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Curr. Issues Mol. Biol., Volume 46, Issue 5 (May 2024) – 68 articles

Cover Story (view full-size image): In this study, we asked whether IFN-I signalling in the CNS is perturbed across the olfactory network in COVID-19 patients. We reconstructed the olfactory pathway from the nasal epithelium to the amygdala, utilizing published datasets of COVID-19 patients’ transcriptomes. We also leveraged published spatially resolved temporal lobe transcriptomes Aβ plaques from AD patients vs. controls, where IFN-I dysregulations have also been identified. We show that IFN-I is dysregulated throughout the olfactory network, and we isolate a gene signature that is shared across the COVID-19 CNS and the spatial response to Αβ pathology, with nine genes associated with an increased risk for Alzheimer’s disease. View this paper
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14 pages, 4090 KiB  
Article
Serine/Arginine-Rich Splicing Factor 7 Knockdown Inhibits Aerobic Glycolysis and Growth in HepG2 Cells by Regulating PKM2 Expression
by Weiye Shi, Xu Yao, Xueyu Cao, Yu Fu and Yingze Wang
Curr. Issues Mol. Biol. 2024, 46(5), 5023-5036; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050301 - 20 May 2024
Viewed by 455
Abstract
Serine/arginine-rich splicing factors (SRSFs), part of the serine/arginine-rich (SR) protein family, play a crucial role in precursor RNA splicing. Abnormal expression of SRSFs in tumors can disrupt normal RNA splicing, contributing to tumor progression. Notably, SRSF7 has been found to be upregulated in [...] Read more.
Serine/arginine-rich splicing factors (SRSFs), part of the serine/arginine-rich (SR) protein family, play a crucial role in precursor RNA splicing. Abnormal expression of SRSFs in tumors can disrupt normal RNA splicing, contributing to tumor progression. Notably, SRSF7 has been found to be upregulated in hepatocellular carcinoma (HCC), yet its specific role and molecular mechanisms in HCC pathogenesis are not fully understood. We investigated the expression and prognostic significance of SRSF7 in HCC using bioinformatics database analysis. In HepG2 cells, the expressions of SRSF7 and glycolytic enzymes were analyzed using qRT-PCR, and Western blot. Glucose uptake and lactate production were quantified using relevant reagent kits. Additionally, cell proliferation, clonogenicity, invasion, and apoptosis were evaluated using MTS assay, clonal formation assay, Transwell assay, and mitochondrial membrane potential assay, respectively. This study demonstrated significant overexpression of SRSF7 in HCC tissue, correlating with poor prognosis. Knockdown of SRSF7 in HepG2 cells resulted in inhibited proliferation, clonogenicity, and invasion, while apoptosis was enhanced. This knockdown also decreased glucose uptake and lactate production, along with a reduction in the expression of glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). Furthermore, SRSF7 downregulation increased the pyruvate kinase muscle 1 (PKM1)/PKM2 ratio. The glycolytic boost due to PKM2 overexpression partially counteracted the effects of SRSF7 silencing on HepG2 cell growth. The knockdown of SRSF7 impairs aerobic glycolysis and growth in HepG2 cells by downregulating PKM2 expression. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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13 pages, 464 KiB  
Article
Improving the Yield of Genetic Diagnosis through Additional Genetic Panel Testing in Hereditary Ophthalmic Diseases
by Jin Gwack, Namsu Kim and Joonhong Park
Curr. Issues Mol. Biol. 2024, 46(5), 5010-5022; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050300 - 20 May 2024
Viewed by 364
Abstract
Numerous hereditary ophthalmic diseases display significant genetic diversity. Consequently, the utilization of gene panel sequencing allows a greater number of patients to receive a genetic diagnosis for their clinical manifestations. We investigated how to improve the yield of genetic diagnosis through additional gene [...] Read more.
Numerous hereditary ophthalmic diseases display significant genetic diversity. Consequently, the utilization of gene panel sequencing allows a greater number of patients to receive a genetic diagnosis for their clinical manifestations. We investigated how to improve the yield of genetic diagnosis through additional gene panel sequencing in hereditary ophthalmic diseases. A gene panel sequencing consisting of a customized hereditary retinopathy panel or hereditary retinitis pigmentosa (RP) panel was prescribed and referred to a CAP-accredited clinical laboratory. If no significant mutations associated with hereditary retinopathy and RP were detected in either panel, additional gene panel sequencing was requested for research use, utilizing the remaining panel. After additional gene panel sequencing, a total of 16 heterozygous or homozygous variants were identified in 15 different genes associated with hereditary ophthalmic diseases. Of 15 patients carrying any candidate variants, the clinical symptoms could be tentatively accounted for by genetic mutations in seven patients. However, in the remaining eight patients, given the in silico mutation predictive analysis, variant allele frequency in gnomAD, inheritance pattern, and genotype–phenotype correlation, fully elucidating the clinical manifestations with the identified rare variant was challenging. Our study highlights the utility of gene panel sequencing in achieving accurate diagnoses for hereditary ophthalmic diseases and enhancing the diagnostic yield through additional gene panel sequencing. Thus, gene panel sequencing can serve as a primary tool for the genetic diagnosis of hereditary ophthalmic diseases, even in cases where a single genetic cause is suspected. With a deeper comprehension of the genetic mechanisms underlying these diseases, it becomes feasible. Full article
(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases 2.0)
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19 pages, 2289 KiB  
Review
Current Knowledge about Gastric Microbiota with Special Emphasis on Helicobacter pylori-Related Gastric Conditions
by Luigi Santacroce, Skender Topi, Lucrezia Bottalico, Ioannis Alexandros Charitos and Emilio Jirillo
Curr. Issues Mol. Biol. 2024, 46(5), 4991-5009; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050299 - 20 May 2024
Viewed by 900
Abstract
The gastric milieu, because of its very low acidic pH, is very harsh for bacterial growth. The discovery of Helicobacter pylori (H.p.) has opened a new avenue for studies on the gastric microbiota, thus indicating that the stomach is not a [...] Read more.
The gastric milieu, because of its very low acidic pH, is very harsh for bacterial growth. The discovery of Helicobacter pylori (H.p.) has opened a new avenue for studies on the gastric microbiota, thus indicating that the stomach is not a sterile environment. Nowadays, new technologies of bacterial identification have demonstrated the existence of other microorganisms in the gastric habitat, which play an important role in health and disease. This bacterium possesses an arsenal of compounds which enable its survival but, at the same time, damage the gastric mucosa. Toxins, such as cytotoxin-associated gene A, vacuolar cytotoxin A, lipopolysaccharides, and adhesins, determine an inflammatory status of the gastric mucosa which may become chronic, ultimately leading to a gastric carcinoma. In the initial stage, H.p. persistence alters the gastric microbiota with a condition of dysbiosis, predisposing to inflammation. Probiotics and prebiotics exhibit beneficial effects on H.p. infection, and, among them, anti-inflammatory, antioxidant, and antibacterial activities are the major ones. Moreover, the association of probiotics with prebiotics (synbiotics) to conventional anti-H.p. therapy contributes to a more efficacious eradication of the bacterium. Also, polyphenols, largely present in the vegetal kingdom, have been demonstrated to alleviate H.p.-dependent pathologies, even including the inhibition of tumorigenesis. The gastric microbiota composition in health and disease is described. Then, cellular and molecular mechanisms of H.p.-mediated damage are clarified. Finally, the use of probiotics, prebiotics, and polyphenols in experimental models and in patients infected with H.p. is discussed. Full article
(This article belongs to the Section Molecular Microbiology)
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23 pages, 354 KiB  
Review
Spatial Multi-Omics in Alzheimer’s Disease: A Multi-Dimensional Approach to Understanding Pathology and Progression
by Yixiao Ma, Wenting Shi, Yahong Dong, Yingjie Sun and Qiguan Jin
Curr. Issues Mol. Biol. 2024, 46(5), 4968-4990; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050298 - 20 May 2024
Viewed by 739
Abstract
Alzheimer’s Disease (AD) presents a complex neuropathological landscape characterized by hallmark amyloid plaques and neurofibrillary tangles, leading to progressive cognitive decline. Despite extensive research, the molecular intricacies contributing to AD pathogenesis are inadequately understood. While single-cell omics technology holds great promise for application [...] Read more.
