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Int. J. Mol. Sci., Volume 24, Issue 18 (September-2 2023) – 738 articles

Cover Story (view full-size image): The structures of histone complexes are master keys to epigenetics. A new protocol, PepGrow, has been introduced for the construction of histone complexes at atomic resolution. The docked histone fragments are used as seeds and the full peptide tails are grown in the binding pocket of the targeted reader proteins. The new protocol combines the advantages of popular program packages such as AutoDock and Modeller, allowing fast generation of complex structures. PepGrow handles the current challenges of structure determination of complexes of flexible and weakly bound peptide tails of histones. View this paper
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26 pages, 3886 KiB  
Review
LOXL2 in Cancer: A Two-Decade Perspective
by Amparo Cano, Pilar Eraso, María J. Mazón and Francisco Portillo
Int. J. Mol. Sci. 2023, 24(18), 14405; https://doi.org/10.3390/ijms241814405 - 21 Sep 2023
Cited by 1 | Viewed by 2030
Abstract
Lysyl Oxidase Like 2 (LOXL2) belongs to the lysyl oxidase (LOX) family, which comprises five lysine tyrosylquinone (LTQ)-dependent copper amine oxidases in humans. In 2003, LOXL2 was first identified as a promoter of tumour progression and, over the course of two decades, numerous [...] Read more.
Lysyl Oxidase Like 2 (LOXL2) belongs to the lysyl oxidase (LOX) family, which comprises five lysine tyrosylquinone (LTQ)-dependent copper amine oxidases in humans. In 2003, LOXL2 was first identified as a promoter of tumour progression and, over the course of two decades, numerous studies have firmly established its involvement in multiple cancers. Extensive research with large cohorts of human tumour samples has demonstrated that dysregulated LOXL2 expression is strongly associated with poor prognosis in patients. Moreover, investigations have revealed the association of LOXL2 with various targets affecting diverse aspects of tumour progression. Additionally, the discovery of a complex network of signalling factors acting at the transcriptional, post-transcriptional, and post-translational levels has provided insights into the mechanisms underlying the aberrant expression of LOXL2 in tumours. Furthermore, the development of genetically modified mouse models with silenced or overexpressed LOXL2 has enabled in-depth exploration of its in vivo role in various cancer models. Given the significant role of LOXL2 in numerous cancers, extensive efforts are underway to identify specific inhibitors that could potentially improve patient prognosis. In this review, we aim to provide a comprehensive overview of two decades of research on the role of LOXL2 in cancer. Full article
(This article belongs to the Special Issue Cell Biology and Functions of the Multifunctional Lysyl Oxidase Family of Proteins 2.0)
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11 pages, 579 KiB  
Review
Hepatocellular Carcinoma Prevention in the Era of Hepatitis C Elimination
by Jeffrey V. Lazarus, Camila A. Picchio and Massimo Colombo
Int. J. Mol. Sci. 2023, 24(18), 14404; https://doi.org/10.3390/ijms241814404 - 21 Sep 2023
Cited by 3 | Viewed by 1643
Abstract
The hepatitis C virus (HCV), a single-stranded RNA virus belonging to the Flaviviridae family, is a major cause of hepatocellular carcinoma (HCC) worldwide. Tumors caused by HCC have an increased mortality rate globally, which is more accentuated in Western countries. The carcinogenic potential [...] Read more.
The hepatitis C virus (HCV), a single-stranded RNA virus belonging to the Flaviviridae family, is a major cause of hepatocellular carcinoma (HCC) worldwide. Tumors caused by HCC have an increased mortality rate globally, which is more accentuated in Western countries. The carcinogenic potential of this virus is mediated through a wide range of mechanisms, spanning from the induction of chronic inflammation to oxidative stress and deregulation of cellular pathways by viral proteins. As the number of new infections continues unabated, HCC-related mortality should be prioritized through early detection, continued prevention of HCV transmission, and treatment of HCV with safe and efficacious direct antiviral agents (DAAs). People who inject drugs (PWID) are a significant reservoir of new HCV infections globally, and in order to eliminate hepatitis C as a global health threat, as set out by the World Health Organization, an integrated approach based on the optimization of care delivery and increased access to harm reduction and treatment for PWID is needed. Thanks to the development of safe and effective antiviral agents, eradication of the infection is now possible in almost all treated patients, leading to a significant reduction but not the elimination of the risk for HCC in cured patients. This is particularly relevant among aged populations who have cofactors of morbidity known to accelerate HCC progression, such as diabetes, obesity, and excessive alcohol consumption. Given the restless accumulation of individuals with cured HCV infection, the implementation of risk-stratified surveillance programs becomes impellent from a cost-effectiveness perspective, whereas the availability of a performant biomarker to predict HCC in cured patients remains an unmet clinical need. Full article
(This article belongs to the Special Issue Hepatitis C Virus: Pathogenetic Mechanisms, Residual Problems after Cure and Hopes for Elimination)
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22 pages, 2466 KiB  
Review
Exploring the Complex and Multifaceted Interplay between Melanoma Cells and the Tumor Microenvironment
by Magdalena Kuras
Int. J. Mol. Sci. 2023, 24(18), 14403; https://doi.org/10.3390/ijms241814403 - 21 Sep 2023
Cited by 1 | Viewed by 1535
Abstract
Malignant melanoma is a very aggressive skin cancer, characterized by a heterogeneous nature and high metastatic potential. The incidence of melanoma is continuously increasing worldwide, and it is one of the most common cancers in young adults. In the past twenty years, our [...] Read more.
Malignant melanoma is a very aggressive skin cancer, characterized by a heterogeneous nature and high metastatic potential. The incidence of melanoma is continuously increasing worldwide, and it is one of the most common cancers in young adults. In the past twenty years, our understanding of melanoma biology has increased profoundly, and disease management for patients with disseminated disease has improved due to the emergence of immunotherapy and targeted therapy. However, a significant fraction of patients relapse or do not respond adequately to treatment. This can partly be explained by the complex signaling between the tumor and its microenvironment, giving rise to melanoma phenotypes with different patterns of disease progression. This review focuses on the key aspects and complex relationship between pathogenesis, genetic abnormalities, tumor microenvironment, cellular plasticity, and metabolic reprogramming in melanoma. By acquiring a deeper understanding of the multifaceted features of melanomagenesis, we can reach a point of more individualized and patient-centered disease management and reduced costs of ineffective treatments. Full article
(This article belongs to the Special Issue Current Concepts and Advances in Diagnosis and Treatment of Cutaneous Melanoma)
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16 pages, 5744 KiB  
Article
Knockdown of BAP31 Downregulates Galectin-3 to Inhibit the Wnt/β-Catenin Signaling Pathway to Modulate 5-FU Chemosensitivity and Cancer Stemness in Colorectal Cancer
by Jingjing Liu, Qi Zhang, Jiyu Wang, Changli Wang, Tian Lan, Tianyi Wang and Bing Wang
Int. J. Mol. Sci. 2023, 24(18), 14402; https://doi.org/10.3390/ijms241814402 - 21 Sep 2023
Cited by 3 | Viewed by 1250
Abstract
Increased stemness is causally linked to the development of chemoresistance in cancers. B-cell receptor-associated protein 31 (BAP31) has been identified to play an oncogenic role in many types of cancer. However, the role of BAP31 in 5-fluorouracil (5-FU) chemosensitivity and stemness of colorectal [...] Read more.
