Flavones isolated from Pseudognaphalium liebmannii with tracheal smooth muscle relaxant properties.

The inflorescences of Pseudognaphalium liebmannii are used as folk medicine to treat various respiratory diseases. In this work, we report the isolation of seven known flavones: 5-hydroxy-3,7-dimethoxyflavone 1, 5,8-dihydroxy-3,7-dimethoxyflavone 2, 5,7-dihydroxy-3,8-dimethoxyflavone 3 (gnaphaliin A), 3,5-dihydroxy-7,8-dimethoxyflavone 4 (gnaphaliin B), 3,5-dihydroxy-6,7,8-trimethoxyflavone 5, 3,5,7-trimethoxyflavone 6 and 3-O-methylquercetin 7. All these flavones except 1 and 6 showed a relaxant effect on guinea pig tracheal preparation with EC50 between 69.91 ± 15.32 and 118.72 ± 7.06 µM. Aminophylline (EC50 = 122.03 ± 7.05 µM) was used as a relaxant reference drug. The active flavones shifted the concentration-response curves of forskolin and nitroprusside leftward, and significantly reduced the EC50 values of these drugs. Furthermore, these flavones dose-dependently inhibited phosphodiesterase (PDE) in an in vitro assay. This reveals that the inflorescences of P. liebmannii contain several flavones with relaxant effect on airway smooth muscle and with PDEs inhibition that contribute to supporting the anti-asthmatic traditional use.

Therapeutic Potential of Melatonin Counteracting Chemotherapy-Induced Toxicity in Breast Cancer Patients: A Systematic Review.

The purpose of this systematic review is to provide an overview of the existing knowledge on the therapeutic potential of melatonin to counteract the undesirable effects of chemotherapy in breast cancer patients. To this aim, we summarized and critically reviewed preclinical- and clinical-related evidence according to the PRISMA guidelines. Additionally, we developed an extrapolation of melatonin doses in animal studies to the human equivalent doses (HEDs) for randomized clinical trials (RCTs) with breast cancer patients. For the revision, 341 primary records were screened, which were reduced to 8 selected RCTs that met the inclusion criteria. We assembled the evidence drawn from these studies by analyzing the remaining gaps and treatment efficacy and suggested future translational research and clinical trials. Overall, the selected RCTs allow us to conclude that melatonin combined with standard chemotherapy lines would derive, at least, a better quality of life for breast cancer patients. Moreover, regular doses of 20 mg/day seemed to increase partial response and 1-year survival rates. Accordingly, this systematic review leads us to draw attention to the need for more RCTs to provide a comprehensive view of the promising actions of melatonin in breast cancer and, given the safety profile of this molecule, adequate translational doses should be established in further RCTs.

Aging-Related Ovarian Failure and Infertility: Melatonin to the Rescue.

Aging has a major detrimental effect on the optimal function of the ovary with changes in this organ preceding the age-related deterioration in other tissues, with the middle-aged shutdown leading to infertility. Reduced fertility and consequent inability to conceive by women in present-day societies who choose to have children later in life leads to increased frustration. Melatonin is known to have anti-aging properties related to its antioxidant and anti-inflammatory actions. Its higher follicular fluid levels relative to blood concentrations and its likely synthesis in the oocyte, granulosa, and luteal cells suggest that it is optimally positioned to interfere with age-associated deterioration of the ovary. Additionally, the end of the female reproductive span coincides with a significant reduction in endogenous melatonin levels. Thus, the aims are to review the literature indicating melatonin production in mitochondria of oocytes, granulosa cells, and luteal cells, identify the multiple processes underlying changes in the ovary, especially late in the cessation of the reproductive life span, summarize the physiological and molecular actions of melatonin in the maintenance of normal ovaries and in the aging ovaries, and integrate the acquired information into an explanation for considering melatonin in the treatment of age-related infertility. Use of supplemental melatonin may help preserve fertility later in life and alleviate frustration in women delaying childbearing age, reduce the necessity of in vitro fertilization-embryo transfer (IVF-ET) procedures, and help solve the progressively increasing problem of non-aging-related infertility in women throughout their reproductive life span. While additional research is needed to fully understand the effects of melatonin supplementation on potentially enhancing fertility, studies published to date suggest it may be a promising option for those struggling with infertility.

Potential of melatonin to reverse epigenetic aberrations in oral cancer: new findings.

