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1
Ishikawa, Chika, Tatsuya Tsuda, Hiroe Konishi, Noboru Nakagawa, and Kiyofumi Yamanishi. "Tetracyclines Modulate Protease-Activated Receptor 2-Mediated Proinflammatory Reactions in Epidermal Keratinocytes." Antimicrobial Agents and Chemotherapy 53, no. 5 (March 2, 2009): 1760–65. http://dx.doi.org/10.1128/aac.01540-08.
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ABSTRACT In addition to their antibiotic effects, tetracyclines have anti-inflammatory action that is often beneficial in the control of inflammatory skin disorders. In this study, we examined the effects of tetracycline (TET) and two of its derivatives, doxycycline (DOX) and minocycline (MIN), on the production of interleukin-8 (IL-8) elicited by the activation of protease-activated receptor 2 (PAR2) in normal human epidermal keratinocytes (NHEK). In NHEK, the production of IL-8 stimulated by an agonist peptide of PAR2, SLIGKIV-NH2, at 100 μM was significantly reduced by TET, DOX, or MIN at 5 and 10 μM, concentrations that are noncytotoxic. The tumor necrosis factor alpha (TNF-α)-induced production of IL-8 was synergistically augmented by SLIGKIV-NH2, and that synergistic increase in the production of IL-8 was suppressed by 100 nM PAR2-specific small interfering RNA. It was also suppressed by TET, DOX, or MIN but not by the 14-membered-ring macrolide antibiotics erythromycin, roxithromycin, and clarithromycin, which also have anti-inflammatory activities, at 10 μM. These results suggest that tetracyclines attenuate the PAR2-IL-8 axis in keratinocytes and thereby effectively modulate proinflammatory responses in the skin.
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Wang, Chun-hui, Jia-min Yang, Yu-bo Guo, Jing Shen, and Xiao-hua Pei. "Anticancer Activity of Tetrandrine by Inducing Apoptosis in Human Breast Cancer Cell Line MDA-MB-231 In Vivo." Evidence-Based Complementary and Alternative Medicine 2020 (June 30, 2020): 1–11. http://dx.doi.org/10.1155/2020/6823520.
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Tetrandrine (TET) is an alkaloid extracted from a traditional Chinese medicinal plant. It exerts remarkable anticancer activity and induces apoptotic cell death in various human cancer cells. The present study aimed to investigate the effects of TET on the inhibition of tumor growth and the induction of apoptosis in MDA-MB-231 breast cancer in xenograft mice. Tumor weight and volume were measured. The histopathological changes in the tumor tissue were observed. Immunohistochemistry analysis of Bcl-2-associated X protein (Bax) and B-cell lymphoma/leukemia-2 (Bcl-2) was carried out. The expression of apoptosis-associated genes and proteins, such as cysteine aspartic acid-specific protease-3 (Caspase-3), Survivin, Bax, Bcl-2, BH3-interacting domain death agonist (Bid), and poly ADP-ribose polymerase (PARP), was measured by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting, respectively. TET inhibited tumor growth and induced apoptosis in TNBC cell line MDA-MB-231. The mechanism underlying this effect might be mediated by TET-upregulated Caspase-3, Bax, and Bid and downregulated by Bcl-2, Survivin, and PARP. Taken together, this study supported the fact that TET is a promising therapeutic agent for the treatment of TNBC, thereby providing experimental evidence for its use in the treatment of breast cancer.
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Borissenko, Ljudmila, and Michael Groll. "Crystal Structure of TET Protease Reveals Complementary Protein Degradation Pathways in Prokaryotes." Journal of Molecular Biology 346, no. 5 (March 2005): 1207–19. http://dx.doi.org/10.1016/j.jmb.2004.12.056.
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Chow, W. A., S. Guo, and F. Valdes-Albini. "HIV protease inhibitor (PI) therapy for liposarcoma." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 9564. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.9564.
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9564 Background: Liposarcomas are the second most common soft-tissue sarcoma. Highly-active anti-retroviral therapy (HAART) with HIV PIs results in “HIV-1 protease inhibitor associated lipodystrophy syndrome,” characterized by peripheral fat wasting, central fat accumulation, insulin resistance, and hyperlipidemia. Based upon this syndrome, we hypothesized that HIV PIs might represent a novel liposarcoma therapy. Methods: SW872, LiSa-2, and FU-DDLS-1 liposarcoma, and control 293 embryonic kidney and HT1080 fibrosarcoma cell lines were treated with HIV PIs and subjected to cellular and molecular assays. Results: Clonogenic assays with SW872 cells using HIV PIs (saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) were performed. Nelfinavir demonstrated the most potent clonogenic inhibition without affecting 293 and HT1080 clonogenicity, and was studied further. Nelfinavir inhibited SW872 and LiSa-2 proliferation dose-dependently, and HT1080 proliferation at the highest concentration, without affecting FU-DDLS-1 nor 293 proliferation. Nelfinavir induced a G1 cell cycle arrest in SW872 and HT1080, but not in 293 cells. It also induced dose-dependent apoptosis in SW872, but not in 293 nor HT1080 cells. Western analyses for sterol regulatory element binding protein-1 (SREBP-1) expression, a key transcriptional regulator of fatty acid and cholesterol synthesis, were performed. Nelfinavir induced expression of SREBP-1 in nelfinavir-sensitive SW872 and LiSa-2 cells, and modestly in HT1080 cells, but not in insensitive FU-DDLS-1 nor 293 cells. Additionally, nelfinavir reduced protein expression of proliferating cell nuclear antigen (PCNA) in sensitive SW872 and LiSa-2 cells, and induced expression of the anti-proliferative protein, p21, as well as pro-apoptotic proteins, Bax and Fas, in a dose-dependent manner. Finally, forced expression of SREBP-1 with a Tet-On inducible SW872 cell line, in the absence of nelfinavir, induced expression of p21, Bax, Fas, reduced expression of PCNA, and inhibited cell proliferation. Conclusions: These studies demonstrate that nelfinavir inhibits cellular proliferation, and induces apoptosis in sensitive-liposarcoma cells through upregulation of SREBP-1. These studies validate nelfinavir as a potential, novel targeted therapy for liposarcoma. No significant financial relationships to disclose.
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Chen, S., D. O. Henry, and M. K. Wong. "The biologic therapy of prostate cancer using plasminogen activator inhibitor-1 (PAI-1)." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 14596. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.14596.
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14596 Background: Treating prostate cancer through the expression of intrinsic biologic modifiers is a relatively unexplored aspect of prostate cancer therapy. Plasminogen Activator Inhibitor-1 (PAI-1) is expressed at low levels in prostate cancer cells. PAI-1 is both an anti-angiogenesis agent, and also potently inhibits tumor proteases responsible for tumor invasion and metastases such as uPA and tPA. Thus we hypothesized that stimulation of tumor endogenous PAI-1 would result in a particularly powerful and profound prostate cancer regression. We present proof-of-concept from our experimental models that demonstrate significant tumor regression in experimental prostate tumors and supports this hypothesis. Methods and Results: Human prostate adenocarcinoma (PC3 cell line) xenograft tumors engineered to conditionally express either PAI-1 or Green Fluorescent Protein (GFP, control) were used to test our hypothesis. Stable cell lines were created that conditionally express either GFP or PAI-1 under the regulation of a doxycycline-responsive promoter (Tet-On). Thus gene expression is switched on in the presence of doxycycline. PC3 tumors were inoculated and allowed to reach at least 200 mm3 in size whereby the tumor-bearing mice were given doxycycline-doped drinking water. Genes were significantly turned on within 48 hours as monitored by the appearance of a GFP signal in control mice. The induction of PAI-1 results in significant inhibition of tumor growth as compared to GFP control. Importantly, in vitro induction of PAI-1 expression in PC-3 has no direct effects on cell growth as compared to any PC-3 control. Histological analysis of these tumors revealed a rich nexus of fine angiogenic vessels at the interface between control tumors and surrounding stroma. PAI-1 secreting tumors were significantly smaller and were pale, bland, and lacked peritumoral vessels. Protease activity measured by in-situ zymography directly on these tumors revealed that this was significantly reduced in PAI-1 expressing tumors as compared to GFP controls. Conclusion: PAI-1 expression results in tumor inhibition through direct anti-angiogenic effects and inhibition of tumor protease activity. No significant financial relationships to disclose.
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Borissenko, Ljudmila, and Michael Groll. "Corrigendum to “Crystal Structure of TET Protease Reveals Complementary Protein Degradation Pathways in Prokaryotes” [J. Mol. Biol. (2005) 346, 1207–1219]." Journal of Molecular Biology 351, no. 1 (August 2005): 247. http://dx.doi.org/10.1016/j.jmb.2005.03.032.
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Byarugaba, Denis K., Godfrey Wokorach, Stephen Alafi, Bernard Erima, Florence Najjuka, Edison A. Mworozi, Hannah Kibuuka, and Fred Wabwire-Mangen. "Whole Genome Sequencing Reveals High Genetic Diversity, Diverse Repertoire of Virulence-Associated Genes and Limited Antibiotic Resistance Genes among Commensal Escherichia coli from Food Animals in Uganda." Microorganisms 11, no. 8 (July 25, 2023): 1868. http://dx.doi.org/10.3390/microorganisms11081868.
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Commensal Escherichia coli with broad repertoire of virulence and antimicrobial resistance (AMR) genes pose serious public health risks as reservoirs of AMR and virulence. This study undertook whole genome characterization of commensal E. coli from food-producing animals in Uganda to investigate their genome variability (resistome and virulome). We established that the E. coli had high genomic diversity with 38 sequence types, 24 FimH types, and 33 O-antigen serotypes randomly distributed within three phylogroups (A, B1, and E). A greater proportion (≥93.65%) of the E. coli were resistant to amoxicillin/clavulanate and ampicillin antibiotics. The isolates were AmpC beta-lactamase producers dominated by blaEC-15 (71.88%) and tet(A) (20.31%) antimicrobial resistant genes besides a diverse armory of virulence-associated genes in the class of exotoxin, adhesins, iron uptake, and serine protease autotransporters which varied by host species. Cattle were found to be the major source of E. coli carrying Shiga toxin genes, whereas swine was the main source of E. coli carrying colicin-like Usp toxin gene. The study underscores the importance of livestock as the carrier of E. coli with antimicrobial resistance and a large repertoire of virulence traits with a potential of causing disease in animals and humans by acquiring more genetic traits.
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Maghsoudi, Nader, Narges Kh Tafreshi, Fariba Khodagholi, Zahra Zakeri, Mitra Esfandiarei, Hamid Hadi-Alijanvand, Marjan Sabbaghian, et al. "Targeting enteroviral 2A protease by a 16-mer synthetic peptide: Inhibition of 2Apro-induced apoptosis in a stable Tet-on HeLa cell line." Virology 399, no. 1 (March 2010): 39–45. http://dx.doi.org/10.1016/j.virol.2009.12.017.
