International Journal of Molecular Sciences

15 pages, 2802 KiB

Open AccessArticle

Somatic Recombination Between an Ancient and a Recent NOTCH2 Gene Variant is Associated with the NOTCH2 Gain-of-Function Phenotype in Chronic Lymphocytic Leukemia

by Rainer Hubmann, Martin Hilgarth, Tamara Löwenstern, Andrea Lienhard, Filip Sima, Manuel Reisinger, Claudia Hobel-Kleisch, Edit Porpaczy, Torsten Haferlach, Gregor Hoermann, Franco Laccone, Christof Jungbauer, Peter Valent, Philipp B. Staber, Medhat Shehata and Ulrich Jäger

Int. J. Mol. Sci. 2024, 25(23), 12581; https://doi.org/10.3390/ijms252312581 (registering DOI) - 22 Nov 2024

Abstract

Constitutively active NOTCH2 signaling is a hallmark in chronic lymphocytic leukemia (CLL). The precise underlying defect remains obscure. Here we show that the mRNA sequence coding for the NOTCH2 negative regulatory region (NRR) is consistently deleted in CLL cells. The most common NOTCH2ΔNRR-DEL2 [...] Read more.

Constitutively active NOTCH2 signaling is a hallmark in chronic lymphocytic leukemia (CLL). The precise underlying defect remains obscure. Here we show that the mRNA sequence coding for the NOTCH2 negative regulatory region (NRR) is consistently deleted in CLL cells. The most common NOTCH2ΔNRR-DEL2 deletion is associated with two intronic single nucleotide variations (SNVs) which either create (CTTAT, G>A for rs2453058) or destroy (CTCGT, A>G for rs5025718) a putative splicing branch point sequence (BPS). Phylogenetic analysis demonstrates that rs2453058 is part of an ancient NOTCH2 gene variant (*1A01) which is associated with type 2 diabetes mellitus (T2DM) and is two times more frequent in Europeans than in East Asians, resembling the differences in CLL incidence. In contrast, rs5025718 belongs to a recent NOTCH2 variant (*1a4) that dominates the world outside Africa. Nanopore sequencing indicates that somatic reciprocal crossing over between rs2453058 (*1A01) and rs5025718 (*1a4) leads to recombined NOTCH2 alleles with altered BPS patterns in NOTCH2*1A01/*1a4 CLL cases. This would explain the loss of the NRR domain by aberrant pre-mRNA splicing and consequently the NOTCH2 gain-of-function phenotype. Together, our findings suggest that somatic recombination of inherited NOTCH2 variants might be relevant to CLL etiology and may at least partly explain its geographical clustering. Full article

(This article belongs to the Special Issue Notch Signaling Pathways)

25 pages, 779 KiB

Open AccessArticle

Improving Antimicrobial Properties of Biopolymer-Based Films in Food Packaging: Key Factors and Their Impact

by Sonia Wardejn, Stanisław Wacławek and Gabriela Dudek

Int. J. Mol. Sci. 2024, 25(23), 12580; https://doi.org/10.3390/ijms252312580 (registering DOI) - 22 Nov 2024

Abstract

Biodegradable films derived from polysaccharides are increasingly considered eco-friendly alternatives to synthetic packaging in the food industry. The study’s purpose was to improve the antimicrobial properties of biopolymer-based films made from starch, chitosan, alginate, and their blends (starch/chitosan and starch/alginate) and to evaluate [...] Read more.

Biodegradable films derived from polysaccharides are increasingly considered eco-friendly alternatives to synthetic packaging in the food industry. The study’s purpose was to improve the antimicrobial properties of biopolymer-based films made from starch, chitosan, alginate, and their blends (starch/chitosan and starch/alginate) and to evaluate the effects of modifiers, i.e., plant extracts, plasticizers, cross-linking agents, and nanofillers. Films were prepared via the Solution Casting Method and modified with various plasticizers, calcium chloride, oxidized sucrose, and nanofiber cellulose (NC). Chestnut, nettle, grape, and graviola extracts were tested for antimicrobial activity against Staphylococcus epidermidis, Escherichia coli, and Candida albicans. The film’s mechanical and hydrophilic properties were studied as well. The chestnut extract showed the strongest antimicrobial properties, leading to its incorporation in all the films. The chitosan films displayed better antibacterial activity against Gram-positive than Gram-negative bacteria but were ineffective against C. albicans. NC significantly improved the mechanical and antimicrobial properties of the chitosan films. The alginate films, modified with various plasticizers cross-linked with calcium chloride, demonstrated the highest antimicrobial efficacy against E. coli. The starch films, cross-linked with oxidized sucrose, exhibited slightly lower antimicrobial resistance due to a more compact structure. Films such as ALG6 and ALG5, including plasticizers EPGOS and PGOS, respectively, indicated optimal hydrophilicity and mechanical properties and achieved the best antimicrobial performance against all the investigated microorganisms. All these findings highlight the potential of these biodegradable films for food packaging, offering enhanced antimicrobial activity that prolongs shelf life and reduces spoilage, making them promising candidates for sustainable food preservation. Full article

(This article belongs to the Special Issue Chitosan Materials: Recent Advances in Modification, Properties and Application)

14 pages, 787 KiB

Open AccessArticle

Morphometric, Biomechanical and Histologic Assessment of Physiologic Ovine Cervical Intervertebral Disc: An Experimental Study and Brief Literature Review

by Nikolaos Gkantsinikoudis, Savvas Koltsakidis, Panagiotis Prodromou, Eleni Aggelidou, Stylianos Kapetanakis, Eleftherios Tsiridis, Ioannis Magras, Dimitra Psalla, George Kazakos, Dimitrios Tzetzis and Aristeidis Kritis

Int. J. Mol. Sci. 2024, 25(23), 12579; https://doi.org/10.3390/ijms252312579 (registering DOI) - 22 Nov 2024

Abstract

The ovine cervical spine model has been established as a representative model of the human cervical spine in the current literature, and is the most commonly used large animal model in studies investigating pathogenesis and treatment strategies for intervertebral disc (IVD) degeneration. However, [...] Read more.