Increased stemness is causally linked to the development of chemoresistance in cancers. B-cell receptor-associated protein 31 (BAP31) has been identified to play an oncogenic role in many types of cancer. However, the role of BAP31 in 5-fluorouracil (5-FU) chemosensitivity and stemness of colorectal cancer (CRC) is still unknown. The aim of this study was to investigate the biological function and molecular mechanism of BAP31 in regulating 5-FU chemosensitivity and stemness. The correlation between BAP31 expression and 5-FU chemosensitivity was examined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide and colony formation assays. Cancer stemness was analyzed using tumor sphere formation and Western blot assays. Western blot and immunofluorescence analyses of the knockdown cell lines were performed to explore the possible mechanisms. Finally, we investigated the function of BAP31 by constructing xenograft nude mouse models in vivo. In this study, we demonstrated that BAP31 was increased in CRC cells, and knockdown of BAP31 reduced the half maximal inhibitory concentration (IC50) of 5-FU, while this effect was reversed by overexpression of BAP31. In addition, knockdown of BAP31 substantially reduced the stemness of CRC cells in vitro. Consistently, knockdown of BAP31 significantly suppressed the tumorigenicity and stemness of CRC in vivo. The functional study further suggested that knockdown of BAP31 downregulated galectin-3 to inhibit the accumulation of β-catenin, which in turn repressed the transcription of downstream target genes (c-MYC, SOX2) of the Wnt/β-catenin signaling pathway. Knockdown of BAP31 reduced stemness by inhibiting the Wnt/β-catenin signaling pathway to increase 5-FU chemosensitivity. Importantly, intrabodies against BAP31 suppressed tumor growth and enhanced the antitumor effects of 5-FU in vivo. Therefore, using intrabodies against BAP31 may be a strategy for improving the antitumor effect of 5-FU in CRC. Full article
(This article belongs to the Section Molecular Oncology)
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16 pages, 2555 KiB  
Article
Biosynthesis of Bacterial Nanocellulose from Low-Cost Cellulosic Feedstocks: Effect of Microbial Producer
by Ekaterina A. Skiba, Nadezhda A. Shavyrkina, Maria A. Skiba, Galina F. Mironova and Vera V. Budaeva
Int. J. Mol. Sci. 2023, 24(18), 14401; https://doi.org/10.3390/ijms241814401 - 21 Sep 2023
Cited by 2 | Viewed by 1215
Abstract
Biodegradable bacterial nanocellulose (BNC) is a highly in-demand but expensive polymer, and the reduction of its production cost is an important task. The present study aimed to biosynthesize BNC on biologically high-quality hydrolyzate media prepared from miscanthus and oat hulls, and to explore [...] Read more.
Biodegradable bacterial nanocellulose (BNC) is a highly in-demand but expensive polymer, and the reduction of its production cost is an important task. The present study aimed to biosynthesize BNC on biologically high-quality hydrolyzate media prepared from miscanthus and oat hulls, and to explore the properties of the resultant BNC depending on the microbial producer used. In this study, three microbial producers were utilized for the biosynthesis of BNC: individual strains Komagataeibacter xylinus B-12429 and Komagataeibacter xylinus B-12431, and symbiotic Medusomyces gisevii Sa-12. The use of symbiotic Medusomyces gisevii Sa-12 was found to have technological benefits: nutrient media require no mineral salts or growth factors, and pasteurization is sufficient for the nutrient medium instead of sterilization. The yield of BNCs produced by the symbiotic culture turned out to be 44–65% higher than that for the individual strains. The physicochemical properties of BNC, such as nanofibril width, degree of polymerization, elastic modulus, Iα allomorph content and crystallinity index, are most notably dependent on the microbial producer type rather than the nutrient medium composition. This is the first study in which we investigated the biosynthesis of BNC on hydrolyzate media prepared from miscanthus and oat hulls under the same conditions but using different microbial producers, and showed that it is advisable to use the symbiotic culture. The choice of a microbial producer is grounded on the yield, production process simplification and properties. The BNC production from technical raw materials would cover considerable demands of BNC for technical purposes without competing with food resources. Full article
(This article belongs to the Special Issue Advanced Degradable Biopolymers)
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17 pages, 2561 KiB  
Article
Physiological and Morphological Implications of Using Composts with Different Compositions in the Production of Cucumber Seedlings
by Anita Zapałowska, Natalia Matłok, Tomasz Piechowiak, Małgorzata Szostek, Czesław Puchalski and Maciej Balawejder
Int. J. Mol. Sci. 2023, 24(18), 14400; https://doi.org/10.3390/ijms241814400 - 21 Sep 2023
Cited by 2 | Viewed by 931
Abstract
Compost has a broad application in terms of the improvement of the soil properties. This research work was conducted to present the molecular implications of using compost obtained from different substrates to improve soil parameters for cucumber seedlings cultivation. In the experiment, the [...] Read more.
Compost has a broad application in terms of the improvement of the soil properties. This research work was conducted to present the molecular implications of using compost obtained from different substrates to improve soil parameters for cucumber seedlings cultivation. In the experiment, the following compost mixtures were used: sewage sludge (80%) + sawdust (20%); sewage sludge (40%) + sawdust (10%) + biodegradable garden and park waste (50%); biodegradable garden and park waste (90%) + sawdust (10%); sewage sludge (80%) + sawdust (20%) + Eisenia fetida; sewage sludge (40%) + sawdust (10%) + biodegradable garden and park waste (50%) + Eisenia fetida; biodegradable garden and park waste (90%) + sawdust (10%) + Eisenia fetida. The final substrate compositions consisted of compost mixtures and deacidified peat(O) (pH 6.97; Corg content—55%, N content—2.3%), serving as a structural additive, in different mass ratios (mass %). The produced plants underwent biometric and physiological measurements as well as enzymatic analyses of stress markers. Based on the conducted studies, it has been found that the substrate productivity depends not only on the content of nutrient components but also on their structure, which is moderated by the proportion of peat in the substrate. The most effective and promising substrate for cucumber seedling production was variant 2 (I), which consisted of 25% compost from sewage sludge (40%) + sawdust (10%) + biodegradable garden and park waste (50%) and 75% deacidified peat. Despite the richness of the other substrates, inferior parameters of the produced seedlings were observed. The analysis of the enzymatic activity of stress markers showed that these substrates caused stress in the plants produced. The study’s results showed that this stress was caused by the presence of Eisenia fetida, which damaged the developing root system of plants in the limited volume of substrate (production containers). The adverse influence of Eisenia fetida on the plants produced could possibly be eliminated by thermal treatment of the compost, although this could lead to significant changes in composition. Full article
(This article belongs to the Section Molecular Plant Sciences)
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10 pages, 2048 KiB  
Article
Scopolamine-Induced Memory Impairment in Mice: Effects of PEA-OXA on Memory Retrieval and Hippocampal LTP
by Carmela Belardo, Serena Boccella, Michela Perrone, Antimo Fusco, Andrea Maria Morace, Federica Ricciardi, Roozbe Bonsale, Ines ELBini-Dhouib, Francesca Guida, Livio Luongo, Giacinto Bagetta, Damiana Scuteri and Sabatino Maione
Int. J. Mol. Sci. 2023, 24(18), 14399; https://doi.org/10.3390/ijms241814399 - 21 Sep 2023
Viewed by 1111
Abstract
Transient global amnesia, both persistent and transient, is a very common neuropsychiatric syndrome. Among animal models for amnesia and testing new drugs, the scopolamine test is the most widely used for transient global amnesia (TGA). This study examined the scopolamine-induced deficits in working [...] Read more.
Transient global amnesia, both persistent and transient, is a very common neuropsychiatric syndrome. Among animal models for amnesia and testing new drugs, the scopolamine test is the most widely used for transient global amnesia (TGA). This study examined the scopolamine-induced deficits in working memory, discriminative memory, anxiety, and motor activity in the presence of intranasal PEA-OXA, a dual antagonist of presynaptic α2 and H3 receptors. Male C57BL/6 mice were treated with intraperitoneal scopolamine (1 mg/kg) with or without pre-treatment (15 min) or post-treatment (15 min) with intranasal PEA-OXA (10 mg/kg). It was seen that scopolamine induced deficits of discriminative and spatial memory and motor deficit. These changes were associated with a loss of synaptic plasticity in the hippocampal dentate gyrus: impaired LTP after lateral entorhinal cortex/perforant pathway tetanization. Furthermore, hippocampal Ach levels were increased while ChA-T expression was reduced following scopolamine administration. PEA-OXA either prevented or restored the scopolamine-induced cognitive deficits (discriminative and spatial memory). However, the same treatment did not affect the altered motor activity or anxiety-like behavior induced by scopolamine. Consistently, electrophysiological analysis showed LTP recovery in the DG of the hippocampus, while the Ach level and ChoA-T were normalized. This study confirms the neuroprotective and pro-cognitive activity of PEA-OXA (probably through an increase in the extracellular levels of biogenic amines) in improving transient memory disorders for which the available pharmacological tools are obsolete or inadequate and not directed on specific pathophysiological targets. Full article
(This article belongs to the Special Issue Proposal of a Special Issue On: Basic, Translational and Clinical Research on Dementia)
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15 pages, 3804 KiB  
Article
Transcriptome-Based WGCNA Analysis Reveals the Mechanism of Drought Resistance Differences in Sweetpotato (Ipomoea batatas (L.) Lam.)
by Jikai Zong, Peitao Chen, Qingqing Luo, Jilong Gao, Ruihua Qin, Chunli Wu, Qina Lv, Tengfei Zhao and Yufan Fu
Int. J. Mol. Sci. 2023, 24(18), 14398; https://doi.org/10.3390/ijms241814398 - 21 Sep 2023
Cited by 1 | Viewed by 1564
Abstract
Sweetpotato (Ipomoea batatas (L.) Lam.) is a globally significant storage root crop, but it is highly susceptible to yield reduction under severe drought conditions. Therefore, understanding the mechanism of sweetpotato resistance to drought stress is helpful for the creation of outstanding germplasm [...] Read more.
