DNA damage may compromise genome integrity and lead to cell death. Cells have evolved a variety of processes to respond to DNA damage including damage repair and tolerance mechanisms, as well as damage checkpoints. The DNA damage tolerance (DDT) pathway promotes the bypass of single-stranded DNA lesions encountered by DNA polymerases during DNA replication. This prevents the stalling of DNA replication. Two mechanistically distinct DDT branches have been characterized. One is translesion synthesis (TLS) in which a replicative DNA polymerase is temporarily replaced by a specialized TLS polymerase that has the ability to replicate across DNA lesions. TLS is mechanistically simple and straightforward, but it is intrinsically error-prone. The other is the error-free template switching (TS) mechanism in which the stalled nascent strand switches from the damaged template to the undamaged newly synthesized sister strand for extension past the lesion. Error-free TS is a complex but preferable process for bypassing DNA lesions. However, our current understanding of this pathway is sketchy. An increasing number of factors are being found to participate or regulate this important mechanism, which is the focus of this editorial.
{"title":"Mechanism of DNA damage tolerance.","authors":"Xin Bi","doi":"10.4331/wjbc.v6.i3.48","DOIUrl":"https://doi.org/10.4331/wjbc.v6.i3.48","url":null,"abstract":"<p><p>DNA damage may compromise genome integrity and lead to cell death. Cells have evolved a variety of processes to respond to DNA damage including damage repair and tolerance mechanisms, as well as damage checkpoints. The DNA damage tolerance (DDT) pathway promotes the bypass of single-stranded DNA lesions encountered by DNA polymerases during DNA replication. This prevents the stalling of DNA replication. Two mechanistically distinct DDT branches have been characterized. One is translesion synthesis (TLS) in which a replicative DNA polymerase is temporarily replaced by a specialized TLS polymerase that has the ability to replicate across DNA lesions. TLS is mechanistically simple and straightforward, but it is intrinsically error-prone. The other is the error-free template switching (TS) mechanism in which the stalled nascent strand switches from the damaged template to the undamaged newly synthesized sister strand for extension past the lesion. Error-free TS is a complex but preferable process for bypassing DNA lesions. However, our current understanding of this pathway is sketchy. An increasing number of factors are being found to participate or regulate this important mechanism, which is the focus of this editorial. </p>","PeriodicalId":23691,"journal":{"name":"World journal of biological chemistry","volume":"6 3","pages":"48-56"},"PeriodicalIF":0.0,"publicationDate":"2015-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549768/pdf/WJBC-6-48.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33964089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The increasing incidence of obesity worldwide and its related cardiometabolic complications is an urgent public health problem. While weight gain results from a negative balance between the energy expenditure and calorie intake, recent research has demonstrated that several small organic molecules containing a four-carbon backbone can modulate this balance by favoring energy expenditure, and alleviating endoplasmic reticulum stress and oxidative stress. Such small molecules include the bacterially produced short chain fatty acid butyric acid, its chemically produced derivative 4-phenylbutyric acid, the main ketone body D-β-hydroxybutyrate - synthesized by the liver - and the recently discovered myokine β-aminoisobutyric acid. Conversely, another butyrate-related molecule, α-hydroxybutyrate, has been found to be an early predictor of insulin resistance and glucose intolerance. In this minireview, we summarize recent advances in the understanding of the mechanism of action of these molecules, and discuss their use as therapeutics to improve metabolic homeostasis or their detection as early biomarkers of incipient insulin resistance.
