 05 Aug 2019

Cited by 49 | Viewed by 7042

Abstract

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor featuring rapid cell proliferation, treatment resistance, and tumor relapse. This is largely due to the coexistence of heterogeneous tumor cell populations with different grades of differentiation, and in particular, to a [...] Read more.

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor featuring rapid cell proliferation, treatment resistance, and tumor relapse. This is largely due to the coexistence of heterogeneous tumor cell populations with different grades of differentiation, and in particular, to a small subset of tumor cells displaying stem cell-like properties. This is the case of glioma stem cells (GSCs), which possess a powerful self-renewal capacity, low differentiation, along with radio- and chemo-resistance. Molecular pathways that contribute to GBM stemness of GSCs include mTOR, Notch, Hedgehog, and Wnt/β-catenin. Remarkably, among the common biochemical effects that arise from alterations in these pathways, autophagy suppression may be key in promoting GSCs self-renewal, proliferation, and pluripotency maintenance. In fact, besides being a well-known downstream event of mTOR hyper-activation, autophagy downregulation is also bound to the effects of aberrantly activated Notch, Hedgehog, and Wnt/β-catenin pathways in GBM. As a major orchestrator of protein degradation and turnover, autophagy modulates proliferation and differentiation of normal neuronal stem cells (NSCs) as well as NSCs niche maintenance, while its failure may contribute to GSCs expansion and maintenance. Thus, in the present review we discuss the role of autophagy in GSCs metabolism and phenotype in relationship with dysregulations of a variety of NSCs controlling pathways, which may provide novel insights into GBM neurobiology. Full article

(This article belongs to the Special Issue Molecular Biology of Brain Tumors)

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45 pages, 1410 KiB

Open AccessReview

Hurdles to Cardioprotection in the Critically Ill

by Louise E See Hoe, Nicole Bartnikowski, Matthew A Wells, Jacky Y Suen and John F Fraser

Int. J. Mol. Sci. 2019, 20(15), 3823; https://doi.org/10.3390/ijms20153823 - 05 Aug 2019

Cited by 4 | Viewed by 4741

Abstract

Cardiovascular disease is the largest contributor to worldwide mortality, and the deleterious impact of heart failure (HF) is projected to grow exponentially in the future. As heart transplantation (HTx) is the only effective treatment for end-stage HF, development of mechanical circulatory support (MCS) [...] Read more.

Cardiovascular disease is the largest contributor to worldwide mortality, and the deleterious impact of heart failure (HF) is projected to grow exponentially in the future. As heart transplantation (HTx) is the only effective treatment for end-stage HF, development of mechanical circulatory support (MCS) technology has unveiled additional therapeutic options for refractory cardiac disease. Unfortunately, despite both MCS and HTx being quintessential treatments for significant cardiac impairment, associated morbidity and mortality remain high. MCS technology continues to evolve, but is associated with numerous disturbances to cardiac function (e.g., oxidative damage, arrhythmias). Following MCS intervention, HTx is frequently the destination option for survival of critically ill cardiac patients. While effective, donor hearts are scarce, thus limiting HTx to few qualifying patients, and HTx remains correlated with substantial post-HTx complications. While MCS and HTx are vital to survival of critically ill cardiac patients, cardioprotective strategies to improve outcomes from these treatments are highly desirable. Accordingly, this review summarizes the current status of MCS and HTx in the clinic, and the associated cardiac complications inherent to these treatments. Furthermore, we detail current research being undertaken to improve cardiac outcomes following MCS/HTx, and important considerations for reducing the significant morbidity and mortality associated with these necessary treatment strategies. Full article

(This article belongs to the Special Issue Positive and Negative Determinants of Ischaemic Injury—Co-Morbidities and Cardioprotection)

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28 pages, 825 KiB

Open AccessReview

Progesterone and Estrogen Signaling in the Endometrium: What Goes Wrong in Endometriosis?

by Ryan M. Marquardt, Tae Hoon Kim, Jung-Ho Shin and Jae-Wook Jeong

Int. J. Mol. Sci. 2019, 20(15), 3822; https://doi.org/10.3390/ijms20153822 - 05 Aug 2019

Cited by 214 | Viewed by 26356

Abstract

In the healthy endometrium, progesterone and estrogen signaling coordinate in a tightly regulated, dynamic interplay to drive a normal menstrual cycle and promote an embryo-receptive state to allow implantation during the window of receptivity. It is well-established that progesterone and estrogen act primarily [...] Read more.

