International Journal of Molecular Sciences

16 pages, 5767 KiB

Open AccessArticle

Structural Reorganization of Imidazolium Ionic Liquids Induced by Pressure-Enhanced Ionic Liquid—Polyethylene Oxide Interactions

by Teng-Hui Wang, Li-Wen Hsu and Hai-Chou Chang

Int. J. Mol. Sci. 2021, 22(2), 981; https://doi.org/10.3390/ijms22020981 - 19 Jan 2021

Cited by 5 | Viewed by 3578

Abstract

Mixtures of polyethylene oxide (PEO, M.W.~900,000) and imidazolium ionic liquids (ILs) are studied using high-pressure Fourier-transform infrared spectroscopy. At ambient pressure, the spectral features in the C–H stretching region reveal that PEO can disturb the local structures of the imidazolium rings of [BMIM] [...] Read more.

Mixtures of polyethylene oxide (PEO, M.W.~900,000) and imidazolium ionic liquids (ILs) are studied using high-pressure Fourier-transform infrared spectroscopy. At ambient pressure, the spectral features in the C–H stretching region reveal that PEO can disturb the local structures of the imidazolium rings of [BMIM]⁺ and [HMIM]⁺. The pressure-induced phase transition of pure 1-butyl-3-methylimidazolium bromide ([BMIM]Br) is observed at a pressure of 0.4 GPa. Pressure-enhanced [BMIM]Br-PEO interactions may assist PEO in dividing [BMIM]Br clusters to hinder the aggregation of [BMIM]Br under high pressures. The C–H absorptions of pure 1-hexyl-3-methylimidazolium bromide [HMIM]Br do not show band narrowing under high pressures, as observed for pure [BMIM]Br. The band narrowing of C–H peaks is observed at 1.5 GPa for the [HMIM]Br-PEO mixture containing 80 wt% of [HMIM]Br. The presence of PEO may reorganize [HMIM]Br clusters into a semi-crystalline network under high pressures. The differences in aggregation states for ambient-pressure phase and high-pressure phase may suggest the potential of [HMIM]Br-PEO (M.W.~900,000) for serving as optical or electronic switches. Full article

(This article belongs to the Special Issue Ionic Liquids: Applications in Energy and Environment)

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24 pages, 30045 KiB

Open AccessArticle

Impact of Selected Signaling Proteins on SNAIL 1 and SNAIL 2 Expression in Ovarian Cancer Cell Lines in Relation to Cells’ Cisplatin Resistance and EMT Markers Level

by Michal Kielbik, Izabela Szulc-Kielbik and Magdalena Klink

Int. J. Mol. Sci. 2021, 22(2), 980; https://doi.org/10.3390/ijms22020980 - 19 Jan 2021

Cited by 16 | Viewed by 3751

Abstract

It has been increasingly recognized that SNAIL1 and SNAIL2, as major EMT-inducers, might also be involved in drug resistance of cancer cells. We sought to determine a relation between SNAIL1/2, E-cadherin and N-cadherin expression, as well as ovarian cancer cells’ resistance to cisplatin [...] Read more.

It has been increasingly recognized that SNAIL1 and SNAIL2, as major EMT-inducers, might also be involved in drug resistance of cancer cells. We sought to determine a relation between SNAIL1/2, E-cadherin and N-cadherin expression, as well as ovarian cancer cells’ resistance to cisplatin and EMT markers’ level. Thus, four ovarian cancer cell lines, were used: A2780, A2780cis, SK-OV-3 and OVCAR-3. We assessed the impact of ERK1/2, AKT and STAT3 proteins (chosen by the profiling activity of over 40 signaling proteins) on SNAIL1/2 expression, along with E-cadherin and N-cadherin levels. We showed that expression of SNAIL1 and N-cadherin are the highest in cisplatin-resistant A2780cis and SK-OV-3 cells, while high SNAIL2 and E-cadherin levels were observed in cisplatin-sensitive A2780 cells. The highest E-cadherin level was noticed in OVCAR-3 cells. SNAIL1/2 expression was dependent on ERK1/2 activity in cisplatin-resistant and potentially invasive SK-OV-3 and OVCAR-3 cells. STAT-3 regulates expression of SNAIL1/2 and leads to the so-called “cadherin switch” in cancer cells, independently of their chemoresistance. In conclusion, SNAIL1, but not SNAIL2, seems to be involved in ovarian cancer cells’ cisplatin resistance. STAT3 is a universal factor determining the expression of SNAIL1/2 in ovarian cancer cells regardless of their chemoresitance or invasive capabilities. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Ovarian Cancer Development and Metastasis 2.0)

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29 pages, 4797 KiB

Open AccessArticle

Isolation and Characterization of Equine Uterine Extracellular Vesicles: A Comparative Methodological Study

by Carmen Almiñana, Alba Rudolf Vegas, Muhittin Tekin, Mubbashar Hassan, Rustem Uzbekov, Thomas Fröhlich, Heinrich Bollwein and Stefan Bauersachs

Int. J. Mol. Sci. 2021, 22(2), 979; https://doi.org/10.3390/ijms22020979 - 19 Jan 2021

Cited by 21 | Viewed by 4768

Abstract

Extracellular vesicles (EVs) have been identified in the uterine fluid in different species and have been pointed as key players in the embryo-maternal dialogue, maternal recognition of pregnancy and establishment of pregnancy. However, little is known about the uterine EVs in the mare. [...] Read more.

Extracellular vesicles (EVs) have been identified in the uterine fluid in different species and have been pointed as key players in the embryo-maternal dialogue, maternal recognition of pregnancy and establishment of pregnancy. However, little is known about the uterine EVs in the mare. Therefore, the present study aimed at characterizing EVs from uterine lavage of cyclic mares by comparing five EVs isolation methods and the combination of them: (1) ultracentrifugation (UC); (2) concentration of lavage volume by Centricon ultrafiltration (CE); (3) the use of CE with different washing steps (phosphate-buffered saline with or without trehalose); (4) size-exclusion chromatography with iZON-qEV columns, and (5) a combination of the methods with best results based on EVs yield, purity, and protein cargo profiles. Transmission electron microscopy and Western blotting confirmed the isolation of EVs by all methods but with quantitative and qualitative differences. Mass spectrometry provided differences in protein profiles between methods, number of identified proteins, and protein classes. Our results indicate that the combination of CE/trehalose/iZON/UC is an optimal method to isolate equine uterine EVs with good yield and purity that can be applied in future studies to determine the role of equine uterine EVs in embryo-maternal interactions. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Reproduction)

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14 pages, 7756 KiB

Open AccessArticle

Venous and Arterial Endothelial Cells from Human Umbilical Cords: Potential Cell Sources for Cardiovascular Research

by Skadi Lau, Manfred Gossen, Andreas Lendlein and Friedrich Jung

Int. J. Mol. Sci. 2021, 22(2), 978; https://doi.org/10.3390/ijms22020978 - 19 Jan 2021

Cited by 26 | Viewed by 4816

Abstract

Although cardiovascular devices are mostly implanted in arteries or to replace arteries, in vitro studies on implant endothelialization are commonly performed with human umbilical cord-derived venous endothelial cells (HUVEC). In light of considerable differences, both morphologically and functionally, between arterial and venous endothelial [...] Read more.

