Biomedicines

11 pages, 445 KB

Open AccessReview

Human Granzyme B Based Targeted Cytolytic Fusion Proteins

by Precious Hlongwane, Neelakshi Mungra, Suresh Madheswaran, Olusiji A. Akinrinmade, Shivan Chetty and Stefan Barth

Biomedicines 2018, 6(2), 72; https://doi.org/10.3390/biomedicines6020072 - 20 Jun 2018

Cited by 28 | Viewed by 7017

Abstract

Cancer immunotherapy aims to selectively target and kill tumor cells whilst limiting the damage to healthy tissues. Controlled delivery of plant, bacterial and human toxins or enzymes has been shown to promote the induction of apoptosis in cancerous cells. The 4th generation of [...] Read more.

Cancer immunotherapy aims to selectively target and kill tumor cells whilst limiting the damage to healthy tissues. Controlled delivery of plant, bacterial and human toxins or enzymes has been shown to promote the induction of apoptosis in cancerous cells. The 4th generation of targeted effectors are being designed to be as humanized as possible—a solution to the problem of immunogenicity encountered with existing generations. Granzymes are serine proteases which naturally function in humans as integral cytolytic effectors during the programmed cell death of cancerous and pathogen-infected cells. Secreted predominantly by cytotoxic T lymphocytes and natural killer cells, granzymes function mechanistically by caspase-dependent or caspase-independent pathways. These natural characteristics make granzymes one of the most promising human enzymes for use in the development of fusion protein-based targeted therapeutic strategies for various cancers. In this review, we explore research involving the use of granzymes as cytolytic effectors fused to antibody fragments as selective binding domains. Full article

(This article belongs to the Special Issue Immuno-Active Cancer Therapeutics)

► Show Figures

Figure 1

17 pages, 1511 KB

Open AccessArticle

Human Depotentiation following Induction of Spike Timing Dependent Plasticity

by Nicole Pedroarena-Leal, Larissa Heidemeyer, Carlos Trenado and Diane Ruge

Biomedicines 2018, 6(2), 71; https://doi.org/10.3390/biomedicines6020071 - 18 Jun 2018

Cited by 9 | Viewed by 5332

Abstract

Depotentiation (DP) is a crucial mechanism for the tuning of memory traces once LTP (Long Term Potentiation) has been induced via learning, artificial procedures, or other activities. Putative unuseful LTP might be abolished via this process. Its deficiency is thought to play a [...] Read more.

Depotentiation (DP) is a crucial mechanism for the tuning of memory traces once LTP (Long Term Potentiation) has been induced via learning, artificial procedures, or other activities. Putative unuseful LTP might be abolished via this process. Its deficiency is thought to play a role in pathologies, such as drug induced dyskinesia. However, since it is thought that it represents a mechanism that is linked to the susceptibility to interference during consolidation of a memory trace, it is an important process to consider when therapeutic interventions, such as psychotherapy, are administered. Perhaps a person with an abnormal depotentiation is prone to lose learned effects very easily or on the other end of the spectrum is prone to overload with previously generated unuseful LTP. Perhaps this process partly explains why some disorders and patients are extremely resistant to therapy. The present study seeks to quantify the relationship between LTP and depotentiation in the human brain by using transcranial magnetic stimulation (TMS) over the cortex of healthy participants. The results provide further evidence that depotentiation can be quantified in humans by use of noninvasive brain stimulation techniques. They provide evidence that a nonfocal rhythmic on its own inefficient stimulation, such as a modified thetaburst stimulation, can depotentiate an associative, focal spike timing-dependent PAS (paired associative stimulation)-induced LTP. Therefore, the depotentiation-like process does not seem to be restricted to specific subgroups of synapses that have undergone LTP before. Most importantly, the induced LTP seems highly correlated with the amount of generated depotentiation in healthy individuals. This might be a phenomenon typical of health and might be distorted in brain pathologies, such as dystonia, or dyskinesias. The ratio of LTP/DP might be a valuable marker for potential distortions of persistence versus deletion of memory traces represented by LTP-like plasticity. Full article

(This article belongs to the Special Issue Neural Mechanisms of Learning)

► Show Figures

Figure 1

14 pages, 1849 KB

Open AccessArticle

Antimicrobial and Antibiofilm Activities of Citrus Water-Extracts Obtained by Microwave-Assisted and Conventional Methods

by Leonardo Caputo, Laura Quintieri, Maria Maddalena Cavalluzzi, Giovanni Lentini and Solomon Habtemariam

Biomedicines 2018, 6(2), 70; https://doi.org/10.3390/biomedicines6020070 - 17 Jun 2018

Cited by 35 | Viewed by 8574

Abstract

Citrus pomace is a huge agro-food industrial waste mostly composed of peels and traditionally used as compost or animal feed. Owing to its high content of compounds beneficial to humans (e.g., flavonoids, phenol-like acids, and terpenoids), citrus waste is increasingly used to produce [...] Read more.

Citrus pomace is a huge agro-food industrial waste mostly composed of peels and traditionally used as compost or animal feed. Owing to its high content of compounds beneficial to humans (e.g., flavonoids, phenol-like acids, and terpenoids), citrus waste is increasingly used to produce valuable supplements, fragrance, or antimicrobials. However, such processes require sustainable and efficient extraction strategies by solvent-free techniques for environmentally-friendly good practices. In this work, we evaluated the antimicrobial and antibiofilm activity of water extracts of three citrus peels (orange, lemon, and citron) against ten different sanitary relevant bacteria. Both conventional extraction methods using hot water (HWE) and microwave-assisted extraction (MAE) were used. Even though no extract fully inhibited the growth of the target bacteria, these latter (mostly pseudomonads) showed a significant reduction in biofilm biomass. The most active extracts were obtained from orange and lemon peel by using MAE at 100 °C for 8 min. These results showed that citrus peel water infusions by MAE may reduce biofilm formation possibly enhancing the susceptibility of sanitary-related bacteria to disinfection procedures. Full article

(This article belongs to the Special Issue Plant Derived Biomedicines)

► Show Figures

Graphical abstract

12 pages, 3149 KB

Open AccessArticle

Assessing Clinical Outcomes in Colorectal Cancer with Assays for Invasive Circulating Tumor Cells

by Yue Zhang, Kevin Zarrabi, Wei Hou, Stefan Madajewicz, Minsig Choi, Stanley Zucker and Wen-Tien Chen

Biomedicines 2018, 6(2), 69; https://doi.org/10.3390/biomedicines6020069 - 6 Jun 2018

Cited by 10 | Viewed by 4764

Abstract

Colorectal carcinoma (CRC) is the second leading cause of cancer-related mortality. The goals of this study are to evaluate the association between levels of invasive circulating tumor cells (iCTCs) with CRC outcomes and to explore the molecular characteristics of iCTCs. Peripheral blood from [...] Read more.

