Current Issues in Molecular Biology

13 pages, 1154 KiB

Open AccessReview

Targeting Cancers with oHSV-Based Oncolytic Viral Immunotherapy

by Rakin Tammam Nasar, Ifeanyi Kingsley Uche and Konstantin G. Kousoulas

Curr. Issues Mol. Biol. 2024, 46(6), 5582-5594; https://doi.org/10.3390/cimb46060334 (registering DOI) - 3 Jun 2024

Abstract

The recent success of cancer immunotherapies, such as immune checkpoint inhibitor (ICIs), monoclonal antibodies (mAbs), cancer vaccines, and adoptive cellular therapies (ACTs), has revolutionized traditional cancer treatment. However, these immunotherapeutic modalities have variable efficacies, and many of them exhibit adverse effects. Oncolytic viral [...] Read more.

The recent success of cancer immunotherapies, such as immune checkpoint inhibitor (ICIs), monoclonal antibodies (mAbs), cancer vaccines, and adoptive cellular therapies (ACTs), has revolutionized traditional cancer treatment. However, these immunotherapeutic modalities have variable efficacies, and many of them exhibit adverse effects. Oncolytic viral Immunotherapy (OViT), whereby viruses are used to directly or indirectly induce anti-cancer immune responses, is emerging as a novel immunotherapy for treating patients with different types of cancer. The herpes simplex virus type-1 (HSV-1) possesses many characteristics that inform its use as an effective OViT agents and remains a leading candidate. Its recent clinical success resulted in the Food and Drug Administration (FDA) approval of Talimogene laherparevec (T-VEC or Imlygic) in 2015 for the treatment of advanced melanoma. In this review, we discuss recent advances in the development of oncolytic HSV-1-based OViTs, their anti-tumor mechanism of action, and efficacy data from recent clinical trials. We envision this knowledge may be used to inform the rational design and application of future oHSV in cancer treatment. Full article

(This article belongs to the Special Issue Research on Virus-Induced Cellular and Molecular Responses)

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21 pages, 9385 KiB

Open AccessArticle

Network Pharmacology Analysis, Molecular Docking Integrated Experimental Verification Reveal the Mechanism of Gynostemma pentaphyllum in the Treatment of Type II Diabetes by Regulating the IRS1/PI3K/Akt Signaling Pathway

by Songqin Yang, Mao Zhao, Mingxing Lu, Yuhan Feng, Xia Zhang, Daoping Wang and Wenwen Jiang

Curr. Issues Mol. Biol. 2024, 46(6), 5561-5581; https://doi.org/10.3390/cimb46060333 (registering DOI) - 1 Jun 2024

Abstract

Gynostemma pentaphyllum (Thunb.) Makino (GP), a plant with homology of medicine and food, as a traditional Chinese medicine, possesses promising biological activities in the prevention and treatment of type 2 diabetes mellitus (T2DM). However, the material basis and the mechanism of action of [...] Read more.

Gynostemma pentaphyllum (Thunb.) Makino (GP), a plant with homology of medicine and food, as a traditional Chinese medicine, possesses promising biological activities in the prevention and treatment of type 2 diabetes mellitus (T2DM). However, the material basis and the mechanism of action of GP in the treatment of T2DM have not been fully elucidated. This study aimed to clarify the active components, potential targets and signaling pathways of GP in treating T2DM. The chemical ingredients of GP were collected by combining UPLC-HRMS analysis and literature research. Network pharmacology revealed that GP had 32 components and 326 potential targets in treating T2DM. The results showed that GP affected T2DM by mediating the insulin resistance signaling pathway, PI3K/Akt signaling pathway and FoxO1 signaling pathway, which had a close relationship with T2DM. Molecular docking results showed that STAT3, PIK3CA, AKT1, EGFR, VEGFA and INSR had high affinity with the active compounds of GP. In vitro, GP extracts obviously increased the glucose uptake and glucose consumption in IR-HepG2 cells. GP extracts increased the levels of PI3K, p-AKT, p-GSK3β and p-FoxO1 and decreased the expression of p-IRS1, p-GS, PEPCK and G6Pase, which indicated that GP could promote glycogen synthesis and inhibit gluconeogenesis by regulating the IRS1/PI3K/Akt signaling pathway. The results demonstrated that GP could improve insulin resistance by promoting glucose uptake and glycogen synthesis and inhibiting gluconeogenesis through regulating the IRS1/PI3K/Akt signaling pathway, which might be a potential alternative therapy for T2DM. Full article

(This article belongs to the Section Bioorganic Chemistry and Medicinal Chemistry)

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10 pages, 1429 KiB

Open AccessBrief Report

Construction of a Synergy Combination Model for Turmeric (Curcuma longa L.) and Black Pepper (Piper nigrum L.) Extracts: Enhanced Anticancer Activity against A549 and NCI-H292 Human Lung Cancer Cells

by Hyun-Ki Cho, Chang-Gyun Park and Heung-Bin Lim

Curr. Issues Mol. Biol. 2024, 46(6), 5551-5560; https://doi.org/10.3390/cimb46060332 (registering DOI) - 1 Jun 2024

Abstract

Extensive research on medicinal herbs for bioactive compounds proposes that they could replace synthetic drugs, reducing side effects and economic burdens. Especially, interest in the synergistic benefits of natural products is increasing, implying that their combined use may enhance therapeutic effectiveness. This study [...] Read more.

Extensive research on medicinal herbs for bioactive compounds proposes that they could replace synthetic drugs, reducing side effects and economic burdens. Especially, interest in the synergistic benefits of natural products is increasing, implying that their combined use may enhance therapeutic effectiveness. This study aimed to explore the synergetic effects of turmeric (Curcuma longa L.) and black pepper (Piper nigrum L.) extract on lung normal (MRC-5) and cancer (A549 and NCI-H292) cell lines. The turmeric extract (TM) only affected the lung cancer cell lines, but it had no impact on the MRC-5 cell line. On the other hand, the black pepper extract (BP) did not cause any damage to either the lung normal or cancer cell lines, even at concentrations of up to 400 µg/mL. Response surface methodology was used to predict the ideal synergistic concentrations (EC₅₀) of TM and BP, which were found to be 48.5 and 241.7 µg/mL, respectively. Notably, the selected condition resulted in higher cytotoxicity compared to the exposure to TM alone, indicating a potent synergetic effect. The rate of curcumin degradation under this combined treatment was significantly decreased to 49.72 ± 5.00 nmol/h/µg for A549 cells and 47.53 ± 4.78 nmol/h/µg for NCI-H292 cells, respectively, as compared to curcumin alone. Taken together, this study confirmed the potent synergistic effect of TM and BP on lung cancer cell lines. Further research is required to identify their specific synergetic mechanisms. Our findings provide crucial foundational data on the synergistic effects of TM and BP. Full article

(This article belongs to the Special Issue Natural Products in Biomedicine and Pharmacotherapy)

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1 pages, 154 KiB

Open AccessRetraction

RETRACTED: Al-Salmi, F.A.; Hamza, R.Z. Efficacy of Vanadyl Sulfate and Selenium Tetrachloride as Anti-Diabetic Agents against Hyperglycemia and Oxidative Stress Induced by Diabetes Mellitus in Male Rats. Curr. Issues Mol. Biol. 2022, 44, 94–104

by Fawziah A. Al-Salmi and Reham Z. Hamza

Curr. Issues Mol. Biol. 2024, 46(6), 5550; https://doi.org/10.3390/cimb46060331 (registering DOI) - 31 May 2024

Abstract

Current Issues in Molecular Biology Editorial Office retracts the article titled “Efficacy of Vanadyl Sulfate and Selenium Tetrachloride as Anti-Diabetic Agents against Hyperglycemia and Oxidative Stress Induced by Diabetes Mellitus in Male Rats” [...] Full article

(This article belongs to the Collection Application of Natural and Pseudo Natural Products in Drug Discovery and Development)

20 pages, 1517 KiB

Open AccessReview

Glutathione in HIV-Associated Neurocognitive Disorders

by Thomas Erdos, Mika Masuda and Vishwanath Venketaraman

Curr. Issues Mol. Biol. 2024, 46(6), 5530-5549; https://doi.org/10.3390/cimb46060330 (registering DOI) - 31 May 2024

Abstract

A large portion of patients with Human Immunodeficiency Virus (HIV) have neurologic sequelae. Those with better-controlled HIV via antiretroviral therapies generally have less severe neurologic symptoms. However, for many patients, antiretrovirals do not adequately resolve symptoms. Since much of the pathogenesis of HIV/AIDS [...] Read more.