Although cardiovascular devices are mostly implanted in arteries or to replace arteries, in vitro studies on implant endothelialization are commonly performed with human umbilical cord-derived venous endothelial cells (HUVEC). In light of considerable differences, both morphologically and functionally, between arterial and venous endothelial cells, we here compare HUVEC and human umbilical cord-derived arterial endothelial cells (HUAEC) regarding their equivalence as an endothelial cell in vitro model for cardiovascular research. No differences were found in either for the tested parameters. The metabolic activity and lactate dehydrogenase, an indicator for the membrane integrity, slightly decreased over seven days of cultivation upon normalization to the cell number. The amount of secreted nitrite and nitrate, as well as prostacyclin per cell, also decreased slightly over time. Thromboxane B2 was secreted in constant amounts per cell at all time points. The Von Willebrand factor remained mainly intracellularly up to seven days of cultivation. In contrast, collagen and laminin were secreted into the extracellular space with increasing cell density. Based on these results one might argue that both cell types are equally suited for cardiovascular research. However, future studies should investigate further cell functionalities, and whether arterial endothelial cells from implantation-relevant areas, such as coronary arteries in the heart, are superior to umbilical cord-derived endothelial cells. Full article

(This article belongs to the Special Issue Future Trends in Biomaterials and Devices for Cells and Tissues)

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22 pages, 993 KiB

Open AccessReview

Autocrine TGF-β in Cancer: Review of the Literature and Caveats in Experimental Analysis

by Hendrik Ungefroren

Int. J. Mol. Sci. 2021, 22(2), 977; https://doi.org/10.3390/ijms22020977 - 19 Jan 2021

Cited by 28 | Viewed by 4600

Abstract

Autocrine signaling is defined as the production and secretion of an extracellular mediator by a cell followed by the binding of that mediator to receptors on the same cell to initiate signaling. Autocrine stimulation often operates in autocrine loops, a type of interaction, [...] Read more.

Autocrine signaling is defined as the production and secretion of an extracellular mediator by a cell followed by the binding of that mediator to receptors on the same cell to initiate signaling. Autocrine stimulation often operates in autocrine loops, a type of interaction, in which a cell produces a mediator, for which it has receptors, that upon activation promotes expression of the same mediator, allowing the cell to repeatedly autostimulate itself (positive feedback) or balance its expression via regulation of a second factor that provides negative feedback. Autocrine signaling loops with positive or negative feedback are an important feature in cancer, where they enable context-dependent cell signaling in the regulation of growth, survival, and cell motility. A growth factor that is intimately involved in tumor development and progression and often produced by the cancer cells in an autocrine manner is transforming growth factor-β (TGF-β). This review surveys the many observations of autocrine TGF-β signaling in tumor biology, including data from cell culture and animal models as well as from patients. We also provide the reader with a critical discussion on the various experimental approaches employed to identify and prove the involvement of autocrine TGF-β in a given cellular response. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Biochemistry)

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17 pages, 3284 KiB

Open AccessArticle

NECTIN4: A Novel Therapeutic Target for Melanoma

by Yuka Tanaka, Maho Murata, Che-Hung Shen, Masutaka Furue and Takamichi Ito

Int. J. Mol. Sci. 2021, 22(2), 976; https://doi.org/10.3390/ijms22020976 - 19 Jan 2021

Cited by 25 | Viewed by 5117

Abstract

Malignant melanoma is the most common lethal skin cancer and causes death in a short time when metastasized. Although BRAF inhibitors (BRAFi) have greatly improved the prognosis of BRAF-mutated melanoma, drug resistance is a major concern even when they are combined with MEK [...] Read more.

Malignant melanoma is the most common lethal skin cancer and causes death in a short time when metastasized. Although BRAF inhibitors (BRAFi) have greatly improved the prognosis of BRAF-mutated melanoma, drug resistance is a major concern even when they are combined with MEK inhibitors. Alternative treatments for BRAFi-resistant melanoma are highly anticipated. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed and associated with progression in tumors. We aimed to investigate the role of NECTIN4 in melanoma and its potency as a therapeutic target using 126 melanoma samples and BRAFi-resistant cells. Immunohistochemically, most of the clinical samples expressed NECTIN4, at least in part. NECTIN4 was highly expressed in BRAF-mutated melanoma and its high expression was associated with disease-free survival. In BRAFi-resistant melanoma cells, NECTIN4 and the PI3K/Akt pathway were upregulated, along with the acquisition of BRAFi resistance. Monomethyl auristatin E, a cytotoxic part of NECTIN4-targeted antibody–drug conjugate, was effective for BRAF-mutated or BRAFi-resistant melanoma cells. NECTIN4 inhibition increased the sensitivity of BRAFi-resistant cells to BRAFi and induced apoptosis. In conclusion, we revealed the expression and roles of NECTIN4 in melanoma. Targeted therapies against NECTIN4 can be a novel treatment strategy for melanoma, even after the acquisition of BRAFi resistance. Full article

(This article belongs to the Special Issue Skin Cancer and Melanoma)

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18 pages, 6696 KiB

Open AccessReview

The Protein Phosphatase PP2A Plays Multiple Roles in Plant Development by Regulation of Vesicle Traffic—Facts and Questions

by Csaba Máthé, Márta M-Hamvas, Csongor Freytag and Tamás Garda

Int. J. Mol. Sci. 2021, 22(2), 975; https://doi.org/10.3390/ijms22020975 - 19 Jan 2021

Cited by 14 | Viewed by 4749

Abstract

The protein phosphatase PP2A is essential for the control of integrated eukaryotic cell functioning. Several cellular and developmental events, e.g., plant growth regulator (PGR) mediated signaling pathways are regulated by reversible phosphorylation of vesicle traffic proteins. Reviewing present knowledge on the relevant role [...] Read more.

The protein phosphatase PP2A is essential for the control of integrated eukaryotic cell functioning. Several cellular and developmental events, e.g., plant growth regulator (PGR) mediated signaling pathways are regulated by reversible phosphorylation of vesicle traffic proteins. Reviewing present knowledge on the relevant role of PP2A is timely. We discuss three aspects: (1) PP2A regulates microtubule-mediated vesicle delivery during cell plate assembly. PP2A dephosphorylates members of the microtubule associated protein family MAP65, promoting their binding to microtubules. Regulation of phosphatase activity leads to changes in microtubule organization, which affects vesicle traffic towards cell plate and vesicle fusion to build the new cell wall between dividing cells. (2) PP2A-mediated inhibition of target of rapamycin complex (TORC) dependent signaling pathways contributes to autophagy and this has possible connections to the brassinosteroid signaling pathway. (3) Transcytosis of vesicles transporting PIN auxin efflux carriers. PP2A regulates vesicle localization and recycling of PINs related to GNOM (a GTP–GDP exchange factor) mediated pathways. The proper intracellular traffic of PINs is essential for auxin distribution in the plant body, thus in whole plant development. Overall, PP2A has essential roles in membrane interactions of plant cell and it is crucial for plant development and stress responses. Full article

(This article belongs to the Special Issue Plant Cell and Organism Development 2.0)

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11 pages, 2129 KiB

Open AccessReview

The Immunopathological and Histological Landscape of COVID-19-Mediated Lung Injury

by Giovanni Zarrilli, Valentina Angerilli, Gianluca Businello, Marta Sbaraglia, Giulia Traverso, Francesco Fortarezza, Stefania Rizzo, Monica De Gaspari, Cristina Basso, Fiorella Calabrese, Angelo Paolo Dei Tos and Matteo Fassan

Int. J. Mol. Sci. 2021, 22(2), 974; https://doi.org/10.3390/ijms22020974 - 19 Jan 2021

Cited by 28 | Viewed by 6348

Abstract

A complete understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) physiopathology and related histopathologic lesions is necessary to improve treatment and outcome of coronavirus disease 2019 (COVID-19) patients. Many studies have focused on autopsy findings in COVID-19-related deaths to try and define [...] Read more.