In the healthy endometrium, progesterone and estrogen signaling coordinate in a tightly regulated, dynamic interplay to drive a normal menstrual cycle and promote an embryo-receptive state to allow implantation during the window of receptivity. It is well-established that progesterone and estrogen act primarily through their cognate receptors to set off cascades of signaling pathways and enact large-scale gene expression programs. In endometriosis, when endometrial tissue grows outside the uterine cavity, progesterone and estrogen signaling are disrupted, commonly resulting in progesterone resistance and estrogen dominance. This hormone imbalance leads to heightened inflammation and may also increase the pelvic pain of the disease and decrease endometrial receptivity to embryo implantation. This review focuses on the molecular mechanisms governing progesterone and estrogen signaling supporting endometrial function and how they become dysregulated in endometriosis. Understanding how these mechanisms contribute to the pelvic pain and infertility associated with endometriosis will open new avenues of targeted medical therapies to give relief to the millions of women suffering its effects. Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction)

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19 pages, 1474 KiB

Open AccessReview

Epidermal Growth Factor Receptor (EGFR) Pathway, Yes-Associated Protein (YAP) and the Regulation of Programmed Death-Ligand 1 (PD-L1) in Non-Small Cell Lung Cancer (NSCLC)

by Ping-Chih Hsu, David M. Jablons, Cheng-Ta Yang and Liang You

Int. J. Mol. Sci. 2019, 20(15), 3821; https://doi.org/10.3390/ijms20153821 - 05 Aug 2019

Cited by 116 | Viewed by 18931

Abstract

The epidermal growth factor receptor (EGFR) pathway is a well-studied oncogenic pathway in human non-small cell lung cancer (NSCLC). A subset of advanced NSCLC patients (15–55%) have EGFR-driven mutations and benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs). Immune checkpoint inhibitors (ICIs) targeting [...] Read more.

The epidermal growth factor receptor (EGFR) pathway is a well-studied oncogenic pathway in human non-small cell lung cancer (NSCLC). A subset of advanced NSCLC patients (15–55%) have EGFR-driven mutations and benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs). Immune checkpoint inhibitors (ICIs) targeting the PD-1/PDL-1 axis are a new anti-cancer therapy for metastatic NSCLC. The anti-PD-1/PDL-1 ICIs showed promising efficacy (~30% response rate) and improved the survival of patients with metastatic NSCLC, but the role of anti-PD-1/PDL-1 ICIs for EGFR mutant NSCLC is not clear. YAP (yes-associated protein) is the main mediator of the Hippo pathway and has been identified as promoting cancer progression, drug resistance, and metastasis in NSCLC. Here, we review recent studies that examined the correlation between the EGFR, YAP pathways, and PD-L1 and demonstrate the mechanism by which EGFR and YAP regulate PD-L1 expression in human NSCLC. About 50% of EGFR mutant NSCLC patients acquire resistance to EGFR-TKIs without known targetable secondary mutations. Targeting YAP therapy is suggested as a potential treatment for NSCLC with acquired resistance to EGFR-TKIs. Future work should focus on the efficacy of YAP inhibitors in combination with immune checkpoint PD-L1/PD-1 blockade in EGFR mutant NSCLC without targetable resistant mutations. Full article

(This article belongs to the Special Issue PD-L1, A Master Regulator of Immunity)

