Search results for: liver X receptor

Authors: Mohsen Ehsanpour, Maryam Ehsanpour, ‎Majid Afkhami, Fatemeh Afkhami ‎

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Heavy metals are increasingly being released into natural waters from geological and anthropogenic sources. The distribution of several heavy metals (Cd, Pb) was investigated in muscle, liver in six different fish species seasonally collected in Persian Gulf (autumn 2009-summer 2010). The concentrations of all metals were lower in flesh than those recorded in liver due to their physiological roles. The THQ index for fish was calculated. Estimation of target hazard quotients calculations for the contaminated fish consumption was calculated to evaluate the effect of pollution on health. Total metal THQs values (Pb and Cd) for adults were 0.05 and 0.04 in Bushehr and Bandar-Genaveh, respectively, and for children they were 0.08 and 0.05 in Bandar-Abbas and Bandar-Lengeh, respectively.

Keywords: Persian Gulf, heavy metals, health risks, THQ index

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Authors: Rabia Göçmen, Gülşah Kanbur, Sinan Sefa Parlat

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Aim of this study is to determine the effects of cellular insulin receptor stimulators on performance, plasma glucose, high density lipoprotein (HDL), low density lipoprotein (LDL), total cholesterol, triglyceride, triiodothyronine (T3) and thyroxine (T4) hormone levels, and incubation features in the breeding Japanese quails (Coturnix japonica). In the study, a total of 84 breeding quails was used, 6 weeks’ age, 24 are male and 60, female. Rations used in experiment are 2900 kcal/kg metabolic energy and 20% crude protein. Water pH is calibrated to 7.45. Ration and water were administered ad-libitum to the animals. As metformin source, metformin-HCl was used and as chrome resource, chromium picolinate was used. Trial groups were formed as control group (basal ration), metformin group (basal ration, added metformin at the level of feed of 20 mg/kg), and chromium picolinate (basal ration, added feed of 1500 ppb Cr) group. When regarded to the results of performance at the end of experiment, it is seen that live weight gain, feed consumption, egg weight, feed conversion ratio (Feed consumption/ egg weight), and egg production were affected at the significant level (p < 0.05). When the results are evaluated in terms of incubation features, hatchability and hatchability of fertile egg ratio were not affected from the treatments. Fertility ratio was significantly affected by metformin and chromium picolinate treatments and fertility rose at the significant level compared to control group (p < 0.05). According to results of experiment, plasma glucose level was not affected by metformin and chromium picolinate treatments. Plasma, total cholesterol, HDL, LDL, and triglyceride levels were significantly affected from insulin receptor stimulators added to ration (p < 0.05). Hormone level of Plasma T3 and T4 were also affected at the significant level from insulin receptor stimulators added to ration (p < 0.05).

Keywords: chromium picolinate, cholesterol, hormone, metformin, quail

Procedia PDF Downloads 195

Authors: Luciano Tarantino, Emanuele Balzano, Paolo Tarantino, Riccardo Aurelio Nasto, Aurelio Nasto

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Liver transplantation (OLT) is contraindicate in Portal Vein tumor Thrombosis (PVTT) from Hepatocellular Carcinoma at hepatic hilum(pH-HCC) Surgery,Thermal ablation and chemotherapy show poorer outcomes Electrochemotherapy (ECT) has been successfully used in patients with pH-HCC with PVTT. We report the results of ECT as downstaging aimed to definitive cure by OLT. F.P. 53 years HBV related Cirrhosis Child-Pugh B7 class; EGDS F2 aesophageal Varices. Diabetes. April 2016 : Enhanced Computed Tomography (CT) detected HCC(n.3 nodules in VII-VIII-VI;diameter range=25 cm) and PVTT of right portal vein. The patient was considered ineligible for OLT. May 2016: first ablation session with percutaneous Radiofrequency-ablation(RFA) of 3 HCC-nodules . August 2016: second ablation session with ECT of PVTT. CT october 2016: disappearance of PVTT and patent right portal vein. No intraparenchymal recurrence. CT march 2017: No recurrence in portal vein and in the left lobe. local recurrence in the VII-VIII segments. May 2017 : transarterial chemoembolization (TACE) of right lobe recurrences. CT October 2017: patent right portal vein. No recurrence. The patient was reconsidered for OLT. He underwent OLT in April 2018. At 36-months follow-up , no intrahepatic recurrence of HCC occurred. March 2021: enhanced CT and PET/CT detected a single small nodule (1.5 cm) uptaking tracer in the left upper pulmonary lobe, no hepatic recurrence . CT-guided FNB showed metastasis from HCC . June 2021: left lung upper lobectomy . At the current time the patient is alive and recurrence-free at 64 months follow-up. ECT Could be aneffective technique as pre-OLT dowstaging in HCC with PVTT.

Keywords: liver tumor ablation, interventional ultrasound, electrochemotherapy, liver transplantation

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Authors: Ludmila A. Gavriliuc, Jerry McLarty, Heather E. Kleiner, J. Michael Mathis

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Abstract -- Background: The citrus coumarine Auraptene (Aur) is an effective chemopreventive agent, as manifested in many models of diseases and cancer. Nuclear factor erythroid 2-related factor (Nrf2) is an important regulator of genes induced by oxidative stress, such as glutathione S-transferases, heme oxygenase-1, and peroxiredoxin 1, by activating the antioxidant response element (ARE). Genetic and biochemical evidence has demonstrated that glutathione (GSH) and glutathione-dependent enzymes, glutathione reductase (GR), glutathione peroxidases (GPs), glutathione S-transferases (GSTs) are responsible for the control of intracellular reduction-oxidation status and participate in cellular adaptation to oxidative stress. The effect of Aur on the activity of GR, GPs (Se-GP and Se-iGP), and content of GSH in the liver, kidney, and spleen is insufficiently explored. Aim: Our goal was the examination of the Aur influence on the redox-system of GSH in Nrf2 wild type and Nrf2 knockout mice via activation of Nrf2 and ARE. Methods: Twenty female mice, 10 Nrf2 wild-type (WT) and 10 Nrf2 (-/-) knockout (KO), were bred and genotyped for our study. The activity of GR, Se-GP, Se-iGP, GST, G6PD, CytP450 reductase, catalase (Cat), and content of GSH were analyzed in the liver, kidney, and spleen using Spectrophotometry methods. The results of the specific activity of enzymes and the amount of GSH were analyzed with ANOVA and Spearman statistical methods. Results: Aur (200 mg/kg) treatment induced hepatic GST, GR, Se-GP activity and inhibited their activity in the spleen of mice, most likely via activation of the ARE through Nrf2. Activation in kidney Se-GP and G6PD by Aur is also controlled, apparently through Nrf2. Results of the non-parametric Spearman correlation analysis indicated the strong positive correlation between GR and G6PD only in the liver in WT control mice (r=+0.972; p < 0.005) and in the kidney KO control mice (r=+0.958; p < 0.005). The observed low content of GSH in the liver of KO mice indicated an increase in its participation in the neutralization of toxic substances with the absence of induction of GSH-dependent enzymes, such as GST, GR, Se-GP, and Se-iGP. Activation of CytP450 in kidney and spleen and Cat in the liver in KO mice probably revealed another regulatory mechanism for these enzymes. Conclusion: Thereby, obtained results testify that Aur can modulate the activity of genes and antioxidant enzymatic redox-system of GSH, responsible for the control of intracellular reduction-oxidation status.

