International Journal of Molecular Sciences

14 pages, 1436 KiB

Open AccessArticle

Blockade of Serotonin 5-HT₆ Receptor Constitutive Activity Alleviates Cognitive Deficits in a Preclinical Model of Neurofibromatosis Type 1

by Emilie Doucet, Katarzyna Grychowska, Pawel Zajdel, Joël Bockaert, Philippe Marin and Carine Bécamel

Int. J. Mol. Sci. 2021, 22(18), 10178; https://doi.org/10.3390/ijms221810178 - 21 Sep 2021

Cited by 7 | Viewed by 3151

Abstract

Neurofibromatosis type 1 (NF1) is a common inherited disorder caused by mutations of the NF1 gene that encodes the Ras-GTPase activating protein neurofibromin, leading to overactivation of Ras-dependent signaling pathways such as the mTOR pathway. It is often characterized by a broad range [...] Read more.

Neurofibromatosis type 1 (NF1) is a common inherited disorder caused by mutations of the NF1 gene that encodes the Ras-GTPase activating protein neurofibromin, leading to overactivation of Ras-dependent signaling pathways such as the mTOR pathway. It is often characterized by a broad range of cognitive symptoms that are currently untreated. The serotonin 5-HT₆ receptor is a potentially relevant target in view of its ability to associate with neurofibromin and to engage the mTOR pathway to compromise cognition in several cognitive impairment paradigms. Here, we show that constitutively active 5-HT₆ receptors contribute to increased mTOR activity in the brain of Nf1^+/− mice, a preclinical model recapitulating some behavioral alterations of NF1. Correspondingly, peripheral administration of SB258585, a 5-HT₆ receptor inverse agonist, or rapamycin, abolished deficits in long-term social and associative memories in Nf1^+/− mice, whereas administration of CPPQ, a neutral antagonist, did not produce cognitive improvement. These results show a key influence of mTOR activation by constitutively active 5-HT₆ receptors in NF1 cognitive symptoms. They provide a proof of concept that 5-HT₆ receptor inverse agonists already in clinical development as symptomatic treatments to reduce cognitive decline in dementia and psychoses, might be repurposed as therapies alleviating cognitive deficits in NF1 patients. Full article

(This article belongs to the Special Issue Pathophysiology of the Serotonin System in the Nervous System and Beyond)

► Show Figures

Figure 1

28 pages, 3283 KiB

Open AccessReview

Valosin-Containing Protein (VCP)/p97: A Prognostic Biomarker and Therapeutic Target in Cancer

by Susan Costantini, Francesca Capone, Andrea Polo, Palmina Bagnara and Alfredo Budillon

Int. J. Mol. Sci. 2021, 22(18), 10177; https://doi.org/10.3390/ijms221810177 - 21 Sep 2021

Cited by 37 | Viewed by 7438

Abstract

Valosin-containing protein (VCP)/p97, a member of the AAA+ ATPase family, is a molecular chaperone recruited to the endoplasmic reticulum (ER) membrane by binding to membrane adapters (nuclear protein localization protein 4 (NPL4), p47 and ubiquitin regulatory X (UBX) domain-containing protein 1 (UBXD1)), where [...] Read more.

Valosin-containing protein (VCP)/p97, a member of the AAA+ ATPase family, is a molecular chaperone recruited to the endoplasmic reticulum (ER) membrane by binding to membrane adapters (nuclear protein localization protein 4 (NPL4), p47 and ubiquitin regulatory X (UBX) domain-containing protein 1 (UBXD1)), where it is involved in ER-associated protein degradation (ERAD). However, VCP/p97 interacts with many cofactors to participate in different cellular processes that are critical for cancer cell survival and aggressiveness. Indeed, VCP/p97 is reported to be overexpressed in many cancer types and is considered a potential cancer biomarker and therapeutic target. This review summarizes the role of VCP/p97 in different cancers and the advances in the discovery of small-molecule inhibitors with therapeutic potential, focusing on the challenges associated with cancer-related VCP mutations in the mechanisms of resistance to inhibitors. Full article

(This article belongs to the Special Issue New Prognostic and Predictive Markers in Cancer Progression 2.0)

► Show Figures

Figure 1

22 pages, 8200 KiB

Open AccessArticle

Novel Silver-Functionalized Poly(ε-Caprolactone)/Biphasic Calcium Phosphate Scaffolds Designed to Counteract Post-Surgical Infections in Orthopedic Applications

by Sara Comini, Rosaria Sparti, Bartolomeo Coppola, Mehdi Mohammadi, Sara Scutera, Francesca Menotti, Giuliana Banche, Anna Maria Cuffini, Paola Palmero and Valeria Allizond

Int. J. Mol. Sci. 2021, 22(18), 10176; https://doi.org/10.3390/ijms221810176 - 21 Sep 2021

Cited by 15 | Viewed by 2692

Abstract

In this study, we designed and developed novel poly(ε-caprolactone) (PCL)-based biomaterials, for use as bone scaffolds, through modification with both biphasic calcium phosphate (BCP), to impart bioactive/bioresorbable properties, and with silver nitrate, to provide antibacterial protection against Staphylococcus aureus, a microorganism involved [...] Read more.

In this study, we designed and developed novel poly(ε-caprolactone) (PCL)-based biomaterials, for use as bone scaffolds, through modification with both biphasic calcium phosphate (BCP), to impart bioactive/bioresorbable properties, and with silver nitrate, to provide antibacterial protection against Staphylococcus aureus, a microorganism involved in prosthetic joint infections (PJIs). Field emission scanning electron microscopy (FESEM) showed that the samples were characterized by square-shaped macropores, and energy dispersive X-ray spectroscopy analysis confirmed the presence of PCL and BCP phases, while inductively coupled plasma–mass spectrometry (ICP–MS) established the release of Ag⁺ in the medium (~0.15–0.8 wt% of initial Ag content). Adhesion assays revealed a significant (p < 0.0001) reduction in both adherent and planktonic staphylococci on the Ag-functionalized biomaterials, and the presence of an inhibition halo confirmed Ag release from enriched samples. To assess the potential outcome in promoting bone integration, preliminary tests on sarcoma osteogenic-2 (Saos-2) cells indicated PCL and BCP/PCL biocompatibility, but a reduction in viability was observed for Ag-added biomaterials. Due to their combined biodegrading and antimicrobial properties, the silver-enriched BCP/PCL-based scaffolds showed good potential for engineering of bone tissue and for reducing PJIs as a microbial anti-adhesive tool used in the delivery of targeted antimicrobial molecules, even if the amount of silver needs to be tuned to improve osteointegration. Full article

(This article belongs to the Special Issue Nanomaterials for Tissue Engineering Applications 2.0)

► Show Figures

Figure 1

17 pages, 3334 KiB

Open AccessReview

Dynamic Crosstalk between Vascular Smooth Muscle Cells and the Aged Extracellular Matrix

by Joao Carlos Ribeiro-Silva, Patricia Nolasco, Jose Eduardo Krieger and Ayumi Aurea Miyakawa

Int. J. Mol. Sci. 2021, 22(18), 10175; https://doi.org/10.3390/ijms221810175 - 21 Sep 2021

Cited by 21 | Viewed by 5673

Abstract

Vascular aging is accompanied by the fragmentation of elastic fibers and collagen deposition, leading to reduced distensibility and increased vascular stiffness. A rigid artery facilitates elastin to degradation by MMPs, exposing vascular cells to greater mechanical stress and triggering signaling mechanisms that only [...] Read more.

Vascular aging is accompanied by the fragmentation of elastic fibers and collagen deposition, leading to reduced distensibility and increased vascular stiffness. A rigid artery facilitates elastin to degradation by MMPs, exposing vascular cells to greater mechanical stress and triggering signaling mechanisms that only exacerbate aging, creating a self-sustaining inflammatory environment that also promotes vascular calcification. In this review, we highlight the role of crosstalk between smooth muscle cells and the vascular extracellular matrix (ECM) and how aging promotes smooth muscle cell phenotypes that ultimately lead to mechanical impairment of aging arteries. Understanding the underlying mechanisms and the role of associated changes in ECM during aging may contribute to new approaches to prevent or delay arterial aging and the onset of cardiovascular diseases. Full article

(This article belongs to the Special Issue Extracellular Matrix Aging, Principles and Consequences)

► Show Figures

Figure 1

17 pages, 13097 KiB

Open AccessArticle

Molecular Dynamics Simulations of Phosphorylated Intrinsically Disordered Proteins: A Force Field Comparison

by Ellen Rieloff and Marie Skepö

Int. J. Mol. Sci. 2021, 22(18), 10174; https://doi.org/10.3390/ijms221810174 - 21 Sep 2021

Cited by 18 | Viewed by 4402

Abstract

Phosphorylation is a common post-translational modification among intrinsically disordered proteins and regions, which helps regulate function by changing the protein conformations, dynamics, and interactions with binding partners. To fully comprehend the effects of phosphorylation, computer simulations are a helpful tool, although they are [...] Read more.

Phosphorylation is a common post-translational modification among intrinsically disordered proteins and regions, which helps regulate function by changing the protein conformations, dynamics, and interactions with binding partners. To fully comprehend the effects of phosphorylation, computer simulations are a helpful tool, although they are dependent on the accuracy of the force field used. Here, we compared the conformational ensembles produced by Amber ff99SB-ILDN+TIP4P-D and CHARMM36m, for four phosphorylated disordered peptides ranging in length from 14–43 residues. CHARMM36m consistently produced more compact conformations with a higher content of bends, mainly due to more stable salt bridges. Based on comparisons with experimental size estimates for the shortest and longest peptide, CHARMM36m appeared to overestimate the compactness. The difference between the force fields was largest for the peptide showing the greatest separation between positively charged and phosphorylated residues, in line with the importance of charge distribution. For this peptide, the conformational ensemble did not change significantly upon increasing the ionic strength from 0 mM to 150 mM, despite a reduction of the salt-bridging probability in the CHARMM36m simulations, implying that salt concentration has negligible effects in this study. Full article

(This article belongs to the Special Issue Frontiers in Protein Structure Research)

► Show Figures

Figure 1

17 pages, 1979 KiB

Open AccessArticle

Silica Nanoparticles Inhibit Responses to ATP in Human Airway Epithelial 16HBE Cells

by Alina Milici, Alicia Sanchez and Karel Talavera

Int. J. Mol. Sci. 2021, 22(18), 10173; https://doi.org/10.3390/ijms221810173 - 21 Sep 2021

Cited by 3 | Viewed by 2285

Abstract

Because of their low cost and easy production, silica nanoparticles (SiNPs) are widely used in multiple manufacturing applications as anti-caking, densifying and hydrophobic agents. However, this has increased the exposure levels of the general population and has raised concerns about the toxicity of [...] Read more.

Because of their low cost and easy production, silica nanoparticles (SiNPs) are widely used in multiple manufacturing applications as anti-caking, densifying and hydrophobic agents. However, this has increased the exposure levels of the general population and has raised concerns about the toxicity of this nanomaterial. SiNPs affect the function of the airway epithelium, but the biochemical pathways targeted by these particles remain largely unknown. Here we investigated the effects of SiNPs on the responses of 16HBE14o- cultured human bronchial epithelial (16HBE) cells to the damage-associated molecular pattern ATP, using fluorometric measurements of intracellular Ca²⁺ concentration. Upon stimulation with extracellular ATP, these cells displayed a concentration-dependent increase in intracellular Ca²⁺, which was mediated by release from intracellular stores. SiNPs inhibited the Ca²⁺ responses to ATP within minutes of application and at low micromolar concentrations, which are significantly faster and more potent than those previously reported for the induction of cellular toxicity and pro-inflammatory responses. SiNPs-induced inhibition is independent from the increase in intracellular Ca²⁺ they produce, is largely irreversible and occurs via a non-competitive mechanism. These findings suggest that SiNPs reduce the ability of airway epithelial cells to mount ATP-dependent protective responses. Full article

(This article belongs to the Special Issue Nanoparticles and Their Interactions with Target Cells, Host Receptors and Soluble Factors)

► Show Figures

Figure 1

19 pages, 3282 KiB

Open AccessArticle

Novel Insights into Epigenetic Regulation of IL6 Pathway: In Silico Perspective on Inflammation and Cancer Relationship

by Saverio Candido, Barbara Maria Rita Tomasello, Alessandro Lavoro, Luca Falzone, Giuseppe Gattuso and Massimo Libra

Int. J. Mol. Sci. 2021, 22(18), 10172; https://doi.org/10.3390/ijms221810172 - 21 Sep 2021

Cited by 31 | Viewed by 3171

Abstract

IL-6 pathway is abnormally hyperactivated in several cancers triggering tumor cell growth and immune system inhibition. Along with genomic mutation, the IL6 pathway gene expression can be affected by DNA methylation, microRNAs, and post-translational modifications. Computational analysis was performed on the Cancer Genome [...] Read more.

IL-6 pathway is abnormally hyperactivated in several cancers triggering tumor cell growth and immune system inhibition. Along with genomic mutation, the IL6 pathway gene expression can be affected by DNA methylation, microRNAs, and post-translational modifications. Computational analysis was performed on the Cancer Genome Atlas (TCGA) datasets to explore the role of IL6, IL6R, IL6ST, and IL6R transmembrane isoform expression and their epigenetic regulation in different cancer types. IL6 was significantly modulated in 70% of tumor types, revealing either up- or down-regulation in an approximately equal number of tumors. Furthermore, IL6R and IL6ST were downregulated in more than 10 tumors. Interestingly, the correlation analysis demonstrated that only the IL6R expression was negatively affected by the DNA methylation within the promoter region in most tumors. Meanwhile, only the IL6ST expression was extensively modulated by miRNAs including miR-182-5p, which also directly targeted all three genes. In addition, IL6 upregulated miR-181a-3p, mirR-214-3p, miR-18a-5p, and miR-938, which in turn inhibited the expression of IL6 receptors. Finally, the patients’ survival rate was significantly affected by analyzed targets in some tumors. Our results suggest the relevance of epigenetic regulation of IL6 signaling and pave the way for further studies to validate these findings and to assess the prognostic and therapeutic predictive value of these epigenetic markers on the clinical outcome and survival of cancer patients. Full article

(This article belongs to the Special Issue Old and New Players in Inflammatory Disorders—in Memory of Dr. Nadia Ferlazzo)

► Show Figures

Figure 1

40 pages, 9845 KiB

Open AccessArticle

Influence of Ce³⁺ Substitution on Antimicrobial and Antibiofilm Properties of ZnCe_xFe_2−xO₄ Nanoparticles (X = 0.0, 0.02, 0.04, 0.06, and 0.08) Conjugated with Ebselen and Its Role Subsidised with γ-Radiation in Mitigating Human TNBC and Colorectal Adenocarcinoma Proliferation In Vitro

by Mohamed K. Abdel-Rafei, Noura M. Thabet, M. I. A. Abdel Maksoud, M. Abd Elkodous, Go Kawamura, Atsunori Matsuda, A. H. Ashour, Ahmed I. El-Batal and Gharieb S. El-Sayyad

Int. J. Mol. Sci. 2021, 22(18), 10171; https://doi.org/10.3390/ijms221810171 - 21 Sep 2021

Cited by 22 | Viewed by 4503

Abstract

Cancers are a major challenge to health worldwide. Spinel ferrites have attracted attention due to their broad theranostic applications. This study aimed at investigating the antimicrobial, antibiofilm, and anticancer activities of ebselen (Eb) and cerium-nanoparticles (Ce-NPs) in the form of ZnCe_xFe [...] Read more.