Sweetpotato (Ipomoea batatas (L.) Lam.) is a globally significant storage root crop, but it is highly susceptible to yield reduction under severe drought conditions. Therefore, understanding the mechanism of sweetpotato resistance to drought stress is helpful for the creation of outstanding germplasm and the selection of varieties with strong drought resistance. In this study, we conducted a comprehensive analysis of the phenotypic and physiological traits of 17 sweetpotato breeding lines and 10 varieties under drought stress through a 48 h treatment in a Hoagland culture medium containing 20% PEG6000. The results showed that the relative water content (RWC) and vine-tip fresh-weight reduction (VTFWR) in XS161819 were 1.17 and 1.14 times higher than those for the recognized drought-resistant variety Chaoshu 1. We conducted RNA-seq analysis and weighted gene co-expression network analysis (WGCNA) on two genotypes, XS161819 and 18-12-3, which exhibited significant differences in drought resistance. The transcriptome analysis revealed that the hormone signaling pathway may play a crucial role in determining the drought resistance in sweetpotato. By applying WGCNA, we identified twenty-two differential expression modules, and the midnight blue module showed a strong positive correlation with drought resistance characteristics. Moreover, twenty candidate Hub genes were identified, including g47370 (AFP2), g14296 (CDKF), and g60091 (SPBC2A9), which are potentially involved in the regulation of drought resistance in sweetpotato. These findings provide important insights into the molecular mechanisms underlying drought resistance in sweetpotato and offer valuable genetic resources for the development of drought-resistant sweetpotato varieties in the future. Full article
(This article belongs to the Special Issue Crop Stress Biology and Molecular Breeding 3.0)
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20 pages, 3342 KiB  
Review
Green Hydrogen Production through Ammonia Decomposition Using Non-Thermal Plasma
by Julia Moszczyńska, Xinying Liu and Marek Wiśniewski
Int. J. Mol. Sci. 2023, 24(18), 14397; https://doi.org/10.3390/ijms241814397 - 21 Sep 2023
Cited by 2 | Viewed by 1993
Abstract
Liquid hydrogen carriers will soon play a significant role in transporting energy. The key factors that are considered when assessing the applicability of ammonia cracking in large-scale projects are as follows: high energy density, easy storage and distribution, the simplicity of the overall [...] Read more.
Liquid hydrogen carriers will soon play a significant role in transporting energy. The key factors that are considered when assessing the applicability of ammonia cracking in large-scale projects are as follows: high energy density, easy storage and distribution, the simplicity of the overall process, and a low or zero-carbon footprint. Thermal systems used for recovering H2 from ammonia require a reaction unit and catalyst that operates at a high temperature (550–800 °C) for the complete conversion of ammonia, which has a negative effect on the economics of the process. A non-thermal plasma (NTP) solution is the answer to this problem. Ammonia becomes a reliable hydrogen carrier and, in combination with NTP, offers the high conversion of the dehydrogenation process at a relatively low temperature so that zero-carbon pure hydrogen can be transported over long distances. This paper provides a critical overview of ammonia decomposition systems that focus on non-thermal methods, especially under plasma conditions. The review shows that the process has various positive aspects and is an innovative process that has only been reported to a limited extent. Full article
(This article belongs to the Special Issue Recent Advances in Plasma Application)
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17 pages, 4903 KiB  
Article
Interaction of Substrates with γ-Secretase at the Level of Individual Transmembrane Helices—A Methodological Approach
by Theresa M. Pauli, Ayse Julius, Francesco Costa, Sabine Eschrig, Judith Moosmüller, Lea Fischer, Christoph Schanzenbach, Fabian C. Schmidt, Martin Ortner and Dieter Langosch
Int. J. Mol. Sci. 2023, 24(18), 14396; https://doi.org/10.3390/ijms241814396 - 21 Sep 2023
Cited by 1 | Viewed by 1124
Abstract
Intramembrane proteases, such as γ secretase, typically recruit multiple substrates from an excess of single-span membrane proteins. It is currently unclear to which extent substrate recognition depends on specific interactions of their transmembrane domains (TMDs) with TMDs of a protease. Here, we investigated [...] Read more.
Intramembrane proteases, such as γ secretase, typically recruit multiple substrates from an excess of single-span membrane proteins. It is currently unclear to which extent substrate recognition depends on specific interactions of their transmembrane domains (TMDs) with TMDs of a protease. Here, we investigated a large number of potential pairwise interactions between TMDs of γ secretase and a diverse set of its substrates using two different configurations of BLaTM, a genetic reporter system. Our results reveal significant interactions between TMD2 of presenilin, the enzymatic subunit of γ secretase, and the TMD of the amyloid precursor protein, as well as of several other substrates. Presenilin TMD2 is a prime candidate for substrate recruitment, as has been shown from previous studies. In addition, the amyloid precursor protein TMD enters interactions with presenilin TMD 4 as well as with the TMD of nicastrin. Interestingly, the Gly-rich interfaces between the amyloid precursor protein TMD and presenilin TMDs 2 and 4 are highly similar to its homodimerization interface. In terms of methodology, the economics of the newly developed library-based method could prove to be a useful feature in related future work for identifying heterotypic TMD−TMD interactions within other biological contexts. Full article
(This article belongs to the Special Issue Structural Biology of Peptides and Proteins in Alzheimer's Disease and Related Disorders)
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20 pages, 3275 KiB  
Article
Arsenite Impairs BRCA1-Dependent DNA Double-Strand Break Repair, a Mechanism Potentially Contributing to Genomic Instability
by Tizia Matthäus, Sandra Stößer, Hatice Yasemin Seren, Vivien M. M. Haberland and Andrea Hartwig
Int. J. Mol. Sci. 2023, 24(18), 14395; https://doi.org/10.3390/ijms241814395 - 21 Sep 2023
Viewed by 1013
Abstract
BRCA1 is a key player in maintaining genomic integrity with multiple functions in DNA damage response (DDR) mechanisms. Due to its thiol-rich zinc-complexing domain, the protein may also be a potential target for redox-active and/or thiol-reactive (semi)metal compounds. The latter includes trivalent inorganic [...] Read more.
BRCA1 is a key player in maintaining genomic integrity with multiple functions in DNA damage response (DDR) mechanisms. Due to its thiol-rich zinc-complexing domain, the protein may also be a potential target for redox-active and/or thiol-reactive (semi)metal compounds. The latter includes trivalent inorganic arsenic, which is indirectly genotoxic via induction of oxidative stress and inhibition of DNA repair pathways. In the present study, we investigated the effect of NaAsO2 on the transcriptional and functional DDR. Particular attention was paid to the potential impairment of BRCA1-mediated DDR mechanisms by arsenite by comparing BRCA1-deficient and -proficient cells. At the transcriptional level, arsenite itself activated several DDR mechanisms, including a pronounced oxidative stress and DNA damage response, mostly independent of BRCA1 status. However, at the functional level, a clear BRCA1 dependency was observed in both cell cycle regulation and cell death mechanisms after arsenite exposure. Furthermore, in the absence of arsenite, the lack of functional BRCA1 impaired the largely error-free homologous recombination (HR), leading to a shift towards the error-prone non-homologous end-joining (NHEJ). Arsenic treatment also induced this shift in BRCA1-proficient cells, indicating BRCA1 inactivation. Although BRCA1 bound to DNA DSBs induced via ionizing radiation, its dissociation was impaired, similarly to the downstream proteins RAD51 and RAD54. A shift from HR to NHEJ by arsenite was further supported by corresponding reporter gene assays. Taken together, arsenite appears to negatively affect HR via functional inactivation of BRCA1, possibly by interacting with its RING finger structure, which may compromise genomic stability. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Heavy Metal Toxicity: From Death to Immortality)
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21 pages, 28282 KiB  
Article
Comparative Analysis of Different Proteins and Metabolites in the Liver and Ovary of Local Breeds of Chicken and Commercial Chickens in the Later Laying Period
by Yuan Tang, Lingqian Yin, Li Liu, Qian Chen, Zhongzhen Lin, Donghao Zhang, Yan Wang and Yiping Liu
Int. J. Mol. Sci. 2023, 24(18), 14394; https://doi.org/10.3390/ijms241814394 - 21 Sep 2023
Viewed by 1031
Abstract
The liver and ovary perform a vital role in egg production in hens. In the later laying period, the egg-laying capacity of female hens, particularly that of local breeds, declines significantly. Hence, it is essential to study the features and conditions of the [...] Read more.
