International Journal of Molecular Sciences

30 pages, 2626 KiB

Open AccessReview

Urtica dioica: Anticancer Properties and Other Systemic Health Benefits from In Vitro to Clinical Trials

by Marc Abi Sleiman, Maria Younes, Roy Hajj, Tommy Salameh, Samir Abi Rached, Rimane Abi Younes, Lynn Daoud, Jean Louis Doumiati, Francesca Frem, Ramza Ishak, Christopher Medawar, Hassan Y. Naim and Sandra Rizk

Int. J. Mol. Sci. 2024, 25(13), 7501; https://doi.org/10.3390/ijms25137501 - 8 Jul 2024

Cited by 3 | Viewed by 3252

Abstract

While conventional medicine has advanced in recent years, there are still concerns about its potential adverse reactions. The ethnopharmacological knowledge established over many centuries and the existence of a variety of metabolites have made medicinal plants, such as the stinging nettle plant, an [...] Read more.

While conventional medicine has advanced in recent years, there are still concerns about its potential adverse reactions. The ethnopharmacological knowledge established over many centuries and the existence of a variety of metabolites have made medicinal plants, such as the stinging nettle plant, an invaluable resource for treating a wide range of health conditions, considering its minimal adverse effects on human health. The aim of this review is to highlight the therapeutic benefits and biological activities of the edible Urtica dioica (UD) plant with an emphasis on its selective chemo-preventive properties against various types of cancer, whereby we decipher the mechanism of action of UD on various cancers including prostate, breast, leukemia, and colon in addition to evaluating its antidiabetic, microbial, and inflammatory properties. We further highlight the systemic protective effects of UD on the liver, reproductive, excretory, cardiovascular, nervous, and digestive systems. We present a critical assessment of the results obtained from in vitro and in vivo studies as well as clinical trials to highlight the gaps that require further exploration for future prospective studies. Full article

(This article belongs to the Special Issue Health Promoting Benefits of Natural Products and Functional Foods)

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21 pages, 10677 KiB

Open AccessArticle

TLR Agonists Modify NK Cell Activation and Increase Its Cytotoxicity in Acute Lymphoblastic Leukemia

by Janet Gallardo-Zapata, Erandi Pérez-Figueroa, Víctor Olivar-López, Aurora Medina-Sansón, Elva Jiménez-Hernández, Enrique Ortega and Carmen Maldonado-Bernal

Int. J. Mol. Sci. 2024, 25(13), 7500; https://doi.org/10.3390/ijms25137500 - 8 Jul 2024

Viewed by 1526

Abstract

Natural killer (NK) cells play a crucial role in innate immunity, particularly in combating infections and tumors. However, in hematological cancers, NK cells often exhibit impaired functions. Therefore, it is very important to activate its endosomal Toll-like receptors (TLRs) as a potential strategy [...] Read more.

Natural killer (NK) cells play a crucial role in innate immunity, particularly in combating infections and tumors. However, in hematological cancers, NK cells often exhibit impaired functions. Therefore, it is very important to activate its endosomal Toll-like receptors (TLRs) as a potential strategy to restore its antitumor activity. We stimulated NK cells from the peripheral blood mononuclear cells from children with acute lymphoblastic leukemia and NK cells isolated, and the NK cells were stimulated with specific TLR ligands (Poly I:C, Imiquimod, R848, and ODN2006) and we evaluated changes in IFN-γ, CD107a, NKG2D, NKp44 expression, Granzyme B secretion, cytokine/chemokine release, and cytotoxic activity. Results revealed that Poly I:C and Imiquimod enhanced the activation of both immunoregulatory and cytotoxic NK cells, increasing IFN-γ, CD107a, NKG2D, and NKp44 expression. R848 activated immunoregulatory NK cells, while ODN2006 boosted CD107a, NKp44, NKG2D, and IFN-γ secretion in cytotoxic NK cells. R848 also increased the secretion of seven cytokines/chemokines. Importantly, R848 and ODN 2006 significantly improved cytotoxicity against leukemic cells. Overall, TLR stimulation enhances NK cell activation, suggesting TLR8 (R848) and TLR9 (ODN 2006) ligands as promising candidates for antitumor immunotherapy. Full article

(This article belongs to the Section Molecular Immunology)

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18 pages, 4484 KiB

Open AccessArticle

KL-Biome (Postbiotic Formulation of Lactiplantibacillus plantarum KM2) Improves Dexamethasone-Induced Muscle Atrophy in Mice

by Yu-Jin Jeong, Jong-Hoon Kim, Ye-Jin Jung, Mi-Sun Kwak, Moon-Hee Sung and Jee-Young Imm

Int. J. Mol. Sci. 2024, 25(13), 7499; https://doi.org/10.3390/ijms25137499 - 8 Jul 2024

Viewed by 1317

Abstract

Sarcopenia refers to an age-related decrease in muscle mass and strength. The gut–muscle axis has been proposed as a promising target to alleviate muscle atrophy. The effect of KL-Biome—a postbiotic preparation comprising heat-killed Lactiplantibacillus plantarum KM-2, its metabolites, and an excipient (soybean powder)—on [...] Read more.

Sarcopenia refers to an age-related decrease in muscle mass and strength. The gut–muscle axis has been proposed as a promising target to alleviate muscle atrophy. The effect of KL-Biome—a postbiotic preparation comprising heat-killed Lactiplantibacillus plantarum KM-2, its metabolites, and an excipient (soybean powder)—on muscle atrophy was evaluated using dexamethasone (DEX)-induced atrophic C2C12 myoblasts and C57BL/6J mice. KL-Biome significantly downregulated the expression of genes (Atrogin-1 and MuRF1) associated with skeletal muscle degradation but increased the anabolic phosphorylation of FoxO3a, Akt, and mTOR in C2C12 cells. Oral administration of KL-Biome (900 mg/kg) for 8 weeks significantly improved muscle mass, muscle function, and serum lactate dehydrogenase levels in DEX-treated mice. KL-Biome administration increased gut microbiome diversity and reversed DEX-mediated gut microbiota alterations. Furthermore, it significantly increased the relative abundances of the genera Subdologranulum, Alistipes, and Faecalibacterium prausnitzii, which are substantially involved in short-chain fatty acid production. These findings suggest that KL-Biome exerts beneficial effects on muscle atrophy by regulating gut microbiota. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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36 pages, 907 KiB

Open AccessReview

Non-Coding RNAs of Mitochondrial Origin: Roles in Cell Division and Implications in Cancer

by Roberto Piergentili and Stefano Sechi

Int. J. Mol. Sci. 2024, 25(13), 7498; https://doi.org/10.3390/ijms25137498 - 8 Jul 2024

Viewed by 1814

Abstract

Non-coding RNAs (ncRNAs) are a heterogeneous group, in terms of structure and sequence length, consisting of RNA molecules that do not code for proteins. These ncRNAs have a central role in the regulation of gene expression and are virtually involved in every process [...] Read more.

Non-coding RNAs (ncRNAs) are a heterogeneous group, in terms of structure and sequence length, consisting of RNA molecules that do not code for proteins. These ncRNAs have a central role in the regulation of gene expression and are virtually involved in every process analyzed, ensuring cellular homeostasis. Although, over the years, much research has focused on the characterization of non-coding transcripts of nuclear origin, improved bioinformatic tools and next-generation sequencing (NGS) platforms have allowed the identification of hundreds of ncRNAs transcribed from the mitochondrial genome (mt-ncRNA), including long non-coding RNA (lncRNA), circular RNA (circRNA), and microRNA (miR). Mt-ncRNAs have been described in diverse cellular processes such as mitochondrial proteome homeostasis and retrograde signaling; however, the function of the majority of mt-ncRNAs remains unknown. This review focuses on a subgroup of human mt-ncRNAs whose dysfunction is associated with both failures in cell cycle regulation, leading to defects in cell growth, cell proliferation, and apoptosis, and the development of tumor hallmarks, such as cell migration and metastasis formation, thus contributing to carcinogenesis and tumor development. Here we provide an overview of the mt-ncRNAs/cancer relationship that could help the future development of new biomedical applications in the field of oncology. Full article

(This article belongs to the Special Issue Cell Division: A Focus on Molecular Mechanisms)

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23 pages, 6068 KiB

Open AccessArticle

Chalcogen Noncovalent Interactions between Diazines and Sulfur Oxides in Supramolecular Circular Chains

by Emna Rahali, Zahra Noori, Youssef Arfaoui and Jordi Poater

Int. J. Mol. Sci. 2024, 25(13), 7497; https://doi.org/10.3390/ijms25137497 - 8 Jul 2024

Viewed by 803

Abstract

The noncovalent chalcogen interaction between SO₂/SO₃ and diazines was studied through a dispersion-corrected DFT Kohn–Sham molecular orbital together with quantitative energy decomposition analyses. For this, supramolecular circular chains of up to 12 molecules were built with the aim of checking [...] Read more.