Cancers are a major challenge to health worldwide. Spinel ferrites have attracted attention due to their broad theranostic applications. This study aimed at investigating the antimicrobial, antibiofilm, and anticancer activities of ebselen (Eb) and cerium-nanoparticles (Ce-NPs) in the form of ZnCe_xFe_2−XO₄ on human breast and colon cancer cell lines. Bioassays of the cytotoxic concentrations of Eb and ZnCe_xFe_2−XO₄, oxidative stress and inflammatory milieu, autophagy, apoptosis, related signalling effectors, the distribution of cells through the cell-cycle phases, and the percentage of cells with apoptosis were evaluated in cancer cell lines. Additionally, the antimicrobial and antibiofilm potential have been investigated against different pathogenic microbes. The ZOI, and MIC results indicated that ZnCe_xFe_2−XO₄; X = 0.06 specimen reduced the activity of a wide range of bacteria and unicellular fungi at low concentration including P. aeruginosa (9.5 mm; 6.250 µg/mL), S. aureus (13.2 mm; 0.390 µg/mL), and Candida albicans (13.5 mm; 0.195 µg/mL). Reaction mechanism determination indicated that after ZnCe_xFe_2−xO₄; X = 0.06 treatment, morphological differences in S.aureus were apparent with complete lysis of bacterial cells, a concomitant decrease in the viable number, and the growth of biofilm was inhibited. The combination of Eb with ZFO or ZnCe_xFe_2−XO₄ with γ-radiation exposure showed marked anti-proliferative efficacy in both cell lines, through modulating the oxidant/antioxidant machinery imbalance, restoring the fine-tuning of redox status, and promoting an anti-inflammatory milieu to prevent cancer progression, which may be a valuable therapeutic approach to cancer therapy and as a promising antimicrobial agent to reduce the pathogenic potential of the invading microbes. Full article

(This article belongs to the Special Issue Functional Nanomaterials for Healthcare)

► Show Figures

Figure 1

19 pages, 13644 KiB

Open AccessArticle

Dnmt3aa but Not Dnmt3ab Is Required for Maintenance of Gametogenesis in Nile Tilapia (Oreochromis niloticus)

by Feilong Wang, Zuliang Qin, Zhiqiang Li, Shuangyi Yang, Tian Gao, Lina Sun and Deshou Wang

Int. J. Mol. Sci. 2021, 22(18), 10170; https://doi.org/10.3390/ijms221810170 - 21 Sep 2021

Cited by 11 | Viewed by 3083

Abstract

Dnmt3a, a de novo methyltransferase, is essential for mammalian germ line DNA methylation. Only one Dnmt3a is identified in mammals, and homozygous mutants of Dnmt3a are lethal, while two Dnmt3a paralogs, dnmt3aa and dnmt3ab, are identified in teleosts due to the [...] Read more.

Dnmt3a, a de novo methyltransferase, is essential for mammalian germ line DNA methylation. Only one Dnmt3a is identified in mammals, and homozygous mutants of Dnmt3a are lethal, while two Dnmt3a paralogs, dnmt3aa and dnmt3ab, are identified in teleosts due to the third round of genome duplication, and homozygous mutants of dnmt3aa and dnmt3ab are viable in zebrafish. The expression patterns and roles of dnmt3aa and dnmt3ab in gonadal development remain poorly understood in teleosts. In this study, we elucidated the precise expression patterns of dnmt3aa and dnmt3ab in tilapia gonads. Dnmt3aa was highly expressed in oogonia, phase I and II oocytes and granulosa cells in ovaries and spermatogonia and spermatocytes in testes, while dnmt3ab was mainly expressed in ovarian granulosa cells and testicular spermatocytes. The mutation of dnmt3aa and dnmt3ab was achieved by CRISPR/Cas9 in tilapia. Lower gonadosomatic index (GSI), increased apoptosis of oocytes and spermatocytes and significantly reduced sperm quality were observed in dnmt3aa^−/− mutants, while normal gonadal development was observed in dnmt3ab^−/− mutants. Consistently, the expression of apoptotic genes was significantly increased in dnmt3aa^−/− mutants. In addition, the 5-methylcytosine (5-mC) level in dnmt3aa^−/− gonads was decreased significantly, compared with that of dnmt3ab^−/− and wild type (WT) gonads. Taken together, our results suggest that dnmt3aa, not dnmt3ab, plays important roles in maintaining gametogenesis in teleosts. Full article

(This article belongs to the Section Molecular Biology)

► Show Figures

Figure 1

14 pages, 12598 KiB

Open AccessArticle

“Take It or Leave It”—Factors Regulating Competence Development and DNA Uptake in Campylobacter jejuni

by Julia C. Golz and Kerstin Stingl

Int. J. Mol. Sci. 2021, 22(18), 10169; https://doi.org/10.3390/ijms221810169 - 21 Sep 2021

Cited by 4 | Viewed by 2540

Abstract

Campylobacter jejuni has a large adaptive potential due to enormous genetic exchange. Factors regulating natural transformation in this food-borne pathogen are largely unknown but of interest for the application of sustained reduction strategies in the food-processing industry. Using a single cell DNA uptake [...] Read more.

Campylobacter jejuni has a large adaptive potential due to enormous genetic exchange. Factors regulating natural transformation in this food-borne pathogen are largely unknown but of interest for the application of sustained reduction strategies in the food-processing industry. Using a single cell DNA uptake assay, we visualized that recognition of methylated C. jejuni DNA was essential for the first step of DNA uptake into a DNase resistant state. Transformation rates using a resistance marker correlated with the fraction of competent bacteria, harboring one to maximally four locations of active DNA uptake, not necessarily being located at the cell pole. Competence developed with rising pH between 6.5 and 7.5 under microaerobic conditions and was nearly insensitive towards growth temperatures between 32 °C and 42 °C, CO₂ concentrations ranging from 0 to 50% and growth rates. However, competence development was abolished at pH 5 or under aerobic stress conditions, in which the bacteria ceased growth but fully survived. The DNA uptake machinery in competent bacteria shut down at slightly acidic pH and was reversibly switched on upon neutralization. It was dependent on the proton motive force and, in contrast to competence development, slightly enhanced under aerobic conditions. The results suggest that natural transformation in C. jejuni occurs in the neutral and microaerobic intestinal environment for enhanced genetic diversity and pre-adaption before host switch. In addition, highly competent bacteria might be shed into the environment, still able to acquire genetic material for increased survival. Full article

(This article belongs to the Special Issue Single-Cell and Single-Molecule Analysis of Microorganism)

► Show Figures

Figure 1

13 pages, 1292 KiB

Open AccessReview

The RhoGEF Trio: A Protein with a Wide Range of Functions in the Vascular Endothelium

by Lanette Kempers, Amber J. M. Driessen, Jos van Rijssel, Martijn A. Nolte and Jaap D. van Buul

Int. J. Mol. Sci. 2021, 22(18), 10168; https://doi.org/10.3390/ijms221810168 - 21 Sep 2021

Cited by 8 | Viewed by 3846

Abstract

Many cellular processes are controlled by small GTPases, which can be activated by guanine nucleotide exchange factors (GEFs). The RhoGEF Trio contains two GEF domains that differentially activate the small GTPases such as Rac1/RhoG and RhoA. These small RhoGTPases are mainly involved in [...] Read more.

Many cellular processes are controlled by small GTPases, which can be activated by guanine nucleotide exchange factors (GEFs). The RhoGEF Trio contains two GEF domains that differentially activate the small GTPases such as Rac1/RhoG and RhoA. These small RhoGTPases are mainly involved in the remodeling of the actin cytoskeleton. In the endothelium, they regulate junctional stabilization and play a crucial role in angiogenesis and endothelial barrier integrity. Multiple extracellular signals originating from different vascular processes can influence the activity of Trio and thereby the regulation of the forementioned small GTPases and actin cytoskeleton. This review elucidates how various signals regulate Trio in a distinct manner, resulting in different functional outcomes that are crucial for endothelial cell function in response to inflammation. Full article

(This article belongs to the Special Issue Advances in Endothelial Cell Biology)

► Show Figures

Figure 1

16 pages, 3123 KiB

Open AccessArticle

The Osteogenic Differentiation of Human Dental Pulp Stem Cells through G0/G1 Arrest and the p-ERK/Runx-2 Pathway by Sonic Vibration

by Won Lee, Su-Rak Eo, Ju-Hye Choi, Yu-Mi Kim, Myeong-Hyun Nam and Young-Kwon Seo

Int. J. Mol. Sci. 2021, 22(18), 10167; https://doi.org/10.3390/ijms221810167 - 21 Sep 2021

Cited by 8 | Viewed by 2909

Abstract

Mechanical/physical stimulations modulate tissue metabolism, and this process involves multiple cellular mechanisms, including the secretion of growth factors and the activation of mechano-physically sensitive kinases. Cells and tissue can be modulated through specific vibration-induced changes in cell activity, which depend on the vibration [...] Read more.