It is now an accepted principle that epigenetic alterations cause cellular dyshomeostasis and functional changes, both of which are essential for the initiation and completion of the tumor cycle. Oral carcinogenesis is no exception in this regard, as most of the tumors in the different subsites of the oral cavity arise from the cross-reaction between (epi)genetic inheritance and the huge challenge of environmental stressors. Currently, the biochemical machinery is put at the service of the tumor program, halting the cell cycle, triggering uncontrolled proliferation, driving angiogenesis and resistance to apoptosis, until the archetypes of the tumor phenotype are reached. Melatonin has the ability to dynamically affect the epigenetic code. It has become accepted that melatonin can reverse (epi)genetic aberrations present in oral and other cancers, suggesting the possibility of enhancing the oncostatic capacity of standard multimodal treatments by incorporating this indolamine as an adjuvant. First steps in this direction confirm the potential of melatonin as a countermeasure to mitigate the detrimental side effects of conventional first-line radiochemotherapy. This single effect could produce synergies of extraordinary clinical importance, allowing doses to be increased and treatments not to be interrupted, ultimately improving patients' quality of life and prognosis. Motivated by the urgency of improving the medical management of oral cancer, many authors advocate moving from in vitro and preclinical research, where the bulk of melatonin cancer research is concentrated, to systematic randomized clinical trials on large cohorts. Recognizing the challenge to improve the clinical management of cancer, our motivation is to encourage comprehensive and robust research to reveal the clinical potential of melatonin in oral cancer control. To improve the outcome and quality of life of patients with oral cancer, here we provide the latest evidence of the oncolytic activity that melatonin can achieve by manipulating epigenetic patterns in oronasopharyngeal tissue.

Influence of the extraction method on the recovery of bioactive phenolic compounds from food industry by-products.

Agro-foodindustries generate colossal amounts of non-edible waste and by-products, easily accessible as raw materials for up-cycling active phytochemicals. Phenolic compounds are particularly relevant in this field given their abundance in plant residues and the market interest of their functionalities (e.g. natural antioxidant activity) as part of nutraceutical, cosmetological and biomedical formulations. In "bench-to-bedside" achievements, sample extraction is essential because valorization benefits from matrix desorption and solubilization of targeted phytocompounds. Specifically, the composition and polarity of the extractant, the optimal sample particle size and sample:solvent ratio, as well as pH, pressure and temperature are strategic for the release and stability of mobilized species. On the other hand, current green chemistry environmental rules require extraction approaches that eliminate polluting consumables and reduce energy needs. Thus, the following pages provide an update on advanced technologies for the sustainable and efficient recovery of phenolics from plant matrices.

The Coronavirus Disease 2019 (COVID-19): Key Emphasis on Melatonin Safety and Therapeutic Efficacy.

Viral infections constitute a tectonic convulsion in the normophysiology of the hosts. The current coronavirus disease 2019 (COVID-19) pandemic is not an exception, and therefore the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, like any other invading microbe, enacts a generalized immune response once the virus contacts the body. Melatonin is a systemic dealer that does not overlook any homeostasis disturbance, which consequently brings into play its cooperative triad, antioxidant, anti-inflammatory, and immune-stimulant backbone, to stop the infective cycle of SARS-CoV-2 or any other endogenous or exogenous threat. In COVID-19, the corporal propagation of SARS-CoV-2 involves an exacerbated oxidative activity and therefore the overproduction of great amounts of reactive oxygen and nitrogen species (RONS). The endorsement of melatonin as a possible protective agent against the current pandemic is indirectly supported by its widely demonstrated beneficial role in preclinical and clinical studies of other respiratory diseases. In addition, focusing the therapeutic action on strengthening the host protection responses in critical phases of the infective cycle makes it likely that multi-tasking melatonin will provide multi-protection, maintaining its efficacy against the virus variants that are already emerging and will emerge as long as SARS-CoV-2 continues to circulate among us.

Punica protopunica Balf., the Forgotten Sister of the Common Pomegranate (Punica granatum L.): Features and Medicinal Properties-A Review.

Punica protopunica Balf. is one of only two species housed by the Punica genera. Punica protopunica. Balf., known as Socotran pomegranate, is an endemic, isolated species found only in Socotra archipelago in the northwestern Indian Ocean, and is considered to be the ancestor of pomegranate. This review stems from the fact that in many Punica granatum L. articles, Punica protopunica Balf. is mentioned, but just in an informative way, without mentioning their taxonomic and genetic relationship and their medicinal properties. It is there where the need arises to know more about this forgotten species: "the other pomegranate tree." A large part of the human population does not know of its existence, since only its "sister" has spread throughout the world. The present review deals with the taxonomy and origin of Punica protopunica Balf., the morphology of the tree, distribution, cultivation, vulnerability, and as well as its relationship with Punica granatum L. It also discusses its uses in traditional medicine, its antioxidant capacity, and the medicinal properties of this forgotten species.

