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Curr. Issues Mol. Biol., Volume 45, Issue 3 (March 2023) – 58 articles

Cover Story (view full-size image): Influenza viruses cause highly contagious respiratory infections and seasonal flu epidemics. The emergence of drug-resistant strains highlights groundbreaking for new antiviral therapeutic approaches. In this study, we provide the first biochemical evidence that 18-hydroxyferruginol (1) and 18-oxoferruginol (2) from Torreya nucifera can inhibit influenza virus infection by modulating the PI3K-Akt and ERK signaling pathways. The consequence of these events is the inhibition of viral RNP export from the nucleus and the disruption of influenza virus replication. Our findings suggest that these abietane diterpenoids have potential as novel antiviral candidates for the development of effective influenza therapies. View this paper
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15 pages, 4608 KiB  
Article
Sucrose Transporter StSUT2 Affects Potato Plants Growth, Flowering Time, and Tuber Yield
by Hui-Ling Gong, Jin-Bao Liu, Clement Igiraneza and Leonce Dusengemungu
Curr. Issues Mol. Biol. 2023, 45(3), 2629-2643; https://doi.org/10.3390/cimb45030172 - 22 Mar 2023
Cited by 1 | Viewed by 1314
Abstract
Background: Sucrose transporters (SUTs) mediate sucrose phloem loading in source tissue and sucrose unloading into sink tissue in potatoes and higher plants, thus playing a crucial role in plant growth and development. In potatoes, the physiological function of the sucrose transporters StSUT1 and [...] Read more.
Background: Sucrose transporters (SUTs) mediate sucrose phloem loading in source tissue and sucrose unloading into sink tissue in potatoes and higher plants, thus playing a crucial role in plant growth and development. In potatoes, the physiological function of the sucrose transporters StSUT1 and StSUT4 has been clarified, whereas the physiological role of StSUT2 is not yet fully understood. Methods and Results: This study analyzed the relative expression of StSUT2 compared to that of StSUT1 and StSUT4 in different tissues from potatoes and its impact on different physiological characteristics by using StSUT2-RNA interference lines. Here, we report a negative effect of StSUT2-RNA interference on plant height, fresh weight, internodes number, leaf area, flowering time, and tuber yield. However, our data indicate that StSUT2 is not involved in carbohydrate accumulation in potato leaves and tubers. In addition, the data of the RNA-seq between the StSUT2-RNA interference line and WT showed that 152 genes were differentially expressed, of which 128 genes were upregulated and 24 genes were downregulated, and the GO and KEGG analyses revealed that differentially expressed genes were mainly related to cell wall composition metabolism. Conclusions: Thus, StSUT2 functions in potato plant growth, flowering time, and tuber yield without affecting carbohydrate accumulation in the leaves and tubers but may be involved in cell wall composition metabolism. Full article
(This article belongs to the Special Issue Functional Genomics and Comparative Genomics Analysis in Plants)
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20 pages, 1640 KiB  
Review
Origin and Emergence of Microglia in the CNS—An Interesting (Hi)story of an Eccentric Cell
by Iasonas Dermitzakis, Maria Eleni Manthou, Soultana Meditskou, Marie-Ève Tremblay, Steven Petratos, Lida Zoupi, Marina Boziki, Evangelia Kesidou, Constantina Simeonidou and Paschalis Theotokis
Curr. Issues Mol. Biol. 2023, 45(3), 2609-2628; https://doi.org/10.3390/cimb45030171 - 22 Mar 2023
Cited by 5 | Viewed by 4193
Abstract
Microglia belong to tissue-resident macrophages of the central nervous system (CNS), representing the primary innate immune cells. This cell type constitutes ~7% of non-neuronal cells in the mammalian brain and has a variety of biological roles integral to homeostasis and pathophysiology from the [...] Read more.
Microglia belong to tissue-resident macrophages of the central nervous system (CNS), representing the primary innate immune cells. This cell type constitutes ~7% of non-neuronal cells in the mammalian brain and has a variety of biological roles integral to homeostasis and pathophysiology from the late embryonic to adult brain. Its unique identity that distinguishes its “glial” features from tissue-resident macrophages resides in the fact that once entering the CNS, it is perennially exposed to a unique environment following the formation of the blood–brain barrier. Additionally, tissue-resident macrophage progenies derive from various peripheral sites that exhibit hematopoietic potential, and this has resulted in interpretation issues surrounding their origin. Intensive research endeavors have intended to track microglial progenitors during development and disease. The current review provides a corpus of recent evidence in an attempt to disentangle the birthplace of microglia from the progenitor state and underlies the molecular elements that drive microgliogenesis. Furthermore, it caters towards tracking the lineage spatiotemporally during embryonic development and outlining microglial repopulation in the mature CNS. This collection of data can potentially shed light on the therapeutic potential of microglia for CNS perturbations across various levels of severity. Full article
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12 pages, 2214 KiB  
Case Report
Stroke-Associating Acute Limb Ischemia Due to the Rupture of a Hydatid Cyst
by Mihaela Lungu, Violeta Diana Oprea, Andrei Lucian Zaharia, Bianca Stan, Laura Rebegea, Dan Iulian Mocanu, Eva Maria Elkan, Elena Niculet and Ana Croitoru
Curr. Issues Mol. Biol. 2023, 45(3), 2597-2608; https://doi.org/10.3390/cimb45030170 - 22 Mar 2023
Viewed by 1569
Abstract
(1) Background: Hydatidosis, or human cystic echinococcosis, is a zoonotic disease. Endemic in some areas, recently it has an increasing incidence in wider regions, determined by population migration. Clinical features depend on the localization and level of infection: asymptomatic or with signs related [...] Read more.
(1) Background: Hydatidosis, or human cystic echinococcosis, is a zoonotic disease. Endemic in some areas, recently it has an increasing incidence in wider regions, determined by population migration. Clinical features depend on the localization and level of infection: asymptomatic or with signs related to hypersensitivity, organic functional deficiencies, expanding mass effects, cyst infection and sudden death. In rare cases, the rupture of a hydatid cyst causes emboli formation by the residual laminated membrane. (2) Methods: We performed an extensive literature review, starting from the case of a 25-year-old patient presenting with neurologic symptoms relevant for acute stroke, associating right upper limb ischemia. (3) Results: Imaging investigations revealed the source of the emboli as the rupture of a hydatid cyst, the patient presenting multiple pericardial and mediastinal localizations. Cerebral imaging confirmed an acute left occipital ischemic lesion, with complete recovery of the neurological deficit after therapy, while surgery for acute brachial artery ischemia had a favorable postoperative evolution. Specific anthelmintic therapy was initiated. An extensive literature review using available databases revealed the scarcity of data on embolism as a consequence of cyst rupture, highlighting the significant risk of clinicians overlooking this possible etiology. (4) Conclusions: An associated allergic reaction should raise the hypothesis of a hydatid cyst rupture as a cause of any level acute ischemic lesion. Full article
(This article belongs to the Special Issue Pathophysiology and Molecular Mechanisms of Acute Stroke)
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17 pages, 2355 KiB  
Article
Alteration of Mesenchymal Stem Cells Isolated from Glioblastoma Multiforme under the Influence of Photodynamic Treatment
by Kalina Tumangelova-Yuzeir, Krassimir Minkin, Ivan Angelov, Ekaterina Ivanova-Todorova, Ekaterina Kurteva, Georgi Vasilev, Jeliazko Arabadjiev, Petar Karazapryanov, Kaloyan Gabrovski, Lidia Zaharieva, Tsanislava Genova and Dobroslav Kyurkchiev
Curr. Issues Mol. Biol. 2023, 45(3), 2580-2596; https://doi.org/10.3390/cimb45030169 - 21 Mar 2023
Cited by 1 | Viewed by 2463
Abstract
The central hypothesis for the development of glioblastoma multiforme (GBM) postulates that the tumor begins its development by transforming neural stem cells into cancer stem cells (CSC). Recently, it has become clear that another kind of stem cell, the mesenchymal stem cell (MSC), [...] Read more.