Mechanical/physical stimulations modulate tissue metabolism, and this process involves multiple cellular mechanisms, including the secretion of growth factors and the activation of mechano-physically sensitive kinases. Cells and tissue can be modulated through specific vibration-induced changes in cell activity, which depend on the vibration frequency and occur via differential gene expression. However, there are few reports about the effects of medium-magnitude (1.12 g) sonic vibration on the osteogenic differentiation of human dental pulp stem cells (HDPSCs). In this study, we investigated whether medium-magnitude (1.12 g) sonic vibration with a frequency of 30, 45, or 100 Hz could affect the osteogenic differentiation of HDPSCs. Their cell morphology changed to a cuboidal shape at 45 Hz and 100 Hz, but the cells in the other groups were elongated. FACS analysis showed decreased CD 73, CD 90, and CD 105 expression at 45 Hz and 100 Hz. Additionally, the proportions of cells in the G0/G1 phase in the control, 30 Hz, 45 Hz, and 100 Hz groups after vibration were 60.7%, 65.9%, 68.3%, and 66.7%, respectively. The mRNA levels of osteogenic-specific markers, including osteonectin, osteocalcin, BMP-2, ALP, and Runx-2, increased at 45 and 100 Hz, and the ALP and calcium content was elevated in the vibration groups compared with those in the control. Additionally, the western blotting results showed that p-ERK, BSP, osteoprotegerin, and osteonectin proteins were upregulated at 45 Hz compared with the other groups. The vibration groups showed higher ALP and calcium content than the control. Vibration, especially at 100 Hz, increased the number of calcified nodes relative to the control group, as evidenced by von Kossa staining. Immunohistochemical staining demonstrated that type I and III collagen, osteonectin, and osteopontin were upregulated at 45 Hz and 100 Hz. These results suggest that medium magnitude vibration at 45 Hz induces the G0/G1 arrest of HDPSCs through the p-ERK/Runx-2 pathway and can serve as a potent stimulator of differentiation and extracellular matrix production. Full article

(This article belongs to the Special Issue The Molecules and Stem Cells in Bone Regeneration)

► Show Figures

Figure 1

15 pages, 3545 KiB

Open AccessArticle

Geomagnetic Field (GMF)-Dependent Modulation of Iron-Sulfur Interplay in Arabidopsis thaliana

by Gianpiero Vigani, Monirul Islam, Viviana Cavallaro, Fabio F. Nocito and Massimo E. Maffei

Int. J. Mol. Sci. 2021, 22(18), 10166; https://doi.org/10.3390/ijms221810166 - 21 Sep 2021

Cited by 8 | Viewed by 2986

Abstract

The geomagnetic field (GMF) is an environmental factor affecting the mineral nutrient uptake of plants and a contributing factor for efficient iron (Fe) uptake in Arabidopsis seedlings. Understanding the mechanisms underlining the impact of the environment on nutrient homeostasis in plants requires disentangling [...] Read more.

The geomagnetic field (GMF) is an environmental factor affecting the mineral nutrient uptake of plants and a contributing factor for efficient iron (Fe) uptake in Arabidopsis seedlings. Understanding the mechanisms underlining the impact of the environment on nutrient homeostasis in plants requires disentangling the complex interactions occurring among nutrients. In this study we investigated the effect of GMF on the interplay between iron (Fe) and sulfur (S) by exposing Arabidopsis thaliana plants grown under single or combined Fe and S deficiency, to near-null magnetic field (NNMF) conditions. Mineral analysis was performed by ICP-MS and capillary electrophoresis, whereas the expression of several genes involved in Fe and S metabolism and transport was assayed by qRT-PCR. The results show that NNMF differentially affects (i) the expression of some Fe- and S-responsive genes and (ii) the concentration of metals in plants, when compared with GMF. In particular, we observed that Cu content alteration in plant roots depends on the simultaneous variation of nutrient availability (Fe and S) and MF intensity (GMF and NNMF). Under S deficiency, NNMF-exposed plants displayed variations of Cu uptake, as revealed by the expression of the SPL7 and miR408 genes, indicating that S availability is an important factor in maintaining Cu homeostasis under different MF intensities. Overall, our work suggests that the alteration of metal homeostasis induced by Fe and/or S deficiency in reduced GMF conditions impacts the ability of plants to grow and develop. Full article

(This article belongs to the Special Issue The Effect of Magnetic Fields on Living Organisms: Biomolecular and Cellular Mechanisms)

► Show Figures

Figure 1

28 pages, 4172 KiB

Open AccessReview

Diversity and Taxonomic Distribution of Endophytic Bacterial Community in the Rice Plant and Its Prospective

by Mohsin Ali, Qurban Ali, Muhammad Aamir Sohail, Muhammad Furqan Ashraf, Muhammad Hamzah Saleem, Saddam Hussain and Lei Zhou

Int. J. Mol. Sci. 2021, 22(18), 10165; https://doi.org/10.3390/ijms221810165 - 21 Sep 2021

Cited by 46 | Viewed by 9051

Abstract

Endophytic bacterial communities are beneficial communities for host plants that exist inside the surfaces of plant tissues, and their application improves plant growth. They benefit directly from the host plant by enhancing the nutrient amount of the plant’s intake and influencing the phytohormones, [...] Read more.

Endophytic bacterial communities are beneficial communities for host plants that exist inside the surfaces of plant tissues, and their application improves plant growth. They benefit directly from the host plant by enhancing the nutrient amount of the plant’s intake and influencing the phytohormones, which are responsible for growth promotion and stress. Endophytic bacteria play an important role in plant-growth promotion (PGP) by regulating the indirect mechanism targeting pest and pathogens through hydrolytic enzymes, antibiotics, biocontrol potential, and nutrient restriction for pathogens. To attain these benefits, firstly bacterial communities must be colonized by plant tissues. The nature of colonization can be achieved by using a set of traits, including attachment behavior and motility speed, degradation of plant polymers, and plant defense evasion. The diversity of bacterial endophytes colonization depends on various factors, such as plants’ relationship with environmental factors. Generally, each endophytic bacteria has a wide host range, and they are used as bio-inoculants in the form of synthetic applications for sustainable agriculture systems and to protect the environment from chemical hazards. This review discusses and explores the taxonomic distribution of endophytic bacteria associated with different genotypes of rice plants and their origin, movement, and mechanism of PGP. In addition, this review accentuates compressive meta data of endophytic bacteria communities associated with different genotypes of rice plants, retrieves their plant-growth-promoting properties and their antagonism against plant pathogens, and discusses the indication of endophytic bacterial flora in rice plant tissues using various methods. The future direction deepens the study of novel endophytic bacterial communities and their identification from rice plants through innovative techniques and their application for sustainable agriculture systems. Full article

(This article belongs to the Special Issue Plant-Microbe Interactions)

► Show Figures

Graphical abstract

31 pages, 8268 KiB

Open AccessReview

Whence CRIPTO: The Reemergence of an Oncofetal Factor in ‘Wounds’ That Fail to Heal

by David W. Freeman, Elisa Rodrigues Sousa, Sofia Karkampouna, Eugenio Zoni, Peter C. Gray, David S. Salomon, Marianna Kruithof-de Julio and Benjamin T. Spike

Int. J. Mol. Sci. 2021, 22(18), 10164; https://doi.org/10.3390/ijms221810164 - 21 Sep 2021

Cited by 6 | Viewed by 4142

Abstract

There exists a set of factors termed oncofetal proteins that play key roles in ontogeny before they decline or disappear as the organism’s tissues achieve homeostasis, only to then re-emerge in cancer. Although the unique therapeutic potential presented by such factors has been [...] Read more.

There exists a set of factors termed oncofetal proteins that play key roles in ontogeny before they decline or disappear as the organism’s tissues achieve homeostasis, only to then re-emerge in cancer. Although the unique therapeutic potential presented by such factors has been recognized for more than a century, their clinical utility has yet to be fully realized1. This review highlights the small signaling protein CRIPTO encoded by the tumor derived growth factor 1 (TDGF1/Tdgf1) gene, an oft cited oncofetal protein whose presence in the cancer literature as a tumor promoter, diagnostic marker and viable therapeutic target continues to grow. We touch lightly on features well established and well-reviewed since its discovery more than 30 years ago, including CRIPTO’s early developmental roles and modulation of SMAD2/3 activation by a selected set of transforming growth factor β (TGF-β) family ligands. We predominantly focus instead on more recent and less well understood additions to the CRIPTO signaling repertoire, on its potential upstream regulators and on new conceptual ground for understanding its mode of action in the multicellular and often stressful contexts of neoplastic transformation and progression. We ask whence it re-emerges in cancer and where it ‘hides’ between the time of its fetal activity and its oncogenic reemergence. In this regard, we examine CRIPTO’s restriction to rare cells in the adult, its potential for paracrine crosstalk, and its emerging role in inflammation and tissue regeneration—roles it may reprise in tumorigenesis, acting on subsets of tumor cells to foster cancer initiation and progression. We also consider critical gaps in knowledge and resources that stand between the recent, exciting momentum in the CRIPTO field and highly actionable CRIPTO manipulation for cancer therapy and beyond. Full article

(This article belongs to the Special Issue Nodal and Cripto-1 Signaling: Re-emergence in Cancer and Biological Role)

► Show Figures

Figure 1

18 pages, 5774 KiB

Open AccessArticle

Multiplex Screening for Interacting Compounds in Paediatric Acute Myeloid Leukaemia

by Lauren V. Cairns, Katrina M. Lappin, Alexander Mutch, Ahlam Ali, Kyle B. Matchett and Ken I. Mills

Int. J. Mol. Sci. 2021, 22(18), 10163; https://doi.org/10.3390/ijms221810163 - 21 Sep 2021

Cited by 1 | Viewed by 2906

Abstract

Paediatric acute myeloid leukaemia (AML) is a heterogeneous disease characterised by the malignant transformation of myeloid precursor cells with impaired differentiation. Standard therapy for paediatric AML has remained largely unchanged for over four decades and, combined with inadequate understanding of the biology of [...] Read more.

