Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology, Endocrine and Metabolic Agents) - Volume 17, Issue 2, 2017

Background: Programmed death-1 ligand 1 (PD-L1) is one of the most important immunoregulatory molecules expressed on the cell surface of many cell types under a variety of physiological and pathological conditions. One of its key functions is the inhibition of T cell effector activities by binding with programmed death-1 (PD-1) expressed on the surface of activated T and B cells. After its binding, PD-1 inhibits signal transduction of the T cell and B cell receptors. This immunosuppressive mechanism is widely used by many tumors to escape the immune attack, thereby favoring tumor progression. The systemic administration of antibodies that block PD-L1/PD-1 interactions to cancer patients is demonstrating unprecedented clinical success. This efficacy is usually explained by the reactivation of tumor-infiltrating T cells that have been inactivated by PD-L1/PD-1 interactions. However, PD-L1 also transmits intracellular signals to cancer cells that favour their survival. This intrinsic intracellular signaling may significantly contribute to tumor growth by conferring cancer cells resistance to apoptotic stimuli including interferons. Conclusion: Here we review the current knowledge on PD-L1 signal transduction in cancer cells and its role in tumor progression and resistance to anti-cancer therapies.

Objective: Pathogen microorganisms use pathogen-encoded factors resembling host factors to elude the host's immune system. Based on molecular mimicry, a hypothesis was developed based on the bioinformatics analysis which represents the microorganism's interference with chicken MHC regulatory factors. Method: The sequences of chicken NLRC5 and CIITA were retrieved from NCBI and ensemble database; so that the regulatory factors were predicted by using STRING tools. Also, Swiss model tools were used to predict the 3D structure of these molecules. The Cluspro 2.0 tool was used inorder to reveal the intramolecular interaction. Moreover, to find out the sequence and structure similarity with microorganism, UniPortKB, VAST and 3D Match tools were used as the experimental instruments. Result: In summary, Roseomonas cervicalis, Acetobacter aceti, Azospirillum sp CAG239, Roseomonas cervicalis, Rickettsiales_bacterium, Lactobacillus_hilgardii, Lactobacillus sakei, Aciduliprofundum boonei, Geoglobus_acetivorans, Pyrococcus horikoshii, Corynebacterium accolens, Hydrocarboniphaga effusa, Rhodopirellula europaea, Protochlamydia amoebophila and Escherichia coli have the protein subunit with detectable similarity with MHC regulatory factors. Conclusion: Bioinformatics analysis discovered mimicry as the new aspect of immune evasion or immune suppression effects of microbial organism in addition to the molecular similarities in MHC regulatory factors which were revealed between mammals and birds.

Introduction: Withdrawal period from abused substance is accompanied by many problems. In some addicted people, relapse to drug-seeking and compulsive abuse develops. On time intervention may reduce relapse in some addicted people by knowing underlying mechanism. Methods and Materials: In this study 48 rats were randomly divided into four groups: pair, isolation, withdrawal pair, and withdrawal isolated. Rats in withdrawal groups after one week for acclimatization were first induced for morphine addiction by injection of increasing dose of morphine (5 mg/kg/rat in the first day to the final dose of 35 mg/kg/rat) for 7 days and then were withdrawn from morphine by the injection of naltrexone (3 mg/kg/rat) in 8 days. In control groups no treatment was applied. On day 14, rats in all groups were first evaluated for avoidance memory and novelty-seeking behavior. Then rats in day 15 were sacrificed and brain immediately removed for the assessment of oxidative stress (OS) status in the hippocampus and prefrontal cortex for malondialdehyde (MDA), glutathione and nitrite/nitrate. Results: Avoidance memory was better in withdrawal pair rats. Novelty-seeking behavior was increased in withdrawal isolated rats. Anxiety was reduced in withdrawal isolated rats. MDA was higher in withdrawal isolated rats. Glutathione and nitrite/nitrate were higher in withdrawal isolated rats. Conclusion: Pair state (socialization) improves avoidance memory, increases anxiety and reduces novelty-seeking behavior in withdrawal period. Also, oxidative stress markers responded differently to withdrawal stress in isolated and pair rats.

