scholarly journals Novel rapid-acting antidepressants: molecular and cellular signaling mechanisms

2017 ◽  
Vol 1 (4) ◽  
Author(s):  
Alexandra M. Thomas ◽  
Ronald S. Duman
Keyword(s):  
Nmda Receptor ◽  
Signaling Pathways ◽  
Neural Circuits ◽  
Cellular Signaling ◽  
Treatment Options ◽  
Time Lag ◽  
Current Understanding ◽  
Signaling Mechanisms ◽  
Research Techniques ◽  
The Brain

Depression is a chronic, debilitating, and common illness. Currently available pharmacotherapies can be helpful but have several major drawbacks, including substantial rates of low or no response and a long therapeutic time lag. In pursuit of better treatment options, recent research has focussed on rapid-acting antidepressants, including the N-methyl-d-aspartate (NMDA) receptor (NMDAR) antagonist ketamine, which affects a range of signaling pathways in ways that are distinct from the mechanisms of typical antidepressants. Because ketamine and similar drugs hold the promise of dramatically improving treatment options for depressed patients, there has been considerable interest in developing new ways to understand how these compounds affect the brain. Here, we review the current understanding of how rapid-acting antidepressants function, including their effects on neuronal signaling pathways and neural circuits, and the research techniques being used to address these questions.

Diabetes and Complications: Cellular Signaling Pathways, Current Understanding and Targeted Therapies

2016 ◽  
Vol 17 (11) ◽  
pp. 1309-1328 ◽  
Author(s):  
Krishna A. Adeshara ◽  
Arundhati G. Diwan ◽  
Rashmi S. Tupe
Keyword(s):  
Signaling Pathways ◽  
Targeted Therapies ◽  
Cellular Signaling ◽  
Current Understanding

scholarly journals Expression of Genes Involved in Axon Guidance: How Much Have We Learned?

2020 ◽  
Vol 21 (10) ◽  
pp. 3566 ◽  
Author(s):  
Sung Wook Kim ◽  
Kyong-Tai Kim
Keyword(s):  
Axon Guidance ◽  
Signaling Pathways ◽  
Neural Circuits ◽  
Review Literature ◽  
Guidance System ◽  
Signal Transduction Pathways ◽  
Guidance Cues ◽  
Molecular Features ◽  
Expression Of Genes ◽  
The Brain

Neuronal axons are guided to their target during the development of the brain. Axon guidance allows the formation of intricate neural circuits that control the function of the brain, and thus the behavior. As the axons travel in the brain to find their target, they encounter various axon guidance cues, which interact with the receptors on the tip of the growth cone to permit growth along different signaling pathways. Although many scientists have performed numerous studies on axon guidance signaling pathways, we still have an incomplete understanding of the axon guidance system. Lately, studies on axon guidance have shifted from studying the signal transduction pathways to studying other molecular features of axon guidance, such as the gene expression. These new studies present evidence for different molecular features that broaden our understanding of axon guidance. Hence, in this review we will introduce recent studies that illustrate different molecular features of axon guidance. In particular, we will review literature that demonstrates how axon guidance cues and receptors regulate local translation of axonal genes and how the expression of guidance cues and receptors are regulated both transcriptionally and post-transcriptionally. Moreover, we will highlight the pathological relevance of axon guidance molecules to specific diseases.

Vitamin C as an Anticancer Agent: Regulation of Signaling Pathways

2020 ◽  
Vol 20 (21) ◽  
pp. 1868-1875
Author(s):  
Ghazala Butt ◽  
Ammad A. Farooqi ◽  
Aima Adylova ◽  
Rukset Attar ◽  
Seher Yilmaz ◽  
...  
Keyword(s):  
Vitamin C ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Scientific Evidence ◽  
Treatment Options ◽  
Published Data ◽  
New Era ◽  
Molecular Oncology ◽  
Anticancer Effects ◽  
Oncogenic Pathways

Treatment options for effective treatment of cancer with minimum off-target effects and maximum clinical outcomes have remained overarching goals in the clinical oncology. Vitamin C has remained in the shadows of controversy since the past few decades; burgeoning evidence has started to shed light on wide-ranging anticancer effects exerted by Vitamin C to induce apoptosis in drug-resistant cancer cells, inhibit uncontrolled proliferation of the cancer cells and metastatic spread. Landmark achievements in molecular oncology have ushered in a new era, and researchers have focused on the identification of oncogenic pathways regulated by Vitamin C in different cancers. However, there are visible knowledge gaps in our understanding related to the ability of Vitamin C to modulate a myriad of transduction cascades. There are scattered pieces of scientific evidence about promising potential of Vitamin C to regulate JAK-STAT, TGF/SMAD, TRAIL and microRNAs in different cancers. However, published data is insufficient and needs to be investigated comprehensively to enable basic and clinical researchers to reap full benefits and promote result-oriented transition of Vitamin C into various phases of clinical trials. In this review, we will emphasize on available evidence related to the regulation of oncogenic cell signaling pathways by Vitamin C in different cancers. We will also highlight the conceptual gaps, which need detailed and cutting-edge research.

A Brief Review on Dual Target of PARP1 and STAT3 for Cancer Therapy: A Novel Perception

2020 ◽  
Vol 16 (2) ◽  
pp. 115-134
Author(s):  
Kaviarasan Lakshmanan ◽  
Gowramma Byran ◽  
Manal Mohammed
Keyword(s):  
Signaling Pathways ◽  
Single Molecule ◽  
Treatment Options ◽  
Poor Response ◽  
Cytotoxic Agents ◽  
Acquired Drug Resistance ◽  
Single Target ◽  
New Strategy ◽  
Cancer Multiple ◽  
Almost All

Background: Cancer is a disease characterized by the uncontrolled growth and spread of abnormal cells. Around the world, over 10 million cancer cases occur annually. Half of all men and one-third of all women will develop some form of cancer during their lifetime. It is one of the most feared diseases, primarily because half of those diagnosed with cancer die from it. There are several treatments available for cancer. Almost all traditional cytotoxic agents suffer from severe toxicities and other undesirable side effects. Objective: In recent years, the development of targeted medicines has made significant achievements. Unfortunately, though these agents can block key regulators of signaling pathways in cancer, multiple compensatory pathways always attenuate pharmacological effect of single-target drugs. In addition, poor response rates and acquired drug resistance also represent a significant barrier to widespread use of targeted medicines. More recently, a number of combinatorial therapies have expanded treatment options, which can directly block several key signaling pathways and create a synergistic effect. Conclusion: Therefore, in order to overcome these barriers, the present investigation aims to develop a new strategy for designing a single molecule with inhibition of two receptors (PARP1 and STAT3) simultaneously and producing enhanced anti-cancer activity with less and/or null toxicity.

scholarly journals Mechanism of CK2.3, a Novel Mimetic Peptide of Bone Morphogenetic Protein Receptor Type IA, Mediated Osteogenesis

2019 ◽  
Vol 20 (10) ◽  
pp. 2500 ◽  
Author(s):  
Vrathasha Vrathasha ◽  
Hilary Weidner ◽  
Anja Nohe
Keyword(s):  
Signaling Pathways ◽  
Treatment Options ◽  
Time Frame ◽  
Bmp Signaling ◽  
C2c12 Cells ◽  
Molecular Sequence ◽  
Sequence Of Events ◽  
Protein Receptor

Background: Osteoporosis is a degenerative skeletal disease with a limited number of treatment options. CK2.3, a novel peptide, may be a potential therapeutic. It induces osteogenesis and bone formation in vitro and in vivo by acting downstream of BMPRIA through releasing CK2 from the receptor. However, the detailed signaling pathways, the time frame of signaling, and genes activated remain largely unknown. Methods: Using a newly developed fluorescent CK2.3 analog, specific inhibitors for the BMP signaling pathways, Western blot, and RT-qPCR, we determined the mechanism of CK2.3 in C2C12 cells. We then confirmed the results in primary BMSCs. Results: Using these methods, we showed that CK2.3 stimulation activated OSX, ALP, and OCN. CK2.3 stimulation induced time dependent release of CK2β from BMPRIA and concurrently CK2.3 colocalized with CK2α. Furthermore, CK2.3 induced BMP signaling depends on ERK1/2 and Smad1/5/8 signaling pathways. Conclusion: CK2.3 is a novel peptide that drives osteogenesis, and we detailed the molecular sequence of events that are triggered from the stimulation of CK2.3 until the induction of mineralization. This knowledge can be applied in the development of future therapeutics for osteoporosis.

scholarly journals Hypoxia-inducible Factor 2α: A Key Player in Tumorigenesis and Metastasis of Pheochromocytoma and Paraganglioma?

2021 ◽  
Author(s):  
Nicole Bechmann ◽  
Graeme Eisenhofer
Keyword(s):  
Extracellular Matrix ◽  
Signaling Pathways ◽  
Metastatic Disease ◽  
Therapeutic Intervention ◽  
Treatment Options ◽  
Hypoxia Inducible Factor ◽  
Germline Mutations ◽  
Driver Mutations ◽  
Mesenchymal Transition ◽  
Therapeutic Relevance

AbstractGermline or somatic driver mutations linked to specific phenotypic features are identified in approximately 70% of all catecholamine-producing pheochromocytomas and paragangliomas (PPGLs). Mutations leading to stabilization of hypoxia-inducible factor 2α (HIF2α) and downstream pseudohypoxic signaling are associated with a higher risk of metastatic disease. Patients with metastatic PPGLs have a variable prognosis and treatment options are limited. In most patients with PPGLs, germline mutations lead to the stabilization of HIF2α. Mutations in HIF2α itself are associated with adrenal pheochromocytomas and/or extra-adrenal paragangliomas and about 30% of these patients develop metastatic disease; nevertheless, the frequency of these specific mutations is low (1.6–6.2%). Generally, mutations that lead to stabilization of HIF2α result in distinct catecholamine phenotype through blockade of glucocorticoid-mediated induction of phenylethanolamine N-methyltransferase, leading to the formation of tumors that lack epinephrine. HIF2α, among other factors, also contributes importantly to the initiation of a motile and invasive phenotype. Specifically, the expression of HIF2α supports a neuroendocrine-to-mesenchymal transition and the associated invasion-metastasis cascade, which includes the formation of pseudopodia to facilitate penetration into adjacent vasculature. The HIF2α-mediated expression of adhesion and extracellular matrix genes also promotes the establishment of PPGL cells in distant tissues. The involvement of HIF2α in tumorigenesis and in multiple steps of invasion-metastasis cascade underscores the therapeutic relevance of targeting HIF2α signaling pathways in PPGLs. However, due to emerging resistance to current HIF2α inhibitors that target HIF2α binding to specific partners, alternative HIF2α signaling pathways and downstream actions should also be considered for therapeutic intervention.

scholarly journals Reduction of food intake by cholecystokinin requires activation of hindbrain NMDA-type glutamate receptors

2011 ◽  
Vol 301 (2) ◽  
pp. R448-R455 ◽  
Author(s):  
Jason Wright ◽  
Carlos Campos ◽  
Thiebaut Herzog ◽  
Mihai Covasa ◽  
Krzysztof Czaja ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Food Intake ◽  
Nmda Receptors ◽  
Receptor Antagonist ◽  
Fourth Ventricle ◽  
Nmda Receptor Antagonist ◽  
Behavioral Pattern ◽  
Vagal Afferents ◽  
Nmda Receptor Antagonists ◽  
The Brain

Intraperitoneal injection of CCK reduces food intake and triggers a behavioral pattern similar to natural satiation. Reduction of food intake by CCK is mediated by vagal afferents that innervate the stomach and small intestine. These afferents synapse in the hindbrain nucleus of the solitary tract (NTS) where gastrointestinal satiation signals are processed. Previously, we demonstrated that intraperitoneal (IP) administration of either competitive or noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists attenuates reduction of food intake by CCK. However, because vagal afferents themselves express NMDA receptors at both central and peripheral endings, our results did not speak to the question of whether NMDA receptors in the brain play an essential role in reduction of feeding by CCK. We hypothesized that activation of NMDA receptors in the NTS is necessary for reduction of food intake by CCK. To test this hypothesis, we measured food intake following IP CCK, subsequent to NMDA receptor antagonist injections into the fourth ventricle, directly into the NTS or subcutaneously. We found that either fourth-ventricle or NTS injection of the noncompetitive NMDA receptor antagonist MK-801 was sufficient to inhibit CCK-induced reduction of feeding, while the same antagonist doses injected subcutaneously did not. Similarly fourth ventricle injection of d-3-(2-carboxypiperazin-4-yl)-1-propenyl-1-phosphoric acid (d-CPPene), a competitive NMDA receptor antagonist, also blocked reduction of food intake following IP CCK. Finally, d-CPPene injected into the fourth ventricle attenuated CCK-induced expression of nuclear c-Fos immunoreactivity in the dorsal vagal complex. We conclude that activation of NMDA receptors in the hindbrain is necessary for the reduction of food intake by CCK. Hindbrain NMDA receptors could comprise a critical avenue for control and modulation of satiation signals to influence food intake and energy balance.

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