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Chembiochem : a European Journal of... Jun 2021Selenium-modified nucleosides are powerful tools to study the structure and function of nucleic acids and their protein interactions. The widespread application of...
Selenium-modified nucleosides are powerful tools to study the structure and function of nucleic acids and their protein interactions. The widespread application of 2-selenopyrimidine nucleosides is currently limited by low yields in established synthetic routes. Herein, we describe the optimization of the synthesis of 2-Se-uridine and 2-Se-thymidine derivatives by thermostable nucleoside phosphorylases in transglycosylation reactions using natural uridine or thymidine as sugar donors. Reactions were performed at 60 or 80 °C and at pH 9 under hypoxic conditions to improve the solubility and stability of the 2-Se-nucleobases in aqueous media. To optimize the conversion, the reaction equilibria in analytical transglycosylation reactions were studied. The equilibrium constants of phosphorolysis of the 2-Se-pyrimidines were between 5 and 10, and therefore differ by an order of magnitude from the equilibrium constants of any other known case. Hence, the thermodynamic properties of the target nucleosides are inherently unfavorable, and this complicates their synthesis significantly. A tenfold excess of sugar donor was needed to achieve 40-48 % conversion to the target nucleoside. Scale-up of the optimized conditions provided four Se-containing nucleosides in 6-40 % isolated yield, which compares favorably to established chemical routes.
Topics: Biocatalysis; Glycosylation; Molecular Structure; Nucleosides; Organoselenium Compounds; Pentosyltransferases; Thermodynamics; Thymidine
PubMed: 33594780
DOI: 10.1002/cbic.202100067 -
International Journal of Environmental... Jul 2021Cardiovascular complications are the leading cause of morbidity and mortality at any stage of chronic kidney disease (CKD). Moreover, the high rate of cardiovascular...
BACKGROUND
Cardiovascular complications are the leading cause of morbidity and mortality at any stage of chronic kidney disease (CKD). Moreover, the high rate of cardiovascular mortality observed in these patients is associated with an accelerated atherosclerosis process that likely starts at the early stages of CKD. Thus, traditional and non-traditional or uremic-related factors represent a link between CKD and cardiovascular risk. Among non-conventional risk factors, particular focus has been placed on anaemia, mineral and bone disorders, inflammation, malnutrition and oxidative stress and, in this regard, connections have been reported between oxidative stress and cardiovascular disease in dialysis patients.
METHODS
We evaluated the oxidation process in different molecular lines (proteins, lipids and genetic material) in 155 non-dialysis patients at different stages of CKD and 45 healthy controls. To assess oxidative stress status, we analyzed oxidized glutathione (GSSG), reduced glutathione (GSH) and the oxidized/reduced glutathione ratio (GSSG/GSH) and other oxidation indicators, including malondialdehyde (MDA) and 8-oxo-2'-deoxyguanosine (8-oxo-dG).
RESULTS
An active grade of oxidative stress was found from the early stages of CKD onwards, which affected all of the molecular lines studied. We observed a heightened oxidative state (indicated by a higher level of oxidized molecules together with decreased levels of antioxidant molecules) as kidney function declined. Furthermore, oxidative stress-related alterations were significantly greater in CKD patients than in the control group.
CONCLUSIONS
CKD patients exhibit significantly higher oxidative stress than healthy individuals, and these alterations intensify as eGFR declines, showing significant differences between CKD stages. Thus, future research is warranted to provide clearer results in this area.
Topics: 8-Hydroxy-2'-Deoxyguanosine; Chronic Disease; Humans; Malondialdehyde; Oxidation-Reduction; Oxidative Stress; Renal Insufficiency, Chronic
PubMed: 34360098
DOI: 10.3390/ijerph18157806 -
Cells May 2023Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor prognosis. Gemcitabine is the first-line therapy for PDAC, but gemcitabine resistance is a major...
Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor prognosis. Gemcitabine is the first-line therapy for PDAC, but gemcitabine resistance is a major impediment to achieving satisfactory clinical outcomes. This study investigated whether methylglyoxal (MG), an oncometabolite spontaneously formed as a by-product of glycolysis, notably favors PDAC resistance to gemcitabine. We observed that human PDAC tumors expressing elevated levels of glycolytic enzymes together with high levels of glyoxalase 1 (GLO1), the major MG-detoxifying enzyme, present with a poor prognosis. Next, we showed that glycolysis and subsequent MG stress are triggered in PDAC cells rendered resistant to gemcitabine when compared with parental cells. In fact, acquired resistance, following short and long-term gemcitabine challenges, correlated with the upregulation of GLUT1, LDHA, GLO1, and the accumulation of MG protein adducts. We showed that MG-mediated activation of heat shock response is, at least in part, the molecular mechanism underlying survival in gemcitabine-treated PDAC cells. This novel adverse effect of gemcitabine, i.e., induction of MG stress and HSR activation, is efficiently reversed using potent MG scavengers such as metformin and aminoguanidine. We propose that the MG blockade could be exploited to resensitize resistant PDAC tumors and to improve patient outcomes using gemcitabine therapy.
Topics: Humans; Gemcitabine; Pyruvaldehyde; Deoxycytidine; Antimetabolites, Antineoplastic; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Heat-Shock Response
PubMed: 37408249
DOI: 10.3390/cells12101414 -
Characterization of deoxyribonucleoside transport mediated by concentrative nucleoside transporters.Biochemical and Biophysical Research... Jun 2021Human concentrative nucleoside transporters (CNTs) are responsible for cellular uptake of ribonucleosides; however, although it is important to better characterize...
Human concentrative nucleoside transporters (CNTs) are responsible for cellular uptake of ribonucleosides; however, although it is important to better characterize CNT-subtype specificity to understand the systemic disposition of deoxyribonucleosides (dNs) and their analogs, the involvement of CNTs in transporting dNs is not fully understood. In this study, using COS-7 cells that transiently expressed CNT1, CNT2, or CNT3, we investigated if CNTs could transport not only ribonucleosides but also dNs, i.e., 2'-deoxyadenosine (dAdo), 2'-deoxyguanosine (dGuo), and 2'-deoxycytidine (dCyd). The cellular uptake study demonstrated that dAdo and dGuo were taken up by CNT2 but not by CNT1. Although dCyd was taken up by CNT1, no significant uptake was detected in COS-7 cells expressing CNT2. Similarly, these dNs were transported by CNT3. The apparent K values of their uptake were as follows: CNT1, K = 141 μM for dCyd; CNT2, K = 62.4 μM and 54.9 μM for dAdo and dGuo, respectively; CNT3, K = 14.7 μM and 34.4 μM for dGuo and dCyd, respectively. These results demonstrate that CNTs contribute not only to ribonucleoside transport but also to the transport of dNs. Moreover, our data indicated that CNT1 and CNT2 selectively transported pyrimidine and purine dNs, respectively, and CNT3 was shown to transport both pyrimidine and purine dNs.
Topics: Animals; Biological Transport, Active; COS Cells; Chlorocebus aethiops; Deoxyadenosines; Deoxycytidine; Deoxyguanosine; Deoxyribonucleosides; Humans; Kinetics; Membrane Transport Proteins; Recombinant Proteins
PubMed: 33910126
DOI: 10.1016/j.bbrc.2021.04.075 -
Journal of Acquired Immune Deficiency... Jan 2022To describe and compare systemic and local pharmacokinetics (PK) and cervicovaginal (CV) pharmacodynamics (PD) of oral tenofovir disoproxil fumarate (TDF) in combination... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To describe and compare systemic and local pharmacokinetics (PK) and cervicovaginal (CV) pharmacodynamics (PD) of oral tenofovir disoproxil fumarate (TDF) in combination with emtricitabine (FTC) with tenofovir (TFV) intravaginal ring (IVR).
DESIGN
Phase I, randomized, parallel-group study. Women (n = 22) used TDF/FTC oral tablets daily or TFV IVR continuously and were assessed at baseline and 14 days.
METHODS
TFV and FTC concentrations were measured in plasma, CV fluid (CVF), and CV tissue. TFV-diphosphate and FTC-triphosphate were assessed in CV tissue. In vitro PD antiviral activities of TFV and FTC (using in vivo concentration ranges) were modeled in the CVF and by infecting CV tissue explants ex vivo with HIV-1BaL.