The central hypothesis for the development of glioblastoma multiforme (GBM) postulates that the tumor begins its development by transforming neural stem cells into cancer stem cells (CSC). Recently, it has become clear that another kind of stem cell, the mesenchymal stem cell (MSC), plays a role in the tumor stroma. Mesenchymal stem cells, along with their typical markers, can express neural markers and are capable of neural transdifferentiation. From this perspective, it is hypothesized that MSCs can give rise to CSC. In addition, MSCs suppress the immune cells through direct contact and secretory factors. Photodynamic therapy aims to selectively accumulate a photosensitizer in neoplastic cells, forming reactive oxygen species (ROS) upon irradiation, initiating death pathways. In our experiments, MSCs from 15 glioblastomas (GB-MSC) were isolated and cultured. The cells were treated with 5-ALA and irradiated. Flow cytometry and ELISA were used to detect the marker expression and soluble-factor secretion. The MSCs’ neural markers, Nestin, Sox2, and glial fibrillary acid protein (GFAP), were down-regulated, but the expression levels of the mesenchymal markers CD73, CD90, and CD105 were retained. The GB-MSCs also reduced their expression of PD-L1 and increased their secretion of PGE2. Our results give us grounds to speculate that the photodynamic impact on GB-MSCs reduces their capacity for neural transdifferentiation. Full article
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19 pages, 3948 KiB  
Article
The Effect of a Diet Enriched with Jerusalem artichoke, Inulin, and Fluoxetine on Cognitive Functions, Neurogenesis, and the Composition of the Intestinal Microbiota in Mice
by Aleksandra Szewczyk, Marta Andres-Mach, Mirosław Zagaja, Agnieszka Kaczmarczyk-Ziemba, Maciej Maj and Joanna Szala-Rycaj
Curr. Issues Mol. Biol. 2023, 45(3), 2561-2579; https://doi.org/10.3390/cimb45030168 - 21 Mar 2023
Cited by 2 | Viewed by 2206
Abstract
The aim of the study was to assess the effect of long-term administration of natural prebiotics: Jerusalem artichoke (topinambur, TPB) and inulin (INU) as well as one of the most popular antidepressants, fluoxetine (FLU), on the proliferation of neural stem cells, learning and [...] Read more.
The aim of the study was to assess the effect of long-term administration of natural prebiotics: Jerusalem artichoke (topinambur, TPB) and inulin (INU) as well as one of the most popular antidepressants, fluoxetine (FLU), on the proliferation of neural stem cells, learning and memory functions, and the composition of the intestinal microbiota in mice. Cognitive functions were assessed using the Morris Water Maze (MWM)Test. Cells were counted using a confocal microscope and ImageJ software. We performed 16S rRNA sequencing to assess changes in the gut microbiome of the mice. The obtained results showed that the 10-week supplementation with TPB (250 mg/kg) and INU (66 mg/kg) stimulates the growth of probiotic bacteria, does not affect the learning and memory process, and does not disturb the proliferation of neural stem cells in the tested animals. Based on this data, we can assume that both TPB and INU seem to be safe for the proper course of neurogenesis. However, 2-week administration of FLU confirmed an inhibitory impact on Lactobacillus growth and negatively affected behavioral function and neurogenesis in healthy animals. The above studies suggest that the natural prebiotics TPB and INU, as natural supplements, may have the potential to enrich the diversity of intestinal microbiota, which may be beneficial for the BGM axis, cognitive functions, and neurogenesis. Full article
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12 pages, 537 KiB  
Brief Report
ParticleChromo3D+: A Web Server for ParticleChromo3D Algorithm for 3D Chromosome Structure Reconstruction
by David Vadnais and Oluwatosin Oluwadare
Curr. Issues Mol. Biol. 2023, 45(3), 2549-2560; https://doi.org/10.3390/cimb45030167 - 17 Mar 2023
Cited by 1 | Viewed by 1018
Abstract
Understanding the three-dimensional (3D) structure of chromatin is invaluable for researching how it functions. One way to gather this information is the chromosome conformation capture (3C) technique and its follow-up technique Hi-C. Here, we present ParticleChromo3D+, a containerized web-based genome structure reconstruction server/tool [...] Read more.
Understanding the three-dimensional (3D) structure of chromatin is invaluable for researching how it functions. One way to gather this information is the chromosome conformation capture (3C) technique and its follow-up technique Hi-C. Here, we present ParticleChromo3D+, a containerized web-based genome structure reconstruction server/tool that provides researchers with a portable and accurate tool for analyses. Additionally, ParticleChromo3D+ provides a more user-friendly way to access its capabilities via a graphical user interface (GUI). ParticleChromo3D+ can save time for researchers by increasing the accessibility of genome reconstruction, easing usage pain points, and offloading computational processing/installation time. Full article
(This article belongs to the Collection Feature Papers in Current Issues in Molecular Biology)
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16 pages, 832 KiB  
Article
Significant Association of Estrogen Receptor-β Isoforms and Coactivators in Breast Cancer Subtypes
by Young Choi and Simcha Pollack
Curr. Issues Mol. Biol. 2023, 45(3), 2533-2548; https://doi.org/10.3390/cimb45030166 - 17 Mar 2023
Viewed by 1369
Abstract
Nuclear receptor coregulators are the principal regulators of Estrogen Receptor (ER)-mediated transcription. ERβ, an ER subtype first identified in 1996, is associated with poor outcomes in breast cancer (BCa) subtypes, and the coexpression of the ERβ1 isoform and AIB-1 and TIF-2 coactivators in [...] Read more.
Nuclear receptor coregulators are the principal regulators of Estrogen Receptor (ER)-mediated transcription. ERβ, an ER subtype first identified in 1996, is associated with poor outcomes in breast cancer (BCa) subtypes, and the coexpression of the ERβ1 isoform and AIB-1 and TIF-2 coactivators in BCa-associated myofibroblasts is associated with high-grade BCa. We aimed to identify the specific coactivators that are involved in the progression of ERβ-expressing BCa. ERβ isoforms, coactivators, and prognostic markers were tested using standard immunohistochemistry. AIB-1, TIF-2, NF-kB, p-c-Jun, and/or cyclin D1 were differentially correlated with ERβ isoform expression in the BCa subtypes and subgroups. The coexpression of the ERβ5 and/or ERβ1 isoforms and the coactivators were found to be correlated with a high expression of P53, Ki-67, and Her2/neu and large-sized and/or high-grade tumors in BCa. Our study supports the notion that ERβ isoforms and coactivators seemingly coregulate the proliferation and progression of BCa and may provide insight into the potential therapeutic uses of the coactivators in BCa. Full article
(This article belongs to the Special Issue Advanced Molecular Solutions for Cancer Therapy)
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12 pages, 1665 KiB  
Article
Development of Digital Droplet PCR Targeting the Influenza H3N2 Oseltamivir-Resistant E119V Mutation and Its Performance through the Use of Reverse Genetics Mutants
by Laura A. E. Van Poelvoorde, François E. Dufrasne, Steven Van Gucht, Xavier Saelens and Nancy H. C. Roosens
Curr. Issues Mol. Biol. 2023, 45(3), 2521-2532; https://doi.org/10.3390/cimb45030165 - 17 Mar 2023
Cited by 2 | Viewed by 1382
Abstract
The monitoring of antiviral-resistant influenza virus strains is important for public health given the availability and use of neuraminidase inhibitors and other antivirals to treat infected patients. Naturally occurring oseltamivir-resistant seasonal H3N2 influenza virus strains often carry a glutamate-to-valine substitution at position 119 [...] Read more.
