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Improved in vivo targeting of BCL-2 phenotypic conversion through hollow gold nanoshell delivery
摘要： Although new cancer therapeutics are discovered at a rapid pace, lack of effective means of delivery and cancer chemoresistance thwart many of the promising therapeutics. We demonstrate a method that confronts both of these issues with the light-activated delivery of a Bcl-2 functional converting peptide, NuBCP-9, using hollow gold nanoshells. This approach has shown not only to increase the efficacy of the peptide 30-fold in vitro but also has shown to reduce paclitaxel resistant H460 lung xenograft tumor growth by 56.4%.
关键词： Bcl-2,Resistant cancer,Apoptosis,Hollow gold nanoshells,NuBCP,Peptide delivery
更新于2025-11-21 11:08:12
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Oxidative stress generated by irradiation of a zinc(II) phthalocyanine induces a dual apoptotic and necrotic response in melanoma cells
摘要： Melanoma is an aggressive form of skin carcinoma, highly resistant to traditional therapies. Photodynamic therapy (PDT) is a non-invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. In this work we evaluated the effect of a cationic zinc(II) phthalocyanine (Pc13) as photosensitizer on a panel of melanoma cells. Incubation with Pc13 and irradiation induced a concentration and light dose-dependent phototoxicity. In order to study the mechanism underlying Pc13-related cell death and to compare the effect of different doses of PDT, the most sensitive melanoma B16F0 cells were employed. By confocal imaging we showed that Pc13 targeted lysosomes and mitochondria. After irradiation, a marked increase in intracellular reactive oxygen species was observed and a complete protection from Pc13 phototoxicity was reached in the presence of the antioxidant trolox. Acridine orange/ethidium bromide staining showed morphological changes indicative of both apoptosis and necrosis. Biochemical hallmarks of apoptosis, including a significant decrease in the expression levels of Bcl-2, Bcl-xL and Bid and mitochondrial membrane permeabilization, were observed at short times post irradiation. The consequent release of cytochrome c to cytosol and caspase-3 activation led to PARP-1 cleavage and DNA fragmentation. Simultaneously, a dose dependent increase of lactate dehydrogenase in the extracellular compartment of treated cells revealed plasma membrane damage characteristic of necrosis. Taken together, these results indicate that a dual apoptotic and necrotic response is triggered by Pc13 PDT-induced oxidative stress, suggesting that combined mechanisms of cell death could result in a potent alternative for melanoma treatment.
关键词： Necrosis,Mitochondrial membrane permeabilization,Apoptosis,Reactive oxygen species,Photodynamic therapy,Cationic phthalocyanine
更新于2025-09-23 15:23:52
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A Low-Cost Flash Photographic System for Visualization of Droplets in Drop-on-Demand Inkjet
摘要： Hepatocellular carcinoma (HCC) is one of the most common and deadly human cancers. The 5-year survival rate is very low. Unfortunately, there are few efficacious therapeutic options. Until recently, Sorafenib has been the only available systemic drug for advanced HCC. However, it has very limited survival benefits, and new therapies are urgently needed. In this study, we investigated the anti-HCC activity of carfilzomib, a second-generation, irreversible proteasome inhibitor, as a single agent and in combination with sorafenib. In vitro, we found that carfilzomib has moderate anticancer activity toward liver cancer cells, but strongly enhances the ability of sorafenib to suppress HCC cell growth, proliferation, migration, invasion, and survival. Remarkably, the drug combination exhibits even more potent antitumor activity when tested in animal tumor models. Mechanistically, the combined treatment activates caspase-dependent and endoplasmic reticulum stress/CHOP-mediated apoptotic pathways, and suppresses epithelial–mesenchymal transition. In conclusion, our results demonstrate that the combination of carfilzomib and sorafenib has synergistic antitumor activities against HCC, providing a potential therapeutic strategy to improve the mortality and morbidity of HCC patients.
