Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 20, Issue 8, 2020

Acromegaly is a rare disease. Improvements in lifespan in these patients have recently been reported due to transsphenoidal surgery (TSS), advances in medical therapy, and strict criteria for defining disease remission. This document reports the opinions of a group of Italian experts who have gathered together their prolonged clinical experience in the diagnostic and therapeutic challenges of acromegaly patients. Both GH and IGF-I (only IGF-I in those treated with Pegvisomant) are needed in the diagnosis and follow-up. Comorbidities (cardio-cerebrovascular disease, sleep apnea, metabolic derangement, neoplasms, and bone/joint disease) should be specifically addressed. Any newly diagnosed patient should be referred to a multidisciplinary team experienced in the treatment of pituitary adenomas.

Any newly diagnosed patient should be referred to a multidisciplinary team experienced in the treatment of pituitary adenomas. The therapeutic management of acromegaly always requires a personalized strategy. Normal age-matched IGF-I values are the treatment goal. Transsphenoidal surgery by an expert neurosurgeon is the primary treatment modality for most patients, especially if there are neurological complications. In patients with poor clinical conditions or who refuse surgery, primary medical treatment should be offered, firstly with somatostatin analogs (SSAs). In patients who do not reach hormonal targets with first-generation depot SSAs, a second pharmacological option with pasireotide LAR or pegvisomant (alone or combined with SSA) should be offered. Irradiation could be proposed to patients with surgical remnants who would like to be free from long-term medical therapies or those with persistent disease activity or tumor growth despite surgery or medical therapy. Since the therapeutic tools available enable therapeutic targets to be achieved in most cases, the challenge is to focus more on the quality of life.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease comparing the inflammation of synovium. Macrophage-like synoviocytes and fibroblast-like synoviocytes (synoviocytes) are crucial ingredients of synovium. Therein, a lot of research has focused on synoviocytes. Researches demonstrated that TLR1, TLR2, TLR3, TLR4, TLR5, TLR6 TLR7 and TLR9 are expressed in synoviocyte. Additionally, the expression of TLR2, TLR3, TLR4 and TLR5 is increased in RA synoviocyte. In this paper, we review the exact role of TLR2, TLR3, TLR4 and TLR5 participate in regulating the production of inflammatory factors in RA synoviocyte. Furthermore, we discuss the role of vasoactive intestinal peptide (VIP), MicroRNA, Monome of Chinese herb and other cells (Monocyte and T cell) influence the function of synoviocyte by regulating TLRs. The activation of toll-like receptors (TLRs) in synoviocyte leads to the aggravation of arthritis, comparing with angiogenesis and bone destruction. Above all, TLRs are promising targets for managing RA.

Background and Objective: Eosinophils are primitive myeloid cells derived from bonemarrow precursors and require the intervention of interleukin (IL)-5 for their survival and persistence in blood and tissues. Under steady-state conditions, they contribute to immune regulation and homeostasis. Under pathological circumstances, eosinophils are involved in host protection against parasites and participate in allergy and inflammation. Discussion: Mostly, in asthma, eosinophils provoke airway damage via the release of granule contents and IL-13 with mucus hypersecretion and differentiation of goblet cells. Then, tissue remodeling follows with the secretion of transforming growth factor-β. Eosinophils are able to kill helminth larvae acting as antigen-presenting cells with the involvement of T helper (h)-2 cells and subsequent antibody response. However, they also exert pro-worm activity with the production of suppressive cytokine (IL- 10 and IL-4) and inhibition of nitric oxide. Eosinophils may play a pathogenic role in the course of chronic and autoimmune disease, e.g., inflammatory bowel disease and eosinophilic gastroenteritis, regulating Th2 responses and promoting a profibrotic effect. In atopic dermatitis, eosinophils are commonly detected and may be associated with disease severity. In cutaneous spontaneous urticaria, eosinophils participate in the formation of wheals, tissue remodeling and modifications of vascular permeability. With regard to tumor growth, it seems that IgE can exert anti-neoplastic surveillance via mast cell and eosinophil-mediated cytotoxicity, the so-called allergo-oncology. From a therapeutic point of view, monoclonal antibodies directed against IL-5 or the IL-5 receptors have been shown to be very effective in patients with severe asthma. Finally, as an alternative treatment, polyphenols for their anti-inflammatory and anti-allergic activities seem to be effective in reducing serum IgE and eosinophil count in bronchoalveolar lavage in murine asthma. Conclusion: Eosinophils are cells endowed with multiple functions and their modulation with monoclonal antibodies and nutraceuticals may be effective in the treatment of chronic disease.

