Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 20, Issue 6, 2020

Background: Cardiovascular disorders are the leading cause of morbidity and mortality throughout the globe. Hypertension is the main risk factor that contributes to the development of many diseases. The use of herbal therapies, medicinal plants and their derivatives for the remedy and management of hypertension is well-recognized and popular among a wide part of the world population. Methods: The aim of the current review was to collect, treat, and critically analyze the published research studies relative to experimental and clinical investigations which have studied the blood pressure lowering abilities of medicinal plant derivatives in the last decade. This review was organized into three principal axes; the first axis was attributed to the in vivo and in vitro experimental studies; the second treated the clinical trials; while, the last one is devoted to analyze the mechanisms of action underlying the therapeutic antihypertensive effectiveness of phytochemicals. Results: Different types of extracts and isolated molecules obtained from a large variety of species demonstrated their efficiency in improving the increase of blood pressure either experimentally or clinically. Medicinal species such as garlic (Allium sativum), celery (Apium graveolens), Black Cumin (Nigella sativa) and Ginseng (Panax) are among the most common and therapeutically used plant derivatives for controlling hypertension while Asteraceae, Apiaceae and Rosaceae are among the botanical families which were frequently studied in the last decade. Isolated compounds such as allicin and apigenin have received more interest in this field. Recent evidence from clinical trials suggests that a wide variety of herbal preparations and plant extracts or natural isolated compounds have a favorable therapeutic impact on blood flow. Interestingly, phytochemicals can either act directly on blood vessels via a vasorelaxant effect involving a variety of signaling cascades or indirectly through inhibiting or stimulating diversity of systems such as angiotensin-converting enzyme (ACE), renin-angiotensin system (RAS) or the diuretic activity. Hence, based on the findings of the present review medicinal plant derivatives could be used as preventive and curative agents in the case of cardiovascular disorders, particularly hypertension and could play a promoting function for the discovery of new antihypertensive agents. Conclusion: The analysis of the published data shows that a great effort remains to be done to investigate the medicinal plants cited as antihypertensive through published ethnopharmacological surveys. The analysis of the literature in this field shows the lack of standardization at the level of experimental study methods as well as the need to study purified molecules. Moreover, the mechanistic studies when they exist remain in the whole partial. On the other hand, few advanced clinical studies have been conducted. Finally, the determination of the efficacy/safety ratio remains absent in almost all studies.

Background: Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are a novel class of non-statin lipid lowering therapy that reduce LDL-cholesterol by 50 - 60%. PCSK9 inhibitors decrease LDL-cholesterol by preventing intracellular degradation of LDL receptors; subsequently, a greater number of LDL-receptors are available on the cell surface to extract circulating LDL. Objective: To describe the origins of PCSK9 inhibitors and their current use in clinical practice. Methods: We performed a narrative review of the PCSK9 inhibitor class of drugs. Results: Current data indicate that PCSK9 inhibitors effectively reduce LDL-cholesterol and are well tolerated and safe. PCSK9 inhibitors have also been shown to reduce cardiovascular event rates in patients with stable atherosclerotic cardiovascular disease and in patients with a recent (up to one year) acute coronary syndrome. Given the costs, chronicity of the treatment and the potential budget impact, PCSK9 inhibitors are often limited to patients with the highest absolute risk for major adverse cardiovascular events despite optimal treatment with high-intensity statin and ezetimibe. Conclusion: PCSK9 inhibitors have a favorable safety, efficacy and tolerability profile. Postmarketing safety surveillance and real-world studies are needed to further support the long-term safety profile of this class of medicine.