Alzheimer’s Disease (AD) presents a complex neuropathological landscape characterized by hallmark amyloid plaques and neurofibrillary tangles, leading to progressive cognitive decline. Despite extensive research, the molecular intricacies contributing to AD pathogenesis are inadequately understood. While single-cell omics technology holds great promise for application in AD, particularly in deciphering the understanding of different cell types and analyzing rare cell types and transcriptomic expression changes, it is unable to provide spatial distribution information, which is crucial for understanding the pathological processes of AD. In contrast, spatial multi-omics research emerges as a promising and comprehensive approach to analyzing tissue cells, potentially better suited for addressing these issues in AD. This article focuses on the latest advancements in spatial multi-omics technology and compares various techniques. Additionally, we provide an overview of current spatial omics-based research results in AD. These technologies play a crucial role in facilitating new discoveries and advancing translational AD research in the future. Despite challenges such as balancing resolution, increasing throughput, and data analysis, the application of spatial multi-omics holds immense potential in revolutionizing our understanding of human disease processes and identifying new biomarkers and therapeutic targets, thereby potentially contributing to the advancement of AD research. Full article
(This article belongs to the Section Molecular Medicine)
17 pages, 7181 KiB  
Article
Immunohistochemical Expression Levels of Epidermal Growth Factor Receptor, Cyclooxygenase-2, and Ki-67 in Canine Cutaneous Squamous Cell Carcinomas
by João Miguel Luís, Rita Files, Cláudia Cardoso, José Pimenta, Gabriela Maia, Filipe Silva, Felisbina L. Queiroga, Justina Prada and Isabel Pires
Curr. Issues Mol. Biol. 2024, 46(5), 4951-4967; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050297 - 19 May 2024
Viewed by 633
Abstract
Squamous cell carcinoma (SCC) stands as the second most prevalent skin cancer in dogs, primarily attributed to UV radiation exposure. Affected areas typically include regions with sparse hair and pale or depigmented skin. The significance of spontaneous canine cutaneous SCC as a model [...] Read more.
Squamous cell carcinoma (SCC) stands as the second most prevalent skin cancer in dogs, primarily attributed to UV radiation exposure. Affected areas typically include regions with sparse hair and pale or depigmented skin. The significance of spontaneous canine cutaneous SCC as a model for its human counterpart is underscored by its resemblance. This study assesses the expression of key markers—Epidermal Growth Factor Receptor (EGFR), Cyclooxygenase-2 (Cox-2), and Ki-67—in canine cutaneous SCC. Our objective is to investigate the association between their expression levels and classical clinicopathological parameters, unraveling the intricate relationships among these molecular markers. In our retrospective analysis of 37 cases, EGFR overexpression manifested in 43.2% of cases, while Cox-2 exhibited overexpression in 97.3%. The EGFR, Cox-2 overexpression, and Ki-67 proliferation indices, estimated through immunohistochemistry, displayed a significant association with the histological grade, but only EGFR labeling is associated with the presence of lymphovascular emboli. The Ki-67 labeling index expression exhibited an association with EGFR and Cox-2. These findings propose that EGFR, Cox-2, and Ki-67 hold promise as valuable markers in canine SCC. EGFR, Cox-2, and Ki-67 may serve as indicators of disease progression, offering insights into the malignancy of a lesion. The implications extend to the potential therapeutic targeting of EGFR and Cox-2 in managing canine SCC. Further exploration of these insights is warranted due to their translational relevance and the development of targeted interventions in the context of canine SCC. Full article
(This article belongs to the Special Issue Future Challenges of Targeted Therapy of Cancers)
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16 pages, 6221 KiB  
Article
Modulation of Sirtuin 3 by N-Acetylcysteine Preserves Mitochondrial Oxidative Phosphorylation and Restores Bisphenol A-Induced Kidney Damage in High-Fat-Diet-Fed Rats
by Anongporn Kobroob, Sirinart Kumfu, Nipon Chattipakorn and Orawan Wongmekiat
Curr. Issues Mol. Biol. 2024, 46(5), 4935-4950; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050296 - 18 May 2024
Viewed by 709
Abstract
Bisphenol A (BPA) and high-fat diets (HFD) are known to adversely affect the kidneys. However, the combined effects of both cases on kidney health and the potential benefits of N-acetylcysteine (NAC) in mitigating these effects have not been investigated. To explore these aspects, [...] Read more.
Bisphenol A (BPA) and high-fat diets (HFD) are known to adversely affect the kidneys. However, the combined effects of both cases on kidney health and the potential benefits of N-acetylcysteine (NAC) in mitigating these effects have not been investigated. To explore these aspects, male Wistar rats were fed with HFD and allocated to receive a vehicle or BPA. At week twelve, the BPA-exposed rats were subdivided to receive a vehicle or NAC along with BPA until week sixteen. Rats fed HFD and exposed to BPA showed renal dysfunction and structural abnormalities, oxidative stress, inflammation, and mitochondrial dysfunction, with alterations in key proteins related to mitochondrial oxidative phosphorylation (OXPHOS), bioenergetics, oxidative balance, dynamics, apoptosis, and inflammation. Treatment with NAC for 4 weeks significantly improved these conditions. The findings suggest that NAC is beneficial in protecting renal deterioration brought on by prolonged exposure to BPA in combination with HFD, and modulation of sirtuin 3 (SIRT3) signaling by NAC appears to play a key role in the preservation of homeostasis and integrity within the mitochondria by enhancing OXPHOS activity, maintaining redox balance, and reducing inflammation. This study provides valuable insights into potential therapeutic strategies for preserving kidney health in the face of environmental and dietary challenges. Full article
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11 pages, 1895 KiB  
Communication
Decreased Memory and Learning Ability Mediated by Bmal1/M1 Macrophages/Angptl2/Inflammatory Cytokine Pathway in Mice Exposed to Long-Term Blue Light Irradiation
by Keiichi Hiramoto, Sayaka Kubo, Keiko Tsuji, Daijiro Sugiyama and Hideo Hamano
Curr. Issues Mol. Biol. 2024, 46(5), 4924-4934; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050295 - 18 May 2024
Viewed by 430
Abstract
Humans are persistently exposed to massive amounts of blue light via sunlight, computers, smartphones, and similar devices. Although the positive and negative effects of blue light on living organisms have been reported, its impact on learning and memory remains unknown. Herein, we examined [...] Read more.
