Antioxidants in Photoaging: From Molecular Insights to Clinical Applications.

Photoaging (PA) is considered a silent disease affecting millions of people globally and is defined as skin damage due to prolonged exposure to ultraviolet radiation (UVR) from the sun. Physiologically, the skin is in a state of renewal and synthesis of components of the extracellular matrix (ECM). However, exposure to UVR affects the production of the ECM, and the functioning and response of skin cells to UVR begins to change, thus expressing clinical and phenotypic characteristics of PA. The primary mechanisms involved in PA are direct damage to the DNA of skin cells, increases in oxidative stress, the activation of cell signaling pathways responsible for the loss of skin integrity, and cytotoxicity. The medical and scientific community has been researching new therapeutic tools that counteract PA, considering that the damage caused by UVR exceeds the antioxidant defense mechanisms of the skin. Thus, in recent years, certain nutraceuticals and phytochemicals have been found to exhibit potential antioxidant and photoprotective effects. Therefore, the main objective of this review is to elucidate the molecular bases of PA and the latest pharmaceutical industry findings on antioxidant treatment against the progression of PA.

Car T Cells in Solid Tumors: Overcoming Obstacles.

Chimeric antigen receptor T cell (CAR T cell) therapy has emerged as a prominent adoptive cell therapy and a therapeutic approach of great interest in the fight against cancer. This approach has shown notorious efficacy in refractory hematological neoplasm, which has bolstered its exploration in the field of solid cancers. However, successfully managing solid tumors presents considerable intrinsic challenges, which include the necessity of guiding the modified cells toward the tumoral region, assuring their penetration and survival in adverse microenvironments, and addressing the complexity of identifying the specific antigens for each type of cancer. This review focuses on outlining the challenges faced by CAR T cell therapy when used in the treatment of solid tumors, as well as presenting optimizations and emergent approaches directed at improving its efficacy in this particular context. From precise localization to the modulation of the tumoral microenvironment and the adaptation of antigen recognition strategies, diverse pathways will be examined to overcome the current limitations and buttress the therapeutic potential of CAR T cells in the fight against solid tumors.

Dietary Polyphenols and Gut Microbiota Cross-Talk: Molecular and Therapeutic Perspectives for Cardiometabolic Disease: A Narrative Review.

The intricate interplay between the gut microbiota and polyphenols has emerged as a captivating frontier in understanding and potentially harnessing the therapeutic potential of these bioactive compounds. Phenolic compounds, renowned for their antioxidant, anti-inflammatory, antidiabetic, and anticancer properties, are subject to intricate transformations within the gut milieu, where the diverse microbial ecosystem exerts profound effects on their metabolism and bioavailability. Conversely, polyphenols exhibit a remarkable capacity to modulate the composition and activity of the gut microbiota, fostering a bidirectional relationship that extends beyond mere nutrient processing. This symbiotic interaction holds significant implications for human health, particularly in cardiometabolic diseases such as diabetes mellitus, metabolic-dysfunction-associated steatotic liver disease, and cardiovascular disease. Through a comprehensive exploration of molecular interactions, this narrative review elucidates the reciprocal dynamics between the gut microbiota and polyphenols, unveiling novel avenues for therapeutic intervention in cardiometabolic disorders. By unravelling the intricate cross-talk between these two entities, this review underscores the multifaceted roles of polyphenols in overall health and the pivotal role of gut microbiota modulation as a promising therapeutic strategy in mitigating the burden of cardiometabolic diseases.

New Evidence on BPA's Role in Adipose Tissue Development of Proinflammatory Processes and Its Relationship with Obesity.

Bisphenol A (BPA) is a xenobiotic with endocrine disruptor properties which interacts with various receptors, eliciting a cellular response. In the plastic industry, BPA is widely used in the production of polycarbonate and epoxy-phenolic resins to provide elastic properties. It can be found in the lining of canned foods, certain plastic containers, thermal printing papers, composite dental fillings, and medical devices, among other things. Therefore, it is a compound that, directly or indirectly, is in daily contact with the human organism. BPA is postulated to be a factor responsible for the global epidemic of obesity and non-communicable chronic diseases, belonging to the obesogenic and diabetogenic group of compounds. Hence, this endocrine disruptor may be responsible for the development of metabolic disorders, promoting in fat cells an increase in proinflammatory pathways and upregulating the expression and release of certain cytokines, such as IL6, IL1ß, and TNFα. These, in turn, at a systemic and local level, are associated with a chronic low-grade inflammatory state, which allows the perpetuation of the typical physiological complications of obesity.

The Role of Specialized Pro-Resolving Lipid Mediators in Inflammation-Induced Carcinogenesis.