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16 pages, 5247 KiB

Open AccessArticle

Anti-Proliferative and Pro-Apoptotic Effects of Licochalcone A through ROS-Mediated Cell Cycle Arrest and Apoptosis in Human Bladder Cancer Cells

by Su Hyun Hong, Hee-Jae Cha, Hyun Hwang-Bo, Min Yeong Kim, So Young Kim, Seon Yeong Ji, JaeHun Cheong, Cheol Park, Hyesook Lee, Gi-Young Kim, Sung-Kwon Moon, Seok Joong Yun, Young-Chae Chang, Wun-Jae Kim and Yung Hyun Choi

Int. J. Mol. Sci. 2019, 20(15), 3820; https://doi.org/10.3390/ijms20153820 - 05 Aug 2019

Cited by 49 | Viewed by 4785

Abstract

Licochalcone A (LCA) is a chalcone that is predominantly found in the root of Glycyrrhiza species, which is widely used as an herbal medicine. Although previous studies have reported that LCA has a wide range of pharmacological effects, evidence for the underlying molecular [...] Read more.

Licochalcone A (LCA) is a chalcone that is predominantly found in the root of Glycyrrhiza species, which is widely used as an herbal medicine. Although previous studies have reported that LCA has a wide range of pharmacological effects, evidence for the underlying molecular mechanism of its anti-cancer efficacy is still lacking. In this study, we investigated the anti-proliferative effect of LCA on human bladder cancer cells, and found that LCA induced cell cycle arrest at G2/M phase and apoptotic cell death. Our data showed that LCA inhibited the expression of cyclin A, cyclin B1, and Wee1, but increased the expression of cyclin-dependent kinase (Cdk) inhibitor p21WAF1/CIP1, and increased p21 was bound to Cdc2 and Cdk2. LCA activated caspase-8 and -9, which are involved in the initiation of extrinsic and intrinsic apoptosis pathways, respectively, and also increased caspase-3 activity, a typical effect caspase, subsequently leading to poly (ADP-ribose) polymerase cleavage. Additionally, LCA increased the Bax/Bcl-2 ratio, and reduced the integrity of mitochondria, which contributed to the discharge of cytochrome c from the mitochondria to the cytoplasm. Moreover, LCA enhanced the intracellular levels of reactive oxygen species (ROS); however, the interruption of ROS generation using ROS scavenger led to escape from LCA-mediated G2/M arrest and apoptosis. Collectively, the present data indicate that LCA can inhibit the proliferation of human bladder cancer cells by inducing ROS-dependent G2/M phase arrest and apoptosis. Full article

(This article belongs to the Special Issue Bioactive Phytochemicals for Cancer Prevention and Treatment)

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18 pages, 3989 KiB

Open AccessArticle

Activity Coefficients for Liquid Organic Reactions: Towards a Better Understanding of True Kinetics with the Synthesis of Jasmin Aldehyde as Showcase

by Philippe M. Heynderickx

Int. J. Mol. Sci. 2019, 20(15), 3819; https://doi.org/10.3390/ijms20153819 - 05 Aug 2019

Cited by 9 | Viewed by 3503

Abstract

The aldol condensation of benzaldehyde and heptanal is taken as an example of reversible liquid phase organic reactions to show that inclusion of activity coefficients reveal distinct differences in conversion and product distribution when different solvents methanol, ethanol, n-propanol, or n-butanol are used. [...] Read more.