Humans are persistently exposed to massive amounts of blue light via sunlight, computers, smartphones, and similar devices. Although the positive and negative effects of blue light on living organisms have been reported, its impact on learning and memory remains unknown. Herein, we examined the effects of widespread blue light exposure on the learning and memory abilities of blue light-exposed mice. Ten-week-old male ICR mice were divided into five groups (five mice/group) and irradiated with blue light from a light-emitting diode daily for 6 months. After 6 months of blue light irradiation, mice exhibited a decline in memory and learning abilities, assessed using the Morris water maze and step-through passive avoidance paradigms. Blue light-irradiated mice exhibited a decreased expression of the clock gene brain and muscle arnt-like 1 (Bmal1). The number of microglia and levels of M1 macrophage CC-chemokine receptor 7 and inducible nitric oxide synthase were increased, accompanied by a decrease in M2 macrophage arginase-1 levels. Levels of angiopoietin-like protein 2 and inflammatory cytokines interleukin-6, tumor necrosis factor-α, and interleukin-1β were elevated. Our findings suggest that long-term blue light exposure could reduce Bmal1 expression, activate the M1 macrophage/Angptl2/inflammatory cytokine pathway, induce neurodegeneration, and lead to a decline in memory. Full article
(This article belongs to the Topic Animal Models of Human Disease 2.0)
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39 pages, 4172 KiB  
Review
Comparing Redox and Intracellular Signalling Responses to Cold Plasma in Wound Healing and Cancer
by Adrian I. Abdo and Zlatko Kopecki
Curr. Issues Mol. Biol. 2024, 46(5), 4885-4923; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050294 - 17 May 2024
Viewed by 850
Abstract
Cold plasma (CP) is an ionised gas containing excited molecules and ions, radicals, and free electrons, and which emits electric fields and UV radiation. CP is potently antimicrobial, and can be applied safely to biological tissue, birthing the field of plasma medicine. Reactive [...] Read more.
Cold plasma (CP) is an ionised gas containing excited molecules and ions, radicals, and free electrons, and which emits electric fields and UV radiation. CP is potently antimicrobial, and can be applied safely to biological tissue, birthing the field of plasma medicine. Reactive oxygen and nitrogen species (RONS) produced by CP affect biological processes directly or indirectly via the modification of cellular lipids, proteins, DNA, and intracellular signalling pathways. CP can be applied at lower levels for oxidative eustress to activate cell proliferation, motility, migration, and antioxidant production in normal cells, mainly potentiated by the unfolded protein response, the nuclear factor-erythroid factor 2-related factor 2 (Nrf2)-activated antioxidant response element, and the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, which also activates nuclear factor-kappa B (NFκB). At higher CP exposures, inactivation, apoptosis, and autophagy of malignant cells can occur via the degradation of the PI3K/Akt and mitogen-activated protein kinase (MAPK)-dependent and -independent activation of the master tumour suppressor p53, leading to caspase-mediated cell death. These opposing responses validate a hormesis approach to plasma medicine. Clinical applications of CP are becoming increasingly realised in wound healing, while clinical effectiveness in tumours is currently coming to light. This review will outline advances in plasma medicine and compare the main redox and intracellular signalling responses to CP in wound healing and cancer. Full article
(This article belongs to the Special Issue Molecular Research on Free Radicals and Oxidative Stress)
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11 pages, 1615 KiB  
Article
Polyhexamethylene Biguanide Reduces High-Risk Human Papilloma Virus Viral Load in Cervical Cell Samples Derived from ThinPrep Pap Test
by Ludovica Di Fraia, Carla Babalini, Marco Calcagno, Sara Proietti, Elisa Lepore and Pietro Di Fraia
Curr. Issues Mol. Biol. 2024, 46(5), 4874-4884; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050293 - 17 May 2024
Viewed by 512
Abstract
Human papilloma virus (HPV) infection and its progression still represent a great medical challenge worldwide. Clinical evidence has demonstrated the beneficial effects of polyhexamethylene biguanide (PHMB) on HPV clinical manifestations; however, evidence of the effect of this molecule on HPV viral load is [...] Read more.
Human papilloma virus (HPV) infection and its progression still represent a great medical challenge worldwide. Clinical evidence has demonstrated the beneficial effects of polyhexamethylene biguanide (PHMB) on HPV clinical manifestations; however, evidence of the effect of this molecule on HPV viral load is still lacking. In this in vitro study, 13 ThinPrep Papanicolaou (Pap) tests were treated with a PHMB solution (0.10 g/100 mL) for 2 h. We observed no cytological changes but a significant reduction in the viral load of high-risk (HR) HPV after PHMB treatment, also revealing a dose-dependent antiviral effect. In addition, by stratifying the obtained results according to HR-HPV genotype, we observed a significant reduction in the viral load of HPV 16, P2 (56, 59, 66), 31, and P3 (35, 39, 68) and a strong decrease in the viral load of HPV 45, 52, and P1 (33, 58). Overall, 85% of the analyzed cervical cell samples exhibited an improvement in HPV viral load after PHMB exposure, while only 15% remain unchanged. For the first time, the data from this pilot study support the activity of PHMB on a specific phase of the HPV viral lifecycle, the one regarding the newly generated virions, reducing viral load and thus blocking the infection of other cervical cells. Full article
(This article belongs to the Special Issue Molecular Mechanism of HPV’s Involvement in Cancers)
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29 pages, 2004 KiB  
Review
Contribution of Endothelial Dysfunction to Cancer Susceptibility and Progression: A Comprehensive Narrative Review on the Genetic Risk Component
by Inês Guerra de Melo, Valéria Tavares, Deolinda Pereira and Rui Medeiros
Curr. Issues Mol. Biol. 2024, 46(5), 4845-4873; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050292 - 16 May 2024
Viewed by 724
Abstract
Venous thromboembolism (VTE) is a challenging clinical obstacle in oncological settings, marked by elevated incidence rates and resulting morbidity and mortality. In the context of cancer-associated thrombosis (CAT), endothelial dysfunction (ED) plays a crucial role in promoting a pro-thrombotic environment as endothelial cells [...] Read more.
Venous thromboembolism (VTE) is a challenging clinical obstacle in oncological settings, marked by elevated incidence rates and resulting morbidity and mortality. In the context of cancer-associated thrombosis (CAT), endothelial dysfunction (ED) plays a crucial role in promoting a pro-thrombotic environment as endothelial cells lose their ability to regulate blood flow and coagulation. Moreover, emerging research suggests that this disorder may not only contribute to CAT but also impact tumorigenesis itself. Indeed, a dysfunctional endothelium may promote resistance to therapy and favour tumour progression and dissemination. While extensive research has elucidated the multifaceted mechanisms of ED pathogenesis, the genetic component remains a focal point of investigation. This comprehensive narrative review thus delves into the genetic landscape of ED and its potential ramifications on cancer progression. A thorough examination of genetic variants, specifically polymorphisms, within key genes involved in ED pathogenesis, namely eNOS, EDN1, ACE, AGT, F2, SELP, SELE, VWF, ICAM1, and VCAM1, was conducted. Overall, these polymorphisms seem to play a context-dependent role, exerting both oncogenic and tumour suppressor effects depending on the tumour and other environmental factors. In-depth studies are needed to uncover the mechanisms connecting these DNA variations to the pathogenesis of malignant diseases. Full article
(This article belongs to the Section Molecular Medicine)
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13 pages, 1803 KiB  
Case Report
Challenging Molecular Diagnosis of Congenital Adrenal Hyperplasia (CAH) Due to 21-Hydroxylase Deficiency: Case Series and Novel Variants of CYP21A2 Gene
by Paola Concolino
Curr. Issues Mol. Biol. 2024, 46(5), 4832-4844; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050291 - 16 May 2024
Viewed by 712
Abstract
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic defects in cortisol synthesis and shows elevated ACTH concentrations, which in turn has downstream effects. The most common variant of CAH, 21-hydroxylase deficiency (21OHD), is the result of pathogenic variants in the [...] Read more.
