International Journal of Molecular Sciences

19 pages, 2777 KiB

Open AccessArticle

Regulation of Transcriptional Activity of Merkel Cell Polyomavirus Large T-Antigen by PKA-Mediated Phosphorylation

by Mar Falquet, Carla Prezioso, Maria Ludvigsen, Jack-Ansgar Bruun, Sara Passerini, Baldur Sveinbjørnsson, Valeria Pietropaolo and Ugo Moens

Int. J. Mol. Sci. 2023, 24(1), 895; https://doi.org/10.3390/ijms24010895 - 03 Jan 2023

Cited by 1 | Viewed by 4508

Abstract

Merkel cell polyomavirus (MCPyV) is the major cause of Merkel cell carcinoma (MCC), an aggressive skin cancer. MCPyV large T-antigen (LTag) and small T-antigen (sTag) are the main oncoproteins involved in MCPyV-induced MCC. A hallmark of MCPyV-positive MCC cells is the expression of [...] Read more.

Merkel cell polyomavirus (MCPyV) is the major cause of Merkel cell carcinoma (MCC), an aggressive skin cancer. MCPyV large T-antigen (LTag) and small T-antigen (sTag) are the main oncoproteins involved in MCPyV-induced MCC. A hallmark of MCPyV-positive MCC cells is the expression of a C-terminal truncated LTag. Protein kinase A (PKA) plays a fundamental role in a variety of biological processes, including transcription by phosphorylating and thereby regulating the activity of transcription factors. As MCPyV LTag has been shown to be phosphorylated and acts as a transcription factor for the viral early and late promoter, we investigated whether LTag can be phosphorylayted by PKA, and whether this affects the transcript activity of LTag. Using a phosphorylation prediction algorithm, serine 191, 203, and 265 were identified as putative phosphorylation sites for PKA. Mass spectrometry of in vitro PKA-phosphorylated peptides confirmed phosphorylation of S203 and S265, but not S191. Full-length LTag inhibited early and late promoter activity of MCPyV, whereas the truncated MKL2 LTag variant stimulated both promoters. Single non-phosphorylable, as well as phosphomimicking mutations did not alter the inhibitory effect of full-length LTag. However, the non-phosphorylable mutations abrogated transactivation of the MCPyV promoters by MKL2 LTag, whereas phosphomimicking substitutions restored the ability of MKL2 LTag to activate the promoters. Triple LTag and MKL2 LTag mutants had the same effect as the single mutants. Activation of the PKA signaling pathway did not enhance MCPyV promoter activity, nor did it affect LTag expression levels in MCPyV-positive Merkel cell carcinoma (MCC) cells. Our results show that phosphorylation of truncated LTag stimulates viral promoter activity, which may contribute to higher levels of the viral oncoproteins LTag and sTag. Interfering with PKA-induced LTag phosphorylation/activity may be a therapeutic strategy to treat MCPyV-positive MCC patients. Full article

(This article belongs to the Special Issue Viruses and Cancers)

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10 pages, 1233 KiB

Open AccessArticle

Myelin Basic Protein in Oligodendrocyte-Derived Extracellular Vesicles as a Diagnostic and Prognostic Biomarker in Multiple Sclerosis: A Pilot Study

by Cristina Agliardi, Franca Rosa Guerini, Milena Zanzottera, Elisabetta Bolognesi, Silvia Picciolini, Domenico Caputo, Marco Rovaris, Maria Barbara Pasanisi and Mario Clerici

Int. J. Mol. Sci. 2023, 24(1), 894; https://doi.org/10.3390/ijms24010894 - 03 Jan 2023

Cited by 11 | Viewed by 3832

Abstract

Approximately 15% of multiple sclerosis (MS) patients develop a progressive form of disease from onset; this condition (primary progressive-PP) MS is difficult to diagnose and treat, and is associated with a poor prognosis. Extracellular vesicles (EVs) of brain origin isolated from blood and [...] Read more.

Approximately 15% of multiple sclerosis (MS) patients develop a progressive form of disease from onset; this condition (primary progressive-PP) MS is difficult to diagnose and treat, and is associated with a poor prognosis. Extracellular vesicles (EVs) of brain origin isolated from blood and their protein cargoes could function as a biomarker of pathological conditions. We verified whether MBP and MOG content in oligodendrocytes-derived EVs (ODEVs) could be biomarkers of MS and could help in the differential diagnosis of clinical MS phenotypes. A total of 136 individuals (7 clinically isolated syndrome (CIS), 18 PPMS, 49 relapsing remitting (RRMS)) and 70 matched healthy controls (HC) were enrolled. ODEVs were enriched from serum by immune-capture with anti-MOG antibody; MBP and MOG protein cargoes were measured by ELISA. MBP concentration in ODEVs was significantly increased in CIS (p < 0.001), RRMS (p < 0.001) and PPMS (p < 0.001) compared to HC and was correlated with disease severity measured by EDSS and MSSS. Notably, MBP concentration in ODEVs was also significantly augmented in PPMS compared to RRMS (p = 0.004) and CIS (p = 0.03). Logistic regression and ROC analyses confirmed these results. A minimally invasive blood test measuring the concentration of MBP in ODEVs is a promising tool that could facilitate MS diagnosis. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Neurological Diseases)

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15 pages, 3447 KiB

Open AccessArticle

Development of a Duplex LAMP Assay with Probe-Based Readout for Simultaneous Real-Time Detection of Schistosoma mansoni and Strongyloides spp. -A Laboratory Approach to Point-Of-Care

by Beatriz Crego-Vicente, Pedro Fernández-Soto, Juan García-Bernalt Diego, Begoña Febrer-Sendra and Antonio Muro

Int. J. Mol. Sci. 2023, 24(1), 893; https://doi.org/10.3390/ijms24010893 - 03 Jan 2023

Cited by 3 | Viewed by 3456

Abstract

Loop-mediated isothermal amplification (LAMP) is the most popular technology for point-of-care testing applications due its rapid, sensitive and specific detection with simple instrumentation compared to PCR-based methods. Many systems for reading the results of LAMP amplifications exist, including real-time fluorescence detection using fluorophore-labelled [...] Read more.

Loop-mediated isothermal amplification (LAMP) is the most popular technology for point-of-care testing applications due its rapid, sensitive and specific detection with simple instrumentation compared to PCR-based methods. Many systems for reading the results of LAMP amplifications exist, including real-time fluorescence detection using fluorophore-labelled probes attached to oligonucleotide sequences complementary to the target nucleic acid. This methodology allows the simultaneous detection of multiple targets (multiplexing) in one LAMP assay. A method for multiplexing LAMP is the amplification by release of quenching (DARQ) technique by using a 5′-quencher modified LAMP primer annealed to 3′-fluorophore-labelled acting as detection oligonucleotide. The main application of multiplex LAMP is the rapid and accurate diagnosis of infectious diseases, allowing differentiation of co-infecting pathogens in a single reaction. Schistosomiasis, caused among other species by Schistosoma mansoni and strongyloidiasis, caused by Strongyloides stercoralis, are the most common helminth-parasite infections worldwide with overlapping distribution areas and high possibility of coinfections in the human population. It would be of great interest to develop a duplex LAMP to detect both pathogens in the same reaction. In this study, we investigate the use of our two previously developed and well-stablished LAMP assays for S. mansoni and Strongyloides spp. DNA detection in a new duplex real-time eight-primer system based on a modified DARQ probe method that can be performed in a portable isothermal fluorimeter with minimal laboratory resources. We also applied a strategy to stabilize the duplexed DARQ-LAMP mixtures at room temperature for use as ready-to-use formats facilitating analysis in field settings as point-of-care diagnostics for schistosomiasis and strongyloidiasis. Full article

(This article belongs to the Special Issue New Strategies for the Diagnosis and Treatment of Diseases Caused by Parasites)

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17 pages, 3626 KiB

Open AccessArticle

Concentration-Dependent Efficacy of Recombinant Human Bone Morphogenetic Protein-2 Using a HA/β-TCP Hydrogel Carrier in a Mini-Pig Vertebral Oblique Lateral Interbody Fusion Model

by Hye-Yeong Lee, Ji-In Kang, Hye-Lan Lee, Gwang-Yong Hwang, Keung-Nyun Kim and Yoon Ha

Int. J. Mol. Sci. 2023, 24(1), 892; https://doi.org/10.3390/ijms24010892 - 03 Jan 2023

Cited by 2 | Viewed by 2188

Abstract

Bone morphogenetic protein-2 (BMP-2) is used in the treatment of degenerative spinal disease and vertebral fractures, spine fusion, dental surgery, and facial surgery. However, high doses are associated with side effects such as inflammation and osteophytes. In this study, we performed spinal fusion [...] Read more.

