Apoptotic Proteins Research Articles

EGCG’s anticancer potential unveiled: triggering apoptosis in lung cancer cell lines through in vitro investigation

Background Novel treatment techniques are needed since lung cancer is still a major worldwide health concern. Green tea contains a component called epigallocatechin-3-gallate (EGCG), which has demonstrated potential anticancer properties. This work sought to understand how EGCG affects the phosphatidylinositol-3-kinase protein kinase B (PI3K/Akt) signaling pathway, which in turn causes apoptosis in H1299 lung cancer cells. Methods In this experiment, multiple dosages of EGCG were applied to five H1299 cells and five A549 cell lines for a duration of 72 h. Apoptotic pathways, cellular responses, and protein expression levels were investigated in relation to EGCG by morphological, biochemical, and proliferation/migration investigations. Results In H1299 and A549 cells, EGCG raised apoptosis rates and, in a dose-dependent way, hindered cell growth. The levels of phosphorylated Akt (p-Akt) and PI3K (p-PI3K) dramatically reduced following EGCG administration, despite no significant alterations in Akt and PI3K expressions. These results imply that EGCG inhibits the activation of the PI3K/Akt signaling pathway, which in turn causes apoptosis in H1299 and A549 cells. Conclusion The research provides insights into the effects of EGCG on proliferation and migratory inhibition, as well as highlighting its potential to induce apoptosis in lung cancer cells. These results support EGCG’s promise as a therapeutic agent in the treatment of lung cancer and further our understanding of the processes underlying its anticancer activities.

Dexmedetomidine alleviates sevoflurane-induced neurotoxicity during late pregnancy by modulating apoptotic pathways and BDNF receptor expression.

To investigate the associations between the neurotoxicity of sevoflurane and the neuroprotection provided by dexmedetomidine, we measured apoptotic gene and protein expression, brain-derived neurotrophic factor (BDNF) levels, and receptor expression, and neuronal apoptosis. Pregnant rats were treated with dexmedetomidine, 2.5% sevoflurane for 6h, or a combination of 2.5% sevoflurane for 6h with dexmedetomidine on gestational day 18 (G18). The apoptotic genes and proteins expression, BDNF and receptor expression, and neuronal apoptosis were assessed in offspring hippocampi on postnatal day 1 (P1) and P41. Dendritic spine density, synaptophysin protein fluorescence staining, and cognitive function were evaluated on P41. Maternal sevoflurane exposure increased Bax mRNA and protein expression, decreased Bcl-2 mRNA and protein expression, enhanced neuronal apoptosis, decreased the ratio of mature BDNF (mBDNF) to proBDNF, reduced mBDNF and tropomyosin receptor kinase B (TrkB) protein expression, and increased p75 neurotrophin receptor (p75NTR) protein expression in the hippocampi of neonatal rats. In juvenile rats, maternal sevoflurane exposure reduced mBDNF and TrkB protein expression, dendritic spine density, the proportion of time spent in the target quadrant, and the number of crossings over the platform while increasing escape latency in the Morris water maze. All abnormalities induced by maternal sevoflurane exposure, except for mBDNF levels on P41, were alleviated by dexmedetomidine. Dexmedetomidine mitigates sevoflurane-induced neuronal development abnormalities and cognitive impairments during late pregnancy by improving hippocampal Bcl-2 and Bax mRNA and protein expression, as well as proBDNF-p75NTR and mBDNF-TrkB protein expression in offspring.

NLRP3 inflammasome-based therapies by natural products: a new development in the context of cancer therapy.

The leucine-rich repeat containing protein (NLR) canonical inflammasome family includes Nod-like receptor protein 3 (NLRP3). Via the mediation of apoptosis proteins and immunological reactions, it controls the pathogenesis of malignancy. Experimental studies showed a relationship among lymphogenesis, cancer metastasis, and NLRP3 expression. Natural products have also been used as lead-based substances in a number of investigations to speed up the creation of novel, specific NLRP3 inhibitors. Via the mediation of apoptotic proteins and immunological responses, it controls the pathogenesis of malignancy. Moreover, it was recently noted that among human cancers, chemotherapy activates NLRP3. Induction of NLRP3 could encourage the generation of IL-1β and IL-22 to facilitate the propagation of malignancy. Additionally, prior research has demonstrated that the usage of NLRP3 in cancer therapy may result in resistance to drugs. The depletion of NLRP3 could affect the survival of cells. Natural products have been used as lead materials in a number of studies to help generate novel, specific NLRP3 antagonists more quickly. In the present review, we examine the mechanism behind the beneficial effects of the natural substances on the inhibition of cancer growth and progression, with special focus on NLRP3 regulation.

