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Cell Chemical Biology Feb 2020Cordycepin (3'-deoxyadenosine) is a major bioactive agent in Cordyceps militaris, a fungus used in traditional Chinese medicine. It has been proposed to have many...
Cordycepin (3'-deoxyadenosine) is a major bioactive agent in Cordyceps militaris, a fungus used in traditional Chinese medicine. It has been proposed to have many beneficial metabolic effects by activating AMP-activated protein kinase (AMPK), but the mechanism of activation remained uncertain. We report that cordycepin enters cells via adenosine transporters and is converted by cellular metabolism into mono-, di-, and triphosphates, which at high cordycepin concentrations can almost replace cellular adenine nucleotides. AMPK activation by cordycepin in intact cells correlates with the content of cordycepin monophosphate and not other cordycepin or adenine nucleotides. Genetic knockout of AMPK sensitizes cells to the cytotoxic effects of cordycepin. In cell-free assays, cordycepin monophosphate mimics all three effects of AMP on AMPK, while activation in cells is blocked by a γ-subunit mutation that prevents activation by AMP. Thus, cordycepin is a pro-drug that activates AMPK by being converted by cellular metabolism into the AMP analog cordycepin monophosphate.
Topics: AMP-Activated Protein Kinases; Cell Proliferation; Cell Survival; Deoxyadenine Nucleotides; Deoxyadenosines; Hep G2 Cells; Humans; Phosphorylation
PubMed: 31991096
DOI: 10.1016/j.chembiol.2020.01.004 -
International Journal of Medical... 2022Podocytes are specialized cells of the glomerulus that play important structural and functional roles in maintaining the filtration barrier. Loss and injury of podocytes...
Podocytes are specialized cells of the glomerulus that play important structural and functional roles in maintaining the filtration barrier. Loss and injury of podocytes are leading factors of glomerular disease and kidney failure. Recent studies found that phosphatase and tensin homolog (PTEN) may play a critical role in maintaining the normal structure and function in podocytes. However, we still understand very little about how PTEN is regulated under podocyte injury conditions. In this study, We therefore investigated whether PTEN could play a role in podocyte injury induced by puromycin aminonucleoside (PAN), and whether dexamethasone (DEX) alleviates podocyte injury by PTEN/PI3K/Akt signaling. Our results showed that PI3K/Akt pathway was activated in podocytes exposed to PAN conditions, accompanied by down-regulation of the PTEN and microtubule-associated light chain 3 (LC3) expression.podocyte-specific knockout of PTEN significantly promoted podocyte injury, The potential renoprotection of overexpressed PTEN in podocytes was partly attributed with an improvement in autophagy and the inhibition of apoptosis.These novel findings also suggest that targeting PTEN might be a novel and promising therapeutic strategy against podocyte injury.
Topics: Autophagy; Phosphatidylinositol 3-Kinases; Podocytes; Proto-Oncogene Proteins c-akt; Puromycin Aminonucleoside
PubMed: 36035365
DOI: 10.7150/ijms.72988 -
Drugs Dec 2020Cladribine is a purine nucleoside analog initially developed in the 1970s as a treatment for various blood cancers. Due to the molecule's ability to preferentially... (Review)
Review
Cladribine is a purine nucleoside analog initially developed in the 1970s as a treatment for various blood cancers. Due to the molecule's ability to preferentially reduce T and B lymphocytes, it has been developed into an oral formulation for the treatment of multiple sclerosis (MS). The unique proposed mechanism of action of cladribine allows for the therapy to be delivered orally over two treatment-week cycles per year, one cycle at the beginning of the first month and one cycle at the beginning of the second month of years 1 and 2, with the potential for no further cladribine treatment required in years 3 and 4. This review summarizes the clinical development program for cladribine tablets in patients with MS, including the efficacy endpoints and results from the 2-year phase III CLARITY study in patients with relapsing-remitting MS (RRMS), the 2-year CLARITY EXTENSION study, and the phase III ORACLE-MS study in patients with a first clinical demyelinating event at risk for developing MS. Efficacy results from the phase II ONWARD study, in which cladribine tablets were administered as an add-on to interferon-β therapy in patients with RRMS, are also summarized. A review of all safety data, including lymphopenia, infections, and malignancies, is provided based on data from all trials in patients with MS, including the initial parenteral formulation studies. Based on these data, cladribine tablets administered at 3.5 mg/kg over 2 years have been approved across the globe for various forms of relapsing MS. The development of cladribine tablets for the treatment of multiple sclerosis: a comprehensive review (MP4 279143 kb).