关键词： Hepatocellular Carcinoma,Proteasome Inhibitor,ER Stress,Apoptosis,Sorafenib,EMT,Carfilzomib,Synergistic Inhibition
更新于2025-09-23 15:23:52
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Retinal photoreceptor apoptosis is associated with impaired serum ionized calcium homeostasis in diabetic retinopathy: An in-vivo analysis
摘要： Purpose: The aim of this work was to study the association of serum ionized calcium with retinal photoreceptor apoptosis on spectral domain optical coherence tomography (SD-OCT) in diabetic retinopathy (DR). Methods: Sixty consecutive cases with Type 2 diabetes mellitus were categorized into three groups: no diabetic retinopathy; non-proliferative DR; proliferative DR. The eye with more severe form of the disease was considered. Twenty healthy controls were also included. Best corrected visual acuity (BCVA) was measured on logMAR scale. Retinal photoreceptor apoptosis was defined as disruption of retinal photoreceptor ellipsoid zone (EZ). Ellipsoid zone disruption was assessed using SD-OCT. Serum levels of total and ionized calcium were measured using standard protocol. Results: EZ disruption was found to be positively associated with serum total calcium and ionized calcium. Also, EZ disruption was found to be positively associated with logMAR BCVA. Conclusion: Increased serum ionized calcium induces retinal photoreceptor apoptosis resulting in increased EZ disruption in DR.
关键词： Ionized calcium,Retinal photoreceptor apoptosis,Diabetic retinopathy,Autophagy,Ellipsoid zone,Spectral-domain optical coherence tomography
更新于2025-09-23 15:23:52
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Hyperbaric oxygen combined with 5-aminolevulinic acid photodynamic therapy inhibited human squamous cell proliferation
摘要： The photodynamic therapy (PDT) depends on the presence of molecular oxygen. Thus, the efficiency of PDT is limited in anoxic regions of tumor tissue and vascular shutdown. It is reported the use of hyperbaric oxygen (HBO) may enhance the efficiency of PDT. However, there are rarely studies about utilizing HBO plus PDT for treatment with human squamous cell carcinoma (SCC). Therefore, this study aimed to investigate and compare the therapeutic effect of combined therapy and PDT alone treatment. Multiple cellular and molecular biology techniques were used in the current study such as CCK-8, western blotting, flow cytometry, MDC staining and immunofluorescence assay. The results of combination index indicated that HBO combination with PDT synergistically inhibited A431 cells proliferation in vitro. In addition, we found that HBO significantly enhanced PDT-induced cell apoptosis via increasing the active caspase-3, active caspase-9, Apaf-1 and Bax levels and down-regulating Bcl-2. Meanwhile, the result of MDC and immunofluorescence assay confirmed that HBO increased PDT-induced autophagosome formation in A431 cells. Interestingly, autophagy inhibitor 3-methyladenine (3-MA) further increased combination-induced cell apoptosis by increasing the levels of active-caspase 9 and Apaf-1. Our results showed that HBO combined with PDT markedly induced A431 cells apoptosis and autophagy. Nevertheless, autophagy play a pro-survival role against apoptosis. Thus, HBO combination with PDT may constitute a promising approach to treat human squamous cell carcinoma in the future.