The liver and ovary perform a vital role in egg production in hens. In the later laying period, the egg-laying capacity of female hens, particularly that of local breeds, declines significantly. Hence, it is essential to study the features and conditions of the ovary and liver during this period. In this research, we characterized the proteins and metabolites in the liver and ovary of 55-week-old Guangyuan gray chickens (Group G) and Hy-Line gray chickens (Group H) by using liquid chromatography chip/electrospray ionization quadruple time-of-flight/mass spectroscopy (LC-MS/MS). In total, 139 differentially expressed proteins (DEPs) and 186 differential metabolites (DMs) were identified in the liver, and 139 DEPs and 36 DMs were identified in the ovary. The upregulated DEPs and DMs in both the liver and ovary of Group G were primarily enriched in pathways involved in amino acid and carbohydrate metabolism. This suggests that energy metabolism was highly active in the Guangyuan gray chickens. In contrast, the upregulated DEPs and DMs in Group H were mainly enriched in pathways associated with lipid metabolism, which may explain the higher egg production and the higher fatty liver rate in Hy-Line gray hens in the later laying period. Additionally, it was found that the unique protein s-(hydroxymethyl) glutathione dehydrogenase (ADH4) in Group G was implicated in functions such as fatty acid degradation, glycolysis, and pyruvate metabolism, whereas the unique proteins, steroid sulfatase (STS), glucosylceramidase (LOC107050229), and phospholipase A2 Group XV (PLA2G15), in Group H were involved in the metabolism of steroid hormones and glycerol phosphate. In conclusion, variations in how carbohydrates, lipids, and amino acids are processed in the liver and ovary of local breeds of chicken and commercial hens towards the end of their laying period could explain the disparities in their egg production abilities. Full article
(This article belongs to the Special Issue Mass Spectrometric Proteomics 2.0)
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11 pages, 1495 KiB  
Article
Circulatory miRNAs as Correlates of Elevated Intra-Pancreatic Fat Deposition in a Mixed Ethnic Female Cohort: The TOFI_Asia Study
by Farha Ramzan, Ivana R. Sequeira-Bisson, Louise W. Lu, Cameron J. Mitchell, Randall F. D’Souza, Mark H. Vickers, Sally D. Poppitt and David Cameron-Smith
Int. J. Mol. Sci. 2023, 24(18), 14393; https://doi.org/10.3390/ijms241814393 - 21 Sep 2023
Viewed by 1398
Abstract
Ectopic lipid accumulation, including intra-pancreatic fat deposition (IPFD), exacerbates type 2 diabetes risk in susceptible individuals. Dysregulated circulating microRNAs (miRNAs) have been identified as correlating with clinical measures of pancreatitis, pancreatic cancer and type 1 diabetes. The aim of the current study was [...] Read more.
Ectopic lipid accumulation, including intra-pancreatic fat deposition (IPFD), exacerbates type 2 diabetes risk in susceptible individuals. Dysregulated circulating microRNAs (miRNAs) have been identified as correlating with clinical measures of pancreatitis, pancreatic cancer and type 1 diabetes. The aim of the current study was therefore to examine the association between circulating abundances of candidate miRNAs, IPFD and liver fat deposition as quantified using magnetic resonance imaging (MRI) and spectroscopy (MRS). Asian Chinese (n = 34; BMI = 26.7 ± 4.2 kg/m2) and European Caucasian (n = 34; BMI = 28.0 ± 4.5 kg/m2) females from the TOFI_Asia cohort underwent MRI and MRS analysis of pancreas (MR-%IPFD) and liver fat (MR-%liver fat), respectively, to quantify ectopic lipid deposition. Plasma miRNA abundances of a subset of circulatory miRNAs associated with IPFD and liver fat deposition were quantified by qRT-PCR. miR-21-3p and miR-320a-5p correlated with MR-%IPFD, plasma insulin and HOMA2-IR, but not MR-%liver fat. MR-%IPFD remained associated with decreasing miR-21-3p abundance following multivariate regression analysis. miR-21-3p and miR-320a were demonstrated to be negatively correlated with MR-%IPFD, independent of ethnicity. For miR-21-3p, this relationship persists with the inclusion of MR-%liver fat in the model, suggesting the potential for a wider application as a specific circulatory correlate of IPFD. Full article
(This article belongs to the Special Issue The Role of microRNA in Human Diseases 2.0)
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9 pages, 1502 KiB  
Brief Report
Soft Tissue Manipulation Alters RANTES/CCL5 and IL-4 Cytokine Levels in a Rat Model of Chronic Low Back Pain
by Carmela L. Marciano, Taylor A. Hiland, Krista L. Jackson, Sierra Street, Carson Maris, Andrew Ehrsam, Julia M. Hum, Mary Terry Loghmani, Tien-Min G. Chu, Kyung S. Kang and Jonathan W. Lowery
Int. J. Mol. Sci. 2023, 24(18), 14392; https://doi.org/10.3390/ijms241814392 - 21 Sep 2023
Viewed by 1016
Abstract
Low back pain (LBP) is a common musculoskeletal complaint that can impede physical function and mobility. Current management often involves pain medication, but there is a need for non-pharmacological and non-invasive interventions. Soft tissue manipulation (STM), such as massage, has been shown to [...] Read more.
Low back pain (LBP) is a common musculoskeletal complaint that can impede physical function and mobility. Current management often involves pain medication, but there is a need for non-pharmacological and non-invasive interventions. Soft tissue manipulation (STM), such as massage, has been shown to be effective in human subjects, but the molecular mechanisms underlying these findings are not well understood. In this paper, we evaluated potential changes in the soft tissue levels of more than thirty pro- or anti-inflammatory cytokines following instrument-assisted STM (IASTM) in rats with chronic, induced LBP using Complete Freund’s Adjuvant. Our results indicate that IASTM is associated with reduced soft tissue levels of Regulated on Activation, Normal T cell Expressed and Secreted (RANTES)/Chemokine (C-C motif) ligand 5 (CCL5) and increased soft tissue levels of Interleukin (IL)-4, which are pro-inflammatory and anti-inflammatory factors, respectively, by 120 min post-treatment. IASTM was not associated with tissue-level changes in C-X-C Motif Chemokine Ligand (CXCL)-5/Lipopolysaccharide-Induced CXC Chemokine (LIX)–which is the murine homologue of IL-8, CXCL-7, Granulocyte-Macrophage-Colony Simulating Factor (GM-CSF), Intercellular Adhesion Molecule (ICAM)-1, IL1-Receptor Antagonist (IL-1ra), IL-6, Interferon-Inducible Protein (IP)-10/CXCL-10, L-selectin, Tumor Necrosis Factor (TNF)-α, or Vascular Endothelial Growth Factor (VEGF) at either 30 or 120 min post-treatment. Combined, our findings raise the possibility that IASTM may exert tissue-level effects associated with improved clinical outcomes and potentially beneficial changes in pro-/anti-inflammatory cytokines in circulation and at the tissue level. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Strategies of Inflammatory Pain)
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18 pages, 1021 KiB  
Review
Microplastics and Kidneys: An Update on the Evidence for Deposition of Plastic Microparticles in Human Organs, Tissues and Fluids and Renal Toxicity Concern
by Edoardo La Porta, Ottavia Exacoustos, Francesca Lugani, Andrea Angeletti, Decimo Silvio Chiarenza, Carolina Bigatti, Sonia Spinelli, Xhuliana Kajana, Andrea Garbarino, Maurizio Bruschi, Giovanni Candiano, Gianluca Caridi, Nicoletta Mancianti, Marta Calatroni, Daniela Verzola, Pasquale Esposito, Francesca Viazzi, Enrico Verrina and Gian Marco Ghiggeri
Int. J. Mol. Sci. 2023, 24(18), 14391; https://doi.org/10.3390/ijms241814391 - 21 Sep 2023
Cited by 1 | Viewed by 2358
Abstract
Plastic pollution became a main challenge for human beings as demonstrated by the increasing dispersion of plastic waste into the environment. Microplastics (MPs) have become ubiquitous and humans are exposed daily to inhalation or ingestion of plastic microparticles. Recent studies performed using mainly [...] Read more.