{"title":"Essential roles of four-carbon backbone chemicals in the control of metabolism.","authors":"Sabrina Chriett, Luciano Pirola","doi":"10.4331/wjbc.v6.i3.223","DOIUrl":"https://doi.org/10.4331/wjbc.v6.i3.223","url":null,"abstract":"<p><p>The increasing incidence of obesity worldwide and its related cardiometabolic complications is an urgent public health problem. While weight gain results from a negative balance between the energy expenditure and calorie intake, recent research has demonstrated that several small organic molecules containing a four-carbon backbone can modulate this balance by favoring energy expenditure, and alleviating endoplasmic reticulum stress and oxidative stress. Such small molecules include the bacterially produced short chain fatty acid butyric acid, its chemically produced derivative 4-phenylbutyric acid, the main ketone body D-β-hydroxybutyrate - synthesized by the liver - and the recently discovered myokine β-aminoisobutyric acid. Conversely, another butyrate-related molecule, α-hydroxybutyrate, has been found to be an early predictor of insulin resistance and glucose intolerance. In this minireview, we summarize recent advances in the understanding of the mechanism of action of these molecules, and discuss their use as therapeutics to improve metabolic homeostasis or their detection as early biomarkers of incipient insulin resistance. </p>","PeriodicalId":23691,"journal":{"name":"World journal of biological chemistry","volume":"6 3","pages":"223-30"},"PeriodicalIF":0.0,"publicationDate":"2015-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549763/pdf/WJBC-6-223.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34133810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kazim Husain, Edu Suarez, Angel Isidro, Wilfredo Hernandez, Leon Ferder
Aim: To investigate the protective effect of paricalcitol and enalapril on renal inflammation and oxidative stress in ApoE-knock out mice.
Methods: Animals treated for 4 mo as group (1) ApoE-knock out plus vehicle, group (2) ApoE-knock out plus paricalcitol (200 ng thrice a week), (3) ApoE-knock out plus enalapril (30 mg/L), (4) ApoE-knock out plus paricalcitol plus enalapril and (5) normal. Blood pressure (BP) was recorded using tail cuff method. The kidneys were isolated for biochemical assays using spectrophotometer and Western blot analyses.
Results: ApoE-deficient mice developed high BP (127 ± 3 mmHg) and it was ameliorated by enalapril and enalapril plus paricalcitol treatments but not with paricalcitol alone. Renal malondialdehyde concentrations, p22(phox), manganese-superoxide dismutase, inducible nitric oxide synthase (NOS), monocyte chemoattractant protein-1, tumor necrosis factor-alpha and transforming growth factor-β1 levels significantly elevated but reduced glutathione, CuZn-SOD and eNOS levels significantly depleted in ApoE-knock out animals compared to normal. Administration of paricalcitol, enalapril and combined together ameliorated the renal inflammation and oxidative stress in ApoE-knock out animals.
Conclusion: Paricalcitol and enalapril combo treatment ameliorates renal inflammation as well as oxidative stress in atherosclerotic animals.
{"title":"Effect of paricalcitol and enalapril on renal inflammation/oxidative stress in atherosclerosis.","authors":"Kazim Husain, Edu Suarez, Angel Isidro, Wilfredo Hernandez, Leon Ferder","doi":"10.4331/wjbc.v6.i3.240","DOIUrl":"https://doi.org/10.4331/wjbc.v6.i3.240","url":null,"abstract":"<p><strong>Aim: </strong>To investigate the protective effect of paricalcitol and enalapril on renal inflammation and oxidative stress in ApoE-knock out mice.</p><p><strong>Methods: </strong>Animals treated for 4 mo as group (1) ApoE-knock out plus vehicle, group (2) ApoE-knock out plus paricalcitol (200 ng thrice a week), (3) ApoE-knock out plus enalapril (30 mg/L), (4) ApoE-knock out plus paricalcitol plus enalapril and (5) normal. Blood pressure (BP) was recorded using tail cuff method. The kidneys were isolated for biochemical assays using spectrophotometer and Western blot analyses.</p><p><strong>Results: </strong>ApoE-deficient mice developed high BP (127 ± 3 mmHg) and it was ameliorated by enalapril and enalapril plus paricalcitol treatments but not with paricalcitol alone. Renal malondialdehyde concentrations, p22(phox), manganese-superoxide dismutase, inducible nitric oxide synthase (NOS), monocyte chemoattractant protein-1, tumor necrosis factor-alpha and transforming growth factor-β1 levels significantly elevated but reduced glutathione, CuZn-SOD and eNOS levels significantly depleted in ApoE-knock out animals compared to normal. Administration of paricalcitol, enalapril and combined together ameliorated the renal inflammation and oxidative stress in ApoE-knock out animals.</p><p><strong>Conclusion: </strong>Paricalcitol and enalapril combo treatment ameliorates renal inflammation as well as oxidative stress in atherosclerotic animals.