To see the other types of publications on this topic, follow the link: Peptidases – Synthèse.
Journal articles on the topic 'Peptidases – Synthèse'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Peptidases – Synthèse.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
LE FLOC’H, N., and B. SEVE. "Le devenir des protéines et des acides aminés dans l’intestin du porc : de la digestion à l’apparition dans la veine porte." INRAE Productions Animales 13, no. 5 (October 22, 2000): 303–14. http://dx.doi.org/10.20870/productions-animales.2000.13.5.3798.
Full textAbstract:
La digestion intestinale des protéines alimentaires fait intervenir des protéases d’origine pancréatique et des peptidases intestinales. Les produits de la digestion sont constitués d’acides aminés libres et de peptides relativement abondants. Acides aminés et peptides sont transportés dans l’entérocyte où ces derniers subissent une hydrolyse. Les acides aminés libres présents dans la veine porte présentent un profil bien différent de celui des protéines alimentaires. En effet, le métabolisme intestinal des acides aminés est très actif. Afin d’assurer la synthèse des protéines constitutives et sécrétées, l’intestin prélève des acides aminés à la fois dans la lumière intestinale et dans le sang artériel. Cet organe renouvelle plus de 50 % de ses protéines par jour et la synthèse de protéines bien particulières comme les mucines engendre des besoins élevés en certains acides aminés comme la thréonine. L’intestin est le principal tissu utilisant la glutamine artérielle et le glutamate alimentaire. Le catabolisme intestinal de ces acides aminés produit de l’alanine, de l’acide aspartique, de la proline et, par l’intermédiaire des enzymes du cycle de l’urée, de l’ornithine, de la citrulline et de l’arginine. Les acides aminés indispensables n’échapperaient pas non plus au catabolisme intestinal. Le rôle de l’intestin ne se limite donc pas à la digestion des protéines et à l’absorption des acides aminés. Son métabolisme modifie profondément la disponibilité des acides aminés alimentaires pour le reste de l’organisme.
2
Dubois, Damien, Olivier Baron, Antony Cougnoux, Julien Delmas, Nathalie Pradel, Michèle Boury, Bernadette Bouchon, et al. "ClbP Is a Prototype of a Peptidase Subgroup Involved in Biosynthesis of Nonribosomal Peptides." Journal of Biological Chemistry 286, no. 41 (July 27, 2011): 35562–70. http://dx.doi.org/10.1074/jbc.m111.221960.
Full textAbstract:
The pks genomic island of Escherichia coli encodes polyketide (PK) and nonribosomal peptide (NRP) synthases that allow assembly of a putative hybrid PK-NRP compound named colibactin that induces DNA double-strand breaks in eukaryotic cells. The pks-encoded machinery harbors an atypical essential protein, ClbP. ClbP crystal structure and mutagenesis experiments revealed a serine-active site and original structural features compatible with peptidase activity, which was detected by biochemical assays. Ten ClbP homologs were identified in silico in NRP genomic islands of closely and distantly related bacterial species. All tested ClbP homologs were able to complement a clbP-deficient E. coli mutant. ClbP is therefore a prototype of a new subfamily of extracytoplasmic peptidases probably involved in the maturation of NRP compounds. Such peptidases will be powerful tools for the manipulation of NRP biosynthetic pathways.
3
Gaikwad, Bhaskar G., and Kritika R. Dwivedy. "Study of Glycogen Synthase and Amino Peptidase." Research Journal of Science and Technology 8, no. 1 (2016): 51. http://dx.doi.org/10.5958/2349-2988.2016.00007.3.
Full text
4
Kumar, Davinder, Virender Kumar, Rakesh Marwaha, and Gajendra Singh. "Oxadiazole-An Important Bioactive Scaffold for Drug Discovery and Development Process Against HIV and Cancer- A Review." Current Bioactive Compounds 15, no. 3 (May 7, 2019): 271–79. http://dx.doi.org/10.2174/1573407213666171017160359.
Full textAbstract:
Background: Acquired immunodeficiency syndrome (AIDS) and cancer treatment have been a major task for research scientists and pharmaceutical industry for the last many years. Seeking to the development, many promising chemical entities especially five-membered heterocyclic rings like oxadiazole have revealed good anticancer and anti HIV activities. The current review enlists some recently developed anti-HIV and anti-cancer oxadiazole moieties. Methods: on the basis of structural modification for the syntheses of new oxadiazole analogs, the new anti-HIV and anti-cancer agents have been summarized, which can improve treatment of AIDs and cancer. Results: The oxadiazole ring is more potent in comparison to some other heterocyclic rings (five and six membered) towards anti-HIV and anti-cancer activities. The important mechanisms involved for anti HIV and anticancer activity are mainly inhibition of enzymes like protease, HIV-integrase, telomerase, histone deacetylase, methionine amino peptidase, thymidylate synthase and focal adhesion kinase and inhibition of some growth factors. Conclusion: By reviving the past literature about 50 most potent oxadiazole derivatives, depending upon activity and structural modifications, have been selected as potent anti-HIV, and anti-cancer agents. Thus, oxadiazole seems to be a ‘privileged structure’ for further screening and syntheses of the new drug analogs against life threatening HIV and cancer like diseases.
5
Ajmer Singh Grewal, Neelam Sharma, Sukhbir Singh, and Sandeep Arora. "Molecular Docking Studies of Phenolic Compounds from Syzygium cumini with Multiple Targets of Type 2 Diabetes." Journal of Pharmaceutical Technology, Research and Management 6, no. 2 (November 2, 2018): 125–33. http://dx.doi.org/10.15415/jptrm.2018.62009.
Full textAbstract:
Treatment of type 2 diabetes without any side effects is still a challenge to the medical system. This leads to increasing demand for natural products with antidiabetic activity with fewer side effects. Syzygium cumini is a traditional herbal medicinal plant and is reported to possess a variety of pharmacological actions. It contains various types of chemical constituents including terpenoids, tannins, anthocyanins, flavonoids and other phenolic compounds. Some flavonoids and other phenolic compounds from S. cumini were reported in literature to have type 2 antidiabetic potential. The main objective of the current investigation was in silico screening of some phenolic compounds from S. cumini against multiple targets associated with type 2 diabetes to explore the mechanism of antidiabetic action and prediction of binding mode using molecular docking studies. In silico docking studies were performed for the selected molecules in the binding site of multiple targets associated with type 2 diabetes (α-glucosidas , dipeptidyl peptidase 4, glycogen synthase kinase 3, glucokinase and glucagon receptor). Amongst the compounds tested in silico, rutin showed appreciable binding with multiple targets of type 2 diabetes including α-glucosidase, dipeptidyl peptidase 4, glycogen synthase kinase 3, and glucagon receptor. Catechin was found to inhibit both α-glucosidase, and dipeptidyl peptidase 4. This information can be utilized for the design and development of potent multi-functional candidate drugs with minimal side effects for type 2 diabetes therapeuticsa.
6
Domínguez-Vías, Germán, Ana Belén Segarra, Manuel Ramírez-Sánchez, and Isabel Prieto. "The Role of High Fat Diets and Liver Peptidase Activity in the Development of Obesity and Insulin Resistance in Wistar Rats." Nutrients 12, no. 3 (February 28, 2020): 636. http://dx.doi.org/10.3390/nu12030636.
Full textAbstract:
High-fat diets (HFD) have been widely associated with an increased risk of metabolic disorders and overweight. However, a high intake of sources that are rich in monounsaturated fatty acids has been suggested as a dietary agent that is able to positively influence energy metabolism and vascular function. The main objective of this study was to analyze the role of dietary fats on hepatic peptidases activities and metabolic disorders. Three diets: standard (S), HFD supplemented with virgin olive oil (VOO), and HFD supplemented with butter plus cholesterol (Bch), were administered over six months to male Wistar rats. Plasma and liver samples were collected for clinical biochemistry and aminopeptidase activities (AP) analysis. The expression of inducible nitric oxide synthase (iNOS) was also determined by Western blot in liver samples. The diet supplement with VOO did not induce obesity, in contrast to the Bch group. Though the VOO diet increased the time that was needed to return to the basal levels of plasma glucose, the fasting insulin/glucose ratio and HOMA2-%B index (a homeostasis model index of insulin secretion and valuation of β-cell usefulness (% β-cell secretion)) were improved. An increase of hepatic membrane-bound dipeptidyl-peptidase 4 (DPP4) activity was found only in VOO rats, even if no differences in fasting plasma glucagon-like peptide 1 (GLP-1) were obtained. Both HFDs induced changes in hepatic pyroglutamyl-AP in the soluble fraction, but only the Bch diet increased the soluble tyrosyl-AP. Angiotensinase activities that are implicated in the metabolism of angiotensin II (AngII) to AngIV increased in the VOO diet, which was in agreement with the higher activity of insulin-regulated-AP (IRAP) in this group. Otherwise, the diet that was enriched with butter increased soluble gamma-glutamyl transferase (GGT) and Leucyl-AP, iNOS expression in the liver, and plasma NO. In summary, VOO increased the hepatic activity of AP that were related to glucose metabolism (DPP4, angiotensinases, and IRAP). However, the Bch diet increased activities that are implicated in the control of food intake (Tyrosine-AP), the index of hepatic damage (Leucine-AP and GGT), and the expression of hepatic iNOS and plasma NO. Taken together, these results support that the source of fat in the diet affects several peptidases activities in the liver, which could be related to alterations in feeding behavior and glucose metabolism.
7
Osman, Christof, Claudia Wilmes, Takashi Tatsuta, and Thomas Langer. "Prohibitins Interact Genetically with Atp23, a Novel Processing Peptidase and Chaperone for the F1FO-ATP Synthase." Molecular Biology of the Cell 18, no. 2 (February 2007): 627–35. http://dx.doi.org/10.1091/mbc.e06-09-0839.
Full textAbstract:
The generation of cellular energy depends on the coordinated assembly of nuclear and mitochondrial-encoded proteins into multisubunit respiratory chain complexes in the inner membrane of mitochondria. Here, we describe the identification of a conserved metallopeptidase present in the intermembrane space, termed Atp23, which exerts dual activities during the biogenesis of the F1FO-ATP synthase. On one hand, Atp23 serves as a processing peptidase and mediates the maturation of the mitochondrial-encoded FO-subunit Atp6 after its insertion into the inner membrane. On the other hand and independent of its proteolytic activity, Atp23 promotes the association of mature Atp6 with Atp9 oligomers. This assembly step is thus under the control of two substrate-specific chaperones, Atp10 and Atp23, which act on opposite sides of the inner membrane. Strikingly, both ATP10 and ATP23 were found to genetically interact with prohibitins, which build up large, ring-like assemblies with a proposed scaffolding function in the inner membrane. Our results therefore characterize not only a novel processing peptidase with chaperone activity in the mitochondrial intermembrane space but also link the function of prohibitins to the F1FO-ATP synthase complex.