Pancreatitis is a fibro-inflammatory disorder of the pancreas that can occur acutely or chronically as a result of the activation of digestive enzymes that damage pancreatic cells, which promotes inflammation. Chronic pancreatitis with persistent fibro-inflammation of the pancreas progresses to pancreatic cancer, which is the fourth leading cause of cancer deaths across the globe. Pancreatic cancer involves cross-talk of inflammatory, proliferative, migratory, and fibrotic mechanisms. In this review, we discuss the role of cytokines in the inflammatory cell storm in pancreatitis and pancreatic cancer and their role in the activation of SDF1α/CXCR4, SOCS3, inflammasome, and NF-ΚB signaling. The aberrant immune reactions contribute to pathological damage of acinar and ductal cells, and the activation of pancreatic stellate cells to a myofibroblast-like phenotype. We summarize several aspects involved in the promotion of pancreatic cancer by inflammation and include a number of regulatory molecules that inhibit that process.

Colorectal cancer (CRC) is one of the most common cancers and a significant cause of tumor- related deaths worldwide. Traditional biomarkers, such as CEA and CA199, are not sensitive enough to provide useful information for early diagnosis and treatment and are rather used to track the clinical progression of the disease. There is growing evidence that microRNAs (miRNA) are potentially superior to traditional biomarkers as promising non-invasive biomarkers for the timely diagnosis and prediction of prognosis or treatment response in the management of CRC. In this review, the latest studies on the dysregulation of miRNAs expression in CRC and the potential for miRNAs to serve as biomarkers were collected. Given the limitations of miRNA, as discussed in this paper, its clinical applications as a diagnostic biomarker should be limited to use in combination with other biomarkers. Further research is necessary to elucidate the clinical applications of miRNA in therapy for CRC.

Background: Breast cancer appears in a strong inclination to metastasize in bone tissue. Several strategies are discussed in combating bone metastasis in breast cancer. However, therapy is only palliative and does not provide any improvement in survival to the majority of patients with advanced cancer. Obese and overweight women with breast cancer are three times more likely to develop metastatic disease compared to normal-weight women with the same treatment regimen. Overweight greatly intensify adipocytes formation in the bone marrow affecting bone metabolism by decreasing osteoblast differentiation and bone formation. Cathepsin K (CTSK), a cysteine protease, effectively degrades several components of the extracellular matrix and has the ability to differentiate adipocytes from bone marrow lineage. Therefore, the purpose of this review is to emphasize the underlying mechanism of CTSK and obesity role in breast cancer metastasis. Methods: Systematic review was performed using PubMed, EMBASE. The evidence of obesity and CTSK in breast cancer skeletal metastasis were analyzed, summarized and compared. Results: The present investigation argues for a specific association of CTSK with breast cancer skeletal metastasis by promoting adipocyte differentiation. The potential tumor-supporting roles of adipocytes are well documented, and in fact, suppressing adipocyte could be a new therapeutic option in the battle against lethal metastatic breast cancers. Conclusion: This review emphasizes CTSK through its multifaceted role in differentiating adipocytes, inflammation, and extracellular degradation, may be a critical factor in an obesity-cancer connection. Thus, integration of CTSK targeting strategies into established traditional therapies seems to hold substantial promise.

