Volume 24, Issue 2

Cytokines are intracellular peptides that serve as immune mediators. The levels of both pro- and anti-inflammatory cytokines have been demonstrated to rise in the event of heat stroke in both human and animal models. Different hyperthermic states, including both normal exercise-induced hyperthermia and classical and exertional heat stroke, result in unique characteristic profiles of plasma cytokines. The complexity of the interaction between pro- and anti-inflammatory cytokines is outlined in the vast number of experimental studies and clinical observations reported in the literature. However, there is no unanimous logic in studying the changes in cytokine levels, and therefore, it is difficult to compare the effects seen in the different reports. The strong inflammatory response to heat stroke increases after the cessation of heat stress and is intricately involved both in damage-generating processes and in repair mechanisms that are put into action during the recovery phase. In surviving individuals, this response diminishes in magnitude as time progresses and eventually subsides to allow return-to-normal homeostasis. A greater magnitude of the inflammatory response is often associated with poor prognosis and even fatalities, suggesting an imbalance of the immune system, which causes an unregulated inflammatory response. This review describes the common known processes relating to the predominant cytokines altered in the event of heat injury. The role of cytokines, specifically in the pathophysiology of heat stroke, is elaborated and depicted as part of a biaxial model pertaining to the physiological and cellular/biochemical aspects of heat stroke.

Background: Bile acids are synthesized in the liver from cholesterol. Methods: This study investigated the impact and expression of different carriers of bile acid in the liver and kidneys. Eight-week-old male mice were used, which were fed for 15 days and divided into two groups: 15 mice fed with standard diet (control group) and another 15 mice fed with a rich diet of 5% cholesterol (second group). Bile acid dosage was based on their oxidation by 7α hydroxyl-steroid dehydrogenize. The mRNA expression was quantitatively analyzed by the real time of polymerase chain reaction (RT-PCR), and the expression of the renal carrier bile acid protein was analyzed by Western blot. Results and conclusions: The expression of bile salt export pump involved in the uptake of bile acids in the basolateral membrane of hepatocytes revealed no differences between the two groups of mice. However, the expression of multidrug resistance-associated protein 2 was reduced in mice of the second group. Moreover, the expressions of organic anion transporting polypeptide 4, organic anion transporting polypeptide 1, and sodium taurocholate co-transporting polypeptide (Ntcp) involved in the uptake of bile acids in the apical pole of hepatocytes are suppressed in mice of the second group. The expression of multidrug resistance-associated protein 3 involved in the secretion of bile acids in the apical membrane of hepatocytes revealed no significant differences between the two groups. In mice of the second group, blood concentration of bile acids on the last day was increased. In those mice, the expression of intestinal bile acid transporter was reduced in the kidneys compared with the control mice.

Background: Primaquine (Pq) metabolic products are responsible for drug-associated hemotoxicity and limit primaquine usage. Methods : Methemoglobin (MetHb)-Pq molecular modeling was used to identify the Pq binding pocket. UPLC, mass spectrometry, and other indirect analytical methods were used to predict the metabolite. MetHb generation, development of oxidative stress, inhibition of antioxidant enzymes, and scanning electron microscope (SEM) were used to characterize the hemotoxic potentials of oxidized Pq (Pq ox ). Results: MetHb binded Pq at the heme site with K D =6.4 μM as evidenced by a difference spectroscopy study. MetHb oxidized Pq through a single e-transfer mechanism to form Pq ox . The analysis of Pq from MetHb-H 2 O 2 peroxidase reaction mixture gave peaks at m/z 300.53 and m/z 243.42, corresponding to the hydroxyl and desamino derivative of Pq, respectively. Similar peaks were absent in Pq or Pq incubated with H 2 O 2 in the same buffer system. A robust increase in MetHb formation, reactive oxygen species generation, and inhibition of antioxidant enzymes were found in red blood cells (RBCs) exposed to Pq ox compared with a parent drug molecule. The RBC membrane exhibited visible damages to plasma membrane (holes) as evidenced by SEM analysis of Pq ox -exposed RBCs. Conclusions: The MetHb-H 2 O 2 system transforms quiescent parent drug molecule to a highly reactive oxidative form to exhibit severe hemolysis. MetHb-H 2 O 2 -mediated Pq hemolytic potentiation that is sensitive to spin trap indicates the role of Pq* radical or other single e-species in the process. The result suggests that MetHb incites the molecular property of the Pq and peroxidase inhibitors can be explored to control drug-associated toxicity.