The ovine cervical spine model has been established as a representative model of the human cervical spine in the current literature, and is the most commonly used large animal model in studies investigating pathogenesis and treatment strategies for intervertebral disc (IVD) degeneration. However, existing data regarding morphometry, biomechanical profiles and the microscopic features of a physiological ovine cervical IVD remain scarce. Hence, the aim of this study was to perform a multimodal morphometric, biomechanical and histologic evaluation of a normal ovine cervical IVD. For this purpose, nine ovine cervical IVDs were harvested from three female sheep, and subjected to morphometrical, biomechanical and histologic analyses. The biomechanical assessment included the performance of cyclic compression, creepand compressive strength tests in a controlledlaboratory environment. Histological evaluation was performed using hematoxylin–eosin, Masson’s trichrome and Alcian blue staining. The results from the morphometric analysis showed that the range of disc heights was 4–9 mm in all surfaces, featuring a constant increase from cranial to caudal levels. Biomechanical evaluation revealed that cyclic loading for 20 cycles was necessary for preconditioning so that the repeatability of the force–displacement hysteresis response is present. The critical failure point was defined at 15.5 MPa, whereas Young’s modulus of elasticity was 1.2 MPa. The histologic assessment demonstrated the presence of a concentric arrangement of collagen lamellae in external annulus fibrosus, along with the sparsely organized internal nucleus pulposus. Ovine cervical IVD represents a complex structure with distinct features that should be considered by researchers in this field in order to optimize the reliability and validity of testing results. Full article

(This article belongs to the Special Issue Regenerative Medicine: Biomaterials and Stem Cell Research)

23 pages, 2521 KiB

Open AccessArticle

Viral-Porphyrin Combo: Photodynamic and Oncolytic Viral Therapy for Potent Glioblastoma Treatment

by Alina S. Nazarenko, Alena O. Shkirdova, Ekaterina A. Orlova, Yulia K. Biryukova, Mikhail F. Vorovitch, Nadezhda M. Kolyasnikova, Aydar A. Ishmukhametov, Vladimir S. Tyurin and Ilya A. Zamilatskov

Int. J. Mol. Sci. 2024, 25(23), 12578; https://doi.org/10.3390/ijms252312578 (registering DOI) - 22 Nov 2024

Abstract

Combined viral and photodynamic therapy for oncological diseases has great potential to treat aggressive tumors such as glioblastomas. A conjugate of vesicular stomatitis virus (VSV) with protoporphyrin IX was prepared, and its oncolytic effects were studied and compared to the effects of the [...] Read more.

Combined viral and photodynamic therapy for oncological diseases has great potential to treat aggressive tumors such as glioblastomas. A conjugate of vesicular stomatitis virus (VSV) with protoporphyrin IX was prepared, and its oncolytic effects were studied and compared to the effects of the individual components. The VSV showed an oncolytic effect on glioblastoma cell lines T98G and LN229 at a virus titer of 10⁵ TCID₅₀/mL. A VSV titer of 10⁴ TCID₅₀/mL was sufficient for neuroblastoma cell death. A study of the effect of VSV in tumor 3D cell modeling found that VSV had a clear viral cytopathic effect on spheroids of T98G and LN229 cells. Conjugation with the porphyrin significantly reduced the viral titer, but when irradiated, lysis of cells was observed. Photodynamic treatment of T98G and LN229 cells and spheroids with protoporphyrin IX as a photosensitizer also had a cytotoxic effect on cells and, to a lesser extent, on the tumoroids, as complete cell death was not achieved for the tumoroids. The combination therapy, which involved sequential photodynamic therapy using protoporphyrin IX as a photosensitizer and treatment with VSV, was shown to significantly enhance efficacy, resulting in complete cell death of both T98G and LN229 cells and tumoroids. The combination treatment allowed for the use of a lower viral titer (10³–10⁴ TCID₅₀/mL) and a lower porphyrin concentration (0.5 μg/mL) to achieve a significant cytotoxic effect. As a result, the implementation of this combination therapy would likely lead to fewer side effects from the treatment. This study clearly demonstrated the excellent perspectives of combination therapy for the treatment of highly aggressive tumors such as glioblastomas. Full article

(This article belongs to the Section Molecular Microbiology)

15 pages, 2057 KiB

Open AccessArticle

The Influence of Juglans regia L. Extract and Ellagic Acid on Oxidative Stress, Inflammation, and Bone Regeneration Biomarkers

by Alina Hanga-Farcas, Luminita Fritea, Gabriela Adriana Filip, Simona Clichici, Laura Gratiela Vicas, Vlad-Alexandru Toma, Eleonora Marian, Felicia Gabriela Gligor, Wael Abu Dayyih and Mariana Eugenia Muresan

Int. J. Mol. Sci. 2024, 25(23), 12577; https://doi.org/10.3390/ijms252312577 (registering DOI) - 22 Nov 2024

Abstract

Bone regeneration is a highly dynamic and complex process that involves hematopoietic stem cells and mesenchymal cells, collagen fibers, non-collagenous proteins and biomolecules from extracellular matrices, and different cytokines and immune cells, as well as growth factors and hormones. Some phytochemicals due to [...] Read more.

Bone regeneration is a highly dynamic and complex process that involves hematopoietic stem cells and mesenchymal cells, collagen fibers, non-collagenous proteins and biomolecules from extracellular matrices, and different cytokines and immune cells, as well as growth factors and hormones. Some phytochemicals due to antioxidant and anti-inflammatory effects can modulate the bone signaling pathways and improve bone healing and thus can be a good candidate for osteoregeneration. The aim of this study was to analyze the impact of Juglans regia L. extract compared to ellagic acid on bone neoformation in rats. The animals with a 5 mm calvaria defect were divided into four groups (n = 10): group 1 was treated with ellagic acid 1% (EA), group 2 was treated with Juglans regia L. extract 10% (JR), group 3 was treated with a biphasic mix of hydroxyapatite and tricalcium phosphate (Ceraform), and group 4 was treated with vehicle inert gel with carboxymethylcellulose (CMC). After 3 weeks of treatment, blood samples were collected for oxidative stress and inflammation assessment. Additionally, the receptor activator of nuclear factor kappa-Β ligand (RANKL) and hydroxyproline levels were quantified in blood. The skull samples were analyzed by scanning electron microscopy in order to detect the modifications in the four groups. The results suggested that JR extract had relevant anti-oxidant effect and bone protective activity and generated the accumulation of Ca and P, demonstrating the potential therapeutic abilities in bone regeneration. Full article

(This article belongs to the Special Issue Therapeutic Potential of Natural Compounds: Insights into Mechanisms, Molecular Docking, and Biological Activities)

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21 pages, 4561 KiB

Open AccessReview

The Estrogen–Autophagy Axis: Insights into Cytoprotection and Therapeutic Potential in Cancer and Infection

by Ying Zhao, Daniel J. Klionsky, Xin Wang, Qiaoying Huang, Zixin Deng and Jin Xiang

Int. J. Mol. Sci. 2024, 25(23), 12576; https://doi.org/10.3390/ijms252312576 (registering DOI) - 22 Nov 2024

Abstract

Macroautophagy, commonly referred to as autophagy, is an essential cytoprotective mechanism that plays a significant role in cellular homeostasis. It has emerged as a promising target for drug development aimed at treating various cancers and infectious diseases. However, the scientific community has yet [...] Read more.

Macroautophagy, commonly referred to as autophagy, is an essential cytoprotective mechanism that plays a significant role in cellular homeostasis. It has emerged as a promising target for drug development aimed at treating various cancers and infectious diseases. However, the scientific community has yet to reach a consensus on the most effective approach to manipulating autophagy, with ongoing debates about whether its inhibition or stimulation is preferable for managing these complex conditions. One critical factor contributing to the variability in treatment responses for both cancers and infectious diseases is estrogen, a hormone known for its diverse biological effects. Given the strong correlations observed between estrogen signaling and autophagy, this review seeks to summarize the intricate molecular mechanisms that underlie the dual cytoprotective effects of estrogen signaling in conjunction with autophagy. We highlight recent findings from studies that involve various ligands, disease contexts, and cell types, including immune cells. Furthermore, we discuss several factors that regulate autophagy in the context of estrogen’s influence. Ultimately, we propose a hypothetical model to elucidate the regulatory effects of the estrogen–autophagy axis on cell fate. Understanding these interactions is crucial for advancing our knowledge of related diseases and facilitating the development of innovative treatment strategies. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 2nd Edition)

15 pages, 2200 KiB

Open AccessArticle

Brain Amyloid-β Peptide Is Associated with Pain Intensity and Cognitive Dysfunction in Osteoarthritic Patients

by Chun-Hsien Wen, Hong-Yo Kang and Julie Y.H. Chan

Int. J. Mol. Sci. 2024, 25(23), 12575; https://doi.org/10.3390/ijms252312575 (registering DOI) - 22 Nov 2024

Abstract

Considerable studies have demonstrated that osteoarthritis (OA) is a risk factor for dementia. The precise mechanisms underlying the association between OA and increased risk for cognitive dysfunction, however, remain unclear. This study aimed at exploring the associations between pro-inflammatory cytokines/chemokines, biomarkers of Alzheimer’s [...] Read more.

Considerable studies have demonstrated that osteoarthritis (OA) is a risk factor for dementia. The precise mechanisms underlying the association between OA and increased risk for cognitive dysfunction, however, remain unclear. This study aimed at exploring the associations between pro-inflammatory cytokines/chemokines, biomarkers of Alzheimer’s disease (AD), pain intensity, and cognitive decline in knee joint OA patients. A total of 50 patients (26 in OA group and 24 in non-OA control group) were enrolled in this prospective, observational study. The visual analogue scale (VAS) score for pain intensity and Cognitive Abilities Screening Instrument (CASI) score for cognitive functions were examined in both groups. The plasma and cerebrospinal fluid (CSF) levels of pro-inflammatory molecules (IL-1β, IL-6, TNF-α, fractalkine, BDNF, MCP-1, and TGF-β), as well as biomarkers of AD (Aβ₄₀, Aβ₄₂, total-tau, and phospho-tau), were measured by multiplex immunoassay. Correlations among plasma or CSF biomarkers and questionnaire scores were assessed using Pearson’s correlation coefficient and simple linear regressions. There were more patients in the OA group whose CASI cutoff percentiles were <P5 or at P5 than in the control group. VAS pain scores were negatively correlated with cognitive domains, including total score, short term memory, attention, mental manipulation, abstract thinking, and judgment, of the CASI score. VAS scores were positively correlated with fractalkine, Aβ₄₀, and Aβ₄₂ in CSF of OA patients. The CSF levels of Aβ₄₀ and Aβ₄₂ in OA patients were negatively correlated with attention and abstract scores in CASI. The findings of this study suggest that knee OA is associated with poor cognitive performance, and this association is particularly pronounced in OA patients with chronic pain. Higher levels of brain AD biomarkers, such as Aβ₄₀ and Aβ₄₂, may partially mediate this relationship. Full article

