Current Issues in Molecular Biology

15 pages, 938 KiB

Open AccessReview

A New Frontier in Cystic Fibrosis Pathophysiology: How and When Clock Genes Can Affect the Inflammatory/Immune Response in a Genetic Disease Model

by Annalucia Carbone, Pamela Vitullo, Sante Di Gioia, Stefano Castellani and Massimo Conese

Curr. Issues Mol. Biol. 2024, 46(9), 10396-10410; https://doi.org/10.3390/cimb46090618 (registering DOI) - 18 Sep 2024

Abstract

Cystic fibrosis (CF) is a monogenic syndrome caused by variants in the CF Transmembrane Conductance Regulator (CFTR) gene, affecting various organ and systems, in particular the lung, pancreas, sweat glands, liver, gastrointestinal tract, vas deferens, and vascular system. While for some [...] Read more.

Cystic fibrosis (CF) is a monogenic syndrome caused by variants in the CF Transmembrane Conductance Regulator (CFTR) gene, affecting various organ and systems, in particular the lung, pancreas, sweat glands, liver, gastrointestinal tract, vas deferens, and vascular system. While for some organs, e.g., the pancreas, a strict genotype-phenotype occurs, others, such as the lung, display a different pathophysiologic outcome in the presence of the same mutational asset, arguing for genetic and environmental modifiers influencing severity and clinical trajectory. CFTR variants trigger a pathophysiological cascade of events responsible for chronic inflammatory responses, many aspects of which, especially related to immunity, are not ascertained yet. Although clock genes expression and function are known modulators of the innate and adaptive immunity, their involvement in CF has been only observed in relation to sleep abnormalities. The aim of this review is to present current evidence on the clock genes role in immune-inflammatory responses at the lung level. While information on this topic is known in other chronic airway diseases (chronic obstructive pulmonary disease and asthma), CF lung disease (CFLD) is lacking in this knowledge. We will present the bidirectional effect between clock genes and inflammatory factors that could possibly be implicated in the CFLD. It must be stressed that besides sleep disturbance and its mechanisms, there are not studies directly addressing the exact nature of clock genes’ involvement in inflammation and immunity in CF, pointing out the directions of new and deepened studies in this monogenic affection. Importantly, clock genes have been found to be druggable by means of genetic tools or pharmacological agents, and this could have therapeutic implications in CFLD. Full article

(This article belongs to the Special Issue Complex Molecular Mechanism of Monogenic Diseases: 3rd Edition)

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27 pages, 2003 KiB

Open AccessReview

Analysis of Beyfortus^® (Nirsevimab) Immunization Campaign: Effectiveness, Biases, and ADE Risks in RSV Prevention

by Hélène Banoun

Curr. Issues Mol. Biol. 2024, 46(9), 10369-10395; https://doi.org/10.3390/cimb46090617 (registering DOI) - 18 Sep 2024

Abstract

Respiratory infections with respiratory syncytial virus (RSV) account for an important part of hospital admissions for acute respiratory infections. Nirsevimab has been developed to reduce the hospital burden of RSV infections. Compared with the product previously used, it has a stronger binding capacity [...] Read more.

Respiratory infections with respiratory syncytial virus (RSV) account for an important part of hospital admissions for acute respiratory infections. Nirsevimab has been developed to reduce the hospital burden of RSV infections. Compared with the product previously used, it has a stronger binding capacity to RSV F protein and a high affinity for FcRn (neonatal receptor for the Fc fragment of IgG), which extends its lifespan. Nirsevimab has been shown to be highly effective in reducing hospitalization rates of RSV infections but a large or unknown number of treated subjects have been excluded in clinical and post-marketing studies. However, analysis of these studies cannot exclude that, in rare cases, nirsevimab facilitates and worsens RSV infection (or other respiratory infections). This could be attributable to antibody-dependent enhancement (ADE) which has been observed with RSV F protein antibodies in inactivated vaccine trials. This risk has been incompletely assessed in pre-clinical and clinical trials (incomplete exploration of nirsevimab effector functions and pharmacokinetics). ADE by disruption of the immune system (not studied and due to FcRn binding) could explain why there is no reduction in all-cause hospital admissions in treated age groups. Given the high price of nirsevimab, the cost-effectiveness of mass immunization campaigns may therefore be debated from an economic as well as a scientific point of view. Full article

(This article belongs to the Section Molecular Medicine)

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18 pages, 4441 KiB

Open AccessArticle

Genetics and Traumatic Brain Injury: Findings from an Exome-Based Study of a 50-Patient Case Series

by Alesya S. Gracheva, Darya A. Kashatnikova, Ivan V. Redkin, Vladislav E. Zakharchenko, Artem N. Kuzovlev and Lyubov E. Salnikova

Curr. Issues Mol. Biol. 2024, 46(9), 10351-10368; https://doi.org/10.3390/cimb46090616 (registering DOI) - 17 Sep 2024

Abstract

Traumatic brain injury (TBI) is the leading cause of global mortality and morbidity. Because TBI is accident-related, the role of genetics in predisposing to TBI has been largely unexplored. However, the likelihood of injury may not be entirely random and may be associated [...] Read more.