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Aprikyan, Andrew A. G., Tomas Vaisar, Vahagn Makaryan, and Jay Heinecke. "Cellular Model of Severe Congenital Neutropenia Reveals the Molecular Mechanism of Mutant Elastase-Mediated Agranulocytosis." Blood 104, no. 11 (November 16, 2004): 1453. http://dx.doi.org/10.1182/blood.v104.11.1453.1453.
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Abstract Severe congenital neutropenia (SCN) or Kostmann’s syndrome defines an inheritable hematopoietic disorder of an impaired neutrophil production in the bone marrow due to a “maturation arrest” at promyelocytic stage of differentiation in the marrow. SCN patients have recurring severe infections and may evolve to develop leukemia. We reported accelerated apoptosis and cell cycle arrest of bone marrow-derived myeloid progenitor cells in SCN patients with acquired, autosomal dominant, as well as autosomal recessive inheritance. We also reported that approximately 80% of these patients have heterozygous mutations in the neutrophil elastase (NE) gene encoding a serine protease normally targeted to azurophil granules. Neither knock-in of mutant elastase nor a knock-out of normal neutrophil elastase caused severe neutropenia in mice. Therefore, we established a cellular model of SCN with tetracycline-regulated expression of mutant NE in human promyelocytic tet-off HL-60 cells. Induced expression of mutant elastase in these cells led to a reduced mitochondrial membrane potential and subsequent caspase-independent apoptosis and cell cycle arrest as determined by flow cytometry. Block of differentiation of DMSO-treated cells was also observed in tet-off HL-60 cells with induced expression of mutant NE, similar to that in SCN patients. This cellular model of SCN very closely recapitulates the human severe neutropenia phenotype. To elucidate the molecular mechanisms of mutant NE-mediated neutropenia, we employed various proteomics methods, including ICAT analysis, two-dimensional gel electrophoresis, immunoprecipitation, LC-MS/MS and identified a number of proteins with altered level of expression including apoptosis and cell cycle regulatory gene products, transcription factor and cytoskeleton proteins. Changes in the protein expression profiles revealed the abnormal molecular events underlying the impaired cell survival and cell cycle arrest and suggested additional pathways implicated in pathogenesis of SCN. Immunostaining of control cells with phalloidin revealed a weak F-actin polymerization in cell periphery, which helps to maintain cell shape flexibility, and intracellular long F-actin filaments supporting the normal cytoskeleton. In contrast, cells expressing mutant NE, exhibited an increased polymerization of F-actin in the periphery, with apparent increase in lamellipodia that may contribute to an increased phosphatydilserine exposure in apoptotic cells expressing mutant elastase. The hyperpolymerization of F-actin, which appears to stem from an elevated level of RhoA, a member of the RAS-superfamily of GTPases, makes the cells more rigid and less flexible thus contributing to impaired cell cycle progression in cells expressing mutant NE. Impaired cell survival in these cells is associated with a significant reduction in the level of phosphorylated PKB/Akt, which in turn appears to be a consequence of a decreased level of PI3kinase in response to expression of mutant NE. Interestingly, G-CSF treatment of mutant NE expressing cells resulted in restoration of the level of phospho-Akt to near normal level comparable to that in control cells with normal NE expression. These data may explain the anti-apoptotic effect of G-CSF in SCN. Thus, these data demonstrate that the cellular model of SCN based on tet-off HL-60/mutNE cells with inducible expression of mutant elastase is useful to unravel the cellular and molecular mechanisms of mutant NE-mediated severe neutropenia.
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Aprikyan, Andrew A., Tomas Vaisar, Vahagn Makaryan, and Jay Heinecke. "A Model of Severe Congenital Neutropenia Reveals Signaling Pathways Mediating Mutant Elastase-Triggered Agranulocytosis." Blood 106, no. 11 (November 16, 2005): 3070. http://dx.doi.org/10.1182/blood.v106.11.3070.3070.
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Abstract Severe congenital neutropenia (SCN; Kostmann’s syndrome or infantile genetic agranulocytosis) defines an inheritable hematopoietic disorder of impaired neutrophil production due to a “maturation arrest” at the promyelocytic stage of differentiation in the bone marrow. SCN patients have recurring severe infections and often develop acute myelogenous leukemia. We and others reported accelerated apoptosis and cell cycle arrest of bone marrow-derived myeloid progenitor cells in SCN patients with autosomal dominant and autosomal recessive inheritance. Heterozygous mutations in the neutrophil elastase (NE) gene encoding a serine protease, are present in a majority of SCN patients, but not in healthy members of the family, thus indicating a key role of mutant NE in pathogenesis of this disorder. To date, there are no animal or cellular models of SCN as both the knock-in of mutant NE as well as the knock-out of normal NE failed to result in neutropenia phenotype in mice. The molecular mechanisms of mutant NE-mediated severe neutropenia remain largely unknown. We hypothesized that mutations in NE expose the protease to a new range of substrates. To explore this proposal, we established a cellular model of SCN based on tetracycline-regulated expression of mutant NE in human promyelocytic tet-off HL-60 cells that very closely recapitulated the human phenotype. Mutant NE expression resulted in a characteristic block of myeloid differentiation - the cellular hallmark of SCN. Expression of the mutant product was associated with a significant reduction in phosphatidylinosytol-3-kinase and phosphorylated PKB/Akt levels and an imbalance of anti-apoptotic Bcl-2 and pro-apoptotic Bax. These alterations contributed to observed dissipation of mitochondrial membrane potential as determined by FACS analysis, aberrant release of cytochrome C, and accelerated apoptosis. Marked changes in actin cytoskeleton that made the cells more rigid appeared to stem from a reduced level of alpha-actinin and elevated level of Rho GTPase. Immunoprecipitation of cell lysates with elastase-specific monoclonal antibodies followed by mass spectrometric analysis revealed that NE interacted with histone H2B, one of the key components of the nucleosome core of the chromatin. Interestingly, the expression level of histone H2B was substantially reduced in cells expressing mutant NE, therefore supporting the notion of altered substrate specificity of mutant NE. Thus, these observations provide the first evidence that mutant NE affects specific signaling pathways that lead to alterations in cytoskeleton and chromatin reorganization, subsequent apoptosis, and a block of myeloid differentiation in SCN. This cellular model of SCN should provide an invaluable tool for screening potential therapeutic agents capable of preventing maturation arrest and leukemogenesis in subjects suffering from severe congenital neutropenia.
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Aprikyan, Andrew A., Vahagn Makaryan, Maxim Totrov, Ruben Abagyan, and David C. Dale. "Small Molecule Inhibitor of Neutrophil Elastase Normalizes Myeloid Differentiation and Improves Impaired Cell Survival Triggered by Elastase Mutations In Patients with Severe Congenital Neutropenia and Acute Myeloid Leukemia." Blood 116, no. 21 (November 19, 2010): 386. http://dx.doi.org/10.1182/blood.v116.21.386.386.
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Abstract Abstract 386 Heterozygous mutations in the neutrophil elastase gene ELANE have been identified as the primary cause of severe congenital neutropenia (SCN) associated with recurring severe infections and evolution to acute myeloid leukemia (AML). As of today, more than 50 substitution, truncation, insertion and deletion mutations have been identified. Animal studies based on knock-in or knockout of ELANE in mice failed to produce severe neutropenia phenotype. We and others previously reported that expression of various mutants but not wild type neutrophil elastase (NE) in human but not murine cells triggers accelerated apoptosis. We also reported that expression of mutant NE (del.145-152), identified in SCN patients one of whom evolved to develop MDS/AML, in human promyelocytic tet-off HL60 cells causes both accelerated apoptosis and characteristic block of myeloid differentiation similar to that seen in bone marrow of SCN patients. Examination of the tertiary structure of NE revealed that most of the mutations leave the active site of the mutant protease intact. We identified a small molecule inhibitor of neutrophil elastase, a derivative of L-malic acid (Merck, USA), that blocked the proteolytic activity of NE by approximately 80% and was capable of restoring impaired myeloid differentiation and normalizing production of myeloid cells expressing del145-152 NE mutant. It is important to note that block of proteolytic activity of NE with the NE-SMI had no adverse effect on control human myeloid progenitor cells expressing wild type NE, thus confirming the gain-of-function effect of NE mutants. More than 20% of SCN patients with NE mutations evolve to develop AML. Molecular modeling and analysis of the tertiary structures of NE available through the Protein Database revealed that 16 different mutations identified in AML patients affect predominantly the N95 or N144 glycosylation sites or the binding pocket of the protease suggesting that altered substrate specificity of the mutant enzyme is the cause of accelerated apoptosis and block of myeloid differentiation in SCN/AML. We sought to obtain bone marrow samples from 2 unrelated SCN/AML patients both on G-CSF treatment harboring either C122Y or insPQ94. Bone marrow purified CD34+ and/or CD34-/CD33+ myeloid progenitors from the patients showed basal level of apoptosis in a range of 20–25%, which gradually increased reaching 40–50% apoptosis by 3 days of culture. Importantly, treatment of primary bone marrow-derived cells with NE-SMI substantially reduced accelerated apoptosis to near initial rate with approximately up to 2-fold reduction of apoptosis by 3 days of culture as determined by flow cytometry. Thus, our findings demonstrate that 1) small molecule inhibitor of neutrophil elastase is effective in blocking accelerated apoptosis triggered by three different NE mutations identified in SCN patients evolved to develop MDS/AML and 2) the small molecule inhibitor of NE is a promising therapeutic agent that should be considered for testing in clinical trials in SCN/AML patients. Disclosures: Dale: Amgen: Consultancy, Research Funding; Merck: Patents & Royalties, Research Support.
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Wen, Wenjun, Shijie Li, and Junping Wang. "The Effects of Tea Polyphenol on Chicken Protein Digestion and the Mechanism under Thermal Processing." Foods 12, no. 15 (July 31, 2023): 2905. http://dx.doi.org/10.3390/foods12152905.
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Meat product is the main food and major source of daily protein intake. Polyphenols are always introduced into many meat products during processing. Some complex interactions may occur between polyphenol and meat protein during the processing, especially thermal processing, which may affect the digestion of protein. In this experiment, chicken protein and tea polyphenol were interacted in simulated systems to explore the effects of the interaction between meat protein and polyphenols on the digestion of meat protein. The mechanism of tea polyphenol inhibiting chicken protein digestion was studied by analyzing the changes of chicken protein in intrinsic fluorescence, surface plasmon resonance (SPR), reactive sulfhydryl group, and solubility in different solvents. The results showed that the chicken protein digestion had a negative correlation with tea polyphenol concentration and interaction temperature, and the meat protein has a higher affinity to EGCG than protease. The mechanism of tea polyphenol inhibiting chicken protein digestion was related to the changing spatial structure of chicken protein and the decreasing activity of proteases. In the simulation system, at low-concentration tea polyphenol, the inhibition of the tea polyphenol on the digestibility of chicken protein might be mainly caused by the changes in chicken protein structure, while at high concentration, the changes in protein structure and the inhibition of proteases activity played a role together. This experiment revealed the effect and the mechanism of polyphenols on the digestion performance of meat protein and provide more references for the further application of polyphenols in meat processing.
