International Journal of Molecular Sciences

15 pages, 443 KiB

Open AccessReview

Progresses and Pitfalls of Epigenetics in Solid Tumors Clinical Trials

by Alice Rossi, Francesca Zacchi, Anna Reni, Michele Rota, Silvia Palmerio, Jessica Menis, Andrea Zivi, Stefano Milleri and Michele Milella

Int. J. Mol. Sci. 2024, 25(21), 11740; https://doi.org/10.3390/ijms252111740 - 31 Oct 2024

Abstract

Epigenetic dysregulation has long been recognized as a significant contributor to tumorigenesis and tumor maintenance, impacting all recognized cancer hallmarks. Although some epigenetic drugs have received regulatory approval for certain hematological malignancies, their efficacy in treating solid tumors has so far been largely [...] Read more.

Epigenetic dysregulation has long been recognized as a significant contributor to tumorigenesis and tumor maintenance, impacting all recognized cancer hallmarks. Although some epigenetic drugs have received regulatory approval for certain hematological malignancies, their efficacy in treating solid tumors has so far been largely disappointing. However, recent advancements in developing new compounds and a deeper understanding of cancer biology have led to success in specific solid tumor subtypes through precision medicine approaches. Moreover, epigenetic drugs may play a crucial role in synergizing with other anticancer treatments, enhancing the sensitivity of cancer cells to various anticancer therapies, including chemotherapy, radiation therapy, hormone therapy, targeted therapy, and immunotherapy. In this review, we critically evaluate the evolution of epigenetic drugs, tracing their development from initial use as monotherapies to their current application in combination therapies. We explore the preclinical rationale, completed clinical studies, and ongoing clinical trials. Finally, we discuss trial design strategies and drug scheduling to optimize the development of possible combination therapies. Full article

(This article belongs to the Special Issue Targeting Epigenetics in Cancer Therapy)

14 pages, 486 KiB

Open AccessArticle

Comparison of n-3 PUFA-Enriched vs. Olive-Oil-Based Lipid Emulsion on Oxidative Stress and Inflammatory Response in Critically Ill Post-Surgery Adults: Secondary Analysis of a Randomized Controlled Trial

by Nerea Cuartero-Corbalán, Fátima Martínez-Lozano Aranaga, Maria Jesús Gómez-Ramos, María B. Gómez-Sánchez, Francisco V. Avilés-Plaza, María A. Núñez-Sánchez and Juana M. Morillas-Ruiz

Int. J. Mol. Sci. 2024, 25(21), 11739; https://doi.org/10.3390/ijms252111739 - 31 Oct 2024

Abstract

Malnutrition in critically ill patients represents a major concern as it can lead to adverse outcomes including increased morbidity and mortality. These patients exhibit an impaired immune response accompanied by increased oxidative stress. Nutritional support, including parenteral nutrition (PN), is critical in these [...] Read more.

Malnutrition in critically ill patients represents a major concern as it can lead to adverse outcomes including increased morbidity and mortality. These patients exhibit an impaired immune response accompanied by increased oxidative stress. Nutritional support, including parenteral nutrition (PN), is critical in these patients. Intravenous lipid emulsions (ILEs), a key component of PN, provide energy and intervene in the modulation of inflammation. This was a secondary study of a randomized clinical trial at the Reina Sofia University Hospital (Murcia, Spain) for critically ill patients following major abdominal surgery that were administered PN supplemented with olive-oil-based ILE (OO-ILE, n = 29) or a mixed-lipid ILE (soybean oil, medium chain triglycerides, OO and fish oil, SMOF-ILE, n = 25). The effects on clinical outcomes, metabolic markers, oxidative stress, and inflammation were evaluated. No significant differences were observed between groups in the clinical parameters and outcomes, oxidative stress, or inflammatory markers. The within-group evaluation demonstrated an increase in total antioxidant capacity in both groups, while OO-ILE increased the levels of 15-F2t-isoprostane. In addition, the results showed that both mixtures reduced the release of IL-1β and IL-6. These findings suggest that both treatments had similar effects on oxidative stress and inflammatory response in this type of patient. Full article

(This article belongs to the Special Issue Gut Microbiota in Human Health)

15 pages, 3371 KiB

Open AccessArticle

Water as a Structural Marker in Gelatin Hydrogels with Different Cross-Linking Nature

by Yuriy F. Zuev, Svetlana R. Derkach, Ivan V. Lunev, Alena A. Nikiforova, Mariya A. Klimovitskaya, Liliya R. Bogdanova, Polina V. Skvortsova, Rauf Kh. Kurbanov, Mariia A. Kazantseva and Olga S. Zueva

Int. J. Mol. Sci. 2024, 25(21), 11738; https://doi.org/10.3390/ijms252111738 - 31 Oct 2024

Abstract

We have studied the molecular properties of water in physically and chemically cross-linked gelatin hydrogels by FTIR-spectroscopy, NMR relaxation, and diffusivity and broadband dielectric spectroscopy, which are sensitive to dynamical properties of water, being a structural marker of polymer network. All experiments demonstrated [...] Read more.