8
Wang, Han, Qingchun Zhou, Jason W. Kesinger, Chad Norris, and Cammi Valdez. "Heme Regulates Exocrine Peptidase Precursor Genes in Zebrafish." Experimental Biology and Medicine 232, no. 9 (October 2007): 1170–80. http://dx.doi.org/10.3181/0703-rm-77.
Full textAbstract:
We previously determined that yquem harbors a mutation in the gene encoding uroporphyrinogen decarboxylase (UROD), the fifth enzyme in heme biosynthesis, and established zebrafish yquem ( yqe tp61) as a vertebrate model for human hepatoery-thropoietic porphyria (HEP). Here we report that six exocrine peptidase precursor genes, carboxypeptidase A, trypsin precursor, trypsin like, chymotrypsinogen B1, chymotrypsinogen 1-like, and elastase 2 like, are downregulated in yquem/urod (−/−), identified initially by microarray analysis of yquem/urod zebrafish and, subsequently, confirmed by in situ hybridization. We then determined downregulation of these six zymogens specifically in the exocrine pancreas of sauternes ( sau tb223) larvae, carrying a mutation in the gene encoding δ-amino-levulinate synthase (ALAS2), the first enzyme in heme biosynthesis. We also found that ptf1a, a transcription factor regulating exocrine zymogens, is downregulated in both yquem/urod (−/−) and sau/alas2 (−/−) larvae. Further, hemin treatment rescues expression of ptf1a and these six zymogens in both yquem/urod (−/−) and sauternes/alas2 (−/−) larvae. Thus, it appears that heme deficiency downregulates ptf1a, which, in turn, leads to downregulation of exocrine zymogens. Our findings provide a better understanding of heme deficiency pathogenesis and enhance our ability to diagnose and treat patients with porphyria or pancreatic diseases.
9
Zhou, Suping, Roger J. Sauvé, Zong Liu, Sasikiran Reddy, Sarabjit Bhatti, Simon D. Hucko, Yang Yong, Tara Fish, and Theodore W. Thannhauser. "Heat-induced Proteome Changes in Tomato Leaves." Journal of the American Society for Horticultural Science 136, no. 3 (May 2011): 219–26. http://dx.doi.org/10.21273/jashs.136.3.219.
Full textAbstract:
Three tomato (Solanum lycopersicum) cultivars [Walter LA3465 (heat-tolerant), Edkawi LA 2711 (unknown heat tolerance, salt-tolerant), and LA1310 (cherry tomato)] were compared for changes in leaf proteomes after heat treatment. Seedlings with four fully expanded leaves were subjected to heat treatment of 39/25 °C at a 16:8 h light–dark cycle for 7 days. Leaves were collected at 1200 hr, 4 h after the light cycle started. For ‘Walter’ LA3465, heat-suppressed proteins were geranylgeranyl reductase, ferredoxin-NADP (+) reductase, Rubisco activase, transketolase, phosphoglycerate kinase precursor, fructose–bisphosphate aldolase, glyoxisomal malate dehydrogenase, catalase, S-adenosyl-L-homocysteine hydrolase, and methionine synthase. Two enzymes were induced, cytosolic NADP-malic enzyme and superoxide dismutase. For ‘Edkawi’ LA2711, nine enzymes were suppressed: ferredoxin-NADP (+) reductase, Rubisco activase, S-adenosylmethionine synthetase, methioine synthase, glyoxisomal malate dehydrogenase, enolase, flavonol synthase, M1 family peptidase, and dihydrolipoamide dehydrogenase. Heat-induced proteins were cyclophilin, fructose-1,6-bisphosphate aldolase, transketolase, phosphoglycolate phosphatase, ATPase, photosystem II oxygen-evolving complex 23, and NAD-dependent epimerase/dehydratase. For cherry tomato LA1310, heat-suppressed proteins were aminotransferase, S-adenosyl-L-homocysteine hydrolase, L-ascorbate peroxidase, lactoylglutathione lyase, and Rubisco activase. Heat-induced enzymes were glyoxisomal malate dehydrogenase, phosphoribulokinasee, and ATP synthase. This research resulted in the identification of proteins that were induced/repressed in all tomato cultivars evaluated (e.g., Rubisco activase, methionine synthase, adenosyl-L-homocysteine hydrolase, and others) and those differentially expressed (e.g., transketolase).
10
Dzikaite, Vijole, Arvydas Kanopka, Jeremy H. Brock, Arunas Kazlauskas, and Öjar Melefors. "A novel endoproteolytic processing activity in mitochondria of erythroid cells and the role in heme synthesis." Blood 96, no. 2 (July 15, 2000): 740–46. http://dx.doi.org/10.1182/blood.v96.2.740.
Full textAbstract:
Abstract The erythroid isoform of aminolevulinate synthase (eALAS) protein is a major control point in erythroid heme synthesis and hemoglobin formation. Erythroid cells were extracted from mouse blood and bone marrow and metabolically labeled with 35S-methionine. This was followed by immunoprecipitation of eALAS protein products. The results show that the N-terminus of the expected full-length 59-kd form of the eALAS protein is truncated in bone marrow erythroid cells by approximately 7 kd. More differentiated erythroid cells in the peripheral blood exhibit very little of this protein truncation. Erythroid cells from the bone marrow were isolated using monoclonal antibody TER-119 and were shown to contain a unique endoprotease activity that could cleave the eALAS protein to the shorter form in vitro. With or without the mitochondrial signal sequence, the eALAS protein could serve as a substrate for the cleavage. This cleavage renders a functional eALAS protein and only removes a domain of unclear function, which has previously been reported to vary in size as a result of alternative RNA splicing. The protease activity was enriched from the membranes of mitochondria from bone marrow cells and was shown to be different from mitochondrial processing peptidase, medullasin, and other known proteases. Apart from the mitochondrial processing peptidase that cleaves the import signal sequence, this is the first description of a mitochondrially located site-specific processing protease activity.
11
Dzikaite, Vijole, Arvydas Kanopka, Jeremy H. Brock, Arunas Kazlauskas, and Öjar Melefors. "A novel endoproteolytic processing activity in mitochondria of erythroid cells and the role in heme synthesis." Blood 96, no. 2 (July 15, 2000): 740–46. http://dx.doi.org/10.1182/blood.v96.2.740.014k42_740_746.
Full textAbstract:
The erythroid isoform of aminolevulinate synthase (eALAS) protein is a major control point in erythroid heme synthesis and hemoglobin formation. Erythroid cells were extracted from mouse blood and bone marrow and metabolically labeled with 35S-methionine. This was followed by immunoprecipitation of eALAS protein products. The results show that the N-terminus of the expected full-length 59-kd form of the eALAS protein is truncated in bone marrow erythroid cells by approximately 7 kd. More differentiated erythroid cells in the peripheral blood exhibit very little of this protein truncation. Erythroid cells from the bone marrow were isolated using monoclonal antibody TER-119 and were shown to contain a unique endoprotease activity that could cleave the eALAS protein to the shorter form in vitro. With or without the mitochondrial signal sequence, the eALAS protein could serve as a substrate for the cleavage. This cleavage renders a functional eALAS protein and only removes a domain of unclear function, which has previously been reported to vary in size as a result of alternative RNA splicing. The protease activity was enriched from the membranes of mitochondria from bone marrow cells and was shown to be different from mitochondrial processing peptidase, medullasin, and other known proteases. Apart from the mitochondrial processing peptidase that cleaves the import signal sequence, this is the first description of a mitochondrially located site-specific processing protease activity.
12
Dasari, Suvarna, and Ralf Kölling. "Role of mitochondrial processing peptidase and AAA proteases in processing of the yeast acetohydroxyacid synthase precursor." FEBS Open Bio 6, no. 7 (June 10, 2016): 765–73. http://dx.doi.org/10.1002/2211-5463.12088.
Full text
13
Kopf, Phillip G., and William B. Campbell. "Endothelial Metabolism of Angiotensin II to Angiotensin III, not Angiotensin (1–7), Augments the Vasorelaxation Response in Adrenal Cortical Arteries." Endocrinology 154, no. 12 (December 1, 2013): 4768–76. http://dx.doi.org/10.1210/en.2013-1160.
Full textAbstract:
Hyperaldosteronism is linked to the development and progression of several different cardiovascular diseases. Angiotensin (Ang) II increases aldosterone secretion and adrenal blood flow. Ang II peptide fragments are produced by various peptidases, and these Angs have diverse and vital physiologic roles. Due to the uncharacteristic vasorelaxation of adrenal arteries by Ang II, we tested the hypothesis that Ang II metabolism contributes to its relaxant activity in adrenal arteries. Metabolism of Angs by bovine adrenal cortical arteries and isolated bovine adrenal vascular cells was measured by liquid chromatography-mass spectrometry. The primary Ang metabolites of adrenal arteries are Ang III and Ang (1–7), with Ang IV produced to a lesser extent. Bovine microvascular endothelial cells produced a similar metabolic profile to adrenal arteries, whereas bovine adrenal artery smooth muscle cells exhibited less metabolism. In preconstricted adrenal arteries, Ang II caused relaxation in picomolar concentrations and constrictions at 10nM. Ang-converting enzyme 2 inhibition augmented this relaxation response, whereas aminopeptidase inhibition did not. Ang III was equipotent to Ang II in relaxing adrenal arteries. Ang IV did not cause relaxation. Nitric oxide synthase inhibition enhanced Ang II-induced constriction of adrenal arteries. Aminopeptidase inhibition increased the concentration range for Ang II-induced constriction of adrenal arteries. Ang III and Ang IV did not change the basal tone but caused constriction of adrenal arteries with nitric oxide synthase inhibition. These data indicate that Ang II metabolism modulates the vascular effects of Ang II in the adrenal vasculature.
14
Bellini, Erika, Viviana Maresca, Camilla Betti, Monica Ruffini Castiglione, Debora Fontanini, Antonella Capocchi, Carlo Sorce, et al. "The Moss Leptodictyum riparium Counteracts Severe Cadmium Stress by Activation of Glutathione Transferase and Phytochelatin Synthase, but Slightly by Phytochelatins." International Journal of Molecular Sciences 21, no. 5 (February 26, 2020): 1583. http://dx.doi.org/10.3390/ijms21051583.
