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Nizar M Mhaidat,1,2 Mousa Al-Smadi,3 Fouad Al-Momani,4 Karem H Alzoubi,1 Iman Mansi,2 Qosay Al-Balas5 1Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, 2Faculty of Pharmaceutical Sciences, Hashemite University, Zarqa, 3Department of Applied Chemical Sciences, 4Department of Applied Biological Sciences, Faculty of Science and Arts, 5Department of Medicinal Chemistry and Pharmacognosy,Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, JordanAbstract: Three derivatives of substituted 1,2,3-thia- or 1,2,3-selenadiazole (4a–c) were prepared and characterized by different chemical techniques. These compounds were evaluated for their antimicrobial and antitumor activities. Compounds 4a (propenoxide derivative), 4b (carbaldehyde derivative), and 4c (benzene derivative) were active against the yeast-like fungi Candida albicans. Compound 4a was active against gram-negative Escherichia coli, and compound 4c was active against the gram-positive Staphylococcus aureus. For the antitumor activity, both compounds 4b and 4c were active against all tested tumor cell lines, namely, SW480, HCT116, C32, MV3, HMT3522, and MCF-7. The activity of compound 4c was greater than that of compound 4b and more than that of the reference antitumor 5-flourouracil against the SW480, HCT116, and MCF-7 tumor cell lines. In conclusion, a number of the prepared 1,2,3-thia- or 1,2,3-selenadiazole compounds showed promising antifungal, antibacterial, and in vitro antitumor activities. Further investigations are required to explore the mechanism by which active compound are inducing their cytotoxicity. Keywords: thiadiazole, selenadiazole, cell lines, antimicrobial activity

Nicotine alleviates cognitive impairment associated with a variety of health conditions. We examined the effect of chronic nicotine treatment on adult-onset hypothyroidism-induced impairment of learning and memory in rats. Hypothyroidism was induced by surgical removal of thyroid glands (thyroidectomy). One month later, chronic nicotine treatment (1 mg/kg sc, twice/day) was instituted for 4-6 weeks. Test of hippocampus-dependent spatial learning and memory in the radial arm water maze showed that hypothyroidism impaired learning as well as short-term and long-term memory retention. Chronic nicotine treatment reversed the hypothyroidism-induced learning and memory impairment. In normal rats, chronic nicotine treatment had no effect on learning and memory. Extracellular recordings from the CA1 region of anesthetized hypothyroid rats showed severe reduction of both early-phase and late-phase long-term potentiation (LTP) magnitude, which was reversed in nicotine-treated hypothyroid rats. These results show that chronic nicotine treatment prevents hypothyroidism-induced impairment of spatial cognition and LTP.

We have shown previously that adult onset hypothyroidism impairs late-phase long-term potentiation (L-LTP) and reduces the protein levels of mitogen-activated protein kinases (MAPKp44/42 (ERK1/2)) in area CA1 of the hippocampus. In the present study, basal and stimulated levels of signaling molecules essential for the expression of L-LTP were determined in area CA1 of the hippocampus. L-LTP was evoked by multiple train high-frequency stimulation (MHFS) in area CA1 of the hippocampus of thyroidectomized and sham control anesthetized adult rats. Immunoblot analysis showed reduction in the basal protein levels of adenylyl cyclase I (ACI), calcium calmodulin-dependent protein kinase IV (CaMKIV), and cyclic-AMP response element-binding protein (CREB; phosphorylated (P-) and total) in hypothyroid rats. A significant increase in the levels of P-CREB, P-MAPKp44 and P-MAPKp42 was seen 4 h after MHFS in sham-operated control animals, but not in hypothyroid animals. The levels of total CREB, total MAPKp44, total MAPKp42 and CaMKIV were elevated in both groups 4 h after MHFS. Our results suggest that in adult hypothyroid rats, the reduced basal level of CaMKIV, MAPKp44/42 and CREB along with the failure of MHFS to induce MAPKp44/42 and CREB phosphorylation may be responsible for L-LTP impairment in the CA1 area during hypothyroidism.

Hypothyroidism impairs synaptic plasticity as well as learning and memory. Clinical reports are conflicting about the ability of thyroid hormone replacement therapy to fully restore the hypothyroidism-induced learning and memory impairment. Recently, we have shown that hypothyroidism impairs LTP and cognition in adult rats. We have studied the effect of thyroxin replacement therapy on hypothyroidism-induced LTP impairment using electrophysiological and molecular approaches. Recording from CA1 region of the hippocampus in anesthetized adult rat indicated that 6 weeks of thyroxin replacement therapy (20 μg/kg/day) fully restored LTP impaired by hypothyroidism. Western blotting showed reduction in phosphorylated (P)-CAMKII, total-CaMKII, neurogranin, and calmodulin basal levels in the CA1 region of the hippocampus of hypothyroid rats. The levels of these molecules were normalized by thyroxin replacement therapy. The hypothyroid-induced elevation of basal calcineurin levels and activity was also normalized by thyroxin treatment. However, thyroxin replacement therapy did not restore hypothyroidism-induced reduction in PKCγ basal protein levels. Additionally, real-time PCR, showed a reduction in basal neurogranin mRNA level that was normalized by thyroxin replacement therapy. In the sham (control) rats, induction of LTP by high-frequency stimulation increases P-CaMKII, and total CaMKII levels as well as CaMKII phosphotransferase activity. However, in hypothyroid rats, the same stimulation protocol induced an increase only in total-CaMKII. Thyroxin treatment normalized the levels and activity of these molecules. The results demonstrated that thyroxin therapy normalized the electrophysiological and molecular effects of hypothyroidism on the CA1 region and emphasized the critical role P-CaMKII plays in hypothyroidism-induced LTP impairment.