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic defects in cortisol synthesis and shows elevated ACTH concentrations, which in turn has downstream effects. The most common variant of CAH, 21-hydroxylase deficiency (21OHD), is the result of pathogenic variants in the CYP21A2 gene and is one of the most common monogenic disorders. However, the genetics of 21OHD is complex and challenging. The CYP21A2 gene is located in the RCCX copy number variation (CNV), a complex, multiallelic, and tandem CNV in the major histocompatibility complex (MHC) class III region on chromosome 6 (band 6p21.3). Here, CYP21A2 and its pseudogene CYP21A1P are located 30 kb apart and share a high nucleotide homology of approximately 98% and 96% in exons and introns, respectively. This high-sequence homology facilitates large structural rearrangements, copy number changes, and gene conversion through intergenic recombination. There is a good genotype–phenotype correlation in 21OHD, and genotyping can be performed to confirm the clinical diagnosis, predict long-term outcomes, and determine genetic counseling. Thus, genotyping in CAH is clinically relevant but the interpretations can be challenging for non-initiated clinicians. Here, there are some concrete examples of how molecular diagnosis can sometimes require the use of multiple molecular strategies. Full article
(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases 2.0)
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17 pages, 5527 KiB  
Article
The Biological Impact of Some Phosphonic and Phosphinic Acid Derivatives on Human Osteosarcoma
by Zakzak Khaled, Gheorghe Ilia, Claudia Watz, Ioana Macașoi, George Drăghici, Vasile Simulescu, Petru Eugen Merghes, Narcis Ion Varan, Cristina Adriana Dehelean, Lavinia Vlaia and Laurențiu Sima
Curr. Issues Mol. Biol. 2024, 46(5), 4815-4831; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050290 - 15 May 2024
Viewed by 397
Abstract
Osteosarcoma malignancy currently represents a major health problem; therefore, the need for new therapy approaches is of great interest. In this regard, the current study aims to evaluate the anti-neoplastic potential of a newly developed phosphinic acid derivative (2-carboxyethylphenylphosphinic acid) and, subsequently, to [...] Read more.
Osteosarcoma malignancy currently represents a major health problem; therefore, the need for new therapy approaches is of great interest. In this regard, the current study aims to evaluate the anti-neoplastic potential of a newly developed phosphinic acid derivative (2-carboxyethylphenylphosphinic acid) and, subsequently, to outline its pharmaco-toxicological profile by employing two different in vitro human cell cultures (keratinocytes—HaCaT—and osteosarcoma SAOS-2 cells), employing different techniques (MTT assay, cell morphology assessment, LDH assay, Hoechst staining and RT-PCR). Additionally, the results obtained are compared with three commercially available phosphorus-containing compounds (P1, P2, P3). The results recorded for the newly developed compound (P4) revealed good biocompatibility (cell viability of 77%) when concentrations up to 5 mM were used on HaCaT cells for 24 h. Also, the HaCaT cultures showed no significant morphological alterations or gene modulation, thus achieving a biosafety profile even superior to some of the commercial products tested herein. Moreover, in terms of anti-osteosarcoma activity, 2-carboxyethylphenylphosphinic acid expressed promising activity on SAOS-2 monolayers, the cells showing viability of only 55%, as well as apoptosis features and important gene expression modulation, especially Bid downregulation. Therefore, the newly developed compound should be considered a promising candidate for further in vitro and in vivo research related to osteosarcoma therapy. Full article
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12 pages, 2842 KiB  
Article
Development of MetaXplore: An Interactive Tool for Targeted Metagenomic Analysis
by Naima Bel Mokhtar, Elias Asimakis, Ioannis Galiatsatos, Amal Maurady, Panagiota Stathopoulou and George Tsiamis
Curr. Issues Mol. Biol. 2024, 46(5), 4803-4814; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050289 - 15 May 2024
Viewed by 493
Abstract
Over the last decades, the analysis of complex microbial communities by high-throughput sequencing of marker gene amplicons has become routine work for many research groups. However, the main challenges faced by scientists who want to make use of the generated sequencing datasets are [...] Read more.
Over the last decades, the analysis of complex microbial communities by high-throughput sequencing of marker gene amplicons has become routine work for many research groups. However, the main challenges faced by scientists who want to make use of the generated sequencing datasets are the lack of expertise to select a suitable pipeline and the need for bioinformatics or programming skills to apply it. Here, we present MetaXplore, an interactive, user-friendly platform that enables the discovery and visualization of amplicon sequencing data. Currently, it provides a set of well-documented choices for downstream analysis, including alpha and beta diversity analysis, taxonomic composition, differential abundance analysis, identification of the core microbiome within a population, and biomarker analysis. These features are presented in a user-friendly format that facilitates easy customization and the generation of publication-quality graphics. MetaXplore is implemented entirely in the R language using the Shiny framework. It can be easily used locally on any system with R installed, including Windows, Mac OS, and most Linux distributions, or remotely via a web server without bioinformatic expertise. It can also be used as a framework for advanced users who can modify and expand the tool. Full article
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16 pages, 1009 KiB  
Review
Genetic Susceptibility in Endothelial Injury Syndromes after Hematopoietic Cell Transplantation and Other Cellular Therapies: Climbing a Steep Hill
by Paschalis Evangelidis, Nikolaos Evangelidis, Panagiotis Kalmoukos, Maria Kourti, Athanasios Tragiannidis and Eleni Gavriilaki
Curr. Issues Mol. Biol. 2024, 46(5), 4787-4802; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050288 - 15 May 2024
Viewed by 639
Abstract
Hematopoietic stem cell transplantation (HSCT) remains a cornerstone in the management of patients with hematological malignancies. Endothelial injury syndromes, such as HSCT-associated thrombotic microangiopathy (HSCT-TMA), veno-occlusive disease/sinusoidal obstruction syndrome (SOS/VOD), and capillary leak syndrome (CLS), constitute complications after HSCT. Moreover, endothelial damage is [...] Read more.
Hematopoietic stem cell transplantation (HSCT) remains a cornerstone in the management of patients with hematological malignancies. Endothelial injury syndromes, such as HSCT-associated thrombotic microangiopathy (HSCT-TMA), veno-occlusive disease/sinusoidal obstruction syndrome (SOS/VOD), and capillary leak syndrome (CLS), constitute complications after HSCT. Moreover, endothelial damage is prevalent after immunotherapy with chimeric antigen receptor-T (CAR-T) and can be manifested with cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Our literature review aims to investigate the genetic susceptibility in endothelial injury syndromes after HSCT and CAR-T cell therapy. Variations in complement pathway- and endothelial function-related genes have been associated with the development of HSCT-TMA. In these genes, CFHR5, CFHR1, CFHR3, CFI, ADAMTS13, CFB, C3, C4, C5, and MASP1 are included. Thus, patients with these variations might have a predisposition to complement activation, which is also exaggerated by other factors (such as acute graft-versus-host disease, infections, and calcineurin inhibitors). Few studies have examined the genetic susceptibility to SOS/VOD syndrome, and the implicated genes include CFH, methylenetetrahydrofolate reductase, and heparinase. Finally, specific mutations have been associated with the onset of CRS (PFKFB4, CX3CR1) and ICANS (PPM1D, DNMT3A, TE2, ASXL1). More research is essential in this field to achieve better outcomes for our patients. Full article
(This article belongs to the Section Molecular Medicine)
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19 pages, 1814 KiB  
Review
A Perfect Storm: The Convergence of Aging, Human Immunodeficiency Virus Infection, and Inflammasome Dysregulation
by Siva Thirugnanam and Namita Rout
Curr. Issues Mol. Biol. 2024, 46(5), 4768-4786; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050287 - 15 May 2024
Viewed by 771
Abstract
The emergence of combination antiretroviral therapy (cART) has greatly transformed the life expectancy of people living with HIV (PWH). Today, over 76% of the individuals with HIV have access to this life-saving therapy. However, this progress has come with a new challenge: an [...] Read more.