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Arias, Éliana, Haiming Li, and Rolf Morosoli. "Effect of protease mutations on the production of xylanases in Streptomyces lividans." Canadian Journal of Microbiology 53, no. 6 (June 2007): 695–701. http://dx.doi.org/10.1139/w07-024.
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Three protease mutants — 7 (tap–), 12 (tap–, ssp–), and 17 (multiple mutations) — of Streptomyces lividans were tested for their influence on protein secretion. Streptomyces lividans grown in xylan secretes 3 xylanases (A, B, and C). Xylanases A (XlnA) and B (XlnB) are secreted by the Sec pathway, whereas xylanase C (XlnC) is secreted by the Tat pathway. The production of XlnA and XlnC was affected in the mutants, suggesting that the mutations interfered with both Sec- and Tat-secretion systems. However, the processing rate for the Sec and Tat precursor was similar to the wild-type strain, indicating that the mutations had no direct effect on secretion. Streptomyces lividans naturally produced 2 forms of XlnB: XlnB1, which contains the catalytic and the xylan-binding domains, and XlnB2, which contains the catalytic domain only. There was no change from the wild-type strain in the ratio of XlnB1/XlnB2 produced by the mutants, indicating that these proteases are not involved in this process. Although XlnA1, partially truncated in its xylan-binding domain, was rapidly degraded to its catalytic domain (XlnA2) in the wild-type strain, the rate of conversion was reduced in the 3 mutants, indicating that the proteases participated to some extent in this proteolytic process.
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Camerer, Eric, Ivo Cornelissen, Hiroshi Kataoka, Daniel N. Duong, Yao-Wu Zheng, and Shaun R. Coughlin. "Roles of protease-activated receptors in a mouse model of endotoxemia." Blood 107, no. 10 (May 15, 2006): 3912–21. http://dx.doi.org/10.1182/blood-2005-08-3130.
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Endotoxemia is often associated with extreme inflammatory responses and disseminated intravascular coagulation. Protease-activated receptors (PARs) mediate cellular responses to coagulation proteases, including platelet activation and endothelial cell reactions predicted to promote inflammation. These observations suggested that PAR activation by coagulation proteases generated in the setting of endotoxemia might promote platelet activation, leukocyte-mediated endothelial injury, tissue damage, and death. Toward testing these hypotheses, we examined the effect of PAR deficiencies that ablate platelet and endothelial activation by coagulation proteases in a mouse endotoxemia model. Although coagulation was activated as measured by thrombin-antithrombin (TAT) production and antithrombin III (ATIII) depletion, Par1–/–, Par2–/–, Par4–/–, Par2–/–:Par4–/–, and Par1–/–:Par2–/– mice all failed to show improved survival or decreased cytokine responses after endotoxin challenge compared with wild type. Thus, our results fail to support a necessary role for PARs in linking coagulation to inflammation or death in this model. Interestingly, endotoxin-induced thrombocytopenia was not diminished in Par4–/– mice. Thus, a mechanism independent of platelet activation by thrombin was sufficient to cause thrombocytopenia in our model. These results raise the possibility that decreases in platelet count in the setting of sepsis may not be caused by disseminated intravascular coagulation but instead report on a sometimes parallel but independent process.
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Polster, Brian M., Karla A. Mark, Rafael Arze, and Derek Hudson. "Calpain-Independent Intracellular Protease Activity Is Elevated in Excitotoxic Cortical Neurons Prior to Delayed Calcium Deregulation and Mitochondrial Dysfunction." Biomolecules 12, no. 7 (July 20, 2022): 1004. http://dx.doi.org/10.3390/biom12071004.
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Glutamate excitotoxicity contributes to many neurodegenerative diseases. Excessive glutamate receptor-mediated calcium entry causes delayed calcium deregulation (DCD) that coincides with abrupt mitochondrial depolarization. We developed cA-TAT, a live-cell protease activity reporter based on a vimentin calpain cleavage site, to test whether glutamate increases protease activity in neuronal cell bodies prior to DCD. Treatment of rat cortical neurons with excitotoxic (100 µM) glutamate increased the low baseline rate of intracellular cA-TAT proteolysis by approximately three-fold prior to DCD and by approximately seven-fold upon calcium deregulation. The glutamate-induced rate enhancement prior to DCD was suppressed by glutamate receptor antagonists, but not by calpain or proteasome inhibitors, whereas DCD-stimulated proteolysis was partly attenuated by the proteasome inhibitor MG132. Further suggesting that cA-TAT cleavage is calpain-independent, cA-TAT fluorescence was observed in immortalized Capn4 knockout fibroblasts lacking the regulatory calpain subunit. About half of the neurons lost calcium homeostasis within two hours of a transient, 20 min glutamate receptor stimulation. These neurons had a significantly (49%) higher mean baseline cA-TAT proteolysis rate than those maintaining calcium homeostasis, suggesting that the unknown protease(s) cleaving cA-TAT may influence DCD susceptibility. Overall, the results indicate that excitotoxic glutamate triggers the activation of calpain-independent neuronal protease activity prior to the simultaneous loss of calcium homeostasis and mitochondrial bioenergetic function.
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Aprikyan, Andrew A., Vahagn Makaryan, Maxim Totrov, Ruben Abagyan, and David C. Dale. "Small Molecule Inhibitor of Neutrophil Elastase and Severe Congenital Neutropenia." Blood 114, no. 22 (November 20, 2009): 552. http://dx.doi.org/10.1182/blood.v114.22.552.552.
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Abstract Abstract 552 Severe congenital neutropenia (SCN) is a rare heritable hematopoietic disorder characterized by maturation arrest at the promyelocytes, recurring severe infections, and evolution to leukemia. Heterozygous mutations in the neutrophil elastase (NE or ELANE) gene (sporadic or autosomal-dominant SCN) or homozygous mutations in the HAX1 gene (autosomal-recessive SCN) are associated with similar clinical phenotype and a block of myeloid differentiation or “maturation arrest” in the marrow. We and others reported that human myeloid progenitor cells expressing mutant elastase exhibit impaired cell survival (Aprikyan et al, 2003, Massullo et al, 2005, Kollner et al, 2006, Grenda et al, 2007). The hetero- and homozygous deletion of NE as well as the knock-in of mutant NE identified in SCN/AML patient failed to produce severe neutropenia phenotype in mice. Thus, the pathomechanism of severe neutropenia remains largely unclear due to the lack of cellular or animal model of SCN with characteristic block of myeloid differentiation and accelerated apoptosis. We established a cellular model of SCN with inducible tet-regulated expression of del.145-152 NE mutant (identified in SCN/AML patients) in human promyelocytic tet-off HL60 cells. The ratio of normal/mutant NE products in these cells is approximately 1:1, which is similar to that expected in SCN patients with heterozygous NE mutation. Expression of mutant NE in the promyelocytic cells results in a characteristic block of myeloid differentiation with ∼70% decline in differentiated neutrophils which is similar to that observed in SCN, whereas induced expression of control wild type NE has no effect on myeloid differentiation. Reduced production of myeloid cells and accelerated apoptosis are also observed upon DMSO or retinoic acid induced granulocytic differentiation of the cells in response to mutant, but not wild type NE expression. Thus, this cellular model of SCN appears to closely recapitulate the human phenotype. Expression of mutant NE resulted in approximately 40% increase in total NE-specific proteolytic activity, suggesting that mutant elastase exhibits at least some proteolytic activity. To date there are more than 50 heterozygous mutations in the NE gene have been identified in pre-leukemic SCN patients. Molecular modeling of the NE tertiary structure revealed that these mutations predominantly affect the N-glycosylation sites or the binding pocket of neutrophil elastase. Importantly, the active site of the mutant protease appears to be intact, which suggests that NE-specific small molecule inhibitors may be useful in preventing accelerated apoptosis and the characteristic block of myeloid differentiation of myeloid progenitor cells. Screening this cellular model of SCN, we identified a proprietary cell-penetrant elastase-specific small molecule inhibitor (compound A, Merck, USA), which inhibits the proteolytic activity of NE by more than 80%. When treated with compound A, control cells with induced expression of wtNE exhibit normal myeloid differentiation and production of myeloid cells, similar to that in untreated cells. These data suggest that human NE is dispensable and that accelerated apoptosis and impaired myeloid differentiation in SCN is due to a gain-of-function effect of pro-apoptotic mutant elastase. Importantly, treatment of human promyelocytic cells expressing del.145-152 mutant NE with this small molecule inhibitor restores impaired production of myeloid cells and improves myeloid differentiation to near normal levels, thus neutralizing the pro-apoptotic effect of mutant NE. These data suggest that small molecule inhibitors of NE may represent a promising therapy in severe congenital neutropenia. We have examined the effect of the inhibitor on bone marrow cells from an SCN patient positive for NE mutation. At the time of bone marrow aspiration the patient was on G-CSF and the patient's freshly isolated bone marrow CD33+ progenitor cells exhibited ∼21% apoptosis, which was gradually increased reaching 43% at 3 days of culture. However, daily treatment of SCN cells with compound A preserved the cell survival rate at the initial value resulting in approximately 2-fold reduction in apoptotic cell death at 3 days of culture. These data demonstrate that the small molecule inhibitor of NE and its analogs should be considered for clinical trials in patients with SCN that is attributable to mutant NE. Disclosures: Dale: Merck: Research support; Amgen: Consultancy, Research Funding, Speaker.
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Park, Junsoo, Rackhyun Park, Minsu Jang, and Yea-In Park. "Therapeutic Potential of EGCG, a Green Tea Polyphenol, for Treatment of Coronavirus Diseases." Life 11, no. 3 (March 4, 2021): 197. http://dx.doi.org/10.3390/life11030197.
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Epigallocatechin gallate (EGCG) is a major catechin found in green tea, and there is mounting evidence that EGCG is potentially useful for the treatment of coronavirus diseases, including coronavirus disease 2019 (COVID-19). Coronaviruses encode polyproteins that are cleaved by 3CL protease (the main protease) for maturation. Therefore, 3CL protease is regarded as the main target of antivirals against coronaviruses. EGCG is a major constituent of brewed green tea, and several studies have reported that EGCG inhibits the enzymatic activity of the coronavirus 3CL protease. Moreover, EGCG has been reported to regulate other potential targets, such as RNA-dependent RNA polymerase and the viral spike protein. Finally, recent studies have demonstrated that EGCG treatment interferes with the replication of coronavirus. In addition, the bioavailability of EGCG and future research prospects are discussed.
