Melatonin and mitochondrial function during ischemia/reperfusion injury

Ischemia/reperfusion (IR) injury occurs in many organs and tissues, and contributes to morbidity and mortality worldwide. Melatonin, an endogenously produced indolamine, provides a strong defense against IR injury. Mitochondrion, an organelle for ATP production and a decider for cell fate, has been validated to be a crucial target for melatonin to exert its protection against IR injury. In this review, we first clarify the mechanisms underlying mitochondrial dysfunction during IR and melatonin’s protection of mitochondria under this condition. Thereafter, special focus is placed on the protective actions of melatonin against IR injury in brain, heart, liver, and others. Finally, we explore several potential future directions of research in this area. Collectively, the information compiled here will serve as a comprehensive reference for the actions of melatonin in IR injury identified to date and will hopefully aid in the design of future research and increase the potential of melatonin as a therapeutic agent.     

Allometric cascade as a unifying principle of body mass effects on metabolism

The power function of basal metabolic rate scaling is expressed as aM(b), where a corresponds to a scaling constant (intercept), M is body mass, and b is the scaling exponent. The 3/4 power law (the best-fit b value for mammals) was developed from Kleiber's original analysis and, since then, most workers have searched for a single cause to explain the observed allometry. Here we present a multiple-causes model of allometry, where the exponent b is the sum of the influences of multiple contributors to metabolism and control. The relative strength of each contributor, with its own characteristic exponent value, is determined by the control contribution. To illustrate its use, we apply this model to maximum versus basal metabolic rates to explain the differing scaling behaviour of these two biological states in mammals. The main difference in scaling is that, for the basal metabolic rate, the O(2) delivery steps contribute almost nothing to the global b scaling exponent, whereas for the maximum metabolic rate, the O(2) delivery steps significantly increase the global b value.     

Molecular mechanisms of melatonin’s inhibitory actions on breast cancers

Melatonin is involved in many physiological functions and it plays an important role in many pathological processes as well. Melatonin has been shown to reduce the incidence of experimentally induced cancers and can significantly inhibit the growth of some human tumors, namely hormone-dependent cancers. The anticancer effects of melatonin have been observed in breast cancer, both in in vivo with models of chemically induced rat mammary tumors, and in vitro studies on human breast cancer cell lines. Melatonin acts at different physiological levels and its antitumoral properties are supported by a set of complex, different mechanisms of action, involving apoptosis activation, inhibition of proliferation, and cell differentiation.     

Extrapineal melatonin: sources,regulation, and potential functions

Endogenous melatonin is synthesized from tryptophan via 5-hydroxytryptamine. It is considered an indoleamine from a biochemical point of view because the melatonin molecule contains a substituted indolic ring with an amino group. The circadian production of melatonin by the pineal gland explains its chronobiotic influence on organismal activity, including the endocrine and non-endocrine rhythms. Other functions of melatonin, including its antioxidant and anti-inflammatory properties, its genomic effects, and its capacity to modulate mitochondrial homeostasis, are linked to the redox status of cells and tissues. With the aid of specific melatonin antibodies, the presence of melatonin has been detected in multiple extrapineal tissues including the brain, retina, lens, cochlea, Harderian gland, airway epithelium, skin, gastrointestinal tract, liver, kidney, thyroid, pancreas, thymus, spleen, immune system cells, carotid body, reproductive tract, and endothelial cells. In most of these tissues, the melatonin-synthesizing enzymes have been identified. Melatonin is present in essentially all biological fluids including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk. In several of these fluids, melatonin concentrations exceed those in the blood. The importance of the continual availability of melatonin at the cellular level is important for its physiological regulation of cell homeostasis, and may be relevant to its therapeutic applications. Because of this, it is essential to compile information related to its peripheral production and regulation of this ubiquitously acting indoleamine. Thus, this review emphasizes the presence of melatonin in extrapineal organs, tissues, and fluids of mammals including humans.     

Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas

Melatonin is an ancient antioxidant. After its initial development in bacteria, it has been retained throughout evolution such that it may be or may have been present in every species that have existed. Even though it has been maintained throughout evolution during the diversification of species, melatonin’s chemical structure has never changed; thus, the melatonin present in currently living humans is identical to that present in cyanobacteria that have existed on Earth for billions of years. Melatonin in the systemic circulation of mammals quickly disappears from the blood presumably due to its uptake by cells, particularly when they are under high oxidative stress conditions. The measurement of the subcellular distribution of melatonin has shown that the concentration of this indole in the mitochondria greatly exceeds that in the blood. Melatonin presumably enters mitochondria through oligopeptide transporters, PEPT1, and PEPT2. Thus, melatonin is specifically targeted to the mitochondria where it seems to function as an apex antioxidant. In addition to being taken up from the circulation, melatonin may be produced in the mitochondria as well. During evolution, mitochondria likely originated when melatonin-forming bacteria were engulfed as food by ancestral prokaryotes. Over time, engulfed bacteria evolved into mitochondria; this is known as the endosymbiotic theory of the origin of mitochondria. When they did so, the mitochondria retained the ability to synthesize melatonin. Thus, melatonin is not only taken up by mitochondria but these organelles, in addition to many other functions, also probably produce melatonin as well. Melatonin’s high concentrations and multiple actions as an antioxidant provide potent antioxidant protection to these organelles which are exposed to abundant free radicals.     

ALKALINE PULP OF CORN STALKS

Pulping of corn stalks was studied in soda,soda-anthraquinone (AQ), kraft and kraft-AQ processes. The time, temperature and alkali concentration were varied in soda process. In respect to kappa number and pulp yield, 1 hour cooking at 1400C in 14% alkali were best conditions for corn stalks pulping. Pulp yield was increased by 5.5% and kappa number was reduced by 4.4 points with an addition of 0.05% AQ in the soda liquor. Breaking length was better in soda-AQ process than soda process but tear strength was inferior. In the kraft process, pulp yield was increased with increasing sulphidity and decreasing active alkali. The effectiveness of AQ in the low and high sulphidity kraft process was studied. Results showed that AQ was more effective in low sulphidity than high sulphidity. Strength properties in kraft processes were better than the soda and soda-AQ processes.     

The effect of polyphloretin phosphate,polyoestradiol phosphate,a diphosphonate and a polyphosphate on calcification induced by dihydrotachysterol in skin,aorta and kidney of rats

Zusammenfassung Zwei Phosphatasehemmer (Polyphloretinphosphat und Polyoestradiolphosphat), ein Polyphosphat (Hexametaphosphat) und ein Diphosphonat (Ethan-1-hydroxy-1,1-diphosphonat) wurden auf ihre Fähigkeit untersucht, Verkalkungen zu verhindern, welche in der Haut, der Aorta und den Nieren von Ratten durch Dihydrotachysterol (DHT) hervorgerufen wurden. Das Diphosphonat erwies sich als der stärkste Hemmer; dann folgten das Polyphosphat und die zwei Phosphatasehemmer. Die Phosphatasehemmer wurden zusätzlich auf ihre Fähigkeit geprüft, die Calciumphosphat-Ausfällung in vitro zu verlangsamen. Polyphloretinphosphat besitzt diese Fähigkeit bei Konzentrationen von 10^–5 M und mehr; Polyoestradiolphosphat ist unwirksam.

---

---

Acknowledgments. This work has been supported by the Swiss National Fund, Grant No. 4564, the U.S. Public Health Service, Grant No. 07266, AB Leo, Hälsingborg, Sweden, and Procter and Gamble Company, Cincinnati, USA.