The monitoring of antiviral-resistant influenza virus strains is important for public health given the availability and use of neuraminidase inhibitors and other antivirals to treat infected patients. Naturally occurring oseltamivir-resistant seasonal H3N2 influenza virus strains often carry a glutamate-to-valine substitution at position 119 in the neuraminidase (E119V-NA). Early detection of resistant influenza viruses is important for patient management and for the rapid containment of antiviral resistance. The neuraminidase inhibition assay allows the phenotypical identification of resistant strains; however, this test often has limited sensitivity with high variability depending on the virus strain, drugs and assays. Once a mutation such as E119V-NA is known, highly sensitive PCR-based genotypic assays can be used to identify the prevalence of such mutant influenza viruses in clinical samples. In this study, based on an existing reverse transcriptase real-time PCR (RT-qPCR) assay, we developed a reverse transcriptase droplet digital PCR assay (RT-ddPCR) to detect and quantify the frequency of the E119V-NA mutation. Furthermore, reverse genetics viruses carrying this mutation were created to test the performance of the RT-ddPCR assay and compare it to the standard phenotypic NA assay. We also discuss the advantage of using an RT-ddPCR instead of qPCR method in the context of viral diagnostics and surveillance. Full article
(This article belongs to the Section Molecular Microbiology)
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16 pages, 3821 KiB  
Article
Mutant K-Ras in Pancreatic Cancer: An Insight on the Role of Wild-Type N-Ras and K-Ras-Dependent Cell Cycle Regulation
by Robert Ferguson, Karen Aughton, Anthony Evans, Victoria Shaw, Jane Armstrong, Adam Ware, Laura Bennett, Eithne Costello and William Greenhalf
Curr. Issues Mol. Biol. 2023, 45(3), 2505-2520; https://doi.org/10.3390/cimb45030164 - 17 Mar 2023
Cited by 2 | Viewed by 1544
Abstract
The development of K-Ras independence may explain the failure of targeted therapy for pancreatic cancer (PC). In this paper, active N as well as K-Ras was shown in all human cell lines tested. In a cell line dependent on mutant K-Ras, it was [...] Read more.
The development of K-Ras independence may explain the failure of targeted therapy for pancreatic cancer (PC). In this paper, active N as well as K-Ras was shown in all human cell lines tested. In a cell line dependent on mutant K-Ras, it was shown that depleting K-Ras reduced total Ras activity, while cell lines described as independent had no significant decline in total Ras activity. The knockdown of N-Ras showed it had an important role in controlling the relative level of oxidative metabolism, but only K-Ras depletion caused a decrease in G2 cyclins. Proteasome inhibition reversed this, and other targets of APC/c were also decreased by K-Ras depletion. K-Ras depletion did not cause an increase in ubiquitinated G2 cyclins but instead caused exit from the G2 phase to slow relative to completion of the S-phase, suggesting that the mutant K-Ras may inhibit APC/c prior to anaphase and stabilise G2 cyclins independently of this. We propose that, during tumorigenesis, cancer cells expressing wild-type N-Ras protein are selected because the protein protects cancer cells from the deleterious effects of the cell cycle-independent induction of cyclins by mutant K-Ras. Mutation independence results when N-Ras activity becomes adequate to drive cell division, even in cells where K-Ras is inhibited. Full article
(This article belongs to the Special Issue New Sight: Molecular Research in Pancreatic Cancer)
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14 pages, 1978 KiB  
Article
Effects of Large Extracellular Vesicles from Kidney Cancer Patients on the Growth and Environment of Renal Cell Carcinoma Xenografts in a Mouse Model
by Matthieu Ferragu, Luisa Vergori, Vincent Le Corre, Sarah Bellal, Maria del Carmen Martinez and Pierre Bigot
Curr. Issues Mol. Biol. 2023, 45(3), 2491-2504; https://doi.org/10.3390/cimb45030163 - 17 Mar 2023
Viewed by 1598
Abstract
Plasma membrane-derived vesicles, also referred to as large extracellular vesicles (lEVs), are implicated in several pathophysiological situations, including cancer. However, to date, no studies have evaluated the effects of lEVs isolated from patients with renal cancer on the development of their tumors. In [...] Read more.
Plasma membrane-derived vesicles, also referred to as large extracellular vesicles (lEVs), are implicated in several pathophysiological situations, including cancer. However, to date, no studies have evaluated the effects of lEVs isolated from patients with renal cancer on the development of their tumors. In this study, we investigated the effects of three types of lEVs on the growth and peritumoral environment of xenograft clear cell renal cell carcinoma in a mouse model. Xenograft cancer cells were derived from patients’ nephrectomy specimens. Three types of lEVs were obtained from pre-nephrectomy patient blood (cEV), the supernatant of primary cancer cell culture (sEV) and from blood from individuals with no medical history of cancer (iEV). Xenograft volume was measured after nine weeks of growth. Xenografts were then removed, and the expression of CD31 and Ki67 were evaluated. We also measured the expression of MMP2 and Ca9 in the native mouse kidney. lEVs from kidney cancer patients (cEV and sEV) tend to increase the size of xenografts, a factor that is related to an increase in vascularization and tumor cell proliferation. cEV also altered organs that were distant from the xenograft. These results suggest that lEVs in cancer patients are involved in both tumor growth and cancer progression. Full article
(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer)
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17 pages, 5707 KiB  
Article
The In Vitro and In Vivo Anticancer Effect of Photomed for Photodynamic Therapy: Comparison with Photofrin and Radachlorin
by Jieun Kim, Johyun Kim, Heewon Yoon, Yoon-Jee Chae, Kiyon Rhew and Ji-Eun Chang
Curr. Issues Mol. Biol. 2023, 45(3), 2474-2490; https://doi.org/10.3390/cimb45030162 - 17 Mar 2023
Cited by 2 | Viewed by 1287
Abstract
To overcome the limitation of conventional cancer treatments, photodynamic therapy (PDT) has been introduced as another treatment option. PDT provides a non-invasive, non-surgical way with reduced toxicity. To improve the antitumor efficacy of PDT, we synthesized a novel photosensitizer, a 3-substituted methyl pyropheophorbide-a [...] Read more.
To overcome the limitation of conventional cancer treatments, photodynamic therapy (PDT) has been introduced as another treatment option. PDT provides a non-invasive, non-surgical way with reduced toxicity. To improve the antitumor efficacy of PDT, we synthesized a novel photosensitizer, a 3-substituted methyl pyropheophorbide-a derivative (Photomed). The purpose of the study was to evaluate the antitumor effect of PDT with Photomed comparing with the clinically approved photosensitizers Photofrin and Radachlorin. The cytotoxicity assay against SCC VII cells (murine squamous cell carcinoma) was performed to determine whether Photomed is safe without PDT and whether Photomed is effective against cancer cells with PDT. An in vivo anticancer efficacy study was also performed using SCC VII tumor-bearing mice. The mice were divided into small-tumor and large-tumor groups to identify whether Photomed-induced PDT is effective for not only small tumors but also large tumors. From in vitro and in vivo studies, Photomed was confirmed to be (1) a safe photosensitizer without laser irradiation, (2) the most effective photosensitizer with PDT against cancers compared to Photofrin and Radachlorin and (3) effective with PDT in treating not only small tumors but also large tumors. In conclusion, Photomed may contribute as a novel, potential photosensitizer for use in PDT cancer treatment. Full article
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13 pages, 789 KiB  
Review
Pesticidal Toxicity of Phosphine and Its Interaction with Other Pest Control Treatments
by Saad M. Alzahrani and Paul R. Ebert
Curr. Issues Mol. Biol. 2023, 45(3), 2461-2473; https://doi.org/10.3390/cimb45030161 - 17 Mar 2023
Cited by 4 | Viewed by 1750
Abstract
Phosphine is the most widely used fumigant for stored grains due to a lack of better alternatives, all of which have serious shortcomings that restrict their use. The extensive use of phosphine has led to the development of resistance among insect pests of [...] Read more.
