International Journal of Molecular Sciences

17 pages, 913 KiB

Open AccessReview

Effect of Abelmoschus esculentus L. (Okra) on Dyslipidemia: Systematic Review and Meta-Analysis of Clinical Studies

by Kabelo Mokgalaboni, Wendy N. Phoswa, Tyson T. Mokgalabone, Sanele Dlamini, Ashwell R. Ndhlala, Perpetua Modjadji and Sogolo L. Lebelo

Int. J. Mol. Sci. 2024, 25(20), 10922; https://doi.org/10.3390/ijms252010922 (registering DOI) - 10 Oct 2024

Abstract

The global prevalence of cardiovascular diseases (CVDs), including dyslipidemia and atherosclerosis, is rising. While pharmacological treatments for dyslipidemia and associated CVDs exist, not all individuals can afford them, and those who do often experience adverse side effects. Preclinical studies have indicated the potential [...] Read more.

The global prevalence of cardiovascular diseases (CVDs), including dyslipidemia and atherosclerosis, is rising. While pharmacological treatments for dyslipidemia and associated CVDs exist, not all individuals can afford them, and those who do often experience adverse side effects. Preclinical studies have indicated the potential benefits of Abelmoschus esculentus and its active phytochemicals in addressing dyslipidemia in rodent models of diabetes. However, there is limited clinical evidence on lipid parameters. Thus, this study aimed to assess the potential impact of Abelmoschus esculentus on dyslipidemia. A literature search was performed on PubMed, Scopus, and Cochrane Library for relevant trials published from inception until 11 August 2024. Data analysis was performed using Jamovi software version 2.4.8 and Review Manager (version 5.4), with effect estimates reported as standardized mean differences (SMDs) and 95% confidence intervals (CI). The evidence from eight studies with nine treatment arms showed that Abelmoschus esculentus reduces total cholesterol (TC), SMD = −0.53 (95% CI: −1.00 to −0.07), p = 0.025), compared to placebo. Additionally, triglyceride (TG) was reduced in Abelmoschus esculentus compared to placebo, SMD = −0.24 (95% CI: −0.46 to −0.02), p = 0.035. Furthermore, low-density lipoprotein (LDL) was also reduced, SMD = −0.35 (95% CI: −0.59 to −0.11), p = 0.004 in Abelmoschus esculentus versus placebo. This remedy substantially increased high-density lipoprotein (HDL), SMD = 0.34 (95% CI: 0.07 to 0.61), p = 0.014). Abelmoschus esculentus substantially improved lipid profile in prediabetes, T2D, obesity, and diabetic nephropathy. While the evidence confirms the potential benefits of Abelmoschus esculentus in reducing dyslipidemia, it is important for future clinical studies to standardize the effective dosage for more reliable results. Therefore, future trials should focus on these markers in well-designed trials with sufficient sample sizes. Furthermore, Abelmoschus esculentus can be supplemented to the diet of the relevant populations to alleviate dyslipidemia. Full article

(This article belongs to the Special Issue Food Science and Molecular Nutrition)

23 pages, 5163 KiB

Open AccessArticle

A Novel Trichinella spiralis Galectin Strengthens the Macrophage ADCC Killing of Larvae via Driving M1 Polarization

by Minmin Weng, Ru Zhang, Zhaoyu Zhang, Jinyi Wu, Wenwen Zheng, Qiqi Lu, Shaorong Long, Ruodan Liu, Zhongquan Wang and Jing Cui

Int. J. Mol. Sci. 2024, 25(20), 10920; https://doi.org/10.3390/ijms252010920 (registering DOI) - 10 Oct 2024

Abstract

Galectin recognizes β-galactosides through its carbohydrate recognition domains (CRDs). This study aimed to determine the biological features of a novel Trichinella spiralis galectin (galactoside-binding lectin family protein, TsGLFP) and its role in driving macrophage M1 polarization and enhancing ADCC killing of larvae. TsGLFP [...] Read more.

Galectin recognizes β-galactosides through its carbohydrate recognition domains (CRDs). This study aimed to determine the biological features of a novel Trichinella spiralis galectin (galactoside-binding lectin family protein, TsGLFP) and its role in driving macrophage M1 polarization and enhancing ADCC killing of larvae. TsGLFP belongs to the galectin family and has two CRDs. The complete TsGLFP cDNA sequence was cloned and then expressed in Escherichia coli BL21. The results of qPCR, Western blot, and indirect immunofluorescence tests (IIFTs) revealed that TsGLFP was expressed in various stages of T. spiralis worms and principally localized at the cuticle and around the female embryos of the nematode. rTsGLFP had the function of agglutinating mouse erythrocytes, and this agglutination activity could be inhibited by lactose. After the mouse macrophage RAW264.7 was incubated with rTsGLFP, the expression level of the M1 genes (iNOS, IL-6, and TNF-α) and NO production were obviously increased. After incubating macrophages with rTsGLFP, there was a noticeable rise in the expression levels of p-IκB-α and p-NF-κB p65. Additionally, rTsGLFP enhanced the macrophage’s ability to kill newborn larvae by ADCC cytotoxicity. When the macrophages were pretreated with the specific p-NF-κB p65 inhibitor PDTC, and then stimulated with rTsGLFP, the expression levels of iNOS, NO, and p-NF-κB p65 and the macrophages’ ADCC cytotoxicity were distinctly decreased. These findings indicated that rTsGLFP enhanced the macrophage ADCC killing of larvae by driving M1 polarization through activating the NF-κB pathway. Full article

(This article belongs to the Section Molecular Pharmacology)

23 pages, 2046 KiB

Open AccessReview

Balancing Tumor Immunotherapy and Immune-Related Adverse Events: Unveiling the Key Regulators

by Jianshang Huang, Lei Xiong, Sainan Tang, Junhao Zhao and Li Zuo

Int. J. Mol. Sci. 2024, 25(20), 10919; https://doi.org/10.3390/ijms252010919 (registering DOI) - 10 Oct 2024

Abstract

Abstract: Tumor immunotherapy has emerged as a promising approach in cancer treatment in recent years, offering vast potential. This method primarily involves targeting and inhibiting the suppressive checkpoints present in different immune cells to enhance their activation, ultimately leading to tumor regression. [...] Read more.

Abstract: Tumor immunotherapy has emerged as a promising approach in cancer treatment in recent years, offering vast potential. This method primarily involves targeting and inhibiting the suppressive checkpoints present in different immune cells to enhance their activation, ultimately leading to tumor regression. However, tumor cells exploit the surrounding immune cells and tissues to establish a tumor microenvironment (TME) that supports their survival and growth. Within the TME, the efficacy of effector immune cells is compromised, as tumor cells exploit inhibitory immune cells to suppress their function. Furthermore, certain immune cells can be co-opted by tumor cells to facilitate tumor growth. While significantly enhancing the body's tumor immunity can lead to tumor regression, it can also result in severe toxic side effects and an inflammatory factor storm. As a consequence, patients often discontinue treatment due to immune-related adverse events (irAEs) or, in extreme cases, succumb to toxic side effects before experiencing tumor regression. In this analysis, we examined several remission regimens for irAEs, each with its own drawbacks, including toxic side effects or suppression of tumor immunotherapy, which is undesirable. A recent research study, specifically aimed at downregulating intestinal epithelial barrier permeability, has shown promising results in reducing the severity of inflammatory bowel disease (IBD) while preserving immune function. This approach effectively reduces the severity of IBD without compromising the levels of TNF-α and IFN-γ, which are crucial for maintaining the efficacy of tumor immunotherapy. Based on the substantial similarities between IBD and ICI colitis (combo immune checkpoint inhibitors-induced colitis), this review proposes that targeting epithelial cells represents a crucial research direction for mitigating irAEs in the future. Full article

(This article belongs to the Section Molecular Biology)

17 pages, 2157 KiB

Open AccessReview

Unveiling the Role of Gut Microbiota and Metabolites in Autoimmune Thyroid Diseases: Emerging Perspectives

by Kai Yan, Xin Sun, Chenxi Fan, Xin Wang and Hongsong Yu

Int. J. Mol. Sci. 2024, 25(20), 10918; https://doi.org/10.3390/ijms252010918 (registering DOI) - 10 Oct 2024

Abstract

Autoimmune thyroid diseases (AITDs) are among the most prevalent organ-specific autoimmune disorders, with thyroid hormones playing a pivotal role in the gastrointestinal system’s structure and function. Emerging evidence suggests a link between AITDs and the gut microbiome, which is a diverse community of [...] Read more.

