Bioimpacts最新文献

Introduction: Immune checkpoint inhibitors (ICIs) have provided noteworthy benefits in multiple cancer patients. However, the efficacy of monotherapy of ICIs was very limited. In this study, we endeavored to explore whether losartan can modulate the solid tumor microenvironment (TME) and improve the therapeutic efficacy of anti-PD-L1 mAb in 4T1 mouse breast tumor model and the underlying mechanism. Methods: The tumor-bearing mice were treated with control agents, losartan, anti-PD-L1 mAb or the dual agents. The blood and tumor tissues were respectively used for ELISA and immunohistochemical analysis. CD8-depletion and lung metastatic experiments were performed. Results: Compared to control group, losartan inhibited the expression of alpha-smooth muscle actin (α-SMA), deposition of collagen I in the tumor tissues. The concentration of transforming growth factor-β1 (TGF-β1) in the serum was low in the losartan treated group. Although losartan alone was ineffective, the combination of losartan and anti-PD-L1 mAb elicited dramatic antitumor effect. Immunohistochemical analysis revealed that there were more intra-tumoral infiltration of CD8⁺ T cells and increased granzyme B production in the combination therapy group. In addition, the size of spleen was smaller in the combination therapy group, compared to monotherapy. The CD8-depleting Abs abrogated the antitumor efficacy of losartan and anti-PD-L1 mAb in vivo. The combination of losartan and anti-PD-L1 mAb significantly inhibited 4T1 tumor cells lung metastatic in vivo. Conclusion: Our results indicated that losartan can modulate the tumor microenvironment, and improve the efficacy of anti-PD-L1 mAb.

Introduction: The inhibition of vascularization into tumor stroma as well as dynamic cell growth is the center of attention. Here, we aimed to examine the role of vandetanib on angiogenesis capacity of breast cancer stem cell (CSCs).

Methods: MDA-MB-231 cells were exposed to different doses of vandetanib and survival rate was monitored. Stimulatory effects of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and epidermal growth factor (EGF) were evaluated in vandetanib-treated MDA-MB-231 cells. In vitro tubulogenesis capacity was studied on the Matrigel surface. The synergistic effects of vandetanib on cell survival were also assessed after PI3K and/or Wnt3a inhibition. Vascular endothelial (VE)-cadherin, matrix metalloproteinase-2 (MMP-2), -9, Wnt3a, and p-Akt/Akt ratio were measured using western blotting.

Results: Vandetanib reduced survival rate in a dose-dependent manner (P<0.05). Proliferative effects associated with VEGF, FGF, and EGF were blunted in these cells pre-exposed to vandetanib (P<0.05). The microcirculation pattern's triple-negative breast cancer (TNBC) was suppressed by 1, 5 µM of vandetanib (P<0.05). Hence 1, 5 µM of vandetanib potentially decreased the population of CD24^- cells. 1 and 5 µM of vandetanib inhibited cell proliferation by blocking PI3K and Wnt3a pathways and decreased the p-Akt/Akt ratio, Wnta3 protein levels (P<0.05). 1 and 5 µM vandetanib combined with PI3K inhibitor diminished metastatic markers including, MMP-2, and MMP-9. The concurrent treatment (PI3K, inhibitor+ 1, 5 µM vandetanib) also considerably reduced epithelial-mesenchymal transition (EMT) markers such as VE-cadherin (P<0.05).

Conclusion: Vandetanib suppressed vasculogenic mimicry (VM) networking through blunting stemness properties, coincided with suppression of VE-cadherin in CSCs.

Introduction: Machine learning methods, coupled with a tremendous increase in computer power in recent years, are promising tools in modern drug design and drug repurposing.

Methods: Machine learning predictive models, publicly available at chemosophia.com, were used to predict the bioactivity of recently synthesized platinum(IV) complexes against different kinds of diseases and medical conditions. Two novel QSAR models based on the BiS algorithm are developed and validated, capable to predict activities against the SARS-CoV virus and its RNA dependent RNA polymerase.

Results: The internal predictive power of the QSAR models was tested by 10-fold cross-validation, giving cross-R² from 0.863 to 0.903. 38 different activities, ranging from antioxidant, antibacterial, and antiviral activities, to potential anti-inflammatory, anti-arrhythmic and anti-malarial activity were predicted for a series of eighteen platinum(IV) complexes.

Conclusion: Complexes 1, 3 and 13 have high generalized optimality criteria and are predicted as potential SARS-CoV RNA dependent RNA polymerase inhibitors.

Introduction: Doxorubicin (DOX) is one of the most common drugs in cancer treatment. However, its partial solubility along with the high incidence of side effects remains a challenge to tackle. To address these issues, we designed a formulation based on graphene oxide (GO) and used it as an anticancer drug delivery system.

Methods: The physical and chemical properties of the formulation were studied using FTIR, SEM, EDX, Mapping, and XRD. Release studies in the in vitro condition were used to evaluate the pH sensitivity of drug release from nanocarriers. Other in vitro studies, including uptake assay, MTT, and apoptosis assay were carried out on the osteosarcoma cell line.