Phosphine is the most widely used fumigant for stored grains due to a lack of better alternatives, all of which have serious shortcomings that restrict their use. The extensive use of phosphine has led to the development of resistance among insect pests of grain, which threatens its status as a reliable fumigant. Understanding the mode of action of phosphine as well as its resistance mechanisms provides insight that may lead to improved phosphine efficacy and pest control strategies. The mechanisms of action in phosphine vary from disrupting metabolism and oxidative stress to neurotoxicity. Phosphine resistance is genetically inherited and is mediated by the mitochondrial dihydrolipoamide dehydrogenase complex. In this regard, laboratory studies have revealed treatments that synergistically enhance phosphine toxicity that may be used to suppress resistance development and enhance efficacy. Here, we discuss the reported phosphine modes of action, mechanisms of resistance and interactions with other treatments. Full article
(This article belongs to the Collection Feature Papers in Current Issues in Molecular Biology)
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9 pages, 277 KiB  
Brief Report
Ubiquitin Is Not a Blood Biomarker of an Early Cognitive Decline in the Polish Elderly
by Oliwia McFarlane, Mariusz Kozakiewicz, Milena Wojciechowska and Kornelia Kędziora-Kornatowska
Curr. Issues Mol. Biol. 2023, 45(3), 2452-2460; https://doi.org/10.3390/cimb45030160 - 16 Mar 2023
Cited by 3 | Viewed by 891
Abstract
Together with development of new pharmaceutical interventions, as well as the introduction of the concept of initial dementia phase, the demand for early diagnosis has been growing. Research on potential blood biomarkers, amazingly attractive, mainly due to the facility of deriving the material, [...] Read more.
Together with development of new pharmaceutical interventions, as well as the introduction of the concept of initial dementia phase, the demand for early diagnosis has been growing. Research on potential blood biomarkers, amazingly attractive, mainly due to the facility of deriving the material, has provided ambiguous results throughout. The existence of an association between ubiquitin and Alzheimer’s disease pathology suggests that it could be a potential neurodegeneration biomarker. The present study aims to identify and assess the relationship between ubiquitin with regard to the adequacy as a biomarker of an initial dementia and cognitive decline in the elderly. Method: The study sample was composed of 230 participants: 109 women and 121 men aged 65 and older. The relationships of plasma ubiquitin levels with cognitive performance, gender, and age were analyzed. The assessments were performed in three groups of cognitive functioning level: cognitively normal, mild cognitive impairment, and mild dementia, of which the subjects were divided with the Mini-Mental State Examination (MMSE). Results: No significant disparities in plasma ubiquitin levels for various levels of cognitive functioning were identified. Significantly higher plasma ubiquitin levels in women were found in comparison to men. No significant differences were found in ubiquitin concentrations based on age. Results suggest that ubiquitin does not meet the requirements for qualification as a blood biomarker of an early cognitive decline. In order to thoroughly evaluate the potential of research on ubiquitin in connection to an early neurodegenerative process, further studies are needed. Full article
8 pages, 1474 KiB  
Communication
Immunohistochemical Analysis of Spermatogenesis in Patients with SARS-CoV-2 Invasion in Different Age Groups
by Grigory A. Demyashkin, Evgeniya Kogan, Tatiana Demura, Dmitry Boldyrev, Matvey Vadyukhin, Vladimir Schekin, Peter Shegay and Andrey Kaprin
Curr. Issues Mol. Biol. 2023, 45(3), 2444-2451; https://doi.org/10.3390/cimb45030159 - 16 Mar 2023
Cited by 1 | Viewed by 2264
Abstract
Based on studies that focused on the effect of SARS-CoV-2 on human tissues, not only pulmonary invasion was revealed, but also impaired testicular function. Thus, the study of the mechanisms of influence of SARS-CoV-2 on spermatogenesis is still relevant. Of particular interest is [...] Read more.
Based on studies that focused on the effect of SARS-CoV-2 on human tissues, not only pulmonary invasion was revealed, but also impaired testicular function. Thus, the study of the mechanisms of influence of SARS-CoV-2 on spermatogenesis is still relevant. Of particular interest is the study of pathomorphological changes in men of different age groups. The purpose of this study was to evaluate immunohistochemical changes in spermatogenesis during SARS-CoV-2 invasion in different age groups. In our study, for the first time, a cohort of COVID-19-positive patients of different age groups was collected, and the following were conducted––confocal microscopy of the testicles and immunohistochemical evaluation of spermatogenesis disorders in SARS-CoV-2 invasion with antibodies to the spike protein, the nucleocapsid protein of the SARS-CoV-2 virus, and angiotensin convertase type 2. An IHC study and confocal microscopy of testicular autopsies from COVID-19-positive patients revealed an increase in the number of S-protein- and nucleocapsid-positively stained spermatogenic cells, which indicates SARS-CoV-2 invasion into them. A correlation was found between the number of ACE2-positive germ cells and the degree of hypospermatogenesis, and in the group of patients with confirmed coronavirus infection older than 45 years, the decrease in spermatogenic function was more pronounced than in the cohort of young people. Thus, our study found a decrease in both spermatogenic and endocrine (Leydig cells) testicular functions in patients with COVID-19 infection. In the elderly, these changes were significantly higher than in the group of young patients. Full article
(This article belongs to the Section Molecular Medicine)
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13 pages, 17664 KiB  
Article
Increased Yield of Extracellular Vesicles after Cytochalasin B Treatment and Vortexing
by Sirina V. Kurbangaleeva, Valeriia Y. Syromiatnikova, Angelina E. Prokopeva, Aleksey M. Rogov, Artur A. Khannanov, Albert A. Rizvanov and Marina O. Gomzikova
Curr. Issues Mol. Biol. 2023, 45(3), 2431-2443; https://doi.org/10.3390/cimb45030158 - 15 Mar 2023
Cited by 3 | Viewed by 1524
Abstract
Extracellular vesicles (EVs) are promising therapeutic instruments and vectors for therapeutics delivery. In order to increase the yield of EVs, a method of inducing EVs release using cytochalasin B is being actively developed. In this work, we compared the yield of naturally occurring [...] Read more.
Extracellular vesicles (EVs) are promising therapeutic instruments and vectors for therapeutics delivery. In order to increase the yield of EVs, a method of inducing EVs release using cytochalasin B is being actively developed. In this work, we compared the yield of naturally occurring extracellular vesicles and cytochalasin B-induced membrane vesicles (CIMVs) from mesenchymal stem cells (MSCs). In order to maintain accuracy in the comparative analysis, the same culture was used for the isolation of EVs and CIMVs: conditioned medium was used for EVs isolation and cells were harvested for CIMVs production. The pellets obtained after centrifugation 2300× g, 10,000× g and 100,000× g were analyzed using scanning electron microscopy analysis (SEM), flow cytometry, the bicinchoninic acid assay, dynamic light scattering (DLS), and nanoparticle tracking analysis (NTA). We found that the use of cytochalasin B treatment and vortexing resulted in the production of a more homogeneous population of membrane vesicles with a median diameter greater than that of EVs. We found that EVs-like particles remained in the FBS, despite overnight ultracentrifugation, which introduced a significant inaccuracy in the calculation of the EVs yield. Therefore, we cultivated cells in a serum-free medium for the subsequent isolation of EVs. We observed that the number of CIMVs significantly exceeded the number of EVs after each step of centrifugation (2300× g, 10,000× g and 100,000× g) by up to 5, 9, and 20 times, respectively. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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9 pages, 1236 KiB  
Case Report
A Novel Nonsense Pathogenic TTN Variant Identified in a Patient with Severe Dilated Cardiomyopathy
by Caterina Micolonghi, Marco Fabiani, Erika Pagannone, Camilla Savio, Marta Ricci, Silvia Caroselli, Vittoria Gambioli, Beatrice Musumeci, Aldo Germani, Giacomo Tini, Camillo Autore, Antonio Pizzuti, Vincenzo Visco, Speranza Rubattu, Simona Petrucci and Maria Piane
Curr. Issues Mol. Biol. 2023, 45(3), 2422-2430; https://doi.org/10.3390/cimb45030157 - 15 Mar 2023
Viewed by 1367
Abstract
Both genetic and environmental factors contribute to the development of dilated cardiomyopathy. Among the genes involved, TTN mutations, including truncated variants, explain 25% of DCM cases. We performed genetic counseling and analysis on a 57-year-old woman diagnosed with severe DCM and presenting relevant [...] Read more.
