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Int. J. Mol. Sci., Volume 25, Issue 22 (November-2 2024) – 627 articles

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19 pages, 3618 KiB  
Review
Combating Tuberculosis via Restoring the Host Immune Capacity by Targeting M. tb Kinases and Phosphatases
by Shahinda S. R. Alsayed and Hendra Gunosewoyo
Int. J. Mol. Sci. 2024, 25(22), 12481; https://doi.org/10.3390/ijms252212481 - 20 Nov 2024
Viewed by 429
Abstract
Mycobacterium tuberculosis (M. tb) is a remarkably versatile pathogen that possesses a unique ability to counteract the host’s defence mechanisms to control the infection. Several mycobacterial protein kinases and phosphatases were found to play a key role in impeding phagosome maturation [...] Read more.
Mycobacterium tuberculosis (M. tb) is a remarkably versatile pathogen that possesses a unique ability to counteract the host’s defence mechanisms to control the infection. Several mycobacterial protein kinases and phosphatases were found to play a key role in impeding phagosome maturation in macrophages and accordingly blocking the phagosome–lysosome fusion, therefore allowing the bacteria to survive. During phagocytosis, both M. tb and the host’s phagocytic cells develop mechanisms to fight each other, resulting in pathogen elimination or survival. In this respect, M. tb uses a phosphorylation-based signal transduction mechanism, whereby it senses extracellular signals from the host and initiates the appropriate adaptation responses. Indeed, the ability of M. tb to exist in different states in the host (persistent quiescent state or actively replicating mode) is mainly mediated through protein phosphorylation/dephosphorylation signalling. The M. tb regulatory and defensive responses coordinate different aspects of the bacilli’s physiology, for instance, cell wall components, metabolic activity, virulence, and growth. Herein, we will discuss the implication of M. tb kinases and phosphatases in hijacking the host immune system, perpetuating the infection. In addition, the role of PknG, MPtpA, MPtpB, and SapM inhibitors in resetting the host immune system will be highlighted. Full article
(This article belongs to the Section Molecular Immunology)
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19 pages, 1623 KiB  
Article
Effect of Pre-Sowing Seed Stimulation on Maize Seedling Vigour
by Paulina Pipiak, Katarzyna Sieczyńska, Dorota Gendaszewska and Monika Skwarek-Fadecka
Int. J. Mol. Sci. 2024, 25(22), 12480; https://doi.org/10.3390/ijms252212480 - 20 Nov 2024
Viewed by 229
Abstract
The aim of this study was to investigate the effects of treating maize (Zea mays L.) seeds with fish collagen hydrolysate (FC) and keratin (KE) derived from animal waste by-products of leather and meat production, as well as poly(hexamethylene biguanide) hydrochloride (P) [...] Read more.
The aim of this study was to investigate the effects of treating maize (Zea mays L.) seeds with fish collagen hydrolysate (FC) and keratin (KE) derived from animal waste by-products of leather and meat production, as well as poly(hexamethylene biguanide) hydrochloride (P) and bentonite (B). This research is in line with the search for new, environmentally friendly methods to increase yields of industrial crops in a way that is compatible with sustainable development. The effect of the binders used was investigated by analysing the grown maize seedlings by determining changes in parameters of chlorophyll fluorescence, photosynthetic pigments, elemental composition and FTIR analysis on maize shoots. The results indicated a slightly higher fresh weight (FW) of shoots in plants treated with fish collagen, PHMB and bentonite (FC+P+B) and FW of roots in plants treated with keratin, PHMB and bentonite (KE+P+B). Unexpectedly, the FW and dry weight (DW) of both roots and shoots of all bentonite-treated plants were significantly higher than the corresponding non-bentonite-treated groups. In addition, changes in chlorophyll-a fluorescence were observed for the keratin, PHMB and bentonite variants. This study showed that the proposed materials could be promising seed pelleting agents to improve seed growth and yield. Full article
(This article belongs to the Section Molecular Plant Sciences)
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17 pages, 312 KiB  
Review
The Role of Alpha-Linolenic Acid and Other Polyunsaturated Fatty Acids in Mental Health: A Narrative Review
by Camilla Bertoni, Cecilia Pini, Alessandra Mazzocchi, Carlo Agostoni and Paolo Brambilla
Int. J. Mol. Sci. 2024, 25(22), 12479; https://doi.org/10.3390/ijms252212479 - 20 Nov 2024
Viewed by 311
Abstract
The present review investigates the relationship between polyunsaturated fatty acids (PUFAs) and mental health disorders, such as dementia, psychosis, schizophrenia, Alzheimer’s disease, anorexia nervosa, and impairment problems in animals and human models. Data were collected from a variety of studies: randomized intervention trials, [...] Read more.
The present review investigates the relationship between polyunsaturated fatty acids (PUFAs) and mental health disorders, such as dementia, psychosis, schizophrenia, Alzheimer’s disease, anorexia nervosa, and impairment problems in animals and human models. Data were collected from a variety of studies: randomized intervention trials, observational and interventional studies, case reports, and epidemiological studies. The evidence suggests that PUFAs are beneficial for mental health, brain function, and behavior. ALA, EPA, and DHA have very significant neuroprotective properties, particularly in inducing changes to the synaptic membrane and modulating brain cell signaling. In the case of neurodegenerative disorders, PUFAs incorporated into cellular membranes have been shown to protect against cell atrophy and death. The formal analyses of the included studies pointed to a decrease in ALA, EPA, and DHA levels in various populations (e.g., children, adolescents, adults, and seniors) presenting with different types of mental disorders. These results indicate that PUFA supplementation may be considered as an innovative therapeutic strategy to reduce the risk of neuronal degeneration. Full article
(This article belongs to the Section Bioactives and Nutraceuticals)
15 pages, 2491 KiB  
Article
Long Noncoding RNA lncRNA-3 Recruits PRC2 for MyoD1 Silencing to Suppress Muscle Regeneration During Aging
by Zong-Kang Zhang, Daogang Guan, Jintao Xu, Xiaofang Li, Ning Zhang, Shanshan Yao, Ge Zhang and Bao-Ting Zhang
Int. J. Mol. Sci. 2024, 25(22), 12478; https://doi.org/10.3390/ijms252212478 - 20 Nov 2024
Viewed by 198
Abstract
Lowered muscle regenerative capacity in the elderly greatly contributes to the development of multiple diseases. The specific roles of long noncoding RNAs (lncRNAs) in muscle regenerative capacity during aging remain unknown. Here, we identify an elevated lncRNA (lncRNA-3), in association with reduced MyoD [...] Read more.
Lowered muscle regenerative capacity in the elderly greatly contributes to the development of multiple diseases. The specific roles of long noncoding RNAs (lncRNAs) in muscle regenerative capacity during aging remain unknown. Here, we identify an elevated lncRNA (lncRNA-3), in association with reduced MyoD expression and suppressed muscle regenerative capacity, in the skeletal muscle of aged mice. LncRNA-3 could interact with both the MyoD1 promoter and RbAp46/48, a subunit of Polycomb repressive complex 2 (PRC2). LncRNA-3 could recruit PRC2 to the MyoD1 promoter and enhance the MyoD1 silencing, which, in turn, suppressed the muscle regenerative capacity. Muscle-specific lncRNA-3 knockdown could restore the muscle regenerative capacity in the aged mice. Exogenous RbAp46/48 binding motif (Rb-motif-2) treatment in skeletal muscle could compete for the lncRNA-3 binding, and therefore, enhance the muscle regenerative capacity in the aged mice. Taken together, lncRNA-3 requires PRC2 for MyoD1 silencing to suppress muscle regenerative capacity during aging. These findings provide a novel therapeutic target and a new strategy to elevate the muscle regenerative capacity in the aged population. Full article
(This article belongs to the Section Molecular Biology)
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24 pages, 6866 KiB  
Article
Novel Exosomal miRNA Expression in Irradiated Human Keratinocytes
by Hebah Almujally, Nizar Abuharfeil and Aseel Sharaireh
Int. J. Mol. Sci. 2024, 25(22), 12477; https://doi.org/10.3390/ijms252212477 - 20 Nov 2024
Viewed by 311
Abstract
The epidermis, the outer layer of the skin, relies on a delicate balance of cell growth and keratinocyte differentiation for its function and renewal. Recent research has shed light on exosomes’ role in facilitating skin communication by transferring molecules like miRNAs, which regulate [...] Read more.