The aldol condensation of benzaldehyde and heptanal is taken as an example of reversible liquid phase organic reactions to show that inclusion of activity coefficients reveal distinct differences in conversion and product distribution when different solvents methanol, ethanol, n-propanol, or n-butanol are used. The purpose of this work is to show a pronounced solvent effect for a given set of identical kinetic parameters, i.e., the same liquid phase kinetics can result in different conversion and yield values, depending on the choice of solvent. It was shown that subsequent parameter estimation without inclusion of the activity coefficients resulted in a pronounced deviation from the ‘true’ kinetics, up to a factor of 30. It is proposed that the usage of average activity coefficients gives already a significant improvement, resulting in acceptable parameter estimates. Full article

(This article belongs to the Special Issue Solution Chemical Kinetics 2.0)

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18 pages, 4053 KiB

Open AccessArticle

Identification and Clinical Validation of a Novel 4 Gene-Signature with Prognostic Utility in Colorectal Cancer

by Pankaj Ahluwalia, Ashis K. Mondal, Chance Bloomer, Sadanand Fulzele, Kimya Jones, Sudha Ananth, Gagandeep K. Gahlay, Saleh Heneidi, Amyn M. Rojiani, Vamsi Kota and Ravindra Kolhe

Int. J. Mol. Sci. 2019, 20(15), 3818; https://doi.org/10.3390/ijms20153818 - 05 Aug 2019

Cited by 39 | Viewed by 5433

Abstract

Colorectal cancer (CRC) is a high burden disease with several genes involved in tumor progression. The aim of the present study was to identify, generate and clinically validate a novel gene signature to improve prediction of overall survival (OS) to effectively manage colorectal [...] Read more.

Colorectal cancer (CRC) is a high burden disease with several genes involved in tumor progression. The aim of the present study was to identify, generate and clinically validate a novel gene signature to improve prediction of overall survival (OS) to effectively manage colorectal cancer. We explored The Cancer Genome Atlas (TCGA), COAD and READ datasets (597 samples) from The Protein Atlas (TPA) database to extract a total of 595 candidate genes. In parallel, we identified 29 genes with perturbations in > 6 cancers which are also affected in CRC. These genes were entered in cBioportal to generate a 17 gene panel with highest perturbations. For clinical validation, this gene panel was tested on the FFPE tissues of colorectal cancer patients (88 patients) using Nanostring analysis. Using multivariate analysis, a high prognostic score (composite 4 gene signature—DPP7/2, YWHAB, MCM4 and FBXO46) was found to be a significant predictor of poor prognosis in CRC patients (HR: 3.42, 95% CI: 1.71–7.94, p < 0.001 *) along with stage (HR: 4.56, 95% CI: 1.35–19.15, p = 0.01 *). The Kaplan-Meier analysis also segregated patients on the basis of prognostic score (log-rank test, p = 0.001 *). The external validation using GEO dataset (GSE38832, 122 patients) corroborated the prognostic score (HR: 2.7, 95% CI: 1.99–3.73, p < 0.001 *). Additionally, higher score was able to differentiate stage II and III patients (130 patients) on the basis of OS (HR: 2.5, 95% CI: 1.78–3.63, p < 0.001 *). Overall, our results identify a novel 4 gene prognostic signature that has clinical utility in colorectal cancer. Full article

(This article belongs to the Section Molecular Oncology)

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19 pages, 4064 KiB

Open AccessArticle

Protein Phosphatase Ppz1 Is Not Regulated by a Hal3-Like Protein in Plant Pathogen Ustilago maydis

by Chunyi Zhang, Antonio de la Torre, José Pérez-Martín and Joaquín Ariño

Int. J. Mol. Sci. 2019, 20(15), 3817; https://doi.org/10.3390/ijms20153817 - 05 Aug 2019

Cited by 5 | Viewed by 3774

Abstract

Ppz enzymes are type-1 related Ser/Thr protein phosphatases that are restricted to fungi. In S. cerevisiae and other fungi, Ppz1 is involved in cation homeostasis and is regulated by two structurally-related inhibitory subunits, Hal3 and Vhs3, with Hal3 being the most physiologically relevant. [...] Read more.

