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Digestive and Liver Disease : Official... Jul 2023The asparaginase-like protein 1 (ASRGL1) catalyzes the hydrolysis of L-asparagine to L-aspartic acid and ammonia. Emerging evidences have shown a strong correlation...
The asparaginase-like protein 1 (ASRGL1) catalyzes the hydrolysis of L-asparagine to L-aspartic acid and ammonia. Emerging evidences have shown a strong correlation between ASRGL1 expression and tumorigenesis. However, the expression and biological function of ASRGL1 in hepatocellular carcinoma (HCC) are still unclear. Here, we explored anti-tumor activity and fundamental mechanisms of ASRGL1 blockade in the HCC progression. Expression levels of ASRGL1 in patients with HCC were higher than those in the adjacent normal tissue. In addition, increased expression of ASRGL1 in HCC patients was correlated with poor overall survival. Knockdown of ASRGL1 gene in HepG2 and Li-7 cell lines inhibited cell proliferation, migration and invasion, but promoted apoptosis in vitro. ASRGL1 knockdown suppressed tumor growth in vivo. Conversely, ASRGL1 overexpression promoted cell proliferation, migration and invasion in HepG2 cells. Through bioinformatics analysis, we found that ASRGL1 might participate in the regulation of the cell cycle. Flow cytometry analysis conformed that ASRGL1 knockdown captured the cell cycle during the G2/M phase. ASRGL1 blockade promoted P53 protein expression and reduced expression of cyclin B and CDK1 proteins, as well as failed to binding. Moreover, CDK1 overexpression was able to reverse the decreased proliferation, migration and invasion of HepG2 cells induced by ASRGL1 knockdown. Collectively, our studies indicate that ASRGL1 blockade functions to inhibit cyclin B/CDK1-dependent cell cycle, leading to G2-to-M phase transition failure and tumor suppression in HCC.
Topics: Humans; Carcinoma, Hepatocellular; Down-Regulation; Liver Neoplasms; Cell Line, Tumor; Cell Proliferation; Hep G2 Cells; Apoptosis; Carcinogenesis; Gene Expression Regulation, Neoplastic; Cell Movement; CDC2 Protein Kinase
PubMed: 36572570
DOI: 10.1016/j.dld.2022.12.003 -
Veterinary Medicine and Science Mar 2024Feline large granular lymphocyte (LGL) lymphoma is an aggressive neoplasia characterised by short survival and poor response to chemotherapy.
BACKGROUND
Feline large granular lymphocyte (LGL) lymphoma is an aggressive neoplasia characterised by short survival and poor response to chemotherapy.
OBJECTIVES
In this study, the effect of different chemotherapeutic agents on the growth kinetics of the feline cell line S87, a non-MHC-restricted feline LGL cell line, was investigated. Where possible, IC (inhibitory concentration 50) values were determined. The IC values of the cell line as lymphoma models can provide clues to the situation in vivo and serve as a basis for studying resistance mechanisms.
METHODS
Cells were incubated with various concentrations of vincristine, doxorubicin, 4-hydroperoxycyclophosphamide, prednisolone, methotrexate and L-asparaginase for 24 and 48 h, respectively.
RESULTS
The IC values could be determined as 14.57 (7.49-28.32) μg/mL at 24 h incubation and 5.72 (4.05-8.07) μg/mL at 48 h incubation for doxorubicin and 9.12 (7.72-10.76) μg/mL at 24 h incubation and 4.53 (3.74-5.47) μg/mL at 48 h incubation for 4-hydroperpoxycyclophosphamide. Treatment with vincristine and methotrexate resulted in relatively high cell resistance whereas L-asparaginase and prednisolone treatment led to a reduction in cell number compared to control while cell viability was not affected (cytostatic effect).
CONCLUSION
Overall, the feline LGL cell line S87 proves to be relatively sensitive to doxorubicin and 4-hydroperoxycyclophosphamide and relatively resistant to treatment with vincristine, prednisolone, methotrexate and L-asparaginase. The results of this study can be used for further investigations on resistance mechanisms in feline LGL lymphoma. Doxorubicin and cyclophosphamide can be interpreted as promising candidates for the therapy of feline LGL lymphomas.