Bone morphogenetic protein-2 (BMP-2) is used in the treatment of degenerative spinal disease and vertebral fractures, spine fusion, dental surgery, and facial surgery. However, high doses are associated with side effects such as inflammation and osteophytes. In this study, we performed spinal fusion surgery on mini-pigs using BMP-2 and a HA/β-TCP hydrogel carrier, and evaluated the degree of fusion and osteophyte growth according to time and dosage. Increasing the dose of BMP-2 led to a significantly higher fusion rate than was observed in the control group, and there was no significant difference between the 8-week and 16-week samples. We also found that the HA + β-TCP hydrogel combination helped maintain the rate of BMP-2 release. In conclusion, the BMP-2-loaded HA/β-TCP hydrogel carrier used in this study overcame the drawback of potentially causing side effects when used at high concentrations by enabling the sustained release of BMP-2. This method is also highly efficient, since it provides mineral matter to accelerate the fusion rate of the spine and improve bone quality. Full article

(This article belongs to the Special Issue Regeneration for Spinal Diseases 3.0)

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25 pages, 3787 KiB

Open AccessReview

Bioprinting Technologies and Bioinks for Vascular Model Establishment

by Zhiyuan Kong and Xiaohong Wang

Int. J. Mol. Sci. 2023, 24(1), 891; https://doi.org/10.3390/ijms24010891 - 03 Jan 2023

Cited by 11 | Viewed by 4570

Abstract

Clinically, large diameter artery defects (diameter larger than 6 mm) can be substituted by unbiodegradable polymers, such as polytetrafluoroethylene. There are many problems in the construction of small diameter blood vessels (diameter between 1 and 3 mm) and microvessels (diameter less than 1 [...] Read more.

Clinically, large diameter artery defects (diameter larger than 6 mm) can be substituted by unbiodegradable polymers, such as polytetrafluoroethylene. There are many problems in the construction of small diameter blood vessels (diameter between 1 and 3 mm) and microvessels (diameter less than 1 mm), especially in the establishment of complex vascular models with multi-scale branched networks. Throughout history, the vascularization strategies have been divided into three major groups, including self-generated capillaries from implantation, pre-constructed vascular channels, and three-dimensional (3D) printed cell-laden hydrogels. The first group is based on the spontaneous angiogenesis behaviour of cells in the host tissues, which also lays the foundation of capillary angiogenesis in tissue engineering scaffolds. The second group is to vascularize the polymeric vessels (or scaffolds) with endothelial cells. It is hoped that the pre-constructed vessels can be connected with the vascular networks of host tissues with rapid blood perfusion. With the development of bioprinting technologies, various fabrication methods have been achieved to build hierarchical vascular networks with high-precision 3D control. In this review, the latest advances in 3D bioprinting of vascularized tissues/organs are discussed, including new printing techniques and researches on bioinks for promoting angiogenesis, especially coaxial printing, freeform reversible embedded in suspended hydrogel printing, and acoustic assisted printing technologies, and freeform reversible embedded in suspended hydrogel (flash) technology. Full article

(This article belongs to the Special Issue 3D Printing and Biomaterials for Biological and Medical Application: Recent Advances)

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15 pages, 3688 KiB

Open AccessArticle

Metabolic Signature of Energy Metabolism Alterations and Excess Nitric Oxide Production in Culture Media Correlate with Low Human Embryo Quality and Unsuccessful Pregnancy

by Romina Pallisco, Giacomo Lazzarino, Gabriele Bilotta, Francesca Marroni, Renata Mangione, Miriam Wissam Saab, Maria Violetta Brundo, Alessandra Pittalà, Giuseppe Caruso, Elena Capoccia, Giuseppe Lazzarino, Barbara Tavazzi, Pasquale Bilotta and Angela Maria Amorini

Int. J. Mol. Sci. 2023, 24(1), 890; https://doi.org/10.3390/ijms24010890 - 03 Jan 2023

Cited by 1 | Viewed by 2107

Abstract

Notwithstanding the great improvement of ART, the overall rate of successful pregnancies from implanted human embryos is definitely low. The current routine embryo quality assessment is performed only through morphological criteria, which has poor predictive capacity since only a minor percentage of those [...] Read more.

Notwithstanding the great improvement of ART, the overall rate of successful pregnancies from implanted human embryos is definitely low. The current routine embryo quality assessment is performed only through morphological criteria, which has poor predictive capacity since only a minor percentage of those in the highest class give rise to successful pregnancy. Previous studies highlighted the potentiality of the analysis of metabolites in human embryo culture media, useful for the selection of embryos for implantation. In the present study, we analyzed in blind 66 human embryo culture media at 5 days after in vitro fertilization with the aim of quantifying compounds released by cell metabolism that were not present as normal constituents of the human embryo growth media, including purines, pyrimidines, nitrite, and nitrate. Only some purines were detectable (hypoxanthine and uric acid) in the majority of samples, while nitrite and nitrate were always detectable. When matching biochemical results with morphological evaluation, it was found that low grade embryos (n = 12) had significantly higher levels of all the compounds of interest. Moreover, when matching biochemical results according to successful (n = 17) or unsuccessful (n = 25) pregnancy, it was found that human embryos from the latter group released higher concentrations of hypoxanthine, uric acid, nitrite, and nitrate in the culture media. Additionally, those embryos that developed into successful pregnancies were all associated with the birth of healthy newborns. These results, although carried out on a relatively low number of samples, indicate that the analysis of the aforementioned compounds in the culture media of human embryos is a potentially useful tool for the selection of embryos for implantation, possibly leading to an increase in the overall rate of ART. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Sperm Activation)

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15 pages, 2840 KiB

Open AccessArticle

Genome Assembly of a Relict Arabian Species of Daphnia O. F. Müller (Crustacea: Cladocera) Adapted to the Desert Life

by Waleed Hamza, Khaled M. Hazzouri, Naganeeswaran Sudalaimuthuasari, Khaled M. A. Amiri, Anna N. Neretina, Shamma E. S. Al Neyadi and Alexey A. Kotov

Int. J. Mol. Sci. 2023, 24(1), 889; https://doi.org/10.3390/ijms24010889 - 03 Jan 2023

Cited by 2 | Viewed by 2815

Abstract

The water flea Daphnia O.F. Müller 1776 (Crustacea: Cladocera) is an important model of recent evolutionary biology. Here, we report a complete genome of Daphnia (Ctenodaphnia) arabica (Crustacea: Cladocera), recently described species endemic to deserts of the United Arab Emirates. In this study, [...] Read more.

The water flea Daphnia O.F. Müller 1776 (Crustacea: Cladocera) is an important model of recent evolutionary biology. Here, we report a complete genome of Daphnia (Ctenodaphnia) arabica (Crustacea: Cladocera), recently described species endemic to deserts of the United Arab Emirates. In this study, genome analysis of D. arabica was carried out to investigate its genomic differences, complexity as well as its historical origins within the subgenus Daphnia (Ctenodaphnia). Hybrid genome assembly of D. arabica resulted in ~116 Mb of the assembled genome, with an N50 of ~1.13 Mb (BUSCO score of 99.2%). From the assembled genome, in total protein coding, 5374 tRNA and 643 rRNA genes were annotated. We found that the D. arabica complete genome differed from those of other Daphnia species deposited in the NCBI database but was close to that of D. cf. similoides. However, its divergence time estimate sets D. arabica in the Mesozoic, and our demographic analysis showed a great reduction in its genetic diversity compared to other Daphnia species. Interestingly, the population expansion in its diversity occurred during the megadrought climate around 100 Ka ago, reflecting the adaptive feature of the species to arid and drought-affected environments. Moreover, the PFAM comparative analysis highlights the presence of the important domain SOSS complex subunit C in D. arabica, which is missing in all other studied species of Daphnia. This complex consists of a few subunits (A, B, C) working together to maintain the genome stability (i.e., promoting the reparation of DNA under stress). We propose that this domain could play a role in maintaining the fitness and survival of this species in the desert environment. The present study will pave the way for future research to identify the genes that were gained or lost in this species and identify which of these were key factors to its adaptation to the harsh desert environment. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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18 pages, 5279 KiB

Open AccessArticle

Comprehensive Profiling of ceRNA (circRNA-miRNA-mRNA) Networks in Hypothalamic-Pituitary-Mammary Gland Axis of Dairy Cows under Heat Stress

by Hanfang Zeng, Haibin Xia, Xinling Wang, Yue Wang, Jian Fang, Shujie Li, Yunfei Zhai and Zhaoyu Han

Int. J. Mol. Sci. 2023, 24(1), 888; https://doi.org/10.3390/ijms24010888 - 03 Jan 2023

Cited by 9 | Viewed by 2281

Abstract

Heat stress (HS) is directly correlated with mammary gland dysfunction and the hypothalamic-pituitary-mammary gland (HPM) axis is involved in regulating stress responses and lactation in dairy cows. Circular RNAs (circRNAs) play major roles in regulating transcription and post-transcription but their expression in the [...] Read more.

