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 Proresolving Lipid Mediators: A Potential Therapeutic Target for Atherosclerosis.

Cardiovascular disease (CVD) is a global public health issue due to its high morbidity, mortality, and economic impact. The implementation of innovative therapeutic alternatives for CVD is urgently required. Specialized proresolving lipid mediators (SPMs) are bioactive compounds derived from ω-3 and ω-6 fatty acids, integrated into four families: Lipoxins, Resolvins, Protectins, and Maresins. SPMs have generated interest in recent years due to their ability to promote the resolution of inflammation associated with the pathogeneses of numerous illnesses, particularly CVD. Several preclinical studies in animal models have evidenced their ability to decrease the progression of atherosclerosis, intimal hyperplasia, and reperfusion injury via diverse mechanisms. Large-scale clinical trials are required to determine the effects of SPMs in humans. This review integrates the currently available knowledge of the therapeutic impact of SPMs in CVD from preclinical and clinical studies, along with the implicated molecular pathways. In vitro results have been promising, and as such, SPMs could soon represent a new therapeutic alternative for CVD.

Etelcalcetide and Paricalcitol in Chronic Kidney Disease: When the Target Is Inflammation.

Introduction: secondary hyperparathyroidism (SHP) is frequent in patients with chronic kidney disease (CKD), particularly in those in dialysis. To treat this complication, the current options available include phosphorus restriction, phosphate binders, the inhibition of parathyroid hormone (PTH) synthesis and secretion by the supplementation of vitamin D or VDR activators, or the use of calcimimetics. Beyond the control of PTH, the effects of the treatment of SHP on other biomarkers of risk may represent an additional benefit for this population. In this study, we explore the benefits of current SHP treatment options, mainly paricalcitol and/or etelcalcetide in the inflammatory state of hemodialysis (HD) patients. Results: the study finally included 142 maintenance HD patients (5 patients were excluded) followed for 6 months (dialysis vintage 26 ± 30 months, mean age 70 years old, 73% women, 81% Spanish white, 47% diabetic). In this case, 52 patients were on regular treatment with paricalcitol for SHP and 25 patients were eligible to initiate etelcalcetide. The baseline serum levels of Ca, P, PTH, Ferritin, albumin, C-reactive protein (CRP), and other variables were measured. We found serum PTH levels showed an improvement after the treatment with etelcalcetide again paricalcitol and no treatment (p < 0.04). Of note, serum levels of CRP were significantly lower in a small group of patients (n = 11) receiving paricalcitol + etelcalcetide compared to paricalcitol or etelcalcetide alone. The proportion of patients with CRP within target ranges (≤1.0 mg/dL) increased significantly after combined treatment (p < 0.001). Conclusions: etelcalcetide proved to safely reduce the PTH levels without significant adverse events and the possibility of a synergic anti-inflammatory effect with the simultaneous use of Paricalcitol in HD patients.

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.

The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror.

Type 2 Diabetes Mellitus (T2DM) is one of the most prevalent chronic metabolic disorders, and insulin has been placed at the epicentre of its pathophysiological basis. However, the involvement of impaired alpha (α) cell function has been recognized as playing an essential role in several diseases, since hyperglucagonemia has been evidenced in both Type 1 and T2DM. This phenomenon has been attributed to intra-islet defects, like modifications in pancreatic α cell mass or dysfunction in glucagon's secretion. Emerging evidence has shown that chronic hyperglycaemia provokes changes in the Langerhans' islets cytoarchitecture, including α cell hyperplasia, pancreatic beta (ß) cell dedifferentiation into glucagon-positive producing cells, and loss of paracrine and endocrine regulation due to ß cell mass loss. Other abnormalities like α cell insulin resistance, sensor machinery dysfunction, or paradoxical ATP-sensitive potassium channels (KATP) opening have also been linked to glucagon hypersecretion. Recent clinical trials in phases 1 or 2 have shown new molecules with glucagon-antagonist properties with considerable effectiveness and acceptable safety profiles. Glucagon-like peptide-1 (GLP-1) agonists and Dipeptidyl Peptidase-4 inhibitors (DPP-4 inhibitors) have been shown to decrease glucagon secretion in T2DM, and their possible therapeutic role in T1DM means they are attractive as an insulin-adjuvant therapy.

