Journal of Cellular Signaling

Research Article Open Access

Nicotiana glauca Induces Apoptosis in Human Rhabdomyosarcoma Cells: Molecular Targets

Natalia Frattini, Nicolas Blanco, Lucía Pronsato, Lorena Milanesi, Andrea Vasconsuelo

Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood [1]. Soft tissue sarcomas refer to a group of cancers that arise in connective and supporting tissues such as muscles, nerves and blood vessels [2]. Most of these tumors are located in the head and neck region, genitourinary tract, and extremities [3]. Childhood rhabdomyosarcoma accounts for approximately 3.5% of cancer cases in children aged 0-14 years, and 2% of cases among adolescents and young adults aged 15-19 years. The incidence of this malignancy is 4.5 per million children [4].

Commentary Open Access

Extracellular Long Non-coding Punisher as Biomarker and Effector In-patient with Coronary Artery Disease via Regulating Endothelial Cell Function

Zhexi Li, Yunjing Sheng, Annisa Mardianing Utami, Mohammed Rabiul Hosen

Coronary artery disease (CAD) stands as one of the foremost contributors to cardiovascular events and death on a global scale. The primary underlying mechanism for CAD is atherosclerosis, which can precipitate severe cardiovascular events, including myocardial infarction and stroke. Despite significant advancements in clinical diagnosis and treatment modalities, the incidence and mortality rates associated with CAD remain alarmingly high, necessitating continuous research into novel biomarkers and therapeutic targets.

Commentary Open Access

Calcitriol Implications on Human Rhabdomyosarcoma: An Unexplored Field

Claudia Buitrago, Ana P. Irazoqui

Calcitriol, the active form of vitamin D₃, is also acknowledged as 1α, 25-dihydroxy vitamin D₃. This steroid hormone is known for its role in calcium homeostasis and bone metabolism. Recent studies suggest that calcitriol also exerts anti-cancer effects in various malignancies. We previously reported (in 2022) that treatment with this steroid hormone triggers apoptosis in RD cells, a known rhabdomyosarcoma (RMS) cell line.

Review Article Open Access

Signaling of Mitogenic and Metabolic Activities by Fibroblast Growth Factors

Patience Salvalina Okoto, Zeina Alraawi, Thallapuranam Krishnaswamy Suresh Kumar

Fibroblast growth factors are signaling molecules that play crucial roles in fundamental processes such as cell migration, proliferation, differentiation, angiogenesis, and cell survival. FGFs signal by forming a complex with tyrosine kinase FGF receptors and cofactors. It is well known that FGFs play diverse roles in different tissues and at different developmental stages due to factors such as receptors, specific FGFs, and environmental conditions such as temperature and pH.

Mini Review Open Access

Combating PDAC Drug Resistance: The Role of Ref-1 Inhibitors in Accelerating Progress in Pancreatic Cancer Research

Eyram K. Kpenu, Mark R. Kelley

Pancreatic Ductal Adenocarcinoma (PDAC) remains one of the most lethal solid tumor diagnoses given its limited treatment options and dismal prognosis. Its complex tumor microenvironment (TME), heterogeneity, and high propensity for drug resistance are major obstacles in developing effective therapies. Here, we highlight the critical role of Redox effector 1 (Ref-1) in PDAC progression and drug resistance, focusing on its redox regulation of key transcription factors (TFs) such as STAT3, HIF1α, and NF-κB, which are pivotal for tumor survival, proliferation, and immune evasion.

Research Article Open Access

Indole Family and Neomycin Sulfate: Inductors of Differentiation in C2C12 and RD cell Lines

Lorena Milanesi, Andrea Vasconsuelo, Lucía Pronsato, Natalia Frattini, Nicolás Blanco

Rhabdomyosarcoma (RMS) is a highly aggressive tumor primarily affecting the pediatric population, that generally originates from a failure in the embryonic differentiation of myogenic precursor cells. Standard treatment involves surgery, chemotherapy and radiation therapy, with a poor prognosis, especially when it spreads to other parts of the body, highlighting the need for new treatment approaches.

Review Article Open Access

Obesity Significantly Modifies Signaling Pathways Associated with Bone Remodeling and Metabolism

Ferah Armutcu, Eugene McCloskey, Mehmet Ince

It is obvious that obesity-related diseases are increasing in parallel with the prevalence of obesity, which has reached epidemic proportions worldwide. Cardiovascular disease, multiple cancers, stroke, type 2 diabetes and many other non-communicable diseases are more likely to develop in people living with obesity compared to those living at a healthy weight. In recent years, deeper investigation of the role of multi-organ interaction mechanisms in obesity and related chronic diseases has contributed to the development of new treatment and prevention strategies for obesity and its related-diseases.

Research Article Open Access

Elevated Interleukin-6 (IL-6) Levels with Ig (G & M) Antibodies in the Recovery Phase of Patients with COVID-19: Indication of Cytokine Storm and Re-infection

John Bolodeoku, Terry Gbaa

The innate immune response to coronavirus disease (COVID-19) by inflammatory cytokines, such as interleukin 6 (IL-6), has been described as an early response, followed by an adaptive immune response with the production of antibodies. IL-6 is produced in response to viral infections and is crucial for the activation of T cells and the differentiation of B cells, which produce antibodies. Immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies are produced during the initial acute period of infection and the recovery period from the period of onset of symptoms.

Research Article Open Access

One-to-one Benefit Provided by Antioxidants to Cultured Skin Fibroblasts from Friedreich Ataxia Patients

Paule Bénit, Malgorzata Rak, Pierre Rustin

As to better understand and characterize the dramatic differences in antioxidant response of human cells harboring mutations in the frataxin gene responsible for Friedreich's ataxia (FRDA), we studied primary cultures of skin fibroblasts derived from five FRDA patients with different major frataxin gene expansion sizes. Since oxidative stress has been previously established to play a critical role in FRDA, among the many enzymes that may modulate oxidative stress sensitivity, we selected some that have previously been shown to be critical in oxidative stress.

Review Article Open Access

ACE 2/Ang (1-7)/Mas, Non-conventional RAS Axis: Endogenous Contributor of Cardio, and Reno-protective Responses

Supriya Sarkar, K. Jayachandra, Bannikuppe Sannanaik Vishwanath

The Renin angiotensin system (RAS) is an intricate pathway that regulates homeostasis. The proliferative arm of RAS that includes angiotensin converting enzyme (ACE), angiotensin II (Ang II), and angiotensin II type 1 receptor (AT1R) contributes to pathophysiological responses such as vasoconstriction, hypertension, and cardiovascular, cerebral, and renal complications. The discovery of angiotensin converting enzyme 2 (ACE 2), the analog of ACE, synthesizes angiotensin (1-7) [Ang (1-7)] from Ang II or even from angiotensin I (Ang I) or angiotensin (1-9) [Ang (1-9)] less efficiently.

Commentary Open Access

LncRNAs, Critical Regulators of Cellular Stress in Cancer: A New Player in the Old Game

Vikash Kumar, Eitan Shaulian

Due to deregulated control of the cell cycle, proliferation and metabolism, cancer cells are constantly exposed to a wide range of stresses, including DNA damage, nutrient deprivation, heat shock, hypoxia, and oxidative stresses, often, in a non-exclusive manner. Maintaining homeostasis, survival, and proliferation under these adverse conditions is a hallmark of cancer cells. Understanding the factors that enable cancer cells to endure such harsh environments is an important topic in cancer pathology.

Research Article Open Access

ALK1 Signaling in Human Cardiac Progenitor Cells Promotes a Pro-angiogenic Secretome

Michayla Moore, Sergey Ryzhov, Douglas B. Sawyer, Carlos Gartner, Calvin P.H. Vary

Pro-angiogenic paracrine/autocrine signaling impacts myocardial repair in cell-based therapies. Activin A receptor-like type 1 (ACVRL1, ALK1) signaling plays a pivotal role in cardiovascular development and maintenance, but its importance in human-derived therapeutic cardiac cells is not well understood. Here, we isolated a subpopulation of human highly proliferative cells (hHiPCs) from adult epicardial tissue and found that they express ALK1, a high affinity receptor for bone morphogenetic protein-9 (BMP9), which signals via SMAD1/5 to regulate paracrine/autocrine signaling and angiogenesis.

Commentary Open Access

Linking Phosphoinositides to Proteins: A Novel Signaling Pipeline

Noah D. Carrillo, Poorwa Awasthi, Jeong Hyo Lee, Tianmu Wen, Mo Chen, Colin Sterling, Trevor J. Wolfe, Vincent L. Cryns, Richard A. Anderson

Phosphoinositide (PIP_n) signaling plays pivotal roles in myriad biological processes and is altered in many diseases including cancer. Canonical PIP_n signaling involves membrane-associated PIP_n lipid second messengers that modulate protein recruitment and activity at membrane focal points. In the nucleus, PIP_n signaling operates separately from membranous compartments defining the paradigm of non-canonical PIP_n signaling.