A complete understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) physiopathology and related histopathologic lesions is necessary to improve treatment and outcome of coronavirus disease 2019 (COVID-19) patients. Many studies have focused on autopsy findings in COVID-19-related deaths to try and define any possible specific pattern. Histopathologic alterations are principally found within lungs and blood vessels, and these abnormalities also seem to have the highest clinical impact. Nevertheless, many of the morphological data collected so far are non-specific, fickle, and possibly associated with other co-existing factors. The aim of this minireview is to describe the main histopathological features related to COVID-19 and the mechanism known as “cytokine storm”. Full article

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

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17 pages, 7088 KiB

Open AccessArticle

Natural Polyhydroxy Flavonoids, Curcuminoids, and Synthetic Curcumin Analogs as α7 nAChRs Positive Allosteric Modulators

by Marta Ximenis, José Mulet, Salvador Sala, Francisco Sala, Manuel Criado, Rosario González-Muñiz and María Jesús Pérez de Vega

Int. J. Mol. Sci. 2021, 22(2), 973; https://doi.org/10.3390/ijms22020973 - 19 Jan 2021

Cited by 7 | Viewed by 3391

Abstract

The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated ion channel that is involved in cognition disorders, schizophrenia, pain, and inflammation. Allosteric modulation of this receptor might be advantageous to reduce the toxicity in comparison with full agonists. Our previous results obtained [...] Read more.

The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated ion channel that is involved in cognition disorders, schizophrenia, pain, and inflammation. Allosteric modulation of this receptor might be advantageous to reduce the toxicity in comparison with full agonists. Our previous results obtained with some hydroxy-chalcones, which were identified as positive allosteric modulators (PAMs) of α7 nAChR, prompted us to evaluate the potential of some structurally related naturally occurring flavonoids and curcuminoids and some synthetic curcumin analogues, with the aim of identifying new allosteric modulators of the α7 nAChR. Biological evaluation showed that phloretin, demethoxycurcumin, and bis-demethoxicurcuming behave as PAMs of α7 nAChR. In addition, some new curcumin derivatives were able to enhance the signal evoked by ACh; the activity values found for the tetrahydrocurcuminoid analog 23 were especially promising. Full article

(This article belongs to the Special Issue Membrane Channels in Health and Diseases)

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Graphical abstract

25 pages, 1624 KiB

Open AccessReview

The Complex Interplay between Endocannabinoid System and the Estrogen System in Central Nervous System and Periphery

by Antonietta Santoro, Elena Mele, Marianna Marino, Andrea Viggiano, Stefania Lucia Nori and Rosaria Meccariello

Int. J. Mol. Sci. 2021, 22(2), 972; https://doi.org/10.3390/ijms22020972 - 19 Jan 2021

Cited by 34 | Viewed by 5784

Abstract

The endocannabinoid system (ECS) is a lipid cell signaling system involved in the physiology and homeostasis of the brain and peripheral tissues. Synaptic plasticity, neuroendocrine functions, reproduction, and immune response among others all require the activity of functional ECS, with the onset of [...] Read more.

The endocannabinoid system (ECS) is a lipid cell signaling system involved in the physiology and homeostasis of the brain and peripheral tissues. Synaptic plasticity, neuroendocrine functions, reproduction, and immune response among others all require the activity of functional ECS, with the onset of disease in case of ECS impairment. Estrogens, classically considered as female steroid hormones, regulate growth, differentiation, and many other functions in a broad range of target tissues and both sexes through the activation of nuclear and membrane estrogen receptors (ERs), which leads to genomic and non-genomic cell responses. Since ECS function overlaps or integrates with many other cell signaling systems, this review aims at updating the knowledge about the possible crosstalk between ECS and estrogen system (ES) at both central and peripheral level, with focuses on the central nervous system, reproduction, and cancer. Full article

(This article belongs to the Special Issue Endocannabinoid System in Health and Disease: Current Situation and Future Perspectives 2.0)

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13 pages, 6528 KiB

Open AccessArticle

Toward Tailoring the Degradation Rate of Magnesium-Based Biomaterials for Various Medical Applications: Assessing Corrosion, Cytocompatibility and Immunological Effects

by Philip Hartjen, Nils Wegner, Parimah Ahmadi, Levi Matthies, Ola Nada, Sandra Fuest, Ming Yan, Christian Knipfer, Martin Gosau, Frank Walther and Ralf Smeets

Int. J. Mol. Sci. 2021, 22(2), 971; https://doi.org/10.3390/ijms22020971 - 19 Jan 2021

Cited by 8 | Viewed by 2984

Abstract

Magnesium (Mg)-based biomaterials hold considerable promise for applications in regenerative medicine. However, the degradation of Mg needs to be reduced to control toxicity caused by its rapid natural corrosion. In the process of developing new Mg alloys with various surface modifications, an efficient [...] Read more.

Magnesium (Mg)-based biomaterials hold considerable promise for applications in regenerative medicine. However, the degradation of Mg needs to be reduced to control toxicity caused by its rapid natural corrosion. In the process of developing new Mg alloys with various surface modifications, an efficient assessment of the relevant properties is essential. In the present study, a WE43 Mg alloy with a plasma electrolytic oxidation (PEO)-generated surface was investigated. Surface microstructure, hydrogen gas evolution in immersion tests and cytocompatibility were assessed. In addition, a novel in vitro immunological test using primary human lymphocytes was introduced. On PEO-treated WE43, a larger number of pores and microcracks, as well as increased roughness, were observed compared to untreated WE43. Hydrogen gas evolution after two weeks was reduced by 40.7% through PEO treatment, indicating a significantly reduced corrosion rate. In contrast to untreated WE43, PEO-treated WE43 exhibited excellent cytocompatibility. After incubation for three days, untreated WE43 killed over 90% of lymphocytes while more than 80% of the cells were still vital after incubation with the PEO-treated WE43. PEO-treated WE43 slightly stimulated the activation, proliferation and toxin (perforin and granzyme B) expression of CD8⁺ T cells. This study demonstrates that the combined assessment of corrosion, cytocompatibility and immunological effects on primary human lymphocytes provide a comprehensive and effective procedure for characterizing Mg variants with tailorable degradation and other features. PEO-treated WE43 is a promising candidate for further development as a degradable biomaterial. Full article

(This article belongs to the Special Issue Optimization of Biomaterials for Reconstructive and Regenerative Medicine)

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31 pages, 2400 KiB

Open AccessReview

Characteristics and Therapeutic Potential of Human Amnion-Derived Stem Cells

by Quan-Wen Liu, Qi-Ming Huang, Han-You Wu, Guo-Si-Lang Zuo, Hao-Cheng Gu, Ke-Yu Deng and Hong-Bo Xin

Int. J. Mol. Sci. 2021, 22(2), 970; https://doi.org/10.3390/ijms22020970 - 19 Jan 2021

Cited by 75 | Viewed by 10292

Abstract

Stem cells including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and adult stem cells (ASCs) are able to repair/replace damaged or degenerative tissues and improve functional recovery in experimental model and clinical trials. However, there are still many limitations and unresolved [...] Read more.

Stem cells including embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and adult stem cells (ASCs) are able to repair/replace damaged or degenerative tissues and improve functional recovery in experimental model and clinical trials. However, there are still many limitations and unresolved problems regarding stem cell therapy in terms of ethical barriers, immune rejection, tumorigenicity, and cell sources. By reviewing recent literatures and our related works, human amnion-derived stem cells (hADSCs) including human amniotic mesenchymal stem cells (hAMSCs) and human amniotic epithelial stem cells (hAESCs) have shown considerable advantages over other stem cells. In this review, we first described the biological characteristics and advantages of hADSCs, especially for their high pluripotency and immunomodulatory effects. Then, we summarized the therapeutic applications and recent progresses of hADSCs in treating various diseases for preclinical research and clinical trials. In addition, the possible mechanisms and the challenges of hADSCs applications have been also discussed. Finally, we highlighted the properties of hADSCs as a promising source of stem cells for cell therapy and regenerative medicine and pointed out the perspectives for the directions of hADSCs applications clinically. Full article

(This article belongs to the Special Issue Amniotic Fluid and Placental Membranes as Sources of Stem Cells: Progress and Challenges)

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14 pages, 2606 KiB

Open AccessCommunication

The Influence of the LINC00961/SPAAR Locus Loss on Murine Development, Myocardial Dynamics, and Cardiac Response to Myocardial Infarction

by Ana-Mishel Spiroski, Rachel Sanders, Marco Meloni, Ian R. McCracken, Adrian Thomson, Mairi Brittan, Gillian A. Gray and Andrew H. Baker

Int. J. Mol. Sci. 2021, 22(2), 969; https://doi.org/10.3390/ijms22020969 - 19 Jan 2021

Cited by 13 | Viewed by 3351

Abstract

Long non-coding RNAs (lncRNAs) have structural and functional roles in development and disease. We have previously shown that the LINC00961/SPAAR (small regulatory polypeptide of amino acid response) locus regulates endothelial cell function, and that both the lncRNA and micropeptide counter-regulate angiogenesis. To assess [...] Read more.

Long non-coding RNAs (lncRNAs) have structural and functional roles in development and disease. We have previously shown that the LINC00961/SPAAR (small regulatory polypeptide of amino acid response) locus regulates endothelial cell function, and that both the lncRNA and micropeptide counter-regulate angiogenesis. To assess human cardiac cell SPAAR expression, we mined a publicly available scRNSeq dataset and confirmed LINC00961 locus expression and hypoxic response in a murine endothelial cell line. We investigated post-natal growth and development, basal cardiac function, the cardiac functional response, and tissue-specific response to myocardial infarction. To investigate the influence of the LINC00961/SPAAR locus on longitudinal growth, cardiac function, and response to myocardial infarction, we used a novel CRISPR/Cas9 locus knockout mouse line. Data mining suggested that SPAAR is predominantly expressed in human cardiac endothelial cells and fibroblasts, while murine LINC00961 expression is hypoxia-responsive in mouse endothelial cells. LINC00961^–/– mice displayed a sex-specific delay in longitudinal growth and development, smaller left ventricular systolic and diastolic areas and volumes, and greater risk area following myocardial infarction compared with wildtype littermates. These data suggest the LINC00961/SPAAR locus contributes to cardiac endothelial cell and fibroblast function and hypoxic response, growth and development, and basal cardiovascular function in adulthood. Full article

(This article belongs to the Special Issue RNAs in Brain and Heart Diseases - EU-CardioRNA COST Action)

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18 pages, 374 KiB

Open AccessReview

The Functions of the Demethylase JMJD3 in Cancer

by Anna Sanchez, Fatma Zohra Houfaf Khoufaf, Mouhamed Idrissou, Frédérique Penault-Llorca, Yves-Jean Bignon, Laurent Guy and Dominique Bernard-Gallon

Int. J. Mol. Sci. 2021, 22(2), 968; https://doi.org/10.3390/ijms22020968 - 19 Jan 2021

Cited by 15 | Viewed by 4729

Abstract

Cancer is a major cause of death worldwide. Epigenetic changes in response to external (diet, sports activities, etc.) and internal events are increasingly implicated in tumor initiation and progression. In this review, we focused on post-translational changes in histones and, more particularly, the [...] Read more.

Cancer is a major cause of death worldwide. Epigenetic changes in response to external (diet, sports activities, etc.) and internal events are increasingly implicated in tumor initiation and progression. In this review, we focused on post-translational changes in histones and, more particularly, the tri methylation of lysine from histone 3 (H3K27me3) mark, a repressive epigenetic mark often under- or overexpressed in a wide range of cancers. Two actors regulate H3K27 methylation: Jumonji Domain-Containing Protein 3 demethylase (JMJD3) and Enhancer of zeste homolog 2 (EZH2) methyltransferase. A number of studies have highlighted the deregulation of these actors, which is why this scientific review will focus on the role of JMJD3 and, consequently, H3K27me3 in cancer development. Data on JMJD3’s involvement in cancer are classified by cancer type: nervous system, prostate, blood, colorectal, breast, lung, liver, ovarian, and gastric cancers. Full article

(This article belongs to the Special Issue Epigenetic Mechanisms and Human Pathology)

13 pages, 2003 KiB

Open AccessArticle

Cellular Redox State Acts as Switch to Determine the Direction of NNT-Catalyzed Reaction in Cystic Fibrosis Cells

by Maria Favia and Anna Atlante

Int. J. Mol. Sci. 2021, 22(2), 967; https://doi.org/10.3390/ijms22020967 - 19 Jan 2021

Cited by 4 | Viewed by 2481

Abstract

The redox states of NAD and NADP are linked to each other in the mitochondria thanks to the enzyme nicotinamide nucleotide transhydrogenase (NNT) which, by utilizing the mitochondrial membrane potential (mΔΨ), catalyzes the transfer of redox potential between these two coenzymes, reducing one [...] Read more.

The redox states of NAD and NADP are linked to each other in the mitochondria thanks to the enzyme nicotinamide nucleotide transhydrogenase (NNT) which, by utilizing the mitochondrial membrane potential (mΔΨ), catalyzes the transfer of redox potential between these two coenzymes, reducing one at the expense of the oxidation of the other. In order to define NNT reaction direction in CF cells, NNT activity under different redox states of cell has been investigated. Using spectrophotometric and western blotting techniques, the presence, abundance and activity level of NNT were determined. In parallel, the levels of NADPH and NADH as well as of mitochondrial and cellular ROS were also quantified. CF cells showed a 70% increase in protein expression compared to the Wt sample; however, regarding NNT activity, it was surprisingly lower in CF cells than healthy cells (about 30%). The cellular redox state, together with the low mΔΨ, pushes to drive NNT reverse reaction, at the expense of its antioxidant potential, thus consuming NADPH to support NADH production. At the same time, the reduced NNT activity prevents the NADH, produced by the reaction, from causing an explosion of ROS by the damaged respiratory chain, in accordance with the reduced level of mitochondrial ROS in NNT-loss cells. This new information on cellular bioenergetics represents an important building block for further understanding the molecular mechanisms responsible for cellular dysfunction in cystic fibrosis. Full article

(This article belongs to the Special Issue Target Dysfunctional Inflammation in Cystic Fibrosis Airway)

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21 pages, 4712 KiB

Open AccessArticle

Metabolomic Profiles in Adipocytes Differentiated from Adipose-Derived Stem Cells Following Exercise Training or High-Fat Diet

by Seita Osawa, Hisashi Kato, Yuki Maeda, Hisashi Takakura, Junetsu Ogasawara and Tetsuya Izawa

Int. J. Mol. Sci. 2021, 22(2), 966; https://doi.org/10.3390/ijms22020966 - 19 Jan 2021

Cited by 4 | Viewed by 3829

Abstract

Controlling the differentiation potential of adipose-derived stem cells (ADSCs) is attracting attention as a new strategy for the prevention and treatment of obesity. Here, we aimed to observe the effect of exercise training (TR) and high-fat diet (HFD) on the metabolic profiles of [...] Read more.