Keywords: auraptene, glutathione, GST, Nrf2

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Authors: Priya Bajaj, Baby Tabassum

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Arsenic is a poisonous metalloid, naturally occurring in soil, air, rocks and ground water. This dreadful metalloid commonly exists as inorganic compound, arsenic trioxide. WHO permitted maximum limit for arsenic in water is 0.01 mg/L, but some affected areas show ground water level of arsenic up to 3 mg/L even. Ground water arsenic pollution has created a number of health problems, viz. keratosis, melanosis, lesions and even skin cancers. The key objective of our nested study was to characterize arsenic induced hepatotoxicity and to find out some herbal protection against it. For the purpose, we selected albino rat (Rattus norvegicus) as model for arsenic induced liver injury and wild turmeric (Curcuma aromatica) leaf extract as remedy for it. The study was performed at acute (1 day) and subacute (7, 14 & 21 days) levels. The LD50 estimated for arsenic trioxide was 14.98 mg/kg body weight. In our investigation, we observed a significant restoration of altered hepatic lipid, cholesterol, protein and glycogen contents as well as liver weight, body-weight and hepato-somatic index by Curcuma aromatica leaf extract before arsenic intoxication. The results reveal excellent protective efficacy of Curcuma aromatica leaf extract that further can be exploited in remediation programme in heavy metal affected areas.

Keywords: arsenic, Curcuma aromatica, glycogen, lipids

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Authors: Özlem Arpacı, Zeliha Soysal, Nuran Diril

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Benzoxazoles are heterocyclic compounds that have a fused benzene and an oxazole ring. These heterocyclic compounds are reported to have antibacterial, antitubercular, antifungal, antiviral, antioxidant and anticancer activities. In this study, some benzoxazole derivatives that have broad antimicrobial and potent antitumoral activities, are investigated their mutagenic activities with using the Ames Test. The Ames test was conducted using Salmonella typhimurium TA98, TA100 and TA102 tester strains in the standard plate incorporation assay in the absence of liver S9 fraction. The results are evaluated using SPSS and none of the benzoxazole derivatives showed mutagenic activity using the Ames test in the absence of S9 liver fraction.

Keywords: benzoxazoles, ames test, mutagenic activity, antimutagenic activity, antitumoral activity

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Authors: B. Sadek, N. Khan, D. Łażewska, K. Kieć-Kononowicz

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The effects of the non-imidazole histamine H3 receptor (H3R) antagonist DL77 in passive avoidance paradigm (PAP) and novel object recognition (NOR) task in MK801-induced cognitive deficits associated with schizophrenia (CDS) in adult male rats, and applying donepezil (DOZ) as a reference drug were investigated. The results show that acute systemic administration of DL77 (2.5, 5, and 10 mg/kg, i.p.) significantly improved MK801-induced (0.1 mg/kg, i.p.) memory deficits in PAP. The ameliorating activity of DL77 (5 mg/kg, i.p.) in MK801-induced deficits was partly reversed when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL, 10 mg/kg, i.p.) or with the antimuscarinic antagonist scopolamine (SCO, 0.1 mg/kg, i.p.), but not with the CNS penetrant H1R antagonist pyrilamine (PYR, 10 mg/kg, i.p.). Moreover, the memory enhancing effect of DL77 (5 mg/kg, i.p.) in MK801-induced memory deficits in PAP was strongly reversed when rats were pretreated with a combination of ZOL (10 mg/kg, i.p.) and SCO (1.0 mg/kg, i.p.). Furthermore, the significant ameliorative effect of DL77 (5 mg/kg, i.p.) on MK801-induced long-term memory (LTM) impairment in NOR test was comparable to the DOZ-provided memory-enhancing effect, and was abrogated when animals were pretreated with the histamine H3R agonist R-(α)-methylhistamine (RAMH, 10 mg/kg, i.p.). However, DL77(5 mg/kg, i.p.) failed to provide procognitive effect on MK801-induced short-term memory (STM) impairment in NOR test. In addition, DL77 (5 mg/kg) did not alter anxiety levels and locomotor activity of animals naive to elevated-plus maze (EPM), demonstrating that improved performances with DL77 (5 mg/kg) in PAP or NOR are unrelated to changes in emotional responding or spontaneous locomotor activity. These results provide evidence for the potential of H3Rs for the treatment of neurodegenerative disorders related to impaired memory function, e.g. CDS.

Keywords: histamine H3 receptor, antagonist, learning, memory impairment, passive avoidance paradigm, novel object recognition

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Authors: Sachin K. Samuchiwal, Barbara Balestrieri, Amanda Paskavitz, Hannah Raff, Joshua A. Boyce

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IL-33, a recently discovered member of the IL-1 cytokine family, binds to the TLR/IL1R super family receptor ST2 and induces type 2 immune responses. IL-33 is constitutively expressed in structural cells at barrier sites such as skin, lung, and intestine, and also inducibly expressed by hematopoietic cells including macrophages. Stimulation of macrophages by Lipopolysaccharide (LPS) can induce de novo IL-33 expression, and also causes the production of prostaglandin-E2 (PGE2) via cyclooxygenase (COX)-2 and microsomal PGE2 synthase-1 (mPGES-1). Because PGE2 can regulate macrophage functions through both autocrine and paracrine mechanisms, the potential interplay of endogenous PGE2 on IL-33 production was explored. Bone-marrow derived murine macrophages (bmMF) that lack either mPGES-1 or EP2 receptor expression were stimulated with LPS in the absence or presence of exogenous PGE2 along with pharmacological agonists and antagonists. The study results demonstrate that endogenous PGE2 markedly enhances LPS-induced IL-33 production by bmMFs via EP2 receptors. Moreover, exogenous PGE2 can amplify LPS-induced IL-33 expression dominantly by EP2 and partly by EP4 receptors by a pathway involving cAMP and exchange protein activated by cAMP (EPAC), but not protein kinase A (PKA). Though both IL-33 production and PGE2 generation in response to LPS require activation of both p38 MAPK and NF-κB, PGE2 did not influence this activation. In conclusion, it is demonstrated that endogenous PGE2 signaling through EP2 and EP4 receptors is a prerequisite for LPS-induced IL-33 production in bmMFs and the underlying cAMP mediated pathway involves EPAC. Since IL-33 is a critical pro-inflammatory cytokine in various pathological disorders, this PGE2-EP2/EP4-cAMP mediated pathway can be exploited to intervene in IL-33 driven pathologies.