Paediatric acute myeloid leukaemia (AML) is a heterogeneous disease characterised by the malignant transformation of myeloid precursor cells with impaired differentiation. Standard therapy for paediatric AML has remained largely unchanged for over four decades and, combined with inadequate understanding of the biology of paediatric AML, has limited the progress of targeted therapies in this cohort. In recent years, the search for novel targets for the treatment of paediatric AML has accelerated in parallel with advanced genomic technologies which explore the mutational and transcriptional landscape of this disease. Exploiting the large combinatorial space of existing drugs provides an untapped resource for the identification of potential combination therapies for the treatment of paediatric AML. We have previously designed a multiplex screening strategy known as Multiplex Screening for Interacting Compounds in AML (MuSICAL); using an algorithm designed in-house, we screened all pairings of 384 FDA-approved compounds in less than 4000 wells by pooling drugs into 10 compounds per well. This approach maximised the probability of identifying new compound combinations with therapeutic potential while minimising cost, replication and redundancy. This screening strategy identified the triple combination of glimepiride, a sulfonylurea; pancuronium dibromide, a neuromuscular blocking agent; and vinblastine sulfate, a vinca alkaloid, as a potential therapy for paediatric AML. We envision that this approach can be used for a variety of disease-relevant screens allowing the efficient repurposing of drugs that can be rapidly moved into the clinic. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapies of Myeloid Leukaemia)

► Show Figures

Figure 1

9 pages, 1835 KiB

Open AccessArticle

Endothelium-Derived Hyperpolarizing Factor (EDHF) Mediates Acetylsalicylic Acid (Aspirin) Vasodilation of Pregnant Rat Mesenteric Arteries

by Helga Helgadóttir, Teresa Tropea, Sveinbjörn Gizurarson and Maurizio Mandalà

Int. J. Mol. Sci. 2021, 22(18), 10162; https://doi.org/10.3390/ijms221810162 - 21 Sep 2021

Cited by 3 | Viewed by 3221

Abstract

Acetylsalicylic acid (aspirin) exhibits a broad range of activities, including analgesic, antipyretic, and antiplatelet properties. Recent clinical studies also recommend aspirin prophylaxis in women with a high risk of pre-eclampsia, a major complication of pregnancy characterized by hypertension. We investigated the effect of [...] Read more.

Acetylsalicylic acid (aspirin) exhibits a broad range of activities, including analgesic, antipyretic, and antiplatelet properties. Recent clinical studies also recommend aspirin prophylaxis in women with a high risk of pre-eclampsia, a major complication of pregnancy characterized by hypertension. We investigated the effect of aspirin on mesenteric resistance arteries and found outdiscovered the molecular mechanism underlying this action. Aspirin (10⁻¹²–10⁻⁶ M) was tested on pregnant rat mesenteric resistance arteries by a pressurized arteriography. Aspirin was investigated in the presence of several inhibitors of: (a) nitric oxide synthase (L-NAME 2 × 10⁻⁴ M); (b) cyclooxygenase (Indomethacin, 10⁻⁵ M); (c) Ca²⁺-activated K⁺ channels (Kca): small conductance (SKca, Apamin, 10⁻⁷ M), intermediate conductance (IKca, TRAM34, 10⁻⁵ M), and big conductance (BKca, paxilline, 10⁻⁵ M); and (d) endothelial-derived hyperpolarizing factor (high KCl, 80 mM). Aspirin caused a concentration-dependent vasodilation. Aspirin-vasodilation was abolished by removal of endothelium or by high KCl. Furthermore, preincubation with either apamin plus TRAM-34 or paxillin significantly attenuated aspirin vasodilation (p < 0.05). For the first time, we showed that aspirin induced endothelium-dependent vasodilation in mesenteric resistance arteries through the endothelial-derived hyperpolarizing factor (EDHF) and calcium-activated potassium channels. By activating this molecular mechanism, aspirin may lower peripheral vascular resistance and be beneficial in pregnancies complicated by hypertension. Full article

(This article belongs to the Special Issue Molecular Vascular Physiology)

► Show Figures

Figure 1

34 pages, 3279 KiB

Open AccessReview

Elucidating the Neuroprotective Role of PPARs in Parkinson’s Disease: A Neoteric and Prospective Target

by Tapan Behl, Piyush Madaan, Aayush Sehgal, Sukhbir Singh, Neelam Sharma, Saurabh Bhatia, Ahmed Al-Harrasi, Sridevi Chigurupati, Ibrahim Alrashdi and Simona Gabriela Bungau

Int. J. Mol. Sci. 2021, 22(18), 10161; https://doi.org/10.3390/ijms221810161 - 21 Sep 2021

Cited by 43 | Viewed by 5467

Abstract

One of the utmost frequently emerging neurodegenerative diseases, Parkinson’s disease (PD) must be comprehended through the forfeit of dopamine (DA)-generating nerve cells in the substantia nigra pars compacta (SN-PC). The etiology and pathogenesis underlying the emergence of PD is still obscure. However, expanding [...] Read more.

One of the utmost frequently emerging neurodegenerative diseases, Parkinson’s disease (PD) must be comprehended through the forfeit of dopamine (DA)-generating nerve cells in the substantia nigra pars compacta (SN-PC). The etiology and pathogenesis underlying the emergence of PD is still obscure. However, expanding corroboration encourages the involvement of genetic and environmental factors in the etiology of PD. The destruction of numerous cellular components, namely oxidative stress, ubiquitin-proteasome system (UPS) dysfunction, autophagy-lysosome system dysfunction, neuroinflammation and programmed cell death, and mitochondrial dysfunction partake in the pathogenesis of PD. Present-day pharmacotherapy can alleviate the manifestations, but no therapy has been demonstrated to cease disease progression. Peroxisome proliferator-activated receptors (PPARs) are ligand-directed transcription factors pertaining to the class of nuclear hormone receptors (NHR), and are implicated in the modulation of mitochondrial operation, inflammation, wound healing, redox equilibrium, and metabolism of blood sugar and lipids. Numerous PPAR agonists have been recognized to safeguard nerve cells from oxidative destruction, inflammation, and programmed cell death in PD and other neurodegenerative diseases. Additionally, various investigations suggest that regular administration of PPAR-activating non-steroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, indomethacin), and leukotriene receptor antagonists (montelukast) were related to the de-escalated evolution of neurodegenerative diseases. The present review elucidates the emerging evidence enlightening the neuroprotective outcomes of PPAR agonists in in vivo and in vitro models experiencing PD. Existing articles up to the present were procured through PubMed, MEDLINE, etc., utilizing specific keywords spotlighted in this review. Furthermore, the authors aim to provide insight into the neuroprotective actions of PPAR agonists by outlining the pharmacological mechanism. As a conclusion, PPAR agonists exhibit neuroprotection through modulating the expression of a group of genes implicated in cellular survival pathways, and may be a propitious target in the therapy of incapacitating neurodegenerative diseases like PD. Full article

(This article belongs to the Special Issue Neuroprotection: Rescue from Neuronal Death in the Brain 2.0)

► Show Figures

Figure 1

22 pages, 1081 KiB

Open AccessReview

The Role of lncRNAs in Rare Tumors with a Focus on HOX Transcript Antisense RNA (HOTAIR)

by Giuseppina Liguori, Margherita Cerrone, Annarosaria De Chiara, Salvatore Tafuto, Maura Tracey de Bellis, Gerardo Botti, Maurizio Di Bonito and Monica Cantile

Int. J. Mol. Sci. 2021, 22(18), 10160; https://doi.org/10.3390/ijms221810160 - 21 Sep 2021

Cited by 6 | Viewed by 4766

Abstract

Rare cancers are identified as those with an annual incidence of fewer than 6 per 100,000 persons and includes both epithelial and stromal tumors from different anatomical areas. The advancement of analytical methods has produced an accurate molecular characterization of most human cancers, [...] Read more.