Controlling the differentiation potential of adipose-derived stem cells (ADSCs) is attracting attention as a new strategy for the prevention and treatment of obesity. Here, we aimed to observe the effect of exercise training (TR) and high-fat diet (HFD) on the metabolic profiles of ADSCs-derived adipocytes. The rats were divided into four groups: normal diet (ND)-fed control (ND-SED), ND-fed TR (ND-TR), HFD-fed control (HFD-SED), and HFD-fed TR (HFD-TR). After 9 weeks of intervention, ADSCs of epididymal and inguinal adipose tissues were differentiated into adipocytes. In the metabolome analysis of adipocytes after isoproterenol stimulation, 116 metabolites were detected. The principal component analysis demonstrated that ADSCs-derived adipocytes segregated into four clusters in each fat pad. Amino acid accumulation was greater in epididymal ADSCs-derived adipocytes of ND-TR and HFD-TR, but lower in inguinal ADSCs-derived adipocytes of ND-TR, than in the respective controls. HFD accumulated several metabolites including amino acids in inguinal ADSCs-derived adipocytes and more other metabolites in epididymal ones. Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that TR mainly affected the pathways related to amino acid metabolism, except in inguinal ADSCs-derived adipocytes of HFD-TR rats. These findings provide a new way to understand the mechanisms underlying possible changes in the differentiation of ADSCs due to TR or HFD. Full article

(This article belongs to the Special Issue Molecular Regulation of Exercise on Adipose Tissue and Related Diseases)

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12 pages, 5811 KiB

Open AccessArticle

Terpenoids from Abies holophylla Attenuate LPS-Induced Neuroinflammation in Microglial Cells by Suppressing the JNK-Related Signaling Pathway

by Lalita Subedi and Silvia Yumnam

Int. J. Mol. Sci. 2021, 22(2), 965; https://doi.org/10.3390/ijms22020965 - 19 Jan 2021

Cited by 4 | Viewed by 2439

Abstract

We have previously reported that phytochemicals from Abies holophylla exhibit anti-inflammatory and neuroprotective effects by decreasing nitrite production and increasing nerve growth factor production. However, the exact mechanism underscoring these effects has not been revealed. In the present study, we aimed to explore [...] Read more.

We have previously reported that phytochemicals from Abies holophylla exhibit anti-inflammatory and neuroprotective effects by decreasing nitrite production and increasing nerve growth factor production. However, the exact mechanism underscoring these effects has not been revealed. In the present study, we aimed to explore the underlying anti-inflammatory mechanisms of A. holophylla and its phytochemicals. We studied various solvent fractions of A. holophylla and found the chloroform and hexane sub-fractions showed the most significant anti-neuroinflammatory effects in lipopolysaccharide (LPS)-activated murine microglia. Concomitantly, the terpenoids isolated from chloroform and hexane fractions showed similar anti-neuroinflammatory effects with significant inhibition of NO and reactive oxygen species production, and decreased protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase. Interestingly, these terpenoids inhibited the phosphorylation of c-Jun N-terminal kinase (JNK), which further inhibited the production of pro-inflammatory mediators, including prostaglandin E2, tumor necrosis factor, and interleukins (IL-6 and IL-1β), with a potency greater than that of the well-known iNOS inhibitor NG-mono-methyl-L-arginine (L-NMMA). These results suggest that the chloroform- and hexane-soluble fraction mediated the mitogen-activated protein kinase (MAPK) inhibition, in particular the JNK pathway, thereby lowering the inflammatory cascades in LPS-activated murine microglia. Thus, our study suggests that the chloroform and hexane fractions of A. holophylla and their terpenoids may be potential drug candidates for drug discovery against LPS-induced neuroinflammation and neuroinflammatory-related neurodegeneration. Full article

(This article belongs to the Section Molecular Neurobiology)

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31 pages, 3102 KiB

Open AccessReview

Characteristics and Cryopreservation of Semen of Sex-Reversed Females of Salmonid Fish

by Sylwia Judycka, Joanna Nynca, Piotr Hliwa and Andrzej Ciereszko

Int. J. Mol. Sci. 2021, 22(2), 964; https://doi.org/10.3390/ijms22020964 - 19 Jan 2021

Cited by 11 | Viewed by 4147

Abstract

Sex reversal has been used as a breeding strategy by salmonid fish to produce genetically and phenotypically single sex populations. Production of all-female fish has great importance for the creation of monosex female triploids of salmonid fish, which are valued for their sterility, [...] Read more.

Sex reversal has been used as a breeding strategy by salmonid fish to produce genetically and phenotypically single sex populations. Production of all-female fish has great importance for the creation of monosex female triploids of salmonid fish, which are valued for their sterility, lack of female maturation, and larger commercial size. Among salmonids, the majority of rainbow trout (Oncorhynchus mykiss) production is based on all-female production with a high proportion of all-female triploid production in Europe. The main aim of this review is to present the recent knowledge regarding sex-reversed females (SRFs) of salmonid fish. We discuss the methods of sex reversal as well as their effects on the morphology and histology of the reproductive tract. We focus on the characteristics of SRF semen as well as the factors determining semen quality. The lower quality of SRF sperm compared to that of normal males has resulted in the need for the artificial maturation of semen. Most importantly, methods of semen storage—both short-term and long-term (cryopreservation)—that can improve hatchery operations are presented with the special emphasis on recent progress in development of efficient cryopreservation procedures and use of cryopreserved semen in hatchery practice. Moreover, we also address the emerging knowledge concerning the proteomic investigations of salmonid sperm, focusing primarily on the proteomic comparison of normal male and SRF testicular semen and presenting changes in SRF rainbow trout sperm proteome after in vitro incubation in artificial seminal plasma. Full article

(This article belongs to the Special Issue Cryopreservation of Gametes and Embryos)

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27 pages, 3083 KiB

Open AccessReview

Exosomes: A Key Piece in Asthmatic Inflammation

by José A. Cañas, José M. Rodrigo-Muñoz, Marta Gil-Martínez, Beatriz Sastre and Victoria del Pozo

Int. J. Mol. Sci. 2021, 22(2), 963; https://doi.org/10.3390/ijms22020963 - 19 Jan 2021

Cited by 19 | Viewed by 4625

Abstract

Asthma is a chronic disease of the airways that has an important inflammatory component. Multiple cells are implicated in asthma pathogenesis (lymphocytes, eosinophils, mast cells, basophils, neutrophils), releasing a wide variety of cytokines. These cells can exert their inflammatory functions throughout extracellular vesicles [...] Read more.