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Aprikyan, Andrew A., Vahagn Makaryan, Qian Si, Kelly Treonze, Nara Markosyan, Paul Finke, Maxim Totrov, Ruben Abagyan, Richard Mumford, and David Dale. "Small Molecule Inhibitor of Neutrophil Elastase Restores Impaired Production of Human Myeloid Cells Observed in Severe Congenital Neutropenia." Blood 110, no. 11 (November 16, 2007): 664. http://dx.doi.org/10.1182/blood.v110.11.664.664.
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Abstract Severe congenital neutropenia (SCN) is a rare hematopoietic disease characterized by maturation arrest at the promyelocytes, recurring severe infections, and evolution to leukemia. Heterozygous mutations in either the neutrophil elastase (NE, ELA2) gene (sporadic or autosomal-dominant SCN) or homozygous mutations in the HAX1 gene (autosomal-recessive SCN) are associated with a similar clinical phenotype and similar block of myeloid differentiation in the marrow. Most studies now indicate that the maturation arrest in SCN is due to accelerated apoptosis of myeloid progenitors triggered by the mutant gene products. The hetero and homozygous deletion of NE in mice as well as the knock-in of mutant NE identified in SCN/AML patient failed to produce severe neutropenia phenotype in mice. We established a cellular model of SCN with inducible expression of del.145–152 NE mutant in human promyelocytic tet-off HL60 cells. Ratio of normal /mutant NE products in these cells is approximately 1:1, similar to that expected in SCN patients with heterozygous NE mutation. Expression of mutant NE in promyelocytic cells resulted in a characteristic block of myeloid differentiation with ∼70% decline in differentiated neutrophils which is similar to that observed in SCN. Cell growth reduction and accelerated apoptosis were also observed in these cells in response to mutant NE expression. Thus, this SCN model appears to closely recapitulate the human phenotype. Analysis of the proteolytic activity of cells expressing mutant elastase revealed approximately 40% increase in total NE-specific activity in response to mutant NE expression compared with controls, suggesting that mutant elastase exhibits at least some proteolytic activity. To date we identified more than 40 heterozygous mutations in the NE gene in pre-leukemic SCN patients, however, the pathomechanism remains unclear. Molecular modeling of the NE tertiary structure revealed that these mutations predominantly affect the N-glycosylation sites or the binding pocket of elastase. Importantly, the active site of the mutant protease appears to be intact, which suggested that NE-specific small molecule inhibitors may be useful in preventing accelerated apoptosis and the block of myeloid differentiation of myeloid cells. Examining this SCN model, we identified a proprietary cell-permeable elastase-specific small molecule inhibitor (compound A, Merck, USA), which inhibited the proteolytic activity of the NE by more than 80%. Our studies indicate that treatment of human promyelocytic cells expressing del.145–152 mutant NE with this small molecule inhibitor restored the impaired production of myeloid cells and improved myeloid differentiation to near normal level. Importantly, the compound A did not impair the growth rate of control cells with normal NE expression. These data suggest that NE-specific small molecule inhibitor and its analogs should be considered in clinical trials in patients with SCN that is attributable to mutant NE.
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Yano, Kazuo, Toshiharu Ito, Hiroki Shigematus, Kohsuke Sasaki, Shuhei Kondo, Shin-Ichiro Kuriya, and Yoji Ishida. "Purification of Proplatelet Formation (PPF) Stimulating Factor: Thrombin/Antithrombin III Complex Stimulates PPF of Megakaryocytes In Vitro and Platelet Production In Vivo." Thrombosis and Haemostasis 85, no. 02 (2001): 349–55. http://dx.doi.org/10.1055/s-0037-1615691.
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SummaryIn this study, the protein which stimulates proplatelet formation (PPF) of megakaryocytes was purified from normal human plasma using 7 steps procedures. Two different protease inhibitors were identified based on their amino acid sequences, i.e. antithrombin III (AT III) and C1 inhibitor. They were included in high density lipoprotein (HDL). HDL was necessary for AT III to be active in PPF in vitro. The biological effects of the AT III /HDL or thrombin-AT III (TAT)/HDL were studied in vitro. PPF of murine megakaryocytes was stimulated by negative control (BSA) (1.8 ± 0.3%), AT III (2.0 ± 0.4%), HDL (1.2 ± 0.9%), AT III /HDL (14.8 ± 2.1%) or TAT/HDL (23.3 ± 3.5%), respectively. TAT/HDL also had a synergistic effect with the mpl ligand, judging by the acetylcholinesterase (AchE) expression of murine megakaryocytes (2.7 fold increase). In vivo subcutaneous administration of AT III alone or TAT for 3 days significantly stimulated thrombocytosis (136% and 144%, respectively, p <0.05) and AT III/HDL showed rapid and further stimulation (150%, p <0.01). These results and the previous studies indicate that megakaryocytopoiesis is regulated by the mpl ligand, while a protease/protease inhibitor complex such as TAT, which is involved in the coagulation cascade associated with platelet consumption, might be one of the regulators in platelet production.
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Nag, Jeetendra, and Rachel Bar-Shavit. "Transcriptional Landscape of PARs in Epithelial Malignancies." International Journal of Molecular Sciences 19, no. 11 (November 2, 2018): 3451. http://dx.doi.org/10.3390/ijms19113451.
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G protein-coupled receptors (GPCRs), the largest family of cell receptors, act as important regulators of diverse signaling pathways. Our understanding of the impact of GPCRs in tumors is emerging, yet there is no therapeutic platform based on GPCR driver genes. As cancer progresses, it disrupts normal epithelial organization and maintains the cells outside their normal niche. The dynamic and flexible microenvironment of a tumor contains both soluble and matrix-immobilized proteases that contribute to the process of cancer advancement. An example is the activation of cell surface protease-activated receptors (PARs). Mammalian PARs are a subgroup of GPCRs that form a family of four members, PAR1–4, which are uniquely activated by proteases found in the microenvironment. PAR1 and PAR2 play central roles in tumor biology, and PAR3 acts as a coreceptor. The significance of PAR4 in neoplasia is just beginning to emerge. PAR1 has been shown to be overexpressed in malignant epithelia, in direct correlation with tumor aggressiveness, but there is no expression in normal epithelium. In this review, the involvement of key transcription factors such as Egr1, p53, Twist, AP2, and Sp1 that control PAR1 expression levels specifically, as well as hormone transcriptional regulation by both estrogen receptors (ER) and androgen receptors (AR) are discussed. The cloning of the human protease-activated receptor 2; Par2 (hPar2) promoter region and transcriptional regulation of estrogen (E2) via binding of the E2–ER complex to estrogen response elements (ERE) are shown. In addition, evidence that TEA domain 4 (TEAD4) motifs are present within the hPar2 promoter is presented since the YAP oncogene, which plays a central part in tumor etiology, acts via the TEAD4 transcription factor. As of now, no information is available on regulation of the hPar3 promoter. With regard to hPar4, only data showing CpG methylation promoter regulation is available. Characterization of the PAR transcriptional landscape may identify powerful targets for cancer therapies.
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Storozhuk, Maksim, Siyun Lee, Jin I. Lee, and Junsoo Park. "Green Tea Consumption and the COVID-19 Omicron Pandemic Era: Pharmacology and Epidemiology." Life 13, no. 3 (March 22, 2023): 852. http://dx.doi.org/10.3390/life13030852.
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In spite of the development of numerous vaccines for the prevention of COVID-19 and the approval of several drugs for its treatment, there is still a great need for effective and inexpensive therapies against this disease. Previously, we showed that green tea and tea catechins interfere with coronavirus replication as well as coronavirus 3CL protease activity, and also showed lower COVID-19 morbidity and mortality in countries with higher green tea consumption. However, it is not clear whether green tea is still effective against the newer SARS-CoV-2 variants including omicron. It is also not known whether higher green tea consumption continues to contribute to lower COVID-19 morbidity and mortality now that vaccination rates in many countries are high. Here, we attempted to update the information regarding green tea in relation to COVID-19. Using pharmacological and ecological approaches, we found that EGCG as well as green tea inhibit the activity of the omicron variant 3CL protease efficiently, and there continues to be pronounced differences in COVID-19 morbidity and mortality between groups of countries with high and low green tea consumption as of December 6, 2022. These results collectively suggest that green tea continues to be effective against COVID-19 despite the new omicron variants and increased vaccination.
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Eljaaly, Khalid, Hani Asfour, Tarek Ibrahim, Osama Ahmed, Nabil Alhakamy, Usama Fahmy, Mohammed Al-Rabia, et al. "503. In vitro Evaluation of Sitagliptin-HIV-1 Trans-activator Transcription Peptide Nano-formula for Antiviral Activity Against SARS-CoV-2: Drug Repurposing Approach." Open Forum Infectious Diseases 8, Supplement_1 (November 1, 2021): S354. http://dx.doi.org/10.1093/ofid/ofab466.702.
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Abstract Background The outbreak of COVID-19 pandemic in China regarded as a major health/economic hazard. The importance of coming up with mechanisms for preventing or treating COVID-19 has been felt across the world. This work aimed at examining the efficiency of Sitagliptin (SIT) and human immunodeficiency virus type 1 (HIV-1) trans-activator transcription peptide (TAT) against SARS-CoV-2. Methods SIT-TAT nano-conjugates were prepared according to a full three-factor bi-level (23) factorial design. SIT concentration (mM, X1), TAT concentration (mM, X2), and pH (X3) were selected as the factors. Particle size (nm, Y1) and zeta potential (mV, Y2) were assessed as responses. Characterization of the optimized formula for Fourier-transformed infrared (FTIR) and Transmission electron microscope was carried out. In addition, IC50 in Vero E6 cells, In vitro 3CL-protease inhibition and docking tests were investigated. Results The prepared complex’s formula was as follows 1: 1 SIT: TAT molar ratio, whereas zeta potential and particle size values were at 34.17 mV and 97.19 nm, respectively. This combination did exhibit its antiviral potentiality against SARS-CoV-2 via IC50 values of 9.083 5.415, and 16.14 µM for TAT, SIT-TAT, and SIT, respectively. In addition, the complex SIT-TAT showed a significant (P < 0.001) viral-3CL-protease inhibitory effect (IC50 = 3.959 µM ± 0.011) in comparison to isolated components (IC50 = 10.93 µM ± 0.25) and TAT (IC50 = 8.128 µM ± 0.42). This was further confirmed via in silico study. Molecular docking investigation has shown promising binding affinity of the formula components towards SARS-CoV-2 main protease (3-CL). Conclusion While offering significant binding interactions with protein’s key pocket residues, an optimized formulation of SIT-TAT could guarantee both the enhanced delivery to the target cells and the improved cellular uptake. The presented findings would guarantee further investigations regarding formula optimization against SARS-CoV-2. Disclosures All Authors: No reported disclosures
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Mayor-Nunez, Diana, Zhanxin Ji, Xiujun Sun, Lucy Teves, J. David Garman, and Michael Tymianski. "Plasmin-resistant PSD-95 inhibitors resolve effect-modifying drug-drug interactions between alteplase and nerinetide in acute stroke." Science Translational Medicine 13, no. 588 (April 7, 2021): eabb1498. http://dx.doi.org/10.1126/scitranslmed.abb1498.
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Neuroprotection for acute ischemic stroke is achievable with the eicosapeptide nerinetide, an inhibitor of the protein-protein interactions of the synaptic scaffolding protein PSD-95. However, nerinetide is subject to proteolytic cleavage if administered after alteplase, a standard-of-care thrombolytic agent that nullifies nerinetide’s beneficial effects. Here, we showed, on the basis of pharmacokinetic data consistent between rats, primates, and humans, that in a rat model of embolic middle cerebral artery occlusion (eMCAO), nerinetide maintained its effectiveness when administered before alteplase. Because of its short plasma half-life, it can be followed by alteplase within minutes without reducing its neuroprotective effectiveness. In addition, the problem of protease sensitivity is solved by substituting cleavage-prone amino acids from their l- to their d-enantiomeric form. Treatment of rats subjected to eMCAO with such an agent, termed d-Tat-l-2B9c, eliminated protease sensitivity and maintained neuroprotective effectiveness. Our data suggest that both the clinical-stage PSD-95 inhibitor nerinetide and protease-resistant agents such as d-Tat-l-2B9c may be practically integrated into existing stroke care workflows and standards of care.
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Kamimura, Y., and K. Hayano. "Properties of protease extracted from tea-field soil." Biology and Fertility of Soils 30, no. 4 (January 5, 2000): 351–55. http://dx.doi.org/10.1007/s003740050015.
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Chen, Chia-Nan, Coney P. C. Lin, Kuo-Kuei Huang, Wei-Cheng Chen, Hsin-Pang Hsieh, Po-Huang Liang, and John T. A. Hsu. "Inhibition of SARS-CoV 3C-like Protease Activity by Theaflavin-3,3'-digallate (TF3)." Evidence-Based Complementary and Alternative Medicine 2, no. 2 (2005): 209–15. http://dx.doi.org/10.1093/ecam/neh081.
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SARS-CoV is the causative agent of severe acute respiratory syndrome (SARS). The virally encoded 3C-like protease (3CLPro) has been presumed critical for the viral replication of SARS-CoV in infected host cells. In this study, we screened a natural product library consisting of 720 compounds for inhibitory activity against 3CLPro. Two compounds in the library were found to be inhibitive: tannic acid (IC50 = 3 µM) and 3-isotheaflavin-3-gallate (TF2B) (IC50 = 7 µM). These two compounds belong to a group of natural polyphenols found in tea. We further investigated the 3CLPro-inhibitory activity of extracts from several different types of teas, including green tea, oolong tea, Puer tea and black tea. Our results indicated that extracts from Puer and black tea were more potent than that from green or oolong teas in their inhibitory activities against 3CLPro. Several other known compositions in teas were also evaluated for their activities in inhibiting 3CLPro. We found that caffeine, (—)-epigallocatechin gallte (EGCg), epicatechin (EC), theophylline (TP), catechin (C), epicatechin gallate (ECg) and epigallocatechin (EGC) did not inhibit 3CLPro activity. Only theaflavin-3,3′-digallate (TF3) was found to be a 3CLPro inhibitor. This study has resulted in the identification of new compounds that are effective 3CLPro inhibitors.
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Oanh, Doan Thi Yen, Ly Thi Minh Hien, Nguyen Kha Duyen, Nguyen Huu Hieu, and Dong Thi Anh Dao. "Effect of enzyme – assisted extraction on total polyphenol content and antioxidant capacity from fresh tea leaves (Camellia sinensis)." Vietnam Journal of Chemistry 61, no. 5 (August 7, 2023): 551–62. http://dx.doi.org/10.1002/vjch.202300109.
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AbstractTea leaves contain high concentration of polyphenols, known as bioactive compounds. In order to increase the extraction yield of polyphenol and the antioxidant capacity of the extract from tea leaves, the combination of cellulase, pectinase and protease in enzyme‐assisted extraction was investigated. By using fractional factorial experimental design to study the two‐enzyme assisted extraction of cellulase and pectinase, three factors including solvent/material ratio, pH and hydrolysis time showed significant effects on the extract properties. The highest total polyphenol content obtained adopting the favorable conditions was 185.9 mg GAE/g of dry material at solvent and material ratio of 5.9, hydrolysis pH of 4.4 and hydrolysis time of 36 minutes. In addition, the antioxidant capacity of the extract was determined at 175.9 mg TE/g of dry material at those optimum experimental conditions. In our test of three‐enzyme (cellulase – pectinase – protease) assisted extraction, the extracts were spray‐dried to observe green tea powder. Results indicated that the TPC, AC and the color sensory quality of the green tea powder decreased compared to the two‐enzyme (cellulase – pectinase) assisted extraction.
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Lafrenie, R. M., L. M. Wahl, J. S. Epstein, I. K. Hewlett, K. M. Yamada, and S. Dhawan. "HIV-1-Tat modulates the function of monocytes and alters their interactions with microvessel endothelial cells. A mechanism of HIV pathogenesis." Journal of Immunology 156, no. 4 (February 15, 1996): 1638–45. http://dx.doi.org/10.4049/jimmunol.156.4.1638.
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Abstract Monocytes are major targets of HIV infection in patients with AIDS. In vitro infection of monocytes with HIV is associated with increased expression of beta 2 integrins, which increases both monocyte aggregation and monocyte/endothelial adhesion as well as monocyte metalloproteinase (MMP-9) expression. Treatment of primary monocytes with soluble HIV-Tat protein mimicked many of the properties of HIV infection of monocytes. Tat treatment up-regulated the expression of the beta 2 integrins, which was associated with the formation of large aggregates of monocytes and increased adhesion to endothelial monolayers. Treatment of monocytes with Tat increased their adhesion to both untreated and TNF-alpha-treated endothelial monolayers, and adhesion was inhibited by inclusion of anti-beta 2 and anti-ICAM-1 Abs. The increased adhesion of activated monocytes was accompanied by substantial disruption of the endothelial monolayers, with retraction or detachment of individual endothelial cells. Tat treatment of monocytes up-regulated the synthesis and release of the protease MMP-9, providing a potential mechanism to explain endothelial cell/basement membrane detachment. Thus, extracellular Tat is capable of activating monocytes even in the absence of HIV infection. Our studies demonstrate that many of the effects of HIV infection on monocyte homotypic and heterotypic adhesion, protease secretion, and disruption of the endothelium can be mimicked by treatment with HIV-Tat protein alone. These results suggest a mechanism where monocytes could be inappropriately activated by HIV-Tat, secreted by HIV-infected cells, causing them to extravasate into underlying tissues and ultimately contribute to tissue damage as seen during the progression of AIDS.
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T, Indhumathi. "Isolation of Alkaline Protease from Fruit Waste and its Application as Detergent." Bioscience Biotechnology Research Communications 16, no. 3 (September 25, 2023): 190–96. http://dx.doi.org/10.21786/bbrc/16.3.9.
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The modernization of the society has made our environment face a series of changes. One among them is the enzymatic method produced by microorganisms from any waste. Considering the fruit waste globally several industrial uses have been fulfilled by the fruit waste. The most abundant enzyme now a days is protease from papaya waste isolated from Bacillus spp. Alkaline protease has been choosen for the detergent industries widely since it has pH range over 7.5. It performs more effectively in decomposing proteins. Since, it is stable over wide temperature and pH range. The aim of the study was to isolate alkaline protease enzyme from fruit waste and its applications as detergent against three different stains such as blood stain, banana stain and tea stain. Papaya fruit waste was used to extract protease enzyme to create a useful detergent for stain removal. The enzyme’s activity was tested at different pH and temperature, and the best results were obtained from three samples. The study suggests that alkaline protease enzyme from papaya waste is effective in removing protein stains and could help manage solid waste while being produced at lower temperature.
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Apolloni, Ann, C. William Hooker, Johnson Mak, and David Harrich. "Human Immunodeficiency Virus Type 1 Protease Regulation of Tat Activity Is Essential for Efficient Reverse Transcription and Replication." Journal of Virology 77, no. 18 (September 15, 2003): 9912–21. http://dx.doi.org/10.1128/jvi.77.18.9912-9921.2003.
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ABSTRACT The human immunodeficiency virus type 1 (HIV-1) Tat protein enhances reverse transcription, but it is not known whether Tat acts directly on the reverse transcription complex or through indirect mechanisms. Since processing of Tat by HIV protease (PR) might mask its presence and, at least in part, explain this lack of data, we asked whether Tat can be cleaved by PR. We used a rabbit reticulocyte lysate (RRL) system to make Tat and PR. HIV-1 PR is expressed as a Gag-Pol fusion protein, and a PR-inactivated Gag-Pol is also expressed as a control. We showed that Tat is specifically cleaved in the presence of PR, producing a protein of approximately 5 kDa. This result suggested that the cleavage site was located in or near the Tat basic domain (amino acids 49 to 57), which we have previously shown to be important in reverse transcription. We created a panel of alanine-scanning mutations from amino acids 45 to 54 in Tat and evaluated functional parameters, including transactivation, reverse transcription, and cleavage by HIV-1 PR. We showed that amino acids 49 to 52 (RKKR) are absolutely required for Tat function in reverse transcription, that mutation of this domain blocks cleavage by HIV-1 PR, and that other pairwise mutations in this region modulate reverse transcription and proteolysis in strikingly similar degrees. Mutation of Tat Y47G48 to AA also down-regulated Tat-stimulated reverse transcription but had little effect on transactivation or proteolysis by HIV PR, suggesting that Y47 is critical for reverse transcription. We altered the tat gene of the laboratory strain NL4-3 to Y47D and Y47N so that overlapping reading frames were not affected and showed that Y47D greatly diminished virus replication and conveyed a reverse transcription defect. We hypothesize that a novel, cleaved form of Tat is present in the virion and that it requires Y47 for its role in support of efficient reverse transcription.