The epidermis, the outer layer of the skin, relies on a delicate balance of cell growth and keratinocyte differentiation for its function and renewal. Recent research has shed light on exosomes’ role in facilitating skin communication by transferring molecules like miRNAs, which regulate gene expression post-transcriptionally. Additionally, these factors lead to skin aging through oxidative stress caused by reactive oxygen species (ROS). In this research project, experiments were conducted to study the impact of Sun2000 solar simulator irradiation on exosomal miRNA profiles in HEKa cells. We hypothesized that acute oxidative stress induced by solar simulator irradiation would alter the expression profile of exosomal miRNAs in HEKa cells. The cells were exposed to different durations of irradiation to induce oxidative stress, and the levels of reactive ROS were measured using the CellROX Deep Red flow cytometry assay kit. Exosomes were isolated from both control and irradiated cells, characterized using DLS and SEM techniques, and their miRNAs were extracted and analyzed using qPCR. Solar simulator irradiation led to a time-dependent increase in intracellular ROS and a decrease in cell viability. Exosomal size increased in irradiated cells. Fifty-nine exosomal miRNAs were differentially expressed in irradiated HEKa cells, including hsa-miR-425-5p, hsa-miR-181b-5p, hsa-miR-196b-5p, hsa-miR-376c-3p, and hsa-miR-15a-5p. This study highlights the significant impact of solar radiation on exosomal miRNA expression in keratinocytes, suggesting their potential role in the cellular response to oxidative stress. Full article
(This article belongs to the Section Biochemistry)
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14 pages, 2370 KiB  
Article
Effect of Constant Illumination on the Morphofunctional State and Rhythmostasis of Rat Livers at Experimental Toxic Injury
by Sevil A. Grabeklis, Maria A. Kozlova, Lyudmila M. Mikhaleva, Alexander M. Dygai, Rositsa A. Vandysheva, Anna I. Anurkina and David A. Areshidze
Int. J. Mol. Sci. 2024, 25(22), 12476; https://doi.org/10.3390/ijms252212476 - 20 Nov 2024
Viewed by 245
Abstract
The effect of dark deprivation on the morphofunctional state and rhythmostasis of the liver under CCl4 toxic exposure has been studied. The relevance of this study is due to the fact that the hepatotoxic effect of carbon tetrachloride on the liver is [...] Read more.
The effect of dark deprivation on the morphofunctional state and rhythmostasis of the liver under CCl4 toxic exposure has been studied. The relevance of this study is due to the fact that the hepatotoxic effect of carbon tetrachloride on the liver is well studied, but there are very few data on the relationship between CCl4 intoxication and circadian biorhythms, and most of the studies consider the susceptibility of the organism in general and of the liver in particular to the influence of CCl4 in some separate periods of the rhythm, but not the influence of this chemical agent on the structure of the whole rhythm. In addition, earlier studies indicate that light disturbance causes certain changes in the morphofunctional state of the liver and the structure of the circadian rhythm of a number of parameters. As a result of this study, we found that the effect of CCl4 in conditions of prolonged dark deprivation causes more significant structural and functional changes in hepatocytes, as well as leading to significant changes in the circadian rhythms of a number of parameters, which was not observed in the action of CCl4 as a monofactor. We assume that the severity of structural and functional changes is due to the light-induced deficiency of melatonin, which has hepatoprotective properties. Thus, the mechanisms of CCl4 action on CRs under conditions of light regime violations leave a large number of questions requiring further study, including the role of melatonin in these processes. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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11 pages, 442 KiB  
Article
Coronavirus Disease 2019-Associated Thrombotic Microangiopathy: A Single-Center Experience
by Marija Malgaj Vrečko, Andreja Aleš-Rigler, Špela Borštnar and Željka Večerić-Haler
Int. J. Mol. Sci. 2024, 25(22), 12475; https://doi.org/10.3390/ijms252212475 - 20 Nov 2024
Viewed by 173
Abstract
Coronavirus disease 2019 (COVID-19) can lead to various multisystem disorders, including thrombotic microangiopathy (TMA). We present here eight patients with COVID-19-associated TMA who were treated at our center. Our aim was to summarize the demographic and clinical characteristics of the patients and discuss [...] Read more.
Coronavirus disease 2019 (COVID-19) can lead to various multisystem disorders, including thrombotic microangiopathy (TMA). We present here eight patients with COVID-19-associated TMA who were treated at our center. Our aim was to summarize the demographic and clinical characteristics of the patients and discuss the possible role of COVID-19. One patient presented with thrombotic thrombocytopenic purpura (TTP) and seven with atypical hemolytic–uremic syndrome (aHUS.) Most patients had no obvious symptoms of COVID-19, and TMA occurred after viremia. Two patients had concomitant non-COVID-19-related triggers for TMA: exposure to tacrolimus and everolimus; first presentation of antiphospholipid syndrome. The patient with TTP was treated with therapeutic plasma exchange (TPE), steroids and caplacizumab, resulting in complete hematologic recovery. Six patients with aHUS were treated with TPE with or without steroids, four of whom received a C5 complement inhibitor and one an intravenous immunoglobulin. One patient with aHUS was treated with a C5 complement inhibitor and a steroid. We observed one partial and one complete recovery of renal function, while five patients experienced renal failure. There were no deaths. We believe that COVID-19 may act as a trigger for TMA in patients who have either pre-existing endothelial injury or an underlying predisposition to complement activation, and may also trigger autoimmune diseases. As a consequence of the different underlying pathophysiologies, the treatment of COVID-19-associated TMA requires a specific approach based on the subtype of the syndrome and possible concomitant triggers. Full article
(This article belongs to the Special Issue Recent Advances in Pathophysiology and Immunology Related to SARS-CoV-2 Infection)
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20 pages, 4799 KiB  
Article
Male Wistar Rats Chronically Fed with a High-Fat Diet Develop Inflammatory and Ionic Transport Angiotensin-(3–4)-Sensitive Myocardial Lesions but Preserve Echocardiographic Parameters
by Thuany Crisóstomo, Rafael Luzes, Matheus Leonardo Lima Gonçalves, Marco Antônio Estrela Pardal, Humberto Muzi-Filho, Glória Costa-Sarmento, Debora B. Mello and Adalberto Vieyra
Int. J. Mol. Sci. 2024, 25(22), 12474; https://doi.org/10.3390/ijms252212474 - 20 Nov 2024
Viewed by 219
Abstract
The central aim of this study was to investigate whether male Wistar rats chronically fed a high-fat diet (HFD) over 106 days present high levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and Na+ and Ca2+ transport alterations in the [...] Read more.
The central aim of this study was to investigate whether male Wistar rats chronically fed a high-fat diet (HFD) over 106 days present high levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and Na+ and Ca2+ transport alterations in the left ventricle, together with dyslipidemia and decreased glucose tolerance, and to investigate the influence of Ang-(3–4). The rats became moderately overweight with an expansion of visceral adiposity. Na+-transporting ATPases, sarco-endoplasmic reticulum Ca2+-ATPase (SERCA2a), and the abundance of Angiotensin II receptors were studied together with lipid and glycemic profiles from plasma and left-ventricle echocardiographic parameters fractional shortening (FS) and ejection fraction (EF). IL-6 and TNF-α increased (62% and 53%, respectively), but returned to normal levels with Angiotensin-(3–4) administration after 106 days. Significant lipidogram alterations accompanied a decrease in glucose tolerance. Angiotensin II receptors abundance did not change. (Na+ + K+)ATPase and ouabain-resistant Na+-ATPase were downregulated and upregulated, respectively, but returned to normal values upon Angiotensin-(3–4) administration. SERCA2a lost its ability to respond to excess ATP. Echocardiography showed no changes in FS or EF. We conclude that being overweight causes an increase in Ang-(3–4)-sensitive IL-6 and TNF-α levels, and ion transport alterations in the left ventricle that could evolve into future heart dysfunction. Full article
(This article belongs to the Special Issue Molecular Research in Obesity and Obesity Related Disorders: 2nd Edition)
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31 pages, 6624 KiB  
Article
Multi-Spectroscopic and Molecular Modeling Studies of Interactions Between Anionic Porphyrin and Human Serum Albumin
by Tadeusz Strózik, Marian Wolszczak, Maria Hilczer, Magdalena Pawlak, Tomasz Wasiak, Piotr Wardęga, Maksim Ionov and Maria Bryszewska
Int. J. Mol. Sci. 2024, 25(22), 12473; https://doi.org/10.3390/ijms252212473 - 20 Nov 2024
Viewed by 229
Abstract
The subject of this study is the interaction between 5,10,15,20-tetrakis (4-sulfonatophenyl)–porphyrin (TSPP), a potential photosensitizer for photodynamic therapy (PDT) and radiotherapy, and human serum albumin (HSA), a crucial protein in the body. The main objective was to investigate the binding mechanisms, structural changes, [...] Read more.
