International Journal of Molecular Sciences

14 pages, 3936 KiB

Open AccessArticle

Angiotensin Type 2 and Mas Receptor Activation Prevents Myocardial Fibrosis and Hypertrophy through the Reduction of Inflammatory Cell Infiltration and Local Sympathetic Activity in Angiotensin II-Dependent Hypertension

by Giovanna Castoldi, Raffaella Carletti, Silvia Ippolito, Andrea Stella, Gianpaolo Zerbini, Sara Pelucchi, Giovanni Zatti and Cira R. T. di Gioia

Int. J. Mol. Sci. 2021, 22(24), 13678; https://doi.org/10.3390/ijms222413678 - 20 Dec 2021

Cited by 18 | Viewed by 3375

Abstract

Compound 21 (C21), an AT2 receptor agonist, and Angiotensin 1-7 (Ang 1-7), through Mas receptor, play an important role in the modulation of the protective arm of the renin-angiotensin system. The aim of this study was to investigate in an experimental model of [...] Read more.

Compound 21 (C21), an AT2 receptor agonist, and Angiotensin 1-7 (Ang 1-7), through Mas receptor, play an important role in the modulation of the protective arm of the renin-angiotensin system. The aim of this study was to investigate in an experimental model of angiotensin II-dependent hypertension whether the activation of the potentially protective arm of the renin-angiotensin system, through AT2 or Mas receptor stimulation, counteracts the onset of myocardial fibrosis and hypertrophy, and whether these effects are mediated by inflammatory mechanism and/or sympathetic activation. Sprague Dawley rats (n = 67) were treated for 1 (n = 25) and 4 (n = 42) weeks and divided in the following groups: (a) Angiotensin II (Ang II, 200 ng/kg/min, osmotic minipumps, sub cutis); (b) Ang II+Compound 21 (C21, 0.3 mg/kg/day, intraperitoneal); (c) Ang II+Ang 1-7 (576 µg/kg/day, intraperitoneal); (d) Ang II+Losartan (50 mg/kg/day, per os); (e) control group (physiological saline, sub cutis). Systolic blood pressure was measured by tail cuff method and, at the end of the experimental period, the rats were euthanized and the heart was excised to evaluate myocardial fibrosis, hypertrophy, inflammatory cell infiltration and tyrosine hydroxylase expression, used as marker of sympathetic activity. Ang II caused a significant increase of blood pressure, myocardial interstitial and perivascular fibrosis and myocardial hypertrophy, as compared to control groups. C21 or Ang 1-7 administration did not modify the increase in blood pressure in Ang II treated rats, but both prevented the development of myocardial fibrosis and hypertrophy. Treatment with losartan blocked the onset of hypertension and myocardial fibrosis and hypertrophy in Ang II treated rats. Activation of AT2 receptors or Mas receptors prevents the onset of myocardial fibrosis and hypertrophy in Ang II-dependent hypertension through the reduction of myocardial inflammatory cell infiltration and tyrosine hydroxylase expression. Unlike what happens in case of treatment with losartan, the antifibrotic and antihypertrophic effects that follow the activation of the AT2 or Mas receptors are independent on the modulation of blood pressure. Full article

(This article belongs to the Special Issue Molecular Interactions of Arterial Hypertension in Its Target Organs)

► Show Figures

Figure 1

17 pages, 2700 KiB

Open AccessArticle

Hormonomic Changes Driving the Negative Impact of Broomrape on Plant Host Interactions with Arbuscular Mycorrhizal Fungi

by Kiril Mishev, Petre I. Dobrev, Jozef Lacek, Roberta Filepová, Bistra Yuperlieva-Mateeva, Anelia Kostadinova and Tsveta Hristeva

Int. J. Mol. Sci. 2021, 22(24), 13677; https://doi.org/10.3390/ijms222413677 - 20 Dec 2021

Cited by 15 | Viewed by 3613

Abstract

Belowground interactions of plants with other organisms in the rhizosphere rely on extensive small-molecule communication. Chemical signals released from host plant roots ensure the development of beneficial arbuscular mycorrhizal (AM) fungi which in turn modulate host plant growth and stress tolerance. However, parasitic [...] Read more.

Belowground interactions of plants with other organisms in the rhizosphere rely on extensive small-molecule communication. Chemical signals released from host plant roots ensure the development of beneficial arbuscular mycorrhizal (AM) fungi which in turn modulate host plant growth and stress tolerance. However, parasitic plants have adopted the capacity to sense the same signaling molecules and to trigger their own seed germination in the immediate vicinity of host roots. The contribution of AM fungi and parasitic plants to the regulation of phytohormone levels in host plant roots and root exudates remains largely obscure. Here, we studied the hormonome in the model system comprising tobacco as a host plant, Phelipanche spp. as a holoparasitic plant, and the AM fungus Rhizophagus irregularis. Co-cultivation of tobacco with broomrape and AM fungi alone or in combination led to characteristic changes in the levels of endogenous and exuded abscisic acid, indole-3-acetic acid, cytokinins, salicylic acid, and orobanchol-type strigolactones. The hormonal content in exudates of broomrape-infested mycorrhizal roots resembled that in exudates of infested non-mycorrhizal roots and differed from that observed in exudates of non-infested mycorrhizal roots. Moreover, we observed a significant reduction in AM colonization of infested tobacco plants, pointing to a dominant role of the holoparasite within the tripartite system. Full article

(This article belongs to the Special Issue Selected Papers from International Conference on Plant Systems Biology and Biotechnology 2020)

► Show Figures

Figure 1

14 pages, 3398 KiB

Open AccessArticle

3D Printed SiOC(N) Ceramic Scaffolds for Bone Tissue Regeneration: Improved Osteogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells

by Yuejiao Yang, Apoorv Kulkarni, Gian Domenico Soraru, Joshua M. Pearce and Antonella Motta

Int. J. Mol. Sci. 2021, 22(24), 13676; https://doi.org/10.3390/ijms222413676 - 20 Dec 2021

Cited by 14 | Viewed by 4994

Abstract

Bone tissue engineering has developed significantly in recent years as there has been increasing demand for bone substitutes due to trauma, cancer, arthritis, and infections. The scaffolds for bone regeneration need to be mechanically stable and have a 3D architecture with interconnected pores. [...] Read more.

Bone tissue engineering has developed significantly in recent years as there has been increasing demand for bone substitutes due to trauma, cancer, arthritis, and infections. The scaffolds for bone regeneration need to be mechanically stable and have a 3D architecture with interconnected pores. With the advances in additive manufacturing technology, these requirements can be fulfilled by 3D printing scaffolds with controlled geometry and porosity using a low-cost multistep process. The scaffolds, however, must also be bioactive to promote the environment for the cells to regenerate into bone tissue. To determine if a low-cost 3D printing method for bespoke SiOC(N) porous structures can regenerate bone, these structures were tested for osteointegration potential by using human mesenchymal stem cells (hMSCs). This includes checking the general biocompatibilities under the osteogenic differentiation environment (cell proliferation and metabolism). Moreover, cell morphology was observed by confocal microscopy, and gene expressions on typical osteogenic markers at different stages for bone formation were determined by real-time PCR. The results of the study showed the pore size of the scaffolds had a significant impact on differentiation. A certain range of pore size could stimulate osteogenic differentiation, thus promoting bone regrowth and regeneration. Full article

(This article belongs to the Special Issue 3D Printing and Biomaterials for Biological and Medical Application)

► Show Figures

Figure 1

15 pages, 901 KiB

Open AccessReview

Endothelial Progenitor Cells and Rheumatoid Arthritis: Response to Endothelial Dysfunction and Clinical Evidences

by Klara Komici, Angelica Perna, Aldo Rocca, Leonardo Bencivenga, Giuseppe Rengo and Germano Guerra

Int. J. Mol. Sci. 2021, 22(24), 13675; https://doi.org/10.3390/ijms222413675 - 20 Dec 2021

Cited by 6 | Viewed by 3744

Abstract

Rheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disease characterized by the swelling of multiple joints, pain and stiffness, and accelerated atherosclerosis. Sustained immune response and chronic inflammation, which characterize RA, may induce endothelial activation, damage and dysfunction. An equilibrium between endothelial damage [...] Read more.

Rheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disease characterized by the swelling of multiple joints, pain and stiffness, and accelerated atherosclerosis. Sustained immune response and chronic inflammation, which characterize RA, may induce endothelial activation, damage and dysfunction. An equilibrium between endothelial damage and repair, together with the preservation of endothelial integrity, is of crucial importance for the homeostasis of endothelium. Endothelial Progenitor Cells (EPCs) represent a heterogenous cell population, characterized by the ability to differentiate into mature endothelial cells (ECs), which contribute to vascular homeostasis, neovascularization and endothelial repair. A modification of the number and function of EPCs has been described in numerous chronic inflammatory and auto-immune conditions; however, reports that focus on the number and functions of EPCs in RA are characterized by conflicting results, and discrepancies exist among different studies. In the present review, the authors describe EPCs’ role and response to RA-related endothelial modification, with the aim of illustrating current evidence regarding the level of EPCs and their function in this disease, to summarize EPCs’ role as a biomarker in cardiovascular comorbidities related to RA, and finally, to discuss the modulation of EPCs secondary to RA therapy. Full article

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

► Show Figures

Figure 1

12 pages, 672 KiB

Open AccessReview

Induced Pluripotent Stem Cells (iPSCs) and Gene Therapy: A New Era for the Treatment of Neurological Diseases

by Giulia Paolini Sguazzi, Valentina Muto, Marco Tartaglia, Enrico Bertini and Claudia Compagnucci

Int. J. Mol. Sci. 2021, 22(24), 13674; https://doi.org/10.3390/ijms222413674 - 20 Dec 2021

Cited by 15 | Viewed by 6121

Abstract

To date, gene therapy has employed viral vectors to deliver therapeutic genes. However, recent progress in molecular and cell biology has revolutionized the field of stem cells and gene therapy. A few years ago, clinical trials started using stem cell replacement therapy, and [...] Read more.

To date, gene therapy has employed viral vectors to deliver therapeutic genes. However, recent progress in molecular and cell biology has revolutionized the field of stem cells and gene therapy. A few years ago, clinical trials started using stem cell replacement therapy, and the induced pluripotent stem cells (iPSCs) technology combined with CRISPR-Cas9 gene editing has launched a new era in gene therapy for the treatment of neurological disorders. Here, we summarize the latest findings in this research field and discuss their clinical applications, emphasizing the relevance of recent studies in the development of innovative stem cell and gene editing therapeutic approaches. Even though tumorigenicity and immunogenicity are existing hurdles, we report how recent progress has tackled them, making engineered stem cell transplantation therapy a realistic option. Full article

(This article belongs to the Special Issue Gene Therapy for Neurological Disorder)

► Show Figures

Figure 1

11 pages, 1983 KiB

Open AccessArticle

nc886, a Non-Coding RNA, Is a New Biomarker and Epigenetic Mediator of Cellular Senescence in Fibroblasts

by Yuna Kim, Hyanggi Ji, Eunae Cho, Nok-Hyun Park, Kyeonghwan Hwang, Wonseok Park, Kwang-Soo Lee, Deokhoon Park and Eunsun Jung

Int. J. Mol. Sci. 2021, 22(24), 13673; https://doi.org/10.3390/ijms222413673 - 20 Dec 2021

Cited by 10 | Viewed by 2939

Abstract

Functional studies of organisms and human models have revealed that epigenetic changes can significantly impact the process of aging. Non-coding RNA (ncRNA), one of epigenetic regulators, plays an important role in modifying the expression of mRNAs and their proteins. It can mediate the [...] Read more.

Functional studies of organisms and human models have revealed that epigenetic changes can significantly impact the process of aging. Non-coding RNA (ncRNA), one of epigenetic regulators, plays an important role in modifying the expression of mRNAs and their proteins. It can mediate the phenotype of cells. It has been reported that nc886 (=vtRNA2-1 or pre-miR-886), a long ncRNA, can suppress tumor formation and photo-damages of keratinocytes caused by UVB. The aim of this study was to determine the role of nc886 in replicative senescence of fibroblasts and determine whether substances capable of controlling nc886 expression could regulate cellular senescence. In replicative senescence fibroblasts, nc886 expression was decreased while methylated nc886 was increased. There were changes of senescence biomarkers including SA-β-gal activity and expression of p16INK4A and p21Waf1/Cip1 in senescent cells. These findings indicate that the decrease of nc886 associated with aging is related to cellular senescence of fibroblasts and that increasing nc886 expression has potential to suppress cellular senescence. AbsoluTea Concentrate 2.0 (ATC) increased nc886 expression and ameliorated cellular senescence of fibroblasts by inhibiting age-related biomarkers. These results indicate that nc886 has potential as a new target for anti-aging and that ATC can be a potent epigenetic anti-aging ingredient. Full article

(This article belongs to the Section Molecular Immunology)

► Show Figures

Figure 1

18 pages, 993 KiB

Open AccessReview

Therapeutic Potential of Mesenchymal Stem Cells (MSCs) and MSC-Derived Extracellular Vesicles for the Treatment of Spinal Cord Injury

by Gang-Un Kim, Soo-Eun Sung, Kyung-Ku Kang, Joo-Hee Choi, Sijoon Lee, Minkyoung Sung, Seung Yun Yang, Seul-Ki Kim, Young In Kim, Ju-Hyeon Lim, Min-Soo Seo and Gun Woo Lee

Int. J. Mol. Sci. 2021, 22(24), 13672; https://doi.org/10.3390/ijms222413672 - 20 Dec 2021

Cited by 43 | Viewed by 5960

Abstract

Spinal cord injury (SCI) is a life-threatening condition that leads to permanent disability with partial or complete loss of motor, sensory, and autonomic functions. SCI is usually caused by initial mechanical insult, followed by a cascade of several neuroinflammation and structural changes. For [...] Read more.