Traumatic brain injury (TBI) is the leading cause of global mortality and morbidity. Because TBI is accident-related, the role of genetics in predisposing to TBI has been largely unexplored. However, the likelihood of injury may not be entirely random and may be associated with certain physical and mental characteristics. In this study, we analyzed the exomes of 50 patients undergoing rehabilitation after TBI. Patients were divided into three groups according to rehabilitation outcome: improvement, no change, and deterioration/death. We focused on rare, potentially functional missense and high-impact variants in genes intolerant to these variants. The concordant results from the three independent groups of patients allowed for the suggestion of the existence of a genetic predisposition to TBI, associated with rare functional variations in intolerant genes, with a prevalent dominant mode of inheritance and neurological manifestations in the genetic phenotypes according to the OMIM database. Forty-four of the 50 patients had one or more rare, potentially deleterious variants in one or more neurological genes. Comparison of these results with those of a 50-sampled matched non-TBI cohort revealed significant differences: P = 2.2 × 10⁻⁶, OR = 4.89 (1.77–13.47). There were no differences in the distribution of the genes of interest between the TBI patient groups. Our exploratory study provides new insights into the impact of genetics on TBI risk and is the first to address potential genetic susceptibility to TBI. Full article

(This article belongs to the Special Issue Metabolism and Molecular Pathology Related Features in Neurological Diseases)

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16 pages, 6210 KiB

Open AccessArticle

Transcriptomic and Metabolic Analysis Reveals Genes and Pathways Associated with Flesh Pigmentation in Potato (Solanum tuberosum) Tubers

by Man Li, Yuting Xiong, Xueying Yang, Yuliang Gao and Kuihua Li

Curr. Issues Mol. Biol. 2024, 46(9), 10335-10350; https://doi.org/10.3390/cimb46090615 (registering DOI) - 17 Sep 2024

Abstract

Anthocyanins, flavonoid pigments, are responsible for the purple and red hues in potato tubers. This study analyzed tubers from four potato cultivars—red RR, purple HJG, yellow QS9, and white JZS8—to elucidate the genetic mechanisms underlying tuber pigmentation. Our transcriptomic analysis identified over 2400 [...] Read more.

Anthocyanins, flavonoid pigments, are responsible for the purple and red hues in potato tubers. This study analyzed tubers from four potato cultivars—red RR, purple HJG, yellow QS9, and white JZS8—to elucidate the genetic mechanisms underlying tuber pigmentation. Our transcriptomic analysis identified over 2400 differentially expressed genes between these varieties. Notably, genes within the flavonoid biosynthesis pathway were enriched in HJG and RR compared to the non-pigmented JZS8, correlating with their higher levels of anthocyanin precursors and related substances. Hierarchical clustering revealed inverse expression patterns for the key genes involved in anthocyanin metabolism between pigmented and non-pigmented varieties. Among these, several MYB transcription factors displayed strong co-expression with anthocyanin biosynthetic genes, suggesting a regulatory role. Specifically, the expression of 16 MYB genes was validated using qRT-PCR to be markedly higher in pigmented HJG and RR versus JZS8, suggesting that these MYB genes might be involved in tuber pigmentation. This study comprehensively analyzed the transcriptome of diverse potato cultivars, highlighting specific genes and metabolic pathways involved in tuber pigmentation. These findings provide potential molecular targets for breeding programs focused on enhancing tuber color. Full article

(This article belongs to the Special Issue Advances in Multi-Omics for Functional Genomics Studies and Molecular Breeding)

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23 pages, 11452 KiB

Open AccessArticle

Exopolysaccharides from the Green Microalga Strain Coelastrella sp. BGV—Isolation, Characterization, and Assessment of Anticancer Potential

by Tanya Toshkova-Yotova, Inna Sulikovska, Vera Djeliova, Zdravka Petrova, Manol Ognyanov, Petko Denev, Reneta Toshkova and Ani Georgieva

Curr. Issues Mol. Biol. 2024, 46(9), 10312-10334; https://doi.org/10.3390/cimb46090614 (registering DOI) - 16 Sep 2024

Abstract

Algal metabolites have been extensively studied as potential anticancer therapeutics. Among them, polysaccharides have attracted much attention because of their beneficial biological effects and safety. In the present research, the chemical characteristics, antitumor, and proapoptotic activities of extracellular polysaccharides (EPS) isolated from a [...] Read more.

Algal metabolites have been extensively studied as potential anticancer therapeutics. Among them, polysaccharides have attracted much attention because of their beneficial biological effects and safety. In the present research, the chemical characteristics, antitumor, and proapoptotic activities of extracellular polysaccharides (EPS) isolated from a new Bulgarian strain of the green microalga Coelastrella sp. BGV were investigated. A fast and convenient method of precipitation with cold ethanol was used to isolate EPS from the culture medium. The chemical characteristics of the isolated EPS were examined by colorimetric and spectrophotometric analyses, HPSEC-RID and HPLC-UV chromatography, and FT-IR spectroscopy. The results showed that the isolated EPS sample consists of three carbohydrate fractions with different molecular weights (11.5 × 10⁴ Da, 30.7 × 10⁴ Da, and 72.4 × 10⁴ Da, respectively) and contains 7.14 (w/w%) protein. HPLC-UV analysis revealed the presence of galactose and fucose. The total uronic acid content in the sample was 4.5 (w/w%). The IR-FT spectrum of EPS revealed the presence of various functional groups typical of a polysaccharide (or proteoglycan) composed primarily of neutral sugars. The anticancer potential of the obtained EPS was assessed using cell lines with cancerous and non-cancerous origins as in vitro experimental models. The results of the performed MTT assay showed that EPS reduced the viability of the cervical and mammary carcinoma cell lines HeLa and MCF-7, while the control non-cancer cell lines BALB/3T3 and HaCaT were less affected. The HeLa cell line showed the highest sensitivity to the effects of EPS and was therefore used for further studies of its anticancer potential. The ability of EPS to inhibit cancer cell migration was demonstrated by wound-healing (scratch) assay. The cell cycle FACS analysis indicated that the EPS treatment induced significant increases in the sub G1 cell population and decreases of the percentages of cells in the G1, S, and G2-M phases, compared to the control. The fluorescent microscopy studies performed using three different staining methods in combination with Annexin V-FITC flow cytometric analysis clearly demonstrate the ability of EPS to induce cancer cell death via the apoptosis pathway. Moreover, an altered pattern and intensity of the immunocytochemical staining for the apoptosis- and proliferation-related proteins p53, bcl2, and Ki67 was detected in EPS-treated HeLa cancer cells as compared to the untreated controls. The obtained results characterize the new local strain of green microalgae Coelastrella sp. BGV as a producer of EPS with selective antitumor activity and provide an opportunity for further studies of its pharmacological and biotechnological potential. Full article

(This article belongs to the Special Issue Phytochemicals in Cancer Chemoprevention and Treatment)

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13 pages, 751 KiB

Open AccessReview

Research Progress on Photoperiod Gene Regulation of Heading Date in Rice

by Jian Song, Liqun Tang, Yongtao Cui, Honghuan Fan, Xueqiang Zhen and Jianjun Wang

Curr. Issues Mol. Biol. 2024, 46(9), 10299-10311; https://doi.org/10.3390/cimb46090613 (registering DOI) - 16 Sep 2024

Abstract

Heading date is a critical physiological process in rice that is influenced by both genetic and environmental factors. The photoperiodic pathway is a primary regulatory mechanism for rice heading, with key florigen genes Hd3a (Heading date 3a) and RFT1 (RICE FLOWERING LOCUS T1) [...] Read more.

Heading date is a critical physiological process in rice that is influenced by both genetic and environmental factors. The photoperiodic pathway is a primary regulatory mechanism for rice heading, with key florigen genes Hd3a (Heading date 3a) and RFT1 (RICE FLOWERING LOCUS T1) playing central roles. Upstream regulatory pathways, including Hd1 and Ehd1, also significantly impact this process. This review aims to provide a comprehensive examination of the localization, cloning, and functional roles of photoperiodic pathway-related genes in rice, and to explore the interactions among these genes as well as their pleiotropic effects on heading date. We systematically review recent advancements in the identification and functional analysis of genes involved in the photoperiodic pathway. We also discuss the molecular mechanisms underlying rice heading date variation and highlight the intricate interactions between key regulatory genes. Significant progress has been made in understanding the molecular mechanisms of heading date regulation through the cloning and functional analysis of photoperiod-regulating genes. However, the regulation of heading date remains complex, and many underlying mechanisms are not yet fully elucidated. This review consolidates current knowledge on the photoperiodic regulation of heading date in rice, emphasizing novel findings and gaps in the research. It highlights the need for further exploration of the interactions among flowering-related genes and their response to environmental signals. Despite advances, the full regulatory network of heading date remains unclear. Further research is needed to elucidate the intricate gene interactions, transcriptional and post-transcriptional regulatory mechanisms, and the role of epigenetic factors such as histone methylation in flowering time regulation. This review provides a detailed overview of the current understanding of photoperiodic pathway genes in rice, setting the stage for future research to address existing gaps and improve our knowledge of rice flowering regulation. Full article

(This article belongs to the Special Issue Advances in Multi-Omics for Functional Genomics Studies and Molecular Breeding)

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35 pages, 3888 KiB

Open AccessReview

Gene Expression Regulation and the Signal Transduction of Programmed Cell Death

by Saqirile, Yuxin Deng, Kexin Li, Wenxin Yan, Ke Li and Changshan Wang

Curr. Issues Mol. Biol. 2024, 46(9), 10264-10298; https://doi.org/10.3390/cimb46090612 (registering DOI) - 16 Sep 2024

Abstract

Cell death is of great significance in maintaining tissue homeostasis and bodily functions. With considerable research coming to the fore, it has been found that programmed cell death presents in multiple modalities in the body, which is not only limited to apoptosis, but [...] Read more.