The noncovalent chalcogen interaction between SO₂/SO₃ and diazines was studied through a dispersion-corrected DFT Kohn–Sham molecular orbital together with quantitative energy decomposition analyses. For this, supramolecular circular chains of up to 12 molecules were built with the aim of checking the capability of diazine molecules to detect SO₂/SO₃ compounds within the atmosphere. Trends in the interaction energies with the increasing number of molecules are mainly determined by the Pauli steric repulsion involved in these σ-hole/π-hole interactions. But more importantly, despite the assumed electrostatic nature of the involved interactions, the covalent component also plays a determinant role in its strength in the involved chalcogen bonds. Noticeably, π-hole interactions are supported by the charge transfer from diazines to SO₂/SO₃ molecules. Interaction energies in these supramolecular complexes are not only determined by the S···N bond lengths but attractive electrostatic and orbital interactions also determine the trends. These results should allow us to establish the fundamental characteristics of chalcogen bonding based on its strength and nature, which is of relevance for the capture of sulfur oxides. Full article

(This article belongs to the Special Issue Noncovalent Interactions and Applications in Materials and Catalysis)

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29 pages, 3304 KiB

Open AccessArticle

Inhibition of Indoleamine 2,3-Dioxygenase Exerts Antidepressant-like Effects through Distinct Pathways in Prelimbic and Infralimbic Cortices in Rats under Intracerebroventricular Injection with Streptozotocin

by Yu Qin, Xiao Hu, Hui-Ling Zhao, Nurhumar Kurban, Xi Chen, Jing-Kun Yi, Yuan Zhang, Su-Ying Cui and Yong-He Zhang

Int. J. Mol. Sci. 2024, 25(13), 7496; https://doi.org/10.3390/ijms25137496 - 8 Jul 2024

Cited by 1 | Viewed by 1437

Abstract

The application of intracerebroventricular injection of streptozotocin (ICV-STZ) is considered a useful animal model to mimic the onset and progression of sporadic Alzheimer’s disease (sAD). In rodents, on day 7 of the experiment, the animals exhibit depression-like behaviors. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting [...] Read more.

The application of intracerebroventricular injection of streptozotocin (ICV-STZ) is considered a useful animal model to mimic the onset and progression of sporadic Alzheimer’s disease (sAD). In rodents, on day 7 of the experiment, the animals exhibit depression-like behaviors. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme catalyzing the conversion of tryptophan (Trp) to kynurenine (Kyn), is closely related to depression and AD. The present study aimed to investigate the pathophysiological mechanisms of preliminary depression-like behaviors in ICV-STZ rats in two distinct cerebral regions of the medial prefrontal cortex, the prelimbic cortex (PrL) and infralimbic cortex (IL), both presumably involved in AD progression in this model, with a focus on IDO-related Kyn pathways. The results showed an increased Kyn/Trp ratio in both the PrL and IL of ICV-STZ rats, but, intriguingly, abnormalities in downstream metabolic pathways were different, being associated with distinct biological effects. In the PrL, the neuroprotective branch of the Kyn pathway was attenuated, as evidenced by a decrease in the kynurenic acid (KA) level and Kyn aminotransferase II (KAT II) expression, accompanied by astrocyte alterations, such as the decrease in glial fibrillary acidic protein (GFAP)-positive cells and increase in morphological damage. In the IL, the neurotoxicogenic branch of the Kyn pathway was enhanced, as evidenced by an increase in the 3-hydroxy-kynurenine (3-HK) level and kynurenine 3-monooxygenase (KMO) expression paralleled by the overactivation of microglia, reflected by an increase in ionized calcium-binding adaptor molecule 1 (Iba1)-positive cells and cytokines with morphological alterations. Synaptic plasticity was attenuated in both subregions. Additionally, microinjection of the selective IDO inhibitor 1-Methyl-DL-tryptophan (1-MT) in the PrL or IL alleviated depression-like behaviors by reversing these different abnormalities in the PrL and IL. These results suggest that the antidepressant-like effects linked to Trp metabolism changes induced by 1-MT in the PrL and IL occur through different pathways, specifically by enhancing the neuroprotective branch in the PrL and attenuating the neurotoxicogenic branch in the IL, involving distinct glial cells. Full article

(This article belongs to the Special Issue Molecular Research on Mental Disorders 2.0)

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18 pages, 3089 KiB

Open AccessReview

Survival Difference of Endometrial Cancer Patients with Peritoneal Metastasis Receiving Cytoreductive Surgery (CRS) with and without Hyperthermic Intraperitoneal Chemotherapy (HIPEC): A Systematic Review and Meta-Analysis

by Ivan Panczel, Miklos Acs, Magdolna Herold, Viktor Madar-Dank, Pompiliu Piso, Hans Jürgen Schlitt, Magdolna Dank, Attila Marcell Szasz and Zoltan Herold

Int. J. Mol. Sci. 2024, 25(13), 7495; https://doi.org/10.3390/ijms25137495 - 8 Jul 2024

Viewed by 1392

Abstract

Although several studies have been completed to investigate the effect of cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) in endometrial cancer with peritoneal metastasis (ECPM), a direct comparison was not performed previously. A meta-analysis was performed to investigate the suspected [...] Read more.

Although several studies have been completed to investigate the effect of cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) in endometrial cancer with peritoneal metastasis (ECPM), a direct comparison was not performed previously. A meta-analysis was performed to investigate the suspected additional survival benefits of CRS plus HIPEC over CRS only. Twenty-one and ten studies with a total number of 1116 and 152 cases investigating CRS only and CRS plus HIPEC were identified, respectively. When all articles were analyzed, the 1-year survival rate was 17.60% higher for CRS plus HIPEC (82.28% vs. 64.68%; p = 0.0102). The same tendency was observed for the 2-year (56.07% vs. 36.95%; difference: 19.12%; p = 0.0014), but not for the 5-year (21.88% vs. 16.45%; difference: 5.43%; p = 0.3918) survival rates. The same clinical significance, but statistically less strong observations, could be made if only the studies published after 2010 were investigated (1-year survival rate: 12.08% and p = 0.0648; 2-year survival rate: 10.90% and p = 0.0988). CRS remains one of the core elements of ECPM treatment, but the addition of HIPEC to CRS can increase the positive clinical outcome, especially in the first 2 years. Full article

(This article belongs to the Special Issue Novel Therapeutic Targets of Solid Cancer)

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21 pages, 9743 KiB

Open AccessArticle

Metformin Prevents Tumor Cell Growth and Invasion of Human Hormone Receptor-Positive Breast Cancer (HR+ BC) Cells via FOXA1 Inhibition

by Christine Song, Dawa Jung, Ayse Tuba Kendi, Jin Kyung Rho, Eun-Joo Kim, Ian Horn, Geoffry L. Curran, Sujala Ghattamaneni, Ji Yeon Shim, Pil Soo Kang, Daehun Kang, Jay B. Thakkar, Sannidhi Dewan, Val J. Lowe and Seung Baek Lee

Int. J. Mol. Sci. 2024, 25(13), 7494; https://doi.org/10.3390/ijms25137494 - 8 Jul 2024

Viewed by 1554

Abstract

Women with type 2 diabetes (T2D) have a higher risk of being diagnosed with breast cancer and have worse survival than non-diabetic women if they do develop breast cancer. However, more research is needed to elucidate the biological underpinnings of these relationships. Here, [...] Read more.