Potential of Melatonin as Adjuvant Therapy of Oral Cancer in the Era of Epigenomics.

The wide variety of epigenetic controls available is rapidly expanding the knowledge of molecular biology even overflowing it. At the same time, it can illuminate unsuspected ways of understanding the etiology of cancer. New emerging therapeutic horizons, then, promise to overcome the current antitumor strategies need. The translational utility of this complexity is particularly welcome in oral cancer (OC), in which natural history is alarmingly disappointing due to the invasive and mutilating surgery, the high relapsing rate, the poor quality of life and the reduced survival after diagnosis. Melatonin activates protective receptor-dependent and receptor-independent processes that prevent tissue cancerisation and inhibit progressive tumor malignancy and metastasis. Related evidence has shown that melatonin pleiotropy encompasses gene expression regulation through all the three best-characterized epigenetic mechanisms: DNA methylation, chromatin modification, and non-coding RNA. OC has received less attention than other cancers despite prognosis is usually negative and there are no significant therapy improvements recorded in the past decade. However, a large research effort is being carried out to elucidate how melatonin´s machinery can prevent epigenetic insults that lead to cancer. In the light of recent findings, a comprehensive examination of biochemistry through which melatonin may reverse epigenetic aberrations in OC is an extraordinary opportunity to take a step forward in the clinical management of patients.

Melatonin: A hypothesis for Kawasaki disease treatment.

Kawasaki disease (KD) is the most common cause of acquired heart disease with unknown etiology among children in developed countries. Acute inflammation of the vasculature, genetic susceptibility and immunopathogenesis based on a transmittable and infectious origin, are the pathologic events involved in the early inflammatory etiology and progression of this disease. However, the exact causes of KD remain unknown. Current proposed recommendations include three therapy lines; firstly, an initial standard therapy with intravenous immunoglobulin (IVIG) followed by aspirin. Secondly, in cases of high risk of coronary lesions, the adjunctive therapy with corticosteroid is commonly considered. Thirdly, in KD patients refractory to the previous therapies, tumor necrosis factor (TNF-α) antagonists are being used to modulate pro-inflammatory cytokines. In view of this status quo, our starting hypothesis is that the ubiquitous and non-toxic neurohormone melatonin could be of critical importance in developing novel adjuvant therapies against KD, as it occurs with a plethora of other diseases. Considering its pleiotropic properties, particularly its antiinflammatory and immunoregulatory capacities, melatonin should be of great therapeutic interest for helping to control the main pathologic features of KD patients. In addition, this multifunctional indole has a safe pharmacological profile, enhancing the therapeutic activity of several drugs and reducing their possible side effects. Consequently, melatonins actions to manage KD need to be tested in further clinical studies.

A History of the Pharmacological Treatment of Bipolar Disorder.

In this paper, the authors review the history of the pharmacological treatment of bipolar disorder, from the first nonspecific sedative agents introduced in the 19th and early 20th century, such as solanaceae alkaloids, bromides and barbiturates, to John Cade's experiments with lithium and the beginning of the so-called "Psychopharmacological Revolution" in the 1950s. We also describe the clinical studies and development processes, enabling the therapeutic introduction of pharmacological agents currently available for the treatment of bipolar disorder in its different phases and manifestations. Those drugs include lithium salts, valproic acid, carbamazepine, new antiepileptic drugs, basically lamotrigine and atypical antipsychotic agents (olanzapine, risperidone, quetiapine, ziprasidone, aripiprazole, asenapine, cariprazine and lurasidone). Finally, the socio-sanitary implications derived from the clinical introduction of these drugs are also discussed.

Melatonin as a versatile molecule to design novel multitarget hybrids against neurodegeneration.

Melatonin is an indoleamine produced mainly in the pineal gland. The natural decline of melatonin levels with aging strongly contributes to the development of neurodegenerative disorders. Pleiotropic actions displayed by melatonin prevent several processes involved in neurodegeneration such as neuroinflammation, oxidative stress, excitotoxicity and/or apoptosis. This review focuses on a number of melatonin hybrids resulting from the juxtaposition of tacrine, berberine, tamoxifen, curcumin, N,N-dibenzyl(N-methyl)amine, among others, with potential therapeutic effects for the treatment of neurodegenerative diseases.