Keywords: bone marrow macrophages, EPAC, IL-33, PGE2

Procedia PDF Downloads 156

Authors: A. M. Taleb, A. G. Tail, A. F. Kara, B. B. Djedouani, C. T. Moussa

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Forensic entomology is the use of insects to aid legal investigations. The main purpose of forensic entomology is to establish the postmortem interval (PMI). In order to estimate the PMI, a forensic entomologist compares the case data with certain reference information relevant to the particular location and time of year. This reference information, including the local distribution of species, are not available in Algeria. Therefore, experiments need to be conducted to provide references for entomological evidence. The objective of this study was to identify the necrophagous flies species which arrive first to carrion using liver baits in Ghardaia, South Algeria. The study was carried out during the spring season in the palmeral of Beni Isguen, Ghardaia which is well known by its hot arid climate. The experiment site (32°28’0’’ N, 3°42’0’’ E), is situated at an altitude of about 526 metres above mean sea level. On April the 4th, 2014, a number of three replicates of liver baited traps were placed in the shade and other three baits were exposed to the sun. Flying insects and larvae were captured and identified. After few minutes, flies invaded the traps which were exposed to the sun. In contrast, no flies were observed in the other traps. A total number of fourty five (45) adult specimens belonging to three taxa were identified: Calliphora vicina (Robineau-Desvoidy, 1830) (Diptera, Calliphoridae) (51.11 %), Lucilia sericata (Meigen, 1826) (Diptera, Calliphoridae) (33.33 %) and Sarcophaga africa (Wiedemann, 1824) (Diptera: Sarcophagidae) (15.55 %). Six hundred and three (603) maggots belonging to two taxa were identified: Calliphora vicina (76.28 %) and Lucilia sericata (23.71 %). The data obtained from this study provides baseline information regarding the carrion fauna of this area. It will also form a basis for similar studies in different geographical and climatological regions of Algeria.

Keywords: forensic entomology, liver baits, necrophagous fly, Ghardaia, South Algeria

Procedia PDF Downloads 338

Authors: Staniek Halina

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The inappropriate trace elements supply such as iron(III) and chromium(III) may be risk factors of many metabolic disorders (e.g., anemia, diabetes, as well cause toxic effect). However, little is known about their mutual interactions and their impact on these disturbances. The effects of Cr(III) supplementation with a deficit or excess supply of Fe(III) in vivo conditions are not known yet. The objective of the study was to investigate the combined effect of different Fe(III) levels in the diet and simultaneous Cr(III) supplementation on the Ca distribution in organs in healthy rats. The assessment was based on a two-factor (2x3) experiment carried out on 54 female Wistar rats (Rattus norvegicus). The animals were randomly divided into 9 groups and for 6 weeks, they were fed semi-purified diets AIN-93 with three different Fe(III) levels in the diet as a factor A [control (C) 45 mg/kg (100% Recommended Daily Allowance for rodents), deficient (D) 5 mg/kg (10% RDA), and oversupply (H) 180 mg/kg (400% RDA)]. The second factor (B) was the simultaneous dietary supplementation with Cr(III) at doses of 1, 50 and 500 mg/kg of the diet. Iron(III) citrate was the source of Fe(III). The complex of Cr(III) with propionic acid, also called Cr₃ or chromium(III) propionate (CrProp), was used as a source of Cr(III) in the diet. The Ca content of analysed samples (liver, kidneys, spleen, heart, and femur) was determined with the Atomic Absorption Spectrometry (AAS) method. It was found that different dietary Fe(III) supply as well as Cr(III) supplementation independently and in combination influenced Ca metabolism in healthy rats. Regardless of the supplementation of Cr(III), the oversupply of Fe(III) (180 mg/kg) decreased the Ca content in the liver and kidneys, while it increased the Ca saturation of bone tissue. High Cr(III) doses lowered the hepatic Ca content. Moreover, it tended to decrease the Ca content in the kidneys and heart, but this effect was not statistically significant. The combined effect of the experimental factors on the Ca content in the liver and the femur was observed. With the increase in the Fe(III) content in the diet, there was a decrease in the Ca level in the liver and an increase in bone saturation, and the additional Cr(III) supplementation intensified those effects. The study proved that the different Fe(III) content in the diet, independently and in combination with Cr(III) supplementation, affected the Ca distribution in organisms of healthy rats.

Keywords: calcium, chromium(III), iron(III), rats, supplementation

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Authors: Dileep Kumar, Janhavi Ramchandra Rao Kumar, Rao

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COVID-19 has ravaged the globe, and it is spreading its Spectre day by day. In the absence of established drugs, this disease has created havoc. Some of the infected persons are symptomatic or asymptomatic. The respiratory system, cardiac system, digestive system, etc. in human beings are affected by this virus. In our present investigation, we have undertaken a study of the Indian Ayurvedic herb, Ocimum sanctum against SARS-CoV-2 using molecular docking and dynamics studies. The docking analysis was performed on the Glide module of Schrödinger suite on two different proteins from SARS-CoV-2 viz. NSP15 Endoribonuclease and spike receptor-binding domain. MM-GBSA based binding free energy calculations also suggest the most favorable binding affinities of carvacrol, β elemene, and β caryophyllene with binding energies of −61.61, 58.23, and −54.19 Kcal/mol respectively with spike receptor-binding domain and NSP15 Endoribonuclease. It rekindles our hope for the design and development of new drug candidates for the treatment of COVID19.

Keywords: molecular docking, COVID-19, ocimum sanctum, binding energy

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Authors: Aidan Ryan, Nahima Miah, Sahaj Kaur, Imogen Sutherland, Mohamed Saleh

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Pulmonary symptoms are a common presentation to the emergency department. Due to a lack of understanding of the underlying pathophysiology, chronic liver disease is not often considered a cause of dyspnea. We present three patients who were admitted with significant respiratory distress secondary to hepatopulmonary syndrome, portopulmonary hypertension, and hepatic hydrothorax. The first is a 27-year-old male with a 6-month history of progressive dyspnea. The patient developed a severe type 1 respiratory failure with a PaO₂ of 6.3kPa and was escalated to critical care, where he was managed with non-invasive ventilation to maintain oxygen saturation. He had an agitated saline contrast echocardiogram, which showed the presence of a possible shunt. A CT angiogram revealed significant liver cirrhosis, portal hypertension, and large para esophageal varices. Ultrasound of the abdomen showed coarse liver echo patter and enlarged spleen. Along with these imaging findings, his biochemistry demonstrated impaired synthetic liver function with an elevated international normalized ratio (INR) of 1.4 and hypoalbuminaemia of 28g/L. The patient was then transferred to a tertiary center for further management. Further investigations confirmed a shunt of 56%, and liver biopsy confirmed cirrhosis suggestive of alpha-1-antitripsyin deficiency. The findings were consistent with a diagnosis of hepatopulmonary syndrome, and the patient is awaiting a liver transplant. The second patient is a 56-year-old male with a 12-month history of worsening dyspnoea, jaundice, confusion. His medical history included liver cirrhosis, portal hypertension, and grade 1 oesophageal varices secondary to significant alcohol excess. On admission, he developed a type 1 respiratory failure with PaO₂ of 6.8kPa requiring 10L of oxygen. CT pulmonary angiogram was negative for pulmonary embolism but showed evidence of chronic pulmonary hypertension, liver cirrhosis, and portal hypertension. An echocardiogram revealed a grossly dilated right heart with reduced function, pulmonary and tricuspid regurgitation, and pulmonary artery pressures estimated at 78mmHg. His biochemical markers showed impaired synthetic liver function with an INR of 3.2, albumin of 29g/L, along with raised bilirubin of 148mg/dL. During his long admission, he was managed with diuretics with little improvement. After three weeks, he was diagnosed with portopulmonary hypertension and was commenced on terlipressin. This resulted in successfully weaning off oxygen, and he was discharged home. The third patient is a 61-year-old male who presented to the local ambulatory care unit for therapeutic paracentesis on a background of decompensated liver cirrhosis. On presenting, he complained of a 2-day history of worsening dyspnoea and a productive cough. Chest x-ray showed a large pleural effusion, increasing in size over the previous eight months, and his abdomen was visibly distended with ascitic fluid. Unfortunately, the patient deteriorated, developing a larger effusion along with an increase in oxygen demand, and passed away. Without underlying cardiorespiratory disease, in the presence of a persistent pleural effusion with underlying decompensated cirrhosis, he was diagnosed with hepatic hydrothorax. While each presented with dyspnoea, the cause and underlying pathophysiology differ significantly from case to case. By describing these complications, we hope to improve awareness and aid prompt and accurate diagnosis, vital for improving outcomes.

