Impact of Melatonin Supplementation in Women with Unexplained Infertility Undergoing Fertility Treatment.

Unexplained infertility occurs when common causes for a couple's inability to conceive have been excluded. Although origins of idiopathic infertility are still unclear, factors, such as an altered oxidative balance, are believed to be involved. Melatonin is an outstanding antioxidant reportedly present in the follicular fluid (FF), which has been suggested as a useful tool in the management of human fertility. Herein, we observed that intrafollicular concentrations of melatonin were blunted in women with unexplained infertility (UI), which was associated with a marked oxidative imbalance in UI patients' FF. Based on these findings, this randomized pilot study was aimed at assessing whether exogenous melatonin ameliorated oxidative stress and improved in vitro fertilization (IVF) success rates in UI. Thus, 3 mg/day or 6 mg/day of melatonin were given to UI patients for a period spanning from the first appointment to control ovarian stimulation until the day of follicular puncture. Our results indicate that melatonin supplementation, irrespective of the two doses tested, ameliorated intrafollicular oxidative balance and oocyte quality in UI patients, and that this translated into a slight increase in the rate of pregnancies/live births. Therefore, although the indoleamine has shown therapeutic potential in this clinical setting, larger clinical trials in populations with different backgrounds are encouraged to corroborate the usefulness of melatonin.

Neuropathic Pain: Delving into the Oxidative Origin and the Possible Implication of Transient Receptor Potential Channels.

Currently, neuropathic pain is an underestimated socioeconomic health problem affecting millions of people worldwide, which incidence may increase in the next years due to chronification of several diseases, such as cancer and diabetes. Growing evidence links neuropathic pain present in several disorders [i.e., spinal cord injury (SCI), cancer, diabetes and alcoholism] to central sensitization, as a global result of mitochondrial dysfunction induced by oxidative and nitrosative stress. Additionally, inflammatory signals and the overload in intracellular calcium ion could be also implicated in this complex network that has not yet been elucidated. Recently, calcium channels namely transient receptor potential (TRP) superfamily, including members of the subfamilies A (TRAP1), M (TRPM2 and 7), and V (TRPV1 and 4), have demonstrated to play a role in the nociception mediated by sensory neurons. Therefore, as neuropathic pain could be a consequence of the imbalance between reactive oxygen species and endogen antioxidants, antioxidant supplementation may be a treatment option. This kind of therapy would exert its beneficial action through antioxidant and immunoregulatory functions, optimizing mitochondrial function and even increasing the biogenesis of this vital organelle; on balance, antioxidant supplementation would improve the patient's quality of life. This review seeks to deepen on current knowledge about neuropathic pain, summarizing clinical conditions and probable causes, the relationship existing between oxidative stress, mitochondrial dysfunction and TRP channels activation, and scientific evidence related to antioxidant supplementation.

Exogenous melatonin supplementation prevents oxidative stress-evoked DNA damage in human spermatozoa.

Reactive oxygen species (ROS) are essential for sperm physiological functions such as capacitation, hyperactivation, and acrosome reaction, on the one hand, and for stimulating the apoptotic processes involved in the regulation of spermatogenesis, on the other hand. However, the imbalance between production and removal of ROS leads to oxidative stress, which is referred to as one of the main factors involved in male infertility. The pineal hormone melatonin, given its low toxicity and well-known antioxidant capacity, could be an excellent candidate to improve sperm quality. For this reason, the objective of the present work was to analyze whether long-term supplementation with melatonin to infertile men affects human sperm quality and the quality of the embryos retrieved from their couples. Our findings showed that the daily supplementation of 6 mg melatonin, as early as after 45 days of treatment, produced an increase in melatonin endogenous levels, indirectly measured as urinary 6-sulfatoxymelatonin (aMT6-s), an enhancement of both urinary and seminal total antioxidant capacity, and a consequent reduction in oxidative damage caused in sperm DNA. Moreover, couples whose men were given melatonin showed a statistically significant increase in the percentage of grade A (embryo with blastomeres of equal size; no cytoplasmic fragmentation), B (embryo with blastomeres of equal size; minor cytoplasmic fragmentation), and C (embryo with blastomeres of distinctly unequal size; significant cytoplasmic fragmentation) embryos at the expense of grade D (embryo with blastomeres of equal or unequal size; severe or complete fragmentation.) embryos which were clearly reduced. In summary, melatonin supplementation improves human sperm quality, which is essential to achieve successful natural and/or assisted reproduction outcome.

