Biphasic Dose Response in Low Level Light Therapy

The use of low levels of visible or near infrared light for reducing pain, inflammation and edema, promoting healing of wounds, deeper tissues and nerves, and preventing cell death and tissue damage has been known for over forty years since the invention of lasers. Despite many reports of positive findings from experiments conducted in vitro, in animal models and in randomized controlled clinical trials, LLLT remains controversial in mainstream medicine. The biochemical mechanisms underlying the positive effects are incompletely understood, and the complexity of rationally choosing amongst a large number of illumination parameters such as wavelength, fluence, power density, pulse structure and treatment timing has led to the publication of a number of negative studies as well as many positive ones. A biphasic dose response has been frequently observed where low levels of light have a much better effect on stimulating and repairing tissues than higher levels of light. The so-called Arndt-Schulz curve is frequently used to describe this biphasic dose response. This review will cover the molecular and cellular mechanisms in LLLT, and describe some of our recent results in vitro and in vivo that provide scientific explanations for this biphasic dose response.     

Oxidative stress-induced ischemic heart disease: protection by antioxidants

Heart disease is one of the major health problems of advanced as well as developing countries of the world. Extensive research through the last decade has shown beyond doubt that free radicals, particularly, reactive oxygen species play a cardinal role in the pathogenesis of oxidative myocardial damage with consequential cardiac malfunction. This review presents a comprehensive account of the present day knowledge regarding the oxygen free radicals involved in the genesis of ischemic heart disease, the mechanism(s) of oxidative myocardial damage and the endogenous as well as exogenous antioxidant defense systems. Furthermore, the role of ischemic pre-conditioning, some antioxidants and the ability of some cardioprotective drugs in providing protection against the ischemic myocardial damage are also discussed. The text of the article comes to an end with a commentary on the future research perspective in the concerned area, which throws a light on the development of combinatorial therapeutics in the treatment of ischemic myocardial disease.     

Inhalational anaesthetics and cardioprotection

The heart has a strong endogenous cardioprotection mechanism that can be triggered by short periods of ischaemia (like during angina) and protects the myocardium during a subsequent ischaemic event (like during a myocardial infarction). This important mechanism, called ischaemic pre-conditioning, has been extensively investigated, but the practical relevance of an intervention by inducing ischaemia is mainly limited to experimental situations. Research that is more recent has shown that many volatile anaesthetics can induce a similar cardioprotection mechanism, which would be clinically more relevant than inducing cardioprotection by ischaemia. In the last few decades, several laboratory investigations have shown that exposure to inhalational anaesthetics leads to a variety of changes in the protein structure of the myocardium. By a functional blockade of these modified (i.e. activated) target enzymes, it was demonstrated that some of these changes in protein structure and distribution can mediate cardioprotection by anaesthetic pre-conditioning. This chapter gives an overview of our current understanding of the signal transduction of this phenomenon. In addition to an intervention before ischaemia (i.e. pre-conditioning), there are two more time windows when a substance may interact with the ischaemia-reperfusion process and might modify the extent of injury: (1) during ischaemia or (2) after ischaemia (i.e. during reperfusion) (postconditioning). In animal experiments, the volatile anaesthetics also interact with these mechanisms (especially immediately after ischaemia), i.e. by post-conditioning. Since ischaemia-reperfusion of the heart routinely occurs in a variety of clinical situations such as during transplant surgery, coronary artery bypass grafting, valve repair or vascular surgery, anaesthetic-induced cardioprotection might be a promising option to protect the myocardium in clinical situations. Initial studies now confirm an effect on surrogate outcome parameters such as length of ICU or in-hospital stay or post-ischaemic troponin release. In this chapter, we will summarize our current understanding of the three mechanisms of anaesthetic cardioprotection exerted by inhalational anaesthetics.     

Antioxidant properties of essential oils. Possible explanations for their anti-inflammatory effects

Pathogenesis and symptoms of inflammatory processes are accompanied and/or initiated by the production of reactive oxygen species (ROS). The effects of essential oils on these processes have been studied with the aid of biochemical model reactions simulating these pathological events. It can be shown that Myrtol Standardized and Eucalyptus oil ameliorate inflammatory processes by interacting with aggressive oxygen radicals of the OH.-type and interfere with leukocyte activation. These activities partially allow attenuation of oxidative attack and damage introduced by infections or environmental impacts.     