The emergence of combination antiretroviral therapy (cART) has greatly transformed the life expectancy of people living with HIV (PWH). Today, over 76% of the individuals with HIV have access to this life-saving therapy. However, this progress has come with a new challenge: an increase in age-related non-AIDS conditions among patients with HIV. These conditions manifest earlier in PWH than in uninfected individuals, accelerating the aging process. Like PWH, the uninfected aging population experiences immunosenescence marked by an increased proinflammatory environment. This phenomenon is linked to chronic inflammation, driven in part by cellular structures called inflammasomes. Inflammatory signaling pathways activated by HIV-1 infection play a key role in inflammasome formation, suggesting a crucial link between HIV and a chronic inflammatory state. This review outlines the inflammatory processes triggered by HIV-1 infection and aging, with a focus on the inflammasomes. This review also explores current research regarding inflammasomes and potential strategies for targeting inflammasomes to mitigate inflammation. Further research on inflammasome signaling presents a unique opportunity to develop targeted interventions and innovative therapeutic modalities for combating HIV and aging-associated inflammatory processes. Full article
(This article belongs to the Collection Feature Papers in Molecular Medicine)
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17 pages, 358 KiB  
Review
The Emerging Role of Human Gut Bacteria Extracellular Vesicles in Mental Disorders and Developing New Pharmaceuticals
by Effrosyni Louka and Vassiliki Lila Koumandou
Curr. Issues Mol. Biol. 2024, 46(5), 4751-4767; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050286 - 15 May 2024
Viewed by 711
Abstract
In recent years, further evidence has emerged regarding the involvement of extracellular vesicles in various human physiopathological conditions such as Alzheimer’s disease, Parkinson’s disease, irritable bowel syndrome, and mental disorders. The biogenesis and cargo of such vesicles may reveal their impact on human [...] Read more.
In recent years, further evidence has emerged regarding the involvement of extracellular vesicles in various human physiopathological conditions such as Alzheimer’s disease, Parkinson’s disease, irritable bowel syndrome, and mental disorders. The biogenesis and cargo of such vesicles may reveal their impact on human health nd disease and set the underpinnings for the development of novel chemical compounds and pharmaceuticals. In this review, we examine the link between bacteria-derived exosomes in the gastrointestinal tract and mental disorders, such as depression and anxiety disorders. Crucially, we focus on whether changes in the gut environment affect the human mental state or the other way around. Furthermore, the possibility of handling bacteria-derived exosomes as vectors of chemicals to treat such conditions is examined. Full article
(This article belongs to the Special Issue Exosomes and Extracellular Vesicles in Neuroprotection)
30 pages, 3426 KiB  
Review
Molecular Basis of Yeasts Antimicrobial Activity—Developing Innovative Strategies for Biomedicine and Biocontrol
by Ana-Maria Georgescu, Viorica Maria Corbu and Ortansa Csutak
Curr. Issues Mol. Biol. 2024, 46(5), 4721-4750; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050285 - 14 May 2024
Viewed by 781
Abstract
In the context of the growing concern regarding the appearance and spread of emerging pathogens with high resistance to chemically synthetized biocides, the development of new agents for crops and human protection has become an emergency. In this context, the yeasts present a [...] Read more.
In the context of the growing concern regarding the appearance and spread of emerging pathogens with high resistance to chemically synthetized biocides, the development of new agents for crops and human protection has become an emergency. In this context, the yeasts present a huge potential as eco-friendly agents due to their widespread nature in various habitats and to their wide range of antagonistic mechanisms. The present review focuses on some of the major yeast antimicrobial mechanisms, their molecular basis and practical applications in biocontrol and biomedicine. The synthesis of killer toxins, encoded by dsRNA virus-like particles, dsDNA plasmids or chromosomal genes, is encountered in a wide range of yeast species from nature and industry and can affect the development of phytopathogenic fungi and other yeast strains, as well as human pathogenic bacteria. The group of the “red yeasts” is gaining more interest over the last years, not only as natural producers of carotenoids and rhodotorulic acid with active role in cell protection against the oxidative stress, but also due to their ability to inhibit the growth of pathogenic yeasts, fungi and bacteria using these compounds and the mechanism of competition for nutritive substrate. Finally, the biosurfactants produced by yeasts characterized by high stability, specificity and biodegrability have proven abilities to inhibit phytopathogenic fungi growth and mycelia formation and to act as efficient antibacterial and antibiofilm formation agents for biomedicine. In conclusion, the antimicrobial activity of yeasts represents a direction of research with numerous possibilities of bioeconomic valorization as innovative strategies to combat pathogenic microorganisms. Full article
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20 pages, 34930 KiB  
Article
A Spatial Transcriptomics Browser for Discovering Gene Expression Landscapes across Microscopic Tissue Sections
by Maria Schmidt, Susanna Avagyan, Kristin Reiche, Hans Binder and Henry Loeffler-Wirth
Curr. Issues Mol. Biol. 2024, 46(5), 4701-4720; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050284 - 13 May 2024
Viewed by 607
Abstract
A crucial feature of life is its spatial organization and compartmentalization on the molecular, cellular, and tissue levels. Spatial transcriptomics (ST) technology has opened a new chapter of the sequencing revolution, emerging rapidly with transformative effects across biology. This technique produces extensive and [...] Read more.
A crucial feature of life is its spatial organization and compartmentalization on the molecular, cellular, and tissue levels. Spatial transcriptomics (ST) technology has opened a new chapter of the sequencing revolution, emerging rapidly with transformative effects across biology. This technique produces extensive and complex sequencing data, raising the need for computational methods for their comprehensive analysis and interpretation. We developed the ST browser web tool for the interactive discovery of ST images, focusing on different functional aspects such as single gene expression, the expression of functional gene sets, as well as the inspection of the spatial patterns of cell–cell interactions. As a unique feature, our tool applies self-organizing map (SOM) machine learning to the ST data. Our SOM data portrayal method generates individual gene expression landscapes for each spot in the ST image, enabling its downstream analysis with high resolution. The performance of the spatial browser is demonstrated by disentangling the intra-tumoral heterogeneity of melanoma and the microarchitecture of the mouse brain. The integration of machine-learning-based SOM portrayal into an interactive ST analysis environment opens novel perspectives for the comprehensive knowledge mining of the organization and interactions of cellular ecosystems. Full article
(This article belongs to the Section Bioinformatics and Systems Biology)
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13 pages, 1778 KiB  
Article
CDDO, an Anti-Inflammatory and Antioxidant Compound, Attenuates Vasospasm and Neuronal Cell Apoptosis in Rats Subjected to Experimental Subarachnoid Hemorrhage
by William Winardi, Yun-Ping Lo, Hung-Pei Tsai, Yu-Hua Huang, Tzu-Ting Tseng and Chia-Li Chung
Curr. Issues Mol. Biol. 2024, 46(5), 4688-4700; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050283 - 13 May 2024
Viewed by 478
Abstract
Subarachnoid hemorrhage (SAH) is a type of stroke caused by bleeding into the subarachnoid space. SAH is a medical emergency and requires prompt treatment to prevent complications such as seizures, stroke, or other brain damage. Treatment options may include surgery, medication, or a [...] Read more.
Subarachnoid hemorrhage (SAH) is a type of stroke caused by bleeding into the subarachnoid space. SAH is a medical emergency and requires prompt treatment to prevent complications such as seizures, stroke, or other brain damage. Treatment options may include surgery, medication, or a combination of both. 2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), a compound with anti-inflammatory and antioxidant properties, is currently being investigated as a potential treatment for various diseases, including chronic kidney disease and pulmonary arterial hypertension. In this study, the effects of CDDO on rats subjected to SAH were evaluated. Male Sprague-Dawley rats were divided into four groups (n = 6/group): (1) control group, (2) SAH group, (3) SAH + low-dose CDDO (10 mg/kg injected into the subarachnoid space at 24 h after SAH) group, and (4) SAH + high-dose CDDO (20 mg/kg) group. CDDO improved SAH-induced poor neurological outcomes and reduced vasospasm in the basal artery following SAH. It also decreased the SAH-induced expression of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 in both the cerebrospinal fluid and serum samples as determined by ELISA. A Western blot analysis confirmed an increase in the p-NF-κB protein level after SAH, but it was significantly decreased with CDDO intervention. Immunofluorescence staining highlighted the proliferation of microglia and astrocytes as well as apoptosis of the neuronal cells after SAH, and treatment with CDDO markedly reduced the proliferation of these glial cells and apoptosis of the neuronal cells. The early administration of CDDO after SAH may effectively mitigate neuronal apoptosis and vasospasm by suppressing inflammation. Full article
(This article belongs to the Special Issue Molecular Mechanism and Regulation in Neuroinflammation)
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42 pages, 3774 KiB  
Review
Oxidative Stress in Breast Cancer: A Biochemical Map of Reactive Oxygen Species Production
by Lyudmila V. Bel’skaya and Elena I. Dyachenko
Curr. Issues Mol. Biol. 2024, 46(5), 4646-4687; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050282 - 13 May 2024
Viewed by 744
Abstract
This review systematizes information about the metabolic features of breast cancer directly related to oxidative stress. It has been shown those redox changes occur at all levels and affect many regulatory systems in the human body. The features of the biochemical processes occurring [...] Read more.