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.

Potential Role of Bioactive Lipids in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that involves a pathological inflammatory response against articular cartilage in multiple joints throughout the body. It is a complex disorder associated with comorbidities such as depression, lymphoma, osteoporosis, and cardiovascular disease (CVD), which significantly deteriorate patients' quality of life and prognosis. This has ignited a large initiative to elucidate the physiopathology of RA, aiming to identify new therapeutic targets and approaches in its multidisciplinary management. Recently, various lipid bioactive products have been proposed to have an essential role in this process, including eicosanoids, specialized pro-resolving mediators, phospholipids/sphingolipids, and endocannabinoids. Dietary interventions using omega-3 polyunsaturated fatty acids or treatment with synthetic endocannabinoid agonists have been shown to significantly ameliorate RA symptoms. Indeed, the modulation of lipid metabolism may be crucial in the pathophysiology and treatment of autoimmune diseases.

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.

Effect of Oral Nutritional Supplements with Sucromalt and Isomaltulose versus Standard Formula on Glycaemic Index, Entero-Insular Axis Peptides and Subjective Appetite in Patients with Type 2 Diabetes: A Randomised Cross-Over Study.

Oral diabetes-specific nutritional supplements (ONS-D) induce favourable postprandial responses in subjects with type 2 diabetes (DM2), but they have not been correlated yet with incretin release and subjective appetite (SA). This randomised, double-blind, cross-over study compared postprandial effects of ONS-D with isomaltulose and sucromalt versus standard formula (ET) on glycaemic index (GI), insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and SA in 16 individuals with DM2. After overnight fasting, subjects consumed a portion of supplements containing 25 g of carbohydrates or reference food. Blood samples were collected at baseline and at 30, 60, 90, 120, 150 and 180 min; and SA sensations were assessed by a visual analogue scale on separate days. Glycaemic index values were low for ONS-D and intermediate for ET (p < 0.001). The insulin area under the curve (AUC0-180 min) (p < 0.02) and GIP AUC (p < 0.02) were lower after ONS-D and higher GLP-1 AUC when compared with ET (p < 0.05). Subjective appetite AUC was greater after ET than ONS-D (p < 0.05). Interactions between hormones, hunger, fullness and GI were found, but not within the ratings of SA; isomaltulose and sucromalt may have influenced these factors.

El aceite de pescado mejora el control de la glicemia sin alterar los lípidos plasmáticos en ratas con tolerancia glucosada anormal / The fish oil betterment the control of the glycemy without alter them lipids plasmatics in rats with abnormal glucosed permissiveness

El objetivo del presente estudio fue determinar el efecto del tratamiento con dosis moderadas de aceite de pescado por tiempo prolongado, sobre el control de la glicemia y lipidos plasmáticos en ratas machas Sprague Dawley espontáneamente intolerante a la glucosa (IG). 37 ratas con tolerancia glucosada anormal fueron divididos en dos grupos, una experimental (19 ratas), que recibió por sonda orogástrica aceite de pescado (MAXEPA) (40 mg/Kg/día) durante 16 semanas y un grupo control constituido por 18 ratas, el cual recibió el mismo volumen de solución salina. Mientras que la glicemia basal y posterior a la sobrecarga glucosada mostraron una mejoría significativa (control basal 118,83 ñ 3,23 30' 165,45 ñ 12,1; 60' 153,1 ñ 10,65; 120 139,9 ñ 4,49 mg/dl vs aceite de pescado basal 108,6 ñ 3,15 [p<0,03]; 30 140,2 ñ 8,83 [p<0,05] mg/dl), sin embargo, los hallazgos sobre el perfil lipídico no fueron significativos