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BMC Cancer Jul 2023Nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil (5-FU)/levo-leucovorin (Levo-LV) was approved for unresectable pancreatic cancer (UR-PC) in March 2020 in Japan....
BACKGROUND
Nanoliposomal irinotecan (nal-IRI) plus 5-fluorouracil (5-FU)/levo-leucovorin (Levo-LV) was approved for unresectable pancreatic cancer (UR-PC) in March 2020 in Japan. Levo-LV is administered by intravenous infusion over 120 min following 90 min intravenous infusion of nal-IRI (conventional method), causing a significant burden on both patients and the outpatient chemotherapy room owing to the prolonged administration time. Thus, from July 2021, we introduced the simultaneous intravenous administration of nal-IRI and Levo-LV (parallel method) with the approval of the institutional regimen committee.
METHODS
We retrospectively reviewed the data of 69 patients with UR-PC who received nal-IRI plus 5-FU/Levo-LV at our hospital between June 2020 and October 2021. We examined the safety of the parallel method and compared the treatment outcomes and administration times between the two methods.
RESULTS
The median age was 66 years (54%, male). Disease statuses were locally advanced, metastatic, and postoperative recurrence after pancreatectomy in 7, 50, and 12 patients, respectively. Nal-IRI plus 5-FU/Levo-LV treatment was second and third-line or later in 35 and 34 patients, respectively. No intravenous line problems were observed during the parallel administration of nal-IRI and Levo-LV. Although there were no significant differences in response rates and adverse events between the two methods, the administration time was significantly shorter in the parallel method than in the conventional method.
CONCLUSION
The parallel administration of nal-IRI and Levo-LV is clinically safe and not inferior in efficacy. Moreover, parallel administration may offer convenience to patients and healthcare workers by reducing administration time.
Topics: Humans; Male; Aged; Female; Irinotecan; Levoleucovorin; Retrospective Studies; Leucovorin; Liposomes; Pancreatic Neoplasms; Fluorouracil; Antineoplastic Combined Chemotherapy Protocols; Camptothecin
PubMed: 37518012
DOI: 10.1186/s12885-023-11205-6 -
Biochemical Pharmacology Aug 2023AHR has been identified as ligand-modulated transcription factor and environmental sensor. However, explanation of its multiple agonistic and antagonistic ligands is far... (Review)
Review
AHR has been identified as ligand-modulated transcription factor and environmental sensor. However, explanation of its multiple agonistic and antagonistic ligands is far from complete. Studies of AHR's role in host-microbiome interaction are currently a fruitful area of research. Microbial products and virulence factors have been identified as AHR agonists. In steady state they are involved in safeguarding intestinal barrier integrity. When virulence factors from pathogenic bacteria are identified by AHR of intestinal immune cells, anti-microbial defense mechanisms are activated by generating reactive oxygen species (ROS) in intestinal epithelial cells and recruited immune cells. ROS production has to be strictly controlled, and anti-inflammatory responses have to be initiated timely in the resolution phase of inflammation to avoid tissue damage and chronic inflammatory responses. Surprisingly, bacteria-generated vitamin B12/cobalamin and vitamin B9/folic acid have been identified as natural AHR antagonists, stimulating the interest of biochemists. Hints for AHR-cobalamin antagonism are pointing to cobalamin-dependent enzymes leading to alterations of TCA cycle intermediates, and TCDD-mediated loss of serum cobalamin. Although we are still at the beginning to understand mechanisms, it is likely that scientific efforts are on a rewarding path to understand novel AHR functions.
Topics: Humans; Vitamin B 12; Folic Acid; Ligands; Receptors, Aryl Hydrocarbon; Reactive Oxygen Species; Inflammation
PubMed: 37336251
DOI: 10.1016/j.bcp.2023.115658 -
Journal of the European Academy of... Nov 2023
Review
Topics: Humans; Methotrexate; Vitiligo; Retrospective Studies; Hypopigmentation; Treatment Outcome
PubMed: 37571807
DOI: 10.1111/jdv.19400 -
BMC Complementary Medicine and Therapies Oct 2023Methotrexate (MTX) is a common chemotherapeutic drug that inhibits DNA synthesis and induces apoptosis. Treatment with MTX increased CD73 expression, which leads to...