Hypothyroidism impairs early long-term potentiation (LTP) in the CA1 but not in the dentate gyrus (DG) of hippocampus of anesthetized adult rats. Protein levels and activities of signaling molecules in both the CA1 and DG of surgically thyroidectomized and sham-operated euthyroid rats were measured. Basal levels of total calmodulin kinase II (CaMKII) protein in both the CA1 and DG were decreased in hypothyroidism. Marked reduction of basal P-CaMKII levels and CaMKII activity was seen in CA1, but not in the DG of the same hypothyroid animals. Basal levels of calmodulin and protein kinase Cgamma (PKCgamma) were decreased in CA1 but remained unchanged in the DG of hypothyroid rats. Basal calcineurin levels and activity, although enhanced in CA1, were reduced in the DG of hypothyroid rats. These findings suggest that the DG may possess a compensatory mechanism whereby calcineurin levels are reduced, to allow sufficient CaMKII activity to produce an apparently normal LTP in hypothyroid rats.

Both hypothyroidism and stress interfere with cognitive function in patients. This study examined the effect of hypothyroidism and stress on hippocampus-dependent learning and memory in rats using the novel radial arm water maze (RAWM), which measures spatial working memory. Hypothyroidism was accomplished by thyroidectomy and 2 weeks later a form of intruder stress was used as the chronic psychosocial stressor. After 4-6 weeks of stress, rats were trained to learn (during the acquisition phase; four trials) and then remember (during two memory test trials occurring 15 and 120 min after the acquisition phase) the within-day location of a hidden escape platform, which was in different arm every day. The number of errors (entry into arms other than the platform arm) was noted. Within-day learning of the platform location was largely unaffected by the experimental manipulations, indicating that rats in all groups were equally capable of finding the platform to escape from the water with similar numbers of errors (P > 0.005). The number of days a rat took to reach a criterion (DTC; a maximum of one error in three consecutive days) indicated that chronic stress or hypothyroidism, alone, resulted in a mild impairment of spatial memory, and the combination of chronic stress and hypothyroidism resulted in a more severe and long-lasting memory impairment. The data indicated that the combination of stress and hypothyroidism produced more deleterious effects on hippocampal function than either chronic stress or hypothyroidism alone.

ObJEcTIVE: To investigate the possible association between response to levothyroxine (L-T4) doses in hypothyroid patients and variation in thyroid stimulating hormone receptor (TSHR) gene and thyroid hormone receptor (THRα) gene. DESIGN: This cross-sectional correlation study included 228 patients with primary hypothyroidism who were using L-T4 replacement therapy. Thyroid function test was performed using standard techniques. Genotyping of rs939348 of the THRα gene, and rs2268458 and rs2239610 of the TSHR gene was performed using the polymerase chain reaction-based restriction fragment length polymorphism assay (Pcr-rFLP). Patient history of illness, medication and compliance data were collected using the patients’ medical files. rESULTS: The THRα rs939348 polymorphism was associated with L-T4 replacement doses in hypothyroid patients and in central obesity. No significant correlation was detected between the examined SNPs to TSHR and L-T4 doses or the different clinical and biochemical parameters. Finally, L-T4 dose was associated with lower bMI, waist circumference and TSH, and higher free T4 (fT4) among hypothyroid patients. cONcLUSIONS: Whereas the two tested TSHR polymorphisms were not associated with the dose of T4, the THRα rs939348 polymorphism was associated with L-T4 dose and central obesity among hypothyroid patients. T4 dose was also associated with multiple beneficial effects among hypothyroid patients.