A large portion of patients with Human Immunodeficiency Virus (HIV) have neurologic sequelae. Those with better-controlled HIV via antiretroviral therapies generally have less severe neurologic symptoms. However, for many patients, antiretrovirals do not adequately resolve symptoms. Since much of the pathogenesis of HIV/AIDS (Autoimmune Deficiency Syndrome) involves oxidative stress either directly, through viral interaction, or indirectly, through inflammatory mechanisms, we have reviewed relevant trials of glutathione supplementation in each of the HIV-associated neurocognitive diseases and have found disease-specific results. For diseases for which trials have not been completed, predicted responses to glutathione supplementation are made based on relevant mechanisms seen in the literature. It is not sufficient to conclude that all HIV-associated neurocognitive disorders (HAND) will benefit from the antioxidant effects of glutathione supplementation. The potential effects of glutathione supplementation in patients with HAND are likely to differ based on the specific HIV-associated neurocognitive disease. Full article

(This article belongs to the Special Issue Infectious Diseases and Molecular Epidemiology: Focus on Pathogenic Microorganisms)

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19 pages, 2839 KiB

Open AccessArticle

Diversity of Expression Patterns of Lr34, Lr67, and Candidate Genes towards Lr46 with Analysis of Associated miRNAs in Common Wheat Hybrids in Response to Puccinia triticina Fungus

by Julia Spychała, Agnieszka Tomkowiak, Aleksandra Noweiska, Roksana Bobrowska, Jan Bocianowski, Aleksandra Sobiech and Michał Tomasz Kwiatek

Curr. Issues Mol. Biol. 2024, 46(6), 5511-5529; https://doi.org/10.3390/cimb46060329 (registering DOI) - 31 May 2024

Abstract

Leaf rust caused by Puccinia triticina (Pt) is one of the most dangerous diseases causing significant losses in common wheat crops. In adult plants resistant to rust, a horizontal adult plant resistance (APR) type is observed, which protects the plant against multiple pathogen [...] Read more.

Leaf rust caused by Puccinia triticina (Pt) is one of the most dangerous diseases causing significant losses in common wheat crops. In adult plants resistant to rust, a horizontal adult plant resistance (APR) type is observed, which protects the plant against multiple pathogen races and is distinguished by greater persistence under production conditions. Crucial pleiotropic slow-rust genes such as Lr34, Lr46, Lr67, and Lr68, in combination with other genes of lesser influence, continue to increase durable resistance to rust diseases. Based on our previous results, we selected four candidate genes for Lr46 out of ten candidates and analysed them for expression before and after inoculation by P. triticina. As part of our study, we also investigated the expression patterns of miRNA molecules complementary to Lr34 and the candidate genes. The aim of the study was to analyse the expression profiles of candidate genes for the Lr46 gene and the Lr34 and Lr67 genes responsible for the differential leaf-rust resistance of hybrid forms of the F1 generation resulting from crosses between the Glenlea cultivar and cultivars from Polish breeding companies. In addition, the expression of five miRNAs (tae-miR9653b, tae-miR5384-3p, tae-miR9780, tae-miR9775 and tae-miR164), complementary to Lr34, and selected candidate genes were analysed using stem-loop RT-PCR and ddPCR. Biotic stress was induced in adult plants by inoculation with Pt fungal spores, under controlled conditions. Plant material was collected before and 6, 12, 24, and 48 h after inoculation (hpi). Differences in expression patterns of Lr34, Lr67, and candidate genes (for Lr46) were analysed by qRT-PCR and showed that gene expression changed at the analysed time points. Identification of molecular markers coupled to the Lr genes studied was also carried out to confirm the presence of these genes in wheat hybrids. qRT-PCR was used to examine the expression levels of the resistance genes. The highest expression of Lr46/Yr29 genes (Lr46-Glu2, Lr46-RLK1, Lr46-RLK2, and Lr46-RLK3) occurred at 12 and 24 hpi, and such expression profiles were obtained for only one candidate gene among the four genes analysed (Lr46-Glu2), indicating that it may be involved in resistance mechanisms of response to Pt infection. Full article

(This article belongs to the Special Issue Advanced Research in Wheat Genome and Breeding)

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23 pages, 5027 KiB

Open AccessArticle

Multiomics Analysis of the PHLDA Gene Family in Different Cancers and Their Clinical Prognostic Value

by Safia Iqbal, Md. Rezaul Karim, Shahnawaz Mohammad, Ramya Mathiyalagan, Md. Niaj Morshed, Deok-Chun Yang, Hyocheol Bae, Esrat Jahan Rupa and Dong Uk Yang

Curr. Issues Mol. Biol. 2024, 46(6), 5488-5510; https://doi.org/10.3390/cimb46060328 (registering DOI) - 30 May 2024

Abstract

The PHLDA (pleckstrin homology-like domain family) gene family is popularly known as a potential biomarker for cancer identification, and members of the PHLDA family have become considered potentially viable targets for cancer treatments. The PHLDA gene family consists of PHLDA1, PHLDA2, and PHLDA3. [...] Read more.

The PHLDA (pleckstrin homology-like domain family) gene family is popularly known as a potential biomarker for cancer identification, and members of the PHLDA family have become considered potentially viable targets for cancer treatments. The PHLDA gene family consists of PHLDA1, PHLDA2, and PHLDA3. The predictive significance of PHLDA genes in cancer remains unclear. To determine the role of pleckstrin as a prognostic biomarker in human cancers, we conducted a systematic multiomics investigation. Through various survival analyses, pleckstrin expression was evaluated, and their predictive significance in human tumors was discovered using a variety of online platforms. By analyzing the protein–protein interactions, we also chose a collection of well-known functional protein partners for pleckstrin. Investigations were also carried out on the relationship between pleckstrins and other cancers regarding mutations and copy number alterations. The cumulative impact of pleckstrin and their associated genes on various cancers, Gene Ontology (GO), and pathway analyses were used for their evaluation. Thus, the expression profiles of PHLDA family members and their prognosis in various cancers may be revealed by this study. During this multiomics analysis, we found that among the PHLDA family, PHLDA1 may be a therapeutic target for several cancers, including kidney, colon, and brain cancer, while PHLDA2 can be a therapeutic target for cancers of the colon, esophagus, and pancreas. Additionally, PHLDA3 may be a useful therapeutic target for ovarian, renal, and gastric cancer. Full article

(This article belongs to the Collection Bioinformatics Approaches to Biomedicine)

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21 pages, 1913 KiB

Open AccessReview

Positive Effects of Physical Activity on Insulin Signaling

by Paulina Małkowska

Curr. Issues Mol. Biol. 2024, 46(6), 5467-5487; https://doi.org/10.3390/cimb46060327 (registering DOI) - 30 May 2024

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Abstract

Physical activity is integral to metabolic health, particularly in addressing insulin resistance and related disorders such as type 2 diabetes mellitus (T2DM). Studies consistently demonstrate a strong association between physical activity levels and insulin sensitivity. Regular exercise interventions were shown to significantly improve [...] Read more.

