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Biomedicine & Pharmacotherapy =... Jun 2024Myocardial infarction (MI) has emerged as the primary cause of global mortality. Managing blood sugar levels could play a vital role in the treatment of MI....
BACKGROUND
Myocardial infarction (MI) has emerged as the primary cause of global mortality. Managing blood sugar levels could play a vital role in the treatment of MI. Dapagliflozin (DPG), a commonly used hypoglycemic drug, has demonstrated efficacy in treating heart failure. However, the impact of DPG on MI remains unclear. We aimed to investigate the effects and mechanisms of DPG in relation to MI.
METHODS AND RESULTS
DPG administration alleviated MI-induced cardiac dysfunction and myocardial fibrosis. We also found that DPG administration mitigated cardiomyocyte apoptosis through TUNEL staining. CD31 and α-Sma staining revealed that DPG promotes post-MI angiogenesis in mice. In vitro, using scratch assays, transwell assays, and tube formation assays, we discovered that DPG enhanced HUVEC proliferation capacity. Mechanistically, DPG promoted the expression of extracellular matrix genes and mitochondrial function-related genes. Additionally, molecular docking identified the interaction between DPG and PXR, which activated PXR and recruited it to the promoters of Pgam2 and Tcap, promoting their expressions, thus facilitating angiogenesis and post-MI heart repair.
CONCLUSIONS
DPG promotes angiogenesis by activating PXR, thereby alleviating cardiac dysfunction and fibrosis after myocardial infarction. This study provides new strategies and targets for the treatment of ischemic disease.
PubMed: 38889638
DOI: 10.1016/j.biopha.2024.116994 -
Cancer Medicine Jun 2024Patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC), which accounts for 85% of all CRC cases, display a poor respond to...
BACKGROUND
Patients with DNA mismatch repair-proficient/microsatellite stable (pMMR/MSS) colorectal cancer (CRC), which accounts for 85% of all CRC cases, display a poor respond to immune checkpoint inhibitors (i.e., anti-PD-1 antibodies). pMMR/MSS CRC patients with locally advanced cancers need effective combined therapies.
METHODS
In this pilot study, we administered six preoperative doses of each 2-week cycle of the anti-PD-1 antibody sintilimab (at a fixed dose of 200 mg), oxaliplatin, and 5-FU/CF (mFOLFOX6) combined with five doses of bevacizumab (the number of doses was reduced to prevent surgical delays) to patients with cT4NxM0 colon or upper rectal cancers. And radical surgery was performed approximately 2 weeks after the last dose of neoadjuvant therapy. The primary endpoint was a pathologic complete response (pCR). We also evaluated major pathologic response (MPR, ≤10% residual viable tumor), radiological and pathological regression, safety, and tumor mutation burden (TMB), and tumor microenvironment (TME) characteristics.
RESULTS
By the cutoff date (September 2023), 22 patients with cT4NxM0 pMMR/MSS colon or upper rectal cancers were enrolled and the median follow-up was 24.7 months (IQR: 21.1-26.1). All patients underwent R0 surgical resection without treatment-related surgical delays. pCR occurred in 12 of 22 resected tumors (54.5%) and MPR occurred in 18 of 22 (81.8%) patients. At the cutoff date, all patients were alive, and 21/22 were recurrence-free. Treatment-related adverse events of grade 3 or higher occurred in of 2/22 (9.1%) patients. Among the pCR tumors, two were found to harbor POLE mutations. The degree of pathological regression was significantly greater than that of radiological regression (p = 1.35 × 10). The number of CD3+/CD4+ cells in the tumor and stroma in pretreated biopsied tissues was markedly lower in pCR tumors than in non-pCR tumors (p = 0.038 and p = 0.015, respectively).
CONCLUSIONS
Neoadjuvant sintilimab combined with bevacizumab and mFOLFOX6 was associated with few side effects, did not delay surgery, and led to pCR and non-pCR in 54.5% and 81.8% of the cases, respectively. Downregulation of CD3/CD4 expression in the tumor and stroma is related to pCR. However, the molecular mechanisms underlying PD-1 blockade-enhanced targeted chemotherapy require further investigation.
Topics: Humans; Male; Female; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Aged; Colorectal Neoplasms; Fluorouracil; Immune Checkpoint Inhibitors; Pilot Projects; Bevacizumab; Antibodies, Monoclonal, Humanized; Leucovorin; DNA Mismatch Repair; Adult; Microsatellite Instability; Oxaliplatin; Neoadjuvant Therapy; Tumor Microenvironment; Organoplatinum Compounds; Programmed Cell Death 1 Receptor; Treatment Outcome
PubMed: 38888366
DOI: 10.1002/cam4.7224 -
Cancer Imaging : the Official... Jun 2024The Response Evaluation Criteria in Solid Tumors (RECIST) are often inadequate for the early assessment of the response to cancer therapy, particularly bevacizumab-based...
Prognostic value of the tumor-to-liver density ratio in patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy. A post-hoc study of the STIC-AVASTIN trial.
BACKGROUND
The Response Evaluation Criteria in Solid Tumors (RECIST) are often inadequate for the early assessment of the response to cancer therapy, particularly bevacizumab-based chemotherapy. In a first cohort of patients with colorectal cancer liver metastases (CRLM), we showed that variations of the tumor-to-liver density (TTLD) ratio and modified size-based criteria determined using computed tomography (CT) data at the first restaging were better prognostic criteria than the RECIST. The aims of this study were to confirm the relevance of these radiological biomarkers as early predictors of the long-term clinical outcome and to assess their correlation with contrast-enhanced ultrasound (CEUS) parameters in a new patient cohort.
METHODS
In this post-hoc study of the multicenter STIC-AVASTIN trial, we retrospectively reviewed CT data of patients with CRLM treated with bevacizumab-based regimens. We determined the size, density and TTLD ratio of target liver lesions at baseline and at the first restaging and also performed a morphologic evaluation according to the MD Anderson criteria. We assessed the correlation of these parameters with progression-free survival (PFS) and overall survival (OS) using the log-rank test and a Cox proportional hazard model. We also examined the association between TTLD ratio and quantitative CEUS parameters.
RESULTS
This analysis concerned 79 of the 137 patients included in the STIC-AVASTIN trial. PFS and OS were significantly longer in patients with tumor size reduction > 15% at first restaging, but were not correlated with TTLD ratio variations. However, PFS was longer in patients with TTLD ratio > 0.6 at baseline and first restaging than in those who did not reach this threshold. In the multivariate analysis, only baseline TTLD ratio > 0.6 was a significant survival predictor. TTLD ratio > 0.6 was associated with improved perfusion parameters.
CONCLUSIONS
Although TTLD ratio variations did not correlate with the long-term clinical outcomes, TTLD absolute values remained a good predictor of survival at baseline and first restaging, and may reflect tumor microvascular features that might influence bevacizumab-based treatment efficiency.
TRIAL REGISTRATION
NCT00489697, registration number of the STIC-AVASTIN trial.
Topics: Humans; Bevacizumab; Colorectal Neoplasms; Liver Neoplasms; Male; Female; Middle Aged; Aged; Retrospective Studies; Prognosis; Tomography, X-Ray Computed; Antineoplastic Combined Chemotherapy Protocols; Adult; Ultrasonography; Liver
PubMed: 38886836
DOI: 10.1186/s40644-024-00722-7 -
Stem Cell Research & Therapy Jun 2024Cartilage is a kind of avascular tissue, and it is difficult to repair itself when it is damaged. In this study, we investigated the regulation of chondrogenic...
BACKGROUND
Cartilage is a kind of avascular tissue, and it is difficult to repair itself when it is damaged. In this study, we investigated the regulation of chondrogenic differentiation and vascular formation in human jaw bone marrow mesenchymal stem cells (h-JBMMSCs) by the long-chain noncoding RNA small nucleolar RNA host gene 1 (SNHG1) during cartilage tissue regeneration.
METHODS
JBMMSCs were isolated from the jaws via the adherent method. The effects of lncRNA SNHG1 on the chondrogenic differentiation of JBMMSCs in vitro were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), Pellet experiment, Alcian blue staining, Masson's trichrome staining, and modified Sirius red staining. RT-qPCR, matrix gel tube formation, and coculture experiments were used to determine the effect of lncRNA SNHG1 on the angiogenesis in JBMMSCs in vitro. A model of knee cartilage defects in New Zealand rabbits and a model of subcutaneous matrix rubber suppositories in nude mice were constructed for in vivo experiments. Changes in mitochondrial function were detected via RT-qPCR, dihydroethidium (DHE) staining, MitoSOX staining, tetramethyl rhodamine methyl ester (TMRM) staining, and adenosine triphosphate (ATP) detection. Western blotting was used to detect the phosphorylation level of signal transducer and activator of transcription 3 (STAT3).
RESULTS
Alcian blue staining, Masson's trichrome staining, and modified Sirius Red staining showed that lncRNA SNHG1 promoted chondrogenic differentiation. The lncRNA SNHG1 promoted angiogenesis in vitro and the formation of microvessels in vivo. The lncRNA SNHG1 promoted the repair and regeneration of rabbit knee cartilage tissue. Western blot and alcian blue staining showed that the JAK inhibitor reduced the increase of STAT3 phosphorylation level and staining deepening caused by SNHG1. Mitochondrial correlation analysis revealed that the lncRNA SNHG1 led to a decrease in reactive oxygen species (ROS) levels, an increase in mitochondrial membrane potential and an increase in ATP levels. Alcian blue staining showed that the ROS inhibitor significantly alleviated the decrease in blue fluorescence caused by SNHG1 knockdown.
CONCLUSIONS
The lncRNA SNHG1 promotes chondrogenic differentiation and angiogenesis of JBMMSCs. The lncRNA SNHG1 regulates the phosphorylation of STAT3, reduces the level of ROS, regulates mitochondrial energy metabolism, and ultimately promotes cartilage regeneration.
Topics: RNA, Long Noncoding; Humans; Animals; Cell Differentiation; Rabbits; Mitochondria; Mesenchymal Stem Cells; Chondrogenesis; Mice; Mice, Nude; Regeneration; Neovascularization, Physiologic; Cartilage; STAT3 Transcription Factor; Angiogenesis
PubMed: 38886785
DOI: 10.1186/s13287-024-03793-2 -
Scientific Reports Jun 2024Age-related macular degeneration (AMD) is one of the major causes of blindness in the elderly worldwide. Anti-vascular endothelial growth factor (VEGF) drugs have been...
Age-related macular degeneration (AMD) is one of the major causes of blindness in the elderly worldwide. Anti-vascular endothelial growth factor (VEGF) drugs have been widely used to treat the neovascular type of AMD (nAMD). However, VEGF acts not only as a pro-angiogenic factor but also as an anti-apoptotic factor in the eyes. In this study, we found that anti-VEGF drugs, including bevacizumab (Bev), ranibizumab (Ran), and aflibercept (Afl), induced epithelial-mesenchymal transition (EMT) in ARPE-19 cells in vitro, accompanied by the induction of CCN2, a potent pro-fibrotic factor. Similarly, intravitreal injection of Afl into mouse eyes resulted in EMT in the retinal pigmented epithelium (RPE). Co-treatment with CCN5, an anti-fibrotic factor that down-regulates CCN2 expression, significantly attenuated the adverse effects of the anti-VEGF drugs both in vitro and in vivo. Inhibition of the VEGF signaling pathway with antagonists of VEGF receptors, SU5416 and ZM323881, induced EMT and up-regulated CCN2 in ARPE-19 cells. Additionally, knock-down of CCN2 with siRNA abolished the adverse effects of the anti-VEGF drugs in ARPE-19 cells. Collectively, these results suggest that anti-VEGF drugs induce EMT in RPE through the induction of CCN2 and that co-treatment with CCN5 attenuates the adverse effects of anti-VEGF drugs in mouse eyes.
Topics: Epithelial-Mesenchymal Transition; Retinal Pigment Epithelium; Animals; Humans; Mice; Vascular Endothelial Growth Factor A; Macular Degeneration; Cell Line; Bevacizumab; CCN Intercellular Signaling Proteins; Angiogenesis Inhibitors; Ranibizumab; Recombinant Fusion Proteins; Signal Transduction; Repressor Proteins; Receptors, Vascular Endothelial Growth Factor
PubMed: 38886213
DOI: 10.1038/s41598-024-63565-z -
Ophthalmology Science 2024To evaluate the safety and efficacy of CBT-001, a multitarget tyrosine kinase inhibitor eyedrop, for pterygia.
A Phase IIa Multicenter, Randomized, Vehicle-Controlled, Dose Escalating Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of CBT-001 Ophthalmic Solution in Patients With Primary or Recurrent Pterygium.
PURPOSE
To evaluate the safety and efficacy of CBT-001, a multitarget tyrosine kinase inhibitor eyedrop, for pterygia.
DESIGN
Phase II clinical trial. Stage 1 was a single center, open-labeled, vehicle-controlled study. Stage 2 was a multicenter, randomized, double-masked, vehicle-controlled trial.
PARTICIPANTS
Patients with primary or recurrent pterygia.
MAIN OUTCOME MEASURES
The primary efficacy end point was lesion vascularity based on masked grading of photographs by an independent reading center. Other end points included dimensions of pterygia and safety.
METHODS
In stage 1, 24 eyes of 24 patients received 1 drop of CBT-001 in a dose escalation fashion (0.02%, 0.05%, and 0.2%) to determine the maximally tolerated dose based on adverse events (AEs) and blood drug levels. In stage 2, subjects were randomly assigned to receive the maximally tolerated dose of CBT-001 or vehicle dosed 3 times a day for 4 weeks with a 20-week follow-up.
RESULTS
In stage 1, the plasma maximum concentration values for all doses of CBT-001 were at or below the limit of detection (0.01 ng/ml). The most commonly reported AEs were mild foreign body sensation and irritation. CBT-001 0.2% was evaluated in stage 2. Baseline demographic characteristics were similar between patients receiving CBT-001 (n = 25) and vehicle (n = 23). After 4 weeks of dosing, the mean change from baseline in pterygium vascularity scores was -0.8 ± 0.7 (mean ± standard deviation) in subjects receiving CBT-001 0.2% and 0.0 ± 0.5 in subjects receiving vehicle ( < 0.001; 95% confidence interval: -1.12, -0.40). Pterygium vascularity scores remained significantly decreased, after the 4-week dosing period, at weeks 8 and 16, but not at week 24. The mean changes from baseline in the length of the pterygia were also significantly lower in subjects receiving CBT-001 compared with vehicle at weeks 2, 4, and 8 ( ≤ 0.014). The most commonly reported AEs were ocular, mild in severity, resolved after therapy, and did not result in discontinuation.
CONCLUSIONS
CBT-001 0.2% decreased pterygia vascularity and lesion length after 4 weeks of dosing with a prolonged effect after dosing. The drug was well tolerated with minimal detected systemic drug levels.
FINANCIAL DISCLOSURES
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
PubMed: 38883924
DOI: 10.1016/j.xops.2024.100502 -
Frontiers in Public Health 2024Progressive glioblastoma (GBM) is a malignancy with extremely poor prognosis. Chemotherapy is one of the approved systemic treatment modalities. The aim of this study is...
BACKGROUND
Progressive glioblastoma (GBM) is a malignancy with extremely poor prognosis. Chemotherapy is one of the approved systemic treatment modalities. The aim of this study is to assess the cost-effectiveness of using bevacizumab (BEV) in combination with lomustine (LOM) regimen for the treatment of progressive glioblastoma in China.
METHODS
The estimation results are derived from a multicenter randomized phase III trial, which demonstrated improved survival in GBM patients receiving BEV+LOM combination therapy. To calculate the incremental cost-effectiveness ratio (ICER) from the perspective of Chinese society, a Markov model was established. Univariate deterministic analysis and probabilistic sensitivity analysis were employed to address the uncertainties within the model.
RESULTS
Compared to LOM monotherapy, the total treatment cost for BEV+LOM combination therapy increased from $2,646.70 to $23,650.98. The health-adjusted life years (QALYs) for BEV+LOM combination therapy increased from 0.26 QALYs to 0.51 QALYs, representing an increment of 0.25 QALYs. The incremental cost-effectiveness ratio (ICER) was $84,071.12. The cost-effectiveness curve indicates that within the willingness-to-pay (WTP) range of $35,906 per QALY, BEV+LOM combination therapy is not a cost-effective treatment option for unresectable malignant pleural mesothelioma patients.
CONCLUSIONS
Taken as a whole, the findings of this study suggest that, from the perspective of payers in China, BEV+LOM combination therapy as a first-line treatment for GBM is not a cost-effective option. However, considering the survival advantages this regimen may offer for this rare disease, it may still be one of the clinical treatment options for this patient population.
Topics: Bevacizumab; Glioblastoma; Humans; Cost-Benefit Analysis; Lomustine; Markov Chains; China; Antineoplastic Combined Chemotherapy Protocols; Quality-Adjusted Life Years; Brain Neoplasms; Cost-Effectiveness Analysis
PubMed: 38883194
DOI: 10.3389/fpubh.2024.1410355 -
Regenerative Therapy Jun 2024Hair loss is one of the common clinical conditions in modern society. Although it is not a serious disease that threatens human life, it brings great mental stress and...
INTRODUCTION
Hair loss is one of the common clinical conditions in modern society. Although it is not a serious disease that threatens human life, it brings great mental stress and psychological burden to patients. This study investigated the role of dendrobium officinale polysaccharide (DOP) in hair follicle regeneration and hair growth and its related mechanisms.
METHODS
After in vitro culture of mouse antennal hair follicles and mouse dermal papilla cells (DPCs), and mouse vascular endothelial cells (MVECs), the effects of DOP upon hair follicles and cells were evaluated using multiple methods. DOP effects were evaluated by measuring tentacle growth, HE staining, immunofluorescence, Western blot, CCK-8, ALP staining, tube formation, scratch test, and Transwell. LDH levels, WNT signaling proteins, and therapeutic mechanisms were also analyzed.
RESULTS
DOP promoted tentacle hair follicle and DPCs growth in mice and the angiogenic, migratory and invasive capacities of MVECs. Meanwhile, DOP was also capable of enhancing angiogenesis and proliferation-related protein expression. Mechanistically, DOP activated the WNT signaling and promoted the expression level of β-catenin, a pivotal protein of the pathway, and the pathway target proteins Cyclin D1, C-Myc, and LDH activity. The promotional effects of DOP on the biological functions of DPCs and MVECs could be effectively reversed by the WNT signaling pathway inhibitor IWR-1.
CONCLUSION
DOP advances hair follicle and hair growth via the activation of the WNT signaling. This finding provides a mechanistic reference and theoretical basis for the clinical use of DOP in treating hair loss.
PubMed: 38883148
DOI: 10.1016/j.reth.2024.04.014 -
Frontiers in Pharmacology 2024Celastrol (Cel) is a widely used main component of Chinese herbal medicine with strong anti-inflammatory, antiviral and antitumor activities. In the present study, we...
Celastrol (Cel) is a widely used main component of Chinese herbal medicine with strong anti-inflammatory, antiviral and antitumor activities. In the present study, we aimed to elucidate the cellular molecular protective mechanism of Cel against diabetes-induced inflammation and endothelial dysfunction. Type 2 diabetes (T2DM) was induced by db/db mice, and osmotic pumps containing Cel (100 μg/kg/day) were implanted intraperitoneally and were calibrated to release the drug for 28 days. In addition, human umbilical vein endothelial cells (HUVECs) were cultured in normal or high glucose and palmitic acid-containing (HG + PA) media in the presence or absence of Cel for 48 h. Cel significantly ameliorated the hyperglycemia-induced abnormalities in nuclear factor (erythroid-derived 2)-like protein 2 (Nrf2) pathway activity and alleviated HG + PA-induced oxidative damage. However, the protective effect of Cel was almost completely abolished in HUVECs transfected with short hairpin (sh)RNA targeting Nrf2, but not by nonsense shRNA. Furthermore, HG + PA reduced the phosphorylation of AMP-activated protein kinase (AMPK), the autophagic degradation of p62/Kelch-like ECH-associated protein 1 (Keap1), and the nuclear localization of Nrf2. However, these catabolic pathways were inhibited by Cel treatment in HUVECs. In addition, compound C (AMPK inhibitors) and reduced Cel-induced Nrf2 activation and angiogenesis in db/db mice. Taking these findings together, the endothelial protective effect of Cel in the presence of HG + PA may be at least in part attributed to its effects to reduce reactive oxygen species (ROS) and inflammation through p62/Keap1-mediated Nrf2 activation.
PubMed: 38881873
DOI: 10.3389/fphar.2024.1360177 -
Scientific Reports Jun 2024We assessed the short-term effects of switching from intravitreal aflibercept (IVA) to intravitreal faricimab (IVF) on ocular blood flow in patients with...
We assessed the short-term effects of switching from intravitreal aflibercept (IVA) to intravitreal faricimab (IVF) on ocular blood flow in patients with treatment-resistant diabetic macular edema (DME). The medical records of 15 patients with DME who had received IVA injection ≥ 3 months before were retrospectively reviewed. The best-corrected visual acuity, central macular thickness (CMT) on optical coherence tomography, and mean blur rate (MBR) of all disc areas on laser speckle flowgraphy were measured before, 1 week after, and 4 weeks after IVA and IVF, respectively. The changes in visual acuity showed no significant difference after switching from IVA to IVF (P = 0.732). The mean CMT decreased significantly during the follow-up period (both P < 0.001). MBR showed no significant difference during the follow-up period (P = 0.26). However, it decreased significantly 4 weeks after IVF (P = 0.01) compared with the baseline value, but not 4 weeks after IVA (P = 0.074). A significant association was observed between decreased MBR and decreased CMT in patients who received IVF (correlation coefficient: 0.501, P = 0.005) but not in those who received IVA (P = 0.735). Thus, IVF maintained ocular blood flow reduction, although no significant differences in visual acuity and CMT changes were observed compared to IVA.
Topics: Humans; Macular Edema; Male; Female; Intravitreal Injections; Recombinant Fusion Proteins; Receptors, Vascular Endothelial Growth Factor; Middle Aged; Diabetic Retinopathy; Aged; Retrospective Studies; Visual Acuity; Tomography, Optical Coherence; Angiogenesis Inhibitors; Regional Blood Flow; Eye
PubMed: 38877041
DOI: 10.1038/s41598-024-63435-8