Topics: Chemistry, Pharmaceutical; Cladribine; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Tablets
PubMed: 33247831
DOI: 10.1007/s40265-020-01422-9 -
Environmental Science and Pollution... Apr 2023Capecitabine (CAP, prodrug) and 5-fluorouracil (5-FU, its active metabolite) are two of the most prominent cytostatics, for which no clear picture can be drawn regarding...
Capecitabine (CAP, prodrug) and 5-fluorouracil (5-FU, its active metabolite) are two of the most prominent cytostatics, for which no clear picture can be drawn regarding potential concentrations of effect for freshwater biota, with CAP being grouped in the least studied cytostatic, whereas 5-FU has been classified as of no and of high environmental risk. Accordingly, the present work aimed to assess the ecotoxicity of CAP and 5-FU in three freshwater species, which included a 72-h assay with the producer Raphidocelis subcapitata; a 96-h assay with the invertebrate secondary consumer Hydra viridissima; and a 96-h assay with embryos of the vertebrate secondary consumer Danio rerio. The following endpoints were monitored: yield and population growth rate for the algae; mortality, morphological alterations, and post-exposure feeding rates for the cnidarian; and mortality, hatching, and malformations for the fish. Overall, organisms' sensitivity to CAP decreased in the following order: R. subcapitata > H. viridissima > D. rerio, whereas for 5-FU, it decreased in the following order: H. viridissima > D. rerio > R. subcapitata. For CAP, no median lethal effective concentrations (LC/EC) were possible to compute for D. rerio, with no significant mortality or malformations registered in embryos exposed at concentrations up to 800 mg L. For R. subcapitata, the ECs were 0.077 and 0.63 mg L for yield and growth rate, respectively, and for H. viridissima, the EC for feeding was 22.0 mg L. For 5-FU, no EC could be computed for R. subcapitata, whilst the EC for H. viridissima mortality and feeding were 55.4 and 67.9 mg L, respectively, and for D. rerio, the LC and EC (hatching and abnormalities) were 4546, 4100, and 2459 mg L, respectively. Assuming similar modes of action for both compounds and their co-occurrence, the combined risk quotient of the two chemicals was determined to be 7.97, which represents a risk for freshwater biota. Anticipating the increased consumption of these compounds and cancer development trends worldwide, these impacts may be further aggravated.
Topics: Animals; Capecitabine; Zebrafish; Fluorouracil; Chlorophyceae; Fresh Water; Water Pollutants, Chemical
PubMed: 36997780
DOI: 10.1007/s11356-023-26505-4 -
The Oncologist May 2020Pancreatic ductal adenocarcinoma (PDAC) remains resistant to chemotherapy and immunotherapy individually because of its desmoplastic stroma and immunosuppressive tumor...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) remains resistant to chemotherapy and immunotherapy individually because of its desmoplastic stroma and immunosuppressive tumor microenvironment. Synergizing cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) immune checkpoint blockade with chemotherapy could overcome these barriers. Here we present results of a phase Ib trial combining ipilimumab and gemcitabine in advanced PDAC.
MATERIALS AND METHODS
This was a single-institution study with a 3 + 3 dose-escalation design. The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included determining the toxicity profile, objective response rate (ORR), median progression-free survival (PFS), and overall survival (OS).
RESULTS
Twenty-one patients were enrolled, 13 during dose escalation and 8 at the MTD. The median age was 66 years, 62% were female, 95% had stage IV disease, and 67% had received at least one prior line of therapy. The primary objective to establish the MTD was achieved at doses of ipilimumab 3 mg/kg and gemcitabine 1,000 mg/m . The most common grade 3 or 4 adverse events were anemia (48%), leukopenia (48%), and neutropenia (43%). The ORR was 14% (3/21), and seven patients had stable disease. Median response duration for the three responders was 11 months, with one response duration of 19.8 months. Median PFS was 2.78 months (95% confidence interval [CI], 1.61-4.83 months), and median OS was 6.90 months (95% CI, 2.63-9.57 months).