Cell death is of great significance in maintaining tissue homeostasis and bodily functions. With considerable research coming to the fore, it has been found that programmed cell death presents in multiple modalities in the body, which is not only limited to apoptosis, but also can be divided into autophagy, pyroptosis, ferroptosis, mitotic catastrophe, entosis, netosis, and other ways. Different forms of programmed cell death have disparate or analogous characteristics with each other, and their occurrence is accompanied by multiple signal transduction and the role of a myriad of regulatory factors. In recent years, scholars across the world have carried out considerable in-depth research on programmed cell death, and new forms of cell death are being discovered continually. Concomitantly, the mechanisms of intricate signaling pathways and regulators have been discovered. More critically, cancer cells tend to choose distinct ways to evade cell death, and different tumors adapt to different manners of death. Therefore, targeting the cell death network has been regarded as an effective tumor treatment strategy for a long time. The objective of our paper is to review the signaling pathways and gene regulation in several typical types of programmed cell death and their correlation with cancer. Full article

(This article belongs to the Special Issue The Significance of Transcription Factors, miRNAs, and lncRNAs in Anticancer Drug Development)

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5 pages, 947 KiB

Open AccessEditorial

Current Landscape of Chronic Inflammatory Dermatoses: Where We Are and Where We Are Heading

by Aleksandra Sójka and Piotr K. Krajewski

Curr. Issues Mol. Biol. 2024, 46(9), 10259-10263; https://doi.org/10.3390/cimb46090611 (registering DOI) - 16 Sep 2024

Abstract

Chronic inflammatory dermatoses represent a heterogeneous group of skin disorders that are often characterized by persistent and relapsing inflammation, with complex underlying pathomechanisms [...] Full article

(This article belongs to the Special Issue Molecular Research in Chronic Dermatoses)

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10 pages, 11741 KiB

Open AccessArticle

mRNA Fragmentation Pattern Detected by SHAPE

by Shanshan Feng, Ting Chen, Yunlong Zhang and Changrui Lu

Curr. Issues Mol. Biol. 2024, 46(9), 10249-10258; https://doi.org/10.3390/cimb46090610 (registering DOI) - 16 Sep 2024

Abstract

The success of messenger RNA (mRNA) vaccines in controlling COVID-19 has warranted further developments in new technology. Currently, their quality control process largely relies on low-resolution electrophoresis for detecting chain breaks. Here, we present an approach using multi-primer reverse transcription sequencing (MPRT-seq) to [...] Read more.

The success of messenger RNA (mRNA) vaccines in controlling COVID-19 has warranted further developments in new technology. Currently, their quality control process largely relies on low-resolution electrophoresis for detecting chain breaks. Here, we present an approach using multi-primer reverse transcription sequencing (MPRT-seq) to identify degradation fragments in mRNA products. Using this in-house-made mRNA containing two antigens and untranslated regions (UTRs), we analyzed the mRNA completeness and degradation pattern at a nucleotide resolution. We then analyzed the sensitive base sequence and its correlation with the secondary structure. Our MPRT-seq mapping shows that certain sequences on the 5′ of bulge–stem–loop structures can result in preferential chain breaks. Our results agree with commonly used capillary electrophoresis (CE) integrity analysis but at a much higher resolution, and can improve mRNA stability by providing information to remove sensitive structures or sequences in the mRNA sequence design. Full article

(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)

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31 pages, 5879 KiB

Open AccessArticle

Associations of SEMA7A, SEMA4D, ADAMTS10, and ADAM8 with KRAS, NRAS, BRAF, PIK3CA, and AKT Gene Mutations, Microsatellite Instability Status, and Cytokine Expression in Colorectal Cancer Tissue

by Błażej Ochman, Piotr Limanówka, Sylwia Mielcarska, Agnieszka Kula, Miriam Dawidowicz, Wiktor Wagner, Dorota Hudy, Monika Szrot, Jerzy Zbigniew Piecuch, Jerzy Piecuch, Zenon Czuba and Elżbieta Świętochowska

Curr. Issues Mol. Biol. 2024, 46(9), 10218-10248; https://doi.org/10.3390/cimb46090609 (registering DOI) - 15 Sep 2024

Abstract

Semaphorins (SEMAs), ADAM, and ADAMTS family members are implicated in various cancer progression events within the tumor microenvironment across different cancers. In this study, we aimed to evaluate the expression of SEMA7A, SEMA4D, ADAM8, and ADAMTS10 in colorectal cancer (CRC) in relation to [...] Read more.

Semaphorins (SEMAs), ADAM, and ADAMTS family members are implicated in various cancer progression events within the tumor microenvironment across different cancers. In this study, we aimed to evaluate the expression of SEMA7A, SEMA4D, ADAM8, and ADAMTS10 in colorectal cancer (CRC) in relation to the mutational landscape of KRAS, NRAS, BRAF, PIK3CA, and AKT genes, microsatellite instability (MSI) status, and clinicopathological features. We also examined the associations between the expression of these proteins and selected cytokines, chemokines, and growth factors, assessed using a multiplex assay. Protein concentrations were quantified using ELISA in CRC tumors and tumor-free surgical margin tissue homogenates. Gene mutations were evaluated via RT-PCR, and MSI status was determined using immunohistochemistry (IHC). GSEA and statistical analyses were performed using R Studio. We observed a significantly elevated expression of SEMA7A in BRAF-mutant CRC tumors and an overexpression of ADAM8 in KRAS 12/13-mutant tumors. The expression of ADAMTS10 was decreased in PIK3CA-mutant CRC tumors. No significant differences in the expression of the examined proteins were observed based on MSI status. The SEMA7A and SEMA4D expressions were correlated with the expression of numerous cytokines associated with various immune processes. The potential immunomodulatory functions of these molecules and their suitability as therapeutic targets require further investigation. Full article