Cancer is a process involving cell mutation, increased proliferation, invasion, and metastasis. Over the years, this condition has represented one of the most concerning health problems worldwide due to its significant morbidity and mortality. At present, the incidence of cancer continues to grow exponentially. Thus, it is imperative to open new avenues in cancer research to understand the molecular changes driving DNA transformation, cell-to-cell interaction derangements, and immune system surveillance decay. In this regard, evidence supports the relationship between chronic inflammation and cancer. In light of this, a group of bioactive lipids derived from polyunsaturated fatty acids (PUFAs) may have a position as novel anti-inflammatory molecules known as the specialized pro-resolving mediators (SPMs), a group of pro-resolutive inflammation agents that could improve the anti-tumor immunity. These molecules have the potential role of chemopreventive and therapeutic agents for various cancer types, and their effects have been documented in the scientific literature. Thus, this review objective centers around understanding the effect of SPMs on carcinogenesis and their potential therapeutic effect.

Exploring the Links between Obesity and Psoriasis: A Comprehensive Review.

Obesity is a major public health issue worldwide since it is associated with the development of chronic comorbidities such as type 2 diabetes, dyslipidemias, atherosclerosis, some cancer forms and skin diseases, including psoriasis. Scientific evidence has indicated that the possible link between obesity and psoriasis may be multifactorial, highlighting dietary habits, lifestyle, certain genetic factors and the microbiome as leading factors in the progress of both pathologies because they are associated with a chronic pro-inflammatory state. Thus, inflammation management in obesity is a plausible target for psoriasis, not only because of the sick adipose tissue secretome profile but also due to the relationship of obesity with the rest of the immune derangements associated with psoriasis initiation and maintenance. Hence, this review will provide a general and molecular overview of the relationship between both pathologies and present recent therapeutic advances in treating this problem.

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.

Electroconvulsive Therapy in Psychiatric Disorders: A Narrative Review Exploring Neuroendocrine-Immune Therapeutic Mechanisms and Clinical Implications.

Electroconvulsive therapy (ECT) is based on conducting an electrical current through the brain to stimulate it and trigger generalized convulsion activity with therapeutic ends. Due to the efficient use of ECT during the last years, interest in the molecular bases involved in its mechanism of action has increased. Therefore, different hypotheses have emerged. In this context, the goal of this review is to describe the neurobiological, endocrine, and immune mechanisms involved in ECT and to detail its clinical efficacy in different psychiatric pathologies. This is a narrative review in which an extensive literature search was performed on the Scopus, Embase, PubMed, ISI Web of Science, and Google Scholar databases from inception to February 2022. The terms "electroconvulsive therapy", "neurobiological effects of electroconvulsive therapy", "molecular mechanisms in electroconvulsive therapy", and "psychiatric disorders" were among the keywords used in the search. The mechanisms of action of ECT include neurobiological function modifications and endocrine and immune changes that take place after ECT. Among these, the decrease in neural network hyperconnectivity, neuroinflammation reduction, neurogenesis promotion, modulation of different monoaminergic systems, and hypothalamus-hypophysis-adrenal and hypothalamus-hypophysis-thyroid axes normalization have been described. The majority of these elements are physiopathological components and therapeutic targets in different mental illnesses. Likewise, the use of ECT has recently expanded, with evidence of its use for other pathologies, such as Parkinson's disease psychosis, malignant neuroleptic syndrome, post-traumatic stress disorder, and obsessive-compulsive disorder. In conclusion, there is sufficient evidence to support the efficacy of ECT in the treatment of different psychiatric disorders, potentially through immune, endocrine, and neurobiological systems.

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.

New Insights on the Role of Connexins and Gap Junctions Channels in Adipose Tissue and Obesity.

Due to the inability to curb the excessive increase in the prevalence of obesity and overweight, it is necessary to comprehend in more detail the factors involved in the pathophysiology and to appreciate more clearly the biochemical and molecular mechanisms of obesity. Thus, understanding the biological regulation of adipose tissue is of fundamental relevance. Connexin, a protein that forms intercellular membrane channels of gap junctions and unopposed hemichannels, plays a key role in adipogenesis and in the maintenance of adipose tissue homeostasis. The expression and function of Connexin 43 (Cx43) during the different stages of the adipogenesis are differentially regulated. Moreover, it has been shown that cell-cell communication decreases dramatically upon differentiation into adipocytes. Furthermore, inhibition of Cx43 degradation or constitutive overexpression of Cx43 blocks adipocyte differentiation. In the first events of adipogenesis, the connexin is highly phosphorylated, which is likely associated with enhanced Gap Junction (GJ) communication. In an intermediate state of adipocyte differentiation, Cx43 phosphorylation decreases, as it is displaced from the membrane and degraded through the proteasome; thus, Cx43 total protein is reduced. Cx is involved in cardiac disease as well as in obesity-related cardiovascular diseases. Different studies suggest that obesity together with a high-fat diet are related to the production of remodeling factors associated with expression and distribution of Cx43 in the atrium.