Heat stress (HS) is directly correlated with mammary gland dysfunction and the hypothalamic-pituitary-mammary gland (HPM) axis is involved in regulating stress responses and lactation in dairy cows. Circular RNAs (circRNAs) play major roles in regulating transcription and post-transcription but their expression in the HPM axis of dairy cows under HS is still unclear. In the present study, we performed RNA sequencing to identify diferentially expressed (DE) circRNAs, DE microRNAs(miRNAs) and DEmRNAs, and performed bioinformatics analysis on those in HPM axis-related tissues of heat-stressed and normal cows. A total of 1680, 1112 and 521 DEcircRNAs, 120, 493 and 108 DEmiRNAs, 274, 6475 and 3134 DEmRNAs were identified in the hypothalamic, pituitary, and mammary gland tissues, respectively. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses indicated that the MAPK signaling pathway is potentially a key pathway. Competitive endogenous RNA (ceRNA) networks related to HS response and lactation regulation were established in three tissues. In conclusion, our results indicate that HS induces differential circRNA expression profiles in HPM axis-related tissues, and the predicted ceRNA network provides a molecular basis for regulating the stress response and lactation regulation in heat-stressed dairy cows. Full article

(This article belongs to the Special Issue Advances in circRNA Biology)

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15 pages, 1120 KiB

Open AccessReview

Oxidative Stress and Immune Response in Melanoma: Ion Channels as Targets of Therapy

by Alessia Remigante, Sara Spinelli, Angela Marino, Michael Pusch, Rossana Morabito and Silvia Dossena

Int. J. Mol. Sci. 2023, 24(1), 887; https://doi.org/10.3390/ijms24010887 - 03 Jan 2023

Cited by 15 | Viewed by 2650

Abstract

Oxidative stress and immune response play an important role in the development of several cancers, including melanoma. Ion channels are aberrantly expressed in tumour cells and regulate neoplastic transformation, malignant progression, and resistance to therapy. Ion channels are localized in the plasma membrane [...] Read more.

Oxidative stress and immune response play an important role in the development of several cancers, including melanoma. Ion channels are aberrantly expressed in tumour cells and regulate neoplastic transformation, malignant progression, and resistance to therapy. Ion channels are localized in the plasma membrane or other cellular membranes and are targets of oxidative stress, which is particularly elevated in melanoma. At the same time, ion channels are crucial for normal and cancer cell physiology and are subject to multiple layers of regulation, and therefore represent promising targets for therapeutic intervention. In this review, we analyzed the effects of oxidative stress on ion channels on a molecular and cellular level and in the context of melanoma progression and immune evasion. The possible role of ion channels as targets of alternative therapeutic strategies in melanoma was discussed. Full article

(This article belongs to the Special Issue The Role of Reactive Oxygen Species (ROS) in the Immune System and Health)

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4 pages, 186 KiB

Open AccessEditorial

Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization

by Andrey V. Kuznetsov and Michael J. Ausserlechner

Int. J. Mol. Sci. 2023, 24(1), 886; https://doi.org/10.3390/ijms24010886 - 03 Jan 2023

Cited by 1 | Viewed by 1666

Abstract

Mitochondria have been recognized as the energy (in the form of ATP)-producing cell organelles, required for cell viability, survival and normal cell function [...] Full article

(This article belongs to the Special Issue Research of Mitochondrial Function, Structure, Dynamics and Intracellular Organization 2.0)

17 pages, 1022 KiB

Open AccessReview

Diagnostic and Prognostic Role of Extracellular Vesicles in Pancreatic Cancer: Current Evidence and Future Perspectives

by Alberto Nicoletti, Marcantonio Negri, Mattia Paratore, Federica Vitale, Maria Elena Ainora, Enrico Celestino Nista, Antonio Gasbarrini, Maria Assunta Zocco and Lorenzo Zileri Dal Verme

Int. J. Mol. Sci. 2023, 24(1), 885; https://doi.org/10.3390/ijms24010885 - 03 Jan 2023

Cited by 9 | Viewed by 3391

Abstract

Pancreatic cancer is one of the most aggressive tumors, with a dismal prognosis due to poor detection rates at early stages, rapid progression, post-surgical complications, and limited effectiveness of conventional oncologic therapies. There are no consistently reliable biomarkers or imaging modalities to accurately [...] Read more.

Pancreatic cancer is one of the most aggressive tumors, with a dismal prognosis due to poor detection rates at early stages, rapid progression, post-surgical complications, and limited effectiveness of conventional oncologic therapies. There are no consistently reliable biomarkers or imaging modalities to accurately diagnose, classify, and predict the biological behavior of this tumor. Therefore, it is imperative to develop new and improved strategies to detect pancreatic lesions in the early stages of cancerization with greater sensitivity and specificity. Extracellular vesicles, including exosome and microvesicles, are membrane-coated cellular products that are released in the outer environment. All cells produce extracellular vesicles; however, this process is enhanced by inflammation and tumorigenesis. Based on accumulating evidence, extracellular vesicles play a crucial role in pancreatic cancer progression and chemoresistance. Moreover, they may represent potential biomarkers and promising therapy targets. The aim of the present review is to review the current evidence on the role of extracellular vesicles in pancreatic cancer. Full article

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

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14 pages, 444 KiB

Open AccessReview

Microglial Activation and Priming in Alzheimer’s Disease: State of the Art and Future Perspectives

by Giulia Bivona, Matilda Iemmolo, Luisa Agnello, Bruna Lo Sasso, Caterina Maria Gambino, Rosaria Vincenza Giglio, Concetta Scazzone, Giulio Ghersi and Marcello Ciaccio

Int. J. Mol. Sci. 2023, 24(1), 884; https://doi.org/10.3390/ijms24010884 - 03 Jan 2023

Cited by 13 | Viewed by 3886

Abstract

Alzheimer’s Disease (AD) is the most common cause of dementia, having a remarkable social and healthcare burden worldwide. Amyloid β (Aβ) and protein Tau aggregates are disease hallmarks and key players in AD pathogenesis. However, it has been hypothesized that microglia can contribute [...] Read more.

Alzheimer’s Disease (AD) is the most common cause of dementia, having a remarkable social and healthcare burden worldwide. Amyloid β (Aβ) and protein Tau aggregates are disease hallmarks and key players in AD pathogenesis. However, it has been hypothesized that microglia can contribute to AD pathophysiology, as well. Microglia are CNS-resident immune cells belonging to the myeloid lineage of the innate arm of immunity. Under physiological conditions, microglia are in constant motion in order to carry on their housekeeping function, and they maintain an anti-inflammatory, quiescent state, with low expression of cytokines and no phagocytic activity. Upon various stimuli (debris, ATP, misfolded proteins, aggregates and pathogens), microglia acquire a phagocytic function and overexpress cytokine gene modules. This process is generally regarded as microglia activation and implies that the production of pro-inflammatory cytokines is counterbalanced by the synthesis and the release of anti-inflammatory molecules. This mechanism avoids excessive inflammatory response and inappropriate microglial activation, which causes tissue damage and brain homeostasis impairment. Once the pathogenic stimulus has been cleared, activated microglia return to the naïve, anti-inflammatory state. Upon repeated stimuli (as in the case of Aβ deposition in the early stage of AD), activated microglia shift toward a less protective, neurotoxic phenotype, known as “primed” microglia. The main characteristic of primed microglia is their lower capability to turn back toward the naïve, anti-inflammatory state, which makes these cells prone to chronic activation and favours chronic inflammation in the brain. Primed microglia have impaired defence capacity against injury and detrimental effects on the brain microenvironment. Additionally, priming has been associated with AD onset and progression and can represent a promising target for AD treatment strategies. Many factors (genetics, environmental factors, baseline inflammatory status of microglia, ageing) generate an aberrantly activated phenotype that undergoes priming easier and earlier than normally activated microglia do. Novel, promising targets for therapeutic strategies for AD have been sought in the field of microglia activation and, importantly, among those factors influencing the baseline status of these cells. The CX3CL1 pathway could be a valuable target treatment approach in AD, although preliminary findings from the studies in this field are controversial. The current review aims to summarize state of the art on the role of microglia dysfunction in AD pathogenesis and proposes biochemical pathways with possible targets for AD treatment. Full article

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

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28 pages, 4383 KiB

Open AccessArticle

The Prolonged Treatment of Salmonella enterica Strains with Human Serum Effects in Phenotype Related to Virulence

by Bożena Futoma-Kołoch, Michał Małaszczuk, Kamila Korzekwa, Małgorzata Steczkiewicz, Andrzej Gamian and Gabriela Bugla-Płoskońska

Int. J. Mol. Sci. 2023, 24(1), 883; https://doi.org/10.3390/ijms24010883 - 03 Jan 2023

Viewed by 4512

Abstract

Salmonella enterica as common pathogens of humans and animals are good model organisms to conduct research on bacterial biology. Because these bacteria can multiply in both the external environments and in the living hosts, they prove their wide adaptability. It has been previously [...] Read more.