Plastic pollution became a main challenge for human beings as demonstrated by the increasing dispersion of plastic waste into the environment. Microplastics (MPs) have become ubiquitous and humans are exposed daily to inhalation or ingestion of plastic microparticles. Recent studies performed using mainly spectroscopy or spectrometry-based techniques have shown astounding evidence for the presence of MPs in human tissues, organs and fluids. The placenta, meconium, breast milk, lung, intestine, liver, heart and cardiovascular system, blood, urine and cerebrovascular liquid are afflicted by MPs’ presence and deposition. On the whole, obtained data underline a great heterogeneity among different tissue and organs of the polymers characterized and the microparticles’ dimension, even if most of them seem to be below 50–100 µm. Evidence for the possible contribution of MPs in human diseases is still limited and this field of study in medicine is in an initial state. However, increasing studies on their toxicity in vitro and in vivo suggest worrying effects on human cells mainly mediated by oxidative stress, inflammation and fibrosis. Nephrological studies are insufficient and evidence for the presence of MPs in human kidneys is still lacking, but the little evidence present in the literature has demonstrated histological and functional alteration of kidneys in animal models and cytotoxicity through apoptosis, autophagy, oxidative stress and inflammation in kidney cells. Overall, the manuscript we report in this review recommends urgent further study to analyze potential correlations between kidney disease and MPs’ exposure in human. Full article
(This article belongs to the Collection Feature Papers in Molecular Pathology, Diagnostics, and Therapeutics)
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17 pages, 1126 KiB  
Review
A Route for Investigating Psoriasis: From the Perspective of the Pathological Mechanisms and Therapeutic Strategies of Cancer
by Xingkang Wu, Yushuang Ma, Lu Wang and Xuemei Qin
Int. J. Mol. Sci. 2023, 24(18), 14390; https://doi.org/10.3390/ijms241814390 - 21 Sep 2023
Cited by 4 | Viewed by 1343
Abstract
Psoriasis is an incurable skin disease that develops in about two-thirds of patients before the age of 40 and requires lifelong treatment; its pathological mechanisms have not been fully elucidated. The core pathological process of psoriasis is epidermal thickening caused by the excessive [...] Read more.
Psoriasis is an incurable skin disease that develops in about two-thirds of patients before the age of 40 and requires lifelong treatment; its pathological mechanisms have not been fully elucidated. The core pathological process of psoriasis is epidermal thickening caused by the excessive proliferation of epidermal keratinocytes, which is similar to the key feature of cancer; the malignant proliferation of cancer cells causes tumor enlargement, suggesting that there is a certain degree of commonality between psoriasis and cancer. This article reviews the pathological mechanisms that are common to psoriasis and cancer, including the interaction between cell proliferation and an abnormal immune microenvironment, metabolic reprogramming, and epigenetic reprogramming. In addition, there are common therapeutic agents and drug targets between psoriasis and cancer. Thus, psoriasis and cancer share a common pathological mechanisms–drug targets–therapeutic agents framework. On this basis, it is proposed that investigating psoriasis from a cancer perspective is beneficial to enriching the research strategies related to psoriasis. Full article
(This article belongs to the Special Issue Progress in the Pathogenesis and Therapeutics of Psoriasis)
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12 pages, 272 KiB  
Communication
Immunosuppressive Therapy of Antibody-Mediated aHUS and TTP
by Kata Kelen, Orsolya Horváth, Éva Kis, Bálint Mikes, Péter Sallay, Zoltán Prohászka, Attila József Szabó and György S. Reusz
Int. J. Mol. Sci. 2023, 24(18), 14389; https://doi.org/10.3390/ijms241814389 - 21 Sep 2023
Viewed by 1030
Abstract
The recent classification of pediatric thrombotic microangiopathies (TMA) takes into consideration mechanisms of disease for guidance to targeted therapies. We present our experience with seven patients with antibody mediated atypical hemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura (TTP). Five children had aHUS [...] Read more.
The recent classification of pediatric thrombotic microangiopathies (TMA) takes into consideration mechanisms of disease for guidance to targeted therapies. We present our experience with seven patients with antibody mediated atypical hemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura (TTP). Five children had aHUS with antibodies against complement factor H (CFH-ab) and two with TTP with antibodies against metalloproteinase ADAMTS13. In the aHUS cases diagnosed and treated before the eculizumab era, CFH-ab was detected using the ELISA assay. Mutational analysis of selected complement genes was performed. TTP was diagnosed if, in addition to microangiopathic hemolytic anemia and thrombocytopenia, ischemic organ involvement and severe deficiency in ADAMTS13 activity were present. Treatment protocol consisted of plasma exchanges (PE) and steroid pulses, followed by the combination of cyclophosphamide and rituximab to achieve long-term immunosuppression. Four patients with CFH-ab and the TTP patients with ADAMTS13 antibodies came into sustained remission. After a median follow-up of 11.7 (range 7.7–12.9) years without maintenance therapy, no disease recurrence was observed; nevertheless, six patients, two had hypertension and two had proteinuria as a late consequence. One patient, with late diagnosis of CFH-ab and additional genetic risk factors who was treated only with PE and plasma substitution, reached end-stage renal disease and was later successfully transplanted using eculizumab prophylaxis. In the cases of antibody-mediated TMAs, PE and early immunosuppressive treatment may result in sustained remission with preserved kidney function. Further data are needed to establish optimal treatment of anti-FH antibody-associated HUS. Full article
(This article belongs to the Special Issue Kidney Diseases: Molecular Pathogenesis and Therapeutic Strategies)
14 pages, 1873 KiB  
Article
Evaluating the Utility of ctDNA in Detecting Residual Cancer and Predicting Recurrence in Patients with Serous Ovarian Cancer
by Jie Wei Zhu, Fabian Wong, Agata Szymiczek, Gabrielle E. V. Ene, Shiyu Zhang, Taymaa May, Steven A. Narod, Joanne Kotsopoulos and Mohammad R. Akbari
Int. J. Mol. Sci. 2023, 24(18), 14388; https://doi.org/10.3390/ijms241814388 - 21 Sep 2023
Cited by 5 | Viewed by 1120
Abstract
Ovarian cancer has a high case fatality rate, but patients who have no visible residual disease after surgery have a relatively good prognosis. The presence of any cancer cells left in the peritoneal cavity after treatment may precipitate a cancer recurrence. In many [...] Read more.
Ovarian cancer has a high case fatality rate, but patients who have no visible residual disease after surgery have a relatively good prognosis. The presence of any cancer cells left in the peritoneal cavity after treatment may precipitate a cancer recurrence. In many cases, these cells are occult and are not visible to the surgeon. Analysis of circulating tumour DNA in the blood (ctDNA) may offer a sensitive method to predict the presence of occult (non-visible) residual disease after surgery and may help predict disease recurrence. We assessed 48 women diagnosed with serous ovarian cancer (47 high-grade and 1 low-grade) for visible residual disease and for ctDNA. Plasma, formalin-fixed paraffin-embedded (FFPE) tumour tissue and white blood cells were used to extract circulating free DNA (cfDNA), tumour DNA and germline DNA, respectively. We sequenced DNA samples for 59 breast and ovarian cancer driver genes. The plasma sample was collected after surgery and before initiating chemotherapy. We compared survival in women with no residual disease, with and without a positive plasma ctDNA test. We found tumour-specific variants (TSVs) in cancer cells from 47 patients, and these variants were sought in ctDNA in their post-surgery plasma. Fifteen (31.9%) of the 47 patients had visible residual disease; of these, all 15 had detectable ctDNA. Thirty-one patients (65.9%) had no visible residual disease; of these, 24 (77.4%) patients had detectable ctDNA. Of the patients with no visible residual disease, those patients with detectable ctDNA had higher mortality (20 of 27 died) than those without detectable ctDNA (3 of 7 died) (HR 2.32; 95% CI: 0.67–8.05), although this difference was not statistically significant (p = 0.18). ctDNA in post-surgical serum samples may predict the presence of microscopic residual disease and may be a predictor of recurrence among women with ovarian cancer. Larger studies are necessary to validate these findings. Full article
(This article belongs to the Special Issue Ovarian Cancer: Advances on Pathophysiology and Therapies)
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11 pages, 653 KiB  
Review
Utility of In Vitro Cellular Models of Low-Dose Lipopolysaccharide in Elucidating the Mechanisms of Anti-Inflammatory and Wound-Healing-Promoting Effects of Lipopolysaccharide Administration In Vivo
by Teruko Honda and Hiroyuki Inagawa
Int. J. Mol. Sci. 2023, 24(18), 14387; https://doi.org/10.3390/ijms241814387 - 21 Sep 2023
Cited by 1 | Viewed by 1098
Abstract
Lipopolysaccharide (LPS) is a bacterial component that activates intracellular signaling pathways upon binding to the Toll-like receptor (TLR)-4/MD-2 complex. It is well known that LPS injected into animals and high-dose (100 ng/mL to 1 μg/mL) LPS treatment to innate immune cells induce an [...] Read more.