Full textAbstract:
In the present work, we investigated the response to Cd in Leptodictyum riparium, a cosmopolitan moss (Bryophyta) that can accumulate higher amounts of metals than other plants, even angiosperms, with absence or slight apparent damage. High-performance liquid chromatography followed by electrospray ionization tandem mass spectrometry of extracts from L. riparium gametophytes, exposed to 0, 36 and 360 µM Cd for 7 days, revealed the presence of γ-glutamylcysteine (γ-EC), reduced glutathione (GSH), and traces of phytochelatins. The increase in Cd concentrations progressively augmented reactive oxygen species levels, with activation of both antioxidant (catalase and superoxide dismutase) and detoxifying (glutathione-S-transferase) enzymes. After Cd treatment, cytosolic and vacuolar localization of thiol peptides was performed by means of the fluorescent dye monochlorobimane and subsequent observation with confocal laser scanning microscopy. The cytosolic fluorescence observed with the highest Cd concentrations was also consistent with the formation of γ-EC-bimane in the cytosol, possibly catalyzed by the peptidase activity of the L. riparium phytochelatin synthase. On the whole, activation of phytochelatin synthase and glutathione-S-transferase, but minimally phytochelatin synthesis, play a role to counteract Cd toxicity in L. riparium, in this manner minimizing the cellular damage caused by the metal. This study strengthens previous investigations on the L. riparium ability to efficiently hinder metal pollution, hinting at a potential use for biomonitoring and phytoremediation purposes.
15
Olalde-Portugal, Víctor, José Luis Cabrera-Ponce, Argel Gastelum-Arellanez, Armando Guerrero-Rangel, Robert Winkler, and Silvia Valdés-Rodríguez. "Proteomic analysis and interactions network in leaves of mycorrhizal and nonmycorrhizal sorghum plants under water deficit." PeerJ 8 (April 23, 2020): e8991. http://dx.doi.org/10.7717/peerj.8991.
Full textAbstract:
For understanding the water deficit stress mechanism in sorghum, we conducted a physiological and proteomic analysis in the leaves of Sorghum bicolor L. Moench (a drought tolerant crop model) of non-colonized and colonized plants with a consortium of arbuscular mycorrhizal fungi. Physiological results indicate that mycorrhizal fungi association enhances growth and photosynthesis in plants, under normal and water deficit conditions. 2D-electrophoresis profiles revealed 51 differentially accumulated proteins in response to water deficit, of which HPLC/MS successfully identified 49. Bioinformatics analysis of protein–protein interactions revealed the participation of different metabolic pathways in nonmycorrhizal compared to mycorrhizal sorghum plants under water deficit. In noninoculated plants, the altered proteins are related to protein synthesis and folding (50S ribosomal protein L1, 30S ribosomal protein S10, Nascent polypeptide-associated complex subunit alpha), coupled with multiple signal transduction pathways, guanine nucleotide-binding beta subunit (Rack1) and peptidyl-prolyl-cis-trans isomerase (ROC4). In contrast, in mycorrhizal plants, proteins related to energy metabolism (ATP synthase-24kDa, ATP synthase β), carbon metabolism (malate dehydrogenase, triosephosphate isomerase, sucrose-phosphatase), oxidative phosphorylation (mitochondrial-processing peptidase) and sulfur metabolism (thiosulfate/3-mercaptopyruvate sulfurtransferase) were found. Our results provide a set of proteins of different metabolic pathways involved in water deficit produced by sorghum plants alone or associated with a consortium of arbuscular mycorrhizal fungi isolated from the tropical rain forest Los Tuxtlas Veracruz, México.
16
Sun, Haiyan, Choon-myung Lee, Shweta Tripathi, Kyung-Bo Kim, and Edward T. Morgan. "Nitric oxide-dependent CYP2B degradation is potentiated by a cytokine-regulated pathway and utilizes the immunoproteasome subunit LMP2." Biochemical Journal 445, no. 3 (July 13, 2012): 377–82. http://dx.doi.org/10.1042/bj20120820.
Full textAbstract:
CYP2B proteins in rat hepatocytes undergo NO-dependent proteolytic degradation, but the mechanisms and the reasons for the specificity towards only certain P450 (cytochrome P450) enzymes are yet unknown. In the present study we found that down-regulation of CYP2B proteins by the NO donor NOC-18 is accelerated by pretreatment of the hepatocytes with IL-1 (interleukin-1β) in the presence of an NO synthase inhibitor, suggesting that an NO-independent action of IL-1 contributes to the lability of CYP2B proteins. The immunoproteasome subunit LMP2 (large multifunctional peptidase 2) was significantly expressed in hepatocytes under basal conditions, and IL-1 induced LMP2 within 6–12 h of treatment. CYP2B protein degradation in response to IL-1 was attenuated by the selective LMP2 inhibitor UK-101, but not by the LMP7 inhibitor IPSI. The results show that LMP2 contributes to the NO-dependent degradation of CYP2B proteins, and suggest that induction of LMP2 may be involved in the potentiation of this degradation by IL-1.
17
Milewski, Sławomir, Fiorenzo Mignini, Rajendra Prasad, and Edward Borowski. "Unusual Susceptibility of a Multidrug-Resistant Yeast Strain to Peptidic Antifungals." Antimicrobial Agents and Chemotherapy 45, no. 1 (January 1, 2001): 223–28. http://dx.doi.org/10.1128/aac.45.1.223-228.2001.
Full textAbstract:
ABSTRACT The susceptibility of Saccharomyces cerevisiae JG436 multidrug transporter deletion mutant, Δpdr5, to several antifungal agents was compared to that of JG436-derived JGCDR1 and JGCaMDR1 transformants, harboring the CDR1 and CaMDR1 genes, encoding the main drug-extruding membrane proteins ofCandida albicans. The JGCDR1 and JGCaMDR1 yeasts demonstrated markedly diminished susceptibility to the azole antifungals, terbinafine and cycloheximide, while that to amphotericin B was unchanged. Surprisingly, JGCDR1 but not JGCaMDR1 cells showed enhanced susceptibility to peptidic antifungals, rationally designed compounds containing inhibitors of glucosamine-6-phosphate synthase. It was found that these antifungal oligopeptides, as well as model oligopeptides built of proteinogenic amino acids, were not effluxed from JGCDR1 cells. Moreover, they were taken up by these cells at rates two to three times higher than by JG436. The tested oligopeptides were rapidly cleaved to constitutive amino acids by cytoplasmic peptidases. Studies on the mechanism of the observed phenomenon suggested that an additive proton motive force generated by Cdr1p stimulated uptake of oligopeptides into JGCDR1 cells, thus giving rise to the higher antifungal activity of FMDP [N 3-(4-methoxyfumaroyl)-l-2,3-diaminopropanoic acid]-peptides.
18
Nakaoku, Yuriko, Satoshi Saito, Yumi Yamamoto, Takakuni Maki, Ryosuke Takahashi, and Masafumi Ihara. "The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates High-fat Induced Cognitive Decline in Tauopathy Model Mice." International Journal of Molecular Sciences 20, no. 10 (May 23, 2019): 2539. http://dx.doi.org/10.3390/ijms20102539.
Full textAbstract:
Vascular risk factors, such as type 2 diabetes mellitus (T2DM), are associated with the increased risk of Alzheimer’s disease. One of the common T2DM medications, dipeptidyl peptidase (DPP)-4 inhibitors, have a minimum risk for hypoglycemia and have recently been suggested to ameliorate β-amyloid pathology. However, conflicting results have been reported regarding the effects of DPP-4 inhibition on cognitive function and tau pathology. Thus, we investigated whether inhibiting DPP-4 affects tau pathology and cognition in a mouse model of tauopathy with hyperglycemia. Male mice overexpressing the P301S mutant human microtubule-associated protein tau gene (PS19) were fed either a low or high-fat diet. PS19 mice were then administered either linagliptin, a DPP-4 inhibitor, or vehicle, from 6 weeks to 8 months of age. Linagliptin-treated mice exhibited higher levels of glucagon-like peptide-1 and decreased fasting blood glucose, compared with the vehicle-treated mice at 8 months. Linagliptin treatment significantly restored spatial reference memory and increased cerebral blood flow without affecting phosphorylation levels of tau or endothelial nitric oxide synthase (eNOS) in the brain. Linagliptin may ameliorate HFD-induced cognitive worsening in tauopathy, at least partially, by increasing cerebral perfusion via the eNOS-independent pathway.
19
Tian, Qing, Ting Li, Weihong Hou, Jianyu Zheng, Laura W. Schrum, and Herbert L. Bonkovsky. "Lon Peptidase 1 (LONP1)-dependent Breakdown of Mitochondrial 5-Aminolevulinic Acid Synthase Protein by Heme in Human Liver Cells." Journal of Biological Chemistry 286, no. 30 (June 9, 2011): 26424–30. http://dx.doi.org/10.1074/jbc.m110.215772.
Full text
20
Bai, T. R., and A. M. Bramley. "Effect of an inhibitor of nitric oxide synthase on neural relaxation of human bronchi." American Journal of Physiology-Lung Cellular and Molecular Physiology 264, no. 5 (May 1, 1993): L425—L430. http://dx.doi.org/10.1152/ajplung.1993.264.5.l425.
Full textAbstract:
This study examines the roles of peptides and nitric oxide (NO) as mediators of inhibitory nonadrenergic, noncholinergic (NANCi) neurons in human and guinea pig airways in vitro. Tissues were contracted with 0.3 microM methacholine (MCh) and relaxation studied before and after the addition of the peptidase alpha-chymotrypsin (alpha-CT) (2 U/ml) and NG-nitro-L-arginine methyl ester (L-NAME 0.1-1.1 mM), an inhibitor of NO synthase, the enzyme catalyzing the formation of NO. alpha-CT alone, in comparison to parallel time controls, inhibited control relaxation to electrical field stimulation (EFS) by 29.2 +/- 8.6% in guinea pig tracheae (n = 9), whereas a small augmentation of relaxation was observed in human bronchi (n = 7). L-NAME inhibited the NANCi response in both guinea pig tracheae and human bronchi: in guinea pig tracheae, maximal inhibition of the alpha-CT-insensitive relaxation was 59.3 +/- 11.5% (SE, P = 0.003) at low frequencies (4-16 Hz) and 28.6 +/- 8.9% (P = 0.08) at 32 Hz; in human bronchi, the maximal inhibition was 37.7 +/- 9.3% (P = 0.008) at 8 or 16 Hz, and 37.9 +/- 5.9% (P = 0.005) at 32 Hz. Inhibition was greater after repeated baseline EFS for 90 min before initiation of contraction with MCh and addition of L-NAME (59.8 +/- 13.9% after repeated baseline EFS, n = 4; vs. 34.9 +/- 6.2% without repeated baseline EFS, n = 9, P = 0.025). Relaxant responses to sodium nitroprusside, vasoactive intestinal peptide, and isoproterenol were not affected by L-NAME. L-Arginine (10 mM), a precursor of NO, partially reversed the effect of L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)
21
LIN, Li, and Peter LOBEL. "Production and characterization of recombinant human CLN2 protein for enzyme-replacement therapy in late infantile neuronal ceroid lipofuscinosis." Biochemical Journal 357, no. 1 (June 25, 2001): 49–55. http://dx.doi.org/10.1042/bj3570049.
