The RND1 Small GTPase: Main Functions and Emerging Role in Oncogenesis

The Rho GTPase family can be classified into classic and atypical members. Classic members cycle between an inactive Guanosine DiPhosphate -bound state and an active Guanosine TriPhosphate-bound state. Atypical Rho GTPases, such as RND1, are predominantly in an active GTP-bound conformation. The role of classic members in oncogenesis has been the subject of numerous studies, while that of atypical members has been less explored. Besides the roles of RND1 in healthy tissues, recent data suggest that RND1 is involved in oncogenesis and response to cancer therapeutics. Here, we present the current knowledge on RND1 expression, subcellular localization, and functions in healthy tissues. Then, we review data showing that RND1 expression is dysregulated in tumors, the molecular mechanisms involved in this deregulation, and the role of RND1 in oncogenesis. For several aggressive tumors, RND1 presents the features of a tumor suppressor gene. In these tumors, low expression of RND1 is associated with a bad prognosis for the patients. Finally, we highlight that RND1 expression is induced by anticancer agents and modulates their response. Of note, RND1 mRNA levels in tumors could be used as a predictive marker of both patient prognosis and response to anticancer agents.

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Mesophyll conductance: the leaf corridors for photosynthesis

Biochemical Society Transactions ◽

10.1042/bst20190312 ◽

2020 ◽

Vol 48 (2) ◽

pp. 429-439 ◽

Cited By ~ 3

Author(s):

Jorge Gago ◽

Danilo M. Daloso ◽

Marc Carriquí ◽

Miquel Nadal ◽

Melanie Morales ◽

...

Keyword(s):

Molecular Mechanisms ◽

Current Knowledge ◽

Main Role ◽

Mesophyll Conductance ◽

Future Studies ◽

Cell Structures ◽

Leaf Tissues ◽

Change Framework ◽

Chloroplast Stroma

Besides stomata, the photosynthetic CO2 pathway also involves the transport of CO2 from the sub-stomatal air spaces inside to the carboxylation sites in the chloroplast stroma, where Rubisco is located. This pathway is far to be a simple and direct way, formed by series of consecutive barriers that the CO2 should cross to be finally assimilated in photosynthesis, known as the mesophyll conductance (gm). Therefore, the gm reflects the pathway through different air, water and biophysical barriers within the leaf tissues and cell structures. Currently, it is known that gm can impose the same level of limitation (or even higher depending of the conditions) to photosynthesis than the wider known stomata or biochemistry. In this mini-review, we are focused on each of the gm determinants to summarize the current knowledge on the mechanisms driving gm from anatomical to metabolic and biochemical perspectives. Special attention deserve the latest studies demonstrating the importance of the molecular mechanisms driving anatomical traits as cell wall and the chloroplast surface exposed to the mesophyll airspaces (Sc/S) that significantly constrain gm. However, even considering these recent discoveries, still is poorly understood the mechanisms about signaling pathways linking the environment a/biotic stressors with gm responses. Thus, considering the main role of gm as a major driver of the CO2 availability at the carboxylation sites, future studies into these aspects will help us to understand photosynthesis responses in a global change framework.

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Regulation of Rho GTPases by RhoGDIs in Human Cancers

Cells ◽

10.3390/cells8091037 ◽

2019 ◽

Vol 8 (9) ◽

pp. 1037 ◽

Cited By ~ 6

Author(s):

Cho ◽

Kim ◽

Baek ◽

Kim ◽

Lee

Keyword(s):

Cell Migration ◽

Cancer Progression ◽

Anticancer Agents ◽

Rho Gtpases ◽

Rho Gtpase ◽

Regulatory Mechanisms ◽

Malignant Phenotype ◽

Cellular Processes ◽

Human Cancers

Rho GDP dissociation inhibitors (RhoGDIs) play important roles in various cellular processes, including cell migration, adhesion, and proliferation, by regulating the functions of the Rho GTPase family. Dissociation of Rho GTPases from RhoGDIs is necessary for their spatiotemporal activation and is dynamically regulated by several mechanisms, such as phosphorylation, sumoylation, and protein interaction. The expression of RhoGDIs has changed in many human cancers and become associated with the malignant phenotype, including migration, invasion, metastasis, and resistance to anticancer agents. Here, we review how RhoGDIs control the function of Rho GTPases by regulating their spatiotemporal activity and describe the regulatory mechanisms of the dissociation of Rho GTPases from RhoGDIs. We also discuss the role of RhoGDIs in cancer progression and their potential uses for therapeutic intervention.