This review systematizes information about the metabolic features of breast cancer directly related to oxidative stress. It has been shown those redox changes occur at all levels and affect many regulatory systems in the human body. The features of the biochemical processes occurring in breast cancer are described, ranging from nonspecific, at first glance, and strictly biochemical to hormone-induced reactions, genetic and epigenetic regulation, which allows for a broader and deeper understanding of the principles of oncogenesis, as well as maintaining the viability of cancer cells in the mammary gland. Specific pathways of the activation of oxidative stress have been studied as a response to the overproduction of stress hormones and estrogens, and specific ways to reduce its negative impact have been described. The diversity of participants that trigger redox reactions from different sides is considered more fully: glycolytic activity in breast cancer, and the nature of consumption of amino acids and metals. The role of metals in oxidative stress is discussed in detail. They can act as both co-factors and direct participants in oxidative stress, since they are either a trigger mechanism for lipid peroxidation or capable of activating signaling pathways that affect tumorigenesis. Special attention has been paid to the genetic and epigenetic regulation of breast tumors. A complex cascade of mechanisms of epigenetic regulation is explained, which made it possible to reconsider the existing opinion about the triggers and pathways for launching the oncological process, the survival of cancer cells and their ability to localize. Full article
(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 2nd Edition)
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16 pages, 855 KiB  
Article
The Molecular Detection of Germline Mutations in the BRCA1 and BRCA2 Genes Associated with Breast and Ovarian Cancer in a Romanian Cohort of 616 Patients
by Liliana-Georgiana Grigore, Viorica-Elena Radoi, Alexandra Serban, Adina Daniela Mihai and Ileana Stoica
Curr. Issues Mol. Biol. 2024, 46(5), 4630-4645; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050281 - 12 May 2024
Viewed by 674
Abstract
The objective of this study was to identify and classify the spectrum of mutations found in the BRCA1 and BRCA2 genes associated with breast and ovarian cancer in female patients in Romania. Germline BRCA1 and BRCA2 mutations were investigated in a cohort of [...] Read more.
The objective of this study was to identify and classify the spectrum of mutations found in the BRCA1 and BRCA2 genes associated with breast and ovarian cancer in female patients in Romania. Germline BRCA1 and BRCA2 mutations were investigated in a cohort of 616 female patients using NGS and/or MLPA methods followed by software-based data analysis and classification according to international guidelines. Out of the 616 female patients included in this study, we found that 482 patients (78.2%) did not have any mutation present in the two genes investigated; 69 patients (11.2%) had a BRCA1 mutation, 34 (5.5%) had a BRCA2 mutation, and 31 (5%) presented different type of mutations with uncertain clinical significance, moderate risk or a large mutation in the BRCA1 gene. Our investigation indicates the most common mutations in the BRCA1 and BRCA2 genes, associated with breast and ovarian cancer in the Romanian population. Our results also bring more data in support of the frequency of the c.5266 mutation in the BRCA1 gene, acknowledged in the literature as a founder mutation in Eastern Europe. We consider that the results of our study will provide necessary data regarding BRCA1 and BRCA2 mutations that would help to create a genetic database for the Romanian population. Full article
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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21 pages, 3927 KiB  
Article
In Silico Analysis of Protein–Protein Interactions of Putative Endoplasmic Reticulum Metallopeptidase 1 in Schizosaccharomyces pombe
by Dalia González-Esparragoza, Alan Carrasco-Carballo, Nora H. Rosas-Murrieta, Lourdes Millán-Pérez Peña, Felix Luna and Irma Herrera-Camacho
Curr. Issues Mol. Biol. 2024, 46(5), 4609-4629; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050280 - 12 May 2024
Viewed by 646
Abstract
Ermp1 is a putative metalloprotease from Schizosaccharomyces pombe and a member of the Fxna peptidases. Although their function is unknown, orthologous proteins from rats and humans have been associated with the maturation of ovarian follicles and increased ER stress. This study focuses on [...] Read more.
Ermp1 is a putative metalloprotease from Schizosaccharomyces pombe and a member of the Fxna peptidases. Although their function is unknown, orthologous proteins from rats and humans have been associated with the maturation of ovarian follicles and increased ER stress. This study focuses on proposing the first prediction of PPI by comparison of the interologues between humans and yeasts, as well as the molecular docking and dynamics of the M28 domain of Ermp1 with possible target proteins. As results, 45 proteins are proposed that could interact with the metalloprotease. Most of these proteins are related to the transport of Ca2+ and the metabolism of amino acids and proteins. Docking and molecular dynamics suggest that the M28 domain of Ermp1 could hydrolyze leucine and methionine residues of Amk2, Ypt5 and Pex12. These results could support future experimental investigations of other Fxna peptidases, such as human ERMP1. Full article
(This article belongs to the Special Issue Structure and Function of Proteins: From Bioinformatics Insights)
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14 pages, 1482 KiB  
Review
Proteogenomics in Nephrology: A New Frontier in Nephrological Research
by Kavya Chavali, Holley Coker, Emily Youngblood and Oleg Karaduta
Curr. Issues Mol. Biol. 2024, 46(5), 4595-4608; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050279 - 11 May 2024
Viewed by 656
Abstract
Proteogenomics represents a transformative intersection in nephrology, uniting genomics, transcriptomics, and proteomics to unravel the molecular intricacies of kidney diseases. This review encapsulates the methodological essence of proteogenomics and its profound implications in chronic kidney disease (CKD) research. We explore the proteogenomic pipeline, [...] Read more.
Proteogenomics represents a transformative intersection in nephrology, uniting genomics, transcriptomics, and proteomics to unravel the molecular intricacies of kidney diseases. This review encapsulates the methodological essence of proteogenomics and its profound implications in chronic kidney disease (CKD) research. We explore the proteogenomic pipeline, highlighting the integrated analysis of genomic, transcriptomic, and proteomic data and its pivotal role in enhancing our understanding of kidney pathologies. Through case studies, we showcase the application of proteogenomics in clear cell renal cell carcinoma (ccRCC) and Autosomal Recessive Polycystic Kidney Disease (ARPKD), emphasizing its potential in personalized treatment strategies and biomarker discovery. The review also addresses the challenges in proteogenomic analysis, including data integration complexities and bioinformatics limitations, and proposes solutions for advancing the field. Ultimately, this review underscores the prospective future of proteogenomics in nephrology, particularly in advancing personalized medicine and providing novel therapeutic insights. Full article
(This article belongs to the Section Molecular Medicine)
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15 pages, 3807 KiB  
Article
Ajania pacifica (Nakai) K. Bremer and Humphries Extract Limits MYC Expression to Induce Apoptosis in Diffuse Large B Cell Lymphoma
by Ye-Rin Woo, Chan-Seong Kwon, Ji-Eun Lee, Byeol-Eun Jeon, Tae-Jin Kim, Joy Choo, Young-Seob Seo and Sang-Woo Kim
Curr. Issues Mol. Biol. 2024, 46(5), 4580-4594; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050278 - 11 May 2024
Viewed by 468
Abstract
The proto-oncogene MYC is frequently dysregulated in patients with diffuse large B-cell lymphoma (DLBCL) and plays a critical role in disease progression. To improve the clinical outcomes of patients with DLBCL, the development of strategies to target MYC is crucial. The use of [...] Read more.