Salmonella enterica as common pathogens of humans and animals are good model organisms to conduct research on bacterial biology. Because these bacteria can multiply in both the external environments and in the living hosts, they prove their wide adaptability. It has been previously demonstrated that prolonged exposition of Salmonella serotype O48 cells to normal human serum led to an increase in resistance to sera in connection with the synthesis of very long O-antigen. In this work, we have studied the phenotype connected to virulence of Salmonella enterica strains that were subjected to consecutive passages in 50% human serum from platelet-poor plasma (SPPP). We found that eight passages in SPPP may not be enough for the bacteria to become serum-resistant (S. Typhimurium ATCC 14028, S. Senftenberg). Moreover, C1q and C3c complement components bound to Salmonellae (S. Typhimurium ATCC 14028, S. Hammonia) membrane proteins, which composition has been changed after passaging in sera. Interestingly, passages in SPPP generated genetic changes within gene fljB, which translated to cells’ motility (S. Typhimurium ATCC 14028, S. Erlangen). One strain, S. Hammonia exposed to a serum developed a multi-drug resistance (MDR) phenotype and two S. Isaszeg and S. Erlangen tolerance to disinfectants containing quaternary ammonium salts (QAS). Furthermore, colonial morphotypes of the serum adaptants were similar to those produced by starter cultures. These observations suggest that overcoming stressful conditions is manifested on many levels. Despite great phenotypic diversity occurring after prolonged exposition to SPPP, morphotypes of colonies remained unchanged in basic media. This work is an example in which stable morphotypes distinguished by altered virulence can be confusing during laboratory work with life-threatening strains. Full article

(This article belongs to the Collection State-of-the-Art Molecular Microbiology in Poland)

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15 pages, 3161 KiB

Open AccessArticle

PLA2G7/PAF-AH as Potential Negative Regulator of the Wnt Signaling Pathway Mediates Protective Effects in BRCA1 Mutant Breast Cancer

by Yue Liao, Susann Badmann, Fabian Kraus, Nicole Elisabeth Topalov, Doris Mayr, Thomas Kolben, Anna Hester, Susanne Beyer, Sven Mahner, Udo Jeschke, Fabian Trillsch, Bastian Czogalla and Alexander Burges

Int. J. Mol. Sci. 2023, 24(1), 882; https://doi.org/10.3390/ijms24010882 - 03 Jan 2023

Cited by 2 | Viewed by 2459

Abstract

Past studies have confirmed that aberrant activation of the Wnt/β-catenin signaling is associated with tumorigenesis and metastasis in breast cancer, while the role of platelet-activating factor acetylhydrolase (PLA2G7/PAF-AH) in this signaling pathway remains unclear. In this study, we analyze the functional impact of [...] Read more.

Past studies have confirmed that aberrant activation of the Wnt/β-catenin signaling is associated with tumorigenesis and metastasis in breast cancer, while the role of platelet-activating factor acetylhydrolase (PLA2G7/PAF-AH) in this signaling pathway remains unclear. In this study, we analyze the functional impact of PAF-AH on BRCA1 mutant breast cancer and explore its relationship to the Wnt signaling pathway. By performing immunohistochemistry, PAF-AH expression and β-catenin expression were examined in both BRCA1 WT and BRCA1 mutant breast cancer specimens. The BRCA1 mutant breast cancer cell line HCC1937 was used for in vitro experiments to assess the impact of PAF-AH on cellular functions. The intracellular distribution of β-catenin depending on PLA2G7/PAF-AH expression was investigated by immunocytochemistry. Significantly higher nuclear expression levels of PAF-AH were found in BRCA1 mutant tissue specimens than in BRCA1 WT samples. Cell viability, proliferation, and the motility rate of HCC1937 were significantly enhanced after PLA2G7 silencing, which indicated a protective role of PAF-AH in breast cancer. Nuclear PAF-AH expressed correlatedly with membranous β-catenin. PLA2G7 silencing provoked the β-catenin translocation from the membrane to the nucleus and activated Wnt signaling downstream genes. Our data showed a protective effect of high PAF-AH expression in BRCA1 mutant breast cancer. PAF-AH may achieve its protective effect by negatively regulating the Wnt pathway. In conclusion, our research sheds new light on the regulatory pathways in BRCA1 mutant breast cancer. Full article

(This article belongs to the Special Issue Breast Cancer Mechanistic Insights and Targeted Therapies)

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19 pages, 4398 KiB

Open AccessArticle

iPSC-Derived MSCs Are a Distinct Entity of MSCs with Higher Therapeutic Potential than Their Donor-Matched Parental MSCs

by Hae-Ri Lee, Soo Kim, Sungho Shin, Seon-Yeong Jeong, Dae-Won Lee, Sun-Ung Lim, Ji Yeon Kang, Mi-Young Son, Cheolju Lee, Kyung-Rok Yu, Myungshin Kim and Il-Hoan Oh

Int. J. Mol. Sci. 2023, 24(1), 881; https://doi.org/10.3390/ijms24010881 - 03 Jan 2023

Cited by 6 | Viewed by 3241

Abstract

Mesenchymal stromal cells derived from induced pluripotent stem cells (iMSCs) have been proposed as alternative sources of primary MSCs with various advantages for cell therapeutic trials. However, precise evaluation of the differences between iMSCs and primary MSCs is lacking due to individual variations [...] Read more.

Mesenchymal stromal cells derived from induced pluripotent stem cells (iMSCs) have been proposed as alternative sources of primary MSCs with various advantages for cell therapeutic trials. However, precise evaluation of the differences between iMSCs and primary MSCs is lacking due to individual variations in the donor cells, which obscure direct comparisons between the two. In this study, we generated donor-matched iMSCs from individual bone marrow-derived MSCs and directly compared their cell-autonomous and paracrine therapeutic effects. We found that the transition from primary MSCs to iMSCs is accompanied by a functional shift towards higher proliferative activity, with variations in differentiation potential in a donor cell-dependent manner. The transition from MSCs to iMSCs was associated with common changes in transcriptomic and proteomic profiles beyond the variations of their individual donors, revealing expression patterns unique for the iMSCs. These iMSC-specific patterns were characterized by a shift in cell fate towards a pericyte-like state and enhanced secretion of paracrine cytokine/growth factors. Accordingly, iMSCs exhibited higher support for the self-renewing expansion of primitive hematopoietic progenitors and more potent immune suppression of allogenic immune responses than MSCs. Our study suggests that iMSCs represent a separate entity of MSCs with unique therapeutic potential distinct from their parental MSCs, but points to the need for iMSC characterization in the individual basis. Full article

(This article belongs to the Special Issue Mesenchymal Stem Cells and Their Derived Products in Aging and Diseases)

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20 pages, 5725 KiB

Open AccessArticle

Alginate Beads Containing Cerium-Doped Mesoporous Glass and Curcumin: Delivery and Stabilization of Therapeutics

by Debora Carrozza, Gianluca Malavasi, Erika Ferrari and Maria Cristina Menziani

Int. J. Mol. Sci. 2023, 24(1), 880; https://doi.org/10.3390/ijms24010880 - 03 Jan 2023

Cited by 1 | Viewed by 1561

Abstract

Cancer is a leading cause of death worldwide, its genesis and progression are caused by homeostatic errors, and reactive oxygen species play a major role in promoting aberrant cancer homeostasis. In this scenario, curcumin could be an interesting candidate due to its versatile [...] Read more.