</p>","PeriodicalId":23691,"journal":{"name":"World journal of biological chemistry","volume":"6 3","pages":"240-8"},"PeriodicalIF":0.0,"publicationDate":"2015-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549765/pdf/WJBC-6-240.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34135065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Steadily increasing evidence supports the idea that genetic diversities in the vascular bed are, in addition to hemodynamic influences, a major contributing factor in determining region-specific cardiovascular disease susceptibility. Members of the phylogenetically highly conserved Hox gene family of developmental regulators have to be viewed as prime candidates for determining these regional genetic differences in the vasculature. During embryonic patterning, the regionally distinct and precisely choreographed expression patterns of HOX transcription factors are essential for the correct specification of positional identities. Apparently, these topographic patterns are to some degree retained in certain adult tissues, including the circulatory system. While an understanding of the functional significance of these localized Hox activities in adult blood vessels is only beginning to emerge, an argument can be made for a role of Hox genes in the maintenance of vessel wall homeostasis and functional integrity on the one hand, and in regulating the development and progression of regionally restricted vascular pathologies, on the other. Initial functional studies in animal models, as well as data from clinical studies provide some level of support for this view. The data suggest that putative genetic regulatory networks of Hox-dependent cardiovascular disease processes include genes of diverse functional categories (extracellular matrix remodeling, transmembrane signaling, cell cycle control, inflammatory response, transcriptional control, etc.), as potential targets in both vascular smooth muscle and endothelial cells, as well as cell populations residing in the adventitia.
{"title":"Topographic patterns of vascular disease: HOX proteins as determining factors?","authors":"Richard P Visconti, Alexander Awgulewitsch","doi":"10.4331/wjbc.v6.i3.65","DOIUrl":"https://doi.org/10.4331/wjbc.v6.i3.65","url":null,"abstract":"<p><p>Steadily increasing evidence supports the idea that genetic diversities in the vascular bed are, in addition to hemodynamic influences, a major contributing factor in determining region-specific cardiovascular disease susceptibility. Members of the phylogenetically highly conserved Hox gene family of developmental regulators have to be viewed as prime candidates for determining these regional genetic differences in the vasculature. During embryonic patterning, the regionally distinct and precisely choreographed expression patterns of HOX transcription factors are essential for the correct specification of positional identities. Apparently, these topographic patterns are to some degree retained in certain adult tissues, including the circulatory system. While an understanding of the functional significance of these localized Hox activities in adult blood vessels is only beginning to emerge, an argument can be made for a role of Hox genes in the maintenance of vessel wall homeostasis and functional integrity on the one hand, and in regulating the development and progression of regionally restricted vascular pathologies, on the other. Initial functional studies in animal models, as well as data from clinical studies provide some level of support for this view. The data suggest that putative genetic regulatory networks of Hox-dependent cardiovascular disease processes include genes of diverse functional categories (extracellular matrix remodeling, transmembrane signaling, cell cycle control, inflammatory response, transcriptional control, etc.), as potential targets in both vascular smooth muscle and endothelial cells, as well as cell populations residing in the adventitia. </p>","PeriodicalId":23691,"journal":{"name":"World journal of biological chemistry","volume":"6 3","pages":"65-70"},"PeriodicalIF":0.0,"publicationDate":"2015-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549770/pdf/WJBC-6-65.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33964091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Iron metabolism is regulated on the cellular and the systemic level. Over the last decade, the liver peptide "hepcidin" has emerged as the body's key irons store regulator. The long postulated "erythroid regulator of iron", however, remained elusive. Last year, evidence was provided, that a previously described myokine "myonectin" may also function as the long sought erythroid regulator of iron. Myonectin was therefore re-named "erythroferrone". This editorial provides a brief discussion on the two functions of erythroferrone and also briefly considers the emerging potential role of transferrin receptor 2 in erythropoiesis.