Both genetic and environmental factors contribute to the development of dilated cardiomyopathy. Among the genes involved, TTN mutations, including truncated variants, explain 25% of DCM cases. We performed genetic counseling and analysis on a 57-year-old woman diagnosed with severe DCM and presenting relevant acquired risk factors for DCM (hypertension, diabetes, smoking habit, and/or previous alcohol and cocaine abuse) and with a family history of both DCM and sudden cardiac death. The left ventricular systolic function, as assessed by standard echocardiography, was 20%. The genetic analysis performed using TruSight Cardio panel, including 174 genes related to cardiac genetic diseases, revealed a novel nonsense TTN variant (TTN:c.103591A > T, p.Lys34531*), falling within the M-band region of the titin protein. This region is known for its important role in maintaining the structure of the sarcomere and in promoting sarcomerogenesis. The identified variant was classified as likely pathogenic based on ACMG criteria. The current results support the need of genetic analysis in the presence of a family history, even when relevant acquired risk factors for DCM may have contributed to the severity of the disease. Full article
(This article belongs to the Special Issue Focus on Molecular Basis of Cardiac Diseases)
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13 pages, 3196 KiB  
Article
Evaluation of Some Benzo[g]Quinazoline Derivatives as Antiviral Agents against Human Rotavirus Wa Strain: Biological Screening and Docking Study
by Hatem A. Abuelizz, Ahmed H. Bakheit, Mohamed Marzouk, Waled M. El-Senousy, Mohamed M. Abdellatif, Gamal A. E. Mostafa and Rashad Al-Salahi
Curr. Issues Mol. Biol. 2023, 45(3), 2409-2421; https://doi.org/10.3390/cimb45030156 - 14 Mar 2023
Cited by 2 | Viewed by 1838
Abstract
Globally, rotavirus (RV) is the most common cause of acute gastroenteritis in infants and toddlers; however, there are currently no agents available that are tailored to treat rotavirus infection in particular. Improved and widespread immunization programs are being implemented worldwide to reduce rotavirus [...] Read more.
Globally, rotavirus (RV) is the most common cause of acute gastroenteritis in infants and toddlers; however, there are currently no agents available that are tailored to treat rotavirus infection in particular. Improved and widespread immunization programs are being implemented worldwide to reduce rotavirus morbidity and mortality. Despite certain immunizations, there are no licensed antivirals that can attack rotavirus in hosts. Benzoquinazolines, chemical components synthesized in our laboratory, were developed as antiviral agents, and showed good activity against herpes simplex, coxsackievirus B4 and hepatitis A and C. In this research project, an in vitro investigation of the effectiveness of benzoquinazoline derivatives 116 against human rotavirus Wa strains was carried out. All compounds exhibited antiviral activity, however compounds 13, 9 and 16 showed the greatest activity (reduction percentages ranged from 50 to 66%). In-silico molecular docking of highly active compounds, which were selected after studying the biological activity of all investigated of benzo[g]quinazolines compounds, was implemented into the protein’s putative binding site to establish an optimal orientation for binding. As a result, compounds 1, 3, 9, and 16 are promising anti-rotavirus Wa strains that lead with Outer Capsid protein VP4 inhibition. Full article
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16 pages, 6632 KiB  
Article
The Potential Inhibitory Role of Acetyl-L-Carnitine on Proliferation, Migration, and Gene Expression in HepG2 and HT29 Human Adenocarcinoma Cell Lines
by Sarah Albogami
Curr. Issues Mol. Biol. 2023, 45(3), 2393-2408; https://doi.org/10.3390/cimb45030155 - 14 Mar 2023
Cited by 2 | Viewed by 2051
Abstract
Malignancies of the liver and colon are the most prevalent forms of digestive system cancer globally. Chemotherapy, one of the most significant treatments, has severe side effects. Chemoprevention using natural or synthetic medications can potentially reduce cancer severity. Acetyl-L-carnitine (ALC) is an acetylated [...] Read more.
Malignancies of the liver and colon are the most prevalent forms of digestive system cancer globally. Chemotherapy, one of the most significant treatments, has severe side effects. Chemoprevention using natural or synthetic medications can potentially reduce cancer severity. Acetyl-L-carnitine (ALC) is an acetylated derivative of carnitine essential for intermediate metabolism in most tissues. This study aimed to investigate the effects of ALC on the proliferation, migration, and gene expression of human liver (HepG2) and colorectal (HT29) adenocarcinoma cell lines. The cell viability and half maximal inhibitory concentration of both cancer cell lines were determined using the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Wound healing after treatment was assessed using a migration assay. Morphological changes were imaged using brightfield and fluorescence microscopy. Post treatment, apoptotic DNA was detected using a DNA fragmentation assay. The relative mRNA expressions of matrix metallopeptidase 9 (MMP9) and vascular endothelial growth factor (VEGF) were evaluated using RT-PCR. The results showed that ALC treatment affects the wound-healing ability of HepG2 and HT29 cell lines. Changes in nuclear morphology were detected under fluorescent microscopy. ALC also downregulates the expression levels of MMP9 and VEGF in HepG2 and HT29 cell lines. Our results indicate that the anticancer action of ALC is likely mediated by a decrease in adhesion, migration, and invasion. Full article
(This article belongs to the Special Issue Adhesion, Metastasis and Inhibition of Cancer Cells)
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12 pages, 4031 KiB  
Article
A Feedback Loop between TGF-β1 and ATG5 Mediated by miR-122-5p Regulates Fibrosis and EMT in Human Trabecular Meshwork Cells
by Munmun Chakraborthy and Aparna Rao
Curr. Issues Mol. Biol. 2023, 45(3), 2381-2392; https://doi.org/10.3390/cimb45030154 - 13 Mar 2023
Viewed by 1234
Abstract
Autophagy is a cell’s evolutionary conserved process for degrading and recycling cellular proteins and removing damaged organelles. There has been an increasing interest in identifying the basic cellular mechanism of autophagy and its implications in health and illness during the last decade. Many [...] Read more.
Autophagy is a cell’s evolutionary conserved process for degrading and recycling cellular proteins and removing damaged organelles. There has been an increasing interest in identifying the basic cellular mechanism of autophagy and its implications in health and illness during the last decade. Many proteinopathies such as Alzheimer’s and Huntington’s disease are reported to be associated with impaired autophagy. The functional significance of autophagy in exfoliation syndrome/exfoliation glaucoma (XFS/XFG), remains unknown though it is presumed to be impaired autophagy to be responsible for the aggregopathy characteristic of this disease. In the current study we have shown that autophagy or ATG5 is enhanced in response to TGF-β1 in human trabecular meshwork (HTM) cells and TGF-β1 induced autophagy is necessary for increased expression of profibrotic proteins and epithelial to mesenchymal (EMT) through Smad3 that lead to aggregopathy. Inhibition of ATG5 by siRNA mediated knockdown reduced profibrotic and EMT markers and increased protein aggregates in the presence of TGF-β1 stimulation. The miR-122-5p, which was increased upon TGF exposure, was also reduced upon ATG5 inhibition. We thus conclude that TGF-β1 induces autophagy in primary HTM cells and a positive feedback loop exists between TGF-β1 and ATG5 that regulated TGF downstream effects mainly mediated by Smad3 signaling with miR-122-5p also playing a role. Full article
(This article belongs to the Collection Feature Papers in Current Issues in Molecular Biology)
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9 pages, 2186 KiB  
Article
Early Fruit Development Regulation-Related Genes Concordantly Expressed with TCP Transcription Factors in Tomato (Solanum lycopersicum)
by Sherif Edris, Aala A. Abulfaraj, Rania M. Makki, Salah Abo-Aba, Mardi M. Algandaby, Jamal Sabir, Robert K. Jansen, Fotouh M. El Domyati and Ahmed Bahieldin
Curr. Issues Mol. Biol. 2023, 45(3), 2372-2380; https://doi.org/10.3390/cimb45030153 - 13 Mar 2023
Viewed by 1430
Abstract
The tomato (Solanum lycopersicum L.) is considered one of the most important vegetable crops globally, both agronomically and economically; however, its fruit development regulation network is still unclear. The transcription factors serve as master regulators, activating many genes and/or metabolic pathways throughout [...] Read more.
The tomato (Solanum lycopersicum L.) is considered one of the most important vegetable crops globally, both agronomically and economically; however, its fruit development regulation network is still unclear. The transcription factors serve as master regulators, activating many genes and/or metabolic pathways throughout the entire plant life cycle. In this study, we identified the transcription factors that are coordinated with TCP gene family regulation in early fruit development by making use of the high-throughput sequencing of RNA (RNAseq) technique. A total of 23 TCP-encoding genes were found to be regulated at various stages during the growth of the fruit. The expression patterns of five TCPs were consistent with those of other transcription factors and genes. There are two unique subgroups of this larger family: class I and class II TCPs. Others were directly associated with the growth and/or ripening of fruit, while others were involved in the production of the hormone auxin. Moreover, it was discovered that TCP18 had an expression pattern that was similar to that of the ethylene-responsive transcription factor 4 (ERF4). Tomato fruit set and overall development are under the direction of a gene called auxin response factor 5 (ARF5). TCP15 revealed an expression that was in sync with this gene. This study provides insight into the potential processes that help in acquiring superior fruit qualities by accelerating fruit growth and ripening. Full article
(This article belongs to the Special Issue Functional Genomics and Comparative Genomics Analysis in Plants)
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21 pages, 1548 KiB  
Review
Natural Products for the Treatment of Pulmonary Hypertension: Mechanism, Progress, and Future Opportunities
by Zuomei Zeng, Xinyue Wang, Lidan Cui, Hongjuan Wang, Jian Guo and Yucai Chen
Curr. Issues Mol. Biol. 2023, 45(3), 2351-2371; https://doi.org/10.3390/cimb45030152 - 13 Mar 2023
Cited by 1 | Viewed by 2623
Abstract
Pulmonary hypertension (PH) is a lethal disease due to the remodeling of pulmonary vessels. Its pathophysiological characteristics include increased pulmonary arterial pressure and pulmonary vascular resistance, leading to right heart failure and death. The pathological mechanism of PH is complex and includes inflammation, [...] Read more.
Pulmonary hypertension (PH) is a lethal disease due to the remodeling of pulmonary vessels. Its pathophysiological characteristics include increased pulmonary arterial pressure and pulmonary vascular resistance, leading to right heart failure and death. The pathological mechanism of PH is complex and includes inflammation, oxidative stress, vasoconstriction/diastolic imbalance, genetic factors, and ion channel abnormalities. Currently, many clinical drugs for the treatment of PH mainly play their role by relaxing pulmonary arteries, and the treatment effect is limited. Recent studies have shown that various natural products have unique therapeutic advantages for PH with complex pathological mechanisms owing to their multitarget characteristics and low toxicity. This review summarizes the main natural products and their pharmacological mechanisms in PH treatment to provide a useful reference for future research and development of new anti-PH drugs and their mechanisms. Full article
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13 pages, 1629 KiB  
Article
Transcriptomic Establishment of Pig Macrophage Polarization Signatures
by Jing Li, Teng Yuan, Anjing Zhang, Peidong Yang, Li He, Keren Long, Chuang Tang, Li Chen, Mingzhou Li and Lu Lu
Curr. Issues Mol. Biol. 2023, 45(3), 2338-2350; https://doi.org/10.3390/cimb45030151 - 12 Mar 2023
Viewed by 2127
Abstract
Macrophages are the foremost controllers of innate and acquired immunity, playing important roles in tissue homeostasis, vasculogenesis, and congenital metabolism. In vitro macrophages are crucial models for understanding the regulatory mechanism of immune responses and the diagnosis or treatment of a variety of [...] Read more.
Macrophages are the foremost controllers of innate and acquired immunity, playing important roles in tissue homeostasis, vasculogenesis, and congenital metabolism. In vitro macrophages are crucial models for understanding the regulatory mechanism of immune responses and the diagnosis or treatment of a variety of diseases. Pigs are the most important agricultural animals and valuable animal models for preclinical studies, but there is no unified method for porcine macrophage isolation and differentiation at present; no systematic study has compared porcine macrophages obtained by different methods. In the current study, we obtained two M1 macrophages (M1_IFNγ + LPS, and M1_GM-CSF) and two M2 macrophages (M2_IL4 + IL10, and M2_M-CSF), and compared the transcriptomic profiles between and within macrophage phenotypes. We observed the transcriptional differences either between or within phenotypes. Porcine M1 and M2 macrophages have consistent gene signatures with human and mouse macrophage phenotypes, respectively. Moreover, we performed GSEA analysis to attribute the prognostic value of our macrophage signatures in discriminating various pathogen infections. Our study provided a framework to guide the interrogation of macrophage phenotypes in the context of health and disease. The approach described here could be used to propose new biomarkers for diagnosis in diverse clinical settings including porcine reproductive and respiratory syndrome virus (PRRSV), African swine fever virus (ASFV), Toxoplasma gondii (T. gondii), porcine circovirus type 2 (PCV2), Haemophilus parasuis serovar 4 (HPS4), Mycoplasma hyopneumoniae (Mhp), Streptococcus suis serotype 2 (SS2), and LPS from Salmonella enterica serotype minnesota Re 595. Full article
(This article belongs to the Topic Animal Models of Human Disease)
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12 pages, 1759 KiB  
Article
Effect of Atorvastatin on Angiogenesis-Related Genes VEGF-A, HGF and IGF-1 and the Modulation of PI3K/AKT/mTOR Transcripts in Bone-Marrow-Derived Mesenchymal Stem Cells
by Adriana Adamičková, Nikola Chomaničová, Andrea Gažová, Juraj Maďarič, Zdenko Červenák, Simona Valášková, Matúš Adamička and Jan Kyselovic
Curr. Issues Mol. Biol. 2023, 45(3), 2326-2337; https://doi.org/10.3390/cimb45030150 - 10 Mar 2023
Cited by 2 | Viewed by 1311
Abstract
Stem cell transplantation represents a unique therapeutic tool in tissue engineering and regenerative medicine. However, it was shown that the post-injection survival of stem cells is poor, warranting a more comprehensive understanding of activated regenerative pathways. Numerous studies indicate that statins improve the [...] Read more.