Autoimmune thyroid diseases (AITDs) are among the most prevalent organ-specific autoimmune disorders, with thyroid hormones playing a pivotal role in the gastrointestinal system’s structure and function. Emerging evidence suggests a link between AITDs and the gut microbiome, which is a diverse community of organisms that are essential for digestion, absorption, intestinal homeostasis, and immune defense. Recent studies using 16S rRNA and metagenomic sequencing of fecal samples from AITD patients have revealed a significant correlation between a gut microbiota imbalance and the severity of AITDs. Progress in animal models of autoimmune diseases has shown that intervention in the gut microbiota can significantly alter the disease severity. The gut microbiota influences T cell subgroup differentiation and modulates the pathological immune response to AITDs through mechanisms involving short-chain fatty acids (SCFAs), lipopolysaccharides (LPSs), and mucosal immunity. Conversely, thyroid hormones also influence gut function and microbiota composition. Thus, there is a bidirectional relationship between the thyroid and the gut ecosystem. This review explores the pathogenic mechanisms of the gut microbiota and its metabolites in AITDs, characterizes the gut microbiota in Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), and examines the interactions between the gut microbiota, thyroid hormones, T cell differentiation, and trace elements. The review aims to enhance understanding of the gut microbiota–thyroid axis and proposes novel approaches to mitigate AITD severity through gut microbiota modulation. Full article

(This article belongs to the Section Molecular Endocrinology and Metabolism)

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10 pages, 894 KiB

Open AccessArticle

Isothiocyanate-Rich Moringa Seed Extract Activates SKN-1/Nrf2 Pathway in Caenorhabditis elegans

by Renalison Farias-Pereira, Pierre Camayoc and Ilya Raskin

Int. J. Mol. Sci. 2024, 25(20), 10917; https://doi.org/10.3390/ijms252010917 (registering DOI) - 10 Oct 2024

Abstract

Moringa oleifera is a tropical tree that has its leaves, fruits, and seeds used as medicine and food. A standardized hydroalcoholic moringa seed extract (MSE) contains up to 40% of an isothiocyanate (MIC-1; moringin), a phytochemical known to have antioxidant and anti-inflammatory properties. [...] Read more.

Moringa oleifera is a tropical tree that has its leaves, fruits, and seeds used as medicine and food. A standardized hydroalcoholic moringa seed extract (MSE) contains up to 40% of an isothiocyanate (MIC-1; moringin), a phytochemical known to have antioxidant and anti-inflammatory properties. Animal studies suggest that MSE may help with diseases, such as edema, colitis, obesity, and diabetes. In vitro studies have shown that MIC-1 activates the Nrf2 pathway, involved in detoxification and antioxidant pathways. To broaden the understanding of the molecular pathways regulated by MSE, we hypothesized that MSE improves the health span in Caenorhabditis elegans by activating the Nrf2 homolog (SKN-1). Our whole RNA-seq data showed that MSE at 0.1 mg/mL (100 µM MIC-1) regulated the expression of a total of 1555 genes, including genes related to C. elegans cuticle, molting cycle, and glutathione metabolism. MSE upregulated several glutathione S transferases (GST), involved in the detoxification of xenobiotics, and other SKN-1 downstream targets. MSE and MIC-1 upregulate skn-1 expression and induce SKN-1 nuclear translocation, suggesting that they activate the SKN-1/Nrf2 pathway. Moreover, the regulation of glutathione metabolism is likely dependent on the SKN-1 pathway, as the gst-4 upregulation by MSE was inhibited in skn-1 knockout mutant. However, MSE decreased survivability and delayed growth rate, while purified MIC-1 increased the lifespan of C. elegans. This study shows that MIC-1 is responsible for SKN-1/Nrf2 activation by MSE; however, components other than MIC-1 within MSE likely cause detrimental effects in C. elegans. Full article

(This article belongs to the Special Issue Caenorhabditis elegans: A Model Organism for Human Health and Disease)

18 pages, 1180 KiB

Open AccessArticle

GDF-15 and mtDNA Deletions Are Useful Biomarkers of Mitochondrial Dysfunction in Insulin Resistance and PCOS

by Vera Varhegyi, Anna Modos, Domonkos Trager, Dora Gerszi, Eszter Maria Horvath, Miklos Sipos, Nandor Acs, Maria Judit Molnar, Szabolcs Varbiro and Aniko Gal

Int. J. Mol. Sci. 2024, 25(20), 10916; https://doi.org/10.3390/ijms252010916 (registering DOI) - 10 Oct 2024

Abstract

There is no literature available about the growth differentiation factor-15 (GDF-15) biomarker in combination with mitochondrial DNA (mtDNA) deletions in insulin resistance (IR), and polycystic ovary syndrome (PCOS); however, it would be useful to achieve optimal metabolic status and improve pregnancy success. In [...] Read more.

There is no literature available about the growth differentiation factor-15 (GDF-15) biomarker in combination with mitochondrial DNA (mtDNA) deletions in insulin resistance (IR), and polycystic ovary syndrome (PCOS); however, it would be useful to achieve optimal metabolic status and improve pregnancy success. In this study, the role of GDF-15 and mtDNA deletions as biomarkers in the pathogenesis of IR and PCOS was investigated. In our study, 81 female patients who were treated for IR and/or PCOS and 41 healthy controls were included. GDF-15 levels in patients showed a marked increase compared to controls. Elevated GDF-15 levels were found in 12 patients; all of them had a BMI > 25 kg/m², which is associated with reactive hyperinsulinemia. The presence of mitochondrial dysfunction was mainly observed in the IR-only subgroup. The increase in plasma levels of GDF-15 and the prevalence of mtDNA deletions is directly proportional to body mass index. The more marked metabolic abnormalities required more intensive drug therapy with a parallel increase in plasma GDF-15 levels. Elevated levels of GDF-15 and the presence of mitochondrial DNA deletions may be a consequence of carbohydrate metabolism disorders in patients and thus a predictor of the process of accelerated aging. Full article

(This article belongs to the Special Issue New Challenges and Perspectives in Polycystic Ovary Syndrome)

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14 pages, 3038 KiB

Open AccessArticle

Role of IL3RA in a Family with Lumbar Spinal Stenosis

by Kai-Ming Liu, Chi-Fan Yang, Weng-Siong H’ng, Hui-Ping Chuang, Eunice Han Xian Khor, Pei-Chun Tsai, Vivia Khosasih, Liang-Suei Lu, Erh-Chan Yeh, Wan-Jia Lin, Feng-Jen Hsieh, Chien-Hsiun Chen, Shiuh-Lin Hwang and Jer-Yuarn Wu

Int. J. Mol. Sci. 2024, 25(20), 10915; https://doi.org/10.3390/ijms252010915 (registering DOI) - 10 Oct 2024

Abstract

Lumbar spinal stenosis (LSS) is a degenerative spinal condition characterized by the narrowing of the spinal canal, resulting in low back pain (LBP) and limited leg mobility. Twin and family studies have suggested that genetics contributes to disease progression. However, the genetic causes [...] Read more.

Lumbar spinal stenosis (LSS) is a degenerative spinal condition characterized by the narrowing of the spinal canal, resulting in low back pain (LBP) and limited leg mobility. Twin and family studies have suggested that genetics contributes to disease progression. However, the genetic causes of familial LSS remain unclear. We performed whole-exome and direct sequencing on seven female patients from a Han Chinese family with LBP, among whom four developed LSS. Based on our genetic findings, we performed gene knockdown studies in human chondrocytes to study possible pathological mechanisms underlying LSS. We found a novel nonsense mutation, c.417C > G (NM_002183, p.Y139X), in IL3RA, shared by all the LBP/LSS cases. Knockdown of IL3RA led to a reduction in the total collagen content of 81.6% in female chondrocytes and 21% in male chondrocytes. The expression of MMP-1, -3, and/or -10 significantly increased, with a more pronounced effect observed in females than in males. Furthermore, EsRb expression significantly decreased following IL3RA knockdown. Moreover, the knockdown of EsRb resulted in increased MMP-1 and -10 expression in chondrocytes from females. We speculate that IL3RA deficiency could lead to a reduction in collagen content and intervertebral disk (IVD) strength, particularly in females, thereby accelerating IVD degeneration and promoting LSS occurrence. Our results illustrate, for the first time, the association between IL3RA and estrogen receptor beta, highlighting their importance and impact on MMPs and collagen in degenerative spines in women. Full article

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

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15 pages, 2981 KiB

Open AccessArticle

Anticancer Activity of Vitamin D, Lumisterol and Selected Derivatives against Human Malignant Melanoma Cell Lines

by Paweł Domżalski, Anna Piotrowska, Robert C. Tuckey and Michał A. Zmijewski

Int. J. Mol. Sci. 2024, 25(20), 10914; https://doi.org/10.3390/ijms252010914 (registering DOI) - 10 Oct 2024

Abstract

Despite the recent development of improved methods of treating melanoma such as targeted therapy, immunotherapy or combined treatment, the number of new cases worldwide is increasing. It is well known that active metabolites of vitamin D₃ and lumisterol (L₃) exert [...] Read more.