Effect of lycopene-enriched olive and argan oils upon lipid serum parameters in Wistar rats.

BACKGROUND: Lycopene has the highest antioxidant activity within carotenoids and is an effective free radical scavenger. Virgin olive oil (VOO) and argan oil (AO) contain trace amounts of a wide variety of phytochemicals which have desirable nutritional properties. The present study intended to assess the effect of various dietary VOO and AO in combination with lycopene consumption on serum biochemical parameters, including total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglycerides (TGs) and phospholipids, as well as on hepatosomatic index (HSI) of rats. RESULTS: Results showed that ingestion of VOO and AO diminished TC, LDL-C, TGs and phospholipid levels, whereas the HDL-C levels augmented in all the groups assayed. The enrichment of VOO and AO with lycopene improved the beneficial effects derived from the consumption of both oils on serum biochemical parameters. A decrease in body weight gain and HSI was detected after the consumption of lycopene-enriched oils. CONCLUSION: These findings suggest that the inclusion of lycopene in VOO and AO may be used as a natural tool to fight against hyperlipidaemic and hypercholesterolaemic-derived disorders.

Chemopreventive effects of resveratrol in a rat model of cerulein-induced acute pancreatitis.

In the past decades, a greater understanding of acute pancreatitis has led to improvement in mortality rates. Nevertheless, this disease continues to be a health care system problem due to its economical costs. Future strategies such as antioxidant supplementation could be very promising, regarding to beginning and progression of the disease. For this reason, this study was aimed at assessing the effect of exogenous administration of resveratrol during the induction process of acute pancreatitis caused by the cholecystokinin analog cerulein in rats. Resveratrol pretreatment reduced histological damage induced by cerulein treatment, as well as hyperamylasemia and hyperlipidemia. Altered levels of corticosterone, total antioxidant status, and glutathione peroxidase were significantly reverted to control levels by the administration of resveratrol. Lipid peroxidation was also counteracted; nevertheless, superoxide dismutase enzyme was overexpressed due to resveratrol pretreatment. Related to immune response, resveratrol pretreatment reduced pro-inflammatory cytokine IL-1ß levels and increased anti-inflammatory cytokine IL-10 levels. In addition, pretreatment with resveratrol in cerulein-induced pancreatitis rats was able to reverse, at least partially, the abnormal calcium signal induced by treatment with cerulein. In conclusion, this study confirms antioxidant and immunomodulatory properties of resveratrol as chemopreventive in cerulein-induced acute pancreatitis.

Tempranillo-derived grape seed extract induces apoptotic cell death and cell growth arrest in human promyelocytic leukemia HL-60 cells.

Although grape seed extract (GSE) has proven to be effective against various cancers, few studies have investigated the effects of GSE on human leukemia. In this study, we analysed the mechanisms involved in the apoptotic effects induced by GSE on human promyelocytic leukemia HL-60 cells. Thus, GSE treatment succeeded in activating caspase-3 (P < 0.05), the activation being dose-dependent and time-dependent. Activation of caspase-3 induced by GSE was accompanied by mitochondrial membrane depolarization (P < 0.05). Moreover, disruption of mitochondrial integrity caused by GSE treatment subsequently led to activation of caspase-9 (P < 0.05), and also produced a slight increase in ROS levels (P < 0.05). Cytotoxic effects elicited by GSE treatment ultimately resulted in extensive S-phase arrest (P < 0.05) and a substantial increase in the intrinsic rate of apoptosis (P < 0.05). Our findings suggest that the GSE induces apoptotic cell death and cell growth inhibition in human leukemic HL-60 cells, which seems to be dependent on mitochondrial damage. Therefore, the GSE obtained from Tempranillo cultivars could be an effective approach to restrain uncontrolled cell proliferation and survival in leukemia cells.