The subject of this study is the interaction between 5,10,15,20-tetrakis (4-sulfonatophenyl)–porphyrin (TSPP), a potential photosensitizer for photodynamic therapy (PDT) and radiotherapy, and human serum albumin (HSA), a crucial protein in the body. The main objective was to investigate the binding mechanisms, structural changes, and potential implications of these interactions for drug delivery and therapeutic applications. Spectroscopic techniques and computational methods were employed to investigate the mechanism and effects of TSPP binding by HSA. The results suggest the possibility of simultaneous binding of three TSPP ions at binding sites of different affinity within albumin. The estimated values of the binding constant Kb for these sites were in the range of 0.6 to 6.6 μM−1. Laser flash photolysis indicated the stabilization of TSPP in the HSA structure, which resulted in prolonged lifetimes of the excited states (singlet and triplet) of porphyrin. Circular dichroism analysis was used to assess the changes in the secondary and tertiary structures of HSA upon TSPP binding. An analysis of the molecular docking results allowed us to identify the preferred TSPP binding sites within HSA and provided information on the specific interactions of amino acids involved in the stabilization of TSPP–HSA complexes. The estimated free energy of the binding of porphyrin at the three most favorable docking sites found in the HSA structure that was considered native were in the range of −80 to −41 kcal/mol. Finally, thermal unfolding studies showed that TSPP increased the stability of the secondary structure of albumin. All these findings contribute to the understanding of the interactions between TSPP and HSA, offering valuable insights for the development of novel cancer therapy approaches. Full article
(This article belongs to the Section Molecular Biophysics)
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6 pages, 656 KiB  
Editorial
Vistas in Signaling Pathways Implicated in HSV-1 Reactivation
by Kostas A. Papavassiliou, Amalia A. Sofianidi, Fotios G. Spiliopoulos, Vassiliki A. Gogou and Athanasios G. Papavassiliou
Int. J. Mol. Sci. 2024, 25(22), 12472; https://doi.org/10.3390/ijms252212472 - 20 Nov 2024
Viewed by 240
Abstract
Ancient Greek physicians, including Hippocrates, documented skin conditions resembling herpes as early as 500 before common era (BCE), but it was not until the 1920s that Lowenstein successfully isolated the herpes virus from human lesions, significantly advancing our understanding of the infection [...] [...] Read more.
Ancient Greek physicians, including Hippocrates, documented skin conditions resembling herpes as early as 500 before common era (BCE), but it was not until the 1920s that Lowenstein successfully isolated the herpes virus from human lesions, significantly advancing our understanding of the infection [...] Full article
(This article belongs to the Special Issue Recent Advances in Herpesviruses)
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19 pages, 2288 KiB  
Article
Astrocyte Dysfunction Reflected in Ischemia-Induced Astrocyte-Derived Extracellular Vesicles: A Pilot Study on Acute Ischemic Stroke Patients
by Timea Forró, Doina Ramona Manu, Lucian Barbu-Tudoran and Rodica Bălașa
Int. J. Mol. Sci. 2024, 25(22), 12471; https://doi.org/10.3390/ijms252212471 - 20 Nov 2024
Viewed by 246
Abstract
Extracellular vesicles (EVs) secreted by astrocytes (ADEVs) mediate numerous biological processes, providing insights into damage, repair, and protection following ischemic stroke (IS). This pilot study aimed to broaden the current knowledge on the astrocyte response to ischemia by dynamically assessing the aquaporin-4 (AQP4) [...] Read more.
Extracellular vesicles (EVs) secreted by astrocytes (ADEVs) mediate numerous biological processes, providing insights into damage, repair, and protection following ischemic stroke (IS). This pilot study aimed to broaden the current knowledge on the astrocyte response to ischemia by dynamically assessing the aquaporin-4 (AQP4) and glial cell line-derived neurotrophic factor (GDNF) as cargo proteins of these vesicles in eighteen acute IS patients and nine controls. EV proteins were detected by Western blotting and followed 24 h (D1), 7 days (D7), and one month (M1) after symptoms onset. The post-ischemic ADEV AQP4 and GDNF levels were higher at D1 compared to the control group (p = 0.006 and p = 0.023). Significant differences were observed in ADEV AQP4 during the three evaluated time points (n = 12, p = 0.013) and between D1 and D7 (z = 2.858, p = 0.012), but not in EV GDNF. There was a positive relationship between the severity of stroke at D1 according to the National Institutes of Health Stroke Scale, and ADEV AQP4 at D1 (r = 0.50, p = 0.031), as well as ADEV GDNF at D1 and D7 (r = 0.49, p = 0.035 and r = 0.53, p = 0.021, respectively). The release of EVs with distinct protein profiles can be an attractive platform for the development of biomarkers in IS. Full article
(This article belongs to the Special Issue Molecular, Cellular, and Blood Biomarkers in Acute Ischemic Stroke)
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10 pages, 4414 KiB  
Article
Knockout of OsGAPDHC7 Gene Encoding Cytosolic Glyceraldehyde-3-Phosphate Dehydrogenase Affects Energy Metabolism in Rice Seeds
by Jin-Young Kim, Ye-Ji Lee, Hyo-Ju Lee, Ji-Yun Go, Hye-Mi Lee, Jin-Shil Park, Yong-Gu Cho, Yu-Jin Jung and Kwon-Kyoo Kang
Int. J. Mol. Sci. 2024, 25(22), 12470; https://doi.org/10.3390/ijms252212470 - 20 Nov 2024
Viewed by 239
Abstract
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a major glycolytic enzyme that plays an important role in several cellular processes, including plant hormone signaling, plant development, and transcriptional regulation. In this study, we divided it into four groups through structural analysis of eight GAPDH genes identified [...] Read more.
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a major glycolytic enzyme that plays an important role in several cellular processes, including plant hormone signaling, plant development, and transcriptional regulation. In this study, we divided it into four groups through structural analysis of eight GAPDH genes identified in the rice genome. Among them, the expression level of five genes of cytosolic GAPDH was shown to be different for each organ. The mutation induction of the GAPDHC7 gene by the CRISPR/Cas9 system revealed that the 7 bp and 2 bp deletion, early end codon, was used in protein production. In addition, the selected mutants showed lower plant heights compared to the wild-type plants. To investigate the effect on carbohydrate metabolism, the expression of the genes of starch-branched enzyme I (SbeI), sucrose synthase (SS), and 3-phosphoglycer phosphokinase (PGK) increased the expression of the SBeI gene threefold in the knockout lines compared to the wild-type (WT) plant, while the expression of the SS and PGK genes decreased significantly. And the starch and soluble sugar content of the knockout lines increased by more than 60% compared to the WT plant. Also, the free amino acid content was significantly increased in the Gln and Asn contents of the knockout lines compared to the WT plants, while the contents of Gly and Ser were decreased. Our results suggest that OsGAPDHC7 has a great influence on energy metabolism, such as pre-harvested sprouting and amino acid content. Full article
(This article belongs to the Special Issue Genetic Analysis Based on CRISPR/Cas9 Technology : 2nd Edition)
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17 pages, 1837 KiB  
Article
A Study of the Community Relationships Between Methanotrophs and Their Satellites Using Constraint-Based Modeling Approach
by Maryam A. Esembaeva, Mikhail A. Kulyashov, Fedor A. Kolpakov and Ilya R. Akberdin
Int. J. Mol. Sci. 2024, 25(22), 12469; https://doi.org/10.3390/ijms252212469 - 20 Nov 2024
Viewed by 254
Abstract
Biotechnology continues to drive innovation in the production of pharmaceuticals, biofuels, and other valuable compounds, leveraging the power of microbial systems for enhanced yield and sustainability. Genome-scale metabolic (GSM) modeling has become an essential approach in this field, which enables a guide for [...] Read more.