Lipopolysaccharide (LPS) is a bacterial component that activates intracellular signaling pathways upon binding to the Toll-like receptor (TLR)-4/MD-2 complex. It is well known that LPS injected into animals and high-dose (100 ng/mL to 1 μg/mL) LPS treatment to innate immune cells induce an inflammatory response. In contrast, LPS is naturally present in the gastrointestinal tract, respiratory tract, and skin of humans and animals, and it has been shown that TLR-4-deficient animals cannot maintain their immune balance and gut homeostasis. LPS from commensal bacteria can help maintain homeostasis against mucosal stimulation in healthy individuals. Oral LPS administration has been shown to be effective in preventing allergic and lifestyle-related diseases. However, this effect was not observed after treatment with LPS at high doses. In mice, oral LPS administration resulted in the detection of LPS at a low concentration in the peritoneal fluid. Therefore, LPS administered at low and high doses have different effects. Moreover, the results of in vitro experiments using low-dose LPS may reflect the effects of oral LPS administration. This review summarizes the utility of in vitro models using cells stimulated with LPS at low concentrations (50 pg/mL to 50 ng/mL) in elucidating the mechanisms of oral LPS administration. Low-dose LPS administration has been demonstrated to suppress the upregulation of proinflammatory cytokines and promote wound healing, suggesting that LPS is a potential agent that can be used for the treatment and prevention of lifestyle-related diseases. Full article
(This article belongs to the Special Issue Advances in Lipopolysaccharide (LPS))
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14 pages, 3339 KiB  
Article
Silibinin Downregulates Types I and III Collagen Expression via Suppression of the mTOR Signaling Pathway
by Sooyeon Choi, Seoyoon Ham, Young In Lee, Jihee Kim, Won Jai Lee and Ju Hee Lee
Int. J. Mol. Sci. 2023, 24(18), 14386; https://doi.org/10.3390/ijms241814386 - 21 Sep 2023
Viewed by 1111
Abstract
Keloid scars are fibro-proliferative conditions characterized by abnormal fibroblast proliferation and excessive extracellular matrix deposition. The mammalian target of the rapamycin (mTOR) pathway has emerged as a potential therapeutic target in keloid disease. Silibinin, a natural flavonoid isolated from the seeds and fruits [...] Read more.
Keloid scars are fibro-proliferative conditions characterized by abnormal fibroblast proliferation and excessive extracellular matrix deposition. The mammalian target of the rapamycin (mTOR) pathway has emerged as a potential therapeutic target in keloid disease. Silibinin, a natural flavonoid isolated from the seeds and fruits of the milk thistle, is known to inhibit the mTOR signaling pathway in human cervical and hepatoma cancer cells. However, the mechanisms underlying this inhibitory effect are not fully understood. This in vitro study investigated the effects of silibinin on collagen expression in normal human dermal and keloid-derived fibroblasts. We evaluated the effects of silibinin on the expressions of collagen types I and III and assessed its effects on the suppression of the mTOR signaling pathway. Our findings confirmed elevated mTOR phosphorylation levels in keloid scars compared to normal tissue specimens. Silibinin treatment significantly reduced collagen I and III expressions in normal human dermal and keloid-derived fibroblasts. These effects were accompanied by the suppression of the mTOR signaling pathway. Our findings suggest the potential of silibinin as a promising therapeutic agent for preventing and treating keloid scars. Further studies are warranted to explore the clinical application of silibinin in scar management. Full article
(This article belongs to the Special Issue Molecular Studies of Natural Compounds and Plant Extracts)
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16 pages, 708 KiB  
Review
Endothelial Dysfunction in Systemic Sclerosis
by Eshaan Patnaik, Matthew Lyons, Kimberly Tran and Debendra Pattanaik
Int. J. Mol. Sci. 2023, 24(18), 14385; https://doi.org/10.3390/ijms241814385 - 21 Sep 2023
Cited by 3 | Viewed by 2864
Abstract
Systemic sclerosis, commonly known as scleroderma, is an autoimmune disorder characterized by vascular abnormalities, autoimmunity, and multiorgan fibrosis. The exact etiology is not known but believed to be triggered by environmental agents in a genetically susceptible host. Vascular symptoms such as the Raynaud [...] Read more.
Systemic sclerosis, commonly known as scleroderma, is an autoimmune disorder characterized by vascular abnormalities, autoimmunity, and multiorgan fibrosis. The exact etiology is not known but believed to be triggered by environmental agents in a genetically susceptible host. Vascular symptoms such as the Raynaud phenomenon often precede other fibrotic manifestations such as skin thickening indicating that vascular dysfunction is the primary event. Endothelial damage and activation occur early, possibly triggered by various infectious agents and autoantibodies. Endothelial dysfunction, along with defects in endothelial progenitor cells, leads to defective angiogenesis and vasculogenesis. Endothelial to mesenchymal cell transformation is another seminal event during pathogenesis that progresses to tissue fibrosis. The goal of the review is to discuss the molecular aspect of the endothelial dysfunction that leads to the development of systemic sclerosis. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Endothelial Dysfunction 3.0)
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12 pages, 1481 KiB  
Communication
ICI 182,780 Attenuates Selective Upregulation of Uterine Artery Cystathionine β-Synthase Expression in Rat Pregnancy
by Jin Bai, Yao Li, Guofeng Yan, Jing Zhou, Alejandra Garcia Salmeron, Olamide Tolulope Fategbe, Sathish Kumar, Xuejin Chen and Dong-Bao Chen
Int. J. Mol. Sci. 2023, 24(18), 14384; https://doi.org/10.3390/ijms241814384 - 21 Sep 2023
Viewed by 1110
Abstract
Endogenous hydrogen sulfide (H2S) produced by cystathionine β-synthase (CBS) and cystathionine-γ lyase (CSE) has emerged as a novel uterine vasodilator contributing to pregnancy-associated increases in uterine blood flow, which safeguard pregnancy health. Uterine artery (UA) H2S production is stimulated [...] Read more.
Endogenous hydrogen sulfide (H2S) produced by cystathionine β-synthase (CBS) and cystathionine-γ lyase (CSE) has emerged as a novel uterine vasodilator contributing to pregnancy-associated increases in uterine blood flow, which safeguard pregnancy health. Uterine artery (UA) H2S production is stimulated via exogenous estrogen replacement and is associated with elevated endogenous estrogens during pregnancy through the selective upregulation of CBS without altering CSE. However, how endogenous estrogens regulate uterine artery CBS expression in pregnancy is unknown. This study was conducted to test a hypothesis that endogenous estrogens selectively stimulate UA CBS expression via specific estrogen receptors (ER). Treatment with E2β (0.01 to 100 nM) stimulated CBS but not CSE mRNA in organ cultures of fresh UA rings from both NP and P (gestational day 20, GD20) rats, with greater responses to all doses of E2β tested in P vs. NP UA. ER antagonist ICI 182,780 (ICI, 1 µM) completely attenuated E2β-stimulated CBS mRNA in both NP and P rat UA. Subcutaneous injection with ICI 182,780 (0.3 mg/rat) of GD19 P rats for 24 h significantly inhibited UA CBS but not mRNA expression, consistent with reduced endothelial and smooth muscle cell CBS (but not CSE) protein. ICI did not alter mesenteric and renal artery CBS and CSE mRNA. In addition, ICI decreased endothelial nitric oxide synthase mRNA in UA but not in mesenteric or renal arteries. Thus, pregnancy-augmented UA CBS/H2S production is mediated by the actions of endogenous estrogens via specific ER in pregnant rats. Full article
(This article belongs to the Special Issue Molecular Research of Vascular Aspects in Pregnancy)
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15 pages, 3325 KiB  
Review
The Effect of Plant-Derived Low-Ratio Linoleic Acid/α-Linolenic Acid on Markers of Glucose Controls: A Systematic Review and Meta-Analysis
by Qiong Wang and Xingguo Wang
Int. J. Mol. Sci. 2023, 24(18), 14383; https://doi.org/10.3390/ijms241814383 - 21 Sep 2023
Cited by 1 | Viewed by 1289
Abstract
The objective of this meta-analysis was to examine the impact of a low-ratio linoleic acid/α-linolenic acid (LA/ALA) diet on the glycemic profile of adults. A comprehensive search was performed across four databases (Web of Science, Scopus, Embase, and PubMed) to evaluate the influence [...] Read more.