Interferential laser therapy in the treatment of shoulder pain and disability from musculoskeletal pathologies: a randomised comparative study.

BACKGROUND: Interference is an important feature of the waves. When two or more in phase light waves meet, a new and reinforced wave is generated. Shoulder pain is a common clinical problem and laser is one of the treatments frequently used to relieve it. OBJECTIVE: To test the safety of interferential laser therapy generated by two independent low level lasers and compare its effectiveness with conventional single laser therapy in the reduction of shoulder musculoskeletal pain and associated disability. DESIGN: Randomised and single-blind controlled clinical trial. SETTING: Physiotherapy Unit and Rehabilitation Department of Ramon y Cajal University Hospital (Madrid). PARTICIPANTS: 200 patients with shoulder musculoskeletal pain were randomly assigned in two groups, 100 people each. INTERVENTIONS: Group I, experimental (n=100) received interferential laser, placing two probes opposite each other over the shoulder joint. Group II, control (n=100) received conventional laser therapy, using a single probe along with a second inactive dummy probe. Lasers used were GaAlAs diode (810 nm, 100 mW), in continuous emission. Laser was applied in contact mode through ten sessions, on 5 shoulder points (7 Joules/point) per session. MAIN OUTCOME MEASURES: visual analogue scale (VAS) score and shoulder pain disability index (SPADI), recorded before and after laser treatment. RESULTS: There were no differences between both groups in the reduction of pain, either assessed by VAS scale (median difference=0, 95% CI of the difference = -.6 to .5, p = 0.81) or SPADI index (median difference = .4, 95% CI of the difference = -2.9 to 3.8, p = 0.80), using the Mann-Whitney U-test. Comparison between the scores recorded before and after the treatment, within each group, showed significant differences for VAS during movement (median difference=3, 95% CI of the difference = 2.07 to 4, p < 0.001) and SPADI index (median difference=3.5, 95% CI of the difference = 2.67 to 3.85, Wilcoxon test, p < 0.001), for both groups. CONCLUSIONS: In this study, the application of two low level lasers in order to generate interference inside the irradiated tissue showed to be a safe therapy. Both interferential and conventional laser therapy reduced shoulder pain and disability. Nevertheless, differences between them were not detected. Future research in this field could include applying this technique with other laser parameters or application forms.

Oxidative stress and immunosenescence: therapeutic effects of melatonin.

Age-associated deterioration in the immune system, which is referred to as immunosenescence, contributes to an increased susceptibility to infectious diseases, autoimmunity, and cancer in the elderly. A summary of major changes associated with aging in immune system is described in this paper. In general, immunosenescence is characterized by reduced levels of peripheral naïve T cells derived from thymus and the loss of immature B lineage cells in the bone marrow. As for macrophages and granulocytes, they show functional decline with advancing age as evidenced by their diminished phagocytic activity and impairment of superoxide generation. The indole melatonin is mainly secreted in the pineal gland although it has been also detected in many other tissues. As circulating melatonin decreases with age coinciding with the age-related decline of the immune system, much interest has been focused on melatonin's immunomodulatory effect in recent years. Here, we underlie the antioxidant and immunoenhancing actions displayed by melatonin, thereby providing evidence for the potential application of this indoleamine as a "replacement therapy" to limit or reverse some of the effects of the changes that occur during immunosenescence.

Urinary 6-sulfatoxymelatonin and total antioxidant capacity increase after the intake of a grape juice cv. Tempranillo stabilized with HHP.

