Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 22, Issue 1, 2022

Abstract: The coronavirus disease 2019 (COVID-19) pandemic has been a challenge for emergency care units worldwide due to the large numbers of patients, the scarcity of information, the medical resources, and the uncertainty regarding the disease's etiology and pathogenesis. The transmission of the virus and a probable post-pandemic of SARS-CoV-2 will depend on how deep this disease, the duration of immunity and the degree of cross immunity between SARS-CoV-2 and other pathogens either bacteria or fungi can be understood. Most mortalities have been related to an atypical pneumonia consisted of a sudden worsening of general condition of the admitted positive COVID-19 patients. The severe thromboembolism, often characterized by violent pulmonary and systemic complications, have been described with a blend of inflammatory-infectious patterns that rapidly shifted into a typical systemic inflammatory response syndrome (SIRS) or into an acute respiratory distress syndrome (ARDS) that eventually concluded into a multi-organ failure (MOF) and death. The fatality rate reported in our Covid-19 structure, SG Moscati Hospital of Taranto province in Italy, was higher in elderly male people with preexisting chronic pulmonary disease (COPD), patients with cancer and preexisting cardio-vascular diseases (CVD). We assumed a different theoretical position to clarify the higher mortality seen among those patients that was not as obvious as it appeared, we thus offered different pathophysiological picture that could help to recent solutions in therapy and prevention.

Abstract: Angiotensin-converting enzyme (ACE) is a zinc-dependent dicarboxypeptidase with two catalytic components, which has an important role in regulating blood pressure by converting angiotensin I to angiotensin II. ACE breaks down other peptides besides angiotensin I and has a variety of physiological effects together with renal growth and reproduction in men. ACE also acts on innate and acquired immune systems by affecting macrophage and neutrophil function, and these outcomes are exacerbated due to the overexpression of ACE. Overexpression of ACE in macrophages imposes antitumor and antimicrobial response, and it enhances the ability of neutrophils to produced super peroxide that has a bactericidal effect. ACE is also known to contribute to the expression of Major Histocompatibility Complex (MHC) class I and MHC class II peptides through enzymatic alterations of these peptides. Apprehending the expression of ACE and its effects on myeloid cell (myelogenous cells) activity can be promising in therapeutic interventions, including treatment of infection and malignancy.

Background & Objective: As cancer is one of the main causes of fatal illnesses in the world, and breast cancer is responsible for an elevated number of deaths in women, it is important to implement measures to prevent this disease. Method: In order to assess the influence of breastfeeding in preventing breast cancer in women, forteen prospective cohort articles are included in this study, and their methodological quality has been assessed through the Newcastle Ottawa quality assessment scale cohort studies. After determining the risk of bias for each case study, those with fewer systematic errors and therefore greater validity, have been selected to demonstrate the relationship they propose exists between breastfeeding and breast cancer. Results: 50% percent of the research included found that breastfeeding does not reduce the risk of breast cancer, while the other 50% argue that it is a protective factor. However, with regards to quality, the case studies that conclude that breastfeeding is not associated with breast cancer have more evidential support. Conclusion: It is difficult to establish whether or not breastfeeding prevents breast cancer, given the diversity of conclusions in the literature. Nevertheless, the findings of this study reinforce the importance of developing strategies to improve long-term women's health in the field of prevention.

Abstract: Plants serve as an important source of medicinal compounds, and their use in various diseases dates back hundreds of years. One such plant-based compound and the discovery of the antimalarial drug, artemisinin, has significantly brought phytomedicines into the spotlight and has enhanced the understanding and, consequently, the application of formulations derived from plants. Traditional Chinese Medicine (TCM), which is based primarily on plants, holds immense potential and is an unexplored source for modern medicine. Many herbs, including Polygonatum sibiricum (PS), are used in Chinese medicine to treat various diseases. Polygonatum sibiricum (PS) belongs to the Liliaceae family and is used not only as a medicinal but also dietary supplement. PS has a highly diverse composition of bioactive compounds such as flavones, homoisoflavanone, alkaloids, lignins, steroid saponins, triterpenoid saponins, polysaccharides, etc. Because of such diverse composition, PS has been used as an anti-aging, anti-inflammatory, anti-osteoporotic agent, as well as an immunity booster, sleep enhancer, etc. Therefore, in this article, we review the therapeutic effect of bioactive compounds such as polysaccharides, saponins, and PS extract in various diseases and their biological activities in fatigue, immunity, sleep, anti-aging, etc.