(This article belongs to the Special Issue Molecular-Based Approaches in Therapy for Gastrointestinal Cancers, 2nd Edition)

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18 pages, 1822 KiB

Open AccessReview

Biochemical Pathways Delivering Distinct Glycosphingolipid Patterns in MDA-MB-231 and MCF-7 Breast Cancer Cells

by Anita Markotić, Jasminka Omerović, Sandra Marijan, Nikolina Režić-Mužinić and Vedrana Čikeš Čulić

Curr. Issues Mol. Biol. 2024, 46(9), 10200-10217; https://doi.org/10.3390/cimb46090608 (registering DOI) - 15 Sep 2024

Abstract

The complex structure of glycosphingolipids (GSLs) supports their important role in cell function as modulators of growth factor receptors and glutamine transporters in plasma membranes. The aberrant composition of clustered GSLs within signaling platforms, so-called lipid rafts, inevitably leads to tumorigenesis due to [...] Read more.

The complex structure of glycosphingolipids (GSLs) supports their important role in cell function as modulators of growth factor receptors and glutamine transporters in plasma membranes. The aberrant composition of clustered GSLs within signaling platforms, so-called lipid rafts, inevitably leads to tumorigenesis due to disturbed growth factor signal transduction and excessive uptake of glutamine and other molecules needed for increased energy and structural molecule cell supply. GSLs are also involved in plasma membrane processes such as cell adhesion, and their transition converts cells from epithelial to mesenchymal with features required for cell migration and metastasis. Glutamine activates the mechanistic target of rapamycin complex 1 (mTORC1), resulting in nucleotide synthesis and proliferation. In addition, glutamine contributes to the cancer stem cell GD2 ganglioside-positive phenotype in the triple-negative breast cancer cell line MDA-MB-231. Thieno[2,3-b]pyridine derivative possesses higher cytotoxicity against MDA-MB-231 than against MCF-7 cells and induces a shift to aerobic metabolism and a decrease in S(6)nLc4Cer GSL-positive cancer stem cells in the MDA-MB-231 cell line. In this review, we discuss findings in MDA-MB-231, MCF-7, and other breast cancer cell lines concerning their differences in growth factor receptors and recent knowledge of the main biochemical pathways delivering distinct glycosphingolipid patterns during tumorigenesis and therapy. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Biology 2024)

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20 pages, 833 KiB

Open AccessReview

The Neuroanatomy of Induced Pluripotent Stem Cells: In Vitro Models of Subcortical Nuclei in Neurodegenerative Disorders

by Alessandro Galgani, Marco Scotto and Filippo S. Giorgi

Curr. Issues Mol. Biol. 2024, 46(9), 10180-10199; https://doi.org/10.3390/cimb46090607 (registering DOI) - 14 Sep 2024

Abstract

Neuromodulatory subcortical systems (NSSs) are monoaminergic and cholinergic neuronal groups that are markedly and precociously involved in the pathogenesis of many neurodegenerative disorders (NDDs), including Parkinson’s and Alzheimer’s diseases. In humans, although many tools have been developed to infer information on these nuclei, [...] Read more.

Neuromodulatory subcortical systems (NSSs) are monoaminergic and cholinergic neuronal groups that are markedly and precociously involved in the pathogenesis of many neurodegenerative disorders (NDDs), including Parkinson’s and Alzheimer’s diseases. In humans, although many tools have been developed to infer information on these nuclei, encompassing neuroimaging and neurophysiological methods, a detailed and specific direct evaluation of their cellular features in vivo has been difficult to obtain until recent years. The development of induced pluripotent stem cell (iPSC) models has allowed research to deeply delve into the cellular and molecular biology of NSS neurons. In fact, iPSCs can be produced easily and non-invasively from patients’ fibroblasts or circulating blood monocytes, by de-differentiating those cells using specific protocols, and then be re-differentiated towards neural phenotypes, which may reproduce the specific features of the correspondent brain neurons (including NSS ones) from the same patient. In this review, we summarized findings obtained in the field of NDDs using iPSCs, with the aim to understand how reliably these might represent in vitro models of NSS. We found that most of the current literature in the field of iPSCs and NSSs in NDDs has focused on midbrain dopaminergic neurons in Parkinson’s disease, providing interesting results on cellular pathophysiology and even leading to the first human autologous transplantation. Differentiation protocols for noradrenergic, cholinergic, and serotoninergic neurons have also been recently defined and published. Thus, it might be expected that in the near future, this approach could extend to other NSSs and other NDDs. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Biology 2024)

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20 pages, 10282 KiB

Open AccessArticle

Molecular Integrative Study on Inhibitory Effects of Pentapeptides on Polymerization and Cell Toxicity of Amyloid-β Peptide (1–42)

by Lianmeng Ye, Nuela Manka’a Che Ajuyo, Zhongyun Wu, Nan Yuan, Zhengpan Xiao, Wenyu Gu, Jiazheng Zhao, Yechun Pei, Yi Min and Dayong Wang

Curr. Issues Mol. Biol. 2024, 46(9), 10160-10179; https://doi.org/10.3390/cimb46090606 (registering DOI) - 14 Sep 2024

Abstract

Alzheimer’s Disease (AD) is a multifaceted neurodegenerative disease predominantly defined by the extracellular accumulation of amyloid-β (Aβ) peptide. In light of this, in the past decade, several clinical approaches have been used aiming at developing peptides for therapeutic use in AD. The use [...] Read more.

Alzheimer’s Disease (AD) is a multifaceted neurodegenerative disease predominantly defined by the extracellular accumulation of amyloid-β (Aβ) peptide. In light of this, in the past decade, several clinical approaches have been used aiming at developing peptides for therapeutic use in AD. The use of cationic arginine-rich peptides (CARPs) in targeting protein aggregations has been on the rise. Also, the process of peptide development employing computational approaches has attracted a lot of attention recently. Using a structure database containing pentapeptides made from 20 L-α amino acids, we employed molecular docking to sort pentapeptides that can bind to Aβ₄₂, then performed molecular dynamics (MD) analyses, including analysis of the binding stability, interaction energy, and binding free energy to screen ligands. Transmission electron microscopy (TEM), circular dichroism (CD), thioflavin T (ThT) fluorescence detection of Aβ₄₂ polymerization, MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay, and the flow cytometry of reactive oxygen species (ROS) were carried out to evaluate the influence of pentapeptides on the aggregation and cell toxicity of Aβ_42. Two pentapeptides (TRRRR and ARRGR) were found to have strong effects on inhibiting the aggregation of Aβ₄₂ and reducing the toxicity of Aβ₄₂ secreted by SH-SY5Y cells, including cell death, reactive oxygen species (ROS) production, and apoptosis. Full article

(This article belongs to the Special Issue Cellular and Molecular Biology Insights into Neurodegenerative Diseases: From Pathogenesis to Therapeutic Targets)

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20 pages, 7362 KiB

Open AccessArticle

Improvement of Docetaxel Efficacy through Simultaneous Blockade of Transcription Factors NF-κB and STAT-3 Using Pentoxifylline and Stattic in Prostate Cancer Cells

by José Roberto Cruz-Lozano, Georgina Hernández-Flores, Pablo Cesar Ortiz-Lazareno, Luis Arturo Palafox-Mariscal, Katia Carolina Vázquez-Ibarra, Karen Lilith González-Martínez, María Martha Villaseñor-García and Alejandro Bravo-Cuellar

Curr. Issues Mol. Biol. 2024, 46(9), 10140-10159; https://doi.org/10.3390/cimb46090605 (registering DOI) - 14 Sep 2024

Abstract

Prostate cancer (PCa) is a common and deadly disease in men. It is often diagnosed at advanced stages, at which point patients are treated mainly with docetaxel (DTX), which is effective but limited by resistance and side effects. Overactivation of the transcription factors [...] Read more.

Prostate cancer (PCa) is a common and deadly disease in men. It is often diagnosed at advanced stages, at which point patients are treated mainly with docetaxel (DTX), which is effective but limited by resistance and side effects. Overactivation of the transcription factors NF-κB and STAT-3 plays a critical role in the development, progression, and chemoresistance of PCa. In this regard, the blockade of NF-κB with pentoxifylline (PTX) or STAT-3 with Stattic (STT) is known to increase the sensitivity of tumor cells to chemotherapy in both in vitro and in vivo models. We investigated whether simultaneous blockade with PTX and STT increases the efficacy of the DTX treatment in inducing apoptosis in metastatic castration-resistant PCa DU-145 cells. Our results showed that the combination of PTX + STT led to higher levels of apoptosis, regardless of whether or not DTX was present in the treatment. Determining caspases and ΔΨm indicates that the intrinsic caspase pathway of apoptosis is principally favored. In addition, this combination inhibited proliferation and colony formation and arrested the cell cycle in the G1 phase. These results indicate that the combination of the PTX + STAT-3 inhibitor could potentiate DTX effectively, opening the possibility of effective treatments in PCa. Full article

(This article belongs to the Special Issue The Significance of Transcription Factors, miRNAs, and lncRNAs in Anticancer Drug Development)

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10 pages, 1746 KiB

Open AccessArticle

Association of Wild-Type TP53 with Downregulation of Lovastatin Sensitivity in Human Non-Small Cell Lung Cancer Cells

by Yu-Yao Chang, Tsung-Ying Yang and Gwo-Tarng Sheu

Curr. Issues Mol. Biol. 2024, 46(9), 10130-10139; https://doi.org/10.3390/cimb46090604 - 13 Sep 2024

Abstract

Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, and reduce cholesterol synthesis. They also have been demonstrated to improve prognosis in patients with various cancers, suggesting a potential anti-cancer effect of statins. However, there is no consensus on the [...] Read more.

Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, and reduce cholesterol synthesis. They also have been demonstrated to improve prognosis in patients with various cancers, suggesting a potential anti-cancer effect of statins. However, there is no consensus on the molecular targets of statins for their anti-cancer effects. Docetaxel (DOC) is a microtubule-stabilizing agent currently used as a chemotherapeutic drug in several cancers, including lung cancer. Interestingly, the anti-cancer effects of either drug that are related to abnormal or wild-type TP53 gene have been implied. Therefore, the drug sensitivity of DOC and lovastatin in human lung cancer cells was evaluated. We found that H1355 (mutant TP53-E285K), CL1 (mutant TP53-R248W), and H1299 (TP53-null) human non-small cell lung cancer cells were more sensitive to lovastatin than A549 and H460 cells expressing wild-type TP53. Conversely, A549 and H460 cells showed higher sensitivity to DOC than H1299 and CL1 cells, as demonstrated by the MTT assay. When endogenous TP53 activity was inhibited by pifithrin-α in A549 and H460 cells, lovastatin sensitivities significantly increased, and cancer cell viabilities markedly reduced. These results indicate that TP53 status is associated with the anti-cancer effect of statins in human lung cancer cells. Mutated or null TP53 status is correlated with higher statin sensitivity. Furthermore, DOC-resistant H1299 (H1299/D8) cells showed significant sensitivity to lovastatin treatment compared to DOC-resistant A549 (A549/D16) cells, indicating a potential application of statins/chemotherapy combination therapy to control wild-type and abnormal TP53-containing human lung tumors. Full article

(This article belongs to the Special Issue Advances in Pharmacotherapeutic Strategies to Prevent Tumor Development, Progression and Treatment Resistance)

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18 pages, 2022 KiB

Open AccessArticle

Bioconversion of L-Tyrosine into p-Coumaric Acid by Tyrosine Ammonia-Lyase Heterologue of Rhodobacter sphaeroides Produced in Pseudomonas putida KT2440

by Carlos G. Calderón, Juan C. Gentina, Oscar Evrard and Leda Guzmán

Curr. Issues Mol. Biol. 2024, 46(9), 10112-10129; https://doi.org/10.3390/cimb46090603 - 12 Sep 2024

Abstract

p-Coumaric acid (p-CA) is a valuable compound with applications in food additives, cosmetics, and pharmaceuticals. However, traditional production methods are often inefficient and unsustainable. This study focuses on enhancing p-CA production efficiency through the heterologous expression of tyrosine ammonia-lyase [...] Read more.

p-Coumaric acid (p-CA) is a valuable compound with applications in food additives, cosmetics, and pharmaceuticals. However, traditional production methods are often inefficient and unsustainable. This study focuses on enhancing p-CA production efficiency through the heterologous expression of tyrosine ammonia-lyase (TAL) from Rhodobacter sphaeroides in Pseudomonas putida KT2440. TAL catalyzes the conversion of L-tyrosine into p-CA and ammonia. We engineered P. putida KT2440 to express TAL in a fed-batch fermentation system. Our results demonstrate the following: (i) successful integration of the TAL gene into P. putida KT2440 and (ii) efficient bioconversion of L-tyrosine into p-CA (1381 mg/L) by implementing a pH shift from 7.0 to 8.5 during fed-batch fermentation. This approach highlights the viability of P. putida KT2440 as a host for TAL expression and the successful coupling of fermentation with the pH-shift-mediated bioconversion of L-tyrosine. Our findings underscore the potential of genetically modified P. putida for sustainable p-CA production and encourage further research to optimize bioconversion steps and fermentation conditions. Full article

(This article belongs to the Collection Feature Papers in Current Issues in Molecular Biology)

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25 pages, 5756 KiB

Open AccessArticle

Impacts of DROSHA (rs10719) and DICER (rs3742330) Variants on Breast Cancer Risk and Their Distribution in Blood and Tissue Samples of Egyptian Patients

by Aly A. M. Shaalan, Essam Al Ageeli, Shahad W. Kattan, Amany I. Almars, Nouf A. Babteen, Abdulmajeed A. A. Sindi, Eman A. Toraih, Manal S. Fawzy and Marwa Hussein Mohamed

Curr. Issues Mol. Biol. 2024, 46(9), 10087-10111; https://doi.org/10.3390/cimb46090602 - 12 Sep 2024

Abstract

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression and play critical roles in tumorigenesis. Genetic variants in miRNA processing genes, DROSHA and DICER, have been implicated in cancer susceptibility and progression in various populations. However, their role in Egyptian patients [...] Read more.

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression and play critical roles in tumorigenesis. Genetic variants in miRNA processing genes, DROSHA and DICER, have been implicated in cancer susceptibility and progression in various populations. However, their role in Egyptian patients with breast cancer (BC) remains unexplored. This study aims to investigate the association of DROSHA rs10719 and DICER rs3742330 polymorphisms with BC risk and clinical outcomes. This case–control study included 209 BC patients and 106 healthy controls. Genotyping was performed using TaqMan assays in blood, tumor tissue, and adjacent non-cancerous tissue samples. Associations were analyzed using logistic regression and Fisher’s exact test. The DROSHA rs10719 AA genotype was associated with a 3.2-fold increased risk (95%CI = 1.23–9.36, p < 0.001), and the DICER rs3742330 GG genotype was associated with a 3.51-fold increased risk (95%CI = 1.5–8.25, p = 0.001) of BC. Minor allele frequencies were 0.42 for rs10719 A and 0.37 for rs3742330 G alleles. The risk alleles were significantly more prevalent in tumor tissue than adjacent normal tissue (rs10719 A: 40.8% vs. 0%; rs3742330 G: 42.7% vs. 0%; p < 0.001). However, no significant associations were observed with clinicopathological features or survival outcomes over a median follow-up of 17 months. In conclusion, DROSHA rs10719 and DICER rs3742330 polymorphisms are associated with increased BC risk and more prevalent in tumor tissue among our cohort, suggesting a potential role in miRNA dysregulation during breast tumorigenesis. These findings highlight the importance of miRNA processing gene variants in BC susceptibility and warrant further validation in larger cohorts and different ethnic populations. Full article

(This article belongs to the Special Issue Advances in Molecular Pathogenesis Regulation in Cancer 2024)

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22 pages, 1956 KiB

Open AccessReview

Progress in the Study of Chemical Structure and Pharmacological Effects of Total Paeony Glycosides Isolated from Radix Paeoniae Rubra

by Yumu Sun, Taiyu Liu and Xueying Zhao

Curr. Issues Mol. Biol. 2024, 46(9), 10065-10086; https://doi.org/10.3390/cimb46090601 - 12 Sep 2024

Abstract

Radix paeoniae rubra, known as red peony root, is derived from the dried roots of Paeonia lactiflora pall or Paeonia veitchii lynch from the Ranunculaceae family. It is recognized for its properties of clearing heat, cooling blood, dispelling stasis, and alleviating pain, [...] Read more.

Radix paeoniae rubra, known as red peony root, is derived from the dried roots of Paeonia lactiflora pall or Paeonia veitchii lynch from the Ranunculaceae family. It is recognized for its properties of clearing heat, cooling blood, dispelling stasis, and alleviating pain, making it one of the most commonly used herbs in traditional Chinese medicine. Total paeony glycosides (TPGs) are identified as the principal active constituents of Radix paeoniae rubra, comprising monoterpenoid compounds with a cage-like pinane structure and monoterpenoids with a lactone structure. This review summarizes the chemical constituents and pharmacological effects of TPGs, with the aim of elucidating their relationships. Full article

(This article belongs to the Section Molecular Pharmacology)

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27 pages, 23025 KiB

Open AccessArticle

Disulfidptosis: A New Target for Parkinson’s Disease and Cancer

by Tingting Liu, Xiangrui Kong and Jianshe Wei

Curr. Issues Mol. Biol. 2024, 46(9), 10038-10064; https://doi.org/10.3390/cimb46090600 - 12 Sep 2024

Abstract

Recent studies have uncovered intriguing connections between Parkinson’s disease (PD) and cancer, two seemingly distinct disease categories. Disulfidptosis has garnered attention as a novel form of regulated cell death that is implicated in various pathological conditions, including neurodegenerative disorders and cancer. Disulfidptosis involves [...] Read more.

Recent studies have uncovered intriguing connections between Parkinson’s disease (PD) and cancer, two seemingly distinct disease categories. Disulfidptosis has garnered attention as a novel form of regulated cell death that is implicated in various pathological conditions, including neurodegenerative disorders and cancer. Disulfidptosis involves the dysregulation of intracellular redox homeostasis, leading to the accumulation of disulfide bonds and subsequent cell demise. This has sparked our interest in exploring common molecular mechanisms and genetic factors that may be involved in the relationship between neurodegenerative diseases and tumorigenesis. The Gene4PD database was used to retrieve PD differentially expressed genes (DEGs), the biological functions of differential expression disulfidptosis-related genes (DEDRGs) were analyzed, the ROCs of DEDRGs were analyzed using the GEO database, and the expression of DEDRGs was verified by an MPTP-induced PD mouse model in vivo. Then, the DEDRGs in more than 9000 samples of more than 30 cancers were comprehensively and systematically characterized by using multi-omics analysis data. In PD, we obtained a total of four DEDRGs, including ACTB, ACTN4, INF2, and MYL6. The enriched biological functions include the regulation of the NF-κB signaling pathway, mitochondrial function, apoptosis, and tumor necrosis factor, and these genes are rich in different brain regions. In the MPTP-induced PD mouse model, the expression of ACTB was decreased, while the expression of ACTN4, INF2, and MYL6 was increased. In pan-cancer, the high expression of ACTB, ACTN4, and MYL6 in GBMLGG, LGG, MESO, and LAML had a poor prognosis, and the high expression of INF2 in LIHC, LUAD, UVM, HNSC, GBM, LAML, and KIPAN had a poor prognosis. Our study showed that these genes were more highly infiltrated in Macrophages, NK cells, Neutrophils, Eosinophils, CD8 T cells, T cells, T helper cells, B cells, dendritic cells, and mast cells in pan-cancer patients. Most substitution mutations were G-to-A transitions and C-to-T transitions. We also found that miR-4298, miR-296-3p, miR-150-3p, miR-493-5p, and miR-6742-5p play important roles in cancer and PD. Cyclophosphamide and ethinyl estradiol may be potential drugs affected by DEDRGs for future research. This study found that ACTB, ACTN4, INF2, and MYL6 are closely related to PD and pan-cancer and can be used as candidate genes for the diagnosis, prognosis, and therapeutic biomarkers of neurodegenerative diseases and cancers. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

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