Topics: Cats; Animals; Vincristine; Asparaginase; Methotrexate; Lymphoma; Doxorubicin; Cell Line; Prednisolone; Lymphocytes; Cat Diseases; Cyclophosphamide
PubMed: 38373050
DOI: 10.1002/vms3.1350 -
Alternative Therapies in Health and... Jan 2024To improve the understanding of aggressive NK-cell leukemia (ANKL) and summarize the progress of its diagnosis and treatment.
OBJECTIVE
To improve the understanding of aggressive NK-cell leukemia (ANKL) and summarize the progress of its diagnosis and treatment.
METHODS
We retrospectively analyzed a case of a patient who was initially diagnosed with T-cell lymphoma (non-specific type) and later transformed into ANKL through examinations such as bone marrow smear, flow cytometry, Q-mNGS, and pathology. We described the patient's diagnostic and treatment journey and conducted a literature review.
RESULTS
The patient presented with concomitant hemophagocytic syndrome upon admission. After treatment with the HLH-94 regimen, the patient developed tumor lysis syndrome, leading to a sudden onset of ventricular tachycardia and respiratory and cardiac arrest on the third day of admission. Despite aggressive resuscitation efforts, the patient did not survive.
CONCLUSIONS
ANKL is rare in the world, and the disease is aggressive, so it is necessary to diagnose early and intervene timely. Bone marrow smear, flow cytometer and Q-mNGS are helpful to identify tumors quickly and determine the direction of diagnosis and treatment. This disease is often accompanied by hemophagocytic syndrome. When the pathogenesis is not clear, it is recommended to treat it with hormone and gamma globulin first, and after clarification, chemotherapy containing L-asparaginase may be added; pay attention to supportive treatment and vigilance against oncolysis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be performed as soon as possible, and the application of targeted drugs may further improve the curative effect. In a word, ANKL needs more data statistics and analysis to guide clinical diagnosis and treatment.
PubMed: 38330588
DOI: No ID Found -
Pharmaceutics Sep 2023The search for new drug-producing microorganisms is one of the most promising situations in current world scientific scenarios. The use of molecular biology as well as...
The search for new drug-producing microorganisms is one of the most promising situations in current world scientific scenarios. The use of molecular biology as well as the cloning of protein and compound genes is already well established as the gold standard method of increasing productivity. Aiming at this increase in productivity, this work aims at the cloning, purification and in silico analysis of l-asparaginase from in Komagataella phaffii ( protein expression systems. The l-asparaginase gene (NCBI OQ439985) has been cloned into strains. Enzyme production was analyzed via the quantification of aspartic B-hydroxamate, followed by purification on a DEAE FF ion exchange column. The in silico analysis was proposed based on the combined use of various technological tools. The enzymatic activity found intracellularly was 2.84 IU/g. A purification factor of 1.18 was observed. The in silico analysis revealed the position of five important amino acid residues for enzymatic activity, and likewise, it was possible to predict a monomeric structure with a C-score of 1.59. The production of the enzyme l-asparaginase from in was demonstrated in this work, being of great importance for the analysis of new methodologies in search of the production of important drugs in therapy.
PubMed: 37765320
DOI: 10.3390/pharmaceutics15092352 -
ACS Omega Jan 2024l-Asparaginase (E.C. 3.5.1.1) is an indispensable analeptic anticancer enzyme used as an amalgam with additional cancer medicines for the cure of acute lymphoblastic...
l-Asparaginase (E.C. 3.5.1.1) is an indispensable analeptic anticancer enzyme used as an amalgam with additional cancer medicines for the cure of acute lymphoblastic leukemia (ALL). The presence of lAparaginase in tomato was confirmed byWestern blotting and DNA sequencing. The l-Asparaginase gene from tomato has been deposited in the NCBI database with accession number: OR736141. Crude enzyme was extracted from the fruit pulp of and the activity was determined by the Nesslerization method. Further, the crude extract was subjected to purification, and kinetic parameters were studied. The percentage yield was calculated to be 6.457, and the purification fold was 0.086. The enzyme showed maximum activity at optimum pH 7.0, optimum temperature 37 °C, and incubation time of 05 min. The Michaelis constant "" and maximum velocity "" values were determined by the Lineweaver-Burk plot, which showed a low value of 0.66 and of 3.846 IU. Cytotoxic studies were carried out for crude and purified l-asparaginase. Purified l-Asparaginase has exhibited anticancer activity against the ALL model system, K-562 cell line, comparable to that of the anticancer compound vinblastine. Hence, l-Asparaginase from the fruit extract of tomato could be used as a nutraceutical to support cancer treatment in acute lymphoblastic leukemia.