Stem cell transplantation represents a unique therapeutic tool in tissue engineering and regenerative medicine. However, it was shown that the post-injection survival of stem cells is poor, warranting a more comprehensive understanding of activated regenerative pathways. Numerous studies indicate that statins improve the therapeutic efficacy of stem cells in regenerative medicine. In the present study, we investigated the effect of the most widely prescribed statin, atorvastatin, on the characteristics and properties of bone-marrow-derived mesenchymal stem cells (BM-MSCs) cultured in vitro. We found that atorvastatin did not decrease the viability of BM-MSCs, nor did it change the expression of MSC cell surface markers. Atorvastatin upregulated the mRNA expression levels of VEGF-A and HGF, whereas the mRNA expression level of IGF-1 was decreased. In addition, the PI3K/AKT signaling pathway was modulated by atorvastatin as indicated by the high mRNA expression levels of PI3K and AKT. Moreover, our data revealed the upregulation of mTOR mRNA levels; however, no change was observed in the BAX and BCL-2 transcripts. We propose that atorvastatin benefits BM-MSC treatment due to its ability to upregulate angiogenesis-related genes expression and transcripts of the PI3K/AKT/mTOR pathway. Full article
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17 pages, 3838 KiB  
Article
Change in Long Non-Coding RNA Expression Profile Related to the Antagonistic Effect of Clostridium perfringens Type C on Piglet Spleen
by Zunqiang Yan, Pengfei Wang, Qiaoli Yang, Xiaoli Gao, Shuangbao Gun and Xiaoyu Huang
Curr. Issues Mol. Biol. 2023, 45(3), 2309-2325; https://doi.org/10.3390/cimb45030149 - 09 Mar 2023
Cited by 1 | Viewed by 1172
Abstract
LncRNAs play important roles in resisting bacterial infection via host immune and inflammation responses. Clostridium perfringens (C. perfringens) type C is one of the main bacteria causing piglet diarrhea diseases, leading to major economic losses in the pig industry worldwide. In [...] Read more.
LncRNAs play important roles in resisting bacterial infection via host immune and inflammation responses. Clostridium perfringens (C. perfringens) type C is one of the main bacteria causing piglet diarrhea diseases, leading to major economic losses in the pig industry worldwide. In our previous studies, piglets resistant (SR) and susceptible (SS) to C. perfringens type C were identified based on differences in host immune capacity and total diarrhea scores. In this paper, the RNA-Seq data of the spleen were comprehensively reanalyzed to investigate antagonistic lncRNAs. Thus, 14 lncRNAs and 89 mRNAs were differentially expressed (DE) between the SR and SS groups compared to the control (SC) group. GO term enrichment, KEGG pathway enrichment and lncRNA-mRNA interactions were analyzed to identify four key lncRNA targeted genes via MAPK and NF-κB pathways to regulate cytokine genes (such as TNF-α and IL-6) against C. perfringens type C infection. The RT-qPCR results for six selected DE lncRNAs and mRNAs are consistent with the RNA-Seq data. This study analyzed the expression profiling of lncRNAs in the spleen of antagonistic and sensitive piglets and found four key lncRNAs against C. perfringens type C infection. The identification of antagonistic lncRNAs can facilitate investigations into the molecular mechanisms underlying resistance to diarrhea in piglets. Full article
(This article belongs to the Special Issue Studying the Function of RNAs Using Omics Approaches)
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13 pages, 3255 KiB  
Article
The Insulin Receptor Substrate 2 Mediates the Action of Insulin on HeLa Cell Migration via the PI3K/Akt Signaling Pathway
by Anabel Martínez Báez, Ivone Castro Romero, Lilia Chihu Amparan, Jose Ramos Castañeda and Guadalupe Ayala
Curr. Issues Mol. Biol. 2023, 45(3), 2296-2308; https://doi.org/10.3390/cimb45030148 - 09 Mar 2023
Cited by 2 | Viewed by 1455
Abstract
Insulin signaling plays an important role in the development and progression of cancer since it is involved in proliferation and migration processes. It has been shown that the A isoform of the insulin receptor (IR-A) is often overexpressed, and its stimulation induces changes [...] Read more.
Insulin signaling plays an important role in the development and progression of cancer since it is involved in proliferation and migration processes. It has been shown that the A isoform of the insulin receptor (IR-A) is often overexpressed, and its stimulation induces changes in the expression of the insulin receptor substrates (IRS-1 and IRS-2), which are expressed differently in the different types of cancer. We study the participation of the insulin substrates IRS-1 and IRS-2 in the insulin signaling pathway in response to insulin and their involvement in the proliferation and migration of the cervical cancer cell line. Our results showed that under basal conditions, the IR-A isoform was predominantly expressed. Stimulation of HeLa cells with 50 nM insulin led to the phosphorylation of IR-A, showing a statistically significant increase at 30 min (p ≤ 0.05). Stimulation of HeLa cells with insulin induces PI3K and AKT phosphorylation through the activation of IRS2, but not IRS1. While PI3K reached the highest level at 30 min after treatment (p ≤ 0.05), AKT had the highest levels from 15 min (p ≤ 0.05) and remained constant for 6 h. ERK1 and ERK2 expression was also observed, but only ERK2 was phosphorylated in a time-dependent manner, reaching a maximum peak 5 min after insulin stimulation. Although no effect on cell proliferation was observed, insulin stimulation of HeLa cells markedly promoted cell migration. Full article
(This article belongs to the Special Issue Adhesion, Metastasis and Inhibition of Cancer Cells)
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12 pages, 2905 KiB  
Article
Abietane Diterpenoids Isolated from Torreya nucifera Disrupt Replication of Influenza Virus by Blocking the Phosphatidylinositol-3-Kinase (PI3K)-Akt and ERK Signaling Pathway
by Jaehoon Bae, Hyung-Jun Kwon, Ji Sun Park, Jinseok Jung, Young Bae Ryu, Woo Sik Kim, Ju Huck Lee, Jae-Ho Jeong, Jae Sung Lim, Woo Song Lee and Su-Jin Park
Curr. Issues Mol. Biol. 2023, 45(3), 2284-2295; https://doi.org/10.3390/cimb45030147 - 09 Mar 2023
Cited by 2 | Viewed by 1523
Abstract
Although vaccines and antiviral drugs are available, influenza viruses continue to pose a significant threat to vulnerable populations globally. With the emergence of drug-resistant strains, there is a growing need for novel antiviral therapeutic approaches. We found that 18-hydroxyferruginol (1) and [...] Read more.
Although vaccines and antiviral drugs are available, influenza viruses continue to pose a significant threat to vulnerable populations globally. With the emergence of drug-resistant strains, there is a growing need for novel antiviral therapeutic approaches. We found that 18-hydroxyferruginol (1) and 18-oxoferruginol (2) isolated from Torreya nucifera exhibited strong anti-influenza activity, with 50% inhibitory concentration values of 13.6 and 18.3 μM against H1N1, 12.8 and 10.8 μM against H9N2, and 29.2 μM (only compound 2) against H3N2 in the post-treatment assay, respectively. During the viral replication stages, the two compounds demonstrated stronger inhibition of viral RNA and protein in the late stages (12–18 h) than in the early stages (3–6 h). Moreover, both compounds inhibited PI3K-Akt signaling, which participates in viral replication during the later stages of infection. The ERK signaling pathway is also related to viral replication and was substantially inhibited by the two compounds. In particular, the inhibition of PI3K-Akt signaling by these compounds inhibited viral replication by sabotaging influenza ribonucleoprotein nucleus-to-cytoplasm export. These data indicate that compounds 1 and 2 could potentially reduce viral RNA and viral protein levels by inhibiting the PI3K-Akt signaling pathway. Our results suggest that abietane diterpenoids isolated from T. nucifera may be potent antiviral candidates for new influenza therapies. Full article
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18 pages, 1142 KiB  
Review
NOTCH Signaling in Osteosarcoma
by Zhenhao Zhang, Wei Wu and Zengwu Shao
Curr. Issues Mol. Biol. 2023, 45(3), 2266-2283; https://doi.org/10.3390/cimb45030146 - 08 Mar 2023
Cited by 5 | Viewed by 1825
Abstract
The combination of neoadjuvant chemotherapy and surgery has been promoted for the treatment of osteosarcoma; however, the local recurrence and lung metastasis rates remain high. Therefore, it is crucial to explore new therapeutic targets and strategies that are more effective. The NOTCH pathway [...] Read more.
The combination of neoadjuvant chemotherapy and surgery has been promoted for the treatment of osteosarcoma; however, the local recurrence and lung metastasis rates remain high. Therefore, it is crucial to explore new therapeutic targets and strategies that are more effective. The NOTCH pathway is not only involved in normal embryonic development but also plays an important role in the development of cancers. The expression level and signaling functional status of the NOTCH pathway vary in different histological types of cancer as well as in the same type of cancer from different patients, reflecting the distinct roles of the Notch pathway in tumorigenesis. Studies have reported abnormal activation of the NOTCH signaling pathway in most clinical specimens of osteosarcoma, which is closely related to a poor prognosis. Similarly, studies have reported that NOTCH signaling affected the biological behavior of osteosarcoma through various molecular mechanisms. NOTCH-targeted therapy has shown potential for the treatment of osteosarcoma in clinical research. After the introduction of the composition and biological functions of the NOTCH signaling pathway, the review paper discussed the clinical significance of dysfunction in osteosarcoma. Then the paper reviewed the recent relevant research progress made both in the cell lines and in the animal models of osteosarcoma. Finally, the paper explored the potential of the clinical application of NOTCH-targeted therapy for the treatment of osteosarcoma. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy)
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18 pages, 2663 KiB  
Article
Identification of a miRNA Panel with a Potential Determinant Role in Patients Suffering from Periodontitis
by Oana Baru, Lajos Raduly, Cecilia Bica, Paul Chiroi, Liviuta Budisan, Nikolay Mehterov, Cristina Ciocan, Laura Ancuta Pop, Smaranda Buduru, Cornelia Braicu, Mandra Badea and Ioana Berindan-Neagoe
Curr. Issues Mol. Biol. 2023, 45(3), 2248-2265; https://doi.org/10.3390/cimb45030145 - 08 Mar 2023
Cited by 1 | Viewed by 1231
Abstract
In recent years, the role of microRNA (miRNA) in post-transcriptional gene regulation has advanced and supports strong evidence related to their important role in the regulation of a wide range of fundamental biological processes. Our study focuses on identifying specific alterations of miRNA [...] Read more.
In recent years, the role of microRNA (miRNA) in post-transcriptional gene regulation has advanced and supports strong evidence related to their important role in the regulation of a wide range of fundamental biological processes. Our study focuses on identifying specific alterations of miRNA patterns in periodontitis compared with healthy subjects. In the present study, we mapped the major miRNAs altered in patients with periodontitis (n = 3) compared with healthy subjects (n = 5), using microarray technology followed by a validation step by qRT-PCR and Ingenuity Pathways Analysis. Compared to healthy subjects, 159 differentially expressed miRNAs were identified among periodontitis patients, of which 89 were downregulated, and 70 were upregulated, considering a fold change of ±1.5 as the cut-off value and p ≤ 0.05. Key angiogenic miRNAs (miR-191-3p, miR-221-3p, miR-224-5p, miR-1228-3p) were further validated on a separate cohort of patients with periodontitis versus healthy controls by qRT-PCR, confirming the microarray data. Our findings indicate a periodontitis-specific miRNA expression pattern representing an essential issue for testing new potential diagnostic or prognostic biomarkers for periodontal disease. The identified miRNA profile in periodontal gingival tissue was linked to angiogenesis, with an important molecular mechanism that orchestrates cell fate. Full article
(This article belongs to the Special Issue Studying the Function of RNAs Using Omics Approaches)
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18 pages, 6770 KiB  
Article
Terpene-Containing Analogues of Glitazars as Potential Therapeutic Agents for Metabolic Syndrome
by Mikhail E. Blokhin, Sergey O. Kuranov, Mikhail V. Khvostov, Vladislav V. Fomenko, Olga A. Luzina, Natalia A. Zhukova, Cham Elhajjar, Tatiana G. Tolstikova and Nariman F. Salakhutdinov
Curr. Issues Mol. Biol. 2023, 45(3), 2230-2247; https://doi.org/10.3390/cimb45030144 - 08 Mar 2023
Cited by 1 | Viewed by 1226
Abstract
Metabolic syndrome is a complex of abnormalities involving impaired glucose and lipid metabolism, which needs effective pharmacotherapy. One way to reduce lipid and glucose levels associated with this pathology is the simultaneous activation of nuclear PPAR-alpha and gamma. For this purpose, we synthesized [...] Read more.
Metabolic syndrome is a complex of abnormalities involving impaired glucose and lipid metabolism, which needs effective pharmacotherapy. One way to reduce lipid and glucose levels associated with this pathology is the simultaneous activation of nuclear PPAR-alpha and gamma. For this purpose, we synthesized a number of potential agonists based on the pharmacophore fragment of glitazars with the inclusion of mono- or diterpenic moiety in the molecular structure. The study of their pharmacological activity in mice with obesity and type 2 diabetes mellitus (C57Bl/6Ay) revealed one substance that was capable of reducing the triglyceride levels in the liver and adipose tissue of mice by enhancing their catabolism and expressing a hypoglycemic effect connected with the sensitization of mice tissue to insulin. It has also been shown to have no toxic effects on the liver. Full article
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17 pages, 678 KiB  
Article
Whole-Genome Analysis of Antimicrobial-Resistant Salmonella enterica Isolated from Duck Carcasses in Hanoi, Vietnam
by Trung Thanh Nguyen, Hoa Vinh Le, Ha Vu Thi Hai, Thanh Nguyen Tuan, Huong Minh Nguyen, Da Pham Xuan, Huyen Tran Thi Thanh and Hao Hong Le Thi
Curr. Issues Mol. Biol. 2023, 45(3), 2213-2229; https://doi.org/10.3390/cimb45030143 - 08 Mar 2023
Cited by 1 | Viewed by 1697
Abstract
Salmonella enterica is one of the most dangerous foodborne pathogens listed by the World Health Organization. In this study, whole-duck samples were collected at wet markets in five districts in Hanoi, Vietnam, in October 2019 to assess their Salmonella infection rates and evaluate [...] Read more.
Salmonella enterica is one of the most dangerous foodborne pathogens listed by the World Health Organization. In this study, whole-duck samples were collected at wet markets in five districts in Hanoi, Vietnam, in October 2019 to assess their Salmonella infection rates and evaluate the susceptibility of the isolated strains to antibiotics currently used in the prophylaxis and treatment of Salmonella infection. Based on the antibiotic resistance profiles, eight multidrug resistance strains were whole-genome-sequenced, and their antibiotic resistance genes, genotypes, multi-locus sequence-based typing (MLST), virulence factors, and plasmids were analyzed. The results of the antibiotic susceptibility test indicate that phenotypic resistance to tetracycline and cefazolin was the most common (82.4%, 28/34 samples). However, all isolates were susceptible to cefoxitin and meropenem. Among the eight sequenced strains, we identified 43 genes associated with resistance to multiple classes of antibiotics such as aminoglycoside, beta-lactam, chloramphenicol, lincosamide, quinolone, and tetracycline. Notably, all strains carried the blaCTX-M-55 gene, which confers resistance to third-generation antibiotics including cefotaxime, cefoperazone, ceftizoxime, and ceftazidime, as well as resistance genes of other broad-spectrum antibiotics used in clinical treatment such as gentamicin, tetracycline, chloramphenicol, and ampicillin. Forty-three different antibiotic resistance genes were predicted to be present in the isolated Salmonella strains’ genomes. In addition, three plasmids were predicted in two strains, 43_S11 and 60_S17. The sequenced genomes also indicated that all strains carried SPI-1, SPI-2, and SPI-3. These SPIs are composed of antimicrobial resistance gene clusters and thus represent a potential threat to public health management. Taken together, this study highlights the extent of multidrug-resistant Salmonella contamination in duck meat in Vietnam. Full article
(This article belongs to the Section Molecular Microbiology)
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