{"title":"Is erythroferrone finally the long sought-after systemic erythroid regulator of iron?","authors":"Alfons Lawen","doi":"10.4331/wjbc.v6.i3.78","DOIUrl":"https://doi.org/10.4331/wjbc.v6.i3.78","url":null,"abstract":"<p><p>Iron metabolism is regulated on the cellular and the systemic level. Over the last decade, the liver peptide \"hepcidin\" has emerged as the body's key irons store regulator. The long postulated \"erythroid regulator of iron\", however, remained elusive. Last year, evidence was provided, that a previously described myokine \"myonectin\" may also function as the long sought erythroid regulator of iron. Myonectin was therefore re-named \"erythroferrone\". This editorial provides a brief discussion on the two functions of erythroferrone and also briefly considers the emerging potential role of transferrin receptor 2 in erythropoiesis. </p>","PeriodicalId":23691,"journal":{"name":"World journal of biological chemistry","volume":"6 3","pages":"78-82"},"PeriodicalIF":0.0,"publicationDate":"2015-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549772/pdf/WJBC-6-78.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33964093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kazim Husain, Wilfredo Hernandez, Rais A Ansari, Leon Ferder
Atherosclerosis is a chronic inflammatory disease associated with cardiovascular dysfunction including myocardial infarction, unstable angina, sudden cardiac death, stroke and peripheral thromboses. It has been predicted that atherosclerosis will be the primary cause of death in the world by 2020. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with cardiovascular risk factors including diabetes mellitus, hypertension, cigarette smoking, dyslipidemia, obesity, and metabolic syndrome. The impairment of the endothelium associated with cardiovascular risk factors creates an imbalance between vasodilating and vasoconstricting factors, in particular, an increase in angiotensin II (Ang II) and a decrease in nitric oxide. The renin-angiotensin system (RAS), and its primary mediator Ang II, also have a direct influence on the progression of the atherosclerotic process via effects on endothelial function, inflammation, fibrinolytic balance, and plaque stability. Anti-inflammatory agents [statins, secretory phospholipase A2 inhibitor, lipoprotein-associated phospholipase A2 inhibitor, 5-lipoxygenase activating protein, chemokine motif ligand-2, C-C chemokine motif receptor 2 pathway inhibitors, methotrexate, IL-1 pathway inhibitor and RAS inhibitors (angiotensin-converting enzyme inhibitors)], Ang II receptor blockers and ranin inhibitors may slow inflammatory processes and disease progression. Several studies in human using anti-inflammatory agents and RAS inhibitors revealed vascular benefits and reduced progression of coronary atherosclerosis in patients with stable angina pectoris; decreased vascular inflammatory markers, improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis. Recent preclinical studies have demonstrated therapeutic efficacy of vitamin D analogs paricalcitol in ApoE-deficient atherosclerotic mice.