Biotechnology continues to drive innovation in the production of pharmaceuticals, biofuels, and other valuable compounds, leveraging the power of microbial systems for enhanced yield and sustainability. Genome-scale metabolic (GSM) modeling has become an essential approach in this field, which enables a guide for targeting genetic modifications and the optimization of metabolic pathways for various industrial applications. While single-species GSM models have traditionally been employed to optimize strains like Escherichia coli and Lactococcus lactis, the integration of these models into community-based approaches is gaining momentum. Herein, we present a pipeline for community metabolic modeling with a user-friendly GUI, applying it to analyze interactions between Methylococcus capsulatus, a biotechnologically important methanotroph, and Escherichia coli W3110 under oxygen- and nitrogen-limited conditions. We constructed models with unmodified and homoserine-producing E. coli strains using the pipeline implemented in the original BioUML platform. The E. coli strain primarily utilized acetate from M. capsulatus under oxygen limitation. However, homoserine produced by E. coli significantly reduced acetate secretion and the community growth rate. This homoserine was taken up by M. capsulatus, converted to threonine, and further exchanged as amino acids. In nitrogen-limited modeling conditions, nitrate and ammonium exchanges supported the nitrogen needs, while carbon metabolism shifted to fumarate and malate, enhancing E. coli TCA cycle activity in both cases, with and without modifications. The presence of homoserine altered cross-feeding dynamics, boosting amino acid exchanges and increasing pyruvate availability for M. capsulatus. These findings suggest that homoserine production by E. coli optimizes resource use and has potential for enhancing microbial consortia productivity. Full article
(This article belongs to the Special Issue Biochemical and Molecular Aspects of Bioremediation of Soils with Organic Pollutants by Microorganisms)
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21 pages, 4891 KiB  
Article
BMAL1—Potential Player of Aberrant Stress Response in Q31L Mice Model of Affective Disorders: Pilot Results
by Kristina Smirnova, Tamara Amstislavskaya and Liudmila Smirnova
Int. J. Mol. Sci. 2024, 25(22), 12468; https://doi.org/10.3390/ijms252212468 - 20 Nov 2024
Viewed by 234
Abstract
Dysregulation in the stress-response system as a result of genetical mutation can provoke the manifestation of affective disorders under stress conditions. Mutations in the human DISC1 gene is one of the main risk factors of affective disorders. It was known that DISC1 regulates [...] Read more.
Dysregulation in the stress-response system as a result of genetical mutation can provoke the manifestation of affective disorders under stress conditions. Mutations in the human DISC1 gene is one of the main risk factors of affective disorders. It was known that DISC1 regulates a large number of proteins including BMAL1, which is involved in the regulation of glucocorticoid synthesis in the adrenal glands and the sensitivity of glucocorticoid receptor target genes. Male mice with a point mutation Q31L in the Disc1 gene were exposed to chronic unpredictable stress (CUS), after which the behavioral and physiological stress response assessed. To assess whether there were any changes in BMAL1 in key brain regions involved in the stress response, immunohistochemistry was applied. It was shown that the Q31L mice had an aberrant behavioral response, especially to the 2 weeks of CUS, which was expressed in unchanged motor activity, increased time of social interaction, and alterations in anxiety and fear-related behavior. Q31L males did not show an increase in blood corticosterone levels after CUS and a decrease in body weight. Immunohistochemical analysis in intact Q31L mice revealed a decrease in BMAL1 immunofluorescence in the CA1 hippocampal area and lateral habenula. Thus, the Q31L mutation of the Disc1 gene disrupts behavioral and physiological stress response and the BMAL1 dysregulation may underlie it, so this protein can act as a molecular target for the treatment of affective disorders. Full article
(This article belongs to the Special Issue Advances in Animal Models in Biomedical Research, 2nd Edition)
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24 pages, 2272 KiB  
Review
Effect of Oxidative Stress on Mitochondrial Damage and Repair in Heart Disease and Ischemic Events
by Paweł Kowalczyk, Sebastian Krych, Karol Kramkowski, Agata Jęczmyk and Tomasz Hrapkowicz
Int. J. Mol. Sci. 2024, 25(22), 12467; https://doi.org/10.3390/ijms252212467 - 20 Nov 2024
Viewed by 249
Abstract
The literature analysis conducted in this review discusses the latest achievements in the identification of cardiovascular damage induced by oxidative stress with secondary platelet mitochondrial dysfunction. Damage to the platelets of mitochondria as a result of their interactions with reactive oxygen species (ROS) [...] Read more.
The literature analysis conducted in this review discusses the latest achievements in the identification of cardiovascular damage induced by oxidative stress with secondary platelet mitochondrial dysfunction. Damage to the platelets of mitochondria as a result of their interactions with reactive oxygen species (ROS) and reactive nitrogen species (RNS) can lead to their numerous ischemic events associated with hypoxia or hyperoxia processes in the cell. Disturbances in redox reactions in the platelet mitochondrial membrane lead to the direct oxidation of cellular macromolecules, including nucleic acids (DNA base oxidation), membrane lipids (lipid peroxidation process) and cellular proteins (formation of reducing groups in repair proteins and amino acid peroxides). Oxidative changes in biomolecules inducing tissue damage leads to inflammation, initiating pathogenic processes associated with faster cell aging or their apoptosis. The consequence of damage to platelet mitochondria and their excessive activation is the induction of cardiovascular and neurodegenerative diseases (Parkinson’s and Alzheimer’s), as well as carbohydrate metabolism disorders (diabetes). The oxidation of mitochondrial DNA can lead to modifications in its bases, inducing the formation of exocyclic adducts of the ethano and propano type. As a consequence, it disrupts DNA repair processes and conduces to premature neoplastic transformation in critical genes such as the p53 suppressor gene, which leads to the development of various types of tumors. The topic of new innovative methods and techniques for the analysis of oxidative stress in platelet mitochondria based on methods such as a nicking assay, oxygen consumption assay, Total Thrombus formation Analysis System (T-Tas), and continuous-flow left ventricular assist devices (CF-LVADs) was also discussed. They were put together into one scientific and research platform. This will enable the facilitation of faster diagnostics and the identification of platelet mitochondrial damage by clinicians and scientists in order to implement adequate therapeutic procedures and minimize the risk of the induction of cardiovascular diseases, including ischemic events correlated with them. A quantitative analysis of the processes of thrombus formation in cardiovascular diseases will provide an opportunity to select specific anticoagulant and thrombolytic drugs under conditions of preserved hemostasis. Full article
(This article belongs to the Special Issue Editorial Board Members’ Collection Series: Cardiovascular Diseases)
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20 pages, 5198 KiB  
Article
Multi-Omics Approaches Uncovered Critical mRNA–miRNA–lncRNA Networks Regulating Multiple Birth Traits in Goat Ovaries
by Weibing Lv, Ren An, Xinmiao Li, Zengdi Zhang, Wanma Geri, Xianrong Xiong, Shi Yin, Wei Fu, Wei Liu, Yaqiu Lin, Jian Li and Yan Xiong
Int. J. Mol. Sci. 2024, 25(22), 12466; https://doi.org/10.3390/ijms252212466 - 20 Nov 2024
Viewed by 219
Abstract
The goat breeding industry on the Tibetan Plateau faces strong selection pressure to enhance fertility. Consequently, there is an urgent need to develop goat lines with higher fertility and adaptability. The ovary, as a key organ determining reproductive performance, is regulated by a [...] Read more.