Asthma is a chronic disease of the airways that has an important inflammatory component. Multiple cells are implicated in asthma pathogenesis (lymphocytes, eosinophils, mast cells, basophils, neutrophils), releasing a wide variety of cytokines. These cells can exert their inflammatory functions throughout extracellular vesicles (EVs), which are small vesicles released by donor cells into the extracellular microenvironment that can be taken up by recipient cells. Depending on their size, EVs can be classified as microvesicles, exosomes, or apoptotic bodies. EVs are heterogeneous spherical structures secreted by almost all cell types. One of their main functions is to act as transporters of a wide range of molecules, such as proteins, lipids, and microRNAs (miRNAs), which are single-stranded RNAs of approximately 22 nucleotides in length. Therefore, exosomes could influence several physiological and pathological processes, including those involved in asthma. They can be detected in multiple cell types and biofluids, providing a wealth of information about the processes that take account in a pathological scenario. This review thus summarizes the most recent insights concerning the role of exosomes from different sources (several cell populations and biofluids) in one of the most prevalent respiratory diseases, asthma. Full article

(This article belongs to the Special Issue Extracellular Vesicles in Inflammation)

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15 pages, 707 KiB

Open AccessReview

The Bioavailability, Extraction, Biosynthesis and Distribution of Natural Dihydrochalcone: Phloridzin

by Lei Tian, Jianxin Cao, Tianrui Zhao, Yaping Liu, Afsar Khan and Guiguang Cheng

Int. J. Mol. Sci. 2021, 22(2), 962; https://doi.org/10.3390/ijms22020962 - 19 Jan 2021

Cited by 58 | Viewed by 5175

Abstract

Phloridzin is an important phytochemical which was first isolated from the bark of apple trees. It is a member of the dihydrochalcones and mainly distributed in the plants of the Malus genus, therefore, the extraction method of phloridzin was similar to those of [...] Read more.

Phloridzin is an important phytochemical which was first isolated from the bark of apple trees. It is a member of the dihydrochalcones and mainly distributed in the plants of the Malus genus, therefore, the extraction method of phloridzin was similar to those of other phenolic substances. High-speed countercurrent chromatography (HSCCC), resin adsorption technology and preparative high-performance liquid chromatography (HPLC) were used to separate and purify phloridzin. Many studies showed that phloridzin had multiple pharmacological effects, such as antidiabetic, anti-inflammatory, antihyperglycaemic, anticancer and antibacterial activities. Besides, the physiological activities of phloridzin are cardioprotective, neuroprotective, hepatoprotective, immunomodulatory, antiobesity, antioxidant and so on. The present review summarizes the biosynthesis, distribution, extraction and bioavailability of the natural compound phloridzin and discusses its applications in food and medicine. Full article

(This article belongs to the Section Molecular Plant Sciences)

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20 pages, 2531 KiB

Open AccessArticle

Oxidation of Hydrogen Sulfide by Quinones: How Polyphenols Initiate Their Cytoprotective Effects

by Kenneth R. Olson, Yan Gao and Karl D. Straub

Int. J. Mol. Sci. 2021, 22(2), 961; https://doi.org/10.3390/ijms22020961 - 19 Jan 2021

Cited by 20 | Viewed by 3234

Abstract

We have shown that autoxidized polyphenolic nutraceuticals oxidize H₂S to polysulfides and thiosulfate and this may convey their cytoprotective effects. Polyphenol reactivity is largely attributed to the B ring, which is usually a form of hydroxyquinone (HQ). Here, we examine the [...] Read more.

We have shown that autoxidized polyphenolic nutraceuticals oxidize H₂S to polysulfides and thiosulfate and this may convey their cytoprotective effects. Polyphenol reactivity is largely attributed to the B ring, which is usually a form of hydroxyquinone (HQ). Here, we examine the effects of HQs on sulfur metabolism using H₂S- and polysulfide-specific fluorophores (AzMC and SSP4, respectively) and thiosulfate sensitive silver nanoparticles (AgNP). In buffer, 1,4-dihydroxybenzene (1,4-DB), 1,4-benzoquinone (1,4-BQ), pyrogallol (PG) and gallic acid (GA) oxidized H₂S to polysulfides and thiosulfate, whereas 1,2-DB, 1,3-DB, 1,2-dihydroxy,3,4-benzoquinone and shikimic acid did not. In addition, 1,4-DB, 1,4-BQ, PG and GA also increased polysulfide production in HEK293 cells. In buffer, H₂S oxidation by 1,4-DB was oxygen-dependent, partially inhibited by tempol and trolox, and absorbance spectra were consistent with redox cycling between HQ autoxidation and H₂S-mediated reduction. Neither 1,2-DB, 1,3-DB, 1,4-DB nor 1,4-BQ reduced polysulfides to H₂S in either 21% or 0% oxygen. Epinephrine and norepinephrine also oxidized H₂S to polysulfides and thiosulfate; dopamine and tyrosine were ineffective. Polyphenones were also examined, but only 2,5-dihydroxy- and 2,3,4-trihydroxybenzophenones oxidized H₂S. These results show that H₂S is readily oxidized by specific hydroxyquinones and quinones, most likely through the formation of a semiquinone radical intermediate derived from either reaction of oxygen with the reduced quinones, or from direct reaction between H₂S and quinones. We propose that polysulfide production by these reactions contributes to the health-promoting benefits of polyphenolic nutraceuticals. Full article

(This article belongs to the Special Issue Advances in the Chemistry of Porphyrins and Related Macrocycles)

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13 pages, 8178 KiB

Open AccessArticle

Substrate Stiffness Mediates Formation of Novel Cytoskeletal Structures in Fibroblasts during Cell–Microspheres Interaction

by Olga Adamczyk, Zbigniew Baster, Maksymilian Szczypior and Zenon Rajfur

Int. J. Mol. Sci. 2021, 22(2), 960; https://doi.org/10.3390/ijms22020960 - 19 Jan 2021

Cited by 4 | Viewed by 3464

Abstract

It is well known that living cells interact mechanically with their microenvironment. Many basic cell functions, like migration, proliferation, gene expression, and differentiation, are influenced by external forces exerted on the cell. That is why it is extremely important to study how mechanical [...] Read more.

It is well known that living cells interact mechanically with their microenvironment. Many basic cell functions, like migration, proliferation, gene expression, and differentiation, are influenced by external forces exerted on the cell. That is why it is extremely important to study how mechanical properties of the culture substrate influence the cellular molecular regulatory pathways. Optical microscopy is one of the most common experimental method used to visualize and study cellular processes. Confocal microscopy allows to observe changes in the 3D organization of the cytoskeleton in response to a precise mechanical stimulus applied with, for example, a bead trapped with optical tweezers. Optical tweezers-based method (OT) is a microrheological technique which employs a focused laser beam and polystyrene or latex beads to study mechanical properties of biological systems. Latex beads, functionalized with a specific protein, can interact with proteins located on the surface of the cellular membrane. Such interaction can significantly affect the cell’s behavior. In this work, we demonstrate that beads alone, placed on the cell surface, significantly change the architecture of actin, microtubule, and intermediate filaments. We also show that the observed molecular response to such stimulus depends on the duration of the cell–bead interaction. Application of cytoskeletal drugs: cytochalasin D, jasplakinolide, and docetaxel, abrogates remodeling effects of the cytoskeleton. More important, when cells are plated on elastic substrates, which mimic the mechanical properties of physiological cellular environment, we observe formation of novel, “cup-like” structures formed by the microtubule cytoskeleton upon interaction with latex beads. These results provide new insights into the function of the microtubule cytoskeleton. Based on these results, we conclude that rigidity of the substrate significantly affects the cellular processes related to every component of the cytoskeleton, especially their architecture. Full article

(This article belongs to the Special Issue Interactions of Cells with Biomaterials for Regenerative Medicine)

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80 pages, 8682 KiB

Open AccessReview

Biological Activities of Some New Secondary Metabolites Isolated from Endophytic Fungi: A Review Study

by Ruihong Zheng, Shoujie Li, Xuan Zhang and Changqi Zhao

Int. J. Mol. Sci. 2021, 22(2), 959; https://doi.org/10.3390/ijms22020959 - 19 Jan 2021

Cited by 85 | Viewed by 7803

Abstract

Secondary metabolites isolated from plant endophytic fungi have been getting more and more attention. Some secondary metabolites exhibit high biological activities, hence, they have potential to be used for promising lead compounds in drug discovery. In this review, a total of 134 journal [...] Read more.