Background: Mediterranean diet (Med-D) has been previously suggested for athletes, but Paralympics usually have a low intake of plant foods. Orthorexia nervosa (ON) can drive dietary intake of both athletes and gym attendees. Objective: We aimed to compare dietary intakes and food habits of elite wheelchair basketball athletes (WBA) and able-bodied individuals who practice or not sport activity and with different fat mass percentage (FM%). Methods: We recruited 15 WBA from the Italian National team and 3 control groups (15 each group): healthy individuals who do not practice any sports activity (NSA) and gym attendees with low (GAL, FM%<17) and high (GAH, FM%>18) FM%. Food consumption was monitored by a 3- d diary, while Med-D scores and ON score were evaluated through standardized questionnaires. In WBA we also assessed Neurogenic Bowel Dysfunction (NBD), GastroEsophageal Reflux Disease (GERD), allergy questionnaire for athletes (AQUA) and Starvation Symptoms Inventory (SSI). Results: In WBA, ON correlated with GERD and SSI. WBA and GAH with eating behavior of ON had higher adherence to Med-D, whereas NSA had less adherence to Med-D. Sub-score, including fruits, vegetables and legumes, was higher in the GAL and GAH groups compared to the WBA and NSA groups. Med-D was inversely related to animal protein intake (PRO-AN) in NSA and GAL. FM% was inversely related to PRO-AN in WBA and GAH, and to ON only in GAH. In WBA, PRO-AN and vegetable protein intake correlated with both carbohydrate and energy intakes. Conclusion: In WBA, commitment to wellness (ON and Med-D adherence) could be a response to gastrointestinal and starvation symptoms. WBA should be involved in setting their own individualized dietary strategies.

Background & Objective: Peganum harmala has been traditionally used to manage rheumatoid arthritis (RA) and other inflammatory conditions. However, its use against RA has not been scientifically evaluated. The current study was designed to assess the anti-arthritic and anti-inflammatory activities of the methanolic extract of P. harmala leaves by in vitro and in vivo methods. Methods: The in vitro assays were carried out to determine the effect of plant extract on inhibition of egg albumin denaturation and human red blood cell membrane (HRBC) stabilization. Moreover, 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity was performed to determine the antioxidant potential. In vivo anti-arthritic activity was performed by determining the curative effect against Complete Freund’s adjuvant (0.1 ml). The plant extract was administered to rats orally at 200, 400 and 600 mg/kg/day for 21 days. Results: The values of IC50 of plant extract in protein denaturation, stabilization of HRBC and DPPH assays were 77.54 mg/ml, 23.90 mg/ml and 58.09 μg/ml, respectively. Moreover, the plant extract significantly attenuated the poly-arthritis and weight loss, anemia and paw edema. The plant extract restored the level of C-reactive protein, rheumatoid factor, alanine transaminase, aspartate transaminase and alkaline phosphatase in poly-arthritic rats. Moreover, the plant extract restored the immune organs’ weight in treated rats. Treatment with P. harmala also significantly subdued the oxidative stress by reinstating superoxide dismutase, reduced glutathione, catalase and malondialdehyde in poly-arthritic rats. The plant extract notably restored the prostaglandin-E2 and tumor necrosis factor (TNF)-α in the serum of poly-arthritic rats. Conclusion: It was concluded that P. harmala extract had potential antioxidant, anti-inflammatory and antiarthritic activities, which primarily might be attributed to alkaloids, flavonoids and phenols.

Background: The link between bilirubin and cardiometabolic outcomes has been previously identified with positive health effects of mild hyperbilirubinaemia. On the other hand, recent evidence has suggested an association between low circulating bilirubin levels and obesity. This study was conducted to assess the association of total bilirubin levels with metabolic and cardiovascular risk factors related to obesity. Methods: A total of 50 obese adults and 50 healthy controls matched for age and sex were enrolled in this study. Anthropometric measurements, fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), HOMA- β (%), lipids profile, monocyte to lymphocyte ratio (MLR), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), uric acid, gamma glutamyl transpeptidase (GGT), AST/ALT ratio and total bilirubin were assessed. Results: Total bilirubin, high density lipoprotein cholesterol (HDL-C) and AST/ALT ratio were significantly lower, whereas fasting insulin, HOMA-IR, total cholesterol, triglycerides, low density lipoprotein cholesterol, NLR, uric acid and GGT were significantly higher in obese adults than in healthy controls. Bilirubin was negatively associated with body mass index, waist circumference, fasting insulin, HOMA-IR, NLR, PLR, uric acid, and positively associated with HDL-C. HDL-C and NLR were the independent predictor variables of total bilirubin. Conclusion: Among all the studied cardio-metabolic risk factors, HDL-C and NRL are the most closely associated variables with total bilirubin levels in obese adults.