CONCLUSION
Gemcitabine and ipilimumab is a safe and tolerable regimen for PDAC with a similar response rate to gemcitabine alone. As in other immunotherapy trials, responses were relatively durable in this study.
IMPLICATIONS FOR PRACTICE
Gemcitabine and ipilimumab is a safe and feasible regimen for treating advanced pancreatic cancer. Although one patient in this study had a relatively durable response of nearly 20 months, adding ipilimumab to gemcitabine does not appear to be more effective than gemcitabine alone in advanced pancreatic cancer.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Humans; Ipilimumab; Male; Pancreatic Neoplasms; Tumor Microenvironment; Gemcitabine
PubMed: 31740568
DOI: 10.1634/theoncologist.2019-0473 -
Biomolecules Oct 2020Gemcitabine-based chemotherapy is the current standard treatment for biliary tract cancers (BTCs) and resistance to gemcitabine remains the clinical challenge. mutation... (Review)
Review
Gemcitabine-based chemotherapy is the current standard treatment for biliary tract cancers (BTCs) and resistance to gemcitabine remains the clinical challenge. mutation has been shown to be associated with poor clinicopathologic characteristics and survival in patients with BTCs, indicating that p53 plays an important role in the treatment of these cancers. Herein, we comprehensively reviewed previous BTC preclinical research and early clinical trials in terms of p53, as well as novel p53-targeted treatment, alone or in combination with either chemotherapy or other targeted therapies in BTCs. Preclinical studies have demonstrated that p53 mutations in BTCs are associated with enhanced gemcitabine resistance, therefore targeting p53 may be a novel therapeutic strategy for treatment of BTCs. Directly targeting mutant p53 by p53 activators, or indirectly by targeting cell cycle checkpoint proteins (Chk1, ataxia telangiectasia related (ATR), and Wee1) leading to synthetic lethality, may be potential future strategies for gemcitabine-resistant p53 mutated BTCs. In contrast, for wild-type p53 BTCs, activation of p53 by inhibition of its negative regulators (MDM2 and wild-type p53-induced phosphatase 1 (WIP1)) may be alternative options. Combination therapies consisting of standard cytotoxic drugs and novel small molecules targeting p53 and related signaling pathways may be the future key standard approach to beat cancer.
Topics: Antimetabolites, Antineoplastic; Biliary Tract Neoplasms; Deoxycytidine; Drug Resistance, Neoplasm; Humans; Tumor Suppressor Protein p53; Gemcitabine
PubMed: 33113997
DOI: 10.3390/biom10111474 -
The Science of the Total Environment Apr 2023Selenium is an element present in trace amounts and different chemical forms. It may exert both beneficial and adverse effects on cellular redox status and on the...
Selenium is an element present in trace amounts and different chemical forms. It may exert both beneficial and adverse effects on cellular redox status and on the generation of reactive oxygen species. 8-oxo-7,8-dihydro-2'deoxyguanosine (8-oxodG) is an oxidized derivative of deoxyguanosine, and a sensitive biomarker of oxidative stress and genotoxicity. The present study assessed the extent to which selenium status was associated with urinary 8-oxodG concentrations in a Northern Italian population. We recruited healthy, non-smoking blood donors living in the Reggio Emilia province during 2017-2019. We measured urinary 8-oxodG concentrations and used restricted cubic spline regression analyses to investigate the association between selenium status (estimated using food frequency questionnaires, urinary concentrations, and serum concentrations of selenium and selenium species) and 8-oxodG/g creatinine. Among 137 participants aged 30-60 years, median urinary selenium and 8-oxodG concentrations were 22.02 μg/L and 3.21 μg/g creatinine, respectively. Serum samples and selenium speciation analyses were available for 104 participants. Median total serum selenium levels and dietary intake were 116.5 μg/L and 78.7 μg/day, respectively. In spline regression analysis, there was little association between dietary, serum, or urinary selenium with 8-oxodG concentrations. In sex-specific analyses, urinary selenium showed a positive association with the endpoint among males. For single selenium species, we observed positive associations with urinary 8-oxodG for serum organic selenium species, and negative associations for inorganic selenium forms. In the most adjusted analysis, urinary 8-oxodG concentrations showed a strong positive association with selenomethione-bound selenium (Se-Met) and a negative association with inorganic tetravalent selenium, selenite. In sex-specific analyses, these associations were considerably stronger in males than in females. Overall, study findings indicate that selenium species exhibited very different patterns of associations with the biomarker of oxidative stress, and that these associations also depended on sex. Background exposure to Se-Met appears to be strongly and positively associated with oxidative stress.