{"title":"Inflammation, oxidative stress and renin angiotensin system in atherosclerosis.","authors":"Kazim Husain, Wilfredo Hernandez, Rais A Ansari, Leon Ferder","doi":"10.4331/wjbc.v6.i3.209","DOIUrl":"https://doi.org/10.4331/wjbc.v6.i3.209","url":null,"abstract":"<p><p>Atherosclerosis is a chronic inflammatory disease associated with cardiovascular dysfunction including myocardial infarction, unstable angina, sudden cardiac death, stroke and peripheral thromboses. It has been predicted that atherosclerosis will be the primary cause of death in the world by 2020. Atherogenesis is initiated by endothelial injury due to oxidative stress associated with cardiovascular risk factors including diabetes mellitus, hypertension, cigarette smoking, dyslipidemia, obesity, and metabolic syndrome. The impairment of the endothelium associated with cardiovascular risk factors creates an imbalance between vasodilating and vasoconstricting factors, in particular, an increase in angiotensin II (Ang II) and a decrease in nitric oxide. The renin-angiotensin system (RAS), and its primary mediator Ang II, also have a direct influence on the progression of the atherosclerotic process via effects on endothelial function, inflammation, fibrinolytic balance, and plaque stability. Anti-inflammatory agents [statins, secretory phospholipase A2 inhibitor, lipoprotein-associated phospholipase A2 inhibitor, 5-lipoxygenase activating protein, chemokine motif ligand-2, C-C chemokine motif receptor 2 pathway inhibitors, methotrexate, IL-1 pathway inhibitor and RAS inhibitors (angiotensin-converting enzyme inhibitors)], Ang II receptor blockers and ranin inhibitors may slow inflammatory processes and disease progression. Several studies in human using anti-inflammatory agents and RAS inhibitors revealed vascular benefits and reduced progression of coronary atherosclerosis in patients with stable angina pectoris; decreased vascular inflammatory markers, improved common carotid intima-media thickness and plaque volume in patients with diagnosed atherosclerosis. Recent preclinical studies have demonstrated therapeutic efficacy of vitamin D analogs paricalcitol in ApoE-deficient atherosclerotic mice. </p>","PeriodicalId":23691,"journal":{"name":"World journal of biological chemistry","volume":"6 3","pages":"209-17"},"PeriodicalIF":0.0,"publicationDate":"2015-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4331/wjbc.v6.i3.209","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34133808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Proteinaceous infectious particles (prions) are unique pathogens as they are devoid of any coding nucleic acid. Whilst it is assumed that prion disease is transmitted by a misfolded isoform of the cellular prion protein, the structural insight of prions is still vague and research for high resolution structural information of prions is still ongoing. In this review, techniques that may contribute to the clarification of the conformation of prions are presented and discussed.
{"title":"Techniques to elucidate the conformation of prions.","authors":"Martin L Daus","doi":"10.4331/wjbc.v6.i3.218","DOIUrl":"https://doi.org/10.4331/wjbc.v6.i3.218","url":null,"abstract":"<p><p>Proteinaceous infectious particles (prions) are unique pathogens as they are devoid of any coding nucleic acid. Whilst it is assumed that prion disease is transmitted by a misfolded isoform of the cellular prion protein, the structural insight of prions is still vague and research for high resolution structural information of prions is still ongoing. In this review, techniques that may contribute to the clarification of the conformation of prions are presented and discussed. </p>","PeriodicalId":23691,"journal":{"name":"World journal of biological chemistry","volume":"6 3","pages":"218-22"},"PeriodicalIF":0.0,"publicationDate":"2015-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549762/pdf/WJBC-6-218.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34133809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Transient neonatal diabetes mellitus 1 (TNDM1) is a rare genetic disorder representing with severe neonatal hyperglycaemia followed by remission within one and a half year and adolescent relapse with type 2 diabetes in half of the patients. Genetic defects in TNDM1 comprise uniparental isodisomy of chromosome 6, duplication of the minimal TNDM1 locus at 6q24, or relaxation of genomically imprinted ZAC1/HYMAI. Whereas the function of HYMAI, a non-coding mRNA, is still unidentified, biochemical and molecular studies show that zinc finger protein 1 regulating apoptosis and cell cycle arrest (ZAC1) behaves as a factor with versatile transcriptional functions dependent on binding to specific GC-rich DNA motives and interconnected regulation of recruited coactivator activities. Genome-wide expression profiling enabled the isolation of a number of Zac1 target genes known to regulate different aspects of β-cell function and peripheral insulin sensitivity. Among these, upregulation of Pparγ and Tcf4 impairs insulin-secretion and β-cell proliferation. Similarly, Zac1-mediated upregulation of Socs3 may attenuate β-cell proliferation and survival by inhibition of growth factor signalling. Additionally, Zac1 directly represses Pac1 and Rasgrf1 with roles in insulin secretion and β-cell proliferation. Collectively, concerted dysregulation of these target genes could contribute to the onset and course of TNDM1. Interestingly, Zac1 overexpression in β-cells spares the effects of stimulatory G-protein signaling on insulin secretion and raises the prospect for tailored treatments in relapsed TNDM1 patients. Overall, these results suggest that progress on the molecular and cellular foundations of monogenetic forms of diabetes can advance personalized therapy in addition to deepening the understanding of insulin and glucose metabolism in general.
{"title":"Role of ZAC1 in transient neonatal diabetes mellitus and glucose metabolism.","authors":"Anke Hoffmann, Dietmar Spengler","doi":"10.4331/wjbc.v6.i3.95","DOIUrl":"10.4331/wjbc.v6.i3.95","url":null,"abstract":"<p><p>Transient neonatal diabetes mellitus 1 (TNDM1) is a rare genetic disorder representing with severe neonatal hyperglycaemia followed by remission within one and a half year and adolescent relapse with type 2 diabetes in half of the patients. Genetic defects in TNDM1 comprise uniparental isodisomy of chromosome 6, duplication of the minimal TNDM1 locus at 6q24, or relaxation of genomically imprinted ZAC1/HYMAI. Whereas the function of HYMAI, a non-coding mRNA, is still unidentified, biochemical and molecular studies show that zinc finger protein 1 regulating apoptosis and cell cycle arrest (ZAC1) behaves as a factor with versatile transcriptional functions dependent on binding to specific GC-rich DNA motives and interconnected regulation of recruited coactivator activities. Genome-wide expression profiling enabled the isolation of a number of Zac1 target genes known to regulate different aspects of β-cell function and peripheral insulin sensitivity. Among these, upregulation of Pparγ and Tcf4 impairs insulin-secretion and β-cell proliferation. Similarly, Zac1-mediated upregulation of Socs3 may attenuate β-cell proliferation and survival by inhibition of growth factor signalling. Additionally, Zac1 directly represses Pac1 and Rasgrf1 with roles in insulin secretion and β-cell proliferation. Collectively, concerted dysregulation of these target genes could contribute to the onset and course of TNDM1. Interestingly, Zac1 overexpression in β-cells spares the effects of stimulatory G-protein signaling on insulin secretion and raises the prospect for tailored treatments in relapsed TNDM1 patients. Overall, these results suggest that progress on the molecular and cellular foundations of monogenetic forms of diabetes can advance personalized therapy in addition to deepening the understanding of insulin and glucose metabolism in general. </p>","PeriodicalId":23691,"journal":{"name":"World journal of biological chemistry","volume":"6 3","pages":"95-109"},"PeriodicalIF":0.0,"publicationDate":"2015-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549774/pdf/WJBC-6-95.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33964095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Darah Ibrahim, Haritharan Weloosamy, Sheh-Hong Lim
Aim: To investigate the impact of agitation speed on pectinase production and morphological changing of Aspergillus niger (A. niger) HFD5A-1 in submerged fermentation.