Background: Metformin is a biguanide that exhibits antidiabetic, anticarcinogenic, and anti-inflammatory properties. Despite well-known pancreatic protective effects, metformin's influence on pancreatic islet β-cell is yet considerably unknown. Protecting the functional insulin-producing β-cells in the pancreas is a key therapeutic challenge in patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM). Objective: The current study aimed to analyze the protective effects of metformin on streptozocin- induced diabetic rats in T1DM in hepatic tissues. Methods: In the present study, male Wistar rats (n=24) were randomly assigned into 2 groups (n=12 for each control and test), and metformin (100 mg/kg/day) was given for 7 weeks. Afterward, diabetes was induced by streptozocin (STZ) at a single dose of 150 mg/kg. Blood glucose was examined daily before and after STZ induction. The animals were euthanized by cervical dislocation 5 days after streptozocin injection, after which liver and pancreas were harvested from each rat. Results: The biochemical analyses revealed that metformin resulted in significantly reduced plasma glucose levels and higher pancreatic insulin levels in the test group. Using a restrictive cut-off of at least 2-FC and an adjusted p-value (q-value) of ≤0.05, a sum of 747 genes for the metformin group were shown to be differentially regulated compared to controls (320 Down and 427 Up), by which they were obtained from the liver. Furthermore, the evidence is attained that metformin may hinder the loss of critical β-cells by reducing inflammatory and apoptosis signaling, promoting fatty acid β-oxidation, and inducing metabolism. Conclusion: Collectively, this study has demonstrated a decrease in blood glucose levels and a rise in insulin-levels and thus consequent prophylactic effects in metformin-given STZ-induced diabetic rats.

Background and Aim: Eradication of hepatitis C virus (HCV) by direct-acting-antiviral- agents (DAAs) was followed by fibrosis regression, but little is available about hepatic steatosis changes after DAAs. The aim of this work was to assess the prevalence of hepatic steatosis among HCV Egyptian patients and the long term changes occuring after viral eradication. Methods: This prospective cohort study included 150 HCV patients with significant fibrosis. They were examined by Transient elastography to evaluate liver stiffness measurement (LSM) and hepatic steatosis before treatment, at SVR12 and 1 year after the end of therapy. Results: LSM showed a significant positive correlation to pretreatment of hepatic steatosis. LSM significantly decreased and hepatic steatosis significantly increased both at SVR12 and one year after DAAs. Patients with steatosis showed significantly higher median LSM and controlled attenuation parameter (CAP) values at: baseline, SVR12, and one year after therapy. Also, the pretreatment steatosis and body mass index (BMI) had a significant negative correlation with fibrosis regression one year after therapy in all studied groups. Conclusion: Hepatic steatosis is common in HCV Egyptian patients and increases after HCV eradication with DAAs. BMI and CAP values are negatively correlated to hepatic fibrosis regression and positively correlated to steatosis progression one year after DAAs. So, HCV patients with hepatic steatosis may need close follow up for atherosclerotic and HCC risk after DAAs, especially if they are overweight.

Background and Objective: Low back pain (LBP) is a frequent symptom. Among the causes that can determine it, lumbar osteoarthritis plays an important role. Therapeutic exercise, according to McKenzie method, has been shown to be effective in the treatment of LBP. Oral supplementation with collagen peptides represents a new therapeutic possibility in osteoarthritis. The aim of this study is to evaluate the combined efficacy of therapeutic exercise and oral administered viscosupplements in the treatment of osteoarthritis-related chronic LBP. Methods: Sixty patients were recruited and randomly divided into two groups (Group A and B). Group A performed only kinesitherapy, Group B carried out the same kinesitherapy combined with the daily administration of food supplements such as Fortigel®, Vitamin C, sodium hyaluronate, manganese and copper, during the whole treatment period. Patients were evaluated at the time of recruitment (T0), at the end of the treatment (T1 - 3 weeks after T0) and 6 weeks after T1 (T2). The outcome measures used were: Visual Analogue Scale (VAS), Oswestry Disability Index (ODI), and Short Form-12 (SF-12). Results: All the outcomes improved significantly at T1 in both groups, but more markedly in group B. Furthermore, in group A at T2, there was a statistically significant worsening in the scores of VAS, ODI and physical component of the SF-12, while in group B, this variation has not been detected. Conclusion: The combination of rehabilitation based on McKenzie back exercises and oral viscosupplementation with Fortigel®, Vitamin C, sodium hyaluronate, manganese and copper represents a valid option in patients with chronic LBP, as it ensures pain relief and improvement in the quality of life and in lumbar spine functionality. These therapeutic benefits are more evident and long-lasting compared to those obtained with rehabilitation alone.