(This article belongs to the Section Molecular Neurobiology)

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21 pages, 6998 KiB

Open AccessArticle

Effect of Dihydroquercetin During Long-Last Growth of Yarrowia lipolytica Yeast: Anti-Aging Potential and Hormetic Properties

by Maxim S. Pusev, Olga I. Klein, Natalya N. Gessler, Galina P. Bachurina, Svetlana Yu. Filippovich, Elena P. Isakova and Yulia I. Deryabina

Int. J. Mol. Sci. 2024, 25(23), 12574; https://doi.org/10.3390/ijms252312574 (registering DOI) - 22 Nov 2024

Abstract

Polyphenols are powerful natural antioxidants with numerous biological activities. They change cell membrane permeability, interact with receptors, intracellular enzymes, and cell membrane transporters, and quench reactive oxygen species (ROS). Yarrowia lipolytica yeast, being similar to mammalian cells, can be used as a model [...] Read more.

Polyphenols are powerful natural antioxidants with numerous biological activities. They change cell membrane permeability, interact with receptors, intracellular enzymes, and cell membrane transporters, and quench reactive oxygen species (ROS). Yarrowia lipolytica yeast, being similar to mammalian cells, can be used as a model to study their survival ability upon long-lasting cultivation, assaying the effect of dihydroquercetin polyphenol (DHQ). The complex assessment of the physiological features of the population assaying cell respiration, survival, ROS detection, and flow cytometry was used. Y. lipolytica showed signs of chronological aging by eight weeks of growth, namely a decrease in the cell number, and size, increased ROS generation, a decrease in colony-forming unit (CFU) and metabolic activity, and decreased respiratory rate and membrane potential. An amount of 150 µM DHQ decreased ROS generation at the 6-week growth stage upon adding an oxidant of 2,2′-azobis (2-amidinopropane) dihydrochloride (AAPH). Moreover, it decreased CFU at 1–4 weeks of cultivation, inhibited cell metabolic activity of the 24-h-old culture and stimulated that on 14–56 days of growth, induced the cell respiration rate in the 24-h-old culture, and blocked alternative mitochondrial oxidase at growth late stages. DHQ serves as a mild pro-oxidant on the first day of age-stimulating anti-stress protection. In the deep stationary stage, it can act as a powerful antioxidant, stabilizing cell redox status and reducing free radical oxidation in mitochondria. It provides a stable state of population. The hormetic effects of DHQ using lower eukaryotes of Y. lipolytica have been previously discussed, which can be used as a model organism for screening geroprotective compounds of natural origin. Full article

(This article belongs to the Special Issue Stress Response Research: Yeast as Models: 2nd Edition)

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16 pages, 2381 KiB

Open AccessArticle

Genome-Wide Association Study and Marker Development for Fusarium Oxysporum Root Rot Resistance in Soybean

by Yuhe Wang, Jinfeng Han, Xiangkun Meng, Maolin Sun, Shuo Qu, Yuanyuan Liu, Yongguang Li, Yuhang Zhan, Weili Teng, Haiyan Li, Xue Zhao and Yingpeng Han

Int. J. Mol. Sci. 2024, 25(23), 12573; https://doi.org/10.3390/ijms252312573 (registering DOI) - 22 Nov 2024

Abstract

Fusarium oxysporum root rot (FORR) is an important disease threatening soybean production. The development of marker-assisted selection (MAS) molecular markers will help accelerate the disease resistance breeding process and achieve the breeding goal of improving soybean disease resistance. This study evaluated the FORR [...] Read more.

Fusarium oxysporum root rot (FORR) is an important disease threatening soybean production. The development of marker-assisted selection (MAS) molecular markers will help accelerate the disease resistance breeding process and achieve the breeding goal of improving soybean disease resistance. This study evaluated the FORR disease resistance of 356 soybean germplasm accessions (SGAs) and screened resistance-related loci using genome-wide association analysis (GWAS) to develop molecular markers for MAS. A total of 1,355,930 high-quality SNPs were analyzed, 150 SNP sites significantly associated with FORR resistance were identified, and these sites were distributed within 41 QTLs. Additionally, 240 candidate genes were screened near these QTL regions, involving multiple functions such as hormone metabolism, signal transduction, stress defense, and growth regulation. Cleaved amplified polymorphic sequence (CAPS) and Kompetitive Allele-Specific PCR (KASP) molecular markers were developed based on candidate genes with significant SNP loci and beneficial haplotypes. The CAPS markers, S15_50486939-CAPS1 and S15_50452626-CAPS2, can effectively distinguish resistant and sensitive genotypes through enzyme digestion. The KASP marker is based on S07_19078765-G/T and exhibits a genotype clustering pattern consistent with disease resistance, demonstrating its application value in breeding. The CAPS and KASP markers developed in this study can provide reliable tools for MAS in FORR disease-resistant varieties. The research results will help reveal the genetic structure of FORR disease resistance and provide support for efficient breeding. Full article

(This article belongs to the Special Issue Plant Responses to Biotic and Abiotic Stresses)

