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1.
Immune Fingerprint in Diabetes: Ocular Surface and Retinal Inflammation.
Amorim, M, Martins, B, Fernandes, R
International journal of molecular sciences. 2023;(12)
Abstract
Diabetes is a prevalent global health issue associated with significant morbidity and mortality. Diabetic retinopathy (DR) is a well-known inflammatory, neurovascular complication of diabetes and a leading cause of preventable blindness in developed countries among working-age adults. However, the ocular surface components of diabetic eyes are also at risk of damage due to uncontrolled diabetes, which is often overlooked. Inflammatory changes in the corneas of diabetic patients indicate that inflammation plays a significant role in diabetic complications, much like in DR. The eye's immune privilege restricts immune and inflammatory responses, and the cornea and retina have a complex network of innate immune cells that maintain immune homeostasis. Nevertheless, low-grade inflammation in diabetes contributes to immune dysregulation. This article aims to provide an overview and discussion of how diabetes affects the ocular immune system's main components, immune-competent cells, and inflammatory mediators. By understanding these effects, potential interventions and treatments may be developed to improve the ocular health of diabetic patients.
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2.
Underestimated Prediabetic Biomarkers: Are We Blind to Their Strategy?
Luís, C, Soares, R, Baylina, P, Fernandes, R
Frontiers in endocrinology. 2022;:805837
Abstract
Type 2 Diabetes (T2D) is currently one of the fastest growing health challenging, a non-communicable disease result of the XXI century lifestyle. Given its growing incidence and prevalence, it became increasingly imperative to develop new technologies and implement new biomarkers for early diagnosis in order to promote lifestyle changes and thus cause a setback of the disease. Promising biomarkers have been identified as predictive of T2D development; however, none of them have yet been implemented in clinical practice routine. Moreover, many prediabetic biomarkers can also represent potential therapeutical targets in disease management. Previous studies have identified the most popular biomarkers, which are being thoroughly investigated. However, there are some biomarkers with promising preliminary results with limited associated studies; hence there is still much to be understood about its mechanisms and associations in T2D pathophysiology. This work identifies and discusses the promising results of Galectin-3, Ophthalmate and Fetuin-A.
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3.
The Impact of Metabolic Syndrome and Type 2 Diabetes Mellitus on Prostate Cancer.
Sousa, AP, Costa, R, Alves, MG, Soares, R, Baylina, P, Fernandes, R
Frontiers in cell and developmental biology. 2022;:843458
Abstract
Prostate cancer (PCa) remains the second most common type of cancer in men worldwide in 2020. Despite its low death rate, the need for new therapies or prevention strategies is critical. The prostate carcinogenesis process is complex and multifactorial. PCa is caused by a variety of mutations and carcinogenic events that constitutes the disease's multifactorial focus, capable of not only remodeling cellular activity, but also modeling metabolic pathways to allow adaptation to the nutritional requirements of the tumor, creating a propitious microenvironment. Some risk factors have been linked to the development of PCa, including Metabolic Syndrome (MetS) and Type 2 Diabetes Mellitus (T2DM). MetS is intrinsically related to PCa carcinogenic development, increasing its aggressiveness. On the other hand, T2DM has the opposite impact, although in other carcinomas its effect is similar to the MetS. Although these two metabolic disorders may share some developmental processes, such as obesity, insulin resistance, and dyslipidemia, their influence on PCa prognosis appears to have an inverse effect, which makes this a paradox. Understanding the phenomena behind this paradoxical behavior may lead to new concepts into the comprehension of the diseases, as well as to evaluate new therapeutical targets. Thus, this review aimed to evaluate the impact of metabolic disorders in PCa's aggressiveness state and metabolism.
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4.
Advances in Vitreoretinal Surgery.