Background: Haloperidol is a classic antipsychotic drug known for its propensity to cause extrapyramidal side effects. Sertraline is an antidepressant drug which has been reported to cause extrapyramidal symptoms. We aimed to see whether treatment with sertraline would worsen the effect of haloperidol on oxidative stress in the brains of mice. Methods: Sertraline (10 or 20 mg/kg), haloperidol (2 mg/kg), haloperidol combined with sertraline or saline was administered daily via the subcutaneous route and mice were euthanized 10 days later when biochemical assays were carried out. Malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (nitrite) levels, total antioxidant capacity (TAC), acetylcholinesterase (AChE), catalase and paraoxonase 1 (PON1) activities were determined in the brain and liver. Results: Sertraline monotherapy did not alter GSH, MDA, TAC or nitrite in the brain. Haloperidol decreased GSH and TAC and increased MDA and nitrite. The combined treatment with sertraline and haloperidol resulted in increased MDA, but to a lesser extent than haloperidol monotherapy. A significant increase in GSH and TAC and decreased nitrite was observed after the combination treatment was compared with haloperidol monotherapy. Catalase activity decreased with sertraline or haloperidol treatment. PON1 activity decreased with sertraline and haloperidol monotherapy and showed a further decrease with the combination therapy compared with haloperidol monotherapy. AChE activity decreased after haloperidol and increased with the combination treatment compared with haloperidol monotherapy. In the liver, GSH was unaltered after sertraline, haloperidol or their combination. MDA increased with sertraline, haloperidol and their combination. TAC decreased after combination therapy. Nitric oxide increased after sertraline, haloperidol or their combination. PON1 activity decreased with sertraline, haloperidol and with sertraline-haloperidol co-treatment. Conclusions: Sertraline did not worsen brain oxidative stress-induced with haloperidol, however, liver peroxidation increased. Sertraline decreased catalase and PON1 activity which might expose the brain to further oxidative insults.

Background: With the success of oocyte donation in vitro fertilization (IVF) in postmenopausal women, the importance of endometrial preparation became obvious. This appears also very crucial for achieving pregnancy after frozen embryo transfer (FET) after failed fresh IVF cycles and FET in subsequent natural cycles. Although there are different methods of preparing endometrium, in this study, another method of preparing the implantation bed using letrozole was scrutinized for its usefulness. Methods: Two hundred and seventy patients between 28 and 40 years of age undergoing IVF due to bilateral tubal blocks were chosen for FET. They had a previous unsuccessful single IVF attempt or had postponed embryo transfer due to the threat of ovarian hyperstimulation syndrome or poor endometrial development. Informed consents were obtained from the participants. One hundred patients had endometrial preparation by gonadotrophin-releasing hormone agonist down-regulation and with hormone replacement therapy, 55 had natural cycle FET, and the remaining 115 patients had letrozole-induced ovulation induction (OI) for endometrial preparation. Results: The clinical and biochemical pregnancy rate or live birth rate was higher in the letrozole OI group than in the other two groups. Conclusions: OI by letrozole and subsequent endometrial preparation as a result of it may be utilized for FET, and this will be cheap and easy to administer, giving better success rates in FET cycles.

Background: Peri-implantitis (PI) and chronic periodontitis (CP) are multifactorial diseases of implant/tooth supporting tissue that are caused by bacterial infection and increased host immune response. T-cell proliferation plays a pivotal role in the orchestration of host response to bacterial infection. BRAF is a positive regulator of T-cell proliferation. The aim of this study was to evaluate for the first time the role of a functional single nucleotide polymorphism (SNP) of the BRAF gene in association to PI and CP. Methods: A total of 194 individuals referred to the Periodontology Department of Shahid Beheshti Dental School, Tehran, Iran, were divided into three groups: 74 patients in the CP group (39 men and 35 women, with mean age of 48.3 years), 38 patients in the PI group (20 men and 18 women, with mean age of 50.2 years), and 82 patients in the healthy periodontium group (39 men and 43 women, with mean age of 45.4 years). DNA was extracted from fresh blood samples collected from the arm vein of participants and was transferred to KBiosience institute (United Kingdom) for genotyping. χ 2 and Kruskal-Wallis tests were conducted using SPSS software v. 19 for statistical analysis (p<0.05). Results: The allele ( C/T ) and genotype ( CC , CT , TT ) frequencies had insignificant differences among the three groups; however, the CC genotype was more prevalent in the healthy condition than in the disease conditions. Conclusions: The BRAF gene polymorphism (rs10487888) may not be a genetic determinant for increasing the risk of CP and PI among the Iranian population. More studies with more sample size in different populations are necessary for determining the effect of this SNP.