Background and Objectives: Non-alcoholic fatty liver disease (NAFLD) is associated with inflammation and subsequent increase in cardiovascular risk. Because of its widespread presence and distribution, invasive diagnostic procedures (i.e., liver biopsy) are reserved for a limited number of subjects. With liver ultrasound, Fatty liver index (FLI) and fibrosis-4 (FIB-4) scores non-invasively assess liver steatosis and fibrosis. We aimed to evaluate the changes in inflammatory markers and FLI/FIB-4 scores in non-obese metformin-treated type 2 diabetes patients (T2DM) with NAFLD. Methods: All subjects underwent abdominal ultrasound aiming for NAFLD stratification (grade 1 to 3 according to its severity). Metabolic parameters (morning glycaemia, HbA1C, lipids, liver function tests), serum inflammatory markers (C-reactive protein, ferritin, and nitric oxide) and FLI/- FIB-4 were calculated. Results: FLI score and ultrasound NAFLD grades were found to correlate (p<0.05). We observed a significant correlation between the levels of ferritin and C-reactive protein (CRP) (p<0.05), and the FLI (p<0.05). Body weight (BW) (p<0.05), waist circumference (WC) (p<0.05), the levels of HbA1c (p<0.05), transferrin (p<0.05), insulin (p<0.05), and FLI score (p<0.05) significantly differed between groups as defined by the severity of NAFLD. Conclusion: This pilot study suggests that the serum inflammatory markers at the average normal values point to the sufficiency of metformin-single therapy in inflammation control in non-obese T2DM patients with NAFLD.

Background: Insulin resistance is a well-known predictor and risk factor for type 2 diabetes mellitus (T2DM). Higher hematocrit induced by higher insulin resistance affects blood rheology. Objective: This study intended to reveal the association between indices of insulin resistance and hemorheological parameters during a 75 g oral glucose tolerance test (75-g OGTT). Methods: A total of 575 healthy young Japanese participants took 75-g OGTT. We then analyzed the association between insulin resistance indices and hematological parameters. Results: The Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was significantly correlated with hematocrit (Ht), hemoglobin (Hb), red blood cell (RBC), white blood cell (WBC), platelet count, lipid parameters and body mass index (BMI). The Matsuda index was negatively correlated with RBC count, WBC count, platelet count, total cholesterol (TC), low-density lipoprotein- cholesterol (LDL-C), triglyceride (TG), and positively correlated with high-density lipoprotein- cholesterol (HDL-C). The disposition index was negatively correlated with Hb, RBC count, LDL-C and BMI, and positively correlated with HDL-C. The Homeostasis Model Assessment of beta cell (HOMA-β) was positively correlated with WBC count, platelet count, TC, LDL-C and TG. The insulinogenic index was positively correlated with WBC count, platelet count and TC. Multiple regression analysis revealed that HOMA-IR was independently associated with TG, and the Matsuda index was independently associated with TG, WBC count, and platelet count. The insulinogenic index was independently associated with WBC count. Conclusion: Cardinal rheological parameters reflected insulin resistance and release even in young healthy Japanese individuals within the physiological range of glycemic control.

Background: Gisekia pharnaceoides Linn. (Aizoaceae), traditionally known as baluka saag or sareli is commonly found in the deep Cholistan region of Pakistan. It is used by the native community for the mitigation of a range of diseases, including inflammatory disorders and gastric ulcers. Objective: This study is designed to evaluate the defensive impact of G. pharnaceoides in acetic acid-induced ulcerative colitis in mice and to discover the mechanism for anti-inflammatory action. Methods: The ethanolic crude extract of G. pharnaceoides (Gp.Cr) was prepared and evaluated for phytochemical substances by preliminary screening and HPLC analysis. Anti-inflammatory activity of Gp.Cr (300 and 500 mg/kg) was examined by administration of 200 μl of 7.5% acetic acid intra- rectally to induce ulcerative colitis and colonic mucosal injury, while mucosal homeostasis was evaluated by disease activity index, colonic ulcer score, and hematological parameters. The anti-inflammatory potential was quantified by assessing antioxidant enzymes (SOD, CAT, GPX-1), lipid peroxides, nitric oxide, and cytokines (IL-1β, IL-6, TNF-α) immunoassays and further analyzed by histological analysis of colon tissues. Results: Phytochemical screening of Gp.Cr revealed the presence of alkaloids, phenols, flavonoids, steroids, tannins, and saponins, while HPLC analysis confirmed the presence of quercetin, gallic acid, coumaric and sinapic acid. In acetic acid-induced ulcerative colitis model, Gp.Cr (300 and 500 mg/kg) along with sulphasalazine (500 mg/kg) decreased disease activity index, ulcer scores, and hematological parameters. Gp.Cr showed a significant anti-inflammatory potential by increasing antioxidant enzymes and decreasing lipid peroxides, nitric oxide, and cytokines levels. Histopathological examination showed a significant decline in ulceration and tissue disruption. Conclusion: Hence, the findings confirmed the effectiveness of G. pharnaceoides crude extract in the treatment of ulcerative colitis and might be a promising remedy to manage inflammatory disorders.

Background & Aim: This meta-analysis was performed to quantify the effects of probiotics on renal and glycemic biomarkers among patients with Diabetic Nephropathy (DN). Methods: Electronic databases were searched on May 10, 2020. All trials that investigated the effect of probiotics on serum glycemic markers (Fasting Plasma Glucose [FPG], Hemoglobin A1C, Insulin, Homeostatic Model Assessment-Insulin Resistance [HOMA-IR], and Quantitative Insulin Sensitivity Check Index [QUICKI]), and renal status markers (Creatinine [Cr], Blood Urea Nitrogen [BUN], and Glomerular Filtration Rate [GFR]) were included. Results: Seven trials that included 340 patients were identified for analysis. The results indicated that probiotics significantly reduced FPG (WMD= -19.08 mg/dl; 95% CI= -32.16, -5.99; P=0.004), HOMA-IR (WMD= -1.88; 95% CI= -3.63, -0.12; P=0.036), and Cr (WMD= -0.18 mg/dl; 95% CI= -0.26, -0.09; P<0.001) levels in DN patients; however, there was no statistically significant change in Hemoglobin A1C, Insulin, QUICKI, BUN, and GFR. Conclusion: This meta-analysis supports the potential use of probiotics in the improvement of some glycemic and renal biomarkers in patients with DN.

Background: Dedicator of Cytokinesis 8 (DOCK8) deficiency, the most frequent cause of autosomal recessive hyper immunoglobulin (Ig)E syndrome, is a rare combined immunodeficiency. Objective: In this study, we report seven patients, with consanguineous parents, with five novel variants within the DOCK8 gene. Methods: For genetic analysis, we performed Whole Exome Sequencing (WES) or targeted sequencing by means of Next-generation sequencing (NGS) for some of the patients. For others, Sanger sequencing, Fluorescence-activated cell sorting (FACS), or polymerase chain reaction (PCR) were used. Results: We report five novel variants within the DOCK8 gene: three deletions (deletion of exons 4-12, 24-30, and 22-27), one frameshift (LRG_196:g.189315dup;p.(Leu1052Profs*7)), and a splice region variant (LRG_196t1:c.741+5G>T). Patients presented with skin lesions, food allergy, candidiasis, otitis, recurrent respiratory infections, short stature, aortic aneurism, gynecomastia, and coarse facial features. Patients had leukocytosis, eosinophilia, lymphopenia, and monocytosis, elevated IgE, IgG, IgA, reduced IgM and IgA levels. Patients had a low percentage of CD3+ and CD4+ cells and a high percentage of CD19+, CD27+CD19+, and recent thymic emigrants T cells. The percentage of natural killer cells was increased in one of the patients while it was decreased in another patient. One patient died due to disseminated intravascular coagulation after hematopoietic stem cell transplantation. Conclusion: We reported novel variants within the DOCK8 gene and highlighted the risk of aneurysms in these patients, which have been rarely reported in these patients.