Journal of Cellular Signaling

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. 

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.

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

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

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.

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.

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.

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. 

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

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

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

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

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

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.

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. 

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.

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.

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.

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).

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

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

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

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

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

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.

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.

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

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.