Spinal cord injury (SCI) is a life-threatening condition that leads to permanent disability with partial or complete loss of motor, sensory, and autonomic functions. SCI is usually caused by initial mechanical insult, followed by a cascade of several neuroinflammation and structural changes. For ameliorating the neuroinflammatory cascades, MSC has been regarded as a therapeutic agent. The animal SCI research has demonstrated that MSC can be a valuable therapeutic agent with several growth factors and cytokines that may induce anti-inflammatory and regenerative effects. However, the therapeutic efficacy of MSCs in animal SCI models is inconsistent, and the optimal method of MSCs remains debatable. Moreover, there are several limitations to developing these therapeutic agents for humans. Therefore, identifying novel agents for regenerative medicine is necessary. Extracellular vesicles are a novel source for regenerative medicine; they possess nucleic acids, functional proteins, and bioactive lipids and perform various functions, including damaged tissue repair, immune response regulation, and reduction of inflammation. MSC-derived exosomes have advantages over MSCs, including small dimensions, low immunogenicity, and no need for additional procedures for culture expansion or delivery. Certain studies have demonstrated that MSC-derived extracellular vesicles (EVs), including exosomes, exhibit outstanding chondroprotective and anti-inflammatory effects. Therefore, we reviewed the principles and patho-mechanisms and summarized the research outcomes of MSCs and MSC-derived EVs for SCI, reported to date. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 3.0)

► Show Figures

Figure 1

16 pages, 2740 KiB

Open AccessArticle

Luteolin Improves Perivascular Adipose Tissue Profile and Vascular Dysfunction in Goto-Kakizaki Rats

by Marcelo Queiroz, Adriana Leandro, Lara Azul, Artur Figueirinha, Raquel Seiça and Cristina M. Sena

Int. J. Mol. Sci. 2021, 22(24), 13671; https://doi.org/10.3390/ijms222413671 - 20 Dec 2021

Cited by 12 | Viewed by 3423

Abstract

We investigated the effects of luteolin on metabolism, vascular reactivity, and perivascular adipose tissue (PVAT) in nonobese type 2 diabetes mellitus animal model, Goto-Kakizaki (GK) rats. Methods: Wistar and GK rats were divided in two groups: (1) control groups treated with vehicle; (2) [...] Read more.

We investigated the effects of luteolin on metabolism, vascular reactivity, and perivascular adipose tissue (PVAT) in nonobese type 2 diabetes mellitus animal model, Goto-Kakizaki (GK) rats. Methods: Wistar and GK rats were divided in two groups: (1) control groups treated with vehicle; (2) groups treated with luteolin (10 mg/kg/day, for 2 months). Several metabolic parameters such as adiposity index, lipid profile, fasting glucose levels, glucose and insulin tolerance tests were determined. Endothelial function and contraction studies were performed in aortas with (PVAT+) or without (PVAT−) periaortic adipose tissue. We also studied vascular oxidative stress, glycation and assessed CRP, CCL2, and nitrotyrosine levels in PVAT. Results: Endothelial function was impaired in diabetic GK rats (47% (GK − PVAT) and 65% (GK + PVAT) inhibition of maximal endothelial dependent relaxation) and significantly improved by luteolin treatment (29% (GK − PVAT) and 22% (GK + PVAT) inhibition of maximal endothelial dependent relaxation, p < 0.01). Vascular oxidative stress and advanced glycation end-products’ levels were increased in aortic rings (~2-fold, p < 0.05) of diabetic rats and significantly improved by luteolin treatment (to levels not significantly different from controls). Periaortic adipose tissue anti-contractile action was significantly rescued with luteolin administration (p < 0.001). In addition, luteolin treatment significantly recovered proinflammatory and pro-oxidant PVAT phenotype, and improved systemic and metabolic parameters in GK rats. Conclusions: Luteolin ameliorates endothelial dysfunction in type 2 diabetes and exhibits therapeutic potential for the treatment of vascular complications associated with type 2 diabetes. Full article

(This article belongs to the Special Issue Preventive and Therapeutic Strategies in Vascular Dysfunction)

► Show Figures

Figure 1

11 pages, 570 KiB

Open AccessReview

Shaping of Monocyte-Derived Dendritic Cell Development and Function by Environmental Factors in Rheumatoid Arthritis

by Frédéric Coutant

Int. J. Mol. Sci. 2021, 22(24), 13670; https://doi.org/10.3390/ijms222413670 - 20 Dec 2021

Cited by 16 | Viewed by 4186

Abstract

Dendritic cells (DC) are heterogeneous cell populations essential for both inducing immunity and maintaining immune tolerance. Chronic inflammatory contexts, such as found in rheumatoid arthritis (RA), severely affect the distribution and the function of DC, contributing to defective tolerance and fueling inflammation. In [...] Read more.

Dendritic cells (DC) are heterogeneous cell populations essential for both inducing immunity and maintaining immune tolerance. Chronic inflammatory contexts, such as found in rheumatoid arthritis (RA), severely affect the distribution and the function of DC, contributing to defective tolerance and fueling inflammation. In RA, the synovial fluid of patients is enriched by a subset of DC that derive from monocytes (Mo-DC), which promote deleterious Th17 responses. The characterization of environmental factors in the joint that impact on the development and the fate of human Mo-DC is therefore of great importance in RA. When monocytes leave the blood and infiltrate inflamed synovial tissues, the process of differentiation into Mo-DC can be influenced by interactions with soluble factors such as cytokines, local acidosis and dysregulated synoviocytes. Other molecular factors, such as the citrullination process, can also enhance osteoclast differentiation from Mo-DC, favoring bone damages in RA. Conversely, biotherapies used to control inflammation in RA, modulate also the process of monocyte differentiation into DC. The identification of the environmental mediators that control the differentiation of Mo-DC, as well as the underlying molecular signaling pathways, could constitute a major breakthrough for the development of new therapies in RA. Full article

(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms)

► Show Figures

Figure 1

16 pages, 821 KiB

Open AccessArticle

Biological Activity, Lipophilicity and Cytotoxicity of Novel 3-Acetyl-2,5-disubstituted-1,3,4-oxadiazolines

by Kinga Paruch, Anna Biernasiuk, Anna Berecka-Rycerz, Anna Hordyjewska and Łukasz Popiołek

Int. J. Mol. Sci. 2021, 22(24), 13669; https://doi.org/10.3390/ijms222413669 - 20 Dec 2021

Cited by 5 | Viewed by 2869

Abstract

Antibiotic resistance is now a global problem, and the lack of effective antimicrobial agents for the treatment of diseases caused by resistant microbes is increasing. The 3-acetyl-2,5-disubstituted-1,3,4-oxadiazolines presented in this article may provide a good starting point for the development of potential new [...] Read more.

Antibiotic resistance is now a global problem, and the lack of effective antimicrobial agents for the treatment of diseases caused by resistant microbes is increasing. The 3-acetyl-2,5-disubstituted-1,3,4-oxadiazolines presented in this article may provide a good starting point for the development of potential new effective antimicrobial agents useful in the treatment of bacterial and fungal infections. Particular attention is drawn to the 1,3,4-oxadiazole derivative marked with the number 29 with 5-nitrofuran-2-yl substituent in its chemical structure. This substance showed a strong bactericidal effect, especially against Staphylococcus spp., and no cytotoxicity to the L929 normal cell line. Full article

(This article belongs to the Special Issue Bioactive Oxadiazoles 2.0)

► Show Figures

Scheme 1

12 pages, 1611 KiB

Open AccessReview

Ionic Regulation of T-Cell Function and Anti-Tumour Immunity

by Pierpaolo Ginefra, Helen Carrasco Hope, Mattia Spagna, Alessandra Zecchillo and Nicola Vannini

Int. J. Mol. Sci. 2021, 22(24), 13668; https://doi.org/10.3390/ijms222413668 - 20 Dec 2021

Cited by 9 | Viewed by 3823

Abstract

The capacity of T cells to identify and kill cancer cells has become a central pillar of immune-based cancer therapies. However, T cells are characterized by a dysfunctional state in most tumours. A major obstacle for proper T-cell function is the metabolic constraints [...] Read more.

The capacity of T cells to identify and kill cancer cells has become a central pillar of immune-based cancer therapies. However, T cells are characterized by a dysfunctional state in most tumours. A major obstacle for proper T-cell function is the metabolic constraints posed by the tumour microenvironment (TME). In the TME, T cells compete with cancer cells for macronutrients (sugar, proteins, and lipid) and micronutrients (vitamins and minerals/ions). While the role of macronutrients in T-cell activation and function is well characterized, the contribution of micronutrients and especially ions in anti-tumour T-cell activities is still under investigation. Notably, ions are important for most of the signalling pathways regulating T-cell anti-tumour function. In this review, we discuss the role of six biologically relevant ions in T-cell function and in anti-tumour immunity, elucidating potential strategies to adopt to improve immunotherapy via modulation of ion metabolism. Full article

(This article belongs to the Special Issue Immune Responses in Cancer Immunology and Immunotherapy)

► Show Figures

Figure 1

12 pages, 1913 KiB

Open AccessArticle

Autoimmunity to the Follicle-Stimulating Hormone Receptor (FSHR) and Luteinizing Hormone Receptor (LHR) in Polycystic Ovarian Syndrome

by Hanna A. Schniewind, Lisa-Marie Sattler, Christoph W. Haudum, Julia Münzker, Waldemar B. Minich, Barbara Obermayer-Pietsch and Lutz Schomburg

Int. J. Mol. Sci. 2021, 22(24), 13667; https://doi.org/10.3390/ijms222413667 - 20 Dec 2021

Cited by 10 | Viewed by 3535

Abstract

Hyperandrogenemia and ovulatory dysfunction are hallmarks of polycystic ovary syndrome (PCOS), pointing to a deranged hypothalamus-pituitary-ovarian (HPO) axis. An autoimmune etiology of PCOS is suspected in a subset of patients due to the relatively high concordance of PCOS with common autoimmune diseases. For [...] Read more.

Hyperandrogenemia and ovulatory dysfunction are hallmarks of polycystic ovary syndrome (PCOS), pointing to a deranged hypothalamus-pituitary-ovarian (HPO) axis. An autoimmune etiology of PCOS is suspected in a subset of patients due to the relatively high concordance of PCOS with common autoimmune diseases. For this reason, we tested the hypothesis that natural autoantibodies (aAb) to the follicle-stimulating hormone receptor (FSHR) or luteinizing hormone receptor (LHR) are prevalent in PCOS. To this end, new luminometric assays for quantifying aAb to the FSHR (FSHR-aAb) or LHR (LHR-aAb) were developed using full-length recombinant human receptors as fusion proteins with luciferase as reporter. Prevalence of FSHR-aAb and LHR-aAb was determined in serum samples from healthy controls and PCOS patients. Steroid hormone profiles were compared between patients with and without FSHR-aAb or LHR-aAb. Signal linearity and detection ranges were characterized and both methods passed basic performance quality checks. The analysis revealed a relatively low prevalence, with 4 out of 430 samples positive for FSHR-aAb in the control versus 11 out of 550 samples in the PCOS group, i.e., 0.9% versus 2.0%, respectively. Similarly, there were only 5 samples positive for LHR-aAb in the control versus 2 samples in the PCOS group, i.e., 1.2% versus 0.4%, respectively. Samples positive for FSHR-aAb displayed steroid hormones in the typical range of PCOS patients, whereas the two samples positive for LHR-aAb showed relatively elevated free testosterone in relation to total testosterone concentrations with unclear significance. We conclude that the FSHR and LHR constitute potential autoantigens in human subjects. However, the prevalence of specific autoantibodies to these receptors is relatively low, both in control subjects and in women with PCOS. It is therefore unlikely that autoimmunity to the LHR or FSHR constitutes a frequent cause of hyperandrogenemia or ovulatory dysfunction in PCOS. Full article

(This article belongs to the Special Issue Molecular Pathophysiology of Uterine and Ovarian Diseases and Dysfunction 2.0)

► Show Figures

Figure 1

16 pages, 783 KiB

Open AccessReview

Glycolysis under Circadian Control

by Jana Zlacká and Michal Zeman

Int. J. Mol. Sci. 2021, 22(24), 13666; https://doi.org/10.3390/ijms222413666 - 20 Dec 2021

Cited by 14 | Viewed by 7062

Abstract

Glycolysis is considered a main metabolic pathway in highly proliferative cells, including endothelial, epithelial, immune, and cancer cells. Although oxidative phosphorylation (OXPHOS) is more efficient in ATP production per mole of glucose, proliferative cells rely predominantly on aerobic glycolysis, which generates ATP faster [...] Read more.

Glycolysis is considered a main metabolic pathway in highly proliferative cells, including endothelial, epithelial, immune, and cancer cells. Although oxidative phosphorylation (OXPHOS) is more efficient in ATP production per mole of glucose, proliferative cells rely predominantly on aerobic glycolysis, which generates ATP faster compared to OXPHOS and provides anabolic substrates to support cell proliferation and migration. Cellular metabolism, including glucose metabolism, is under strong circadian control. Circadian clocks control a wide array of metabolic processes, including glycolysis, which exhibits a distinct circadian pattern. In this review, we discuss circadian regulations during metabolic reprogramming and key steps of glycolysis in activated, highly proliferative cells. We suggest that the inhibition of metabolic reprogramming in the circadian manner can provide some advantages in the inhibition of oxidative glycolysis and a chronopharmacological approach is a promising way to treat diseases associated with up-regulated glycolysis. Full article

(This article belongs to the Special Issue Molecular Research of Glycolysis)

► Show Figures

Figure 1

19 pages, 15648 KiB

Open AccessArticle

Natural vs. Synthetic Phosphate as Efficient Heterogeneous Compounds for Synthesis of Quinoxalines

by Abbas Amini, Azadeh Fallah, Ahmad Sedaghat, Ahmad Gholami, Chun Cheng and Anju R. Gupta

Int. J. Mol. Sci. 2021, 22(24), 13665; https://doi.org/10.3390/ijms222413665 - 20 Dec 2021

Cited by 4 | Viewed by 2957

Abstract

Natural phosphate (NP) and synthetic fluorapatite phosphate (SFAP) were proposed as stable, inexpensive, readily available and recyclable catalysts for the condensation of 1,2-diamines with 1,2-dicarbonyls in methanol to afford quinoxaline at room temperature. NP provided as high as 92–99% yield for quinoxalines in [...] Read more.

Natural phosphate (NP) and synthetic fluorapatite phosphate (SFAP) were proposed as stable, inexpensive, readily available and recyclable catalysts for the condensation of 1,2-diamines with 1,2-dicarbonyls in methanol to afford quinoxaline at room temperature. NP provided as high as 92–99% yield for quinoxalines in short reaction times (i.e., 1–45 min), while SFAP created quinoxalines with 87–97% yield in 60–120 min. From the chemical analyses, X-ray fluoresecency, X-ray diffraction, energy dispersive X-ray and Fourier-transform infrared spectroscopy methods, two main phases (CaO, P₂O₅) appeared in NP together with other low content phases (SiO₂, Fe₂O₃). Compared to other phases, apatite (CaO and P₂O₅ as Ca10(PO₄)₆) played a major role in the catalytic activity of NP. SFAP with similar Ca/P atomic ratio showed a relatively lower catalytic activity than NP for the condensation of 1,2-diamine with 1,2-dicarbonyl in methanol at ambient temperature. To investigate the recyclability of catalysts, the surface properties of NP and 6-recycled NP were investigated using scanning electron microscopy, energy dispersive X-ray and Brunauer–Emmett–Teller and Barrett–Joyner–Halenda methods. Some differences were observed in NP and 6-recycled NP’s particle size, surface area, the volume and size of pores, and the content of elements; nevertheless, the use–reuse process did not noticeably change the catalytic property of NP. Full article

(This article belongs to the Special Issue Nanobiomaterials for Precision Medicinal Systems)

► Show Figures

Figure 1

11 pages, 4359 KiB

Open AccessArticle

Over-Expression of Rose RrLAZY1 Negatively Regulates the Branch Angle of Transgenic Arabidopsis Inflorescence

by Dan Li, Mingyuan Zhao, Xiaoyan Yu, Lanyong Zhao, Zongda Xu and Xu Han

Int. J. Mol. Sci. 2021, 22(24), 13664; https://doi.org/10.3390/ijms222413664 - 20 Dec 2021

Cited by 1 | Viewed by 2934

Abstract

Branch angle is a key shoot architecture trait that strongly influences the ornamental and economic value of garden plants. However, the mechanism underlying the control of branch angle, an important aspect of tree architecture, is far from clear in roses. In the present [...] Read more.

