OPEN ACCESS ARTICLE – Moving to the Rhythm with Clock (Circadian) Genes, Autophagy, mTOR, and SIRT1 in Degenerative Disease and Cancer – Current Neurovascular Research

Journal: Current Neurovascular Research

Author(s):  Kenneth Maiese


Background: The mammalian circadian clock and its associated clock genes are increasingly been recognized as critical components for a number of physiological and disease processes that extend beyond hormone release, thermal regulation, and sleep-wake cycles. New evidence suggests that clinical behavior disruptions that involve prolonged shift work and even space travel may negatively impact circadian rhythm and lead to multi-system disease.

Methods: In light of the significant role circadian rhythm can hold over the body’s normal physiology as well as disease processes, we examined and discussed the impact circadian rhythm and clock genes hold over lifespan, neurodegenerative disorders, and tumorigenesis.

Results: In experimental models, lifespan is significantly reduced with the introduction of arrhythmic mutants and leads to an increase in oxidative stress exposure. Interestingly, patients with Alzheimer’s disease and Parkinson’s disease may suffer disease onset or progression as a result of alterations in the DNA methylation of clock genes as well as prolonged pharmacological treatment for these disorders that may lead to impairment of circadian rhythm function. Tumorigenesis also can occur with the loss of a maintained circadian rhythm and lead to an increased risk for nasopharyngeal carcinoma, breast cancer, and metastatic colorectal cancer. Interestingly, the circadian clock system relies upon the regulation of the critical pathways of autophagy, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) as well as proliferative mechanisms that involve the wingless pathway of Wnt/β-catenin pathway to foster cell survival during injury and block tumor cell growth.

Conclusion: Future targeting of the pathways of autophagy, mTOR, SIRT1, and Wnt that control mammalian circadian rhythm may hold the key for the development of novel and effective therapies against aging- related disorders, neurodegenerative disease, and tumorigenesis.

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Upcoming Thematic Issue – Oxidative Stress in Neurodegenerative and Psychiatric Disorders – Current Psychopharmacology


Most Accessed Article – Warming Up to New Possibilities with the Capsaicin Receptor TRPV1: mTOR, AMPK, and Erythropoietin – Current Neurovascular Research

Journal: Current Neurovascular Research

Author(s): Kenneth Maiese.


Background: Transient receptor potential (TRP) channels are a superfamily of ion channels termed after the trp gene in Drosophila that are diverse in structure and control a wide range of biological functions including cell development and growth, thermal regulation, and vascular physiology. Of significant interest is the transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor, also known as the capsaicin receptor and the vanilloid receptor 1, that is a non-selective cation channel sensitive to a host of external stimuli including capsaicin and camphor, venoms, acid/basic pH changes, and temperature.

Methods: Given the multiple modalities that TRPV1 receptors impact in the body, we examined and discussed the role of these receptors in vasomotor control, metabolic disorders, cellular injury, oxidative stress, apoptosis, autophagy, and neurodegenerative disorders and their overlap with other signal transduction pathways that impact trophic factors.

Results: Surprisingly, TRPV1 receptors do not rely entirely upon calcium signaling to affect cellular biology, but also have a close relationship with the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), and protein kinase B (Akt) that have roles in pain sensitivity, stem cell development, cellular survival, and cellular metabolism. These pathways with TRPV1 converge in the signaling of growth factors with recent work highlighting a relationship with erythropoietin (EPO). Angiogenesis and endothelial tube formation controlled by EPO requires, in part, the activation of TRPV1 receptors in conjunction with Akt and AMPK pathways.
Conclusion: TRPV1 receptors could prove to become vital to target disorders of vascular origin and neurodegeneration. Broader and currently unrealized implementations for both EPO and TRPV1 receptors can be envisioned for for the development of novel therapeutic strategies in multiple systems of the body.


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Editor’s Choice – “The Role of Oxidative Stress in Methamphetamine-induced Toxicity and Sources of Variation in the Design of Animal Studies”

Journal: Current Neuropharmacology

Author(s): Kate McDonnell-Dowling and John P Kelly



Background: The prevalence of methamphetamine (MA) use has increased in recent years. In order to assess how this drug produces its effects, both clinical and preclinical studies have recently begun to focus on oxidative stress as an important biochemical mechanism in mediating these effects.

Objective: The purpose of this review is to illustrate the variation in the design of preclinical studies investigating MA exposure on oxidative stress parameters in animal models.

Method: The experimental variables investigated and summarised include MA drug treatment, measurements of oxidative stress and antioxidant treatments that ameliorate the harmful effects of MA.

Results: These preclinical studies differ greatly in their experimental design with respect to the dose of MA (ranging between 0.25 and 20 mg/kg), the dosing regime (acute, binge or chronic), the time of measurement of oxidative stress (0.5 h to 2 wks after last MA administration), the antioxidant system targeted and finally the use of antioxidants including the route of administration (i.p. or p.o.), the frequency of exposure and the time of exposure (preventative or therapeutic).

Conclusion: The findings in this paper suggest that there is a large diversity among these studies and so the interpretation of these results is challenging. For this reason, the development of guidelines and how best to assess oxidative stress in animal models may be beneficial. The use of these simple recommendations mean that results will be more comparable between laboratories and that future results generated will give us a greater understanding of the contribution of this important biochemical mechanism and its implications for the clinical scenario.

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Podcast: Thiopurine Biotransformation and Pharmacological Effects

Author: Dr. Marco Pelin

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Testimonial by Dr Hugo Juarez Olguin!

Hugo Juarez Olguin

Dr. Hugo Juarez Olguin

Laboratory of Pharmacology, National Institute of Pediatrics,

Av Imán #1, 3er piso, Col Cuicuilco, CP 04530,

Mexico City, Mexico 

Contributed Article: Oleic Acid Protects Against Oxidative Stress Exacerbated by Cytarabine and Doxorubicin in Rat Brain”


Open Access Article – “Morphine as a Potential Oxidative Stress-Causing Agent”

Mini-Reviews in Organic Chemistry

Author(s): Jitka Skrabalova, Zdenka Drastichova and Jiri Novotny

MROCAbstract: Morphine exhibits important pharmacological effects for which it has been used in medical practice for quite a long time. However, it has a high addictive potential and can be abused. Long-term use of this drug can be connected with some pathological consequences including neurotoxicity and neuronal dysfunction, hepatotoxicity, kidney dysfunction, oxidative stress and apoptosis. Therefore, most studies examining the impact of morphine have been aimed at determining the effects induced by chronic morphine exposure in the brain, liver, cardiovascular system and macrophages. It appears that different tissues may respond to morphine diversely and are distinctly susceptible to oxidative stress and subsequent oxidative damage of biomolecules. Importantly, production of reactive oxygen/nitrogen species induced by morphine, which have been observed under different experimental conditions, can contribute to some pathological processes, degenerative diseases and organ dysfunctions occurring in morphine abusers or morphine-treated patients. This review attempts to provide insights into the possible relationship between morphine actions and oxidative stress.

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Testimonial by Dr. Branislav Rovcanin!

5-6-2016 3-57-56 PM

Dr. Branislav Rovcanin

Contributed Article: Molecular Dissection of Renal Ischemia-Reperfusion: Oxidative Stress and Cellular Events”



Upcoming Thematic Issue – Organic Compounds as Modulators of Oxidative Stress: Chemical and Biological Aspects

Hottopic-COC-Sibel Suzen

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Pro-oxidant- Antioxidant Balance (PAB) in Rheumatoid Arthritis and its Relationship to Disease Activity

Author(s): Maryam Sahebari, Farzaneh Shakeri, Hamideh Ghodrati Azadi, Mohammad Hassan Arjmand, Majid Ghayour-Mobarhan, Mohammad Reza Parizadehand Daryoush Hamidi Alamdari.


Background: Rheumatoid arthritis (RA) is an autoimmune disease that tends to be progressive and chronic. Previous studies showed that oxidative stress has a main role in pathology of RA. The aim of this study was the easy elucidation of oxidative stress through pro-oxidant-antioxidant balance (PAB) in these patients.

Method: The sera of 130 RA patients and 130 age-matched healthy subjects (HS) were collected and the PAB was measured. According to the normal value of PAB in HS, the patients were divided into two groups; patients with increased serum PAB and those with normal serum PAB values. In patients with increased PAB value, the correlation of PAB value with RA disease activity [(DAS28ESR)], biochemical parameters, and BMI were determined.

Results: Significantly higher serum PAB values were found in the whole RA group of patients (88.69±39.42 HK) in comparison to HS (53.57±25.10 HK), p 0.05. There was no significant correlation between PAB values and RA disease activity. In patients with elevated serum PAB value; serum cholesterol, triglycerides and BMI were significantly higher in comparison to patients with normal values.

Conclusion: The PAB test can show the oxidative stress in RA patients. Further research should be done to determine the potency of the PAB assay as a tool for monitoring adverse effect of oxidative stress in RA, as well as the effect of antioxidant therapies in the outcomes.

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Current Rheumatology Reviews, 11(1): 28-33.