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Turkish Journal of Ophthalmology Jun 2024To examine changes in tear oxidative stress levels and tear film functions in patients with blepharoptosis and dermatochalasis following conjunctiva-Müller muscle...
OBJECTIVES
To examine changes in tear oxidative stress levels and tear film functions in patients with blepharoptosis and dermatochalasis following conjunctiva-Müller muscle resection (CMMR) and blepharoplasty surgeries.
MATERIALS AND METHODS
This prospective study included 32 healthy controls and 62 patients with blepharoptosis or dermatochalasis. CMMR surgery was performed in 20 eyes and upper blepharoplasty was performed in 42 eyes. Tear oxidative stress markers (8-hydroxy-2’-deoxyguanosine [8-OHdG] and 4-hydroxy-2-nonenal [4-HNE]) were quantified by enzyme-linked immunosorbent assay and tear film functions were evaluated preoperatively and at 1 and 6 months postoperatively. The same assessments were performed in the control group at the same time points.
RESULTS
Preoperative tear 8-OHdG and 4-HNE levels were lower in healthy controls (52.8±13.5 ng/mL and 27.8±6.4 ng/mL, respectively) compared to patients with dermatochalasis (86.1±37.2 ng/mL and 29.8±11.1 ng/mL, respectively) and blepharoptosis (90.4±39.3 ng/mL and 43.1±4.2 ng/mL, respectively) (p<0.001). 8-OHdG levels were increased at 1 month after CMMR, while both markers were decreased 1 month postoperatively in the blepharoplasty group (p=0.034). Schirmer 1 and OSDI scores did not change throughout the visits in both patient groups, but a temporary decrease in tear break-up time (TBUT) was observed after CMMR (p=0.017).
CONCLUSION
Dermatochalasis and blepharoptosis were associated with higher tear oxidative stress levels. CMMR surgery caused a temporary decrease in TBUT scores and an increase in oxidative stress in the first postoperative month.
Topics: Humans; Oxidative Stress; Blepharoptosis; Female; Male; Prospective Studies; Tears; Blepharoplasty; Middle Aged; Conjunctiva; Oculomotor Muscles; 8-Hydroxy-2'-Deoxyguanosine; Adult; Biomarkers; Enzyme-Linked Immunosorbent Assay; Aged; Aldehydes
PubMed: 38836622
DOI: 10.4274/tjo.galenos.2024.02697 -
Journal of Bioenergetics and... Aug 2024Numerous studies have indicated that N-methyladenosine (mA) and lncRNAs play pivotal roles in human cancer. However, the underlying functions and mechanisms of mA-lncRNA...
Numerous studies have indicated that N-methyladenosine (mA) and lncRNAs play pivotal roles in human cancer. However, the underlying functions and mechanisms of mA-lncRNA in the physiological processes of breast cancer remain unclear. Here, we found that DSCAM-AS1 is an mA-modified lncRNA that was overexpressed in breast cancer tissues and cells, indicating poor clinical prognosis. Gain/loss functional assays suggested that DSCAM-AS1 inhibited erastin-induced ferroptosis in breast cancer cells. Mechanistically, there were remarkable mA modification sites on both the 3'-UTR of DSCAM-AS1 and the endogenous antioxidant factor SLC7A11. MA methyltransferase methyltransferase-like 3 (METTL3) methylated both SLC7A11 and DSCAM-AS1. Moreover, DSCAM-AS1 recognized mA sites on the SLC7A11 mRNA, thereby enhancing its stability. Taken together, these findings indicated a potential therapeutic strategy for breast cancer ferroptosis in an mA-dependent manner.
Topics: Humans; RNA, Long Noncoding; Ferroptosis; Breast Neoplasms; Female; Methyltransferases; Cell Line, Tumor; Animals; Amino Acid Transport System y+; Adenosine; Mice; Disease Progression
PubMed: 38833042
DOI: 10.1007/s10863-024-10024-z -
Cell Death & Disease Jun 2024Glioma is the most common and aggressive type of primary malignant brain tumor. The N6-methyladenosine (m6A) modification widely exists in eukaryotic cells and plays an...