Despite the recent development of improved methods of treating melanoma such as targeted therapy, immunotherapy or combined treatment, the number of new cases worldwide is increasing. It is well known that active metabolites of vitamin D₃ and lumisterol (L₃) exert photoprotective and antiproliferative effects on the skin, while UV radiation is a major environmental risk factor for melanoma. Thus, many natural metabolites and synthetic analogs of steroidal and secosteroidal molecules have been tested on various cancer cells and in animal models. In this study, we tested the anti-melanoma properties of several natural derivatives of vitamin D₃ and L₃ in comparison to 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃). A significant decrease in melanoma cell proliferation and cell mobility was observed for selected derivatives, with (25R)-27-hydroxyL₃ showing the highest potency (lowest IC50) in A375 cells but lower potency in SK-MEL-28 cells, whereas the parent L₃ failed to inhibit proliferation. The efficacy (% inhibition) by 1,24,25(OH)₃D₃ and 1,25(OH)₂D₃ were similar in both cell types. 1,25(OH)₂D₃ showed higher potency than 1,24,25(OH)₃D₃ in SK-MEL-28 cells, but lower potency in A375 cells for the inhibition of proliferation. As for 1,25(OH)₂D₃, but not the other derivatives tested, treatment of melanoma cells with 1,24,25(OH)₃D₃ markedly increased the expression of CYP24A1, enhanced translocation of the vitamin D receptor (VDR) from the cytoplasm to the nucleus and also decreased the expression of the proliferation marker Ki67. The effects of the other compounds tested were weaker and occurred only under certain conditions. Our data indicate that 1,24,25(OH)₃D₃, which has undergone the first step in 1,25(OH)₂D₃ inactivation by being hydroxylated at C24, still shows anti-melanoma properties, displaying higher potency than 1,25(OH)₂D₃ in SK-MEL-28 cells. Furthermore, hydroxylation increases the potency of some of the lumisterol hydroxy-derivatives, as in contrast to L₃, (25R)-27(OH)L₃ effectively inhibits proliferation and migration of the human malignant melanoma cell line A375. Full article

(This article belongs to the Special Issue The Role of Vitamin D in Human Health and Diseases 4.0)

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10 pages, 1438 KiB

Open AccessReview

Genotype–Phenotype Correlation of GNAS Gene: Review and Disease Management of a Hotspot Mutation

by Lorenzo Cipriano, Rosario Ferrigno, Immacolata Andolfo, Roberta Russo, Daniela Cioffi, Maria Cristina Savanelli, Valeria Pellino, Antonella Klain, Achille Iolascon and Carmelo Piscopo

Int. J. Mol. Sci. 2024, 25(20), 10913; https://doi.org/10.3390/ijms252010913 (registering DOI) - 10 Oct 2024

Abstract

Defects of the GNAS gene have been mainly associated with pseudohypoparathyroidism Ia. To date, pathogenic missense, frameshift, non-sense and splicing variants have been described in all the 13 exons of the GNAS gene. Of them, a specific mutation, namely the 4 bp deletion [...] Read more.

Defects of the GNAS gene have been mainly associated with pseudohypoparathyroidism Ia. To date, pathogenic missense, frameshift, non-sense and splicing variants have been described in all the 13 exons of the GNAS gene. Of them, a specific mutation, namely the 4 bp deletion c.565_568delGACT, is currently considered a mutation hotspot. Recent articles performed genotype–phenotype correlations in patients with GNAS-related pseudohypoparathyroidism Ia (PHP1a) but a specific focus on this hotspot is still lacking. We reported two cases, from our department, of PHP1a associated with c.565_568delGACT deletion and performed a literature review of all the previously reported cases of the 4 bp deletion hotspot. We found a higher prevalence of brachydactyly, round face, intellectual disability and subcutaneous/heterotopic ossifications in patients with the c.565_568delGACT as compared to the other variants in the GNAS gene. The present study highlights the different prevalence of some clinical features in patients with the c.565_568delGACT variant in the GNAS gene, suggesting the possibility of a personalized diagnostic follow-up and surveillance for these patients. Full article

(This article belongs to the Special Issue Molecular Progression of Genome-Related Diseases)

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25 pages, 16716 KiB

Open AccessArticle

Marker-Assisted Selection of Jacalin-Related Lectin Genes OsJRL45 and OsJRL40 Derived from Sea Rice 86 Enhances Salt Tolerance in Rice

by Xiaolin Yin, Qinmei Gao, Feng Wang, Weihao Liu, Yiting Luo, Shuixiu Zhong, Jiahui Feng, Rui Bai, Liangbi Chen, Xiaojun Dai and Manzhong Liang

Int. J. Mol. Sci. 2024, 25(20), 10912; https://doi.org/10.3390/ijms252010912 (registering DOI) - 10 Oct 2024

Abstract

Soil salinization limits rice growth and is an important restriction on grain yield. Jacalin-related lectins are involved in multiple stress responses, but their role in salt stress responses and use as molecular markers for salt tolerance remain poorly understood. Salt stress treatments and [...] Read more.

Soil salinization limits rice growth and is an important restriction on grain yield. Jacalin-related lectins are involved in multiple stress responses, but their role in salt stress responses and use as molecular markers for salt tolerance remain poorly understood. Salt stress treatments and RT-qPCR analyses of Sea Rice 86 (SR86), 9311, and Nipponbare (Nip) showed that OsJRL45 and OsJRL40 enhanced tolerance of salt stress in SR86. Molecular markers based on sequence differences in SR86 and the salt-sensitive variety, 9311, in the intergenic region between OsJRL45 and OsJRL40 were validated in recombinant inbred lines derived from SR86 and 9311, hybrid populations, and common rice varieties. Yeast two-hybrid and bimolecular fluorescence complementation demonstrated that OsJRL45 and OsJRL40 interacted. Co-transformation of Nip with OsJRL45 and OsJRL40 derived from SR86 had no effect on the mature phenotype in T₂ plants; however, salt stress at the three-leaf stage led to significant increases in CAT, POD, SOD, and Pro contents, but reduced MDA content in transgenic plants. Transcriptomic analysis identified 834 differentially expressed genes in transgenic plants under salt stress. GO and KEGG enrichment analyses indicated that metabolic pathways related to antioxidant responses and osmotic balance were crucial for salt-stress tolerance. Thus, molecular markers based on nucleotide differences in OsJRL45 and OsJRL40 provide a novel method for identifying salt-tolerant rice varieties. Full article

(This article belongs to the Special Issue Abiotic Stress Tolerance and Genetic Diversity in Plants, 2nd Edition)

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44 pages, 2827 KiB

Open AccessReview

Blood-Based Biomarkers in Alzheimer’s Disease: Advancing Non-Invasive Diagnostics and Prognostics

by Mrinmay Dhauria, Ritwick Mondal, Shramana Deb, Gourav Shome, Dipanjan Chowdhury, Shramana Sarkar and Julián Benito-León

Int. J. Mol. Sci. 2024, 25(20), 10911; https://doi.org/10.3390/ijms252010911 (registering DOI) - 10 Oct 2024

Abstract

Alzheimer’s disease (AD), the most prevalent form of dementia, is expected to rise dramatically in incidence due to the global population aging. Traditional diagnostic approaches, such as cerebrospinal fluid analysis and positron emission tomography, are expensive and invasive, limiting their routine clinical use. [...] Read more.