Topics: Male; Female; Humans; 8-Hydroxy-2'-Deoxyguanosine; Deoxyguanosine; Selenium; Creatinine; Oxidative Stress; Biomarkers
PubMed: 36702271
DOI: 10.1016/j.scitotenv.2023.161584 -
Cancer Treatment and Research... 2023The combination of endocrine treatment with cycline-dependent-kinase 4/6 inhibitor is the new standard of treatment in hormone receptor-positive HER2 negative metastatic...
BACKGROUND
The combination of endocrine treatment with cycline-dependent-kinase 4/6 inhibitor is the new standard of treatment in hormone receptor-positive HER2 negative metastatic breast cancer. The optimal subsequent treatment after CDK4/6 inhibitor remain unclear. As recommended by standard guidelines, capecitabine, an oral chemotherapy is a therapeutic option in endocrine resistant metastatic breast cancer. The objective of this study was to evaluate capecitabine efficacy after disease progression under combination of ET and CDK4/6 inhibitor in a hormone receptor positive metastatic breast cancer population.
PATIENTS AND METHODS
Patients progressing under CDK 4/6 inhibitor plus ET and treated with capecitabine, between January 2016 and December 2020, were retrospectively included. Primary endpoint was time to treatment failure (TTF) on capecitabine. Logistic regression were used to identify predictive factors: exclusive bone versus visceral metastases, first-line versus ≥ 2 lines of combination therapy, aromatase inhibitor (AI) versus fulvestrant.
RESULTS
Fifty-six patients with a 62-year median age (IC95% 42-81) were analyzed. The CDK 4/6 inhibitor and ET combination was prescribed in first-line setting in 26 patients (46%). Twenty-five patients (44%) had exclusive bone metastasis. Median TTF was 6.1 months. Six patients discontinued capecitabine due to toxicity. Outcomes were not significantly different regardless of metastases localization, ET, and treatment line of the combination of CDK 4/6 inhibitor and ET. Median PFS was 7.1 months. Median OS was 41.3 months.
CONCLUSION
Compared to other data of capecitabine prescribed in patients with hormonal resistant MBC, this retrospective study suggests that capecitabine remains effective after CDK 4/6 inhibitor plus ET progression, regardless of therapeutic-line setting and metastases localization.
MICRO ABSTRACT
Cycline dependant kinase 4/6 inhibitor plus endocrine therapy have become the standard of care in metastatic hormone receptor positive (HR+) breast cancer (BC). Few data reported the optimal subsequent therapy after progression under the combination. Capecitabine is a therapeutic option in endocrine resistant HR+/HER2- metastatic breast cancer. Data evaluating efficacy of capecitabine after disease progression on endocrine therapy plus cycline-dependant kinase 4/6 inhibitor are poor. This study showed a 6.1-month median time to treatment failure on capecitabine. Capecitabine remained effective regardless of therapeutic-line setting and metastases localization.
Topics: Humans; Female; Capecitabine; Breast Neoplasms; Retrospective Studies; Receptor, ErbB-2; Antineoplastic Agents; Protein Kinase Inhibitors; Disease Progression
PubMed: 37390791
DOI: 10.1016/j.ctarc.2023.100738 -
Annals of Neurology Aug 2019Thymidine kinase 2, encoded by the nuclear gene TK2, is required for mitochondrial DNA maintenance. Autosomal recessive TK2 mutations cause depletion and multiple...
OBJECTIVE
Thymidine kinase 2, encoded by the nuclear gene TK2, is required for mitochondrial DNA maintenance. Autosomal recessive TK2 mutations cause depletion and multiple deletions of mtDNA that manifest predominantly as a myopathy usually beginning in childhood and progressing relentlessly. We investigated the safety and efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies.