Red grapes contain elevated amounts of antioxidant compounds (polyphenols) that may potentially prevent cell aging, cardiovascular disease and oxidation-related disorders. Since functional drinks are presently one of the most dynamic sectors of the market, the present work was aimed at evaluating the possible antioxidant effect of an experimental grape juice in terms of urinary 6-sulfatoxymelatonin (aMT6-s) and total antioxidant capacity in young (20 ± 10 yr-old), middle-aged (45 ± 10 yr-old) and elderly (75 ± 10 yr-old) individuals. Grapes (Vitis vinifera cv. Tempranillo) were de-stemmed, racked and pressed. The juice was subsequently stabilized by high hydrostatic pressure (HHP). Participants consumed 200 mL of grape juice twice a day (as the lunch and dinner desserts) for 5 days. First-void morning urines were collected before treatment (basal values), the day immediately after the last ingestion of juice (assay), and one day afterwards (post-assay). aMT6-s and total antioxidant capacity were quantified using commercial ELISA and colorimetric assay kits, respectively. The intake of grape juice cv. Tempranillo induced a significant increase of urinary aMT6-s and total antioxidant capacity in the three groups of age analyzed as compared to their corresponding basal and post-assay values. These functional/nutraceutical properties may be of interest for a prospective commercialization of the grape juice. The novel technology used for juice stabilization may be suitable for introducing into the market a product with high sensory and nutritional quality, as it has been shown in this study.

Melatonin is able to delay endoplasmic reticulum stress-induced apoptosis in leukocytes from elderly humans.

The mechanisms regulating neutrophil apoptosis are basically unaffected by the aging process. However, a significant impairment of cell survival occurs in elderly individuals following neutrophil challenge with pro-inflammatory stimuli, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). The goal of the present study was to prove the effects of melatonin supplementation on apoptosis induced by calcium signaling in human leukocytes from elderly volunteers. Treatments with the specific inhibitor of cytosolic calcium re-uptake, thapsigargin, and/or the calcium mobilizing agonist, N-formyl-methionyl-leucyl-phenylalanine (fMLP), induced mitochondrial membrane depolarization, caspase activation, phosphatidylserine (PS) externalization, and DNA fragmentation in leukocytes from both young and elderly volunteers, although such effects were much more evident in aged leukocytes. Importantly, melatonin treatment substantially preserved mitochondrial membrane potential, reversed caspase activation, reduced PS exposure and forestalled DNA fragmentation in leukocytes from both age groups. In conclusion, melatonin is able to delay endoplasmic reticulum stress-induced apoptosis in aged leukocytes and may counteract, at the cellular level, age-related degenerative phenomena linked to oxidative stress.

Assessment of the Potential Role of Tryptophan as the Precursor of Serotonin and Melatonin for the Aged Sleep-wake Cycle and Immune Function: Streptopelia Risoria as a Model.

In the present review we summarize the relationship between the amino acid, tryptophan, the neurotransmitter, serotonin, and the indole, melatonin, with the rhythms of sleep/wake and the immune response along with the possible connections between the alterations in these rhythms due to aging and the so-called "serotonin and melatonin deficiency state." The decrease associated with aging of the brain and circulating levels of serotonin and melatonin seemingly contributes to the alterations of both the sleep/wake cycle and the immune response that typically accompany old age. The supplemental administration of tryptophan, e.g. the inclusion of tryptophan-enriched food in the diet, might help to remediate these age-related alterations due to its capacity of raise the serotonin and melatonin levels in the brain and blood. Herein, we also summarize a set of studies related to the potential role that tryptophan, and its derived product melatonin, may play in the restoration of the aged circadian rhythms of sleep/wake and immune response, taking the ringdove (Streptopeliarisoria) as a suitable model.

Chrononutrition applied to formula milks to consolidate infants' sleep/wake cycle.