PubMed: 38284052
DOI: 10.1021/acsomega.3c07633 -
The Journal of Veterinary Medical... Jun 2024L-Asparaginase (L-Asp) is often used to induce remission in feline large-cell gastrointestinal lymphoma (LCGIL). However, no study has evaluated the efficacy and adverse...
L-Asparaginase (L-Asp) is often used to induce remission in feline large-cell gastrointestinal lymphoma (LCGIL). However, no study has evaluated the efficacy and adverse events following the initial use of this drug as a first-line treatment in feline LCGIL. We retrospectively reviewed medical records of cats with LCGIL treated with L-Asp to induce remission. This study included 43 cats. The response rate (RR) after the first administration of L-Asp was 37.2% (Complete remission: 7.0 %, partial remission: 30.2%). RR was significantly higher in cases with primary gastric lesions (64.3%) than in those with primary intestinal lesions (24.1%) (P=0.018), and it was also higher in cases without anemia (57.1%) than those with anemia (15.0%) (P=0.009). The most common adverse event was hyperammonemia, which occurred in 10 of 12 cases where we could compare plasma ammonia concentrations before and after the first dose of L-Asp. Plasma phosphate concentrations were also significantly increased (P<0.001) within 24 hr after the first dose. Decreased appetite, vomiting, and diarrhea were also observed in five, three, and seven cases, respectively, and Grade 3 or higher gastrointestinal signs were observed as adverse events in three cases. The median overall survival of all cats was 150 days (range, 5-1,065 days), and the median progression-free survival was 104 days (range, 2-978 days). In conclusion, L-Asp was effective to induce remission, and severe adverse events were uncommon in feline LCGIL.
PubMed: 38825481
DOI: 10.1292/jvms.23-0453 -
Clinical Hematology International 2023Asparaginase-associated pancreatitis complicates 2-10% of patients treated for acute lymphoblastic leukemia, causing morbidity and discontinuation of asparaginase...
Asparaginase-associated Pancreatitis Complicated by Pancreatic Fluid Collection Treated with Endoscopic Cistogastrostomy in Pediatric Acute Lymphoblastic Leukemia: A Case Report and Systematic Review of the Literature.
Asparaginase-associated pancreatitis complicates 2-10% of patients treated for acute lymphoblastic leukemia, causing morbidity and discontinuation of asparaginase administration. Among acute complications, pancreatic fluid collections can be managed conservatively, but intervention is indicated when associated with persistent insulin therapy need and recurrent abdominal pain. Endoscopic treatment has become the standard approach in adult patients, with increasing favorable evidence in children. This work compares the characteristics of a pediatric oncology patient treated at our institution with reported literature experiences, showing feasibility, safety and effectiveness of endoscopic approach.
PubMed: 38817959
DOI: 10.46989/001c.90958 -
F1000Research 2023On the occasion of the 20th anniversary of the discovery of acrylamide in food, an analysis of patents related to the mitigation of this compound in food products... (Review)
Review
On the occasion of the 20th anniversary of the discovery of acrylamide in food, an analysis of patents related to the mitigation of this compound in food products obtained through immersion frying was carried out. For this purpose, a comprehensive search, compilation, and information analysis were conducted using free online databases such as Google Patents, Patenscope, and Lens. The search yielded a total of 79 patents within the considered time period (2002-2022). The countries with the highest number of granted patents were the United States, the European Union, and South Korea. The patents were classified into four main approaches: raw material modification (49%), application of pre-treatments (27%), process modification (16%), and measurement techniques (8%). Among the results, Frito-Lay, an American company, stands out as the food industry company with the highest number of granted patents, totaling 15. Based on this review, it is concluded that while a significant number of patents have been granted in recent years, there is still a lag in developing countries. Furthermore, more studies are needed to determine acrylamide in starchy food matrices subjected to immersion frying different from potatoes.
