Search results for: altered methionine metabolism

Authors: Nigatu Tadesse, Ying Liu, Juan Li, Hong Ming Liu

Abstract:

Gastric carcinogenesis is a lengthy process of histopathological transition from normal to atrophic gastritis (AG) to intestinal metaplasia (GIM), dysplasia toward gastric cancer (GC). The stage of GIM identified as precancerous lesions with resistance to H-pylori eradication and recurrence after endoscopic surgical resection therapies. GIM divided in to two morphologically distinct phenotypes such as complete GIM bearing intestinal type morphology whereas the incomplete type has colonic type morphology. The incomplete type GIM considered to be the greatest risk factor for the development of GC. Studies indicated the expression of the caudal type homeobox 2 (CDX2) gene is responsible for the development of complete GIM but its progressive downregulation from incomplete metaplasia toward advanced GC identified as the risk for IM progression and neoplastic transformation. The downregulation of CDX2 gene have promoted cell growth and proliferation in gastric and colon cancers and ascribed in chemo-treatment inefficacies. CDX2 downregulated through promoter region hypermethylation in which the methylation frequency positively correlated with the dietary history of the patients, suggesting the role of diet as methyl carbon donor sources such as methionine. However, the metabolism of exogenous methionine is yet unclear. Targeting exogenous methionine metabolism has become a promising approach to limits tumor cell growth, proliferation and progression and increase treatment outcome. This review article discusses molecular alterations that could shed light on the potential of exogenous methionine metabolisms, such as gut microbiota alteration as sources of methionine to host cells, metabolic pathway signaling via PI3K/AKt/mTORC1-c-MYC to rewire exogenous methionine and signature of increased gene methylation index, cell growth and proliferation in GIM, with insights to new treatment avenue via targeting methionine metabolism, and the need for future integrated studies on molecular alterations and metabolomics to uncover altered methionine metabolism and characterization of CDX2 methylation in gastric intestinal metaplasia for potential therapeutic exploitation.

Keywords: altered methionine metabolism, Intestinal metaplesia, CDX2 gene, gastric cancer

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Authors: Nigatu Tadesse, Li Juan, Liuhong Ming

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Gastric cancer (GC) is the fifth most common and fourth deadly cancer in the world with limited treatment options at late advanced stage in which surgical therapy is not recommended with chemotherapy remain as the mainstay of treatment. However, the occurrence of chemoresistance as well as intera-tumoral and inter-tumoral heterogeneity of response to targeted and immunotherapy underlined a clear unmet treatment need in gastroenterology. Several molecular and cellular alterations ascribed for chemo resistance in GC including cancer stem cells (CSC) and tumor microenvironment (TME) remodeling. Cancer cells including CSC bears higher metabolic demand and major changes in TME involves alterations of gut microbiota interacting with nutrients metabolism. Metabolic upregulation in lipids, carbohydrates, amino acids, fatty acids biosynthesis pathways identified as a common hall mark in GC. Metabolic addiction to methionine metabolism occurs in many cancer cells to promote the biosynthesis of S-Adenosylmethionine (SAM), a universal methyl donor molecule for high rate of transmethylation in GC and promote cell proliferation. Targeting methionine metabolism found to promotes chemo-sensitivity with treatment non-heterogeneity. Methionine restriction (MR) promoted the arrest of cell cycle at S/G2 phase and enhanced downregulation of GC cells resistance to apoptosis (including ferroptosis), which suggests the potential of synergy with chemotherapies acting at S-phase of the cell cycle as well as inducing cell apoptosis. Accumulated evidences showed both the biogenesis as well as intracellular metabolism of exogenous methionine could be safe and effective target for therapy either alone or in combination with chemotherapies. This review article provides an over view of the upregulation in methionine biosynthesis pathway and the molecular signaling through the PI3K/Akt/mTOR-c-MYC axis to promote metabolic reprograming through activating the expression of L-type aminoacid-1 (LAT1) transporter and overexpression of Methionine adenosyltransferase 2A(MAT2A) for intercellular metabolic conversion of exogenous methionine to SAM in GC, and the potential of targeting with novel therapeutic agents such as methioninase (METase), Methionine adenosyltransferase 2A (MAT2A), c-MYC, methyl like transferase 16 (METTL16) inhibitors that are currently under clinical trial development stages and future perspectives.

Keywords: gastric cancer, methionine metabolism, pi3k/akt/mtorc1-c-myc axis, gut microbiota, MAT2A, c-MYC, METTL16, methioninase

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Authors: K. A. El-Battawy, W. S. El-Nattat

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The aim of the present investigation was to evaluate the impact of methionine on the preservation, acrosomal integrity, DNA integrity and post thawing motility of extended goat semen. Semen samples were diluted with a Tris-based extender containing the additive methionine 1.5, 2.5 and 5mM then the diluted samples were kept in glass tubes and cooled from 37°C to 5°C in a cold cabinet, and maintained at 5°C. Sperm motility (SM%), alive sperm (AS%), sperm abnormalities (SA%) acrosomal integrity and DNA integrity were determined at 5°C for periods of 0,24, 48and 72 h of liquid storage. Furthermore, the influence of methionine on post-thawing motility was assessed. The results elaborated that the addition of methionine and L-tyrosine particularly 2.5mM of methionine significantly improved SM% and reduced dead sperm %. Furthermore, the addition of 2.5mM methionine improved post-thawing motility (43.75 ± 1.25% vs. 32.50 ± 3.23 in the control group). Moreover, the frequency of acrosomal defects was lower in treated groups than in control. In conclusion, the addition of methionine induced remarkable physiological effects on goat semen quality during conservation for 7-days-long period at 5°C and improved its freezability.