The diet of the first Europeans from Atapuerca.

Hominin dietary specialization is crucial to understanding the evolutionary changes of craniofacial biomechanics and the interaction of food processing methods' effects on teeth. However, the diet-related dental wear processes of the earliest European hominins remain unknown because most of the academic attention has focused on Neandertals. Non-occlusal dental microwear provides direct evidence of the effect of chewed food particles on tooth enamel surfaces and reflects dietary signals over time. Here, we report for the first time the direct effect of dietary abrasiveness as evidenced by the buccal microwear patterns on the teeth of the Sima del Elefante-TE9 and Gran Dolina-TD6 Atapuerca hominins (1.2-0.8 million years ago - Myr) as compared with other Lower and Middle Pleistocene populations. A unique buccal microwear pattern that is found in Homo antecessor (0.96-0.8 Myr), a well-known cannibal species, indicates dietary practices that are consistent with the consumption of hard and brittle foods. Our findings confirm that the oldest European inhabitants ingested more mechanically-demanding diets than later populations because they were confronted with harsh, fluctuating environmental conditions. Furthermore, the influence of grit-laden food suggests that a high-quality meat diet from butchering processes could have fueled evolutionary changes in brain size.

Mechanism of action of relaxant effect of Agastache mexicana ssp.mexicana essential oil in guinea-pig trachea smooth muscle.

CONTEXT: Agastache mexicana ssp. mexicana (Kunth) Lint & Epling (Lamiaceae), popularly known as 'toronjil morado', is used in Mexican traditional medicine for the treatment of several diseases such as hypertension, anxiety and respiratory disorders. OBJECTIVE: This study investigates the relaxant action mechanism of A. mexicana ssp. mexicana essential oil (AMEO) in guinea-pig isolated trachea model. MATERIALS AND METHOD: AMEO was analyzed by GC/MS. The relaxant effect of AMEO (5-50 µg/mL) was tested in guinea-pig trachea pre-contracted with carbachol (3 × 10 - 6 M) or histamine (3 × 10 - 5 M) in the presence or absence of glibenclamide (10 - 5 M), propranolol (3 × 10 - 6 M) or 2',5'-dideoxyadenosine (10 - 5 M). The antagonist effect of AMEO (10-300 µg/mL) against contractions elicited by carbachol (10 - 15-10 - 3 M), histamine (10 - 15-10 - 3 M) or calcium (10-300 µg/mL) was evaluated. RESULTS: Essential oil composition was estragole, d-limonene and linalyl anthranilate. AMEO relaxed the carbachol (EC50 = 18.25 ± 1.03 µg/mL) and histamine (EC50 = 13.3 ± 1.02 µg/mL)-induced contractions. The relaxant effect of AMEO was not modified by the presence of propranolol, glibenclamide or 2',5'-dideoxyadenosine, suggesting that effect of AMEO is not related to ß2-adrenergic receptors, ATP-sensitive potassium channels or adenylate cyclase activation. AMEO was more potent to antagonize histamine (pA2' = -1.507 ± 0.122) than carbachol (pA2' = -2.180 ± 0.357). Also, AMEO antagonized the calcium chloride-induced contractions. CONCLUSION: The results suggest that relaxant effect of AMEO might be due to blockade of calcium influx in guinea-pig trachea smooth muscle. It is possible that estragole and d-limonene could contribute majority in the relaxant effect of AMEO.

Gnaphaliin A and gnaphaliin B synergize the relaxant effect of salbutamol but not of ipratropium in guinea pig trachea.

OBJECTIVE: This work was aimed to investigate the pharmacodynamic interactions between gnaphaliins A and B with ipratropium bromide (IBR) and salbutamol (SAL) using the guinea pig trachea model through application of the combination index (CI)-isobologram equation. METHODS: The guinea pig trachea rings in isolated chamber with Krebs-Henseleit solution (37°C) were contracted with carbachol (3 µm), and then, concentration-relaxant effect curves were constructed for individual drugs and in combination at fixed constant ratios (1 : 1, 3 : 1 and 1 : 3). Median effect and combination index (CI)-isobologram equations were used for determining interactions. KEY FINDINGS: Gnaphaliin A and gnaphaliin B showed clear synergistic interaction with salbutamol, reducing the dose of salbutamol more than sevenfolds to produce the same relaxant effect. However, the combination of either flavonoids with ipratropium bromide showed no interaction. CONCLUSIONS: Applying the combination index-isobologram method, we determined that gnaphaliin A and gnaphaliin B have synergistic effect with salbutamol due probably to their inhibitory effect on phosphodiesterases to maintain high levels of cAMP in the tracheal smooth muscle. However, these compounds did not show any effect with ipratropium.

Development of HuperTacrines as non-toxic, cholinesterase inhibitors for the potential treatment of Alzheimer's disease.

This paper describes our preliminary results on the ADMET, synthesis, biochemical evaluation, and molecular modeling of racemic HuperTacrines (HT), new hybrids resulting from the juxtaposition of huperzine A and tacrine for the potential treatment of Alzheimer's disease (AD). The synthesis of these HT was executed by Friedländer-type reactions of 2-amino-6-oxo-1,6-dihydropyridine-3-carbonitriles, or 7-amino-2-oxo-1,2,3,4-tetrahydro-1,6-naphthyridine- 8-carbonitriles, with cyclohexanone. In the biochemical evaluation, initial and particular attention was devoted to test their toxicity on human hepatoma cells, followed by the in vitro inhibition of human cholinesterases (hAChE, and hBuChE), and the kinetics/mechanism of the inhibition of the most potent HT; simultaneous molecular modeling on the best HT provided the key binding interactions with the human cholinesterases. >From these analyses, (±)-5-amino-3-methyl- 3,4,6,7,8,9-hexahydrobenzo[b][1,8]naphthyridin-2(1H)-one (HT1) and (±)-5-amino-3-(2,6-dichlorophenyl)-3,4,6,7,8,9- hexahydrobenzo[b][1,8]naphthyridin-2(1H)-one (HT3) have emerged as characterized by extremely low liver toxicity reversible mixed-type, selective hAChE and, quite selective irreversible hBuChEIs, respectively, showing also good druglike properties for AD-targeted drugs.

Assessment of paraspinal muscle hardness in subjects with a mild single scoliosis curve: a preliminary myotonometer study.

OBJECTIVE: The purpose of this study was to evaluate the hardness of the paraspinal muscles in the convexity and concavity of patients with scoliosis curvatures and in the upper trapezius (UT) muscle in subjects with mild idiopathic scoliosis (IS) and to observe the correlation between the myotonometer (MYO) measurements and the value of body mass index (BMI) and the Cobb angle. METHODS: The sample included 13 patients with a single-curve mild IS (Risser sign ≤ 4) at thoracic, lumbar, or thoracolumbar level (mean Cobb angle of 11.53º). Seven females and 6 males were recruited, with a mean age of 12.84 ± 3.06 (9-18) years. A MYO was used to examine the differences in muscle hardness on both sides of the scoliosis curvature at several points: (a) apex of the curve, (b) upper and lower limits of the curve, and (c) the midpoint between the apex and the upper limit and between the apex and the lower limit. The UT was also explored. RESULTS: Although the MYO recorded lower values in all points on the concave side of the scoliosis, there were no significant differences in the comparison between sides (P > .05). No association was observed between BMI and MYO values, whereas the Cobb angle negatively correlated with muscle hardness only at 2 points on the convex side. CONCLUSION: The preliminary findings show that, in subjects with a single-curve mild IS, muscular hardness in the UT and paraspinal muscles, as assessed using a MYO, was not found to differ between the concave and the convex sides at different reference levels.

Toxic rather than neuropharmacological effect of Ternstroemia sylvatica fruits and identification of 28-O-[ß-l-6-rhamnopyranosyl]-R1-barrigenol as a new compound with toxic effects in mice.