Topics: Acrylamide; Cooking; Food Analysis; Patents as Topic; Starch
PubMed: 38434634
DOI: 10.12688/f1000research.140948.1 -
The Application of Clinical Genetics 2023L-asparaginase is a vital component for the treatment of childhood acute lymphoblastic leukemia (ALL); however, hypersensitivity reactions and hepatotoxicity hinder its...
Evaluating the Frequencies of , and Variant Alleles and Their Association with L-Asparaginase Hypersensitivity in Pediatric Acute Lymphoblastic Leukemia in Addis Ababa, Ethiopia.
INTRODUCTION
L-asparaginase is a vital component for the treatment of childhood acute lymphoblastic leukemia (ALL); however, hypersensitivity reactions and hepatotoxicity hinder its anti-neoplastic efficacy. Previous reports indicated that genetic variants in , and genes might be associated with hypersensitivity reactions and with liver function.
OBJECTIVE
In this study, it was investigated whether this association also exists in a pediatric ALL cohort from Ethiopia.
METHODS
Three variants rs4958351, rs73062673, and rs6021191 were genotyped in a cohort of 160 patients. Association analysis to investigate the association with hypersensitivity reactions was performed using logistic regression analyses. Besides these variants, a variant in (rs738409) was genotyped to assess the association with liver function.
RESULTS
Genotype frequencies of rs4958351, rs73062673, and rs6021191 were higher/lower than previously reported. One hundred and forty-four patients were included in the association analysis of which, 18 (12.5%) developed L-ASP hypersensitivity. Though the frequency of hypersensitivity was higher in patients that carried the risk alleles of the three investigated genes, no statistically significant differences were observed. Association analysis between rs738409 and liver function could not be investigated due to a lack of clinical information.
CONCLUSION
In conclusion, none of the tested genes did predict L-asparaginase hypersensitivity in an Ethiopian pediatric ALL patients.
PubMed: 37551203
DOI: 10.2147/TACG.S404695 -
Advanced Science (Weinheim,... Aug 2023L-Asparaginase (ASP) is well-known for its excellent efficacy in treating hematological malignancies. Unfortunately, the intrinsic shortcomings of ASP, namely high...
L-Asparaginase (ASP) is well-known for its excellent efficacy in treating hematological malignancies. Unfortunately, the intrinsic shortcomings of ASP, namely high immunogenicity, severe toxicity, short half-life, and poor stability, restrict its clinical usage. Poly(ethylene glycol) conjugation (PEGylation) of ASP is an effective strategy to address these issues, but it is not ideal in clinical applications due to complex chemical synthesis procedures, reduced ASP activity after conjugation, and pre-existing anti-PEG antibodies in humans. Herein, the authors genetically engineered an elastin-like polypeptide (ELP)-fused ASP (ASP-ELP), a core-shell structured tetramer predicted by AlphaFold2, to overcome the limitations of ASP and PEG-ASP. Notably, the unique thermosensitivity of ASP-ELP enables the in situ formation of a sustained-release depot post-injection with zero-order release kinetics over a long time. The in vitro and in vivo studies reveal that ASP-ELP possesses increased activity retention, improved stability, extended half-life, mitigated immunogenicity, reduced toxicity, and enhanced efficacy compared to ASP and PEG-ASP. Indeed, ASP-ELP treatment in leukemia or lymphoma mouse models of cell line-derived xenograft (CDX) shows potent anti-cancer effects with significantly prolonged survival. The findings also indicate that artificial intelligence (AI)-assisted genetic engineering is instructive in designing protein-polypeptide conjugates and may pave the way to develop next-generation biologics to enhance cancer treatment.
Topics: Animals; Mice; Humans; Asparaginase; Artificial Intelligence; Neoplasms; Peptides; Hematologic Neoplasms
PubMed: 37271878
DOI: 10.1002/advs.202300469