Women with type 2 diabetes (T2D) have a higher risk of being diagnosed with breast cancer and have worse survival than non-diabetic women if they do develop breast cancer. However, more research is needed to elucidate the biological underpinnings of these relationships. Here, we found that forkhead box A1 (FOXA1), a forkhead family transcription factor, and metformin (1,1-dimethylbiguanide hydrochloride), a medication used to treat T2D, may impact hormone-receptor-positive (HR+) breast cancer (BC) tumor cell growth and metastasis. Indeed, fourteen diabetes-associated genes are highly expressed in only three HR+ breast cancer cell lines but not the other subtypes utilizing a 53,805 gene database obtained from NCBI GEO. Among the diabetes-related genes, FOXA1, MTA3, PAK4, FGFR3, and KIF22 were highly expressed in HR+ breast cancer from 4032 breast cancer patient tissue samples using the Breast Cancer Gene Expression Omnibus. Notably, elevated FOXA1 expression correlated with poorer overall survival in patients with estrogen-receptor-positive/progesterone-receptor-positive (ER+/PR+) breast cancer. Furthermore, experiments demonstrated that loss of the FOXA1 gene inhibited tumor proliferation and invasion in vitro using MCF-7 and T47D HR+ breast cancer cell lines. Metformin, an anti-diabetic medication, significantly suppressed tumor cell growth in MCF-7 cells. Additionally, either metformin treatment or FOXA1 gene deletion enhanced tamoxifen-induced tumor growth inhibition in HR+ breast cancer cell lines within an ex vivo three-dimensional (3D) organoid model. Therefore, the diabetes-related medicine metformin and FOXA1 gene inhibition might be a new treatment for patients with HR+ breast cancer when combined with tamoxifen, an endocrine therapy. Full article

(This article belongs to the Special Issue Cell and Molecular Perspectives in Breast Cancer)

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24 pages, 7137 KiB

Open AccessArticle

Quantitative Proteomic Analysis of Macrophages Infected with Trypanosoma cruzi Reveals Different Responses Dependent on the SLAMF1 Receptor and the Parasite Strain

by Alfonso Herreros-Cabello, Javier del Moral-Salmoral, Esperanza Morato, Anabel Marina, Beatriz Barrocal, Manuel Fresno and Núria Gironès

Int. J. Mol. Sci. 2024, 25(13), 7493; https://doi.org/10.3390/ijms25137493 - 8 Jul 2024

Viewed by 974

Abstract

Chagas disease is caused by the intracellular protozoan parasite Trypanosoma cruzi. This disease affects mainly rural areas in Central and South America, where the insect vector is endemic. However, this disease has become a world health problem since migration has spread it [...] Read more.

Chagas disease is caused by the intracellular protozoan parasite Trypanosoma cruzi. This disease affects mainly rural areas in Central and South America, where the insect vector is endemic. However, this disease has become a world health problem since migration has spread it to other continents. It is a complex disease with many reservoirs and vectors and high genetic variability. One of the host proteins involved in the pathogenesis is SLAMF1. This immune receptor acts during the infection of macrophages controlling parasite replication and thus affecting survival in mice but in a parasite strain-dependent manner. Therefore, we studied the role of SLAMF1 by quantitative proteomics in a macrophage in vitro infection and the different responses between Y and VFRA strains of Trypanosoma cruzi. We detected different significant up- or downregulated proteins involved in immune regulation processes, which are SLAMF1 and/or strain-dependent. Furthermore, independently of SLAMF1, this parasite induces different responses in macrophages to counteract the infection and kill the parasite, such as type I and II IFN responses, NLRP3 inflammasome activation, IL-18 production, TLR7 and TLR9 activation specifically with the Y strain, and IL-11 signaling specifically with the VFRA strain. These results have opened new research fields to elucidate the concrete role of SLAMF1 and discover new potential therapeutic approaches for Chagas disease. Full article

(This article belongs to the Section Molecular Microbiology)

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19 pages, 5547 KiB

Open AccessArticle

Small and Large Extracellular Vesicles of Porcine Seminal Plasma Differ in Lipid Profile

by Pablo Martínez-Díaz, Ana Parra, Christian M. Sanchez-López, Josefina Casas, Xiomara Lucas, Antonio Marcilla, Jordi Roca and Isabel Barranco

Int. J. Mol. Sci. 2024, 25(13), 7492; https://doi.org/10.3390/ijms25137492 - 8 Jul 2024

Cited by 1 | Viewed by 907

Abstract

Seminal plasma contains a heterogeneous population of extracellular vesicles (sEVs) that remains poorly characterized. This study aimed to characterize the lipidomic profile of two subsets of differently sized sEVs, small (S-) and large (L-), isolated from porcine seminal plasma by size-exclusion chromatography and [...] Read more.

Seminal plasma contains a heterogeneous population of extracellular vesicles (sEVs) that remains poorly characterized. This study aimed to characterize the lipidomic profile of two subsets of differently sized sEVs, small (S-) and large (L-), isolated from porcine seminal plasma by size-exclusion chromatography and characterized by an orthogonal approach. High-performance liquid chromatography–high-resolution mass spectrometry was used for lipidomic analysis. A total of 157 lipid species from 14 lipid classes of 4 major categories (sphingolipids, glycerophospholipids, glycerolipids, and sterols) were identified. Qualitative differences were limited to two cholesteryl ester species present only in S-sEVs. L-sEVs had higher levels of all quantified lipid classes due to their larger membrane surface area. The distribution pattern was different, especially for sphingomyelins (more in S-sEVs) and ceramides (more in L-sEVs). In conclusion, this study reveals differences in the lipidomic profile of two subsets of porcine sEVs, suggesting that they differ in biogenesis and functionality. Full article

(This article belongs to the Special Issue New Progress in Extracellular Vesicles)

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20 pages, 9507 KiB

Open AccessArticle

Insects as a Prospective Source of Biologically Active Molecules and Pharmaceuticals—Biochemical Properties and Cell Toxicity of Tenebrio molitor and Zophobas morio Cell-Free Larval Hemolymph

by Teodora Knežić, Miloš Avramov, Vanja Tatić, Miloš Petrović, Ivana Gadjanski and Željko D. Popović

Int. J. Mol. Sci. 2024, 25(13), 7491; https://doi.org/10.3390/ijms25137491 - 8 Jul 2024

Cited by 2 | Viewed by 1436

Abstract

Insects are of great interest as novel sources of alternative proteins and biologically active compounds, primarily anticancer agents. Protein-rich insect larval hemolymph is a prospective candidate for pharmaceutical and food industry-related research. In this study, selected biochemical properties and cell toxicity of larval [...] Read more.

Insects are of great interest as novel sources of alternative proteins and biologically active compounds, primarily anticancer agents. Protein-rich insect larval hemolymph is a prospective candidate for pharmaceutical and food industry-related research. In this study, selected biochemical properties and cell toxicity of larval hemolymph from two mealworm species, Tenebrio molitor and Zophobas morio, were analyzed. Total proteins and carbohydrates, antioxidant capacity, and the level of lipid peroxidation were determined. Human cancer (U-87) and normometabolic (MRC-5) cells were treated with different concentrations of larval hemolymph proteins, and the effects on cell viability were assayed 24, 48, and 72 h after treatments. Z. morio hemolymph was shown to be richer in total proteins, showing a higher antioxidant capacity and lipid peroxidation level than T. molitor hemolymph, which was richer in total carbohydrates. Cytotoxicity assays showed that T. molitor and Z. morio hemolymphs differently affect the viability of U-87 and MRC-5 cells in cell type-, dose-, and time-dependent manners. Hemolymph from both species was more cytotoxic to U-87 cells than to MRC-5 cells, which was particularly prominent after 48 h. Additionally, a more potent cytotoxic effect of Z. morio hemolymph was observed on both cell lines, likely due to its higher antioxidant capacity, compared to T. molitor hemolymph. Full article

(This article belongs to the Special Issue Insects and Their Derived Products: Emerging Themes and Future Research Directions)

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11 pages, 2048 KiB

Open AccessArticle

Unveiling the Cutting-Edge Impact of Polarized Macrophage-Derived Extracellular Vesicles and MiRNA Signatures on TGF-β Regulation within Lung Fibroblasts

by Alvise Casara, Maria Conti, Nicol Bernardinello, Mariaenrica Tinè, Simonetta Baraldo, Graziella Turato, Umberto Semenzato, Alessandro Celi, Paolo Spagnolo, Marina Saetta, Manuel G. Cosio, Tommaso Neri, Davide Biondini and Erica Bazzan

Int. J. Mol. Sci. 2024, 25(13), 7490; https://doi.org/10.3390/ijms25137490 - 8 Jul 2024

Viewed by 841

Abstract

Depending on local cues, macrophages can polarize into classically activated (M1) or alternatively activated (M2) phenotypes. This study investigates the impact of polarized macrophage-derived Extracellular Vesicles (EVs) (M1 and M2) and their cargo of miRNA-19a-3p and miRNA-425-5p on TGF-β production in lung fibroblasts. [...] Read more.