Physical activity is integral to metabolic health, particularly in addressing insulin resistance and related disorders such as type 2 diabetes mellitus (T2DM). Studies consistently demonstrate a strong association between physical activity levels and insulin sensitivity. Regular exercise interventions were shown to significantly improve glycemic control, highlighting exercise as a recommended therapeutic strategy for reducing insulin resistance. Physical inactivity is closely linked to islet cell insufficiency, exacerbating insulin resistance through various pathways including ER stress, mitochondrial dysfunction, oxidative stress, and inflammation. Conversely, physical training and exercise preserve and restore islet function, enhancing peripheral insulin sensitivity. Exercise interventions stimulate β-cell proliferation through increased circulating levels of growth factors, further emphasizing its role in maintaining pancreatic health and glucose metabolism. Furthermore, sedentary lifestyles contribute to elevated oxidative stress levels and ceramide production, impairing insulin signaling and glucose metabolism. Regular exercise induces anti-inflammatory responses, enhances antioxidant defenses, and promotes mitochondrial function, thereby improving insulin sensitivity and metabolic efficiency. Encouraging individuals to adopt active lifestyles and engage in regular exercise is crucial for preventing and managing insulin resistance and related metabolic disorders, ultimately promoting overall health and well-being. Full article

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

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13 pages, 933 KiB

Open AccessArticle

Application of the TaqMan ARMS-PCR Approach for Genotyping Drug-Induced Hearing Loss Using Dried Blood Samples

by Jiefeng Tan, Xiaoqing Zhang, Xue Wei and Min Ding

Curr. Issues Mol. Biol. 2024, 46(6), 5454-5466; https://doi.org/10.3390/cimb46060326 (registering DOI) - 29 May 2024

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Abstract

A single nucleotide variant in mitochondrial DNA (mtDNA) 1555A>G is associated with drug-induced hearing loss. For the 1555A>G mutation site, 1555A wild-type and 1555G mutant-type plasmids were constructed, respectively. In this study, a PCR method based on the TaqMan amplification refractory mutation system [...] Read more.

A single nucleotide variant in mitochondrial DNA (mtDNA) 1555A>G is associated with drug-induced hearing loss. For the 1555A>G mutation site, 1555A wild-type and 1555G mutant-type plasmids were constructed, respectively. In this study, a PCR method based on the TaqMan amplification refractory mutation system was proposed to detect mtDNA 1555A>G. A common upstream primer, a common TaqMan probe, and two downstream allele-specific primers with mismatched bases were designed. One-step amplification and detection of the wild-type and mutant type at the 1555 site were realized for the deafness-related gene through two reactions. Based on this detection method, the minimum detection limit of the wild-type and mutant type detection systems for plasmids was 50 copies/μL. The minimum sensitivity for the detection of nucleic acids in real dried blood spot (DBS) samples was 0.1 ng/μL. In the normal DBS DNA sample, the detection limit of the mutation abundance reached 0.78%. The specificity of the detection method was 100%, and the coefficient of variation was less than 3.36%. This approach was validated using clinical DNA extracted from 113 DBS samples of newborns. Additionally, it showed 100% agreement with bi-directional Sanger sequencing. It can be used as an optional method for the clinical detection of deafness-related genes. Full article

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

18 pages, 1546 KiB

Open AccessReview

Molecular Mechanisms in the Design of Novel Targeted Therapies for Neurodegenerative Diseases

by Ilona Nowak, Marlena Paździor, Robert Sarna and Marcel Madej

Curr. Issues Mol. Biol. 2024, 46(6), 5436-5453; https://doi.org/10.3390/cimb46060325 (registering DOI) - 29 May 2024

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Abstract

Neurodegenerative diseases are a diverse group of diseases characterized by a progressive loss of neurological function due to damage to nerve cells in the central nervous system. In recent years, there has been a worldwide increase in the expanding associated with increasing human [...] Read more.

Neurodegenerative diseases are a diverse group of diseases characterized by a progressive loss of neurological function due to damage to nerve cells in the central nervous system. In recent years, there has been a worldwide increase in the expanding associated with increasing human life expectancy. Molecular mechanisms control many of the essential life processes of cells, such as replication, transcription, translation, protein synthesis and gene regulation. These are complex interactions that form the basis for understanding numerous processes in the organism and developing new diagnostic and therapeutic approaches. In the context of neurodegenerative diseases, molecular basis refers to changes at the molecular level that cause damage to or degeneration of nerve cells. These may include protein aggregates leading to pathological structures in brain cells, impaired protein transport in nerve cells, mitochondrial dysfunction, inflammatory processes or genetic mutations that impair nerve cell function. New medical therapies are based on these mechanisms and include gene therapies, reduction in inflammation and oxidative stress, and the use of miRNAs and regenerative medicine. The aim of this study was to bring together the current state of knowledge regarding selected neurodegenerative diseases, presenting the underlying molecular mechanisms involved, which could be potential targets for new forms of treatment. Full article

(This article belongs to the Special Issue Molecular Genetics and Genomics in Brain Disorders)

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16 pages, 2641 KiB

Open AccessArticle

Small Peptide Derived from SFRP5 Suppresses Melanogenesis by Inhibiting Wnt Activity

by Yoon-Seo Choi, Jin-Gwen Hong, Dong-Young Lim, Min-Seo Kim, Sang-Hoon Park, Hee-Cheol Kang, Won-Sang Seo and Jongsung Lee

Curr. Issues Mol. Biol. 2024, 46(6), 5420-5435; https://doi.org/10.3390/cimb46060324 (registering DOI) - 29 May 2024

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Abstract

Melanocytes, located in the epidermis’ basal layer, are responsible for melanin pigment production, crucial for skin coloration and protection against UV radiation-induced damage. Melanin synthesis is intricately regulated by various factors, including the Wnt signaling pathway, particularly mediated by the microphthalmia-associated transcription factor [...] Read more.

Melanocytes, located in the epidermis’ basal layer, are responsible for melanin pigment production, crucial for skin coloration and protection against UV radiation-induced damage. Melanin synthesis is intricately regulated by various factors, including the Wnt signaling pathway, particularly mediated by the microphthalmia-associated transcription factor (MITF). While MITF is recognized as a key regulator of pigmentation, its regulation by the Wnt pathway remains poorly understood. This study investigates the role of Sfrp5pepD, a peptide antagonist of the Wnt signaling pathway, in modulating melanogenesis and its potential therapeutic implications for pigmentary disorders. To tackle this issue, we investigated smaller peptides frequently utilized in cosmetics or pharmaceuticals. Nevertheless, there is a significant scarcity of reports on peptides associated with melanin-related signal modulation or inhibiting melanin production. Results indicate that Sfrp5pepD effectively inhibits Wnt signaling by disrupting the interaction between Axin-1 and β-catenin, thus impeding downstream melanogenic processes. Additionally, Sfrp5pepD suppresses the interaction between MITF and β-catenin, inhibiting their nuclear translocation and downregulating melanogenic enzyme expression, ultimately reducing melanin production. These inhibitory effects are validated in cell culture models suggesting potential clinical applications for hyperpigmentation disorders. Overall, this study elucidates the intricate interplay between Wnt signaling and melanogenesis, highlighting Sfrp5pepD as a promising therapeutic agent for pigmentary disorders. Sfrp5pepD, with a molecular weight of less than 500 Da, is anticipated to penetrate the skin unlike SFRPs. This suggests a strong potential for their use as cosmetics or transdermal absorption agents. Additional investigation into its mechanisms and clinical significance is necessary to enhance its effectiveness in addressing melanin-related skin conditions. Full article

(This article belongs to the Section Molecular Medicine)

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23 pages, 1849 KiB

Open AccessReview

Unravelling the Mysteries of the Sonic Hedgehog Pathway in Cancer Stem Cells: Activity, Crosstalk and Regulation

by Carlo Berrino and Aadilah Omar

Curr. Issues Mol. Biol. 2024, 46(6), 5397-5419; https://doi.org/10.3390/cimb46060323 (registering DOI) - 29 May 2024

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Abstract

The Sonic Hedgehog (Shh) signalling pathway plays a critical role in normal development and tissue homeostasis, guiding cell differentiation, proliferation, and survival. Aberrant activation of this pathway, however, has been implicated in the pathogenesis of various cancers, largely due to its role in [...] Read more.