RESULTS
Adverse events (AEs) were more common with oral TDF/FTC use (P < 0.01). The median CVF TFV concentrations were 106 ng/mL after use of TFV IVR vs. 102 ng/mL for TDF/FTC. The median TFV and TFV-diphosphate concentrations in CV tissue were >100-fold higher among IVR users. The median CVF FTC concentrations were 103 ng/mL. FTC and FTC-triphosphate were detected in all CV tissues from TDF/FTC users. HIV inhibitory activity of CVF increased significantly with treatment in both cohorts (P < 0.01) but was higher in TFV IVR users (P < 0.01). In vitro inhibition of tissue infection with ex vivo administration of TFV and FTC was dose dependent, with maximal efficacy achieved with 10 µg/mL TFV, 1 µg/mL FTC, and 0.1 µg/mL of TFV and FTC combined.
CONCLUSIONS
Both products were safe and increased mucosal HIV inhibitory activity. In addition to systemic protection, oral TDF/FTC displays a PK/PD profile compatible with CV mucosal antiviral activity. TFV IVR resulted in fewer AEs, lower TFV plasma concentrations, higher CVF and tissue TFV and TFV-DP concentrations, and greater anti-HIV activity in CVF.
Topics: Administration, Intravaginal; Administration, Oral; Anti-HIV Agents; Emtricitabine; Female; Genitalia; HIV Infections; Humans; Tenofovir
PubMed: 34878438
DOI: 10.1097/QAI.0000000000002820 -
Journal of Cancer Research and... 2022There is no consensus for palliative chemotherapy regimen in metastatic gallbladder cancer. We did a retrospective study to compare the treatment outcome in patients of...
AIMS
There is no consensus for palliative chemotherapy regimen in metastatic gallbladder cancer. We did a retrospective study to compare the treatment outcome in patients of metastatic gallbladder cancer treated with either gemcitabine + cisplatin (regimen A) or oral capecitabine (regimen B) alone.
SUBJECTS AND METHODS
A total of 67 patients between January 2015 and September 15 treated with either regimen A or regimen B were retrospectively evaluated. Statistical analysis was done in June 2019. Kaplan-Meir and Log rank test were used to compare survival between two arms.
RESULTS
Out of 67 patients, 31/67 (46%) received regimen A, and 36/67 (54%) received regimen B. Male to female ratio was 1:3. About 42% patients in regimen A and 20% in regimen B required palliative stenting. Median number of chemotherapy cycles was 4 in both regimen A (range 1->6) and regimen B (range 1->6). Patients receiving 3 cycles and 6 cycles of chemotherapy in regimen A and regimen B was 68% and 31% versus 70% and 63%, respectively (P = 0.86). Response assessment as any response (complete response + partial response + disease was stable) after 3 cycles and 6 cycles was 71% and 57% (P = 0.20), 44% and 39% (P = 0.29), in regimen A and B, respectively. Median survival was 23 weeks (range 2-106 weeks) in regimen A and 15 weeks (range 4-83 weeks) in regimen B (P = 0.40).
CONCLUSIONS
The present study shows gemcitabine and cisplatin has nonsignificant better survival compared to oral capecitabine. However, oral capecitabine is more convenient and easy to administer. Studies with larger sample size are needed to further establish the standard chemotherapy guidelines.
Topics: Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Cisplatin; Deoxycytidine; Female; Fluorouracil; Gallbladder Neoplasms; Humans; Male; Retrospective Studies; Treatment Outcome; Gemcitabine
PubMed: 36149144
DOI: 10.4103/jcrt.JCRT_896_19 -
Cancer Medicine Aug 2020Gemcitabine (GEM) plus nab-paclitaxel (NabP) (GEM 1000 mg/m IV over 30 minutes + NabP 125 mg/m IV given days 1, 8, and 15 every 28 days) is one of the two standard...
BACKGROUND
Gemcitabine (GEM) plus nab-paclitaxel (NabP) (GEM 1000 mg/m IV over 30 minutes + NabP 125 mg/m IV given days 1, 8, and 15 every 28 days) is one of the two standard of care combination therapies for metastatic pancreatic ductal adenocarcinoma (PDAC). Our cancer center has utilized GEM-NabP given every two-weeks due to tolerability and patient convenience. Here, we review the safety and efficacy of this modified regimen.
METHODS
Metastatic PDAC patients (pts) who initiated front-line or second-line GEM-NabP during 2013-2017 were retrospectively reviewed. Primary objective was overall survival. Secondary objectives were disease control rate, progression-free survival, and the incidence of dose delays and/or adjustments.