The YAP/TAZ Signaling Pathway in the Tumor Microenvironment and Carcinogenesis: Current Knowledge and Therapeutic Promises.

The yes-associated protein (YAP) and the transcriptional coactivator with PDZ-binding motif (TAZ) are transcriptional coactivators, members of the Hippo signaling pathway, which play a critical role in cell growth regulation, embryonic development, regeneration, proliferation, and cancer origin and progression. The mechanism involves the nuclear binding of the un-phosphorylated YAP/TAZ complex to release the transcriptional enhanced associate domain (TEAD) from its repressors. The active ternary complex is responsible for the aforementioned biological effects. Overexpression of YAP/TAZ has been reported in cancer stem cells and tumor resistance. The resistance involves chemotherapy, targeted therapy, and immunotherapy. This review provides an overview of YAP/TAZ pathways' role in carcinogenesis and tumor microenvironment. Potential therapeutic alternatives are also discussed.

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.

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.

Attitudes of Medical Students Towards Psychiatry in Venezuela: a 6-Year Longitudinal Study.

OBJECTIVE: The authors evaluated changes in attitude towards psychiatry of medical students in one medical school in Venezuela. METHODS: Balon's modified questionnaire was administered to first and sixth-year medical students to analyze their attitude towards psychiatry. The answers were compared with McNemar's test. RESULTS: The students' negative perception of psychiatry increased by the end of medical school with 45% of sixth-year students reportedly feeling uncomfortable when working with patients with psychiatric illness compared to only 8.3% of first-year medical students. Interest in specializing in psychiatry decreased from 2.6% in first-year medical students to 0% in sixth-year medical students (p=0.001). CONCLUSION: Different factors may lead to the loss of interest in psychiatry of medical students in Venezuela, such as little time spent with patients, being in contact only with patients with psychosis, stigma about psychiatry among medical doctors and friends, feeling more comfortable with other specialties, and other specialties having a higher perceived status and being better paid.

Epicardial Adipose Tissue, Adiponectin and Leptin: A Potential Source of Cardiovascular Risk in Chronic Kidney Disease.

The importance of cardiometabolic factors in the inception and progression of atherosclerotic cardiovascular disease is increasingly being recognized. Beyond diabetes mellitus and metabolic syndrome, other factors may be responsible in patients with chronic kidney disease (CKD) for the high prevalence of cardiovascular disease, which is estimated to be 5- to 20-fold higher than in the general population. Although undefined uremic toxins are often blamed for part of the increased risk, visceral adipose tissue, and in particular epicardial adipose tissue (EAT), have been the focus of intense research in the past two decades. In fact, several lines of evidence suggest their involvement in atherosclerosis development and its complications. EAT may promote atherosclerosis through paracrine and endocrine pathways exerted via the secretion of adipocytokines such as adiponectin and leptin. In this article we review the current knowledge of the impact of EAT on cardiovascular outcomes in the general population and in patients with CKD. Special reference will be made to adiponectin and leptin as possible mediators of the increased cardiovascular risk linked with EAT.

Diabetes and Impaired Fasting Glucose Prediction Using Anthropometric Indices in Adults from Maracaibo City, Venezuela.

To determine the predictive power of various anthropometric indices for the identification of dysglycemic states in Maracaibo, Venezuela. A cross-sectional study with randomized, multi-staged sampling was realized in 2230 adult subjects of both genders who had their body mass index (BMI), waist circumference (WC) and waist-height ratio (WHR) determined. Diagnoses of type 2 diabetes mellitus (DM2) and impaired fasting glucose (IFG) were made following ADA 2015 criteria. ROC curves were used to evaluate the predictive power of each anthropometric parameter. Area under the curve (AUC) values were compared through Delong's test. Of the total 2230 individuals (52.6 % females), 8.4 % were found to have DM2, and 19.5 % had IFG. Anthropometric parameters displayed greater predictive power regarding newly diagnosed diabetics, where WHR was the most important predictor in both females (AUC = 0.808; CI 95 % 0.715-0.900. Sensitivity: 82.8 %; specificity: 76.2 %) and males (AUC = 0.809; CI 95 % 0.736-0.882. Sensitivity: 78.6 %; specificity: 68.1 %), although all three parameters appeared to have comparable predictive power in this subset. In previously diagnosed diabetic subjects, WHR was superior to both WC and BMI in females, and WHR and WC were both superior to BMI in males. Lower predictive values were found for IFG in both genders. Accumulation of various altered anthropometric measurements was associated with increased odds ratios for both newly and previously diagnosed DM2. The predictive power of anthropometric measurements was greater for DM2 than IFG. We suggest assessment of as many available parameters as possible in the clinical setting.