Depending on local cues, macrophages can polarize into classically activated (M1) or alternatively activated (M2) phenotypes. This study investigates the impact of polarized macrophage-derived Extracellular Vesicles (EVs) (M1 and M2) and their cargo of miRNA-19a-3p and miRNA-425-5p on TGF-β production in lung fibroblasts. EVs were isolated from supernatants of M0, M1, and M2 macrophages and quantified using nanoscale flow cytometry prior to fibroblast stimulation. The concentration of TGF-β in fibroblast supernatants was measured using ELISA assays. The expression levels of miRNA-19a-3p and miRNA-425-5p were assessed via TaqMan-qPCR. TGF-β production after stimulation with M0-derived EVs and with M1-derived EVs increased significantly compared to untreated fibroblasts. miRNA-425-5p, but not miRNA-19a-3p, was significantly upregulated in M2-derived EVs compared to M0- and M1-derived EVs. This study demonstrates that EVs derived from both M0 and M1 polarized macrophages induce the production of TGF-β in fibroblasts, with potential regulation by miRNA-425-5p. Full article

(This article belongs to the Special Issue Cutting-Edge Research and Applications of Extracellular Microvesicles in Disease Management)

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18 pages, 4866 KiB

Open AccessArticle

Deficiency of ValRS-m Causes Male Infertility in Drosophila melanogaster

by Xin Duan, Haolin Wang, Zhixian Cao, Na Su, Yufeng Wang and Ya Zheng

Int. J. Mol. Sci. 2024, 25(13), 7489; https://doi.org/10.3390/ijms25137489 - 8 Jul 2024

Viewed by 950

Abstract

Drosophila spermatogenesis involves the renewal of germline stem cells, meiosis of spermatocytes, and morphological transformation of spermatids into mature sperm. We previously demonstrated that Ocnus (ocn) plays an essential role in spermatogenesis. The ValRS-m (Valyl-tRNA synthetase, mitochondrial) gene [...] Read more.

Drosophila spermatogenesis involves the renewal of germline stem cells, meiosis of spermatocytes, and morphological transformation of spermatids into mature sperm. We previously demonstrated that Ocnus (ocn) plays an essential role in spermatogenesis. The ValRS-m (Valyl-tRNA synthetase, mitochondrial) gene was down-regulated in ocn RNAi testes. Here, we found that ValRS-m-knockdown induced complete sterility in male flies. The depletion of ValRS-m blocked mitochondrial behavior and ATP synthesis, thus inhibiting the transition from spermatogonia to spermatocytes, and eventually, inducing the accumulation of spermatogonia during spermatogenesis. To understand the intrinsic reason for this, we further conducted transcriptome-sequencing analysis for control and ValRS-m-knockdown testes. The differentially expressed genes (DEGs) between these two groups were selected with a fold change of ≥2 or ≤1/2. Compared with the control group, 4725 genes were down-regulated (dDEGs) and 2985 genes were up-regulated (uDEGs) in the ValRS-m RNAi group. The dDEGs were mainly concentrated in the glycolytic pathway and pyruvate metabolic pathway, and the uDEGs were primarily related to ribosomal biogenesis. A total of 28 DEGs associated with mitochondria and 6 meiosis-related genes were verified to be suppressed when ValRS-m was deficient. Overall, these results suggest that ValRS-m plays a wide and vital role in mitochondrial behavior and spermatogonia differentiation in Drosophila. Full article

(This article belongs to the Special Issue Signaling Molecules Involved in Gametes Development, Differentiation and Fertilization, 2nd Edition)

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17 pages, 1089 KiB

Open AccessArticle

Gene Expression and Phenotypic Assessment of Egg Quality across Developmental Stages of Atlantic Cod throughout the Spawning Season

by María Fernández Míguez, Pablo Presa, Velmurugu Puvanendran, Helge Tveiten, Øyvind J. Hansen and Montse Pérez

Int. J. Mol. Sci. 2024, 25(13), 7488; https://doi.org/10.3390/ijms25137488 - 8 Jul 2024

Viewed by 1000

Abstract

Egg quality in fishes is commonly determined by fertilisation success and cleavage patterns as a phenotypic outcome of underlying regulatory mechanisms. Although these phenotypic estimators of egg quality are useful in farming conditions, these “good quality” egg batches do not always translate to [...] Read more.

Egg quality in fishes is commonly determined by fertilisation success and cleavage patterns as a phenotypic outcome of underlying regulatory mechanisms. Although these phenotypic estimators of egg quality are useful in farming conditions, these “good quality” egg batches do not always translate to good larval growth and survival. The identification of genes involved in embryonic development may help find links between genetic factors of maternal origin and egg quality. Herein, the relative expression of seven stage-specific developmental genes of Atlantic cod was analysed using quantitative PCR to understand the function during embryogenesis and its relationship with egg quality. Genes ccnb2 and pvalb1 showed significant differential expression between developmental stages and significant upregulation from blastula and somite stages, respectively. The comparison of spawning batches showed that the relative gene expression of genes ccnb2, acta, tnnt3 and pvalb1 was significantly higher from the middle of the spawning season where phenotypic quality estimators establish the best egg quality. Moreover, a positive significant correlation was observed between quality estimators based on egg morphology and the genetic expression of genes acta and acta1 during somitogenesis. This study suggests that the combination of quality estimators, genetics and batch timing could help optimise reproductive protocols for commercial stocks of Atlantic cod. Full article

(This article belongs to the Special Issue Fish Gamete and Embryo Quality: Molecular Advances and Biotechnological Applications)

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13 pages, 8437 KiB

Open AccessArticle

Altered Inflammatory State and Mitochondrial Function Identified by Transcriptomics in Paediatric Congenital Heart Patients Prior to Surgical Repair

by Francesca Bartoli-Leonard, Amy G. Harris, Kelly Saunders, Julie Madden, Carrie Cherrington, Karen Sheehan, Mai Baquedano, Giulia Parolari, Andrew Bamber and Massimo Caputo

Int. J. Mol. Sci. 2024, 25(13), 7487; https://doi.org/10.3390/ijms25137487 - 8 Jul 2024

Viewed by 929

Abstract

Congenital heart disease (CHD) remains the most common birth defect, with surgical intervention required in complex cases. Right ventricle (RV) function is known to be a major predictor of sustained cardiac health in these patients; thus, by elucidating the divergent profiles between CHD [...] Read more.

Congenital heart disease (CHD) remains the most common birth defect, with surgical intervention required in complex cases. Right ventricle (RV) function is known to be a major predictor of sustained cardiac health in these patients; thus, by elucidating the divergent profiles between CHD and the control through tissue analysis, this study aims to identify new avenues of investigation into the mechanisms surrounding reduced RV function. Transcriptomic profiling, in-silico deconvolution and functional network analysis were conducted on RV biopsies, identifying an increase in the mitochondrial dysfunction genes RPPH1 and RMPR (padj = 4.67 × 10⁻¹³², 2.23 × 10⁻¹⁰⁷), the cytotoxic T-cell markers CD8a, LAGE3 and CD49a (p = 0.0006, p < 0.0001, and p = 0.0118) and proinflammatory caspase-1 (p = 0.0055) in CHD. Gene-set enrichment identified mitochondrial dysfunctional pathways, predominately changes within oxidative phosphorylation processes. The negative regulation of mitochondrial functions and metabolism was identified in the network analysis, with dysregulation of the mitochondrial complex formation. A histological analysis confirmed an increase in cellular bodies in the CHD RV tissue and positive staining for both CD45 and CD8, which was absent in the control. The deconvolution of bulk RNAseq data suggests a reduction in CD4+ T cells (p = 0.0067) and an increase in CD8+ T cells (p = 0.0223). The network analysis identified positive regulation of the immune system and cytokine signalling clusters in the inflammation functional network, as there were lymphocyte activation and leukocyte differentiation. Utilising RV tissue from paediatric patients undergoing CHD cardiac surgery, this study identifies dysfunctional mitochondrial pathways and an increase in inflammatory T-cell presence prior to reparative surgery. Full article

(This article belongs to the Special Issue RNA-Seq in Human Health and Disease)

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13 pages, 3538 KiB

Open AccessArticle

The Long-Distance Transport of Jasmonates in Salt-Treated Pea Plants and Involvement of Lipid Transfer Proteins in the Process

by Gulnara Vafina, Guzel Akhiyarova, Alla Korobova, Ekaterina I. Finkina, Dmitry Veselov, Tatiana V. Ovchinnikova and Guzel Kudoyarova

Int. J. Mol. Sci. 2024, 25(13), 7486; https://doi.org/10.3390/ijms25137486 - 8 Jul 2024

Viewed by 821

Abstract

The adaption of plants to stressful environments depends on long-distance responses in plant organs, which themselves are remote from sites of perception of external stimuli. Jasmonic acid (JA) and its derivatives are known to be involved in plants’ adaptation to salinity. However, to [...] Read more.