Impact of Secondhand Smoke and E-Cigarette Exposure on Placental Apoptotic and Growth-Regulatory Proteins in Mouse Pregnancy.

Apoptosis is critical in placental development, and its dysregulation is linked to pregnancy complications such as intrauterine growth restriction (IUGR) and preeclampsia (PE). Environmental exposures, particularly secondhand smoke (SHS) and e-cigarettes (eCigs), may contribute to placental dysfunction through apoptotic pathways. This study examined the effects of SHS and eCig exposure on placental apoptosis and growth-regulatory proteins in a murine model. C57BL/6 pregnant mice were exposed to SHS or eCigs at two critical gestational time points: early trophoblast invasion (E12.5 to E18.5) and established invasion (E14.5 to E18.5). Placental tissues were collected and analyzed for pro-apoptotic and anti-apoptotic markers, heat shock proteins, insulin-like growth factor-binding proteins (IGFBPs), and growth regulators. SHS exposure increased pro-apoptotic markers (BAD, Fas/FasL) and decreased mitochondrial function markers (cytochrome c), indicating compromised cellular survival. Both SHS and eCig exposure reduced anti-apoptotic markers (BCL-2, HSP27, survivin) and growth regulators (IGF-1, IGFBPs). SHS and eCig exposure create a pro-apoptotic environment in the placenta, potentially impairing fetal development through altered apoptotic and growth-regulatory pathways. These findings underscore the risks of environmental exposures during pregnancy, highlighting the need for strategies to minimize maternal exposure to SHS and eCigs.

Synthesis and Biological Evaluation of Quercetagetin Derivatives as the Inhibitors of Mcl-1 and Bcl-2 Against Leukemia.

B-cell lymphoma-2 (Bcl-2) family proteins are fundamental regulators of intrinsic cell apoptosis, and overexpression of apoptotic proteins (Bcl-2 and Mcl-1) is a characteristic of many haematological malignancies. Thus, it is necessary to discover novel inhibitors to treat leukemia. In the current study, we synthesized a series of quercetagetin derivatives (compounds 2a-2t, 3a-3j and 4a-4g) and evaluated their anticancer activities on four leukemia cells (U937, K562, K562R and KG-1). Among those synthesized derivatives, compounds 2a exhibited the best antiproliferative activity (IC50 = 0.276, 0.159, 0.312 and 0.271 µM to U937, K562, K562R and KG-1, respectively). In addition, 2a induced apoptosis in K562 and markedly arrested the cell cycle G2/M phase of K562. The Western blot assay showed that 2a is a potential inhibitor that can effectively suppress the expression of Bcl-2 and Mcl-1. The molecular docking study predicted that 2a had firm interactions with the active pockets of Bcl-2 and Mcl-1. Finally, in silico pharmacokinetic evaluation of 2a indicated its potential as an anti-leukemia drug lead in the future.

Treatment of Staphylococcus aureus-infected diabetic wounds by melatonin loaded nanocarriers

One of the complication of diabetes mellitus is chronic wounds. The healing of wounds in diabetic patients is retarded by the elevation in the pro-inflammatory cytokines secretion and free radicles accumulation. Wound management in diabetic patients requires preventing bacterial biofilm development. Due to the wound healing activity of chitosan (CS), lecithin (Le) and melatonin (M), the present study aimed to load melatonin on CS/Le NPs and examine their effect on diabetic wounds infected with Staphylococcus aureus. Melatonin loaded chitosan/lecithin nanoparticles (M-CS/Le NPs) were physically characterized and their antioxidant, anti-inflammatory and antimicrobial activities were examined in vitro. Male Sprague Dawley rats included two division (non-diabetic and diabetic) which were further divided in nine groups. Diabetes induction and follow up throughout the experimental period was confirmed by measuring the levels of fructosamine and blood glucose. Full-thickness wounds was induced in both non-diabetic and diabetic animals followed by infection with Staphylococcus aureus according to the experimental design. The wound healing effect of M-CS/Le NPs was evaluated through measurements of the oxidative stress, inflammatory cytokines and apoptotic proteins. Our results showed the anti-microbial, free radical scavenging and hemolysis inhibition effects of M-CS/Le NPs in vitro. Moreover, the preparation of M-CS/Le NPs decreased the dose of used melatonin (when compared to free melatonin). M-CS/Le NPs significantly decreased the wound area percent in treated infected wounds of both non-diabetic and diabetic rats more than free melatonin or unloaded CS/Le NPs. In conclusion, M-CS/Le NPs promoted the wound healing in Staphylococcus aureus-infected wounds in diabetic rats.