Background: The increase in global obesity rates over the past three decades has been remarkable, a true epidemic, both in developed and in developing countries. The projections, based on current trends, suggest an increase in the prevalence of obesity at 60% in adult men, 40% in adult women and 25% in children in 2050. Given the limitations of lifestyle and surgery interventions bariatric, drug therapy approaches for the treatment of obesity, therefore become important options. Aim: The purpose of this review is a review of the literature, based on research on MEDLINE until 2019, on the possible pharmacological options in the treatment of obesity. Results: Currently, the FDA has approved several molecules for the treatment of obesity, both in monotherapy and in combination. Pharmacological monotherapies focus mainly on a single protein target and include orlistat, lorcaserin and liraglutide while the combination molecules propose a multitarget approach and include phentermine/topiramate and naltrexone/bupropion. All the approved drugs showed, in the different studies, a weight reduction of at least 5%, compared to placebo, in 52 weeks of observation. Phentermine-topiramate and liraglutide have been associated with the highest probability of at least 5% weight loss. Liraglutide and naltrexone-bupropion had the lowest rates of therapy discontinuation due to adverse events. Conclusion: The drugs, associated with the standard diet and/or exercise protocols, represent a good therapeutic opportunity to allow not only weight loss but also to reduce the risk of developing diseases caused by obesity, particularly cardiovascular diseases, and to maintain the set objectives over time. However, future research on the pharmacological treatment of obesity should encourage greater personalization of therapy, given the differences in safety, efficacy and response to therapy, in the different subpopulations of patients with obesity.

Objectives: Vascular dysfunction is common in obesity. Insulin can directly modulate arterial function, but its role is unclear in obesity. We examined the influence of adiposity on direct effects of insulin on human artery responses. Methods: 22 healthy women were stratified by median BMI into lower (LA) (n=11) and higher adiposity (HA) (n=11). Small arteries from gluteal biopsies were tested for contractile responses to Noradrenaline (NA), the endothelium-dependent dilator Carbachol and the endothelium-independent dilator sodium nitroprusside were examined before and after incubation with 100 mU/ml human insulin. Results: Contractile responses were similar in the two groups. Insulin reduced NA-induced contraction in HA [3.5 (2.4-4.6) vs. 2.4 (1.4-3.4) mN/mm: p=0.004] but not those from LA [4.1 (2.8-5.3) vs. 3.7 (2.5-5.0) mN/mm: p=0.33]. Endothelium-dependent dilation (EDD) was significantly reduced in arteries from women in the HA (34.7 (18.8-50.6%)) compared to those from women in the LA (62.3 (46.2- 78.4); p=0.013). Insulin improved EDD (change in maximal dilation before/after insulin (%)) in arteries from the HA (37.7 (18.0 to 57.3) but not the LA (6.3 (-6.5 to 19.1), p=0.007. Conclusion: Reduced EDD evident in arteries from HA subjects improve by incubating in insulin. Hyperinsulinaemia may be necessary in maintaining endothelial function in obesity.

Aims: The present study was performed in order to analyze the antihypertensive activity of Micromeria graeca (L.) Benth. ex Rchb. Background: Micromeria graeca (L.) Benth. ex Rchb is an aromatic and medicinal plant belonging to the Lamiaceae family. This herb is used to treat various pathologies such as cardiovascular disorders. Meanwhile, its pharmacological effects on the cardiovascular system have not been studied. Objective: The present study aimed to evaluate the effect of aqueous extract of aerial parts of Micromeria graeca (AEMG) on the cardiovascular system in normotensive and hypertensive rats. Methods: In this study, the cardiovascular effect of AEMG was evaluated using in vivo and in vitro investigations. In order to assess the acute effect of AEMG on the cardiovascular system, anesthetized L-NAME-hypertensive and normotensive rats received AEMG (100 mg/kg) orally and arterial blood pressure parameters were monitored during six hours. In the sub-chronic study, rats were orally treated for one week, followed by blood pressure assessment during one week of treatment. Blood pressure was measured using a tail-cuff and a computer-assisted monitoring device. In the second experiment, isolated rat aortic ring pre-contracted with Epinephrine (EP) or KCl was used to assess the vasorelaxant effect of AEMG. Results: Oral administration of AEMG (100 mg/kg) provoked a decrease of arterial blood pressure parameters in hypertensive rats. In addition, AEMG induced a vasorelaxant effect in thoracic aortic rings pre-contracted with EP (10 μM) or KCl (80 mM). This effect was attenuated in the presence of propranolol and methylene blue. While in the presence of glibenclamide, L-NAME, nifedipine or Indomethacin, the vasorelaxant effect was not affected. Conclusion: This study showed that Micromeria graeca possesses a potent antihypertensive effect and relaxes the vascular smooth muscle through β-adrenergic and cGMP pathways.