Full textAbstract:
Late infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal recessive childhood disease caused by mutations in the CLN2 gene, which encodes the lysosomal enzyme tripeptidyl peptidase I. As a step towards understanding the protein and developing therapeutics for the disease, we have produced and characterized recombinant human CLN2 (ceroid lipofuscinosis, neuronal 2) protein from Chinese-hamster ovary cells engineered to secrete high levels of the enzyme. The protein was secreted as an inactive soluble proenzyme of ≈ 65kDa that appears as a monomer by gel filtration. Upon acidification, the protein is processed to mature form and acquires activity. The enzyme is efficiently delivered to the lysosomes of LINCL fibroblasts by mannose 6-phosphate-receptor-mediated endocytosis (EC50≈ 2nM), where it remains active for long periods of time (t1/2≈ 12 days). In addition, the enzyme is taken up by rat cerebellar granule neurons by mannose 6-phosphate-dependent and -independent mechanisms. Treatment of LINCL fibroblasts with recombinant CLN2 protein restores normal enzyme activity and ameliorates accumulation of the major storage protein, mitochondrial ATP synthase subunit c.
22
Long, Jonathan Z., Alexander M. Roche, Charles A. Berdan, Sharon M. Louie, Amanda J. Roberts, Katrin J. Svensson, Florence Y. Dou, et al. "Ablation of PM20D1 reveals N-acyl amino acid control of metabolism and nociception." Proceedings of the National Academy of Sciences 115, no. 29 (July 2, 2018): E6937—E6945. http://dx.doi.org/10.1073/pnas.1803389115.
Full textAbstract:
N-acyl amino acids (NAAs) are a structurally diverse class of bioactive signaling lipids whose endogenous functions have largely remained uncharacterized. To clarify the physiologic roles of NAAs, we generated mice deficient in the circulating enzyme peptidase M20 domain-containing 1 (PM20D1). Global PM20D1-KO mice have dramatically reduced NAA hydrolase/synthase activities in tissues and blood with concomitant bidirectional dysregulation of endogenous NAAs. Compared with control animals, PM20D1-KO mice exhibit a variety of metabolic and pain phenotypes, including insulin resistance, altered body temperature in cold, and antinociceptive behaviors. Guided by these phenotypes, we identify N-oleoyl-glutamine (C18:1-Gln) as a key PM20D1-regulated NAA. In addition to its mitochondrial uncoupling bioactivity, C18:1-Gln also antagonizes certain members of the transient receptor potential (TRP) calcium channels including TRPV1. Direct administration of C18:1-Gln to mice is sufficient to recapitulate a subset of phenotypes observed in PM20D1-KO animals. These data demonstrate that PM20D1 is a dominant enzymatic regulator of NAA levels in vivo and elucidate physiologic functions for NAA signaling in metabolism and nociception.
23
Polytarchou, Christos, Raymond Pfau, Maria Hatziapostolou, and Philip N. Tsichlis. "The JmjC Domain Histone Demethylase Ndy1 Regulates Redox Homeostasis and Protects Cells from Oxidative Stress." Molecular and Cellular Biology 28, no. 24 (October 6, 2008): 7451–64. http://dx.doi.org/10.1128/mcb.00688-08.
Full textAbstract:
ABSTRACT The histone H3 demethylase Ndy1/KDM2B protects cells from replicative senescence. Changes in the metabolism of reactive oxygen species (ROS) are important for establishing senescence, suggesting that Ndy1 may play a role in redox regulation. Here we show that Ndy1 protects from H2O2-induced apoptosis and G2/M arrest and inhibits ROS-mediated signaling and DNA damage, while knockdown of Ndy1 has the opposite effects. Consistent with these observations, whereas Ndy1 overexpression promotes H2O2 detoxification, Ndy1 knockdown inhibits it. Ndy1 promotes the expression of genes encoding the antioxidant enzymes aminoadipic semialdehyde synthase (Aass), NAD(P)H quinone oxidoreductase-1 (Nqo1), peroxiredoxin-4 (Prdx4), and serine peptidase inhibitor b1b (Serpinb1b) and represses the expression of interleukin-19. At least two of these genes (Nqo1 and Prdx4) are regulated directly by Ndy1, which binds to specific sites within their promoters and demethylates promoter-associated histone H3 dimethylated at K36 and histone H3 trimethylated at K4. Simultaneous knockdown of Aass, Nqo1, Prdx4, and Serpinb1b in Ndy1-expressing cells to levels equivalent to those detected in control cells was sufficient to suppress the Ndy1 redox phenotype.
24
Akoumianakis, Ioannis, Ileana Badi, Gillian Douglas, Surawee Chuaiphichai, Laura Herdman, Nadia Akawi, Marios Margaritis, et al. "Insulin-induced vascular redox dysregulation in human atherosclerosis is ameliorated by dipeptidyl peptidase 4 inhibition." Science Translational Medicine 12, no. 541 (April 29, 2020): eaav8824. http://dx.doi.org/10.1126/scitranslmed.aav8824.
Full textAbstract:
Recent clinical trials have revealed that aggressive insulin treatment has a neutral effect on cardiovascular risk in patients with diabetes despite improved glycemic control, which may suggest confounding direct effects of insulin on the human vasculature. We studied 580 patients with coronary atherosclerosis undergoing coronary artery bypass surgery (CABG), finding that high endogenous insulin was associated with reduced nitric oxide (NO) bioavailability ex vivo in vessels obtained during surgery. Ex vivo experiments with human internal mammary arteries and saphenous veins obtained from 94 patients undergoing CABG revealed that both long-acting insulin analogs and human insulin triggered abnormal responses of post–insulin receptor substrate 1 downstream signaling ex vivo, independently of systemic insulin resistance status. These abnormal responses led to reduced NO bioavailability, activation of NADPH oxidases, and uncoupling of endothelial NO synthase. Treatment with an oral dipeptidyl peptidase 4 inhibitor (DPP4i) in vivo or DPP4i administered to vessels ex vivo restored physiological insulin signaling, reversed vascular insulin responses, reduced vascular oxidative stress, and improved endothelial function in humans. The detrimental effects of insulin on vascular redox state and endothelial function as well as the insulin-sensitizing effect of DPP4i were also validated in high-fat diet-fed ApoE−/− mice treated with DPP4i. High plasma DPP4 activity and high insulin were additively related with higher cardiac mortality in patients with coronary atherosclerosis undergoing CABG. These findings may explain the inability of aggressive insulin treatment to improve cardiovascular outcomes, raising the question whether vascular insulin sensitization with DPP4i should precede initiation of insulin treatment and continue as part of a long-term combination therapy.
25
Greenblatt, Matthew Blake, Dong Yeon Shin, Hwanhee Oh, Ki-Young Lee, Bo Zhai, Steven P. Gygi, Sutada Lotinun, et al. "MEKK2 mediates an alternative β-catenin pathway that promotes bone formation." Proceedings of the National Academy of Sciences 113, no. 9 (February 16, 2016): E1226—E1235. http://dx.doi.org/10.1073/pnas.1600813113.
Full textAbstract:
Proper tuning of β-catenin activity in osteoblasts is required for bone homeostasis, because both increased and decreased β-catenin activity have pathologic consequences. In the classical pathway for β-catenin activation, stimulation with WNT ligands suppresses constitutive phosphorylation of β-catenin by glycogen synthase kinase 3β, preventing β-catenin ubiquitination and proteasomal degradation. Here, we have found that mitogen-activated protein kinase kinase kinase 2 (MAP3K2 or MEKK2) mediates an alternative pathway for β-catenin activation in osteoblasts that is distinct from the canonical WNT pathway. FGF2 activates MEKK2 to phosphorylate β-catenin at serine 675, promoting recruitment of the deubiquitinating enzyme, ubiquitin-specific peptidase 15 (USP15). USP15 in turn prevents the basal turnover of β-catenin by inhibiting its ubiquitin-dependent proteasomal degradation, thereby enhancing WNT signaling. Analysis of MEKK2-deficient mice and genetic interaction studies between Mekk2- and β-catenin–null alleles confirm that this pathway is an important physiologic regulator of bone mass in vivo. Thus, an FGF2/MEKK2 pathway mediates an alternative nonclassical pathway for β-catenin activation, and this pathway is a key regulator of bone formation by osteoblasts.
26
Ezaki, J., M. Takeda-Ezaki, and E. Kominami. "Tripeptidyl Peptidase I, the Late Infantile Neuronal Ceroid Lipofuscinosis Gene Product, Initiates the Lysosomal Degradation of Subunit c of ATP Synthase." Journal of Biochemistry 128, no. 3 (September 1, 2000): 509–16. http://dx.doi.org/10.1093/oxfordjournals.jbchem.a022781.
Full text
27
Morissette, Guillaume, Thierry Sabourin, Albert Adam, and François Marceau. "Inhibition of human and rabbit arterial smooth muscle cell migration mediated by the kinin B1 receptor: role of receptor density and released mediators." Canadian Journal of Physiology and Pharmacology 84, no. 11 (November 2006): 1107–19. http://dx.doi.org/10.1139/y06-031.
Full textAbstract:
Bradykinin (BK)-related peptides are suspected to negatively influence diverse functions in vascular smooth muscle cells (SMCs), notably via stimulation of the inducible B1 receptor (B1R), and have been shown to inhibit the migration of rat SMCs. The present study had several objectives: (i) to test whether B1R mediates the inhibition of migration of arterial SMCs from additional species (the human and the rabbit); (ii) whether B1R density influences this action and whether autocrine NO or prostanoid release modulate it; and (iii) the possible signaling interaction between the B1R and phosphatidylinositol-3 kinase (PI-3K) has been addressed. The peptidase resistant B1R agonist Sar-[D-Phe8]des-Arg9-BK (10 nmol/L – 1 μmol/L) was an inhibitor of migration in human or rabbit arterial SMCs in a wound closure assay, more effectively if the medium composition allowed a high B1R expression (20% fetal bovine serum (FBS) + interleukin-1β (IL-1β) in human SMCs, 10% FBS in rabbit cells). The effect of the B1R agonist on motility was abrogated by a B1R antagonist, B-9858, but not by the B2R antagonist Hoe 140; a peptidase-resistant B2R agonist, [Phe8Ψ(CH2-NH)-Arg9]BK, had a marginal or no effect on migration. Sar-[D-Phe8]des-Arg9-BK (1 μmol/L) did not significantly influence SMC proliferation. The B1R-mediated inhibition of SMC migration was not affected by pharmacological inhibition of the nitric oxide synthases or cyclooxygenases-1 or -2, but was correlated to an inhibition of PI-3K in both types of SMCs. The inhibition of SMC migration mediated by the kinin B1R is likely independent from NO or prostanoid release, applicable to several species, and correlated to receptor density and the inhibition of PI-3K.
28
Badmus, Olufunto O., and Lawrence A. Olatunji. "Glucocorticoid exposure causes disrupted glucoregulation, cardiac inflammation and elevated dipeptidyl peptidase-4 activity independent of glycogen synthase kinase-3 in female rats." Archives of Physiology and Biochemistry 125, no. 5 (June 18, 2018): 414–22. http://dx.doi.org/10.1080/13813455.2018.1479426.