Branch angle is a key shoot architecture trait that strongly influences the ornamental and economic value of garden plants. However, the mechanism underlying the control of branch angle, an important aspect of tree architecture, is far from clear in roses. In the present study, we isolated the RrLAZY1 gene from the stems of Rosa rugosa ‘Zilong wochi’. Sequence analysis showed that the encoded RrLAZY1 protein contained a conserved GΦL (A/T) IGT domain, which belongs to the IGT family. Quantitative real-time PCR (qRT-PCR) analyses revealed that RrLAZY1 was expressed in all tissues and that expression was highest in the stem. The RrLAZY1 protein was localized in the plasma membrane. Based on a yeast two-hybrid assay and bimolecular fluorescence complementation experiments, the RrLAZY1 protein was found to interact with auxin-related proteins RrIAA16. The over-expression of the RrLAZY1 gene displayed a smaller branch angle in transgenic Arabidopsis inflorescence and resulted in changes in the expression level of genes related to auxin polar transport and signal transduction pathways. This study represents the first systematic analysis of the LAZY1 gene family in R. rugosa. The results of this study will provide a theoretical basis for the improvement of rose plant types and molecular breeding and provide valuable information for studying the regulation mechanism of branch angle in other woody plants. Full article

(This article belongs to the Section Molecular Plant Sciences)

► Show Figures

Figure 1

17 pages, 8697 KiB

Open AccessArticle

Effects of Microvesicles Derived from NK Cells Stimulated with IL-1β on the Phenotype and Functional Activity of Endothelial Cells

by Kseniia Markova, Valentina Mikhailova, Yulia Milyutina, Andrey Korenevsky, Anastasia Sirotskaya, Veronika Rodygina, Elizaveta Tyshchuk, Polina Grebenkina, Andrey Simbirtsev, Sergey Selkov and Dmitry Sokolov

Int. J. Mol. Sci. 2021, 22(24), 13663; https://doi.org/10.3390/ijms222413663 - 20 Dec 2021

Cited by 5 | Viewed by 3106

Abstract

Microvesicles (MVs) are plasma extracellular vesicles ranging from 100 (150) to 1000 nm in diameter. These are generally produced by different cells through their vital activity and are a source of various protein and non-protein molecules. It is assumed that MVs can mediate [...] Read more.

Microvesicles (MVs) are plasma extracellular vesicles ranging from 100 (150) to 1000 nm in diameter. These are generally produced by different cells through their vital activity and are a source of various protein and non-protein molecules. It is assumed that MVs can mediate intercellular communication and modulate cell functions. The interaction between natural killer cells (NK cells) and endothelial cells underlies multiple pathological conditions. The ability of MVs derived from NK cells to influence the functional state of endothelial cells in inflammatory conditions has yet to be studied well. In this regard, we aimed to study the effects of MVs derived from NK cells of the NK-92 cell line stimulated with IL-1β on the phenotype, caspase activity, proliferation and migration of endothelial cells of the EA.hy926 cell line. Endothelial cells were cultured with MVs derived from cells of the NK-92 cell line after their stimulation with IL-1β. Using flow cytometry, we evaluated changes in the expression of endothelial cell surface molecules and endothelial cell death. We evaluated the effect of MVs derived from stimulated NK cells on the proliferative and migratory activity of endothelial cells, as well as the activation of caspase-3 and caspase-9 therein. It was established that the incubation of endothelial cells with MVs derived from cells of the NK-92 cell line stimulated with IL-1β and with MVs derived from unstimulated NK cells, leads to the decrease in the proliferative activity of endothelial cells, appearance of the pan leukocyte marker CD45 on them, caspase-3 activation and partial endothelial cell death, and reduced CD105 expression. However, compared with MVs derived from unstimulated NK cells, a more pronounced effect of MVs derived from cells of the NK-92 cell line stimulated with IL-1β was found in relation to the decrease in the endothelial cell migratory activity and the intensity of the CD54 molecule expression on them. The functional activity of MVs is therefore mediated by the conditions they are produced under, as well as their internal contents. Full article

(This article belongs to the Special Issue Thrombo-Inflammatory Extracellular Vesicles)

► Show Figures

Figure 1

25 pages, 947 KiB

Open AccessReview

Obesity and Bone: A Complex Relationship

by Giuseppe Rinonapoli, Valerio Pace, Carmelinda Ruggiero, Paolo Ceccarini, Michele Bisaccia, Luigi Meccariello and Auro Caraffa

Int. J. Mol. Sci. 2021, 22(24), 13662; https://doi.org/10.3390/ijms222413662 - 20 Dec 2021

Cited by 102 | Viewed by 12147

Abstract

There is a large literature on the relationship between obesity and bone. What we can conclude from this review is that the increase in body weight causes an increase in BMD, both for a mechanical effect and for the greater amount of estrogens [...] Read more.

There is a large literature on the relationship between obesity and bone. What we can conclude from this review is that the increase in body weight causes an increase in BMD, both for a mechanical effect and for the greater amount of estrogens present in the adipose tissue. Nevertheless, despite an apparent strengthening of the bone witnessed by the increased BMD, the risk of fracture is higher. The greater risk of fracture in the obese subject is due to various factors, which are carefully analyzed by the Authors. These factors can be divided into metabolic factors and increased risk of falls. Fractures have an atypical distribution in the obese, with a lower incidence of typical osteoporotic fractures, such as those of hip, spine and wrist, and an increase in fractures of the ankle, upper leg, and humerus. In children, the distribution is different, but it is not the same in obese and normal-weight children. Specifically, the fractures of the lower limb are much more frequent in obese children. Sarcopenic obesity plays an important role. The authors also review the available literature regarding the effects of high-fat diet, weight loss and bariatric surgery. Full article

(This article belongs to the Special Issue Bone Development and Growth)

► Show Figures

Figure 1

13 pages, 4492 KiB

Open AccessArticle

New Inhibitors of Laccase and Tyrosinase by Examination of Cross-Inhibition between Copper-Containing Enzymes

by Dinesh Chaudhary, Fangchen Chong, Trilok Neupane, Joonhyeok Choi and Jun-Goo Jee

Int. J. Mol. Sci. 2021, 22(24), 13661; https://doi.org/10.3390/ijms222413661 - 20 Dec 2021

Cited by 5 | Viewed by 3000

Abstract

Coppers play crucial roles in the maintenance homeostasis in living species. Approximately 20 enzyme families of eukaryotes and prokaryotes are known to utilize copper atoms for catalytic activities. However, small-molecule inhibitors directly targeting catalytic centers are rare, except for those that act against [...] Read more.