Background: Lactate dehydrogenase (LDH) is a group of oxidoreductase isoenzymes catalyzing the reversible reaction between pyruvate and lactate. The five isoforms of this enzyme, formed from two subunits, vary in isoelectric points and these isoforms have different substrate affinity, inhibition constants and electrophoretic mobility. These diverse biochemical properties play a key role in its cellular, tissue and organ specificity. Though LDH is predominantly present in the cytoplasm, it has a multi-organellar location as well. Objective: The primary objective of this review article is to provide an update in parallel, the previous and recent biochemical views and its clinical significance in different diseases. Methods: With the help of certain inhibitors, its active site three-dimensional view, reactions mechanisms and metabolic pathways have been sorted out to a greater extent. Overexpression of LDH in different cancers plays a principal role in anaerobic cellular metabolism, hence several inhibitors have been designed to employ as novel anticancer agents. Discussion: LDH performs a very important role in overall body metabolism and some signals can induce isoenzyme switching under certain circumstances, ensuring that the tissues consistently maintain adequate ATP supply. This enzyme also experiences some posttranslational modifications, to have diversified metabolic roles. Different toxicological and pathological complications damage various organs, which ultimately result in leakage of this enzyme in serum. Hence, unusual LDH isoform level in serum serves as a significant biomarker of different diseases. Conclusion: LDH is an important diagnostic biomarker for some common diseases like cancer, thyroid disorders, tuberculosis, etc. In general, LDH plays a key role in the clinical diagnosis of various common and rare diseases, as this enzyme has a prominent role in active metabolism.

Background and Objectives: The present review critically discusses the high occurrence rate, insulin resistance and type-2 diabetes in tobacco exposed individuals. Tobacco extracts and smoke contain a large number of toxic materials and a significant number of those are metabolic disintegrators. Discussion: Glucose and lipid homeostasis is severely impaired by this compound. Tobacco exposure contributes to adverse effects by impairing the physical, biochemical and molecular mechanisms in the tissues. The immunological components are damaged by tobacco with high production of proinflammatory cytokines (IL-6, TNF-∞) and augmentation of inflammatory responses. These events result in damages to cytoskeletal structures of different tissues. Degradation of matrix structure (by activation of different types of MMPs) results in the permanent damages to the tissues and their metabolic functions. Cellular antioxidant defense system mostly cannot or hardly nullify CS-induced ROS production that activates polymorphonuclear neutrophils (PMNs), which are a major source of cytokines and chemokines (TNFα, IL6, IL8, INFγ). Additive effects of these immediately promote the low energy-metabolism as well as inflammation. Oxidative stress, mitochondrial dysfunction, and inflammation contribute to the direct nicotine toxicity via nAChRs in diabetes. The investigator identified that skeletal muscle insulin-resistance occurs in smokers due to phosphorylation of insulin receptor substrate1 (IRS1) at Ser-636 position. Conclusion: Tobacco exposure initiates free radical related immunological impairment, DNA damage, and inflammation. So, the present analysis is of importance to figure out the mechanistic layout of tobacco-induced tissue damage and its possible therapeutic interventions.

Objective: Multiple sclerosis (MS) is a chronic neurodegenerative disease of the central nervous system. The most common disease phenotype is Relapsing-Remitting MS (RRMS). Beta interferons are the first line of RRMS patients’ treatment. Interferon-inducible protein 16 (IFI16) as a DNA sensing molecule and its downstream complex stimulator of interferon genes (STING) play a critical role in the activation of type I interferons. Hence we aimed to evaluate the expression rate of IFI16 and STING in RRMS patients’ blood under a different type of IFNβ treatment. Methods: In the present study, 99 individuals participated. The participants were divided into 4 groups: 28 control subjects, 25 new cases of RRMS patients, 25 RRMS patients treated with IFNβ-1a (B1a), 21 RRMS patients treated with IFNβ-1b (B1b). The EDTA-treated blood samples were taken and transferred at standard conditions to the Cellular and Molecular Research Center of Shahrekord University of Medical Sciences, RNA was extracted and converted into cDNA. To evaluate the expression of IFI16 and STING, the Real-Time PCR method using SYBR Green/ROX qPCR master mix was performed done. The level of genes expression was measured using 2–ΔΔCt method. The obtained data were analyzed using SPSS v22 software. Results: Comparison of the IFI and STING mRNA expression in blood samples in association with gender and age showed no significant differences (p>0.05). Also, the evaluation of IFI16 mRNA level revealed that the IFI16 genes’ expressions were remarkably higher in the new case group compared to the control group, however, STING expression did not show any significant difference. The mRNA levels of IFI16 and STING in IFNβ-treated groups were significantly lower than the new case group (p<0.001). Also, the genes’ expressions in both the IFNβ-treated groups were significantly lower compared to the control group (p<0.001). In the assessment of the correlation of IFI16 and STING expressions with age and sex in different research groups, no statistically significant differences were seen (p>0.05). Conclusion: Perhaps the IFNβ therapy decreases the IFI16 and STING expression in a STINGdependent pathway as a negative feedback mechanism for regulation of the immune system and suppression of pro-inflammatory cytokines production. The important role of DNA sensing molecules and STING-dependent pathway in MS gives a new insight into future treatment based on STING-direct therapies.