Keywords: dyspnea, hepatic hydrothorax, hepatopulmonary syndrome, portopulmonary syndrome

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Authors: Chowon Kim, Yoo-Kyung Kim, Kyeong Yeon Park, Hyun-Shik Lee

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Perfluoroalkyl compounds (PFCs) are globally distributed synthetic compounds that are known to adversely affect human health. Developmental toxicity assessment of PFCs is important to facilitate the evaluation of their environmental impact. In the present study, we assessed the developmental toxicity and teratogenicity of PFCs with different numbers of carbon atoms on Xenopus embryogenesis. An initial frog embryo teratogenicity assay-Xenopus (FETAX) assay was performed that identified perfluorohexanoic (PFHxA) and perfluoroheptanoic (PFHpA) acids as potential teratogens and developmental toxicants. The mechanism underlying this teratogenicity was also investigated by measuring the expression of tissue-specific biomarkers such as phosphotyrosine‑binding protein, xPTB (liver); NKX2.5 (heart); and Cyl18 (intestine). Whole‑mount in situ hybridization, reverse transcriptase‑polymerase chain reaction (RT-PCR), and histologic analyses detected severe defects in the liver and heart following exposure to PFHxA or PFHpA. In addition, immunoblotting revealed that PFHpA significantly increased the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK), while PFHxA slightly increased these, as compared with the control. These results suggest that PFHxA and PFHpA are developmental toxicants and teratogens, with PFHpA producing more severe effects on liver and heart development through the induction of ERK and JNK phosphorylation.

Keywords: PFCs, ERK, JNK, xenopus

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Authors: Seyedeh Sepideh Amini, Navideh Aghaei Amirkhizi, Seyedeh Paniz Amini, Seyed Soheil Sayyahi, Mohammad Reza Davar Panah

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CT-Scan is one of the lateral and sectional imaging methods that produce 3D-images with use of rotational x-ray tube around central axis. This study is about evaluation and calculation of effective doses around heart organs such as breast, lung and liver with CT-Scan 128 dual sources with TLD_100 and RANDO Phantom by spiral, flash and conventional protocols. In results, it is showed that in spiral protocol organs have maximum effective dose and minimum in flash protocol. Thus flash protocol advised for children and risk persons.

Keywords: X-ray computed tomography, dosimetry, TLD-100, RANDO, phantom

Procedia PDF Downloads 446

Authors: Thanthrige Thiunuwan Priyathilaka, Don Anushka Sandaruwan Elvitigala, Bong-Soo Lim, Hyung-Bok Jeong, Jehee Lee

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Toll like receptors (TLRs) are a phylogeneticaly conserved family of pattern recognition receptors, which participates in the host immune responses against various pathogens and pathogen derived mitogen. TLR21, a non-mammalian type, is almost restricted to the fish species even though those can be identified rarely in avians and amphibians. Herein, this study was carried out to identify and characterize TLR21 from rock bream (Oplegnathus fasciatus) designated as RbTLR21, at transcriptional and genomic level. In this study, the full length cDNA and genomic sequence of RbTLR21 was identified using previously constructed cDNA sequence database and BAC library, respectively. Identified RbTLR21 sequence was characterized using several bioinformatics tools. The quantitative real time PCR (qPCR) experiment was conducted to determine tissue specific expressional distribution of RbTLR21. Further, transcriptional modulation of RbTLR21 upon the stimulation with Streptococcus iniae (S. iniae), rock bream iridovirus (RBIV) and Edwardsiella tarda (E. tarda) was analyzed in spleen tissues. The complete coding sequence of RbTLR21 was 2919 bp in length which can encode a protein consisting of 973 amino acid residues with molecular mass of 112 kDa and theoretical isoelectric point of 8.6. The anticipated protein sequence resembled a typical TLR domain architecture including C-terminal ectodomain with 16 leucine rich repeats, a transmembrane domain, cytoplasmic TIR domain and signal peptide with 23 amino acid residues. Moreover, protein folding pattern prediction of RbTLR21 exhibited well-structured and folded ectodomain, transmembrane domain and cytoplasmc TIR domain. According to the pair wise sequence analysis data, RbTLR21 showed closest homology with orange-spotted grouper (Epinephelus coioides) TLR21with 76.9% amino acid identity. Furthermore, our phylogenetic analysis revealed that RbTLR21 shows a close evolutionary relationship with its ortholog from Danio rerio. Genomic structure of RbTLR21 consisted of single exon similar to its ortholog of zebra fish. Sevaral putative transcription factor binding sites were also identified in 5ʹ flanking region of RbTLR21. The RBTLR 21 was ubiquitously expressed in all the tissues we tested. Relatively, high expression levels were found in spleen, liver and blood tissues. Upon induction with rock bream iridovirus, RbTLR21 expression was upregulated at the early phase of post induction period even though RbTLR21 expression level was fluctuated at the latter phase of post induction period. Post Edwardsiella tarda injection, RbTLR transcripts were upregulated throughout the experiment. Similarly, Streptococcus iniae induction exhibited significant upregulations of RbTLR21 mRNA expression in the spleen tissues. Collectively, our findings suggest that RbTLR21 is indeed a homolog of TLR21 family members and RbTLR21 may be involved in host immune responses against bacterial and DNA viral infections.

Keywords: rock bream, toll like receptor 21 (TLR21), pattern recognition receptor, genomic characterization

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Authors: Liang Ning, Chung Hau Yin

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Angiogenesis is the process of new blood vessel development. It has been recognized as a therapeutic target for blocking cancer growth four decades ago. Vascular sprouting is initiated by pro-angiogenic factors. Vascular endothelial cell growth factor (VEGF) plays a central role in angiogenic initiation, many patients with cancer or ocular neovascularization have been benefited from anti-VEGF therapy. Emerging approaches impacting in the later stages of vessel remodeling and maturation are expected to improve clinical efficacy. TIE receptor as well as the corresponding angiopoietin ligands, were identified as another endothelial cell specific receptor tyrosine kinase signaling system. Much efforts were made to reduce the activity of angiopoietin-TIE receptor axis. Two eudesmane-type sesquiterpenes from laggera alata, namely, 15-dihydrocostic acid and ilicic acid were found with strong anti-angiogenic properties in zebrafish model. Meanwhile, the mRNA expression levels of VEGFR2 and TIE2 pathway related genes were down-regulated in the sesquiterpenes treated zebrafish embryos. Besides, in human umbilical vein endothelial cells (HUVECs), the sesquiterpenes have the ability to inhibit VEGF-induced HUVECs proliferation and migration at non-toxic concentration. Moreover, angiopoietin-2 induced TIE2 phosphorylation was inhibited by the sesquiterpenes, the inhibitory effect was detected in angiopoietin-1 induced HUVECs proliferation as well. Thus, we hypothesized the anti-angiogenic activity of the compounds may via the inhibition of VEGF and TIE2 related pathways. How the compounds come into play as the pathways inhibitors need to be evaluated in the future.

Keywords: Laggera alata, eudesmane-type sesquiterpene, anti-angiogenesis, VEGF, angiopoietin, TIE2

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Authors: Deepak Mohan, Sushma Sharma, Mohammad Asif

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Diclofenac sodium being one of the most common non-steroidal anti-inflammatory drugs is normally used as painkiller and to reduce inflammation. The drug is known to alter the enzymatic activities of acid and alkaline phosphatase, glutamate oxaloacetate transaminase and glutamate pyruvate transaminases. The drug also results in change in the concentration of proteins and lipids in the body. The present study is an attempt to study different biochemical changes electrophoretically due to administration of different doses of diclofenac (4mg/kg/body weight and 14mg/kg/body weight) on liver and testes of mice from 7-28 days of investigation. Homogenization of the tissue was done, supernatant separated was loaded in the gel and native polyacrylamide gel electrophoresis was conducted. Diclofenac administration resulted in alterations of all these biochemical parameters which were observed in native polyacrylamide gel electrophoretic studies. The severe degenerative changes as observed during later stages of the experiment showed correlation with increase or decrease in the activities of all the enzymes studied in the present investigation. Image analysis of gel in liver showed a decline of 7.4 and 5.3 % in low and high dose group after 7 days whereas a decline of 9.6 and 7.5% was registered after 28 days of investigation. Similar analysis for testis also showed an appreciable decline in the activity of alkaline phosphatase after 28 days. Gel analysis of serum was also performed to find a correlation in the enzymatic activities between the tissue and blood.

Keywords: diclofenac, inflammation, polyacrylamide, phosphatase

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Authors: Esra Sengul, R. G. Aktas, M. E. Sitar, H. Isan

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Hepatocellular carcinoma (HCC) is a hepatocellular tumor commonly found on the surface of the chronic liver. HepG2 is the most commonly used cell type in HCC studies. The main proteins remaining in the blood serum after separation of plasma fibrinogen are albumin and globulin. The fact that the albumin showed hepatocellular damage and reflect the synthesis capacity of the liver was the main reason for our use. Alpha-Fetoprotein (AFP) is an albumin-like structural embryonic globulin found in the embryonic cortex, cord blood, and fetal liver. It has been used as a marker in the follow-up of tumor growth in various malign tumors and in the efficacy of surgical-medical treatments, so it is a good protein to look at with albumins. We have seen the morphological changes of dimethyl sulfoxide (DMSO) on HepG2 and decided to investigate its biochemical effects. We examined the effects of DMSO, which is used in cell cultures, on albumin, AFP and total protein at low doses. Material Method: Cell Culture: Medium was prepared in cell culture using Dulbecco's Modified Eagle Media (DMEM), Fetal Bovine Serum Dulbecco's (FBS), Phosphate Buffered Saline and trypsin maintained at -20 ° C. Fixation of Cells: HepG2 cells, which have been appropriately developed at the end of the first week, were fixed with acetone. We stored our cells in PBS at + 4 ° C until the fixation was completed. Area Calculation: The areas of the cells are calculated in the ImageJ (IJ). Microscope examination: The examination was performed with a Zeiss Inverted Microscope. Daytime photographs were taken at 40x, 100x 200x and 400x. Biochemical Tests: Protein (Total): Serum sample was analyzed by a spectrophotometric method in autoanalyzer. Albumin: Serum sample was analyzed by a spectrophotometric method in autoanalyzer. Alpha-fetoprotein: Serum sample was analyzed by ECLIA method. Results: When liver cancer cells were cultured in medium with 1% DMSO for 4 weeks, a significant difference was observed when compared with the control group. As a result, we have seen that DMSO can be used as an important agent in the treatment of liver cancer. Cell areas were reduced in the DMSO group compared to the control group and the confluency ratio increased. The ability to form spheroids was also significantly higher in the DMSO group. Alpha-fetoprotein was lower than the values of an ordinary liver cancer patient and the total protein amount increased to the reference range of the normal individual. Because the albumin sample was below the specimen value, the numerical results could not be obtained on biochemical examinations. We interpret all these results as making DMSO a caretaking aid. Since each one was not enough alone we used 3 parameters and the results were positive when we refer to the values of a normal healthy individual in parallel. We hope to extend the study further by adding new parameters and genetic analyzes, by increasing the number of samples, and by using DMSO as an adjunct agent in the treatment of liver cancer.

Keywords: hepatocellular carcinoma, HepG2, dimethyl sulfoxide, cell culture, ELISA

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Authors: Mustafa M. Donma, Orkide Donma

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Obesity and weight gain are associated with increased risk of developing cardiovascular diseases and the progression of liver fibrosis. Aspartate transaminase–to-platelet count ratio index (AST-to-PLT, APRI) and fibrosis-4 (FIB-4) were primarily considered as the formulas capable of differentiating hepatitis from cirrhosis. Recently, they have found clinical use as measures of liver fibrosis and cardiovascular risk. However, their status in children has not been evaluated in detail yet. The aim of this study is to determine APRI and FIB-4 status in obese (OB) children and compare them with values found in children with normal body mass index (N-BMI). A total of sixty-eight children examined in the outpatient clinics of the Pediatrics Department in Tekirdag Namik Kemal University Medical Faculty were included in the study. Two groups were constituted. In the first group, thirty-five children with N-BMI, whose age- and sex-dependent BMI indices vary between 15 and 85 percentiles, were evaluated. The second group comprised thirty-three OB children whose BMI percentile values were between 95 and 99. Anthropometric measurements and routine biochemical tests were performed. Using these parameters, values for the related indices, BMI, APRI, and FIB-4, were calculated. Appropriate statistical tests were used for the evaluation of the study data. The statistical significance degree was accepted as p<0.05. In the OB group, values found for APRI and FIB-4 were higher than those calculated for the N-BMI group. However, there was no statistically significant difference between the N-BMI and OB groups in terms of APRI and FIB-4. A similar pattern was detected for triglyceride (TRG) values. The correlation coefficient and degree of significance between APRI and FIB-4 were r=0.336 and p=0.065 in the N-BMI group. On the other hand, they were r=0.707 and p=0.001 in the OB group. Associations of these two indices with TRG have shown that this parameter was strongly correlated (p<0.001) both with APRI and FIB-4 in the OB group, whereas no correlation was calculated in children with N-BMI. Triglycerides are associated with an increased risk of fatty liver, which can progress to severe clinical problems such as steatohepatitis, which can lead to liver fibrosis. Triglycerides are also independent risk factors for cardiovascular disease. In conclusion, the lack of correlation between TRG and APRI as well as FIB-4 in children with N-BMI, along with the detection of strong correlations of TRG with these indices in OB children, was the indicator of the possible onset of the tendency towards the development of fatty liver in OB children. This finding also pointed out the potential risk for cardiovascular pathologies in OB children. The nature of the difference between APRI vs FIB-4 correlations in N-BMI and OB groups (no correlation versus high correlation), respectively, may be the indicator of the importance of involving age and alanine transaminase parameters in addition to AST and PLT in the formula designed for FIB-4.

Keywords: APRI, children, FIB-4, obesity, triglycerides

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Authors: Kittitara Chunlakittiphan, Patompong Satapornpong

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Introduction: The variation of genetics affects how our body responds to pharmaceuticals elucidates the correlation between long-term use of medical cannabis and adverse drug reactions (ADRs). Medical cannabis is regarded as the treatment for chronic pain, cancer pain, acute pain, psychological disorders, multiple sclerosis and migraine management. However, previous studies have shown that delta-9-Tetrahydrocannabinol (THC), an ingredient found in cannabis, was the cause of ADRs in CB1 receptors found in humans. Previous research suggests that distributions of the cannabinoid type 1 (CB1) receptor gene and pharmacogenetic markers, which vary amongst different populations, might affect incidences of ADRs. Although there is an evident need to investigate the level of the CB1 receptor gene (rs806365), studies on the distribution of CB1-pharmacogenetics markers in Thai patients are limited. Objective: Therefore, the aim of this study is to investigate the distribution of the rs806365 polymorphism in Thai patients who have been treated with medical cannabis. Materials and Methods: We enrolled 31 Thai patients with THC-induced ADRs and 34 THC-tolerant controls to take part in this study. All patients with THC-induced ADRs were accessed through a review of medical records by physicians. EDTA blood of 3ml was collected to obtain the CNR1 gene (rs806365) and genotyping of this gene was conducted using the real-time PCR ViiA7 (ABI, Foster City, CA, USA) following the manufacturer’s instruction. Results: The sample consisted of 65 patients (40/61.54%) were females and (25/38.46%) were males, with an age range of 19-87 years, who have been treated with medical cannabis. In this study, the most common THC-induced ADRs were dry mouth and/or dry throat, tachycardia, nausea, and arrhythmia. Across the whole sample, we found that 52.31% of Thai patients carried a heterozygous variant (rs806365, CT allele). Moreover, the number of rs806365 (CC, homozygous variant) carriers totaled seventeen people (26.15%) amongst the subjects of Thai patients treated with medical cannabis. Furthermore, 17 out of 22 patients (77.27%) who experienced severe ADRs: Tachycardia and/or arrhythmia, carried an abnormal rs806365 gene (CT and CC alleles). Conclusions: The results propose that the rs806365 gene is widely distributed amongst the Thai population and there is a link between this gene and vulnerability to developing THC-induced ADRs after being treated with medical cannabis. Therefore, it is necessary to screen for the rs806365 gene before using medical cannabis to treat a patient.

Keywords: rs806365, THC-induced adverse drug reactions, CB1 receptor, Thai population

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Authors: Ilirian Laçi, Alketa Spahiu

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Modality of treatment in hepatocellular carcinoma (HCC) patients depends on the stage of the disease. The Barcelona Clinic Liver Cancer Classification (BCLC) is the preferred staging system. There are many patients initially present with intermediate-stage disease. For these patients, transarterial chemoembolization (TACE) is the treatment of choice. The differences in individual factors that are not captured by the BCLC framework, such as the tumor growth pattern, degree of hypervascularity, and vascular supply, complicate further evaluation of these patients. Because of these differences, not all patients benefit equally from TACE. Several tools have been devised to aid the decision-making process, which have shown promising initial results but have failed external evaluation and have not been translated to the clinic aspects. Criteria for treatment decisions in daily clinical practice are needed in all stages of the disease.

Keywords: hepatocellular carcinoma, transarterial chemoembolization, TACE, liver

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Authors: Sourav Ray, Christoph Stein, Marcus Weber

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A new class of drug candidates, initially derived from mathematical modeling of ligand-receptor interactions, activate the μ-opioid receptor (MOR) preferentially at acidic extracellular pH-levels, as present in injured tissues. This is of commercial interest because it may preclude the adverse effects of conventional MOR agonists like fentanyl, which include but are not limited to addiction, constipation, sedation, and apnea. Animal studies indicate the importance of taking the pH value of the chemical environment of MOR into account when designing new drugs. Hydrogen bonds (HBs) play a crucial role in stabilizing protein secondary structure and molecular interaction, such as ligand-protein interaction. These bonds may depend on the pH value of the chemical environment. For the MOR, antagonist naloxone and agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) form HBs with ionizable residue HIS 297 at physiological pH to modulate signaling. However, such interactions were markedly reduced at acidic pH. Although fentanyl-induced signaling is also diminished at acidic pH, HBs with HIS 297 residue are not observed at either acidic or physiological pH for this strong agonist of the MOR. Molecular dynamics (MD) simulations can provide greater insight into the interaction between the ligand of interest and the HIS 297 residue. Amino acid protonation states are adjusted to the model difference in system acidity. Unbiased and unrestrained MD simulations were performed, with the ligand in the proximity of the HIS 297 residue. Ligand-receptor complexes were embedded in 1-palmitoyl-2-oleoyl-sn glycero-3-phosphatidylcholine (POPC) bilayer to mimic the membrane environment. The occurrence of HBs between the different ligands and the HIS 297 residue of MOR at acidic and physiological pH values were tracked across the various simulation trajectories. No HB formation was observed between fentanyl and HIS 297 residue at either acidic or physiological pH. Naloxone formed some HBs with HIS 297 at pH 5, but no such HBs were noted at pH 7. Interestingly, DAMGO displayed an opposite yet more pronounced HB formation trend compared to naloxone. Whereas a marginal number of HBs could be observed at even pH 5, HBs with HIS 297 were more stable and widely present at pH 7. The HB formation plays no and marginal role in the interaction of fentanyl and naloxone, respectively, with the HIS 297 residue of MOR. However, HBs play a significant role in the DAMGO and HIS 297 interaction. Post DAMGO administration, these HBs might be crucial for the remediation of opioid tolerance and restoration of opioid sensitivity. Although experimental studies concur with our observations regarding the influence of HB formation on the fentanyl and DAMGO interaction with HIS 297, the same could not be conclusively stated for naloxone. Therefore, some other supplementary interactions might be responsible for the modulation of the MOR activity by naloxone binding at pH 7 but not at pH 5. Further elucidation of the mechanism of naloxone action on the MOR could assist in the formulation of cost-effective naloxone-based treatment of opioid overdose or opioid-induced side effects.

Keywords: effect of system acidity, hydrogen bond formation, opioid action, receptor activation

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Authors: Moetazza M. Alshafei, Ahmed M. Mabrouk, Emtenan M. Hanafi, Manal M. Ramadan, Reda M. S. Korany, Seham S. Kassem, Dina Mostafa Mohammed

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Metabolic syndrome (MeS) is a major health problem with a high incidence of obese individuals worldwide. Increased related morbidity of diabetes, hypertension and fatty liver disease, and complicated cardiovascular disease are inevitable. Boswellia serrata gum (Bos) is a promising traditional medicinal plant; it has several pharmacological properties, including anti-inflammatory, antioxidant, and antilipase activities. Probiotics (Bac) supplements have good benefits on health and MeS, whether it is supplemented in combination with prebiotics or alone. Microencapsulation helps to mask unpalatable taste and odor and deliver active ingredients to targeted organs. Methodology MeS rat model was produced by feeding rats with a high fat, high CHO diet (HFD). Bos was extracted, and both Bos and the probiotic were microencapsulated with a spray drier. Female rats were divided into 5 groups (N8). HFD control, control normal receiving basic diet, HFD treated, from the start of the experiment, either with encapsulated Bos, Bac and Bos or Bac only, all treatments were received for eight weeks (after approval from NRC animal ethical committee). Serum was collected to analyze lipid profile, blood sugar, liver and kidney functions, antioxidants, leptin, and progesterone. Rat's organs and body fat were weighed and collected for histopathology. Statistical analysis was done by use of one way Anova test in the SPSS program. Results showed control of elevated body weight, lipid profile, and glucose levels as well as decrease of body fat index and improvement of histopathology of liver and heart, especially in combination. Conclusion: We concluded that both microencapsulated Bos and probiotics have a controlling effect on MeS parameters.

Keywords: metabolic syndrome, Boswellia serata, probiotic, micro-encapsulation, histopathology, liver steatosis

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Authors: Marina Lazar Chandy, N. Kannan, Rajendra Patil, Vinod Mathew, Ajmal Mohamed, P. K. Sreeja, Renju Jose

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Introduction- Arecoline, a major constituent of arecanut has shown to have some effect on liver. The use of arecanut is found to be the most common etiological factor for the development of Oral Submucous fibrosis (O.S.M.F). The effect of arecanut usage on liver in patients with O.S.M.F needs to be assessed. Lipids play a role in structural maintenance of cell. Alterations of lipid profile were noted in cancer patients. O.S.M.F being a precancerous lesion can have some effect on the level of lipids in the body. Objectives: This study was done to assess the alterations in liver enzymes (Serum Glutamic Pyruvic Transaminase(S.G.P.T ,Serum Glutamic Oxaloacetic Transaminase(S.G.O.T)) and lipid metabolism (High Density Lipoprotien(H.D.L) and Apo Lipoprotien A1 (Apo A1)) in patients with O.S.M.F. Methods-130 patients were taken for the study,100 patients with O.S.M.F and 30 as control group without O.S.M.F. Fasting blood sugar levels were taken, centrifuged and analyzed for S.G.P.T,S.G.O.T, H.D.L and Apo A1 using semi automated spectrophotometer. Results: After statistical analysis, it was concluded that there is an elevation of levels of S.G.P.T, S.G.O.T, and decreased levels of H.D.L, Apo A1 for O.S.M.F group when compared with control group. With increased grade of O.S.M.F. and duration of habit, S.G.P.T. & S.G.O.T. increased whereas, H.D.L. & Apo A1 decreased. All the values were statistically significant at p<0.01.

Keywords: apolipoprotien A1, high density lipoprotien, oral submucous fibrosis, serum glutamic oxaloacetic transaminase

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Authors: B. J. Mahen, N. E. Lloyd-Gale, S. Johnson, W. P. Rakowicz, M. J. Harris, A. D. Miller

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Background: Migraine is a leading cause of disability in the world. Calcitonin gene-related peptide (CGRP) receptor antagonists offer an approach to migraine prophylaxis by inhibiting the inflammatory and vasodilatory effects of CGRP. In recent years, NICE licensed the use of three CGRP-receptor antagonists: Fremanezumab, Galcanezumab, and Erenumab. Here, we present the outcomes of CGRP-antagonist treatment in a cohort of patients who suffer from episodic or chronic migraine and have failed at least three oral prophylactic therapies. Methods: We offered CGRP antagonists to 86 patients who met the NICE criteria to start therapy. We recorded the number of headache days per month (HDPM) at 0 weeks, 3 months, and 12 months. Of those, 26 patients were switched to an alternative treatment due to poor response or side effects. Of the 112 total cases, 9 cases did not sufficiently maintain their headache diary, and 5 cases were not followed up at 3 months. We have therefore included 98 sets of data in our analysis. Results: Fremanezumab achieved a reduction in HDPM by 51.7% at 3 months (p<0.0001), with 63.7% of patients meeting NICE criteria to continue therapy. Patients trialed on Galcanezumab attained a reduction in HDPM by 47.0% (p=0.0019), with 51.6% of patients meeting NICE criteria to continue therapy. Erenumab, however, only achieved a reduction in HDPM by 17.0% (p=0.29), and this was not statistically significant. Furthermore, 34.4%, 9.7%, and 4.9% of patients taking Fremanezumab, Galcanezumab, and Erenumab, respectively, continued therapy beyond 12 months. Of those who attempted drug holidays following 12 months of treatment, migraine symptoms relapsed in 100% of cases. Conclusion: We observed a significant improvement in HDPM amongst episodic and chronic migraine patients following treatment with Fremanezumab or Galcanezumab.

Keywords: migraine, CGRP, fremanezumab, galcanezumab, erenumab

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Authors: Sabrina Barsky, Ashley Monks

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In humans, exercise improves symptoms of various pathological states, although exercise adaptations seem to differ in response to sex. Skeletal muscle anabolism is thought to be regulated by androgen receptor (AR) through poorly specified mechanisms. Interactions of AR and exercise on muscle phenotype remain inconclusive in males, and undetermined in females. We hypothesized that sex differences in exercise adaptations are regulated by the androgenic system and the type of exercise performed. Here we examined interactions between a muscle-specific AR overexpression transgene (HSA-AR) and forced aerobic exercise paradigm on muscle and adipose exercise adaptation in male and female rats. We used dual-energy X-ray absorptiometry (DXA) to examine body composition adaptations post 9-week exercise protocol. We replicated the effects of HSA-AR on body composition, with males only having increased % lean mass and reduced % fat mass (P<0.05). Aerobic exercise improved lean body phenotype significantly, with lesser indices of total and % fat mass (P<0.01) in both sexes. Sex-specific effects of exercise included decreased total body mass (P<0.01) in males and increased lean mass % (P<0.001) in females. Surprisingly, neither AR manipulation nor exercise affected bone parameters in either sex. This varied response in total mass and lean mass according to exercise presents a sexually dimorphic response to exercise. Neither sex showed an interaction between HSA-AR and forced aerobic exercise on body composition. Future work is proposed to examine the effects of exercise type (aerobic versus resistance) and the role of gonadal androgens in sexually dimorphic exercise-mediated mitochondrial adaptations. This work implicates the development of sex-specific exercise therapies.

Keywords: androgen receptor, forced exercise, muscle physiology, sexual dimorphism

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Authors: Ihtisham Bukhari

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In the current study, we enrolled a 46, XY phenotypically female patient bearing testes in her inguinal canal. DNA sequencing of the AR gene detected a missense mutation C.1715A > G (p. Y572C) in exon 2 which is already known to cause Complete androgen insensitivity syndrome (CAIS). We further studied the effects of this mutation on the testicular histopathology of the patient. No spermatocytes were seen in the surface spreading of testicular tissues while H&E staining showed that seminiferous tubules predominantly have only Sertoli cells. To confirm this meiotic failure is likely due to the current AR mutation we performed mRNA expression of genes associated with AR pathway, expression and location of the associated proteins in testicular tissues. Western blot and real-time PCR data showed that the patient had high levels of expression of AMH, SOX9, and INNB in testis. Tubules were stained with SOX9 and AMH which revealed Sertoli cell maturation arrest. Therefore, we suggest that AR mutation enhances AMH expression which ultimately leads to failure in the maturation of Sertoli cells and failure in spermatogenesis.

Keywords: androgen receptor, spermatogenesis, infertility, Sertoli cell only syndrome

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Authors: Elham Sharif, Nasser Rizk, Sirin Abu Aqel, Ofelia Masoud

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Background: Previous studies have investigated the association of rs1544410, rs7975232 and rs731236 polymorphisms in vitamin D receptor gene and its impact on diseases such as cancer, diabetes and hypertension in different ethnic backgrounds. Aim: The aim of this study is to investigate the association between VDR polymorphisms using three SNP’s (rs1544410, rs7975232 and rs731236) and the severity of the significant lesion in coronary arteries among angiographically diagnosed CAD. Methods: A prospective-retrospective study was conducted on 192 CAD patients enrolled from the cardiology department-Heart Hospital HMC, grouped in 96 subjects with significant stenosis and 96 with non-significant stenosis with a mean age between 30 and 75 years old. Genotyping was performed for the following SNPs rs1544410, rs7975232 and rs731236 using TaqMan assay by the Real Time PCR, ABI 7500 in Health Sciences Labs at Qatar University Biomedical Research Center. Results: The results showed that both groups have matched age and gender distribution but patients with the significant stenosis have significantly higher; BMI (p=0.047); smoking status (p=0.039); FBS (p= 0.031); CK-MB (p=0.025) and Troponin (p=0.002) than the patients with non–significant lesion. Among the traditional risk factors, smoking increases the odds of the severe stenotic lesion in CAD patients by 1.984, with 95% CI between 1.024 – 7.063, with p= 0.042.HWE showed deviations of the rs1544410 and rs731236 among the study subjects. The most frequent genotype in distribution of rs7975232 is the AA among the significant stenosis patients, while the heterozygous AC was the frequent genotype in distribution among the non-significant stenosis group. The carriers of CC genotype in rs7975232 increased the risk of having significant coronary arteries stenotic lesion by 1.83 with 95% CI (1.020 – 3.280), p=0.043. No association was found between the rs7975232 with vitamin D and VDBP. Conclusion: There is a significant association between rs7975232 and the severity of CAD lesion. The carrier of CC genotype in rs7975232 increased the risk of having significant coronary arteries atherosclerotic lesion especially in patients with smoking history independent of vitamin D.

Keywords: vitamin D, vitamin D receptor, polymorphism, coronary harat disease

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Authors: Isaac Gbadura Adanlawo, Olusola Olalekan Elekofehinti

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This work investigated the antihyperglycemic, antioxidant and antihyperlipidemic effects of saponins from the fruit of Solanum anguivi, a plant generally used in folk medicine to treat diabetes and hypertension and to compare its effect with metformin in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced in albino rats by administration of STZ (65 mg/kg) intraperitoneally. Saponin (40 and 100 mg/kg) was administered by oral gavage once daily for 21 days. Metformin (200 mg/kg b.w.) was administered as the positive control. The effect of saponin on blood glucose, serum lipids and enzymatic antioxidants defense systems, like superoxide dismutase (SOD), catalase (CAT), as well as MDA levels in serum, liver and pancreas were studied. Saponins from S. anguivi fruits reduced the blood glucose, total cholesterol (TC), triglycerides (TG) and low-density lipoprotein (LDL) levels in STZ-diabetic rats. They also significantly abolished the increase in MDA level in serum, liver and pancreas of diabetic rats. The activities of SOD and CAT in serum, liver and pancreas were significantly increased as well as concentration of HDL in the serum. Metformin had the same effect as saponin but saponins seems to be more potent in reducing serum TC, TG, LDL, and MDA, and increasing SOD and CAT. Conclusions: These results suggest that saponins from S. anguivi fruits have anti-diabetic and antihypercholesterolemic, antihypertriglyceridemic antiperoxidative activities mediated through their antioxidant properties. Also, saponins appeared to have more hypolipidemic, antiperoxidative and antioxidant activity than metformin.

Keywords: saponin, diabetes, metformin, streptozotocin, Solanum anguivi

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Authors: Jillian M. Hagel, Joseph E. Tucker, Peter J. Facchini

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With the aim of establishing a holistic approach for the treatment of central nervous system (CNS) disorders, we are pursuing a drug development program rapidly progressing through discovery and characterization phases. The drug candidates identified in this program are referred to as neuroplastogens owing to their ability to mediate neuroplasticity, which can be beneficial to patients suffering from anxiety, depression, or posttraumatic stress disorder. These and other related neuropsychiatric conditions are associated with the onset of neuronal atrophy, which is defined as a reduction in the number and/or productivity of neurons. The stimulation of neuroplasticity results in an increase in the connectivity between neurons and promotes the restoration of healthy brain function. We have synthesized a substantial catalogue of proprietary indolethylamine derivatives based on the general structures of serotonin (5-hydroxytryptamine) and psychedelic molecules such as N,N-dimethyltryptamine (DMT) and psilocin (4-hydroxy-DMT) that function as neuroplastogens. A primary objective in our screening protocol is the identification of derivatives associated with a significant reduction in hallucination, which will allow administration of the drug at a dose that induces neuroplasticity and triggers other efficacious outcomes in the treatment of targeted CNS disorders but which does not cause a psychedelic response in the patient. Both neuroplasticity and hallucination are associated with engagement of the 5HT2A receptor, requiring drug candidates differentially coupled to these two outcomes at a molecular level. We use novel and proprietary artificial intelligence algorithms to predict the mode of binding to the 5HT2A receptor, which has been shown to correlate with the hallucinogenic response. Hallucination is tested using the mouse head-twitch response model, whereas mouse marble-burying and sucrose preference assays are used to evaluate anxiolytic and anti-depressive potential. Neuroplasticity is assays using dendritic outgrowth assays and cell-based ELISA analysis. Pharmacokinetics and additional receptor-binding analyses also contribute the selection of lead candidates. A summary of the program is presented.

Keywords: neuroplastogen, non-hallucinogenic, drug development, anxiety, depression, PTSD, indolethylamine derivatives, psychedelic-inspired, 5-HT2A receptor, computational chemistry, head-twitch response behavioural model, neurite outgrowth assay

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