Coppers play crucial roles in the maintenance homeostasis in living species. Approximately 20 enzyme families of eukaryotes and prokaryotes are known to utilize copper atoms for catalytic activities. However, small-molecule inhibitors directly targeting catalytic centers are rare, except for those that act against tyrosinase and dopamine-β-hydroxylase (DBH). This study tested whether known tyrosinase inhibitors can inhibit the copper-containing enzymes, ceruloplasmin, DBH, and laccase. While most small molecules minimally reduced the activities of ceruloplasmin and DBH, aside from known inhibitors, 5 of 28 tested molecules significantly inhibited the function of laccase, with the K_i values in the range of 15 to 48 µM. Enzyme inhibitory kinetics classified the molecules as competitive inhibitors, whereas differential scanning fluorimetry and fluorescence quenching supported direct bindings. To the best of our knowledge, this is the first report on organic small-molecule inhibitors for laccase. Comparison of tyrosinase and DBH inhibitors using cheminformatics predicted that the presence of thione moiety would suffice to inhibit tyrosinase. Enzyme assays confirmed this prediction, leading to the discovery of two new dual tyrosinase and DBH inhibitors. Full article

(This article belongs to the Section Biochemistry)

► Show Figures

Figure 1

30 pages, 36061 KiB

Open AccessArticle

Metformin Treatment Attenuates Brain Inflammation and Rescues PACAP/VIP Neuropeptide Alterations in Mice Fed a High-Fat Diet

by Mawj Mandwie, Jocelyn Karunia, Aram Niaz, Kevin A. Keay, Giuseppe Musumeci, Claire Rennie, Kristine McGrath, Ghaith Al-Badri and Alessandro Castorina

Int. J. Mol. Sci. 2021, 22(24), 13660; https://doi.org/10.3390/ijms222413660 - 20 Dec 2021

Cited by 15 | Viewed by 4392

Abstract

High-fat diet (HFD)-induced comorbid cognitive and behavioural impairments are thought to be the result of persistent low-grade neuroinflammation. Metformin, a first-line medication for the treatment of type-2 diabetes, seems to ameliorate these comorbidities, but the underlying mechanism(s) are not clear. Pituitary adenylate cyclase-activating [...] Read more.

High-fat diet (HFD)-induced comorbid cognitive and behavioural impairments are thought to be the result of persistent low-grade neuroinflammation. Metformin, a first-line medication for the treatment of type-2 diabetes, seems to ameliorate these comorbidities, but the underlying mechanism(s) are not clear. Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) are neuroprotective peptides endowed with anti-inflammatory properties. Alterations to the PACAP/VIP system could be pivotal during the development of HFD-induced neuroinflammation. To unveil the pathogenic mechanisms underlying HFD-induced neuroinflammation and assess metformin’s therapeutic activities, (1) we determined if HFD-induced proinflammatory activity was present in vulnerable brain regions associated with the development of comorbid behaviors, (2) investigated if the PACAP/VIP system is altered by HFD, and (3) assessed if metformin rescues such diet-induced neurochemical alterations. C57BL/6J male mice were divided into two groups to receive either standard chow (SC) or HFD for 16 weeks. A further HFD group received metformin (HFD + M) (300 mg/kg BW daily for 5 weeks) via oral gavage. Body weight, fasting glucose, and insulin levels were measured. After 16 weeks, the proinflammatory profile, glial activation markers, and changes within the PI3K/AKT intracellular pathway and the PACAP/VIP system were evaluated by real-time qPCR and/or Western blot in the hypothalamus, hippocampus, prefrontal cortex, and amygdala. Our data showed that HFD causes widespread low-grade neuroinflammation and gliosis, with regional-specific differences across brain regions. HFD also diminished phospho-AKT^(Ser473) expression and caused significant disruptions to the PACAP/VIP system. Treatment with metformin attenuated these neuroinflammatory signatures and reversed PI3K/AKT and PACAP/VIP alterations caused by HFD. Altogether, our findings demonstrate that metformin treatment rescues HFD-induced neuroinflammation in vulnerable brain regions, most likely by a mechanism involving the reinstatement of PACAP/VIP system homeostasis. Data also suggests that the PI3K/AKT pathway, at least in part, mediates some of metformin’s beneficial effects. Full article

(This article belongs to the Special Issue Neuropeptides in Endocrine, Metabolic and Neuroimmune Disorders)

► Show Figures

Figure 1

27 pages, 2593 KiB

Open AccessReview

Molecular Targets of Natural Compounds with Anti-Cancer Properties

by Małgorzata Kubczak, Aleksandra Szustka and Małgorzata Rogalińska

Int. J. Mol. Sci. 2021, 22(24), 13659; https://doi.org/10.3390/ijms222413659 - 20 Dec 2021

Cited by 59 | Viewed by 5779

Abstract

Cancer is the second leading cause of death in humans. Despite rapid developments in diagnostic methods and therapies, metastasis and resistance to administrated drugs are the main obstacles to successful treatment. Therefore, the main challenge should be the diagnosis and design of optimal [...] Read more.

Cancer is the second leading cause of death in humans. Despite rapid developments in diagnostic methods and therapies, metastasis and resistance to administrated drugs are the main obstacles to successful treatment. Therefore, the main challenge should be the diagnosis and design of optimal therapeutic strategies for patients to increase their chances of responding positively to treatment and increase their life expectancy. In many types of cancer, a deregulation of multiple pathways has been found. This includes disturbances in cellular metabolism, cell cycle, apoptosis, angiogenesis, or epigenetic modifications. Additionally, signals received from the microenvironment may significantly contribute to cancer development. Chemical agents obtained from natural sources seem to be very attractive alternatives to synthetic compounds. They can exhibit similar anti-cancer potential, usually with reduced side effects. It was reported that natural compounds obtained from fruits and vegetables, e.g., polyphenols, flavonoids, stilbenes, carotenoids and acetogenins, might be effective against cancer cells in vitro and in vivo. Several published results indicate the activity of natural compounds on protein expression by its influence on transcription factors. They could also be involved in alterations in cellular response, cell signaling and epigenetic modifications. Such natural components could be used in our diet for anti-cancer protection. In this review, the activities of natural compounds, including anti-cancer properties, are described. The influence of natural agents on cancer cell metabolism, proliferation, signal transduction and epigenetic modifications is highlighted. Full article

(This article belongs to the Section Molecular Plant Sciences)

► Show Figures

Figure 1

16 pages, 2841 KiB

Open AccessArticle

Molecular Characterization of U-box E3 Ubiquitin Ligases (TaPUB2 and TaPUB3) Involved in the Positive Regulation of Drought Stress Response in Arabidopsis

by Jae Ho Kim, Moon Seok Kim, Dae Yeon Kim, Joseph Noble Amoah and Yong Weon Seo

Int. J. Mol. Sci. 2021, 22(24), 13658; https://doi.org/10.3390/ijms222413658 - 20 Dec 2021

Cited by 7 | Viewed by 2706

Abstract

Plant U-box E3 ubiquitin ligase (PUB) is involved in various environmental stress conditions. However, the molecular mechanism of U-box proteins in response to abiotic stress in wheat remains unknown. In this study, two U-box E3 ligase genes (TaPUB2 and TaPUB3), which [...] Read more.

Plant U-box E3 ubiquitin ligase (PUB) is involved in various environmental stress conditions. However, the molecular mechanism of U-box proteins in response to abiotic stress in wheat remains unknown. In this study, two U-box E3 ligase genes (TaPUB2 and TaPUB3), which are highly expressed in response to adverse abiotic stresses, were isolated from common wheat, and their cellular functions were characterized under drought stress. Transient expression assay revealed that TaPUB2 was localized in the cytoplasm and Golgi apparatus, whereas TaPUB3 was expressed only in the Golgi apparatus in wheat protoplasts. Additionally, TaPUB2 and TaPUB3 underwent self-ubiquitination. Moreover, TaPUB2/TaPUB3 heterodimer was identified in yeast and the cytoplasm of wheat protoplasts using a pull-down assay and bimolecular fluorescence complementation analysis. Heterogeneous overexpression of TaPUB2 and TaPUB3 conferred tolerance to drought stress. Taken together, these results implied that the heterodimeric form of U-box E3 ubiquitin ligases (TaPUB2/TaPUB3) responded to abiotic stress and roles as a positive regulator of drought stress tolerance. Full article

(This article belongs to the Special Issue Drought Stress Tolerance in Plants in 2021)

► Show Figures

Figure 1

3 pages, 177 KiB

Open AccessEditorial

Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules

by Anne Vejux

Int. J. Mol. Sci. 2021, 22(24), 13657; https://doi.org/10.3390/ijms222413657 - 20 Dec 2021

Cited by 10 | Viewed by 1913

Abstract

Neurodegenerative diseases are the most common chronic neurological pathologies associated with age, with a major impact on the patient’s quality of life [...] Full article

(This article belongs to the Special Issue Cell Death, Inflammation and Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Cytoprotective Molecules)

23 pages, 2472 KiB

Open AccessReview

Regulatory Peptides in Asthma

by Katarzyna Kaczyńska, Dominika Zając, Piotr Wojciechowski and Monika Jampolska

Int. J. Mol. Sci. 2021, 22(24), 13656; https://doi.org/10.3390/ijms222413656 - 20 Dec 2021

Cited by 17 | Viewed by 4069

Abstract

Numerous regulatory peptides play a critical role in the pathogenesis of airway inflammation, airflow obstruction and hyperresponsiveness, which are hallmarks of asthma. Some of them exacerbate asthma symptoms, such as neuropeptide Y and tachykinins, while others have ameliorating properties, such as nociception, neurotensin [...] Read more.

Numerous regulatory peptides play a critical role in the pathogenesis of airway inflammation, airflow obstruction and hyperresponsiveness, which are hallmarks of asthma. Some of them exacerbate asthma symptoms, such as neuropeptide Y and tachykinins, while others have ameliorating properties, such as nociception, neurotensin or β-defensin 2. Interacting with peptide receptors located in the lungs or on immune cells opens up new therapeutic possibilities for the treatment of asthma, especially when it is resistant to available therapies. This article provides a concise review of the most important and current findings regarding the involvement of regulatory peptides in asthma pathology. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma 2.0)

► Show Figures

Figure 1

10 pages, 990 KiB

Open AccessReview

Recent Advances in the Inhibition of the IL-4 Cytokine Pathway for the Treatment of Allergen-Induced Asthma

by Oliver Massey and Cenk Suphioglu

Int. J. Mol. Sci. 2021, 22(24), 13655; https://doi.org/10.3390/ijms222413655 - 20 Dec 2021

Cited by 17 | Viewed by 5052

Abstract

The IL-4 and IL-13 cytokine pathways play integral roles in stimulating IgE inflammation, with the IL-4 cytokine being a major cytokine in the etiology of thunderstorm asthma, atopic dermatitis, and allergic rhinitis. The increasing prevalence of thunderstorm asthma in the younger population and [...] Read more.

The IL-4 and IL-13 cytokine pathways play integral roles in stimulating IgE inflammation, with the IL-4 cytokine being a major cytokine in the etiology of thunderstorm asthma, atopic dermatitis, and allergic rhinitis. The increasing prevalence of thunderstorm asthma in the younger population and the lessening efficacy of corticosteroids and other anti-inflammatories has created a need for more effective pharmaceuticals. This review summarizes the IL-4 and IL-13 pathways while highlighting and discussing the current pathway inhibitors aimed at treating thunderstorm asthma and atopic dermatitis, as well as the potential efficacy of peptide therapeutics in this field. Full article

(This article belongs to the Section Molecular Immunology)

► Show Figures

Figure 1

11 pages, 1616 KiB

Open AccessArticle

Padlock Probe-Based Generation of DNAzymes for the Colorimetric Detection of Antibiotic Resistance Genes

by Rick Conzemius, Ariadne Haunold and Ivan Barišić

Int. J. Mol. Sci. 2021, 22(24), 13654; https://doi.org/10.3390/ijms222413654 - 20 Dec 2021

Viewed by 3872

Abstract

The increasing emergence of multidrug- and pan-resistant pathogens requires rapid and cost-efficient diagnostic tools to contain their further spread in healthcare facilities and the environment. The currently established diagnostic technologies are of limited utility for efficient infection control measures because they are either [...] Read more.

The increasing emergence of multidrug- and pan-resistant pathogens requires rapid and cost-efficient diagnostic tools to contain their further spread in healthcare facilities and the environment. The currently established diagnostic technologies are of limited utility for efficient infection control measures because they are either cultivation-based and time-consuming or require sophisticated assays that are expensive. Furthermore, infectious diseases are unfortunately most problematic in countries with low-resource settings in their healthcare systems. In this study, we developed a cost-efficient detection technology that uses G-quadruplex DNAzymes to convert a chromogenic substrate resulting in a color change in the presence of antibiotic resistance genes. The assay is based on padlock probes capable of high-multiplex reactions and targets 27 clinically relevant antibiotic resistance genes associated with sepsis. In addition to an experimental proof-of-principle using synthetic target DNA, the assay was evaluated with multidrug-resistant clinical isolates. Full article

(This article belongs to the Special Issue Protein and Nucleotide Engineering for Diagnoses and Biosensing)

► Show Figures

Figure 1

21 pages, 4842 KiB

Open AccessArticle

Mapping Resistance to Argentinean Fusarium (Graminearum) Head Blight Isolates in Wheat

by Carolina Sgarbi, Ismael Malbrán, Luciana Saldúa, Gladys Albina Lori, Ulrike Lohwasser, Mian Abdur Rehman Arif, Andreas Börner, Marcos Yanniccari and Ana Maria Castro

Int. J. Mol. Sci. 2021, 22(24), 13653; https://doi.org/10.3390/ijms222413653 - 20 Dec 2021

Cited by 5 | Viewed by 2566

Abstract

Fusarium head blight (FHB) of wheat, caused by Fusarium graminearum (Schwabe), is a destructive disease worldwide, reducing wheat yield and quality. To accelerate the improvement of scab tolerance in wheat, we assessed the International Triticeae Mapping Initiative mapping population (ITMI/MP) for Type I [...] Read more.

Fusarium head blight (FHB) of wheat, caused by Fusarium graminearum (Schwabe), is a destructive disease worldwide, reducing wheat yield and quality. To accelerate the improvement of scab tolerance in wheat, we assessed the International Triticeae Mapping Initiative mapping population (ITMI/MP) for Type I and II resistance against a wide population of Argentinean isolates of F. graminearum. We discovered a total of 27 additive QTLs on ten different (2A, 2D, 3B, 3D, 4B, 4D, 5A, 5B, 5D and 6D) wheat chromosomes for Type I and Type II resistances explaining a maximum of 15.99% variation. Another four and two QTLs for thousand kernel weight in control and for Type II resistance, respectively, involved five different chromosomes (1B, 2D, 6A, 6D and 7D). Furthermore, three, three and five QTLs for kernel weight per spike in control, for Type I resistance and for Type II resistance, correspondingly, involved ten chromosomes (2A, 2D, 3B, 4A, 5A, 5B, 6B, 7A, 7B, 7D). We were also able to detect five and two epistasis pairs of QTLs for Type I and Type II resistance, respectively, in addition to additive QTLs that evidenced that FHB resistance in wheat is controlled by a complex network of additive and epistasis QTLs. Full article

(This article belongs to the Special Issue Genetics and Breeding of Wheat 2.0)

► Show Figures

Figure 1

17 pages, 3293 KiB

Open AccessArticle

Partial Agonistic Actions of Sex Hormone Steroids on TRPM3 Function

by Eleonora Persoons, Sara Kerselaers, Thomas Voets, Joris Vriens and Katharina Held

Int. J. Mol. Sci. 2021, 22(24), 13652; https://doi.org/10.3390/ijms222413652 - 20 Dec 2021

Cited by 8 | Viewed by 2583

Abstract

Sex hormone steroidal drugs were reported to have modulating actions on the ion channel TRPM3. Pregnenolone sulphate (PS) presents the most potent known endogenous chemical agonist of TRPM3 and affects several gating modes of the channel. These includes a synergistic action of PS [...] Read more.

Sex hormone steroidal drugs were reported to have modulating actions on the ion channel TRPM3. Pregnenolone sulphate (PS) presents the most potent known endogenous chemical agonist of TRPM3 and affects several gating modes of the channel. These includes a synergistic action of PS and high temperatures on channel opening and the PS-induced opening of a noncanonical pore in the presence of other TRPM3 modulators. Moreover, human TRPM3 variants associated with neurodevelopmental disease exhibit an increased sensitivity for PS. However, other steroidal sex hormones were reported to influence TRPM3 functions with activating or inhibiting capacity. Here, we aimed to answer how DHEAS, estradiol, progesterone and testosterone act on the various modes of TRPM3 function in the wild-type channel and two-channel variants associated with human disease. By means of calcium imaging and whole-cell patch clamp experiments, we revealed that all four drugs are weak TRPM3 agonists that share a common steroidal interaction site. Furthermore, they exhibit increased activity on TRPM3 at physiological temperatures and in channels that carry disease-associated mutations. Finally, all steroids are able to open the noncanonical pore in wild-type and DHEAS also in mutant TRPM3. Collectively, our data provide new valuable insights in TRPM3 gating, structure-function relationships and ligand sensitivity. Full article

(This article belongs to the Special Issue TRPM Channels)

► Show Figures

Figure 1

15 pages, 730 KiB

Open AccessReview

A Pleiotropic Role of the Hepatitis B Virus Core Protein in Hepatocarcinogenesis

by Caroline Lefeuvre, Hélène Le Guillou-Guillemette and Alexandra Ducancelle

Int. J. Mol. Sci. 2021, 22(24), 13651; https://doi.org/10.3390/ijms222413651 - 20 Dec 2021

Cited by 14 | Viewed by 2972

Abstract

Chronic hepatitis B virus (HBV) infection is one of the most common factors associated with hepatocellular carcinoma (HCC), which is the sixth most prevalent cancer among all cancers worldwide. However, the pathogenesis of HBV-mediated hepatocarcinogenesis is unclear. Evidence currently available suggests that the [...] Read more.

Chronic hepatitis B virus (HBV) infection is one of the most common factors associated with hepatocellular carcinoma (HCC), which is the sixth most prevalent cancer among all cancers worldwide. However, the pathogenesis of HBV-mediated hepatocarcinogenesis is unclear. Evidence currently available suggests that the HBV core protein (HBc) plays a potential role in the development of HCC, such as the HBV X protein. The core protein, which is the structural component of the viral nucleocapsid, contributes to almost every stage of the HBV life cycle and occupies diverse roles in HBV replication and pathogenesis. Recent studies have shown that HBc was able to disrupt various pathways involved in liver carcinogenesis: the signaling pathways implicated in migration and proliferation of hepatoma cells, apoptosis pathways, and cell metabolic pathways inducing the development of HCC; and the immune system, through the expression and production of proinflammatory cytokines. In addition, HBc can modulate normal functions of hepatocytes through disrupting human host gene expression by binding to promoter regions. This HBV protein also promotes HCC metastasis through epigenetic alterations, such as micro-RNA. This review focuses on the molecular pathogenesis of the HBc protein in HBV-induced HCC. Full article

(This article belongs to the Topic Clinical, Translational and Basic Research on Liver Diseases)

► Show Figures

Figure 1

28 pages, 1832 KiB

Open AccessReview

Role of Circulating Biomarkers in Platinum-Resistant Ovarian Cancer

by Carolina Maria Sassu, Innocenza Palaia, Serena Maria Boccia, Giuseppe Caruso, Giorgia Perniola, Federica Tomao, Violante Di Donato, Angela Musella and Ludovico Muzii

Int. J. Mol. Sci. 2021, 22(24), 13650; https://doi.org/10.3390/ijms222413650 - 20 Dec 2021

Cited by 10 | Viewed by 3520

Abstract

Ovarian cancer (OC) is the second most common cause of death in women with gynecological cancer. Considering the poor prognosis, particularly in the case of platinum-resistant (PtR) disease, a huge effort was made to define new biomarkers able to help physicians in approaching [...] Read more.

Ovarian cancer (OC) is the second most common cause of death in women with gynecological cancer. Considering the poor prognosis, particularly in the case of platinum-resistant (PtR) disease, a huge effort was made to define new biomarkers able to help physicians in approaching and treating these challenging patients. Currently, most data can be obtained from tumor biopsy samples, but this is not always available and implies a surgical procedure. On the other hand, circulating biomarkers are detected with non-invasive methods, although this might require expensive techniques. Given the fervent hope in their value, here we focused on the most studied circulating biomarkers that could play a role in PtR OC. Full article

(This article belongs to the Special Issue Chemotherapeutic Agents in Gynecological Cancers: Drug Design, Development and Therapy)

► Show Figures

Figure 1

18 pages, 1739 KiB

Open AccessArticle

Protective Effect of Dinitrosyl Iron Complexes Bound with Hemoglobin on Oxidative Modification by Peroxynitrite

by Olga V. Kosmachevskaya, Elvira I. Nasybullina, Konstantin B. Shumaev, Natalia N. Novikova and Alexey F. Topunov

Int. J. Mol. Sci. 2021, 22(24), 13649; https://doi.org/10.3390/ijms222413649 - 20 Dec 2021

Cited by 13 | Viewed by 2134

Abstract

Dinitrosyl iron complexes (DNICs) are a physiological form of nitric oxide (^•NO) in an organism. They are able not only to deposit and transport ^•NO, but are also to act as antioxidant and antiradical agents. However, the mechanics of hemoglobin-bound [...] Read more.

Dinitrosyl iron complexes (DNICs) are a physiological form of nitric oxide (^•NO) in an organism. They are able not only to deposit and transport ^•NO, but are also to act as antioxidant and antiradical agents. However, the mechanics of hemoglobin-bound DNICs (Hb-DNICs) protecting Hb against peroxynitrite-caused, mediated oxidative modification have not yet been scrutinized. Through EPR spectroscopy we show that Hb-DNICs are destroyed under the peroxynitrite action in a dose-dependent manner. At the same time, DNICs inhibit the oxidation of tryptophan and tyrosine residues and formation of carbonyl derivatives. They also prevent the formation of covalent crosslinks between Hb subunits and degradation of a heme group. These effects can arise from the oxoferryl heme form being reduced, and they can be connected with the ability of DNICs to directly intercept peroxynitrite and free radicals, which emerge due to its homolysis. These data show that DNICs may ensure protection from myocardial ischemia. Full article

(This article belongs to the Special Issue Physico-Chemistry of Dinitrosyl Iron Complexes as a Determinant of Their Biological Activity)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Int. J. Mol. Sci., Volume 22, Issue 24 (December-2 2021) – 505 articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI