Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 20, Issue 9, 2020

Background and Objective: Diabetic foot syndrome (DFS) is a common long-term complication of diabetes mellitus. DFS has recently been associated with adverse effects that could further impair the quality of life of diabetic patients, and increase the social and economic burden, morbidity, and premature mortality of the disease. The main physio-pathological basis of DFS is due to diabetesinduced neuropathy and angiopathy in the lower limbs and feet. Patients diagnosed with DFS must significantly modify their daily habits in order to cope with signs and symptoms of DFS and this can alter their quality of life. The objective of this review is to summarize the evidence regarding the economic, physical and social limitations which can affect the quality of life (QoL) in patients with DFS, the effects of ulcers and amputations on QoL outcomes. Results: Different aspects related to DFS such as physical alterations, psychological complaints and even disorders, socio-economic difficulties can affect the quality of life of these patients. However, the QoL related to low socio-economic factors gave mixed results and physical activity, education and type of footwear can influence the outcomes. There is a general gender-dependent higher prevalence of DFS in men, although it depends on the geographical area. DFS often co-occurs with other diabetes-induced complications (retinopathy, nephropathy and cardiovascular disorders) and comorbid obesity generally worsens it. Conclusion: Accessibility to health services aimed at reducing inequalities and constant health education and promotion and care regarding psychological and socio-economic issues should be continuously undertaken for individuals with DFS in order to improve their QoL.

The increase in lifespan in the 20th century entails an increase in the elderly population. This brings a new challenge for society, causing people to have physical and mental limitations caused by age-related diseases, such as frailty. Frailty is clinically characterized by multisystem pathophysiological processes, such as chronic inflammation, immune activation, dysregulation of the musculoskeletal and endocrine systems, oxidative stress, energy imbalances, mitochondrial dysfunction, and sarcopenia. The elderly should consume energy in amounts close to those in what is currently accepted as a balanced diet. However, an increase in protein intake may be recommended for elderly people as long as there is no kidney damage. This increase could help fight the loss of muscle mass associated with age. Additionally, vitamin and mineral intakes are often insufficient in their diets. Therefore, the diet should be adapted not only to their age, but also to the pathologies associated with aging. Through these measures, we can reduce the prevalence of comorbidity and thereby increase health span. Therefore, both physical and nutritional interventions, including functional foods and nutraceuticals, should be taken into account.

Objective: The most common multifactorial neurodegenerative disorder occurring in old age is Alzheimer’s disease. The neuropathological hallmarks of that disorder are amyloid plaques with the presence of β -amyloid aggregates, intraneuronal tau protein tangles, and chronic inflammation. Brain cells such as microglia and astrocytes are inflammatory cells associated with Alzheimer’s disease and involved in the production of inflammatory mediators, such as cytokines and chemokines. Chemokines consist of a large family of protein mediators with low molecular weight, which able to control the migration and residence of all immune cells. In pathological conditions, such as Alzheimer’s disease, chemokines contribute to the inflammatory response by recruiting T cells and controlling microglia/ macrophages activation. Methods: The present study focuses on the role that chemokines and their receptors play in Alzheimer's disease and in processes such as inflammation and oxidative stress. Results: Chemokines are important mediators in AD and inflammation. They promote Aβ deposition and TAU hyperphosphorylation aggravating and increasing the progression of AD. Moreover, they affect the processing of senile plaques and produce abnormal TAU phosphorylation. Conclusion: There is no cure for AD but the therapeutic potential of chemokines to control the development of the disease may be a field of study to consider in the future.

Background & Objectives: In old people, both innate and adaptive immune responses are impaired, thus leading to a condition of systemic inflamm-ageing, even including the involvement of the central nervous system (CNS). Aims: Here, main mechanisms of the immune ageing and neuro-inflammation will be discussed along with the dietary approaches for the modulation of age related diseases. Discussion: Neuroinflammation is caused by the passage of inflammatory mediators through the brain blood barrier to CNS. Then, in the brain, antigenic stimulation of microglia and/or its activation by peripheral cytokines lead to a robust production of free radicals with another wave of proinflammatory cytokines which, in turn, causes massive neuronal damage. Also, infiltrating T cells [T helper (h) and T cytotoxic cells] contribute to neuronal damage. Additionally, a peripheral imbalance between inflammatory Th17 cells and anti-inflammatory T regulatory cells seems to be prevalent in the aged brain, thus leading to a proinflammatory profile. Alzheimer’s disease, Parkinson’s disease and multiple sclerosis will be described as typical neurodegenerative diseases. Finally, modulation of the immune response thanks to the anti-oxidant and anti-inflammatory effects exerted by dietary products and nutraceuticals in ageing will be discussed. Special emphasis will be placed on polyunsaturated fatty acids, polyphenols, micronutrients and pre-probiotics and synbiotics. Conclusion: Ageing is characterized by an imbalance subversion of the immune system with a condition of inflamm-ageing. Neuroinflammation and neurodegenerative diseases seem to be a central manifestation of a peripheral perturbation of the immune machinery. Dietary products and nutraceuticals may lead to a down-regulation of the oxidative and pro-inflammatory profile in ageing.

Background: Cardiovascular prevention and rehabilitation programmes (CVPRP) are an established model of care designed to improve risk factor management. They have been successfully implemented in a variety of settings, in patients with coronary heart disease (CHD). Objective: To assess the long term impact of a nurse-coordinated, multidisciplinary, CVPRP in patients with CHD in the reduction of lipid profile and medication prescription in clinical practice. Methods: The study used an analytical, experimental, population based, prospective and longitudinal design. In Spain, the study was conducted in the Valencian Community, including two randomized hospitals. Coronary patients were prospectively and consecutively identified in both hospitals. The intervention hospital carried out an 8-week CVPRP. Results: The proportion of patients achieving improved standards of preventive care increased in the intervention hospital compared with the usual care hospital, mainly regarding LDL-C concentrations. Furthermore, an increased prescription of statins was found in the intervention group. However, there were no statistically significant differences in triglycerides and glucose levels. Conclusion: The EUROACTION nurse-led CVPRP enabled coronary patients to control lipid profile to the European targets. A large proportion of patients were prescribed statin therapy as cardioprotective medication with favorable changes in medication for coronary patients. To improve the potential for cardiovascular prevention, we need local preventive cardiology programmes adapted to the health policy of individual countries.

Background: Frailty syndrome is characterized by multisystem dysregulation frequently found in older individuals or even in younger patients with chronic disabling diseases such as cardiovascular diseases. Objective: To determine whether peripheral blood cell count, and its subpopulations, red blood cell and platelets, morphology and different ratios (neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and red blood distribution width-to-platelet ratio) are associated with cardiac frail patients, and through this to improve the prediction of frailty status in patients with cardiovascular diseases. Methods: An observational, retrospective, cohort study enrolling 179 patients with cardiovascular disease divided into two groups: non-frail group (100 pts) and frail group (79 pts), a cohort detached from the Frail.RO study. The frailty was evaluated based on the Fried criteria; haematological markers, sociodemographic data, and variables related to cardiovascular diseases and comorbidities were also recorded. Results: Lower lymphocytes, platelet count, and neutrophil-to-lymphocyte ratio were significantly associated with a more severe frailty syndrome. Regarding red blood cells, haemoglobin concentration and red cell distribution width significantly correlated with the severity of the frailty syndrome. Receiver operating characteristic curve analysis for these markers associated with the frailty syndrome revealed an acceptable sensitivity of 66 % and specificity of 65% to identify frail individuals. Malnutrition and hypercholesterolemia are relevant predictors for identifying frailty in hospitalized cardiovascular patients. Conclusion: The evaluation of peripheral blood cell composition routinely measured in clinical practice can represent a valuable, but limited indicator, to diagnose frailty syndrome and eventually, the effects of interventions in frail patients with cardiovascular diseases.

Agammaglobulinemia is a type of primary antibody deficiencies, characterized by severe reduction in serum level of all types of immunoglobulins level and absence of B cells in the peripheral blood. X-linked and various autosomal recessive/dominant mutations have been identified underlying the pathogenesis of this disorder. Affected patients present a broad range of clinical manifestations, including respiratory infections, gastrointestinal complications, Enterovirus infections, autoimmunity, and malignancies. This disease can be controlled by different therapeutic strategies. In this review, we describe different aspects of agammaglobulinemia such as epidemiology, pathogenesis, clinical phenotype, diagnosis, management, and prognosis of congenital agammaglobulinemia.

Mirabegron is a β3-agonist drug approved by the FDA for use in 2012 and administered in overactive bladder. Activating of adrenergic receptors leads to the relaxation of the detrusor muscle. According to the latest research and reports, it also has lipolytic activity, affecting the reduction of mainly brown adipose tissue (BAT) but also of white adipose tissue (WAT). This results in a decrease in body weight and triglyceride concentration and an increase in lipoprotein lipase activity, as well as in the level of free fatty acids or adipokines in the plasma. The drug indirectly participates in the regulation of carbohydrate metabolism, influencing the increase in insulin sensitivity, supporting cellular uptake of glucose. However, due to the elevation of blood pressure and pulse, as a supplement, the drug should be taken with care to avoid cardiovascular complications. In our review, below, we present a description and discussion of available studies in terms of mirabegron action on the exercise capacity of the body in the context of its potential use as a doping agent.

Biologics are an innovative class of drugs that can selectively influence immunological responses at a cellular level. Although their use is usually restricted to some specific diseases, such as autoimmune pathologies and tumors, their “off-label” administration has increased widely in the last years. Drug treatment may induce hypersensitivity reactions which currently lack any gold standard therapy but maybe a future field of application for biologics. Agents like anti-IgE (Omalizumab) and Tumor Necrosis Factor-α inhibitors might be used in immediate-type and cell-mediated hypersensitivity caused by medications, respectively, and the first trials in that direction are being reported in the literature. In fact, the refined immunological mechanisms involved in the pathogenesis of drug hypersensitivity might respond successfully to this new class of drugs.

Background: Chemistry as experimental science began in the seventeenth century, when it began moving away from being one of the alchemical doctrines and toward analyzing matter and its transformations using scientific methods. Previously, the ancient Pre-Socratic philosophy through observation of nature was concerned with the laws that govern the natural world and the property of matter. Later, the Hellenistic Alexandrian culture took possession of the Hermetic doctrines of the Egyptians, mixing them with pre-Socratic thought and Gnosticism. At this historical moment, therefore, there was a fusion of the Greek philosophical patrimony and the Hellenistic and Alexandrian influences on medicine. The Hermetic gnosis evolved over time to become alchemy and then to usher in the birth of chemical science. Many doctors were wandering philosophers who dealt with cosmogony to understand the body and diseases and to discover new healing drugs for treatment, and thus they were the first chemist therapists. Methods: The influence of ancient physicians through the pre-Socratic philosophy for these prochemical theories and practice has been researched through ancient texts, so these texts have been referenced to determine the legacy of paleo-chemicals doctrines. Results: The study of various texts in particular from the Pre-Socratic age and the eminent physicians underline that, despite a different approach to the cosmogonic concepts of nature and the matter, the medicine of that age had an important influence on chemistry as an experimental science, especially concerning therapy with drugs. Conclusion: The Pre-Socratic philosophers have influenced the medical practice and guided it toward the concept of the properties of matter for medical treatment and an understanding of the causes of diseases.

Osteoporosis is one of the major health issues associated with menopause-related estrogen deficiency. Various reports suggest that the hormonal changes related to menopausal transition may lead to the derangement of redox homeostasis and ultimately oxidative stress. Estrogen deficiency and oxidative stress may enhance the expression of genes involved in inflammation. All these factors may contribute, in synergy, to the development of postmenopausal osteoporosis. Previous studies suggest that estrogen may act as an antioxidant to protect the bone against oxidative stress, and as an antiinflammatory agent in suppressing pro-inflammatory and pro-osteoclastic cytokines. Thus, the focus of the current review is to examine the relationship between estrogen deficiency, oxidative stress and inflammation, and the impacts of these phenomena on skeletal health in postmenopausal women.

Background: There is a need for rapid and accurate diagnostic biomarker for diagnosis of Salmonella fever. Aims: The aim of the present study was to assess the importance of procalcitonin (PCT), Soluble Triggering Receptors expressed on Myeloid Cells 1 (sTREM1) and C- reactive protein (CRP) in the diagnosis of enteric fever with positive blood culture for S.typhi. Methods: Blood samples were withdrawn from 200 patients with suspected enteric fever and subjected for the determination of CRP, PCT and sTREM-1. Results: The sensitivity and specificity for PCT cut off were 97.7% & 82.5%, for CRP the sensitivity and specificity were 95.3% and 77% and for s-TREM-1 the sensitivity and specificity were 95.3% & 77%. Conclusion: S-TREM-1 may be considered as a novel biomarker for the diagnosis of enteric fever with good sensitivity and specificity.

Background: Triple immunosuppressive therapy is associated with several gastrointestinal disorders. The aim of this study was to investigate the effects induced by the triple immunosuppressive therapy on the gastrointestinal tract of rats. Methods: Male Wistar rats were randomly assigned into three experimental groups: Control: filtered water; TAC + MPS + PRED: treated with Tacrolimus plus Mycophenolate Sodium plus Prednisone; and CSA + AZA + PRED: treated with Cyclosporine plus Azathioprine plus Prednisone. The treatment was done for 14 days by gavage. Gastric emptying and contractility were evaluated by the Alternating Current Biosusceptometry (ACB) and Electrogastrography (EGG). Histological, biochemical and hematological analyses were also performed. Results: Gastric emptying time was slower in the CSA + AZA + PRED group in comparison with control (p<0.01) and TAC + MPS + PRED groups (p<0.001). Animals treated with TAC + MPS + PRED showed accelerated gastric emptying (p<0.05) compared to control. The amplitude of gastric contractions in both immunosuppressed groups was higher than observed in the control. The frequency of gastric contractions for the CSA + AZA + PRED group was also increased (p<0.01). Results obtained by EGG were similar to those recorded with the ACB. The thickness of the circular layer from stomach muscle decreased in both immunosuppressed groups, while the longitudinal layer was reduced only in the CSA + AZA + PRED group. Conclusion: Triple immunosuppressive therapy alters gastric motility, compromises the muscular layers and the association between CSA, AZA, and PRED provokes the major alterations in the structure and gastric function. Specific gastrointestinal side effects resulting from different immunosuppressive therapies still need to be elucidated in order to provide more effective and personalized therapy for patients.

Aims: The current investigation aimed to assess the antioxidant, antidiabetic and antilipidemic effects of the aqueous extract of aerial part of Cotula cinerea (C. cinerea). Background: Cotula cinerea (Del). which belongs to the Asteraceae family is commonly used traditionally for the treatment of diabetes. Objective: The objective of the study was to study the effect of the aqueous C. cinerea extract on glucose and lipid metabolism in normal and streptozotocin-induced diabetic rats using a single and repeated oral administration. Methods: A preliminary phytochemical screening and the quantification of phenolic and flavonoid contents as well as the antioxidant activity using three methods (DPPH, FRAP and ABTS) were carried out. The effect of a single and repeated (15 days of treatment) oral administration of the aqueous extract of aerial part of Cotula cinerea (AEAPCC) at a dose of 20 mg/kg on glucose and lipid profile was examined in normal and streptozotocin-induced diabetic rats. Additionally, histopathological examination of the pancreas and liver was carried out according to the Hematoxylin-Eosin method. Results: AEAPCC (20 mg/kg) showed a significant blood glucose-lowering activity in both normal and diabetic rats after a single and repeated oral administration during 15 days. The aqueous extract was also able to decrease the plasma triglycerides levels in both normal and diabetic rats after 15 days of oral treatment at a dose of 20 mg/Kg while no effect was observed on plasma cholesterol levels. In addition, the results show that AEAPCC exhibits an in vitro antioxidant activity using different tests. Histopathological analysis of the pancreas and liver of AEAPCC-treated diabetic rats has revealed that AEAPCC had a beneficial effect on the architecture of these organs while no improvement of glucose tolerance was noticed using the glucose tolerance test. Furthermore, the results showed that the extract is rich in several phytochemical compounds and exhibited an important antioxidant activity. The phytochemical screening revealed that AEAPCC contains polyphenolic compounds, flavonoids, tannins, alkaloids, saponins, quinones, sterols, terpenoids, anthroquinones and reducing sugars. Whereas, it is free from glycosides. Conclusion: In conclusion, this study demonstrates that Cotula cinerea possesses a beneficial effect on diabetes. Further investigations are required to study the mechanism of action of the antidiabetic effect of this plant.

Background: The vessel restenosis is related to the inflammatory events in subendothelial space. It is proposed that the inflammatory agents affect the prostaglandin synthesis pathway. In this study, we investigated the COX-1, COX-2, PTGDS and miRNA-520a-5p expression levels and the serum 15-Deoxy-Δ^12,14-PGJ2 metabolite values in patients with the stenosed and re-stenosed vessels. Furthermore, the associations between genes and miR-520 were evaluated in the monocyte transfection studies. Methods: The subjects (n=60) were included three groups; healthy subjects (control (stenosis < 5%), stent no restenosis (SNR, restenosis < 5%) and in-stent restenosis (ISR, restenosis > 70%)). The miRNA and gene expression levels were measured by RT-qPCR technique. 15-Deoxy-Δ^12,14-PGJ2 values were measured by the ELISA technique. The miR-520 was transfected into myocytes using PEI polymer. Results: The monocyte COX-1, COX-2 and PTGDS gene expression levels and the serum 15-Deoxy- Δ^12,14-PGJ2 values increased significantly in the patients. Furthermore, the miR-520 correlated conversely with the COX-1, and PTGDS gene expression levels. Conclusion: The results showed that the PGD2 synthesis pathway is active in the patients and, miR- 520 may be involved in the function of this pathway.

Background: Extrarenal 1α,25-dihydroxyvitamin D3 (1,25-D) locally produced by immune cells plays crucial roles in the regulation of the immune system. However, in vivo status of extrarenal 1,25-D and 25-hydroxyvitamin D (25-D) in acute inflammatory conditions are unknown. Objective: The aim of this study was to determine the extrarenal 1,25-D level in circulation in bilaterally nephrectomized rats, induced by low-dose lipopolysaccharide (LPS). Methods: Renal 1,25-D synthesis was terminated through bilateral nephrectomy in rats. The rats received intraperitoneal LPS (50 μg/kg BW) three times and the experiment was ended 24 hours after nephrectomy. Serum 1,25-D, 25-D, calcium, phosphorus, intact parathyroid hormone, and calcitonin levels were measured and immunohistochemistry was applied to detect the sources of extrarenal 1,25- D synthesis. Results: Circulatory 1,25-D concentration remarkably increased in both LPS-treated and non-treated bilaterally nephrectomized rats. Elevated circulatory 1,25-D did not have hypercalcemic endocrinal effects. The increased 1,25-D level also resulted in a concurrent rapid and dramatic depletion of circulatory 25-D. Conclusion: Extrarenal 1,25-D could enter into the systemic circulation and, therefore, might have systemic effects besides its autocrine and paracrine functions.

Background: Alpha-lipoic acid (ALA) was used in the treatment of diabetic peripheral neuropathy (DPN) using different routes, doses and treatment durations. The aim of this work is to assess the efficacy of oral 600mg ALA twice daily over 6 months in the treatment of patients with DPN. Methods: This is a prospective, single-center, double-blinded, placebo-controlled study conducted at the outpatient clinic of Mansoura Specialized Hospital, Mansoura University. A total of 200 patients with DPN were randomly assigned to add on treatment with either oral 600mg twice daily ALA (n=100) or placebo (n=100) for 6 months. Treatment outcome was assessed using vibration perception threshold (VPT), neurological symptom score (NSS), neurological disability score (NDS), and visual analog scale (VAS) for pain at baseline and at each visit (1, 3 and 6 months) after the start of treatment. Results: Comparison between the study groups regarding the baseline data revealed no statistically significant differences. with respect to the outcome parameters, no significant differences were found between the studied groups at baseline. However, in subsequent visits, ALA-treated patients had significantly better results regarding almost all the outcome parameters (NSS, NDS, VAS, VPT). Mild nausea was reported in 6 patients. None of the studied patients discontinued treatment. Conclusion: Oral 600mg ALA twice-daily treatment for DPN over 6 months is effective, safe and tolerable.

Background: Erectile dysfunction (ED) is a significant but underestimated complication during diabetes mellitus (DM). Currently, few special treatments are available clinically due to the lack of specific therapeutic targets. Genomic analysis can be helpful to find potential targets. In this study, the gene expression under diabetic ED condition was analyzed using a gene array, and the significance of the outcomes was evaluated through clinical data. Methods: The expressions of 15923 genes were analyzed using R software. Differential expression genes (DEGs) were identified through the constructed volcano plot. The function enrichment of Gene Ontology (GO) and KEGG was screened with the DAVID online tool. The interaction between these DEGs was revealed through constructing a protein-protein interaction network and the hub genes were uncovered using the STRING and Cytoscape tool. Lastly, the data of diabetic ED patients were applied to verify the bioinformatics findings. Results: The study showed that 75 genes in the rat penile tissues were upregulated, while 97 genes were downregulated on the diabetic ED condition. These genes were mainly involved in extracellular matrix composition, collagen fibril organization, as well as protein digestion & absorption. Additionally, insulin-related signaling pathways were affected. The clinical analysis indicated that insulin resistance was associated with the diabetic ED severity. Notably, the bioinformatics analysis also suggested that ferroptosis pathway was probably activated under the diabetic ED condition. Conclusion: The impaired protein synthesis induced by deficient insulin signaling is an important cause of the diabetic ED. The improvement of protein synthesis through restoring insulin function may be potentially useful for diabetic ED therapy.

Background: Numerous reports explaining the beneficial health effects of soluble fibres and probiotics on lifestyle disorders have been published. However, a little information is available on coadministration of soluble fibres such as gum acacia & inulin and probiotic lactobacilli. Therefore, in the present study, we have evaluated the synergistic effects of soluble fibres and probiotic fermented milk on adiposity, insulin resistance and dyslipidemia in C57BL/6 mice fed high-fat and sucrose diet for 18 weeks. Objective: To explore the synergistic effect of soluble fibres (gum acacia/inulin) and Lactobacillus casei NCDC19 fermented milk on adiposity, insulin resistance and lipid mobilization genes in dietinduced obese mice. Methods: C57BL/6 mice were divided randomly into three groups (n = 9/group) according to their body weights. The HFS group was fed high-fat and sucrose diet, the HFS-GFM group was fed HFS diet incorporated with gum acacia (7%, w/w) along with L. casei NCDC19 fermented milk and HFSIFM group was fed HFS diet incorporated with inulin (7%, w/w) along with L. casei NCDC19 fermented milk. Results: At the end of the experiment, final body weight, epididymal fat (E.fat) weight, and adipocyte size were found to be lower in groups received either gum acacia or inulin in combination with L. casei NCDC19 fermented milk (HFS-GFM or HFS-IFM). Also, fasting blood glucose, serum insulin, triglycerides, and VLDL-cholesterol levels were decreased significantly in both HFS-GFM and HFSIFM fed groups. Furthermore, relative mRNA expression of genes (cpt1, foxa2, pgc1β, and pparα) related to fatty acid oxidation enhanced significantly in the liver. In E.fat pad, expression of adiponectin was upregulated, whereas, leptin expression was reduced considerably. Also, expression of fasting-induced adipose factor enhanced significantly in the distal ileum of mice in HFS-GFM and HFS-IFM groups. Conclusion: Overall, we demonstrate that co-administration of soluble fibres viz. gum acacia, inulin and L. casei NCDC19 fermented milk exhibited the anti-adiposity effects, improved insulin sensitivity and dyslipidemia in mice via modulation of lipid mobilization genes.