Keywords: methionine, acrosome, semen, cryopreservation

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Authors: Komala Arsi, Ann M. Donoghue, Dan J. Donoghue

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Methionine is an essential dietary amino acid necessary to promote growth and health of poultry. Synthetic methionine is commonly used as a supplement in conventional poultry diets and is temporarily allowed in organic poultry feed for lack of natural and organically approved sources of methionine. It has been a challenge to find a natural, sustainable and cost-effective source for methionine which reiterates the pressing need to explore potential alternatives of methionine for organic poultry production. Fish have high concentrations of methionine, but wild-caught fish are expensive and adversely impact wild fish populations. Asian carp (AC) is an invasive species and its utilization has the potential to be used as a natural methionine source. However, to our best knowledge, there is no proven technology to utilize this fish as a methionine source. In this study, we co-extruded Asian carp and soybean meal to form a dry-extruded, methionine-rich AC meal. In order to formulate rations with the novel extruded carp meal, the product was tested on cecectomized roosters for its amino acid digestibility and total metabolizable energy (TMEn). Excreta was collected and the gross energy, protein content of the feces was determined to calculate Total Metabolizable Energy (TME). The methionine content, digestibility and TME values were greater for the extruded AC meal than control diets. Carp meal was subsequently tested as a methionine source in feeds formulated for broilers, and production performance (body weight gain and feed conversion ratio) was assessed in comparison with broilers fed standard commercial diets supplemented with synthetic methionine. In this study, broiler chickens were fed either a control diet with synthetic methionine or a treatment diet with extruded AC meal (8 replicates/treatment; n=30 birds/replicate) from day 1 to 42 days of age. At the end of the trial, data for body weights, feed intake and feed conversion ratio (FCR) was analyzed using one-way ANOVA with Fisher LSD test for multiple comparisons. Results revealed that birds on AC diet had body weight gains and feed intake comparable to diets containing synthetic methionine (P > 0.05). Results from the study suggest that invasive AC-derived fish meal could potentially be an effective and inexpensive source of sustainable natural methionine for organic poultry farmers.

Keywords: Asian carp, methionine, organic, poultry

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Authors: I. Upadhyaya, K. Arsi, A. M. Donoghue, C. N. Coon, M. Schlumbohm, M. N. Riaz, M. B. Farnell, A. Upadhyay, A. J. Davis, D. J. Donoghue

Abstract:

Methionine, a sulfur containing amino acid, is essential for healthy poultry production. Synthetic methionine is commonly used as a supplement in conventional poultry. However, for organic poultry, a natural, cost effective source of methionine that can replace synthetic methionine is unavailable. Invasive Asian carp (AC) are a potential natural methionine source; however, there is no proven technology to utilize this fish methionine. Commercially available rendering is environmentally challenging due to the offensive smell produced during production. We explored extrusion technology as a potential cost effective alternative to fish rendering. We also determined the amino acid composition, digestible amino acids and total metabolizable energy (TMEn) for the extruded AC fish meal. Dry extrusion of AC was carried out by mixing the fish with soybean meal (SBM) in a 1:1 proportion to reduce high moisture in the fishmeal using an Insta Pro Jr. dry extruder followed by drying and grinding of the product. To determine the digestible amino acids and TMEn of the extruded product, a colony of cecectomized Bovans White Roosters was used. Adult roosters (48 weeks of age) were fasted for 30 h and tube fed 35 grams of 3 treatments: (1) extruded AC fish meal, (2) SBM and (3) corn. Excreta from each individual bird was collected for the next 48 h. An additional 10 unfed roosters served as endogenous controls. The gross energy and protein content of the feces from the treatments were determined to calculate the TMEn. Fecal samples and treatment feeds were analyzed for amino acid content and percent digestible amino acid. Results from the analysis suggested that addition of Asian carp increased the methionine content of SBM from 0.63 to 0.83%. Also, the digestibility of amino acid and the TMEn values were greater for the AC meal with SBM than SBM alone. The dry extruded AC meal analysis is indicative that the product can replace SBM alone and enhance natural methionine in a standard poultry ration. The results from feed formulation using different concentrations of the AC fish meal depict a potential diet which can supplement the required methionine content in organic poultry production.

Keywords: Asian carp, extrusion, natural methionine, organic poultry

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Authors: Fatimah A. Alhomaid, Nadia H. Mahmoud, Maha A. Al-Qaraawi

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The present study was designed to induce hyperhomocysteinemia (HHcy) in elderly male and female rats. Also,to evaluate, the effect of (HHcy) as a risk factor for cerebrovascular disease and brain atrophy and folate supplementation on serum levels of Hcy, total cholesterol, low density lipoprotein cholesterol (LDLc), high density lipoprotein cholesterol (HDLc), triglycerides, pyridoxal phosphate , folate also, histopathological examination of brain and cerebrovascular vessels In this work 50 male and 50 female elderly albino rats were used and divided into five groups. The first group served as control, the second and third group received two different dose of L-methionine, the fourth and fifth group received fortified diet with folate powder plus L-methionine. Our results showed that homocysteine levels in male and female rats that received low and high dose of methionine were higher than in the control group, while the levels of folate significantly decreased in male rats only. Induced hyperhomocysteinemia in elderly male and female rats led to significant increase in serum level of cholesterol, LDLc and triglycerides but serum level of HDLc were significantly lower in methionine treated male and female rats than in control. Our results showed that a strong positive correlation between all these parameters and homocysteine except HDLc levels which correlate negatively to Hcy levels. Administration of folate to methionine treated male rats led to insignificant changes in the level of cholesterol when compared to control group but this level was found to be significantly decrease in female rats received small dose of methionine. When the level of cholesterol compared to the same dose of methionine treated group we found a significant decrease in both male and female rats. LDLc and triglycerides level significantly decrease in male rats only versus the control rats, while when compared to low and high dose of methionine a significant decreased occurs. A significant increase in serum level of HDLc in male and female rats when compared to both control and methionine treated groups. In male and female rats supplemented with folate we found an increased serum levels of folate when compared to rats received both dose of methionine. The levels of pyridoxal phosphate significantly decreased in all treated rats compared to the control group and its level were increased with supplementation of folate versus the rats received small and large dose of methionine. It can be concluded that hyperhomocysteinemia may be an additional risk factor for cerebrovascular atherosclesosis and brain atrophy in elderly people and diatery supplementation with folate blocking the activity of homocysteine and may be considered as a therapeutic possibility.

Keywords: hyperhomocysteinemia, brain atrophy, cerebrovascular, L-methionine, pyridoxal phosphate

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Authors: M. Bagheri Varzaneh, H. R. Rahmani, R. Jahanian

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The present study aimed to investigate the effects of copper-methionine on ascites incidence and hematological, morphological and enzymatic responses in broiler chickens. A total of 480 one-day-old Ross 308 broiler chicks were used in a completely randomized design in a 2×3 factorial arrangement of treatments including two ambient temperatures (thermoneutral and cold stress) and three copper levels (0, 100, and 200 mg/kg as copper-methionine) with 4 replicates (20 birds in each replicate). Broilers were kept in an environmentally-controlled room from 1 to 28 days; then, half of them exposed to cold temperature from 28 to 45 days of age. The birds were sacrificed at days 38 and 45 of age. Heparinized blood samples were collected to measure hematocrit, hemoglobin concentration, red blood cell (RBC) count, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Heart, lungs, liver, and spleen were collected and weighed separately on a sensitive digital scale. At d 38 of age, none of hematological variables, enzymatic parameters, and relative weights of organs were affected by treatments. Ascitic broilers were observed in group subjected to cold temperature and control diet (without supplemental copper) at d 45 of age. Relative weight of lungs and relative weight of heart in broilers fed on copper-methionine supplemented diets in cold temperature were lower compared with other groups. Relative liver weight, ALT, AST activities, and hematological parameters such as hematocrit, hemoglobin concentration, red blood cell count in ascitic broilers were significantly increased. In contrast, a significant decrease of the relative weight of spleen was shown in these chickens. The results showed that dietary supplementation with copper–methionine can decrease probability of ascites incidence in broilers chicks, especially under cold condition.

Keywords: ascites, cold temperature, copper-methionine, cold-stressed broiler

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Authors: Noor Khan, Hira Waris

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This study was conducted on genetically male tilapia (GMT) fry reared in glass aquarium for three months to examine the synergetic effect of essential amino acids (EAA) supplementation on growth, body composition, and enzyme activities. Fish having average body weight of 16.56 ± 0.42g were fed twice a day on artificial feed (20% crude protein) procured from Oryza Organics (commercial feed) supplemented with EAA; methionine (M) and lysine (L) designated as T1 (0.3%M and 2%L), T2 (0.6%M and 4%L), T3 (0.9%M and 6%L) and control without EAA. Significantly higher growth performance was observed in T1, followed by T2, T3, and control. The results revealed that whole-body dry matter and crude protein were significantly higher (p ≤ 0.05) in T3 (0.9% and 6%) feeding fish, while the crude fat was lower (p ≤ 0.05) in a similar group of fish. Additionally, protease, amylase, and lipase activities were also observed maximum (p ≤ 0.05) in response to T3 than other treatments and control. However, the EAA, especially lysine and methionine, were found significantly higher (p ≤ 0.05) in T1 compared to other treatments. Conclusively, the addition of EAA, methionine, and lysine in the feed not only enhanced the growth performance of GMT fry but also improved body proximate composition and essential amino acid profile.

Keywords: genetically male tilapia, body composition, digestive enzyme activities, amino acid profile

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Authors: Sonia Mahajan Dinesh, Anant Dinesh, Madhavi Tripathi, Vinod Kumar Ramteke, Rajnish Sharma, Anupam Mondal

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Background: Neo-adjuvant chemotherapy plays an important role in treatment of breast cancer by decreasing the tumour load and it offers an opportunity to evaluate response of primary tumour to chemotherapy. Standard anatomical imaging modalities are unable to accurately reflect the response to chemotherapy until several cycles of drug treatment have been completed. Metabolic imaging using tracers like 18F-fluorodeoxyglucose (FDG) as a marker of glucose metabolism or amino acid tracers like L-methyl-11C methionine (MET) have potential role for the measurement of treatment response. In this study, our objective was to compare these two PET tracers for assessment of response to neoadjuvant chemotherapy, in locally advanced breast carcinoma. Methods: In our prospective study, 20 female patients with histology proven locally advanced breast carcinoma underwent PET-CT imaging using FDG and MET before and after three cycles of neoadjuvant chemotherapy (CAF regimen). Thereafter, all patients were taken for MRM and the resected specimen was sent for histo-pathological analysis. Tumour response to the neoadjuvant chemotherapy was evaluated by PET-CT imaging using PERCIST criteria and correlated with histological results. Responses calculated were compared for statistical significance using paired t- test. Results: Mean SUVmax for primary lesion in FDG PET and MET PET was 15.88±11.12 and 5.01±2.14 respectively (p<0.001) and for axillary lymph nodes was 7.61±7.31 and 2.75±2.27 respectively (p=0.001). Statistically significant response in primary tumour and axilla was noted on both FDG and MET PET after three cycles of NAC. Complete response in primary tumour was seen in only 1 patient in FDG and 7 patients in MET PET (p=0.001) whereas there was no histological complete resolution of tumor in any patient. Response to therapy in axillary nodes noted on both PET scans were similar (p=0.45) and correlated well with histological findings. Conclusions: For the primary breast tumour, FDG PET has a higher sensitivity and accuracy than MET PET and for axilla both have comparable sensitivity and specificity. FDG PET shows higher target to background ratios so response is better predicted for primary breast tumour and axilla. Also, FDG-PET is widely available and has the advantage of a whole body evaluation in one study.

Keywords: 11C-methionine, 18F-FDG, breast carcinoma, neoadjuvant chemotherapy

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Authors: Mir Hussain Nawaz, Lyudmila Nedyalkova, Haizhong Zhu, Wael M. Rabeh

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In this study, we aim to biochemically and structurally characterize the interactions of human HK2 with the mitochondria in addition to the role of its N-terminal domain in catalysis and stability of the full-length enzyme. Here, we solved the crystal structure of human HK2 in complex with glucose and glucose-6-phosphate (PDB code: 2NZT), where it is a homodimer with catalytically active N- and C-terminal domains linked by a seven-turn α-helix. Different from the inactive N-terminal domains of isozymes 1 and 3, the N- domain of HK2 not only capable to catalyze a reaction but it is responsible for the thermodynamic stabilizes of the full-length enzyme. Deletion of first α-helix of the N-domain that binds to the mitochondria altered the stability and catalytic activity of the full-length HK2. In addition, we found the linker helix between the N- and C-terminal domains to play an important role in controlling the catalytic activity of the N-terminal domain. HK2 is a major step in the regulation of glucose metabolism in cancer making it an ideal target for the development of new anticancer therapeutics. Characterizing the structural and molecular mechanisms of human HK2 and its role in cancer metabolism will accelerate the design and development of new cancer therapeutics that are safe and cancer specific.

Keywords: cancer metabolism, enzymology, drug discovery, protein stability

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Authors: Thouraya Majoul

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Obesity is now a real public health issue throughout the world, and it is well-established that obesity leads to cardiovascular diseases. The prevention and treatment of obesity using nutritional supplements has become a realistic and effective approach. This study was carried out to analyze the incidence of a high-fat diet on rat heart metabolism as well as on fatty acids composition, then to investigate the eventual protective effects of a grape seed extract (GSE). The experimental design consisted of three rat groups subjected to three different conditions; standard (SD), high-fat diet (HFD) and HFD+GSE (HG). We showed that GSE counteracted the effect of HFD on fatty acid composition, namely, docosapentaenoic acid, docosahexaenoic acid, arachidonic acid (ARA), palmitic acid (PA) and palmitoleic acid. Besides, GSE treatment restored HFD-altered metabolic pathways through the recovery of some cardiac enzyme activities such as lipase, glucose 6 phosphate dehydrogenase and pyruvate dehydrogenase. The cardiac lactate level and lactate dehydrogenase activity were also analyzed in relation to HFD and GSE administration. To our knowledge, this is the first study showing the anti-obesity and cardioprotective effects of GSE in relation to fatty acid composition and some cardiac enzymes, supporting its role as a therapeutic agent of obesity.

Keywords: Grape seed extract, phenolic, obesity, cardioprotective, lipotoxicity, energy metabolism

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Authors: Abdulrahman Al-Soqeer, Osamah Fahmy

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This research was aimed to investigate the possibility of using Prosopis juliflora pods as a fodder source for poultry. The study have shown that the inclusion of ground Prosopis pods in a broiler diet added some positive effects on broiler performance such as improving carcasses weight and reducing the weights of the inedible parts. The obtained results encourage repeating the experiment with an increased percentage of Prosopis supplementation in the broiler diets, using some treatments on the Prosopis pods to reduce the undesirable effects of the antinutritional factors in the pods and to increase the percentage of the essential amino acids present in the pods (lysine, methionine, arginine, histidine, isoleucine, leucine and phenylealanine) up to the limits recommended for broilers by NRC 1990.

Keywords: amino acids, arginine, broilers, lysine, methionine

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Authors: Awadhesh Kishore

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One of the most unique characteristics of rabbit feeding behaviour is caecotrophy, which involves the excretion and immediate consumption of specific faeces known as soft faeces. Caecotrophy in rabbits is the instinctual behaviour of eating soft faeces; reduced caecotrophy decreases rabbit growth and lipid synthesis in the liver. Caecotroph ingestion is highest when rabbits are fed a diet high in indigestible fibre. The colon produces two types of waste: hard and soft pellets. The hard pellets are expelled, but the soft pellets are re-ingested by the rabbit directly upon being expelled from the anus by twisting itself around and sucking in those pellets as they emerge from the anus. The type of alfalfa hay in the feed of the rabbits does not affect volatile fatty acid concentration, the pattern of fermentation, or pH in the faeces. The cecal content and the soft faeces contain significant amounts of retinoids and carotenoids, while in the tissues (blood, liver, and kidney), these pigments do not occur in substantial amounts. Preventing caecotrophy reduced growth and altered lipid metabolism, depressing the development of new approaches for rabbit feeding and production. Relative abundance is depressed for genes related to metabolic pathways such as vitamin C and sugar metabolism, vitamin B2 metabolism, and bile secretion. The key microorganisms that regulate the rapid growth performance of rabbits may provide useful references for future research and the development of microecological preparations.

Keywords: caecocolonic microorganisms, caecotrophy, fasting caecotrophy, rabbits, soft pellets

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Authors: Mona Alharbi

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Melioidosis has emerged as a lethal disease. Unfortunately, the molecular mechanisms of virulence and pathogenicity of Burkholderia pseudomallei remain unknown. However, proteomics research has selected putative targets in B. pseudomallei that might play roles in the B. pseudomallei virulence. BPSL 2418 putative protein has been predicted as a free methionine sulfoxide reductase and interestingly there is a link between the level of the methionine sulfoxide in pathogen tissues and its virulence. Therefore in this work, we describe the cloning expression, purification, and crystallization of BPSL 2418 and the solution of its 3D structure using X-ray crystallography. Also, we aimed to identify the substrate binding and reduced forms of the enzyme to understand the role of BPSL 2418. The gene encoding BPSL2418 from B. pseudomallei was amplified by PCR and reclone in pETBlue-1 vector and transformed into E. coli Tuner DE3 pLacI. BPSL2418 was overexpressed using E. coli Tuner DE3 pLacI and induced by 300μM IPTG for 4h at 37°C. Then BPS2418 purified to better than 95% purity. The pure BPSL2418 was crystallized with PEG 4000 and PEG 6000 as precipitants in several conditions. Diffraction data were collected to 1.2Å resolution. The crystals belonged to space group P2 21 21 with unit-cell parameters a = 42.24Å, b = 53.48Å, c = 60.54Å, α=γ=β= 90Å. The BPSL2418 binding MES was solved by molecular replacement with the known structure 3ksf using PHASER program. The structure is composed of six antiparallel β-strands and four α-helices and two loops. BPSL2418 shows high homology with the GAF domain fRMsrs enzymes which suggest that BPSL2418 might act as methionine sulfoxide reductase. The amino acids alignment between the fRmsrs including BPSL 2418 shows that the three cysteines that thought to catalyze the reduction are fully conserved. BPSL 2418 contains the three conserved cysteines (Cys⁷⁵, Cys⁸⁵ and Cys¹⁰⁹). The active site contains the six antiparallel β-strands and two loops where the disulfide bond formed between Cys⁷⁵ and Cys¹⁰⁹. X-ray structure of free methionine sulfoxide binding and native forms of BPSL2418 were solved to increase the understanding of the BPSL2418 catalytic mechanism.

Keywords: X-Ray Crystallography, BPSL2418, Burkholderia pseudomallei, Melioidosis

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Authors: Mona G. Alharbi

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A new family of methionine-sulfoxide reductase (Msr) was recently discovered and was named free methionine sulfoxide reductase (fRMsr). This family includes enzymes with a reductase activity toward the free R isomer of a methionine sulfoxide substrate. The fRMsrs have a GAF domain topology, a domain, which was previously identified as having in some cases a cyclic nucleotide phosphodiesterase activity. The classification of fRMsrs as GAF domains revealed a new function can be added to the GAF domain family. Interestingly the four members identified in the fRMsr family share the GAF domain structure and the presence of three conserved cysteines in the active site with free R methionine sulfoxide substrate specificity. This thesis presents the crystal structures of reduced, free Met-SO substrate-bound and MES-bound forms of a new fRMsr from Burkholderia pseudomallei (BPSL2418). BPSL2418 was cloned, overexpressed and purified to enable protein crystallization. The crystallization trials for reduced, Met-SO-bound and MES-bound forms of BPSL2418 were prepared and reasonable crystals of each form were produced. The crystal structures of BPSL2418MES, BPSL2418Met-SO and BPSL2418Reduced were solved at 1.18, 1.4 and 2.0Å, respectively by molecular replacement. The BPSL2418MES crystal belongs to space group P 21 21 21 while BPSL2418Met-SO and BPSL2418Reduced crystals belong to space group P 1 21 1. All three forms share the GAF domain structure of six antiparallel β-strands and four α-helices with connecting loops. The antiparallel β-strands (β1, β2, β5 and β6) are located in the center of the BPSL2418 structure flanked on one side by a three α-helices (α1, α2 and α4) and on the other side by a (loop1, β3, loop2, α3, β4 loop4) unit where loop4 forms a capping flap and covers the active site. The structural comparison of the three forms of BPSL2418 indicates that the catalytically important cysteine is CYS109, where the resolving cysteine is CYS75, which forms a disulfide bond with CYS109. They also suggest that the third conserved cysteine in the active site, CYS85, which is located in α3, is a non-essential cysteine for the catalytic function but it may play a role in the binding of the substrate. The structural comparison of the three forms reveals that conformational changes appear in the active site particularly involving loop4 and CYS109 during catalysis. The 3D structure of BPSL2418 shows strong structure similarity to fRMsrs enzymes, which further suggests that BPSL2418 acts as a free Met-R-SO reductase and shares the catalytic mechanism of fRMsr family.

Keywords: Burkholderia pseudomallei, GAF domain protein, methionine sulfoxide reductase, protein crystallization

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Authors: Dmitry Yu. Korulkin, Raissa A. Muzychkina

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In review the generalized data about biosynthetic routs formation anthraquinone molecules in natural cells. The basic possibilities of various ways of biosynthesis of different quinoid substances are shown.

Keywords: anthraquinones, biochemical evolution, biosynthesis, metabolism

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Authors: H. Haseena Banu, D. Karthick, R. Stalin, E. Nandha Kumar, T. P. Sachidanandam, P. Shanthi

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Background of the study: Type 2 diabetes is emerging as the predominant metabolic disorder in the world among adults characterized mainly by the resistance of the insulin sensitive tissues towards insulin followed by the decrease in the insulin secretion. The treatment for this disease usually involves treatment with oral synthetic drugs which are known to cause several side effects. Therefore, identification of new biomarkers as therapeutic target is the need of the hour. miRNAs are small, non–protein-coding RNAs that negatively regulate gene expression by promoting degradation and/or inhibit the translation of target mRNAs and have emerged as biomarkers in predicting diabetes mellitus. Objective of the study: To elucidate the therapeutic role of gallic acid in modulating the alterations in glucose metabolism induced by miRNAs 194 and 135a in Type 2 diabetic rats. Materials and Methods: T2D was induced in rats by feeding them with a high fat diet for 2 weeks followed by intraperitoneal injection of 35 mg/kg/body weight (b.wt.) of streptozotocin. Microarrays were used to assess the expression of miRNAs in control, diabetic and gallic acid treated rats. Gene expression studies were carried out by RT PCR analysis. Results: Forty one miRNAs were differentially expressed in Type 2 diabetic rats. Among these, the expression of miRNA 194 was significantly decreased whereas miRNA 135a was significantly increased in Type 2 diabetic rats. The glucose metabolism was also altered significantly in skeletal muscle of Type 2 diabetic rats. Conclusion: T2D is associated with alterations in the expression of miRNAs in skeletal muscle. Both these miRNAs 194 and 135a play an important role in glucose metabolism in skeletal muscle of diabetic rats. Gallic acid effectively ameliorated the alterations in glucose metabolism. Hence, both these miRNAs can serve as biomarkers and therapeutic targets in diabetes mellitus. The study also establishes the role of gallic acid as therapeutic agent. Acknowledgment: The financial assistance provided in the form of ICMR women scientist by ICMR DHR INDIA is gratefully acknowledged here.

Keywords: gallic acid, high fat diet, type 2 diabetes mellitus, miRNAs

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Authors: Ragy Raafat Gaber Attaalla

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PIP: This review, based on 2 large-scale studies, discusses the pharmacology and physiology of oral steroid contraceptives (OCs). The pharmacological distinction between synthetic and naturally occurring steroids centers on changes in biological activity dependent on compound formulation and an individual's metabolism. OC mechanism of action is explained as the main prevention of ovulation by interference with gonadotropin-releasing hormone. Since some 52 metabolic alterations have been reported in OC users, these phenomena are dealt with in 3 categories: 1) effects on the primary target organs of the female reproductive tract (ovary, myometrium, endometrium, cervix, vagina, breasts, and hypothalamus), 2) general metabolic effects (serum proteins, carbohydrate metabolism, lipid metabolism, water and electrolyte metabolism, body weight, tryptophan metabolism, and vitamins and minerals), and 3) effects on other organ systems (liver, central nervous system, skin, genitourinary, gastrointestinal tract, eye, immune phenomena, and effect on subsequent fertility). The choice of the proper OC formulation and use of OCs by adolescents are discussed. Assessment of OC safety, contraindications, and patient monitoring are provided.

Keywords: steroid oral contraceptives, ovulation, female reproductive tract, metabolic effects

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Authors: A. Bouaouiche, M. S. Boulakoud

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The functioning of the pineal gland, the transducer body of environmental information to the neuroendocrine system is subject to a circadian rhythm. Melatonin is the main neuro-hormone expressing this operation. It is synthesized in the pinealocytes after conversion serotonin via N-acetyl-transferase enzyme, itself subject to a photoperiodic modulation (activation dark inhibition by light). Some authors have suggested that melatonin is involved in diabetic disease and found that it could have a diabetogenic effect. To this study the effect of this hormone on glucose metabolism has long been subject to controversy. Agreeing in effect and hyperinsulinemic hypoglycemic effect. In order to illustrate the level of interaction of melatonin with neuro-immune- corticotropin axis and its impact on carbohydrate metabolism, we studied the impact homeostatic (glucose) through the solicitation of two control systems (gland pineal and corticotropin axis). We then found that melatonin could have an indirect influence on insulin control (glucose metabolism) to the levels of the growth hormone axis (somatostatin) and adrenocorticotropic (corticotropin). In addition, we have suggested that melatonin might limit the hyperglycemic action of corticosteroids by direct action at peripheral level.

Keywords: pinéal gland, melatonin, neuro-immuno-corticotrop, metabolism

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Authors: Mona M. Salem, Khaled S. Al-Hagla, Hany M. Ayad

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The concept of urban metabolism has increasingly been employed in a diverse range of disciplines as a mean to analyze and theorize the city. Urban ecology has a particular focus on the implications of applying the metabolism concept to the urban realm. This approach has been developed by a few researchers, though it has rarely if ever been used in policy development for city planning. The aim of this research is to use ecologically informed urban planning interventions to increase the sustainability of urban metabolism; with special focus on land stock as a most important city resource by developing a system dynamic based DSS. This model identifies two critical management strategy variables for the Strategic Urban Plan Alexandria SUP 2032. As a result, this comprehensive and precise quantitative approach is needed to monitor, measure, evaluate and observe dynamic urban changes working as a decision support system (DSS) for policy making.

Keywords: ecology, land resource, LULCC, management, metabolism, model, scenarios, system dynamics, urban development

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Authors: Fazilet Özlem Çekiç, Seyda Yılmaz

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Salinity and drought are important environmental problems in the world and have negative effects on plant metabolism. Gamma-aminobutyric acid (GABA), four-carbon non-protein amino acid, is a significant component of the free amino acid pool. GABA is widely distributed in prokaryotic and eukaryotic organisms. Environmental stress factors increase GABA accumulation in plants. Our aim was to evaluate the effect of gibberellic acid (GA) on GABA metabolism system during drought and salt stress factors in Phaseolus vulgaris L. plants. GABA, Glutamate dehydrogenase (GDH) activity, chlorophyll, and lipid peroxidation (MDA) analyses were determined. According to our results we can suggest that GA play a role in GABA metabolism during salt and drought stresses in bean plants. Also GABA shunt is an important metabolic pathway and key signaling allowing to adapt to drought and salt stresses.

Keywords: gibberellic acid, GABA, Phaseolus vulgaris L., salinity, drought

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Authors: S. M. Ali, S. I. Mohamed

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Reduction of feed cost for broiler production is at most importance in decreasing the cost of production. The objectives of this study were to evaluate the use of synthetic amino acids (L-lysine – DL-methionine) instead of super concentrate and groundnut cake versus meat powder as protein sources. A total of 180 male broiler chicks (Cobb – strain) at 15 day of age (DOA) were selected according to their average body weight (380 g) from a broiler chicks flock at Elbashair Farm. The chicks were randomly divided into six groups of 30 chicks. Each group was further sub divided into three replicates with 10 birds. Six experimental diets were formulated. The first diet contained groundnut cake and super concentrate as the control (GNC + C); in the second diet, meat powder and super concentrate (MP + C) were used. The third diet contained groundnut cake and amino acids (GNC + AA); the forth diet contained meat powder and amino acids (MP + AA). The fifth diet contained groundnut cake, meat powder and super concentrate (GNC + MP + C) and the sixth diet contained groundnut cake, meat powder and amino acids (GNC + MP + AA). The formulated rations were randomly assigned for the different sub groups in a completely randomized design of six treatments and three replicates. Weekly feed intake, body weight and mortality were recorded and body weight gain and feed conversion ratio were calculated. At the end of the experiment (49 DOA), nine birds from each treatment were slaughtered. Live body weight, carcass weight, head, shank, and some internal organs (gizzard, heart, liver, small intestine, and abdominal fat pad) weights were taken. For the overall experimental period the (GNC + C +MP) consumed significantly (P≤0.01) the highest cumulative feed while the (MP + AA) group consumed the lowest amount of feed. The (GNC + C) and the (GNC + AA) groups had the heaviest live body weight while (MP + AA) had the lowest live body weight. The overall FCR was significantly (P≤0.01) the best for (GNC + AA) group while the (MP + AA) reported the worst FCR. However, the (GNC + AA) had significantly (P≤0.01) the lowest AFP. The (GNC + MP + Con) group had the highest dressing % while the (MP + AA) group had the lowest dressing %. It is concluded that amino acids can be used instead of super concentrate in broiler feeding with perfect performance and less cost and that meat powder is not advisable to be used with amino acids.

Keywords: broiler chickens, DL-lysine, methionine, performance

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Authors: Mladen Milicevic

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In this paper, subjective film sound will be addressed as it gets represented in narrative cinema. First, 'meta-diegetic' sound will be briefly explained followed by transition to “oneiric” sound. The representation of oneiric sound refers to a situation where film characters are experiencing some sort of an altered state of consciousness. Looking at an antlered state of consciousness in terms of human brain processes will point out to the cinematic ways of expression, which 'mimic' those processes. Using several examples for different films will illustrate these points.

Keywords: oneiric, ASC, film, sound

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Authors: Vadim Makarov, Stewart T.Cole

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PBTZ169 is novel drug candidate with high efficacy in animals models, and its combination treatment of PBTZ169 with BDQ and pyrazinamide was shown to be more efficacious than the standard treatment for tuberculosis in a mouse model. The target of PBTZ169 is famous DprE1, an essential enzyme in cell wall biosynthesis. The crystal structure of the DprE1-PBTZ169 complex reveals formation of a semimercaptal adduct with Cys387 in the active site and explains the irreversible inactivation of the enzyme. Furthermore, this drug candidate demonstrated during preclinical research ‘drug like’ properties what made it an attractive drug candidate to treat tuberculosis in humans. During first clinical trials several cohorts of the healthy volunteers were treated by the single doses of PBTZ169 as well as two weeks repeated treatment was chosen for two maximal doses. As expected PBTZ169 was well tolerated, and no significant toxicity effects were observed during the trials. The study of the metabolism shown that human metabolism of PBTZ169 is very different from microbial or animals compound transformation. So main pathway of microbial, mice and less rats metabolism connected with reduction processes, but human metabolism mainly connected with oxidation processes. Due to this difference we observed several metabolites of PBTZ169 in humans with antitubercular activity, and now we can conclude that animal antituberculosis activity of PBTZ169 is a result not only activity of the drug itself, but it is a result of the sum activity of the drug and its metabolites. Direct antimicrobial plasma activity was studied, and such activity was observed for 24 hours after human treatment for some doses. This data gets high chance for good efficacy of PBTZ169 in human for treatment TB infection. Second phase of clinical trials was started summer of 2017 and continues to the present day. Available data will be presented.

Keywords: clinical trials, DprE1, PBTZ169, metabolism

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Authors: Ayat Bani Rashaid, Zain Khasawneh, Mazin Alqhazo, Shreen Nusair, Mohammad El-Khateeb, Mahmoud Bashtawi

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Autism Spectrum disorder (ASD) is a psychiatric disorder with unknown etiology that mainly affects children in the first three years of life. Alterations of amino acid levels are believed to contribute to ASD. The levels of six essential amino acids (methionine, histidine, valine, leucine, threonine, and phenylalanine), five conditional amino acids (proline, tyrosine, glutamine, cysteine, and cystine), and five non-essential amino acids (asparagine, aspartic acid, alanine, serine, and glutamic acid) in hair samples of children with ASD (n = 25) were analyzed and compared to corresponding levels in healthy age-matched controls (n = 25). The results showed that the levels of methionine, alanine, and asparagine were significantly lower in the hair samples of ASD group compared to those of the control group (p ≤ 0.05). However, the levels of glutamic acid were significantly higher in the ASD group than the control group (p ≤ 0.05). The current findings could contribute towards further understanding of ASD etiology and provide specialists with a hair amino acid profile utilized as a biomarker for early diagnosis of ASD. Such biomarkers could participate in future developments of therapies that reduce ASD-related symptoms.

Keywords: autism spectrum disorder, amino acids, liquid chromatography-tandem mass spectrometry, human hair

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Authors: Nahid Banihashemi

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An emerging important area of the life sciences is systems biology, which involves understanding the integrated behavior of large numbers of components interacting via non-linear reaction terms. A centrally important problem in this area is an understanding of the co-metabolism of protein and carbohydrate, as it has been clearly demonstrated that the ratio of these metabolites in diet is a major determinant of obesity and related chronic disease. In this regard, we have considered a systems biology model for the co-metabolism of carbon and nitrogen in colonies of the fungus Mucor mucedo. Oscillations are an important diagnostic of underlying dynamical processes of this model. The maintenance of specific patterns of oscillation and its relation to the robustness of this system are the important issues which have been targeted in this paper. In this regard, parametric sensitivity approach as a theoretical approach has been considered for the analysis of the robustness of this model. As a result, the parameters of the model which produce the largest sensitivities have been identified. Furthermore, the largest changes that can be made in each parameter of the model without losing the oscillations in biomass production have been computed. The results are obtained from the implementation of parametric sensitivity analysis in Matlab.

Keywords: system biology, parametric sensitivity analysis, robustness, carbon and nitrogen co-metabolism, Mucor mucedo

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Authors: Suliman Khan, Rabeea Siddique, Mengzhou Xue

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Background: Patients with neurological disorders often display altered circadian rhythms. The disrupted circadian rhythms through chronic jetlag or shiftwork are thought to increase the risk and severity of human disease, including cancer, psychiatric, and related brain diseases. In this study, we investigated the impact of shiftwork or chronic jetlag (CJL) like conditions on mice’s brains. Transcriptome profiling based on RNA sequencing revealed that genes associated with serious neurological disorders were differentially expressed in the nucleus accumbens (NAc) and prefrontal cortex (PFC). According to the qPCR analysis, several key regulatory genes associated with neurological disorders were significantly altered in the NAc, PFC, hypothalamus, hippocampus, and striatum. Serotonin levels and the expression levels of serotonin transporters and receptors were significantly altered in mice treated with CJL. Overall, these results indicate that CJL may increase the risk of neurological disorders by disrupting the key regulatory genes, biological functions, serotonin, and corticosterone. These molecular linkages can further be studied to investigate the mechanism underlying CJL or shiftwork-mediated neurological disorders in order to develop treatment strategies.

Keywords: chronic jetlag, molecular profiles, brain disorders, circadian rhythms

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Authors: D. Nagalakshmi, S. Parashuramulu K. Sadasiva Rao, G. Aruna, L. Vikram

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The zinc (Zn) is the second most abundant trace element in mammals and birds, forming structural component of over 300 enzymes, playing an important role in anti-oxidant defense, immune response and reproduction. Organic trace minerals are more readily absorbed from the digestive tract and more biologically available compared with its inorganic salt. Thus, the present study was undertaken on 60 adult female Sprague Dawley rats (275±2.04 g) for experimental duration of 12 weeks to investigate the effect of dietary Zn supplementation from various organic sources on immunity, reproduction, oxidative defense mechanism and blood biochemical profile. The rats were randomly allotted to 30 replicates (2 per replicate) which were in turn randomly allotted to 5 dietary treatments varying in Zn source i.e., one inorganic source (Zn carbonate) and 4 organic sources (Zn-proteinate, Zn-propionate, Zn-amino acid complex and Zn-methionine) so as to supply NRC recommended Zn concentration (12 ppm Zn). Supplementation of organic Zn had no effect on various haematological and serum biochemical constituents compared to inorganic Zn fed rats. The TBARS and protein carbonyls concentration in liver indicative of oxidative stress was comparable between various organic and inorganic groups. The glutathione reductase activity in haemolysate (P<0.05) and reduced glutathione concentration in liver (P<0.01) was higher when fed organic Zn and RBC catalase activity was higher (P<0.01) on Zn methionine compared to other organic sources tested and the inorganic source. The humoral immune response assessed as antibody titres against sheep RBC was higher (P<0.05) when fed organic sources of zinc compared to inorganic source. The cell mediated immune response expressed as delayed type hypersensitivity reaction was higher (P<0.05) in rats fed Zn propionate with no effect of other organic Zn sources. The serum progesterone concentration was higher (P<0.05) in rats fed organic Zn sources compared to inorganic zinc. The data on ovarian folliculogenesis indicated that organic Zn supplementation increased (P<0.05) the number of graafian follicles and corpus luteum with no effect on primary, secondary and tertiary follicle number. The study indicated that rats fed organic sources of Zn had higher antioxidant enzyme activities, immune response and serum progesterone concentration with higher number of mature follicles. Though the effect of feeding various organic sources were comparable, rats fed zinc methionine had higher antioxidant activity and cell mediated immune response was higher in rats on Zn propionate.

Keywords: organic zinc, immune, rats, reproductive

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Authors: Chin-Yuan Hsu, Yu-Lung Chuang

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The expression, concentration, and activity of mitochondrial energy-utilized molecules and cellular energy-regulated molecules decreased with age in the trophocytes and oenocytes of honeybees (Apis mellifera), but those of cellular energy-metabolized molecules is unknown. In this study, the expression, concentration, and activity of cellular energy-metabolized molecules were assayed in the trophocytes and fat cells of young and old worker bees by using the techniques of cell and biochemistry. The results showed that (i) the •-hydroxylacyl-coenzyme A dehydrogenase (HOAD) activity/citrate synthase (CS) activity ratio, non-esterified fatty acids concentrations, the expression of eukaryotic initiation factor 4E, and the expression of phosphorylated eIF4E binding protein 1 decreased with age; (ii) fat and glycogen accumulation increased with age; and (iii) the pyruvate dehydrogenase (PDH) activity/citrate synthase (CS) activity ratio was not correlated with age. These finding indicated that •-oxidation (HOAD/CS) and protein synthsis decreased with age. Glycolysis (PDH/CS) was unchanged with age. The most likely reason is that sugars are the vital food of worker bees. Taken together these data reveal that young workers have higher cellular energy metabolism than old workers and that aging results in a decline in the cellular energy metabolism in worker honeybees.

Keywords: aging, energy, honeybee, metabolism

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Authors: Laura Acevedo-Pacheco, Janet Alejandra Gutierrez-Uribe, Lucia Elizabeth Cruz-Suarez, Segio Othon Serna-Saldivar

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Seaweeds can generate changes in the metabolism of lipids; as a consequence, this may diminish cholesterol and other lipids in the blood. However, the consumption of marine algae may also alter the functions of other organs. Therefore, the objective of this research was to study the effect of two different sorts of algae (Ecklonia arborea and Silvetia compressa) in the metabolism of lipids, as well as, in the physiology of the liver. Wistar male rats were fed for two months with independent diets composed of 20% of fat and 2.5% of E. arborea and S. compressa each. Blood parameters (cholesterol, lipoproteins, triglycerides, hepatic enzymes) and triglycerides in the liver were quantified, and also hepatic histology analyses were performed. While S. compressa reduced 18% total cholesterol compared to the positive control, E. arborea increased it 5.8%. Animals fed with S. compressa presented a decrement, compared to the positive control, not only in low density lipoproteins levels (53%) but also in triglycerides (67%). The presence of steatosis in the histologies and the high levels of triglycerides showed an evident lipid accumulation in hepatic tissues of rats fed with both algae. These results indicate that even though S. compressa showed a promising resource to decrease total cholesterol and low-density lipoproteins in blood, a detrimental effect was observed in liver physiology. Further investigations should be made to find out if toxic compounds associated with these seaweeds may cause liver damage especially in terms of heavy metals.

Keywords: brown algae, Eisenia arborea, hepatic metabolism, lipidemic metabolism, Pelvetia compressa, steatosis

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