The proto-oncogene MYC is frequently dysregulated in patients with diffuse large B-cell lymphoma (DLBCL) and plays a critical role in disease progression. To improve the clinical outcomes of patients with DLBCL, the development of strategies to target MYC is crucial. The use of medicinal plants for developing anticancer drugs has garnered considerable attention owing to their diverse mechanisms of action. In this study, 100 plant extracts of flora from the Republic of Korea were screened to search for novel agents with anti-DLBCL effects. Among them, Ajania pacifica (Nakai) K. Bremer and Humphries extract (APKH) efficiently suppressed the survival of DLBCL cells, while showing minimal toxicity toward normal murine bone marrow cells. APKH suppressed the expression of anti-apoptotic BCL2 family members, causing an imbalance between the pro-apoptotic and anti-apoptotic BCL2 members. This disrupted mitochondrial membrane potential, cytochrome c release, and pro-caspase-3 activation and eventually led to DLBCL cell death. Importantly, MYC expression was markedly downregulated by APKH and ectopic expression of MYC in DLBCL cells abolished the pro-apoptotic effects of APKH. These results demonstrate that APKH exerts anti-DLBCL effects by inhibiting MYC expression. Moreover, when combined with doxorubicin, an essential component of the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone), APKH synergistically enhanced the therapeutic effect of doxorubicin. This indicates that APKH may overcome drug resistance, which is common in patients with refractory/relapsed DLBCL. To identify compounds with anti-DLBCL activities in APKH, the chemical profile analysis of APKH was performed using UPLC-QTOF/MSe analysis and assessed for its anticancer activity. Based on the UPLC-QTOF/MSe chemical profiling, it is conceivable that APKH may serve as a novel agent targeting MYC and sensitizing drug-resistant DLBCL cells to CHOP chemotherapy. Further studies to elucidate how the compounds in APKH exert tumor-suppressive role in DLBCL are warranted. Full article
(This article belongs to the Special Issue Natural Products and Their Biological Activities)
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15 pages, 949 KiB  
Article
SARS-CoV-2-Induced Type I Interferon Signaling Dysregulation in Olfactory Networks Implications for Alzheimer’s Disease
by George D. Vavougios, Theodoros Mavridis, Triantafyllos Doskas, Olga Papaggeli, Pelagia Foka and Georgios Hadjigeorgiou
Curr. Issues Mol. Biol. 2024, 46(5), 4565-4579; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050277 - 10 May 2024
Viewed by 1542
Abstract
Type I interferon signaling (IFN-I) perturbations are major drivers of COVID-19. Dysregulated IFN-I in the brain, however, has been linked to both reduced cognitive resilience and neurodegenerative diseases such as Alzheimer’s. Previous works from our group have proposed a model where peripheral induction [...] Read more.
Type I interferon signaling (IFN-I) perturbations are major drivers of COVID-19. Dysregulated IFN-I in the brain, however, has been linked to both reduced cognitive resilience and neurodegenerative diseases such as Alzheimer’s. Previous works from our group have proposed a model where peripheral induction of IFN-I may be relayed to the CNS, even in the absence of fulminant infection. The aim of our study was to identify significantly enriched IFN-I signatures and genes along the transolfactory route, utilizing published datasets of the nasal mucosa and olfactory bulb amygdala transcriptomes of COVID-19 patients. We furthermore sought to identify these IFN-I signature gene networks associated with Alzheimer’s disease pathology and risk. Gene expression data involving the nasal epithelium, olfactory bulb, and amygdala of COVID-19 patients and transcriptomic data from Alzheimer’s disease patients were scrutinized for enriched Type I interferon pathways. Gene set enrichment analyses and gene–Venn approaches were used to determine genes in IFN-I enriched signatures. The Agora web resource was used to identify genes in IFN-I signatures associated with Alzheimer’s disease risk based on its aggregated multi-omic data. For all analyses, false discovery rates (FDR) <0.05 were considered statistically significant. Pathways associated with type I interferon signaling were found in all samples tested. Each type I interferon signature was enriched by IFITM and OAS family genes. A 14-gene signature was associated with COVID-19 CNS and the response to Alzheimer’s disease pathology, whereas nine genes were associated with increased risk for Alzheimer’s disease based on Agora. Our study provides further support to a type I interferon signaling dysregulation along the extended olfactory network as reconstructed herein, ranging from the nasal epithelium and extending to the amygdala. We furthermore identify the 14 genes implicated in this dysregulated pathway with Alzheimer’s disease pathology, among which HLA-C, HLA-B, HLA-A, PSMB8, IFITM3, HLA-E, IFITM1, OAS2, and MX1 as genes with associated conferring increased risk for the latter. Further research into its druggability by IFNb therapeutics may be warranted. Full article
(This article belongs to the Special Issue Advanced Research in Neuroinflammation)
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14 pages, 1059 KiB  
Review
Adverse Skeletal Muscle Adaptations in Individuals Born Preterm—A Comprehensive Review
by Nick L. Dobson, Danielle E. Levitt, Hui Ying Luk and Heather L. Vellers
Curr. Issues Mol. Biol. 2024, 46(5), 4551-4564; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050276 - 10 May 2024
Cited by 1 | Viewed by 750
Abstract
Infants born preterm face an increased risk of deleterious effects on lung and brain health that can significantly alter long-term function and quality of life and even lead to death. Moreover, preterm birth is also associated with a heightened risk of diabetes and [...] Read more.
Infants born preterm face an increased risk of deleterious effects on lung and brain health that can significantly alter long-term function and quality of life and even lead to death. Moreover, preterm birth is also associated with a heightened risk of diabetes and obesity later in life, leading to an increased risk of all-cause mortality in young adults born prematurely. While these preterm-birth-related conditions have been well characterized, less is known about the long-term effects of preterm birth on skeletal muscle health and, specifically, an individual’s skeletal muscle hypertrophic potential later in life. In this review, we discuss how a confluence of potentially interrelated and self-perpetuating elements associated with preterm birth might converge on anabolic and catabolic pathways to ultimately blunt skeletal muscle hypertrophy, identifying critical areas for future research. Full article
(This article belongs to the Collection Molecular Mechanisms in Human Diseases)
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18 pages, 310 KiB  
Article
Serum Levels of Zinc, Albumin, Interleukin-6 and CRP in Patients with Unipolar and Bipolar Depression: Cross Sectional Study
by Tihana Bagarić, Alma Mihaljević-Peleš, Milena Skočić Hanžek, Maja Živković, Ana Kozmar and Dunja Rogić
Curr. Issues Mol. Biol. 2024, 46(5), 4533-4550; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050275 - 9 May 2024
Viewed by 468
Abstract
Unipolar (UD) and bipolar depression (BDD) show a high degree of similarity in clinical presentations, which complicates the differential diagnosis of these disorders. The aim of this study was to investigate the serum levels of interleukin 6 (IL-6), C-reactive protein (CRP), albumin (Alb), [...] Read more.