RESULTS
From a total of 235 patients, 140 pts received GEM-NabP front-line while 95 pts received GEM-NabP second-line. Median dosing was 600 mg/m at fixed-dose rate for GEM and 125 mg/m for NabP given predominantly (~90%) every two-weeks. Eastern Cooperative Group performance status of 0 and 1 pts had front-line OS of 12.7 and 9.6 months and when given second-line had OS of 8 months and 7.3 months, respectively. ECOG 0 and 1 pts had front-line progression-free survival (PFS) of 5.3 months and 2.8 months and second-line PFS was 3.5 months and 2.4 months, respectively. Treatment was well tolerated with limited dose modifications.
CONCLUSION
Our analysis revealed safety with every two-week low dose GEM-NabP while maintaining efficacy. Patient schedule convenience should factor into metastatic incurable malignancies. We suggest the use of every two-week GEM-NabP particularly in patients desiring a modified schedule.
Topics: Adenocarcinoma; Aged; Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Deoxycytidine; Female; Humans; Male; Paclitaxel; Retrospective Studies; Gemcitabine
PubMed: 32519420
DOI: 10.1002/cam4.3229 -
Scientific Reports Oct 2023To further explore the pharmacological effect of pachymaran, this article studied the inhibition of pachymaran on oxidative stress and genetic damage induced by...
To further explore the pharmacological effect of pachymaran, this article studied the inhibition of pachymaran on oxidative stress and genetic damage induced by formaldehyde. 40 adult Kunming male mice were randomly divided into four groups with different interventions. One week later, the contents of serum SOD, GR, MDA, DNA-protein crosslink (DPC), 8-hydroxydeoxyguanosine (8-OHDG) and DNA adduct were determined by ELISA. The results showed that there were statistically significant differences in the contents of SOD, GR and MDA among the four groups (P < 0.01). The activity of SOD and GR increased along with the increase of pachymaran dosage (SOD: r = 0.912, P < 0.01; GR: r = 0.857, P < 0.01), while the content of MDA showing a significant negative correlation (r = - 0.893, P < 0.01). There were statistically significant differences in the levels of DPC, 8-OHDG and DNA adduct among the four groups (DPC and DNA adduct: P < 0.01, 8-OHDG: P < 0.05), the concentration decreased along with the increase of pachymaran dosage (DPC: r = - 0.855, P < 0.01; 8-OHDG:r = - 0.412, P < 0.05, DNA adduct: γ = - 0.869, P < 0.01). It can be inferred that pachymaran can inhibit oxidative stress and DNA damage induced by formaldehyde with the dose-effect relationship.
Topics: Mice; Animals; Male; DNA Adducts; 8-Hydroxy-2'-Deoxyguanosine; DNA Damage; Oxidative Stress; Formaldehyde; Proteins; Superoxide Dismutase; Deoxyguanosine
PubMed: 37838763
DOI: 10.1038/s41598-023-44788-y -
Environment International Feb 2021Oxidative stress has been suggested to be one of the key drivers of health impact of particulate matter (PM). More studies on the oxidative potential of PM alone, but...
BACKGROUND
Oxidative stress has been suggested to be one of the key drivers of health impact of particulate matter (PM). More studies on the oxidative potential of PM alone, but fewer studies have comprehensively evaluated the effects of external and internal exposure to PM compositions on oxidative stress in population.
OBJECTIVE
To comprehensively investigate the exposure-response relationship between PM and its main compositions with oxidative stress indicators.
METHODS
We conducted a cross-sectional study including 768 participants exposed to particulates. Environmental levels of fine particulate matter (PM), polycyclic aromatic hydrocarbons (PAHs) and metals in PM were measured, and urinary levels of PAHs metabolites and metals were measured as internal dose, respectively. Multivariable linear regression models were used to analyze the correlations of PM exposure and urinary levels of 8-hydroxy-2́'-deoxyguanosine (8-OHdG), and 8-iso-prostaglandin-F2α (8-iso-PGF2α) and malondialdehyde (MDA).