Consumption effect of a formula with extended release carbohydrates on the glycemic response and post prandial insulin in healthy individuals.

There are specific formulas of enteral nutrition to improve glycemic control in diabetic patients containing different types of carbohydrates which glycemic response should be investigated. The consumption effect of a formula with carbohydrates with extended release was determined on the glycemic response and postprandial insulin in 21 healthy individuals (11 men and 10 women) from 17 to 25 years old, who consumed in two different time the polymeric enteral formula for diabetics and the reference food (white bread) in a quantity of 50 g of available carbohydrates. The glycemia was measured at 0, 15, 30, 45, 60, 75, 90, 105 and 120 min and the insulin concentrations in fasting and within 120 min. The area in the glycemic curve was measured being the lowest the formula 11718.20. ± 1112.38 than in white bread 13269.18 ± 1351.05 (P<0.001). The glycemic index (GI) resulted to be intermediate (63.33±5.22) and lower when compared to the GT ranks published for the reference food (80-96). A lower concentration of glycemia occurred after the consumption of the formula, without increments in the insulin requirements; thus, assuming an adequate use in diabetic and a more extended feeling of fullness. This effect and the glycated hemoglobin should be studied after the extended consumption in people with diabetes.

Glucococorticoid-induced death of pancreatic Beta cells: an organized chaos.

Glucocorticoids (GC) are renowned for their pleiotropic effects in all organ systems, their ubiquitous use in numerous clinical settings, and the abundant adverse effects they may exert, particularly in the endocrine-metabolic sphere. Although hyperglycemia and insulin resistance are well-defined GC-induced diabetogenic phenomena, an added component of direct injury to pancreatic ß cells (PBC) may also participate in this scenario. Indeed, the apoptotic capacity of GC is widely recognized, and PBC do not escape this situation. No unified pathway has been characterized regarding GC-induced cell death; instead, it appears to depend on the specific machinery of each cell type, determining a great heterogeneity in GC-dependent apoptotic mechanisms among different tissues. In PBC, GC can induce the expression or activation of pro-apoptotic proteins (Bax, BAD, p38), repress anti-apoptotic proteins (Bcl-2), deactivate pro-survival mechanisms (cAMP-PKA signaling) and sensitize the cell to death induced by oxidative stress, fatty acids, hyperglycemia and cytokines. Although proliferative pathways (TGF-ß, H-ras) are activated simultaneously - and an increase in PBC mass may be observed initially - pro-apoptotic and anti-proliferative mechanisms appear to eventually overcome their pro-survival counterparts, due to their synergic and aggregative action. Key molecules such as p38 and the cAMP-PKA system may be promising therapeutic targets in the prevention of GC-induced cell death.

The role of adiponectin in endothelial dysfunction and hypertension.

It has been two decades since the discovery of adiponectin, and today its role in insulin resistance, inflammation, and atherosclerosis are areas of major interest. Production of adiponectin is reduced in all inflammatory processes and states of insulin resistance such as obesity, type 2 diabetes mellitus, and coronary artery disease. Adiponectin regulates carbohydrate metabolism, and may also regulate vascular homeostasis by affecting important signaling pathways in endothelial cells and modulating inflammatory responses in the subendothelial space. Clinical studies have demonstrated a relationship between serum adiponectin concentrations and the activity of the renin-angiotensin-aldosterone system (RAAS), causing changes in blood pressure. Antihypertensive therapy with angiotensin II receptor blockers (ARBs) has been demonstrated to increase adiponectin levels in 3-6 months. Adiponectin has also been shown to play a role in cardiac injury in modulation of pro-survival reactions, cardiac energy metabolism, and inhibition of hypertrophic remodeling. The effects of adiponectin on the cardiovascular system are believed to be partially mediated by the activation of 5' adenosine monophosphate-activated protein kinase (AMPK) and cyclooxygenase-2 (COX-2) pathways, reducing endothelial cell apoptosis, promoting nitric oxide production, decreasing tumor necrosis factor-alpha (TNF-α) activity, and preventing atherosclerotic proliferation and smooth muscle cell migration. Further evaluation of biologically active forms of adiponectin and its receptor should help to clarify how obesity affects the cardiovascular system.