Background: Ghrelin, a recently isolated gastric hormone, is an endogenous ligand for growth hormone secretagogue receptors. There is novel evidence that ghrelin might be expressed in rat ovaries, placental tissues, and the uterus. It has been reported to have modulatory effects on smooth muscle contractility. In this study, we investigated the effects of ghrelin on spontaneous and oxytocin-induced contractions in the rat uterus in vitro and tried to detect its signaling pathway. Methods: Myometrium strips were removed from virgin female albino Wister rats and placed in a jacketed tissue bath. After initiation of spontaneous contractions, ghrelin was added to the tissue bath alone or after administration of indomethacin or N G -nitro-L-arginine methyl ester (L-NAME) or propranolol HCl. Student’s t-test was used for statistical analysis. Results: Our results revealed an inhibitory effect of ghrelin on both spontaneous and oxytocin-induced myometrial contractions. This effect was not affected by the application of indomethacin or L-NAME but was blocked after propranolol HCl administration. Conclusions: Ghrelin has an inhibitory effect on basal and oxytocin-induced rat myometrial contractions in vitro, and this myometrial response to ghrelin might be mediated by β-receptor signaling pathway.

Background: The aim of this study was to investigate whether thiols are involved in the nitrergic neurotransmission in mouse duodenum. Methods: The effects of thiol-modulating agents, ethacrynic acid (100 μM), a non-specific sulfhydryl alkylator, and diamide (100 μM), an alkylating agent that oxidizes protein sulfhydryl groups and depletes intracellular glutathione, on relaxations to nitrergic stimulation (electrical field stimulation, EFS;10 Hz, 25 V, 1 ms, 15 s-train), S-nitrosoglutathione (GSNO; 5 μM), S-nitroso-acetylpenicillamine (SNAP; 5 μM), and S-nitrosocysteine (CysNO; 10 μM) were investigated. Moreover, the effects of buthionine sulfoximine (100 μM), an inhibitor of γ-glutamylcysteine synthetase, and sulfobromophthalein (100 μM), an inhibitor of glutathione-S-transferase, were studied on relaxant responses to EFS and S-nitrosothiols in mouse duodenum. Results: Exogenous free thiol, glutathione (GSH, 100 μM) did not influence relaxation to EFS, GSNO, SNAP, and CysNO. Ethacrynic acid and diamide significantly decreased relaxation of duodenum to EFS, GSNO, SNAP, and CysNO. This inhibition was prevented by addition of GSH. Buthionine sulfoximine and sulfobromophthalein significantly decreased relaxation to EFS and GSNO but did not influence relaxation to SNAP and CysNO. The inhibitory effect of buthionine sulfoximine and sulfobromophthalein on the relaxant response to EFS and GSNO was prevented by addition of GSH. Conclusions: These results suggest that relaxation to nitrergic stimulation is thiol-dependent, and nitrosothiols, possibly S-nitrosoglutathione may play a role, as an intermediate compound in nitrergic neurotransmission in mouse duodenum.

Background: There is an age-long claim that the Musa paradisiaca root is used to manage reproductive dysfunction, most especially sexual dysfunction (as an aphrodisiac), but there are no data in the open scientific literature that have refuted or supported this claim and the effects of M. paradisiaca root on the testes. Therefore, this study was aimed at investigating the effect of oral administration of the aqueous extract of M. paradisiaca root on the testicular function parameters of male rat testes. Methods: Sexually matured male albino rats (138.67±5.29 g) were randomly assigned into four groups, A, B, C, and D, that respectively received 0.5 mL (3.6 mL/kg body weight) of distilled water and 25, 50, and 100 mg/kg body weight of the extract, orally, once daily, for 14 days. Results: The extract significantly increased (p<0.05) the testes-body weight ratio, total protein, sialic acid, glycogen, cholesterol, activities of alkaline phosphatase, γ-glutamyltransferase, acid phosphatase, and the concentration of testicular testosterone. In contrast, the extract decreased the concentrations of both luteinizing and follicle-stimulating hormones in the serum of the animals. The results revealed that oral administration of M. paradisiaca root extract at doses of 25, 50, and 100 mg/kg body weight enhanced the testosterone-dependent normal functioning of the testes. Conclusions: Overall, the aqueous extract of M. paradisiaca stimulated the normal functioning of the testes and exhibited both androgenic and anabolic properties. The results may explain the rationale behind the folkloric beneficial effect of the plant in the management of reproductive dysfunction.

Background: Bilateral temporal lobe agenesis/hypogenesis along with middle cranial fossa arachnoid cysts (ACs) is extremely rare, and very few cases have been reported in the literature. Methods: We present the case of 2-year-old female presenting with chief complaints of headache, vomiting, and fever. There was a history of premature delivery in the seventh month and up-rolling of eyes since birth. Results: Magnetic resonance imaging findings revealed bilateral temporal lobe agenesis with bilateral ACs, along with encephalomalacia in both parietal lobes. Ultrasound abdomen findings and biochemical tests revealed renal parenchymal disease. The lipid profile analysis revealed highly elevated triglyceride levels to 457.4 mg% and also enhanced very-low-density lipoprotein levels to 91.5 mg%. Presently, the patient is being treated on conservative lines. Conclusions: To our knowledge, this is the first report of an unusual association between bilateral temporal lobe agenesis associated with renal parenchymal disease and dyslipidaemia.