Secondary metabolites isolated from plant endophytic fungi have been getting more and more attention. Some secondary metabolites exhibit high biological activities, hence, they have potential to be used for promising lead compounds in drug discovery. In this review, a total of 134 journal articles (from 2017 to 2019) were reviewed and the chemical structures of 449 new metabolites, including polyketides, terpenoids, steroids and so on, were summarized. Besides, various biological activities and structure-activity relationship of some compounds were aslo described. Full article

(This article belongs to the Section Biochemistry)

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16 pages, 7470 KiB

Open AccessArticle

Interactome Analysis of iPSC Secretome and Its Effect on Macrophages In Vitro

by Luca Tamò, Kleanthis Fytianos, Fabienne Caldana, Cedric Simillion, Anis Feki, Izabela Nita, Manfred Heller, Thomas Geiser and Amiq Gazdhar

Int. J. Mol. Sci. 2021, 22(2), 958; https://doi.org/10.3390/ijms22020958 - 19 Jan 2021

Cited by 5 | Viewed by 3882

Abstract

Induced pluripotent stem cell secretome (iPSC-CM) mitigate organ injury and help in repair. Macrophages play a critical role in tissue repair and regeneration and can be directed to promote tissue repair by iPSC-CM, although the exact mechanisms are not known. In the current [...] Read more.

Induced pluripotent stem cell secretome (iPSC-CM) mitigate organ injury and help in repair. Macrophages play a critical role in tissue repair and regeneration and can be directed to promote tissue repair by iPSC-CM, although the exact mechanisms are not known. In the current investigative study, we evaluated the possible mechanism by which iPSC-CM regulates the phenotype and secretory pattern of macrophages in vitro. Macrophages were obtained from human peripheral blood mononuclear cells and differentiated to various subpopulations and treated with either iPSC-CM or control media in vitro. Macrophage phenotype was assessed by flow cytometry, gene expression changes by qRT PCR and secretory pattern by multiplex protein analysis. The protein and gene interaction network revealed the involvement of Amyloid precursor protein (APP) and ELAV-like protein 1 (ELAVL-1) both present in the iPSC-CM to play an important role in regulating the macrophage phenotype and their secretory pattern. This exploratory study reveals, in part, the possible mechanism and identifies two potential targets by which iPSC-CM regulate macrophages and help in repair and regeneration. Full article

(This article belongs to the Special Issue hiPSC-Derived Cells as Models for Drug Discovery)

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15 pages, 503 KiB

Open AccessArticle

The Prognostic Impact of Retinoid X Receptor and Thyroid Hormone Receptor alpha in Unifocal vs. Multifocal/Multicentric Breast Cancer

by Alaleh Zati Zehni, Falk Batz, Aurelia Vattai, Till Kaltofen, Svenja Schrader, Sven-Niclas Jacob, Jan-Niclas Mumm, Helene Hildegard Heidegger, Nina Ditsch, Sven Mahner, Udo Jeschke and Theresa Vilsmaier

Int. J. Mol. Sci. 2021, 22(2), 957; https://doi.org/10.3390/ijms22020957 - 19 Jan 2021

Cited by 14 | Viewed by 2999

Abstract

The aim of this study was to assess the prognostic value of the steroid hormone receptor expression, counting the retinoid X receptor (RXR) and thyroid hormone receptors (THRs), on the two different breast cancer (BC) entities: multifocal/multicentric versus unifocal. The overall and disease-free [...] Read more.

The aim of this study was to assess the prognostic value of the steroid hormone receptor expression, counting the retinoid X receptor (RXR) and thyroid hormone receptors (THRs), on the two different breast cancer (BC) entities: multifocal/multicentric versus unifocal. The overall and disease-free survival were considered as the prognosis determining aspects and analyzed by uni- and multi-variate analysis. Furthermore, histopathological grading and TNM staging (T = tumor size, N = lymph node involvement, M = distant metastasis) were examined in relation to RXR and THRs expression. A retrospective statistical analysis was carried out on survival-related events in a series of 319 sporadic BC patients treated at the Department of Gynecology and Obstetrics at the Ludwig-Maximillian’s University in Munich between 2000 and 2002. The expression of RXR and THRs, including its two major isoforms THRα1 and THRα2, was analyzed by immunohistochemistry and showed to have a significant correlation for both BC entities in regard to survival analysis. Patients with multifocal/multicentric BC were exposed to a significantly worse disease-free survival (DFS) when expressing RXR. Patients with unifocal BC showed a significantly worse DFS when expressing THRα1. In contrast, a statistically significant positive association between THRα2 expression and enhanced DFS in multifocal/multicentric BC was shown. Especially the RXR expression in multifocal/multicentric BC was found to play a remarkably contradictory role for BC prognosis. The findings imply the need for a critical review of possible molecular therapies targeting steroid hormone receptors in BC treatment. Our results strengthen the need to further investigate the behavior of the nuclear receptor family, especially in relation to BC focality. Full article

(This article belongs to the Section Biochemistry)

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15 pages, 1129 KiB

Open AccessReview

Antiinflammatory Actions of Klotho: Implications for Therapy of Diabetic Nephropathy

by Marlena Typiak and Agnieszka Piwkowska

Int. J. Mol. Sci. 2021, 22(2), 956; https://doi.org/10.3390/ijms22020956 - 19 Jan 2021

Cited by 61 | Viewed by 7297

Abstract

Klotho was initially introduced as an antiaging molecule. Klotho deficiency significantly reduces lifespan, and its overexpression extends it and protects against various pathological phenotypes, especially renal disease. It was shown to regulate phosphate and calcium metabolism, protect against oxidative stress, downregulate apoptosis, and [...] Read more.

Klotho was initially introduced as an antiaging molecule. Klotho deficiency significantly reduces lifespan, and its overexpression extends it and protects against various pathological phenotypes, especially renal disease. It was shown to regulate phosphate and calcium metabolism, protect against oxidative stress, downregulate apoptosis, and have antiinflammatory and antifibrotic properties. The course of diabetes mellitus and diabetic nephropathy resembles premature cellular senescence and causes the activation of various proinflammatory and profibrotic processes. Klotho was shown to exert many beneficial effects in these disorders. The expression of Klotho protein is downregulated in early stages of inflammation and diabetic nephropathy by proinflammatory factors. Therefore, its therapeutic effects are diminished in this disorder. Significantly lower urine levels of Klotho may serve as an early biomarker of renal involvement in diabetes mellitus. Recombinant Klotho administration and Klotho overexpression may have immunotherapeutic potential for the treatment of both diabetes and diabetic nephropathy. Therefore, the current manuscript aims to characterize immunopathologies occurring in diabetes and diabetic nephropathy, and tries to match them with antiinflammatory actions of Klotho. It also gives reasons for Klotho to be used in diagnostics and immunotherapy of these disorders. Full article

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

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13 pages, 3580 KiB

Open AccessArticle

Mechanical Stress Induces Ca²⁺-Dependent Signal Transduction in Erythroblasts and Modulates Erythropoiesis

by Francesca Aglialoro, Asena Abay, Nurcan Yagci, Minke A. E. Rab, Lars Kaestner, Richard van Wijk, Marieke von Lindern and Emile van den Akker

Int. J. Mol. Sci. 2021, 22(2), 955; https://doi.org/10.3390/ijms22020955 - 19 Jan 2021

Cited by 14 | Viewed by 3685

Abstract

Bioreactors are increasingly implemented for large scale cultures of various mammalian cells, which requires optimization of culture conditions. Such upscaling is also required to produce red blood cells (RBC) for transfusion and therapy purposes. However, the physiological suitability of RBC cultures to be [...] Read more.