Anti-anginal effects of partial fatty acid oxidation inhibitors

Angina pectoris can result in an imbalance between oxygen supply and demand of the heart muscle, resulting in a compromised energy supply to the heart muscle. Currently, the primary approach to treating angina is aimed either at decreasing muscle oxygen demand, or increasing oxygen supply to the muscle. An alternative approach is to increase cardiac efficiency by increasing the amount of cardiac work at a given level of oxygen consumed. This can be achieved by inhibiting myocardial fatty acid oxidation, which leads to an increase in glucose oxidation. Consequently, lactate and proton production decrease, and as a result cardiac efficiency is improved. The approach of partial fatty acid oxidation (pFOX) inhibition is beneficial in the treatment of angina pectoris, both as a monotherapy and when used in combination with conventional therapy. pFOX inhibitors not only lessen the severity and symptoms of an angina attack, they also decrease the incidence of angina attacks in patients with coronary artery disease. The approach of optimizing energy substrate preference in the heart is a new and effective approach to treating angina pectoris.     

Biphasic dose response in low level light therapy - an update

Low-level laser (light) therapy (LLLT) has been known since 1967 but still remains controversial due to incomplete understanding of the basic mechanisms and the selection of inappropriate dosimetric parameters that led to negative studies. The biphasic dose-response or Arndt-Schulz curve in LLLT has been shown both in vitro studies and in animal experiments. This review will provide an update to our previous (Huang et al. 2009) coverage of this topic. In vitro mediators of LLLT such as adenosine triphosphate (ATP) and mitochondrial membrane potential show biphasic patterns, while others such as mitochondrial reactive oxygen species show a triphasic dose-response with two distinct peaks. The Janus nature of reactive oxygen species (ROS) that may act as a beneficial signaling molecule at low concentrations and a harmful cytotoxic agent at high concentrations, may partly explain the observed responses in vivo. Transcranial LLLT for traumatic brain injury (TBI) in mice shows a distinct biphasic pattern with peaks in beneficial neurological effects observed when the number of treatments is varied, and when the energy density of an individual treatment is varied. Further understanding of the extent to which biphasic dose responses apply in LLLT will be necessary to optimize clinical treatments.     

Gallic acid: A promising genoprotective and hepatoprotective bioactive compound against cyclophosphamide induced toxicity in mice

Cyclophosphamide (CP) is a potent chemotherapeutic agent and is also known to interact with specific biological molecules and produce numerous side effects such as genotoxicity, neurotoxicity, reproductive toxicity and nephrotoxicity. CP induces genotoxicity by generating oxygen/nitrogen derived free radicals during chemotherapy and causes DNA damage. Hence, to overcome such side effects of chemotherapeutic agents antioxidants are recommended. Gallic acid (GA) a phenolic compound is commonly exists in variety of fruits and in many plants. In the present study, genoprotecive effects of GA against CP induced genotoxicity in Swiss albino mice were evaluated by using comet assay, bone marrow, and peripheral micronucleus (MN) assays. CP produced oxidative stress induced hepatic damage was assessed by estimating the activity of liver superoxide dismutase (SOD), reduced glutathione content (GSH), and also by examining the histological alterations induced by CP in hepatic tissue of mice. It was noticed that, GA pretreatment significantly reduced the frequency of MN and DNA strand breaks induced by CP. GA also protected the hepatic tissue against CP induced reactive oxygen species (ROS) mediated damage and was evident by increased levels of liver SOD and GSH. GA ameliorated the histological changes induced by CP in hepatic tissue. These findings suggest that, GA is a versatile antioxidant with promising protection against CP induced genotoxicity and hepatic damage in Swiss albino mice.     

Pathophysiology of soft tissue repair.

Inflammation with subsequent migration of leucocytes and connective tissue cells to the site of damage, together with the release of cytokines by these cells are essential for healing in common sports injuries. Injury to the musculotendinous unit resulting from either blunt trauma, tears or laceration, heal primarily by formation of granulation tissue and scarring. Early diagnosis with appropriate therapy may minimize any potential loss of function. Ligament repair also follows a classical healing response, although the quality of healing is site dependent and may be related to exposure to synovial fluid. In contrast, cartilage, which is avascular, lacks the inflammatory response seen in other connective tissues and this frequently results in poor tissue repair with subsequent degeneration of the injured cartilage. Mechanisms of repair in these tissues are described.     

Adenosine receptor targeting in health and disease

INTRODUCTION: The adenosine receptors A(1), A(2A), A(2B) and A(3) are important and ubiquitous mediators of cellular signaling that play vital roles in protecting tissues and organs from damage. In particular, adenosine triggers tissue protection and repair by different receptor-mediated mechanisms, including increasing the oxygen supply:demand ratio, pre-conditioning, anti-inflammatory effects and the stimulation of angiogenesis. AREAS COVERED: The state of the art of the role of adenosine receptors which have been proposed as targets for drug design and discovery, in health and disease, and an overview of the ligands for these receptors in clinical development. EXPERT OPINION: Selective ligands of A(1), A(2A), A(2B) and A(3) adenosine receptors are likely to find applications in the treatment of pain, ischemic conditions, glaucoma, asthma, arthritis, cancer and other disorders in which inflammation is a feature. The aim of this review is to provide an overview of the present knowledge regarding the role of these adenosine receptors in health and disease.     

The role of reduced glutathione during the course of acute haemolysis in glucose-6-phosphate dehydrogenase deficient patients: clinical and pharmacodynamic aspects

Tissue hypoperfusion leads to cellular oxidative and peroxidative damage due to biochemical disorders in the oxygen and substrate metabolism. The metabolic turnover of glutathione (GSH) represents one the main cytoprotective systems against the peroxide attack and the depletion or defect in resynthesis of this compound is accompanied by pathological consequences. In the present study the clinical effects of glutathione depletion were investigated in conditions of acute tissue hypoxia due to marked haemolysis in glucose-6-phosphate dehydrogenase deficient patients (favism syndrome). In these subjects a significant marker of the tissue oxidative damage was represented by the uric acid blood levels, presumably linked to xanthine-hypoxanthine altered metabolism. To antagonize the effects of oxyradical pathology, reduced glutathione was administered to a group of patients and the results confirmed the cytoprotective role played by the GSH supplementation. The GSH action was evident on the tissue metabolism and this supports the opinion that reduced glutathione could represent a new and interesting therapeutic approach in marked and acute hypoxic conditions.     

To prevent,protect and save the ischemic heart: antioxidants revisited

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) formation increases in the post-ischemic myocardium and represents a mechanism of post ischemic injury. ROS, which are formed during reperfusion, trigger lipid peroxidation, oxidize proteins and cause DNA strand breaks, all interfering with and potentially damaging normal cellular function. Oxidative stress is associated with poor recovery of left ventricular function after a sustained period of ischemia and, according to several studies, it contributes significantly to the acceleration of necrosis and thus extension of infarction, apoptosis, arrhythmiogenesis and endothelial dysfunction. Accordingly, targeting the generation of ROS with various antioxidants has been shown to improve left ventricular function after the restoration of flow. Apart from mechanical or pharmacological interventions that open the occluded artery, the heart has endogenous mechanisms of protection, called ischemic pre-conditioning and ischemic post-conditioning. Opening of the mitochondrial ATP-sensitive potassium channels and subsequent generation of ROS is considered to be a pivotal step in the mechanisms of pre- and post-conditioning. Notably, ROS play an ambiguous role in the protection of myocardium and can be both effective and harmful. Thus, the role of antioxidants in the attenuation of the effects of pre-and post-conditioning in vivo remains controversial.     

Antioxidant therapy in acute central nervous system injury: current state

Free radicals are highly reactive molecules generated predominantly during cellular respiration and normal metabolism. Imbalance between cellular production of free radicals and the ability of cells to defend against them is referred to as oxidative stress (OS). OS has been implicated as a potential contributor to the pathogenesis of acute central nervous system (CNS) injury. After brain injury by ischemic or hemorrhagic stroke or trauma, the production of reactive oxygen species (ROS) may increase, sometimes drastically, leading to tissue damage via several different cellular molecular pathways. Radicals can cause damage to cardinal cellular components such as lipids, proteins, and nucleic acids (e.g., DNA), leading to subsequent cell death by modes of necrosis or apoptosis. The damage can become more widespread due to weakened cellular antioxidant defense systems. Moreover, acute brain injury increases the levels of excitotoxic amino acids (such as glutamate), which also produce ROS, thereby promoting parenchymatous destruction. Therefore, treatment with antioxidants may theoretically act to prevent propagation of tissue damage and improve both the survival and neurological outcome. Several such agents of widely varying chemical structures have been investigated as therapeutic agents for acute CNS injury. Although a few of the antioxidants showed some efficacy in animal models or in small clinical studies, these findings have not been supported in comprehensive, controlled trials in patients. Reasons for these equivocal results may include, in part, inappropriate timing of administration or suboptimal drug levels at the target site in CNS. Better understanding of the pathological mechanisms of acute CNS injury would characterize the exact primary targets for drug intervention. Improved antioxidant design should take into consideration the relevant and specific harmful free radical, blood brain barrier (BBB) permeability, dose, and time administration. Novel combinations of drugs providing protection against various types injuries will probably exploit the potential synergistic effects of antioxidants in stroke.     