UNLABELLED: Some 30% of pre-weaning infants present problems of sleep during the night, especially those who are bottle-fed. The solution is for them to be breast-fed for as long as possible, or, if this is not possible, for the formula milk to reproduce breast-milk's natural circadian variations in the concentrations of tryptophan and those nucleotides which have a beneficial effect in consolidating the circadian sleep-wake cycle. OBJECTIVE: To study in pre-weaning infants the effect on nocturnal sleep of the administration of formula milk dissociated into its day/night components. MATERIALS AND METHODS: A prospective study was carried out on 30 pre-weaning infants of 4-20 weeks in age who preferentially showed sleep problems. The day dissociated formula, administered from 06:00-18:00, had lower levels of tryptophan and carbohydrates, and higher levels of proteins together with cytosine-5P, guanosine-5P, and inosine-5P. The night dissociated formula, administered from 18:00-06:00, had lower levels of proteins and medium-chain triglycerides, higher levels of tryptophan and carbohydrates, together with adenosine-5P and uridine-5P. In a random, double-blind, design, three one-week diets were administered: Diet A (Control): normal initiation milk; Diet B: 06:00-18:00 normal initiation milk, 18:00-06:00 dissociated night formula; and Diet C: day/night formulas with the schedule given above. The sleep patterns were analyzed by means of actimeters (Actiwatch). Statistical analysis consisted of an ANOVA with a Scheffe F-test, taking a value of p<0.05 to be statistically significant. RESULTS: The children receiving the week of Diet C (with the day/night formulas in synchrony with the environment) showed increased hours of actual sleep (7.68 +/- 0.54 h vs. 6.77 +/- 0.12 h for the Diet A control) and improved sleep latency (0.44 +/- 0.04 h vs. 0.60 +/- 0.08 h for the Diet A control). The same children receiving the Diet B in another different week showed an improvement in sleep efficiency (76.43 +/- 3.4% vs. the Diet A control 69.86 +/- 0.94%) and sleep latency (0.45 +/- 0.04 h vs. the Diet A control 0.60 +/- 0.08h) The parents also reported, in response to follow-up questions, an improvement in the sleep of their infants during the Diet C week. CONCLUSION: Day/night infant formula milks designed according to the principles of chrononutrition help to consolidate the sleep/wake rhythm in bottle-fed infants.

Tratamiento homeopático de las cefaleas vasculares primarias en servicio de urgencias / Homeopathic treatment of vascular cephaleas in the emergency service

Se realizó un ensayo clínico aleatorizado fase II temprana, abierto, secuencial para evaluar la eficacia de los remedios homeopáticos en los pacientes que acudieron a consulta por cefalea vascular primaria al cuerpo de guardia del Policlínico "Carlos J. Finlay" y a la consulta de medicina natural y tradicional del Hospital "Octavio de la Concepción y de la Pedraja" en el período comprendido entre octubre de 1997 hasta noviembre de 1998. La muestra se recogió de 60 pacientes entre los 15 y 60 años de edad, a los que se les aplicó una encuesta. Los datos se procesaron de forma computarizada y se expusieron en textos y gráficos. Mediante esta terapéutica se logró la desaparición de la cefalea en el 85% y su alivio en el 15% de los pacientes. De 142 síntomas neurovegetativos combinados se logró la desaparición de 121 (85.2%) y el alivio de 21 (14.7%); por los resultados obtenidos se concluye considerando el esquema propuesto como útil, eficaz e inócuo.

An open early phase II ramdomized clinical trial was carried out to evaluate homeopathic medications in patients treated for primary vascular cephalea at the emergency room of "Carlos Juan Finlay" Clinic and at the Natural and Traditional Medicine Department in the Öctavio de la Concepcion y de la Pedraja" Hospital from October 1997 to November 1998. The sample was taken from 60 patients aged 15 to 60 years. Data were collected and processed in a computer and later represented into graphics and charts. Due to the afore mentioned, cephalea dissapeared in 85% of patients while 15% relieved. 121 out of the 142 combined neurovegetative symptoms dissapear and 21 aliviated. Taking into account these results, it can be said that the suggested treatment is useful, accurate and inoccous.