RESULTS
The concentration of both PM and total PAHs was significantly correlated with increased urinary 8-OHdG, 8-iso-PGF2α and MDA levels (all p < 0.05). The levels of 4 essential metals all showed significant exposure-response increase in urinary 8-OHdG in both current and non-current smokers (all p < 0.05); ambient selenium, cobalt and zinc were found to be significantly correlated with urinary 8-iso-PGF2α (p = 0.002, 0.003, 0.01, respectively); only selenium and cobalt were significantly correlated with urinary MDA (p < 0.001, 0.01, respectively). Furthermore, we found each one-unit increase in urinary total OH-PAHs generated a 0.32 increase in urinary 8-OHdG, a 0.22 increase in urinary 8-iso-PGF2α and a 0.19 increase in urinary MDA (all p < 0.001). Furthermore, it was found that the level of 12 urinary metals all showed significant and positive correlations with three oxidative stress biomarkers in all subjects (all p < 0.001).
CONCLUSIONS
Our systematic molecular epidemiological study showed that particulate matter components could induce increased oxidative stress on DNA and lipid. It may be more important to monitor and control the harmful compositions in PM rather than overall particulate mass.
Topics: 8-Hydroxy-2'-Deoxyguanosine; Biomarkers; Cross-Sectional Studies; Deoxyguanosine; Humans; Oxidative Stress; Particulate Matter; Polycyclic Aromatic Hydrocarbons
PubMed: 33383389
DOI: 10.1016/j.envint.2020.106341 -
Chinese Medical Journal Nov 2023Dual regimen dolutegravir (DTG) plus lamivudine (3TC) has demonstrated non-inferior efficacy compared to DTG-based three-drug regimens (3DRs), yet directly comparative...
BACKGROUND
Dual regimen dolutegravir (DTG) plus lamivudine (3TC) has demonstrated non-inferior efficacy compared to DTG-based three-drug regimens (3DRs), yet directly comparative data regarding the efficacy and safety of DTG + 3TC and bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) for therapy-naïve people with human immunodeficiency virus (HIV)-1 (PWH) are still limited. We aimed to assess the antiviral potency and safety profiles of DTG + 3TC vs. B/F/TAF based on antiretroviral therapy (ART)-naïve PWH in China.
METHODS
This retrospective multicenter study enrolled PWH initiating ART with DTG + 3TC or B/F/TAF from 2020 to 2022 in Guangdong and Guangxi. We analyzed response rates based on target not detected (TND) status using intention-to-treat (ITT) analysis. Subgroups were formed based on baseline viral load (VL) (<100,000 vs . ≥100,000 copies/mL) and CD4 + cell count (<200 vs . ≥200 cell/µL). Median time to TND VL was assessed by Kaplan-Meier method. We also measured changes from baseline in CD4 + cell counts, CD4/CD8 ratio, lipid parameters, weight, creatinine (Cr), estimated glomerular filtration rate (eGFR), and drug-related adverse effects (DRAEs).
RESULTS
We enrolled 280 participants, including 137 (48.9%) on DTG + 3TC and 143 (51.1%) on B/F/TAF. At week 48, 96.4% (132/137) on DTG+3TC and 100% (143/143) on B/F/TAF achieved TND ( P = 0.064). At week 12, TND responses were higher with B/F/TAF (78.3% [112/143]) than DTG+3TC (30.7% [42/137]) ( P <0.001). This trend held across subgroups. B/F/TAF achieved TND faster (12 weeks) than DTG+3TC (24 weeks) ( P <0.001). No differences were seen in CD4 + cell count and CD4/CD8 ratio, except in the high-VL subgroup, where B/F/TAF showed better recovery. DRAEs were significantly lower with B/F/TAF (4.9% [7/143]) than with DTG + 3TC (13.1% [18/137]) ( P = 0.016). Lipid parameters, body weight, and Cr increased in both groups over 48 weeks, with DTG+3TC showing a more favorable effect on triglycerides, high-density lipoprotein (HDL) cholesterol, and weight gain.
CONCLUSIONS
In this real-life study, B/F/TAF led to a faster viral decline and fewer DRAEs compared to DTG+3TC. No significant difference was observed in the TND rate at week 48, regardless of baseline VL and CD4 + cell count. CD4 + recovery was superior for B/F/TAF in participants with high VL. The DTG + 3TC regimen had less impact on metabolic changes than B/F/TAF.
Topics: Adult; Humans; Anti-HIV Agents; China; Emtricitabine; HIV Infections; HIV-1; Lamivudine; Lipids; Retrospective Studies
PubMed: 37914678
DOI: 10.1097/CM9.0000000000002907