Qosay A Al-Balas,1 Munia F Sowaileh,1 Mohammad A Hassan,1 Amjad M Qandil,1,2 Karem H Alzoubi,3 Nizar M Mhaidat,3 Ammar M Almaaytah,4 Omar F Khabour51Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan; 2Pharmaceutical Sciences Department, College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; 3Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan; 4Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan; 5Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid, JordanBackground: The dipeptidyl peptidase-IV (DPP-IV) enzyme is considered a pivotal target for controlling normal blood sugar levels in the body. Incretins secreted in response to ingestion of meals enhance insulin release to the blood, and DPP-IV inactivates these incretins within a short period and stops their action. Inhibition of this enzyme escalates the action of incretins and induces more insulin to achieve better glucose control in diabetic patients. Thus, inhibition of this enzyme will lead to better control of blood sugar levels.Methods: In this study, computer-aided drug design was used to help establish a novel N-substituted aminobenzamide scaffold as a potential inhibitor of DPP-IV. CDOCKER software available from Discovery Studio 3.5 was used to evaluate a series of designed compounds and assess their mode of binding to the active site of the DPP-IV enzyme. The designed compounds were synthesized and tested against a DPP-IV enzyme kit provided by Enzo Life Sciences. The synthesized compounds were characterized using proton and carbon nuclear magnetic resonance, mass spectrometry, infrared spectroscopy, and determination of melting point.Results: Sixty-nine novel compounds having an N-aminobenzamide scaffold were prepared, with full characterization. Ten of these compounds showed more in vitro activity against DPP-IV than the reference compounds, with the most active compounds scoring 38% activity at 100 µM concentration.Conclusion: The N-aminobenzamide scaffold was shown in this study to be a valid scaffold for inhibiting the DPP-IV enzyme. Continuing work could unravel more active compounds possessing the same scaffold.Keywords: diabetes mellitus, dipeptidyl peptidase-IV, aminobenzamide derivatives, hypoglycemic activity, CDOCKER software

Context: The human granzyme B protein (GrB), which is encoded by granzyme B gene (GZMB), plays a major role in eliminating cancer cells. Polymorphisms of GZMB gene such as Q55R, P94A, and Y247H have been shown to affect GrB activity and the subsequent cancer risk. Aims: In this study, we examined possible association between GZMB gene polymorphisms and susceptibility to colorectal cancer (CRC). In addition, the contribution of the examined polymorphisms to colorectal cancer metastasis to lymph node and distant organ was investigated. Materials and Methods: A total of 50 venous blood samples collected from CRC patients were analyzed to identify the Q55R, P94A, and Y247H polymorphisms. As a control group, 20 healthy subjects were enrolled in the study. The Q55R, P94A, and Y247H polymorphisms were genotyped by polymerase chain reaction and sequencing method. Statistical Analysis: Data analysis was carried out using the statistical package SPSS version 17 to compute all descriptive statistics. Chi-square and Fisher exact tests (if the expected value in any cell is less than 5) were used to evaluate the genotype distribution and allele frequencies of the studied polymorphism. Results: The results revealed that the distribution of Q55R, P94A, and Y247H are not significantly different in CRC patients compared to the controls. In addition, no association between Q55R, P94A, and Y247H polymorphisms and its metastasis to lymph node and distant organ was detected. Conclusions: These results suggest that GZMB Q55R, P94A, and Y247H polymorphisms are not significantly associated with colon cancer incidence, or metastasis to lymph node and distant organ. However, this study was limited by its relatively small sample size; thus, to confirm current findings, a bigger multicenter design study is warranted.

The human hepatic lipase ( LIPC) gene encodes hepatic lipase, an enzyme involved in lipoprotein metabolism and regulation. Therefore, variants in LIPC gene may influence plasma lipoprotein levels. In this study, the association of LIPC C-514T and G-250A polymorphisms with plasma lipid profiles in 348 young Jordanians was investigated. Genotyping of C-514T and G-250A was performed by polymerase chain reaction and subsequent digestion with DraI and NiaIII restriction enzymes, respectively, while Roche analyzer was used to determine plasma total cholesterol, triglycerides, low-and high-density lipoprotein. The G-250 and C-514 alleles were most abundant in Jordanians with 79 and 80% frequencies, respectively. Additionally, no difference was found in the lipid–lipoprotein profile between the different genotype groups of C-514T or G-250A polymorphisms, even when males and females were examined separately ( P ≫ 0.05). In young Jordanian adults, the examined LIPC polymorphisms seem to play a limited role in determining the lipid profile.

Background Statins have several effects beyond their well-known antihyperlipidemic activity, which include immunomodulatory, antioxidative and anticoagulant effects. In this study, we have tested the possible antimicrobial activity of statins against a range of standard bacterial strains and bacterial clinical isolates. Methods Minimum inhibitory concentrations (MIC) values were evaluated and compared among three members of the statins drug (atorvastatin, simvastatin, and rosuvastatin). Results It was revealed that statins are able to induce variable degrees of antibacterial activity with atorvastatin, and simvastatin being the more potent than rosuvastatin. Methicillin-sensitive staphylococcus aureus (MSSA), methicillin-resistant staphylococcus aureus (MRSA), vancomycin-susceptible enterococci (VSE), vancomycin-resistant enterococcus (VRE), acinetobacter baumannii, staphylococcus epidermidis, and enterobacter aerogenes, were more sensitive to both atorvastatin, and simvastatin compared to rosuvastatin. On the other hand, escherichia coli, proteus mirabilis, and enterobacter cloacae were more sensitive to atorvastatin compared to both simvastatin and rosuvastatin. Furthermore, most clinical isolates were less sensitive to statins compared to their corresponding standard strains. Conclusion Our findings might raise the possibility of a potentially important antibacterial class effect for statins especially, atorvastatin and simvastatin.