Ppz enzymes are type-1 related Ser/Thr protein phosphatases that are restricted to fungi. In S. cerevisiae and other fungi, Ppz1 is involved in cation homeostasis and is regulated by two structurally-related inhibitory subunits, Hal3 and Vhs3, with Hal3 being the most physiologically relevant. Remarkably, Hal3 and Vhs3 have moonlighting properties, as they participate in an atypical heterotrimeric phosphopantothenoyl cysteine decarboxylase (PPCDC), a key enzyme for Coenzyme A biosynthesis. Here we identify and functionally characterize Ppz1 phosphatase (UmPpz1) and its presumed regulatory subunit (UmHal3) in the plant pathogen fungus Ustilago maydis. UmPpz1 is not an essential protein in U. maydis and, although possibly related to the cell wall integrity pathway, is not involved in monovalent cation homeostasis. The expression of UmPpz1 in S. cerevisiae Ppz1-deficient cells partially mimics the functions of the endogenous enzyme. In contrast to what was found in C. albicans and A. fumigatus, UmPpz1 is not a virulence determinant. UmHal3, an unusually large protein, is the only functional PPCDC in U. maydis and, therefore, an essential protein. However, when overexpressed in U. maydis or S. cerevisiae, UmHal3 does not reproduce Ppz1-inhibitory phenotypes. Indeed, UmHal3 does not inhibit UmPpz1 in vitro (although ScHal3 does). Therefore, UmHal3 might not be a moonlighting protein. Full article

(This article belongs to the Collection Feature Papers in Molecular Microbiology)

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21 pages, 3830 KiB

Open AccessArticle

Supercritical Fluid Extract of Angelica sinensis and Zingiber officinale Roscoe Ameliorates TNBS-Induced Colitis in Rats

by Jia Liu, Ling Yu, Nuolan Mo, Hai Lan, Yan Zhang, Xin Liu and Qing Wu

Int. J. Mol. Sci. 2019, 20(15), 3816; https://doi.org/10.3390/ijms20153816 - 05 Aug 2019

Cited by 7 | Viewed by 4227

Abstract

Inflammatory bowel disease (IBD) is a worldwide healthcare problem calling for the development of new therapeutic drugs. Angelica sinensis and Zingiber officinale Roscoe are two common dietetic Chinese herbs, which are traditionally used for complementary treatment of gastrointestinal disorders. As bioactive constituents, volatile [...] Read more.

Inflammatory bowel disease (IBD) is a worldwide healthcare problem calling for the development of new therapeutic drugs. Angelica sinensis and Zingiber officinale Roscoe are two common dietetic Chinese herbs, which are traditionally used for complementary treatment of gastrointestinal disorders. As bioactive constituents, volatile and pungent substances of these two herbs could be effectively extracted together by supercritical fluid extraction. In this study, the supercritical fluid extract of Angelica sinensis and Zingiber officinale Roscoe (AZ-SFE) was obtained by an optimized extraction process and it was chemically characterized. The anti-inflammatory effect and underlying mechanism of AZ-SFE were evaluated in a lipopolysaccharide (LPS)-induced RAW264.7 cell model and a 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced colitis rat model. AZ-SFE notably inhibited the production of NO in LPS-stimulated macrophages, and it inhibited the proliferation of Concanavalin A (Con A)-induced splenocytes with suppression of the Th1 immune response. In vivo, the study demonstrated that AZ-SFE significantly alleviated disease activity, colonic shortening, macroscopic damage and histological injury of TNBS-treated rats with reduction of oxidative stress, suppression of inflammatory cytokines, and modulation of hepcidin and serum iron. These findings suggested that AZ-SFE may be a promising supplement for current IBD therapy. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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18 pages, 642 KiB

Open AccessReview

Dual Role of Reactive Oxygen Species in Muscle Function: Can Antioxidant Dietary Supplements Counteract Age-Related Sarcopenia?

by Simona Damiano, Espedita Muscariello, Giuliana La Rosa, Martina Di Maro, Paolo Mondola and Mariarosaria Santillo

Int. J. Mol. Sci. 2019, 20(15), 3815; https://doi.org/10.3390/ijms20153815 - 05 Aug 2019

Cited by 64 | Viewed by 7074

Abstract

Sarcopenia is characterized by the progressive loss of skeletal muscle mass and strength. In older people, malnutrition and physical inactivity are often associated with sarcopenia, and, therefore, dietary interventions and exercise must be considered to prevent, delay, or treat it. Among the pathophysiological [...] Read more.