Objectives: The angiotensin converting enzyme 2 (ACE2)/angiotensin-(1- 7)/Mas pathway has been expected to act as a protective arm of the renin-angiotensin system. Recently, the role of ACE2 in glucose metabolism has been highlighted. We previously reported that olmesartan increases ACE2 expression in injured arteries. Therefore, we hypothesized that treatment with olmesartan would improve glucose metabolism via ACE2 activation. Here, we investigated the effect of olmesartan on glucose metabolism using ACE2-deficient mice (ACE2KO). Methods: Ten-week-old WT and ACE2-deficient mice (ACE2KO) were employed in this study. Olmesartan or valsartan was administered intraperitoneally at a dose of 1.5 mg/kg/day in 8 weeks old mice. Insulin resistance was evaluated by oral glucose tolerance test and insulin tolerance test. Morphological changes in adipose tissue as well as adipocyte differentiation and inflammatory response and histological changes in the pancreas were examined. Results: ACE2KO showed significantly higher fasting blood glucose level and blood glucose level at 30 min after glucose load in the oral glucose tolerance test. Treatment with olmesartan reduced blood glucose level at 30 min after glucose load in both WT and ACE2KO, but valsartan did not. Treatment with olmesartan increased adipocyte number and reduced mean adipocyte size only in WT, but not in ACEKO. Treatment with olmesartan also prevented the reduced size of pancreatic islets in ACE2KO. Conclusion: The present study demonstrated that ACE2KO exhibited abnormal glucose metabolism. Treatment with olmesartan improved glucose metabolism in WT more than in ACEKO mice, indicating the possible existence of an ACE2-dependent pathway induced by olmesartan.

Background: Now-a-days, discovery of bioactive compounds of plant origin is playing very important role in treatment of various ailments without any side effect world widely. Since, time immemorial, plants have been utilized as a source of Traditional System of Medicine and in India, one of the well known system is Ayurvedic System of Medicine that has been flourishing since thousands years for treatment of allergy, asthma and other inflammatory diseases. Objectives: To inhibit leukotrienes by a purified fraction of Ocimum tenuiflorum in HL- 60 cell lines. To investigate anti-inflammatory activities of a purified Fraction of Ocimum tenuiflorum in an OVA induced asthma model in BALB/c mice. Methods: Plant materials of Ocimum tenuiflorum whole plants were collected after identification and authentication from Vidisha, (M.P.), India and were shade dried, pulverized to powder and extracted after de-fatting in MEOH and DCM and then tested for LTC4, LTA4 and COX-2 inhibitory activities in HL-60 Cell lines. RTPCR was performed to determine the LTC4-synthase mRNA expression. The bio-active purified fraction PM-OT was then tested in vivo in an OVA-induced asthma model in BALB/c mice and inhibition of inflammation was assessed via in vivo imaging tomography. Results: The PM-OT inhibited activities of LTC4 by 52%, LTA4 by 25% and COX-2 by 99% in HL-60 cells and LTC4-synthase mRNA expression in HL-60 Cells. Intra-gastric administration of PM-OT at 100mg/kg body weight along with HPMC led to a reduction in an OVA-induced lung inflammation in asthma model in BALB/c mice. Conclusion: A purified PM-OT fraction showed significant anti-inflammatory activities both in vitro and in vivo, which supported its traditional use in the treatment of inflammatory lung disease and asthma.