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Gallo, Navarro, Franco, and Andreu. "A2A Receptor Homodimer-Disrupting Sequence Efficiently Delivered by a Protease-Resistant, Cyclic CPP Vector." International Journal of Molecular Sciences 20, no. 19 (October 5, 2019): 4937. http://dx.doi.org/10.3390/ijms20194937.
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G-protein-coupled receptors associate into dimers/oligomers whose function is not well understood. One approach to investigate this issue is to challenge oligomerization by peptides replicating transmembrane domains and to study their effect on receptor functionality. The disruptor peptides are typically delivered by means of cell-penetrating vectors such as the human immunodeficiency virus (HIV) transcription trans-activation protein Tat. In this paper we report a cyclic, Tat-like peptide that significantly improves its linear analogue in targeting interreceptor sequences in the transmembrane space. The same cyclic Tat-like vector fused to a transmembrane region not involved in receptor oligomerization was totally ineffective. Besides higher efficacy, the cyclic version has enhanced proteolytic stability, as shown by trypsin digestion experiments.
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Trubiani, O., S. Guarnieri, R. Paganelli, and R. di Primio. "Involvement of Caspase-3 in the Cleavage of Terminal Transferase." International Journal of Immunopathology and Pharmacology 15, no. 3 (September 2002): 201–8. http://dx.doi.org/10.1177/039463200201500306.
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To investigate the in vivo role of caspase-3 in Terminal Transferase metabolism DMSO-treated RPMI-8402, a human pre-T cell line was used. In DMSO treated samples 3H-dGTP incorporation and TdT phosphorylation occurs after 4 hours of treatment. After 8 hours cells undergo TdT proteolysis in addition to its inactivation. The cleavage of TdT into 32- and 58-KDa proteolytic fragments occurred simultaneously with the activation of Caspase-3, but preceded changes associated with the apoptotic process described after 48 hours of treatment. The Caspase-3 peptide inhibitor V, used as a specific inhibitor, prevented TdT proteolysis prolonging its activity and rescued cells from apoptosis. Our experiments suggest that TdT is a nuclear substrate for Caspase-3, the main apoptotic effector protease in many cell types, and that the cleavage of TdT represents a primary step in a signal cascade leading to pre-T cell apoptosis.
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Jang, Minsu, Yea-In Park, Yeo-Eun Cha, Rackhyun Park, Sim Namkoong, Jin I. Lee, and Junsoo Park. "Tea Polyphenols EGCG and Theaflavin Inhibit the Activity of SARS-CoV-2 3CL-Protease In Vitro." Evidence-Based Complementary and Alternative Medicine 2020 (September 17, 2020): 1–7. http://dx.doi.org/10.1155/2020/5630838.
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COVID-19, a global pandemic, has caused over 750,000 deaths worldwide as of August 2020. A vaccine or remedy for SARS-CoV-2, the virus responsible for COVID-19, is necessary to slow down the spread and lethality of COVID-19. However, there is currently no effective treatment available against SARS-CoV-2. In this report, we demonstrated that EGCG and theaflavin, the main active ingredients of green tea and black tea, respectively, are potentially effective to inhibit SARS-CoV-2 activity. Coronaviruses require the 3CL-protease for the cleavage of its polyprotein to make individual proteins functional. EGCG and theaflavin showed inhibitory activity against the SARS-CoV-2 3CL-protease in a dose-dependent manner, and the half inhibitory concentration (IC50) was 7.58 μg/ml for EGCG and 8.44 μg/ml for theaflavin. In addition, we did not observe any cytotoxicity for either EGCG or theaflavin at the concentrations tested up to 40 μg/ml in HEK293T cells. These results suggest that upon further study, EGCG and theaflavin can be potentially useful to treat COVID-19.
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Osmulski, Paweł A., Przemysław Karpowicz, Elżbieta Jankowska, Jonathan Bohmann, Andrew M. Pickering, and Maria Gaczyńska. "New Peptide-Based Pharmacophore Activates 20S Proteasome." Molecules 25, no. 6 (March 22, 2020): 1439. http://dx.doi.org/10.3390/molecules25061439.
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The proteasome is a pivotal element of controlled proteolysis, responsible for the catabolic arm of proteostasis. By inducing apoptosis, small molecule inhibitors of proteasome peptidolytic activities are successfully utilized in treatment of blood cancers. However, the clinical potential of proteasome activation remains relatively unexplored. In this work, we introduce short TAT peptides derived from HIV-1 Tat protein and modified with synthetic turn-stabilizing residues as proteasome agonists. Molecular docking and biochemical studies point to the α1/α2 pocket of the core proteasome α ring as the binding site of TAT peptides. We postulate that the TATs’ pharmacophore consists of an N-terminal basic pocket-docking “activation anchor” connected via a β turn inducer to a C-terminal “specificity clamp” that binds on the proteasome α surface. By allosteric effects—including destabilization of the proteasomal gate—the compounds substantially augment activity of the core proteasome in vitro. Significantly, this activation is preserved in the lysates of cultured cells treated with the compounds. We propose that the proteasome-stimulating TAT pharmacophore provides an attractive lead for future clinical use.
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Mani, Santhosh K., Sundaravadivel Balasubramanian, Juozas A. Zavadzkas, Laura B. Jeffords, William T. Rivers, Michael R. Zile, Rupak Mukherjee, Francis G. Spinale, and Dhandapani Kuppuswamy. "Calpain inhibition preserves myocardial structure and function following myocardial infarction." American Journal of Physiology-Heart and Circulatory Physiology 297, no. 5 (November 2009): H1744—H1751. http://dx.doi.org/10.1152/ajpheart.00338.2009.
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Cardiac pathology, such as myocardial infarction (MI), activates intracellular proteases that often trigger programmed cell death and contribute to maladaptive changes in myocardial structure and function. To test whether inhibition of calpain, a Ca2+-dependent cysteine protease, would prevent these changes, we used a mouse MI model. Calpeptin, an aldehydic inhibitor of calpain, was intravenously administered at 0.5 mg/kg body wt before MI induction and then at the same dose subcutaneously once per day. Both calpeptin-treated ( n = 6) and untreated ( n = 6) MI mice were used to study changes in myocardial structure and function after 4 days of MI, where end-diastolic volume (EDV) and left ventricular ejection fraction (EF) were measured by echocardiography. Calpain activation and programmed cell death were measured by immunohistochemistry, Western blotting, and TdT-mediated dUTP nick-end labeling (TUNEL). In MI mice, calpeptin treatment resulted in a significant improvement in EF [EF decreased from 67 ± 2% pre-MI to 30 ± 4% with MI only vs. 41 ± 2% with MI + calpeptin] and attenuated the increase in EDV [EDV increased from 42 ± 2 μl pre-MI to 73 ± 4 μl with MI only vs. 55 ± 4 μl with MI + calpeptin]. Furthermore, calpeptin treatment resulted in marked reduction in calpain- and caspase-3-associated changes and TUNEL staining. These studies indicate that calpain contributes to MI-induced alterations in myocardial structure and function and that it could be a potential therapeutic target in treating MI patients.
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Posma, Jens, Rene van Oerle, Diane Fens, Jose govers Riemslag, Julia Mueller, Stefan Heitmeier, Hugo ten Cate, and Henri M. H. Spronk. "Interrogation of the Coagulation Cascade Acute Coronary Syndrome Using Novel Elisa-Based Assays for Single Protease Quantification." Blood 132, Supplement 1 (November 29, 2018): 5013. http://dx.doi.org/10.1182/blood-2018-99-118353.
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Abstract Background: Acute coronary syndrome (ACS), the main contributor to myocardial infarction, is a thrombotic complication of atherosclerosis. Growing evidence supports a role for the intrinsic coagulation cascade in various thrombotic diseases. To gain more inside in the contribution of the intrinsic coagulation cascade in an ACS, we developed novel, ELISA-based assays for the quantification of Kallikrein, activated factor XII (FXIIa), FXIa, FXa, FIXa, and thrombin in complex with a physiological inhibitor. Methods: During this prospective cohort study, blood from patients with a first ACS (n=61) was collected upon admission (before heparin injection(t=0), and after 1(t=1) and 6 (t=2) months. Plasma levels of Kallikrein-C1inhibitor (K-C1inh), FXIIa-C1inh, FXIa-C1inh, FXIa-α1 anti trypsin, FXIa-antithrombin (AT), FIXa-AT, FXa-AT, and thrombin-AT(TAT) were measured using newly developed ELISA's and compared to apparently healthy controls (n=60). Methods were validated according to the EP5-protocol for within- and -between run variability. Results: The inter coefficients of variability for K-C1inh is 11.9%, FXIa-α1-AT 14.4%, FXIa-AT 13.7%, FIXa-AT 4.9%, FXa-AT 2.6% and TAT 8.6 %. Levels of FXIa-α1-AT, FXI- ΑΤ, FIXa-AT and TAT were all significantly elevated in plasma from ACS patients at time of the acute event compared to healthy control: FXIa-α1 anti trypsin respectively 202.8 (IQR 156.6 - 283.4) vs 29.0 pM (IQR 0.00 - 101.0); FXIa-AT levels were respectively 35.9 pM (IQR 23.9 - 43.4) vs 28.0 pM (IQR 23.3 - 34.0); FIXa-AT respectively 102.0pM (IQR 87.4 - 123.0) vs 90.5 pM (IQR 83.2 - 104.3); TAT respectively 5.59 (IQR 3.91 - 9.85) vs 2.26 pM (IQR 1.78 - 2.71)(Fig1). Plasma levels of FXIa-α1-AT, FXIa-AT FIXa-AT, and TAT decreased during follow up. Additionally, FXIa-α1-AT, FXIa-AT FIXa-AT, and TAT were higher in patients with ST-elevated myocardial infarction (STEMI) compared to subjects with non-STEMI or angina pectoris. Conclusion: Elisa based profiling of the coagulation proteases provide a highly sensitive and reproducible method used to distinguish the different activation states of single proteases in the coagulation cascade. With these novel assays we show that FXIa-α1-AT, FXIa-AT FIXa-AT, and TAT are significantly elevated in patients with ACS. Additionally, patients with STEMI have a more pronounced hypercoagulable state than non-STEMI and angina pectoris patients. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
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Dubiel, Wolfgang, Katherine Ferrell, and Martin Rechsteiner. "Tat-Bindung Protein 7 is a Subunit of the 26S Protease." Biological Chemistry Hoppe-Seyler 375, no. 4 (January 1994): 237–40. http://dx.doi.org/10.1515/bchm3.1994.375.4.237.
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Coronado, Mônika A., Ian Gering, Marc Sevenich, Danilo S. Olivier, Mohammadamin Mastalipour, Marcos S. Amaral, Dieter Willbold, and Raphael J. Eberle. "The Importance of Epigallocatechin as a Scaffold for Drug Development against Flaviviruses." Pharmaceutics 15, no. 3 (March 1, 2023): 803. http://dx.doi.org/10.3390/pharmaceutics15030803.
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Arboviruses such as Dengue, yellow fever, West Nile, and Zika are flaviviruses vector-borne RNA viruses transmitted biologically among vertebrate hosts by blood-taking vectors. Many flaviviruses are associated with neurological, viscerotropic, and hemorrhagic diseases, posing significant health and socioeconomic concerns as they adapt to new environments. Licensed drugs against them are currently unavailable, so searching for effective antiviral molecules is still necessary. Epigallocatechin molecules, a green tea polyphenol, have shown great virucidal potential against flaviviruses, including DENV, WNV, and ZIKV. The interaction of EGCG with the viral envelope protein and viral protease, mainly identified by computational studies, describes the interaction of these molecules with viral proteins; however, how the viral NS2B/NS3 protease interacts with epigallocatechin molecules is not yet fully deciphered. Consequently, we tested the antiviral potential of two epigallocatechin molecules (EGC and EGCG) and their derivative (AcEGCG) against DENV, YFV, WNV, and ZIKV NS2B/NS3 protease. Thus, we assayed the effect of the molecules and found that a mixture of the molecules EGC (competitive) and EGCG (noncompetitive) inhibited the virus protease of YFV, WNV, and ZIKV more effectively with IC50 values of 1.17 ± 0.2 µM, 0.58 ± 0.07 µM, and 0.57 ± 0.05 µM, respectively. As these molecules fundamentally differ in their inhibitory mode and chemical structure, our finding may open a new line for developing more effective allosteric/active site inhibitors to combat flaviviruses infection.
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Suzuka, Iwao, Yasunori Koga-Ban, Takuji Sasaki, Yuzo Minobe, and Junji Hashimoto. "Identification of cDNA clones for rice homologs of the human immunodeficiency virus-1 Tat binding protein and subunit 4 of human 26S protease (proteasome)." Plant Science 103, no. 1 (January 1994): 33–40. http://dx.doi.org/10.1016/0168-9452(94)03986-0.
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Assiry, Ali A., Shaeesta Khaleelahmed Bhavikatti, Fahad A. Althobaiti, Roshan Noor Mohamed, and Mohmed Isaqali Karobari. "Evaluation of In Vitro Antiprotease Activity of Selected Traditional Medicinal Herbs in Dentistry and Its In Silico PASS Prediction." BioMed Research International 2022 (June 6, 2022): 1–8. http://dx.doi.org/10.1155/2022/5870443.
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Background. Dental/oral diseases are one of the significant public health problems globally. Herbal medicines for managing oral diseases are considered an effective alternative to synthetic compounds due to their lower side effect. Azadirachta indica, Terminalia chebula, Camellia sinensis, and Piper nigrum are used to control and prevent oral inflammations in dentistry. In this study, we have evaluated the protease inhibition activity of these plant extracts, and further, the binding mode of the active ingredient of these plants with trypsin was studied using molecular docking. Methods. In this study, protease inhibition activity was carried out using aqueous extracts of the plant parts such as Azadirachta indica (neem) twig, Terminalia chebula (Haritaki) fruit, Camellia sinensis (green tea) powder, and Piper nigrum (kali miri) seed. Next, to explore the binding mode of active ingredients azadirachtin, chebuligenic acid, catechin, and piperine with trypsin, we employed a molecular docking study using AutoDock4.2. Results. The results revealed that the Azadirachta indica plant extract showed an IC50 value of 96.19 μg mL-1, Camellia sinensis IC50 value of 188.50 μg mL-1, Piper nigrum IC50 value of 371.20 μg mL-1, and Terminalia chebula IC50 value of 639.48 μg mL-1, when compared with standard drug diclofenac sodium, had IC50 value 93.00 μg mL-1. Further, the docking result reveals that all the main active ingredients of these plants have significant binding affinity and prefer the same binding pocket of trypsin. Conclusion. Hence, our results show the importance of traditional plants Azadirachta indica, Terminalia chebula, green tea, and Piper nigrum to control oral disease conditions. As they show significant protease inhibition activity, hence, the active ingredient could act as a potential anti-inflammatory agent and further help to prevent or control oral disease conditions such as gingivitis and periodontitis.
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Ye, Jianghua, Qi Zhang, Miao Jia, Yuhua Wang, Ying Zhang, Xiaoli Jia, Xinyu Zheng, and Haibin Wang. "The Effects of Rock Zones and Tea Tree Varieties on the Growth and Quality of Wuyi Rock Tea Based on the OPLS-DA Model and Machine Learning." Agriculture 14, no. 4 (April 3, 2024): 573. http://dx.doi.org/10.3390/agriculture14040573.
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Rock zones have an important influence on the yield and quality of Wuyi rock tea. In this study, OPLS-DA combined with machine learning was used to analyze the effects of different rock zones and tea tree varieties on the physicochemical properties of rhizosphere soil, the growth of the tea tree and the quality of the tea leaves using tea trees in different rock zones. The results showed that rock zones had significant effects on rhizosphere soil physicochemical indexes, soil enzyme activities, tea tree growth and tea quality indexes, while there was little difference between different tea tree varieties. The interaction analysis showed that the physicochemical indexes of rhizosphere soil in different rock zones significantly affected tea quality, while also affecting growth indexes. The main indexes affecting tea yield and caffeine content were soil pH, available nitrogen, total phosphorus, total nitrogen and available phosphorus, while the main indexes affecting tea quality were available potassium, organic matter, total potassium, protease, polyphenol oxidase and urease. Analyses of PCA, OPLS-DA models and KNN and ANN machine learning showed that different rock zones could be effectively distinguished from each other with 100% accuracy, while different tea varieties had little difference and could not be distinguished. TOPSIS analysis found that the physicochemical indexes most affected by rock zone were available nitrogen, available potassium and sucrose, and the quality indexes most affected by rock zone were tea polyphenols and theanine. The growth index most affected by rock zone was tea yield. It was evident that the key difference between tea trees in different rock zones was yield and quality, with high yields in continent zones, and good quality in semi-rock zones and rock zones. This study provides a crucial foundation for tea-plantation management, the artificial regulation of tea yield and the quality of different rock zones of Wuyi rock tea.
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Patel, Ashish, Alkesh Patel, Rahul Hemani, Riddhi Solanki, Janki Kansara, Gargi Patel, Sayantan Pradhan, and Tushar Bambharoliya. "Exploring the in-silico approach for assessing the potential of natural compounds as a SARS-CoV-2 main protease inhibitors." Organic Communications 14, no. 1 (March 26, 2021): 58–72. http://dx.doi.org/10.25135/acg.oc.97.2012.1895.
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The SARS-CoV-2 virus emerged as a major cause of the COVID-19 pandemic in December 2019. Many attempts have been made to block the viral infection by targeting various processes like its entry, uncoating, replication, activating T cells response, and rising antibody titer. Also, many drugs are repurposed like remdesivir, dexamethasone, tocilizumab, hydroxychloroquine based on their established therapeutic efficacy against other viruses in the past. Natural products (NP) consist of a promising candidate and are needed to evaluate those molecules with molecular docking for preliminary screening and in vitro studies. Therefore, in the present study, a total of 12 active constituents from natural products like Ashwagandha, Tinospora cordifolia, Tea, Neem and lemon balm were docked, using the Autodock tool, onto the crystal structure of SARS CoV-2 main protease (PDB ID-5R80), to study their capability to act as main protease (Mpro) COVID-19 inhibitors. All NPs derivatives displayed good binding energies (ΔG) ranging from -8.8 to -5.2 kcal/mol, but berberine, epicatechin, and rosmarinic acid were found most potent, among others. Therefore, good binding energy, drug-likeness, and efficient pharmacokinetics suggest the potential of NPs derivatives as SARS-CoV-2 main protease (Mpro) inhibitors. However, further research is necessary to investigate the ability of these compounds as COVID-19 inhibitors.
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Hamzah, Haidar Ali, Junoretta Haviva Ernanto, Putri Mahirah Afladhanti, and Theodorus Theodorus. "POTENSI DAUN TEH HIJAU (Camellia sinensis) SEBAGAI INHIBITOR MAIN PROTEASE (Mpro) COVID-19: SEBUAH STUDI MOLECULAR DOCKING." Jurnal Ilmiah Ibnu Sina (JIIS): Ilmu Farmasi dan Kesehatan 7, no. 2 (October 31, 2022): 212–22. http://dx.doi.org/10.36387/jiis.v7i2.789.
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Green tea is an herbal plant that has active compounds including anti-inflammatory, antioxidant, anti-allergic, and antiviral compounds. A previous study, flavonoid compound in tea leaves has been proven as antiviral. The development of effective antiviral drugs against COVID-19 remains a challenge for researchers across the world. A previous study investigated the role of the main protease enzyme (Mpro) which is useful in the viral life cycle as a promising drug target. This study aims to know the potential compounds of green tea leaves as a COVID-19 Mpro inhibitor using molecular docking. 12 compounds and lopinavir were used. Lipinski analysis was carried out to assess potential compounds as a drug. Docking was carried out by Autodock Tools 1.5.6 and Autodock Vina. The visualization was carried out by Discovery Studio v16. The results showed that all compounds compiled the criteria as a drug based on Lipinski rules. Catechin and epicatechin have the same energy bond as lopinavir with a binding energy of -7.1 kcal/mol. Catechin gallate and epicatechin gallate have the strongest energy bond with a binding energy of -9.0 and -8.2 kcal/mol. All compounds bind in the active site of the COVID-19 Mpro so they are competitive inhibitor. Catechin gallate is the strongest inhibitors.
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Khusniati, Tatik. "PRESERVATION OF MILKS WITH ADDITION OF ANTIBACTERIAL AND AROMATIC SUPPLEMENTS PRODUCED IN JAPAN." ASEAN Journal on Science and Technology for Development 25, no. 1 (November 19, 2017): 1–13. http://dx.doi.org/10.29037/ajstd.225.
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The good antibacterial and aromatic supplements produced in Japan for preservation of milks at storage was investigated. Nineteen sweet and herb materials were made juices as supplements to preserve the milks. Bacterial counts, pH, protease activities and lipase activities of supplemented milks, and antibacterial activities of supplements were detected by total plate counts, glass electrode pH meter, azocasein, modified Dole extraction and turbidity methods. Eleven of nineteen milks added 10% of honey, garlic, ginger, horseradish, “sansho”, “yuzu”, green perilla, “nira”, green tea, bamboo leaf and “yomogi” were selected as good supplemented milks based on pH of these milks closed to pH of milks, the lower bacterial counts, protease activities and lipase activities of these milks than that without supplements, at 5 days before up to 10 days after use by date (P<0.05), consumed materials and antibacterial activities of these supplements in inhibiting Pseudomonas fluorescens P. 33 in the nutrient media.
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Steemson, John D., Nicole J. Moreland, Deborah Williamson, Julie Morgan, Philip E. Carter, and Thomas Proft. "Survey of the bp/tee genes from clinical group A streptococcus isolates in New Zealand – implications for vaccine development." Journal of Medical Microbiology 63, no. 12 (December 1, 2014): 1670–78. http://dx.doi.org/10.1099/jmm.0.080804-0.
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Group A streptococcus (GAS) is responsible for a wide range of diseases ranging from superficial infections, such as pharyngitis and impetigo, to life-threatening diseases, such as toxic shock syndrome and acute rheumatic fever (ARF). GAS pili are hair-like extensions protruding from the cell surface and consist of highly immunogenic structural proteins: the backbone pilin (BP) and one or two accessory pilins (AP1 and AP2). The protease-resistant BP builds the pilus shaft and has been recognized as the T-antigen, which forms the basis of a major serological typing scheme that is often used as a supplement to M typing. A previous sequence analysis of the bp gene (tee gene) in 39 GAS isolates revealed 15 different bp/tee types. In this study, we sequenced the bp/tee gene from 100 GAS isolates obtained from patients with pharyngitis, ARF or invasive disease in New Zealand. We found 20 new bp/tee alleles and four new bp/tee types/subtypes. No association between bp/tee type and clinical outcome was observed. We confirmed earlier reports that the emm type and tee type are associated strongly, but we also found exceptions, where multiple tee types could be found in certain M/emm type strains, such as M/emm89. We also reported, for the first time, the existence of a chimeric bp/tee allele, which was assigned into a new subclade (bp/tee3.1). A strong sequence conservation of the bp/tee gene was observed within the individual bp/tee types/subtypes (>97 % sequence identity), as well as between historical and contemporary New Zealand and international GAS strains. This temporal and geographical sequence stability provided further evidence for the potential use of the BP/T-antigen as a vaccine target.
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Yao, Junting, Weining Yin, Yuqing Chen, Xiaoling Chen, Yangyang Jiang, Tao Wang, Chengbang Ma, et al. "Conjugation of a Cationic Cell-Penetrating Peptide with a Novel Kunitzin-like Trypsin Inhibitor: New Insights for Enhancement of Peptide Bioactivities." Pharmaceutics 14, no. 9 (August 27, 2022): 1805. http://dx.doi.org/10.3390/pharmaceutics14091805.
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Cationic cell-penetrating peptides (CPPs), such as transactivator of transcription (TAT) peptide, have been proposed as effective drug carriers to improve intracellular delivery of biological macromolecules. Amphibian skin-derived Kunitz-type trypsin inhibitors (KTIs), short counterparts of KTIs from plant sources, were found to possess potent serine protease inhibitory activity. However, poor transmembrane permeability of these molecules has largely hindered the study of the full spectrum of their biological actions. As a result, this study aimed to extend the biological activities of amphibian KTIs by their conjugation to cationic CPPs. Herein, a novel peptide (kunitzin-OV2) and its phenylalanine-substituted analogue F9-kunitzin-OV2 (F9-KOV2) were evaluated for inhibition of trypsin/chymotrypsin and showed weak antibacterial activity against Escherichia coli (E. coli). As expected, the conjugation to TAT peptide did not increase membrane lysis compared with the original kunitzin-OV2, but effectively assisted this complex to enter cells. TAT-kunitzin-OV2 (TAT-KOV2) exhibited a 32-fold increase in antibacterial activity and an enhanced bactericidal rate against E. coli. In addition, the conjugation enabled the parent peptides to exhibit antiproliferative activity against cancer cells. Interestingly, TAT-F9-kunitzin-OV2 (TAT-F9-KOV2) showed stronger antiproliferative activity against human breast cancer (MCF-7) and human glioblastoma (U251MG) cell lines, which TAT-KOV2 did not possess. Moreover, TAT-F9-KOV2 showed a 20–25-fold increase in antiproliferative capacity against human lung cancer (H157, H460) cell lines compared with TAT-KOV2. Therefore, the conjugation of CPPs effectively solves the problem of cell penetration that short KTIs lack and provides evidence for new potential applications for their subsequent development as new antibacterial and anticancer agents.
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Friesen, P. D., and M. S. Nissen. "Gene organization and transcription of TED, a lepidopteran retrotransposon integrated within the baculovirus genome." Molecular and Cellular Biology 10, no. 6 (June 1990): 3067–77. http://dx.doi.org/10.1128/mcb.10.6.3067-3077.1990.
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A single copy of the retrotransposon TED, from the moth Trichoplusia ni (a lepidopteran noctuid), was identified within the DNA genome of the baculovirus Autographa californica nuclear polyhedrosis virus. Determination of the complete nucleotide sequence (7,510 base pairs) of the integrated copy indicated that TED belongs to the family of retrotransposons that includes Drosophila melanogaster elements 17.6 and gypsy and thus represents the first nondipteran member of this invertebrate group to be identified. The internal portion of TED, flanked by long terminal repeats (LTRs), is composed of three long open reading frames comparable in size and location to the gag, pol, and env genes of the vertebrate retroviruses. Sequence similarity with the dipteran elements was the highest within individual domains of TED open reading frame 2 (pol region) that are also conserved among the retroviruses and encode protease, reverse transcriptase, and integrase functions, respectively. Mapping the 5' and 3' termini of TED RNAs indicated that the LTRs have a retroviral U3-R-U5 structural organization that is capable of directing the synthesis of transcripts that represent potential substrates for reverse transcription and intermediates in transposition. Abundant RNAs were also initiated from a site within the 5' LTR that matches the consensus motif for the promoter of late, hyperexpressed baculovirus genes. The presence of this viruslike promoter within TED and its subsequent activation only after integration within the viral genome suggest a possible symbiotic relationship with the baculovirus that could extend transposon host range.
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Friesen, P. D., and M. S. Nissen. "Gene organization and transcription of TED, a lepidopteran retrotransposon integrated within the baculovirus genome." Molecular and Cellular Biology 10, no. 6 (June 1990): 3067–77. http://dx.doi.org/10.1128/mcb.10.6.3067.
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A single copy of the retrotransposon TED, from the moth Trichoplusia ni (a lepidopteran noctuid), was identified within the DNA genome of the baculovirus Autographa californica nuclear polyhedrosis virus. Determination of the complete nucleotide sequence (7,510 base pairs) of the integrated copy indicated that TED belongs to the family of retrotransposons that includes Drosophila melanogaster elements 17.6 and gypsy and thus represents the first nondipteran member of this invertebrate group to be identified. The internal portion of TED, flanked by long terminal repeats (LTRs), is composed of three long open reading frames comparable in size and location to the gag, pol, and env genes of the vertebrate retroviruses. Sequence similarity with the dipteran elements was the highest within individual domains of TED open reading frame 2 (pol region) that are also conserved among the retroviruses and encode protease, reverse transcriptase, and integrase functions, respectively. Mapping the 5' and 3' termini of TED RNAs indicated that the LTRs have a retroviral U3-R-U5 structural organization that is capable of directing the synthesis of transcripts that represent potential substrates for reverse transcription and intermediates in transposition. Abundant RNAs were also initiated from a site within the 5' LTR that matches the consensus motif for the promoter of late, hyperexpressed baculovirus genes. The presence of this viruslike promoter within TED and its subsequent activation only after integration within the viral genome suggest a possible symbiotic relationship with the baculovirus that could extend transposon host range.
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Farooq, Taimoor Hassan, Uttam Kumar, Jing Mo, Awais Shakoor, Jun Wang, Muhammad Haroon U. Rashid, Muhammad Aammar Tufail, Xiaoyong Chen, and Wende Yan. "Intercropping of Peanut–Tea Enhances Soil Enzymatic Activity and Soil Nutrient Status at Different Soil Profiles in Subtropical Southern China." Plants 10, no. 5 (April 27, 2021): 881. http://dx.doi.org/10.3390/plants10050881.
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Intercropping is one of the most widely used agroforestry techniques, reducing the harmful impacts of external inputs such as fertilizers. It also controls soil erosion, increases soil nutrients availability, and reduces weed growth. In this study, the intercropping of peanut (Arachishypogaea L.) was done with tea plants (Camellia oleifera), and it was compared with the mono-cropping of tea and peanut. Soil health and fertility were examined by analyzing the variability in soil enzymatic activity and soil nutrients availability at different soil depths (0–10 cm, 10–20 cm, 20–30 cm, and 30–40 cm). Results showed that the peanut–tea intercropping considerably impacted the soil organic carbon (SOC), soil nutrient availability, and soil enzymatic responses at different soil depths. The activity of protease, sucrase, and acid phosphatase was higher in intercropping, while the activity of urease and catalase was higher in peanut monoculture. In intercropping, total phosphorus (TP) was 14.2%, 34.2%, 77.7%, 61.9%; total potassium (TK) was 13.4%, 20%, 27.4%, 20%; available phosphorus (AP) was 52.9%, 26.56%, 61.1%; 146.15% and available potassium (AK) was 11.1%, 43.06%, 46.79% higher than the mono-cropping of tea in respective soil layers. Additionally, available nitrogen (AN) was 51.78%, 5.92%, and 15.32% lower in the 10–20 cm, 20–30 cm, and 30–40 cm layers of the intercropping system than in the mono-cropping system of peanut. Moreover, the soil enzymatic activity was significantly correlated with SOC and total nitrogen (TN) content across all soil depths and cropping systems. The depth and path analysis effect revealed that SOC directly affected sucrase, protease, urease, and catalase enzymes in an intercropping system. It was concluded that an increase in the soil enzymatic activity in the intercropping pattern improved the reaction rate at which organic matter decomposed and released nutrients into the soil environment. Enzyme activity in the decomposition process plays a vital role in forest soil morphology and function. For efficient land use in the cropping system, it is necessary to develop coherent agroforestry practices. The results in this study revealed that intercropping certainly enhance soil nutrients status and positively impacts soil conservation.
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Chen, Yiyong, Xiumin Fu, Xin Mei, Ying Zhou, Bing Du, Youying Tu, and Ziyin Yang. "Characterization of functional proteases from flowers of tea ( Camellia sinensis ) plants." Journal of Functional Foods 25 (August 2016): 149–59. http://dx.doi.org/10.1016/j.jff.2016.05.017.
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Yang, H., K. Landis-Piwowar, T. H. Chan, and Q. P. Dou. "Green Tea Polyphenols as Proteasome Inhibitors: Implication in Chemoprevention." Current Cancer Drug Targets 11, no. 3 (March 1, 2011): 296–306. http://dx.doi.org/10.2174/156800911794519743.
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