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11 pages, 1032 KiB

Open AccessArticle

Antimicrobial Peptide CATH-2 Attenuates Avian Pathogenic E. coli-Induced Inflammatory Response via NF-κB/NLRP3/MAPK Pathway and Lysosomal Dysfunction in Macrophages

by Yating Xu, Liuyi Xu, Tingting Zhang, Hongliang Tian, Yi Lu, Sha Jiang, Xuefeng Cao, Zhiwei Li, Xiaoxiang Hu, Rendong Fang and Lianci Peng

Int. J. Mol. Sci. 2024, 25(23), 12572; https://doi.org/10.3390/ijms252312572 - 22 Nov 2024

Abstract

Cathelicidins have anti-inflammatory activity and chicken cathelicidin-2 (CATH-2) has shown to modulate immune response, but the underlying mechanism of its anti-inflammation is still unclear. Therefore, in this study, we investigated the anti-inflammatory activity of CATH-2 on murine peritoneal macrophages during avian pathogenic E. [...] Read more.

Cathelicidins have anti-inflammatory activity and chicken cathelicidin-2 (CATH-2) has shown to modulate immune response, but the underlying mechanism of its anti-inflammation is still unclear. Therefore, in this study, we investigated the anti-inflammatory activity of CATH-2 on murine peritoneal macrophages during avian pathogenic E. coli (APEC) infection. The results showed that CATH-2 priming significantly reduced the production of IL-1β, IL-6, IL-1α, and IL-12. In addition, CATH-2 significantly attenuated APEC-induced caspase-1 activation and the formation of an adaptor (ASC) of NLRP3 inflammasome, indicating that CATH-2 inhibits APEC-induced NLRP3 inflammasome activation. Furthermore, CATH-2 remarkably inhibited NF-κB and MAPK signaling pathways activation. Moreover, CATH-2 significantly inhibited mRNA expression of cathepsin B and inhibited lysosomal acidification, demonstrating that CATH-2 disrupts lysosomal function. In addition, promoting lysosomal acidification using ML-SA1 hampered the anti-inflammatory effect of CATH-2 on APEC-infected cells. In conclusion, our study reveals that CATH-2 inhibits APEC-induced inflammation via the NF-κB/NLRP3/MAPK pathway through the dysfunction of lysosome. Full article

(This article belongs to the Special Issue Antimicrobial and Antiviral Peptides)

15 pages, 735 KiB

Open AccessArticle

Pleiotropic Associations with Alzheimer’s Disease and Physical Activity: Sex Differences and the Effects of Environment

by Yury Loika, Elena Loiko, Irina Culminskaya and Alexander M. Kulminski

Int. J. Mol. Sci. 2024, 25(23), 12571; https://doi.org/10.3390/ijms252312571 - 22 Nov 2024

Abstract

Abstract: Physical activity (PA) is a modifiable factor in mitigating/preventing Alzheimer’s disease (AD). It is crucial to identify the conditions under which PA’s effects on AD risk would be beneficial. This study aims to gain insights into pleiotropic predisposition to AD and [...] Read more.

Abstract: Physical activity (PA) is a modifiable factor in mitigating/preventing Alzheimer’s disease (AD). It is crucial to identify the conditions under which PA’s effects on AD risk would be beneficial. This study aims to gain insights into pleiotropic predisposition to AD and PA within and across sexes and environmental effects. We performed a genome-wide association study (GWAS) of pleiotropic AD-PA associations in individuals (65 years and older) of European ancestry in a US sample (14,628 individuals), for men and women separately and combined, and contrasted them with the UK biobank (204,789 individuals) to elucidate the effects of the environment. Fisher’s method and Wald's test were used for estimating the significance of pleiotropic associations and differences between the samples. We identified genetic markers in 60 loci with significant pleiotropic associations. Of them, 91.7% of loci exhibited antagonistic relationships characterized by a misalignment of the signs of the associations of the same alleles with AD and PA and a correlation between these phenotypes. Only 16.7% of associations were replicated in the UKB. Phosphorylation and the regulation of transcription were identified as more pronounced biological mechanisms of AD-PA pleiotropy in females and males, respectively. Our results demonstrate the intrinsic heterogeneity of AD-PA pleiotropy and suggest that PA should be used as an intervention against AD with caution, after identifying groups of individuals and combinations of gene–environment interactions with beneficial effects. Full article

(This article belongs to the Special Issue The Molecular and Cellular Mechanisms of Neurodegenerative Diseases, 2nd Edition)

14 pages, 2472 KiB

Open AccessArticle

Surface Display of Multiple Metal-Binding Domains in Deinococcus radiodurans Alleviates Cadmium and Lead Toxicity in Rice

by Liangyan Wang, Yudong Wang, Shang Dai and Binqiang Wang

Int. J. Mol. Sci. 2024, 25(23), 12570; https://doi.org/10.3390/ijms252312570 - 22 Nov 2024

Abstract

Cadmium (Cd) and lead (Pb) are the primary hazardous heavy metals that accumulate in crops and pose substantial risks to public health via the food chain. Limiting the migration of these toxic metals from contaminated environments to rice is the most direct and [...] Read more.