Full text
29
Maruhashi, Tatsuya, and Yukihito Higashi. "Pathophysiological Association between Diabetes Mellitus and Endothelial Dysfunction." Antioxidants 10, no. 8 (August 18, 2021): 1306. http://dx.doi.org/10.3390/antiox10081306.
Full textAbstract:
Endothelial dysfunction plays a critical role in atherosclerosis progression, leading to cardiovascular complications. There are significant associations between diabetes mellitus, oxidative stress, and endothelial dysfunction. Oxidative stress is increased by chronic hyperglycemia and acute glucose fluctuations induced by postprandial hyperglycemia in patients with diabetes mellitus. In addition, selective insulin resistance in the phosphoinositide 3-kinase/Akt/endothelial nitric oxide (NO) synthase pathway in endothelial cells is involved in decreased NO production and increased endothelin-1 production from the endothelium, resulting in endothelial dysfunction. In a clinical setting, selecting an appropriate therapeutic intervention that improves or augments endothelial function is important for preventing diabetic vascular complications. Hypoglycemic drugs that reduce glucose fluctuations by decreasing the postprandial rise in blood glucose levels, such as glinides, α-glucosidase inhibitors and dipeptidyl peptidase 4 inhibitors, and hypoglycemic drugs that ameliorate insulin sensitivity, such as thiazolidinediones and metformin, are expected to improve or augment endothelial function in patients with diabetes. Glucagon-like peptide 1 receptor agonists, metformin, and sodium-glucose cotransporter 2 inhibitors may improve endothelial function through multiple mechanisms, some of which are independent of glucose control or insulin signaling. Oral administration of antioxidants is not recommended in patients with diabetes due to the lack of evidence for the efficacy against diabetic complications.
30
Choi, Bongkun, Eun-Young Kim, Ji-Eun Kim, Soyoon Oh, Si-On Park, Sang-Min Kim, Hyuksu Choi, Jae-Kwan Song, and Eun-Ju Chang. "Evogliptin Suppresses Calcific Aortic Valve Disease by Attenuating Inflammation, Fibrosis, and Calcification." Cells 10, no. 1 (January 1, 2021): 57. http://dx.doi.org/10.3390/cells10010057.
Full textAbstract:
Calcific aortic valve disease (CAVD) accompanies inflammatory cell infiltration, fibrosis, and ultimately calcification of the valve leaflets. We previously demonstrated that dipeptidyl peptidase-4 (DPP-4) is responsible for the progression of aortic valvular calcification in CAVD animal models. As evogliptin, one of the DPP-4 inhibitors displays high specific accumulation in cardiac tissue, we here evaluated its therapeutic potency for attenuating valvular calcification in CAVD animal models. Evogliptin administration markedly reduced calcific deposition accompanied by a reduction in proinflammatory cytokine expression in endothelial nitric oxide synthase-deficient mice in vivo, and significantly ameliorated the mineralization of the primary human valvular interstitial cells (VICs), with a reduction in the mRNA expression of bone-associated and fibrosis-related genes in vitro. In addition, evogliptin ameliorated the rate of change in the transaortic peak velocity and mean pressure gradients in our rabbit model as assessed by echocardiography. Importantly, evogliptin administration in a rabbit model was found to suppress the effects of a high-cholesterol diet and of vitamin D2-driven fibrosis in association with a reduction in macrophage infiltration and calcific deposition in aortic valves. These results have indicated that evogliptin prohibits inflammatory cytokine expression, fibrosis, and calcification in a CAVD animal model, suggesting its potential as a selective therapeutic agent for the inhibition of valvular calcification during CAVD progression.
31
Xu, Su, David E. Sleat, Michel Jadot, and Peter Lobel. "Glial fibrillary acidic protein is elevated in the lysosomal storage disease classical late-infantile neuronal ceroid lipofuscinosis, but is not a component of the storage material." Biochemical Journal 428, no. 3 (May 27, 2010): 355–62. http://dx.doi.org/10.1042/bj20100128.
Full textAbstract:
Classical late-infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal neurodegenerative disease of children caused by mutations in TPP1, the gene encoding the lysosomal protease tripeptidyl peptidase 1. LINCL is characterized by lysosomal accumulation of storage material of which only a single protein component, subunit c of mitochondrial ATP synthase, has been well established to date. Identification of other protein constituents of the storage material could provide useful insights into the pathophysiology of disease and the natural substrates for TPP1. We have therefore initiated a proteomic analysis of storage material in brain from a LINCL mouse model. One protein, GFAP (glial fibrillary acidic protein), was found to be elevated in the LINCL mice compared with normal controls in both isolated storage bodies and a lysosome-enriched subcellular fraction that contains storage material. To determine whether GFAP accumulates within the lysosome in LINCL, we examined its intracellular distribution using subcellular fractionation and morphological methods. These experiments demonstrate that GFAP is not a component of the storage material in LINCL, suggesting that reports of GFAP storage in other NCLs may need to be re-examined. A number of other proteins were elevated in the storage material and/or lysosome-enriched fraction from the LINCL mice, but it remains unclear whether these proteins are true constituents of the storage material or, like GFAP, whether they associate with this material upon purification.
32
Watson, N., J. Maclagan, and P. J. Barnes. "Vagal control of guinea pig tracheal smooth muscle: lack of involvement of VIP or nitric oxide." Journal of Applied Physiology 74, no. 4 (April 1, 1993): 1964–71. http://dx.doi.org/10.1152/jappl.1993.74.4.1964.
Full textAbstract:
Contractions of the vagally innervated guinea pig tracheal tube preparation were induced by 1) stimulation of the preganglionic cervical vagus nerve (PGS), 2) activation of postganglionic intrinsic nerves by use of transmural stimulation (TMS) in the presence of hexamethonium, and 3) exogenous application of spasmogens, acetylcholine (ACh) and histamine. Contractions were recorded as increases in intraluminal pressure of the sealed Krebs-filled tube preparation. In the absence of basal tone, contractions induced by both PGS and TMS were monophasic. When the tone was raised with histamine (1 microM), the rapid contractions were followed by a slow relaxation during TMS but not during PGS. There was no evidence for any involvement of the putative inhibitory nonadrenergic noncholinergic neurotransmitters vasoactive intestinal peptide (VIP) and nitric oxide (NO) in the response to PGS, because neither the peptidase alpha-chymotrypsin nor the NO synthase inhibitor NG-nitro-L-arginine affected PGS-induced contractions. However, both alpha-chymotrypsin and NG-nitro-L-arginine facilitated contractions induced by TMS, suggesting that both VIP and NO are involved in responses to TMS. The facilitation of TMS-induced contractions by NG-nitro-L-arginine was unaffected by epithelium removal. Therefore, neither VIP nor NO appears to be released during PGS, but both are released during TMS, and the generation of NO during TMS is independent of the epithelium.
33
Srivani, Gowru, Ramyakrishna Sharvirala, Prabhakar Reddy Veerareddy, Dilipkumar Pal, and Gangarapu Kiran. "GSK-3 Inhibitors as New Leads to Treat Type-II Diabetes." Current Drug Targets 22, no. 13 (September 7, 2021): 1555–67. http://dx.doi.org/10.2174/1389450122666210120144428.
Full textAbstract:
In India as well as globally, diabetes is in a state of high risk and next to cardiovascular disease. As per the WHO, the risk of diabetes is expected to rise about 511 million by 2030. In quest of novel targets for type-2 diabetes, many targets were elucidated, such as Glycogen Synthase Kinase-3 (GSK-3), Dipeptidyl Peptidase (DPP-IV), PPAR-γ, α-Glucosidase, α-Amylase, GLP-1, and SGLT. Among the targets, GSK-3 was reported to be an effective target for the treatment of diabetes. In the metabolism of glycogen, GSK is a regulatory enzyme for the biosynthesis of glycogen (glycogenesis). It catalyzes the synthesis of a linear unbranched molecule with 1,4-α-glycosidic linkages. GSK-3 family has two isoenzymes, namely α and β, which differ in their Nand C- terminal sequences and are semi-conservative multifunctional serine/threonine kinase enzymes. In this chapter, we discuss an overview of general diabetic mechanisms and how GSK-3 modulation may influence these processes. Mutation in the GSK-3 complex causes diabetes. Synthetic and natural scaffolds modulate GSK-3 against diabetes and leading to its optimization for the development of GSK-3 inhibitors. This review mainly focuses on the development of GSK-3 inhibitors and highlights current and potential future therapeutic approaches that support the notion of targeting glucose metabolism with novel antidiabetic agents.
34
Batchu, Sri Nagarjun, Veera Ganesh Yerra, Youan Liu, Suzanne L. Advani, Thomas Klein, and Andrew Advani. "The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Directly Enhances the Contractile Recovery of Mouse Hearts at a Concentration Equivalent to that Achieved with Standard Dosing in Humans." International Journal of Molecular Sciences 21, no. 16 (August 11, 2020): 5756. http://dx.doi.org/10.3390/ijms21165756.
Full textAbstract:
Despite a similar mechanism of action underlying their glucose-lowering effects in type 2 diabetes, dipeptidyl peptidase-4 (DPP-4) inhibitors have diverse molecular structures, raising the prospect of agent-specific, glucose-independent actions. To explore the issue of possible DPP-4 inhibitor cardiac heterogeneity, we perfused different DPP-4 inhibitors to beating mouse hearts ex vivo, at concentrations equivalent to peak plasma levels achieved in humans with standard dosing. We studied male and female mice, young non-diabetic mice, and aged diabetic high fat diet-fed mice and observed that linagliptin enhanced recovery after ischemia-reperfusion, whereas sitagliptin, alogliptin, and saxagliptin did not. DPP-4 transcripts were not detected in adult mouse cardiomyocytes by RNA sequencing and the addition of linagliptin caused ≤0.2% of cardiomyocyte genes to be differentially expressed. In contrast, incubation of C166 endothelial cells with linagliptin induced cell signaling characterized by phosphorylation of Akt and endothelial nitric oxide synthase, whereas the nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine increased serine 16 phosphorylation of the calcium regulatory protein, phospholamban in cardiomyocytes. Furthermore, linagliptin increased cardiomyocyte cGMP when cells were co-cultured with C166 endothelial cells, but not when cardiomyocytes were cultured alone. Thus, at a concentration comparable to that achieved in patients, linagliptin has direct effects on mouse hearts. The effects of linagliptin on cardiomyocytes are likely to be either off-target or indirect, mediated through NO generation by the adjacent cardiac endothelium.
35
Liu, Feng, Guo-Dong Huang, Jia-Zhen Tang, and Yu-Huan Peng. "DPP4 inhibitors promote biological functions of human endothelial progenitor cells by targeting the SDF-1/CXCR4 signaling pathway." Archives of Biological Sciences 68, no. 1 (2016): 207–16. http://dx.doi.org/10.2298/abs150506143l.