BACKGROUND
Methotrexate (MTX) is a common chemotherapeutic drug that inhibits DNA synthesis and induces apoptosis. Treatment with MTX increased CD73 expression, which leads to higher levels of extracellular adenosine. Adenosine levels are also high in the tumor microenvironment through Cancer cells metabolism. That promotes the survival of cancer cells and contributes to tumor immune evasion through the Adenosine 2a Receptor. A2A receptor antagonists are an emerging class of agents that treat cancers by enhancing immunotherapy, both as monotherapy and in combination with other therapeutic agents. Caffeine is an adenosine receptor antagonist. Herein, we demonstrate the ability of a novel well prepared and characterized nano formula CAF-FA-CS-NPs (D4) for A2aR blockade when combination with MTX to improve its antitumor efficacy by enhancing the immune system and eliminating immune suppression.
METHODS
CAF-FA-CS-NPs (D4) were prepared and characterized for particle size, loading efficiency, and release profile. Molecular docking was used to validate the binding affinity of caffeine and folic acid to A2A receptor. The effects of the nano formula were evaluated on human liver cancer cells (HepG2), breast cancer cells (MCF-7), and MDA-MB-231, as well as normal human cells (WI-38). Different combination ratios of MTX and D4 were studied to identify the optimal combination for further genetic studies.
RESULTS
Molecular docking results validated that caffeine and folic acid have binding affinity to A2A receptor. The CS-NPs were successfully prepared using ionic gelation method, with caffeine and folic acid being loaded and conjugated to the nanoparticles through electrostatic interactions. The CAF loading capacity in D4 was 77.9 ± 4.37% with an encapsulation efficiency of 98.5 ± 0.37. The particle size was optimized through ratio variations. The resulting nanoparticles were fully characterized. The results showed that (D4) had antioxidant activity and cytotoxicity against different cancer cells. The combination of D4 with MTX (IC50 D4 + 0.5 IC50 MTX) resulted in the downregulation of Bcl-2, FOXP3, CD39, and CD73 gene expression levels and upregulation of Bax and A2AR gene expression levels in HepG2 cells.
CONCLUSIONS
This study suggests that CAF-FA-CS-NPs (D4) in combination with MTX may be a promising candidate for cancer immunotherapy, by inhibiting A2aR signaling and leading to improved immune activation and anti-tumor activity of MTX.
Topics: Humans; Methotrexate; Folic Acid; Chitosan; Receptor, Adenosine A2A; Caffeine; Molecular Docking Simulation; Neoplasms; Nanoparticles; Immunotherapy; Adenosine; Tumor Microenvironment
PubMed: 37891562
DOI: 10.1186/s12906-023-04212-4 -
British Journal of Pharmacology Nov 2023Activated fibroblasts deposit fibrotic matrix in chronic kidney disease (CKD) and G-protein coupled receptors (GPCRs) are the most druggable therapeutic targets. Here,...
BACKGROUND AND PURPOSE
Activated fibroblasts deposit fibrotic matrix in chronic kidney disease (CKD) and G-protein coupled receptors (GPCRs) are the most druggable therapeutic targets. Here, we set out to establish a transcriptional profile that identifies activated kidney fibroblasts and the GPCRs that they express.
EXPERIMENTAL APPROACH
RNA sequencing and single cell qRT-PCR were performed on mouse kidneys after unilateral ureteral obstruction (UUO). Candidate expression was evaluated in mice with UUO or diabetes or injected with adriamycin or folic acid. Intervention studies were conducted in mice with diabetes or UUO. Correlative histology was performed in human kidney tissue.