Chemotoxic and phototoxic effects of liposomal co-delivery of green synthesized silver nanoparticles and ZnPcS4 for enhanced photodynamic therapy in MCF-7 breast cancer cells: An in vitro study.

Chemotoxic and phototoxic effects of liposomal co-delivery of green synthesized silver nanoparticles and ZnPcS4 for enhanced photodynamic therapy in MCF-7 breast cancer cells: An in vitro study.

Effect of polysaccharides and saponins from Polygonatum kingianum against uranium-induced renal injury in rats.

Effect of polysaccharides and saponins from Polygonatum kingianum against uranium-induced renal injury in rats.

Shikonin Ameliorates Rotenone-Induced Neurotoxicity Through Inhibition of Apoptosis via IGF-1R/PI3K/AKT Pathway in a Parkinson's Disease-Associated SH-SY5Y Cell Model.

Parkinson's disease (PD) is the second most common multifactorial neurodegenerative disorder caused by several genetics and environmental factors. Rotenone a pesticide with mitotoxicity causes cytosolic proteopathy resulting in PD-associated apoptosis and modulations in cell survival pathways. Shikonin, a naphthoquinone compound extracted from the Lithospermum erythrorhizon herb, was investigated in this study for its neuroprotective properties and underlying molecular mechanisms against rotenone-induced cellular apoptosis and survival in SH-SY5Y cells. The molecular docking analysis of apoptotic proteins against Shikonin revealed that they showed a binding affinity with BAD. Shikonin effectively countered the loss of cell viability induced by rotenone, rescued annexin-positive apoptotic cells, and dose-dependently suppressed the generation of reactive oxygen species. Pre-treatment with Shikonin prevented the morphological aberrations like shrining of neurites leading to decreased LDH leakage and NO release caused due to the rotenone treatment. The α-synucleinopathy is a prime hallmark of PD, Shikonin mitigated the rotenone-induced aggregation of α-synuclein as seen from confocal imaging. Furthermore, Shikonin treatment reversed the rotenone-induced excessive production of reactive oxygen species, activation of caspases (-8 and -3), and mitochondrial dysfunction, as evidenced by the restoration of mitochondrial membrane potential and cellular ATP levels. Western blot and qPCR analysis revealed that Shikonin heightened the IGF1R/PI3K/AKT signaling associated with cell survival while concurrently downregulating rotenone-induced intrinsic apoptotic pathways. These findings underscore Shikonin as a promising candidate to prevent the onset of pesticide-induced Parkinson's disease and potentially other oxidative stress-related neurodegenerative disorders.

New O-alkyl Chalcone Derivative Exhibits Antiproliferative Potential in Colorectal and Cervical Cancer Cells by Inducing G0/G1 Cell Cycle Arrest and Mitochondrial-mediated Apoptosis.

The main objective of the study was to investigate potential anticancer activity in vitro of newly synthesized O-alkyl chalcone derivative (E)-1-(3-metoxy- 4-propoxyphenyl)-5-methylhex-1-en-3-on, (Chalcone 5) on cervical HeLa, colorectal HCT-116 carcinoma cells and healthy MRC-5 cells. Using the MTT assay, the cytotoxic effect of Chalcone 5 and reference substances dehydrozingerone and cisplatin were assessed. Using flow cytometry analysis, the labeling process with Annexin V-FITC/7-AAD was carried out to assess the type of cell death, while labeling with PI was used to examine the cell cycle progression in Chalcone 5 treated HeLa and HCT-116 cells. JC-10 probe was used to observe changes in the mitochondrial membrane potential after Chalcone 5 therapy. The expression and cellular localization of the important apoptotic proteins Bcl-2, Bax, caspase 3, and cytochrome c were investigated using flow cytometry and immunofluorescence techniques. The treatment of HeLa and HCT-116 cells with Chalcone 5 selectively induced cytotoxicity, and apoptosis and increased the expression of active Bax and caspase-3 while decreasing the expression of Bcl-2, compared to healthy MRC5 cells. Furthermore, Chalcone 5 decreased mitochondrial membrane potential and caused the release of cytochrome c from mitochondria, thereby triggering the mitochondrial inner apoptotic pathway. Moreover, Chalcone 5 arrested cell cycle progression in the G0/G1 phase in both HeLa and HCT-116 cells. According to the study's findings, Chalcone 5 is a potentially useful candidate drug for additional in vivo research on its anticancer properties against cervical and colon cancer.