The objective of this meta-analysis was to examine the impact of a low-ratio linoleic acid/α-linolenic acid (LA/ALA) diet on the glycemic profile of adults. A comprehensive search was performed across four databases (Web of Science, Scopus, Embase, and PubMed) to evaluate the influence of the low-ratio LA/ALA. Relevant references were screened up until February 2023. Intervention effects were analyzed by calculating change values as weighted mean differences (WMD) and 95% confidence intervals (CI) using fixed-effects models. Additionally, subgroup analysis and meta-regression were employed to investigate potential sources of heterogeneity. Twenty-one randomized controlled trials (RCTs) were included, and the low-ratio LA/ALA diet had no significant effect on fasting blood sugar (FBS, WMD: 0.00 mmol/L, 95% CI: −0.06, 0.06, p = 0.989, I2 = 0.0%), insulin levels (WMD: 0.20 μIU/mL, 95% CI: −0.23, 0.63, p = 0.360, I2 = 3.2%), homeostatic model assessment insulin resistance (HOMA-IR, WMD: 0.09, 95% CI: −0.06, 0.23, p = 0.243, I2 = 0.0%), and hemoglobin A1c (HbA1c, WMD: −0.01%, 95% CI: −0.07, 0.06, p = 0.836, I2 = 0.0%). Based on subgroup analyses, it was observed that the impact of a low-ratio LA/ALA diet on elevated plasma insulin (WMD: 1.31 μIU/mL, 95% CI: 0.08, 2.54, p = 0.037, I2 = 32.0%) and HOMA-IR (WMD: 0.47, 95% CI: 0.10, 0.84, p = 0.012, I2 = 0.0%) levels exhibited greater prominence in North America compared to Asian and European countries. Publication bias was not detected for FBS, insulin, HOMA-IR, and HbA1c levels according to the Begg and Egger tests. Furthermore, the conducted sensitivity analyses indicated stability, as the effects of the low-ratio LA/ALA diet on various glycemic and related metrics remained unchanged even after removing individual studies. Overall, based on the available studies, it can be concluded that the low-ratio LA/ALA diet has limited impact on blood glucose-related biomarker levels. Full article
(This article belongs to the Special Issue Fatty Acids and Metabolic Syndrome)
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13 pages, 1070 KiB  
Article
Emerging Role of Decoy Receptor-2 as a Cancer Risk Predictor in Oral Potentially Malignant Disorders
by Lucas de Villalaín, Saúl Álvarez-Teijeiro, Tania Rodríguez-Santamarta, Álvaro Fernández del Valle, Eva Allonca, Juan P. Rodrigo, Juan Carlos de Vicente and Juana M. García-Pedrero
Int. J. Mol. Sci. 2023, 24(18), 14382; https://doi.org/10.3390/ijms241814382 - 21 Sep 2023
Viewed by 672
Abstract
The aim of this study was to evaluate the expression of the senescence markers, Decoy Receptor 2 (DcR2) and Differentiated Embryo-Chondrocyte expressed gen 1 (DEC1), in oral potentially malignant disorders (OPMDs) to ascertain their possible association with oral cancer risk. The immunohistochemical analysis [...] Read more.
The aim of this study was to evaluate the expression of the senescence markers, Decoy Receptor 2 (DcR2) and Differentiated Embryo-Chondrocyte expressed gen 1 (DEC1), in oral potentially malignant disorders (OPMDs) to ascertain their possible association with oral cancer risk. The immunohistochemical analysis of DcR2 and DEC1 expression (along with p16 and Ki67 expression) was carried out in 60 patients with clinically diagnosed oral leukoplakia. Fifteen cases (25%) subsequently developed an invasive carcinoma. Correlations between protein marker expression, histological grade and oral cancer risk were assessed. DcR2, DEC1 and Ki67 protein expressions were found to correlate significantly with increased oral cancer risk, and also with an increased grade of dysplasia. Multivariate analysis demonstrated that DcR2 and Ki67 expression are independent predictors of oral cancer development. Our results evidence for the first time the potential of DcR2 as an early biomarker to assess oral cancer risk in patients with oral leukoplakia (HR = 59.7, p = 0.015), showing a superior predictive value to histology (HR = 4.225, p = 0.08). These findings reveal that the increased expression of DcR2 and DEC1 occurred frequently in OPMDs. In addition, DcR2 expression emerges as a powerful biomarker for oral cancer risk assessment in patients with oral leukoplakia. Full article
(This article belongs to the Special Issue Molecular Pathogenesis of Oral Potentially Malignant Disorders Transformation)
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17 pages, 2751 KiB  
Article
A Side-by-Side Comparison of Wildtype and Variant Melanocortin 1 Receptor Signaling with Emphasis on Protection against Oxidative Damage to DNA
by Sonia Cerdido, José Sánchez-Beltrán, Ana Lambertos, Marta Abrisqueta, Lidia Padilla, Cecilia Herraiz, Conchi Olivares, Celia Jiménez-Cervantes and José C. García-Borrón
Int. J. Mol. Sci. 2023, 24(18), 14381; https://doi.org/10.3390/ijms241814381 - 21 Sep 2023
Cited by 2 | Viewed by 908
Abstract
Common variants of the MC1R gene coding the α-melanocyte stimulating hormone receptor are associated with light skin, poor tanning, blond or red hair, and increased melanoma risk, due to pigment-dependent and -independent effects. This complex phenotype is usually attributed to impaired activation of [...] Read more.
Common variants of the MC1R gene coding the α-melanocyte stimulating hormone receptor are associated with light skin, poor tanning, blond or red hair, and increased melanoma risk, due to pigment-dependent and -independent effects. This complex phenotype is usually attributed to impaired activation of cAMP signaling. However, several MC1R variants show significant residual coupling to cAMP and efficiently activate mitogenic extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling. Yet, residual signaling and the key actions of wildtype and variant MC1R have never been assessed under strictly comparable conditions in melanocytic cells of identical genetic background. We devised a strategy based on CRISPR-Cas9 knockout of endogenous MC1R in a human melanoma cell line wildtype for BRAF, NRAS and NF1, followed by reconstitution with epitope-labeled MC1R constructs, and functional analysis of clones expressing comparable levels of wildtype, R151C or D294H MC1R. The proliferation rate, shape, adhesion, motility and sensitivity to oxidative DNA damage were compared. The R151C and D294H RHC variants displayed impaired cAMP signaling, intracellular stability similar to the wildtype, triggered ERK1/2 activation as effectively as the wildtype, and afforded partial protection against oxidative DNA damage, although less efficiently than the wildtype. Therefore, common melanoma-associated MC1R variants display biased signaling and significant genoprotective activity. Full article
(This article belongs to the Special Issue Advances in Pathogenesis and Treatment of Skin Cancer)
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17 pages, 4442 KiB  
Article
Myogenetic Oligodeoxynucleotide Induces Myocardial Differentiation of Murine Pluripotent Stem Cells
by Mina Ishioka, Yuma Nihashi, Yoichi Sunagawa, Koji Umezawa, Takeshi Shimosato, Hiroshi Kagami, Tatsuya Morimoto and Tomohide Takaya
Int. J. Mol. Sci. 2023, 24(18), 14380; https://doi.org/10.3390/ijms241814380 - 21 Sep 2023
Viewed by 1650
Abstract
An 18-base myogenetic oligodeoxynucleotide (myoDN), iSN04, acts as an anti-nucleolin aptamer and induces myogenic differentiation of skeletal muscle myoblasts. This study investigated the effect of iSN04 on murine embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). In the undifferentiated state, iSN04 [...] Read more.
An 18-base myogenetic oligodeoxynucleotide (myoDN), iSN04, acts as an anti-nucleolin aptamer and induces myogenic differentiation of skeletal muscle myoblasts. This study investigated the effect of iSN04 on murine embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). In the undifferentiated state, iSN04 inhibited the proliferation of ESCs and iPSCs but did not affect the expression of pluripotent markers. In the differentiating condition, iSN04 treatment of ESCs/iPSCs from day 5 onward dramatically induced differentiation into Nkx2-5+ beating cardiomyocytes with upregulation of Gata4, Isl1, and Nkx2-5, whereas iSN04 treatment from earlier stages completely inhibited cardiomyogenesis. RNA sequencing revealed that iSN04 treatment from day 5 onward contributes to the generation of cardiac progenitors by modulating the Wnt signaling pathway. Immunostaining showed that iSN04 suppressed the cytoplasmic translocation of nucleolin and restricted it to the nucleoli. These results demonstrate that nucleolin inhibition by iSN04 facilitates the terminal differentiation of cardiac mesoderm into cardiomyocytes but interferes with the differentiation of early mesoderm into the cardiac lineage. This is the first report on the generation of cardiomyocytes from pluripotent stem cells using a DNA aptamer. Since iSN04 did not induce hypertrophic responses in primary-cultured cardiomyocytes, iSN04 would be useful and safe for the regenerative therapy of heart failure using stem cell-derived cardiomyocytes. Full article
(This article belongs to the Special Issue Advanced Research on Nucleic Acids: Therapeutic Potential and Applications)
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16 pages, 2123 KiB  
Article
A Decrease in Maternal Iron Levels Is the Predominant Factor Suppressing Hepcidin during Pregnancy in Mice
by Sheridan L. Helman, Sarah J. Wilkins, Jennifer C. J. Chan, Gunter Hartel, Daniel F. Wallace, Gregory J. Anderson and David M. Frazer
Int. J. Mol. Sci. 2023, 24(18), 14379; https://doi.org/10.3390/ijms241814379 - 21 Sep 2023
Viewed by 851
Abstract
In order to supply adequate iron during pregnancy, the levels of the iron regulatory hormone hepcidin in the maternal circulation are suppressed, thereby increasing dietary iron absorption and storage iron release. Whether this decrease in maternal hepcidin is caused by changes in factors [...] Read more.