We have studied the molecular properties of water in physically and chemically cross-linked gelatin hydrogels by FTIR-spectroscopy, NMR relaxation, and diffusivity and broadband dielectric spectroscopy, which are sensitive to dynamical properties of water, being a structural marker of polymer network. All experiments demonstrated definite reinforcement of the hydrogel net structure and an increase in the amount of hydrate water. FTIR experiments have shown that the chemical cross-linking of gelatin molecules initiates an increase in the collagen-like triple helices “strength”, as a result of infused restriction on protein molecular mobility. The “strengthening” of protein chains hinders the mobility of protein fragments, introducing complex modifications into the structural properties of water which are remained practically unchanged up to up to 30–40 °C. Full article

(This article belongs to the Collection Feature Papers in Molecular Informatics)

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14 pages, 4703 KiB

Open AccessArticle

Effect of Slow-Release Urea on Yield and Quality of Euryale ferox

by Peng Wu, Tian-Yu Wang, Yu-Hao Wang, Ai-Lian Liu, Shu-Ping Zhao, Kai Feng and Liang-Jun Li

Int. J. Mol. Sci. 2024, 25(21), 11737; https://doi.org/10.3390/ijms252111737 - 31 Oct 2024

Abstract

Slow-release urea, as an environmentally friendly fertiliser, can provide a continuous and uniform supply of nutrients needed by the crop, reduce the amount and frequency of fertiliser application, and promote the uptake and utilisation of nitrogen in crops. The production of E. ferox [...] Read more.

Slow-release urea, as an environmentally friendly fertiliser, can provide a continuous and uniform supply of nutrients needed by the crop, reduce the amount and frequency of fertiliser application, and promote the uptake and utilisation of nitrogen in crops. The production of E. ferox is often dominated by the application of quick-acting fertilisers, resulting in serious problems of over-fertilisation, inappropriate periods of fertilisation, eutrophication of soil and water due to fertilisation, and difficulties in applying fertilisers. Therefore, in this study, different amounts (CK, T1, T2, T3, T4, T5) of SRU (Slow-release Urea) were first applied, and T3 (18.8 kg·667 m⁻²) was found to significantly improve both yield and quality. Further, it was found that under different SRU (CK, S1, S2, S3, S4) application period treatments, application of 18.8 kg·667 m⁻² at AFP20 (S2) period significantly increased the yield and quality of E. ferox. In the seed kernels of E. ferox, the total yield, soluble sugar content, total starch, and flavonoid content increased significantly by 10.35%, 36.40%, 5.91%, and 22.80%, respectively, compared with CK. In addition, the expression of key sugar transporter genes (EfSWEETs), flavonoid synthesis-related genes (EfPAL, EfDFR, etc.), and starch synthesis-related enzyme activities (SBE, SSS, GBSS) were significantly increased. By exploring the quantity of application and application period of SRU, this study was carried out to investigate the in-depth effect of SRU on the growth and development of E. ferox and to provide technical references for the increase in E. ferox yield, the improvement in E. ferox quality, and the simplification of fertiliser application. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

14 pages, 5517 KiB

Open AccessArticle

Transcriptome and WGCNA Analyses Reveal Key Genes Regulating Anthocyanin Biosynthesis in Purple Sprout of Pak Choi (Brassica rapa L. ssp. chinensis)

by Chaomin Xu, Hui Huang, Chen Tan, Liwei Gao, Shubei Wan, Bo Zhu, Daozong Chen and Bin Zhu

Int. J. Mol. Sci. 2024, 25(21), 11736; https://doi.org/10.3390/ijms252111736 - 31 Oct 2024

Abstract

Chinese cabbage is rich in vitamins, fibre, and nutrients and is one of the primary vegetables consumed in autumn and winter in South Asia. ‘Purple pak choi’ sprouts are particularly rich in anthocyanins and are favoured by consumers. However, reports on the regulation [...] Read more.

Chinese cabbage is rich in vitamins, fibre, and nutrients and is one of the primary vegetables consumed in autumn and winter in South Asia. ‘Purple pak choi’ sprouts are particularly rich in anthocyanins and are favoured by consumers. However, reports on the regulation of anthocyanin synthesis in purple pak choi sprouts do not exist. In this study, we examined the phenotypic development of purple pak choi sprouts after germination. The total anthocyanin content increased from 0.02 to 0.52 mg/g FW from days 0 to 6. RNA-seq data analysis revealed an increase in differentially expressed genes corresponding to the development of purple pak choi sprouts. Expression pattern analysis of genes associated with the anthocyanin biosynthesis pathway revealed a significant upregulation of structural genes during the purple phase, suggesting that the transcription factors PAP2 and MYBL2 may play crucial regulatory roles. BraPAP2.A03, BraTT8.A09, and BraMYBL2.A07 exhibited strong interactions with key genes in the anthocyanin biosynthesis pathway, specifically BraDFR.A09. Furthermore, the expression of BraPAP2.A03 aligned with the expression patterns of most anthocyanin biosynthesis-related genes, whereas those of BraTT8.A09 and BraMYBL2.A07 corresponded with the expression pattern of BraDFR.A09. These results provide valuable insights into regulatory mechanisms underlying anthocyanin synthesis in purple pak choi sprouts. Full article

(This article belongs to the Special Issue Advances in Brassica Crop Metabolism and Genetics)

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33 pages, 2073 KiB

Open AccessReview

Molecular Mechanism for Malignant Progression of Gastric Cancer within the Tumor Microenvironment

by Tasuku Matsuoka and Masakazu Yashiro

Int. J. Mol. Sci. 2024, 25(21), 11735; https://doi.org/10.3390/ijms252111735 - 31 Oct 2024

Abstract

Abstract: Gastric cancer (GC) is one of the most common cancers worldwide. Most patients are diagnosed at the progressive stage of GC, and progress in the development of effective anti-GC drugs has been insufficient. The tumor microenvironment (TME) regulates various functions of [...] Read more.

Abstract: Gastric cancer (GC) is one of the most common cancers worldwide. Most patients are diagnosed at the progressive stage of GC, and progress in the development of effective anti-GC drugs has been insufficient. The tumor microenvironment (TME) regulates various functions of tumor cells, and interactions between the cellular and molecular components of the TME—e.g., inflammatory cells, fibroblasts, vasculature cells, and innate and adaptive immune cells—promote the aggressiveness of cancer cells and dissemination to distant organs. This review summarizes the roles of various TME cells and molecules in regulating the malignant progression and metastasis of GC. We also address the important roles of signaling pathways in mediating the interaction between cancer cells and the different components of the GC TME. Finally, we discuss the implications of these molecular mechanisms for developing novel and effective therapies targeting molecular and cellular components of the GC TME to control the malignant progression of GC. Full article

(This article belongs to the Special Issue Tumor Microenvironments: Molecular Mechanisms and Signaling Pathways Involved in Metastatic Progression)

22 pages, 1546 KiB

Open AccessArticle

Transcriptomic Response of Rhizobium leguminosarum to Acidic Stress and Nutrient Limitation Is Versatile and Substantially Influenced by Extrachromosomal Gene Pool

by Kamil Żebracki, Piotr Koper, Magdalena Wójcik, Małgorzata Marczak and Andrzej Mazur

Int. J. Mol. Sci. 2024, 25(21), 11734; https://doi.org/10.3390/ijms252111734 - 31 Oct 2024

Abstract

Multipartite genomes are thought to confer evolutionary advantages to bacteria by providing greater metabolic flexibility in fluctuating environments and enabling rapid adaptation to new ecological niches and stress conditions. This genome architecture is commonly found in plant symbionts, including nitrogen-fixing rhizobia, such as [...] Read more.

Multipartite genomes are thought to confer evolutionary advantages to bacteria by providing greater metabolic flexibility in fluctuating environments and enabling rapid adaptation to new ecological niches and stress conditions. This genome architecture is commonly found in plant symbionts, including nitrogen-fixing rhizobia, such as Rhizobium leguminosarum bv. trifolii TA1 (RtTA1), whose genome comprises a chromosome and four extrachromosomal replicons (ECRs). In this study, the transcriptomic responses of RtTA1 to partial nutrient limitation and low acidic pH were analyzed using high-throughput RNA sequencing. RtTA1 growth under these conditions resulted in the differential expression of 1035 to 1700 genes (DEGs), which were assigned to functional categories primarily related to amino acid and carbohydrate metabolism, ribosome and cell envelope biogenesis, signal transduction, and transcription. These results highlight the complexity of the bacterial response to stress. Notably, the distribution of DEGs among the replicons indicated that ECRs played a significant role in the stress response. The transcriptomic data align with the Rhizobium pangenome analysis, which revealed an over-representation of functional categories related to transport, metabolism, and regulatory functions on ECRs. These findings confirm that ECRs contribute substantially to the ability of rhizobia to adapt to challenging environmental conditions. Full article

(This article belongs to the Collection Feature Papers in Molecular Genetics and Genomics)

19 pages, 1120 KiB

Open AccessArticle

Trastuzumab-Mediated Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) Enhances Natural Killer Cell Cytotoxicity in HER2-Overexpressing Ovarian Cancer

by Sa Deok Hong, Nar Bahadur Katuwal, Min Sil Kang, Mithun Ghosh, Seong Min Park, Tae Hoen Kim, Young Seok Baek, Seung Ryeol Lee and Yong Wha Moon

Int. J. Mol. Sci. 2024, 25(21), 11733; https://doi.org/10.3390/ijms252111733 - 31 Oct 2024

Abstract

Ovarian cancer is the deadliest gynecologic cancer. Although human epidermal growth factor receptor-2 (HER2) overexpression, a poor prognostic molecular marker in ovarian cancer, is found in almost 30% of ovarian cancer cases, there are no established therapies for HER2-overexpressing ovarian cancer. In this [...] Read more.

Ovarian cancer is the deadliest gynecologic cancer. Although human epidermal growth factor receptor-2 (HER2) overexpression, a poor prognostic molecular marker in ovarian cancer, is found in almost 30% of ovarian cancer cases, there are no established therapies for HER2-overexpressing ovarian cancer. In this study, we investigated the efficacy of combined samfenet, a biosimilar compound of trastuzumab, and natural killer (NK) cells in preclinical model of HER2-overexpressing ovarian cancer. Firstly, we screened the HER2 expression in three ovarian cancer cell lines and eight ovarian cancer patient-derived tumor xenograft (PDTX) samples. Then, immunohistochemistry and silver in situ hybridization (SISH) were performed following clinical criteria. HER2-overexpressing cells exhibited the highest sensitivity to samfenet compared with low-HER2-expressing cells. In addition, the combination of samfenet with natural killer (NK) cells resulted in significantly enhanced sensitivity to HER2-overexpressing cells and showed a significant antitumor effect on PDTX mice compared with monotherapy. It is known that anti-HER2-humanized IgG1 monoclonal antibodies, including trastuzumab, induce antibody-dependent cellular cytotoxicity (ADCC). Consequently, the combination of samfenet with NK cells demonstrated NK cell-mediated ADCC, as confirmed using an in vitro NK cytotoxicity assay and in vivo antitumor efficacy. A transferase dUTP nick end labeling (TUNEL) assay using xenografted tumors further supported the ADCC effects based on the increase in the number of apoptotic cells in the combination group. Furthermore, high HER2 expression was associated with shorter progression-free survival and overall survival based on public mRNA expression data. In this study, we demonstrated that the combination of samfenet and NK cell therapy could be a promising treatment strategy for patients with HER2-overexpressing ovarian cancer, through ADCC effects. Therefore, this study supports a rationale for further clinical studies of the combination of samfenet and NK cells as a therapy for patients with HER2-overexpressing ovarian cancer. Full article