METHODS
We administered deoxynucleoside monophosphates and deoxynucleoside to 16 TK2-deficient patients under a compassionate use program.
RESULTS
In 5 patients with early onset and severe disease, survival and motor functions were better than historically untreated patients. In 11 childhood and adult onset patients, clinical measures stabilized or improved. Three of 8 patients who were nonambulatory at baseline gained the ability to walk on therapy; 4 of 5 patients who required enteric nutrition were able to discontinue feeding tube use; and 1 of 9 patients who required mechanical ventilation became able to breathe independently. In motor functional scales, improvements were observed in the 6-minute walk test performance in 7 of 8 subjects, Egen Klassifikation in 2 of 3, and North Star Ambulatory Assessment in all 5 tested. Baseline elevated serum growth differentiation factor 15 levels decreased with treatment in all 7 patients tested. A side effect observed in 8 of the 16 patients was dose-dependent diarrhea, which did not require withdrawal of treatment. Among 12 other TK2 patients treated with deoxynucleoside, 2 adults developed elevated liver enzymes that normalized following discontinuation of therapy.
INTERPRETATION
This open-label study indicates favorable side effect profiles and clinical efficacy of deoxynucleoside monophosphate and deoxynucleoside therapies for TK2 deficiency. ANN NEUROL 2019;86:293-303.
Topics: Adult; Child; Child, Preschool; Compassionate Use Trials; Deoxyribonucleosides; Female; Humans; Male; Muscular Diseases; Thymidine Kinase; Walk Test
PubMed: 31125140
DOI: 10.1002/ana.25506 -
Aging Mar 2024CR6-interacting factor 1 (CRIF1), a multifunctional protein that affects mitochondrial function and cell senescence, plays a regulatory role in heart-related diseases....
BACKGROUND
CR6-interacting factor 1 (CRIF1), a multifunctional protein that affects mitochondrial function and cell senescence, plays a regulatory role in heart-related diseases. However, whether CRIF1 participates in myocardial senescence by regulating mitochondrial function remains unclear.
METHODS
Doxorubicin (DOX)-induced C57BL/6 mice to construct mouse myocardial senescence model, and the myocardial function indicators including lactate dehydrogenase (LDH) and Creatine kinase isoform MB (CK-MB) were assessed. The expression of CRIF1 was detected by western blot. Myocardial pathological changes were examined by transthoracic echocardiography and haematoxylin and eosin (H&E) staining. Cell senescence was detected by SA-β-gal staining. JC-1 staining was used to detect mitochondrial membrane potential. Biochemical kits were used to examine oxidative stress-related factors. Additionally, AC16 cardiomyocytes were treated with DOX to mimic the cellular senescence model . Cell activity was detected by cell counting kit-8 (CCK-8) assay. Co-immunoprecipitation (CO-IP) was used to verify the relationship between CRIF1 and peroxidasin (PXDN).
RESULTS
The CRIF1 expression was significantly decreased in DOX-induced senescent mice and AC16 cells. Overexpression of CRIF1 significantly ameliorated DOX-induced myocardial dysfunction and myocardial senescence. Additionally, CRIF1 overexpression attenuated DOX-induced oxidative stress and myocardial mitochondrial dysfunction. Consistently, CRIF1 overexpression also inhibited DOX-induced oxidative stress and senescence in AC16 cells. Moreover, CRIF1 was verified to bind to PXDN and inhibited PXDN expression. The inhibitory effects of CRIF1 overexpression on DOX-induced oxidative stress and senescence in AC16 cells were partly abolished by PXDN expression.
CONCLUSIONS
CRIF1 plays a protective role against DOX-caused mitochondrial dysfunction and myocardial senescence partly through downregulating PXDN.
Topics: Mice; Animals; Mice, Inbred C57BL; Doxorubicin; Myocardium; Oxidative Stress; Myocytes, Cardiac; Mitochondrial Diseases; Apoptosis; Deoxyribonucleosides; Purine Nucleosides
PubMed: 38517371
DOI: 10.18632/aging.205664