Colorectal carcinoma (CRC) is the second leading cause of cancer-related mortality. The goals of this study are to evaluate the association between levels of invasive circulating tumor cells (iCTCs) with CRC outcomes and to explore the molecular characteristics of iCTCs. Peripheral blood from 93 patients with Stage I–IV CRC was obtained and assessed for the detection and characterization of iCTCs using a functional collagen-based adhesion matrix (CAM) invasion assay. Patients were followed and assessed for overall survival. Tumor cells isolated by CAM were characterized using cell culture and microarray analyses. Of 93 patients, 88 (95%) had detectable iCTCs, ranging over 0–470 iCTCs/mL. Patients with Stage I–IV disease exhibited median counts of 0.0 iCTCs/mL (n = 6), 13.0 iCTCs/mL (n = 12), 41.0 iCTCs/mL (n = 12), and 133.0 iCTCs/mL (n = 58), respectively (p < 0.001). Kaplan–Meier curve analysis demonstrated a significant survival benefit in patients with low iCTC counts compared with in patients with high iCTC counts (log-rank p < 0.001). Multivariable Cox model analysis revealed that iCTC count was an independent prognostic factor of overall survival (p = 0.009). Disease stage (p = 0.01, hazard ratio 1.66; 95% confidence interval: 1.12–2.47) and surgical intervention (p = 0.03, HR 0.37; 95% CI: 0.15–0.92) were also independent prognostic factors. Gene expression analysis demonstrated the expression of both endothelial and tumor progenitor cell biomarkers in iCTCs. CAM-based invasion assay shows a high detection sensitivity of iCTCs that inversely correlated with overall survival in CRC patients. Functional and gene expression analyses showed the phenotypic mosaics of iCTCs, mimicking the survival capability of circulating endothelial cells in the blood stream. Full article

(This article belongs to the Special Issue Cancer Biomarkers and Targets in Digestive Organs)

► Show Figures

Figure 1

10 pages, 683 KB

Open AccessReview

HIF Oxygen Sensing Pathways in Lung Biology

by Andrés A. Urrutia and Julián Aragonés

Biomedicines 2018, 6(2), 68; https://doi.org/10.3390/biomedicines6020068 - 6 Jun 2018

Cited by 27 | Viewed by 8461

Abstract

Cellular responses to oxygen fluctuations are largely mediated by hypoxia-inducible factors (HIFs). Upon inhalation, the first organ inspired oxygen comes into contact with is the lungs, but the understanding of the pulmonary HIF oxygen-sensing pathway is still limited. In this review we will [...] Read more.

Cellular responses to oxygen fluctuations are largely mediated by hypoxia-inducible factors (HIFs). Upon inhalation, the first organ inspired oxygen comes into contact with is the lungs, but the understanding of the pulmonary HIF oxygen-sensing pathway is still limited. In this review we will focus on the role of HIF1α and HIF2α isoforms in lung responses to oxygen insufficiency. In particular, we will discuss novel findings regarding their role in the biology of smooth muscle cells and endothelial cells in the context of hypoxia-induced pulmonary vasoconstriction. Moreover, we will also discuss recent studies into HIF-dependent responses in the airway epithelium, which have been even less studied than the HIF-dependent vascular responses in the lungs. In summary, we will review the biological functions executed by HIF1 or HIF2 in the pulmonary vessels and epithelium to control lung responses to oxygen fluctuations as well as their pathological consequences in the hypoxic lung. Full article

(This article belongs to the Special Issue Hypoxia)

► Show Figures

Graphical abstract

7 pages, 188 KB

Open AccessReview

Learning and Unlearning of Pain

by Larissa Cordier and Martin Diers

Biomedicines 2018, 6(2), 67; https://doi.org/10.3390/biomedicines6020067 - 5 Jun 2018

Cited by 21 | Viewed by 7745

Abstract

This review provides an overview of learning mechanisms and memory aspects for the development of chronic pain. Pain can be influenced in important ways by an individual’s personality, by family, and by the sociocultural environment in which they live. Therefore, learning mechanisms can [...] Read more.

This review provides an overview of learning mechanisms and memory aspects for the development of chronic pain. Pain can be influenced in important ways by an individual’s personality, by family, and by the sociocultural environment in which they live. Therefore, learning mechanisms can explain why pain experience and pain behavior can increase or decrease. Linking pain with positive consequences or removing negative consequences can contribute significantly to the chronification of pain. We will provide an overview of treatment options that use the characteristics of extinction. Operant extinction training and cognitive behavioral approaches show promising results for the treatment of chronic pain. Full article

(This article belongs to the Special Issue Neural Mechanisms of Learning)

21 pages, 1376 KB

Open AccessReview

Noncanonical NF-κB in Cancer

by Matthew Tegowski and Albert Baldwin

Biomedicines 2018, 6(2), 66; https://doi.org/10.3390/biomedicines6020066 - 5 Jun 2018

Cited by 53 | Viewed by 7851

Abstract

The NF-κB pathway is a critical regulator of immune responses and is often dysregulated in cancer. Two NF-κB pathways have been described to mediate these responses, the canonical and the noncanonical. While understudied compared to the canonical NF-κB pathway, noncanonical NF-κB and its [...] Read more.

The NF-κB pathway is a critical regulator of immune responses and is often dysregulated in cancer. Two NF-κB pathways have been described to mediate these responses, the canonical and the noncanonical. While understudied compared to the canonical NF-κB pathway, noncanonical NF-κB and its components have been shown to have effects, usually protumorigenic, in many different cancer types. Here, we review noncanonical NF-κB pathways and discuss its important roles in promoting cancer. We also discuss alternative NF-κB-independent functions of some the components of noncanonical NF-κB signaling. Finally, we discuss important crosstalk between canonical and noncanonical signaling, which blurs the two pathways, indicating that understanding the full picture of NF-κB regulation is critical to deciphering how this broad pathway promotes oncogenesis. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)

► Show Figures

Graphical abstract

11 pages, 577 KB

Open AccessReview

Utilizing Peptide Ligand GPCRs to Image and Treat Pancreatic Cancer

by Gail L. Matters and John F. Harms

Biomedicines 2018, 6(2), 65; https://doi.org/10.3390/biomedicines6020065 - 2 Jun 2018

Cited by 9 | Viewed by 5970

Abstract

It is estimated that early detection of pancreatic ductal adenocarcinoma (PDAC) could increase long-term patient survival by as much as 30% to 40% (Seufferlein, T. et al., Nat. Rev. Gastroenterol. Hepatol. 2016, 13, 74–75). There is an unmet need for reagents [...] Read more.