(This article belongs to the Special Issue Novel Therapeutic Strategies for Gynecological Cancer: Molecular Biological Insights)

22 pages, 18634 KiB

Open AccessArticle

Biochar Composite with Enhanced Performance Prepared Through Microbial Modification for Water Pollutant Removal

by Bolun Zhang, Ruqi Li, Yangyang Zheng, Siji Chen, Yingjie Su, Wei Zhou, Qi Sui and Dadong Liang

Int. J. Mol. Sci. 2024, 25(21), 11732; https://doi.org/10.3390/ijms252111732 - 31 Oct 2024

Abstract

This study developed mycelial biochar composites, BQH-AN and BQH-MV, with stable physicochemical properties and significantly improved adsorption capabilities through microbial modification. The results showed that the specific surface area and porosity of BQH-AN (3547.47 m² g⁻¹ and 2.37 cm³ g [...] Read more.

This study developed mycelial biochar composites, BQH-AN and BQH-MV, with stable physicochemical properties and significantly improved adsorption capabilities through microbial modification. The results showed that the specific surface area and porosity of BQH-AN (3547.47 m² g⁻¹ and 2.37 cm³ g⁻¹) and BQH-MV (3205.59 m² g⁻¹ and 2.46 cm³ g⁻¹) were significantly higher than those of biochar BQH (2641.31 m² g⁻¹ and 1.81 cm³ g⁻¹), which was produced without microbial treatment. In adsorption experiments using rhodamine B (RhB), tetracycline hydrochloride (TC), and Cr (VI), BQH-AN showed maximum adsorption capacities of 1450.79 mg g⁻¹ for RhB, 1608.43 mg g⁻¹ for TC, and 744.15 mg g⁻¹ for Cr(VI). BQH-MV showed similarly strong performance, with 1329.85 mg g⁻¹ for RhB, 1526.46 mg g⁻¹ for TC, and 752.27 mg g⁻¹ for Cr(VI). These values were not only higher than those of BQH but also outperformed most other biochar adsorbents. Additionally, after five reuse cycles, the pollutant removal efficiency of the mycelial biochar composites remained above 69%, demonstrating excellent regenerative ability. This study not only produced biochar with superior adsorption properties but also highlighted microbial modification as an effective way to enhance lignocellulosic biochar performance, paving the way for further biomass development. Full article

(This article belongs to the Special Issue Design, Synthesis, and Bioapplications of Multifunctional Materials)

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19 pages, 13268 KiB

Open AccessArticle

High-Salt Diet Accelerates Neuron Loss and Anxiety in APP/PS1 Mice Through Serpina3n

by Kaige Ma, Chenglin Zhang, Hanyue Zhang, Chanyuan An, Ge Li, Lixue Cheng, Mai Li, Minghe Ren, Yudan Bai, Zichang Liu, Shengfeng Ji, Xiyue Liu, Jinman Gao, Zhichao Zhang, Xiaolin Wu and Xinlin Chen

Int. J. Mol. Sci. 2024, 25(21), 11731; https://doi.org/10.3390/ijms252111731 - 31 Oct 2024

Abstract

High salt (HS) consumption is an independent risk factor for neurodegenerative diseases such as dementia, stroke, and cerebral small vessel disease related to cognitive decline. Recently, Alzheimer’s disease-like pathology changes have been reported as consequences of a HS diet in wild-type (wt) mice. [...] Read more.

High salt (HS) consumption is an independent risk factor for neurodegenerative diseases such as dementia, stroke, and cerebral small vessel disease related to cognitive decline. Recently, Alzheimer’s disease-like pathology changes have been reported as consequences of a HS diet in wild-type (wt) mice. However, it has not been revealed how HS diets accelerate the progress of Alzheimer’s disease (AD) in APP/PS1 mice. Here, we fed APP/PS1 mice a HS diet or normal diet (ND) for six months; the effects of the HS/ND on wt mice were also observed. The results of our behavior test reveal that the HS diet exacerbates anxiety, β-amyloid overload, neuron loss, and synapse damage in the hippocampi of APP/PS1 mice; this was not observed in HS-treated wt mice. RNA sequencing shows that nearly all serpin family members were increased in the hippocampus of HS-treated APP/PS1 mice. Gene function analysis showed that a HS diet induces neurodegeneration, including axon dysfunction and neuro-ligand-based dysfunction, and regulates serine protein inhibitor activities. The mRNA and protein levels of Serpina3n were dramatically increased. Upregulated Serpina3n may be the key for β-amyloid aggregation and neuronal loss in the hippocampus of HS-treated APP/PS1 mice. Serpina3n inhibition attenuated the anxiety and increased the number of neurons in the hippocampal CA1(cornu ammonis) region of APP/PS1 mice. Our study provides novel insights into the mechanisms by which excessive HS diet deteriorates anxiety in AD mice. Therefore, decreasing daily dietary salt consumption constitutes a pivotal public health intervention for mitigating the progression of neuropathology, especially for old patients and those with neurodegenerative disease. Full article

(This article belongs to the Special Issue Drug Design and Development for Neurological Diseases)

29 pages, 6971 KiB

Open AccessArticle

Honey Enriched with Additives Alleviates Behavioral, Oxidative Stress, and Brain Alterations Induced by Heavy Metals and Imidacloprid in Zebrafish

by Emanuela Paduraru, Roxana Jijie, Ira-Adeline Simionov, Cristina-Maria Gavrilescu, Tudor Ilie, Diana Iacob, Andreea Lupitu, Cristian Moisa, Claudia Muresan, Lucian Copolovici, Dana M. Copolovici, Gabriela Mihalache, Florin Daniel Lipsa, Gheorghe Solcan, Gabriela-Alexandra Danelet, Mircea Nicoara, Alin Ciobica and Carmen Solcan

Int. J. Mol. Sci. 2024, 25(21), 11730; https://doi.org/10.3390/ijms252111730 - 31 Oct 2024

Abstract

Environmental concerns have consistently been a focal point for the scientific community. Pollution is a critical ecological issue that poses significant threats to human health and agricultural production. Contamination with heavy metals and pesticides is a considerable concern, a threat to the environment, [...] Read more.

Environmental concerns have consistently been a focal point for the scientific community. Pollution is a critical ecological issue that poses significant threats to human health and agricultural production. Contamination with heavy metals and pesticides is a considerable concern, a threat to the environment, and warrants special attention. In this study, we investigated the significant issues arising from sub-chronic exposure to imidacloprid (IMI), mercury (Hg), and cadmium (Cd), either alone or in combination, using zebrafish (Danio rerio) as an animal model. Additionally, we assessed the potential protective effects of polyfloral honey enriched with natural ingredients, also called honey formulation (HF), against the combined sub-chronic toxic effects of the three contaminants. The effects of IMI (0.5 mg·L⁻¹), Hg (15 μg·L⁻¹), and Cd (5 μg·L⁻¹), both individually and in combination with HF (500 mg·L⁻¹), on zebrafish were evaluated by quantifying acetylcholinesterase (AChE) activity, lipid peroxidation (MDA), various antioxidant enzyme activities like superoxide dismutase and glutathione peroxidase (SOD and GPx), 2D locomotor activity, social behavior, histological and immunohistochemical factors, and changes in body element concentrations. Our findings revealed that all concentrations of pollutants may disrupt social behavior, diminish swimming performances (measured by total distance traveled, inactivity, and swimming speed), and elevate oxidative stress (OS) biomarkers of SOD, GPx, and MDA in zebrafish over the 21-day administration period. Fish exposed to IMI and Hg + Cd + IMI displayed severe lesions and increased GFAP (Glial fibrillary acidic protein) and S100B (S100 calcium-binding protein B) protein expression in the optic tectum and cerebellum, conclusively indicating astrocyte activation and neurotoxic effects. Furthermore, PCNA (Proliferating cell nuclear antigen) staining revealed reduced cell proliferation in the IMI-exposed group, contrasting with intensified proliferation in the Hg + Cd group. The nervous system exhibited significant damage across all studied concentrations, confirming the observed behavioral changes. Moreover, HF supplementation significantly mitigated the toxicity induced by contaminants and reduced OS. Therefore, the exposure to chemical mixtures offers a more complete picture of adverse impacts on aquatic ecosystems and the supplementation with bioactive compounds can help to reduce the toxicity induced by exposure to environmental pollutants. Full article

(This article belongs to the Special Issue Mechanisms of Neurotoxicity)

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45 pages, 797 KiB

Open AccessReview

Systematic Review on Working Mechanisms of Signaling Pathways in Fibrosis During Shockwave Therapy

by Lot Demuynck, Sarah Moonen, Filip Thiessen, Ina Vrints, Peter Moortgat, Jill Meirte, Eric van Breda and Ulrike Van Daele

Int. J. Mol. Sci. 2024, 25(21), 11729; https://doi.org/10.3390/ijms252111729 - 31 Oct 2024

Abstract

Fibrosis is characterized by scarring and hardening of tissues and organs. It can affect every organ system, and so could result in organ failure due to the accumulation of extracellular matrix proteins. Previous studies suggest that mechanical forces (such as shockwave therapy, SWT) [...] Read more.