Pain: friend or foe

Pain, the most urgent of symptoms usually signals the presence of potential or on-going injury to tissue which requires attention. The warning that pain provides is, therefore, a good thing and in a way friendly. When pain continues or resumes after the healing process of injury is complete, it is no longer signalling on-going tissue damage but becomes a disease in its own right. That, in essence, is the presentation of most chronic pain syndromes referred to Pain Clinics for investigation and treatment.     

缺血性脑血管疾病治疗的抗氧化应激策略

自由基是细胞呼吸及正常代谢过程中产生的高活性分子 ,氧化应激 (OS)是细胞内自由基生成和清除能力失衡 ,是缺血性脑血管疾病重要病理反应过程。缺血性脑损伤后 ,活性氧自由基 (ROS)增加 ,以不同的细胞分子机制引起组织损伤。自由基可以损伤细胞内脂质、蛋白质、核酸等重要物质 ,继而通过坏死或凋亡的方式引起细胞死亡。抗氧化剂可防止脑组织损伤 ,改善神经细胞存活率及功能。本文就治疗缺血性脑血管疾病的抗氧化剂作一综述 ,并分析动物与临床试验结果不一致的原因 ,提出缺血性脑血管疾病治疗的抗氧化应激策略。     

Complement components of the innate immune system in health and disease in the CNS

The innate immune system and notably the complement (C) system play important roles in host defense to recognise and kill deleterious invaders or toxic entities, but activation at inappropriate sites or to an excessive degree can cause severe tissue damage. C has been implicated as a factor in the exacerbation and propagation of tissue injury in numerous diseases including neurodegenerative disorders. In this article, we review the evidence indicating that brain cells can synthesise a full lytic C system and also express specific C inhibitors (to protect from C activation and C lysis) and C receptors (involved in cell activation, chemotaxis and phagocytosis). We also summarise the mechanisms involved in the antibody-independent activation of the classical pathway of C in Alzheimer's disease, Huntington's disease and Pick's disease. Although the primary role of C activation on a target cell is to induce cell lysis (particularly of neurons), we present evidence indicating that C (C3a, C5a, sublytic level of C5b-9) may also be involved in pro- as well as anti-inflammatory activities. Moreover, we discuss evidence suggesting that local C activation may contribute to tissue remodelling activities during repair in the CNS.     

Low level laser therapy modulates kinin receptors mRNA expression in the subplantar muscle of rat paw subjected to carrageenan-induced inflammation

Low level laser therapy (LLLT) has been used clinically in order to treat inflammatory processes. In this work, we evaluated if LLLT alters kinin receptors mRNA expression in the carrageenan-induced rat paw edema. Experimental groups were designed as followed: A1 (Control-saline), A2 (Carrageenan-only), A3 (Carrageenan+laser 660 nm) and A4 (Carrageenan+laser 684 nm). Edema was measured by a plethysmometer. Subplantar tissue was collected for kinin receptors mRNA quantification by Real time-PCR. LLLT of both 660 and 684 nm wavelengths administrated 1 h after carrageenan injection was able to promote the reduction of edema produced by carrageenan. In the A2 group, B1 receptor expression presented a significantly increase when compared to control group. Kinin B1 receptor mRNA expression significantly decreased after LLLT's 660 or 684 nm wavelength. Kinin B2 receptor mRNA expression also diminished after both laser irradiations. Our results suggest that expression of both kinin receptors is modulated by LLLT, possibly contributing to its anti-inflammatory effect.     

