Current critical thinking has displaced the elaborated beta amyloid theory as the underlying unitary mechanism of Alzheimer disease (AD) in favor of concerted, long-term disruption or dysregulation of broad-based physiological processes. We present a critical discussion in which a chronic state of systemic proinflammation sustained over the course of several decades and engendered by ongoing metabolic or autoimmune disease is predicted to promote severe disruptions of central neurological processes. Specifically, long-term functional rundown of microglial-mediated phagocytic activity in concert with aberrant expression and cellular deposition of beta amyloid and tau protein facilitates formation of senile plaques and neurofibrillary tangles. Within this functional context, we hypothesize that early initiation events in the pathophysiology of AD may operationally involve a convergence of dysregulated peripheral and central constitutive nitric oxide signaling pathways resulting from a chronic state of systemic proinflammation and leading to severely dysfunctional "hyperactivated" microglia.

• MeSH
• Alzheimer Disease * metabolism   pathology   physiopathology   MeSH
• Humans MeSH
• Microglia * metabolism   pathology   MeSH
• Nitric Oxide metabolism   MeSH
• Signal Transduction * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Editorial MeSH
• Names of Substances
• Nitric Oxide MeSH

The primordial origin of abiotic nitrogen fixation, which is not dependent on prokaryotes, reflects the importance of available nitrogenous compounds as an essential requirement for the emergence of life and evolutionary biodiversity. It has been hypothesized that synthesis of oxidized nitrogen in the form of nitrate (NO3-) and nitrite (NO2-), occurred in the prebiotic anoxic Hadean atmosphere. The sustained influx of atmospheric NO3- and NO2- into prebiotic Hadean oceans have been proposed to provide the essential substrates for abiotic synthesis of compounds such as ammonia (NH3) within oceanic alkaline hydrothermal vents in the seafloor. Because NH3 is an essential chemical precursor for nitrogen-containing molecular components of proteins and nucleic acids, abiotic production in high concentrations within Hadean oceanic alkaline hydrothermal vents is required for the emergence of diverse life forms. The chemical evolution of nitrogenous compounds includes the functional development of alkaloids. This commentary aims to critically discuss the possible origin of nitrogen-containing alkaloids and evolutionary processes in higher organisms, including the diverse biomedical mechanisms involved.

• MeSH
• Alkaloids * MeSH
• Biodiversity * MeSH
• Biological Evolution * MeSH
• Hydrothermal Vents * MeSH
• Oceans and Seas MeSH
• Publication type
• Editorial MeSH
• Geographicals
• Oceans and Seas MeSH
• Names of Substances
• Alkaloids * MeSH

Nitric oxide (NO) represents a key signaling molecule in multiple regulatory pathways underlying vascular, metabolic, immune, and neurological function across animal phyla. Our brief critical discussion is focused on the multiple roles of the NO signaling pathways in the maintenance of basal physiological states of readiness in diverse cell types mediating innate immunological functions and in the facilitation of proinflammatory-mediated adaptive immunological responses associated with viral infections. Prior studies have reinforced the critical importance of constitutive NO signaling pathways in the homeostatic maintenance of the vascular endothelium, and state-dependent changes in innate immunological responses have been associated with a functional override of NO-mediated inhibitory tone. Accordingly, convergent lines of evidence suggest that dysregulation of NO signaling pathways, as well as canonical oxidative effects of inducible NO, may provide a permissive cellular environment for viral entry and replication. In immunologically compromised individuals, functional override and chronic rundown of inhibitory NO signaling systems promote aberrant expression of unregulated proinflammatory pathways resulting in widespread metabolic insufficiencies and structural damage to autonomous cellular and organ structures. We contend that restoration of normative NO tone via combined pharmaceutical, dietary, or complex behavioral interventions may partially reverse deleterious physiological conditions brought about by viral infection linked to unregulated adaptive immune responses.

• MeSH
• Antiviral Agents pharmacology   MeSH
• Humans MeSH
• Nitric Oxide pharmacology   MeSH
• Oxidation-Reduction MeSH
• Signal Transduction MeSH
• Severe acute respiratory syndrome-related coronavirus drug effects   immunology   MeSH
• Inflammation metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Editorial MeSH
• Names of Substances
• Antiviral Agents MeSH
• Nitric Oxide MeSH

Over the past two decades, a major goal of our research group has been elucidation of the functional roles of several key regulatory molecules in proinflammatory preconditioning involved in the pathophysiology of seemingly diverse human disease states. By necessity, operational definitions of proinflammation must be intrinsically fluid based on recent advances in our understanding of complex regulation of innate and adaptive immune processes. Similar to systemic acute stress, a physiological proinflammatory state appears to be a key autoregulatory mechanism for maintaining optimal immune surveillance against potentially infective microorganisms, viruses, and toxic xenobiotics. Perturbation of normative biochemical and molecular mosaics of ongoing proinflammatory tone, exemplified by altered expression of pro- and anti-inflammatory cytokines and their respective protein complexes, is hypothesized to be a common modality for initiation and full expression of various autoimmune diseases and comorbid syndromes evolving from metabolic and metastatic diseases. The newly reported presence of "free" (extracellular) mitochondria exponentially adds to our hypothesis that in conditions of acute stress, a new source of potential ATP producers may be recruited and present to deal with such an acute process. Furthermore, given this phenomenon, an early surveillance role and a dysfunctional chronic inflammation-prolonging component may also be surmised.

• MeSH
• Alarmins immunology   metabolism   MeSH
• Anti-Inflammatory Agents metabolism   MeSH
• Autoimmune Diseases blood   immunology   MeSH
• Extracellular Space immunology   metabolism   MeSH
• Humans MeSH
• Inflammation Mediators metabolism   MeSH
• Mitochondria immunology   metabolism   MeSH
• Mitophagy immunology   MeSH
• Inflammation blood   immunology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Editorial MeSH
• Names of Substances
• Alarmins MeSH
• Anti-Inflammatory Agents MeSH
• Inflammation Mediators MeSH

The objective of our concise review is to elaborate an evidence-based integrative medicine model that incorporates functional linkages of key aspects of cortically-driven mind-body training procedures to biochemical and molecular processes driving enhanced cellular bioenergetics and whole-body metabolic advantage. This entails the adoption of a unified biological systems approach to selectively elucidate basic biochemical and molecular events responsible for achieving physiological relaxation of complex cellular structures. We provide accumulated evidence in support of the potential synergy of voluntary breathing exercises in combination with meditation and/or complementary cognitive tasks to promote medically beneficial enhancements in whole-body relaxation, anti-stress mechanisms, and restorative sleep. Accordingly, we propose that the widespread metabolic and physiological advantages emanating from a sustained series of complementary mind-body exercises will ultimately engender enhanced functional integration of cortical and limbic areas controlling voluntary respiratory processes with autonomic brainstem neural pattern generators. Finally, a unified mechanism is proposed that links behaviorally-mediated enhancements of whole-body metabolic advantage to optimization of synchronous regulation of mitochondrial oxygen utilization via recycling of nitrite and nitric oxide by iron-sulfur centers of coupled respiratory complexes and nitrite reductases.

• MeSH
• Breathing Exercises methods   psychology   MeSH
• Respiration MeSH
• Energy Metabolism physiology   MeSH
• Humans MeSH
• Meditation methods   psychology   MeSH
• Mitochondria metabolism   physiology   MeSH
• Nitrite Reductases metabolism   MeSH
• Nitric Oxide metabolism   MeSH
• Relaxation Therapy methods   psychology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Nitrite Reductases MeSH
• Nitric Oxide MeSH

Stress affects cellular aging and inflammatory and chromosomal processes, including telomere length, thereby potentially compromising health and facilitating disease onset and progression. Stress-related diseases and strategies to manage stress usually require integrative or behavioral therapeutic approaches that also operate on cellular levels. Mind-body medicine (MBM) uses the interaction between the mind, body, behavior, and the environment to correct physical and psychological malfunctions, thus ameliorating disease states and improving health. The relaxation response (RR) is a physiological opponent of stress and the stress response (SR) (i.e., fight-or-flight response), also invoking molecular anti-stress processes. Techniques that elicit the RR are at the core of practically all MBM interventions. We surmise that these techniques can also affect chromosomal and telomere processes, molecular aging, and the modulation of inflammatory states on cellular levels.

• MeSH
• Chronic Disease MeSH
• Telomere Homeostasis physiology   MeSH
• Humans MeSH
• Stress, Psychological complications   MeSH
• Mind-Body Therapies methods   psychology   MeSH
• Relaxation Therapy methods   MeSH
• Cellular Senescence physiology   MeSH
• Aging physiology   MeSH
• Telomere physiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH