Psycho-Neuro-Endocrine-Immunological Basis of the Placebo Effect: Potential Applications beyond Pain Therapy.

The placebo effect can be defined as the improvement of symptoms in a patient after the administration of an innocuous substance in a context that induces expectations regarding its effects. During recent years, it has been discovered that the placebo response not only has neurobiological functions on analgesia, but that it is also capable of generating effects on the immune and endocrine systems. The possible integration of changes in different systems of the organism could favor the well-being of the individuals and go hand in hand with conventional treatment for multiple diseases. In this sense, classic conditioning and setting expectations stand out as psychological mechanisms implicated in the placebo effect. Recent advances in neuroimaging studies suggest a relationship between the placebo response and the opioid, cannabinoid, and monoaminergic systems. Likewise, a possible immune response conditioned by the placebo effect has been reported. There is evidence of immune suppression conditioned through the insular cortex and the amygdala, with noradrenalin as the responsible neurotransmitter. Finally, a conditioned response in the secretion of different hormones has been determined in different studies; however, the molecular mechanisms involved are not entirely known. Beyond studies about its mechanism of action, the placebo effect has proved to be useful in the clinical setting with promising results in the management of neurological, psychiatric, and immunologic disorders. However, more research is needed to better characterize its potential use. This review integrates current knowledge about the psycho-neuro-endocrine-immune basis of the placebo effect and its possible clinical applications.

Specialized Pro-Resolving Lipid Mediators: The Future of Chronic Pain Therapy?

Chronic pain (CP) is a severe clinical entity with devastating physical and emotional consequences for patients, which can occur in a myriad of diseases. Often, conventional treatment approaches appear to be insufficient for its management. Moreover, considering the adverse effects of traditional analgesic treatments, specialized pro-resolving lipid mediators (SPMs) have emerged as a promising alternative for CP. These include various bioactive molecules such as resolvins, maresins, and protectins, derived from ω-3 polyunsaturated fatty acids (PUFAs); and lipoxins, produced from ω-6 PUFAs. Indeed, SPMs have been demonstrated to play a central role in the regulation and resolution of the inflammation associated with CP. Furthermore, these molecules can modulate neuroinflammation and thus inhibit central and peripheral sensitizations, as well as long-term potentiation, via immunomodulation and regulation of nociceptor activity and neuronal pathways. In this context, preclinical and clinical studies have evidenced that the use of SPMs is beneficial in CP-related disorders, including rheumatic diseases, migraine, neuropathies, and others. This review integrates current preclinical and clinical knowledge on the role of SPMs as a potential therapeutic tool for the management of patients with CP.

Role of Endocrine-Disrupting Chemicals in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: A Comprehensive Review.

Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disorder, affecting around 25% of the population worldwide. It is a complex disease spectrum, closely linked with other conditions such as obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome, which may increase liver-related mortality. In light of this, numerous efforts have been carried out in recent years in order to clarify its pathogenesis and create new prevention strategies. Currently, the essential role of environmental pollutants in NAFLD development is recognized. Particularly, endocrine-disrupting chemicals (EDCs) have a notable influence. EDCs can be classified as natural (phytoestrogens, genistein, and coumestrol) or synthetic, and the latter ones can be further subdivided into industrial (dioxins, polychlorinated biphenyls, and alkylphenols), agricultural (pesticides, insecticides, herbicides, and fungicides), residential (phthalates, polybrominated biphenyls, and bisphenol A), and pharmaceutical (parabens). Several experimental models have proposed a mechanism involving this group of substances with the disruption of hepatic metabolism, which promotes NAFLD. These include an imbalance between lipid influx/efflux in the liver, mitochondrial dysfunction, liver inflammation, and epigenetic reprogramming. It can be concluded that exposure to EDCs might play a crucial role in NAFLD initiation and evolution. However, further investigations supporting these effects in humans are required.

Exploring Phytotherapeutic Alternatives for Obesity, Insulin Resistance and Diabetes Mellitus.

At present, the pathologic spectrum of obesity-insulin resistance (IR)-diabetes mellitus (DM) represents not only a pressing matter in public health but also a paramount object of study in biomedical research, as they constitute major risk factors for cardiovascular disease (CVD), and other chronic non-communicable diseases (NCD). Phytotherapy, the use of medicinal herbs (MH) with treatment purposes, offers a wide array of opportunities for innovation in the management of these disorders; mainly as pharmacological research on small molecules accumulates. Several MH has displayed varied mechanisms of action relevant to the pathogenesis of obesity, IR and DM, including immunological and endocrine modulation, reduction of inflammation and oxidative stress (OS), regulation of appetite, thermogenesis and energy homeostasis, sensitisation to insulin function and potentiation of insulin release, among many others. However, the clinical correlates of these molecular phenomena remain relatively uncertain, with only a handful of MH boasting convincing clinical evidence in this regard. This review comprises an exploration of currently available preclinical and clinical research on the role of MH in the management of obesity, IR, and DM.

Phytotherapy for Cardiovascular Disease: A Bench-to-Bedside Approach.