Background: Arsenic is a naturally occurring contaminant in water. Its chronic exposure has been linked to several health problems, including cancer. Children are most affected by their exposure due to physiological conditions and certain nutrients, known to decrease the toxicity of the metalloid. Objective: The main objective was to analyze the food intake and nutritional status in children exposure to arsenic in water. Methods: A transversal study was conducted on cases of a historical cohort comprising forty three children, from two communities, Guanajuato, Mexico. The children were selected from the previous study, where they had 0.01 to 5.9 mg /kg of arsenic in hair (in both communities). The anthropometric variables included weight and height determined through BMI. Results: The average age was 11 ± 0.8 years old. Twenty-six percent of children were underweight and 19% were overweight and the correlation was negative between the arsenic levels reported in the previous study with the current BMI value (r= -0.5931; IC=- 0.1096-0.8361; p=0.0198). Only 26% had an adequate energy intake (1717±288kcal). The consumption of protein, folic acid, zinc and fiber was low according to RDA. The children used to have mainly soda, fried foods and processed foods. The water source was mainly bottled water in 58.1% of children´s families. The average consumption of milk was 250ml and its source was cow stables in 49%, with a significant difference between the two communities, regarding the origin of milk and water. Conclusion: The dietary intake was poor in quality and quantity with low intake in vitamins and micronutrients that are important for metabolism and lower toxicity of arsenic. The correlation between BMI and arsenic levels should be studied, since poor diet and poor nutritional status could exacerbate the complications of the metalloid.

Background: Diabetic foot ulcer is a common disorder involving diabetic patients. Appling new indicators of the severity of diabetic foot infection may help the practitioners to develop more efficient diagnosis and treatment strategies. Methods: In this study, 70 diabetic patients with a foot ulcer, admitted to the infectious diseases ward of Tabriz education and treatment center between 2015 and 2016, were enrolled. The severity of infection was determined according to the Infectious Diseases Society of America clinical practice guideline. Twenty of these patients were excluded and further examinations were performed on 50 patients. On the first day of hospitalization and before antibiotic therapy, Erythrocyte Sedimentation Rate (ESR), C-reactive protein (CRP), Procalcitonin (PCT), White blood cells (WBCs), Fasting blood sugar (FBS) and HbA1C were measured. The level of these factors was then compared across four severity groups. Results: Pulse rate, respiratory rate, body temperature and leukocyte count were significantly higher in the patients with severe infection. ESR and CRP were higher in patients with more severe infection, but PCT and HbA1C level were not in accordance with the infection's severity. Conclusion: In conclusion, ESR and CRP level can be more successfully used to discriminate patients, according to the severity of the infection.

Objective: To evaluate the hypolipidemic and antioxidant effects of aqueous extract leaves of Anvillea radiata (AEL of A. radiata) in normal and streptozotocin (STZ) induced diabetic rats. In addition, the determination of total polyphenol and total flavonoid contents in the AEL of A. radiate was performed. Methods: The effects of oral administration of AEL of A. Radiata (10 mg/kg) on the plasma total cholesterol (TC), triglyceride (TG) and high-density lipoprotein-cholesterol (HDL-C) concentrations were measured in both normal and diabetic rats. The antioxidant capacity was realized by the method of DPPH. Total polyphenol, as well as, flavonoid contents of the AEL of A. radiata were determined by Folin-Ciocalteu method and colorimetric AlCl3 method, respectively. Results: AEL of A. radiate (10 mg/kg) showed a strong hypolipidemic effect both in normoglycaemic and in STZ rats after 15 days of daily treatment. In normal rats, AEL of A. radiata induced a significant decrease in plasma triglyceride levels (p<0.0001). Moreover, plasma cholesterol total levels reduced significantly (p<0.05; p<0.0001) both in normal and diabetic rats, respectively. In contrast, plasma HDL-C levels showed a significant increase (p<0.05; p<0.01) both in normal and in STZ induced diabetic rats, respectively. On the other side, AEL of A. radiata showed important antioxidant activity and revealed the inhibitory concentration of 50% of free radicals (IC50) (IC50=343.41 mg/ml). Concerning the quantitative determination of total polyphenol and flavonoid contents, which were equal to 70.28 mg of gallic acid equivalent per gram of extract (mg EAG/g) and 16.38 mg of quercetin equivalent per gram of extract (EQ/g), respectively. Conclusion: AEL of A. radiata (10 mg/kg) shows the potential hypolipidemic and antioxidant effects in both normal and STZ-induced diabetic rats.