Full textAbstract:
Dipeptidyl peptidase 4 (DPP4) inhibitors(oral hypoglycemic agents)have beneficial effects during the early stages of diabetes. In this study, we evaluated the role of DPP4inhibitorsonthe biological functions of cultured human endothelial progenitor cells (EPCs). After treating EPCs with the DPP4 inhibitors sitagliptin and vildagliptin, we examined the mRNA expression of DPP4, vascular endothelial growth factor (VEGF),VEGF receptor 2 (VEGFR-2),endothelial nitric oxide synthase (eNOS), caspase-3,stromal cell-derived factor-1 (SDF-1), chemokine (C-X-C motif) receptor 4 (CXCR4) were measured by RT-PCR. The protein expression of SDF-1 and CXCR4 was determined by Western blot; cell proliferation was tested by the MTT method, and DPP4 activity was determined by a DPP4 assay. Our results revealed that DPP4 expression and activity were inhibited following the treatment with various doses of DPP4 inhibitors. Cell proliferation and the expression of VEGF, VEGFR-2andeNOS were up regulated, while cell apoptosis was inhibited by DPP4 inhibitors in a dose-dependent manner. DPP4 inhibitors activated the SDF-1/CXCR4 signaling pathway, shown by the elevated expression of SDF-1/CXCR4. This further proved that after the SDF-1/CXCR4 signaling pathway was blocked by its inhibitor ADM3100, the effects of DPP4 inhibitors on the proliferation and apoptosis, and the expression of VEGF, VEGFR-2and eNOS of EPCs were significantly reduced. These findings suggest that DPP4 inhibitors promote the biological functions of human EPCs by up regulating the SDF-1/CXCR4 signaling pathway.
36
Shin, Kwang-Soo, Nak-Jung Kwon, Young Hwan Kim, Hee-Soo Park, Gi-Seok Kwon, and Jae-Hyuk Yu. "Differential Roles of the ChiB Chitinase in Autolysis and Cell Death of Aspergillus nidulans." Eukaryotic Cell 8, no. 5 (March 13, 2009): 738–46. http://dx.doi.org/10.1128/ec.00368-08.
Full textAbstract:
ABSTRACT Autolysis is a natural event that occurs in most filamentous fungi. Such self-degradation of fungal cells becomes a predominant phenomenon in the absence of the regulator of G protein signaling FlbA in Aspergillus nidulans. Among a number of potential hydrolytic enzymes in the A. nidulans genome, the secreted endochitinase ChiB was shown to play a major role in autolysis. In this report, we investigate the roles of ChiB in fungal autolysis and cell death processes through genetic, biochemical, and cellular analyses using a set of critical mutants. Determination of mycelial mass revealed that, while the flbA deletion (ΔflbA) mutant autolyzed completely after a 3-day incubation, the ΔflbA ΔchiB double mutant escaped from hyphal disintegration. These results indicate that ChiB is necessary for the ΔflbA-induced autolysis. However, importantly, both ΔflbA and ΔflbA ΔchiB strains displayed dramatically reduced cell viability compared to the wild type. These imply that ChiB is dispensable for cell death and that autolysis and cell death are separate processes. Liquid chromatography-tandem mass spectrometry analyses of the proteins that accumulate at high levels in the ΔflbA and ΔflbA ΔchiB mutants identify chitinase (ChiB), dipeptidyl peptidase V (DppV), O-glycosyl compound hydrolase, β-N-acetylhexosaminidase (NagA), and myo-inositol-1-phosphate synthase (InoB). Functional characterization of these four genes reveals that the deletion of nagA results in reduced cell death. A working model bridging G protein signaling and players in autolysis/cell death is proposed.
37
Ihara, Madoka, Hiroshi Asanuma, Satoru Yamazaki, Hisakazu Kato, Yoshihiro Asano, Yoshihiro Shinozaki, Hidezo Mori, et al. "An interaction between glucagon-like peptide-1 and adenosine contributes to cardioprotection of a dipeptidyl peptidase 4 inhibitor from myocardial ischemia-reperfusion injury." American Journal of Physiology-Heart and Circulatory Physiology 308, no. 10 (May 15, 2015): H1287—H1297. http://dx.doi.org/10.1152/ajpheart.00835.2014.
Full textAbstract:
Dipeptidyl peptidase 4 (DPP4) inhibitors suppress the metabolism of the potent antihyperglycemic hormone glucagon-like peptide-1 (GLP-1). DPP4 was recently shown to provide cardioprotection through a reduction of infarct size, but the mechanism for this remains elusive. Known interactions between DPP4 and adenosine deaminase (ADA) suggest an involvement of adenosine signaling in DPP4 inhibitor-mediated cardioprotection. We tested whether the protective mechanism of the DPP4 inhibitor alogliptin against myocardial ischemia-reperfusion injury involves GLP-1- and/or adenosine-dependent signaling in canine hearts. In anesthetized dogs, the coronary artery was occluded for 90 min followed by reperfusion for 6 h. A 4-day pretreatment with alogliptin reduced the infarct size from 43.1 ± 2.5% to 17.1 ± 5.0% without affecting collateral flow and hemodynamic parameters, indicating a potent antinecrotic effect. Alogliptin also suppressed apoptosis as demonstrated by the following analysis: 1) reduction in the Bax-to-Bcl2 ratio; 2) cytochrome c release, 3) an increase in Bad phosphorylation in the cytosolic fraction; and 4) terminal deoxynucleotidyl transferase dUTP nick end labeling assay. This DPP4 inhibitor did not affect blood ADA activity or adenosine concentrations. In contrast, the nonselective adenosine receptor blocker 8-( p-sulfophenyl)theophylline (8SPT) completely blunted the effect of alogliptin. Alogliptin did not affect Erk1/2 phosphorylation, but it did stimulate phosphorylation of Akt, glycogen synthase kinase-3β, and cAMP response element-binding protein (CREB). Only 8SPT prevented alogliptin-induced CREB phosphorylation. In conclusion, the DPP4 inhibitor alogliptin suppresses ischemia-reperfusion injury via adenosine receptor- and CREB-dependent signaling pathways.
38
Cheng, Fong-Chi, Jin-Jye Feng, Kuo-Hsin Chen, Hideyo Imanishi, Masaki Fujishima, Hideo Takekoshi, Yo Naoki, and Minoru Shimoda. "Chlorella powder inhibits the activities of peptidase cathepsin S, PLA2, cyclooxygenase-2, thromboxane synthase, tyrosine phosphatases, tumor necrosis factor-α converting enzyme, calpain and kinases." International Journal of Food Sciences and Nutrition 60, sup1 (January 2009): 89–98. http://dx.doi.org/10.1080/09637480802225512.
Full text
39
Shin, Jung-Ho, Alan G. Sulpizio, Aaron Kelley, Laura Alvarez, Shannon G. Murphy, Lixin Fan, Felipe Cava, Yuxin Mao, Mark A. Saper, and Tobias Dörr. "Structural basis of peptidoglycan endopeptidase regulation." Proceedings of the National Academy of Sciences 117, no. 21 (May 11, 2020): 11692–702. http://dx.doi.org/10.1073/pnas.2001661117.
Full textAbstract:
Most bacteria surround themselves with a cell wall, a strong meshwork consisting primarily of the polymerized aminosugar peptidoglycan (PG). PG is essential for structural maintenance of bacterial cells, and thus for viability. PG is also constantly synthesized and turned over; the latter process is mediated by PG cleavage enzymes, for example, the endopeptidases (EPs). EPs themselves are essential for growth but also promote lethal cell wall degradation after exposure to antibiotics that inhibit PG synthases (e.g., β-lactams). Thus, EPs are attractive targets for novel antibiotics and their adjuvants. However, we have a poor understanding of how these enzymes are regulated in vivo, depriving us of novel pathways for the development of such antibiotics. Here, we have solved crystal structures of the LysM/M23 family peptidase ShyA, the primary EP of the cholera pathogenVibrio cholerae. Our data suggest that ShyA assumes two drastically different conformations: a more open form that allows for substrate binding and a closed form, which we predicted to be catalytically inactive. Mutations expected to promote the open conformation caused enhanced activity in vitro and in vivo, and these results were recapitulated in EPs from the divergent pathogensNeisseria gonorrheaeandEscherichia coli. Our results suggest that LysM/M23 EPs are regulated via release of the inhibitory Domain 1 from the M23 active site, likely through conformational rearrangement in vivo.
40
Shawky, Lamiaa M., Ahmed A. Morsi, Eman El Bana, and Safaa Masoud Hanafy. "The Biological Impacts of Sitagliptin on the Pancreas of a Rat Model of Type 2 Diabetes Mellitus: Drug Interactions with Metformin." Biology 9, no. 1 (December 25, 2019): 6. http://dx.doi.org/10.3390/biology9010006.
Full textAbstract:
Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is a beneficial class of antidiabetic drugs. However, a major debate about the risk of developing pancreatitis is still existing. The aim of the work was to study the histological and immunohistochemical effects of sitagliptin on both endocrine and exocrine pancreases in a rat model of type 2 diabetes mellitus and to correlate these effects with the biochemical findings. Moreover, a possible synergistic effect of sitagliptin, in combination with metformin, was also evaluated. Fifty adult male rats were used and assigned into five equal groups. Group 1 served as control. Group 2 comprised of untreated diabetic rats. Group 3 diabetic rats received sitagliptin. Group 4 diabetic rats received metformin. Group 5 diabetic rats received both combined. Treatments were given for 4 weeks after the induction of diabetes. Blood samples were collected for biochemical assay before the sacrification of rats. Pancreases were removed, weighed, and were processed for histological and immunohistochemical examination. In the untreated diabetic group, the islets appeared shrunken with disturbed architecture and abnormal immunohistochemical reactions for insulin, caspase-3, and inducible nitric oxide synthase (iNOS). The biochemical findings were also disturbed. Morphometrically, there was a significant decrease in the islet size and islet number. Treatment with sitagliptin, metformin, and their combination showed an improvement, with the best response in the combined approach. No evidence of pancreatic injury was identified in the sitagliptin-treated groups. In conclusion, sitagliptin had a cytoprotective effect on beta-cell damage. Furthermore, the data didn’t indicate any detrimental effects of sitagliptin on the exocrine pancreas.
41
Pickup, Katherine E., Felicitas Pardow, José Carbonell-Caballero, Antonios Lioutas, José Luis Villanueva-Cañas, Roni H. G. Wright, and Miguel Beato. "Expression of Oncogenic Drivers in 3D Cell Culture Depends on Nuclear ATP Synthesis by NUDT5." Cancers 11, no. 9 (September 10, 2019): 1337. http://dx.doi.org/10.3390/cancers11091337.