Cancer is a leading cause of death worldwide, its genesis and progression are caused by homeostatic errors, and reactive oxygen species play a major role in promoting aberrant cancer homeostasis. In this scenario, curcumin could be an interesting candidate due to its versatile antioxidant, anti-inflammatory, anti-tumor, anti-HIV, and anti-infection properties. Nonetheless, the major problem related to its use is its poor oral bioavailability, which can be overcome by encapsulating it into small particles, such as hydrogel beads containing mesoporous silica. In this work, various systems have been synthesized: starting from mesoporous silica glasses (MGs), cerium-containing MGs have been produced; then, these systems have been loaded with 4 to 6% of curcumin. Finally, various MGs at different compositions have been included in alginate beads. In vitro studies showed that these hybrid materials enable the stabilization and effective delivery of curcumin and that a synergic effect can be achieved if Ce³⁺/Ce⁴⁺ and curcumin are both part of the beads. From swelling tests, it is possible to confirm a controlled curcumin release compartmentalized into the gastrointestinal tract. For all beads obtained, a curcumin release sufficient to achieve the antioxidant threshold has been reached, and a synergic effect of cerium and curcumin is observed. Moreover, from catalase mimetic activity tests, we confirm the well-known catalytic activity of the couple Ce³⁺/Ce⁴⁺. In addition, an extremely good radical scavenging effect of curcumin has been demonstrated. In conclusion, these systems, able to promote an enzymatic-like activity, can be used as drug delivery systems for curcumin-targeted dosing. Full article

(This article belongs to the Special Issue Biomaterials and Their Composites for Biomedical Applications and Beyond)

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18 pages, 4175 KiB

Open AccessArticle

Double Stimuli-Responsive di- and Triblock Copolymers of Poly(N-isopropylacrylamide) and Poly(1-vinylimidazole): Synthesis and Self-Assembly

by Elena Yu. Kozhunova, Anna V. Plutalova, Andrey V. Sybachin, Alexander V. Chertovich and Elena V. Chernikova

Int. J. Mol. Sci. 2023, 24(1), 879; https://doi.org/10.3390/ijms24010879 - 03 Jan 2023

Viewed by 1927

Abstract

For the first time, double stimuli-responsive properties of poly(N-isopropylacrylamide) (PNIPA) and poly(1-vinylimidazole) (PVIM) block copolymers in aqueous solutions were studied. The synthesis of PNIPA₆₀-b-PVIM₉₀ and PNIPA₂₈-b-PVIM₆₂-b-PNIPA₂₉ was performed using [...] Read more.

For the first time, double stimuli-responsive properties of poly(N-isopropylacrylamide) (PNIPA) and poly(1-vinylimidazole) (PVIM) block copolymers in aqueous solutions were studied. The synthesis of PNIPA₆₀-b-PVIM₉₀ and PNIPA₂₈-b-PVIM₆₂-b-PNIPA₂₉ was performed using reversible addition–fragmentation chain transfer (RAFT) polymerization. The polymers were characterized by size exclusion chromatography and ¹H NMR spectroscopy. The conformational behavior of the polymers was studied using dynamic light scattering (DLS) and fluorescence spectroscopy (FS). It was found that PNIPA and block copolymers conformation and ability for self-assembly in aqueous medium below and above cloud point temperature depend on the locus of hydrophobic groups derived from the RAFT agent within the chain. Additionally, the length of PVIM block, its locus in the chain and charge perform an important role in the stabilization of macromolecular micelles and aggregates below and above cloud point temperature. At 25 °C the average hydrodynamic radius (R_h) of the block copolymer particles at pH 3 is lower than at pH 9 implying the self-assembling of macromolecules in the latter case. Cloud points of PNIPA₆₀-b-PVIM₉₀ are ~43 °C and ~37 °C at a pH of 3 and 9 and of PNIPA₂₈-b-PVIM₆₂-b-PNIPA₂₉ they are ~35 °C and 31 °C at a pH of 3 and 9. Around cloud point independently of pH, the R_h value for triblock copolymer rises sharply, achieves the maximum value, then falls and reaches the constant value, while for diblock copolymer, it steadily grows after reaching cloud point. The information about polarity of microenvironment around polymer obtained by FS accords with DLS data. Full article

(This article belongs to the Special Issue Synthesis of Advanced Polymer Materials)

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17 pages, 1445 KiB

Open AccessReview

Choroid Plexus Aquaporins in CSF Homeostasis and the Glymphatic System: Their Relevance for Alzheimer’s Disease

by Cristina Municio, Laura Carrero, Desireé Antequera and Eva Carro

Int. J. Mol. Sci. 2023, 24(1), 878; https://doi.org/10.3390/ijms24010878 - 03 Jan 2023

Cited by 13 | Viewed by 5071

Abstract

The glymphatic system, a fluid-clearance pathway involved in brain waste clearance, is known to be impaired in neurological disorders, including Alzheimer’s disease (AD). For this reason, it is important to understand the specific mechanisms and factors controlling glymphatic function. This pathway enables the [...] Read more.

The glymphatic system, a fluid-clearance pathway involved in brain waste clearance, is known to be impaired in neurological disorders, including Alzheimer’s disease (AD). For this reason, it is important to understand the specific mechanisms and factors controlling glymphatic function. This pathway enables the flow of cerebrospinal fluid (CSF) into the brain and subsequently the brain interstitium, supported by aquaporins (AQPs). Continuous CSF transport through the brain parenchyma is critical for the effective transport and drainage of waste solutes, such as toxic proteins, through the glymphatic system. However, a balance between CSF production and secretion from the choroid plexus, through AQP regulation, is also needed. Thus, any condition that affects CSF homeostasis will also interfere with effective waste removal through the clearance glymphatic pathway and the subsequent processes of neurodegeneration. In this review, we highlight the role of AQPs in the choroid plexus in the modulation of CSF homeostasis and, consequently, the glymphatic clearance pathway, with a special focus on AD. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Neurodegenerative Diseases)

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11 pages, 5531 KiB

Open AccessCommunication

Dihydroceramides Derived from Bacteroidetes Species Sensitize TRPV1 Channels

by Nora Ludwig, Isaac S. Demaree, Chiaki Yamada, Amilia Nusbaum, Frank C. Nichols, Fletcher A. White, Alexandru Movila and Alexander G. Obukhov

Int. J. Mol. Sci. 2023, 24(1), 877; https://doi.org/10.3390/ijms24010877 - 03 Jan 2023

Cited by 1 | Viewed by 1648

Abstract

Bacterial colonization of open wounds is common, and patients with infected wounds often report significantly elevated pain sensitivity at the wound site. Transient Receptor Potential Vanilloid Type 1 (TRPV1) channels are known to play an important role in pain signaling and may be [...] Read more.

Bacterial colonization of open wounds is common, and patients with infected wounds often report significantly elevated pain sensitivity at the wound site. Transient Receptor Potential Vanilloid Type 1 (TRPV1) channels are known to play an important role in pain signaling and may be sensitized under pro-inflammatory conditions. Bacterial membrane components, such as phosphoethanolamine dihydroceramide (PEDHC), phosphoglycerol dihydroceramide (PGDHC), and lipopolysaccharide (LPS), are released in the environment from the Gram-negative bacteria of the Bacteroidetes species colonizing the infected wounds. Here, we used intracellular calcium imaging and patch-clamp electrophysiology approaches to determine whether bacterially derived PEDHC, PGDHC, or LPS can modulate the activity of the TRPV1 channels heterologously expressed in HEK cells. We found that PEDHC and PGDHC can sensitize TRPV1 in a concentration-dependent manner, whereas LPS treatment does not significantly affect TRPV1 activity in HEK cells. We propose that sensitization of TRPV1 channels by Bacteroidetes-derived dihydroceramides may at least in part underlie the increased pain sensitivity associated with wound infections. Full article

(This article belongs to the Special Issue Targeting TRP Channels for Pain, Itch and Inflammation Relief)

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22 pages, 6592 KiB

Open AccessArticle

Activated Leukocyte Cell Adhesion Molecule (ALCAM), a Potential ‘Seed’ and ‘Soil’ Receptor in the Peritoneal Metastasis of Gastrointestinal Cancers

by Yi Ming Yang, Lin Ye, Fiona Ruge, Ziqian Fang, Ke Ji, Andrew J. Sanders, Shuqin Jia, Chunyi Hao, Q. Ping Dou, Jiafu Ji and Wen G. Jiang

Int. J. Mol. Sci. 2023, 24(1), 876; https://doi.org/10.3390/ijms24010876 - 03 Jan 2023

Cited by 3 | Viewed by 2814

Abstract

Activated Leukocyte Cell Adhesion Molecule (ALCAM/CD166) is a cell–cell adhesion protein conferring heterotypic and homotypic interactions between cells of the same type and different types. It is aberrantly expressed in various cancer types and has been shown to be a regulator of cancer [...] Read more.