Review Article Open Access

Evaluation of Plasmodium berghei Models in Malaria Research

Sarah Oluwatobi Otun, Richard Graca, Olalekan Onisuru, Ikechukwu Achilonu

As a key model organism for studying malaria, Plasmodium berghei provides essential information on pathophysiology, host immunological responses, and possible targets for treating this debilitating illness. This narrative review compares other Plasmodium species models, including P. falciparum and P. vivax, to assess the evolution, traits, and applicability of P. berghei models. We discuss the development of P. berghei research and its historical background, emphasizing its advantages in genetic modification and experimental accessibility.

Commentary Open Access

Targeting Lipid Metabolism for Better Management of Coronavirus SARS-COV-2 Infections: Intervention, Antiviral Drug Development, and Challenges

Yuting Wang, Peiran Chen, Ming-Liang He

The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), although has faded from public view, the virus itself remains highly active and continues to mutate, continuously causing infections. The population faces the risk of severe outcomes caused by virus infection (e.g., multi-organ tissue injury and acute respiratory distress syndrome (ARDS)). Furthermore, patients with chronic diseases (cardiovascular diseases, diabetes) are at risk of developing severe sequelae or even elevated mortality. 

Commentary Open Access

Can Yerba Maté (Ilex paraguariensis A.-St.-Hil) and Its Constituents Affect Health and Obesity?

Alexander V. Sirotkin

The present commentary is a short narrative review of the available data concerning the influence of Yerba Maté, its relatives and constituents on health with special attention to its anti-obesity effects and their physiological mechanisms. The possible adverse side-effects of Yerba Maté, form and doses of its consumption are discussed.

Review Article Open Access

Navigating the Adipocyte Precursor Niche: Cell-Cell Interactions, Regulatory Mechanisms and Implications for Adipose Tissue Homeostasis

Devesh Kesharwani, Aaron Clifford Brown

Support for stem cell self-renewal and differentiation hinges upon the intricate microenvironment termed the stem cell 'niche'. Within the adipose tissue stem cell niche, diverse cell types, such as endothelial cells, immune cells, mural cells, and adipocytes, intricately regulate the function of adipocyte precursors. These interactions, whether direct or indirect, play a pivotal role in governing the balance between self-renewal and differentiation of adipocyte precursors into adipocytes. 

Mini Review Open Access

Signaling Modifications Associated with Obesity and Dysbiosis and Their Impact on Metabolic Disorders

Ferah Armutcu, Eugene McCloskey

The gut microbiota plays a crucial role in various physiological functions such as the production of essential compounds like short-chain fatty acids and vitamins, as well as in controlling inflammation, immune response, and maintaining intestinal barrier integrity. The imbalance in microbial composition, termed dysbiosis, is closely associated with both the pathogenesis of obesity and the development of obesity-related metabolic disorders such as metabolic syndrome and type 2 diabetes (T2D).

Commentary Open Access

Teaching an Old Drug a New Trick: Targeting Treatment Resistance in Genitourinary Cancers

Karina Aguilar, Anuj K. Sharma, Tianyu Yang, Dipen Mehta, Chandramukhi S. Panda, Vinata B. Lokeshwar

In the quest for improving the clinical outcome of patients with metastatic genitourinary cancers, including metastatic renal cell carcinoma (mRCC), the emphasis often is on finding new targeted therapies. However, two studies by Jordan et al. (Oncogenesis 2020) and Wang et al. (Cancer Cell Int 2022) demonstrate the feasibility of improving the efficacy of a modestly effective drug Sorafenib against mRCC by attacking a mechanism hijacked by RCC cells for inactivating Sorafenib.

Review Article Open Access

Role of Exosomal MicroRNAs in Modulating the Response of Cancer Cells to Paclitaxel Treatment

Lanqing Zhao, Cheng Lv, Hui Xie, Xiaoxu Ding

MicroRNAs (miRNAs) play important roles in gene regulation and have been implicated in various human diseases, including cancer. MiRNAs can be packaged in exosomes and transferred between cells. These exosomal miRNAs regulate intercellular communication and influence almost all aspects of cancer biology, including proliferation, apoptosis, invasion, metastasis, and angiogenesis.

Research Article Open Access

Phorbol-12-Myristate-13-Acetate (PMA) Reactivates Replication from HIV-1 Latency and Induces Jurkat Cell Death

Xue Wang, Jiangqin Zhao, Indira Hewlett

HIV-1 has the capability to establish latency during early infection in CD4+ cells, posing a significant challenge to the efforts aimed at curing HIV-1/AIDS. One extensively explored strategy to address this viral latency is the "shock-and-kill" approach. This involves reactivating viral replication using latency reversal agents (LRAs) to induce the death of infected cells. Regrettably, no LRAs with proven effectiveness have been identified thus far.

Research Article Open Access

Monitoring Transcription of miR-15a and miR-124 in Mesenchymal Stem Cells from Adipose Tissue Origin Differentiated into Pancreatic Beta-cells

Hadi Rajabi

MicroRNAs are small, noncoding pieces of nucleic acid with the potential to control mRNA translation. These sequences participate in the regulation of cell dynamic growth and differentiation. In this study, the expression of miR-15a and miR-124 was monitored in adipose-derived tissue stem cells committed to pancreatic β cells in vitro over 28 days. In the current experiment, adipose-derived mesenchymal stem cells were incubated in an induction medium to accelerate differentiation toward the endocrine pancreatic lineage for 28 days with a three-stage protocol.

Research Article Open Access

MKP-2 Deficiency Leads to Lipolytic and Inflammatory Response to Fasting in Mice

Sadie Junkins, Gabrielle Westenberger, Jacob Sellers, Isabel Martinez, Nabin Ghimire, Cassandra Secunda, Morgan Welch, Urja Patel, Kisuk Min, Ahmed Lawan

The liver plays a crucial role in maintaining homeostasis for lipid and glucose. Hepatic lipid synthesis is regulated by nutritional signals in response to fasting and refeeding. It is known that overnutrition regulates MAPK-dependent pathways that control lipid metabolism in the liver by activating MAPK phosphatase-2 (MKP-2). Uncertainty still exists regarding the regulatory mechanisms and effects of MKP-2 on hepatic response to fasting.

Review Article Open Access

Specific Subcellular Localization of Phosphoinositide-Specific Phospholipase C enzymes in Different Human Osteosarcoma Cell Lines

Matteo Corradini, Marta Checchi, Marta Benincasa, Marzia Ferretti, Francesco Cavani, Carla Palumbo, Vincenza Rita Lo Vasco

The role of signal transduction in cancer progression is well established and actively studied, including in osteosarcoma. The signal transduction pathways involved in the regulation of calcium metabolism are being intensively studied, with particular regard to phosphoinositide-specific phospholipase C (PLC) signaling. This family of enzymes helps to modulate calcium metabolism and is interconnected with additional signaling molecules belonging to different pathways.

Review Article Open Access

Retinoic Acid Induced Cell Signaling as a Counter Against Disease

Justin H. Franco, Zhixing K. Pan

Many disease processes result from disruption of physiologic cell signaling pathways. Cancer often develops from the loss of cell cycle regulation, while inflammatory disease results from dysregulated immune activity. Likewise, many microbial infections avoid immune clearance by interfering with cellular antimicrobial pathways. Retinoic Acid (RA) is a dynamic compound, derived from vitamin A, that can regulate various signaling pathways. 

Review Article Open Access

Optogenetics Sheds Light on Brown and Beige Adipocytes

Aaron Clifford Brown

Excessive food intake leads to lipid accumulation in white adipose tissue, triggering inflammation, cellular stress, insulin resistance, and metabolic syndrome. In contrast, the dynamic energy expenditure and heat generation of brown and beige adipose tissue, driven by specialized mitochondria, render it an appealing candidate for therapeutic strategies aimed at addressing metabolic disorders.

Review Article Open Access

DIS3L2: Unveiling a New Player in Tumorigenesis, with a Key Role in Colorectal Cancer

Juan F. García-Moreno, Paulo Matos, Luísa Romão

DIS3L2 is a 3’-5’ exoribonuclease that recognizes and degrades uridylated transcripts in an exosome-independent manner and participates in several RNA degradation pathways, such as the nonsense-mediated mRNA decay, or the surveillance of aberrant structured non-coding RNAs. Although some studies have linked DIS3L2 to tumorigenesis and cancer-related processes, its exact role in the development and progression of cancer

Research Article Open Access

Presence of Elevated Interleukin – 6 (IL-6) in the Blood of COVID-19 Convalescent Patients (40 – 93 Days) Post Onset of Symptoms Could be an Indicator of Ongoing Activation of the Immune System

John Bolodeoku, C Anyaeche, M Bass, TK Kim

IL-6 concentrations rise with the onset of COVID-19 infection and is detected in 68% of patients on admission but is expected to reduce after the acute phase. IL-6 concentrations at time points: (2-7 days), (6-11 days), (11-15 days) and (13-20 days) after intensive care unit (ICU) admission showed the highest level of IL-6 concentrations at time point 2-7 days, we decided to characterize IL-6 concentrations in serum samples collected in the sera of COVID-19 convalescent patients (40 – 93 days) post onset of symptoms.

Research Article Open Access

Depleting Cellular Retinoic Acid Binding Protein 1 Impairs UPR^mt

Chin-Wen Wei, Thomas Lerdall, Fatimah Najjar, Li-Na Wei

Mitochondrial dysfunction underlines neurodegenerative diseases which are mostly characterized by progressive degeneration of neurons. We previously reported that Cellular retinoic acid Binding protein 1 (Crabp1) knockout (CKO) mice spontaneously developed age-dependent motor degeneration, with defects accumulated in spinal motor neurons (MNs), the only cell type in spinal cord that expresses CRABP1.