CONTEXT: Fruits of Ternstroemia sylvatica Schltdl. and Cham. (Theaceae) are used in Mexican traditional medicine to alleviate anxiety, sleep disorders and seizures; however, the active principles have not been identified. OBJECTIVE: To identify the neuroactive principles of T. sylvatica fruits using neuropharmacological tests on mice. MATERIALS AND METHODS: The methanol and aqueous extracts of pericarp or seeds of T. sylvatica fruits were intraperitoneally administered (1-562 mg/kg, single doses) to mice. The exploratory cylinder, hole board, open field, Rota-rod and sodium pentobarbital-induced hypnosis tests were used to evaluate the CNS depressant effect after 30 min single administration of extracts. From aqueous seeds extract, triterpene glycoside 28-O-[ß-l-6-rhamnopyranosyl]-R1-barrigenol was isolated an active compound. RESULTS: Crude extracts of T. sylvatica fruits, separated from seed and pericarp, showed sedative effect in mice. The aqueous (ED50 = 4.9 ± 0.8 mg/kg) seed extracts is the most active among them. This extract also decrease locomotor activity and disrupt motor coordination of mice. This extract was also the most toxic extract (LD50 = 5.0 ± 1.4 mg/kg; i.p.). The triterpene glycoside 28-O-[ß-l-6-rhamnopyranosyl]-R1-barrigenol was identified in this extract as one of the active sedative compounds (ED50 = 0.12 ± 0.01 mg/kg) also with toxic effect (LD50 = 1.11 ± 0.23 mg/kg). CONCLUSION: The results suggest that T. sylvatica fruits has toxic activity rather than CNS depressant activity in mice and that this effect might be related to the presence of 28-O-[ß-l-6-rhamnopyranosyl]-R1-barrigenol, one of the active principles of T. sylvatica fruits with sedative and toxic effect.

PP2A ligand ITH12246 protects against memory impairment and focal cerebral ischemia in mice.

ITH12246 (ethyl 5-amino-2-methyl-6,7,8,9-tetrahydrobenzo[b][1,8]naphthyridine-3-carboxylate) is a 1,8-naphthyridine described to feature an interesting neuroprotective profile in in vitro models of Alzheimer's disease. These effects were proposed to be due in part to a regulatory action on protein phosphatase 2A inhibition, as it prevented binding of its inhibitor okadaic acid. We decided to investigate the pharmacological properties of ITH12246, evaluating its ability to counteract the memory impairment evoked by scopolamine, a muscarinic antagonist described to promote memory loss, as well as to reduce the infarct volume in mice suffering phototrombosis. Prior to conducting these experiments, we confirmed its in vitro neuroprotective activity against both oxidative stress and Ca(2+) overload-derived excitotoxicity, using SH-SY5Y neuroblastoma cells and rat hippocampal slices. Using a predictive model of blood-brain barrier crossing, it seems that the passage of ITH12246 is not hindered. Its potential hepatotoxicity was observed only at very high concentrations, from 0.1 mM. ITH12246, at the concentration of 10 mg/kg i.p., was able to improve the memory index of mice treated with scopolamine, from 0.22 to 0.35, in a similar fashion to the well-known Alzheimer's disease drug galantamine 2.5 mg/kg. On the other hand, ITH12246, at the concentration of 2.5 mg/kg, reduced the phototrombosis-triggered infarct volume by 67%. In the same experimental conditions, 15 mg/kg melatonin, used as control standard, reduced the infarct volume by 30%. All of these findings allow us to consider ITH12246 as a new potential drug for the treatment of neurodegenerative diseases, which would act as a multifactorial neuroprotectant.

Land- and water-based exercise intervention in women with fibromyalgia: the al-Andalus physical activity randomised controlled trial.

BACKGROUND: The al-Andalus physical activity intervention study is a randomised control trial to investigate the effectiveness of a land- and water-based exercise intervention for reducing the overall impact of fibromyalgia (primary outcome), and for improving tenderness and pain-related measures, body composition, functional capacity, physical activity and sedentary behaviour, fatigue, sleep quality, health-related quality of life, and cognitive function (secondary outcomes) in women with fibromyalgia. METHODS/DESIGN: One hundred eighty women with fibromyalgia (age range: 35-65 years) will be recruited from local associations of fibromyalgia patients in Andalucía (Southern Spain). Patients will be randomly assigned to a usual care (control) group (n = 60), a water-based exercise intervention group (n = 60) or a land-based exercise intervention group (n = 60). Participants in the usual care group will receive general physical activity guidelines and participants allocated in the intervention groups will attend three non-consecutive training sessions (60 min each) per week during 24 weeks. Both exercise interventions will consist of aerobic, muscular strength and flexibility exercises. We will also study the effect of a detraining period (i.e., 12 weeks with no exercise intervention) on the studied variables. DISCUSSION: Our study attempts to reduce the impact of fibromyalgia and improve patients' health status by implementing two types of exercise interventions. Results from this study will help to assess the efficacy of exercise interventions for the treatment of fibromyalgia. If the interventions would be effective, this study will provide low-cost and feasible alternatives for health professionals in the management of fibromyalgia. Results from the al-Andalus physical activity intervention will help to better understand the potential of regular physical activity for improving the well-being of women with fibromyalgia. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01490281.