Background: G protein-coupled bile acid receptor (TGR5) is involved in a number of metabolic diseases. The aim of this study was to identify the role of TGR5 after Roux-en-Y gastric bypass (GBP). Methods: Wild type and TGR5 knockout mice (tgr5-/-) were fed a high-fat diet (HFD) to establish the obesity model. GBP was performed. The changes in body weight and food intake were measured. The levels of TGR5 and peptide YY (PYY) were evaluated by RT-PCR, Western blot, and ELISA. Moreover, the L-cells were separated from wild type and tgr5-/- mice. The levels of PYY in L-cells were evaluated by ELISA. Results: The body weights were significantly decreased after GBP in wild type mice (p<0.05), but not tgr5-/- mice (p>0.05). Food intake was reduced after GBP in wild type mice, but also not significantly affected in tgr5-/- mice (p>0.05). The levels of PYY were significantly increased after GBP compared with the sham group (p<0.05); however, in tgr5-/- mice the expression of PYY was not significantly affected (p>0.05). After INT-777 stimulation in L-cells obtained from murine intestines, the levels of PYY were significantly increased in L-cells tgr5+/+ (p<0.05). Conclusion: Our study suggests that GBP up-regulated the expression of TGR5 in murine intestines, and increased the levels of PYY, which further reduced food intake and decreased the body weight.

Background: Identifying predictive factors that contribute to changes in body weight may well be an interesting approach to the management of obesity. Objective: This study was firstly aimed at examining the effect of a one-year lifestyle program based on improvements in the habitual diet and increased levels of physical activity on weight loss. Secondly, it was focused on identifying anthropometric, and serum hormonal, metabolic and haematochemical factors which can be associated with the degree of weight loss in Kg. Methods: 488 overweight or obese subjects, 383 women and 105 men, aged 18-67 years, were enrolled in the study. Body mass index, waist circumference, serum blood glucose, lipids, uric acid, creatinine, insulin, TSH, FT3, FT4, and 24-h urine catecholamines were measured. Results: Weight loss was positively associated with BMI (P < 0.01), waist circumference (P < 0.01), uric acid (P < 0.01), creatinine (P < 0.05), smoking (P < 0.01), and negatively correlated with age (P < 0.01), total cholesterol (P < 0.05), LDL-cholesterol (P < 0.01), HDL cholesterol (P < 0.05). In a multiple regression model considering weight loss as a dependent variable, and smoking, age, BMI, uric acid, creatinine, total cholesterol, LDL-cholesterol and HDL cholesterol as independent variables, weight loss maintained a direct independent relationship with BMI (P < 0.001), uric acid (P < 0.05), LDL-cholesterol (P < 0.05), and HDL-cholesterol (P < 0.05), and an inverse independent association with cholesterol (P < 0.01). Conclusion: This study suggests that higher BMI and uric acid levels, and lower total cholesterol concentrations are associated with a greater potential to lose weight.

Background: Metabolic syndrome (MetS) is a combination of metabolic disorders with increased risks for several diseases, such as cardiovascular diseases and diabetes. It is associated with the presence of various inflammatory molecules. Vitamin D plays an important role in the regulation of metabolism homeostasis. Objective: The main goal of this work is to investigate vitamin D levels among Algerian MetS patients and its possible outcomes on key molecules of the immune response, as well, the immunomodulatory effects of its active metabolite. Methods: We evaluated vitamin D status by the electrochemiluminescence method, Nitric Oxide (NO) levels by the Griess method and Matrix Metalloproteinases (MMPs) activities such as MMP-2 and MMP-9 by zymography in plasma of patients and healthy controls (HC). The immunomodulatory effects of the active metabolite of vitamin D (α-25 (OH)2D3) on the production of NO, IL-6, IL-10, TGF- β and s-CTLA-4 were assessed by Griess method and ELISA, in peripheral blood mononuclear cells (PBMCs) of Algerian MetS patients and HC. MMPs activities were also determined ex-vivo, while iNOS expression was assessed by immunofluorescence staining. Results: Severe vitamin D deficiency was registered in Algerian MetS patients. The deficiency was found to be associated with an elevated in vivo NO production and high MMPs activity. Interestingly, α-25 (OH)2D3 declined the NO/iNOS system and IL-6 production, as well as MMPs activities. However, the ex-vivo production of IL-10, TGF-β increased in response to the treatment. We observed in the same way, the implication of s-CTLA-4 in MetS, which was markedly up-regulated with α-25 (OH)2D3. Conclusion: Our report indicated the relationship between MetS factors and Vitamin D deficiency. The ex-vivo findings emphasize its impact on maintaining regulated immune balance.

Background: Despite significant progress in the diagnosis of contact dermatitis, the identification by specific tests or biomarkers remains an unsolved issue, particularly when needed for the confirmation of the occupational origin of the disease. Objective: To characterize the plasma proteome profile in occupational dermatitis in workers of paint industry. Methods: The study has a case-control design, comparing exposed workers with and without occupational contact dermatitis, matched for age, gender, occupational history, and comorbidities. An immunological assay (Human XL Cytokine Array Kit – ARY022B, R&D Systems) was used to measure the plasma levels of 105 cytokines and chemokines in a pooled sample of the cases and a pooled sample of the controls. Results: A 1.5-fold increase was noticed for interleukin 3, interleukin 10, and leptin in cases, as compared to controls. Fibroblast growth factor-7 and growth/differentiation factor-15 showed a 1.4-fold increase, while interleukin 19, interleukin 31, and macrophage inflammatory protein 3a had only a 1.3- fold increase. The leukemia inhibitory factor was the only plasma cytokine that showed a 1.3-fold decrease. All other cytokines had a variation of less than 1.2-fold between cases and controls. Conclusion: The recognition of the molecular signatures is very important for an accurate and indisputable diagnosis of occupational contact dermatitis. In workers from the paint industry, plasma levels of interleukins 3, 10, 13 and 19, fibroblast growth factor-7, and growth/differentiation factor-15, together with leukemia inducible factor, may differentiate subjects with contact dermatitis from those without skin lesions.

Objective: Lipemia is one of the causes of interference in immunoassay and LC-MS/MS methods. Increased prevalence of vitamin D deficiency in the US, where obesity is gradually increasing, raises the suspicion that high levels of fat diet and blood lipid levels interfere with vitamin D measurement results. The focus of this study was to investigate the effect of blood lipid profiles on vitamin D results and prevent the matrix effect. Material and Methods: In this study, 25OH vitamin D3 (25OHD3) levels of 100 samples consecutively accepted to biochemistry laboratory regardless of age and sex were measured by the LC-MS/MS method, and each sample was restudied after 1/10 dilution. After dilution restudy, two groups were obtained-group 1 (results deviating below 20%) and group 2 (results deviating above 20%)—and the difference between the groups was investigated. There were 79 patients in group 1 and 21 patients in group 2. In our study, lipid profiles (triglyceride, total cholesterol, HDL, LDL) from the same samples of consecutive vitamin D patients were studied. Results: It was observed that the triglyceride, total cholesterol HDL, LDL, and 25OHD3 measurements of group 1 and group 2 were similar (p > 0.05). While the mean vitamin D value in the second group was 9.94 ± 7.85, the mean vitamin D value after dilution was measured as 39.23 ± 18.13 and was statistically significant. 25OHD3 concentrations of 21 patients out of 100 were found to be falsely low. Measurements were repeated to confirm the results. Conclusion: The matrix effect caused by exogenous and endogenous interferences in the blood could be a hidden factor increasing the prevalence of vitamin D deficiency by causing falsely low 25OHD3 values. Suspicious results should be remeasured by a dilution study.