Review Article Open Access

Understanding Elongasome Unit of Mycobacterium and its Comparative Analysis with Other Model Organisms

Preeti Jain

The reported incidences of 10.6 million tuberculosis cases worldwide with 1.6 million deaths in 2021 indicate that this disease, caused by Mycobacterium tuberculosis pathogen is difficult to treat and requires exploring newer possible therapeutic interventions. To identify novel drug targets, it is important to understand the basic physiological processes of each pathogen in detail. Cell division is the fundamental physiological process which maintains the replicative state of bacteria. 

Review Article Open Access

The Human Gut Phageome: Identification and Roles in the Diseases

Mohsen Nabi-Afjadi, Samane Teymouri, Fatemeh Nafe Monfared, Seyed Mostafa Noorbakhsh Varnosfaderani, Hossein Halimi

The human gut is a complex environment that contains a diversity of microorganisms commonly known as the microbiome. Numerous factors influence the composition of human gut bacterial communities, either contributing to homeostasis or the instability associated with a variety of diseases.

Commentary Open Access

Activation of the 5-hydroxytryptamine Degradation System in Cells and Organ Injury

Jihua Fu

This paper summarizes the research results of Fu et al. on the pathological mechanism of organ injury. A hypothesis was proposed that "organ injury is a consequence of the activation of the 5-hydroxytryptamine degradation system (5DS) axis in cells". The basic composition of the 5DS axis in cells and the principle of its activation leading to cell lesions were determined.

Review Article Open Access

Structural Insights into Protein-Ligand Interactions of Small Leucine Rich Repeat Proteoglycans with a Large Number of Binding Partners: An Overview

Norio Matsushima, Hiroki Miyashita, Dashdavaa Batkhishig, Robert H. Kretsinger

Small leucine rich repeat proteoglycans (SLRPs) exist in the extracellular matrix. SLRPs contain tandem arrays of LRRs flanked by cysteine clusters at the both N- and C-termini. The extreme N- and/or C-termini contain low complexity sequences, glycosaminoglycan (GAG) chain and/or sulfated tyrosine residues in some members of SLRPs.

Commentary Open Access

The Finer Points of Podocyte Sphingolipid Metabolism in Diabetic Kidney Disease

Alla Mitrofanova, Rachel Njeim, Alessia Fornoni

Diabetic kidney disease (DKD) is a common complication of diabetes, characterized by kidney damage. Podocytes are specialized, terminally differentiated cells in the kidney’s filtration barrier that are key responders to the metabolic and environmental changes that occur in diabetes. Change in the function and in the number of podocytes is the main signature of the development and progression of DKD.

Commentary Open Access

F-ATP Synthase Inhibitory Factor 1 in Regulation of Mitochondrial Permeability Transition Pore and Metabolic Reprogramming

Lishu Guo

Mitochondrial permeability transition pore (PTP) plays an important role in mitochondrial physiology and cell fate. Emerging studies highlight PTP forms from F-ATP synthase, but whether F-ATP synthase inhibitory factor 1 (IF1) regulates the activity of PTP is basically unknown. We have recently demonstrated that IF1 interacts with p53-CyPD complex and promotes opening of the PTP, and IF1 is necessary for the formation of p53-CyPD complex.

Mini Review Open Access

Improving Cancer Epigenetic Therapy; A Glimpse of NRF2

Tahereh Kashkoulinejad-Kouhi

One of the mechanisms used by epigenetic therapy is the elevation of host cell-derived double stranded RNA (dsRNA) baseline levels through overexpression of genomic repetitive elements especially Alu retroelements. The dsRNAs trigger immunogenic responses since immune system cannot distinguish between endogenous and exogenous dsRNAs derived from viral infections; hence called “Viral mimicry response”. These dsRNAs are recognized by pattern recognition receptors (PRRs) such as MDA-5

Review Article Open Access

Understanding Chromosome Replication and Segregation Unit of Mycobacterium and Its Comparative Analysis with Model Organisms: From Drug Targets to Drug Identification

Preeti Jain

Bacterium maintains its pathogenicity in the host by continuing replication and adopting temporal and spatial coordination of cell division steps such as cell wall synthesis, DNA replication, chromosome segregation, Z ring assembly, septum formation and finally cytokinesis. This multistep process requires spatiotemporal assembly of macromolecular complexes and is probably regulated by redundant and multifunctional activities of cell replication and division proteins. 

Mini Review Open Access

A Study on the Usage of Probiotics as a Safer Antipyretic

Shantanu Shrivastava, Nimisha Bhatu

Most medicines and supplements which include probiotics have both expected clinical outcomes and unwanted side effects, which plays a major role when considering them as a mode of treatment. This review is an update about the advantages and disadvantages associated with the use of probiotics as part of a safe therapeutic armamentarium in health and other diseases. The advantages of probiotics run across multiple tissue systems in the body and a has a wide age spectrum.

Research Article Open Access

Novel Drug Development for Treatment of COVID-19 by In Silico Analysis: Identification of SARS-Cov-2 Inhibiting Streptomyces Compounds

Jayant Kumar, Prachiti Gholap, Thulasi G Pillai

In accordance with the present epidemiological paradigm, viral mutations of the virus are on the rise, and their natural effects are being selected for at a higher rate than normal. According to the World Health Organization (WHO), the global COVID-19 pandemic induced by the Delta and Omicron strain of the SARS-CoV-2 virus could propagate and disseminate more rapidly than other viruses thanks to its many mutations, and these also caused some very significant health problems. 

Review Article Open Access

Potential Mechanism of CDC42 Promoting HCC Metastasis

Miaoling Tang, Rongni Feng, Jun Li

Hepatocellular carcinoma (HCC) is an aggressive malignancy with increasing morbidity and mortality worldwide. The migration and motility of HCC tumor cells are enhanced by the formation of invadopodia, which comprise membrane protrusions at the leading edge. Previous studies have showed that cell division cycle 42 (CDC42) plays an essential role in remodeling the cytoskeleton, which is associated with invadopodia formation and thus mediates cellular movement.

Original Research Open Access

A Computational Investigation on Rho-related GTP-binding Protein RhoB through Molecular Modeling and Molecular Dynamics Simulation Study

Shamrat Kumar Paul, Chowdhury Lutfun Nahar Metu, Sunita Kumari Sutihar, Md. Saddam, Bristi Paul, Md. Lutful Kabir, Md. Mostofa Uddin Helal

An indispensable member of the Rho family, RhoB is an isoprenylated small GTPases that modulate the cellular cytoskeletal organization. While DNA gets damaged, it takes part in the neoplastic apoptotic mechanism. In this study, we evaluated the structure of Rho-related GTP-binding protein RhoB due to the unavailability of 3D structure in the protein data bank database.

Commentary Open Access

Targeting SCUBE3 in Hepatocellular Carcinoma

Teng Liu, Xia Yang, Ke Wang, Qiang Luo

HCC is one of the most common malignant tumors. The life and health of humans are gravely threatened by HCC because of its hidden onset, high recurrence rate, poor therapeutic effect, and high mortality. It is essential to explore the particular pathological mechanisms of HCC in order to increase the rate of early diagnosis and enhance patient therapy outcomes.

Mini Review Open Access

Purinergic P2X7 Receptor as a Potential Targeted Therapy for COVID-19-associated Lung Cancer Progression

Hamidreza Zalpoor, Abdullatif Akbari, Mohsen Nabi-Afjadi, Ali Norouzi, Farhad Seif, Majid Pornour

Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection is a serious threat to lung cancer patients. Hereby, we hypothesize that Coronavirus disease 2019 (COVID-19) may contribute to lung cancer progression by increasing extracellular adenosine triphosphate (ATP) levels and hyperactivating the purinergic P2X purinoceptor 7 receptor (P2X7R).

Review Article Open Access

Augmenting Venetoclax Activity Through Signal Transduction in AML

Ian Michael Bouligny, Keri Renee Maher, Steven Grant

Venetoclax, a small-molecule B-cell lymphoma 2 (BCL-2) inhibitor, selectively eradicates leukemic stem cells (LSCs). While venetoclax has revolutionized the treatment of acute myeloid leukemia (AML), treatment failure and disease relapse are common. Mechanisms underlying venetoclax resistance are surprisingly heterogeneous.

Mini Review Open Access

Radiation-induced Bystander Effect and Its Possible Countermeasures

Goutam Ghosh

Ionizing radiation has been indispensable to medical diagnosis. In cancer, radiation therapy or radiotherapy (RT) offers patients a better chance of survival. It destroys cancer by depositing high-energy radiation on the cancer tissues, though it may directly damage a few normal cells. 

Original Research Open Access

Resveratrol and Astaxanthin Protect Primary Human Nasal Epithelial Cells Cultured at an Air-liquid Interface from an Acute Oxidant Exposure

Ayaho Yamamoto, Peter D. Sly, Nelufa Begum, Abrey J. Yeo, Emmanuelle Fantino

Oxidative stress (OS) in the airway epithelium is associated with cell damage, inflammation, and mitochondrial dysfunction that may initiate or worsen respiratory disease. However, it is unclear whether exogenous antioxidants can provide protection to the airway epithelium from OS. Resveratrol and astaxanthin are nutritional compounds that have shown diverse benefits including protection against OS and inflammation in various situations.

Research Article Open Access

Redox Homeostasis in Well-differentiated Primary Human Nasal Epithelial Cells

Ayaho Yamamoto, Peter D. Sly, Anna Henningham, Nelufa Begum, Abrey J. Yeo, Emmanuelle Fantino

Oxidative stress (OS) in the airway epithelium is associated with inflammation, cell damage, and mitochondrial dysfunction that may initiate or worsen respiratory disease. Redox regulation maintains the equilibrium of pro-oxidant/antioxidant reactions but can be disturbed by environmental exposures. The mechanism(s) underlying the induction and impact of OS on airway epithelium and how these influences on respiratory disease is poorly understood.

Case Report Open Access

Targeting the Complex Protein Network of MYCN-amplified Anaplastic Ependymoma: A Case Report

Michael P. Castro

The MYCN oncoprotein has been notoriously undruggable and is infamous for causing aggressive cancer with poor outcomes in children and adults. Following surgery, radiation, and chemotherapy, patients who develop progressive disease have few treatment options. An analysis of the dysregulated protein network caused by MYCN amplification suggested co-targeting PLK1, AURKA, CKS1, AKT, MTOR, and USP7 would be useful to take advantage of synthetic lethal vulnerabilities

Commentary Open Access

New Insights into the Proteolytic Regulation of the Structural Protein Junctophilin-2 by Calpain

Gunnar Weninger, Stephan E. Lehnart

Junctophilin-2 (JP2) is a key structural protein of junctional membrane complexes (JMCs) that stabilize contacts between the sarcoplasmic reticulum and transverse tubules required for excitation-contraction (EC) coupling in cardiomyocytes. Under pathophysiological conditions, the intracellular cysteine protease Calpain activated by disturbed intracellular Ca2+ homeostasis cleaves JP2 and, hence, disturbs EC coupling.

Commentary Open Access

Can Mono- or Combination Therapy of Metformin with Cimetidine and Ibuprofen be a Promising Potential Therapy for Breast Cancer?

Samaneh Mostafavi, Hamidreza Zalpoor, Zuhair Mohammad Hassan

Metformin (MET), either alone or in combination with other drugs, has been considered a promising drug in cancer therapy. MET via activation of adenosine monophosphate-activated protein kinase (AMPK) signaling pathway and inhibiting the mammalian target of rapamycin (mTOR) mediates tumor proliferation. Moreover, as an antagonist of the histamine H2-receptor (H2R), cimetidine (CIM) is also attributed to several immune-stimulatory responses in non-immunogenic cancers. 

Commentary Open Access

Oxidative DNA Damage: A Role in Altering Neuronal Function

Adib Behrouzi, Mark R. Kelley, Jill C. Fehrenbacher

A role for oxidative stress in the etiology of myriad neuropathologies is well accepted. However, the specific effects of oxidative DNA damage in the onset or promotion of neuronal dysfunction have been less studied. In our recent publication by Behrouzi et al. (Oxidative DNA Damage and Cisplatin Neurotoxicity Is Exacerbated by Inhibition of OGG1 Glycosylase Activity and APE1 Endonuclease Activity in Sensory Neurons), inhibition of enzymes that play a role in repairing oxidative DNA damage exacerbated neurotoxic effects of the chemotherapeutic agent, cisplatin. 

Commentary Open Access

New Aspects in the Mechanism of Action of ALDH1A1 and 1A3 Isoforms in Carcinogenesis

Martina Poturnajova, Miroslava Matuskova

The ALDH gene superfamily encodes a group of evolutionarily-related proteins catalyzing the irreversible oxidation of aldehyde substrates to their corresponding carboxylic acids. Aldehyde dehydrogenases (ALDH) isoforms 1A1 and 1A3 belong to intracellular enzymes with a broad spectrum of functions linked with an advanced stage of solid tumors and the stemness potential of the neoplastic cells.

Commentary Open Access

Repurposed Anti-IL-6 Therapeutics, Another Way to Quell the Cytokine Storm in Tuberculosis

Funmilayo Grâce Boni, Insaf Hamdi, Liadrine Moukendza Koundi, Lamine Baba-Moussa

Study on ‘‘cytokine storms’’ has been braced up in infectious diseases. The pertinence of this research begins to be evident in tuberculosis as it was observed that increased levels of Interleukin-6 (IL-6) were connected with disease severity. The IL-6 blockers therapeutics approaches for tuberculosis are currently a key line of research, with many in progress clinical trials, as IL-6 has become an important factor of the immune response to tuberculosis.

Mini Review Open Access

MAGIs: Junctional Scaffolds Linking Inter-Cellular Junction Architecture, Actin Cytoskeleton Dynamics, and Signaling Pathways

Lisa Heron-Milhavet, Alexandre Djiane

MAGIs (membrane-associated guanylate-kinases (MAGUK) inverted) are apical scaffolds conserved across evolution, which regulate cellular junctions. Low expression of MAGIs has been associated with tumorigenesis in a wide variety of cancers. This “tumor-suppressive” function of MAGIs has stimulated many studies to better understand the processes they control, and how their misregulation could contribute to cancer progression.

Review Article Open Access

Phosphoinositide-Specific Phospholipases C in Psychiatric Diseases and Suicide

Vincenza Rita Lo Vasco

Mood disorders represent a major medical need requiring chronic treatment. About one million people die by suicide worldwide each year, both as a consequence of major depression or not. Multiple deficits, including cell atrophy and loss, were described in the brains of mood disorders affected patients and in experimental animal models. Numerous changes in gene expression and activity were described in limbic and cortical brain regions. 

Research Article Open Access

The Effect of Diet Induced Obesity on Serotonin in Zebrafish

Leen Uyttebroek, Samuel Van Remoortel, Laura Buyssens, Nastasia Popowycz, Guy Hubens, Jean-Pierre Timmermans, Luc van Nassauw

Obesity is a worldwide epidemic and a major risk factor for numerous diseases. The regulation of feeding behavior and body weight depends on a wide range of neuronal pathways influencing satiety and hunger. Serotonin (5-HT) is one of those players identified to have a profound effect on energy homeostasis. The effect of obesity on 5-HT metabolism in the gastrointestinal (GI) tract and its underlying mechanisms still needs to be further elaborated. 

Commentary Open Access

Insights from Natural Product PHGDH Inhibitor Studies

Zhaodan Wang, Xueqin Chen, Qingxiang Sun

Cancer cells often exhibit a reprogrammed metabolism to accommodate their higher proliferation rates. Serine is a building block for de novo nucleic acids synthesis, and cancer cells typically require more of it. PHGDH is the rate limiting enzyme in human serine synthesis steps and is often highly expressed in cancer. 

Mini Review Open Access

Novel Therapeutic Strategies for Exosome-Related Diseases

Hiroshi Ageta, Kunihiro Tsuchida

Exosomes, a type of extracellular vesicles (EVs), are secreted from cells and taken up again by other cell types. They have attracted attention as new intercellular communication factors involved in various biological processes. Multivesicular bodies (MVBs) are intracellular organelles that are sources of exosomes. Recently, molecular regulatory mechanisms of EVs and MVBs mediated by ubiquitin and ubiquitin-like proteins (UBLs) have been elucidated. 

Review Article Open Access

Low-level Laser Therapy in the Oral Cavity: A Retrospection in the Future

Eirini Papamanoli, Kyriaki Kyriakidou, Ioannis K Karoussis

Lasers have gained rather broad application in the field of medicine, as well as in dentistry. Different wave lengths are appropriate for a variety of uses, such as hemostasis, antimicrobial effect, tissue section and excision. Low level laser therapy (LLLT) is particularly interesting, since it stands out for its biostimulatory effect on tissues.

Mini Review Open Access

The Role of FCH Domain Only 1 (FCHO1) as an Oncogene in Lung Cancer

Myung-Haing Cho, Seung Jin Park, Soon-Kyung Hwang

Lung cancer is the leading cause of cancer-related death in men and women with a 5-year survival rate of 18%. The PI3K/Akt pathway plays a role in non-small cell lung cancer tumorigenesis and progression. FCH domain only 1(FCHO1) is overexpressed in lung cancer and promotes entry into mitosis and G1/S phase transition, leading to cancer cell growth. Our group has investigated the relationship between FCHO1 and the Akt signaling pathway, which plays an important role in lung cancer growth.

Review Article Open Access

C-di-GMP and Its Role in Regulation of Natural Products Production

Olaf Latta, Andreas Bechthold

Among clinical and industrial important microorganisms Streptomyces are the largest source of natural products. But only a fraction of all Biosynthetic Gene Clusters in their genome is active under laboratory conditions. During the last years research has clarified the role of cyclic dimeric 3`-5` guanosine monophosphate, c-di-GMP, as an ubiquitous secondary messenger.

Review Article Open Access

c-JUN n-Terminal Kinase (JNK) Signaling in Autosomal Dominant Polycystic Kidney Disease

Abigail O. Smith, Julie A. Jonassen, Kenley M. Preval, Roger J. Davis, Gregory J. Pazour

Polycystic kidney disease is an inherited degenerative disease in which the uriniferous tubules are replaced by expanding fluid-filled cysts that ultimately destroy organ function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form, afflicting approximately 1 in 1,000 people and is caused by mutations in the transmembrane proteins polycystin-1 (Pkd1) and polycystin-2 (Pkd2).

Research Article Open Access

Expression and Localization of Phosphoinositide-Specific Phospholipases C in Cultured, Differentiating and Stimulated Human Osteoblasts

Sara Daisy Casoni, Alessia Romanelli, Marta Checchi, Serena Truocchio, Marzia Ferretti, Carla Palumbo, Vincenza Rita Lo Vasco

The osteoblasts contribute to bone homeostasis maintaining the bone mass, and intervene in bone injuries repair. Insights in the events leading to the proliferation and differentiation of osteoblasts might allow uncover potential molecular targets to control the complex mechanisms underlying bone remodeling. Signal transduction pathways contribute to the differentiation and metabolic activities of osteoblasts, with special regard to calcium-related signaling, including the Phosphoinositide (PI) pathway.

Letter to the Editor Open Access

AID and APOBEC3 Involvements in Non-Conventional IgD Class Switch Recombination in Mice

Melissa Ferrad, Nour Ghazzaui, Hussein Issaoui, Jeanne Cook-Moreau, Yves Denizot

In mature B-cells, class switch recombination (CSR) substitutes the constant (C) μ gene with other C genes (such as γ, ε and α) thereby generating IgG, IgE and IgA antibodies with new effector functions but same the antigenic specificity compared to IgM. CSR is a complex process with I-promoter transcription, targeting of the DNA-editing enzyme activation-induced deaminase (AID) to specific DNA switch (S) regions preceding C regions (except C_δ), generation of double strand breaks and recruitment of DNA repair factors for the end-joining process. 

Review Article Open Access

Interferon Gamma, MHC Class I Regulation and Immunotherapy

Maria Gómez-Herranz, Magdalena Pilch, Ted Hupp, Sachin Kote

The activation of endogenous IFNγ signaling pathway or the administration of recombinant IFNγ increases the expression of MHC-I. MHC-I molecules are core elements for antigen recognition in tumor cells. A better understanding of the regulation of their expression would contribute to counteracting tumor immune escape and enduring permanent tumor rejection. Efficient and functional expression of HLAs dramatically impacts the number of tumor-associated antigens presented to CTL for cell recognition. 

Review Article Open Access

Differentiation and Subtype Specification of Enteric Neurons: Current Knowledge of Transcription Factors, Signaling Molecules and Signaling Pathways Involved

Nastasia Popowycz, Leen Uyttebroek, Guy Hubens, Luc van Nassauw

The enteric nervous system is the largest component of the autonomic nervous system. It contains a broad network of interconnected plexuses and enteric neuronal subtypes which are in charge of the normal functioning of the gastrointestinal tract. Vagal and sacral neural crest cells are at the basis of the enteric nervous system development. These cells undergo multiple processes such as migration, proliferation and differentiation to finally form a functional enteric nervous system.

Review Article Open Access

TRPM8 Channels and SOCE: Modulatory Crosstalk between Na⁺ and Ca²⁺ Signaling

Guilherme Henrique Souza Bomfim

The electrochemical driving forces across the plasma membrane both in excitable and non-excitable mammalian cells are finely regulated by different ion channels, pumps, and exchangers that are essential for a wide range of biological processes. The modulation between sodium (Na⁺), calcium (Ca²⁺), and intracellular downstream pathways is tightly linked through several mechanisms that generate spatiotemporal ion waves. 

Commentary Open Access

The Outcome of Tumor Ablation Therapies is Determined by Stress Signaling Networks

Mladen Korbelik

Increasingly prominent roles in interventional oncology are held by various tumor ablation therapies performed by direct applications of local acute trauma-inducing insult to the targeted lesion aiming for its rapid in situ destruction. These therapies include treatments based on various forms of thermal energy delivery (photothermal, cryoablation, microwave ablation, radiofrequency ablation), non-thermal illumination (photodynamic therapy), electric field exposure, or high hydrostatic pressure

Review Article Open Access

Aberrant Signaling Pathways in Cancer Cells: Application of Nanomaterials

Indrajit Roy, Goutam Ghosh

Cell signaling pathways involve several proteins, called kinases, to pass on vital messages from the transmembrane-proteins, e.g., receptor tyrosine kinases (RTKs) to the nucleus of a cell through a cascade of processes for various activities such as controlled cell division, proliferation, apoptosis, metabolism, DNA replication and repair. Alterations in these signaling proteins combined with genetic and/or epigenetic mutations spawn various types of cancer that empowers the cells to ignore or maneuver the immune signals and carry on felonious activities such as uncontrolled cell division and growth, genetic instability, angiogenesis around the tumor in hypoxia, eluding the body’s immune system, cell migration, and invasion of surrounding healthy cells.

Review Article Open Access

Anti-tumor Mechanisms of Short-chain Fatty Acids, and the Relationship between the Gut Microbiome, Carcinogenesis, Tumor Growth, and Proliferation in Colorectal Carcinoma

Tadashi Ohara, Yasuyuki Taki

We reviewed the anti-tumor mechanisms of short-chain fatty acids (SCFAs) as well as the relationship between the gut microbiome and the pathology of colorectal carcinoma (CRC). According to our in silico analysis of human CRC cell lines, it was shown that SCFAs suppress various genes and transcription factors that participate in tumor growth/proliferation and cell turnover, and butyric acid displayed the strongest inhibitory effects among SCFAs.

Review Article Open Access

Guanylin Peptides Signaling: Insights into Guanylate Cyclase C Dependent and Independent Signaling Pathways

Ivan Strinic, Nikola Habek, Aleksandra Dugandžic

Guanylin peptides (GPs) and their receptor, guanylate cyclase C (GC-C), have recently become a topic of great interest in metabolic research. Guanylin and uroguanylin are the most investigated GPs and they belong to a larger family of natriuretic peptides. GPs play a physiological role in regulation of electrolyte balance via the intestine and the kidney by regulating the energy balance via their action in the brain.

Research Article Open Access

Chronic IL-1 Exposed AR⁺ PCa Cell Lines Show Conserved Loss of IL-1 Sensitivity and Evolve Both Conserved and Unique Differential Gene Expression Profiles

Shayna E. Thomas-Jardin, Mohammed S. Kanchwala, Haley Dahl, Vivian Liu, Rohan Ahuja, Reshma Soundharrajan, Nicole Roos, Sydney Diep, Amrit Sandhu, Chao Xing, Nikki A. Delk

Inflammation drives prostate cancer (PCa) progression. While inflammation is a cancer hallmark, the underlying mechanisms mediating inflammation-induced PCa are still under investigation. Interleukin-1 (IL-1) is an inflammatory cytokine that promotes cancer progression, including PCa metastasis and castration resistance. We previously found that acute IL-1 exposure represses PCa androgen receptor (AR) expression concomitant with the upregulation of pro-survival proteins, causing de novo accumulation of castration-resistant PCa cells.

Mini Review Open Access

ZBP1, a dsRNA Sensor for Cell Death and Inflammation

Wei Mo, Jiahuai Han

ZBP1 has aroused a wide interest since it was identified as the first cytosolic dsDNA sensor ahead of the finding of cGAS in 2013. However, the investigations on ZBP1 declined when researchers found the binding of ZBP1 with dsDNA is not absolutely required for the activation of innate response.

Review Article Open Access

Ethanol Consumption and Sepsis: Mechanisms of Organ Damage

Alessandra Oliveira Silva, Clare C. Prohaska, Carla Speroni Ceron

Sepsis is highly prevalent, and is one of the main causes of mortality among hospitalized patients. Ethanol consumption in large quantities compromises the normal functioning of the body, leading to dysfunction of multiple different organ systems. The association between sepsis and ethanol is not fully understood, but it is well accepted that ethanol

Mini Review Open Access

Novel Treatments Targeting the Dysregulated Cell Signaling Pathway during Sepsis

Justin H. Franco, Xiaohuan Chen, Zhixing K. Pan

Previously characterized as a purely immune mediated disease, sepsis is now recognized as a dysregulated multisystem response against a pathogen. Recognition of the infectious agent by pathogen recognition receptors (PRRs) can initiate activation of the NF-κB signaling pathway and promote the secretion of proinflammatory cytokines. During sepsis, the activation of NF-κB is dysregulated and results in cytokine storm, or the pathologic release of cytokines.

Mini Review Open Access

Plasminogen Activator Inhibitor-1 and Oncogenesis in the Liver Disease

Da-eun Nam, Hae Chang Seong, Young S. Hahn

Hepatocellular carcinoma (HCC) is a significant cause of cancer mortality worldwide. Chronic hepatic inflammation and fibrosis play a critical role in the development of HCC. Liver fibrosis develops as a result of response to injury such that a persistent and excessive wound healing response induces extracellular matrix (ECM) deposition leading to HCC.

Review Article Open Access

TTK: A Promising Target in Malignant Tumors

Weiping Yao, Mingyun Jiang, Minjun Zhang, Haibo Zhang, Xiaodong Liang

TTK is a dual-specific protein kinase that phosphorylates serine and threonine. The spindle assembly checkpoint (SAC) acts as a molecular monitoring mechanism that regulates mitosis and ensures accurate separation of chromosomes. TTK is a key regulator of the SAC. Activated TTK localizes to kinetochores and activates SAC function. Simultaneously, TTK promotes error correction by phosphorylating several substrates. 

Review Article Open Access

Hydrogen Peroxide-induced Cell Death in Mammalian Cells

Tamutenda Chidawanyika, Surachai Supattapone

Hydrogen peroxide (H₂O₂) is an important intra- and extra-cellular signaling molecule that can determine cell fate. At low concentrations, H₂O₂ plays roles in proliferation, immunity, and metabolism. Cellular exposure to higher non-physiologic concentrations of H₂O₂ can result in oxidative stress.

Review Article Open Access

Targeting Cullin-RING E3 Ubiquitin Ligase 4 by Small Molecule Modulators

Kenneth Wu, Benjamin D. Hopkins, Roberto Sanchez, Robert J. DeVita, Zhen-Qiang Pan

Cullin-RING E₃ ubiquitin ligase 4 (CRL₄) plays an essential role in cell cycle progression. Recent efforts using high throughput screening and follow up hit-to-lead studies have led to identification of small molecules 33-11 and KH-4-43 that inhibit E₃ CRL₄’s core ligase complex and exhibit anticancer potential.

Review Article Open Access

A Brief Update on STAT3 Signaling: Current Challenges and Future Directions in Cancer Treatment

Keisuke Taniguchi, Momomi Tsugane, Akira Asai

Signal transducer and activator of transcription (STAT) 3 plays a key role not only in regulating a variety of biological properties, including survival, proliferation, and metastasis of cancer cells, but also in modifying the tumor microenvironment to promote angiogenesis and immunosuppression, rendering STAT3 a valuable target in cancer.

Review Article Open Access

Function of Mitogen-Activated Protein Kinases in Hepatic Inflammation

Gabrielle Westenberger, Jacob Sellers, Savanie Fernando, Sadie Junkins, Sung Min Han, Kisuk Min, Ahmed Lawan

The western diet and overuse of anti-inflammatory medication have caused a great deal of stress on the liver. Obesity and the associated inflammatory state in insulin-responsive tissues result in the release of pro-inflammatory cytokine that activates the stress-responsive MAPKs, p38 MAPK, and JNK. These MAPKs have figured prominently as critical effectors in physiological and pathophysiological hepatic inflammation.

Review Article Open Access

NH₂-Terminal Cleavage of Cardiac Troponin I Signals Adaptive Response to Cardiac Stressors

Chad M. Warren, Monika Halas, Han-Zhong Feng, Beata M. Wolska, Jian-Ping Jin, R. John Solaro

Cardiac sarcomeres express a variant of troponin I (cTnI) that contains a unique N-terminal extension of ~30 amino acids with regulatory phosphorylation sites. The extension is important in the control of myofilament response to Ca²⁺, which contributes to the neuro-humoral regulation of the dynamics of cardiac contraction and relaxation.

Review Article Open Access

APE1/Ref-1 – One Target with Multiple Indications: Emerging Aspects and New Directions

Mahmut Mijiti, Rachel Caston, Silpa Gampala, Melissa L. Fishel, Jill C. Fehrenbacher, Mark R. Kelley

In the realm of DNA repair, base excision repair (BER) protein, APE1/Ref-1 (Apurinic/Apyrimidinic Endonuclease 1/Redox Effector - 1, also called APE1) has been studied for decades. However, over the past decade, APE1 has been established as a key player in reduction-oxidation (redox) signaling. In the review by Caston et al. (The multifunctional APE1 DNA repair-redox signaling protein as a drug target in human disease), multiple roles of APE1 in cancer and other diseases are summarized. 

Commentary Open Access

SPOCK1: New Mechanistic Insight into Liver Fibrosis

Zhipeng Du, Yuhui Fan, Dean Tian

Chronic liver diseases with different etiologies can provoke a fibrotic wound-healing response, which leads to liver fibrosis. Liver fibrosis is characterized by abnormal deposition and distribution of extracellular matrix (ECM), which restricts the regeneration of normal liver, and finally results in liver cirrhosis, liver failure or even hepatocellular carcinoma (HCC).

Review Article Open Access

Altering CAR Construct Design to Ameliorate CAR-T Cell Therapy Associated Cytokine Release Syndrome

Zhicheng Du, Shijun Zha, Yu Yang Ng, Shu Wang

Cytokine release syndrome represents a significant barrier to the widespread application of chimeric antigen receptor (CAR)-T cell therapies. We performed a broad analysis of preclinical and clinical studies that tested different designs of the CAR construct to tune CAR signaling, with an emphasis on effects of CAR designs on cytokine release from activated CAR-T cells. 

Commentary Open Access

APE1/Ref-1 as a Novel Target for Retinal Diseases

Curtis Heisel, Jonah Yousif, Mahmut Mijiti, Kostas Charizanis, Mitchel Brigell, Timothy W. Corson, Mark R. Kelley

APE1/Ref-1 (also called Ref-1) has been extensively studied for its role in DNA repair and reduction-oxidation (redox) signaling. The review titled: “The multifunctional APE1 DNA repair-redox signaling protein as a drug target in human disease” by Caston et. al. summarizes the molecular functions of Ref-1 and the role it plays in a number of diseases, with a specific focus on various types of cancer.

Review Article Open Access

HGF/MET Signalling and DNA Damage Response: Strategies to Conquer Radiotherapy Resistance in Head and Neck Cancer

Aaran Vijayakumaran, Mahvash Tavassoli

Head and neck squamous cell carcinomas (HNSCCs) are a group of aggressive and genetically complex cancers, derived from the mucosal epithelium in the oral cavity, pharynx, and larynx. Radiotherapy, often combined with chemotherapy remains the mainstay treatment options for patients.

Commentary Open Access

Macrophages in Oral Tissues

Vitor CM Neves, Jing Zhao, Ana J Caetano, Paul T Sharpe

The balance between cell removal following tissue damage and new cell formation to facilitate repair has long been linked to the behaviour of inflammatory macrophages and their interactions with tissue-resident non-immune cells. The main aim of the inflammatory response is to modulate the tissue environment by removing unwanted cells and recruiting cells and soluble factors from the bloodstream to help protect the damaged tissue against infective foreign bodies.

Commentary Open Access

Phosphorylation of RIAM Activates Its Adaptor Function in Mediating Integrin Signaling

Baihao Su, Jinhua Wu

Extracellular matrix (ECM) surrounding cells in solid tissue provides mechanical support and communicates with cells through cell adhesion molecules (CAMs) at the cell surface. Integrin is a major group of CAMs represented by a family of αβ heterodimeric single transmembrane receptors. 

Commentary Open Access

Ectodomain Shedding May Play a Pivotal Role in Disease Severity in COVID-19

Rui Yamaguchi, Yasuo Yamaguchi

Ectodomain shedding mediated by a disintegrin and metalloprotease 10/17 (ADAM10/17) modulates the function of immune effector cells and may be involved in the novel coronavirus disease COVID-19. Toll-like receptor 7/8 (TLR7/8) recognizes single-strand RNA from viruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, the virus that causes COVID-19) during the innate immune response

Commentary Open Access

Cancer-associated Molecular Abnormalities in Human NK cells

Gulnur K. Zakiryanova, Michael R. Shurin

Cancer is one of the leading causes of death worldwide. The immune system plays an important role in all steps of cancer development, growth and spreading as was repeatedly proven in a variety of experimental and clinical studies. Among the immune cells, Natural Killer cells, or NK cells, are critical to the innate immunity as one of the key effector cells of cancer immunosurveillance.

Research Article Open Access

Effects of a CB₂ Subtype Selective Agonist ABK5-1 on Cytokine Production in Microglia

Yaliang Tang, Barbara Wolk, Debra A. Kendall

Neuroinflammation is closely associated with various diseases including neuropathic pain. Microglia are immune cells in the central nervous system which are the main players of immunity and inflammation. Since microglia are activated by nerve injury, and they produce proinflammatory mediators to cause neuropathic pain, targeting activated microglia is considered to be a strategy for treating neuropathic pain.

Short Communication Open Access

Neoadjuvant Therapy (NAT) in Localized Pancreatic Cancer: Should We Do It and What Should We Do?

Shreya Prasad Goyal, Morana Vojnic, Jung-in Yang, Jyothi Jose, Elliot Newman, Muhammad Wasif Saif

In 2019, approximately 56,770 new cases of pancreatic cancer were diagnosed in the United States, resulting in an estimated 45,750 deaths. Pancreatic cancer is one of the leading causes of cancer-related death, with a fiveyear survival rate of 9%. Based on the eighth edition of the American Joint Committee on Cancer (AJCC) staging system for pancreatic adenocarcinoma, multi-center analyses have validated that poorer prognosis is associated with node-positive disease (N1 and N2).

Review Article Open Access

Possible Therapeutic Use of Natural Compounds Against COVID-19

Nabab Khan, Xuesong Chen, Jonathan D. Geiger

The outbreak of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has led to coronavirus disease-19 (COVID-19); a pandemic disease that has resulted in devastating social, economic, morbidity and mortality burdens. SARS-CoV-2 infects cells following receptor-mediated endocytosis and priming by cellular proteases.

Review Article Open Access

Wnt Signaling Cascades and Their Role in Coronary Artery Health and Disease

Nadisha Weerackoon, Kushan L. Gunawardhana, Arya Mani

The Wnt signaling is classified as two distinct pathways of canonical Wnt/β-catenin signaling, and the non-canonical pathways of planar cell polarity and Wnt/Ca²⁺ pathways. However, the scientific discoveries in recent years have shown that canonical and noncanonical Wnts pathways are intertwined and have complex interaction with other major signaling pathways such as hedgehog, Hippo and TOR signaling.

Commentary Open Access

S1P Generation by Sphingosine Kinase-2 in Recruited Macrophages Resolves Lung Inflammation by Blocking STING Signaling in Alveolar Macrophages

Jagdish C Joshi, Bhagwati Joshi, Ian Rochford, Dolly Mehta

Acute respiratory distress syndrome (ARDS) is the major cause of mortality among hospitalized acute lung injury (ALI) patients. Lung macrophages play an important role in maintaining the tissue-fluid homeostasis following injury. We recently showed that circulating monocytes recruited into the alveolar space suppressed the stimulator of type 1 interferon genes (STING) signaling in alveolar macrophages through sphingosine-1-phosphate (S1P). 

Research Article Open Access

The Role of Membrane-embedded DUOX2 on Ectodomain Shedding via G protein-coupled Receptor Signaling

Rui Yamaguchi, Reona Yamaguchi, Arisa Sakamoto, Shinji Narahara, Hiroyuki Sugiuchi, Yasuo Yamaguchi

Protease-activated receptors (PARs) and the neurokinin 1 receptor (NK1R) belong to the G protein-coupled receptor (GPCR) family. In this review, we focus on the regulatory mechanism of ectodomain shedding by ADAM10/17 metalloprotease via GPCR signaling. PAR2 and NK1R induce membrane blebbing, resulting in phosphatidylserine externalization in the cellular membrane, which is required for ADAM10/17 metalloprotease activation. Membrane-embedded dual oxidase 2 (DUOX2) has NADPH oxidase and peroxidas

Research Article Open Access

FOXP1 Interacts with MyoD to Repress its Transcription and Myoblast Conversion

Woodring E. Wright, Chuan Li, Chang-xue Zheng, Haley O. Tucker

Forkhead transcription factors (TFs) often dimerize outside their extensive family, whereas bHLH transcription factors typically dimerize with E12/E47. Based on structural similarities, we predicted that a member of the former, Forkhead Box P1 (FOXP1), might heterodimerize with a member of the latter, MYOD1 (MyoD).

Review Article Open Access

Interrelation among TLR4, EGFR and Rab Proteins Induced by LPS

Jinling Zhuang, Xiaolei Liu, Guixi Mo, Jie Fan, Jing Tang

TLR4, as an on-membrane receptor of LPS, plays a crucial part in the process of sepsis, and EGFR phosphorylation promotes cell inflammation in response to LPS, which plays an indispensable role in modulating LPS/TLR4 signaling pathway. However, the mechanism of interaction between TLR4 and EGFR signaling is still unclear.

Commentary Open Access

PRMT1-catalyzed SMAD7 Arginine Methylation Bridges EMT and Stemness

Jian Qin, Jian Xu

Epithelial-mesenchymal transition (EMT), a lineage transition from epithelium to mesenchyme, is induced by a convergence of signaling pathways and often driven by TGFß/SMAD signaling. Except for its critical roles on cell shape and motility during cancer invasion and metastasis, TGFß/SMAD activation-induced EMT has also been reported to be involved in cancer stem cell (CSC) generation.

Commentary Open Access

Kinetin/N6-furfuryladenine: A New Neurodegenerative Disease Lead from an Old Plant Cytokine

Tamara Maiuri, Ray Truant

N6-fufuryladenine (N6FFA), or kinetin, has a long history as a plant cytokine with practical applications in agriculture. This adenosine analog is now commonplace in natural product small molecule chemical screening libraries, and as such has been discovered as active in mammalian disease pathways that include Parkinson’s disease, Huntington’s disease (HD) and Familial Dysautonomia.

Review Article Open Access

The Role of TIGAR-mediated Metabolic Processes in Autophagy and Cell Survival

Dingmei Zhang, Mei Li, Zheng-Hong Qin

Autophagy is the one of the essential pathways for maintaining homeostasis of cells and plays an important regulatory role in cell survival and death. Tp53-induced glycolysis and apoptosis regulator (TIGAR) is a Tp53 target protein and is not only involved in the regulation of metabolism, cell cycle progression and radiation response, but also plays a role in autophagy.

Review Article Open Access

The Possible Role of Molecular Vibration in Intracellular Signalling

Werner Jaross

The exchange of information within the cell is extremely complex. Besides the well-studied chemical signalling, physical signalling is required to fulfil spatial and temporal aspects. The Golgi apparatus and the microtubule skeleton system are the decisive structures for numerous intracellular transport tasks.

Review Article Open Access

A Novel Regulatory Pathway of Desmoglein-3 in Keratinocyte Stress Response

Ambreen Rehman, Hong Wan

The desmosomal cadherin Desmoglein-3 (Dsg3) is a core adhesion component in desmosome junctions that occur with high frequency in the stratified squamous epithelial membrane lining the skin and mucous membrane. Dsg3 is identified as a major target of the circulating autoantibodies in Pemphigus Vulgaris (PV), an autoimmune blistering skin disease, and many signaling pathways have been demonstrated to be activated by PV-IgG targeting Dsg3, highlighting its role as a surface regulator in cell signa

Review Article Open Access

Improving Obesity and Insulin Resistance by Targeting Skeletal Muscle MKP-1

Anton M. Bennett, Ahmed Lawan

Obesity has reached a global epidemic and it predisposes to the development of insulin resistance, type 2 diabetes and related metabolic diseases. Current interventions against obesity and/or type 2 diabetes such as calorie restriction, exercise, genetic manipulations or established pharmacological treatments have not been successful for many patients with obesity and/or type 2 diabetes.

Commentary Open Access

Role of PI3K/Akt/GSK-3 Pathway in Emesis and Potential New Antiemetics

Weixia Zhong, Darmani NA

Nausea and vomiting are protective defense mechanisms by which vomit competent species avoid ingestion of potentially toxic substances. More specifically, vomiting is the act of forceful expulsion of gastrointestinal contents through the mouth, whereas nausea is an unpleasant painless subjective feeling that one will imminently vomit.

Commentary Open Access

A Novel Regulatory Mechanism to Regulate the Deubiquitinating Activity of USP25 by Oligomerization

Ying Li, Bing Liu, David Reverter

Protein ubiquitination is a major post-translational mechanism that regulates fate and function of many proteins in the cell, either by regulating their abundance by the 26S-proteasome-ubiquitin system or by modulating protein activity by the attachment of the ubiquitin modifier

Mini Review Open Access

Refining the Class IIa HDAC/MEF2 Paradigm in Muscle Biology: More than Meets the Eye

F. Dequiedt, Thomas Cherrier

For several decades, the transcription factor MEF2 (myocyte enhancer factor-2) has been known as a master regulator of myogenesis that orchestrates the first step in muscle formation: the differentiation of myoblasts into myocytes. Because of its importance during myoblast differentiation, the potential roles of MEF2 during later steps of myogenesis, in particular myocyte fusion, could not be properly investigated.

Review Article Open Access

NOXA the BCL-2 Family Member behind the Scenes in Cancer Treatment

Alison Dumont, Steven Lohard, Laurent Maillet, Philippe P Juin, Sophie Barillé-Nion

NOXA is a critical mediator of stress responses to anticancer drugs. This BH3-only protein sets the apoptotic threshold in cancer cells in response to chemotherapies by counteracting the prosurvival BCL-2 family protein MCL-1. A complex and dynamic network relying on both highly controlled gene transcription activity and protein degradation by proteasome, regulates cellular NOXA levels from low in steady state to rapidly enhanced upon stressful condition.

Research Article Open Access

Galectin 3 and Glial Cells of the CNS: A Fruitful Crosstalk with Remyelinating Potential

Laura A. Pasquini

Galectin-3 (Gal-3), the only chimera-like galectin, has three structural domains: (a) the NH2 terminal domain containing serine phosphorylation, important for nuclear localization, secretion and oligomerization; (b) a sequence susceptible to metalloprotease (MMP) cleavage; and (c) a C-terminal domain containing the carbohydrate recognition domain (CRD) and an anti-death motif.

Research Article Open Access

Dendorbium Nobile Lindl. Alkaloids Suppress NF-κB and NLRP3 Signaling Pathways to Attenuate Lipopolysaccharide-induced Neuroinflammation

Jiaojiao Liu, Bo Liu, Xi He, Wu Qin, Jingshan Shi

The important immune cells in the brain are called microglia acting as the central junction between neuroinflammation and neurodegenerative diseases. In patients of cognitive disorders and Alzheimer’s disease (AD) animal models, amoebic morphology and inflammatory pathways are activated to release numerous cells in the inflammatory factors by active microglia.