Full textAbstract:
The growth of cancer cells as oncospheres in three-dimensional (3D) culture provides a robust cell model for understanding cancer progression, as well as for early drug discovery and validation. We have previously described a novel pathway in breast cancer cells, whereby ADP (Adenosine diphosphate)-ribose derived from hydrolysis of poly (ADP-Ribose) and pyrophosphate (PPi) are converted to ATP, catalysed by the enzyme NUDT5 (nucleotide diphosphate hydrolase type 5). Overexpression of the NUDT5 gene in breast and other cancer types is associated with poor prognosis, increased risk of recurrence and metastasis. In order to understand the role of NUDT5 in cancer cell growth, we performed phenotypic and global expression analysis in breast cancer cells grown as oncospheres. Comparison of two-dimensional (2D) versus 3D cancer cell cultures from different tissues of origin suggest that NUDT5 increases the aggressiveness of the disease via the modulation of several key driver genes, including ubiquitin specific peptidase 22 (USP22), RAB35B, focadhesin (FOCAD) and prostagladin E synthase (PTGES). NUDT5 functions as a master regulator of key oncogenic pathways and of genes involved in cell adhesion, cancer stem cell (CSC) maintenance and epithelial to mesenchyme transition (EMT). Inhibiting the enzymatic activities of NUDT5 prevents oncosphere formation and precludes the activation of cancer driver genes. These findings highlight NUDT5 as an upstream regulator of tumour drivers and may provide a biomarker for cancer stratification, as well as a novel target for drug discovery for combinatorial drug regimens for the treatment of aggressive cancer types and metastasis.
42
PAVLOV, Pavel F., Per MOBERG, Xiao-Ping ZHANG, and Elzbieta GLASER. "Chemical cleavage of the overexpressed mitochondrial F1β precursor with CNBr: a new strategy to construct an import-competent preprotein." Biochemical Journal 341, no. 1 (June 24, 1999): 95–103. http://dx.doi.org/10.1042/bj3410095.
Full textAbstract:
We have isolated a soluble import-competent 15 kDa N-terminal fragment of the overexpressed Nicotiana plumbaginifolia F1β precursor of the ATP synthase (N15pF1β). The isolation was achieved after chemical cleavage, with CNBr, of the insoluble precursor collected in inclusion bodies, followed by purification of the fragment using ion-exchange chromatography. The purity of the final product was estimated to be more than 99%. N15pF1β contained a presequence of 54 amino acid residues (except for the N-terminal methionine residue) and 82 N-terminal residues of the mature protein. N15pF1β was shown to be imported into isolated potato tuber mitochondria and to be processed by the isolated mitochondrial processing peptidase (MPP) integrated into the cytochrome bc1 complex of the respiratory chain. Addition of N15pF1β at micromolar concentrations resulted in the inhibition of import of F1β precursor and alternative oxidase precursor, synthesized in vitro, into isolated mitochondria as well as the processing of these precursors catalysed by the isolated MPP-bc1 complex. N15pF1β conjugated via a biotin link to avidin blocked import sites even after the reisolation of mitochondria and inhibited the import of the mitochondrial precursors, indicating that it can be used as a substrate for the generation of a stable translocation intermediate. Our results present a novel procedure for the production of an N-terminal fragment of the F1β precursor that contains all information necessary for mitochondrial targeting and processing and that can be used for structural and functional studies of the mitochondrial protein import system. This procedure has a general value because it can be used for the production of chemical quantities of any mitochondrial import substrate and presequence peptide.
43
Rademaker, Jan L. W., Hélène Herbet, Marjo J. C. Starrenburg, Sabri M. Naser, Dirk Gevers, William J. Kelly, Jeroen Hugenholtz, Jean Swings, and Johan E. T. van Hylckama Vlieg. "Diversity Analysis of Dairy and Nondairy Lactococcus lactis Isolates, Using a Novel Multilocus Sequence Analysis Scheme and (GTG)5-PCR Fingerprinting." Applied and Environmental Microbiology 73, no. 22 (September 21, 2007): 7128–37. http://dx.doi.org/10.1128/aem.01017-07.
Full textAbstract:
ABSTRACT The diversity of a collection of 102 lactococcus isolates including 91 Lactococcus lactis isolates of dairy and nondairy origin was explored using partial small subunit rRNA gene sequence analysis and limited phenotypic analyses. A subset of 89 strains of L. lactis subsp. cremoris and L. lactis subsp. lactis isolates was further analyzed by (GTG)5-PCR fingerprinting and a novel multilocus sequence analysis (MLSA) scheme. Two major genomic lineages within L. lactis were found. The L. lactis subsp. cremoris type-strain-like genotype lineage included both L. lactis subsp. cremoris and L. lactis subsp. lactis isolates. The other major lineage, with a L. lactis subsp. lactis type-strain-like genotype, comprised L. lactis subsp. lactis isolates only. A novel third genomic lineage represented two L. lactis subsp. lactis isolates of nondairy origin. The genomic lineages deviate from the subspecific classification of L. lactis that is based on a few phenotypic traits only. MLSA of six partial genes (atpA, encoding ATP synthase alpha subunit; pheS, encoding phenylalanine tRNA synthetase; rpoA, encoding RNA polymerase alpha chain; bcaT, encoding branched chain amino acid aminotransferase; pepN, encoding aminopeptidase N; and pepX, encoding X-prolyl dipeptidyl peptidase) revealed 363 polymorphic sites (total length, 1,970 bases) among 89 L. lactis subsp. cremoris and L. lactis subsp. lactis isolates with unique sequence types for most isolates. This allowed high-resolution cluster analysis in which dairy isolates form subclusters of limited diversity within the genomic lineages. The pheS DNA sequence analysis yielded two genetic groups dissimilar to the other genotyping analysis-based lineages, indicating a disparate acquisition route for this gene.
44
Lo, Sorena, Lee Ann MacMillan-Crow, and Nirmala Parajuli. "Renal cold storage followed by transplantation impairs proteasome function and mitochondrial protein homeostasis." American Journal of Physiology-Renal Physiology 316, no. 1 (January 1, 2019): F42—F53. http://dx.doi.org/10.1152/ajprenal.00316.2018.
Full textAbstract:
Identifying pathways related to renal cold storage (CS) that lead to renal damage after transplantation (Tx) will help us design novel pathway-specific therapies to improve graft outcome. Our recent report showed that mitochondrial function was compromised after CS alone, and this was exacerbated when CS was combined with Tx (CS/Tx). The goal of this study was to determine whether the proteasome exacerbates mitochondrial dysfunction after CS/Tx. We exposed the kidneys of male Lewis rats (in vivo) and rat renal proximal tubular (NRK) cells (in vitro) to CS/Tx or rewarming (CS/RW), respectively. To compare CS-induced effects, in vivo kidney Tx without CS exposure (autotransplantation; ATx) was also used. Our study provides the first evidence that the chymotrypsin-like (ChT-L) peptidase activity of the proteasome declined only after CS/Tx or CS/RW, but not after CS or ATx. Interestingly, key mitochondrial proteins involved with respiration [succinate dehydrogenase complex, subunit A (SDHA), a complex II subunit, and ATP5B, an ATP synthase/complex V subunit] were detected in the detergent-insoluble fraction after CS/Tx or CS/RW, with compromised complex V activity. Pharmacological inhibition of ChT-L activity in NRK cells decreased the activity of mitochondrial complexes I, II, and V and also increased the levels of SDHA and ATP5B in the insoluble fraction. On the other hand, inhibiting mitochondrial respiration in NRK cells with antimycin A compromised ChT-L function and increased the amounts of SDHA and ATP5B in the insoluble fraction. Our results suggest that mitochondrial respiratory dysfunction during CS precedes compromised ChT-L function after CS/Tx and proteasome dysfunction further alters mitochondrial protein homeostasis and decreases respiration in the kidneys after CS/Tx. Therefore, therapeutics that preserve mitochondrial and proteasome function during CS may provide beneficial outcomes following transplantation.
45
Ban, Kiwon, Kyoung-Han Kim, Chan-Kyung Cho, Meghan Sauvé, Eleftherios P. Diamandis, Peter H. Backx, Daniel J. Drucker, and Mansoor Husain. "Glucagon-Like Peptide (GLP)-1(9-36)Amide-Mediated Cytoprotection Is Blocked by Exendin(9-39) Yet Does Not Require the Known GLP-1 Receptor." Endocrinology 151, no. 4 (February 19, 2010): 1520–31. http://dx.doi.org/10.1210/en.2009-1197.
Full textAbstract:
The widely expressed dipeptidyl peptidase-4 enzyme rapidly cleaves the gut hormone glucagon-like peptide-1 [GLP-1(7-36)amide] at the N terminus to generate GLP-1(9-36)amide. Both intact GLP-1(7-36)amide and GLP-1(9-36)amide exert cardioprotective actions in rodent hearts; however, the mechanisms underlying the actions of GLP-1(9-36)amide remain poorly understood. We used mass spectrometry of coronary effluents to demonstrate that isolated mouse hearts rapidly convert infused GLP-1(7-36)amide to GLP-1(9-36)amide. After ischemia-reperfusion (I/R) injury of isolated mouse hearts, administration of GLP-1(9-36)amide or exendin-4 improved functional recovery and reduced infarct size. The direct actions of these peptides were studied in cultured neonatal mouse cardiomyocytes. Both GLP-1(9-36)amide and exendin-4 increased levels of cAMP and phosphorylation of ERK1/2 and the phosphoinositide 3-kinase target protein kinase B/Akt. In I/R injury models in vitro, both peptides improved mouse cardiomyocyte viability and reduced lactate dehydrogenase release and caspase-3 activation. These effects were attenuated by inhibitors of ERK1/2 and phosphoinositide 3-kinase. Unexpectedly, the cardioprotective actions of GLP-1(9-36)amide were blocked by exendin(9-39) yet preserved in Glp1r−/− cardiomyocytes. Furthermore, GLP-1(9-36)amide, but not exendin-4, improved the survival of human aortic endothelial cells undergoing I/R injury, actions sensitive to the nitric oxide synthase inhibitor, N(G)-nitro-l-arginine methyl ester (L-NAME). In summary, our findings demonstrate separate actions for GLP-1(9-36)amide vs. the GLP-1R agonist exendin-4 and reveal the existence of a GLP-1(9-36)amide-responsive, exendin(9-39)-sensitive, cardioprotective signaling pathway distinct from that associated with the classical GLP-1 receptor.
46
Chen, Ya-Hui, Hui-Ling Chen, Cheng-Maw Ho, Hung-Yen Chen, Shu-Li Ho, Rey-Heng Hu, Po-Huang Lee, and Mei-Hwei Chang. "Preclinical Application of Reduced Manipulated Processing Strategy to Collect Transplantable Hepatocytes: A Pilot and Feasibility Study." Journal of Personalized Medicine 11, no. 5 (April 21, 2021): 326. http://dx.doi.org/10.3390/jpm11050326.