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Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge

Cells ◽

10.3390/cells10030629 ◽

2021 ◽

Vol 10 (3) ◽

pp. 629

Author(s):

Jorge Gutiérrez-Cuevas ◽

Ana Sandoval-Rodriguez ◽

Alejandra Meza-Rios ◽

Hugo Christian Monroy-Ramírez ◽

Marina Galicia-Moreno ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiac Dysfunction ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Peroxisome Proliferator ◽

White Adipocyte ◽

Peroxisome Proliferator Activated Receptors ◽

And Oxidative Stress

Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.

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High CD169 Monocyte/Lymphocyte Ratio Reflects the Immunophenotyping Disruption and Predicts Oxygen Need in COVID-19 Patients

10.20944/preprints202105.0731.v1 ◽

2021 ◽

Author(s):

Antonella Minutolo ◽

Vita Petrone ◽

Marialaura Fanelli ◽

Marco Iannetta ◽

Martina Giudice ◽

...

Keyword(s):

Disease Progression ◽

Inflammatory Markers ◽

Predictive Marker ◽

Pulmonary Involvement ◽

Mrna Levels ◽

Healthy Donors ◽

Respiratory Outcome ◽

Early Biomarker

Background: CD169 has been found overexpressed in the blood of COVID-19 patients and identified as a biomarker in the early disease. We have analysed CD169 in blood cells of COVID-19 patients to assess its role as predictive marker of the disease. Methods : The ratio of the CD169 Median median Fluorescence fluorescence Intensity intensity of CD169 between monocytes and lymphocytes (CD169 RMFI ) was analysed by flow cytometry in blood samples of COVID-19 patients (COV) and healthy donors (HD ) and correlated with immunophenotyping, inflammatory markers, cytokines mRNA expression, pulmonary involvement and disease progression. Results: CD169 RMFI increased in COV but not in HD. CD169 RMFI correlated with T-cell differentiation and exhaustion markers as well as with B cells maturation and differentiation. In vitro stimulation of PBMCs of HD with SARS-CoV-2 Spike spike protein induced CD169 RMFI together with IL-6 and IL-10 gene expression. Likewise, CD169 RMFI correlated with blood cytokine mRNA levels, inflammatory markers, and pneumonia severity in patients which that had not received any treatment at sampling. Notably, in untreated patients, CD169 RMFI reflected the respiratory outcome during hospitalization. Conclusion : Considering the immunological role of CD169 and its involvement during the infection and the progression of COVID-19, it could be considered as an early biomarker to evaluate disease progression and clinical outcome.

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The Role of Cancer-Associated Fibroblasts in Prostate Cancer Tumorigenesis

Cancers ◽

10.3390/cancers12071887 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1887 ◽

Cited By ~ 1

Author(s):

Francesco Bonollo ◽

George N. Thalmann ◽

Marianna Kruithof-de Julio ◽

Sofia Karkampouna

Keyword(s):

Prostate Cancer ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Current Knowledge ◽

Therapy Resistance ◽

Cancer Associated Fibroblasts ◽

Metastatic Progression ◽

Normal Prostate ◽

Prostate Tumorigenesis

Tumors strongly depend on their surrounding tumor microenvironment (TME) for growth and progression, since stromal elements are required to generate the optimal conditions for cancer cell proliferation, invasion, and possibly metastasis. Prostate cancer (PCa), though easily curable during primary stages, represents a clinical challenge in advanced stages because of the acquisition of resistance to anti-cancer treatments, especially androgen-deprivation therapies (ADT), which possibly lead to uncurable metastases such as those affecting the bone. An increasing number of studies is giving evidence that prostate TME components, especially cancer-associated fibroblasts (CAFs), which are the most abundant cell type, play a causal role in PCa since the very early disease stages, influencing therapy resistance and metastatic progression. This is highlighted by the prognostic value of the analysis of stromal markers, which may predict disease recurrence and metastasis. However, further investigations on the molecular mechanisms of tumor–stroma interactions are still needed to develop novel therapeutic approaches targeting stromal components. In this review, we report the current knowledge of the characteristics and functions of the stroma in prostate tumorigenesis, including relevant discussion of normal prostate homeostasis, chronic inflammatory conditions, pre-neoplastic lesions, and primary and metastatic tumors. Specifically, we focus on the role of CAFs, to point out their prognostic and therapeutic potential in PCa.

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Regulation of ST6GAL1 sialyltransferase expression in cancer cells

Glycobiology ◽

10.1093/glycob/cwaa110 ◽

2020 ◽

Author(s):

Kaitlyn A Dorsett ◽

Michael P Marciel ◽

Jihye Hwang ◽

Katherine E Ankenbauer ◽

Nikita Bhalerao ◽

...

Keyword(s):

Cancer Cells ◽

Translational Regulation ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Sialic Acids ◽

Invasion Resistance ◽

Cell Behaviors ◽

Molecular Events ◽

Wide Range

Abstract The ST6GAL1 sialyltransferase, which adds α2–6 linked sialic acids to N-glycosylated proteins, is overexpressed in a wide range of human malignancies. Recent studies have established the importance of ST6GAL1 in promoting tumor cell behaviors such as invasion, resistance to cell stress, and chemoresistance. Furthermore, ST6GAL1 activity has been implicated in imparting cancer stem cell characteristics. However, despite the burgeoning interest in the role of ST6GAL1 in the phenotypic features of tumor cells, insufficient attention has been paid to the molecular mechanisms responsible for ST6GAL1 upregulation during neoplastic transformation. Evidence suggests that these mechanisms are multifactorial, encompassing genetic, epigenetic, transcriptional, and post-translational regulation. The purpose of this review is to summarize current knowledge regarding the molecular events that drive enriched ST6GAL1 expression in cancer cells.

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The role of the zinc transporter SLC30A2/ZnT2 in transient neonatal zinc deficiency

Metallomics ◽

10.1039/c7mt00162b ◽

2017 ◽

Vol 9 (10) ◽

pp. 1352-1366 ◽

Cited By ~ 18

Author(s):

Yarden Golan ◽

Taiho Kambe ◽

Yehuda G. Assaraf

Keyword(s):

Zinc Deficiency ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Gene Mutations ◽

Zinc Transporter ◽

Loss Of Function ◽

Breastfed Infants ◽

Nursing Mothers ◽

Novel Approaches

Transient neonatal zinc deficiency (TNZD) results from loss of function mutations in theSLC30A2/ZnT2gene. Nursing mothers harboring this defective zinc transporter produce zinc-deficient milk. Consequently, their exclusively breastfed infants develop severe zinc deficiency. The present review summarizes our current knowledge onSLC30A2/ZnT2gene mutations and highlights the molecular mechanisms underlying this zinc deficiency. We further propose novel approaches for the early diagnosis and prevention of TNZD.

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Hepcidin links gluco-toxicity to pancreatic beta cell dysfunction by inhibiting Pdx-1 expression

Endocrine Connections ◽

10.1530/ec-16-0115 ◽

2017 ◽

Vol 6 (3) ◽

pp. 121-128 ◽

Cited By ~ 3

Author(s):

Xuhua Mao ◽

Hucheng Chen ◽

Junmin Tang ◽

Liangliang Wang ◽

Tingting Shu

Keyword(s):

High Glucose ◽

Molecular Mechanisms ◽

Cell Function ◽

Pancreatic Beta Cell ◽

Mrna Levels ◽

Β Cell ◽

Min6 Cells ◽

Hepcidin Expression ◽

Insulin Synthesis

Objective Gluco-toxicity is a term used to convey the detrimental effect of hyperglycemia on β-cell function through impaired insulin synthesis. Although it is known that the expression and activity of several key insulin transcription regulators is inhibited, other molecular mechanisms that mediate gluco-toxicity are poorly defined. Our objective was to explore the role of hepcidin in β-cell gluco-toxicity. Design We first confirmed that high glucose levels inhibited hepcidin expression in the mouse insulinoma cell line, MIN6. The downregulation of hepcidin decreased Pdx-1 expression, which reduced insulin synthesis. Methods MIN6 cells were exposed to high glucose concentrations (33.3 mmol/L). Glucose-stimulated insulin secretion (GSIS) and serum hepcidin levels were measured by ELISA. The mRNA levels of insulin1, insulin2, Pdx-1 and hepcidin were measured by real-time polymerase chain reaction. Western blot analysis was used to detect the changes in PDX-1 expression. Transient overexpression with hepcidin was used to reverse the downregulation of Pdx-1 and insulin synthesis induced by gluco-toxicity. Results Exposure of MIN6 cells to high glucose significantly decreased GSIS and inhibited insulin synthesis as well as Pdx-1 transcriptional activity and expression at both the mRNA and protein levels. High glucose also decreased hepcidin expression and secretion. Hepcidin overexpression in MIN6 cells partially reversed the gluco-toxicity-induced downregulation of Pdx-1 and insulin expression and improved GSIS. The restoration of insulin synthesis by transfection of a hepcidin overexpression plasmid confirmed the role of hepcidin in mediating the gluco-toxic inhibition of insulin synthesis. Conclusions Our observations suggest that hepcidin is associated with gluco-toxicity-reduced pancreatic β-cell insulin synthesis in type 2 diabetes by inhibiting Pdx-1 expression.