The Sonic Hedgehog (Shh) signalling pathway plays a critical role in normal development and tissue homeostasis, guiding cell differentiation, proliferation, and survival. Aberrant activation of this pathway, however, has been implicated in the pathogenesis of various cancers, largely due to its role in regulating cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells with the ability to self-renew, differentiate, and initiate tumour growth, contributing significantly to tumorigenesis, recurrence, and resistance to therapy. This review focuses on the intricate activity of the Shh pathway within the context of CSCs, detailing the molecular mechanisms through which Shh signalling influences CSC properties, including self-renewal, differentiation, and survival. It further explores the regulatory crosstalk between the Shh pathway and other signalling pathways in CSCs, highlighting the complexity of this regulatory network. Here, we delve into the upstream regulators and downstream effectors that modulate Shh pathway activity in CSCs. This review aims to cast a specific focus on the role of the Shh pathway in CSCs, provide a detailed exploration of molecular mechanisms and regulatory crosstalk, and discuss current and developing inhibitors. By summarising key findings and insights gained, we wish to emphasise the importance of further elucidating the interplay between the Shh pathway and CSCs to develop more effective cancer therapies. Full article

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

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18 pages, 3159 KiB

Open AccessReview

Changing the Landscape of Solid Tumor Therapy from Apoptosis-Promoting to Apoptosis-Inhibiting Strategies

by Razmik Mirzayans

Curr. Issues Mol. Biol. 2024, 46(6), 5379-5396; https://doi.org/10.3390/cimb46060322 - 28 May 2024

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Abstract

The many limitations of implementing anticancer strategies under the term “precision oncology” have been extensively discussed. While some authors propose promising future directions, others are less optimistic and use phrases such as illusion, hype, and false hypotheses. The reality is revealed by practicing [...] Read more.

The many limitations of implementing anticancer strategies under the term “precision oncology” have been extensively discussed. While some authors propose promising future directions, others are less optimistic and use phrases such as illusion, hype, and false hypotheses. The reality is revealed by practicing clinicians and cancer patients in various online publications, one of which has stated that “in the quest for the next cancer cure, few researchers bother to look back at the graveyard of failed medicines to figure out what went wrong”. The message is clear: Novel therapeutic strategies with catchy names (e.g., synthetic “lethality”) have not fulfilled their promises despite decades of extensive research and clinical trials. The main purpose of this review is to discuss key challenges in solid tumor therapy that surprisingly continue to be overlooked by the Nomenclature Committee on Cell Death (NCCD) and numerous other authors. These challenges include: The impact of chemotherapy-induced genome chaos (e.g., multinucleation) on resistance and relapse, oncogenic function of caspase 3, cancer cell anastasis (recovery from late stages of apoptosis), and pitfalls of ubiquitously used preclinical chemosensitivity assays (e.g., cell “viability” and tumor growth delay studies in live animals) that score such pro-survival responses as “lethal” events. The studies outlined herein underscore the need for new directions in the management of solid 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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15 pages, 2393 KiB

Open AccessArticle

Association of Glycoprotein IIIa PlA1/A2 Polymorphism with Risk of Stroke: Updated Meta-Analysis

by Camelia Alexandra Coadă, Mihai Lupu, Iulia Florea, Stella Di Constanzo, Sara Coluccelli and Ioan Şimon

Curr. Issues Mol. Biol. 2024, 46(6), 5364-5378; https://doi.org/10.3390/cimb46060321 (registering DOI) - 28 May 2024

Viewed by 196

Abstract

Cardiovascular diseases are the main cause of death in the world, with ischemic heart disease (i.e., myocardial infarction) and cerebrovascular disease (i.e., stroke) taking the highest toll. Advances in diagnosis and treatment have led to a significant alleviation of ischemic complications, specifically in [...] Read more.

Cardiovascular diseases are the main cause of death in the world, with ischemic heart disease (i.e., myocardial infarction) and cerebrovascular disease (i.e., stroke) taking the highest toll. Advances in diagnosis and treatment have led to a significant alleviation of ischemic complications, specifically in the realm of pharmacotherapy and interventional devices, while pharmacogenomics has yet to be fully leveraged to improve the burden of disease. Atherothrombotic events might occur earlier or respond worse to treatment in patients with genetic variants of GP IIb/IIIa. Therefore, we aimed to quantitate the involvement of the PlA2 variant in the risk of cerebral stroke events. A systematic search and meta-analysis were performed by pooling the risks of individual studies. A total of 31 studies comprising 5985 stroke patients and 7886 controls were analyzed. A meta-analysis of four studies on hemorrhagic stroke patients showed no association with the PIA2 rs5918(C) polymorphism in both fixed-effect (OR = 0.90 95%CI [0.71; 1.14]; p = 0.398) and random-effect models (OR = 0.86 95%CI [0.62; 1.20]; p-value = 0.386). The power of this analysis was below <30%, indicating a limited ability to detect a true effect. An analysis of the 28 studies on ischemic stroke revealed a significant association with the PIA2 rs5918(C) allele in both fixed-effect (OR = 1.16 95%CI [1.06; 1.27]; p = 0.001) and random-effect models (OR = 1.20 95%CI [1.04; 1.38]; p-value = 0.012), with a power of >80%. The PIA2 allele was associated with an increased risk of ischemic stroke. No association was found with hemorrhagic stroke, most likely due to the small number of available studies, which resulted in a lack of power. Full article

(This article belongs to the Special Issue Cerebrovascular Diseases: From Pathogenesis to Treatment)

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12 pages, 3454 KiB

Open AccessCommunication

Complete Mitogenome of “Pumpo” (Bos taurus), a Top Bull from a Peruvian Genetic Nucleus, and Its Phylogenetic Analysis

by Richard Estrada, Deyanira Figueroa, Yolanda Romero, Wuesley Yusmein Alvarez-García, Diorman Rojas, Wigoberto Alvarado, Jorge L. Maicelo, Carlos Quilcate and Carlos I. Arbizu

Curr. Issues Mol. Biol. 2024, 46(6), 5352-5363; https://doi.org/10.3390/cimb46060320 - 28 May 2024

Viewed by 364

Abstract

The mitochondrial genome of Pumpo (Bos taurus), a prominent breed contributing to livestock farming, was sequenced using the Illumina HiSeq 2500 platform. Assembly and annotation of the mitochondrial genome were achieved through a multifaceted approach employing bioinformatics tools such as Trim [...] Read more.

The mitochondrial genome of Pumpo (Bos taurus), a prominent breed contributing to livestock farming, was sequenced using the Illumina HiSeq 2500 platform. Assembly and annotation of the mitochondrial genome were achieved through a multifaceted approach employing bioinformatics tools such as Trim Galore, SPAdes, and Geseq, followed by meticulous manual inspection. Additionally, analyses covering tRNA secondary structure and codon usage bias were conducted for comprehensive characterization. The 16,341 base pair mitochondrial genome comprises 13 protein-coding genes, 22 tRNA genes, and 2 rRNA genes. Phylogenetic analysis places Pumpo within a clade predominantly composed of European cattle, reflecting its prevalence in Europe. This comprehensive study underscores the importance of mitochondrial genome analysis in understanding cattle evolution and highlights the potential of genetic improvement programs in livestock farming, thus contributing to enhanced livestock practices. Full article

(This article belongs to the Special Issue Mitochondrial Genome 2024)

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15 pages, 1662 KiB

Open AccessArticle

Endocrine and Transcriptome Changes Associated with Testicular Growth and Differentiation in Atlantic Salmon (Salmo salar L.)

by Vetle Skjold, Sergey Afanasyev, Erik Burgerhout, Lene Sveen, Kjell-Arne Rørvik, Vasco Felipe Cardoso Neves Mota, Jens-Erik Dessen and Aleksei Krasnov

Curr. Issues Mol. Biol. 2024, 46(6), 5337-5351; https://doi.org/10.3390/cimb46060319 - 27 May 2024

Viewed by 175

Abstract

Sexual maturation of Atlantic salmon males is marked by dramatic endocrine changes and rapid growth of the testes, resulting in an increase in the gonad somatic index (GSI). We examined the association of gonadal growth with serum sex steroids, as well as pituitary [...] Read more.

Sexual maturation of Atlantic salmon males is marked by dramatic endocrine changes and rapid growth of the testes, resulting in an increase in the gonad somatic index (GSI). We examined the association of gonadal growth with serum sex steroids, as well as pituitary and testicular gene expression levels, which were assessed with a DNA oligonucleotide microarray. The testes transcriptome was stable in males with a GSI < 0.08% despite the large difference between the smallest and the largest gonads. Fish with a GSI ≥ 0.23% had 7–17 times higher serum levels of five male steroids and a 2-fold increase in progesterone, without a change in cortisol and related steroids. The pituitary transcriptome showed an upregulation of the hormone-coding genes that control reproduction and behavior, and structural rearrangement was indicated by the genes involved in synaptic transmission and the differentiation of neurons. The observed changes in the abundance of testicular transcripts were caused by the regulation of transcription and/or disproportional growth, with a greater increase in the germinative compartment. As these factors could not be separated, the transcriptome results are presented as higher or lower specific activities (HSA and LSA). LSA was observed in 4268 genes, including many genes involved in various immune responses and developmental processes. LSA also included genes with roles in female reproduction, germinal cell maintenance and gonad development, responses to endocrine and neural regulation, and the biosynthesis of sex steroids. Two functional groups prevailed among HSA: structure and activity of the cilia (95 genes) and meiosis (34 genes). The puberty of A. salmon testis is marked by the predominance of spermatogenesis, which displaces other processes; masculinization; and the weakening of external regulation. Results confirmed the known roles of many genes involved in reproduction and pointed to uncharacterized genes that deserve attention as possible regulators of sexual maturation. Full article

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

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15 pages, 1262 KiB

Open AccessReview

Is the Hedgehog Pathway Involved in the Pathophysiology of Schizophrenia? A Systematic Review of Current Evidence of Neural Molecular Correlates and Perspectives on Drug Development

by Antonio Del Casale, Martina Nicole Modesti, Giovanna Gentile, Cecilia Guariglia, Stefano Ferracuti, Maurizio Simmaco and Marina Borro

Curr. Issues Mol. Biol. 2024, 46(6), 5322-5336; https://doi.org/10.3390/cimb46060318 - 27 May 2024

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Abstract

Among the pathophysiological correlates of schizophrenia, recent research suggests a potential role for the Hedgehog (Hh) signalling pathway, which has been traditionally studied in embryonic development and oncology. Its dysregulation may impact brain homeostasis, neuroplasticity, and potential involvement in neural processes. This systematic [...] Read more.

Among the pathophysiological correlates of schizophrenia, recent research suggests a potential role for the Hedgehog (Hh) signalling pathway, which has been traditionally studied in embryonic development and oncology. Its dysregulation may impact brain homeostasis, neuroplasticity, and potential involvement in neural processes. This systematic review provides an overview of the involvement of Hh signalling in the pathophysiology of schizophrenia and antipsychotic responses. We searched the PubMed and Scopus databases to identify peer-reviewed scientific studies focusing on Hh and schizophrenia, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, finally including eight studies, including three articles focused on patients with schizophrenia, two animal models of schizophrenia, two animal embryo studies, and one cellular differentiation study. The Hh pathway is crucial in the development of midbrain dopaminergic neurons, neuroplasticity mechanisms, regulating astrocyte phenotype and function, brain-derived neurotrophic factor expression, brain glutamatergic neural transmission, and responses to antipsychotics. Overall, results indicate an involvement of Hh in the pathophysiology of schizophrenia and antipsychotic responses, although an exiguity of studies characterises the literature. The heterogeneity between animal and human studies is another main limitation. Further research can lead to better comprehension and the development of novel personalised drug treatments and therapeutic interventions. Full article

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

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15 pages, 758 KiB

Open AccessReview

Molecular Biological Research on the Pathogenic Mechanism of Retinoblastoma

by Xiangyi Ma, Xinyu Li, Qi Sun, Fuxiao Luan and Jing Feng

Curr. Issues Mol. Biol. 2024, 46(6), 5307-5321; https://doi.org/10.3390/cimb46060317 - 27 May 2024

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Abstract

Retinoblastoma (RB) is the most common intraocular malignant tumor in children, primarily attributed to the bi-allelic loss of the RB1 gene in the developing retina. Despite significant progress in understanding the basic pathogenesis of RB, comprehensively unravelling the intricate network of genetics and [...] Read more.

Retinoblastoma (RB) is the most common intraocular malignant tumor in children, primarily attributed to the bi-allelic loss of the RB1 gene in the developing retina. Despite significant progress in understanding the basic pathogenesis of RB, comprehensively unravelling the intricate network of genetics and epigenetics underlying RB tumorigenesis remains a major challenge. Conventional clinical treatment options are limited, and despite the continuous identification of genetic loci associated with cancer pathogenesis, the development of targeted therapies lags behind. This review focuses on the reported genomic and epigenomic alterations in retinoblastoma, summarizing potential therapeutic targets for RB and providing insights for research into targeted therapies. Full article

(This article belongs to the Collection Molecular Mechanisms in Human Diseases)

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16 pages, 3720 KiB

Open AccessReview

Single-Cell Sequencing Technology in Ruminant Livestock: Challenges and Opportunities

by Avery Lyons, Jocelynn Brown and Kimberly M. Davenport

Curr. Issues Mol. Biol. 2024, 46(6), 5291-5306; https://doi.org/10.3390/cimb46060316 - 27 May 2024

Viewed by 234

Abstract

Advancements in single-cell sequencing have transformed the genomics field by allowing researchers to delve into the intricate cellular heterogeneity within tissues at greater resolution. While single-cell omics are more widely applied in model organisms and humans, their use in livestock species is just [...] Read more.