In order to supply adequate iron during pregnancy, the levels of the iron regulatory hormone hepcidin in the maternal circulation are suppressed, thereby increasing dietary iron absorption and storage iron release. Whether this decrease in maternal hepcidin is caused by changes in factors known to regulate hepcidin expression, or by other unidentified pregnancy factors, is not known. To investigate this, we examined iron parameters during pregnancy in mice. We observed that hepatic iron stores and transferrin saturation, both established regulators of hepcidin production, were decreased in mid and late pregnancy in normal and iron loaded dams, indicating an increase in iron utilization. This can be explained by a significant increase in maternal erythropoiesis, a known suppressor of hepcidin production, by mid-pregnancy, as indicated by an elevation in circulating erythropoietin and an increase in spleen size and splenic iron uptake. Iron utilization increased further in late pregnancy due to elevated fetal iron demand. By increasing maternal iron levels in late gestation, we were able to stimulate the expression of the gene encoding hepcidin, suggesting that the iron status of the mother is the predominant factor influencing hepcidin levels during pregnancy. Our data indicate that pregnancy-induced hepcidin suppression likely occurs because of reductions in maternal iron reserves due to increased iron requirements, which predominantly reflect stimulated erythropoiesis in mid-gestation and increased fetal iron requirements in late gestation, and that there is no need to invoke other factors, including novel pregnancy factor(s), to explain these changes. Full article
(This article belongs to the Section Molecular Endocrinology and Metabolism)
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17 pages, 786 KiB  
Review
Assessment of Inflammatory Hematological Ratios (NLR, PLR, MLR, LMR and Monocyte/HDL–Cholesterol Ratio) in Acute Myocardial Infarction and Particularities in Young Patients
by Bogdan-Sorin Tudurachi, Larisa Anghel, Andreea Tudurachi, Radu Andy Sascău and Cristian Stătescu
Int. J. Mol. Sci. 2023, 24(18), 14378; https://doi.org/10.3390/ijms241814378 - 21 Sep 2023
Cited by 8 | Viewed by 1981
Abstract
Cardiovascular disease, particularly coronary artery disease (CAD), remains a predominant cause of mortality globally. Factors such as atherosclerosis and inflammation play significant roles in the pathogenesis of CAD. The nexus between inflammation and CAD is underscored by the role of immune cells, such [...] Read more.
Cardiovascular disease, particularly coronary artery disease (CAD), remains a predominant cause of mortality globally. Factors such as atherosclerosis and inflammation play significant roles in the pathogenesis of CAD. The nexus between inflammation and CAD is underscored by the role of immune cells, such as neutrophils, lymphocytes, monocytes, and macrophages. These cells orchestrate the inflammatory process, a core component in the initiation and progression of atherosclerosis. The activation of these pathways and the subsequent lipid, fibrous element, and calcification accumulation can result in vessel narrowing. Hematological parameters derived from routine blood tests offer insights into the underlying inflammatory state. Recent studies have highlighted the potential of inflammatory hematological ratios, such as the neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, monocyte/lymphocyte ratio and lymphocyte/monocyte ratio. These parameters are not only accessible and cost-effective but also mirror the degree of systemic inflammation. Several studies have indicated a correlation between these markers and the severity, prognosis, and presence of CAD. Despite the burgeoning interest in the relationship between inflammatory markers and CAD, there remains a paucity of data exploring these parameters in young patients with acute myocardial infarction. Such data could offer valuable insights into the unique pathophysiology of early-onset CAD and improve risk assessment and predictive strategies. Full article
(This article belongs to the Special Issue Molecular Biomarkers in Cardiovascular Disease)
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18 pages, 2720 KiB  
Article
Slowed Intestinal Transit Induced by Less Mucus in Intestinal Goblet Cell Piezo1-Deficient Mice through Impaired Epithelial Homeostasis
by Feifei Fang, Ying Liu, Yilin Xiong, Xueyan Li, Gangping Li, Yudong Jiang, Xiaohua Hou and Jun Song
Int. J. Mol. Sci. 2023, 24(18), 14377; https://doi.org/10.3390/ijms241814377 - 21 Sep 2023
Viewed by 1029
Abstract
Mucus secreted by goblet cells (GCs) may play an important role in intestinal transit function. Our previous study found that Piezo1 protein is essential for GC function; however, the effect of GC Piezo1 on intestinal transit function is unclear. Our study aimed to [...] Read more.
Mucus secreted by goblet cells (GCs) may play an important role in intestinal transit function. Our previous study found that Piezo1 protein is essential for GC function; however, the effect of GC Piezo1 on intestinal transit function is unclear. Our study aimed to investigate the effect of Piezo1 in GCs on intestinal transit and the potential mechanism. We compared intestinal mucus, fecal form, intestinal transit time, intestinal epithelial cell composition, and stem cell function in WT and GC-specific Piezo1-deficient (Piezo1ΔGC) mice. Our results revealed a correlation between mucus and intestinal transit: the less mucus there was, the slower the intestinal transit. Piezo1 deficiency in GCs led to decreased mucus synthesis and also disrupted the ecological niche of colon stem cells (CSCs). Through organoid culture, we found that the capacity of proliferation and differentiation in Piezo1ΔGC mouse CSCs was significantly decreased, which also led to a reduced source of GCs. Further studies found that the reduced Wnt and Notch signals in colon crypts might be the potential mechanism. These results indicated the importance of GC Piezo1 in intestinal transit function, which acts by maintaining the homeostasis of intestinal epithelial cells and mucus. Full article
(This article belongs to the Special Issue Gastrointestinal Diseases: Molecular Mechanism, Diagnostics, and Novel Therapeutic Approaches)
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16 pages, 3255 KiB  
Article
Resistant and Susceptible Pinus thunbergii ParL. Show Highly Divergent Patterns of Differentially Expressed Genes during the Process of Infection by Bursaphelenchus xylophilus
by Tingyu Sun, Mati Ur Rahman, Xiaoqin Wu and Jianren Ye
Int. J. Mol. Sci. 2023, 24(18), 14376; https://doi.org/10.3390/ijms241814376 - 21 Sep 2023
Viewed by 866
Abstract
Pine wilt disease (PWD) is a devastating disease that threatens pine forests worldwide, and breeding resistant pines is an important management strategy used to reduce its impact. A batch of resistant seeds of P. thunbergii was introduced from Japan. Based on the resistant [...] Read more.
Pine wilt disease (PWD) is a devastating disease that threatens pine forests worldwide, and breeding resistant pines is an important management strategy used to reduce its impact. A batch of resistant seeds of P. thunbergii was introduced from Japan. Based on the resistant materials, we obtained somatic plants through somatic embryogenesis. In this study, we performed transcriptome analysis to further understand the defense response of resistant somatic plants of P. thunbergii to PWD. The results showed that, after pine wood nematode (PWN) infection, resistant P. thunbergii stimulated more differential expression genes (DEGs) and involved more regulatory pathways than did susceptible P. thunbergii. For the first time, the alpha-linolenic acid metabolism and linoleic acid metabolism were intensively observed in pines resisting PWN infection. The related genes disease resistance protein RPS2 (SUMM2) and pathogenesis-related genes (PR1), as well as reactive oxygen species (ROS)-related genes were significantly up-expressed in order to contribute to protection against PWN inoculation in P. thunbergii. In addition, the diterpenoid biosynthesis pathway was significantly enriched only in resistant P. thunbergii. These findings provided valuable genetic information for future breeding of resistant conifers, and could contribute to the development of new diagnostic tools for early screening of resistant pine seedlings based on specific PWN-tolerance-related markers. Full article
(This article belongs to the Special Issue Advances in Plant Breeding and Resistance)
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