Sarcopenia is characterized by the progressive loss of skeletal muscle mass and strength. In older people, malnutrition and physical inactivity are often associated with sarcopenia, and, therefore, dietary interventions and exercise must be considered to prevent, delay, or treat it. Among the pathophysiological mechanisms leading to sarcopenia, a key role is played by an increase in reactive oxygen and nitrogen species (ROS/RNS) levels and a decrease in enzymatic antioxidant protection leading to oxidative stress. Many studies have evaluated, in addition to the effects of exercise, the effects of antioxidant dietary supplements in limiting age-related muscle mass and performance, but the data which have been reported are conflicting. In skeletal muscle, ROS/RNS have a dual function: at low levels they increase muscle force and adaptation to exercise, while at high levels they lead to a decline of muscle performance. Controversial results obtained with antioxidant supplementation in older persons could in part reflect the lack of univocal effects of ROS on muscle mass and function. The purpose of this review is to examine the molecular mechanisms underlying the dual effects of ROS in skeletal muscle function and the analysis of literature data on dietary antioxidant supplementation associated with exercise in normal and sarcopenic subjects. Full article

(This article belongs to the Special Issue Physiological and Pathological Role of ROS: Benefits and Limitations of Antioxidant Treatment)

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19 pages, 3625 KiB

Open AccessArticle

SUSD2 Proteolytic Cleavage Requires the GDPH Sequence and Inter-Fragment Disulfide Bonds for Surface Presentation of Galectin-1 on Breast Cancer Cells

by Mitch E. Patrick and Kristi A. Egland

Int. J. Mol. Sci. 2019, 20(15), 3814; https://doi.org/10.3390/ijms20153814 - 05 Aug 2019

Cited by 8 | Viewed by 4229

Abstract

Galectin-1 (Gal-1) is a 14 kDa protein that has been well characterized for promoting cancer metastasis and tumor immune evasion. By localizing to the cancer cell surface, Gal-1 induces T cell apoptosis through binding T cell surface receptors. The transmembrane protein, Sushi Domain [...] Read more.

Galectin-1 (Gal-1) is a 14 kDa protein that has been well characterized for promoting cancer metastasis and tumor immune evasion. By localizing to the cancer cell surface, Gal-1 induces T cell apoptosis through binding T cell surface receptors. The transmembrane protein, Sushi Domain Containing 2 (SUSD2), has been previously shown to be required for Gal-1 surface presentation in breast cancer cells. Western immunoblot analysis revealed that SUSD2 is cleaved into two fragments. However, the significance of this cleavage for Gal-1 surface localization has not been investigated. To define the location of cleavage, a mutagenesis analysis of SUSD2 was performed. Our studies demonstrated that SUSD2 is cleaved at its glycine-aspartic acid-proline-histidine (GDPH) amino acid sequence. Generation of a noncleavable SUSD2 mutant (GDPH∆-SUSD2) showed that SUSD2 cleavage was required for SUSD2 and Gal-1 plasma membrane localization. Noncleavable cysteine mutants were also unable to present Gal-1 at the cell surface, further demonstrating that SUSD2 cleavage is required for Gal-1 surface presentation. Treatment with the serine protease inhibitor, Pefabloc SC, inhibited SUSD2 cleavage in a dose dependent manner, suggesting that SUSD2 is cleaved by a serine protease. Therefore, identification and inhibition of this protease may provide a new therapeutic tool for inhibiting SUSD2 and Gal-1′s combined tumorigenic function in breast cancer. Full article

(This article belongs to the Special Issue Galectins in Cancer and Translational Research 2.0)

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Int. J. Mol. Sci., Volume 20, Issue 15 (August-1 2019) – 236 articles

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