Forsythiaside A Reduces Acetaminophen Hepatotoxic Metabolism by Inhibiting Pregnane X Receptor.

Overdose intake of acetaminophen (APAP) causes liver injury involving hepatic drug metabolism and activation of oxidative stress pathways, and forsythiaside A (FA) has hepatoprotective pharmacological activity, but knowledge of the mechanism of FA treatment for APAP liver injury is still lacking the literature. In this study, we investigated the effects of FA on the pregnane X receptor (PXR) by molecular docking and reporter gene assays. In addition, we explored the effects of FA on oxidative stress, endoplasmic reticulum stress (ERS), apoptosis, and hepatic pathology by interfering with PXR in ex vivo and in vivo models. The results showed that FA decreased the PXR protein expression level and effectively reduced the oxidative stress level in the APAP model. In addition, FA reduced the expression of ERS pathway ProteinkinaseR-likeERkinase (PERK)-translation initiation factor 2 (eIF-2α)-activating transcription factor 4 (ATF4) by inhibiting PXR, and at the same time, decreased the expression of apoptotic proteins C/EBP homologous protein (CHOP), Bax, Caspase 3, and Caspase 7, and elevated the expression of apoptosis-suppressing protein Bcl-2, which ultimately treated the hepatic pathology injury of APAP in mice. The present study confirmed that FA improved APAP metabolism by inhibiting PXR-mediated CYP1A2 and CYP3A11 and alleviated APAP-induced hepatic impairment by inhibiting hepatic oxidative stress, ERS, and apoptosis.

Identification of ALDH2 as a novel target for the treatment of acute kidney injury in kidney transplantation based on WGCNA and machine learning algorithms and exploration of its potential mechanism of action using animal experiments.

Acute kidney injury (AKI) after kidney transplantation is one of the main causes of graft loss and poor patient prognosis, and it is important to explore new targets for treating AKI in kidney transplantation. Based on the kidney transplantation AKI-related dataset GSE30718, the most relevant modular genes for AKI among them were firstly screened using WGCNA and intersected with the DEGs, and the intersected genes were used as candidate genes for kidney transplantation AKI. Second, machine learning algorithms were utilized to identify the key genes among them, and the HPA database was used to explore the expression landscape. Next, we constructed a rat renal IRI model and explored the role of key genes in renal IRI. Finally, we combined ssGSEA enrichment analysis with animal experiments to further validate the potential mechanism of action of key genes. In total, we identified 98 of the most relevant modular genes for AKI and 417 DEGs, which intersected to yield a total of 24 AKI candidate genes. Next, we intersected the key genes identified by three types of machine learning, namely, Random Forest, LASSO regression analysis and SVM, and obtained a total of 1 intersected gene as ALDH2, which we used as a key gene in kidney transplantation AKI. Using the HPA database, we found that ALDH2 has a high expression level in renal tissues and is mainly located in renal tubular epithelial cells. Next, we found in a rat renal IRI model that increasing the expression of ALDH2 alleviated the impairment of renal function and decreased the expression of NGAL, a marker of tubular injury, and BAX, an apoptotic protein, as well as reducing the expression of the inflammatory factors IL1β and IL6. Finally, using ssGSEA enrichment analysis and animal experiments, we further found that ALDH2 was able to inhibit the activation of the MAPK signaling pathway. ALDH2 may serve as a novel target for the treatment of kidney transplantation AKI, and increasing the expression level of ALDH2 has a protective effect on renal IRI, and this protective effect may be achieved by inhibiting the MAPK signaling pathway.

Discovery of novel JQ1 derivatives as dual ferroptosis and apoptosis inducers for the treatment of triple-negative breast cancer.

Discovery of novel JQ1 derivatives as dual ferroptosis and apoptosis inducers for the treatment of triple-negative breast cancer.

Tyrosol promotes skin flap survival by downregulating the p38/NF-κB signaling pathway

Tyrosol promotes skin flap survival by downregulating the p38/NF-κB signaling pathway

Chlorpyrifos-oxon results in autophagic flux dysfunction contributing to neuronal apoptosis via a ROS/AMPK/CHOP activation pathway

Chlorpyrifos-oxon results in autophagic flux dysfunction contributing to neuronal apoptosis via a ROS/AMPK/CHOP activation pathway

Zn2+ protects H9C2 cardiomyocytes by alleviating MAMs-associated apoptosis and calcium signaling dysregulation.