The adaption of plants to stressful environments depends on long-distance responses in plant organs, which themselves are remote from sites of perception of external stimuli. Jasmonic acid (JA) and its derivatives are known to be involved in plants’ adaptation to salinity. However, to our knowledge, the transport of JAs from roots to shoots has not been studied in relation to the responses of shoots to root salt treatment. We detected a salt-induced increase in the content of JAs in the roots, xylem sap, and leaves of pea plants related to changes in transpiration. Similarities between the localization of JA and lipid transfer proteins (LTPs) around vascular tissues were detected with immunohistochemistry, while immunoblotting revealed the presence of LTPs in the xylem sap of pea plants and its increase with salinity. Furthermore, we compared the effects of exogenous MeJA and salt treatment on the accumulation of JAs in leaves and their impact on transpiration. Our results indicate that salt-induced changes in JA concentrations in roots and xylem sap are the source of accumulation of these hormones in leaves leading to associated changes in transpiration. Furthermore, they suggest the possible involvement of LTPs in the loading/unloading of JAs into/from the xylem and its xylem transport. Full article

(This article belongs to the Special Issue Phytohormones: Important Participators in Plant Growth and Development: 2nd Edition)

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17 pages, 36014 KiB

Open AccessArticle

Hair Growth Promoting Effects of 15-Hydroxyprostaglandin Dehydrogenase Inhibitor in Human Follicle Dermal Papilla Cells

by Hye Won Lim, Hak Joong Kim, Chae Young Jeon, Yurim Lee, Mujun Kim, Jinsick Kim, Soon Re Kim, Sanghwa Lee, Dong Chul Lim, Hee Dong Park, Byung Cheol Park and Dong Wook Shin

Int. J. Mol. Sci. 2024, 25(13), 7485; https://doi.org/10.3390/ijms25137485 - 8 Jul 2024

Cited by 1 | Viewed by 1659

Abstract

Prostaglandin E₂ (PGE₂) is known to be effective in regenerating tissues, and bimatoprost, an analog of PGF_2α, has been approved by the FDA as an eyelash growth promoter and has been proven effective in human hair follicles. Thus, [...] Read more.

Prostaglandin E₂ (PGE₂) is known to be effective in regenerating tissues, and bimatoprost, an analog of PGF_2α, has been approved by the FDA as an eyelash growth promoter and has been proven effective in human hair follicles. Thus, to enhance PGE₂ levels while improving hair loss, we found dihydroisoquinolinone piperidinylcarboxy pyrazolopyridine (DPP), an inhibitor of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), using DeepZema^®, an AI-based drug development program. Here, we investigated whether DPP improved hair loss in human follicle dermal papilla cells (HFDPCs) damaged by dihydrotestosterone (DHT), which causes hair loss. We found that DPP enhanced wound healing and the expression level of alkaline phosphatase in DHT-damaged HFDPCs. We observed that DPP significantly down-regulated the generation of reactive oxygen species caused by DHT. DPP recovered the mitochondrial membrane potential in DHT-damaged HFDPCs. We demonstrated that DPP significantly increased the phosphorylation levels of the AKT/ERK and activated Wnt signaling pathways in DHT-damaged HFDPCs. We also revealed that DPP significantly enhanced the size of the three-dimensional spheroid in DHT-damaged HFDPCs and increased hair growth in ex vivo human hair follicle organ culture. These data suggest that DPP exhibits beneficial effects on DHT-damaged HFDPCs and can be utilized as a promising agent for improving hair loss. Full article

(This article belongs to the Special Issue Molecular Research Progress of Skin and Skin Diseases)

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20 pages, 2522 KiB

Open AccessArticle

Pulmonary Vascular Responses to Chronic Intermittent Hypoxia in a Guinea Pig Model of Obstructive Sleep Apnea

by Elena Olea, Esther Valverde-Pérez, Inmaculada Docio, Jesus Prieto-Lloret, Philip I. Aaronson and Asunción Rocher

Int. J. Mol. Sci. 2024, 25(13), 7484; https://doi.org/10.3390/ijms25137484 - 8 Jul 2024

Viewed by 1148

Abstract

Experimental evidence suggests that chronic intermittent hypoxia (CIH), a major hallmark of obstructive sleep apnea (OSA), boosts carotid body (CB) responsiveness, thereby causing increased sympathetic activity, arterial and pulmonary hypertension, and cardiovascular disease. An enhanced circulatory chemoreflex, oxidative stress, and NO signaling appear [...] Read more.

Experimental evidence suggests that chronic intermittent hypoxia (CIH), a major hallmark of obstructive sleep apnea (OSA), boosts carotid body (CB) responsiveness, thereby causing increased sympathetic activity, arterial and pulmonary hypertension, and cardiovascular disease. An enhanced circulatory chemoreflex, oxidative stress, and NO signaling appear to play important roles in these responses to CIH in rodents. Since the guinea pig has a hypofunctional CB (i.e., it is a natural CB knockout), in this study we used it as a model to investigate the CB dependence of the effects of CIH on pulmonary vascular responses, including those mediated by NO, by comparing them with those previously described in the rat. We have analyzed pulmonary artery pressure (PAP), the hypoxic pulmonary vasoconstriction (HPV) response, endothelial function both in vivo and in vitro, and vascular remodeling (intima–media thickness, collagen fiber content, and vessel lumen area). We demonstrate that 30 days of the exposure of guinea pigs to CIH (FiO₂, 5% for 40 s, 30 cycles/h) induces pulmonary artery remodeling but does not alter endothelial function or the contractile response to phenylephrine (PE) in these arteries. In contrast, CIH exposure increased the systemic arterial pressure and enhanced the contractile response to PE while decreasing endothelium-dependent vasorelaxation to carbachol in the aorta without causing its remodeling. We conclude that since all of these effects are independent of CB sensitization, there must be other oxygen sensors, beyond the CB, with the capacity to alter the autonomic control of the heart and vascular function and structure in CIH. Full article

(This article belongs to the Special Issue Nitric Oxide Biosynthesis Pathway and Nitric Oxide Signaling in Human Diseases)

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17 pages, 2593 KiB

Open AccessArticle

Evidence of Gas Phase Glucosyl Transfer and Glycation in the CID/HCD-Spectra of S-Glucosylated Peptides

by Alicja K. Buchowiecka

Int. J. Mol. Sci. 2024, 25(13), 7483; https://doi.org/10.3390/ijms25137483 - 8 Jul 2024

Viewed by 1067

Abstract

Protein cysteine S-glycosylation is a relatively rare and less well characterized post-translational modification (PTM). Creating reliable model proteins that carry this modification is challenging. The lack of available models or natural S-glycosylated proteins significantly hampers the development of mass-spectrometry-based (MS-based) methodologies for detecting [...] Read more.

Protein cysteine S-glycosylation is a relatively rare and less well characterized post-translational modification (PTM). Creating reliable model proteins that carry this modification is challenging. The lack of available models or natural S-glycosylated proteins significantly hampers the development of mass-spectrometry-based (MS-based) methodologies for detecting protein cysteine S-glycosylation in real-world proteomic studies. There is also limited MS-sequencing data describing it as easier to create synthetic S-glycopeptides. Here, we present the results of an in-depth manual analysis of automatically annotated CID/HCD spectra for model S-glucopeptides. The CID spectra show a long series of y/b-fragment ions with retained S-glucosylation, regardless of the dominant m/z signals corresponding to neutral loss of 1,2-anhydroglucose from the precursor ions. In addition, the spectra show signals manifesting glucosyl transfer from the cysteine position onto lysine, arginine (Lys, Arg) side chains, and a peptide N-terminus. Other spectral evidence indicates that the N-glucosylated initial products of transfer are converted into N-fructosylated (i.e., glycated) structures due to Amadori rearrangement. We discuss the peculiar transfer of the glucose oxocarbenium ion (Glc+) to positively charged guanidinium residue (ArgH+) and propose a mechanism for the gas-phase Amadori rearrangement involving a 1,2-hydride ion shift. Full article

(This article belongs to the Special Issue Molecular Advances in Analytical Techniques for Biological and Medical Research)

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17 pages, 6422 KiB

Open AccessArticle

Mechanism of Abnormal Activation of MEK1 Induced by Dehydroalanine Modification

by Yue Zhao, Shan-Shan Du, Chao-Yue Zhao, Tian-Long Li, Si-Cheng Tong and Li Zhao

Int. J. Mol. Sci. 2024, 25(13), 7482; https://doi.org/10.3390/ijms25137482 - 8 Jul 2024

Cited by 1 | Viewed by 928

Abstract

Mitogen-activated protein kinase kinase 1 (MAPK kinase 1, MEK1) is a key kinase in the mitogen-activated protein kinase (MAPK) signaling pathway. MEK1 mutations have been reported to lead to abnormal activation that is closely related to the malignant growth and spread of various [...] Read more.

Mitogen-activated protein kinase kinase 1 (MAPK kinase 1, MEK1) is a key kinase in the mitogen-activated protein kinase (MAPK) signaling pathway. MEK1 mutations have been reported to lead to abnormal activation that is closely related to the malignant growth and spread of various tumors, making it an important target for cancer treatment. Targeting MEK1, four small-molecular drugs have been approved by the FDA, including Trametinib, Cobimetinib, Binimetinib, and Selumetinib. Recently, a study showed that modification with dehydroalanine (Dha) can also lead to abnormal activation of MEK1, which has the potential to promote tumor development. In this study, we used molecular dynamics simulations and metadynamics to explore the mechanism of abnormal activation of MEK1 caused by the Dha modification and predicted the inhibitory effects of four FDA-approved MEK1 inhibitors on the Dha-modified MEK1. The results showed that the mechanism of abnormal activation of MEK1 caused by the Dha modification is due to the movement of the active segment, which opens the active pocket and exposes the catalytic site, leading to sustained abnormal activation of MEK1. Among four FDA-approved inhibitors, only Selumetinib clearly blocks the active site by changing the secondary structure of the active segment from α-helix to disordered loop. Our study will help to explain the mechanism of abnormal activation of MEK1 caused by the Dha modification and provide clues for the development of corresponding inhibitors. Full article

(This article belongs to the Special Issue Computational Simulation of Macromolecular Processes Involved in Disease)

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17 pages, 4309 KiB

Open AccessArticle

A Combined Metabolome and Transcriptome Reveals the Lignin Metabolic Pathway during the Developmental Stages of Peel Coloration in the ‘Xinyu’ Pear

by Cuicui Jiang, Keliang Lyu, Shaomin Zeng, Xiao’an Wang and Xiaoming Chen

Int. J. Mol. Sci. 2024, 25(13), 7481; https://doi.org/10.3390/ijms25137481 - 8 Jul 2024

Viewed by 879

Abstract

Sand pear is the main cultivated pear species in China, and brown peel is a unique feature of sand pear. The formation of brown peel is related to the activity of the cork layer, of which lignin is an important component. The formation [...] Read more.

Sand pear is the main cultivated pear species in China, and brown peel is a unique feature of sand pear. The formation of brown peel is related to the activity of the cork layer, of which lignin is an important component. The formation of brown peel is intimately associated with the biosynthesis and accumulation of lignin; however, the regulatory mechanism of lignin biosynthesis in pear peel remains unclear. In this study, we used a newly bred sand pear cultivar ‘Xinyu’ as the material to investigate the biosynthesis and accumulation of lignin at nine developmental stages using metabolomic and transcriptomic methods. Our results showed that the 30 days after flowering (DAF) to 50DAF were the key periods of lignin accumulation according to data analysis from the assays of lignin measurement, scanning electron microscope (SEM) observation, metabolomics, and transcriptomics. Through weighted gene co-expression network analysis (WGCNA), positively correlated modules with lignin were identified. A total of nine difference lignin components were identified and 148 differentially expressed genes (DEGs), including 10 structural genes (PAL1, C4H, two 4CL genes, HCT, CSE, two COMT genes, and two CCR genes) and MYB, NAC, ERF, and TCP transcription factor genes were involved in lignin metabolism. An analysis of RT-qPCR confirmed that these DEGs were involved in the biosynthesis and regulation of lignin. These findings further help us understand the mechanisms of lignin biosynthesis and provide a theoretical basis for peel color control and quality improvement in pear breeding and cultivation. Full article

(This article belongs to the Special Issue Molecular Genetics and Plant Breeding 4.0)

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22 pages, 1472 KiB

Open AccessArticle

Effects of Recombinant α₁-Microglobulin on Early Proteomic Response in Risk Organs after Exposure to ¹⁷⁷Lu-Octreotate

by Charlotte Ytterbrink, Emman Shubbar, Toshima Z. Parris, Britta Langen, Malin Druid, Emil Schüler, Sven-Erik Strand, Bo Åkerström, Magnus Gram, Khalil Helou and Eva Forssell-Aronsson

Int. J. Mol. Sci. 2024, 25(13), 7480; https://doi.org/10.3390/ijms25137480 - 8 Jul 2024

Viewed by 972

Abstract

Recombinant α₁-microglobulin (A1M) is proposed as a protector during ¹⁷⁷Lu-octreotate treatment of neuroendocrine tumors, which is currently limited by bone marrow and renal toxicity. Co-administration of ¹⁷⁷Lu-octreotate and A1M could result in a more effective treatment by protecting healthy [...] Read more.

Recombinant α₁-microglobulin (A1M) is proposed as a protector during ¹⁷⁷Lu-octreotate treatment of neuroendocrine tumors, which is currently limited by bone marrow and renal toxicity. Co-administration of ¹⁷⁷Lu-octreotate and A1M could result in a more effective treatment by protecting healthy tissue, but the radioprotective action of A1M is not fully understood. The aim of this study was to examine the proteomic response of kidneys and bone marrow early after ¹⁷⁷Lu-octreotate and/or A1M administration. Mice were injected with ¹⁷⁷Lu-octreotate and/or A1M, while control mice received saline or A1M vehicle solution. Bone marrow, kidney medulla, and kidney cortex were sampled after 24 h or 7 d. The differential protein expression was analyzed with tandem mass spectrometry. The dosimetric estimation was based on ¹⁷⁷Lu activity in the kidney. PHLDA3 was the most prominent radiation-responsive protein in kidney tissue. In general, no statistically significant difference in the expression of radiation-related proteins was observed between the irradiated groups. Most canonical pathways were identified in bone marrow from the ¹⁷⁷Lu-octreotate+A1M group. Altogether, a tissue-dependent proteomic response followed exposure to ¹⁷⁷Lu-octreotate alone or together with A1M. Combining ¹⁷⁷Lu-octreotate with A1M did not inhibit the radiation-induced protein expression early after exposure, and late effects should be further studied. Full article

(This article belongs to the Section Molecular Informatics)

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12 pages, 848 KiB

Open AccessArticle

Association between Visceral Adipose Tissue Metabolism and Cerebral Glucose Metabolism in Patients with Cognitive Impairment

by Mi-Hee Yu, Ji Sun Lim, Hyon-Ah Yi, Kyoung Sook Won and Hae Won Kim

Int. J. Mol. Sci. 2024, 25(13), 7479; https://doi.org/10.3390/ijms25137479 - 8 Jul 2024

Viewed by 935

Abstract

Visceral adipose tissue (VAT) dysfunction has been recently recognized as a potential contributor to the development of Alzheimer’s disease (AD). This study aimed to explore the relationship between VAT metabolism and cerebral glucose metabolism in patients with cognitive impairment. This cross-sectional prospective study [...] Read more.

