Low-energy visible light (LEVL) has been shown to stimulate cell functions. This is called "photobiostimulation" and has been used successfully over the last three decades for treating a range of conditions, including soft tissue injuries, severe wounds, chronic pain, and more. Nevertheless, the mechanism of photobiostimulative processes is still being debated. It is obvious that, in order to interact with the living cell, light has to be absorbed by intracellular chromophores. In a search for chromophores responsible for photobiostimulation, endogenous porphyrins, mitochondrial and membranal cytochromes, and flavoproteins were found to be suitable candidates. The above-mentioned chromophores are photosensitizers that generate reactive oxygen species (ROS) following irradiation. As the cellular redox state has a key role in maintaining the viability of the cell, changes in ROS may play a significant role in cell activation. In the present review, we summarize evidence demonstrating that various ROS and antioxidants are produced following LEVL illumination. We found that very little evidence for NO formation in illuminated non-vascular smooth muscle cells exists in the literature. We suggest that the change in the cellular redox state which plays a pivotal role in maintaining cellular activities leads to photobiostimulative processes.

Background: Diabetes mellitus type 2 (DM2) is a risk factor for developing heart failure but there is no specific therapy for diabetic heart disease. Sodium glucose transporter 2 inhibitors (SGLT2I) are recently developed diabetic drugs that primarily work on the kidney. Clinical data describing the cardiovascular benefits of SGLT2Is highlight the potential therapeutic benefit of these drugs in the prevention of cardiovascular events and heart failure. However, the underlying mechanism of protection remains unclear. We investigated the effect of Dapagliflozin-SGLT2I, on diabetic cardiomyopathy in a mouse model of DM2. Methods: Cardiomyopathy was induced in diabetic mice (db/db) by subcutaneous infusion of angiotensin II (ATII) for 30 days using an osmotic pump. Dapagliflozin (1.5 mg/kg/day) was administered concomitantly in drinking water. Male homozygous, 12-14 weeks old WT or db/db mice (n = 4-8/group), were used for the experiments. Isolated cardiomyocytes were exposed to glucose (17.5-33 mM) and treated with Dapagliflozin in vitro. Intracellular calcium transients were measured using a fluorescent indicator indo-1. Results: Angiotensin II infusion induced cardiomyopathy in db/db mice, manifested by cardiac hypertrophy, myocardial fibrosis and inflammation (TNFα, TLR4). Dapagliflozin decreased blood glucose (874 ± 111 to 556 ± 57 mg/dl, p < 0.05). In addition it attenuated fibrosis and inflammation and increased the left ventricular fractional shortening in ATII treated db/db mice. In isolated cardiomyocytes Dapagliflozin decreased intracellular calcium transients, inflammation and ROS production. Finally, voltage-dependent L-type calcium channel (CACNA1C), the sodium-calcium exchanger (NCX) and the sodium-hydrogen exchanger 1 (NHE) membrane transporters expression was reduced following Dapagliflozin treatment. Conclusion: Dapagliflozin was cardioprotective in ATII-stressed diabetic mice. It reduced oxygen radicals, as well the activity of membrane channels related to calcium transport. The cardioprotective effect manifested by decreased fibrosis, reduced inflammation and improved systolic function. The clinical implication of our results suggest a novel pharmacologic approach for the treatment of diabetic cardiomyopathy through modulation of ion homeostasis.

The role of the proapototic Bax gene in ischemia-reperfusion (I/R) injury was studied in three groups of mice: homozygotic knockout mice lacking the Bax gene (Bax(-/-)), heterozygotic mice (Bax(+/-)), and wild-type mice (Bax(+/+)). Isolated hearts were subjected to ischemia (30 min, 37 degrees C) and then to 120 min of reperfusion. The left ventricular developed force of Bax-deficient vs. Bax(+/+) hearts at stabilization and at 120 min of reperfusion was 1,411 +/- 177 vs. 1,161 +/- 137 mg and 485 +/- 69 vs. 306 +/- 68 mg, respectively. Superior cardiac function of Bax(-/-) hearts after I/R was accompanied by a decrease in creatine kinase release, caspase 3 activity, irreversible ischemic injury, and the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cardiomyocytes. Electron microscopic evaluation revealed reduced damage to mitochondria and the nuclear chromatin structure in Bax-deficient mice. In the Bax(+/-) hearts, the damage markers were moderate. The superior tolerance of Bax knockout hearts to I/R injury recommends this gene as a potential target for therapeutic intervention in patients with severe and intractable myocardial ischemia.

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Low energy visible light (LEVL) irradiation has beenshown to exert some beneficial effects on various cell cultures. For example, it increases the fertilizing capability of sperm cells, promotes cell proliferation, induces sprouting of neurons, and more. To learn about the mechanism of photobiostimulation, we studied the relationship between increased intracellular calcium ( Life on earth is entirely dependent upon the interaction of sunlight with cells especially in plant photosynthesis (1). Sunlight also has medical benefits, which have been exploited for over thousands of years in ancient Egypt, India, and China in treating skin diseases, psoriasis, vitiligo, and even cancer (2). Recent observations show that even low energy visible light (LEVL) 1 can serve as a medical tool. For example, LEVL increases the rate of wound healing (3), enhances the fertilizing capability of sperm cells (4), and increases the rate of healing bone defects (5). In vitro studies have found that LEVL increases proliferation of cells as fibroblasts (6), keratinocytes (7), and lymphocytes (8) and induces the respiratory burst in neutrophils (9). The mechanism of photobiostimulation by LEVL is still unclear. It has been suggested that reactive oxygen species (ROS), which can be produced by photosensitization of endogenous cell chromophores such as cytochromes (10) [Ca 2ϩ ] i followed by myosin phosphorylation and cell contractions (26). Growth factors and hormones were shown to stimulate ROS production, which were dependent on [Ca 2ϩ ] i rise (27). The relationship between ROS and [Ca 2ϩ ] i has been suggested to involve the redox-sensitive transcription factor N␤, which was found to change [Ca 2ϩ ] i homeostasis in response to changes in the redox state of thiol groups (28). The kinetics that characterize the [Ca 2ϩ ] i elevation have been shown to be an important parameter determining the kind of signal that will be evoked. Livingston et al. (29) showed that high concentrations of oxidants (Ͼ50 M) caused a sustained increase in [Ca 2ϩ ] i , whereas a transient increase in [Ca 2ϩ ] i was observed following administration of a low concentration of oxidants. More than a 4-fold increase in the [Ca 2ϩ ] i level was obtained in photodynamic treatment of mouse myeloma cells that had been enriched with exogenous photosensitizers before illumination, whereas only a slight increase in [Ca 2ϩ ] i was observed in irradiated cells without exogenous photosensitizers (30).Only a few works have dealt with calcium/ROS changes following LEVL irradiation. In this study, we have investigated * The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.§ The article describes research performed by Ronit Lavi as partial fulfillment of the requirements for her Ph.D. degree at Bar-Ilan University. To whom correspondence should be addressed. Tel.: 972-3-5317797; Fax: 972-3-...