KEY RESULTS
Transcription factor 21 (Tcf21)+ cells that expressed 2 or 3 of Postn, Acta2 and Pdgfra were highly enriched for fibrogenic genes and were defined as activated kidney fibroblasts. Tcf21+ α-smooth muscle actin (α-SMA)+ interstitial cells accumulated in kidneys of mice with UUO or diabetes or injected with adriamycin or folic acid, whereas renin-angiotensin system blockade attenuated increases in Tcf21 in diabetic mice. Fifty-six GPCRs were up-regulated in single Tcf21+ kidney fibroblasts, the most up-regulated being Adgra2 and S1pr3. Adenosine receptors, Adora2a/2b, were up-regulated in Tcf21+ fibroblasts and the adenosine receptor antagonist, caffeine decreased Tcf21 upregulation and kidney fibrosis in UUO mice. TCF21, ADGRA2, S1PR3 and ADORA2A/2B were each detectable in α-SMA+ interstitial cells in human kidney samples.
CONCLUSION AND IMPLICATIONS
Tcf21 is a marker of kidney fibroblasts that are enriched for fibrogenic genes in CKD. Further analysis of the GPCRs expressed by these cells may identify new targets for treating CKD.
LINKED ARTICLES
This article is part of a themed issue on Translational Advances in Fibrosis as a Therapeutic Target. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.22/issuetoc.
Topics: Animals; Humans; Mice; Basic Helix-Loop-Helix Transcription Factors; Diabetes Mellitus, Experimental; Doxorubicin; Fibroblasts; Fibrosis; Folic Acid; Kidney; Kidney Diseases; Mice, Inbred C57BL; Receptors, G-Protein-Coupled; Renal Insufficiency, Chronic; Transcription Factors; Ureteral Obstruction
PubMed: 37115600
DOI: 10.1111/bph.16101 -
Nature Reviews. Gastroenterology &... Dec 2023
Topics: Humans; Transcription Factors; Folic Acid
PubMed: 37919387
DOI: 10.1038/s41575-023-00868-y -
Biomedical and Environmental Sciences :... Aug 2023
Topics: Humans; Folic Acid; Folic Acid Deficiency
PubMed: 37711093
DOI: 10.3967/bes2023.108 -
Diabetes Care Oct 2023We examined whether intake of methyl donor nutrients, including vitamins B2, B6, and B12 and folate, from foods and/or supplements is associated with type 2 diabetes...
OBJECTIVE
We examined whether intake of methyl donor nutrients, including vitamins B2, B6, and B12 and folate, from foods and/or supplements is associated with type 2 diabetes risk.
RESEARCH DESIGN AND METHODS
We included 203,644 women and men from the Nurses' Health Study (1984-2016), Nurses' Health Study 2 (1991-2017), and Health Professionals Follow-Up Study (1986-2016). Dietary data were collected every 2-4 years with use of semiquantitative food-frequency questionnaires. Cox proportional hazards models with time-varying covariates were used to evaluate associations between each nutrient and type 2 diabetes risk. We combined cohort-specific hazard ratios (HRs) using inverse variance-weighted fixed-effects meta-analyses.
RESULTS
During 4,900,181 person-years of follow-up, we documented 19,475 incident type 2 diabetes cases. In multivariable-adjusted meta-analyses, participants in the highest quintiles of total vitamin B2 and B6 intakes had lower risk of diabetes compared with those in the lowest quintiles (HR 0.93 [95% CI 0.89, 0.98] for B2 and 0.93 [0.89, 0.97] for B6). With stratification by source, significant associations remained for B2 from food but not from supplements. Neither association for B6 from food nor association for B6 from supplements attained significance. No association was observed between total B12 intake and diabetes. However, B12 from food was marginally associated with higher diabetes risk (1.05 [1.00-1.11]) but not after additional adjustment for red meat intake (1.04 [0.99-1.10]). No evidence of association was observed between intakes of folate and diabetes.
CONCLUSIONS
The results of our study suggest that higher intake of vitamin B2 and B6, especially B2 from food sources, may be associated with a modestly lower type 2 diabetes risk.
Topics: Male; Female; Humans; Diabetes Mellitus, Type 2; Incidence; Follow-Up Studies; Eating; Dietary Supplements; Folic Acid; Riboflavin
PubMed: 37643330
DOI: 10.2337/dc23-0662 -
Reproductive Toxicology (Elmsford, N.Y.) Sep 2023There is emerging evidence suggesting that folate status during pregnancy may play a role in fetal programming of metabolic disease. Therefore, this systematic review... (Review)
Review
There is emerging evidence suggesting that folate status during pregnancy may play a role in fetal programming of metabolic disease. Therefore, this systematic review aims to summarize and systematize the current evidence surrounding the relationship between maternal folate status during pregnancy and offspring metabolic programming, focusing on both animal and human studies. PubMed, Web of Science and Scopus databases were searched in order to identify studies conducted on pregnant women or in animals studying the association between maternal folate exposure and at least one metabolic syndrome outcome in offspring after birth (weight, blood pressure, glucose regulation parameters, triglycerides and high-density lipoprotein cholesterol (HDL-C) levels). The quality of included studies was assessed using SYRCLE Risk of Bias Tools for animal studies and NHLBI Study Quality Assessment Tools for observational studies and randomized controlled trials. Among the 10 "good" or "fair" studies that investigated excessive folate exposure during the perigestational period, 7 animal studies and 1 human study reported a positive association with development of metabolic outcomes in offspring. On the other hand, 6 of the 7 "good" or "fair" included human studies compared adequate versus low folate exposure, showing a lack of association (n = 3) or a protective effect (n = 3) regarding offspring's dysmetabolism. In conclusion, there is strong evidence from animal trials suggesting that excessive folate intake in early phases of development programs for metabolic dysfunction. While human evidence regarding excessive maternal folate exposure is currently scarce, human studies suggest that folate adequacy in pregnancy is not detrimental for metabolic function of the offspring.
Topics: Animals; Pregnancy; Humans; Female; Folic Acid; Maternal Exposure
PubMed: 37442213
DOI: 10.1016/j.reprotox.2023.108439 -
Current Rheumatology Reports Dec 2023This review aims to critically evaluate the potential benefit of either oral or subcutaneous administration of methotrexate (MTX) in various immune-mediated inflammatory... (Review)
Review
PURPOSE
This review aims to critically evaluate the potential benefit of either oral or subcutaneous administration of methotrexate (MTX) in various immune-mediated inflammatory disorders (IMIDs) through analysis of efficacy, toxicity, pharmacokinetics and pharmacodynamics of both administration routes.
RECENT FINDINGS
Recent studies comparing the efficacy of oral versus subcutaneous MTX administration in IMIDs have revealed contradicting results. Some reported higher efficacy with subcutaneous administration, while others found no significant difference. Regarding toxicity, some studies have challenged the notion that subcutaneous administration is better tolerated than oral administration, while others have supported this. Pharmacokinetic studies suggest higher plasma bioavailability and increased accumulation of MTX-polyglutamates (MTX-PGs) in red blood cells (RBCs) with subcutaneous administration during the initial treatment phase. However, after several months, similar intracellular drug levels are observed with both administration routes. There is no conclusive evidence supporting the superiority of either oral or subcutaneous MTX administration in terms of efficacy and adverse events in IMIDs. Subcutaneous administration leads to higher plasma bioavailability and initial accumulation of MTX-PGs in RBCs, but the difference seems to disappear over time. Given the variable findings, the choice of administration route may be based on shared decision-making, offering patients the option of either oral or subcutaneous administration of MTX based on individual preferences and tolerability. Further research is needed to better understand the impact of MTX-PGs in various blood cells and TDM on treatment response and adherence to MTX therapy.
Topics: Humans; Methotrexate; Antirheumatic Agents; Injections, Subcutaneous; Administration, Oral; Immunomodulating Agents
PubMed: 37768405
DOI: 10.1007/s11926-023-01116-7