Rare cancers are identified as those with an annual incidence of fewer than 6 per 100,000 persons and includes both epithelial and stromal tumors from different anatomical areas. The advancement of analytical methods has produced an accurate molecular characterization of most human cancers, suggesting a “molecular classification” that has allowed the establishment of increasingly personalized therapeutic strategies. However, the limited availability of rare cancer samples has resulted in very few therapeutic options for these tumors, often leading to poor prognosis. Long non coding RNAs (lncRNAs) are a class of non-coding RNAs mostly involved in tumor progression and drug response. In particular, the lncRNA HOX transcript antisense RNA (HOTAIR) represents an emergent diagnostic, prognostic and predictive biomarker in many human cancers. The aim of this review is to highlight the role of HOTAIR in rare cancers, proposing it as a new biomarker usable in the management of these tumors. Full article

(This article belongs to the Special Issue HOX Genes in Development and Disease)

► Show Figures

Figure 1

27 pages, 10576 KiB

Open AccessArticle

Endothelial Colony-Forming Cells Dysfunctions Are Associated with Arterial Hypertension in a Rat Model of Intrauterine Growth Restriction

by Stephanie Simoncini, Hanna Coppola, Angela Rocca, Isaline Bachmann, Estelle Guillot, Leila Zippo, Françoise Dignat-George, Florence Sabatier, Romain Bedel, Anne Wilson, Nathalie Rosenblatt-Velin, Jean-Baptiste Armengaud, Steeve Menétrey, Anne-Christine Peyter, Umberto Simeoni and Catherine Yzydorczyk

Int. J. Mol. Sci. 2021, 22(18), 10159; https://doi.org/10.3390/ijms221810159 - 21 Sep 2021

Cited by 5 | Viewed by 3524

Abstract

Infants born after intrauterine growth restriction (IUGR) are at risk of developing arterial hypertension at adulthood. The endothelium plays a major role in the pathogenesis of hypertension. Endothelial colony-forming cells (ECFCs), critical circulating components of the endothelium, are involved in vasculo-and angiogenesis and [...] Read more.

Infants born after intrauterine growth restriction (IUGR) are at risk of developing arterial hypertension at adulthood. The endothelium plays a major role in the pathogenesis of hypertension. Endothelial colony-forming cells (ECFCs), critical circulating components of the endothelium, are involved in vasculo-and angiogenesis and in endothelium repair. We previously described impaired functionality of ECFCs in cord blood of low-birth-weight newborns. However, whether early ECFC alterations persist thereafter and could be associated with hypertension in individuals born after IUGR remains unknown. A rat model of IUGR was induced by a maternal low-protein diet during gestation versus a control (CTRL) diet. In six-month-old offspring, only IUGR males have increased systolic blood pressure (tail-cuff plethysmography) and microvascular rarefaction (immunofluorescence). ECFCs isolated from bone marrow of IUGR versus CTRL males displayed a decreased proportion of CD31+ versus CD146+ staining on CD45− cells, CD34 expression (flow cytometry, immunofluorescence), reduced proliferation (BrdU incorporation), and an impaired capacity to form capillary-like structures (Matrigel test), associated with an impaired angiogenic profile (immunofluorescence). These dysfunctions were associated with oxidative stress (increased superoxide anion levels (fluorescent dye), decreased superoxide dismutase protein expression, increased DNA damage (immunofluorescence), and stress-induced premature senescence (SIPS; increased beta-galactosidase activity, increased p16^INK4a, and decreased sirtuin-1 protein expression). This study demonstrated an impaired functionality of ECFCs at adulthood associated with arterial hypertension in individuals born after IUGR. Full article

(This article belongs to the Special Issue Endothelial Progenitor Cells in Health and Disease)

► Show Figures

Figure 1

12 pages, 2683 KiB

Open AccessArticle

Role of the Endocannabinoid/Endovanilloid System in the Modulation of Osteoclast Activity in Paget’s Disease of Bone

by Marco Paoletta, Antimo Moretti, Sara Liguori, Alessandra Di Paola, Chiara Tortora, Maura Argenziano, Francesca Rossi and Giovanni Iolascon

Int. J. Mol. Sci. 2021, 22(18), 10158; https://doi.org/10.3390/ijms221810158 - 21 Sep 2021

Cited by 3 | Viewed by 2658

Abstract

The role of the endocannabinoid/endovanilloid (EC/EV) system in bone metabolism has recently received attention. Current literature evidences the modulation of osteoclasts and osteoblasts through the activation or inhibition of cannabinoid receptors in various pathological conditions with secondary involvement of bone tissue. However, this [...] Read more.

The role of the endocannabinoid/endovanilloid (EC/EV) system in bone metabolism has recently received attention. Current literature evidences the modulation of osteoclasts and osteoblasts through the activation or inhibition of cannabinoid receptors in various pathological conditions with secondary involvement of bone tissue. However, this role is still unclear in primary bone diseases. Paget’s disease of the bone (PDB) could be considered a disease model for analyzing the role of the EC/EV system on osteoclasts (OCs), speculating the potential use of specific agents targeting this system for managing metabolic bone disorders. The aim of the study is to analyze OCs expression of EC/EV system in patients with PDB and to compare OCs activity between this population and healthy people. Finally, we investigate whether specific agents targeting EC/EV systems are able to modulate OCs activity in this metabolic bone disorder. We found a significant increase in cannabinoid receptor type 2 (CB2) protein expression in patients with PDB, compared to healthy controls. Moreover, we found a significant reduction in multi-nucleated tartrate-resistant acid phosphatase (TRAP)–positive OCs and resorption areas after treatment with JWH-133. CB2 could be a molecular target for reducing the activity of OCs in PDB, opening new therapeutic scenarios for the management of this condition. Full article

(This article belongs to the Special Issue Metabolic Bone Diseases: Molecular Biology, Pathophysiology and Therapy 2.0)

► Show Figures

Figure 1

25 pages, 2918 KiB

Open AccessReview

BH3 Mimetics in Hematologic Malignancies

by Pavel Klener, Dana Sovilj, Nicol Renesova and Ladislav Andera

Int. J. Mol. Sci. 2021, 22(18), 10157; https://doi.org/10.3390/ijms221810157 - 21 Sep 2021

Cited by 14 | Viewed by 5179

Abstract

Hematologic malignancies (HM) comprise diverse cancers of lymphoid and myeloid origin, including lymphomas (approx. 40%), chronic lymphocytic leukemia (CLL, approx. 15%), multiple myeloma (MM, approx. 15%), acute myeloid leukemia (AML, approx. 10%), and many other diseases. Despite considerable improvement in treatment options and [...] Read more.

Hematologic malignancies (HM) comprise diverse cancers of lymphoid and myeloid origin, including lymphomas (approx. 40%), chronic lymphocytic leukemia (CLL, approx. 15%), multiple myeloma (MM, approx. 15%), acute myeloid leukemia (AML, approx. 10%), and many other diseases. Despite considerable improvement in treatment options and survival parameters in the new millennium, many patients with HM still develop chemotherapy‑refractory diseases and require re-treatment. Because frontline therapies for the majority of HM (except for CLL) are still largely based on classical cytostatics, the relapses are often associated with defects in DNA damage response (DDR) pathways and anti-apoptotic blocks exemplified, respectively, by mutations or deletion of the TP53 tumor suppressor, and overexpression of anti-apoptotic proteins of the B-cell lymphoma 2 (BCL2) family. BCL2 homology 3 (BH3) mimetics represent a novel class of pro-apoptotic anti-cancer agents with a unique mode of action—direct targeting of mitochondria independently of TP53 gene aberrations. Consequently, BH3 mimetics can effectively eliminate even non-dividing malignant cells with adverse molecular cytogenetic alterations. Venetoclax, the nanomolar inhibitor of BCL2 anti-apoptotic protein has been approved for the therapy of CLL and AML. Numerous venetoclax-based combinatorial treatment regimens, next-generation BCL2 inhibitors, and myeloid cell leukemia 1 (MCL1) protein inhibitors, which are another class of BH3 mimetics with promising preclinical results, are currently being tested in several clinical trials in patients with diverse HM. These pivotal trials will soon answer critical questions and concerns about these innovative agents regarding not only their anti-tumor efficacy but also potential side effects, recommended dosages, and the optimal length of therapy as well as identification of reliable biomarkers of sensitivity or resistance. Effective harnessing of the full therapeutic potential of BH3 mimetics is a critical mission as it may directly translate into better management of the aggressive forms of HM and could lead to significantly improved survival parameters and quality of life in patients with urgent medical needs. Full article