Advancements in single-cell sequencing have transformed the genomics field by allowing researchers to delve into the intricate cellular heterogeneity within tissues at greater resolution. While single-cell omics are more widely applied in model organisms and humans, their use in livestock species is just beginning. Studies in cattle, sheep, and goats have already leveraged single-cell and single-nuclei RNA-seq as well as single-cell and single-nuclei ATAC-seq to delineate cellular diversity in tissues, track changes in cell populations and gene expression over developmental stages, and characterize immune cell populations important for disease resistance and resilience. Although challenges exist for the use of this technology in ruminant livestock, such as the precise annotation of unique cell populations and spatial resolution of cells within a tissue, there is vast potential to enhance our understanding of the cellular and molecular mechanisms underpinning traits essential for healthy and productive livestock. This review intends to highlight the insights gained from published single-cell omics studies in cattle, sheep, and goats, particularly those with publicly accessible data. Further, this manuscript will discuss the challenges and opportunities of this technology in ruminant livestock and how it may contribute to enhanced profitability and sustainability of animal agriculture in the future. Full article

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

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34 pages, 1029 KiB

Open AccessReview

Plant-Derived Compounds: A Promising Tool for Dental Caries Prevention

by Konstantinos Tzimas, Maria Antoniadou, Theodoros Varzakas and Chrysoula (Chrysa) Voidarou

Curr. Issues Mol. Biol. 2024, 46(6), 5257-5290; https://doi.org/10.3390/cimb46060315 - 26 May 2024

Viewed by 179

Abstract

There is a growing shift from the use of conventional pharmaceutical oral care products to the use of herbal extracts and traditional remedies in dental caries prevention. This is attributed to the potential environmental and health implications of contemporary oral products. This comprehensive [...] Read more.

There is a growing shift from the use of conventional pharmaceutical oral care products to the use of herbal extracts and traditional remedies in dental caries prevention. This is attributed to the potential environmental and health implications of contemporary oral products. This comprehensive review aims at the analysis of plant-derived compounds as preventive modalities in dental caries research. It focuses on data collected from 2019 until recently, trying to emphasize current trends in this topic. The research findings suggest that several plant-derived compounds, either aqueous or ethanolic, exhibit notable antibacterial effects against Streptococcus mutans and other bacteria related to dental caries, with some extracts demonstrating an efficacy comparable to that of chlorhexidine. Furthermore, in vivo studies using plant-derived compounds incorporated in food derivatives, such as lollipops, have shown promising results by significantly reducing Streptococcus mutans in high-risk caries children. In vitro studies on plant-derived compounds have revealed bactericidal and bacteriostatic activity against S. mutans, suggesting their potential use as dental caries preventive agents. Medicinal plants, plant-derived phytochemicals, essential oils, and other food compounds have exhibited promising antimicrobial activity against oral pathogens, either by their anti-adhesion activity, the inhibition of extracellular microbial enzymes, or their direct action on microbial species and acid production. However, further research is needed to assess their antimicrobial activity and to evaluate the cytotoxicity and safety profiles of these plant-derived compounds before their widespread clinical use can be recommended. Full article

(This article belongs to the Special Issue Molecular Insights into Food-Derived Natural Products and Their Biological Activities)

15 pages, 5344 KiB

Open AccessArticle

Functional Validation of Different Alternative Splicing Variants of the Chrysanthemum lavandulifolium ClNUM1 Gene in Tobacco

by Wenxin Zhang, Hai Wang, Yuning Guo, Xueying Hao, Yanxi Li, Wenting He, Xiang Zhao, Shiyi Cai and Xuebin Song

Curr. Issues Mol. Biol. 2024, 46(6), 5242-5256; https://doi.org/10.3390/cimb46060314 - 25 May 2024

Viewed by 226

Abstract

The Asteraceae are widely distributed throughout the world, with diverse functions and large genomes. Many of these genes remain undiscovered and unstudied. In this study, we discovered a new gene ClNUM1 in Chrysanthemum lavandulifolium and studied its function. In this study, bioinformatics, RT-qPCR, [...] Read more.

The Asteraceae are widely distributed throughout the world, with diverse functions and large genomes. Many of these genes remain undiscovered and unstudied. In this study, we discovered a new gene ClNUM1 in Chrysanthemum lavandulifolium and studied its function. In this study, bioinformatics, RT-qPCR, paraffin sectioning, and tobacco transgenics were utilized to bioinformatically analyze and functionally study the three variable splice variants of the unknown gene ClNUM1 cloned from C. lavandulifolium. The results showed that ClNUM1.1 and ClNUM1.2 had selective 3′ splicing and selective 5′ splicing, and ClNUM1.3 had selective 5′ splicing. When the corresponding transgenic tobacco plants were subjected to abiotic stress treatment, in the tobacco seedlings, the ClNUM1.1 gene and the ClNUM1.2 gene enhanced salt and low-temperature tolerance and the ClNUM1.3 gene enhanced low-temperature tolerance; in mature tobacco plants, the ClNUM1.1 gene was able to enhance salt and low-temperature tolerance, and the ClNUM1.2 and ClNUM1.3 genes were able to enhance low-temperature tolerance. In summary, there are differences in the functions of the different splice variants and the different seedling stages of transgenic tobacco, but all of them enhanced the resistance of tobacco to a certain extent. The analysis and functional characterization of the ClNUM1 gene provided new potential genes and research directions for abiotic resistance breeding in Chrysanthemum. Full article

(This article belongs to the Special Issue Molecular Breeding and Genetics Research in Plants)

19 pages, 481 KiB

Open AccessReview

The Role of Oxytocin in Polycystic Ovary Syndrome: A Systematic Review

by Nicoletta Cera, Joana Pinto and Duarte Pignatelli

Curr. Issues Mol. Biol. 2024, 46(6), 5223-5241; https://doi.org/10.3390/cimb46060313 - 25 May 2024

Viewed by 255

Abstract

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder that affects women of reproductive age, representing the primary cause of anovulatory infertility. The nonapeptide oxytocin (OT) plays an important role in cognitive, emotional, and reproductive functions in human beings. Oxytocin receptors are [...] Read more.

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder that affects women of reproductive age, representing the primary cause of anovulatory infertility. The nonapeptide oxytocin (OT) plays an important role in cognitive, emotional, and reproductive functions in human beings. Oxytocin receptors are expressed in several body parts, including the ovaries. Despite this, the possible role played by oxytocin in symptoms of PCOS is not clear. The present systematic review aimed at understanding the presence of possible oxytocin level alterations in PCOS, the connection between alterations of OT levels and the symptoms of PCOS, and the effect of oxytocin administration in PCOS. After a systematic search in the principal databases, eight studies, five human and three animal, were included. Four human studies and one animal study highlighted the role played by oxytocin in fertility issues related to PCOS. Three human and two animal studies investigated the role of body weight and OT levels. Studies that analyzed oxytocin basal levels in women agreed that PCOS is associated with a reduction in the serum level of oxytocin. Two human studies and one animal study agreed about lower levels of oxytocin, confirming a possible implication of the dysfunction of OT in the pathogenesis of PCOS. Full article

(This article belongs to the Special Issue Current Advances in Oxytocin Research)

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29 pages, 1204 KiB

Open AccessReview

Soil and Mineral Nutrients in Plant Health: A Prospective Study of Iron and Phosphorus in the Growth and Development of Plants

by Mujtaba Aamir Bhat, Awdhesh Kumar Mishra, Sheezma Nazir Shah, Mudasir Ahmad Bhat, Saima Jan, Safikur Rahman, Kwang-Hyun Baek and Arif Tasleem Jan

Curr. Issues Mol. Biol. 2024, 46(6), 5194-5222; https://doi.org/10.3390/cimb46060312 - 24 May 2024

Viewed by 295

Abstract

Plants being sessile are exposed to different environmental challenges and consequent stresses associated with them. With the prerequisite of minerals for growth and development, they coordinate their mobilization from the soil through their roots. Phosphorus (P) and iron (Fe) are macro- and micronutrient; [...] Read more.

Plants being sessile are exposed to different environmental challenges and consequent stresses associated with them. With the prerequisite of minerals for growth and development, they coordinate their mobilization from the soil through their roots. Phosphorus (P) and iron (Fe) are macro- and micronutrient; P serves as an important component of biological macromolecules, besides driving major cellular processes, including photosynthesis and respiration, and Fe performs the function as a cofactor for enzymes of vital metabolic pathways. These minerals help in maintaining plant vigor via alterations in the pH, nutrient content, release of exudates at the root surface, changing dynamics of root microbial population, and modulation of the activity of redox enzymes. Despite this, their low solubility and relative immobilization in soil make them inaccessible for utilization by plants. Moreover, plants have evolved distinct mechanisms to cope with these stresses and coregulate the levels of minerals (Fe, P, etc.) toward the maintenance of homeostasis. The present study aims at examining the uptake mechanisms of Fe and P, and their translocation, storage, and role in executing different cellular processes in plants. It also summarizes the toxicological aspects of these minerals in terms of their effects on germination, nutrient uptake, plant–water relationship, and overall yield. Considered as an important and indispensable component of sustainable agriculture, a separate section covers the current knowledge on the cross-talk between Fe and P and integrates complete and balanced information of their effect on plant hormone levels. Full article

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

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16 pages, 5614 KiB

Open AccessArticle

HDAC9 and miR-512 Regulate CAGE-Promoted Anti-Cancer Drug Resistance and Cellular Proliferation

by Minjeong Yeon, Nayeon Kwon, Jaewhoon Jeoung and Dooil Jeoung

Curr. Issues Mol. Biol. 2024, 46(6), 5178-5193; https://doi.org/10.3390/cimb46060311 - 24 May 2024

Viewed by 247

Abstract

Histone deacetylase 9 (HDAC9) is known to be upregulated in various cancers. Cancer-associated antigens (CAGEs) are cancer/testis antigens that play an important role in anti-cancer drug resistance. This study aimed to investigate the relationship between CAGEs and HDAC9 in relation to [...] Read more.

Histone deacetylase 9 (HDAC9) is known to be upregulated in various cancers. Cancer-associated antigens (CAGEs) are cancer/testis antigens that play an important role in anti-cancer drug resistance. This study aimed to investigate the relationship between CAGEs and HDAC9 in relation to anti-cancer drug resistance. AGS^R cells with an anti-cancer drug-resistant phenotype showed higher levels of CAGEs and HDAC9 than normal AGS cells. CAGEs regulated the expression of HDAC9 in AGS and AGS^R cells. CAGEs directly regulated the expression of HDAC9. Rapamycin, an inducer of autophagy, increased HDAC9 expression in AGS, whereas chloroquine decreased HDAC9 expression in AGS^R cells. The downregulation of HDAC9 decreased the autophagic flux, invasion, migration, and tumor spheroid formation potential in AGS^R cells. The TargetScan analysis predicted that miR-512 was a negative regulator of HDAC9. An miR-512 mimic decreased expression levels of CAGEs and HDAC9. The miR-512 mimic also decreased the autophagic flux, invasion, migration, and tumor spheroid forming potential of AGS^R cells. The culture medium of AGS^R increased the expression of HDAC9 and autophagic flux in AGS. A human recombinant CAGE protein increased HDAC9 expression in AGS cells. AGS^R cells displayed higher tumorigenic potential than AGS cells. Altogether, our results show that CAGE–HDAC9–miR-512 can regulate anti-cancer drug resistance, cellular proliferation, and autophagic flux. Our results can contribute to the understanding of the molecular roles of HDAC9 in anti-cancer drug resistance. Full article

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

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17 pages, 13213 KiB

Open AccessArticle

Combining RNAscope, Immunohistochemistry (IHC) and Digital Image Analysis to Assess Podoplanin (PDPN) Protein and PDPN_mRNA Expression on Formalin-Fixed Paraffin-Embedded Normal Human Placenta Tissues

by Larisa Cristina Tomescu, Andrei Alexandru Cosma, Mihaela Pasca Fenesan, Eugen Melnic, Vergil Petrovici, Simona Sarb, Monica Chis, Ioan Sas, Domenico Ribatti, Anca Maria Cimpean and Florica Ramona Dorobantu

Curr. Issues Mol. Biol. 2024, 46(6), 5161-5177; https://doi.org/10.3390/cimb46060310 - 24 May 2024

Viewed by 333

Abstract

The expression and function of podoplanin (PDPN) in the normal human placenta has been debated in placental evaluation. This study emphasizes the importance of a multimodal approach of PDPN expression in normal human placentas. A complete examination is performed using immunohistochemistry, RNAscope and [...] Read more.

The expression and function of podoplanin (PDPN) in the normal human placenta has been debated in placental evaluation. This study emphasizes the importance of a multimodal approach of PDPN expression in normal human placentas. A complete examination is performed using immunohistochemistry, RNAscope and automated Digital Image examination (DIA) interpretation. QuPath DIA-based analysis automatically generated the stromal and histological scores of PDPN expression for immunohistochemistry and RNAscope stains. The umbilical cord’s isolated fibroblasts and luminal structures expressed PDPN protein and PDPN_mRNA. RNAscope detected PDPN_mRNA upregulation in syncytial placental knots trophoblastic cells, but immunohistochemistry did not certify this at the protein level. The study found a significant correlation between the IHC and RNAscope H-Score (p = 0.033) and Allred Score (p = 0.05). A successful multimodal strategy for PDPN assessment in human placentas confirmed PDPN expression heterogeneity in the full-term human normal placenta and umbilical cord at the protein and mRNA level. In placental syncytial knots trophoblastic cells, PDPN showed mRNA overexpression, suggesting a potential role in placenta maturation. Full article

(This article belongs to the Special Issue Molecular Research in Reproductive Biology, 2nd Edition)

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14 pages, 899 KiB

Open AccessReview

Genetics and Epigenetics in Acquired Hemophilia A: From Bench to Bedside

by Nikolaos Evangelidis, Nikolaos Kotsiou, Paschalis Evangelidis, Vlasios I. Alevizopoulos, Iasonas Dermitzakis, Sofia Chissan, Sofia Vakalopoulou and Eleni Gavriilaki

Curr. Issues Mol. Biol. 2024, 46(6), 5147-5160; https://doi.org/10.3390/cimb46060309 - 23 May 2024

Viewed by 310

Abstract

Acquired hemophilia A (AHA) is a bleeding disorder characterized by the immunological inhibition of factor VIII (FVIII) of the hemostatic pathway leading to hemorrhagic events. Different domains of FVIII are the target of autoantibodies (mainly immunoglobulin (Ig) G) leading to the deficiency of [...] Read more.

Acquired hemophilia A (AHA) is a bleeding disorder characterized by the immunological inhibition of factor VIII (FVIII) of the hemostatic pathway leading to hemorrhagic events. Different domains of FVIII are the target of autoantibodies (mainly immunoglobulin (Ig) G) leading to the deficiency of FVIII. Several factors have been associated with the activation of the auto-immunity towards FVIII. Emerging evidence implicates CD4+ T cell activation in mediating this autoimmune response, with their involvement like that observed in congenital hemophilia A. Several genes such as HLA II DRB*16, DQB1*0502, and CTLA-4 + 49 are responsible for the pathogenesis of AHA. Epigenetic modifications and mainly long-coding RNAS (lncRNAs) are potentially contributing to the pathogenesis of AHA. The treatment approach of AHA includes the management of acute bleeding events and the administration of immunosuppressive medications. This review aimed to summarize the published data on the genetics and epigenetics of AHA. The severity and the mortality of this disease are creating an emerging need for further research in the field of the genetics and epigenetics of acquired hemorrhagic disorder. Full article

(This article belongs to the Special Issue Genomic Analysis of Common Disease)

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16 pages, 4922 KiB

Open AccessArticle

Identification of Key Hypolipidemic Components and Exploration of the Potential Mechanism of Total Flavonoids from Rosa sterilis Based on Network Pharmacology, Molecular Docking, and Zebrafish Experiment

by Boxiao Wu, Churan Li, Xulu Luo, Huan Kan, Yonghe Li, Yingjun Zhang, Xiaoping Rao, Ping Zhao and Yun Liu

Curr. Issues Mol. Biol. 2024, 46(6), 5131-5146; https://doi.org/10.3390/cimb46060308 - 23 May 2024

Viewed by 365

Abstract

Hyperlipidemia is a prevalent chronic metabolic disease that severely affects human health. Currently, commonly used clinical therapeutic drugs are prone to drug dependence and toxic side effects. Dietary intervention for treating chronic metabolic diseases has received widespread attention. Rosa sterilis is a characteristic [...] Read more.

Hyperlipidemia is a prevalent chronic metabolic disease that severely affects human health. Currently, commonly used clinical therapeutic drugs are prone to drug dependence and toxic side effects. Dietary intervention for treating chronic metabolic diseases has received widespread attention. Rosa sterilis is a characteristic fruit tree in China whose fruits are rich in flavonoids, which have been shown to have a therapeutic effect on hyperlipidemia; however, their exact molecular mechanism of action remains unclear. Therefore, this study aimed to investigate the therapeutic effects of R. sterilis total flavonoid extract (RS) on hyperlipidemia and its possible mechanisms. A hyperlipidemic zebrafish model was established using egg yolk powder and then treated with RS to observe changes in the integral optical density in the tail vessels. Network pharmacology and molecular docking were used to investigate the potential mechanism of action of RS for the treatment of hyperlipidemia. The results showed that RS exhibited favorable hypolipidemic effects on zebrafish in the concentration range of 3.0–30.0 μg/mL in a dose-dependent manner. Topological and molecular docking analyses identified HSP90AA1, PPARA, and MMP9 as key targets for hypolipidemic effects, which were exerted mainly through lipolytic regulation of adipocytes and lipids; pathway analysis revealed enrichment in atherosclerosis, chemical carcinogenic-receptor activation pathways in cancers, and proteoglycans in prostate cancer and other cancers. Mover, chinensinaphthol possessed higher content and better target binding ability, which suggested that chinensinaphthol might be an important component of RS with hypolipidemic active function. These findings provide a direction for further research on RS interventions for the treatment of hyperlipidemia. Full article

(This article belongs to the Special Issue A Focus on the Molecular Basis of Cardiovascular Diseases)

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14 pages, 839 KiB

Open AccessArticle

Succinimide Derivatives as Acetylcholinesterase Inhibitors—In Silico and In Vitro Studies

by Błażej Grodner, Dariusz Maciej Pisklak and Łukasz Szeleszczuk

Curr. Issues Mol. Biol. 2024, 46(6), 5117-5130; https://doi.org/10.3390/cimb46060307 - 22 May 2024

Viewed by 363

Abstract

We studied the effect of succinimide derivatives on acetylcholinesterase activity due to the interest in compounds that influence this enzyme’s activity, which could help treat memory issues more effectively. The following parameters were established for this purpose based on kinetic investigations of the [...] Read more.

We studied the effect of succinimide derivatives on acetylcholinesterase activity due to the interest in compounds that influence this enzyme’s activity, which could help treat memory issues more effectively. The following parameters were established for this purpose based on kinetic investigations of the enzyme in the presence of succinimide derivatives: the half-maximal inhibitory concentration, the maximum rate, the inhibition constant, and the Michaelis–Menten constant. Furthermore, computational analyses were performed to determine the energy required for succinimide derivatives to dock with the enzyme’s active site. The outcomes acquired in this manner demonstrated that all compounds inhibited acetylcholinesterase in a competitive manner. The values of the docking energy parameters corroborated the kinetic parameter values, which indicated discernible, albeit slight, variations in the inhibitory intensity among the various derivatives. Full article

(This article belongs to the Special Issue Synthesis and Theoretical Study of Bioactive Molecules)

17 pages, 528 KiB

Open AccessReview

HIV-1 Structural Proteins or Cell-Signaling Factors? That Is the Question!

by Michele Pellegrino, Francesca Giordano, Francesca De Amicis, Maria Marra, Paola Tucci, Stefania Marsico and Stefano Aquaro

Curr. Issues Mol. Biol. 2024, 46(6), 5100-5116; https://doi.org/10.3390/cimb46060306 - 22 May 2024

Viewed by 304

Abstract

The biological activity of structural HIV-1 proteins is not limited to ensuring a productive viral infection but also interferes with cellular homeostasis through intra- and extracellular signaling activation. This interference induces genomic instability, increases the lifespan of the infected cell by inhibiting apoptosis, [...] Read more.

The biological activity of structural HIV-1 proteins is not limited to ensuring a productive viral infection but also interferes with cellular homeostasis through intra- and extracellular signaling activation. This interference induces genomic instability, increases the lifespan of the infected cell by inhibiting apoptosis, and subverts cell senescence, resulting in unrestricted cell proliferation. HIV structural proteins are present in a soluble form in the lymphoid tissues and blood of infected individuals, even without active viral replication. The HIV matrix protein p17, the envelope glycoprotein gp120, the transenvelope protein gp41, and the capsid protein p24 interact with immune cells and deregulate the biological activity of the immune system. The biological activity of HIV structural proteins is also demonstrated in endothelial cells and some tumor cell lines, confirming the ability of viral proteins to promote cell proliferation and cancer progression, even in the absence of active viral replication. This review corroborates the hypothesis that HIV structural proteins, by interacting with different cell types, contribute to creating a microenvironment that is favorable to the evolution of cancerous pathologies not classically related to AIDS. Full article

(This article belongs to the Special Issue Research on Virus-Induced Cellular and Molecular Responses)

15 pages, 923 KiB

Open AccessArticle

Low Cell Bioenergetic Metabolism Characterizes Chronic Lymphocytic Leukemia Patients with Unfavorable Genetic Factors and with a Better Response to BTK Inhibition

by Simone Mirabilii, Monica Piedimonte, Esmeralda Conte, Daniele Mirabilii, Francesca Maria Rossi, Riccardo Bomben, Antonella Zucchetto, Valter Gattei, Agostino Tafuri and Maria Rosaria Ricciardi

Curr. Issues Mol. Biol. 2024, 46(6), 5085-5099; https://doi.org/10.3390/cimb46060305 - 22 May 2024

Viewed by 357

Abstract

Chronic Lymphocytic Leukemia (CLL) is an indolent malignancy characterized by the accumulation of quiescent mature B cells. However, these cells are transcriptionally and translationally active, implicating an active metabolism. The recent literature suggests that CLL cells have an oxidative-type phenotype. Given the role [...] Read more.

Chronic Lymphocytic Leukemia (CLL) is an indolent malignancy characterized by the accumulation of quiescent mature B cells. However, these cells are transcriptionally and translationally active, implicating an active metabolism. The recent literature suggests that CLL cells have an oxidative-type phenotype. Given the role of cell metabolism, which is able to influence the outcome of treatments, in other neoplasms, we aimed to assess its prognostic role in CLL patients by determining the ex vivo bioenergetic metabolic profile of CLL cells, evaluating the correlation with the patient clinical/biological characteristics and the in vivo response to BTK inhibitor treatment. Clustering analysis of primary samples identified two groups, characterized by low (CLL low) or high (CLL high) bioenergetic metabolic rates. Compared to the CLL high, CLL with lower bioenergetic metabolic rates belonged to patients characterized by a statistically significant higher white blood cell count and by unfavorable molecular genetics. More importantly, patients in the CLL low cluster displayed a better and more durable response to the BTK inhibitor ibrutinib, thus defining a bioenergetic metabolic subgroup that can benefit the most from this therapy. 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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Curr. Issues Mol. Biol., Volume 46, Issue 6 (June 2024) – 33 articles

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