Ribeiro, L, Oliveira, J, Kuroiwa, D, Kolko, M, Fernandes, R, Junior, O, Moraes, N, Vasconcelos, H, Oliveira, T, Maia, M
Journal of clinical medicine. 2022;(21)
Abstract
Advances in vitreoretinal surgery provide greater safety, efficacy, and reliability in the management of the several vitreoretinal diseases that benefit from surgical treatment. The advances are divided into the following topics: scleral buckling using chandelier illumination guided by non-contact visualization systems; sclerotomy/valved trocar diameters; posterior vitrectomy systems and ergonomic vitrectomy probes; chromovitrectomy; vitreous substitutes; intraoperative visualization systems including three-dimensional technology, systems for intraoperative optical coherence tomography, new instrumentation in vitreoretinal surgery, anti-VEGF injection before vitrectomy and in eyes with proliferative diabetic retinopathy, and new surgical techniques; endoscopic surgery; the management of subretinal hemorrhages; gene therapy; alternative techniques for refractory macular hole; perspectives for stem cell therapy and the prevention of proliferative vitreoretinopathy; and, finally, the Port Delivery System. The main objective of this review is to update the reader on the latest changes in vitreoretinal surgery and to provide an understanding of how each has impacted the improvement of surgical outcomes.
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5.
The controversial role of glucose in the diabetic kidney.
Fernandes, R
Porto biomedical journal. 2021;(1):e113
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Abstract
The kidneys play an important role in maintaining glucose homeostasis being the main mechanisms, the gluconeogenesis, renal glucose consumption and glucose reabsorption in the proximal tubules. In this review, we present the main research into the role of glycogen-the stored form of glucose, and how it accumulates in the cells, providing new information on the link between diabetes and diabetic kidney disease. In the last 10 years, research under the scope of renal insulin handling, glucose transport in the proximal tubules, renal gluconeogenesis and renal insulin resistance, made possible to relate the roles of glucose and glycogen in the kidney with other several organs, like the liver. On the one hand, insulin positively regulates kidney uptake and degradation, and there is probably a specific action and resistance to insulin at the renal site. Moreover, insulin regulates the bioavailability of the sodium-glucose co-transporters-SGLT2 inhibitor, and inhibits renal gluconeogenesis. Only the liver and kidneys can supply glucose to the circulation through the process of gluconeogenesis, which involves the synthesis of glucose again from non-glycemic substrates; and the decomposition of stored glycogen. In the mind of nephrologists, diabetologists and scientists, glucose metabolism in the kidney is the focus, with the relevant success of inhibitors in reducing kidney and cardiovascular diseases in individuals with diabetes. However, these new data led to the intriguing paradigm that many of the beneficial effects on the renal and cardiovascular system appear to be independent of the systemic glucose-lowering actions of these agents. The goal of this work puts in context a highly relevant research area for renal glucose metabolism, of glycogen accumulation and metabolism in the diabetic kidney.
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6.
Extracellular Vesicles and MicroRNA: Putative Role in Diagnosis and Treatment of Diabetic Retinopathy.
Martins, B, Amorim, M, Reis, F, Ambrósio, AF, Fernandes, R
Antioxidants (Basel, Switzerland). 2020;(8)
Abstract
Diabetic retinopathy (DR) is a complex, progressive, and heterogenous retinal degenerative disease associated with diabetes duration. It is characterized by glial, neural, and microvascular dysfunction, being the blood-retinal barrier (BRB) breakdown a hallmark of the early stages. In advanced stages, there is formation of new blood vessels, which are fragile and prone to leaking. This disease, if left untreated, may result in severe vision loss and eventually legal blindness. Although there are some available treatment options for DR, most of them are targeted to the advanced stages of the disease, have some adverse effects, and many patients do not adequately respond to the treatment, which demands further research. Oxidative stress and low-grade inflammation are closely associated processes that play a critical role in the development of DR. Retinal cells communicate with each other or with another one, using cell junctions, adhesion contacts, and secreted soluble factors that can act in neighboring or long-distance cells. Another mechanism of cell communication is via secreted extracellular vesicles (EVs), through exchange of material. Here, we review the current knowledge on deregulation of cell-to-cell communication through EVs, discussing the changes in miRNA expression profiling in body fluids and their role in the development of DR. Thereafter, current and promising therapeutic agents for preventing the progression of DR will be discussed.
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7.
A state of the art review on the novel mediator asprosin in the metabolic syndrome.
Luís, C, Fernandes, R, Soares, R, von Hafe, P
Porto biomedical journal. 2020;(6):e108
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Abstract
Metabolic syndrome is a complex and heterogeneous pathology characterized by a cluster of biochemical, clinical, and metabolic factors that came together in raising the risk of cardiovascular diseases, type 2 diabetes mellitus, and all-cause mortality. Some of these features are well defined in this syndrome like: obesity, inflammation, hypertension, insulin resistance, atherosclerotic dyslipidemias, endothelial dysfunction, and inflammation. This circuit is intermediated by a complex network of hormones, cytokines, transcription factors, and adipokines, among others. Some like leptin, adiponectin, Plasminogen activator inhibitor-1, interleukin-6, Tumor necrosis factor, and their influence on the metabolic syndrome are well described in the literature and new players are described continuously. One novel player was described in 2016 by Romere et al as a fasting-induced glycogenic protein hormone named asprosin. In order to perform a state-of-the-art, nonsystematic review of asprosin, a study of the available literature was carried out in the main database (Pubmed) and the results were studied and correlated to better understand the mechanism of action of this hormone. Asprosin is not only associated with the metabolic syndrome features like glucose and lipid metabolism, insulin resistance, obesity and inflammation but also in other pathologies metabolic syndrome related like diabetic retinopathy, polycystic ovary syndrome and anorexia nervosa. A limited number of pathways were already unveiled although much more research is needed to better understand the therapeutical potential of asprosin in the metabolic syndrome.
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8.
Sweet Stress: Coping With Vascular Dysfunction in Diabetic Retinopathy.
Santiago, AR, Boia, R, Aires, ID, Ambrósio, AF, Fernandes, R
Frontiers in physiology. 2018;:820
Abstract
Oxidative stress plays key roles in the pathogenesis of retinal diseases, such as diabetic retinopathy. Reactive oxygen species (ROS) are increased in the retina in diabetes and the antioxidant defense system is also compromised. Increased ROS stimulate the release of pro-inflammatory cytokines, promoting a chronic low-grade inflammation involving various signaling pathways. An excessive production of ROS can lead to retinal endothelial cell injury, increased microvascular permeability, and recruitment of inflammatory cells at the site of inflammation. Recent studies have started unraveling the complex crosstalk between retinal endothelial cells and neuroglial cells or leukocytes, via both cell-to-cell contact and secretion of cytokines. This crosstalk is essential for the maintenance of the integrity of retinal vascular structure. Under diabetic conditions, an aberrant interaction between endothelial cells and other resident cells of the retina or invading inflammatory cells takes place in the retina. Impairment in the secretion and flow of molecular signals between different cells can compromise the retinal vascular architecture and trigger angiogenesis. In this review, the synergistic contributions of redox-inflammatory processes for endothelial dysfunction in diabetic retinopathy will be examined, with particular attention paid to endothelial cell communication with other retinal cells.
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9.
Polysaccharide K and Coriolus versicolor extracts for lung cancer: a systematic review.
Fritz, H, Kennedy, DA, Ishii, M, Fergusson, D, Fernandes, R, Cooley, K, Seely, D
Integrative cancer therapies. 2015;14(3):201-11
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Plain language summary
Lung cancer is the second most commonly diagnosed cancer, generally has a poor prognosis and is the leading cause of cancer mortality. PSK is an immune modulating polysaccharide from the mushroom Coriolus versicolor which has been used in Japan in combination with standard cancer therapy for over 30 years. This systematic review looked at the evidence for the use of PSK in lung cancer and included 11 controlled human trials and 17 preclinical studies. 15 of the 17 preclinical studies supported the anticancer effects of PSK, whilst two studies showed no significant effects. No harmful or negative effects were seen in any of the studies. The review explores the mechanisms by which PSK exerts its anticancer effects. 5 of the human trials were non-randomised and suggest an increased survival of lung cancer patients who received PSK alongside chemo- or radiotherapy, although these studies have methodological weaknesses. All 6 randomised human trials showed benefits on at least one of the following study endpoints: parameters of immune function, body weight, performance score, tumour-related symptoms, or survival. No major adverse effects were reported in the studies reviewed above. There are no known contraindications for use during chemotherapy or radiation therapy. The authors conclude that PSK may significantly improve immune function, tumour-related symptoms, and survival in patients with lung cancer, when used as adjunctive therapy alongside or following standard chemotherapy or radiation therapy, or surgery. PSK appears to increase the tolerability of chemotherapy and reduce limiting factors such as bone marrow suppression.
Abstract
BACKGROUND Polysaccharide K, also known as PSK or Krestin, is derived from the Coriolus versicolor mushroom and is widely used in Japan as an adjuvant immunotherapy for a variety of cancer including lung cancer. Despite reported benefits, there has been no English language synthesis of PSK for lung cancer. To address this knowledge gap, we conducted a systematic review of PSK for the treatment of lung cancer. METHODS We searched PubMed, EMBASE, CINAHL, the Cochrane Library, AltHealth Watch, and the Library of Science and Technology from inception to August 2014 for clinical and preclinical evidence pertaining to the safety and efficacy of PSK or other Coriolus versicolor extracts for lung cancer. RESULTS Thirty-one reports of 28 studies were included for full review and analysis. Six studies were randomized controlled trials, 5 were nonrandomized controlled trials, and 17 were preclinical studies. Nine of the reports were Japanese language publications. Fifteen of 17 preclinical studies supported anticancer effects for PSK through immunomodulation and potentiation of immune surveillance, as well as through direct tumor inhibiting actions in vivo that resulted in reduced tumor growth and antimetastatic effects. Nonrandomized controlled trials showed improvement of various survival measures including median survival and 1-, 2-, and 5-year survival. Randomized controlled trials showed benefits on a range of endpoints, including immune parameters and hematological function, performance status and body weight, tumor-related symptoms such as fatigue and anorexia, as well as survival. Although there were conflicting results for impact on some of the tumor-related symptoms and median survival, overall most randomized controlled trials supported a positive impact for PSK on these endpoints. PSK was safely administered following and in conjunction with standard radiation and chemotherapy. CONCLUSIONS PSK may improve immune function, reduce tumor-associated symptoms, and extend survival in lung cancer patients. Larger, more rigorous randomized controlled trials for PSK in lung cancer patients are warranted.
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10.
The Place of Dipeptidyl Peptidase-4 Inhibitors in Type 2 Diabetes Therapeutics: A "Me Too" or "the Special One" Antidiabetic Class?
Godinho, R, Mega, C, Teixeira-de-Lemos, E, Carvalho, E, Teixeira, F, Fernandes, R, Reis, F
Journal of diabetes research. 2015;:806979
Abstract
Incretin-based therapies, the most recent therapeutic options for type 2 diabetes mellitus (T2DM) management, can modify various elements of the disease, including hypersecretion of glucagon, abnormal gastric emptying, postprandial hyperglycaemia, and, possibly, pancreatic β cell dysfunction. Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) increase glucagon-like peptide-1 (GLP-1) availability and correct the "incretin defect" seen in T2DM patients. Clinical studies have shown good glycaemic control with minimal risk of hypoglycaemia or any other adverse effects, despite the reports of pancreatitis, whose association remains to be proved. Recent studies have been focusing on the putative ability of DPP-4 inhibitors to preserve pancreas function, in particular due to the inhibition of apoptotic pathways and stimulation of β cell proliferation. In addition, other cytoprotective effects on other organs/tissues that are involved in serious T2DM complications, including the heart, kidney, and retina, have been increasingly reported. This review outlines the therapeutic potential of DPP-4 inhibitors for the treatment of T2DM, focusing on their main features, clinical applications, and risks, and discusses the major challenges for the future, in particular the possibility of becoming the preferred therapy for T2DM due to their ability to modify the natural history of the disease and ameliorate nephropathy, retinopathy, and cardiovascular complications.