It is estimated that early detection of pancreatic ductal adenocarcinoma (PDAC) could increase long-term patient survival by as much as 30% to 40% (Seufferlein, T. et al., Nat. Rev. Gastroenterol. Hepatol. 2016, 13, 74–75). There is an unmet need for reagents that can reliably identify early cancerous or precancerous lesions through various imaging modalities or could be employed to deliver anticancer treatments specifically to tumor cells. However, to date, many PDAC tumor-targeting strategies lack selectivity and are unable to discriminate between tumor and nontumor cells, causing off-target effects or unclear diagnoses. Although a variety of approaches have been taken to identify tumor-targeting reagents that can effectively direct therapeutics or imaging agents to cancer cells (Liu, D. et al., J. Controlled Release 2015, 219, 632–643), translating these reagents into clinical practice has been limited, and it remains an area open to new methodologies and reagents (O’Connor, J.P. et al., Nat. Rev. Clin. Oncol. 2017, 14, 169–186). G protein–coupled receptors (GPCRs), which are key target proteins for drug discovery and comprise a large proportion of currently marketed therapeutics, hold significant promise for tumor imaging and targeted treatment, particularly for pancreatic cancer. Full article

(This article belongs to the Special Issue Cancer Biomarkers and Targets in Digestive Organs)

► Show Figures

Figure 1

16 pages, 236 KB

Open AccessConference Report

Frontiers in Gastrointestinal Oncology: Advances in Multi-Disciplinary Patient Care

by Nelson S. Yee, Eugene J. Lengerich, Kathryn H. Schmitz, Jennifer L. Maranki, Niraj J. Gusani, Leila Tchelebi, Heath B. Mackley, Karen L. Krok, Maria J. Baker, Claire De Boer and Julian D. Yee

Biomedicines 2018, 6(2), 64; https://doi.org/10.3390/biomedicines6020064 - 1 Jun 2018

Cited by 8 | Viewed by 4952

Abstract

Cancers of the digestive system remain highly lethal; therefore, the care of patients with malignant diseases of the digestive tract requires the expertise of providers from multiple health disciplines. Progress has been made to advance the understanding of epidemiology and genetics, diagnostic and [...] Read more.

Cancers of the digestive system remain highly lethal; therefore, the care of patients with malignant diseases of the digestive tract requires the expertise of providers from multiple health disciplines. Progress has been made to advance the understanding of epidemiology and genetics, diagnostic and screening evaluation, treatment modalities, and supportive care for patients with gastrointestinal cancers. At the Multi-Disciplinary Patient Care in Gastrointestinal Oncology conference at the Hershey Country Club in Hershey, Pennsylvania on 29 September 2017, the faculty members of the Penn State Health Milton S. Hershey Medical Center presented a variety of topics that focused on this oncological specialty. In this continuing medical education-certified conference, updates on the population sciences including health disparities and resistance training were presented. Progress made in various diagnostic evaluation and screening procedures was outlined. New developments in therapeutic modalities in surgical, radiation, and medical oncology were discussed. Cancer genetic testing and counseling and the supportive roles of music and arts in health and cancer were demonstrated. In summary, this disease-focused medical conference highlighted the new frontiers in gastrointestinal oncology, and showcase the multi-disciplinary care provided at the Penn State Cancer Institute. Full article

(This article belongs to the Special Issue Cancer Biomarkers and Targets in Digestive Organs)

► Show Figures

Graphical abstract

15 pages, 10658 KB

Open AccessArticle

Assisted Tip Sonication Approach for Graphene Synthesis in Aqueous Dispersion

by Ahmed F. Ghanem and Mona H. Abdel Rehim

Biomedicines 2018, 6(2), 63; https://doi.org/10.3390/biomedicines6020063 - 28 May 2018

Cited by 37 | Viewed by 7738

Abstract

Graphene (G) is a newcomer material that holds promising properties for many applications. The production of high quality G with a good yield is a long-standing goal for many researchers. This work emphasizes synthesis of dispersed graphene nanoplatelets (DGP) through aqueous dispersion technique [...] Read more.

Graphene (G) is a newcomer material that holds promising properties for many applications. The production of high quality G with a good yield is a long-standing goal for many researchers. This work emphasizes synthesis of dispersed graphene nanoplatelets (DGP) through aqueous dispersion technique in surfactant/water solution with the aid of tip sonication. A chemical method was also used to prepare graphene oxide (GO) and reduced graphene oxide (RGO) for comparison. Elemental analysis revealed the C:O ratio to be 12:1 for DGP but much lower for other graphene structures. Optical characterization of DGP, GO and RGO with UV and Raman spectroscopy confirmed the ideal structure of DGP. Moreover, X-ray diffraction (XRD) revealed the amorphous structure of DGP. Transmission electron microscope (TEM) imaging showed that DGP was composed of a few flat layers, unlike the wrinkled and partially bent multilayered G. Topological study of the DGP surface with scanning electron microscope (SEM) depicted its rough surface with (r_a) value of 35 nm, as revealed using an atomic force microscope (AFM). Electrochemical measurements confirmed the higher conductivity of DGP over graphene prepared by chemical method due to lack of structural defects. Its perfect structure facilitates the mobility of charge carriers that makes it preferable in optoelectronic applications. Full article

(This article belongs to the Special Issue Impact of Nanobiotechnology (Nanomedicine) on the Future of Medicine: The Road toward Precision Medicine)

► Show Figures

Graphical abstract

9 pages, 2198 KB

Open AccessArticle

Deubiquitinylase USP47 Promotes RelA Phosphorylation and Survival in Gastric Cancer Cells

by Lara Naghavi, Martin Schwalbe, Ahmed Ghanem and Michael Naumann

Biomedicines 2018, 6(2), 62; https://doi.org/10.3390/biomedicines6020062 - 22 May 2018

Cited by 20 | Viewed by 5607

Abstract

Every year, gastric cancer causes around 819,000 deaths worldwide. The incidence of gastric cancer in the western world is slowly declining, but the prognosis is unpromising. In Germany, the 5-year-survival rate is around 32%, and the average life span after diagnosis is 6 [...] Read more.

Every year, gastric cancer causes around 819,000 deaths worldwide. The incidence of gastric cancer in the western world is slowly declining, but the prognosis is unpromising. In Germany, the 5-year-survival rate is around 32%, and the average life span after diagnosis is 6 to 9 months. Therapy of gastric cancer patients comprises a gastrectomy and perioperative or adjuvant chemotherapy. However, resistance of gastric cancer cells to these agents is widespread; thus, improved chemotherapeutic approaches are required. Nuclear factor kappa B (NF-κB) transcription factors are associated with anti-apoptosis, carcinogenesis, and chemoresistance, and thus, constitute attractive targets for therapeutic intervention. In immunoblots, we show that ubiquitin specific protease 47 (USP47) promotes β-transducin repeat-containing protein (βTrCP) stability and phosphorylation of RelA. Furthermore, after knockdown of USP47 by RNA interference, we analyzed in gastric cancer cell lines metabolic activity/viability in an MTT assay, and apoptotic cell death by Annexin V staining and poly(ADP-Ribose) polymerase (PARP)-1, caspase 3, and caspase 8 cleavage, respectively. We found that USP47 contributes to cell viability and chemoresistance in NCI-N87 gastric carcinoma cells treated with etoposide and camptothecin. Inhibition of USP47 might be a suitable strategy to downregulate NF-κB activity, and to overcome chemoresistance in gastric cancer. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)

► Show Figures

Graphical abstract

11 pages, 3526 KB

Open AccessArticle

Osteocytes Specific GSK3 Inhibition Affects In Vitro Osteogenic Differentiation

by Jessika Bertacchini, Maria Sara Magarò, Francesco Potì and Carla Palumbo

Biomedicines 2018, 6(2), 61; https://doi.org/10.3390/biomedicines6020061 - 21 May 2018

Cited by 9 | Viewed by 4599

Abstract

Osteocytes, the most important regulators of bone processes, are producers of molecules (usually proteins) that act as signals in order to communicate with nearby cells. These factors control cell division (proliferation), differentiation, and survival. Substantial evidence showed different signaling pathways activated by osteocytes [...] Read more.

Osteocytes, the most important regulators of bone processes, are producers of molecules (usually proteins) that act as signals in order to communicate with nearby cells. These factors control cell division (proliferation), differentiation, and survival. Substantial evidence showed different signaling pathways activated by osteocytes and involved in osteoblast differentiation, in particular in the last decade, when the Wingless-related integration site (WNT) pathway assumed a critical large importance. WNT activation by inhibiting glycogen synthase kinase 3 (GSK-3) causes bone anabolism, making GSK3 a potential therapeutic target for bone diseases. In our study, we hypothesized an important role of the osteocyte MLO-Y4 conditioned medium in controlling the differentiation process of osteoblast cell line 2T3. We found an effect of diminished differentiation capability of 2T3 upon conditioning with medium from murine long bone osteocyte-Y4 cells (MLO-Y4) pre-treated with GSK3 inhibitor CHIR2201. The novel observations of this study provide knowledge about the inhibition of GSK3 in MLO-Y4 cells. This strategy could be used as a plausible target in osteocytes in order to regulate bone resorption mediated by a loss of osteoblasts activity through a paracrine loop. Full article

► Show Figures

Graphical abstract

17 pages, 421 KB

Open AccessReview

Metabolic Regulation of Hypoxia-Inducible Transcription Factors: The Role of Small Molecule Metabolites and Iron

by Peter S. J. Bailey and James A. Nathan

Biomedicines 2018, 6(2), 60; https://doi.org/10.3390/biomedicines6020060 - 17 May 2018

Cited by 38 | Viewed by 8589

Abstract

Hypoxia-inducible transcription factors (HIFs) facilitate cellular adaptations to low-oxygen environments. However, it is increasingly recognised that HIFs may be activated in response to metabolic stimuli, even when oxygen is present. Understanding the mechanisms for the crosstalk that exists between HIF signalling and metabolic [...] Read more.

Hypoxia-inducible transcription factors (HIFs) facilitate cellular adaptations to low-oxygen environments. However, it is increasingly recognised that HIFs may be activated in response to metabolic stimuli, even when oxygen is present. Understanding the mechanisms for the crosstalk that exists between HIF signalling and metabolic pathways is therefore important. This review focuses on the metabolic regulation of HIFs by small molecule metabolites and iron, highlighting the latest studies that explore how tricarboxylic acid (TCA) cycle intermediates, 2-hydroxyglutarate (2-HG) and intracellular iron levels influence the HIF response through modulating the activity of prolyl hydroxylases (PHDs). We also discuss the relevance of these metabolic pathways in physiological and disease contexts. Lastly, as PHDs are members of a large family of 2-oxoglutarate (2-OG) dependent dioxygenases that can all respond to metabolic stimuli, we explore the broader role of TCA cycle metabolites and 2-HG in the regulation of 2-OG dependent dioxygenases, focusing on the enzymes involved in chromatin remodelling. Full article

(This article belongs to the Special Issue Hypoxia)

► Show Figures

Graphical abstract

19 pages, 1059 KB

Open AccessReview

The NF-κB Activating Pathways in Multiple Myeloma

by Payel Roy, Uday Aditya Sarkar and Soumen Basak

Biomedicines 2018, 6(2), 59; https://doi.org/10.3390/biomedicines6020059 - 16 May 2018

Cited by 71 | Viewed by 9877

Abstract

Multiple myeloma(MM), an incurable plasma cell cancer, represents the second most prevalent hematological malignancy. Deregulated activity of the nuclear factor kappaB (NF-κB) family of transcription factors has been implicated in the pathogenesis of multiple myeloma. Tumor microenvironment-derived cytokines and cancer-associated genetic mutations signal [...] Read more.

Multiple myeloma(MM), an incurable plasma cell cancer, represents the second most prevalent hematological malignancy. Deregulated activity of the nuclear factor kappaB (NF-κB) family of transcription factors has been implicated in the pathogenesis of multiple myeloma. Tumor microenvironment-derived cytokines and cancer-associated genetic mutations signal through the canonical as well as the non-canonical arms to activate the NF-κB system in myeloma cells. In fact, frequent engagement of both the NF-κB pathways constitutes a distinguishing characteristic of myeloma. In turn, NF-κB signaling promotes proliferation, survival and drug-resistance of myeloma cells. In this review article, we catalog NF-κB activating genetic mutations and microenvironmental cues associated with multiple myeloma. We then describe how the individual canonical and non-canonical pathways transduce signals and contribute towards NF-κB -driven gene-expressions in healthy and malignant cells. Furthermore, we discuss signaling crosstalk between concomitantly triggered NF-κB pathways, and its plausible implication for anomalous NF-κB activation and NF-κB driven pro-survival gene-expressions in multiple myeloma. Finally, we propose that mechanistic understanding of NF-κB deregulations may provide for improved therapeutic and prognostic tools in multiple myeloma. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)

► Show Figures

Graphical abstract

18 pages, 1928 KB

Open AccessReview

The Crosstalk of Endoplasmic Reticulum (ER) Stress Pathways with NF-κB: Complex Mechanisms Relevant for Cancer, Inflammation and Infection

by M. Lienhard Schmitz, M. Samer Shaban, B. Vincent Albert, Anke Gökçen and Michael Kracht

Biomedicines 2018, 6(2), 58; https://doi.org/10.3390/biomedicines6020058 - 16 May 2018

Cited by 115 | Viewed by 13545

Abstract

Stressful conditions occuring during cancer, inflammation or infection activate adaptive responses that are controlled by the unfolded protein response (UPR) and the nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) signaling pathway. These systems can be triggered by chemical compounds [...] Read more.

Stressful conditions occuring during cancer, inflammation or infection activate adaptive responses that are controlled by the unfolded protein response (UPR) and the nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) signaling pathway. These systems can be triggered by chemical compounds but also by cytokines, toll-like receptor ligands, nucleic acids, lipids, bacteria and viruses. Despite representing unique signaling cascades, new data indicate that the UPR and NF-κB pathways converge within the nucleus through ten major transcription factors (TFs), namely activating transcription factor (ATF)4, ATF3, CCAAT/enhancer-binding protein (CEBP) homologous protein (CHOP), X-box-binding protein (XBP)1, ATF6α and the five NF-κB subunits. The combinatorial occupancy of numerous genomic regions (enhancers and promoters) coordinates the transcriptional activation or repression of hundreds of genes that collectively determine the balance between metabolic and inflammatory phenotypes and the extent of apoptosis and autophagy or repair of cell damage and survival. Here, we also discuss results from genetic experiments and chemical activators of endoplasmic reticulum (ER) stress that suggest a link to the cytosolic inhibitor of NF-κB (IκB)α degradation pathway. These data show that the UPR affects this major control point of NF-κB activation through several mechanisms. Taken together, available evidence indicates that the UPR and NF-κB interact at multiple levels. This crosstalk provides ample opportunities to fine-tune cellular stress responses and could also be exploited therapeutically in the future. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)

► Show Figures

Graphical abstract

2 pages, 1291 KB

Open AccessCorrection

Correction: Riedlinger, T. et al. The Direct and Indirect Roles of NF-κB in Cancer: Lessons from Oncogenic Fusion Proteins and Knock-In Mice. Biomedicines, 2018, 6, 36

by Tabea Riedlinger, Jana Haas, Julia Busch, Bart Van de Sluis, Michael Kracht and M. Lienhard Schmitz

Biomedicines 2018, 6(2), 57; https://doi.org/10.3390/biomedicines6020057 - 16 May 2018

Cited by 2 | Viewed by 3771

Abstract

We would like to report an error in a previously published paper[...] Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)

► Show Figures

Figure 1

20 pages, 2520 KB

Open AccessReview

Hypoxia, Metabolism and Immune Cell Function

by Ewelina Krzywinska and Christian Stockmann

Biomedicines 2018, 6(2), 56; https://doi.org/10.3390/biomedicines6020056 - 15 May 2018

Cited by 151 | Viewed by 13338

Abstract

Hypoxia is a hallmark of inflamed, infected or damaged tissue, and the adaptation to inadequate tissue oxygenation is regulated by hypoxia-inducible factors (HIFs). HIFs are key mediators of the cellular response to hypoxia, but they are also associated with pathological stress such as [...] Read more.

Hypoxia is a hallmark of inflamed, infected or damaged tissue, and the adaptation to inadequate tissue oxygenation is regulated by hypoxia-inducible factors (HIFs). HIFs are key mediators of the cellular response to hypoxia, but they are also associated with pathological stress such as inflammation, bacteriological infection or cancer. In addition, HIFs are central regulators of many innate and adaptive immunological functions, including migration, antigen presentation, production of cytokines and antimicrobial peptides, phagocytosis as well as cellular metabolic reprogramming. A characteristic feature of immune cells is their ability to infiltrate and operate in tissues with low level of nutrients and oxygen. The objective of this article is to discuss the role of HIFs in the function of innate and adaptive immune cells in hypoxia, with a focus on how hypoxia modulates immunometabolism. Full article

(This article belongs to the Special Issue Hypoxia)

► Show Figures

Figure 1

11 pages, 893 KB

Open AccessArticle

Short-Term Soy Protein Isolate Feeding Prevents Liver Steatosis and Reduces Serum ALT and AST Levels in Obese Female Zucker Rats

by Reza Hakkak, C. Heath Gauss, Andrea Bell and Soheila Korourian

Biomedicines 2018, 6(2), 55; https://doi.org/10.3390/biomedicines6020055 - 14 May 2018

Cited by 42 | Viewed by 6445

Abstract

Non-alcoholic fatty liver disease is a common liver disorder worldwide and is associated with obesity. We investigated effects of obesity and short-term intake of soy protein with isoflavones (SPI) on body weight change, energy intake, liver steatosis, and serum aspartate aminotransferase (AST), alanine [...] Read more.

Non-alcoholic fatty liver disease is a common liver disorder worldwide and is associated with obesity. We investigated effects of obesity and short-term intake of soy protein with isoflavones (SPI) on body weight change, energy intake, liver steatosis, and serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and leptin levels. Seventeen lean and seventeen obese (fa/fa) female Zucker rats were randomly assigned to either casein or SPI diet for 8 weeks. Body weight was recorded twice weekly; feed intake was measured weekly. Livers were examined histologically, and serum AST, ALT, and leptin levels were measured. Obese soy-fed (OS) rats gained more weight but had lower liver steatosis than obese casein-fed (OC) rats. Energy intake for OS versus OC rats were only different at weeks 2 and 3. Serum AST and ALT levels were lower in OS versus OC rats. Obesity increased serum leptin levels for both diets. In summary, short-term SPI intake reduced liver steatosis, and the only time points at which the mean energy intakes of OS and OC rats differed were at weeks 2 and 3, where OS rats had a higher mean energy intake, which may have accounted for the increased body weight in OS rats. Full article

► Show Figures

Graphical abstract

7 pages, 1910 KB

Open AccessCommunication

Comparison of Synthetic Media Designed for Expansion of Adipose-Derived Mesenchymal Stromal Cells

by Michelle Lensch, Angela Muise, Lisa White, Michael Badowski and David Harris

Biomedicines 2018, 6(2), 54; https://doi.org/10.3390/biomedicines6020054 - 14 May 2018

Cited by 20 | Viewed by 4389

Abstract

Mesenchymal stromal cells (MSCs) are multipotent cells that can differentiate into various cell types, such as osteoblasts, myocytes, and adipocytes. This characteristic makes the cells a useful tool in developing new therapies for a number of common maladies and diseases. The utilization of [...] Read more.

Mesenchymal stromal cells (MSCs) are multipotent cells that can differentiate into various cell types, such as osteoblasts, myocytes, and adipocytes. This characteristic makes the cells a useful tool in developing new therapies for a number of common maladies and diseases. The utilization of animal-derived growth serum, such as fetal bovine serum (FBS), for the expansion of MSCs has traditionally been used for cell culture. However, in clinical applications, animal-derived products present limitations and safety concerns for the recipient, as exposure to animal (xeno-) antigens and infectious agents is possible. Multiple synthetic, xeno-free media have been developed to combat these limitations of animal-derived growth serum and have the potential to be used in ex vivo MSC expansion for clinical use. The goal of this study was to determine if xeno-free media are adequate to significantly and efficiently expand MSCs derived from adipose tissue. MSCs were cultured in both standard FBS-containing as well as xeno-free media. The media were compared for cell yield, viability, and phenotypic expression via flow cytometry and directed differentiation. The xeno-free media that were tested were StemMACS MSC Expansion Media (Miltenyi Biotec, Bergisch Gladbach, Germany), PLTMax Human Platelet Lysate (Sigma-Aldrich, St. Louis, MO, USA), and MesenCult-hPL media (Stemcell Technologies, Vancouver, BC, Canada). All xeno-free media showed promise as a feasible replacement for animal-derived growth serums. The xeno-free media expanded MSCs more quickly than the FBS-containing medium and also showed great similarity in cell viability and phenotypic expression. In fact, each xeno-free media produced a greater viable cell yield than the standard FBS-containing medium. Full article

► Show Figures

Figure 1

13 pages, 2231 KB

Open AccessReview

Artificially Expanded Genetic Information Systems for New Aptamer Technologies

by Elisa Biondi and Steven A. Benner

Biomedicines 2018, 6(2), 53; https://doi.org/10.3390/biomedicines6020053 - 9 May 2018

Cited by 63 | Viewed by 7252

Abstract

Directed evolution was first applied to diverse libraries of DNA and RNA molecules a quarter century ago in the hope of gaining technology that would allow the creation of receptors, ligands, and catalysts on demand. Despite isolated successes, the outputs of this technology [...] Read more.

Directed evolution was first applied to diverse libraries of DNA and RNA molecules a quarter century ago in the hope of gaining technology that would allow the creation of receptors, ligands, and catalysts on demand. Despite isolated successes, the outputs of this technology have been somewhat disappointing, perhaps because the four building blocks of standard DNA and RNA have too little functionality to have versatile binding properties, and offer too little information density to fold unambiguously. This review covers the recent literature that seeks to create an improved platform to support laboratory Darwinism, one based on an artificially expanded genetic information system (AEGIS) that adds independently replicating nucleotide “letters” to the evolving “alphabet”. Full article

(This article belongs to the Special Issue Engineering Aptamers for Biomedical Applications)

► Show Figures

Figure 1

16 pages, 850 KB

Open AccessReview

Adiponectin Signaling Pathways in Liver Diseases

by Tania Gamberi, Francesca Magherini, Alessandra Modesti and Tania Fiaschi

Biomedicines 2018, 6(2), 52; https://doi.org/10.3390/biomedicines6020052 - 7 May 2018

Cited by 83 | Viewed by 8464

Abstract

In the liver, adiponectin regulates both glucose and lipid metabolism and exerts an insulin-sensitizing effect. The binding of adiponectin with its specific receptors induces the activation of a proper signaling cascade that becomes altered in liver pathologies. This review describes the different signaling [...] Read more.

In the liver, adiponectin regulates both glucose and lipid metabolism and exerts an insulin-sensitizing effect. The binding of adiponectin with its specific receptors induces the activation of a proper signaling cascade that becomes altered in liver pathologies. This review describes the different signaling pathways in healthy and diseased hepatocytes, also highlighting the beneficial role of adiponectin in autophagy activation and hepatic regeneration. Full article

(This article belongs to the Special Issue Adiponectin and Its Receptor Interactions in Human Disease)

► Show Figures

Figure 1

15 pages, 1048 KB

Open AccessReview

Cell-Penetrating Peptides to Enhance Delivery of Oligonucleotide-Based Therapeutics

by Graham McClorey and Subhashis Banerjee

Biomedicines 2018, 6(2), 51; https://doi.org/10.3390/biomedicines6020051 - 5 May 2018

Cited by 140 | Viewed by 11515

Abstract

The promise of nucleic acid based oligonucleotides as effective genetic therapies has been held back by their low bioavailability and poor cellular uptake to target tissues upon systemic administration. One such strategy to improve upon delivery is the use of short cell-penetrating peptides [...] Read more.

The promise of nucleic acid based oligonucleotides as effective genetic therapies has been held back by their low bioavailability and poor cellular uptake to target tissues upon systemic administration. One such strategy to improve upon delivery is the use of short cell-penetrating peptides (CPPs) that can be either directly attached to their cargo through covalent linkages or through the formation of noncovalent nanoparticle complexes that can facilitate cellular uptake. In this review, we will highlight recent proof-of-principle studies that have utilized both of these strategies to improve nucleic acid delivery and discuss the prospects for translation of this approach for clinical application. Full article

(This article belongs to the Special Issue Antisense Therapy)

► Show Figures

Figure 1

13 pages, 794 KB

Open AccessReview

Mammary Stem Cells and Breast Cancer Stem Cells: Molecular Connections and Clinical Implications

by Toni Celià-Terrassa

Biomedicines 2018, 6(2), 50; https://doi.org/10.3390/biomedicines6020050 - 4 May 2018

Cited by 19 | Viewed by 10315

Abstract

Cancer arises from subpopulations of transformed cells with high tumor initiation and repopulation ability, known as cancer stem cells (CSCs), which share many similarities with their normal counterparts. In the mammary gland, several studies have shown common molecular regulators between adult mammary stem [...] Read more.

Cancer arises from subpopulations of transformed cells with high tumor initiation and repopulation ability, known as cancer stem cells (CSCs), which share many similarities with their normal counterparts. In the mammary gland, several studies have shown common molecular regulators between adult mammary stem cells (MaSCs) and breast cancer stem cells (bCSCs). Cell plasticity and self-renewal are essential abilities for MaSCs to maintain tissue homeostasis and regenerate the gland after pregnancy. Intriguingly, these properties are similarly executed in breast cancer stem cells to drive tumor initiation, tumor heterogeneity and recurrence after chemotherapy. In addition, both stem cell phenotypes are strongly influenced by external signals from the microenvironment, immune cells and supportive specific niches. This review focuses on the intrinsic and extrinsic connections of MaSC and bCSCs with clinical implications for breast cancer progression and their possible therapeutic applications. Full article

(This article belongs to the Special Issue Stem Cells and Cancer Therapeutics)

► Show Figures

Graphical abstract

10 pages, 630 KB

Open AccessReview

Neural Oscillatory Correlates for Conditioning and Extinction of Fear

by Carlos Trenado, Nicole Pedroarena-Leal, Laura Cif, Michael Nitsche and Diane Ruge

Biomedicines 2018, 6(2), 49; https://doi.org/10.3390/biomedicines6020049 - 1 May 2018

Cited by 19 | Viewed by 10211

Abstract

The extinction of conditioned-fear represents a hallmark of current exposure therapies as it has been found to be impaired in people suffering from post-traumatic stress disorder (PTSD) and anxiety. A large body of knowledge focusing on psychophysiological animal and human studies suggests the [...] Read more.

The extinction of conditioned-fear represents a hallmark of current exposure therapies as it has been found to be impaired in people suffering from post-traumatic stress disorder (PTSD) and anxiety. A large body of knowledge focusing on psychophysiological animal and human studies suggests the involvement of key brain structures that interact via neural oscillations during the acquisition and extinction of fear. Consequently, neural oscillatory correlates of such mechanisms appear relevant regarding the development of novel therapeutic approaches to counterbalance abnormal activity in fear-related brain circuits, which, in turn, could alleviate fear and anxiety symptoms. Here, we provide an account of state-of-the-art neural oscillatory correlates for the conditioning and extinction of fear, and also deal with recent translational efforts aimed at fear extinction by neural oscillatory modulation. Full article

(This article belongs to the Special Issue Neural Mechanisms of Learning)

► Show Figures

Graphical abstract

13 pages, 2842 KB

Open AccessArticle

Neuroprotective and Anti-Inflammatory Effects of Rhus coriaria Extract in a Mouse Model of Ischemic Optic Neuropathy

by Saba Khalilpour, Ghazaleh Behnammanesh, Fouad Suede, Mohammed O. Ezzat, Jayadhisan Muniandy, Yasser Tabana, Mohamed B. K. Ahamed, Ali Tamayol, Amin Malik Shah Majid, Enrico Sangiovanni, Mario Dell’Agli and Aman Shah Majid

Biomedicines 2018, 6(2), 48; https://doi.org/10.3390/biomedicines6020048 - 23 Apr 2018

Cited by 27 | Viewed by 7776

Abstract

Modulating oxidative stresses and inflammation can potentially prevent or alleviate the pathological conditions of diseases associated with the nervous system, including ischemic optic neuropathy. In this study we evaluated the anti-neuroinflammatory and neuroprotective activities of Rhus coriaria (R. coriaria) extract in vivo. [...] Read more.

Modulating oxidative stresses and inflammation can potentially prevent or alleviate the pathological conditions of diseases associated with the nervous system, including ischemic optic neuropathy. In this study we evaluated the anti-neuroinflammatory and neuroprotective activities of Rhus coriaria (R. coriaria) extract in vivo. The half maximal inhibitory concentration (IC₅₀) for DPPH, ABTS and β–carotene were 6.79 ± 0.009 µg/mL, 10.94 ± 0.09 µg/mL, and 6.25 ± 0.06 µg/mL, respectively. Retinal ischemia was induced by optic nerve crush injury in albino Balb/c mice. The anti-inflammatory activity of ethanolic extract of R. coriaria (ERC) and linoleic acid (LA) on ocular ischemia was monitored using Fluorescence Molecular Tomography (FMT). Following optic nerve crush injury, the mice treated with 400 mg/kg of ERC and LA exhibited an 84.87% and 86.71% reduction of fluorescent signal (cathepsin activity) respectively. The results of this study provide strong scientific evidence for the neuroprotective activity of the ERC, identifying LA as one of the main components responsible for the effect. ERC may be useful and worthy of further development for its adjunctive utilization in the treatment of optic neuropathy. Full article

(This article belongs to the Special Issue Anti-inflammatory Activity of Plant Polyphenols)

► Show Figures

Graphical abstract

19 pages, 2245 KB

Open AccessReview

Hypoxia and Chromatin: A Focus on Transcriptional Repression Mechanisms

by Michael Batie, Luis Del Peso and Sonia Rocha

Biomedicines 2018, 6(2), 47; https://doi.org/10.3390/biomedicines6020047 - 22 Apr 2018

Cited by 43 | Viewed by 9643

Abstract

Hypoxia or reduced oxygen availability has been studied extensively for its ability to activate specific genes. Hypoxia-induced gene expression is mediated by the HIF transcription factors, but not exclusively so. Despite the extensive knowledge about how hypoxia activates genes, much less is known [...] Read more.

Hypoxia or reduced oxygen availability has been studied extensively for its ability to activate specific genes. Hypoxia-induced gene expression is mediated by the HIF transcription factors, but not exclusively so. Despite the extensive knowledge about how hypoxia activates genes, much less is known about how hypoxia promotes gene repression. In this review, we discuss the potential mechanisms underlying hypoxia-induced transcriptional repression responses. We highlight HIF-dependent and independent mechanisms as well as the potential roles of dioxygenases with functions at the nucleosome and DNA level. Lastly, we discuss recent evidence regarding the involvement of transcriptional repressor complexes in hypoxia. Full article

(This article belongs to the Special Issue Hypoxia)

► Show Figures

Graphical abstract

11 pages, 27677 KB

Open AccessCase Report

Tumor Molecular Profiling for an Individualized Approach to the Treatment of Hepatocellular Carcinoma: A Patient Case Study

by Kristine Posadas, Anita Ankola, Zhaohai Yang and Nelson S. Yee

Biomedicines 2018, 6(2), 46; https://doi.org/10.3390/biomedicines6020046 - 17 Apr 2018

Cited by 5 | Viewed by 5198

Abstract

Hepatocellular carcinoma (HCC) is increasing in incidence, and the associated mortality rate remains among the highest. For advanced HCC, sorafenib has been shown to slightly prolong survival, and regorafenib and nivolumab, both recently approved by the United States Food and Drug Administration (FDA), [...] Read more.