Aim: We hypothesized that IL-1β concentrations are augmented in overweight adolescents, who do not display metabolic syndrome. Additionally, we aimed to correlate the IL-1β concentrations with several established risk factors for CVD. Methods: Overweight or control subjects, aging from 14-18 years, were classified according to their adjusted body mass index and evaluated for biochemical and anthropometric parameters. The proinflammatory cytokine IL-1β was assessed in the serum. Results: Increased body fat percentage, waist circumference, triglycerides, total cholesterol, Very Low-Density Lipoprotein (VLDL) cholesterol, Low-Density Lipoprotein (LDL) cholesterol, Castelli I index, IL-1β, and IL-8 levels, were observed in overweight adolescents. No differences were observed in systolic blood pressure, diastolic blood pressure, glucose or High-Density Lipoprotein (HDL) cholesterol. Positive correlations between IL-1β with anthropometric and or biochemical parameters were found. Conclusion: In conclusion, increased IL-1β levels correlate to dyslipidemic factors and may further support low-grade inflammation. IL-1β may further predict the early onset of cardiovascular disease in this population, taking into consideration its important regulatory role.

Background: The Human Leukocyte Antigen (HLA) class II genes, particularly the HLADR and -DQ loci, have been shown to play a crucial role in Type 1 Diabetes (T1D) development. Objective: This study is the first to examine the contribution of the HLA-DR/DQ alleles and haplotypes to T1D susceptibility in Jordanians. Methods: Polymerase chain reaction sequence-specific primers (PCR-SSP) were used to genotype 41 Jordanian healthy controls and 50 insulin-dependent diabetes mellitus (IDDM) patients. Results: The following alleles were found to be significant high risk alleles in T1D Jordanian patients: DRB1*04 (OR=3.95, p<0.001), DRB1*0301(OR=5.27, p<0.001), DQA1*0301 (OR=5.67, p<0.001), DQA1*0501(OR=3.18, p=0.002), DQB1*0201(OR=2.18, p=0.03), DQB1*0302 (OR=5.67, p<0.001). However, Jordanians harboring the DRB1*0701 (OR=0.37, p=0.01), DRB1*1101 (OR=0.2, p=0.01), DQA1*0505 (OR=0.31, p=0.02), DQA1*0103 (OR=0.33, p=0.04), DQA1*0201 (OR=0.45, p=0.04), DQB1*0301 (OR=0.23, p=0.001), DQB1*0501 (OR=0.18, p=0.009) alleles had a significantly lower risk of developing T1D. Conclusion: A strong positive association of DRB1*04-DQA1*0301-DQBl*0302 (OR=5.67, p<0.001) and DRB1*0301-DQA1*0501-DQB1*0201 (OR=6.24, p<0.001) putative haplotypes with IDDM was evident in Jordanian IDDM patients whereas DRB1*1101-DQA1*0505- DQB1*0301 (OR=0.23, p=0.03) was shown to have a protective role against T1D in Jordanians. Our findings show that specific HLA class II alleles and haplotypes are significantly associated with susceptibility to T1D in Jordanians.

Background: It was observed that type II diabetes mellitus associated with chronic liver failure improved after stem cell transplantation. However, there were no adequate studies regarding this issue. The aim of this study was to evaluate the effect of stem cell transplantation on associated type II diabetes mellitus and on the liver function tests. Methods: This pilot study included 30 patients of post-hepatitis chronic liver failure who were classified into two groups: Group I included patients with chronic liver cell failure associated with type 2 diabetes. Group II included patients without type II diabetes. Autologous CD34+ and CD133+ stem cells were percutaneously infused into the portal vein. Responders (regarding the improvement of diabetes as well as improvement of liver condition) and non-responders were determined. Patients were followed up for one, three and six months after the intervention evaluating their three-hour glucose tolerance test, C- peptide (Fasting and postprandial), Child-Pugh score and performance score one month, three months, and six months after stem cell therapy. Results: Both synthetic and excretory functions of the liver were improved in 10 patients (66.66 %) of group I and in 12 patients (80 %) of group II. Significant improvement in the Oral Glucose Tolerance Test in the responders of both the groups was well defined from the 3rd month and this was comparable to changes in liver function tests and Child-Pugh score. Conclusion: Successful stem cell therapy in chronic liver cell failure patients can improve but not cure the associating type 2 diabetes by improving insulin resistance.

Objective: To evaluate the plasma cytokine levels during T cell-mediated inflammatory responses and compare the metabolic markers between overweight and obese perimenopausal women without systemic diseases. Methods: Sixty perimenopausal women were divided into two groups (overweight and obese). Participants in both groups had their waist-to-height ratio (WHtR) measured and blood samples collected for the evaluation of estradiol, fasting glucose, leptin, high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, IL-10, IL-17A levels, and lipid profile. Results: In univariate analysis, women with obesity showed increased WHtR, fasting glucose, leptin, and IL-6 (p < 0.05) levels; however, significant differences were not observed in IL-10 or IL-17A (p > 0.05) levels. In the receiver operating characteristic curve, the highest areas under the curve were shown for leptin (0.856) and IL-6 (0.706). IL-6 levels correlated with both hs-CRP (r = 0.302, p = 0.020) and leptin (r = 0.294, p = 0.022). However, in multivariate analysis, IL-6 was not associated with a greater likelihood of obesity (OR = 1.61; 95% CI: 0.82-3.15; p = 0.16), when potential confounders were considered. Conclusion: IL-6 levels varied between overweight and obese perimenopausal women, and this association was weaker when adjusted for other clinical variables.

Background: A possible relationship between thyroid hormones and glucose metabolism in diabetes has already been established. Objectives: We aimed to evaluate the thyroid function markers and their relationship with inflammation, which is considered as a pathogenic condition of diabetes. Methods: This cross-sectional study included 276 patients with type 2 diabetes. Serum levels of thyroid (TSH, FT4, and FT3) and inflammatory markers (CRP, IL-6, and TNF-α) were measured. Results: The mean age of the subjects was 55.2 years and mean diabetes duration of 16.8 years. The inflammatory markers showed significant differences with the tertiles of TSH and thyroid hormones. TSH was significantly correlated with inflammatory markers, IL-6 (r = 0.13, P = 0.020) and TNF-α (r = 0.17, P = 0.003), while FT4 had a correlation only with TNF-α (r = 0.25, P = <0.001). FT3 was negatively correlated with inflammatory marker IL-6 (r = -0.14, P = 0.020), HbA1c (r = -0.12, P = 0 .040), and HOMA-IR (r = -0.17, P = 0.010). Conclusion: Abnormalities in the thyroid hormone metabolism are related to the increased inflammatory activity as well as insulin resistance, and are associated with the disorders of glucose metabolism.

Background: In recent years, natural products have received great attention for cancer prevention owing to their various health benefits, noticeable lack of toxicity and side effects, and the limitations of chemotherapeutic agents. Andrographolide, a labdane diterpenoid is a principal bioactive constituent of Andrographis paniculata Nees, exhibits significant anticancer activity. Objective: The efficacy of andrographolide on colon cancer cells is yet to be elucidated completely. Therefore, we investigated the anticancer efficiency of andrographolide in colon cancer DLD1 cell line. Methods: Antiproliferative activity of andrographolide on DLD1 cells was evaluated by MTT assay, LDH release assay, morphological analysis and colony formation assay. Induction of apoptosis was determined by DAPI staining, Annexin V-FITC staining assay, and caspase-3 activation assay. Role of andrographolide induced cellular reactive oxygen species (ROS) and its association with apoptosis induction in DLD1 cells was elucidated by DCFDA dye. Synergistic ability of andrographolide with 5- fluorouracil (5-FU) and paclitaxel (PTX) was evaluated by MTT assay. Results: Results of the present study indicated that andrographolide declined cell viability of DLD1 cells in a concentration and time-dependent manner. Andrographolide induced apoptosis via nuclear condensation, phosphatidylserine externalization and caspase-3 activation. It also augmented cellular ROS levels which were in turn associated with apoptosis induction in DLD1 cells. Moreover, andrographolide displayed synergistic activity with 5-FU and PTX against DLD1 cells. Conclusion: The present study showed that andrographolide demonstrated antiproliferative and apoptotic properties, moreover it also displayed synergistic effect with chemotherapeutic drugs in colon cancer DLD1 cells.

Objective: ShenQi compound (SQC) is a traditional herbal formula, which has been used to treat Type 2 diabetes mellitus (T2DM) and complications for years. The aim of this study was to explore the preventive and protective effects of SQC recipe on the skeletal muscle of diabetic macrovasculopathy mice, which provides a theoretical basis for the clinical use of this formula. Methods: We evaluated the effect of SQC in a diabetic vasculopathy mouse model by detecting a series of blood indicators (blood glucose, lipids and insulin) and performing histological observations. Meanwhile, we explored the molecular mechanism of SQC treatment on skeletal muscle by genome expression profiles. Results: The results indicated that SQC could effectively improve blood glucose, serum lipids (total cholesterol (TC), Triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)) and insulin (INS) levels in diabetic vasculopathy mice, as well as alleviating skeletal muscle tissue damage for diabetic macrovasculopathy. Meanwhile, compared with rosiglitazone, SQC showed a better effect on blood glucose fluctuation. Moreover, the gene microarray analysis indicated that SQC might improve T2DM by affecting biological functions related to cell death and cell adhesion. Moreover, 7 genes (Celsr2, Rilpl1, Dlx6as, 2010004M13Rik, Anapc13, Gm6097, Ddx39b) might be potential therapeutic targets of SQC. Conclusion: All these results indicate that SQC is an effective preventive and protective drug for skeletal muscle in diabetic macrovasculopathy, and could alleviate skeletal muscle tissue damage through affecting biological functions related to cell death and cell adhesion.

Introduction: Nonalcoholic fatty liver disease (NAFLD) is closely associated with metabolic syndrome (MetS), insulin resistance (IR) and chronic inflammation. Although familial Mediterranean fever (FMF) patients have no symptoms in the periods between attacks, their subclinical inflammation continues. The aim of the present study was to determine the NAFLD frequency in FMF patients and to evaluate their MetS, IR and lipid profiles. Methods: The study included 54 FMF patients and 54 control subjects. The clinical and demographic characteristics of the subjects were recorded, and the patients’ Pras disease severity score was calculated. IR was determined using the homeostasis model assessment (HOMA) index. MetS was diagnosed using the revised National Cholesterol Education Program Adult Treatment Panel III criteria (NCEP ATP III). Hepatic ultrasonography was used to diagnose NAFLD. Results: NAFLD was observed in 15 FMF patients (27.8%) and 14 controls (25.9%). The difference between the groups was not significant (p=0.828). Similarly, no significant difference was found between the two groups for MetS frequency and HOMA index levels. Fasting plasma glucose was significantly higher in FMF patients, whereas differences between the two groups were not significant for lipid levels and other parameters. When FMF patients with and without NAFLD were compared, no significant difference was found in Pras disease severity score, duration of the disease and daily colchicine dose. Conclusion: The present study showed that NAFLD frequency was not increased in FMF patients, and that patients’ MetS frequency, IR and lipid profiles were not different from control subjects.

Background: Subclinical hyperthyroidism is defined by a subnormal serum thyroidstimulating hormone (TSH) level with normal free thyroxine (FT4) and free triiodothyronine (FT3) levels. Its prevalence varies from 0.6% to 16% in the elderly and can increase to 20% in patients receiving thyroid hormone replacement therapy. Thyroid disease and/or replacement therapy are frequently associated with cardiovascular involvement. Cases Presentation: We report three clinical cases of patients with initial subclinical hyperthyroidism and cardiological manifestations, including supraventricular and ventricular extrasystoles, prolapse of the mitral valve with severe regurgitation, higher mean heart rate and deterioration of the arrhythmias on arrhythmogenic dysplasia substrate. Conclusion: We discuss the role of appropriate and early correction of thyroid dysfunction in improving cardiological manifestations.

Background: Known as a rare disease, Kimura disease is a chronic, allergic and inflammatory process. It may overlap other allergic conditions, as well. Case Presentation: This study is going to present a 36-year-old woman, with cough, dyspnea and bone pain. Other differential diagnoses were excluded during the investigations. The definite diagnosis was made by excisional biopsy and pathological investigations. Conclusion: This was a rare medical condition with remarkable diagnostic challenge.