Oxidative Stress and Neurodegenerative Diseases: A Review of Upstream and Downstream Antioxidant Therapeutic Options

Free radicals are common outcome of normal aerobic cellular metabolism. In-built antioxidant system of body plays its decisive role in prevention of any loss due to free radicals. However, imbalanced defense mechanism of antioxidants, overproduction or incorporation of free radicals from environment to living system leads to serious penalty leading to neuro-degeneration. Neural cells suffer functional or sensory loss in neurodegenerative diseases. Apart from several other environmental or genetic factors, oxidative stress (OS) leading to free radical attack on neural cells contributes calamitous role to neuro-degeneration. Though, oxygen is imperative for life, imbalanced metabolism and excess reactive oxygen species (ROS) generation end into a range of disorders such as Alzheimer’s disease, Parkinson’s disease, aging and many other neural disorders. Toxicity of free radicals contributes to proteins and DNA injury, inflammation, tissue damage and subsequent cellular apoptosis. Antioxidants are now being looked upon as persuasive therapeutic against solemn neuronal loss, as they have capability to combat by neutralizing free radicals. Diet is major source of antioxidants, as well as medicinal herbs are catching attention to be commercial source of antioxidants at present. Recognition of upstream and downstream antioxidant therapy to oxidative stress has been proved an effective tool in alteration of any neuronal damage as well as free radical scavenging. Antioxidants have a wide scope to sequester metal ions involved in neuronal plaque formation to prevent oxidative stress. In addition, antioxidant therapy is vital in scavenging free radicals and ROS preventing neuronal degeneration in post-oxidative stress scenario.Key Words: ROS, oxidative stress, antioxidants, neurodegenerative diseases, rns, amyloid, catalase, phagocytes.     

Alcohol and the cardiovascular system: molecular mechanisms for beneficial and harmful action

Alcohol can be beneficial or harmful to the cardiovascular system, depending on the amount consumed and the characteristics of the consumer. Of the numerous cellular and molecular mechanisms that are thought to explain the beneficial effects of moderate drinking, this article discusses four, involving (1) high density lipoproteins, (2) cellular signaling, (3) platelet function in blood clot formation, and (4) stimulation of blood clot dissolution. Although light-to-moderate drinking can protect against coronary artery disease, heavy alcohol consumption can damage the cardiovascular system, resulting in maladies such as heart muscle disorders, irregular heart rhythms, high blood pressure, and strokes. This article summarizes representative epidemiological and animal studies on these cardiovascular consequences of chronic heavy alcohol consumption and reviews mechanisms that have been suggested to explain alcohol's effects.     

NGF and heart: Is there a role in heart disease?

The review emphasizes the role of NGF, the most representative member of the neurotrophins family, in cardiac physiopathology with a particular focus on healing and sprouting processes occurring after tissue damage. Cardiac and circulating NGF levels dramatically increase following myocardial injury (MI). A very early rise of this neurotrophin is indeed observed soon after MI (hours). Such a rise may lead to sympathetic nerve sprouting which may underlie the later genesis of arrhythmias but may also favor the healing process. At later times (months after), when heart failure develops, the opposite is detected and NGF tissue levels are below the normal range, an event that may in turn participate to defective innervation and cardiac failure. Through a careful analysis of preclinical and clinical studies, this review proposes that time is the key variable when studying these opposite changes in NGF expression observed following MI and attempting to interpret and correlate them with cardiac physiopathology. The examination of the results leads to the speculation that NGF modulation may be a pharmacological target for interventions in specific stages of heart dysfunction following MI.     

Bone healing effects of diode laser (808 nm) on a rat tibial fracture model

Low level laser therapies (LLLT) have analgesic, vasodilatory and anti-inflammatory effects. The present study investigated the effects of LLLT with a diode laser (808 nm) device on the healing of the rat tibial fracture. Forty eight, 8-week-old, male Sprague-Dawley rats were used for this study. After creating the tibial fracture model, the animals were randomly divided into laser and control groups. The animals were euthanized for histopathological and radiological evaluation. The biomechanical strength of the fractures was evaluated using a bending test. The histopathological and radiological evaluations suggested that the laser group developed new bone formations much earlier than those of the control group. The maximum tolerance force of the laser group was significantly higher than that of the control group (p<0.05). These findings suggest positive effects of LLLT in accelerating the bone healing process, especially in the early stage of bone formation.