The goat breeding industry on the Tibetan Plateau faces strong selection pressure to enhance fertility. Consequently, there is an urgent need to develop goat lines with higher fertility and adaptability. The ovary, as a key organ determining reproductive performance, is regulated by a complex transcriptional network involving numerous protein-coding and non-coding genes. However, the molecular mechanisms of the key mRNA–miRNA–lncRNA regulatory network in goat ovaries remain largely unknown. This study focused on the histology and differential mRNA/miRNA/lncRNA between Chuanzhong black goat (CBG, high productivity, multiple births) and Tibetan goat (TG, strong adaptability, single birth) ovaries. Histomorphological analysis showed that the medulla proportion in CBG ovaries was significantly reduced compared to TG. RNA-Seq and small RNA-Seq analysis identified 1218 differentially expressed (DE) mRNAs, 100 DE miRNAs, and 326 DE lncRNAs, which were mainly enriched in ovarian steroidogenesis, oocyte meiosis, biosynthesis of amino acids and protein digestion, and absorption signaling pathways. Additionally, five key mRNA–miRNA–lncRNA interaction networks regulating goat reproductive performance were identified, including TCL1B–novel68_mature–ENSCHIT00000010023, AKAP6–novel475_mature–ENSCHIT00000003176, GLI2–novel68_mature–XR_001919123.1, ITGB5–novel65_star–TCONS_00013850, and VWA2–novel71_mature–XR_001919911.1. Further analyses showed that these networks mainly affected ovarian function and reproductive performance by regulating biological processes such as germ cell development and oocyte development, which also affected the plateau adaptive capacity of the ovary by participating in the individual immune and metabolic capacities. In conclusion, we identified numerous mRNA–miRNA–lncRNA interaction networks involved in regulating ovarian function and reproductive performance in goats. This discovery offers new insights into the molecular breeding of Tibetan Plateau goats and provides a theoretical foundation for developing new goat lines with high reproductive capacity and strong adaptability to the plateau environment. Full article
(This article belongs to the Special Issue Molecular Studies in Endocrinology and Reproductive Biology—Second Edition)
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25 pages, 6147 KiB  
Review
The Gut–Heart Axis: Molecular Perspectives and Implications for Myocardial Infarction
by Katherine Rivera, Leticia Gonzalez, Liena Bravo, Laura Manjarres and Marcelo E. Andia
Int. J. Mol. Sci. 2024, 25(22), 12465; https://doi.org/10.3390/ijms252212465 - 20 Nov 2024
Viewed by 593
Abstract
Myocardial infarction (MI) remains the leading cause of death globally, imposing a significant burden on healthcare systems and patients. The gut–heart axis, a bidirectional network connecting gut health to cardiovascular outcomes, has recently emerged as a critical factor in MI pathophysiology. Disruptions in [...] Read more.
Myocardial infarction (MI) remains the leading cause of death globally, imposing a significant burden on healthcare systems and patients. The gut–heart axis, a bidirectional network connecting gut health to cardiovascular outcomes, has recently emerged as a critical factor in MI pathophysiology. Disruptions in this axis, including gut dysbiosis and compromised intestinal barrier integrity, lead to systemic inflammation driven by gut-derived metabolites like lipopolysaccharides (LPSs) and trimethylamine N-oxide (TMAO), both of which exacerbate MI progression. In contrast, metabolites such as short-chain fatty acids (SCFAs) from a balanced microbiota exhibit protective effects against cardiac damage. This review examines the molecular mediators of the gut–heart axis, considering the role of factors like sex-specific hormones, aging, diet, physical activity, and alcohol consumption on gut health and MI outcomes. Additionally, we highlight therapeutic approaches, including dietary interventions, personalized probiotics, and exercise regimens. Addressing the gut–heart axis holds promise for reducing MI risk and improving recovery, positioning it as a novel target in cardiovascular therapy. Full article
(This article belongs to the Special Issue Molecular Advances and Insights on Diagnosis, Prevention and Therapeutics of Cardiovascular Diseases)
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27 pages, 1245 KiB  
Review
Remodeling of the Intracardiac Ganglia During the Development of Cardiovascular Autonomic Dysfunction in Type 2 Diabetes: Molecular Mechanisms and Therapeutics
by Anthony J. Evans and Yu-Long Li
Int. J. Mol. Sci. 2024, 25(22), 12464; https://doi.org/10.3390/ijms252212464 - 20 Nov 2024
Viewed by 197
Abstract
Type 2 diabetes mellitus (T2DM) is one of the most significant health issues worldwide, with associated healthcare costs estimated to surpass USD 1054 billion by 2045. The leading cause of death in T2DM patients is the development of cardiovascular disease (CVD). In the [...] Read more.
Type 2 diabetes mellitus (T2DM) is one of the most significant health issues worldwide, with associated healthcare costs estimated to surpass USD 1054 billion by 2045. The leading cause of death in T2DM patients is the development of cardiovascular disease (CVD). In the early stages of T2DM, patients develop cardiovascular autonomic dysfunction due to the withdrawal of cardiac parasympathetic activity. Diminished cardiac parasympathetic tone can lead to cardiac arrhythmia-related sudden cardiac death, which accounts for 50% of CVD-related deaths in T2DM patients. Regulation of cardiovascular parasympathetic activity is integrated by neural circuitry at multiple levels including afferent, central, and efferent components. Efferent control of cardiac parasympathetic autonomic tone is mediated through the activity of preganglionic parasympathetic neurons located in the cardiac extensions of the vagus nerve that signals to postganglionic parasympathetic neurons located in the intracardiac ganglia (ICG) on the heart. Postganglionic parasympathetic neurons exert local control on the heart, independent of higher brain centers, through the release of neurotransmitters, such as acetylcholine. Structural and functional alterations in cardiac parasympathetic postganglionic neurons contribute to the withdrawal of cardiac parasympathetic tone, resulting in arrhythmogenesis and sudden cardiac death. This review provides an overview of the remodeling of parasympathetic postganglionic neurons in the ICG, and potential mechanisms contributing to the withdrawal of cardiac parasympathetic tone, ventricular arrhythmogenesis, and sudden cardiac death in T2DM. Improving cardiac parasympathetic tone could be a therapeutic avenue to reduce malignant ventricular arrhythmia and sudden cardiac death, increasing both the lifespan and improving quality of life of T2DM patients. Full article
(This article belongs to the Special Issue Cellular and Molecular Progression of Cardiovascular Diseases)
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17 pages, 2008 KiB  
Review
Ferroptosis and Its Potential Role in the Physiopathology of Skeletal Muscle Atrophy
by Chen-Chen Sun, Jiang-Ling Xiao, Chen Sun and Chang-Fa Tang
Int. J. Mol. Sci. 2024, 25(22), 12463; https://doi.org/10.3390/ijms252212463 - 20 Nov 2024
Viewed by 291
Abstract
Skeletal muscle atrophy is a major health concern, severely affecting the patient’s mobility and life quality. In the pathological process of skeletal muscle atrophy, with the progressive decline in muscle quality, strength, and function, the incidence of falling, fracture, and death is greatly [...] Read more.
Skeletal muscle atrophy is a major health concern, severely affecting the patient’s mobility and life quality. In the pathological process of skeletal muscle atrophy, with the progressive decline in muscle quality, strength, and function, the incidence of falling, fracture, and death is greatly increased. Unfortunately, there are no effective treatments for this devastating disease. Thus, it is imperative to investigate the exact pathological molecular mechanisms underlying the development of skeletal muscle atrophy and to identify new therapeutic targets. Decreased muscle mass, strength, and muscle fiber cross-sectional area are typical pathological features and manifestations of skeletal muscle atrophy. Ferroptosis, an emerging type of programmed cell death, is characterized by iron-dependent oxidative damage, lipid peroxidation, and reactive oxygen species accumulation. Notably, the understanding of its role in skeletal muscle atrophy is emerging. Ferroptosis has been found to play an important role in the intricate interplay between the pathological mechanisms of skeletal muscle atrophy and its progression caused by multiple factors. This provides new opportunities and challenges in the treatment of skeletal muscle atrophy. Therefore, we systematically elucidated the ferroptosis mechanism and its progress in skeletal muscle atrophy, aiming to provide a comprehensive insight into the intricate relationship between ferroptosis and skeletal muscle atrophy from the perspectives of iron metabolism and lipid peroxidation and to provide new insights for targeting the pathways related to ferroptosis and the treatment of skeletal muscle atrophy. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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12 pages, 2319 KiB  
Review
Continuous Use During Disuse: Mechanisms and Effects of Spontaneous Activity of Unloaded Postural Muscle
by Boris S. Shenkman, Vitaliy E. Kalashnikov, Kristina A. Sharlo, Olga V. Turtikova, Roman O. Bokov and Timur M. Mirzoev
Int. J. Mol. Sci. 2024, 25(22), 12462; https://doi.org/10.3390/ijms252212462 - 20 Nov 2024
Viewed by 244
Abstract
In most mammals, postural soleus muscles are involved in the maintenance of the stability of the body in the gravitational field of Earth. It is well established that immediately after a laboratory rat is exposed to conditions of weightlessness (parabolic flight) or simulated [...] Read more.