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Mucin-1 (MUC1) as a promising molecular target in anticancer therapy

Postępy Higieny i Medycyny Doświadczalnej ◽

10.5604/01.3001.0013.0310 ◽

2019 ◽

Vol 73 ◽

pp. 53-64

Author(s):

Agnieszka Gornowicz ◽

Anna Bielawska ◽

Bożena Popławska ◽

Krzysztof Bielawski

Keyword(s):

Tumor Cells ◽

Anticancer Agents ◽

Intracellular Signaling ◽

Current Knowledge ◽

P53 Protein ◽

Chemotherapeutic Agents ◽

Therapeutic Effects ◽

Mucin 1 ◽

Shock Proteins

Mucin 1 (MUC1) has been recognized by the National Cancer Institute as one of the most promising molecular targets in cancer therapy. Its overexpression has been demonstrated in many epithelial tumors,especially in breast cancer, whichis associated with poor prognosis. Mucin 1 is an important barrier to the penetration of drugs and takes part in the inhibition of apoptosis in tumor cells. MUC1 triggers the activation of several pathways of intracellular signaling. MUC1 interactions with ICAM-1, E-selectin, galectin-3, EGFR, ERα estrogen receptor, p53 protein, heat shock proteins HSP70 and HSP90 have been demonstrated. The MUC1 membrane subunit contributes to the activation of the ERK1 and ERK2 kinases by the induction of the Ras-Raf-Mek-Erk pathway. In addition, the role of MUC1 in the activation of the WNT/β-catenin/TCF7L2 pathway and the induction of transcription of the cyclin D1 gene was confirmed. Numerous studies have shown that blockade of MUC1 by monoclonal antibodies or small molecule inhibitors may promote therapeutic effects and contribute to increased susceptibility of tumor cells to chemotherapeutic agents. The combined effect of the anti-MUC1 antibody with novel anticancer agents may have a better therapeutic effect than monotherapy. This article reviews the current knowledge about the role of MUC1 in the development and progression of cancer as well as potential novel strategies based on mucin 1 in antineoplastic therapy.

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The Relevance of MicroRNAs in the Pathogenesis and Prognosis of HCV-Disease: The Emergent Role of miR-17-92 in Cryoglobulinemic Vasculitis

Viruses ◽

10.3390/v12121364 ◽

2020 ◽

Vol 12 (12) ◽

pp. 1364

Author(s):

Serena Lorini ◽

Laura Gragnani ◽

Anna Linda Zignego

Keyword(s):

Gene Expression ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Public Health Problem ◽

Lymphoproliferative Disorders ◽

Major Public Health Problem ◽

Cryoglobulinemic Vasculitis ◽

Association Analyses ◽

Non Invasive

Hepatitis C virus (HCV) is a major public health problem. HCV is a hepatotropic and lymphotropic virus that leads to hepatocellular carcinoma (HCC) and lymphoproliferative disorders such as cryoglobulinemic vasculitis (CV) and non-Hodgkin’s lymphoma (NHL). The molecular mechanisms by which HCV induces these diseases are not fully understood. MicroRNAs (miRNAs) are small non-coding molecules that negatively regulate post-transcriptional gene expression by decreasing their target gene expression. We will attempt to summarize the current knowledge on the role of miRNAs in the HCV life cycle, HCV-related HCC, and lymphoproliferative disorders, focusing on both the functional effects of their deregulation as well as on their putative role as biomarkers, based on association analyses. We will also provide original new data regarding the miR 17-92 cluster in chronically infected HCV patients with and without lymphoproliferative disorders who underwent antiviral therapy. All of the cluster members were significantly upregulated in CV patients compared to patients without CV and significantly decreased in those who achieved vasculitis clinical remission after viral eradication. To conclude, miRNAs play an important role in HCV infection and related oncogenic processes, but their molecular pathways are not completely clear. In some cases, they may be potential therapeutic targets or non-invasive biomarkers of tumor progression.

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