Visceral adipose tissue (VAT) dysfunction has been recently recognized as a potential contributor to the development of Alzheimer’s disease (AD). This study aimed to explore the relationship between VAT metabolism and cerebral glucose metabolism in patients with cognitive impairment. This cross-sectional prospective study included 54 patients who underwent ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) brain and torso positron emission tomography/computed tomography (PET/CT), and neuropsychological evaluations. VAT metabolism was measured by ¹⁸F-FDG torso PET/CT, and cerebral glucose metabolism was measured using ¹⁸F-FDG brain PET/CT. A voxel-based analysis revealed that the high-VAT-metabolism group exhibited a significantly lower cerebral glucose metabolism in AD-signature regions such as the parietal and temporal cortices. In the volume-of-interest analysis, multiple linear regression analyses with adjustment for age, sex, and white matter hyperintensity volume revealed that VAT metabolism was negatively associated with cerebral glucose metabolism in AD-signature regions. In addition, higher VAT metabolism was correlated with poorer outcomes on cognitive assessments, including the Korean Boston Naming Test, Rey Complex Figure Test immediate recall, and the Controlled Oral Word Association Test. In conclusion, our study revealed significant relationships among VAT metabolism, cerebral glucose metabolism, and cognitive function. This suggests that VAT dysfunction actively contributes to the neurodegenerative processes characteristic of AD, making VAT dysfunction targeting a novel AD therapy approach. Full article

(This article belongs to the Special Issue Molecular Research in Obesity and Obesity Related Disorders: 2nd Edition)

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14 pages, 2215 KiB

Open AccessArticle

DNA Methylation of the Autonomous Pathway Is Associated with Flowering Time Variations in Arabidopsis thaliana

by Hongjie Xie, Xinchen Li, Yuli Sun, Lei Lin, Keke Xu, Huan Lu, Biao Cheng, Siming Xue, Dan Cheng and Sheng Qiang

Int. J. Mol. Sci. 2024, 25(13), 7478; https://doi.org/10.3390/ijms25137478 - 8 Jul 2024

Viewed by 1054

Abstract

Plant flowering time is affected by endogenous and exogenous factors, but its variation patterns among different populations of a species has not been fully established. In this study, 27 Arabidopsis thaliana accessions were used to investigate the relationship between autonomous pathway gene methylation, [...] Read more.

Plant flowering time is affected by endogenous and exogenous factors, but its variation patterns among different populations of a species has not been fully established. In this study, 27 Arabidopsis thaliana accessions were used to investigate the relationship between autonomous pathway gene methylation, gene expression and flowering time variation. DNA methylation analysis, RT-qPCR and transgenic verification showed that variation in the flowering time among the Arabidopsis populations ranged from 19 to 55 days and was significantly correlated with methylation of the coding regions of six upstream genes in the autonomous pathway, FLOWERING LOCUS VE (FVE), FLOWERING LOCUS Y (FY), FLOWERING LOCUS D (FLD), PEPPER (PEP), HISTONE DEACETYLASE 5 (HAD5) and Pre-mRNA Processing Protein 39-1 (PRP39-1), as well as their relative expression levels. The expression of FVE and FVE(CS) was modified separately through degenerate codon substitution of cytosine and led to earlier flowering of transgenic plants by 8 days and 25 days, respectively. An accurate determination of methylated sites in FVE and FVE(CS) among those transgenic plants and the recipient Col-0 verified the close relationship between the number of methylation sites, expression and flowering time. Our findings suggest that the methylation variation of these six key upstream transcription factors was associated with the gene expression level of the autonomous pathway and flowering time in Arabidopsis. The FVE(CS) and FVE genes in transgenic plants tended to be hypermethylated, which could be a protective mechanism for plants. However, modification of gene sequences through degenerate codon substitution to reduce cytosine can avoid hypermethylated transferred genes in transgenic plants. It may be possible to partially regulate the flowering of plants by modified trans-epigenetic technology. Full article

(This article belongs to the Special Issue Molecular and Structural Research Advances in Model Plants)

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20 pages, 1609 KiB

Open AccessReview

Role of Oxidative Stress and Inflammation in Doxorubicin-Induced Cardiotoxicity: A Brief Account

by Roberta Vitale, Stefania Marzocco and Ada Popolo

Int. J. Mol. Sci. 2024, 25(13), 7477; https://doi.org/10.3390/ijms25137477 - 8 Jul 2024

Cited by 2 | Viewed by 1772

Abstract

Cardiotoxicity is the main side effect of several chemotherapeutic drugs. Doxorubicin (Doxo) is one of the most used anthracyclines in the treatment of many tumors, but the development of acute and chronic cardiotoxicity limits its clinical usefulness. Different studies focused only on the [...] Read more.

Cardiotoxicity is the main side effect of several chemotherapeutic drugs. Doxorubicin (Doxo) is one of the most used anthracyclines in the treatment of many tumors, but the development of acute and chronic cardiotoxicity limits its clinical usefulness. Different studies focused only on the effects of long-term Doxo administration, but recent data show that cardiomyocyte damage is an early event induced by Doxo after a single administration that can be followed by progressive functional decline, leading to overt heart failure. The knowledge of molecular mechanisms involved in the early stage of Doxo-induced cardiotoxicity is of paramount importance to treating and/or preventing it. This review aims to illustrate several mechanisms thought to underlie Doxo-induced cardiotoxicity, such as oxidative and nitrosative stress, inflammation, and mitochondrial dysfunction. Moreover, here we report data from both in vitro and in vivo studies indicating new therapeutic strategies to prevent Doxo-induced cardiotoxicity. Full article

(This article belongs to the Special Issue Molecular Pharmacology of Cardiovascular Disease, 2nd Edition)

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43 pages, 859 KiB

Open AccessReview

Associations between Diabetes Mellitus and Selected Cancers

by Monika Pliszka and Leszek Szablewski

Int. J. Mol. Sci. 2024, 25(13), 7476; https://doi.org/10.3390/ijms25137476 - 8 Jul 2024

Cited by 1 | Viewed by 1739

Abstract

Cancer is one of the major causes of mortality and is the second leading cause of death. Diabetes mellitus is a serious and growing problem worldwide, and its prevalence continues to grow; it is the 12th leading cause of death. An association between [...] Read more.

Cancer is one of the major causes of mortality and is the second leading cause of death. Diabetes mellitus is a serious and growing problem worldwide, and its prevalence continues to grow; it is the 12th leading cause of death. An association between diabetes mellitus and cancer has been suggested for more than 100 years. Diabetes is a common disease diagnosed among patients with cancer, and evidence indicates that approximately 8–18% of patients with cancer have diabetes, with investigations suggesting an association between diabetes and some particular cancers, increasing the risk for developing cancers such as pancreatic, liver, colon, breast, stomach, and a few others. Breast and colorectal cancers have increased from 20% to 30% and there is a 97% increased risk of intrahepatic cholangiocarcinoma or endometrial cancer. On the other hand, a number of cancers and cancer therapies increase the risk of diabetes mellitus. Complications due to diabetes in patients with cancer may influence the choice of cancer therapy. Unfortunately, the mechanisms of the associations between diabetes mellitus and cancer are still unknown. The aim of this review is to summarize the association of diabetes mellitus with selected cancers and update the evidence on the underlying mechanisms of this association. Full article

(This article belongs to the Special Issue The Relationship, Mechanisms, and Treatment Strategies of Diabetes Mellitus and Related Diseases)

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24 pages, 17704 KiB

Open AccessArticle

HER4 Affects Sensitivity to Tamoxifen and Abemaciclib in Luminal Breast Cancer Cells and Restricts Tumor Growth in MCF-7-Based Humanized Tumor Mice

by Veruschka Albert, Christina Bruss, Deniz Tümen, Gerhard Piendl, Florian Weber, Edgar Dahl, Stephan Seitz, Olaf Ortmann, Anja K. Wege and Gero Brockhoff

Int. J. Mol. Sci. 2024, 25(13), 7475; https://doi.org/10.3390/ijms25137475 - 8 Jul 2024

Viewed by 1425

Abstract

The impact of the HER4 receptor on the growth and treatment of estrogen receptor-positive breast cancer is widely uncertain. Using CRISPR/Cas9 technology, we generated stable HER4 knockout variants derived from the HER4-positive MCF-7, T-47D, and ZR-75-1 breast cancer cell lines. We investigated tumor [...] Read more.