(This article belongs to the Special Issue Quo Vadis Cancer Research? On Molecular Mechanisms and Drug Discovery)

► Show Figures

Figure 1

22 pages, 17418 KiB

Open AccessArticle

Membrane Interactions of Latarcins: Antimicrobial Peptides from Spider Venom

by Parvesh Wadhwani, Saiguru Sekaran, Erik Strandberg, Jochen Bürck, Archana Chugh and Anne S. Ulrich

Int. J. Mol. Sci. 2021, 22(18), 10156; https://doi.org/10.3390/ijms221810156 - 21 Sep 2021

Cited by 8 | Viewed by 3253

Abstract

A group of seven peptides from spider venom with diverse sequences constitute the latarcin family. They have been described as membrane-active antibiotics, but their lipid interactions have not yet been addressed. Using circular dichroism and solid-state ¹⁵N-NMR, we systematically characterized and compared [...] Read more.

A group of seven peptides from spider venom with diverse sequences constitute the latarcin family. They have been described as membrane-active antibiotics, but their lipid interactions have not yet been addressed. Using circular dichroism and solid-state ¹⁵N-NMR, we systematically characterized and compared the conformation and helix alignment of all seven peptides in their membrane-bound state. These structural results could be correlated with activity assays (antimicrobial, hemolysis, fluorescence vesicle leakage). Functional synergy was not observed amongst any of the latarcins. In the presence of lipids, all peptides fold into amphiphilic α-helices as expected, the helices being either surface-bound or tilted in the bilayer. The most tilted peptide, Ltc2a, possesses a novel kind of amphiphilic profile with a coiled-coil-like hydrophobic strip and is the most aggressive of all. It indiscriminately permeabilizes natural membranes (antimicrobial, hemolysis) as well as artificial lipid bilayers through the segregation of anionic lipids and possibly enhanced motional averaging. Ltc1, Ltc3a, Ltc4a, and Ltc5a are efficient and selective in killing bacteria but without causing significant bilayer disturbance. They act rather slowly or may even translocate towards intracellular targets, suggesting more subtle lipid interactions. Ltc6a and Ltc7, finally, do not show much antimicrobial action but can nonetheless perturb model bilayers. Full article

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

► Show Figures

Figure 1

14 pages, 2663 KiB

Open AccessArticle

Wound Healing Effect of Gintonin Involves Lysophosphatidic Acid Receptor/Vascular Endothelial Growth Factor Signaling Pathway in Keratinocytes

by Sun-Hye Choi, Kyung-Jong Won, Rami Lee, Han-Sung Cho, Sung-Hee Hwang and Seung-Yeol Nah

Int. J. Mol. Sci. 2021, 22(18), 10155; https://doi.org/10.3390/ijms221810155 - 21 Sep 2021

Cited by 11 | Viewed by 3511

Abstract

Gintonin, a novel compound of ginseng, is a ligand of the lysophosphatidic acid (LPA) receptor. The in vitro and in vivo skin wound healing effects of gintonin remain unknown. Therefore, the objective of this study was to investigate the effects of gintonin on [...] Read more.

Gintonin, a novel compound of ginseng, is a ligand of the lysophosphatidic acid (LPA) receptor. The in vitro and in vivo skin wound healing effects of gintonin remain unknown. Therefore, the objective of this study was to investigate the effects of gintonin on wound healing-linked responses, especially migration and proliferation, in skin keratinocytes HaCaT. In this study, 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide assay, Boyden chamber migration assay, scratch wound healing assay, and Western blot assay were performed. A tail wound mouse model was used for the in vivo test. Gintonin increased proliferation, migration, and scratch closure in HaCaT cells. It also increased the release of vascular endothelial growth factor (VEGF) in HaCaT cells. However, these increases, induced by gintonin, were markedly blocked by treatment with Ki16425, an LPA inhibitor, PD98059, an ERK inhibitor, 1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis (acetoxymethyl ester), a calcium chelator, and U73122, a PLC inhibitor. The VEGF receptor inhibitor axitinib also attenuated gintonin-enhanced HaCaT cell proliferation. Gintonin increased the phosphorylation of AKT and ERK1/2 in HaCaT cells. In addition, gintonin improved tail wound healing in mice. These results indicate that gintonin may promote wound healing through LPA receptor activation and/or VEGF release-mediated downstream signaling pathways. Thus, gintonin could be a beneficial substance to facilitate skin wound healing. Full article

(This article belongs to the Section Molecular Pharmacology)

► Show Figures

Figure 1

17 pages, 4198 KiB

Open AccessArticle

Uncovering miRNA-mRNA Regulatory Modules in Developing Xylem of Pinus massoniana via Small RNA and Degradome Sequencing

by Tengfei Shen, Mengxuan Xu, Haoran Qi, Yuanheng Feng, Zhangqi Yang and Meng Xu

Int. J. Mol. Sci. 2021, 22(18), 10154; https://doi.org/10.3390/ijms221810154 - 21 Sep 2021

Cited by 15 | Viewed by 2813

Abstract

Xylem is required for the growth and development of higher plants to provide water and mineral elements. The thickening of the xylem secondary cell wall (SCW) not only improves plant survival, but also provides raw materials for industrial production. Numerous studies have found [...] Read more.

Xylem is required for the growth and development of higher plants to provide water and mineral elements. The thickening of the xylem secondary cell wall (SCW) not only improves plant survival, but also provides raw materials for industrial production. Numerous studies have found that transcription factors and non-coding RNAs regulate the process of SCW thickening. Pinus massoniana is an important woody tree species in China and is widely used to produce materials for construction, furniture, and packaging. However, the target genes of microRNAs (miRNAs) in the developing xylem of P. massoniana are not known. In this study, a total of 25 conserved miRNAs and 173 novel miRNAs were identified via small RNA sequencing, and 58 differentially expressed miRNAs were identified between the developing xylem (PM_X) and protoplasts isolated from the developing xylem (PM_XP); 26 of these miRNAs were significantly up-regulated in PM_XP compared with PM_X, and 32 were significantly down-regulated. A total of 153 target genes of 20 conserved miRNAs and 712 target genes of 113 novel miRNAs were verified by degradome sequencing. There may be conserved miRNA-mRNA modules (miRNA-MYB, miRNA-ARF, and miRNA-LAC) involved in softwood and hardwood formation. The results of qRT-PCR-based parallel validation were in relatively high agreement. This study explored the potential regulatory network of miRNAs in the developing xylem of P. massoniana and provides new insights into wood formation in coniferous species. Full article

(This article belongs to the Special Issue Plant Non-coding RNAs in the Era of Biological Big Data)

► Show Figures

Figure 1

15 pages, 10759 KiB

Open AccessArticle

Adipose Tissue-Derived Stromal Cells Alter the Mechanical Stability and Viscoelastic Properties of Gelatine Methacryloyl Hydrogels

by Francisco Drusso Martinez-Garcia, Martine Margaretha Valk, Prashant Kumar Sharma, Janette Kay Burgess and Martin Conrad Harmsen

Int. J. Mol. Sci. 2021, 22(18), 10153; https://doi.org/10.3390/ijms221810153 - 21 Sep 2021

Cited by 18 | Viewed by 3251

Abstract

The extracellular matrix provides mechanical cues to cells within it, not just in terms of stiffness (elasticity) but also time-dependent responses to deformation (viscoelasticity). In this work, we determined the viscoelastic transformation of gelatine methacryloyl (GelMA) hydrogels caused by adipose tissue-derived stromal cells [...] Read more.