关键词： human squamous cell carcinoma,5-aminolevulinic acid photodynamic therapy,apoptosis,autophagy,hyperbaric oxygen
更新于2025-09-23 15:23:52
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Functional chlorin gold nanorods enable to treat breast cancer by photothermal/photodynamic therapy
摘要： Background: The existing chemo/radiotherapy fail to eliminate cancer cells due to the restriction of either drug resistance or radio tolerance. The predicament urges researchers to continuously explore alternative strategy for achieving a potent curative effect. Methods: Functional chlorin gold nanorods (Ce6-AuNR@SiO2-d-CPP) were fabricated aiming at treating breast cancer by photothermal/photodynamic therapy (PTT/PDT). The nanostructure was developed by synthesizing Au nanorods as the photothermal conversion material, and by coating the pegylated mesoporous SiO2 as the shell for entrapping photosensitizer Ce6 and for linking the D-type cell penetrating peptide (d-CPP). The function of Ce6-AuNR@SiO2-d-CPP was verified on human breast cancer MCF-7 cells and MCF-7 cells xenografts in nude mice. Results: Under combinational treatment of PTT and PDT, Ce6-AuNR@SiO2-d-CPP demonstrated a strong cytotoxicity and apoptosis inducing effects in breast cancer cells in vitro, and a robust treatment efficacy in breast cancer-bearing nude mice. The uptake mechanism involved the energy-consuming caveolin-mediated endocytosis, and Ce6-AuNR@SiO2-d-CPP in PTT/PDT mode could induce apoptosis by multiple pathways in breast cancer cells. Conclusion: Ce6-AuNR@SiO2-d-CPP demonstrated a robust efficacy in the treatment of breast cancer by photothermal/photodynamic therapy. Therefore, the present study could offer a new promising strategy to treat the refractory breast cancer.
关键词： PTT/PDT,apoptosis,cellular uptake,functional chlorin gold nanorods,cell penetrating peptide,cytotoxicity
更新于2025-09-23 15:23:52
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Apoptosis-induced Proliferation in UV-Irradiated Human Conjunctival Epithelial Cells
摘要： A pterygium is a benign growth that develops on the conjunctiva and, in some cases, extends to the cornea and interferes with vision. Excessive exposure to ultraviolet (UV) light is one of the causes of pterygium development. We previously reported that UV-induced apoptosis is led by production of reactive oxygen species (ROS) that activate p38 mitogen-activated protein kinase (MAPK) in human conjunctival epithelial (HCE) cells. Also, ROS-dependent induction of interleukin-11 (IL-11) has been reported to upregulate MAPK pathways, which results in compensatory proliferation. In this study, we examined the effect of UV exposure on HCE cells, in terms of change in apoptosis, ROS generation, phosphorylation of c-Jun N-terminal kinase (JNK), levels of IL-11 (a key cytokine in tissue repair and compensatory proliferation), production of activator protein 1 (AP-1), and expression of c-myc, c-fos and c-jun (which provides evidence of healthy cell proliferation). Apoptosis in HCE cells was induced by UV light irradiation (312 nm, 4.94 mW/cm2). Apoptosis was measured using the Muse Annexin V and Dead Cell Assay Kit. ROS generation was measured by using 5-(and 6-) chloromethyl-2?7?-dichlorodihydrofluorescein diacetate, acetyl ester. JNK phosphorylation, IL-11 levels and AP-1 production were measured by enzyme-linked immunosorbent assays (ELISAs). Imnunocytochemical staining was used to measure c-myc, c-fos and c-jun expression. UV irradiation increased ROS generation, phosphorylation of JNK, and apoptotic cell count. IL-11 levels and AP-1 production were significantly increased by UV irradiation. The irradiated cells had increased expression of c-myc, c-fos and c-jun, and treatment of the cells with IL-11 significantly increased expression of c-myc, c-fos and c-jun. These results suggest that the release of IL-11 from UV-induced apoptotic HCE cells and surrounding healthy cells could promote proliferation to maintain homeostasis.
关键词： conjunctiva,compensatory proliferation,apoptosis,interleukin-11 (IL-11),Ultraviolet (UV)
更新于2025-09-23 15:22:29
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Activation of Nrf2/HO-1 pathway protects retinal ganglion cells from a rat chronic ocular hypertension model of glaucoma
摘要： Objective The objective of this work was to find out the effects of nuclear factor erythroid 2-related factor/heme oxygenase-1 (Nrf2/HO-1) pathway on retinal ganglion cell (RGC) injury in glaucoma. Methods The chronic ocular hypertension (COH) rat models of glaucoma were constructed, and intraocular pressure (IOP) and RGC numbers were detected at different time points. Additionally, rats were divided into normal group (normal control rats), model group (COH model rats), and model + tBHQ group (COH model rats treated with Nrf activator, tBHQ). RGC apoptosis was detected by using TUNEL staining, and the expressions of Nrf2/HO-1 were detected by qRT-PCR and western blotting. Results COH model rats showed significant IOP elevation and the increased mRNA and protein expressions of Nrf2 and HO-1 from 1 to 6 weeks after operation, with the evidently decreased RGC numbers at 4 weeks and 6 weeks after operation (all P < 0.05). Besides, rats in the model group had increased apoptosis index (AI) of RGCs and the elevated mRNA and protein expressions of Nrf2/HO-1 with remarkably reduced RGC numbers when compared with normal control rats, but the model rats treated with tBHQ exhibited an apparent decrease in AI of RGCs, as well as remarkable increases in RGC numbers and the mRNA and protein expression of Nrf2/HO-1 (all P < 0.05). Conclusion Activation of Nrf2/HO-1 pathway significantly reduced the apoptosis and injury of RGCs in rats with chronic ocular hypertension (COH), thereby protecting RGCs in glaucoma, which could be a promising clinical target to prevent RGC degeneration in glaucoma.
关键词： Apoptosis,Nrf2/HO-1 pathway,Glaucoma,Retinal ganglion cells
更新于2025-09-23 15:22:29
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A digital controlled pulse generator for a novel tumor therapy combining irreversible electroporation with nanosecond pulse stimulation
摘要： The irreversible electroporation with microsecond electric pulses is a new ablation technique adopted in the tumor therapy worldwide. On the other hand, the nsPEF (nanosecond pulsed electric field) has been proved to provide a means to induce immunogenic cell death and elicits antitumor immunity, which is under intensive in-vitro and in-vivo studies and in clinical trials. Normally, one needs two different types of electric pulse generators for producing the pulses in the ranges of nanosecond and microsecond, respectively. In order to realize these two types of tumor treatments in complementary and optimize electrical pulse parameters, we have developed a compact high-voltage pulse generator with a wide pulse width tuning range, based on a capacitor discharging configuration digitally controlled by a silicon carbide MOSFET switching array through a pair of optic-coupler drivers. The developed digital pulse generator is capable of adjusting: pulse width over 100ns-100μs, voltage over 0-2kV and repetition rate up to 1.2 kHz. The pulse generator is designed in simulation, implemented and verified in experiments. The pulse generator is shown to deliver a complementary treatment on Murine melanoma B16 cell lines, i.e. triggering the cell early apoptosis under the 300ns pulse stimulation while a complete killing under the 100ns pulses. The pulse generator is further demonstrated to induce antitumor immunity in a preliminary in vivo study on the mice model.
关键词： apoptosis,Silicon Carbide MOSFET array,irreversible electroporation,nanosecond pulse stimulation
更新于2025-09-23 15:21:01
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Benign prostatic hyperplasia treatment using plasmonic nanoparticles irradiated by laser in a rat model
摘要： Objective: In the current study we have stimulated the efficacy of plasmonic nanoparticles (NPs) by laser hyperthermia to achieve a less invasive method for tumor photothermal therapy of benign prostatic hyperplasia (BPH). Methods: The levels of apoptosis on induced BPH in rats were assessed after treatment and revealed and recorded by various assayed. Moreover, the expression of caspases was considered to demonstrate the apoptotic pathways due to laser induced plasmonic NPs. Results: In the Laser + NPs group prostate size of induced BPH decreased. Laser + NPs also decreased prostate specific antigen in comparison with the BPH groups. Furthermore, Laser + NPs attenuated BPH histopathologic indices in the rats. Laser + NPs induced apoptosis in prostatic epithelial cells via caspase-1 pathway. Conclusions: Altogether, the approach and findings from this study can be applied to introduce the laser irritated NPs method as a novel and less invasive therapy for patients suffering from BPH.
关键词： Photothermal therapy,Caspase,Laser,Benign prostatic hyperplasia,Apoptosis,Plasmonic nanoparticles
更新于2025-09-23 15:21:01