In most mammals, postural soleus muscles are involved in the maintenance of the stability of the body in the gravitational field of Earth. It is well established that immediately after a laboratory rat is exposed to conditions of weightlessness (parabolic flight) or simulated microgravity (hindlimb suspension/unloading), a sharp decrease in soleus muscle electrical activity occurs. However, starting from the 3rd day of mechanical unloading, soleus muscle electrical activity begins to increase and reaches baseline levels approximately by the 14th day of hindlimb suspension. This phenomenon, observed in the course of rat hindlimb suspension, was named the “spontaneous electrical activity of postural muscle”. The present review discusses spinal mechanisms underlying the development of such spontaneous activity of rat soleus muscle and the effect of this activity on intracellular signaling in rat soleus muscle during mechanical unloading. Full article
(This article belongs to the Special Issue Molecular Insight into Skeletal Muscle Atrophy and Regeneration)
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14 pages, 927 KiB  
Review
Strategies for Modifying Adenoviral Vectors for Gene Therapy
by Anna Muravyeva and Svetlana Smirnikhina
Int. J. Mol. Sci. 2024, 25(22), 12461; https://doi.org/10.3390/ijms252212461 - 20 Nov 2024
Viewed by 286
Abstract
Adenoviral vectors (AdVs) are effective vectors for gene therapy due to their broad tropism, large capacity, and high transduction efficiency, making them widely used as oncolytic vectors and for creating vector-based vaccines. This review also considers the application of adenoviral vectors in oncolytic [...] Read more.
Adenoviral vectors (AdVs) are effective vectors for gene therapy due to their broad tropism, large capacity, and high transduction efficiency, making them widely used as oncolytic vectors and for creating vector-based vaccines. This review also considers the application of adenoviral vectors in oncolytic virotherapy and gene therapy for inherited diseases, analyzing strategies to enhance their efficacy and specificity. However, despite significant progress in this field, the use of adenoviral vectors is limited by their high immunogenicity, low specificity to certain cell types, and limited duration of transgene expression. Various strategies and technologies aimed at improving the characteristics of adenoviral vectors are being developed to overcome these limitations. Significant attention is being paid to the creation of tissue-specific promoters, which allow for the controlled expression of transgenes, as well as capsid modifications that enhance tropism to target cells, which also play a key role in reducing immunogenicity and increasing the efficiency of gene delivery. This review focuses on modern approaches to adenoviral vector modifications made to enhance their effectiveness in gene therapy, analyzing the current achievements, challenges, and prospects for applying these technologies in clinical practice, as well as identifying future research directions necessary for successful clinical implementation. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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19 pages, 5951 KiB  
Article
Biallelic Germline BRCA1 Frameshift Mutations Associated with Isolated Diminished Ovarian Reserve
by Anne Helbling-Leclerc, Marie Falampin, Abdelkader Heddar, Léa Guerrini-Rousseau, Maud Marchand, Iphigenie Cavadias, Nathalie Auger, Brigitte Bressac-de Paillerets, Laurence Brugieres, Bernard S. Lopez, Michel Polak, Filippo Rosselli and Micheline Misrahi
Int. J. Mol. Sci. 2024, 25(22), 12460; https://doi.org/10.3390/ijms252212460 - 20 Nov 2024
Viewed by 407
Abstract
The use of next-generation sequencing (NGS) has recently enabled the discovery of genetic causes of primary ovarian insufficiency (POI) with high genetic heterogeneity. In contrast, the causes of diminished ovarian reserve (DOR) remain poorly understood. Here, we identified by NGS and whole exome [...] Read more.
The use of next-generation sequencing (NGS) has recently enabled the discovery of genetic causes of primary ovarian insufficiency (POI) with high genetic heterogeneity. In contrast, the causes of diminished ovarian reserve (DOR) remain poorly understood. Here, we identified by NGS and whole exome sequencing (WES) the cause of isolated DOR in a 14-year-old patient. Two frameshift mutations in BRCA1 (NM_007294.4) were found: in exon 8 (c.470_471del; p.Ser157Ter) and in exon 11 (c.791_794del, p.Ser264MetfsTer33). Unexpectedly, the patient presented no signs of Fanconi anemia (FA), i.e., no developmental abnormalities or indications of bone marrow failure. However, high chromosomal fragility was found in the patient’s cells, consistent with an FA diagnosis. RT-PCR and Western-blot analysis support the fact that the c. 791_794del BRCA1 allele is transcribed and translated into a shorter protein (del11q), while no expression of the full-length BRCA1 protein was found. DNA damage response (DDR) studies after genotoxic agents demonstrate normal activation of the early stages of the DDR and FANC/BRCA pathway. This is consistent with the maintenance of residual repair activity for the del11q BRCA1 isoform. Our observation is the first implication of bi-allelic BRCA1 mutations in isolated ovarian dysfunction or infertility in humans, without clinical signs of FA, and highlights the importance of BRCA1 in ovarian development and function. Full article
(This article belongs to the Special Issue Advances in Genetics of Human Reproduction)
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18 pages, 10499 KiB  
Article
Oxidative Stress-Associated Alteration of circRNA and Their ceRNA Network in Differentiating Neuroblasts
by Ebrahim Mahmoudi, Behnaz Khavari and Murray J. Cairns
Int. J. Mol. Sci. 2024, 25(22), 12459; https://doi.org/10.3390/ijms252212459 - 20 Nov 2024
Viewed by 205
Abstract
Oxidative stress from environmental exposures is thought to play a role in neurodevelopmental disorders; therefore, understanding the underlying molecular regulatory network is essential for mitigating its impacts. In this study, we analysed the competitive endogenous RNA (ceRNA) network mediated by circRNAs, a novel [...] Read more.
Oxidative stress from environmental exposures is thought to play a role in neurodevelopmental disorders; therefore, understanding the underlying molecular regulatory network is essential for mitigating its impacts. In this study, we analysed the competitive endogenous RNA (ceRNA) network mediated by circRNAs, a novel class of regulatory molecules, in an SH-SY5Y cell model of oxidative stress, both prior to and during neural differentiation, using RNA sequencing and in silico analysis. We identified 146 differentially expressed circRNAs, including 93 upregulated and 53 downregulated circRNAs, many of which were significantly co-expressed with mRNAs that potentially interact with miRNAs. We constructed a circRNA–miRNA–mRNA network and identified 15 circRNAs serving as hubs within the regulatory axes, with target genes enriched in stress- and neuron-related pathways, such as signaling by VEGF, axon guidance, signaling by FGFR, and the RAF/MAP kinase cascade. These findings provide insights into the role of the circRNA-mediated ceRNA network in oxidative stress during neuronal differentiation, which may help explain the regulatory mechanisms underlying neurodevelopmental disorders associated with oxidative stress. Full article
(This article belongs to the Special Issue Targeting Oxidative Stress for Disease)
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19 pages, 6201 KiB  
Article
In Vitro Cell Model Investigation of Alpha-Synuclein Aggregate Morphology Using Spectroscopic Imaging
by Priyanka Swaminathan, Therése Klingstedt, Vasileios Theologidis, Hjalte Gram, Johan Larsson, Lars Hagen, Nina B. Liabakk, Odrun A. Gederaas, Per Hammarström, K. Peter R. Nilsson, Nathalie Van Den Berge and Mikael Lindgren
Int. J. Mol. Sci. 2024, 25(22), 12458; https://doi.org/10.3390/ijms252212458 - 20 Nov 2024
Viewed by 415
Abstract
Recently, it has been hypothesized that alpha-synuclein protein strain morphology may be associated with clinical subtypes of alpha-synucleinopathies, like Parkinson’s disease and multiple system atrophy. However, direct evidence is lacking due to the caveat of conformation-specific characterization of protein strain morphology. Here we [...] Read more.
Recently, it has been hypothesized that alpha-synuclein protein strain morphology may be associated with clinical subtypes of alpha-synucleinopathies, like Parkinson’s disease and multiple system atrophy. However, direct evidence is lacking due to the caveat of conformation-specific characterization of protein strain morphology. Here we present a new cell model based in vitro method to explore various alpha-synuclein (αsyn) aggregate morphotypes. We performed a spectroscopic investigation of the HEK293 cell model, transfected with human wildtype-αsyn and A53T-αsyn variants, using the amyloid fibril-specific heptameric luminescent oligomeric thiophene h-FTAA. The spectral profile of h-FTAA binding to aggregates displayed a blue-shifted spectrum with a fluorescence decay time longer than in PBS, suggesting a hydrophobic binding site. In vitro spectroscopic binding characterization of h-FTAA with αsyn pre-formed fibrils suggested a binding dissociation constant Kd < 100 nM. The cells expressing the A53T-αsyn and human wildtype-αsyn were exposed to recombinant pre-formed fibrils of human αsyn. The ensuing intracellular aggregates were stained with h-FTAA followed by an evaluation of the spectral features and fluorescence lifetime of intracellular αsyn/h-FTAA, in order to characterize aggregate morphotypes. This study exemplifies the use of cell culture together with conformation-specific ligands to characterize strain morphology by investigating the spectral profiles and fluorescence lifetime of h-FTAA, based upon its binding to a certain αsyn aggregate. This study paves the way for toxicity studies of different αsyn strains in vitro and in vivo. Accurate differentiation of specific alpha-synucleinopathies is still limited to advanced disease stages. However, early subtype-specific diagnosis is of the utmost importance for prognosis and treatment response. The potential association of αsyn aggregates morphotypes detected in biopsies or fluids to disease phenotypes would allow for subtype-specific diagnosis in subclinical disease stage and potentially reveal new subtype-specific treatment targets. Notably, the method may be applied to the entire spectrum of neurodegenerative diseases by using a combination of conformation-specific ligands in a physicochemical environment together with other types of polymorphic amyloid variants and assess the conformation-specific features of various protein pathologies. Full article
(This article belongs to the Section Molecular Biology)
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11 pages, 2313 KiB  
Article
Exposure to Radiofrequency Electromagnetic Fields Enhances Melanin Synthesis by Activating the P53 Signaling Pathway in Mel-Ab Melanocytes
by Ju Hwan Kim, Dong-Jun Kang, Jun Young Seok, Mi-Hye Kim, Dong-Seok Kim, Sang-Bong Jeon, Hyung-Do Choi, Jung Ick Moon, Nam Kim and Hak Rim Kim
Int. J. Mol. Sci. 2024, 25(22), 12457; https://doi.org/10.3390/ijms252212457 - 20 Nov 2024
Viewed by 352
Abstract
The skin is the largest body organ that can be physiologically affected by exposure to radiofrequency electromagnetic fields (RF-EMFs). We investigated the effect of RF-EMFs on melanogenesis; Mel-Ab melanocytes were exposed to 1760 MHz radiation with a specific absorption rate of 4.0 W/kg [...] Read more.
The skin is the largest body organ that can be physiologically affected by exposure to radiofrequency electromagnetic fields (RF-EMFs). We investigated the effect of RF-EMFs on melanogenesis; Mel-Ab melanocytes were exposed to 1760 MHz radiation with a specific absorption rate of 4.0 W/kg for 4 h/day over 4 days. Exposure to the RF-EMF led to skin pigmentation, with a significant increase in melanin production in Mel-Ab melanocytes. The phosphorylation level of cAMP response element binding protein (CREB) and the expression of microphthalmia-associated transcription factor (MITF), which regulate the expression of tyrosinase, were significantly increased in Mel-Ab after RF-EMF exposure. Interestingly, the expression of tyrosinase was significantly increased, but tyrosinase activity was unchanged in the RF-EMF-exposed Mel-Ab cells. Additionally, the expression of p53 and melanocortin 1 receptor (MC1R), which regulate MITF expression, was significantly increased. These results suggest that the RF-EMF induces melanogenesis by increasing phospho-CREB and MITF activity. Importantly, when Mel-Ab cells were incubated at 38 °C, the melanin production and the levels of tyrosinase significantly decreased, indicating that the increase in melanin synthesis by RF-EMF exposure is not due to a thermal effect. In conclusion, RF-EMF exposure induces melanogenesis in Mel-Ab cells through the increased expression of tyrosinase via the activation of MITF or the phosphorylation of CREB, which are initiated by the activation of p53 and MC1R. Full article
(This article belongs to the Special Issue Molecular Research Progress of Skin and Skin Diseases)
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25 pages, 5814 KiB  
Article
The Generation of Genetically Engineered Human Induced Pluripotent Stem Cells Overexpressing IFN-β for Future Experimental and Clinically Oriented Studies
by Olga Sheveleva, Elena Protasova, Elena Grigor’eva, Nina Butorina, Valeriia Kuziaeva, Daniil Antonov, Victoria Melnikova, Sergey Medvedev and Irina Lyadova
Int. J. Mol. Sci. 2024, 25(22), 12456; https://doi.org/10.3390/ijms252212456 - 20 Nov 2024
Viewed by 297
Abstract
Induced pluripotent stem cells (iPSCs) can be generated from various adult cells, genetically modified and differentiated into diverse cell populations. Type I interferons (IFN-Is) have multiple immunotherapeutic applications; however, their systemic administration can lead to severe adverse outcomes. One way of overcoming the [...] Read more.
Induced pluripotent stem cells (iPSCs) can be generated from various adult cells, genetically modified and differentiated into diverse cell populations. Type I interferons (IFN-Is) have multiple immunotherapeutic applications; however, their systemic administration can lead to severe adverse outcomes. One way of overcoming the limitation is to introduce cells able to enter the site of pathology and to produce IFN-Is locally. As a first step towards the generation of such cells, here, we aimed to generate human iPSCs overexpressing interferon-beta (IFNB, IFNB-iPSCs). IFNB-iPSCs were obtained by CRISPR/Cas9 editing of the previously generated iPSC line K7-4Lf. IFNB-iPSCs overexpressed IFNB RNA and produced a functionally active IFN-β. The cells displayed typical iPSC morphology and expressed pluripotency markers. Following spontaneous differentiation, IFNB-iPSCs formed embryoid bodies and upregulated endoderm, mesoderm, and some ectoderm markers. However, an upregulation of key neuroectoderm markers, PAX6 and LHX2, was compromised. A negative effect of IFN-β on iPSC neuroectoderm differentiation was confirmed in parental iPSCs differentiated in the presence of a recombinant IFN-β. The study describes new IFN-β-producing iPSC lines suitable for the generation of various types of IFN-β-producing cells for future experimental and clinical applications, and it unravels an inhibitory effect of IFN-β on stem cell neuroectoderm differentiation. Full article
(This article belongs to the Special Issue Diversity of Induced Pluripotent Stem Cells)
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23 pages, 7668 KiB  
Article
Impact of Reduced Saliva Production on Intestinal Integrity and Microbiome Alterations: A Sialoadenectomy Mouse Model Study
by Kanna Maita, Hisako Fujihara, Mitsuki Matsumura, Moeko Miyakawa, Ryoko Baba, Hiroyuki Morimoto, Ryoko Nakayama, Yumi Ito, Koji Kawaguchi and Yoshiki Hamada
Int. J. Mol. Sci. 2024, 25(22), 12455; https://doi.org/10.3390/ijms252212455 - 20 Nov 2024
Viewed by 297
Abstract
This study investigates the effect of reduced saliva production on intestinal histological structure and microbiome composition using a sialoadenectomy murine model, evaluating differences in saliva secretion, body weight, intestinal histopathological changes, and microbiome alteration using 16S rRNA gene sequencing across three groups (control, [...] Read more.