At present, cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide, and global trends suggest that this panorama will persist or worsen in the near future. Thus, optimization of treatment strategies and the introduction of novel therapeutic alternatives for CVD represent key objectives in contemporary biomedical research. In recent years, phytotherapy-defined as the therapeutic use of whole or minimally modified plant components-has ignited large scientific interest, with a resurgence of abundant investigation on a wide array of medicinal herbs (MH) for CVD and other conditions. Numerous MH have been observed to intervene in the pathophysiology of CVD via a myriad of molecular mechanisms, including antiinflammatory, anti-oxidant, and other beneficial properties, which translate into the amelioration of three essential aspects of the pathogenesis of CVD: Dyslipidemia, atherosclerosis, and hypertension. Although the preclinical data in this scenario is very rich, the true clinical impact of MH and their purported mechanisms of action is less clear, as large-scale robust research in this regard is in relatively early stages and faces important methodological challenges. This review offers a comprehensive look at the most prominent preclinical and clinical evidence currently available concerning the use of MH in the treatment of CVD from a bench-to-bedside approach.

Is "Leptin Resistance" Another Key Resistance to Manage Type 2 Diabetes?

Although novel pharmacological options for the treatment of type 2 diabetes mellitus (DM2) have been observed to modulate the functionality of several key organs in glucose homeostasis, successful regulation of insulin resistance (IR), body weight management, and pharmacological treatment of obesity remain notable problems in endocrinology. Leptin may be a pivotal player in this scenario, as an adipokine which centrally regulates appetite and energy balance. In obesity, excessive caloric intake promotes a low-grade inflammatory response, which leads to dysregulations in lipid storage and adipokine secretion. In turn, these entail alterations in leptin sensitivity, leptin transport across the blood-brain barrier and defects in post-receptor signaling. Furthermore, hypothalamic inflammation and endoplasmic reticulum stress may increase the expression of molecules which may disrupt leptin signaling. Abundant evidence has linked obesity and leptin resistance, which may precede or occur simultaneously to IR and DM2. Thus, leptin sensitivity may be a potential early therapeutic target that demands further preclinical and clinical research. Modulators of insulin sensitivity have been tested in animal models and small clinical trials with promising results, especially in combination with agents such as amylin and GLP-1 analogs, in particular, due to their central activity in the hypothalamus.

Dietary flavonoids improve urinary arsenic elimination among Mexican women.

Inorganic arsenic (iAs) exposure increases risk of several diseases, including cancer. Some nutrients such as flavonoids enhance glutathione activity, which in turn play a key role in iAs elimination. Our objective was to explore whether dietary non-soy flavonoids are associated with iAs metabolism. We hypothesized that the intake of flavonoids belonging to the following groups, flavan-3-ols, flavone, flavonol, flavanone, and anthocyanidin, is positively associated with urinary dimethylarsinic acid (DMA), which is the most soluble iAs metabolite excreted. We performed a cross-sectional study that included 1027 women living in an arsenic-contaminated area of northern Mexico. Flavonoid intake was estimated using a validated food frequency questionnaire. Concentration of urinary iAs and its metabolites (monomethylarsonic acid and DMA) were determined by high performance liquid chromatography ICP-MS. Results showed positive significant associations between DMA and the flavonoid groups flava-3-ols (ß= 0.0112) and flavones (ß= 0.0144), as well as the individual intake of apigenin (ß= 0.0115), luteolin (ß= 0.0138), and eriodictyol (ß= 0.0026). Our findings suggest that certain non-soy flavonoids may improve iAs elimination; however, there is still very limited information available regarding the consumption of flavonoids and iAs metabolism.

Corneal cross-linking for Acanthamoeba keratitis in an orthokeratology patient after swimming in contaminated water.

PURPOSE: To report a case of Acanthamoeba keratitis diagnosed using confocal microscopy in a patient corrected by orthokeratology and treated with corneal crosslinking (CXL) after failure to respond to medical treatment. METHODS: After diagnosis, the patient was treated with several medications until CXL was applied during one 30-min session using ultraviolet A radiation and application of riboflavin. The clinical signs of the disease observed using slit-lamp biomicroscopy and confocal microscopy were evaluated and the visual acuity was measured during the course of the infection and treatment over a period of 30 months including 12 months of medical treatment, 9 months after cross-linking and amniotic membrane transplant and 9 months after penetrating keratoplasty and cataract extraction. RESULTS: In this case, confocal microscopy facilitated early diagnosis of an Acanthamoeba infection even if other signs and symptoms might be confounding. CXL was more effective than aggressive medication against the microorganism. After CXL, the symptoms and the corneal appearance improved significantly but the ulcer did not heal completely. After amniotic membrane transplantation, the patient underwent penetrating keratoplasty (PK) with no rejection, and the visual function substantially improved over 9 months of follow-up. CONCLUSIONS: Swimming in contaminated water might represent a risk for orthokeratology patients. CXL was effective for treating Acanthamoeba keratitis in an orthokeratology patient to eliminate active and cystic forms of the microorganism. Confocal microscopy was useful to confirm the diagnosis in the presence of confounding clinical signs observed during a conventional slit-lamp examination. Both CXL and confocal microscopy are essential to the outcome of PK.

Pterostilbene: Biomedical applications.

Resveratrol and its naturally dimethylated analog, pterostilbene, show similar biological activities. However, the higher in vivo bioavailability of pterostilbene represents a fundamental advantage. The main focus of this review is on biomedical applications of pterostilbene. The metabolism and pharmacokinetics of this stilbene in inflammatory dermatoses and photoprotection, cancer prevention and therapy, insulin sensitivity, blood glycemia and lipid levels, cardiovascular diseases, aging, and memory and cognition are addressed. Safety and toxicity, as well as recommendations for future research and biomedical uses, are discussed. This review includes comparisons between pterostilbene and other polyphenols, with particular emphasis on resveratrol. Potential benefits of using combinations of different polyphenols are considered. Based on present evidences we conclude that pterostilbene is an active phytonutrient and also a potential drug with multiple biomedical applications.

Natural polyphenols in cancer therapy.

Natural polyphenols are secondary metabolites of plants involved in defense against different types of stress. Extracts containing these compounds have been used for thousands of years in traditional eastern medicine. Polyphenols act on multiple targets in pathways and mechanisms related to carcinogenesis, tumor cell proliferation and death, inflammation, metastatic spread, angiogenesis, or drug and radiation resistance. Nevertheless, reported effects claimed for polyphenols are controversial, since correlations between in vitro effects and in vivo evidence are poorly established. The main discrepancy between health claims versus clinical observations is the frequent use of nonphysiologically relevant concentrations of these compounds and their metabolites in efficacy and mechanistic studies. The present review will discuss how in vivo administration correlates with polyphenol metabolism, toxicity, and bioavailability. Analysis of the general application of polyphenols in cancer therapy will be complemented by potential applications in the therapy of specific tumors, including melanoma, colorectal and lung cancers. Possible pharmaceutical formulations, structural modifications, combinations, and delivery systems aimed to increase bioavailability and/or biological effects will be discussed. Final remarks will include recommendations for future research and developments.

Oestradiol or genistein rescues neurons from amyloid beta-induced cell death by inhibiting activation of p38.

Oestrogenic compounds have been postulated as neuroprotective agents. This prompted us to investigate their mechanism action in neurons in primary culture. Cells were pretreated with physiological concentrations of 17-beta estradiol (0.2 nm) or with nutritionally relevant concentrations of genistein (0.5 microm), and 48 h later treated with 5 microm of amyloid beta (Abeta) for 24 h. We found that Abeta increased oxidative stress, measured as peroxide levels or oxidized glutathione/reduced glutathione ratio, which in turn, caused phosphorylation of p38 MAP kinase. Amyloid beta subsequently induced neuronal death. Inhibiting the MAP kinase pathway prevented cell death, confirming the role of p38 in the toxic effect of Abeta. All these effects were prevented when cells were pretreated for 48 h with oestradiol or genistein. Therefore, oestrogenic compounds rescue neurons from Abeta-induced cell death by preventing oxidative stress, which in turn inhibits the activation of p38, protecting neurons from cell death. Because hormone replacement therapy with oestradiol could cause serious setbacks, the potential therapeutic effect of phyto-oestrogens for the prevention of Abeta-associated neurodegenerative disorders should be more carefully studied in clinical research.

Tumor cytotoxicity by endothelial cells. Impairment of the mitochondrial system for glutathione uptake in mouse B16 melanoma cells that survive after in vitro interaction with the hepatic sinusoidal endothelium.

High GSH content associates with high metastatic activity in B16-F10 melanoma cells cultured to low density (LD B16M). GSH homeostasis was investigated in LD B16M cells that survive after adhesion to the hepatic sinusoidal endothelium (HSE). Invasive B16M (iB16M) cells were isolated using anti-Met-72 monoclonal antibodies and flow cytometry-coupled cell sorting. HSE-derived NO and H(2)O(2) caused GSH depletion and a decrease in gamma-glutamylcysteine synthetase activity in iB16M cells. Overexpression of gamma-glutamylcysteine synthetase heavy and light subunits led to a rapid recovery of cytosolic GSH, whereas mitochondrial GSH (mtGSH) further decreased during the first 18 h of culture. NO and H(2)O(2) damaged the mitochondrial system for GSH uptake (rates in iB16M were approximately 75% lower than in LD B16M cells). iB16M cells also showed a decreased activity of mitochondrial complexes II, III, and IV, less O(2) consumption, lower ATP levels, higher O(2) and H(2)O(2) production, and lower mitochondrial membrane potential. In vitro growing iB16M cells maintained high viability (>98%) and repaired HSE-induced mitochondrial damages within 48 h. However, iB16M cells with low mtGSH levels were highly susceptible to TNF-alpha-induced oxidative stress and death. Therefore depletion of mtGSH levels may represent a critical target to challenge survival of invasive cancer cells.