Alzheimer’s disease (AD), the most prevalent form of dementia, is expected to rise dramatically in incidence due to the global population aging. Traditional diagnostic approaches, such as cerebrospinal fluid analysis and positron emission tomography, are expensive and invasive, limiting their routine clinical use. Recent advances in blood-based biomarkers, including amyloid-beta, phosphorylated tau, and neurofilament light, offer promising non-invasive alternatives for early AD detection and disease monitoring. This review synthesizes current research on these blood-based biomarkers, highlighting their potential to track AD pathology and enhance diagnostic accuracy. Furthermore, this review uniquely integrates recent findings on protein-protein interaction networks and microRNA pathways, exploring novel combinations of proteomic, genomic, and epigenomic biomarkers that provide new insights into AD’s molecular mechanisms. Additionally, we discuss the integration of these biomarkers with advanced neuroimaging techniques, emphasizing their potential to revolutionize AD diagnostics. Although large-scale validation is still needed, these biomarkers represent a critical advancement toward more accessible, cost-effective, and early diagnostic tools for AD. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series: “Molecular Research in Alzheimer’s Disease”)

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20 pages, 1958 KiB

Open AccessArticle

Assessing the Toxicity of Metal- and Carbon-Based Nanomaterials In Vitro: Impact on Respiratory, Intestinal, Skin, and Immune Cell Lines

by Juliana Carrillo-Romero, Gartze Mentxaka, Adrián García-Salvador, Alberto Katsumiti, Susana Carregal-Romero and Felipe Goñi-de-Cerio

Int. J. Mol. Sci. 2024, 25(20), 10910; https://doi.org/10.3390/ijms252010910 (registering DOI) - 10 Oct 2024

Abstract

The field of nanotechnology has experienced exponential growth, with the unique properties of nanomaterials (NMs) being employed to enhance a wide range of products across diverse industrial sectors. This study examines the toxicity of metal- and carbon-based NMs, with a particular focus on [...] Read more.

The field of nanotechnology has experienced exponential growth, with the unique properties of nanomaterials (NMs) being employed to enhance a wide range of products across diverse industrial sectors. This study examines the toxicity of metal- and carbon-based NMs, with a particular focus on titanium dioxide (TiO₂), zinc oxide (ZnO), silica (SiO₂), cerium oxide (CeO₂), silver (Ag), and multi-walled carbon nanotubes (MWCNTs). The potential health risks associated with increased human exposure to these NMs and their effect on the respiratory, gastrointestinal, dermal, and immune systems were evaluated using in vitro assays. Physicochemical characterisation of the NMs was carried out, and in vitro assays were performed to assess the cytotoxicity, genotoxicity, reactive oxygen species (ROS) production, apoptosis/necrosis, and inflammation in cell lines representative of the systems evaluated (3T3, Caco-2, HepG2, A549, and THP-1 cell lines). The results obtained show that 3T3 and A549 cells exhibit high cytotoxicity and ROS production after exposure to ZnO NMs. Caco-2 and HepG2 cell lines show cytotoxicity when exposed to ZnO and Ag NMs and oxidative stress induced by SiO₂ and MWCNTs. THP-1 cell line shows increased cytotoxicity and a pro-inflammatory response upon exposure to SiO₂. This study emphasises the importance of conducting comprehensive toxicological assessments of NMs given their physicochemical interactions with biological systems. Therefore, it is of key importance to develop robust and specific methodologies for the assessment of their potential health risks. Full article

(This article belongs to the Special Issue Toxicity of Nanoparticles)

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25 pages, 1598 KiB

Open AccessReview

Obesity Control and Supplementary Nutraceuticals as Cofactors of Brain Plasticity in Multiple Sclerosis Populations

by Lorena Ciumărnean, Oliviu-Florențiu Sârb, Nicu-Cătălin Drăghici, Octavia Sălăgean, Mircea-Vasile Milaciu, Olga-Hilda Orășan, Călin-Vasile Vlad, Irina-Maria Vlad, Teodora Alexescu, Ioana Para, Simina-Felicia Țărmure, Elisabeta-Ioana Hirișcău and Gabriela-Bombonica Dogaru

Int. J. Mol. Sci. 2024, 25(20), 10909; https://doi.org/10.3390/ijms252010909 - 10 Oct 2024

Abstract

Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammation, demyelination, and neurodegeneration within the central nervous system. Brain plasticity, the brain’s ability to adapt its structure and function, plays a crucial role in mitigating MS’s impact. This paper explores the potential benefits [...] Read more.

Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammation, demyelination, and neurodegeneration within the central nervous system. Brain plasticity, the brain’s ability to adapt its structure and function, plays a crucial role in mitigating MS’s impact. This paper explores the potential benefits of lifestyle changes and nutraceuticals on brain plasticity in the MS population. Lifestyle modifications, including physical activity and dietary adjustments, can enhance brain plasticity by upregulating neurotrophic factors, promoting synaptogenesis, and reducing oxidative stress. Nutraceuticals, such as vitamin D, omega-3 fatty acids, and antioxidants like alpha lipoic acid, have shown promise in supporting brain health through anti-inflammatory and neuroprotective mechanisms. Regular physical activity has been linked to increased levels of brain-derived neurotrophic factor and improved cognitive function. Dietary interventions, including caloric restriction and the intake of polyphenols, can also positively influence brain plasticity. Integrating these lifestyle changes and nutraceuticals into the management of MS can provide a complementary approach to traditional therapies, potentially improving neurological outcomes and enhancing the quality of life for the MS population. Full article

(This article belongs to the Special Issue Advances in Nutritional Approach to the Neurodegenerative Diseases)

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18 pages, 2824 KiB

Open AccessArticle

Molecular Characterization of Sterol C4-Methyl Oxidase in Leishmania major

by Yu Ning, Somrita Basu, Fong-fu Hsu, Mei Feng, Michael Zhuo Wang and Kai Zhang

Int. J. Mol. Sci. 2024, 25(20), 10908; https://doi.org/10.3390/ijms252010908 - 10 Oct 2024

Abstract

Sterol biosynthesis requires the oxidative removal of two methyl groups from the C-4 position by sterol C-4-demethylase and one methyl group from the C-14 position by sterol C-14-demethylase. In Leishmania donovani, a CYP5122A1 (Cytochrome P450 family 5122A1) protein was recently identified as [...] Read more.

Sterol biosynthesis requires the oxidative removal of two methyl groups from the C-4 position by sterol C-4-demethylase and one methyl group from the C-14 position by sterol C-14-demethylase. In Leishmania donovani, a CYP5122A1 (Cytochrome P450 family 5122A1) protein was recently identified as the bona fide sterol C-4 methyl oxidase catalyzing the initial steps of C-4-demethylation. Besides CYP5122A1, Leishmania parasites possess orthologs to ERG25 (ergosterol pathway gene 25), the canonical sterol C-4 methyl oxidase in Saccharomyces cerevisiae. To determine the contribution of CYP5122A1 and ERG25 in sterol biosynthesis, we assessed the essentiality of these genes in Leishmania major, which causes cutaneous leishmaniasis. Like in L. donovani, CYP5122A1 in L. major could only be deleted in the presence of a complementing episome. Even with strong negative selection, L. major chromosomal CYP5122A1-null mutants retained the complementing episome in both promastigote and amastigote stages, demonstrating its essentiality. In contrast, the L. major ERG25-null mutants were fully viable and replicative in culture and virulent in mice. Deletion and overexpression of ERG25 did not affect the sterol composition, indicating that ERG25 is not required for C-4-demethylation. These findings suggest that CYP5122A1 is the dominant and possibly only sterol C-4 methyl oxidase in Leishmania, and inhibitors of CYP5122A1 may have strong therapeutic potential against multiple Leishmania species. Full article

(This article belongs to the Section Molecular Microbiology)

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18 pages, 22909 KiB

Open AccessArticle

Integrated Biological Experiments and Proteomic Analyses of Nicotiana tabacum Xylem Sap Revealed the Host Response to Tomato Spotted Wilt Orthotospovirus Infection

by Hongping Feng, Waiwai Mon, Xiaoxia Su, Yu Li, Shaozhi Zhang, Zhongkai Zhang and Kuanyu Zheng

Int. J. Mol. Sci. 2024, 25(20), 10907; https://doi.org/10.3390/ijms252010907 - 10 Oct 2024

Abstract

The plant vascular system is not only a transportation system for delivering nutrients but also a highway transport network for spreading viruses. Tomato spotted wilt orthotospovirus (TSWV) is among the most destructive viruses that cause serious losses in economically important crops worldwide. However, [...] Read more.

The plant vascular system is not only a transportation system for delivering nutrients but also a highway transport network for spreading viruses. Tomato spotted wilt orthotospovirus (TSWV) is among the most destructive viruses that cause serious losses in economically important crops worldwide. However, there is minimal information about the long-distance movements of TSWV in the host plant vascular system. In this this study, we confirm that TSWV virions are present in the xylem as observed by transmission electron microscopy (TEM). Further, a quantitative proteomic analysis based on label-free methods was conducted to reveal the uniqueness of protein expression in xylem sap during TSWV infection. Thus, this study identified and quantified 3305 proteins in two groups. Furthermore, TSWV infection induced three viral structural proteins, N, Gn and Gc, and 315 host proteins differentially expressed in xylem (163 up-regulated and 152 down-regulated). GO enrichment analysis showed up-regulated proteins significantly enriched in homeostasis, wounding, defense response, and DNA integration terms, while down-regulated proteins significantly enriched in cell wall biogenesis/xyloglucan metabolic process-related terms. KEGG enrichment analysis showed that the differentially expressed proteins (DEPs) were most strongly associated with plant-pathogen interaction, MAPK signaling pathway, and plant hormone signal transduction. Cluster analysis of DEPs function showed the DEPs can be categorized into cell wall metabolism-related proteins, antioxidant proteins, PCD-related proteins, host defense proteins such as receptor-like kinases (RLKs), salicylic acid binding protein (SABP), pathogenesis related proteins (PR), DNA methylation, and proteinase inhibitor (PI). Finally, parallel reaction monitoring (PRM) validated 20 DEPs, demonstrating that the protein abundances were consistent between label-free and PRM data. Finally, 11 genes were selected for RT-qPCR validation of the DEPs and label-free-based proteomic analysis concordant results. Our results contribute to existing knowledge on the complexity of host plant xylem system response to virus infection and provide a basis for further study of the mechanism underlying TSWV long-distance movement in host plant vascular system. Full article

(This article belongs to the Special Issue Advances in Plant Virus Diseases and Virus-Induced Resistance)

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7 pages, 234 KiB

Open AccessCommunication

Serpin Family B Member 2 Polymorphisms in Patients with Diabetic Kidney Disease: An Association Study

by Maria Tziastoudi, Georgios Pissas, Spyridon Golfinopoulos, Georgios Filippidis, Christina Poulianiti, Evangelia E. Tsironi, Efthimios Dardiotis, Theodoros Eleftheriadis and Ioannis Stefanidis

Int. J. Mol. Sci. 2024, 25(20), 10906; https://doi.org/10.3390/ijms252010906 - 10 Oct 2024

Abstract

Diabetic kidney disease (DKD) is a serious microvascular complication of type 2 diabetes mellitus (T2DM). Despite the numerous genetic loci that have been associated with the disease in T2DM, the genetic architecture of DKD remains unclear until today. In contrast to SERPINE1, [...] Read more.

Diabetic kidney disease (DKD) is a serious microvascular complication of type 2 diabetes mellitus (T2DM). Despite the numerous genetic loci that have been associated with the disease in T2DM, the genetic architecture of DKD remains unclear until today. In contrast to SERPINE1, the contribution of SERPINB2 has not been examined in DKD. Therefore, we conducted the first genetic association study of SERPINB2 to elucidate its role in DKD. In total, the study involved 197 patients with DKD, 155 patients with T2DM without microvascular complications (diabetic kidney disease, diabetic retinopathy, and diabetic neuropathy), and 246 healthy controls. The generalized odds ratio (OR_G) was calculated to estimate the risk on DKD development. The present association study regarding SERPINB2 SNPs (rs4941230, rs3819335, rs13381217, rs6140) did not reveal any significant association between SERPINB2 variants and DKD. Additional studies in other populations are necessary to further investigate the role of this gene in the progression of diabetes mellitus and development of DKD. Full article

(This article belongs to the Special Issue Molecular Mechanism of Diabetic Kidney Disease)

29 pages, 3375 KiB

Open AccessReview

Lymphocytes Change Their Phenotype and Function in Systemic Lupus Erythematosus and Lupus Nephritis

by Eleni Moysidou, Michalis Christodoulou, Georgios Lioulios, Stamatia Stai, Theodoros Karamitsos, Theodoros Dimitroulas, Asimina Fylaktou and Maria Stangou

Int. J. Mol. Sci. 2024, 25(20), 10905; https://doi.org/10.3390/ijms252010905 (registering DOI) - 10 Oct 2024

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disease, characterized by considerable changes in peripheral lymphocyte structure and function, that plays a critical role in commencing and reviving the inflammatory and immune signaling pathways. In healthy individuals, B lymphocytes have a major role [...] Read more.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease, characterized by considerable changes in peripheral lymphocyte structure and function, that plays a critical role in commencing and reviving the inflammatory and immune signaling pathways. In healthy individuals, B lymphocytes have a major role in guiding and directing defense mechanisms against pathogens. Certain changes in B lymphocyte phenotype, including alterations in surface and endosomal receptors, occur in the presence of SLE and lead to dysregulation of peripheral B lymphocyte subpopulations. Functional changes are characterized by loss of self-tolerance, intra- and extrafollicular activation, and increased cytokine and autoantibody production. T lymphocytes seem to have a supporting, rather than a leading, role in the disease pathogenesis. Substantial aberrations in peripheral T lymphocyte subsets are evident, and include a reduction of cytotoxic, regulatory, and advanced differentiated subtypes, together with an increase of activated and autoreactive forms and abnormalities in follicular T cells. Up-regulated subpopulations, such as central and effector memory T cells, produce pre-inflammatory cytokines, activate B lymphocytes, and stimulate cell signaling pathways. This review explores the pivotal roles of B and T lymphocytes in the pathogenesis of SLE and Lupus Nephritis, emphasizing the multifaceted mechanisms and interactions and their phenotypic and functional dysregulations. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Autoimmune Disorders)

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11 pages, 1540 KiB

Open AccessArticle

Circulating Immune Complexes and Complement Activation in Sensitized Kidney Transplant Recipients

by Maria Stella Trivyza, Charikleia Stergiopoulou, Sotiris Tsakas, Theodoros Ntrinias, Marios Papasotiriou, Nikolaos Karydis, Evangelos Papachristou and Dimitrios S. Goumenos

Int. J. Mol. Sci. 2024, 25(20), 10904; https://doi.org/10.3390/ijms252010904 - 10 Oct 2024

Abstract

Chronic antibody-mediated rejection in kidney transplantation is a common cause of graft loss in the late post-transplant period. In this process, the role of the classical complement activation pathway is crucial due to the formation of immune complexes between donor-specific antibodies (DSAs) and [...] Read more.

Chronic antibody-mediated rejection in kidney transplantation is a common cause of graft loss in the late post-transplant period. In this process, the role of the classical complement activation pathway is crucial due to the formation of immune complexes between donor-specific antibodies (DSAs) and donor antigens and the attachment of the C1q complement fragment. This study aimed to determine the levels of circulating C1q immunocomplexes (CIC-C1q) and complement activation (CH50), in sensitized kidney transplant recipients (KTRs). In this cross-sectional study we used serum samples from KTRs with de novo or preformed DSAs (n = 14), KTRs without DSAs (n = 28), and 22 subjects with no history of chronic kidney disease (controls). C1q immunocomplexes and CH50 concentration in serum were measured with the enzyme immunoassay (EIA) kit MicroVue CIC-C1q (Quidel, Athens, OH, USA) and EIA kit MicroVue CH50 (Quidel, OH, USA), respectively. Higher concentrations of CIC-C1q was observed in KTRs with DSAs in comparison with controls and with KTRs with no DSAs (6.8 ± 2.7 and 4.8 ± 1.9 vs. 5.0 ± 1.2 μg Eq/mL, respectively, p < 0.01). We found no difference in CIC-C1q between KTRs with no DSAs and controls. CIC-C1q levels were positively correlated with DSA titer. CH50 levels were decreased in KTRs with DSAs in comparison with controls and KTRs with no DSAs (39 ± 15 vs. 68 ± 40 and 71 ± 34 U Eq/mL, respectively, p < 0.01). There was no difference in CH50 between DSA-negative KTRs and controls. Kidney transplant recipients with DSAs had increased serum levels of C1q immunocomplexes and increased classical pathway complement activation. Full article

(This article belongs to the Special Issue Molecular Mechanisms in Organ Transplantation)

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31 pages, 12504 KiB

Open AccessArticle

Metabolomic Analysis of Histological Composition Variability of High-Grade Serous Ovarian Cancer Using ¹H HR MAS NMR Spectroscopy

by Agnieszka Skorupa, Mateusz Klimek, Mateusz Ciszek, Sławomir Pakuło, Tomasz Cichoń, Bartosz Cichoń, Łukasz Boguszewicz, Andrzej Witek and Maria Sokół

Int. J. Mol. Sci. 2024, 25(20), 10903; https://doi.org/10.3390/ijms252010903 - 10 Oct 2024

Abstract

In this work, the HR MAS NMR (high-resolution magic-angle spinning nuclear magnetic resonance) spectroscopy technique was combined with standard histological examinations to investigate the metabolic features of high-grade serous ovarian cancer (HGSOC) with a special focus on the relation between a metabolic profile [...] Read more.

In this work, the HR MAS NMR (high-resolution magic-angle spinning nuclear magnetic resonance) spectroscopy technique was combined with standard histological examinations to investigate the metabolic features of high-grade serous ovarian cancer (HGSOC) with a special focus on the relation between a metabolic profile and a cancer cell fraction. The studied group consisted of 44 patients with HGSOC and 18 patients with benign ovarian tumors. Normal ovarian tissue was also excised from 13 control patients. The metabolic profiles of 138 tissue specimens were acquired on a Bruker Avance III 400 MHz spectrometer. The NMR spectra of the HGSOC samples could be discriminated from those acquired from the non-transformed tissue and were shown to depend on tumor purity. The most important features that differentiate the samples with a high fraction of cancer cells from the samples containing mainly fibrotic stroma are the increased intensities in the spectral regions corresponding to phosphocholine/glycerophosphocholine, phosphoethanolamine/serine, threonine, uridine nucleotides and/or uridine diphosphate (UDP) nucleotide sugars. Higher levels of glutamine, glutamate, acetate, lysine, alanine, leucine and isoleucine were detected in the desmoplastic stroma within the HGSOC lesions compared to the stroma of benign tumors. The HR MAS NMR analysis of the metabolic composition of the epithelial and stromal compartments within HGSOC contributes to a better understanding of the disease’s biology. Full article

(This article belongs to the Special Issue Metabolomics in Oncology)

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15 pages, 3428 KiB

Open AccessArticle

ddPCR Overcomes the CRISPR-Cas13a-Based Technique for the Detection of the BRAF p.V600E Mutation in Liquid Biopsies

by Irina Palacín-Aliana, Noemí García-Romero, Josefa Carrión-Navarro, Pilar Puig-Serra, Raul Torres-Ruiz, Sandra Rodríguez-Perales, David Viñal, Víctor González-Rumayor and Ángel Ayuso-Sacido

Int. J. Mol. Sci. 2024, 25(20), 10902; https://doi.org/10.3390/ijms252010902 - 10 Oct 2024

Abstract

The isolation of circulating tumoral DNA (ctDNA) present in the bloodstream brings about the opportunity to detect genomic aberrations from the tumor of origin. However, the low amounts of ctDNA present in liquid biopsy samples makes the development of highly sensitive techniques necessary [...] Read more.

The isolation of circulating tumoral DNA (ctDNA) present in the bloodstream brings about the opportunity to detect genomic aberrations from the tumor of origin. However, the low amounts of ctDNA present in liquid biopsy samples makes the development of highly sensitive techniques necessary to detect targetable mutations for the diagnosis, prognosis, and monitoring of cancer patients. Here, we employ standard genomic DNA (gDNA) and eight liquid biopsy samples from different cancer patients to examine the newly described CRISPR-Cas13a-based technology in the detection of the BRAF p.V600E actionable point mutation and appraise its diagnostic capacity with two PCR-based techniques: quantitative Real-Time PCR (qPCR) and droplet digital PCR (ddPCR). Regardless of its lower specificity compared to the qPCR and ddPCR techniques, the CRISPR-Cas13a-guided complex was able to detect inputs as low as 10 pM. Even though the PCR-based techniques have similar target limits of detection (LoDs), only the ddPCR achieved a 0.1% variant allele frequency (VAF) detection with elevated reproducibility, thus standing out as the most powerful and suitable tool for clinical diagnosis purposes. Our results also demonstrate how the CRISPR-Cas13a can detect low amounts of the target of interest, but its base-pair specificity failed in the detection of actionable point mutations at a low VAF; therefore, the ddPCR is still the most powerful and suitable technique for these purposes. Full article

(This article belongs to the Special Issue New Diagnostic Tools and Biomarkers in Oncological Diseases: 2nd Edition)

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4 pages, 159 KiB

Open AccessEditorial

Disorders in Brain Development and Nervous System: Key Molecules and Pathology

by Kazuhiko Nakadate and Kiyoharu Kawakami

Int. J. Mol. Sci. 2024, 25(20), 10901; https://doi.org/10.3390/ijms252010901 - 10 Oct 2024

Abstract

Brain development is an extremely complex and essential biological process that begins at the start of life and continues throughout an individual’s lifespan [...] Full article

(This article belongs to the Special Issue Disorders in Brain Development and Nervous System: Key Molecules and Pathology)

34 pages, 1880 KiB

Open AccessReview

A Review of Biomarkers of Amyotrophic Lateral Sclerosis: A Pathophysiologic Approach

by Rawiah S. Alshehri, Ahmad R. Abuzinadah, Moafaq S. Alrawaili, Muteb K. Alotaibi, Hadeel A. Alsufyani, Rajaa M. Alshanketi and Aysha A. AlShareef

Int. J. Mol. Sci. 2024, 25(20), 10900; https://doi.org/10.3390/ijms252010900 - 10 Oct 2024

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. The heterogeneous nature of ALS at the clinical, genetic, and pathological levels makes it challenging to develop diagnostic and prognostic tools that fit all disease [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. The heterogeneous nature of ALS at the clinical, genetic, and pathological levels makes it challenging to develop diagnostic and prognostic tools that fit all disease phenotypes. Limitations associated with the functional scales and the qualitative nature of mainstay electrophysiological testing prompt the investigation of more objective quantitative assessment. Biofluid biomarkers have the potential to fill that gap by providing evidence of a disease process potentially early in the disease, its progression, and its response to therapy. In contrast to other neurodegenerative diseases, no biomarker has yet been validated in clinical use for ALS. Several fluid biomarkers have been investigated in clinical studies in ALS. Biofluid biomarkers reflect the different pathophysiological processes, from protein aggregation to muscle denervation. This review takes a pathophysiologic approach to summarizing the findings of clinical studies utilizing quantitative biofluid biomarkers in ALS, discusses the utility and shortcomings of each biomarker, and highlights the superiority of neurofilaments as biomarkers of neurodegeneration over other candidate biomarkers. Full article

(This article belongs to the Special Issue From Molecular Insights to Novel Therapies: Neurological Diseases)

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23 pages, 8983 KiB

Open AccessArticle

Ultra-Pressurized Deposition of Hydrophobic Chitosan Surface Coating on Wood for Fungal Resistance

by Suelen P. Facchi, Débora A. de Almeida, Karen K. B. Abrantes, Paula C. dos S. Rodrigues, Dauri J. Tessmann, Elton G. Bonafé, Marcelo F. da Silva, Mazeyar P. Gashti, Alessandro F. Martins and Lúcio Cardozo-Filho

Int. J. Mol. Sci. 2024, 25(20), 10899; https://doi.org/10.3390/ijms252010899 - 10 Oct 2024

Abstract

Fungi (Neolentinus lepideus, Nl, and Trametes versicolor, Tv) impart wood rot, leading to economic and environmental issues. To overcome this issue, toxic chemicals are commonly employed for wood preservation, impacting the environment and human health. Surface coatings based [...] Read more.

Fungi (Neolentinus lepideus, Nl, and Trametes versicolor, Tv) impart wood rot, leading to economic and environmental issues. To overcome this issue, toxic chemicals are commonly employed for wood preservation, impacting the environment and human health. Surface coatings based on antimicrobial chitosan (CS) of high molar mass (145 × 10⁵ Da) were tested as wood preservation agents using an innovative strategy involving ultra-pressurizing CS solutions to deposit organic coatings on wood samples. Before coating deposition, the antifungal activity of CS in diluted acetic acid (AcOOH) solutions was evaluated against the rot fungi models Neolentinus lepideus (Nl) and Trametes versicolor (Tv). CS effectively inhibited fungal growth, particularly in solutions with concentrations equal to or higher than 0.125 mg/mL. Wood samples (Eucalyptus sp. and Pinus sp.) were then coated with CS under ultra-pressurization at 70 bar. The polymeric coating deposition on wood was confirmed through X-ray photoelectron spectroscopy (XPS), energy dispersive X-ray spectroscopy (EDS), scanning electron microscopy (SEM) images, and water contact angle measurements. Infrared spectroscopy (FTIR) spectra of the uncoated and coated samples suggested that CS does not penetrate the bulk of the wood samples due to its high molar mass but penetrates in the surface pores, leading to its impregnation in wood samples. Coated and uncoated wood samples were exposed to fungi (Tv and Nl) for 12 weeks. In vivo testing revealed that Tv and Nl fungi did not grow on wood samples coated with CS, whereas the fungi proliferated on uncoated samples. CS of high molar mass has film-forming properties, leading to a thin hydrophobic film on the wood surface (water contact angle of 118°). This effect is mainly attributed to the high molar mass of CS and the hydrogen bonding interactions established between CS chains and cellulose. This hydrophobic film prevents water interaction, resulting in a stable coating with insignificant leaching of CS after the stability test. The CS coating can offer a sustainable strategy to prevent wood degradation, overcoming the disadvantages of toxic chemicals often used as wood preservative agents. Full article

(This article belongs to the Special Issue Bioactive Materials with Antimicrobial Properties: 2nd Edition)

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20 pages, 4410 KiB

Open AccessArticle

Implementation of an Immunoassay Based on the MVA-T7pol-Expression System for Rapid Identification of Immunogenic SARS-CoV-2 Antigens: A Proof-of-Concept Study

by Satendra Kumar, Liangliang Nan, Georgia Kalodimou, Sylvia Jany, Astrid Freudenstein, Christine Brandmüller, Katharina Müller, Philipp Girl, Rosina Ehmann, Wolfgang Guggemos, Michael Seilmaier, Clemens-Martin Wendtner, Asisa Volz, Gerd Sutter, Robert Fux and Alina Tscherne

Int. J. Mol. Sci. 2024, 25(20), 10898; https://doi.org/10.3390/ijms252010898 - 10 Oct 2024

Abstract

The emergence of hitherto unknown viral pathogens presents a great challenge for researchers to develop effective therapeutics and vaccines within a short time to avoid an uncontrolled global spread, as seen during the coronavirus disease 2019 (COVID-19) pandemic. Therefore, rapid and simple methods [...] Read more.

The emergence of hitherto unknown viral pathogens presents a great challenge for researchers to develop effective therapeutics and vaccines within a short time to avoid an uncontrolled global spread, as seen during the coronavirus disease 2019 (COVID-19) pandemic. Therefore, rapid and simple methods to identify immunogenic antigens as potential therapeutical targets are urgently needed for a better pandemic preparedness. To address this problem, we chose the well-characterized Modified Vaccinia virus Ankara (MVA)-T7pol expression system to establish a workflow to identify immunogens when a new pathogen emerges, generate candidate vaccines, and test their immunogenicity in an animal model. By using this system, we detected severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) nucleoprotein (N)-, and spike (S)-specific antibodies in COVID-19 patient sera, which is in line with the current literature and our observations from previous immunogenicity studies. Furthermore, we detected antibodies directed against the SARS-CoV-2-membrane (M) and -ORF3a proteins in COVID-19 patient sera and aimed to generate recombinant MVA candidate vaccines expressing either the M or ORF3a protein. When testing our candidate vaccines in a prime-boost immunization regimen in humanized HLA-A2.1-/HLA-DR1-transgenic H-2 class I-/class II-knockout mice, we were able to demonstrate M- and ORF3a-specific cellular and humoral immune responses. Hence, the established workflow using the MVA-T7pol expression system represents a rapid and efficient tool to identify potential immunogenic antigens and provides a basis for future development of candidate vaccines. Full article

(This article belongs to the Special Issue Viral Infection and Virology Methods)

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9 pages, 8828 KiB

Open AccessArticle

Myeloid GSK3α Deficiency Reduces Lesional Inflammation and Neovascularization during Atherosclerotic Progression

by Sarvatit Patel, Nisarg Shah, Brooke D’Mello, Anson Lee and Geoff H. Werstuck

Int. J. Mol. Sci. 2024, 25(20), 10897; https://doi.org/10.3390/ijms252010897 - 10 Oct 2024

Abstract

The molecular mechanisms by which cardiovascular risk factors promote the development of atherosclerosis are poorly understood. We have recently shown that genetic ablation of myeloid glycogen synthase kinase (GSK)-3α attenuates atherosclerotic lesion development in low-density lipoprotein receptor-deficient (Ldlr^−/−) mice. However, the [...] Read more.

The molecular mechanisms by which cardiovascular risk factors promote the development of atherosclerosis are poorly understood. We have recently shown that genetic ablation of myeloid glycogen synthase kinase (GSK)-3α attenuates atherosclerotic lesion development in low-density lipoprotein receptor-deficient (Ldlr^−/−) mice. However, the precise contributions of GSK3α/β in atherogenesis are not known. The aim of this study is to investigate the effect of GSK3α and/or β deficiency on lesional inflammation and plaque vascularization. Five-week-old female Ldlr^−/− mice were fed a high-fat diet for 10 weeks to establish atherosclerotic lesions. Mice were harvested at 15 weeks of age and atherosclerotic lesions were characterized. The results indicate that, in addition to significantly reducing plaque volume, GSK3α-deficiency decreases inflammation, reduces vasa vasorum density at the aortic sinus, and reduces plasma c-reactive protein (CRP) levels. GSK3β-deficiency is associated with decreased plasma CRP levels but does not affect lesional inflammation or vascularization. These results suggest GSK3α may be an applicable target for the development of novel anti-atherogenic therapies. Full article

(This article belongs to the Special Issue GSK3 as a Master Regulator of Cellular Processes, 2nd Edition)

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14 pages, 2414 KiB

Open AccessArticle

Identification of Powdery Mildew Resistance-Related Genes in Butternut Squash (Cucurbita moschata)

by Yiqian Fu, Yanping Hu, Jingjing Yang, Daolong Liao, Pangyuan Liu, Changlong Wen and Tianhai Yun

Int. J. Mol. Sci. 2024, 25(20), 10896; https://doi.org/10.3390/ijms252010896 - 10 Oct 2024

Abstract

Powdery mildew infection is a significant challenge in butternut squash (Cucurbita moschata) production during winter in Hainan, China. The tropical climate of Hainan promotes powdery mildew infection, resulting in substantial yield losses. By utilizing transcriptome and genome sequencing data, SNPs and [...] Read more.

Powdery mildew infection is a significant challenge in butternut squash (Cucurbita moschata) production during winter in Hainan, China. The tropical climate of Hainan promotes powdery mildew infection, resulting in substantial yield losses. By utilizing transcriptome and genome sequencing data, SNPs and potential genes associated with powdery mildew resistance in butternut squash were identified. The analysis of differentially expressed genes (DEGs) following powdery mildew infection revealed several genes involved in resistance, with particular focus on a resistance (R) gene cluster that may be linked to the observed resistance. Two MLO genes in clade V from Cucurbita moschata may not be directly associated with resistance in the two genotypes studied. These findings are expected to contribute to the development of genetic tools for improving powdery mildew resistance in Cucurbita crops, thereby reducing yield losses and enhancing the sustainability of butternut squash production in Hainan and other regions. Full article

(This article belongs to the Special Issue Genetics and Molecular Breeding of Cucurbitaceous Crops)

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20 pages, 3745 KiB

Open AccessArticle

Antibiofilm and Antimicrobial Potentials of Novel Synthesized Sulfur Camphor Derivatives

by Anna Duda-Madej, Szymon Viscardi, Katarzyna Pacyga, Robert Kupczyński, Wanda Mączka, Małgorzata Grabarczyk, Paweł Pacyga, Ewa Topola, Michał Ostrówka, Jacek Bania, Antoni Szumny and Katarzyna Wińska

Int. J. Mol. Sci. 2024, 25(20), 10895; https://doi.org/10.3390/ijms252010895 - 10 Oct 2024

Abstract

The question being posed by scientists around the world is how different chemical modifications of naturally occurring compounds will affect their antimicrobial properties. In the current study, sulfur derivatives of camphor containing a sulfur atom were tested to detect their antimicrobial and antibiofilm [...] Read more.

The question being posed by scientists around the world is how different chemical modifications of naturally occurring compounds will affect their antimicrobial properties. In the current study, sulfur derivatives of camphor containing a sulfur atom were tested to detect their antimicrobial and antibiofilm potentials. The new compounds were tested on eight Gram-positive strains (S. aureus (3 isolates), S. epidermidis (4 isolates), and E. faecalis (1 isolate)) and eight Gram-negative strains (E. coli (6 isolates), A. baumannii (1 isolate), and P. aeruginosa (1 isolate)). The ability of the strains to eradicate a biofilm was evaluated under standard stationary and flow-through conditions using the Bioflux system. Two synthesized compounds, namely rac-thiocamphor (1a) and (S, S)-(+)-thiocamphor (2a), exhibited an effect on the 24 h biofilm formed by the Gram-positive strains. Our results are an important contribution to the science of natural compounds and allow us to classify our sulfur derivatives of camphor as potential prophylactic agents in treating skin infections, antiseptics, and disinfectants. The Gram-negative strains were excluded from further stages of the tests due to their high activity (MIC ≥ 512 µg/mL). On the other hand, the compound with the strongest antimicrobial activity against the Gram-positive strains was 2a, as it led led to a reductions in cell viability of 17–52% (for MIC), 37–66% (for 2MIC), and 40–94% (for 4MIC). In addition, the experimental retention index of thiocamphor was calculated for the first time. Full article

(This article belongs to the Special Issue Antimicrobial Agents: Natural Products or Synthetic Compounds)

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24 pages, 2349 KiB

Open AccessArticle

Intratumoral Heterogeneity and Metabolic Cross-Feeding in a Three-Dimensional Breast Cancer Culture: An In Silico Perspective

by Jorge E. Arellano-Villavicencio, Aarón Vázquez-Jiménez, Juan José Oropeza-Valdez, Cristian Padron-Manrique, Heriberto Prado-García, Armando R. Tovar and Osbaldo Resendis-Antonio

Int. J. Mol. Sci. 2024, 25(20), 10894; https://doi.org/10.3390/ijms252010894 - 10 Oct 2024

Abstract

Today, the intratumoral composition is a relevant factor associated with the progression and aggression of cancer. Although it suggests a metabolic interdependence among the subpopulations inside the tumor, a detailed map of how this interdependence contributes to the malignant phenotype is still lacking. [...] Read more.

Today, the intratumoral composition is a relevant factor associated with the progression and aggression of cancer. Although it suggests a metabolic interdependence among the subpopulations inside the tumor, a detailed map of how this interdependence contributes to the malignant phenotype is still lacking. To address this issue, we developed a systems biology approach integrating single-cell RNASeq and genome-scale metabolic reconstruction to map the metabolic cross-feeding among the subpopulations previously identified in the spheroids of MCF7 breast cancer. By calibrating our model with expression profiles and the experimental growth rate, we concluded that the reverse Warburg effect emerges as a mechanism to optimize community growth. Furthermore, through an in silico analysis, we identified lactate, alpha-ketoglutarate, and some amino acids as key metabolites whose disponibility alters the growth rate of the spheroid. Altogether, this work provides a strategy for assessing how space and intratumoral heterogeneity influence the metabolic robustness of cancer, issues suggesting that computational strategies should move toward the design of optimized treatments. Full article

(This article belongs to the Special Issue Deciphering the Dynamics: Exploring Tumor Evolution in Cancer)

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15 pages, 1583 KiB

Open AccessArticle

Proteomics Analysis on the Effects of Oxidative Stress and Antioxidants on Proteins Involved in Sterol Transport and Metabolism in Human Telomerase Transcriptase-Overexpressing-Retinal Pigment Epithelium Cells

by R. Scott Duncan, Andrew Keightley, Adam A. Lopez, Conner W. Hall and Peter Koulen

Int. J. Mol. Sci. 2024, 25(20), 10893; https://doi.org/10.3390/ijms252010893 - 10 Oct 2024

Abstract

Age-related macular degeneration (AMD) is the most prevalent ocular disease in the elderly, resulting in blindness. Oxidative stress plays a role in retinal pigment epithelium (RPE) pathology observed in AMD. Tocopherols are potent antioxidants that prevent cellular oxidative damage and have been shown [...] Read more.

Age-related macular degeneration (AMD) is the most prevalent ocular disease in the elderly, resulting in blindness. Oxidative stress plays a role in retinal pigment epithelium (RPE) pathology observed in AMD. Tocopherols are potent antioxidants that prevent cellular oxidative damage and have been shown to upregulate the expression of cellular antioxidant proteins. Here, we determined whether oxidative stress and tocopherols, using either normal cellular conditions or conditions of sublethal cellular oxidative stress, alter the expression of proteins mediating sterol uptake, transport, and metabolism. Human telomerase transcriptase-overexpressing RPE cells (hTERT-RPE) were used to identify differential expression of proteins resulting from treatments. We utilized a proteomics strategy to identify protein expression changes in treated cells. After the identification and organization of data, we divided the identified proteins into groups related to biological function: cellular sterol uptake, sterol transport and sterol metabolism. Exposure of cells to conditions of oxidative stress and exposure to tocopherols led to similar protein expression changes within these three groups, suggesting that α-tocopherol (αT) and γ-tocopherol (γT) can regulate the expression of sterol uptake, transport and metabolic proteins in RPE cells. These data suggest that proteins involved in sterol transport and metabolism may be important for RPE adaptation to oxidative stress, and these proteins represent potential therapeutic targets. Full article

(This article belongs to the Special Issue Retinal Diseases: From Molecular Pathology to Therapies—2nd Edition)

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14 pages, 2272 KiB

Open AccessArticle

Functional and Physiological Characterization of Tyrosine Decarboxylases from Olea europaea L. Involved in the Synthesis of the Main Phenolics in Olive Fruit and Virgin Olive Oil

by Pilar Luaces, Rosario Sánchez, Jesús Expósito, Antonio J. Pérez-Pulido, Ana G. Pérez and Carlos Sanz

Int. J. Mol. Sci. 2024, 25(20), 10892; https://doi.org/10.3390/ijms252010892 - 10 Oct 2024

Abstract

The phenolic composition of virgin olive oil (VOO) primarily depends on the phenolic content of the olive fruit. The purpose of this work was to characterize the first metabolic step in the synthesis of tyrosol (Ty) and hydroxytyrosol (HTy), whose derivatives are by [...] Read more.

The phenolic composition of virgin olive oil (VOO) primarily depends on the phenolic content of the olive fruit. The purpose of this work was to characterize the first metabolic step in the synthesis of tyrosol (Ty) and hydroxytyrosol (HTy), whose derivatives are by far the predominant phenolics in both olive fruit and VOO. To this end, two genes encoding tyrosine/DOPA decarboxylase enzymes, OeTDC1 and OeTDC2, have been identified and functionally and physiologically characterized. Both olive TDC proteins exclusively accept aromatic amino acids with phenolic side chains, such as tyrosine and 3,4-dihydroxyphenylalanine (DOPA), as substrates to produce tyramine and dopamine, respectively. These proteins exhibited a higher affinity for DOPA than for tyrosine, and the catalytic efficiency of both proteins was greater when DOPA was used as a substrate. Both olive TDC genes showed a fairly similar expression profile during olive fruit ontogeny, with OeTDC1 consistently expressed at higher levels than OeTDC2. Expression was particularly intense during the first few weeks after fruit set, coinciding with the active accumulation of Ty and HTy derivatives. The data suggest that both olive TDCs are responsible for the initial step in the synthesis of the most important phenolics, both quantitatively and functionally, in VOO. Full article

(This article belongs to the Special Issue Molecular and Metabolic Regulation of Plant Secondary Metabolism)

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Int. J. Mol. Sci., Volume 25, Issue 20 (October-2 2024) – 53 articles

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