Zn2+ protects H9C2 cardiomyocytes by alleviating MAMs-associated apoptosis and calcium signaling dysregulation.

The combined effects of HSV-1 glycoprotein D and aluminum hydroxide on human neuroblastoma cells: Insights into oxidative DNA damage, apoptosis, and epigenetic modifications.

The combined effects of HSV-1 glycoprotein D and aluminum hydroxide on human neuroblastoma cells: Insights into oxidative DNA damage, apoptosis, and epigenetic modifications.

Immunomodulatory lectin from Cordia myxa targets PI3K/AKT signalling mediated apoptosis to regress both in-vitro and in-vivo tumour.

Immunomodulatory lectin from Cordia myxa targets PI3K/AKT signalling mediated apoptosis to regress both in-vitro and in-vivo tumour.

Design, Synthesis, and Cytotoxicity Evaluation of Novel Indolin-2-One Based Molecules on Hepatocellular Carcinoma HepG2 Cells as Protein Kinase Inhibitors

A series of indolinone-based derivatives were designed and synthesized using the hybrid pharmacophoric design approach as cytotoxic kinase inhibitors. The cytotoxic effects of the designed molecules were tested against MCF-7 and HepG-2 cell lines. Compounds 9 and 20 were the most cytotoxic, with IC50 values against HepG-2 and MCF-7 cells ranging from 2.53 to 7.54 µM. Additionally, compounds 9 and 20 were also found to be slightly more cytotoxic than indirubin with 2.2–2.7-fold higher cytotoxicity with HepG-2 cells. CDK-2 and CDK-4 kinase enzyme inhibition assay showed that compound 9 had a higher inhibitory effect (4.8-fold) than indirubin against CDK-2 and comparable inhibition against CDK-4. Moreover, compound 20 displayed nanomolar inhibitory action against both EGFR kinase and VFGFR-2 enzyme, which were around 8.8- and 5.4-fold higher than the IC50 values of indirubin. Compounds 9 and 20 induced cell cycle arrest at the G1 phase on HepG2 cells. The levels of the key apoptotic proteins assessed revealed elevated levels of the Bax/Bcl-2 ratio, which in turn initiated the caspase3/7 cascade that led to the activation of both intrinsic and extrinsic apoptotic pathways. The cell cycle inhibitory proteins p53 and p21 were significantly upregulated upon treatment with compounds 9 and 20. The docking results revealed that compound 9 exhibits stronger binding affinity to CDK-2 than indirubin, and compound 20 showed a similar binding mode to sorafenib with VEGFR-2.

Nab-Paclitaxel Promotes Radiosensitization by Inducing DNA Damage and Inhibiting Macrophage M2 Polarization in Cholangiocarcinoma.

Background: Nab-paclitaxel effectively inhibits tumor proliferation and modulates macrophage polarization to improve the tumor microenvironment. However, its potential to achieve radiosensitization in cholangiocarcinoma remains to be elucidated. Materials and Methods: The proliferation inhibition and radiosensitizing effects of nab-paclitaxel were assessed using cell counting kit-8 and colony formation assays in NOZ and TFK1 cell lines. Cell apoptosis, cell cycle progression, DNA damage, and macrophage polarization status were analyzed via flow cytometry immunofluorescence, enzyme-linked immunosorbent assay, and qRT-PCR. A tumor-bearing mouse model was established to validate radiosensitization invivo. Potentially related genes and proteins involved in nab-paclitaxel-induced radiosensitization were identified through RNA transcriptome sequencing and Western blotting. Results: Nab-paclitaxel exhibited significant radiosensitizing effects on cholangiocarcinoma cells. Combined with radiotherapy, nab-paclitaxel increased DNA damage, promoted apoptosis, and effectively inhibited M2 polarization of macrophages invivo and in vitro. The radiosensitizing effect is involved in the activation of the AMP-dependent protein kinase (AMPK) signaling pathway. Nab-paclitaxel significantly upregulated phosphorylated AMPKα, apoptotic proteins as zinc finger matrin-type 3, and nuclear factor kappa-B levels following radiation exposure. Conclusions: Our study confirmed the radiosensitizing effect of nab-paclitaxel on cholangiocarcinoma cells through a dual effect of antitumor proliferation and inhibition of M2 macrophage polarization, and the underlying mechanism involved activation of the AMPK signaling pathway.