Fibrosis is characterized by scarring and hardening of tissues and organs. It can affect every organ system, and so could result in organ failure due to the accumulation of extracellular matrix proteins. Previous studies suggest that mechanical forces (such as shockwave therapy, SWT) initiate a process of mechanotransduction and thus could regulate fibrosis. Nevertheless, it is largely unexamined which pathways are exactly involved in the application of SWT and can regulate fibrosis. The present article seeks to elucidate the underlying effect of SWT on fibrosis. Evidence shows that SWT activates macrophage activity, fibroblast activity, collagen amount and orientation and apoptosis, which ultimately lead to an adaptation of inflammation, proliferation, angiogenesis and apoptosis. The included articles reveal that other proteins and pathways can be activated depending on the energy levels and frequency of SWT. These findings demonstrate that SWT has beneficial effects on fibrosis by influencing the proteins and pathways. Based on these data, which highlights the underlying mechanisms, we can make preliminary conclusions about the treatment modalities of SWT in scar formation, such as the energy levels and frequencies that are necessary to prevent or treat fibrotic tissue. Full article

(This article belongs to the Section Molecular Biology)

25 pages, 3602 KiB

Open AccessArticle

The Benefits of Whole-Exome Sequencing in the Differential Diagnosis of Hypophosphatasia

by Oleg S. Glotov, Natalya A. Zhuchenko, Maria S. Balashova, Aleksandra N. Raspopova, Victoria V. Tsai, Alexandr N. Chernov, Iana V. Chuiko, Lavrentii G. Danilov, Lyudmila D. Morozova and Andrey S. Glotov

Int. J. Mol. Sci. 2024, 25(21), 11728; https://doi.org/10.3390/ijms252111728 - 31 Oct 2024

Abstract

Hypophosphatasia (HPP) is a rare inherited disorder characterized by the decreased activity of tissue-nonspecific alkaline phosphatase (TNSALP), caused by mutations in the ALPL gene. The aim of this study was to conduct differential diagnostics in HPP patients using whole-exome sequencing (WES). The medical [...] Read more.

Hypophosphatasia (HPP) is a rare inherited disorder characterized by the decreased activity of tissue-nonspecific alkaline phosphatase (TNSALP), caused by mutations in the ALPL gene. The aim of this study was to conduct differential diagnostics in HPP patients using whole-exome sequencing (WES). The medical records of HPP patients and the genetic testing of the ALPL gene were reviewed. Seven patients were recruited and underwent WES using the Illumina or MGI sequencing platforms. All of the exome samples were matched onto a GRCh38.p13 reference genome assembly by using the Genome Analysis ToolKit (GATK) and the BWA MEM read aligner. We present the clinical and molecular findings of the seven patients referred for genetic analyses due to a clinical and biochemical suspicion of HPP. In two patients out of three (with identified heterozygous variants in the ALPL gene), we also identified c.682T>A in exon 3 of the WNT10A gene and c.3470del in exon 23 of the SMC1A gene variants for the first time. In four patients, variants in the ALPL gene were not detected, but WES allowed us to identify for the first time rare variants (c.5651A>C in exon 36 of the TRIO gene, c.880T>G in exon 6 of the TRPV4 gene, c.32078-1G>T in intron 159 of the TTN gene, c.47720_47721del in exon 235 of the TTN gene, and c.1946G>A in exon 15 of the SLC5A1 gene) and to conduct differential diagnostics with HPP. Using WES, for the first time, we demonstrate the possibility of early differential diagnostics in HPP patients with other rare genetic diseases. Full article

(This article belongs to the Topic Bone-Related Diseases: From Molecular Mechanisms to Therapy Development)

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23 pages, 3340 KiB

Open AccessArticle

Genome-Wide Association Study of Sweet Potato Storage Root Traits Using GWASpoly, a Gene Dosage-Sensitive Model

by Robert R. Bowers, Tyler J. Slonecki, Bode A. Olukolu, G. Craig Yencho and Phillip A. Wadl

Int. J. Mol. Sci. 2024, 25(21), 11727; https://doi.org/10.3390/ijms252111727 - 31 Oct 2024

Abstract

Sweet potato (Ipomoea batatas) is an important food crop that plays a pivotal role in preserving worldwide food security. Due to its polyploid genome, high heterogeneity, and phenotypic plasticity, sweet potato genetic characterization and breeding is challenging. Genome-wide association studies (GWASs) [...] Read more.

Sweet potato (Ipomoea batatas) is an important food crop that plays a pivotal role in preserving worldwide food security. Due to its polyploid genome, high heterogeneity, and phenotypic plasticity, sweet potato genetic characterization and breeding is challenging. Genome-wide association studies (GWASs) can provide important resources for breeders to improve breeding efficiency and effectiveness. GWASpoly was used to identify 28 single nucleotide polymorphisms (SNPs), comprising 21 unique genetic loci, associated with sweet potato storage root traits including dry matter (4 loci), subjective flesh color (5 loci), flesh hue angle (3 loci), and subjective skin color and skin hue angle (9 loci), in 384 accessions from the USDA sweet potato germplasm collection. The I. batatas ‘Beauregard’ and I. trifida reference genomes were utilized to identify candidate genes located within 100 kb from the SNPs that may affect the storage traits of dry matter, flesh color, and skin color. These candidate genes include transcription factors (especially Myb, bHLH, and WRKY family members), metabolite transporters, and metabolic enzymes and associated proteins involved in starch, carotenoid, and anthocyanin synthesis. A greater understanding of the genetic loci underlying sweet potato storage root traits will enable marker-assisted breeding of new varieties with desired traits. This study not only reinforces previous research findings on genes associated with dry matter and β-carotene content but also introduces novel genetic loci linked to these traits as well as other root characteristics. Full article

(This article belongs to the Special Issue Vegetable Genetics and Genomics, 3rd Edition)

17 pages, 4196 KiB

Open AccessArticle

In Vitro vs. In Vivo Transcriptomic Approach Revealed Core Pathways of Nitrogen Deficiency Response in Tea Plant (Camellia sinensis (L.) Kuntze)

by Lidiia Samarina, Lyudmila Malyukova, Songbo Wang, Aleksandr Bobrovskikh, Alexey Doroshkov, Ruset Shkhalakhova, Karina Manakhova, Natalia Koninskaya, Alexandra Matskiv, Alexey Ryndin, Elena Khlestkina and Yuriy Orlov

Int. J. Mol. Sci. 2024, 25(21), 11726; https://doi.org/10.3390/ijms252111726 - 31 Oct 2024

Abstract

For the first time, we used an in vitro vs. in vivo experimental design to reveal core pathways under nitrogen deficiency (ND) in an evergreen tree crop. These pathways were related to lignin biosynthesis, cell redox homeostasis, the defense response to fungus, the [...] Read more.

For the first time, we used an in vitro vs. in vivo experimental design to reveal core pathways under nitrogen deficiency (ND) in an evergreen tree crop. These pathways were related to lignin biosynthesis, cell redox homeostasis, the defense response to fungus, the response to Karrikin, amino acid transmembrane transport, the extracellular region, the cellular protein catabolic process, and aspartic-type endopeptidase activity. In addition, the mitogen-activated protein kinase pathway and ATP synthase (ATP)-binding cassette transporters were significantly upregulated under nitrogen deficiency in vitro and in vivo. Most of the MAPK downstream genes were related to calcium signaling (818 genes) rather than hormone signaling (157 genes). Moreover, the hormone signaling pathway predominantly contained auxin- and abscisic acid-related genes, indicating the crucial role of these hormones in ND response. Overall, 45 transcription factors were upregulated in both experiments, 5 WRKYs, 3 NACs, 2 MYBs, 2 ERFs, HD-Zip, RLP12, bHLH25, RADIALIS-like, and others, suggesting their ND regulation is independent from the presence of a root system. Gene network reconstruction displayed that these transcription factors participate in response to fungus/chitin, suggesting that nitrogen response and pathogen response have common regulation. The upregulation of lignin biosynthesis genes, cytochrome genes, and strigalactone response genes was much more pronounced under in vitro ND as compared to in vivo ND. Several cell wall-related genes were closely associated with cytochromes, indicating their important role in flavanols biosynthesis in tea plant. These results clarify the signaling mechanisms and regulation of the response to nitrogen deficiency in evergreen tree crops. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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27 pages, 21466 KiB

Open AccessArticle

Identifying Calmodulin and Calmodulin-like Protein Members in Canavalia rosea and Exploring Their Potential Roles in Abiotic Stress Tolerance

by Qianqian Ding, Zengwang Huang, Zhengfeng Wang, Shuguang Jian and Mei Zhang

Int. J. Mol. Sci. 2024, 25(21), 11725; https://doi.org/10.3390/ijms252111725 - 31 Oct 2024

Abstract

Calmodulins (CaMs) and calmodulin-like proteins (CMLs) belong to families of calcium-sensors that act as calcium ion (Ca²⁺) signal-decoding proteins and regulate downstream target proteins. As a tropical halophyte, Canavalia rosea shows great resistance to multiple abiotic stresses, including high salinity/alkalinity, extreme [...] Read more.

Calmodulins (CaMs) and calmodulin-like proteins (CMLs) belong to families of calcium-sensors that act as calcium ion (Ca²⁺) signal-decoding proteins and regulate downstream target proteins. As a tropical halophyte, Canavalia rosea shows great resistance to multiple abiotic stresses, including high salinity/alkalinity, extreme drought, heat, and intense sunlight. However, investigations of calcium ion signal transduction involved in the stress responses of C. rosea are limited. The CaM and CML gene families have been identified and characterized in many other plant species. Nevertheless, there is limited available information about these genes in C. rosea. In this study, a bioinformatic analysis, including the gene structures, conserved protein domains, phylogenetic relationships, chromosome distribution, and gene synteny, was comprehensively performed to identify and characterize CrCaMs and CrCMLs. A spatio-temporal expression assay in different organs and environmental conditions was then conducted using the RNA sequencing technique. Additionally, several CrCaM and CrCML members were then cloned and functionally characterized using the yeast heterogeneous expression system, and some of them were found to change the tolerance of yeast to heat, salt, alkalinity, and high osmotic stresses. The results of this study provide a foundation for understanding the possible roles of the CrCaM and CrCML genes, especially for halophyte C. rosea’s natural ecological adaptability for its native habitats. This study also provides a theoretical basis for further study of the physiological and biochemical functions of plant CaMs and CMLs that are involved in tolerance to multiple abiotic stresses. Full article

(This article belongs to the Special Issue Abiotic Stresses in Plants: From Molecules to Environment—2nd Edition)

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12 pages, 600 KiB

Open AccessReview

Understanding the Anticancer Properties of Honey

by Simona Martinotti, Gregorio Bonsignore and Elia Ranzato

Int. J. Mol. Sci. 2024, 25(21), 11724; https://doi.org/10.3390/ijms252111724 - 31 Oct 2024

Abstract

Uncontrolled cell growth that possesses the capacity to exhibit malignant behavior is referred to as cancer. The cytotoxic drugs used to fight cancer are associated with several adverse effects and are not always readily available or affordable, especially in developing countries. These issues [...] Read more.

Uncontrolled cell growth that possesses the capacity to exhibit malignant behavior is referred to as cancer. The cytotoxic drugs used to fight cancer are associated with several adverse effects and are not always readily available or affordable, especially in developing countries. These issues are in addition to the shortcomings of the current cancer treatment regimen. According to growing research, honey is not cytotoxic to normal cells but is highly and particularly cytotoxic to tumor cells, suggesting that honey may display anticancer effects. Research has shown that honey affects a number of cell signaling pathways; however, at the moment, the precise method is not completely known. Full article

(This article belongs to the Special Issue The Role of Natural Compounds in Cancer and Inflammation)

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12 pages, 2301 KiB

Open AccessArticle

Developing Adventitious Root Meristems Induced by Layering for Plant Chromosome Preparation

by Xu Yan, Zizhou Wu, Honglin Wang, Yanchun Zuo and Zhouhe Du

Int. J. Mol. Sci. 2024, 25(21), 11723; https://doi.org/10.3390/ijms252111723 - 31 Oct 2024

Abstract

Chromosome numbers and morphology are important characteristics of a species and its evolution. Root tips are the most commonly used tissue as a source of actively dividing cells for chromosome visualization in plants. Previously, rapidly growing root tips were collected from germinating kernels [...] Read more.

Chromosome numbers and morphology are important characteristics of a species and its evolution. Root tips are the most commonly used tissue as a source of actively dividing cells for chromosome visualization in plants. Previously, rapidly growing root tips were collected from germinating kernels or from seedlings growing in pots or fields. However, the use of adventitious roots (ARs) derived from aerial tissue as meristems for chromosome visualization has always been overlooked. Here, we successfully induced ARs in 11 materials that were investigated, with the exception of Sorghum nitidum. Using ARs meristem we obtained high-quality chromosome spreads for Morus alba, Broussonetia papyrifera, Lolium multiflorum, Sorghum sudanense, S. propinquum, S. bicolor × S. sudanense, Zea mays, Z. mexicana, Glycine max, Medicago sativa, and Brassica napus. The results reported here demonstrate that layering is an alternative and effective method for producing meristematic cells for high-quality chromosome preparation in plant species producing ARs. For species that produce ARs by layering, this protocol is particularly valuable for the development of cost-effective and high-throughput non-invasive cytogenetic studies. Full article

(This article belongs to the Special Issue Advances in Plant Genomics and Genetics: 2nd Edition)

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Graphical abstract

32 pages, 1265 KiB

Open AccessArticle

Concordance Between Biochemical and Molecular Diagnosis Obtained by WES in Mexican Patients with Inborn Errors of Intermediary Metabolism: Utility for Therapeutic Management

by Marcela Vela-Amieva, Miguel Angel Alcántara-Ortigoza, Ariadna González-del Angel, Liliana Fernández-Hernández, Miriam Erandi Reyna-Fabián, Bernardette Estandía-Ortega, Sara Guillén-López, Lizbeth López-Mejía, Leticia Belmont-Martínez, Rosa Itzel Carrillo-Nieto, Isabel Ibarra-González, Seung-Woo Ryu, Hane Lee and Cynthia Fernández-Lainez

Int. J. Mol. Sci. 2024, 25(21), 11722; https://doi.org/10.3390/ijms252111722 - 31 Oct 2024

Abstract

Biochemical phenotyping has been the milestone for diagnosing and managing patients affected by inborn errors of intermediary metabolism (IEiM); however, identifying the genotype responsible for these monogenic disorders greatly contributes to achieving these goals. Herein, whole-exome sequencing (WES) was used to determine the [...] Read more.

Biochemical phenotyping has been the milestone for diagnosing and managing patients affected by inborn errors of intermediary metabolism (IEiM); however, identifying the genotype responsible for these monogenic disorders greatly contributes to achieving these goals. Herein, whole-exome sequencing (WES) was used to determine the genotypes of 95 unrelated Mexican pediatric patients suspected of having IEiM. They were classified into those bearing specific biochemical abnormalities (Group 1), and those presenting unspecific biochemical profiles (Group 2). The overall concordance between the initial biochemical diagnosis and final genotypic diagnoses was 72.6% (N = 69/95 patients), with the highest concordance achieved in Group 1 (91.3%, N = 63/69), whereas the concordance was limited in Group 2 (23.07%). This finding suggests that previous biochemical phenotyping correlated with the high WES diagnostic success. Concordance was high for urea cycle disorders (94.1%) and organic acid disorders (77.4%). The identified mutational spectrum comprised 83 IEiM-relevant variants (pathogenic, likely pathogenic, and variants of uncertain significance or VUS), including three novel ones, distributed among 29 different genes responsible for amino acid, organic acid, urea cycle, carbohydrate, and lipid disorders. Inconclusive WES results (7.3%, N = 7/95) relied on monoallelic pathogenic genotypes or those involving two VUS for autosomal-recessive IEiMs. A second monogenic disease was observed in 10.5% (N = 10/95) of the patients. According to the WES results, modifications in treatment had to be made in 33.6% (N = 32/95) of patients, mainly attributed to the presence of a second monogenic disease, or to an actionable trait. This study includes the largest cohort of Mexican patients to date with biochemically suspected IEiM who were genetically diagnosed through WES, underscoring its importance in medical management. Full article

(This article belongs to the Special Issue Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances)

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