The impact of the HER4 receptor on the growth and treatment of estrogen receptor-positive breast cancer is widely uncertain. Using CRISPR/Cas9 technology, we generated stable HER4 knockout variants derived from the HER4-positive MCF-7, T-47D, and ZR-75-1 breast cancer cell lines. We investigated tumor cell proliferation as well as the cellular and molecular mechanisms of tamoxifen, abemaciclib, AMG232, and NRG1 treatments as a function of HER4 in vitro. HER4 differentially affects the cellular response to tamoxifen and abemaciclib treatment. Most conspicuous is the increased sensitivity of MCF-7 in vitro upon HER4 knockout and the inhibition of cell proliferation by NRG1. Additionally, we assessed tumor growth and immunological effects as responses to tamoxifen and abemaciclib therapy in humanized tumor mice (HTM) based on MCF-7 HER4-wildtype and the corresponding HER4-knockout cells. Without any treatment, the enhanced MCF-7 tumor growth in HTM upon HER4 knockout suggests a tumor-suppressive effect of HER4 under preclinical but human-like conditions. This phenomenon is associated with an increased HER2 expression in MCF-7 in vivo. Independent of HER4, abemaciclib and tamoxifen treatment considerably inhibited tumor growth in these mice. However, abemaciclib-treated hormone receptor-positive breast cancer patients with tumor-associated mdm2 gene copy gains or pronounced HER4 expression showed a reduced event-free survival. Evidently, the presence of HER4 affects the efficacy of tamoxifen and abemaciclib treatment in different estrogen receptor-positive breast cancer cells, even to different extents, and is associated with unfavorable outcomes in abemaciclib-treated patients. Full article

(This article belongs to the Special Issue Recent Advances in Breast Cancer Research, 2nd Edition)

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12 pages, 2371 KiB

Open AccessReview

Applications of SPECT and PET Imaging for the Physiological Evaluation of Lower Extremity Peripheral Artery Disease

by Eleanor T. Rimmerman and Mitchel R. Stacy

Int. J. Mol. Sci. 2024, 25(13), 7474; https://doi.org/10.3390/ijms25137474 - 8 Jul 2024

Viewed by 1215

Abstract

Peripheral artery disease (PAD) is classified as the narrowing or complete occlusion of the lower extremity arteries due to atherosclerosis. The risk of developing PAD increases with increased age and risk factors such as smoking, diabetes, hypertension, and hypercholesterolemia. Current treatment for PAD [...] Read more.

Peripheral artery disease (PAD) is classified as the narrowing or complete occlusion of the lower extremity arteries due to atherosclerosis. The risk of developing PAD increases with increased age and risk factors such as smoking, diabetes, hypertension, and hypercholesterolemia. Current treatment for PAD involves lifestyle and symptom management, statin and antiplatelet therapy, and/or surgical interventions to improve quality of life with varying efficacy. PAD affects approximately 5 to 6 percent of the global population, with this global burden continuing to increase. Despite the increase in disease prevalence, no gold standard functional diagnostic tool has been established for enabling early detection of the disease, appropriate medical management, and prediction of adverse outcomes for PAD patients. The visualization and quantification of the physiological consequences of PAD are possible by way of nuclear imaging: specifically, via scintigraphy, single-photon emission computed tomography (SPECT), and positron emission tomography (PET) imaging. These non-invasive modalities, when combined with targeted radionuclides, possess utility for detecting functional perfusion deficits and provide unique insight into muscle tissue- and vascular-level characteristics of PAD patients. This review discusses the past, present, and emerging applications of hybrid nuclear imaging modalities in the evaluation and monitoring of patients with PAD. Full article

(This article belongs to the Special Issue Molecular Probe: Recent Research and Future Challenges)

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20 pages, 12753 KiB

Open AccessArticle

Genome-Wide Analysis of the Auxin/Indoleacetic Acid (Aux/IAA) Gene Family in Autopolyploid Sugarcane (Saccharum spontaneum)

by Xiaojin Huang, Munsif Ali Shad, Yazhou Shu, Sikun Nong, Xianlong Li, Songguo Wu, Juan Yang, Muhammad Junaid Rao, Muhammad Zeshan Aslam, Xiaoti Huang, Dige Huang and Lingqiang Wang

Int. J. Mol. Sci. 2024, 25(13), 7473; https://doi.org/10.3390/ijms25137473 - 8 Jul 2024

Cited by 2 | Viewed by 1376

Abstract

The auxin/indoleacetic acid (Aux/IAA) family plays a central role in regulating gene expression during auxin signal transduction. Nonetheless, there is limited knowledge regarding this gene family in sugarcane. In this study, 92 members of the IAA family were identified in Saccharum [...] Read more.

The auxin/indoleacetic acid (Aux/IAA) family plays a central role in regulating gene expression during auxin signal transduction. Nonetheless, there is limited knowledge regarding this gene family in sugarcane. In this study, 92 members of the IAA family were identified in Saccharum spontaneum, distributed on 32 chromosomes, and classified into three clusters based on phylogeny and motif compositions. Segmental duplication and recombination events contributed largely to the expansion of this superfamily. Additionally, cis-acting elements in the promoters of SsIAAs involved in plant hormone regulation and stress responsiveness were predicted. Transcriptomics data revealed that most SsIAA expressions were significantly higher in stems and basal parts of leaves, and at nighttime, suggesting that these genes might be involved in sugar transport. QRT-PCR assays confirmed that cold and salt stress significantly induced four and five SsIAAs, respectively. GFP-subcellular localization showed that SsIAA23 and SsIAA12a were localized in the nucleus, consistent with the results of bioinformatics analysis. In conclusion, to a certain extent, the functional redundancy of family members caused by the expansion of the sugarcane IAA gene family is related to stress resistance and regeneration of sugarcane as a perennial crop. This study reveals the gene evolution and function of the SsIAA gene family in sugarcane, laying the foundation for further research on its mode of action. Full article

(This article belongs to the Special Issue Genetics- and Genomics-Based Crop Improvement and Breeding : 2nd Edition)

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14 pages, 2375 KiB

Open AccessCommunication

The Degradation of Botulinum Neurotoxin Light Chains Using PROTACs

by Yien Che Tsai, Loren Kozar, Zo P. Mawi, Konstantin Ichtchenko, Charles B. Shoemaker, Patrick M. McNutt and Allan M. Weissman

Int. J. Mol. Sci. 2024, 25(13), 7472; https://doi.org/10.3390/ijms25137472 - 8 Jul 2024

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Abstract

Botulinum neurotoxins are some of the most potent natural toxins known; they cause flaccid paralysis by inhibiting synaptic vesicle release. Some serotypes, notably serotype A and B, can cause persistent paralysis lasting for several months. Because of their potency and persistence, botulinum neurotoxins [...] Read more.

Botulinum neurotoxins are some of the most potent natural toxins known; they cause flaccid paralysis by inhibiting synaptic vesicle release. Some serotypes, notably serotype A and B, can cause persistent paralysis lasting for several months. Because of their potency and persistence, botulinum neurotoxins are now used to manage several clinical conditions, and there is interest in expanding their clinical applications using engineered toxins with novel substrate specificities. It will also be beneficial to engineer toxins with tunable persistence. We have investigated the potential use of small-molecule proteolysis-targeting chimeras (PROTACs) to vary the persistence of modified recombinant botulinum neurotoxins. We also describe a complementary approach that has potential relevance for botulism treatment. This second approach uses a camelid heavy chain antibody directed against botulinum neurotoxin that is modified to bind the PROTAC. These strategies provide proof of principle for the use of two different approaches to fine tune the persistence of botulinum neurotoxins by selectively targeting their catalytic light chains for proteasomal degradation. Full article

(This article belongs to the Special Issue Advances in Clostridial and Related Neurotoxins 2.0)

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Int. J. Mol. Sci., Volume 25, Issue 13 (July-1 2024) – 690 articles

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