The extracellular matrix provides mechanical cues to cells within it, not just in terms of stiffness (elasticity) but also time-dependent responses to deformation (viscoelasticity). In this work, we determined the viscoelastic transformation of gelatine methacryloyl (GelMA) hydrogels caused by adipose tissue-derived stromal cells (ASCs) through mathematical modelling. GelMA-ASCs combination is of interest to model stem cell-driven repair and to understand cell-biomaterial interactions in 3D environments. Immortalised human ASCs were embedded in 5%, 10%, and 15% (w/v) GelMA hydrogels and evaluated for 14 d. GelMA had a concentration-dependent increase in stiffness, but cells decreased this stiffness over time, across concentrations. Viscoelastic changes in terms of stress relaxation increased progressively in 5% GelMA, while mathematical Maxwell analysis showed that the relative importance (R_i) of the fastest Maxwell elements increased proportionally. The 10% GelMA only showed differences at 7 d. In contrast, ASCs in 15% GelMA caused slower stress relaxation, increasing the R_i of the slowest Maxwell element. We conclude that GelMA concentration influenced the stiffness and number of Maxwell elements. ASCs changed the percentage stress relaxation and R_i of Maxwell elements transforming hydrogel viscoelasticity into a more fluid environment over time. Overall, 5% GelMA induced the most favourable ASC response. Full article

(This article belongs to the Special Issue Molecular Morphology and Function of Stromal Cells)

► Show Figures

Figure 1

22 pages, 889 KiB

Open AccessReview

The Effect of Resveratrol on the Cardiovascular System from Molecular Mechanisms to Clinical Results

by Roland Gal, Laszlo Deres, Kalman Toth, Robert Halmosi and Tamas Habon

Int. J. Mol. Sci. 2021, 22(18), 10152; https://doi.org/10.3390/ijms221810152 - 21 Sep 2021

Cited by 55 | Viewed by 8513

Abstract

Cardiovascular diseases are the leading causes of death worldwide. The cardioprotective effects of natural polyphenols such as resveratrol (3,5,4-trihydroxystilbene) have been extensively investigated throughout recent decades. Many studies of RES have focused on its favorable effects on pathological conditions related to cardiovascular diseases [...] Read more.

Cardiovascular diseases are the leading causes of death worldwide. The cardioprotective effects of natural polyphenols such as resveratrol (3,5,4-trihydroxystilbene) have been extensively investigated throughout recent decades. Many studies of RES have focused on its favorable effects on pathological conditions related to cardiovascular diseases and their risk factors. The aim of this review was to summarize the wide beneficial effects of resveratrol on the cardiovascular system, including signal transduction pathways of cell longevity, energy metabolism of cardiomyocytes or cardiac remodeling, and its anti-inflammatory and antioxidant properties. In addition, this paper discusses the significant preclinical and human clinical trials of recent years with resveratrol on cardiovascular system. Finally, we present a short overview of antiviral and anti-inflammatory properties and possible future perspectives on RES against COVID-19 in cardiovascular diseases. Full article

(This article belongs to the Special Issue Health Benefits of Resveratrol 3.0)

► Show Figures

Figure 1

27 pages, 1757 KiB

Open AccessReview

Therapeutic Potential of Human Stem Cell Implantation in Alzheimer’s Disease

by Hau Jun Chan, Yanshree, Jaydeep Roy, George Lim Tipoe, Man-Lung Fung and Lee Wei Lim

Int. J. Mol. Sci. 2021, 22(18), 10151; https://doi.org/10.3390/ijms221810151 - 21 Sep 2021

Cited by 22 | Viewed by 7064

Abstract

Alzheimer’s disease (AD) is a progressive debilitating neurodegenerative disease and the most common form of dementia in the older population. At present, there is no definitive effective treatment for AD. Therefore, researchers are now looking at stem cell therapy as a possible treatment [...] Read more.

Alzheimer’s disease (AD) is a progressive debilitating neurodegenerative disease and the most common form of dementia in the older population. At present, there is no definitive effective treatment for AD. Therefore, researchers are now looking at stem cell therapy as a possible treatment for AD, but whether stem cells are safe and effective in humans is still not clear. In this narrative review, we discuss both preclinical studies and clinical trials on the therapeutic potential of human stem cells in AD. Preclinical studies have successfully differentiated stem cells into neurons in vitro, indicating the potential viability of stem cell therapy in neurodegenerative diseases. Preclinical studies have also shown that stem cell therapy is safe and effective in improving cognitive performance in animal models, as demonstrated in the Morris water maze test and novel object recognition test. Although few clinical trials have been completed and many trials are still in phase I and II, the initial results confirm the outcomes of the preclinical studies. However, limitations like rejection, tumorigenicity, and ethical issues are still barriers to the advancement of stem cell therapy. In conclusion, the use of stem cells in the treatment of AD shows promise in terms of effectiveness and safety. Full article

(This article belongs to the Special Issue Molecular Research on Neurodegenerative Diseases 2.0)

► Show Figures

Graphical abstract

17 pages, 1270 KiB

Open AccessReview

Eosinophils as Drivers of Severe Eosinophilic Asthma: Endotypes or Plasticity?

by Glenn Van Hulst, Fabrice Bureau and Christophe J. Desmet

Int. J. Mol. Sci. 2021, 22(18), 10150; https://doi.org/10.3390/ijms221810150 - 21 Sep 2021

Cited by 24 | Viewed by 9087

Abstract

Asthma is now recognized as a heterogeneous disease, encompassing different phenotypes driven by distinct pathophysiological mechanisms called endotypes. Common phenotypes of asthma, referred to as eosinophilic asthma, are characterized by the presence of eosinophilia. Eosinophils are usually considered invariant, terminally differentiated effector cells [...] Read more.

Asthma is now recognized as a heterogeneous disease, encompassing different phenotypes driven by distinct pathophysiological mechanisms called endotypes. Common phenotypes of asthma, referred to as eosinophilic asthma, are characterized by the presence of eosinophilia. Eosinophils are usually considered invariant, terminally differentiated effector cells and have become a primary therapeutic target in severe eosinophilic asthma (SEA) and other eosinophil-associated diseases (EADs). Biological treatments that target eosinophils reveal an unexpectedly complex role of eosinophils in asthma, including in SEA, suggesting that “not all eosinophils are equal”. In this review, we address our current understanding of the role of eosinophils in asthma with regard to asthma phenotypes and endotypes. We further address the possibility that different SEA phenotypes may involve differences in eosinophil biology. We discuss how these differences could arise through eosinophil “endotyping”, viz. adaptations of eosinophil function imprinted during their development, or through tissue-induced plasticity, viz. local adaptations of eosinophil function through interaction with their lung tissue niches. In doing so, we also discuss opportunities, technical challenges, and open questions that, if addressed, might provide considerable benefits in guiding the choice of the most efficient precision therapies of SEA and, by extension, other EADs. Full article

(This article belongs to the Special Issue Recent Research on Eosinophils)

► Show Figures

Figure 1

17 pages, 533 KiB

Open AccessReview

Biomarkers for Ehlers-Danlos Syndromes: There Is a Role?

by Laura Caliogna, Viviana Guerrieri, Salvatore Annunziata, Valentina Bina, Alice Maria Brancato, Alberto Castelli, Eugenio Jannelli, Alessandro Ivone, Federico Alberto Grassi, Mario Mosconi and Gianluigi Pasta

Int. J. Mol. Sci. 2021, 22(18), 10149; https://doi.org/10.3390/ijms221810149 - 20 Sep 2021

Cited by 13 | Viewed by 6156

Abstract

Ehlers-Danlos syndromes (EDS) are an inherited heterogeneous group of connective tissue disorders characterized by an abnormal collagen synthesis affecting skin, ligaments, joints, blood vessels, and other organs. It is one of the oldest known causes of bruising and bleeding, and it was described [...] Read more.

Ehlers-Danlos syndromes (EDS) are an inherited heterogeneous group of connective tissue disorders characterized by an abnormal collagen synthesis affecting skin, ligaments, joints, blood vessels, and other organs. It is one of the oldest known causes of bruising and bleeding, and it was described first by Hippocrates in 400 BC. In the last years, multiple gene variants involved in the pathogenesis of specific EDS subtypes have been identified; moreover, new clinical diagnostic criteria have been established. New classification models have also been studied in order to differentiate overlapping conditions. Moreover, EDS shares many characteristics with other similar disorders. Although distinguishing between these seemingly identical conditions is difficult, it is essential in ensuring proper patient care. Currently, there are many genetic and molecular studies underway to clarify the etiology of some variants of EDS. However, the genetic basis of the hypermobile type of EDS (hEDS) is still unknown. In this review, we focused on the study of two of the most common forms of EDS—classic and hypermobile—by trying to identify possible biomarkers that could be of great help to confirm patients’ diagnosis and their follow up. Full article

(This article belongs to the Special Issue Biomarkers in Rare Diseases 2.0)

Journal Menu

Journal Browser

Int. J. Mol. Sci., Volume 22, Issue 18 (September-2 2021) – 520 articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI