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Frontiers in Immunology 2024Vitamin E, which is also known as tocopherol, is a compound with a polyphenol structure. Its esterified derivative, Vitamin E succinate (VES), exhibits unique anticancer...
BACKGROUND
Vitamin E, which is also known as tocopherol, is a compound with a polyphenol structure. Its esterified derivative, Vitamin E succinate (VES), exhibits unique anticancer and healthcare functions as well as immunomodulatory effects. Natural polysaccharides are proved to be a promising material for nano-drug delivery systems, which show excellent biodegradability and biocompatibility. In this study, we employed a novel polysaccharide-vitamin E succinate polymer (BSP-VES) micelles to enhance the tumor targeting and anti-colon cancer effect of andrographolide (AG).
METHODS
BSP-VES polymer was synthesized through esterification and its structure was confirmed using 1H NMR. AG@BSP-VES was prepared via the dialysis method and the drug loading, entrapment efficiency, stability, and safety were assessed. Furthermore, the tumor targeting ability of AG@BSP-VES was evaluated through targeted cell uptake and imaging. The antitumor activity of AG@BSP-VES was measured using MTT assay, Live&Dead cell staining, and cell scratch test.
RESULTS
In this study, we successfully loaded AG into BSP-VES micelles (AG@BSP-VES), which exhibited good stability, biosafety and sustained release effect. In addition, AG@BSP-VES also showed excellent internalization capability into CT26 cells compared with NCM460 cells . Meanwhile, the specific delivery of AG@BSP-VES micelles into subcutaneous and colon tumors was observed compared with normal colon tissues during the whole experiment process (1-24 h). What's more, AG@BSP-VES micelles exhibited significant antitumor activities than BSP-VES micelles and free AG.
CONCLUSION
The study provides a meaningful new idea and method for application in drug delivery system and targeted treatment of colon cancer based on natural polysaccharides.
Topics: Micelles; Animals; Colonic Neoplasms; Diterpenes; Humans; Mice; Cell Line, Tumor; Polysaccharides; Antineoplastic Agents; Drug Delivery Systems; Xenograft Model Antitumor Assays; Drug Carriers; Nanoparticles; Nanoparticle Drug Delivery System; Mice, Nude; Mice, Inbred BALB C
PubMed: 38911867
DOI: 10.3389/fimmu.2024.1380229 -
International Journal of Nanomedicine 2024Combination therapy offers superior therapeutic results compared to monotherapy. However, the outcomes of combination therapy often fall short of expectations, mainly...
BACKGROUND
Combination therapy offers superior therapeutic results compared to monotherapy. However, the outcomes of combination therapy often fall short of expectations, mainly because of increased toxicity from drug interactions and challenges in achieving the desired spatial and temporal distribution of drug delivery. Optimizing synergistic drug combination ratios to ensure uniform targeting and distribution across space and time, particularly in vivo, is a significant challenge. In this study, cRGD-coated liposomes encapsulating optimized synergistic cepharanthine (CEP; a chemotherapy drug) and IR783 (a phototherapy agent) were developed for combined chemotherapy and photothermal therapy in vitro and in vivo.
METHODS
An MTT assay was used to evaluate the combination index of CEP and IR783 in five cell lines. The cRGD-encapsulated liposomes were prepared via thin-film hydration, and unencapsulated liposomes served as controls for the loading of CEP and IR783. Fluorescence and photothermal imaging were used to assess the efficacy of CEP and IR783 encapsulated in liposomes at an optimal synergistic ratio, both in vitro and in vivo.
RESULTS
The combination indices of CEP and IR783 were determined in five cell lines. As a proof-of-concept, the optimal synergistic ratio (1:2) of CEP to IR783 in 4T1 cells was evaluated in vitro and in vivo. The average diameter of the liposomes was approximately 100 nm. The liposomes effectively retained the encapsulated CEP and IR783 in vitro at the optimal synergistic molar ratio for over 7 d. In vivo fluorescence imaging revealed that the fluorescence signal from cRGD-CEP-IR783-Lip was detectable at the tumor site at 4 h post-injection and peaked at 8 h. In vivo photothermal imaging of tumor-bearing mice indicated an increase in tumor temperature by 32°C within 200 s. Concurrently, cRGD-CEP-IR783-Lip demonstrated a significant therapeutic effect and robust biosafety in the in vivo antitumor experiments.
CONCLUSION
The combination indices of CEP and IR783 were successfully determined in vitro in five cell lines. The cRGD-coated liposomes encapsulated CEP and IR783 at an optimal synergistic ratio, exhibiting enhanced antitumor effects and targeting upon application in vitro and in vivo. This study presents a novel concept and establishes a research framework for synergistic chemotherapy and phototherapy treatment.
Topics: Liposomes; Animals; Cell Line, Tumor; Humans; Female; Mice; Indoles; Photothermal Therapy; Benzylisoquinolines; Mice, Inbred BALB C; Peptides, Cyclic; Drug Synergism; Antineoplastic Agents; Combined Modality Therapy; Cell Survival; Drug Delivery Systems; Benzodioxoles
PubMed: 38911506
DOI: 10.2147/IJN.S457008 -
Cureus May 2024The objective of this systematic review is to determine the effects of IL-17 inhibitors on major adverse cardiovascular events (MACEs) in patients with either psoriasis... (Review)
Review
The Impact of Interleukin-17 Inhibitors on Major Adverse Cardiovascular Events in Psoriasis or Psoriatic Arthritis Patients Naive to Biologic Agents: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
The objective of this systematic review is to determine the effects of IL-17 inhibitors on major adverse cardiovascular events (MACEs) in patients with either psoriasis (PsO) or psoriatic arthritis (PsA). A systematic literature search in three databases (Medline, Embase, and the Cochrane Library for Randomized Controlled Trials) was conducted on December 7, 2022 for randomized controlled trials of patients with PsO/PsA treated with IL-17 inhibitors that reported confirmed MACEs. Two reviewers screened titles and abstracts and identified papers for full-text review. Exclusion criteria included trials that included the previous use of biological disease-modifying anti-rheumatic drugs. The Mantel-Haenszel random-effect method was utilized to calculate risk ratios and heterogeneity was measured by χ test and I statistics. Funnel plot analysis was undertaken to detect potential publication bias. Of the 919 references identified, nine RCT studies were included in the meta-analysis (n=2,096 patients). There was no statistically significant correlation between the use of IL-17 inhibitors and change in risk of MACEs (Risk Ratio 0.56; 95% CI 0.15 to 2.14; p= 0.40). Subgroup analysis of secukinumab or ixekizumab also did not demonstrate these changes. Additionally, there was no detectable dose-dependent effect of IL-17 inhibitors. In conclusion, IL-17 inhibitor use is not correlated with a change in MACE risk in patients with PsO/PsA who previously did not receive biologic disease-modifying anti-rheumatic drugs.
PubMed: 38910708
DOI: 10.7759/cureus.60980 -
BMJ Open Jun 2024Biological disease-modifying antirheumatic drugs (bDMARDs) have revolutionised the treatment of inflammatory arthritis (IA). However, many people with IA still require...
PERI-operative biologic DMARD management: Stoppage or COntinuation during orthoPaEdic operations (the PERISCOPE trial) - a study protocol for a pragmatic, UK multicentre, superiority randomised controlled trial with an internal pilot, economic evaluation and nested qualitative study.
INTRODUCTION
Biological disease-modifying antirheumatic drugs (bDMARDs) have revolutionised the treatment of inflammatory arthritis (IA). However, many people with IA still require planned orthopaedic surgery to reduce pain and improve function. Currently, bDMARDs are withheld during the perioperative period due to potential infection risk. However, this predisposes patients to IA flares and loss of disease control. The question of whether to stop or continue bDMARDs in the perioperative period has not been adequately addressed in a randomised controlled trial (RCT).
METHODS AND ANALYSIS
PERISCOPE is a multicentre, superiority, pragmatic RCT investigating the stoppage or continuation of bDMARDs. Participants will be assigned 1:1 to either stop or continue their bDMARDs during the perioperative period. We aim to recruit 394 adult participants with IA. Potential participants will be identified in secondary care hospitals in the UK, screened by a delegated clinician. If eligible and consenting, baseline data will be collected and randomisation completed. The primary outcome will be the self-reported PROMIS-29 (Patient Reported Outcome Measurement Information System) over the first 12 weeks postsurgery. Secondary outcome measures are as follows: PROMIS - Health Assessment Questionnaire (PROMIS-HAQ), EQ-5D-5L, Disease activity: generic global Numeric Rating Scale (patient and clinician), Self-Administered Patient Satisfaction scale, Health care resource use and costs, Medication use, Surgical site infection, delayed wound healing, Adverse events (including systemic infections) and disease-specific outcomes (according to IA diagnosis). The costs associated with stopping and continuing bDMARDs will be assessed. A qualitative study will explore the patients' and clinicians' acceptability and experience of continuation/stoppage of bDMARDs in the perioperative period and the impact postoperatively.
ETHICS AND DISSEMINATION
Ethical approval for this study was received from the West of Scotland Research Ethics Committee on 25 April 2023 (REC Ref: 23/WS/0049). The findings from PERISCOPE will be submitted to peer-reviewed journals and feed directly into practice guidelines for the use of bDMARDs in the perioperative period.
TRIAL REGISTRATION NUMBER
ISRCTN17691638.
Topics: Humans; Orthopedic Procedures; United Kingdom; Antirheumatic Agents; Pragmatic Clinical Trials as Topic; Perioperative Care; Qualitative Research; Multicenter Studies as Topic; Pilot Projects; Cost-Benefit Analysis; Biological Products
PubMed: 38910007
DOI: 10.1136/bmjopen-2024-084997 -
Scientific Reports Jun 2024Metabolites exploration of the ethyl acetate extract of Fusarium solani culture broth that was isolated from Euphorbia tirucalli root afforded five compounds;...
Metabolites exploration of the ethyl acetate extract of Fusarium solani culture broth that was isolated from Euphorbia tirucalli root afforded five compounds; 4-hydroxybenzaldehyde (1), 4-hydroxybenzoic acid (2), tyrosol (3), azelaic acid (4), malic acid (5), and fusaric acid (6). Fungal extract as well as its metabolites were evaluated for their anti-inflammatory and anti-hyperpigmentation potential via in vitro cyclooxygenases and tyrosinase inhibition assays, respectively. Azelaic acid (4) exhibited powerful and selective COX-2 inhibition followed by fusaric acid (6) with IC values (2.21 ± 0.06 and 4.81 ± 0.14 μM, respectively). As well, azelaic acid (4) had the most impressive tyrosinase inhibitory effect with IC value of 8.75 ± 0.18 μM compared to kojic acid (IC = 9.27 ± 0.19 μM). Exclusive computational studies of azelaic acid and fusaric acid with COX-2 were in good accord with the in vitro results. Interestingly, this is the first time to investigate and report the potential of compounds 3-6 to inhibit cyclooxygenase enzymes. One of the most invasive forms of skin cancer is melanoma, a molecular docking study using a set of enzymes related to melanoma suggested pirin to be therapeutic target for azelaic acid and fusaric acid as a plausible mechanism for their anti-melanoma activity.
Topics: Fusarium; Anti-Inflammatory Agents; Dicarboxylic Acids; Molecular Docking Simulation; Melanoma; Humans; Cyclooxygenase 2; Fusaric Acid; Monophenol Monooxygenase; Computer Simulation; Cyclooxygenase Inhibitors
PubMed: 38909081
DOI: 10.1038/s41598-024-63958-0 -
Journal of Orthopaedic Surgery (Hong... 2024To investigate the disease activity in real-world patients with rheumatoid arthritis (RA) who switched from originator etanercept (ETN) to biosimilar YLB113. Forty one...
To investigate the disease activity in real-world patients with rheumatoid arthritis (RA) who switched from originator etanercept (ETN) to biosimilar YLB113. Forty one RA patients who switched from ETN to YLB113 were divided into 2 groups based on the Disease Activity Score based on the 28-joint count (DAS28) 12 months after switching (R group: DAS28 < 2.6, N group: DAS28 ≥ 2.6), and the baseline characteristics were statistically examined. A receiver operating characteristics (ROC) analysis was performed to estimate the cut-off value of DAS28 at baseline to achieve remission 12 months after switching. There was no significant difference in the DAS28 at baseline and 12 months after switching ( = .83). Sixteen out of the 20 patients in remission at baseline achieved remission after switching. A univariate analysis revealed the rheumatoid factor ( = .04) and DAS28 ( < .001) at baseline were significantly lower in the R group than in the N group. Furthermore, logistic regression analysis revealed DAS28 was an independent factor ( = .004) for achieving remission 12 months after switching. An ROC curve analysis showed the optimal cut-off value for DAS28 at baseline to achieve remission at 12 months after switching was 2.5. RA patients who achieved remission using originator ETN, were able to maintain remission even if they switched to YLB113.
Topics: Humans; Arthritis, Rheumatoid; Etanercept; Male; Female; Middle Aged; Biosimilar Pharmaceuticals; Antirheumatic Agents; Retrospective Studies; Follow-Up Studies; Drug Substitution; Adult; Aged; Treatment Outcome; Remission Induction; Severity of Illness Index
PubMed: 38907590
DOI: 10.1177/10225536241265818 -
Respiratory Research Jun 2024Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease (ILD) with a high mortality rate. The antifibrotic medications pirfenidone and nintedanib...
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease (ILD) with a high mortality rate. The antifibrotic medications pirfenidone and nintedanib have been in use since 2014 for this disorder and are associated with improved rate of lung function decline. Less is known about their long-term outcomes outside of the clinical trial context.
METHODS
The Pulmonary Fibrosis Foundation Patient Registry was used for this study. Patients with an IPF diagnosis made within a year of enrollment were included. The treated group was defined as patients receiving either pirfenidone or nintedanib for at least 180 days. The untreated group did not have any record of antifibrotic use. Demographic data, comorbidities, serial lung function, hospitalization, and vital status data were collected from the registry database. The primary outcomes were transplant-free survival, time to first respiratory hospitalization, and time to 10% absolute FVC decline. Time-to-event analyses were performed utilizing Cox proportional hazards models and the log-rank test. Model covariates included age, gender, smoking history, baseline lung function, comorbidities, and oxygen use.
RESULTS
The registry contained 1212 patients with IPF; ultimately 288 patients met inclusion criteria for the treated group, and 101 patients were designated as untreated. Patients treated with antifibrotics were significantly younger (69.8 vs. 72.6 years, p = 0.008) and less likely to have smoked (61.1% ever smokers vs. 72.3% never smokers, p = 0.04). No significant differences were seen in race, gender, comorbidities, or baseline pulmonary function between groups. The primary outcome of transplant-free survival was not significantly different between the two groups (adjusted HR 0.799, 95% CI 0.534-1.197, p = 0.28). Time to respiratory hospitalization was significantly shorter in the treated group (adjusted HR 2.12, 95% CI 1.05-4.30, p = 0.04). No significant difference in time to pulmonary function decline was seen between groups.
CONCLUSIONS
This multicenter study demonstrated 63% of newly diagnosed IPF patients had continuous antifibrotic usage. Antifibrotics were not associated with improved transplant-free survival or pulmonary function change but was associated with an increased hazard of respiratory hospitalization. Future studies should further investigate the role of antifibrotic therapy in clinically important outcomes in real-world patients with IPF and other progressive ILDs.
Topics: Humans; Male; Registries; Female; Idiopathic Pulmonary Fibrosis; Aged; Middle Aged; Antifibrotic Agents; Treatment Outcome; Pyridones; Indoles; Time Factors
PubMed: 38907239
DOI: 10.1186/s12931-024-02883-2 -
RMD Open Jun 2024
Topics: Humans; Arthritis, Rheumatoid; Prognosis; Antirheumatic Agents; Clinical Decision-Making; Female; Male; Middle Aged
PubMed: 38906542
DOI: 10.1136/rmdopen-2024-004382 -
Medicine Jun 2024Hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening syndrome for which early recognition and treatment are essential for improving outcomes. HLH...
INTRODUCTION
Hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening syndrome for which early recognition and treatment are essential for improving outcomes. HLH is characterized by uncontrolled immune activation leading to fever, cytopenias, hepatosplenomegaly, coagulation abnormalities, and elevated typical markers. This condition can be genetic or secondary, with the latter often triggered by infections. Here, we present a unique case of HLH secondary to acute otitis media (AOM), a common ear infection.
PATIENT CONCERNS
We describe a 4-year-old boy who initially presented with a high fever and otalgia, later diagnosed with bilateral AOM. Despite antibiotic treatment, his condition deteriorated.
DIAGNOSIS
The patient fulfilled diagnostic criteria for HLH.
INTERVENTIONS
Aggressive treatment by using combination therapy with immunoglobulins, intravenous steroids (dexamethasone), cyclosporine, and etoposide was performed.
OUTCOMES
After 1 month of treatment, improvement in the otologic symptoms was observed, and hematological findings gradually improved and normalized.
LESSIONS
The link between AOM and HLH may be associated with inflammatory responses and immunological mechanisms, highlighting the importance of considering HLH in severe infection cases. This case emphasizes the need for prompt diagnosis and management, especially in secondary HLH scenarios, to improve patient outcomes. It is imperative to be aware of the potential correlation between these 2 conditions, and healthcare professionals should consider the likelihood of HLH.
Topics: Humans; Lymphohistiocytosis, Hemophagocytic; Male; Child, Preschool; Otitis Media; Acute Disease; Dexamethasone; Cyclosporine; Etoposide; Immunoglobulins, Intravenous
PubMed: 38905364
DOI: 10.1097/MD.0000000000038616 -
Science Advances Jun 2024Autophagy-targeting chimera (AUTAC) has emerged as a powerful modality that can selectively degrade tumor-related pathogenic proteins, but its low bioavailability and...
Autophagy-targeting chimera (AUTAC) has emerged as a powerful modality that can selectively degrade tumor-related pathogenic proteins, but its low bioavailability and nonspecific distribution significantly restrict their therapeutic efficacy. Inspired by the guanine structure of AUTAC molecules, we here report supramolecular artificial Nano-AUTACs (GM NPs) engineered by AUTAC molecule GN [an indoleamine 2,3-dioxygenase (IDO) degrader] and nucleoside analog methotrexate (MTX) through supramolecular interactions for tumor-specific protein degradation. Their nanostructures allow for precise localization and delivery into cancer cells, where the intracellular acidic environment can disrupt the supramolecular interactions to release MTX for eradicating tumor cells, modulating tumor-associated macrophages, activating dendritic cells, and inducing autophagy. Specifically, the induced autophagy facilitates the released GN for degrading immunosuppressive IDO to further enhance effector T cell activity and inhibit tumor growth and metastasis. This study offers a unique strategy for building a nanoplatform to advance the field of AUTAC in tumor immunotherapy.
Topics: Immunotherapy; Animals; Mice; Humans; Autophagy; Cell Line, Tumor; Proteolysis; Neoplasms; Nanoparticles; Methotrexate; Indoleamine-Pyrrole 2,3,-Dioxygenase; Dendritic Cells
PubMed: 38905336
DOI: 10.1126/sciadv.adn8079