Hepatocellular carcinoma (HCC) is increasing in incidence, and the associated mortality rate remains among the highest. For advanced HCC, sorafenib has been shown to slightly prolong survival, and regorafenib and nivolumab, both recently approved by the United States Food and Drug Administration (FDA), may produce clinical benefits to a limited extent. Systemic chemotherapy has been shown to produce a modest response, but there is no clinically valid biomarker that can be used to predict which patients may benefit. In this case study, we present two patients with metastatic HCC, they received systemic treatment using capecitabine, oxaliplatin, and either bevacizumab or sorafenib. The tumor response to treatment was determined by the progression-free survival (PFS). Molecular profiling of the tumors showed differential expression of biochemical markers and different mutational status of the TP53 and β-catenin (CTNNB1) genes. We hypothesize that the PFS correlates with the tumor molecular profiles, which may be predictive of the therapeutic response to systemic chemotherapy. Further investigation is indicated to correlate tumor biomarkers and treatment responses, with the objective of personalizing the therapies for patients with advanced HCC. Full article

(This article belongs to the Special Issue Cancer Biomarkers and Targets in Digestive Organs)

► Show Figures

Graphical abstract

14 pages, 2017 KB

Open AccessReview

NF-κB, the Importance of Being Dynamic: Role and Insights in Cancer

by Federica Colombo, Samuel Zambrano and Alessandra Agresti

Biomedicines 2018, 6(2), 45; https://doi.org/10.3390/biomedicines6020045 - 17 Apr 2018

Cited by 36 | Viewed by 6994

Abstract

In this review, we aim at describing the results obtained in the past years on dynamics features defining NF-κB regulatory functions, as we believe that these developments might have a transformative effect on the way in which NF-κB involvement in cancer is studied. [...] Read more.

In this review, we aim at describing the results obtained in the past years on dynamics features defining NF-κB regulatory functions, as we believe that these developments might have a transformative effect on the way in which NF-κB involvement in cancer is studied. We will also describe technical aspects of the studies performed in this context, including the use of different cellular models, culture conditions, microscopy approaches and quantification of the imaging data, balancing their strengths and limitations and pointing out to common features and to some open questions. Our emphasis in the methodology will allow a critical overview of literature and will show how these cutting-edge approaches can contribute to shed light on the involvement of NF-κB deregulation in tumour onset and progression. We hypothesize that this “dynamic point of view” can be fruitfully applied to untangle the complex relationship between NF-κB and cancer and to find new targets to restrain cancer growth. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)

► Show Figures

Graphical abstract

12 pages, 9150 KB

Open AccessReview

Subunit-Specific Role of NF-κB in Cancer

by Barbara Kaltschmidt, Johannes F. W. Greiner, Hussamadin M. Kadhim and Christian Kaltschmidt

Biomedicines 2018, 6(2), 44; https://doi.org/10.3390/biomedicines6020044 - 17 Apr 2018

Cited by 94 | Viewed by 10530

Abstract

The transcription factor NF-κB is a key player in inflammation, cancer development, and progression. NF-κB stimulates cell proliferation, prevents apoptosis, and could promote tumor angiogenesis as well as metastasis. Extending the commonly accepted role of NF-κB in cancer formation and progression, different NF-κB [...] Read more.

The transcription factor NF-κB is a key player in inflammation, cancer development, and progression. NF-κB stimulates cell proliferation, prevents apoptosis, and could promote tumor angiogenesis as well as metastasis. Extending the commonly accepted role of NF-κB in cancer formation and progression, different NF-κB subunits have been shown to be active and of particular importance in distinct types of cancer. Here, we summarize overexpression data of the NF-κB subunits RELA, RELB, and c-REL (referring to the v-REL, which is the oncogene of Reticuloendotheliosis virus strain T) as well as of their upstream kinase inhibitor, namely inhibitor of κB kinases (IKK), in different human cancers, assessed by database mining. These data argue against a universal mechanism of cancer-mediated activation of NF-κB, and suggest a much more elaborated mode of NF-κB regulation, indicating a tumor type-specific upregulation of the NF-κB subunits. We further discuss recent findings showing the diverse roles of NF-κB signaling in cancer development and metastasis in a subunit-specific manner, emphasizing their specific transcriptional activity and the role of autoregulation. While non-canonical NF-κB RELB signaling is described to be mostly present in hematological cancers, solid cancers reveal constitutive canonical NF-κB RELA or c-REL activity. Providing a linkage to cancer therapy, we discuss the recently described pivotal role of NF-κB c-REL in regulating cancer-targeting immune responses. In addition, current strategies and ongoing clinical trials are summarized, which utilize genome editing or drugs to inhibit the NF-κB subunits for cancer treatment. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)

► Show Figures

Graphical abstract

47 pages, 18194 KB

Open AccessReview

The Many Roles of Ubiquitin in NF-κB Signaling

by Gilles Courtois and Marie-Odile Fauvarque

Biomedicines 2018, 6(2), 43; https://doi.org/10.3390/biomedicines6020043 - 10 Apr 2018

Cited by 49 | Viewed by 10129

Abstract

The nuclear factor κB (NF-κB) signaling pathway ubiquitously controls cell growth and survival in basic conditions as well as rapid resetting of cellular functions following environment changes or pathogenic insults. Moreover, its deregulation is frequently observed during cell transformation, chronic inflammation or autoimmunity. [...] Read more.

The nuclear factor κB (NF-κB) signaling pathway ubiquitously controls cell growth and survival in basic conditions as well as rapid resetting of cellular functions following environment changes or pathogenic insults. Moreover, its deregulation is frequently observed during cell transformation, chronic inflammation or autoimmunity. Understanding how it is properly regulated therefore is a prerequisite to managing these adverse situations. Over the last years evidence has accumulated showing that ubiquitination is a key process in NF-κB activation and its resolution. Here, we examine the various functions of ubiquitin in NF-κB signaling and more specifically, how it controls signal transduction at the molecular level and impacts in vivo on NF-κB regulated cellular processes. Full article

(This article belongs to the Special Issue Roles of NF-κB in Cancer and Their Therapeutic Approaches)

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Biomedicines, Volume 6, Issue 2 (June 2018) – 36 articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI