NAD precursors, mitochondria targeting compounds and ADPribosylation inhibitors in treatment of inflammatory diseases and cancer

: Mitochondrial dysfunction and oxidative stress are prominent features of a plethora of human disorders. Dysregulation of mitochondrial functions represents a common pathogenic mechanism of diseases such as neurodegenerative disorders and cancer. The maintenance of the Nicotinamide adenine dinucleotide (NAD+ ) pool, and a positive NAD+ /NADH ratio, are essential for mitochondrial and cell functions. The synthesis and degradation of NAD+ and transport of its key intermediates among cell compartments play an important role to maintain optimal NAD levels, for regulation of NAD+ -utilizing enzymes, such as sirtuins (Sirt), poly-ADP-ribose polymerases, and CD38/157 enzymes, either intracellularly as well as extracellularly. In this review, we present and discuss the links between NAD+ , NAD+ -consuming enzymes, mitochondria functions, and diseases. Attempts to treat various diseases with supplementation of NAD+ cycling intermediates and inhibitors of sirtuins and ADP-ribosyl transferases may highlight a possible therapeutic approach for therapy of cancer and neurodegenerative diseases.

Download Full-text

Age-Dependent Decline in Neuron Growth Potential and Mitochondria Functions in Cortical Neurons

Cells ◽

10.3390/cells10071625 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1625

Author(s):

Theresa C. Sutherland ◽

Arthur Sefiani ◽

Darijana Horvat ◽

Taylor E. Huntington ◽

Yuanjiu Lei ◽

...

Keyword(s):

Cortical Neurons ◽

Traumatic Injury ◽

Axon Growth ◽

Neurite Growth ◽

Growth Potential ◽

Mitochondrial Functions ◽

Cord Injury ◽

Age Dependent ◽

Mitochondria Functions ◽

The Impact

The age of incidence of spinal cord injury (SCI) and the average age of people living with SCI is continuously increasing. However, SCI is extensively modeled in young adult animals, hampering translation of research to clinical applications. While there has been significant progress in manipulating axon growth after injury, the impact of aging is still unknown. Mitochondria are essential to successful neurite and axon growth, while aging is associated with a decline in mitochondrial functions. Using isolation and culture of adult cortical neurons, we analyzed mitochondrial changes in 2-, 6-, 12- and 18-month-old mice. We observed reduced neurite growth in older neurons. Older neurons also showed dysfunctional respiration, reduced membrane potential, and altered mitochondrial membrane transport proteins; however, mitochondrial DNA (mtDNA) abundance and cellular ATP were increased. Taken together, these data suggest that dysfunctional mitochondria in older neurons may be associated with the age-dependent reduction in neurite growth. Both normal aging and traumatic injury are associated with mitochondrial dysfunction, posing a challenge for an aging SCI population as the two elements can combine to worsen injury outcomes. The results of this study highlight this as an area of great interest in CNS trauma.

Download Full-text

GSK3β, a Master Kinase in the Regulation of Adult Stem Cell Behavior

Cells ◽

10.3390/cells10020225 ◽

2021 ◽

Vol 10 (2) ◽

pp. 225

Author(s):

Claire Racaud-Sultan ◽

Nathalie Vergnolle

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Adult Stem Cells ◽

Glycogen Synthase ◽

Inflammatory Diseases ◽

Adult Stem Cell ◽

Leukemic Cells ◽

Cell Phenotype ◽

Epithelial Regeneration ◽

Cell Functions

In adult stem cells, Glycogen Synthase Kinase 3β (GSK3β) is at the crossroad of signaling pathways controlling survival, proliferation, adhesion and differentiation. The microenvironment plays a key role in the regulation of these cell functions and we have demonstrated that the GSK3β activity is strongly dependent on the engagement of integrins and protease-activated receptors (PARs). Downstream of the integrin α5β1 or PAR2 activation, a molecular complex is organized around the scaffolding proteins RACK1 and β-arrestin-2 respectively, containing the phosphatase PP2A responsible for GSK3β activation. As a consequence, a quiescent stem cell phenotype is established with high capacities to face apoptotic and metabolic stresses. A protective role of GSK3β has been found for hematopoietic and intestinal stem cells. Latters survived to de-adhesion through PAR2 activation, whereas formers were protected from cytotoxicity through α5β1 engagement. However, a prolonged activation of GSK3β promoted a defect in epithelial regeneration and a resistance to chemotherapy of leukemic cells, paving the way to chronic inflammatory diseases and to cancer resurgence, respectively. In both cases, a sexual dimorphism was measured in GSK3β-dependent cellular functions. GSK3β activity is a key marker for inflammatory and cancer diseases allowing adjusted therapy to sex, age and metabolic status of patients.