Cadmium (Cd) and lead (Pb) are the primary hazardous heavy metals that accumulate in crops and pose substantial risks to public health via the food chain. Limiting the migration of these toxic metals from contaminated environments to rice is the most direct and crucial remediation approach. Bioremediation with microorganisms has been extensively utilized for managing heavy metal contamination in the natural environment, and the interplay between microbes and crops is important to alleviate heavy metal stress. Here, we express Lpp-OmpA fused with two metal-binding domains (PbBD and MTT5) in the outer membrane of Deinococcus radiodurans to enhance both Cd and Pb adsorption. Our results showed that the recombinant strain LOPM, which displayed an increased tolerance to both Cd and Pb stress, exhibited a 4.9-fold higher Cd adsorption and 3.2-fold higher Pb adsorption compared to wild-type strain R1. After LOPM cells colonized the rice root, Cd content reduced to 47.0% in root and 43.4% in shoot; Pb content reduced to 55.4% in root and 26.9% in shoot, as compared to the plant’s exposure to Cd and Pb. In addition, cells of LOPM strain colonized on rice roots alleviate Cd- and Pb-induced oxidative stress by reducing ROS levels and enhancing antioxidant enzyme activities in rice. This study supplies a promising application of genetic-engineering extremophile bacteria in reducing heavy metal accumulation and toxicity in rice. Full article

(This article belongs to the Special Issue Physiology and Molecular Biology of Plant Stress Tolerance)

15 pages, 2232 KiB

Open AccessArticle

Molecular Composition and Kinetics of B Cells During Ibrutinib Treatment in Patients with Chronic Lymphocytic Leukemia

by Sólja Remisdóttir Veyhe, Oriane Cédile, Sara Kamuk Dahlmann, Jakub Krejcik, Niels Abildgaard, Thor Høyer, Michael Boe Møller, Mads Thomassen, Karen Juul-Jensen, Henrik Frederiksen, Karen Dybkær, Marcus Høy Hansen and Charlotte Guldborg Nyvold

Int. J. Mol. Sci. 2024, 25(23), 12569; https://doi.org/10.3390/ijms252312569 - 22 Nov 2024

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of B cells due to constitutive B-cell receptor (BCR) signaling, leading to apoptosis resistance and increased proliferation. This study evaluates the effects of the Bruton Tyrosine Kinase (BTK) inhibitor ibrutinib on the molecular composition, [...] Read more.

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of B cells due to constitutive B-cell receptor (BCR) signaling, leading to apoptosis resistance and increased proliferation. This study evaluates the effects of the Bruton Tyrosine Kinase (BTK) inhibitor ibrutinib on the molecular composition, clonality, and kinetics of B cells during treatment in CLL patients. Employing a multi-omics approach of up to 3.2 years of follow-up, we analyzed data from 24 CLL patients, specifically focusing on nine patients treated with ibrutinib monotherapy. In this study, clonal stability was observed within the ibrutinib-treated group following an effective initial clinical response, where clonotype frequencies of residual CLL cells remained high and stable, ranging from 74.9% at 1.5 years to 87.7% at approximately 3 years. In contrast, patients treated with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax exhibited substantial reductions in clonal frequencies, approaching molecular eradication. Deep whole-exome sequencing revealed minimal genomic progression in the ibrutinib group, maintaining somatic drivers and variant allele frequencies (VAF) above 0.2 throughout treatment. At the single-cell level, the NF-κB pathway inhibition and apoptotic signals were detected or even augmented during treatment in ibrutinib-treated patients. These findings may corroborate the role of ibrutinib in stabilizing the genomic landscape of CLL cells, preventing significant genomic evolution despite maintaining a high clonal burden within the residual B-cell compartment. Full article

(This article belongs to the Special Issue Next-Generation Sequencing and Whole-Genome Sequencing in Molecular Research)

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19 pages, 2782 KiB

Open AccessArticle

Evaluation of Salt Resistance of Six Apple Rootstocks

by Lun Li, Guolin Chen, Qingrong Sun, Qing Wang, Sen Wang, Haibo Wang, Zhihua Ni, Caina Jiang, Linguang Li and Tianhong Li

Int. J. Mol. Sci. 2024, 25(23), 12568; https://doi.org/10.3390/ijms252312568 - 22 Nov 2024

Abstract

Apples (Malus domestica Borkh) are important fruits in China; however, salt stress is severe in northern regions, and the key to plant resistance to salt stress lies in the rootstock. Therefore, it is necessary to explore rootstocks with strong salt resistance for [...] Read more.

Apples (Malus domestica Borkh) are important fruits in China; however, salt stress is severe in northern regions, and the key to plant resistance to salt stress lies in the rootstock. Therefore, it is necessary to explore rootstocks with strong salt resistance for the development of the apple industry. This study used tissue culture seedlings of six apple rootstocks, namely, ‘71−3−150’, ‘54−118’, ‘M9T337’, ‘GM256’, ‘ML176’, and ‘ML2’, as experimental materials. The seedlings were treated with a medium containing 150 mM NaCl, and the physiological indicators and related gene expression responses of several rootstocks were studied after salt stress. The results showed that salt stress affects the growth of both the aboveground and underground parts of plants. Through physiological indicators and the related gene expression responses of rootstocks, it was observed that salt stress significantly increased Na⁺ contents in different rootstocks. Simultaneously, the activity of various antioxidant enzymes and the expression levels of related genes also increased. In summary, by analyzing the parameters of various physiological indicators, it can be concluded that among the studied rootstocks, the ‘71−3−150’ and ‘54−118’ rootstocks have the strongest resistance to salt stress, while the ‘M9T337’ and ‘GM256’ rootstocks exhibit moderate resistance, and the ‘ML176’ and ‘ML2’ rootstocks have the weakest resistance. Full article

(This article belongs to the Section Molecular Plant Sciences)

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40 pages, 15332 KiB

Open AccessReview

Photocrosslinkable Biomaterials for 3D Bioprinting: Mechanisms, Recent Advances, and Future Prospects

by Yushang Lai, Xiong Xiao, Ziwei Huang, Hongying Duan, Liping Yang, Yuchu Yang, Chenxi Li and Li Feng

Int. J. Mol. Sci. 2024, 25(23), 12567; https://doi.org/10.3390/ijms252312567 - 22 Nov 2024

Abstract

Constructing scaffolds with the desired structures and functions is one of the main goals of tissue engineering. Three-dimensional (3D) bioprinting is a promising technology that enables the personalized fabrication of devices with regulated biological and mechanical characteristics similar to natural tissues/organs. To date, [...] Read more.