Background: Obesity is a major health problem associated with increased comorbidities, which are partially triggered by inflammation. Proinflammatory macrophage infiltration in adipose tissue of individuals with obesity increases chronic inflammation. Obesity is associated with elevated plasma levels of saturated fatty acids, such as palmitic acid (PA), which promotes inflammation in vivo and in vitro. Infusions of Lampaya medicinalis Phil. (Verbenaceae) are used in the folk medicine of Northern Chile to counteract inflammation of rheumatic diseases. Hydroethanolic extract of lampaya (HEL) contains spectrophotometrically defined compounds that may contribute to the observed effect on inflammation. Methods: We evaluated the phytochemical composition of HEL by high-performance liquid chromatography coupled to diode array detection (HPLC-DAD) and liquid chromatography-electrospray ionization- tandem mass spectrometry (LC-ESI-MS/MS). We assessed whether the exposure to HEL affects PA-induced expression of proinflammatory factors in THP-1 macrophages. Results: HPLC-DAD and LC-ESI-MS/MS analyses showed the presence of considerable amounts of flavonoids in HEL. The PA-induced phosphorylation of the inflammatory pathway mediators IKK and NF-ΚB, as well as the elevated expression and secretion of proinflammatory cytokines (IL-6, TNF-α), were reduced in cells pre-exposed to HEL. Conclusion: These findings give new insights about the effect of HEL reducing IKK/NF-ΚB proinflammatory pathway, likely explained by the number of flavonoids contained in the extract. More studies would be needed to define the possible role of Lampaya as a preventive approach in subjects with obesity whose circulating PA might contribute to chronic inflammation.

Background: Bisphenol A (BPA) is a xenobiotic that causes oxidative stress in various organs in living organisms. Blood cells are also an endpoint where BPA is known to cause oxidative stress. Blood cells, especially red blood cells (RBCs), are crucial for maintaining homeostasis and overall wellbeing of the organism. They are highly susceptible to oxidative stress induced by xenobiotics. However, there is limited data about the oxidative stress induced by BPA in blood, especially in red blood cells. This study was carried out to evaluate BPA induced oxidative stress in human RBCs in vitro and its amelioration by melatonin. Objective: To find if melatonin exerts a protective effect on the oxidative stress induced by the BPA in human red blood cells in vitro. Methods: The erythrocyte suspensions (2 ml) were divided into six groups and treated with 0, 50, 100, 150, 200, and 250 μg/ml of BPA. Another set of erythrocyte suspension with similar BPA treatment and 50 μM Melatonin per group was also set. Incubations lasted for 12 hrs in the dark. Lipid peroxidation, glutathione, glutathione reductase, catalase, and superoxide dismutase were measured as indicators of oxidative stress. Results: BPA caused a significant increase in lipid peroxidation. A decrease in GSH levels was also observed. The activities of all the studied antioxidants also decreased with BPA treatment. Melatonin was seen to mitigate the oxidative stress induced by BPA. Conclusion: Treatment of red blood cells with BPA caused an increase in oxidative stress, while melatonin decreased the induced oxidative stress.

Background: Single nucleotide polymorphisms (SNPs) of IL-28B and/or ICAM-1 could have a role in expecting a response from HCV infected patients to direct antiviral agents (DAAs). Objective: The aim of the current study was to investigate the impact of IL-28B rs12979860 and rs8099917, and, ICAM-1 rs281437 SNPs on response to treatment with sofosbuvir + Daclatsvir ± Ribavirin, among HCV-infected Egyptian patients. Methods: Whole blood genomic DNA was extracted from 120 participants (80 HCV-infected patients and 40 healthy volunteers). HCV-infected patients were subdivided into responders and nonresponders to DAAs. Liver function testing, anti-HCV antibodies, HCV-RNA viral load and HCV genotyping were performed. IL-28B and ICAM-1 SNPs were evaluated by real-time PCR. Results: ALT and AST levels were significantly higher among non-responder HCV infected patients (P = 0.001*). 90% of the patients had HCV genotype 4a and the remaining 10% had 4l genotype. Allelic discrimination revealed that IL-28B rs12979860 T, IL-28B rs809917 T and ICAM-1 rs281437 C alleles were more frequent among HCV-infected patients (responders or non-responders) than controls. However, IL-28B rs8099917 G allele was more frequent among healthy controls. Regarding the response to DAAs treatment, HCV-infected patients with IL-28B rs8099917 GG genotype showed a significantly earlier viral response compared to those carrying TT alleles. ICAM-1 rs281437 CT alleles were non significantly more frequent among responders. However, IL-28B rs12979860 alleles did not show any difference. Conclusion: Genotyping of IL-28B rs8099917 is a useful independent tool for expecting a response of Egyptian HCV-infected patients to DAAs.

Objectives: Previously, it was found that the para-nonylphenol (p-NP) impairs the osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs); thus the aim of the present study was to evaluate the mechanism of the impairment. Methods: rBMSCs after 3rd passage cultured in osteogenic media in the presence of 0, 0.5 and 2.5 μM p-NP for 5, 10, 15 and 20 days. The study investigated the viability of the cells using MTT assays. The mineralization was studied using Alizarin red quantification analysis. Using a flame-photometer, the electrolytes (sodium and potassium) were measured, and the level of calcium as well as ALT, AST, ALP and LDH was determined by commercial kits. The level of total-antioxidant, MDA and the activity of SOD and CAT were estimated with the help of a spectrophotometer. Gene expression was studied using rt-PCR. Results: The p-NP treatment of osteogenic differentiated MSCs showed intracellular electrolyte imbalance and variation of cellular metabolism. In addition, we observed oxidative stress due to the reduction of total antioxidant capacity and the imbalance of antioxidant enzymes activity. Investigating the genes involved in the osteogenic differentiation of MSCs to osteoblast showed that the 2.5 μM of p-NP reduced the expression of the ALP, SMAD, BMP and RUNX2 genes. Conclusion: The study concludes that this pollutant via influencing the genomics and metabolic imbalance, as well as oxidative induction, caused a reduction of mineralization and differentiation of MSCs. This environmental pollutant might cause osteoporosis, which necessitates raising public awareness, especially to those who live in the industrial area to prevent its drastic effect.

Background: Prediabetes, defined as impaired glucose tolerance and/or impaired fasting glucose, is a risk factor for future type 2 diabetes, dyslipidemia, cardiovascular disease and all-cause mortality. High serum levels of ischemia modified albumin (IMA) and malondialdehyde (MDA) as oxidative stress markers were determined in diabetes, however, no studies have investigated these markers together in prediabetes. The aim of the present study was to investigate the circulating levels of both IMA and MDA in a cohort of prediabetic adults. The possible associations between both markers and the atherogenic index of plasma (AIP) were also evaluated. Methods: This study enrolled 100 adults with prediabetes and 50 healthy controls matched for age and sex. Anthropometric measurements, fasting and 2-hour post load glucose, glycosylated hemoglobin (A1c), lipids profile, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), high sensitivity C-reactive protein (hs-CRP), AIP, IMA and MDA were assessed. Results: IMA, MDA, hs-CRP and AIP were significantly higher in adults with prediabetes than in healthy controls. Male gender, fasting and post load glucose, A1c, fasting insulin, TGs, HDL-C, hs- CRP, AIP and MDA were independent predictor variables of IMA, whereas male gender, WC, fasting and post load glucose, A1c, fasting insulin, TC, TGs, LDL-C, HDL-C, hs-CRP and AIP were independent predictor variables of MDA. Conclusion: The elevation of IMA concomitantly with MDA reflecting the antioxidant status in prediabetes, and their associations with hs-CRP and AIP should reinforce the idea of screening and treatment of prediabetes.