Unipolar (UD) and bipolar depression (BDD) show a high degree of similarity in clinical presentations, which complicates the differential diagnosis of these disorders. The aim of this study was to investigate the serum levels of interleukin 6 (IL-6), C-reactive protein (CRP), albumin (Alb), and zinc (Zn) in patients with UD, BDD, and healthy controls (HC). A total of 211 samples were collected: 131 patient samples (65 UD and 68 BDD) and 80 HC. The Montgomery–Asberg Depression Rating Scale (MADRS), along with the Hamilton Depression Rating Scale (HAMD-17), were administered to patient groups to evaluate symptoms. A cross-sectional study was performed to analyse the serum levels of IL-6, CRP, albumin, and zinc. The concentration of CRP was determined using the immunoturbidimetry method, zinc using the colorimetric method, and albumin using the colorimetric method with bromocresol green on the Alinity c device. IL-6 cytokine concentration in serum samples was ascertained using a commercial enzyme immunoassay, ELISA. We found no significant differences in serum concentrations of zinc, albumin, CRP, and IL-6 between the groups of patients with unipolar and bipolar depression. There was a significant statistical difference (p < 0.001) between serum levels of all investigated parameters in both groups of depressed patients in comparison with HC. Furthermore, correlations with specific items on HAMD-17; (namely, hypochondrias, work and activities, somatic symptoms-general, and weight loss) and on MADRS (concentration difficulties, lassitude) were observed in both patient groups. These findings confirm the presence of low-grade inflammation in depression, thus adding better insight into the inflammation hypothesis directed to explain the aetiology of depressive disorders. Our results do not indicate potential biomarkers for distinguishing between unipolar and bipolar depression. Full article
(This article belongs to the Special Issue Molecules at Play in Neurological Diseases 2024)
14 pages, 586 KiB  
Review
Role of NR5A1 Gene Mutations in Disorders of Sex Development: Molecular and Clinical Features
by Giovanni Luppino, Malgorzata Wasniewska, Roberto Coco, Giorgia Pepe, Letteria Anna Morabito, Alessandra Li Pomi, Domenico Corica and Tommaso Aversa
Curr. Issues Mol. Biol. 2024, 46(5), 4519-4532; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050274 - 9 May 2024
Viewed by 535
Abstract
Disorders/differences of sex development (DSDs) are defined as broad, heterogenous groups of congenital conditions characterized by atypical development of genetic, gonadal, or phenotypic sex accompanied by abnormal development of internal and/or external genitalia. NR5A1 gene mutation is one of the principal genetic alterations [...] Read more.
Disorders/differences of sex development (DSDs) are defined as broad, heterogenous groups of congenital conditions characterized by atypical development of genetic, gonadal, or phenotypic sex accompanied by abnormal development of internal and/or external genitalia. NR5A1 gene mutation is one of the principal genetic alterations implicated in causing DSD. This review outlines the role of NR5A1 gene during the process of gonadal development in humans, provides an overview of the molecular and functional characteristics of NR5A1 gene, and discusses potential clinical phenotypes and additional organ diseases due to NR5A1 mutations. NR5A1 mutations were analyzed in patients with 46,XY DSD and 46,XX DSD both during the neonatal and pubertal periods. Loss of function of the NR5A1 gene causes several different phenotypes, including some associated with disease in additional organs. Clinical phenotypes may vary, even among patients carrying the same NR5A1 variant, indicating that there is no specific genotype–phenotype correlation. Genetic tests are crucial diagnostic tools that should be used early in the diagnostic pathway, as early as the neonatal period, when gonadal dysgenesis is the main manifestation of NR5A1 mutation. NR5A1 gene mutations could be mainly associated with amenorrhea, ovarian failure, hypogonadism, and infertility during puberty. Fertility preservation techniques should be considered as early as possible. Full article
(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases 2.0)
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13 pages, 6416 KiB  
Article
Evaluation of the Therapeutical Effect of Matricaria Chamomilla Extract vs. Galantamine on Animal Model Memory and Behavior Using 18F-FDG PET/MRI
by Roxana Iacob, Matei Palimariciuc, Tudor Florea, Cosmin Vasilica Pricope, Cristina Mariana Uritu, Bogdan Ionel Tamba, Teodor Marian Ionescu, Cati Raluca Stolniceanu, Wael Jalloul, Romeo Petru Dobrin, Lucian Hritcu, Oana Cioanca, Monica Hancianu, Alexandru Gratian Naum and Cipriana Stefanescu
Curr. Issues Mol. Biol. 2024, 46(5), 4506-4518; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050273 - 9 May 2024
Viewed by 508
Abstract
The memory-enhancing activity of Matricaria chamomilla hydroalcoholic extract (MCE) is already being investigated by behavioral and biochemical assays in scopolamine-induced amnesia rat models, while the effects of scopolamine (Sco) on cerebral glucose metabolism are examined as well. Nevertheless, the study of the metabolic [...] Read more.
The memory-enhancing activity of Matricaria chamomilla hydroalcoholic extract (MCE) is already being investigated by behavioral and biochemical assays in scopolamine-induced amnesia rat models, while the effects of scopolamine (Sco) on cerebral glucose metabolism are examined as well. Nevertheless, the study of the metabolic profile determined by an enriched MCE has not been performed before. The present experiments compared metabolic quantification in characteristic cerebral regions and behavioral characteristics for normal, only diseased, diseased, and MCE- vs. Galantamine (Gal)-treated Wistar rats. A memory deficit was induced by four weeks of daily intraperitoneal Sco injection. Starting on the eighth day, the treatment was intraperitoneally administered 30 min after Sco injection for a period of three weeks. The memory assessment comprised three maze tests. Glucose metabolism was quantified after the 18F-FDG PET examination. The right amygdala, piriform, and entorhinal cortex showed the highest differential radiopharmaceutical uptake of the 50 regions analyzed. Rats treated with MCE show metabolic similarity with normal rats, while the Gal-treated group shows features closer to the diseased group. Behavioral assessments evidenced a less anxious status and a better locomotor activity manifested by the MCE-treated group compared to the Gal-treated group. These findings prove evident metabolic ameliorative qualities of MCE over Gal classic treatment, suggesting that the extract could be a potent neuropharmacological agent against amnesia. Full article
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17 pages, 7769 KiB  
Article
A Novel Approach Using Reduced Graphene Oxide for the Detection of ALP and RUNX2 Osteogenic Biomarkers
by Elena Alina Chiticaru and Mariana Ioniță
Curr. Issues Mol. Biol. 2024, 46(5), 4489-4505; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46050272 - 8 May 2024
Viewed by 618
Abstract
In this work, we propose a new technique involving the modification of commercial screen-printed carbon electrodes with electrochemically reduced graphene oxide to serve as the starting point of a future electrochemical biosensor for the detection of two osteogenic biomarkers: alkaline phosphatase (ALP) and [...] Read more.
In this work, we propose a new technique involving the modification of commercial screen-printed carbon electrodes with electrochemically reduced graphene oxide to serve as the starting point of a future electrochemical biosensor for the detection of two osteogenic biomarkers: alkaline phosphatase (ALP) and Runt-related transcription factor 2 (RUNX2). The electrodes were characterized after each modification by cyclic voltammetry and electrochemical impedance spectroscopy, showing the appropriate electrochemical characteristics for each modification type. The results obtained from scanning electron microscopy, Raman spectroscopy, X-ray photoelectron spectroscopy, and contact angle measurements are well correlated with each other, demonstrating the successful modification of the electrodes with graphene oxide and its subsequent reduction. The bioreceptors were immobilized on the electrodes by physical adsorption, which was confirmed by electrochemical methods, structural characterization, and contact angle measurements. Finally, the functionalized electrodes were incubated with the specific target analytes and the detection relied on monitoring the electrochemical changes occurring after the hybridization process. Our results indicated that the pilot platform has the ability to detect the two biomarkers up to 1 nM, with increased sensitivity observed for RUNX2, suggesting that after further optimizations, it has a high potential to be employed as a future biosensor. Full article
(This article belongs to the Special Issue Molecular Imaging of Cells and Tissues)
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