Results: in vitro release studies confirmed that the synthesized formulation provides a better payload release profile in acidic conditions, which is usually the case in the tumor site. On the OS cell line, the cytotoxicity of the DOX-loaded nanocarrier (IC50=0.293 μg/mL) and early apoptosis rate (33.80 % ) were higher in comparison to free DOX (IC50=0.472 μg/mL, and early apoptosis rate= 8.31 % ) after 48 hours.

Conclusion: In summary, our results suggest a DOX-loaded graphene oxide carrier as a potential platform for targeting cancer cells.

Introduction: Silibinin is a natural flavonoid compound known to induce apoptosis in cancer cells. Despite silibinin's safety and efficacy as an anticancer drug, its effects on inducing immunogenic cell death (ICD) are largely unknown. Herein, we have evaluated the stimulating effects of silibinin on ICD in cancer cells treated with silibinin alone or in combination with chemotherapy. Methods: The anticancer effect of silibinin, alone or in combination with doxorubicin or oxaliplatin (OXP), was assessed using the MTT assay. Compusyn software was used to analyze the combination therapy data. Western blotting was conducted to examine the level of STAT3 activity. Flow cytometry was used to analyze calreticulin (CRT) and apoptosis. The heat shock protein (HSP70), high mobility group box protein1 (HMGB1), and IL-12 levels were assessed by ELISA. Results: Compared to the negative control groups, silibinin induced ICD in CT26 and B16F10 cells and significantly enhanced the induction of this type of cell death by doxorubicin, and these changes were allied with substantial increases in the level of damage-associated molecular patterns (DAMPs) including CRT, HSP70, and HMGB1. Furthermore, conditioned media from cancer cells exposed to silibinin and doxorubicin was found to stimulate IL-12 secretion in dendritic cells (DCs), suggesting the link of this treatment with the induction of Th1 response. Silibinin did not augment the ICD response induced by OXP. Conclusion: Our findings showed that silibinin can induce ICD and it potentiates the induction of this type of cell death induced by chemotherapy in cancer cells.

Introduction: Computational modeling is one of the best non-invasive approaches to predicting the functional behavior of the mitral valve (MV) in health and disease. Mitral valve prolapse (MVP) due to partial or complete chordae tendineae rapture is the most common valvular disease and results in mitral regurgitation (MR).

Methods: In this study, Image-based fluid-structure interaction (FSI) models of the human MV are developed in the normal physiological and posterior leaflet prolapse conditions. Detailed geometry of the healthy human MV is derived from Computed Tomography imaging data. To provide prolapse condition, some chords attached to the posterior leaflet are removed from the healthy valve. Both normal and prolapsed valves are embedded separately in a straight tubular blood volume and simulated under physiological systolic pressure loads. The Arbitrary Lagrangian-Eulerian finite element method is used to accommodate the deforming intersection boundaries of the blood and MV.

Results: The stress values in the mitral components, and also flow patterns including the regurgitant flow rates are obtained and compared in both conditions through the simulation. These simulations have the potential to improve the treatment of patients with MVP, and also help surgeons to have more realistic insight into the dynamics of the MV in health and prolapse.

Conclusion: In the prolapse model, computational results show incomplete leaflet coaptation, higher MR severity, and also a significant increment of posterior leaflet stress compared to the normal valve. Moreover, it is found more deviation of the regurgitant jet towards the left atrium wall due to the posterior leaflet prolapse.

Introduction: Induction of a protective immune response against Leishmania major requires the activation of both TH1 and CD8⁺ T lymphocytes. Because L. major is an intra-phagosomal parasite, its antigens do not have access to MHC-I. The present study aimed to evaluate the effect of cysteine peptidase A (CPA)/cysteine peptidase B (CPB) conjugated to α-AL2O3 on autophagy induction in L. major infected macrophages and subsequent activation of cytotoxic CD8⁺ T lymphocytes.

Methods: Recombinant CPA and CPB of L. major were produced in expression vectors and purified. Aldehyde functionalized α-AL2O3 were conjugated to hydrazine-modified CPA/CPB by a chemical bond was confirmed by Fourier-transform infrared spectroscopy (FTIR). The High efficient internalization of α-AL2O3 conjugated CPA/CPB to macrophages was confirmed using a fluorescence microscope and flowcytometry. Induction of the acidic autophagosome and LC3 conversion in macrophages was determined by acridine orange (AO) staining and western blot. Autophagy-activated macrophages were used for CD8⁺ T cell priming. Cytotoxic activity of the primed CD8⁺ T cell against L. major infected macrophages was measured using apoptosis assay.

Results: α-AL2O3 conjugated CPA/CPB enhances macrophages antigen uptake and increases acidic vacuole formation and LC-3I to LC-3II conversion. Co-culture of autophagy-activated macrophages with CD8⁺ T cells augmented CD8⁺ T cells priming and proliferation more than in other study groups. These primed CD8⁺ T cells induce significant apoptotic death of L. major infected macrophages compared with non-primed CD8⁺ T cells.

Conclusion: α-AL2O3 nanoparticles enhance the cross-presentation of L. major antigens to CD8⁺ T cells by inducing autophagy. This finding supports the positive role of autophagy and encourages the use of α-AL2O3 in vaccine design.

Salt sensitivity defines a state characterized by a highly reactive blood pressure to changes in salt intake. The salt-sensitive phenotype is strongly associated with hypertension, visceral adiposity/metabolic syndrome, and ageing. Obesity accounts for around 70% of hypertension in young adults, and 30% to 50% of adult hypertensives carry the salt-sensitive phenotype. It is estimated that the salt-sensitive phenotype is responsible for high blood pressure in over 600 million adults. But is the salt-sensitive phenotype correctable? Interventional, controlled, clinical trials in obese adolescents and young obese adults, demonstrated that weight-reducing lifestyle modifications revert the salt-sensitive to the salt-resistant phenotype, and restored the faulty production of nitric oxide. Correction of the salt-sensitive phenotype lowers the blood pressure by reducing its reactivity to dietary salt. In a random sample of obese adults subjected to lifestyle modifications, those who were salt-resistant at baseline, were also normotensive and failed to further lower their blood pressure despite a 12% drop in body weight. The salt-resistant phenotype protects the metabolically healthy obese from hypertension, even if their salt consumption is comparable to that of salt-sensitive obese. In summary, at early stages, the elevated blood pressure of obesity, is determined by epigenetic changes leading to a state of salt-sensitivity.

Introduction: In late December 2019, a sudden severe respiratory illness of unknown origin was reported in China. In early January 2020, the cause of COVID-19 infection was announced a new coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Examination of the SARS-CoV-2 genome sequence revealed a close resemblance to the previously reported SARS-CoV and coronavirus Middle East respiratory syndrome (MERS-CoV). However, initial testing of drugs used against SARS-CoV and MERS-CoV has been ineffective in controlling SARS-CoV-2. One of the key strategies to fight the virus is to look at how the immune system works against the virus, which has led to a better understanding of the disease and the development of new therapies and vaccine designs. Methods: This review discussed the innate and acquired immune system responses and how immune cells function against the virus to shed light on the human body's defense strategies. Results: Although immune responses have been revealed critical to eradicating infections caused by coronaviruses, dysregulated immune responses can lead to immune pathologies thoroughly investigated. Also, the benefit of mesenchymal stem cells, NK cells, Treg cells, specific T cells, and platelet lysates have been submitted as promising solutions to prevent the effects of infection in patients with COVID-19. Conclusion: It has been concluded that none of the above has undoubtedly been approved for the treatment or prevention of COVID-19, but clinical trials are underway better to understand the efficacy and safety of these cellular therapies.

Introduction: Pluripotent stem cells have been used by various researchers to differentiate and characterize endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) for the clinical treatment of vascular injuries. Studies continue to differentiate and characterize the cells with higher vascularization potential and low risk of malignant transformation to the recipient. Unlike previous studies, this research aimed to differentiate induced pluripotent stem (iPS) cells into endothelial progenitor cells (EPCs) and VSMCs using a step-wise technique. This was achieved by elucidating the spatio-temporal expressions of the stage-specific genes and proteins during the differentiation process. The presence of highly expressed oncogenes in iPS cells was also investigated during the differentiation period.

Methods: Induced PS cells were differentiated into lateral mesoderm cells (Flk1⁺). The Flk1⁺ populations were isolated on day 5.5 of the mesodermal differentiation period. Flk1⁺ cells were further differentiated into EPCs and VSMCs using VEGF₁₆₅ and platelet-derived growth factor-BB (PDGF-BB), respectively, and then characterized using gene expression levels, immunocytochemistry (ICC), and western blot (WB) methods. During the differentiation steps, the expression levels of the marker genes and proto-oncogenic Myc and Klf4 genes were simultaneously studied.

Results: The optimal time for the isolation of Flk1⁺ cells was on day 5.5. EPCs and VSMCs were differentiated from Flk1⁺ cells and characterized with EPC-specific markers, including Kdr, Pecam1, CD133, Cdh5, Efnb2, Vcam1; and VSMC-specific markers, including Acta2, Cnn1, Des, and Myh11. Differentiated cells were validated based on their temporal gene expressions, protein synthesis, and localization at certain time points. Significant decreases in Myc and Klf4 gene expression levels were observed during the EPCs and VSMC differentiation period.

Conclusion: EPCs and VSMCs were successfully differentiated from iPS cells and characterized by gene expression levels, ICC, and WB. We observed significant decreases in oncogene expression levels in the differentiated EPCs and VSMCs. In terms of safety, the described methodology provided a better safety margin. EPCs and VSMC obtained using this method may be good candidates for transplantation and vascular regeneration.