Constructing scaffolds with the desired structures and functions is one of the main goals of tissue engineering. Three-dimensional (3D) bioprinting is a promising technology that enables the personalized fabrication of devices with regulated biological and mechanical characteristics similar to natural tissues/organs. To date, 3D bioprinting has been widely explored for biomedical applications like tissue engineering, drug delivery, drug screening, and in vitro disease model construction. Among different bioinks, photocrosslinkable bioinks have emerged as a powerful choice for the advanced fabrication of 3D devices, with fast crosslinking speed, high resolution, and great print fidelity. The photocrosslinkable biomaterials used for light-based 3D printing play a pivotal role in the fabrication of functional constructs. Herein, this review outlines the general 3D bioprinting approaches related to photocrosslinkable biomaterials, including extrusion-based printing, inkjet printing, stereolithography printing, and laser-assisted printing. Further, the mechanisms, advantages, and limitations of photopolymerization and photoinitiators are discussed. Next, recent advances in natural and synthetic photocrosslinkable biomaterials used for 3D bioprinting are highlighted. Finally, the challenges and future perspectives of photocrosslinkable bioinks and bioprinting approaches are envisaged. Full article

(This article belongs to the Special Issue Bioprinting: Progress and Challenges)

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18 pages, 3461 KiB

Open AccessArticle

Chemical Composition, Physiological and Morphological Variations in Salvia subg. Perovskia Populations in Response to Different Salinity Levels

by Zahra Ghaffari, Mehdi Rahimmalek, Mohammad R. Sabzalian, Ahmad Arzani, Razieh Kiani, Shima Gharibi, Katarzyna Wróblewska and Antoni Szumny

Int. J. Mol. Sci. 2024, 25(23), 12566; https://doi.org/10.3390/ijms252312566 - 22 Nov 2024

Abstract

This study evaluated the salinity tolerance of five populations of Salvia subg. Perovskia (S. abrotanoides and S. yadngii). The aims of the study were to assess essential oil components, as well as growth and physiological parameters of two Salvia species in [...] Read more.

This study evaluated the salinity tolerance of five populations of Salvia subg. Perovskia (S. abrotanoides and S. yadngii). The aims of the study were to assess essential oil components, as well as growth and physiological parameters of two Salvia species in response to salt stress. Four different levels of salinity (0, 60, 90, and 120 mM NaCl) were applied. The effects of various concentrations of NaCl on essential oil content, composition, growth, water relation, proline, lipid peroxidation (MDA), hydrogen peroxide content, and antioxidant enzyme activity, as well as Na and K contents in leaves and the roots were evaluated. The results revealed that root dry weight loss was higher than that of shoots, indicating root vulnerability due to direct exposure to the salt stress. The lowest and highest oil content was obtained in PATKH (0.6%) at 60 mM and PABAD (0.6%) in 90 mM to 2.16% in PABSM population under 120 mM NaCl. Based on GC-MS analysis, 1,8-cineol (11.64 to 22.02%), camphor (2.67 to 27.14%), bornyl acetate (2.12 to 11.07%), borneol (2.38 to 24.37%), β-caryophyllene (3.24 to 7.58%), α-humulene (2.97 to 7.92%), and δ-3-carene (5.31 to 26.65%) were the most abundant compounds. Based on the principal component analysis (PCA), the most salinity-tolerant populations belonged to P. abrotanoides species. These populations are characterized by high root stress tolerance index (STI), root elements, and relative water content (RWC) with elevated levels of salinity stress. Finally, the findings might be useful in unraveling the salinity tolerance mechanisms for integrating stress tolerance with medicinal qualities in future studies. Full article

(This article belongs to the Special Issue Advanced Plant Molecular Responses to Abiotic Stresses)

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24 pages, 1707 KiB

Open AccessArticle

The Oncogenic Role of VWA8-AS1, a Long Non-Coding RNA, in Epstein–Barr Virus-Associated Oral Squamous Cell Carcinoma: An Integrative Transcriptome and Functional Analysis

by Sawarot Srisathaporn, Chamsai Pientong, Chukkris Heawchaiyaphum, Thawaree Nukpook, Sirinart Aromseree and Tipaya Ekalaksananan

Int. J. Mol. Sci. 2024, 25(23), 12565; https://doi.org/10.3390/ijms252312565 - 22 Nov 2024

Abstract

Dysregulated long non-coding RNA (lncRNA) expression is linked to various cancers and may be influenced by oncogenic Epstein–Barr virus (EBV) infection, a known and detectable risk factor in oral squamous cell carcinoma (OSCC) patients. However, research on the oncogenic role of EBV-induced lncRNAs [...] Read more.