This study investigates the effect of reduced saliva production on intestinal histological structure and microbiome composition using a sialoadenectomy murine model, evaluating differences in saliva secretion, body weight, intestinal histopathological changes, and microbiome alteration using 16S rRNA gene sequencing across three groups (control, sham, and sialoadenectomy). For statistical analysis, one-way analysis of variance and multiple comparisons using Bonferroni correction were performed. p-values < 0.05 were considered statistically significant. Microbiome analysis was performed using Qiime software. The results show that reduced saliva secretion leads to structural changes in the intestinal tract, including shorter and atrophic villi, deformed Paneth cells, decreased goblet cell density, and immunohistochemical changes in epidermal growth factor and poly(ADP-ribose) polymerase-1, especially at three months after surgery. They also showed significant alterations in the intestinal microbiome, including increased Lactobacillaceae and altered populations of Ruminococcaceae and Peptostreptococcaceae, suggesting potential inflammatory responses and decreased short-chain fatty acid production. However, by 12 months after surgery, these effects appeared to be normalized, indicating potential compensatory mechanisms. Interestingly, sham-operated mice displayed favorable profiles, possibly due to immune activation from minor surgical intervention. This study underscores saliva’s essential role in intestinal condition, emphasizing the “oral–gut axis” and highlighting broader implications for the relationship between oral and systemic health. Full article
(This article belongs to the Special Issue Recent Research on Cell and Molecular Biology)
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17 pages, 7325 KiB  
Article
Bioinformatics and Expression Analyses of the TaATLa Gene Subfamily in Wheat (Triticum aestivum L.)
by Yifei Chen, Kexin Zhao, Heng Chen, Luzhen Wang, Shuai Yan, Lei Guo, Jianjun Liu, Haosheng Li, Danping Li, Wenjia Zhang, Xiaoyan Duan, Xiukun Liu, Xinyou Cao and Xin Gao
Int. J. Mol. Sci. 2024, 25(22), 12454; https://doi.org/10.3390/ijms252212454 - 20 Nov 2024
Viewed by 203
Abstract
Amino acids are the main form of nitrogen in plants, and their transport across cell membranes relies on amino acid transporters (AATs). Among the plant AATs, the TaATLa subfamily comprises 18 members, yet the bioinformatics characteristics and functions of TaATLa genes in common [...] Read more.
Amino acids are the main form of nitrogen in plants, and their transport across cell membranes relies on amino acid transporters (AATs). Among the plant AATs, the TaATLa subfamily comprises 18 members, yet the bioinformatics characteristics and functions of TaATLa genes in common wheat remain poorly understood due to their complex genomes. This study performed genomic analyses of TaATLas. These analyses included chromosome distributions, evolutionary relationships, collinearity, gene structures, and expression patterns. An analysis of cis-acting elements and predicted miRNA-TaATLas regulatory networks suggests that TaATLas are regulated by light, hormones, and stress signals. Functional assays revealed that TaATLa6 transports glutamine (Gln), glutamate (Glu), and aspartate (Asp) in yeast. In contrast, TaATLa4 specifically transports Gln and Asp. Furthermore, TaATLas exhibits diverse gene expression patterns, with TaATLa4-7D enhancing yeast heat tolerance in a heterologous expression system, indicating its potential role in adapting to environmental stress by regulating amino acid transport and distribution. This study sheds light on the functional roles of TaATLa genes, with implications for improving nitrogen use in wheat and other crop species. Full article
(This article belongs to the Section Molecular Biology)
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15 pages, 769 KiB  
Review
The Evolving Role of Cannabidiol-Rich Cannabis in People with Autism Spectrum Disorder: A Systematic Review
by Bilal Jawed, Jessica Elisabetta Esposito, Riccardo Pulcini, Syed Khuram Zakir, Matteo Botteghi, Francesco Gaudio, Daniele Savio, Caterina Martinotti, Stefano Martinotti and Elena Toniato
Int. J. Mol. Sci. 2024, 25(22), 12453; https://doi.org/10.3390/ijms252212453 - 20 Nov 2024
Viewed by 263
Abstract
Autism spectrum disorder (ASD) is a neurological disease and lifelong condition. The treatment gap in ASD has led to growing interest in alternative therapies, particularly in phytocannabinoids, which are naturally present in Cannabis sativa. Studies indicate that treatment with cannabidiol (CBD)-rich cannabis [...] Read more.
Autism spectrum disorder (ASD) is a neurological disease and lifelong condition. The treatment gap in ASD has led to growing interest in alternative therapies, particularly in phytocannabinoids, which are naturally present in Cannabis sativa. Studies indicate that treatment with cannabidiol (CBD)-rich cannabis may possess the potential to improve fundamental ASD symptoms as well as comorbid symptoms. This systematic review aims to assess the safety and efficacy of CBD-rich cannabis in alleviating the symptoms of ASD in both children and adults, addressing the treatment gap and growing interest in CBD as an alternative treatment. A comprehensive literature search was conducted in February 2024 using the PUBMED and Scopus databases while following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search focused on studies from 2020 onward involving human populations diagnosed with ASD and treated with CBD. Four studies met the inclusion criteria and were analyzed. The review included 353 participants with ASD from studies conducted in Israel, Turkey, and Brazil. The studies varied in design, sample size, dose, and treatment duration. Dosages of CBD were often combined with trace amounts of THC. Improvements were noted in behavioral symptoms, social responsiveness, and communication, but cognitive benefits were less consistent. Adverse effects ranged in severity. Mild effects such as somnolence and decreased appetite were common, while more concerning effects, including increased aggression, led to some cases of treatment discontinuation. CBD-rich cannabis shows promise in improving behavioral symptoms associated with ASD. However, variations in study designs, dosages, and outcome measures highlight the need for standardized assessment tools and further research to understand pharmacological interactions and optimize treatment protocols. Despite the mild adverse effects observed, larger, well-controlled trials are necessary to establish comprehensive safety and efficacy profiles. Full article
(This article belongs to the Section Molecular Neurobiology)
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18 pages, 1514 KiB  
Article
Probenecid Inhibits Extracellular Signal-Regulated Kinase and c-Jun N-Terminal Kinase Mitogen-Activated Protein Kinase Pathways in Regulating Respiratory Syncytial Virus Response
by Les P. Jones, Harrison C. Bergeron, David E. Martin, Jackelyn Murray, Fred D. Sancilio and Ralph A. Tripp
Int. J. Mol. Sci. 2024, 25(22), 12452; https://doi.org/10.3390/ijms252212452 - 20 Nov 2024
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Abstract
We examined the effect of probenecid in regulating the ERK and JNK downstream MAPK pathways affecting respiratory syncytial virus replication. Background: We have previously shown that probenecid inhibits RSV, influenza virus, and SARS-CoV-2 replication in vitro in preclinical animal models and in humans. [...] Read more.
We examined the effect of probenecid in regulating the ERK and JNK downstream MAPK pathways affecting respiratory syncytial virus replication. Background: We have previously shown that probenecid inhibits RSV, influenza virus, and SARS-CoV-2 replication in vitro in preclinical animal models and in humans. In a Phase two randomized, placebo-controlled, single-blind, dose range-finding study using probenecid to treat non-hospitalized patients with symptomatic, mild-to-moderate COVID-19, we previously showed that a 1000 mg twice daily treatment for 5 days reduced the median time to viral clearance from 11 to 7 days, and a 500 mg twice daily treatment for 5 days reduced the time to viral clearance from 11 to 9 days more than the placebo. Methods: In this study, we sought to determine the mechanism of action of the probenecid inhibition of RSV replication in human respiratory epithelial (A549) cells. Results: We show that probenecid inhibits the RSV-induced phosphorylation of JNKs and ERKs and the downstream phosphorylation of c-jun, a component of the AP-1 transcription complex needed for virus replication. The inhibition of JNKs by probenecid reversed the repression of transcription factor HNF-4. Conclusion: The probenecid inhibition of JNK and ERK phosphorylation involves the MAPK pathway that precludes virus replication. Full article
(This article belongs to the Special Issue MAPK Signaling Cascades in Human Health and Diseases 2.0)
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