Download Full-text

Power Failure of Mitochondria and Oxidative Stress in Neurodegeneration and Its Computational Models

Antioxidants ◽

10.3390/antiox10020229 ◽

2021 ◽

Vol 10 (2) ◽

pp. 229

Author(s):

JunHyuk Woo ◽

Hyesun Cho ◽

YunHee Seol ◽

Soon Ho Kim ◽

Chanhyeok Park ◽

...

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dysfunction ◽

Computational Models ◽

Neuronal Damage ◽

Living Organism ◽

The Body ◽

Mitochondrial Functions ◽

A Cell ◽

The Brain ◽

And Oxidative Stress

The brain needs more energy than other organs in the body. Mitochondria are the generator of vital power in the living organism. Not only do mitochondria sense signals from the outside of a cell, but they also orchestrate the cascade of subcellular events by supplying adenosine-5′-triphosphate (ATP), the biochemical energy. It is known that impaired mitochondrial function and oxidative stress contribute or lead to neuronal damage and degeneration of the brain. This mini-review focuses on addressing how mitochondrial dysfunction and oxidative stress are associated with the pathogenesis of neurodegenerative disorders including Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and Parkinson’s disease. In addition, we discuss state-of-the-art computational models of mitochondrial functions in relation to oxidative stress and neurodegeneration. Together, a better understanding of brain disease-specific mitochondrial dysfunction and oxidative stress can pave the way to developing antioxidant therapeutic strategies to ameliorate neuronal activity and prevent neurodegeneration.

Download Full-text

Atorvastatin disrupts primary human brain microvascular endothelial cell functions via prenylation‐dependent mitochondrial inhibition and oxidative stress

Fundamental and Clinical Pharmacology ◽

10.1111/fcp.12615 ◽

2020 ◽

Author(s):

Qian Tan ◽

Danfang Yu ◽

Lin Song

Keyword(s):

Oxidative Stress ◽

Endothelial Cell ◽

Human Brain ◽

Microvascular Endothelial Cell ◽

Brain Microvascular Endothelial Cell ◽

Cell Functions ◽

Microvascular Endothelial ◽

And Oxidative Stress

Download Full-text

The transcriptional program, functional heterogeneity, and clinical targeting of mast cells

Journal of Experimental Medicine ◽

10.1084/jem.20170910 ◽

2017 ◽

Vol 214 (9) ◽

pp. 2491-2506 ◽

Cited By ~ 45

Author(s):

Gökhan Cildir ◽

Harshita Pant ◽

Angel F. Lopez ◽

Vinay Tergaonkar

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Immunoglobulin E ◽

Inflammatory Diseases ◽

Small Population ◽

Transcriptional Program ◽

Cell Functions ◽

New Concepts ◽

Health And Disease ◽

Ige Mediated

Mast cells are unique tissue-resident immune cells that express an array of receptors that can be activated by several extracellular cues, including antigen–immunoglobulin E (IgE) complexes, bacteria, viruses, cytokines, hormones, peptides, and drugs. Mast cells constitute a small population in tissues, but their extraordinary ability to respond rapidly by releasing granule-stored and newly made mediators underpins their importance in health and disease. In this review, we document the biology of mast cells and introduce new concepts and opinions regarding their role in human diseases beyond IgE-mediated allergic responses and antiparasitic functions. We bring to light recent discoveries and developments in mast cell research, including regulation of mast cell functions, differentiation, survival, and novel mouse models. Finally, we highlight the current and future opportunities for therapeutic intervention of mast cell functions in inflammatory diseases.

Download Full-text

Discovery of a Novel Small-Molecule Interleukin-6 Inhibitor through Virtual Screening Using Artificial Intelligence

Medicinal Chemistry ◽

10.2174/1573406418666211116144243 ◽

2021 ◽

Vol 18 ◽

Author(s):

Yoshiaki Sato ◽

Ikuo Kashiwakura ◽

Masaru Yamaguchi ◽

Hironori Yoshino ◽

Takeshi Tanaka ◽

...

Keyword(s):

Artificial Intelligence ◽

Small Molecule ◽

Interleukin 6 ◽

Inflammatory Diseases ◽

Biological Activities ◽

Inhibitory Effect ◽

Dependent Manner ◽

Cell Functions ◽

Dependent Cell ◽

Dose Dependent

Background: Interleukin-6 (IL-6) is a multifunctional cytokine involved in various cell functions and diseases. Thus far, several IL-6 inhibitors, such as, humanized monoclonal antibody have been used to block excessive IL-6 signaling causing autoimmune and inflammatory diseases. However, anti-IL-6 and anti-IL-6 receptor monoclonal antibodies have some clinical disadvantages, such as a high cost, unfavorable injection route, and tendency to mask infectious diseases. While a small-molecule IL-6 inhibitor would help mitigate these issues, none are currently available. Objective: The present study evaluated the biological activities of identified compounds on IL-6 stimulus. Methods: We virtually screened potential IL-6 binders from a compound library using INTerprotein’s Engine for New Drug Design (INTENDD®) followed by the identification of more potent IL-6 binders with artificial intelligence (AI)-guided INTENDD®. The biological activities of the identified compounds were assessed with the IL-6-dependent cell line 7TD1. Results: The compounds showed the suppression of IL-6-dependent cell growth in a dose-dependent manner. Furthermore, the identified compound inhibited expression of IL-6-induced phosphorylation of signal transducer and activator of transcription 3 in a dose-dependent manner. Conclusion: Our screening compound demonstrated an inhibitory effect on IL-6 stimulus. These findings may serve as a basis for the further development of small-molecule IL-6 inhibitors.

Download Full-text

86 Effect of invitro culture conditions on mitochondria functions in mouse embryos

Reproduction Fertility and Development ◽

10.1071/rdv32n2ab86 ◽

2020 ◽

Vol 32 (2) ◽

pp. 169

Author(s):

M. Czernik ◽

D. Winiarczyk ◽

S. Sampino ◽

P. Greda ◽

J. A. Modlinski ◽

...

Keyword(s):

Embryo Development ◽

Copy Number ◽

Energy Demand ◽

Mitochondrial Membrane ◽

Mitochondrial Dynamics ◽

Culture Conditions ◽

Mouse Embryos ◽

Mtdna Copy Number ◽

Mitochondrial Functions ◽

Mitochondria Functions

Mitochondria provide the energy for oocyte maturation, fertilisation, and embryo formation via oxidative phosphorylation. Consequently, any adverse influence on mitochondrial function may negatively affect the development of pre-implantation embryos especially because there is no mitochondrial DNA (mtDNA) replication until post-implantation. Studies in the field of mitochondrial dynamics have identified an intriguing link between energy demand/supply balance and mitochondrial architecture, which may suggest that inappropriate culture conditions may inhibit mitochondrial functions, which may negatively affect embryo development. We wanted to check whether invitro culture (IVC) conditions of mouse embryos affect mitochondrial functionality. The IVC as well as naturally matted (NM) mouse embryos at the 2-cell and blastocyst stage were subjected to mitochondrial analysis (distribution, organisation, and mitochondrial membrane potential), and expression of mRNA and proteins involved in regulation of mitochondria functions, as well as number of mtDNA copies, were evaluated. Significance level was set at 0.05. We observed that the mitochondria in 2-cell IVC embryos were less numerous and localised mainly in the pericortical region of the cytoplasm, whereas mitochondria in NM embryos were numerous and homogeneously distributed in both blastomeres. Drastic differences were observed in blastocysts. Mitochondria in the IVC group were fragmented, rounded, and aggregated mainly in the perinuclear region of the cells, whereas mitochondria of NM blastocysts were numerous and created an elongated mitochondrial network along the cells. Time-lapse analysis showed reduced mitochondrial and mitochondrial membrane activity in IVC blastocysts. Moreover, our results indicate the IVC group had reduced mRNA expression of mitofusin 1, mitofusin 2, and optic atrophy 1 responsible for mitochondrial fusion. Additionally, mtDNA copy number for IVC blastocysts (398 887.45±30 608.65) was significantly lower than that of NM blastocysts (593 367.12±66 540.32; P<0.02). Furthermore, no significant differences were found in mtDNA copy number of IVC 2-cell embryos when compared with NM embryos. The results obtained clearly showed that IVC conditions affect proper mitochondrial functionality and hence embryo development.

Download Full-text

Metabolic defects in splenic B cell compartments from patients with liver cirrhosis

Cell Death and Disease ◽

10.1038/s41419-020-03060-1 ◽

2020 ◽

Vol 11 (10) ◽

Author(s):

Man Huang ◽

Xiaoju Liu ◽

Haocheng Ye ◽

Xin Zhao ◽

Juanjuan Zhao ◽

...

Keyword(s):

Liver Cirrhosis ◽

B Cells ◽

B Cell ◽

Memory B Cells ◽

Rna Seq ◽

Vaccine Responses ◽

Cell Functions ◽

Metabolic Defects ◽

Cell Compartments ◽

Cirrhotic Patients

Abstract Liver cirrhosis is associated with defective vaccine responses and increased infections. Dysregulated B cell compartments in cirrhotic patients have been noticed but not well characterized, especially in the spleen. Here, we comprehensively investigated B cell perturbations from the spleens and peripheral blood of cirrhotic patients. We found that liver cirrhosis significantly depleted both switched and nonswitched splenic memory B cells, which was further confirmed histologically. Bulk RNA-seq revealed significant metabolic defects as the potential mechanism for the impaired splenic B cell functions. Functionally, the splenic memory B cells from cirrhotic patients showed strong metabolic defects and reduced proliferation compared with those from healthy controls. Thus, liver cirrhosis extensively disturbs the splenic and peripheral B cell compartments, which may contribute to defective humoral immunity during liver cirrhosis.

Download Full-text

Cannabinoids as Key Regulators of Inflammasome Signaling: A Current Perspective

Frontiers in Immunology ◽

10.3389/fimmu.2020.613613 ◽

2021 ◽

Vol 11 ◽

Author(s):

Santosh V. Suryavanshi ◽

Igor Kovalchuk ◽

Olga Kovalchuk

Keyword(s):

Cannabis Sativa ◽

Inflammatory Diseases ◽

Protein Complexes ◽

Synthetic Cannabinoids ◽

Inflammasome Activation ◽

Published Evidence ◽

Current Perspective ◽

Novel Drugs ◽

Human Disorders ◽

Pharmacologically Active

Inflammasomes are cytoplasmic inflammatory signaling protein complexes that detect microbial materials, sterile inflammatory insults, and certain host-derived elements. Inflammasomes, once activated, promote caspase-1–mediated maturation and secretion of pro-inflammatory cytokines, interleukin (IL)-1β and IL-18, leading to pyroptosis. Current advances in inflammasome research support their involvement in the development of chronic inflammatory disorders in contrast to their role in regulating innate immunity. Cannabis (marijuana) is a natural product obtained from the Cannabis sativa plant, and pharmacologically active ingredients of the plant are referred to as cannabinoids. Cannabinoids and cannabis extracts have recently emerged as promising novel drugs for chronic medical conditions. Growing evidence indicates the potent anti-inflammatory potential of cannabinoids, especially Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), and synthetic cannabinoids; however, the mechanisms remain unclear. Several attempts have been made to decipher the role of cannabinoids in modulating inflammasome signaling in the etiology of chronic inflammatory diseases. In this review, we discuss recently published evidence on the effect of cannabinoids on inflammasome signaling. We also discuss the contribution of various cannabinoids in human diseases concerning inflammasome regulation. Lastly, in the milieu of coronavirus disease-2019 (COVID-19) pandemic, we confer available evidence linking inflammasome activation to the pathophysiology of COVID-19 suggesting overall, the importance of cannabinoids as possible drugs to target inflammasome activation in or to support the treatment of a variety of human disorders including COVID-19.

Download Full-text