Activated Leukocyte Cell Adhesion Molecule (ALCAM/CD166) is a cell–cell adhesion protein conferring heterotypic and homotypic interactions between cells of the same type and different types. It is aberrantly expressed in various cancer types and has been shown to be a regulator of cancer metastasis. In the present study, we investigated potential roles of ALCAM in the peritoneal transcoelomic metastasis in gastrointestinal cancers, a metastatic type commonly occurred in gastro-intestinal and gynaecological malignancies and resulting in poor clinical outcomes. Specifically, we studied whether ALCAM acts as both a ‘seed’ receptor in these tumour cells and a ‘soil’ receptor in peritoneal mesothelial cells during cancer metastasis. Gastric cancer and pancreatic cancer tissues with or without peritoneal metastasis were compared for their levels of ALCAM expression. The impact of ALCAM expression in these tumours was also correlated to the patients’ clinical outcomes, namely peritoneal metastasis-free survival. In addition, cancer cells of gastric and pancreatic origins were used to create cell models with decreased or increased levels of ALCAM expression by genetic knocking down or overexpression, respectively. Human peritoneal mesothelial cells were also genetically transfected to generate cell models with different profiles of ALCAM expression. These cell models were used in the tumour-mesothelial interaction assay to assess if and how the interaction was influenced by ALCAM. Both gastric and pancreatic tumour tissues from patients who developed peritoneal metastases had higher levels of ALCAM transcript than those without. Patients who had tumours with high levels of ALCAM had a much shorter peritoneal metastasis free survival compared with those who had low ALCAM expression (p = 0.006). ALCAM knockdown of the mesothelial cell line MET5A rendered the cells with reduced interaction with both gastric cancer cells and pancreatic cancer cells. Likewise, levels of ALCAM in both human gastric and pancreatic cancer cells were also a determining factor for their adhesiveness to mesothelial cells, a process that was likely to be triggered the phosphorylation of the SRC kinase. A soluble ALCAM (sALCAM) was found to be able to inhibit the adhesiveness between cancer cells and mesothelial cells, mechanistically behaving like a SRC kinase inhibitor. ALCAM is an indicator of peritoneal metastasis in both gastric and pancreatic cancer patients. It acts as not only a potential peritoneal ‘soil’ receptor of tumour seeding but also a ‘soil’ receptor in peritoneal mesothelial cells during cancer metastasis. These findings have an important therapeutic implication for treating peritoneal transcoelomic metastases. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Oncology in UK)

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20 pages, 4778 KiB

Open AccessArticle

The Antimicrobial Peptide Cathelicidin Exerts Immunomodulatory Effects via Scavenger Receptors

by Ryo Amagai, Toshiya Takahashi, Hitoshi Terui, Taku Fujimura, Kenshi Yamasaki, Setsuya Aiba and Yoshihide Asano

Int. J. Mol. Sci. 2023, 24(1), 875; https://doi.org/10.3390/ijms24010875 - 03 Jan 2023

Cited by 4 | Viewed by 2489

Abstract

An active form of cathelicidin antimicrobial peptide, LL-37, has immunomodulatory and stimulatory effects, though the specific pathways are not clear. The purpose of this study was to identify the cellular pathways by which LL-37 amplifies the inflammation induced by damage-associated molecular patterns (DAMPs). [...] Read more.

An active form of cathelicidin antimicrobial peptide, LL-37, has immunomodulatory and stimulatory effects, though the specific pathways are not clear. The purpose of this study was to identify the cellular pathways by which LL-37 amplifies the inflammation induced by damage-associated molecular patterns (DAMPs). We performed DNA microarray, reverse transcription polymerase chain reaction, immunoblotting, and proximity ligation assays using cultured keratinocytes treated with LL-37 and/or the DAMP poly(I:C), a synthetic double-stranded RNA. In contrast to the combination of LL-37 and poly(I:C), LL-37 alone induced genes related to biological metabolic processes such as VEGFA and PTGS2 (COX-2). Inhibition of FPR2, a known receptor for cathelicidin, partially suppressed the induction of VEGFA and PTGS2. Importantly, VEGFA and PTGS2 induced by LL-37 alone were diminished by the knockdown of scavenger receptors including SCARB1 (SR-B1), OLR1 (SR-E1), and AGER (SR-J1). Moreover, LL-37 alone, as well as the combination of LL-37 and poly(I:C), showed proximity to the scavenger receptors, indicating that LL-37 acts via scavenger receptors and intermediates between them and poly(I:C). These results showed that the broad function of cathelicidin is generally dependent on scavenger receptors. Therefore, inhibitors of scavenger receptors or non-functional mock cathelicidin peptides may serve as new anti-inflammatory and immunosuppressive agents. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Skin Autoimmunity and Hypersensitivity)

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12 pages, 2391 KiB

Open AccessArticle

Conjugated Linoleic Acids Have Anti-Inflammatory Effects in Cultured Endothelial Cells

by Carina A. Valenzuela, Ella J. Baker, Elizabeth A. Miles and Philip C. Calder

Int. J. Mol. Sci. 2023, 24(1), 874; https://doi.org/10.3390/ijms24010874 - 03 Jan 2023

Cited by 5 | Viewed by 1801

Abstract

Conjugated linoleic acid (CLA) isomers may have a role in preventing atherosclerosis through the modulation of inflammation, particularly of the endothelium. However, whether low concentrations of CLAs are able to affect basal unstimulated endothelial cell (EC) responses is not clear. The aim of [...] Read more.

Conjugated linoleic acid (CLA) isomers may have a role in preventing atherosclerosis through the modulation of inflammation, particularly of the endothelium. However, whether low concentrations of CLAs are able to affect basal unstimulated endothelial cell (EC) responses is not clear. The aim of this study was to evaluate the effects of two CLAs (cis-9, trans-11 (CLA9,11) and trans-10, cis-12 (CLA10,12)) on the basal inflammatory responses by ECs. EA.hy926 cells (HUVEC lineage) were cultured under standard conditions and exposed to individual CLAs for 48 h. Both CLAs were incorporated into ECs in a dose-dependent manner. CLA9,11 (1 μM) significantly decreased concentrations of MCP-1 (p < 0.05), IL-6 (p < 0.05), IL-8 (p < 0.01) and RANTES (p < 0.05) in the culture medium. CLA10,12 (10 μM) decreased the concentrations of MCP-1 (p < 0.05) and RANTES (p < 0.05) but increased the concentration of IL-6 (p < 0.001). At 10 μM both CLAs increased the relative expression of the NFκβ subunit 1 gene (p < 0.01 and p < 0.05, respectively), while decreasing the relative expression of PPARα (p < 0.0001), COX-2 (p < 0.0001) and IL-6 (p < 0.0001) genes. CLA10,12 increased the relative expression of the gene encoding IκK-β at 10 μM compared with CLA9,11 (p < 0.05) and increased the relative expression of the gene encoding IκBα at 1 and 10 μM compared with linoleic acid (both p < 0.05). Neither CLA affected the adhesion of monocytes to ECs. These results suggest that low concentrations of both CLA9,11 and CLA10,12 have modest anti-inflammatory effects in ECs. Thus, CLAs may influence endothelial function and the risk of vascular disease. Nevertheless, at these low CLA concentrations some pro-inflammatory genes are upregulated while others are downregulated, suggesting complex effects of CLAs on inflammatory pathways. Full article

(This article belongs to the Special Issue Nutraceuticals in the Prevention and Treatment of Inflammatory Diseases)

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16 pages, 3510 KiB

Open AccessArticle

Genome-Wide Association Studies of Seven Root Traits in Soybean (Glycine max L.) Landraces

by Seong-Hoon Kim, Rupesh Tayade, Byeong-Hee Kang, Bum-Soo Hahn, Bo-Keun Ha and Yoon-Ha Kim

Int. J. Mol. Sci. 2023, 24(1), 873; https://doi.org/10.3390/ijms24010873 - 03 Jan 2023

Cited by 4 | Viewed by 3203

Abstract

Soybean [Glycine max (L.) Merr.], an important oilseed crop, is a low-cost source of protein and oil. In Southeast Asia and Africa, soybeans are widely cultivated for use as traditional food and feed and industrial purposes. Given the ongoing changes in global [...] Read more.

Soybean [Glycine max (L.) Merr.], an important oilseed crop, is a low-cost source of protein and oil. In Southeast Asia and Africa, soybeans are widely cultivated for use as traditional food and feed and industrial purposes. Given the ongoing changes in global climate, developing crops that are resistant to climatic extremes and produce viable yields under predicted climatic conditions will be essential in the coming decades. To develop such crops, it will be necessary to gain a thorough understanding of the genetic basis of agronomic and plant root traits. As plant roots generally lie beneath the soil surface, detailed observations and phenotyping throughout plant development present several challenges, and thus the associated traits have tended to be ignored in genomics studies. In this study, we phenotyped 357 soybean landraces at the early vegetative (V2) growth stages and used a 180 K single-nucleotide polymorphism (SNP) soybean array in a genome-wide association study (GWAS) conducted to determine the phenotypic relationships among root traits, elucidate the genetic bases, and identify significant SNPs associated with root trait-controlling genomic regions/loci. A total of 112 significant SNP loci/regions were detected for seven root traits, and we identified 55 putative candidate genes considered to be the most promising. Our findings in this study indicate that a combined approach based on SNP array and GWAS analyses can be applied to unravel the genetic basis of complex root traits in soybean, and may provide an alternative high-resolution marker strategy to traditional bi-parental mapping. In addition, the identified SNPs, candidate genes, and diverse variations in the root traits of soybean landraces will serve as a valuable basis for further application in genetic studies and the breeding of climate-resilient soybeans characterized by improved root traits. Full article

(This article belongs to the Special Issue Comparative Genomics and Functional Genomics Analysis in Plants)

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19 pages, 4144 KiB

Open AccessArticle

Topographically Distinguished Microbiome Taxonomy and Stress-Response Genes of Royal Belum Rainforest and Raja Muda Musa Peat Swamp Revealed through Metagenomic Inquisition

by Mohd Fadzli Ahmad, Hasdianty Abdullah, Muhammad Naim Hassan, Muhammad Imran Jamaludin, Ashvini Sivam, Kazuhiro Komatsu, Irni Suhayu Sapian, Halimah Alias, Mohd Noor Mat Isa, Victor S. Kuwahara and Nor Suhaila Yaacob

Int. J. Mol. Sci. 2023, 24(1), 872; https://doi.org/10.3390/ijms24010872 - 03 Jan 2023

Viewed by 2397

Abstract

Soil ecosystems are home to a diverse range of microorganisms, but they are only partially understood because no single-cell sequencing or whole-community sequencing provides a complete picture of these complex communities. Using one of such metagenomics approaches, we succeeded in monitoring the microbial [...] Read more.

Soil ecosystems are home to a diverse range of microorganisms, but they are only partially understood because no single-cell sequencing or whole-community sequencing provides a complete picture of these complex communities. Using one of such metagenomics approaches, we succeeded in monitoring the microbial diversity and stress-response gene in the soil samples. This study aims to test whether known differences in taxonomic diversity and composition are reflected in functional gene profiles by implementing whole gene sequencing (WGS) metagenomic analysis of geographically dispersed soils from two distinct pristine forests. The study was commenced by sequencing three rainforest soil samples and three peat swamp soil samples. Soil richness effects were assessed by exploring the changes in specific functional gene abundances to elucidate physiological constraints acting on different soil systems and identify variance in functional pathways relevant to soil biogeochemical cycling. Proteobacteria shows abundances of microbial diversity for 52.15% in Royal Belum Reserved Forest and 48.28% in Raja Musa; 177 out of 1,391,841 and 449 out of 3,586,577 protein coding represent acidic stress-response genes for Royal Belum and Raja Musa, respectively. Raja Musa indicates pH 2.5, which is extremely acidic. The analysis of the taxonomic community showed that Royal Belum soils are dominated by bacteria (98% in Sungai Kooi (SK), 98% in Sungai Papan (SP), and 98% in Sungai Ruok (SR), Archaea (0.9% in SK, 0.9% in SP, and 1% in SR), and the remaining were classed under Eukaryota and viruses. Likewise, the soils of Raja Muda Musa are also dominated by bacteria (95% in Raja Musa 1 (RM1), 98% in Raja Musa 2 (RM2), and 96% in Raja Musa 3 (RM3)), followed by Archaea (4% in RM1, 1% in RM2, and 3% in RM3), and the remaining were classed under Eukaryota and viruses. This study revealed that RBFR (Royal Belum Foresr Reserve) and RMFR (Raja Musa Forest Reserve) metagenomes contained abundant stress-related genes assigned to various stress-response pathways, many of which did not show any difference among samples from both sites. Our findings indicate that the structure and functional potential of the microbial community will be altered by future environmental potential as the first glimpse of both the taxonomic and functional composition of soil microbial communities. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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13 pages, 62543 KiB

Open AccessCommunication

Microglia in Cultured Porcine Retina: Qualitative Immunohistochemical Analyses of Reactive Microglia in the Outer Retina

by Kjell Johansson and Camilla Mohlin

Int. J. Mol. Sci. 2023, 24(1), 871; https://doi.org/10.3390/ijms24010871 - 03 Jan 2023

Viewed by 1724

Abstract

A late stage of several retinal disorders is retinal detachment, a complication that results in rapid photoreceptor degeneration and synaptic damages. Experimental retinal detachment in vivo is an invasive and complicated method performed on anesthetized animals. As retinal detachment may result in visual [...] Read more.

A late stage of several retinal disorders is retinal detachment, a complication that results in rapid photoreceptor degeneration and synaptic damages. Experimental retinal detachment in vivo is an invasive and complicated method performed on anesthetized animals. As retinal detachment may result in visual impairment and blindness, research is of fundamental importance for understanding degenerative processes. Both morphological and ethical issues make the porcine retina a favorable organotypic model for studies of the degenerative processes that follow retinal detachment. In the cultured retina, photoreceptor degeneration and synaptic injuries develop rapidly and correlate with resident microglial cells’ transition into a reactive phenotype. In this immunohistochemical study, we have begun to analyze the transition of subsets of reactive microglia which are known to localize close to the outer plexiform layer (OPL) in degenerating in vivo and in vitro retina. Biomarkers for reactive microglia included P2Ry12, CD63 and CD68 and the general microglial markers were CD11b, Iba1 and isolectin B₄ (IB₄). The reactive microglia markers labeled microglia subpopulations, suggesting that protective or harmful reactive microglia may be present simultaneously in the injured retina. Our findings support the usage of porcine retina cultures for studies of photoreceptor injuries related to retinal detachment. Full article

(This article belongs to the Special Issue Advanced Research in Retina)

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12 pages, 3642 KiB

Open AccessArticle

Exploring the Potential Energy Surface of Pt₆ Sub-Nano Clusters Deposited over Graphene

by Daniel Barrena-Espés, Sergio Boneta, Victor Polo and Julen Munárriz

Int. J. Mol. Sci. 2023, 24(1), 870; https://doi.org/10.3390/ijms24010870 - 03 Jan 2023

Cited by 1 | Viewed by 1517

Abstract

Catalytic systems based on sub-nanoclusters deposited over different supports are promising for very relevant chemical transformations such as many electrocatalytic processes as the ORR. These systems have been demonstrated to be very fluxional, as they are able to change shape and interconvert between [...] Read more.

Catalytic systems based on sub-nanoclusters deposited over different supports are promising for very relevant chemical transformations such as many electrocatalytic processes as the ORR. These systems have been demonstrated to be very fluxional, as they are able to change shape and interconvert between each other either alone or in the presence of adsorbates. In addition, an accurate representation of their catalytic activity requires the consideration of ensemble effects and not a single structure alone. In this sense, a reliable theoretical methodology should assure an accurate and extensive exploration of the potential energy surface to include all the relevant structures and with correct relative energies. In this context, we applied DFT in conjunction with global optimization techniques to obtain and analyze the characteristics of the many local minima of Pt₆ sub-nanoclusters over a carbon-based support (graphene)—a system with electrocatalytic relevance. We also analyzed the magnetism and the charge transfer between the clusters and the support and paid special attention to the dependence of dispersion effects on the ensemble characteristics. We found that the ensembles computed with and without dispersion corrections are qualitatively similar, especially for the lowest-in-energy clusters, which we attribute to a (mainly) covalent binding to the surface. However, there are some significant variations in the relative stability of some clusters, which would significantly affect their population in the ensemble composition. Full article

(This article belongs to the Special Issue Multi-Metallic Systems: From Strong Cooperative Bonds to Weak M-M Interactions)

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22 pages, 5017 KiB

Open AccessArticle

Fluoroplast Doped by Ag₂O Nanoparticles as New Repairing Non-Cytotoxic Antibacterial Coating for Meat Industry

by Sergey V. Gudkov, Ruibin Li, Dmitriy A. Serov, Dmitriy E. Burmistrov, Ilya V. Baimler, Alexey S. Baryshev, Alexander V. Simakin, Oleg V. Uvarov, Maxim E. Astashev, Natalia B. Nefedova, Sergey Y. Smolentsev, Andrey V. Onegov, Mikhail A. Sevostyanov, Alexey G. Kolmakov, Mikhail A. Kaplan, Andrey Drozdov, Eteri R. Tolordava, Anastasia A. Semenova, Andrey B. Lisitsyn and Vasily N. Lednev

Int. J. Mol. Sci. 2023, 24(1), 869; https://doi.org/10.3390/ijms24010869 - 03 Jan 2023

Cited by 4 | Viewed by 2829

Abstract

Foodborne infections are an important global health problem due to their high prevalence and potential for severe complications. Bacterial contamination of meat during processing at the enterprise can be a source of foodborne infections. Polymeric coatings with antibacterial properties can be applied to [...] Read more.

Foodborne infections are an important global health problem due to their high prevalence and potential for severe complications. Bacterial contamination of meat during processing at the enterprise can be a source of foodborne infections. Polymeric coatings with antibacterial properties can be applied to prevent bacterial contamination. A composite coating based on fluoroplast and Ag₂O NPs can serve as such a coating. In present study, we, for the first time, created a composite coating based on fluoroplast and Ag₂O NPs. Using laser ablation in water, we obtained spherical Ag₂O NPs with an average size of 45 nm and a ζ-potential of −32 mV. The resulting Ag₂O NPs at concentrations of 0.001–0.1% were transferred into acetone and mixed with a fluoroplast-based varnish. The developed coating made it possible to completely eliminate damage to a Teflon cutting board. The fluoroplast/Ag₂O NP coating was free of defects and inhomogeneities at the nano level. The fluoroplast/Ag₂O NP composite increased the production of ROS (H₂O₂, OH radical), 8-oxogualnine in DNA in vitro, and long-lived active forms of proteins. The effect depended on the mass fraction of the added Ag₂O NPs. The 0.01–0.1% fluoroplast/NP Ag₂O coating exhibited excellent bacteriostatic and bactericidal properties against both Gram-positive and Gram-negative bacteria but did not affect the viability of eukaryotic cells. The developed PTFE/NP Ag₂O 0.01–0.1% coating can be used to protect cutting boards from bacterial contamination in the meat processing industry. Full article

(This article belongs to the Special Issue Biopolymers as Nanoparticles Carriers)

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15 pages, 3974 KiB

Open AccessArticle

Integrative Proteome Analysis Revels 3-Hydroxybutyrate Exerts Neuroprotective Effect by Influencing Chromatin Bivalency

by Xin-Liang Zhu, Huan Du, Lei-Lei Wang, Er-Ling Hu, Ning Li, Hai-Xia Lu, Guo-Qiang Chen and Xiao-Yun Lu

Int. J. Mol. Sci. 2023, 24(1), 868; https://doi.org/10.3390/ijms24010868 - 03 Jan 2023

Cited by 1 | Viewed by 2084

Abstract

3-hydroxybutyrate (3OHB) has been proved to act as a neuroprotective molecule in multiple neurodegenerative diseases. Here, we employed a quantitative proteomics approach to assess the changes of the global protein expression pattern of neural cells upon 3OHB administration. In combination with a disease-related, [...] Read more.

3-hydroxybutyrate (3OHB) has been proved to act as a neuroprotective molecule in multiple neurodegenerative diseases. Here, we employed a quantitative proteomics approach to assess the changes of the global protein expression pattern of neural cells upon 3OHB administration. In combination with a disease-related, protein-protein interaction network we pinpointed a hub marker, histone lysine 27 trimethylation, which is one of the key epigenetic markers in multiple neurodegenerative diseases. Integrative analysis of transcriptomic and epigenomic datasets highlighted the involvement of bivalent transcription factors in 3OHB-mediated disease protection and its alteration of neuronal development processes. Transcriptomic profiling revealed that 3OHB impaired the fate decision process of neural precursor cells by repressing differentiation and promoting proliferation. Our study provides a new mechanism of 3OHB’s neuroprotective effect, in which chromatin bivalency is sensitive to 3OHB alteration and drives its neuroprotective function both in neurodegenerative diseases and in neural development processes. Full article

(This article belongs to the Section Molecular Neurobiology)

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19 pages, 2637 KiB

Open AccessArticle

Protein-Coding Region Derived Small RNA in Exosomes from Influenza A Virus–Infected Cells

by Malgorzata Kwasnik, Wojciech Socha, Bartosz Czech, Magdalena Wasiak, Jerzy Rola and Wojciech Rozek

Int. J. Mol. Sci. 2023, 24(1), 867; https://doi.org/10.3390/ijms24010867 - 03 Jan 2023

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Abstract

Exosomes may function as multifactorial mediators of cell-to-cell communication, playing crucial roles in both physiological and pathological processes. Exosomes released from virus-infected cells may contain RNA and proteins facilitating infection spread. The purpose of our study was to analyze how the small RNA [...] Read more.

Exosomes may function as multifactorial mediators of cell-to-cell communication, playing crucial roles in both physiological and pathological processes. Exosomes released from virus-infected cells may contain RNA and proteins facilitating infection spread. The purpose of our study was to analyze how the small RNA content of exosomes is affected by infection with the influenza A virus (IAV). Exosomes were isolated by ultracentrifugation after hemadsorption of virions and their small RNA content was identified using high-throughput sequencing. As compared to mock-infected controls, 856 RNA transcripts were significantly differentially expressed in exosomes from IAV-infected cells, including fragments of 458 protein-coding (pcRNA), 336 small, 28 long intergenic non-coding RNA transcripts, and 33 pseudogene transcripts. Upregulated pcRNA species corresponded mainly to proteins associated with translation and antiviral response, and the most upregulated among them were RSAD2, CCDC141 and IFIT2. Downregulated pcRNA species corresponded to proteins associated with the cell cycle and DNA packaging. Analysis of differentially expressed pseudogenes showed that in most cases, an increase in the transcription level of pseudogenes was correlated with an increase in their parental genes. Although the role of exosome RNA in IAV infection remains undefined, the biological processes identified based on the corresponding proteins may indicate the roles of some of its parts in IAV replication. Full article

(This article belongs to the Special Issue Exosomes and Extracellular Vesicles in Health and Diseases)

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Inflammation in Urological Malignancies: The Silent Killer

by Martina Catalano, Giandomenico Roviello, Raffaella Santi, Donata Villari, Pietro Spatafora, Ilaria Camilla Galli, Francesco Sessa, Francesco Lupo Conte, Enrico Mini, Tommaso Cai and Gabriella Nesi

Int. J. Mol. Sci. 2023, 24(1), 866; https://doi.org/10.3390/ijms24010866 - 03 Jan 2023

Cited by 6 | Viewed by 2114

Abstract

Several studies have investigated the role of inflammation in promoting tumorigenesis and cancer progression. Neoplastic as well as surrounding stromal and inflammatory cells engage in well-orchestrated reciprocal interactions to establish an inflammatory tumor microenvironment. The tumor-associated inflammatory tissue is highly plastic, capable of [...] Read more.

Several studies have investigated the role of inflammation in promoting tumorigenesis and cancer progression. Neoplastic as well as surrounding stromal and inflammatory cells engage in well-orchestrated reciprocal interactions to establish an inflammatory tumor microenvironment. The tumor-associated inflammatory tissue is highly plastic, capable of continuously modifying its phenotypic and functional characteristics. Accumulating evidence suggests that chronic inflammation plays a critical role in the development of urological cancers. Here, we review the origins of inflammation in urothelial, prostatic, renal, testicular, and penile cancers, focusing on the mechanisms that drive tumor initiation, growth, progression, and metastasis. We also discuss how tumor-associated inflammatory tissue may be a diagnostic marker of clinically significant tumor progression risk and the target for future anti-cancer therapies. Full article

(This article belongs to the Special Issue Inflammation and Cancer 2021)

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Int. J. Mol. Sci., Volume 24, Issue 1 (January-1 2023) – 895 articles

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