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Sichuan Da Xue Xue Bao. Yi Xue Ban =... May 2024To investigate the effect of Sanshentongmai (SSTM) mixture on the regulation of oxidative damage to rat cardiomyocytes (H9C2) through microRNA-146a and its mechanism.
OBJECTIVE
To investigate the effect of Sanshentongmai (SSTM) mixture on the regulation of oxidative damage to rat cardiomyocytes (H9C2) through microRNA-146a and its mechanism.
METHODS
H9C2 were cultured , HO was used as an oxidant to create an oxidative damage model in H9C2 cells. SSTM intervention was administered to the H9C2 cells. Then, the changes in HO-induced oxidative damage in H9C2 cells and the expression of microRNA-146a were observed to explore the protective effect of SSTM on H9C2 and its mechanism. H9C2 cells cultured were divided into 3 groups, including a control group, a model group of HO-induced oxidative damage (referred to hereafter as the model group), and a group given HO modeling plus SSTM intervention at 500 μg/L for 72 h (referred to hereafter as the treatment group). The cell viability was measured by CCK8 assay. In addition, the levels of N-terminal pro-brain natriuretic peptide (Nt-proBNP), nitric oxide (NO), high-sensitivity C-reactive protein (Hs-CRP), and angiotensin were determined by enzyme-linked immunosorbent assay (ELISA). The expression level of microRNA-146a was determined by real-time PCR (RT-PCR).
RESULT
H9C2 cells were pretreated with SSTM at mass concentrations ranging from 200 to 1500 μg/L. Then, CCK8 assay was performed to measure cell viability and the findings showed that the improvement in cell proliferation reached its peak when the mass concentration of SSTM was 500 μg/L, which was subsequently used as the intervention concentration. ELISA was performed to measure the indicators related to heart failure, including Nt-proBNP, NO, Hs-CRP, and angiotensin Ⅱ. Compared with those of the control group, the expressions of Nt-proBNP and angiotensin Ⅱ in the treatment group were up-regulated (<0.05), while the expression of NO was down-regulated (<0.05). There was no significant difference in the expression of Hs-CRP between the treatment group and the control group. These findings indicate that SSTM could effectively ameliorate oxidative damage in H9C2 rat cardiomyocytes. Finally, according to the RT-PCR findings for the expression of microRNA-146a in each group, HO treatment at 15 μmol/L could significantly reduce the expression of microRNA-146a, and the expression of microRNA-146a in the treatment group was nearly doubled compared with that in the model group. There was no significant difference between the treatment group and the control group.
CONCLUSION
SSTM can significantly resist the HO-induced oxidative damage of H9C2 cells and may play a myocardial protective role by upregulating microRNA-146a.
Topics: Myocytes, Cardiac; Animals; MicroRNAs; Rats; Oxidative Stress; Hydrogen Peroxide; Drugs, Chinese Herbal; Up-Regulation; Cell Survival; Cell Line; Drug Combinations
PubMed: 38948270
DOI: 10.12182/20240560601 -
PeerJ 2024Fibroblast growth factor 21 (FGF21) is a key hormone factor that regulates glucose and lipid homeostasis. Exercise may regulate its effects and affect disease states.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Fibroblast growth factor 21 (FGF21) is a key hormone factor that regulates glucose and lipid homeostasis. Exercise may regulate its effects and affect disease states. Therefore, we sought to determine how exercise affects FGF21 concentrations in adults.
METHODS
The review was registered in the International Prospective Systematic Review (PROSPERO, CRD42023471163). The Cochrane Library, PubMed, and Web of Science databases were searched for studies through July 2023. Studies that assessed the effects of exercise training on FGF21 concentration in adults were included. The random effect model, data with standardized mean difference (SMD), and 95% confidence intervals (CI) were used to evaluate the pooled effect size of exercise training on FGF21. The risk of heterogeneity and bias were evaluated. A total of 12 studies involving 401 participants were included.
RESULTS
The total effect size was 0.3 (95% CI [-0.3-0.89], = 0.33) when comparing participants who exercised to those who were sedentary. However, subgroup analysis indicated that concurrent exercise and a duration ≥10 weeks significantly decreased FGF21 concentrations with an effect size of -0.38 (95% CI [-0.74--0.01], < 0.05) and -0.38 (95% CI [-0.63--0.13], < 0.01), respectively.
CONCLUSION
Concurrent exercise and longer duration may be more efficient way to decrease FGF21 concentrations in adults with metabolic disorder.
Topics: Fibroblast Growth Factors; Humans; Exercise; Adult
PubMed: 38948228
DOI: 10.7717/peerj.17615 -
PeerJ 2024Ischemic stroke (IS) is a disease with a high mortality and disability rate worldwide, and its incidence is increasing per year. Angiogenesis after IS improves blood...
β-asarone induces viability and angiogenesis and suppresses apoptosis of human vascular endothelial cells after ischemic stroke by upregulating vascular endothelial growth factor A.
Ischemic stroke (IS) is a disease with a high mortality and disability rate worldwide, and its incidence is increasing per year. Angiogenesis after IS improves blood supply to ischemic areas, accelerating neurological recovery. β-asarone has been reported to exhibit a significant protective effect against hypoxia injury. The ability of β-asarone to improve IS injury by inducing angiogenesis has not been distinctly clarified. The experimental rats were induced with middle cerebral artery occlusion (MCAO), and oxygen-glucose deprivation (OGD) model cells were constructed using human microvascular endothelial cell line (HMEC-1) cells. Cerebral infarction and pathological damage were first determined triphenyl tetrazolium chloride (TTC) and hematoxylin and eosin (H&E) staining. Then, cell viability, apoptosis, and angiogenesis were assessed by utilizing cell counting kit-8 (CCK-8), flow cytometry, spheroid-based angiogenesis, and tube formation assays in OGD HMEC-1 cells. Besides, angiogenesis and other related proteins were identified with western blot. The study confirms that β-asarone, like nimodipine, can ameliorate cerebral infarction and pathological damage. β-asarone can also upregulate vascular endothelial growth factor A (VEGFA) and endothelial nitric oxide synthase (eNOS) and induce phosphorylation of p38. Besides, the study proves that β-asarone can protect against IS injury by increasing the expression of VEGFA. experiments affirmed that β-asarone can induce viability and suppress apoptosis in OGD-mediated HMEC-1 cells and promote angiogenesis of OGD HMEC-1 cells by upregulating VEGFA. This establishes the potential for β-asarone to be a latent drug for IS therapy.
Topics: Allylbenzene Derivatives; Anisoles; Apoptosis; Ischemic Stroke; Humans; Vascular Endothelial Growth Factor A; Cell Survival; Animals; Up-Regulation; Rats; Endothelial Cells; Male; Cell Line; Rats, Sprague-Dawley; Neovascularization, Physiologic; Angiogenesis
PubMed: 38948219
DOI: 10.7717/peerj.17534 -
PeerJ 2024The integration of diagnostic methods holds promise for advancing the surveillance of malaria transmission in both endemic and non-endemic regions. Serological assays...
BACKGROUND
The integration of diagnostic methods holds promise for advancing the surveillance of malaria transmission in both endemic and non-endemic regions. Serological assays emerge as valuable tools to identify and delimit malaria transmission, serving as a complementary method to rapid diagnostic tests (RDT) and thick smear microscopy. Here, we evaluate the potential of antibodies directed against peptides encompassing the entire amino acid sequence of the MSP-1 Sal-I strain as viable serological biomarkers for exposure.
METHODS
We screened peptides encompassing the complete amino acid sequence of the Merozoite Surface Protein 1 (MSP-1) Sal-I strain as potential biomarkers for exposure. Here, immunodominant peptides specifically recognized by antibodies from individuals infected with were identified using the SPOT-synthesis technique followed by immunoblotting. Two 15-mer peptides were selected based on their higher and specific reactivity in immunoblotting assays. Subsequently, peptides p70 and p314 were synthesized in soluble form using SPPS (Solid Phase Peptide Synthesis) and tested by ELISA (IgG, and subclasses).
RESULTS
This study unveils the presence of IgG antibodies against the peptide p314 in most -infected individuals from the Brazilian Amazon region. B-cell epitope prediction further supports the utilization of p314 as a potential biomarker for evaluating malaria transmission, strengthened by its amino acid sequence being part of a conserved block of MSP-1. Indeed, compared to patients infected with and uninfected individuals never exposed to malaria, -infected patients have a notably higher recognition of p314 by IgG1 and IgG3.
Topics: Humans; Malaria, Vivax; Merozoite Surface Protein 1; Plasmodium vivax; Biomarkers; Antibodies, Protozoan; Immunoglobulin G; Adult; Female; Male; Middle Aged; Peptides; Enzyme-Linked Immunosorbent Assay; Young Adult; Adolescent; Amino Acid Sequence
PubMed: 38948214
DOI: 10.7717/peerj.17632 -
The Lancet Regional Health. Western... Jun 2024Type 2 diabetes (T2DM) remains a challenge to treat despite the expansion of various therapeutic classes. Visepegenatide (PB-119) is a once a week, subcutaneous,...
Efficacy and safety of visepegenatide, a long-acting weekly GLP-1 receptor agonist as monotherapy in type 2 diabetes mellitus: a randomised, double-blind, parallel, placebo-controlled phase 3 trial.
BACKGROUND
Type 2 diabetes (T2DM) remains a challenge to treat despite the expansion of various therapeutic classes. Visepegenatide (PB-119) is a once a week, subcutaneous, glucagon-like peptide-1 receptor agonist (GLP-1 RA) injection without the requirement of dose titration that has shown glycaemic control and safety profile in two phase 2 studies conducted in China and the United States, respectively. The aim of this study was to evaluate the efficacy and safety of visepegenatide as a monotherapy in treatment-naïve patients with T2DM.
METHODS
This was a multicentre, double-blind, parallel, placebo-controlled, phase 3 trial conducted in 30 centres in China. Adult participants (aged 18-75 years) with T2DM, glycated haemoglobin (HbA1c) of 7.5%-11.0% [58.47-96.73 mmol/mol], body mass index (BMI) of 18-40 kg/m, and who had been treated with diet and exercise alone for at least 8 weeks before the screening visit were eligible for enrolment. After a 4-week placebo injection run-in period, participants with HbA1c of 7.0%-10.5% [53.0-91.3 mmol/mol] and fasting plasma glucose (FPG) < 15 mmol/L were randomised in a ratio of 1:1 to receive visepegenatide (150 μg) or placebo subcutaneous injections once a week for 24 weeks. The treatment was extended to another 28 weeks during which all participants received visepegenatide. The primary outcome was a change in HbA1c from baseline to week 24. This study was registered with ClinicalTrials.gov, as NCT04504370.
FINDINGS
Between November 2, 2020, and November 2, 2022, we randomly assigned 273 adult participants to the visepegenatide (n = 137) and placebo (n = 136) groups. In total, 257 (94.12%) participants, 131 (95.6%) on visepegenatide, and 126 (92.6%) on placebo, completed the double-blinded treatment period. At baseline, the mean (SD) HbA1c was 8.47% (0.81) [69.07 [8.81] mmol/mol], which rapidly decreased to 7.63% (0.80) [59.94 [8.70] mmol/mol] with visepegenatide by week 4 of treatment, and the change from baseline was significantly greater than that in the placebo group (-0.82% [-0.90 to -0.74]; [-8.99 [-9.89 to -8.10] mmol/mol] -0.30% [-0.41 to -0.19]; [-3.30 [-4.50 to -2.09] mmol/mol]). At week 24, when evaluating the effects of treatment with treatment policy estimand, the least square mean (LSM change in HbA1c from baseline was -1.36 (95% confidence interval [CI] -1.52 to -1.20) [-14.84 [-16.60 to -13.08] mmol/mol] in the visepegenatide group -0.63 (-0.79 to -0.46) [-6.84 [-8.61 to -5.07] mmol/mol] in the placebo group. The reduction in HbA1c was significantly greater with visepegenatide than placebo (LSM difference -0.73, 95% CI -0.96 to -0.50; p < 0.001). When evaluating the treatment estimand with hypothetic policy, the LSM change in HbA1c from baseline in the visepegenatide group (-1.37 [-1.53 to -1.20]) [-14.95 [-16.76 to -13.14] mmol/mol] was significantly greater than the placebo group (-0.63 [-0.81 to -0.45]) [6.90 (-8.89 to -4.90) mmol/mol]. The LSM difference was (-0.74, 95% CI -0.98 to -0.49; [-8.00 [-10.50 to -5.50] mmol/mol]; p < 0.001]. A significantly greater proportion of the visepegenatide group achieved a target HbA1c level of <7% (<53 mmol/mol) than the placebo (50.4% 14.2%; p < 0.05) and stringent HbA1c level of ≤6.5% (≤48 mmol/mol) (26.7% 7.9%), respectively. There was also a significantly greater improvement in FPG, 2-h postprandial glucose, homeostasis model assessment (HOMA) of beta cell function, post-prandial insulin, fasting, and post-prandial C-peptide level (p < 0.05) with visepegenatide treatment. The number (3 [2.2%]) of participants who received rescue therapy in the visepegenatide group was remarkably lower compared with those (17 [12.5%]) in the placebo group (p < 0.05). During the extended treatment period, visepegenatide consistently maintained the efficacy till week 52 confirmed by all the above endpoints. The reduction in HbA1c at week 52 was -1.39% (-1.58 to -1.19) [-15.14 [-17.28 to -13.01] mmol/mol], which was even greater than that at week 24. There was also a significant improvement in HOMA-insulin resistance (p = 0.004) at week 52 compared with the baseline value. For the placebo→visepegenatide group, which received visepegenatide in the extended treatment period, a notable decrease in HbA1c at week 52 compared to baseline was observed. The change from baseline in HbA1c was -1.49% (-1.68 to -1.30) [-16.27 [-18.37 to -14.16] mmol/mol]. The outcome was in the same direction as the visepegenatide group from the double-blind treatment period. Comprehensive benefits of visepegenatide including weight loss, improvement in lipid profile, and reduction in blood pressure have been demonstrated in this study. Visepegenatide reduced the body weight in a BMI-dependent manner that was prominent in BMI ˃32 kg/m with a mean (SD) reduction of -4.77 (13.94) kg at week 52 (p < 0.05). Incidences of gastrointestinal adverse events were less common than other weekly GLP-1 RA in the market, and most of the adverse events were mild and moderate in nature, occurring in the first weeks of the treatment, and were transient. No serious hypoglycaemia or grade 2 hypoglycaemia (blood glucose: ≤3 mmol/L) was reported during the study.
INTERPRETATION
As a monotherapy, visepegenatide provided rapid without the risk of hypoglycaemia, significant, and sustainable glycaemic control by improving islet β-cell function and insulin resistance. Treatment with visepegenatide induced early treatment response in reducing HbA1c and maintaining glycaemic control for 52 weeks. Meanwhile, visepegenatide provided a comprehensive benefit in body weight loss, lipids, and blood pressure reduction. Visepegenatide had a better safety profile than other weekly GLP-1 RA in participants with T2DM even without the requirement of dose titration. Visepegenatide would provide an optimal treatment approach with its high benefit and low-risk balance.
FUNDING
PegBio Co., Ltd.
PubMed: 38948164
DOI: 10.1016/j.lanwpc.2024.101101 -
Theranostics 2024: Recent evidence highlights the pivotal role of mitochondrial dysfunction in mood disorders, but the mechanism involved remains unclear. We studied whether the...
: Recent evidence highlights the pivotal role of mitochondrial dysfunction in mood disorders, but the mechanism involved remains unclear. We studied whether the Hippo/YAP/14-3-3η signaling pathway mediates mitochondrial abnormalities that result in the onset of major depressive disorder (MDD) in a mouse model. : The ROC algorithm was used to identify a subpopulation of mice that were exposed to chronic unpredictable mild stress (CUMS) and exhibited the most prominent depressive phenotype (Dep). Electron microscopy, biochemical assays, quantitative PCR, and immunoblotting were used to evaluate synaptic and mitochondrial changes in the basolateral amygdala (BLA). RNA sequencing was used to explore changes in the Hippo pathway and downstream target genes. pharmacological inhibition and immunoprecipitation was used to confirm YAP/14-3-3η interaction and its role in neuronal mitochondrial dysfunction. We used virus-mediated gene overexpression and knockout in YAP transgenic mice to verify the regulatory effect of the Hippo/YAP/14-3-3η pathway on depressive-like behavior. : Transcriptomic data identified a large number of genes and signaling pathways that were specifically altered from the BLA of Dep mice. Dep mice showed notable synaptic impairment in BLA neurons, as well as mitochondrial damage characterized by abnormal mitochondrial morphology, compromised function, impaired biogenesis, and alterations in mitochondrial marker proteins. The Hippo signaling pathway was activated in Dep mice during CUMS, and the transcriptional regulatory activity of YAP was suppressed by phosphorylation of its Ser127 site. 14-3-3η was identified as an important co-regulatory factor of the Hippo/YAP pathway, as it can respond to chronic stress and regulate cytoplasmic retention of YAP. Importantly, the integrated Hippo/YAP/14-3-3η pathway mediated neuronal mitochondrial dysfunction and depressive behavior in Dep mice. : The integrated Hippo/YAP/14-3-3η pathway in the BLA neuron is critical in mediating depressive-like behaviors in mice, suggesting a causal role for this pathway in susceptibility to chronic stress-induced depression. This pathway therefore may present a therapeutic target against mitochondrial dysfunction and synaptic impairment in MDD.
Topics: Animals; Disease Models, Animal; Mice; Mitochondria; YAP-Signaling Proteins; Signal Transduction; Hippo Signaling Pathway; Basolateral Nuclear Complex; Protein Serine-Threonine Kinases; Male; Stress, Psychological; 14-3-3 Proteins; Adaptor Proteins, Signal Transducing; Depressive Disorder, Major; Depression; Mice, Inbred C57BL; Neurons; Mice, Transgenic
PubMed: 38948066
DOI: 10.7150/thno.92676 -
Theranostics 2024Current treatments for ocular angiogenesis primarily focus on blocking the activity of vascular endothelial growth factor (VEGF), but unfavorable side effects and...
Current treatments for ocular angiogenesis primarily focus on blocking the activity of vascular endothelial growth factor (VEGF), but unfavorable side effects and unsatisfactory efficacy remain issues. The identification of novel targets for anti-angiogenic treatment is still needed. We investigated the role of tsRNA-1599 in ocular angiogenesis using endothelial cells, a streptozotocin (STZ)-induced diabetic model, a laser-induced choroidal neovascularization model, and an oxygen-induced retinopathy model. CCK-8 assays, EdU assays, transwell assays, and matrigel assays were performed to assess the role of tsRNA-1599 in endothelial cells. Retinal digestion assays, Isolectin B4 (IB4) staining, and choroidal sprouting assays were conducted to evaluate the role of tsRNA-1599 in ocular angiogenesis. Transcriptomic analysis, metabolic analysis, RNA pull-down assays, and mass spectrometry were utilized to elucidate the mechanism underlying angiogenic effects mediated by tsRNA-1599. tsRNA-1599 expression was up-regulated in experimental ocular angiogenesis models and endothelial cells in response to angiogenic stress. Silencing of tsRNA-1599 suppressed angiogenic effects in endothelial cells and inhibited pathological ocular angiogenesis . Mechanistically, tsRNA-1599 exhibited little effect on VEGF signaling but could cause reduced glycolysis and NAD/NADH production in endothelial cells by regulating the expression of HK2 gene through interacting with YBX1, thus affecting endothelial effects. Targeting glycolytic reprogramming of endothelial cells by a tRNA-derived small RNA represents an exploitable therapeutic approach for ocular neovascular diseases.
Topics: Animals; Glycolysis; Mice; Endothelial Cells; Choroidal Neovascularization; Humans; Y-Box-Binding Protein 1; Angiogenesis Inhibitors; Hexokinase; Diabetes Mellitus, Experimental; Mice, Inbred C57BL; Male; Disease Models, Animal; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A; Diabetic Retinopathy; Human Umbilical Vein Endothelial Cells; RNA, Small Untranslated
PubMed: 38948065
DOI: 10.7150/thno.96946 -
Theranostics 2024Device implantation frequently triggers cardiac remodeling and fibrosis, with monocyte-driven inflammatory responses precipitating arrhythmias. This study investigates...
Device implantation frequently triggers cardiac remodeling and fibrosis, with monocyte-driven inflammatory responses precipitating arrhythmias. This study investigates the role of mA modification enzymes METTL3 and METTL14 in these responses and explores a novel therapeutic strategy targeting these modifications to mitigate cardiac remodeling and fibrosis. Peripheral blood mononuclear cells (PBMCs) were collected from patients with ventricular septal defects (VSD) who developed conduction blocks post-occluder implantation. The expression of METTL3 and METTL14 in PBMCs was measured. METTL3 and METTL14 deficiencies were induced to evaluate their effect on angiotensin II (Ang II)-induced myocardial inflammation and fibrosis. mA modifications were analyzed using methylated RNA immunoprecipitation followed by quantitative PCR. NF-κB pathway activity and levels of monocyte migration and fibrogenesis markers (CXCR2 and TGF-β1) were assessed. An erythrocyte microvesicle-based nanomedicine delivery system was developed to target activated monocytes, utilizing the METTL3 inhibitor STM2457. Cardiac function was evaluated via echocardiography. Significant upregulation of METTL3 and METTL14 was observed in PBMCs from patients with VSD occluder implantation-associated persistent conduction block. Deficiencies in METTL3 and METTL14 significantly reduced Ang II-induced myocardial inflammation and fibrosis by decreasing mA modification on and mRNAs. This disruption reduced NF-κB pathway activation, lowered CXCR2 and TGF-β1 levels, attenuated monocyte migration and fibrogenesis, and alleviated cardiac remodeling. The erythrocyte microvesicle-based nanomedicine delivery system effectively targeted inflamed cardiac tissue, reducing inflammation and fibrosis and improving cardiac function. Inhibiting METTL3 and METTL14 in monocytes disrupts the NF-κB feedback loop, decreases monocyte migration and fibrogenesis, and improves cardiac function. Targeting mA modifications of monocytes with STM2457, delivered via erythrocyte microvesicles, reduces inflammation and fibrosis, offering a promising therapeutic strategy for cardiac remodeling associated with device implantation.
Topics: Humans; Methyltransferases; Monocytes; Fibrosis; Male; Animals; NF-kappa B; Erythrocytes; Adenosine; Female; Methylation; Mice; Transforming Growth Factor beta1; Cell-Derived Microparticles; Leukocytes, Mononuclear; Angiotensin II; Receptors, Interleukin-8B; Ventricular Remodeling; Myocardium; Nanomedicine
PubMed: 38948064
DOI: 10.7150/thno.95664 -
Theranostics 2024Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC), but acquired resistance during the treatment greatly limits its clinical efficiency....
Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC), but acquired resistance during the treatment greatly limits its clinical efficiency. Lipid metabolic disorder plays an important role in hepatocarcinogenesis. However, whether and how lipid metabolic reprogramming regulates sorafenib resistance of HCC cells remains vague. Sorafenib resistant HCC cells were established by continuous induction. UHPLC-MS/MS, proteomics, and flow cytometry were used to assess the lipid metabolism. ChIP and western blot were used to reflect the interaction of signal transducer and activator of transcription 3 (STAT3) with glycerol-3-phosphate acyltransferase 3 (GPAT3). Gain- and loss-of function studies were applied to explore the mechanism driving sorafenib resistance of HCC. Flow cytometry and CCK8 in and tumor size in were used to evaluate the sorafenib sensitivity of HCC cells. Our metabolome data revealed a significant enrichment of triglycerides in sorafenib-resistant HCC cells. Further analysis using proteomics and genomics techniques demonstrated a significant increase in the expression of GPAT3 in the sorafenib-resistant groups, which was found to be dependent on the activation of STAT3. The restoration of GPAT3 resensitized HCC cells to sorafenib, while overexpression of GPAT3 led to insensitivity to sorafenib. Mechanistically, GPAT3 upregulation increased triglyceride synthesis, which in turn stimulated the NF-κB/Bcl2 signaling pathway, resulting in apoptosis tolerance upon sorafenib treatment. Furthermore, our and studies revealed that pan-GPAT inhibitors effectively reversed sorafenib resistance in HCC cells. Our data demonstrate that GPAT3 elevation in HCC cells reprograms triglyceride metabolism which contributes to acquired resistance to sorafenib, which suggests GPAT3 as a potential target for enhancing the sensitivity of HCC to sorafenib.
Topics: Sorafenib; Carcinoma, Hepatocellular; Liver Neoplasms; Humans; Drug Resistance, Neoplasm; Cell Line, Tumor; Animals; STAT3 Transcription Factor; Mice; Antineoplastic Agents; Mice, Nude; Xenograft Model Antitumor Assays; Lipid Metabolism; Apoptosis; Gene Expression Regulation, Neoplastic; Signal Transduction
PubMed: 38948063
DOI: 10.7150/thno.92646 -
Theranostics 2024Immune checkpoint inhibitors (ICI) are routinely used in advanced clear cell renal cell carcinoma (ccRCC). However, a substantial group of patients does not respond to...
Immune checkpoint inhibitors (ICI) are routinely used in advanced clear cell renal cell carcinoma (ccRCC). However, a substantial group of patients does not respond to ICI therapy. Radiation is a promising approach to increase ICI response rates since it can generate anti-tumor immunity. Targeted radionuclide therapy (TRT) is a systemic radiation treatment, ideally suited for precision irradiation of metastasized cancer. Therefore, the aim of this study is to explore the potential of combined TRT, targeting carbonic anhydrase IX (CAIX) which is overexpressed in ccRCC, using [Lu]Lu-DOTA-hG250, and ICI for the treatment of ccRCC. In this study, we evaluated the therapeutic and immunological action of [Lu]Lu-DOTA-hG250 combined with aPD-1/a-CTLA-4 ICI. First, the biodistribution of [Lu]Lu-DOTA-hG250 was investigated in BALB/cAnNRj mice bearing Renca-CAIX or CT26-CAIX tumors. Renca-CAIX and CT26-CAIX tumors are characterized by poor versus extensive T-cell infiltration and homogeneous versus heterogeneous PD-L1 expression, respectively. Tumor-absorbed radiation doses were estimated through dosimetry. Subsequently, [Lu]Lu-DOTA-hG250 TRT efficacy with and without ICI was evaluated by monitoring tumor growth and survival. Therapy-induced changes in the tumor microenvironment were studied by collection of tumor tissue before and 5 or 8 days after treatment and analyzed by immunohistochemistry, flow cytometry, and RNA profiling. Biodistribution studies showed high tumor uptake of [Lu]Lu-DOTA-hG250 in both tumor models. Dose escalation therapy studies in Renca-CAIX tumor-bearing mice demonstrated dose-dependent anti-tumor efficacy of [Lu]Lu-DOTA-hG250 and remarkable therapeutic synergy including complete remissions when a presumed subtherapeutic TRT dose (4 MBq, which had no significant efficacy as monotherapy) was combined with aPD-1+aCTLA-4. Similar results were obtained in the CT26-CAIX model for 4 MBq [Lu]Lu-DOTA-hG250 + a-PD1. analyses of treated tumors revealed DNA damage, T-cell infiltration, and modulated immune signaling pathways in the TME after combination treatment. Subtherapeutic [Lu]Lu-DOTA-hG250 combined with ICI showed superior therapeutic outcome and significantly altered the TME. Our results underline the importance of investigating this combination treatment for patients with advanced ccRCC in a clinical setting. Further investigations should focus on how the combination therapy should be optimally applied in the future.
Topics: Animals; Carcinoma, Renal Cell; Mice; Immune Checkpoint Inhibitors; Kidney Neoplasms; Carbonic Anhydrase IX; Humans; Cell Line, Tumor; Radioisotopes; Lutetium; Female; Antigens, Neoplasm; Tissue Distribution; Tumor Microenvironment; Tumor Protein, Translationally-Controlled 1; Xenograft Model Antitumor Assays; Combined Modality Therapy; Mice, Inbred BALB C; Antibodies, Monoclonal
PubMed: 38948062
DOI: 10.7150/thno.96944