Dysregulated long non-coding RNA (lncRNA) expression is linked to various cancers and may be influenced by oncogenic Epstein–Barr virus (EBV) infection, a known and detectable risk factor in oral squamous cell carcinoma (OSCC) patients. However, research on the oncogenic role of EBV-induced lncRNAs in OSCC is limited. To identify lncRNA-associated EBV infection and OSCC carcinogenesis, the differential expression of RNA-seq datasets from paired normal adjacent and OSCC tissues, and microarray data from EBV-negative and EBV-positive SCC25 cells, were identified and selected, respectively, for interaction, functional analysis, and CCK-8 cell proliferation, wound healing, and invasion Transwell assays. In OSCC tissues, 6731 differentially expressed lncRNAs were identified when compared to normal tissues from RNA-seq datasets, with 295 linked to EBV-induced OSCC carcinogenesis from microarray datasets. The EBV-induced lncRNA VWA8-AS1 showed significant upregulation in EBV-positive SCC25 cells and EBV-infected adjacent and OSCC tissue samples. VWA8-AS1 potentially promotes OSCC via the lncRNA–miRNA–mRNA axis or direct protein interactions, affecting various cellular processes. Studies in OSCC cell lines revealed that elevated VWA8-AS1 levels enhanced cell migration and invasion. This study demonstrates VWA8-AS1’s contribution to tumor progression and possible interactions with its targets in OSCC, offering insights for future research on functional mechanisms and therapeutic targets in EBV-associated OSCC. Full article

(This article belongs to the Section Molecular Oncology)

18 pages, 6242 KiB

Open AccessArticle

New Approaches to the Creation of Highly Efficient Pd-Ag and Pd-Cu Membranes and Modeling of Their Hydrogen Permeability

by Iliya Petriev, Polina Pushankina and Michail Drobotenko

Int. J. Mol. Sci. 2024, 25(23), 12564; https://doi.org/10.3390/ijms252312564 - 22 Nov 2024

Abstract

Thin-film membranes of Pd-Ag and Pd-Cu alloys capable of releasing hydrogen in a wide temperature range have been developed. The surface activation of the membranes with a nanostructured coating made it possible to intensify hydrogen transport through Pd-containing membranes at low temperatures. This [...] Read more.

Thin-film membranes of Pd-Ag and Pd-Cu alloys capable of releasing hydrogen in a wide temperature range have been developed. The surface activation of the membranes with a nanostructured coating made it possible to intensify hydrogen transport through Pd-containing membranes at low temperatures. This effect was achieved by accelerating limiting surface processes by increasing the active area of the membrane. Surface-activated membranes demonstrated the highest values of hydrogen flux over the entire temperature range, which reached up to 49.4 mmol s⁻¹ m⁻² for Pd-Ag membranes and up to 32.9 mmol s⁻¹ m⁻² for Pd-Cu membranes. Membranes modified with filiform nanoparticles demonstrated a hydrogen flux up to 12 times higher than that of membranes with a smooth surface. Based on the results obtained, a theoretical model of hydrogen transport through metal membranes was developed, taking into account the effect of the state of the membrane surface on hydrogen transport at low temperatures. This model makes it possible to predict hydrogen flows in the entire temperature range much more accurately compared to other existing models. The selectivity and stability of the developed membranes over a long period of operation have been confirmed. The study of the effect of the surface activation of Pd-based membranes on the intensification of hydrogen permeability has shown the success of the method developed, which in turn opens up wide opportunities for creating low-temperature, highly efficient membrane hydrogen filters based on palladium and other devices based on them. Full article

(This article belongs to the Special Issue Ion and Molecule Transport in Membrane Systems 5.0)

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18 pages, 4307 KiB

Open AccessArticle

Activation of Purinergic P2Y2 Receptor Protects the Kidney Against Renal Ischemia and Reperfusion Injury in Mice

by Kyuho Jeong, Jihyun Je, Theodomir Dusabimana, Jacques Karekezi, Tatang Aldi Nugroho, Edvard Ntambara Ndahigwa, Seung Pil Yun, Hye Jung Kim, Hwajin Kim and Sang Won Park

Int. J. Mol. Sci. 2024, 25(23), 12563; https://doi.org/10.3390/ijms252312563 - 22 Nov 2024

Abstract

Extracellular ATP plays an important role in renal physiology as well as the pathogenesis of acute kidney injury induced by renal ischemia and reperfusion (IR). Expression of the purinergic P2Y2 receptor has been shown on inflammatory and structural cells of the kidney, and [...] Read more.

Extracellular ATP plays an important role in renal physiology as well as the pathogenesis of acute kidney injury induced by renal ischemia and reperfusion (IR). Expression of the purinergic P2Y2 receptor has been shown on inflammatory and structural cells of the kidney, and P2Y2R is preferably activated by ATP (or UTP). Here, we investigated the molecular mechanism of P2Y2R during IR injury by using P2Y2R knockout (KO) mice and a selective P2Y2R agonist, MRS2768. After renal IR, P2Y2R KO mice showed greater increases in plasma creatinine, tubular damage and neutrophil infiltration, and significant induction of proinflammatory cytokines and apoptotic markers than wild-type (WT) mice. In contrast, treatment with MRS2768 reduced plasma creatinine levels, tubular damage and inflammation, and renal apoptosis in mice subjected to renal IR. In cultured human proximal tubular HK-2 cells, MRS2768 upregulated P2Y2R mRNA levels and decreased TNF-α/cycloheximide-induced apoptosis and inflammation. Importantly, P2Y2R activation by MRS2768 increased the phosphorylation of protein kinase C (PKC), Src, and phosphatidylinositol 3-kinase (PI3K)/Akt. In addition, the inhibition of PI3K/Akt abolished the protective effects of MRS2768 against TNF-α/cycloheximide-induced apoptosis and inflammation in HK-2 cells. In conclusion, activation of P2Y2R protects against tubular apoptosis and inflammation during renal IR via the PKC/Src/Akt pathway, suggesting P2Y2R is a promising therapeutic target for acute kidney injury. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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