Commentary Open Access

Using Mitochondrial Trifunctional Protein Deficiency to Understand Maternal Health

Jason W. Miklas, Hannele Ruohola-Baker

Fatty acid oxidation disorders unfortunately can result in the sudden unexplained death of infants. Mitochondrial trifunctional protein (MTP) deficiency is one such disease where long-chain fatty acids cannot be fully oxidized through beta-oxidation which, can lead to cardiac arrythmias in an infant.

Review Article Open Access

Is Citrate A Critical Signal in Immunity and Inflammation?

Alessia Zotta, Zbigniew Zaslona, Luke A. O’Neill

When immune cells are activated, they undergo metabolic change in order to have sufficient energy to function effectively. The Krebs cycle is one of the most important pathways involved in this response and citrate, a critical component of this pathway, regulates carbohydrate and lipid metabolism.

Commentary Open Access

Kv1.3 Potassium Channels: Promising Therapeutic Targets in Hematological Malignancies

Theresa Lowinus, Tanima Bose, Luca Simeoni, Burkhart Schraven, Ursula Bommhardt

Voltage-gated Kv1.3 potassium channels control the membrane potential, cellular activation and cell death. Kv1.3 channels have been extensively studied in autoimmune disorders and are promising drug targets for the treatment of solid cancer.

Editorial Open Access

Machine Learning for Healthcare: Emerging Challenges and Opportunities in Disease Diagnosis

Sachin Kumar Deshmukh

Diagnosis is a process that identifies, explains, or establishes the individual’s disease from its symptoms and signs. Early and precise diagnosis is crucial since it influences the efficacy of treatment and avoids longterm complications for the infected person. Further, in the case of infectious diseases, undiagnosed patients can transmit the disease to a healthy population unknowingly. Besides, most of the diseases evolve with the time that significantly affects the clinical outcomes.

Mini Review Open Access

Metabolic Syndrome is an Important Cornerstone in the Health-disease Line and Pathological Organ Interaction

Ferah Armutcu, Suheyla Akyol, Huseyin Vural

Today, metabolic syndrome (MS) has been regarded as a very important disease due to its complex multifactorial etiology and damage to different organs. In general, obesity, dyslipidemia, hypertension, hyperglycemia, and insulin resistance are the main metabolic abnormalities of the MS. Compared with the others; in particular, insulin resistance and central obesity are considered the main causes in the pathogenesis

Review Article Open Access

Role of Sphingolipid Signaling in Glomerular Diseases: Focus on DKD and FSGS

Alla Mitrofanova, Yelena Drexler, Sandra Merscher, Alessia Fornoni

Being a sophisticated and highly organized living system, mammals harbor a large number of biomolecular machineries which represent a dynamic and complex network of interconnections responsible for the effective operation, development and survivability of their body cells. Sphingolipids are a special class of lipids in eukaryotic cells, which have recently gained the attention of researchers because of their involvement in several fundamental processes of living cells, including proliferation

Commentary Open Access

Distinct Phosphorylation of STAT1 Confers Distinct DNA Binding and Gene-regulatory Properties

Hozaifa Metwally, Tadamitsu Kishimoto

Signal transducer and activator of transcription 1 (STAT1) protein plays a pivotal role in various biological processes especially the regulation of innate and adaptive immune responses. Phosphorylation represents a key step in the activation of STAT1 and its transcriptional outcome. Binding of various extracellular ligands to their specific cell-surface receptors activates different phosphorylation of STAT1 followed by a distinct change of gene expression patterns.

Mini Review Open Access

The Effect of Glucocorticoids on Angiogenesis in the Treatment of Solid Tumors

Bing Liu, Julie E. Goodwin

Glucocorticoids (GCs) are defined by their role in maintaining glucose homeostasis and natural GCs are a class of corticosteroids secreted by the adrenal cortex. Cortisol is the most important natural GC in humans. Cellular cortisol levels are regulated by the tissue-specific metabolic enzymes 11β-hydroxysteroid dehydrogenase 1 and 2 (11β-HSD 1 and 2); 11β-HSD 1 converts inactive cortisone to active cortisol, while 11β-HSD 2 has the opposite function.

Commentary Open Access

Novel Hippocampal Interaction between Spexin and Corticotropin Releasing Factor

Jin Bai, Chengyuan Lin

Nowadays, people pay more and more attention to homeostatic regulation, which is the detrimental effect of stress on physiological and psychological well-being and cannot be ignored. The public perception of anxiety has been associated with the hypothalamic hormones, because of the pivotal role of the hypothalamic-pituitaryadrenal axis to promote the pituitary-adrenal functions and endocrine responses.

Commentary Open Access

DNA Nanotechnology Engineered Vesicle for Mimicking Biomolecular Signaling

Ruizi Peng, Yingzi Ma, Yan Zhou, Yongbo Peng, Xiaofang Zheng, Qiang Zhang

Bio-inspired strategy is kind of interesting to fabricate devices and perform dynamic operations [1]. Various devices have been made, such as airplane, radar and submarine. In life science, as the fundamental entity, million years’ evolution enables cell becomes the most successful functionality.

Brief Report Open Access

Prospective Evaluation of Effect of Metformin on Activation of AMP-activated Protein Kinase (AMPK) and Disease Control in a Sub-group Analysis of Patients with GI Malignancies

Amandeep Godara, Nauman S. Siddiqui, Hilal Hachem, Philip N. Tsichlis, Robert E. Martell, Muhammad Wasif Saif

Observational studies have demonstrated association of metformin with reduced cancer incidence and mortality in multiple cancer types, including gastrointestinal (GI) malignancies. Anti-neoplastic effects of metformin are believed through many mechanisms including activation of AMP-activated protein kinase, which controls mammalian target of rapamycin (mTOR) growth regulatory pathway.

Commentary Open Access

Ubiquitin Proteasome System Regulates Biological Particles Interaction in Particle Disease (PD) via NF-κB Signaling

Xiaolei Hu, Xiaomian Wu

Considering their outstanding mechanical character, it is inevitable to utilize titanium and titanium composite for biomedical engineering application [1-6]. However, the particles releasing from these bulks or composites of biomaterials after long term implanting in human body will cause cell apoptosis or cell death, inflammation, bone

Editorial Open Access

COVID-19 Clinical Research

Jeffrey Chi, David Chitty, Meeyoung Lee, Nausheen Hakim, Shamsah Lakhani, Lakshmi Rajdev, Xinhua Zhu, Muhammad Wasif Saif

While the global COVID-19 pandemic has challenged the entire humanity and health systems, it also triggered researchers to urgently perform clinical trials to assess the safety and efficacy of many agents and modalities to combat COVID-19. As of April 22, over 650 clinical studies have been registered both in USA and internationally. Results from these studies are also coming at a brisk pace in this unprecedented emergency.

Commentary Open Access

Cyclic Nucleotide Signaling Pathways in Apicomplexan Parasites Provide a Valuable Source for Novel Drug Targets

Annette Kaiser

Malaria is one of the most important disabling human, tropical disease caused by different Plasmodium species, which are protozoan parasites belonging to the Apicomplexa. The Apicomplexan parasites have a plastid like structure the “apicoplast” and comprise the genera Plasmodium, Toxoplasma and Cryptosporidium causing malaria, toxoplasmosis, and cryptosporidiosis.

Perspective Open Access

Activation of NLRP3 Inflammosome by N4-Acetyl Cytidine and Its Consequences

Hua Bai

N4-acetylcytidine (N4A) is an organic compound and a metabolite of transferrable ribonucleic acid. Its molecular formula is C11H15N3O6. Earlier studies suggest that N4A was mainly found on tRNA and 18S rRNA, while recent studies have shown that there is also a large amount of N4A on mRNA, whose abundance is not even lower than the m7G cap modification carried by mRNA.

Commentary Open Access

Manipulating Oxidative Stress Following Ionizing Radiation

Adriana Haimovitz-Friedman, Aviram Mizrachi, Edgar A. Jaimes

It is now well accepted that the ionizing radiation-generated reactive oxygen species (ROS), that constitute ~2/3 of the effects of external beam radiation, do not only produce direct tumor cell death, but also affect the surrounding microenvironment. Moreover, this indirect effect of radiation may result in systemic effects, specifically the initiation of an inflammatory response.

Commentary Open Access

Emerging Role of TRPML1 Mucolipin Endolysosomal Channel in Cancer

Giorgio Santoni, Matteo Santoni, Massimo Nabissi, Oliviero Marinelli, Consuelo Amantini, Maria Beatrice Morelli

The transient receptor potential mucolipin 1 (TRPML1) is an endolysosomal channel belonging to the TRP family. Clinically, mutations of TRPML1 have been responsible for a severe lysosomal storage disorder called mucolipidosis type IV.

Short Communication Open Access

Flow Cytometric Characterization of Accidental Cell Death Highlights Connections to Regulated Cell Death

Gary Warnes

Damage-Associated Molecular Patterns (DAMPs) are known by their nature to cause inflammatory responses in numerous disease states from cancer, trauma to age related diseases (e.g. atherosclerosis, Alzheimer’s and Parkinson’s diseases), these molecules are released by cells undergoing cell death.