Full textAbstract:
Background: The complex isolation and purification process of hepatocytes for transplantation is labor intensive and with great contamination risk. Here, as a pilot and feasibility study, we examined in vitro and in vivo hepatocyte isolation feasibility and cell function of Cell Saver® Elite®, an intraoperative blood-cell-recovery system. Methods: Rat and pig liver cells were collected using this system and then cultured in vitro, and their hepatocyte-specific enzymes were characterized. We then transplanted the hepatocytes in an established acute liver–injured (retrorsine+D-galactosamine-treated) rat model for engraftment. Recipient rats were sacrificed 1, 2, and 4 weeks after transplantation, followed by donor-cell identification and histological, serologic, and immunohistopathological examination. To demonstrate this Cell Saver® strategy is workable in the first place, traditional (classical) strategy, in our study, behaved as certainty during the cell manufacturing process for monitoring quality assurance throughout the course, from the start of cell isolation to post-transplantation. Results: We noted that in situ collagenase perfusion was followed by filtration, centrifugation, and collection in the Cell Saver® until the process ended. Most (>85%) isolated cells were hepatocytes (>80% viability) freshly demonstrating hepatocyte nuclear factor 4α and carbamoyl-phosphate synthase 1 (a key enzyme in the urea cycle), and proliferating through intercellular contact in culture, with expression of albumin and CYP3A4. After hepatocyte transplantation in dipeptidyl peptidase IV (−/−) rat liver, wild-type donor hepatocytes engrafted and repopulated progressively in 4 weeks with liver functional improvement. Proliferating donor hepatocyte–native biliary ductular cell interaction was identified. Post-transplantation global liver functional recovery after Cell Saver and traditional methods was comparable. Conclusions: Cell Saver® requires reduced manual manipulation for isolating transplantable hepatocytes.
47
Al-awar, Amin, Nikoletta Almási, Renáta Szabó, Istvan Takacs, Zsolt Murlasits, Gergő Szűcs, Szilvia Török, Anikó Pósa, Csaba Varga, and Krisztina Kupai. "Novel Potentials of the DPP-4 Inhibitor Sitagliptin against Ischemia-Reperfusion (I/R) Injury in Rat Ex-Vivo Heart Model." International Journal of Molecular Sciences 19, no. 10 (October 18, 2018): 3226. http://dx.doi.org/10.3390/ijms19103226.
Full textAbstract:
Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral anti-diabetic drugs, implicated in pleiotropic secondary cardioprotective effects. The aim of the study was to unveil the unknown and possible cardioprotective targets that can be exerted by sitagliptin (Sitg) against ischemia-reperfusion (I/R) injury. Male wistar rats received 2 weeks’ Sitg oral treatment of different doses (25, 50, 100, and 150 mg/kg/day), or saline as a Control. Hearts were then isolated and subjected to two different I/R injury protocols: 10 min perfusion, 45 min regional ischemia, and 120 min reperfusion for infarct size (IS) measurement, or: 10 min perfusion, 45 min regional ischemia and 10 min reperfusion for biochemical analysis: nitric oxide synthases (NOSs) and DPP-4 activity, glucagon-like peptide-1 (GLP-1), Calcium, transient receptor potential vanilloid (TRPV)-1 and calcitonin gene-related peptide (CGRP) levels, transient receptor potential canonical (TRPC)-1 and e-NOS protein expression. NOS inhibitor (l-NAME) and TRPV-1 inhibitor (Capsazepine) were utilized to confirm the implication of both signaling mechanisms in DPP-4 inhibition-induced at the level of IS. Findings show that Sitg (50 mg) resulted in significant decrease in IS and DPP-4 activity, and significant increase in GLP-1, NOS activity, e-NOS expression, TRPV-1 level and TRPC-1 expression, compared to controls. Results of CGRP are in line with TRPV-1, as a downstream regulatory effect. NOS system and transient receptor potential (TRP) channels can contribute to DPP-4 inhibition-mediated cardioprotection against I/R injury using Sitagliptin.
48
Király, Kornél, Balázs Szalay, Judit Szalai, István Barna, Klára Gyires, Mathieu Verbeken, and András Z. Rónai. "Intrathecally injected Ile-Pro-Ile, an inhibitor of membrane ectoenzyme dipeptidyl peptidase IV, is antihyperalgesic in rats by switching the enzyme from hydrolase to synthase functional mode to generate endomorphin 2." European Journal of Pharmacology 620, no. 1-3 (October 2009): 21–26. http://dx.doi.org/10.1016/j.ejphar.2009.08.018.
Full text
49
Ye, Yumei, Kyle T. Keyes, Congfang Zhang, Jose R. Perez-Polo, Yu Lin, and Yochai Birnbaum. "The myocardial infarct size-limiting effect of sitagliptin is PKA-dependent, whereas the protective effect of pioglitazone is partially dependent on PKA." American Journal of Physiology-Heart and Circulatory Physiology 298, no. 5 (May 2010): H1454—H1465. http://dx.doi.org/10.1152/ajpheart.00867.2009.
Full textAbstract:
Pioglitazone (PIO) and glucagon-like peptide-1 (GLP-1) analogs limit infarct size (IS) in experimental models. The effects of the dipeptidyl-peptidase-IV inhibitors, which increase the endogenous levels of GLP-1, on myocardial protection, are unknown. We studied whether sitagliptin (SIT) and PIO have additive effects on IS limitation in the mouse. Mice received 3-day or 14-day oral SIT (300 mg·kg−1·day−1), PIO (5 mg·kg−1·day−1), SIT + PIO, or vehicle. In addition, mice received intravenous H-89 [20 mg/kg, a protein kinase A (PKA) inhibitor] or vehicle 1 h before ischemia. Rats underwent 30 min myocardial ischemia and 4 h reperfusion. SIT, PIO, and SIT + PIO for 3 days significantly reduced IS (24.3 ± 2.7, 23.0 ± 0.8, and 14.7 ± 0.9%) compared with controls (46.2 ± 2.8%). H-89 completely blocked the effect of SIT and partially blocked the PIO effect. SIT, but not PIO, increased cAMP levels. PKA activity was increased by PIO and to a greater extent by SIT. PIO, but not SIT, increased cytosolic phospholipase A2 and cyclooxygenase-2 activity. Accordingly, 6-keto-PGF1α and 15-deoxy-PGJ2 increased by PIO but not SIT. In contrast, SIT, and to a lesser extent PIO, increased 15-epi-lipoxin A4 levels. H-89 completely blocked the effect of SIT and PIO on 15-epi-lipoxin A4 levels. PIO, and to a greater extent SIT, increased endothelial nitric oxide synthase and cAMP response element-binding protein phosphorylation, an effect that was blocked by H-89. With a 14-day pretreatment experiment, IS was 46.4 ± 1.0% in the control group, 16.9 ± 0.6% in SIT ( P < 0.001), 19.1 ± 1.1% in PIO ( P = 0.014), and 12.9 ± 0.7% in SIT + PIO ( P < 0.001). We found that SIT and PIO limit IS using different pathways. The protective effect of SIT is via cAMP-dependent PKA activation, whereas PIO mediates its effects via both PKA-dependent and -independent pathways.
50
Stachorski, Lena, Veera Raghavan Thangapandi, Dirk Reinhardt, and Jan-Henning Klusmann. "Characterization Of Oncogenes On Chromosome 21 Identified By shRNA-Based Viability Screening." Blood 122, no. 21 (November 15, 2013): 1201. http://dx.doi.org/10.1182/blood.v122.21.1201.1201.
Full textAbstract:
Abstract Children with trisomy 21 (Down syndrome, DS) are predisposed to develop acute megakaryoblastic leukemia (DS-AMKL) as well as the antecedent transient leukemia (DS-TL). Mutations in the hematopoietic transcription factor GATA1 have been found in nearly all children with DS-AMKL and DS-TL, but not in other malignancies. Recent whole genome sequencing efforts strongly supported the hypothesis that the triad of fetal origin, trisomy 21 and GATA1s-mutation are sufficient to cause DS-TL. Thus, the presence of an extra copy of hsa21 perturbs fetal hematopoiesis to provide a GATA1s sensitive background during leukemogenesis. To decipher the deregulated oncogenic gene network on hsa21, we conducted a shRNA-based viability screening. GATA1s-mutated DS-AMKL cell line CMK as well as non-DS-AML cell lines (K562, M-07) as control were lentivirally transduced and the effect of the knock-down was evaluated by cell viability and proliferation assays. Upon knock-down we found 42 genes conferring a profound selective growth disadvantage in DS-AMKL cell lines. Interestingly, 31 out of those candidate genes are located in one particular chromosomal region (21q22.1-21q22.3) and in addition 11 (out of 14 tested) are overexpressed in DS-AMKL compared to non-DS-AMKL. In a secondary functional validation screening the effects of the knock-down on the cell lines were analyzed by competition assays, apoptosis assays and cell viability assays as well as colony forming assays. Furthermore, differentiation and morphology were characterized using immunophenotyping and cytospins, respectively. We could demonstrate that the potential oncogenes participate in different cellular processes affecting proliferation, cell viability, apoptosis or differentiation. To further delineate the impact of 11 selected candidates on normal hematopoiesis, we characterized their effects in gain- and loss-of-function studies (confirmed by qRT-PCR) using CD34+ hematopoietic stem and progenitor cells (HSPCs). Four of those genes (USP25 [ubiquitin specific peptidase 25], BACH1 [BTB and CNC homology 1, basic leucine zipper transcription factor 1], U2AF1 [U2 small nuclear RNA auxiliary factor 1] and C21orf33) inhibited megakaryocytic and erythroid in vitro differentiation upon knockdown. The fraction of cells expressing early and late megakaryocytic markers CD41 and CD42b or early erythroid marker CD36 was reduced by 2-20-fold (P<0.001). Inversely, the knock-down of those four genes and two other genes (ATP5O [ATP synthase, H+ transporting, mitochondrial F1 complex, O subunit] and C21orf45) enhanced the myeloid differentiation propensity of CD34+-HSPCs (2.1-13.4-fold increase of CD14+-monocytic cells, P<0.001). The opposite effect was observed in gain-of-function studies. Ectopic expression of six genes (hU2AF1, mC21orf33, hIFNGR2 [interferon gamma receptor 2], hWDR4 [WD repeat domain 4] or mGABPA [GA binding protein transcription factor, alpha subunit 60kDa]) resulted in a radical switch in lineage commitment with a drastic change from erythroid to megakaryocytic differentiation (CD41+ 1.7-2.4-fold increase, P<0.001, CD235a+ [late erythroid marker] 3-300-fold reduction, P<0.001). Thus, we found a remarkable number of genes regulating erythroid and megakaryocytic differentiation as well as proliferation in normal hematopoiesis. Given the genetic background during trisomy 21-mediated leukemogenesis, we propose a complex interactive network located in one particular region on hsa21. Deregulation of this network might result in synergistic effects on hematopoietic differentiation, which promotes transformation of GATA1s-mutated fetal hematopoietic progenitor cells. Disclosures: No relevant conflicts of interest to declare.