Methods: A. niger HFM5A-1 was isolated from a rotted pomelo. The inoculum preparation was performed by adding 5.0 mL of sterile distilled water containing 0.1% Tween 80 to a sporulated culture. Cultivation was carried out with inoculated 1 × 10(7) spores/mL suspension and incubated at 30 °C with different agitation speed for 6 d. The samples were withdrawn after 6 d cultivation time and were assayed for pectinase activity and fungal growth determination. The culture broth was filtered through filter paper (Whatman No. 1, London) to separate the fungal mycelium. The cell-free culture filtrate containing the crude enzyme was then assayed for pectinase activity. The biomass was dried at 80 °C until constant weight. The fungal cell dry weight was then expressed as g/L. The 6 d old fungal mycelia were harvested from various agitation speed, 0, 50, 100, 150, 200 and 250 rpm. The morphological changing of samples was then viewed under the light microscope and scanning electron microscope.
Results: In the present study, agitation speed was found to influence pectinase production in a batch cultivation system. However, higher agitation speeds than the optimal speed (150 rpm) reduced pectinase production which due to shear forces and also collision among the suspended fungal cells in the cultivation medium. Enzyme activity increased with the increasing of agitation speed up to 150 rpm, where it achieved its maximal pectinase activity of 1.559 U/mL. There were significant different (Duncan, P < 0.05) of the pectinase production with the agitation speed at static, 50, 100, 200 and 250 rpm. At the static condition, a well growth mycelial mat was observed on the surface of the cultivation medium and sporulation occurred all over the fungal mycelial mat. However with the increased in agitation speed, the mycelial mat turned slowly to become a single circular pellet. Thus, it was found that agitation speed affected the morphological characteristics of the fungal hyphae/mycelia of A. niger HFD5A-1 by altering their external as well as internal cell structures.
Conclusion: Exposure to higher shear stress with an increasing agitation speed could result in lower biomass yields as well as pectinase production by A. niger HFD5A-1.
{"title":"Effect of agitation speed on the morphology of Aspergillus niger HFD5A-1 hyphae and its pectinase production in submerged fermentation.","authors":"Darah Ibrahim, Haritharan Weloosamy, Sheh-Hong Lim","doi":"10.4331/wjbc.v6.i3.265","DOIUrl":"https://doi.org/10.4331/wjbc.v6.i3.265","url":null,"abstract":"<p><strong>Aim: </strong>To investigate the impact of agitation speed on pectinase production and morphological changing of Aspergillus niger (A. niger) HFD5A-1 in submerged fermentation.</p><p><strong>Methods: </strong>A. niger HFM5A-1 was isolated from a rotted pomelo. The inoculum preparation was performed by adding 5.0 mL of sterile distilled water containing 0.1% Tween 80 to a sporulated culture. Cultivation was carried out with inoculated 1 × 10(7) spores/mL suspension and incubated at 30 °C with different agitation speed for 6 d. The samples were withdrawn after 6 d cultivation time and were assayed for pectinase activity and fungal growth determination. The culture broth was filtered through filter paper (Whatman No. 1, London) to separate the fungal mycelium. The cell-free culture filtrate containing the crude enzyme was then assayed for pectinase activity. The biomass was dried at 80 °C until constant weight. The fungal cell dry weight was then expressed as g/L. The 6 d old fungal mycelia were harvested from various agitation speed, 0, 50, 100, 150, 200 and 250 rpm. The morphological changing of samples was then viewed under the light microscope and scanning electron microscope.</p><p><strong>Results: </strong>In the present study, agitation speed was found to influence pectinase production in a batch cultivation system. However, higher agitation speeds than the optimal speed (150 rpm) reduced pectinase production which due to shear forces and also collision among the suspended fungal cells in the cultivation medium. Enzyme activity increased with the increasing of agitation speed up to 150 rpm, where it achieved its maximal pectinase activity of 1.559 U/mL. There were significant different (Duncan, P < 0.05) of the pectinase production with the agitation speed at static, 50, 100, 200 and 250 rpm. At the static condition, a well growth mycelial mat was observed on the surface of the cultivation medium and sporulation occurred all over the fungal mycelial mat. However with the increased in agitation speed, the mycelial mat turned slowly to become a single circular pellet. Thus, it was found that agitation speed affected the morphological characteristics of the fungal hyphae/mycelia of A. niger HFD5A-1 by altering their external as well as internal cell structures.</p><p><strong>Conclusion: </strong>Exposure to higher shear stress with an increasing agitation speed could result in lower biomass yields as well as pectinase production by A. niger HFD5A-1.</p>","PeriodicalId":23691,"journal":{"name":"World journal of biological chemistry","volume":"6 3","pages":"265-71"},"PeriodicalIF":0.0,"publicationDate":"2015-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.4331/wjbc.v6.i3.265","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34135067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hyaluronan is a rapidly turned over component of the vertebrate extracellular matrix. Its levels are determined, in part, by the hyaluronan synthases, HAS1, HAS2, and HAS3, and three hyaluronidases, HYAL1, HYAL2 and HYAL3. Hyaluronan binding proteins also regulate hyaluronan levels although their involvement is less well understood. To date, two genetic disorders of hyaluronan metabolism have been reported in humans: HYAL1 deficiency (Mucopolysaccharidosis IX) in four individuals with joint pathology as the predominant phenotypic finding and HAS2 deficiency in a single person having cardiac pathology. However, inherited disorders and induced mutations affecting hyaluronan metabolism have been characterized in other species. Overproduction of hyaluronan by HAS2 results in skin folding and thickening in shar-pei dogs and the naked mole rat, whereas a complete deficiency of HAS2 causes embryonic lethality in mice due to cardiac defects. Deficiencies of murine HAS1 and HAS3 result in a predisposition to seizures. Like humans, mice with HYAL1 deficiency exhibit joint pathology. Mice lacking HYAL2 have variably penetrant developmental defects, including skeletal and cardiac anomalies. Thus, based on mutant animal models, a partial deficiency of HAS2 or HYAL2 might be compatible with survival in humans, while complete deficiencies of HAS1, HAS3, and HYAL3 may yet be recognized.
{"title":"Biology of hyaluronan: Insights from genetic disorders of hyaluronan metabolism.","authors":"Barbara Triggs-Raine, Marvin R Natowicz","doi":"10.4331/wjbc.v6.i3.110","DOIUrl":"https://doi.org/10.4331/wjbc.v6.i3.110","url":null,"abstract":"<p><p>Hyaluronan is a rapidly turned over component of the vertebrate extracellular matrix. Its levels are determined, in part, by the hyaluronan synthases, HAS1, HAS2, and HAS3, and three hyaluronidases, HYAL1, HYAL2 and HYAL3. Hyaluronan binding proteins also regulate hyaluronan levels although their involvement is less well understood. To date, two genetic disorders of hyaluronan metabolism have been reported in humans: HYAL1 deficiency (Mucopolysaccharidosis IX) in four individuals with joint pathology as the predominant phenotypic finding and HAS2 deficiency in a single person having cardiac pathology. However, inherited disorders and induced mutations affecting hyaluronan metabolism have been characterized in other species. Overproduction of hyaluronan by HAS2 results in skin folding and thickening in shar-pei dogs and the naked mole rat, whereas a complete deficiency of HAS2 causes embryonic lethality in mice due to cardiac defects. Deficiencies of murine HAS1 and HAS3 result in a predisposition to seizures. Like humans, mice with HYAL1 deficiency exhibit joint pathology. Mice lacking HYAL2 have variably penetrant developmental defects, including skeletal and cardiac anomalies. Thus, based on mutant animal models, a partial deficiency of HAS2 or HYAL2 might be compatible with survival in humans, while complete deficiencies of HAS1, HAS3, and HYAL3 may yet be recognized. </p>","PeriodicalId":23691,"journal":{"name":"World journal of biological chemistry","volume":"6 3","pages":"110-20"},"PeriodicalIF":0.0,"publicationDate":"2015-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549756/pdf/WJBC-6-110.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34133804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}