Glioma is the most common and aggressive type of primary malignant brain tumor. The N6-methyladenosine (m6A) modification widely exists in eukaryotic cells and plays an important role in the occurrence and development of human tumors. However, the function and mechanism of heterogeneous nuclear ribonucleoprotein C (HNRNPC), an RNA-binding protein and m6A reader in gliomas remains to be comprehensively and extensively explored. Herein, we found that HNRNPC mRNA and protein overexpression were associated with a poor prognosis for patients with gliomas, based on the data from TCGA, the CGGA, and the TMAs. Biologically, HNRNPC knockdown markedly repressed malignant phenotypes of glioma in vitro and in vivo, whereas ectopic HNRNPC expression had the opposite effect. Integrative RNA sequencing and MeRIP sequencing analyses identified interleukin-1 receptor-associated kinase 1 (IRAK1) as a downstream target of HNRNPC. The glioma public datasets and tissue microarrays (TMAs) data indicated that IRAK1 overexpression was associated with poor prognosis, and IRAK1 knockdown significantly repressed malignant biological behavior in vitro. Mechanistically, HNRNPC maintains the mRNA stability of IRAK1 in an m6A-dependent manner, resulting in activation of the mitogen-activated protein kinase (MAPK) signaling pathway, which was necessary for the malignant behavior of glioma. Our findings demonstrate the HNRNPC-IRAK1-MAPK axis as a crucial carcinogenic factor for glioma and the novel underlying mechanism of IRAK1 upregulation, which provides a rationale for therapeutically targeting epitranscriptomic modulators in glioma.
Topics: Humans; Glioma; Interleukin-1 Receptor-Associated Kinases; RNA, Messenger; Disease Progression; Heterogeneous-Nuclear Ribonucleoprotein Group C; Cell Line, Tumor; MAP Kinase Signaling System; Mice; RNA Stability; Mice, Nude; Animals; Gene Expression Regulation, Neoplastic; Brain Neoplasms; Female; Male; Adenosine; Prognosis
PubMed: 38830885
DOI: 10.1038/s41419-024-06736-0 -
Pharmacology & Therapeutics Jul 2024N-methyladenosine (mA) is one of the most common modifications of RNA in eukaryotic cells and is involved in mRNA metabolism, including stability, translation,... (Review)
Review
N-methyladenosine (mA) is one of the most common modifications of RNA in eukaryotic cells and is involved in mRNA metabolism, including stability, translation, maturation, splicing, and export. mA also participates in the modification of multiple types of non-coding RNAs, such as microRNAs, long non-coding RNAs, and circular RNAs, thereby affecting their metabolism and functions. Increasing evidence has revealed that mA regulators, such as writers, erasers, and readers, perform mA-dependent modification of ncRNAs, thus affecting cancer progression. Moreover, ncRNAs modulate mA regulators to affect cancer development and progression. In this review, we summarize recent advances in understanding mA modification and ncRNAs and provide insights into the interaction between mA modification and ncRNAs in cancer. We also discuss the potential clinical applications of the mechanisms underlying the interplay between mA modifications and ncRNAs in acute myeloid leukemia (AML). Therefore, clarifying the mutual regulation between mA modifications and ncRNAs is of great significance to identify novel therapeutic targets for AML and has great clinical application prospects.
Topics: Humans; Adenosine; Leukemia, Myeloid, Acute; RNA, Untranslated; Animals
PubMed: 38830387
DOI: 10.1016/j.pharmthera.2024.108671 -
Annals of Internal Medicine Jun 2024Hong SJ, Lee SJ, Suh Y, et al; T-PASS (Ticagrelor Monotherapy in Patients Treated With New-Generation Drug-Eluting Stents for Acute Coronary Syndrome) Investigators.... (Randomized Controlled Trial)
Randomized Controlled Trial
Hong SJ, Lee SJ, Suh Y, et al; T-PASS (Ticagrelor Monotherapy in Patients Treated With New-Generation Drug-Eluting Stents for Acute Coronary Syndrome) Investigators. Circulation. 2024;149:562-573. 37878786.
Topics: Ticagrelor; Humans; Acute Coronary Syndrome; Drug-Eluting Stents; Dual Anti-Platelet Therapy; Platelet Aggregation Inhibitors; Aspirin; Percutaneous Coronary Intervention; Male; Female; Middle Aged; Treatment Outcome
PubMed: 38830214
DOI: 10.7326/ANNALS-24-00207-JC -
ASAIO Journal (American Society For... Jun 2024Drug treatments for coronavirus disease 2019 (COVID-19) dramatically improve patient outcomes, and although extracorporeal membrane oxygenation (ECMO) has significant...
Drug treatments for coronavirus disease 2019 (COVID-19) dramatically improve patient outcomes, and although extracorporeal membrane oxygenation (ECMO) has significant use in these patients, it is unknown whether ECMO affects drug dosing. We used an ex vivo adult ECMO model to measure ECMO circuit effects on concentrations of specific COVID-19 drug treatments. Three identical ECMO circuits used in adult patients were set up. Circuits were primed with fresh human blood (temperature and pH maintained within normal limits). Three polystyrene jars with 75 ml fresh human blood were used as controls. Remdesivir, GS-441524, nafamostat, and tocilizumab were injected in the circuit and control jars at therapeutic concentrations. Samples were taken from circuit and control jars at predefined time points over 6 h and drug concentrations were measured using validated assays. Relative to baseline, mean (± standard deviation [SD]) study drug recoveries in both controls and circuits at 6 h were significantly lower for remdesivir (32.2% [±2.7] and 12.4% [±2.1], p < 0.001), nafamostat (21.4% [±5.0] and 0.0% [±0.0], p = 0.018). Reduced concentrations of COVID-19 drug treatments in ECMO circuits is a clinical concern. Remdesivir and nafamostat may need dose adjustments. Clinical pharmacokinetic studies are suggested to guide optimized COVID-19 drug treatment dosing during ECMO.
Topics: Extracorporeal Membrane Oxygenation; Humans; Adenosine Monophosphate; Alanine; COVID-19 Drug Treatment; Antibodies, Monoclonal, Humanized; Antiviral Agents; Guanidines; Benzamidines; COVID-19; SARS-CoV-2; Adenosine
PubMed: 38829573
DOI: 10.1097/MAT.0000000000002120 -
Oncology Research 2024Chimeric antigen receptor T (CAR-T) cell therapy has achieved marked therapeutic success in ameliorating hematological malignancies. However, there is an extant void in...
BACKGROUND
Chimeric antigen receptor T (CAR-T) cell therapy has achieved marked therapeutic success in ameliorating hematological malignancies. However, there is an extant void in the clinical guidelines concerning the most effective chemotherapy regimen prior to chimeric antigen receptor T (CAR-T) cell therapy, as well as the optimal timing for CAR-T cell infusion post-chemotherapy.
MATERIALS AND METHODS
We employed cell-derived tumor xenograft (CDX) murine models to delineate the optimal pre-conditioning chemotherapy regimen and timing for CAR-T cell treatment. Furthermore, transcriptome sequencing was implemented to identify the therapeutic targets and elucidate the underlying mechanisms governing the treatment regimen.
RESULTS
Our preclinical evaluation determined that a combination of cyclophosphamide and fludarabine, followed by the infusion of CD19 CAR-T cells five days subsequent to the chemotherapy, exerts the most efficacious therapeutic effect in B-cell hematological malignancies. Concurrently, RNA-seq data indicated that the therapeutic efficacy predominantly perturbs tumor cell metabolism, primarily through the inhibition of key mitochondrial targets, such as C-Jun Kinase enzyme (C-JUN).
CONCLUSION
In summary, the present study offers critical clinical guidance and serves as an authoritative reference for the deployment of CD19 CAR-T cell therapy in the treatment of B-cell hematological malignancies.
Topics: Vidarabine; Cyclophosphamide; Animals; Mice; Humans; Immunotherapy, Adoptive; Antigens, CD19; Xenograft Model Antitumor Assays; Receptors, Chimeric Antigen; Hematologic Neoplasms; Cell Line, Tumor; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy
PubMed: 38827326
DOI: 10.32604/or.2024.049792 -
International Journal of Biological... Jun 2024Intramuscular fat (IMF) content is mainly determined by intramuscular preadipocyte adipogenesis. Epigenetic modifications are known to have a regulatory effect on IMF....
Intramuscular fat (IMF) content is mainly determined by intramuscular preadipocyte adipogenesis. Epigenetic modifications are known to have a regulatory effect on IMF. As N6-methyladenosine (mA) is the most abundant epigenetic modification in eukaryotic RNAs. In the present study, we used mA methylation and RNA sequencing (seq) to identify the mA-modified RNAs associated with the adipogenic differentiation of intramuscular preadipocytes. Among them, the expression and mA level of phosphorylase kinase subunit G1 (PHKG1) were found to be significantly changed during adipogenesis. Further studies revealed that knockdown of the methylase METTL3 decreased the mA methylation of PHKG1 and led to a reduction in PHKG1. Moreover, knockdown of PHKG1 promoted adipogenic differentiation by upregulating the expression of adipogenic genes. In addition, we found that the IMF content in the longissimus thoracis (LT) of Bamei (BM) pigs was greater than that in Large White (LW) pigs, whereas the mA and PHKG1 expression levels were lower in BM pigs. These findings indicate that the mA level and expression of PHKG1 were significantly correlated with IMF content and meat quality. In conclusion, this study sheds light on the mechanism by which mA modification regulates IMF deposition.
Topics: Animals; Adipocytes; Methylation; Swine; Adipogenesis; Adenosine; Phosphorylase Kinase; Lipid Metabolism; Muscle, Skeletal; Cell Differentiation
PubMed: 38825295
DOI: 10.1016/j.ijbiomac.2024.132728 -
Antiviral Research Jul 2024Hepatitis E is an underestimated disease, leading to estimated 20 million infections and up to 70,000 deaths annually. Infections are mostly asymptomatic, but can reach...
Hepatitis E is an underestimated disease, leading to estimated 20 million infections and up to 70,000 deaths annually. Infections are mostly asymptomatic, but can reach mortality rates up to 25% in pregnant women or become chronic in immunocompromised patients. Hepatitis E virus (HEV) infection have been associated with a range of extrahepatic manifestations, including a spectrum of neurological symptoms. Current therapy options are limited to non-specific antivirals like ribavirin, but recently, repurposed viral polymerase inhibitors like sofosbuvir and NITD008 were described to inhibit HEV replication. Here, we evaluated the efficacy of these drugs in various neuronal-derived cell lines to determine their potency outside the liver. Our findings indicate that both drugs, especially sofosbuvir, exhibited reduced efficacy in neuronal cells compared to hepatic cells. These results should be taken into account in the development of direct-acting antivirals for HEV and their potency at extrahepatic replication sites.
Topics: Sofosbuvir; Antiviral Agents; Humans; Hepatitis E virus; Virus Replication; Neurons; Cell Line; Hepatitis E; Adenosine
PubMed: 38825018
DOI: 10.1016/j.antiviral.2024.105922 -
Cancer Letters Jul 2024The mechanism underlying N6-methyladenosine (m6A) modification in bladder cancer (BC) remains elusive. We identified that the RBM15/METTL3 complex enhances m6A...
The mechanism underlying N6-methyladenosine (m6A) modification in bladder cancer (BC) remains elusive. We identified that the RBM15/METTL3 complex enhances m6A modification and promotes the ENO1 protein translation efficiency through its 359A site by depending on YTHDF1 in BC cells. In the tumor microenvironment, TGF-β effectively stimulates RBM15/METTL3 expression to improve ENO1 mRNA m6A modification through the Smad2/3 pathway. Reduced ENO1 m6A levels hamper tumor proliferation both in vitro and in vivo. Mechanistically, ENO1 augments PCNA protein stability by reducing its K48-linked ubiquitination and thus prevents protein degradation through the endoplasmic reticulum-associated degradation pathway. According to the subsequent experiments, the ENO1 inhibitor significantly reduced tumor proliferation both in vitro and in vivo. Our study highlights the significance of RBM15/METTL3 complex-mediated ENO1 mRNA m6A modification in ENO1 expression. It also reveals a novel mechanism by which ENO1 promotes BC progression, thereby suggesting that ENO1 can be a therapeutic target for BC.
Topics: Urinary Bladder Neoplasms; Humans; Ubiquitination; Tumor Suppressor Proteins; DNA-Binding Proteins; Adenosine; Animals; Phosphopyruvate Hydratase; Cell Line, Tumor; Disease Progression; Cell Proliferation; RNA-Binding Proteins; Mice; Methyltransferases; Gene Expression Regulation, Neoplastic; Protein Biosynthesis; Mice, Nude; Biomarkers, Tumor; Proliferating Cell Nuclear Antigen
PubMed: 38823761
DOI: 10.1016/j.canlet.2024.217002