Bioreactors are increasingly implemented for large scale cultures of various mammalian cells, which requires optimization of culture conditions. Such upscaling is also required to produce red blood cells (RBC) for transfusion and therapy purposes. However, the physiological suitability of RBC cultures to be transferred to stirred bioreactors is not well understood. PIEZO1 is the most abundantly expressed known mechanosensor on erythroid cells. It is a cation channel that translates mechanical forces directly into a physiological response. We investigated signaling cascades downstream of PIEZO1 activated upon transitioning stationary cultures to orbital shaking associated with mechanical stress, and compared the results to direct activation of PIEZO1 by the chemical agonist Yoda1. Erythroblasts subjected to orbital shaking displayed decreased proliferation, comparable to incubation in the presence of a low dose of Yoda1. Epo (Erythropoietin)-dependent STAT5 phosphorylation, and Calcineurin-dependent NFAT dephosphorylation was enhanced. Phosphorylation of ERK was also induced by both orbital shaking and Yoda1 treatment. Activation of these pathways was inhibited by intracellular Ca²⁺ chelation (BAPTA-AM) in the orbital shaker. Our results suggest that PIEZO1 is functional and could be activated by the mechanical forces in a bioreactor setup, and results in the induction of Ca²⁺-dependent signaling cascades regulating various aspects of erythropoiesis. With this study, we showed that Yoda1 treatment and mechanical stress induced via orbital shaking results in comparable activation of some Ca²⁺-dependent pathways, exhibiting that there are direct physiological outcomes of mechanical stress on erythroblasts. Full article

(This article belongs to the Section Molecular Biology)

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23 pages, 2679 KiB

Open AccessReview

Impact of SMTP Targeting Plasminogen and Soluble Epoxide Hydrolase on Thrombolysis, Inflammation, and Ischemic Stroke

by Keiji Hasumi and Eriko Suzuki

Int. J. Mol. Sci. 2021, 22(2), 954; https://doi.org/10.3390/ijms22020954 - 19 Jan 2021

Cited by 25 | Viewed by 4932

Abstract

Stachybotrys microspora triprenyl phenol (SMTP) is a large family of small molecules derived from the fungus S. microspora. SMTP acts as a zymogen modulator (specifically, plasminogen modulator) that alters plasminogen conformation to enhance its binding to fibrin and subsequent fibrinolysis. Certain SMTP [...] Read more.

Stachybotrys microspora triprenyl phenol (SMTP) is a large family of small molecules derived from the fungus S. microspora. SMTP acts as a zymogen modulator (specifically, plasminogen modulator) that alters plasminogen conformation to enhance its binding to fibrin and subsequent fibrinolysis. Certain SMTP congeners exert anti-inflammatory effects by targeting soluble epoxide hydrolase. SMTP congeners with both plasminogen modulation activity and anti-inflammatory activity ameliorate various aspects of ischemic stroke in rodents and primates. A remarkable feature of SMTP efficacy is the suppression of hemorrhagic transformation, which is exacerbated by conventional thrombolytic treatments. No drug with such properties has been developed yet, and SMTP would be the first to promote thrombolysis but suppress disease-associated bleeding. On the basis of these findings, one SMTP congener is under clinical study and development. This review summarizes the discovery, mechanism of action, pharmacological activities, and development of SMTP. Full article

(This article belongs to the Special Issue Small Molecules, Influence of Molecular Pathways)

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22 pages, 7459 KiB

Open AccessArticle

Steroidal Regulation of Oviductal microRNAs Is Associated with microRNA-Processing in Beef Cows

by Angela Maria Gonella-Diaza, Everton Lopes, Kauê Ribeiro da Silva, Ricardo Perecin Nociti, Gabriella Mamede Andrade, Jorge Eduardo Atuesta-Bustos, Juliano Coelho da Silveira, Flávio Vieira Meirelles and Mario Binelli

Int. J. Mol. Sci. 2021, 22(2), 953; https://doi.org/10.3390/ijms22020953 - 19 Jan 2021

Cited by 12 | Viewed by 3613

Abstract

Information on molecular mechanisms through which sex-steroids regulate oviductal function to support early embryo development is lacking. Here, we hypothesized that the periovulatory endocrine milieu affects the miRNA processing machinery and miRNA expression in bovine oviductal tissues. Growth of the preovulatory follicle was [...] Read more.

Information on molecular mechanisms through which sex-steroids regulate oviductal function to support early embryo development is lacking. Here, we hypothesized that the periovulatory endocrine milieu affects the miRNA processing machinery and miRNA expression in bovine oviductal tissues. Growth of the preovulatory follicle was controlled to obtain cows that ovulated a small follicle (SF) and subsequently bore a small corpus luteum (CL; SF-SCL) or a large follicle (LF) and large CL (LF-LCL). These groups differed in the periovulatory plasmatic sex-steroid’s concentrations. Ampulla and isthmus samples were collected on day four of the estrous cycle. Abundance of DROSHA, DICER1, and AGO4 transcripts was greater in the ampulla than the isthmus. In the ampulla, transcription of these genes was greater for the SF-SCL group, while the opposite was observed in the isthmus. The expression of the 88 most abundant miRNAs and 14 miRNAs in the ampulla and 34 miRNAs in isthmus were differentially expressed between LF-LCL and SF-SCL groups. Integration of transcriptomic and miRNA data and molecular pathways enrichment showed that important pathways were inhibited in the SF-SCL group due to miRNA control. In conclusion, the endocrine milieu affects the miRNA expression in the bovine oviduct in a region-specific manner. Full article

(This article belongs to the Special Issue Molecular and Physiological Regulation of Mammalian Oocyte and Embryo Development)

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20 pages, 22622 KiB

Open AccessReview

A Peek Inside the Machines of Bacterial Nucleotide Excision Repair

by Thanyalak Kraithong, Silas Hartley, David Jeruzalmi and Danaya Pakotiprapha

Int. J. Mol. Sci. 2021, 22(2), 952; https://doi.org/10.3390/ijms22020952 - 19 Jan 2021

Cited by 19 | Viewed by 7515

Abstract

Double stranded DNA (dsDNA), the repository of genetic information in bacteria, archaea and eukaryotes, exhibits a surprising instability in the intracellular environment; this fragility is exacerbated by exogenous agents, such as ultraviolet radiation. To protect themselves against the severe consequences of DNA damage, [...] Read more.

Double stranded DNA (dsDNA), the repository of genetic information in bacteria, archaea and eukaryotes, exhibits a surprising instability in the intracellular environment; this fragility is exacerbated by exogenous agents, such as ultraviolet radiation. To protect themselves against the severe consequences of DNA damage, cells have evolved at least six distinct DNA repair pathways. Here, we review recent key findings of studies aimed at understanding one of these pathways: bacterial nucleotide excision repair (NER). This pathway operates in two modes: a global genome repair (GGR) pathway and a pathway that closely interfaces with transcription by RNA polymerase called transcription-coupled repair (TCR). Below, we discuss the architecture of key proteins in bacterial NER and recent biochemical, structural and single-molecule studies that shed light on the lesion recognition steps of both the GGR and the TCR sub-pathways. Although a great deal has been learned about both of these sub-pathways, several important questions, including damage discrimination, roles of ATP and the orchestration of protein binding and conformation switching, remain to be addressed. Full article

(This article belongs to the Special Issue Recognition of DNA Lesions)

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