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opencc-zeroFeb 2020View details →

Stochastic fluctuations in apoptotic threshold of tumor cells can enhance apoptosis and combat fractional killing

Fractional killing, which is a significant impediment to successful chemotherapy, is observed even in a population of genetically identical cancer cells exposed to apoptosis-inducing agents. This phenomenon arises not from genetic mutation but from cell-to-cell variation in the activation timing and level of the proteins that regulate apoptosis. To understand the mechanism behind the phenomenon, we formulate complex fractional killing processes as a first-passage time (FPT) problem with a stochastically fluctuating boundary. Analytical calculations are performed for the FPT distribution in a toy model of stochastic p53 gene expression, where the cancer cell is killed only when the p53 expression level crosses an activity apoptotic threshold. Counterintuitively, we find that threshold fluctuations can effectively enhance cellular killing by significantly decreasing the mean time that the p53 protein reaches the threshold level for the first time. Moreover, faster fluctuations lead to the killing of more cells. These qualitative results imply that dynamic variability in threshold is an unneglectable stochastic source, and can be taken as a strategy for combating fractional killing of cancer cells.

opencc-zeroMay 2019View details →

Data from: Thyroid hormone protects primary cortical neurons exposed to hypoxia by reducing DNA methylation and apoptosis

Traumatic Brain Injury (TBI) is associated with disruption of cerebral blood flow leading to localized brain hypoxia. Thyroid hormone (TH) treatment, administered shortly after injury, has been shown to promote neural protection in rodent TBI models. The mechanism of TH protection, however, is not established. We used mouse primary cortical neurons to investigate the effectiveness and possible pathways of T3-promoted cell survival after exposure to hypoxic injury. Cultured primary cortical neurons were exposed to hypoxia (0.2% oxygen) for 7 hours with or without T3 (5 nM). T3 treatment enhanced DNA 5-hydroxymethylcytosine (5-hmc) levels and attenuated the hypoxia-induced increase in DNA 5-methylcytosine (5-mc). In the presence of T3, mRNA expression of Tet family genes was increased and DNA methyltransferases, (Dnmt) 3a and Dnmt3b, were downregulated, compared to conditions in the absence of T3. These T3-induced changes decreased hypoxia-induced DNA de novo methylation, which reduced hypoxia-induced neuronal damage and apoptosis. We utilized RNA-seq to characterize T3-regulated genes in cortical neurons under hypoxic conditions and identified 22 genes that were upregulated and 15 genes that were downregulated. Krupple-like factor 9 (KLF9), a multifunctional transcription factor that plays a key role in CNS development, was highly upregulated by T3 treatment in hypoxic conditions. Knockdown of the KLF9 gene resulted in early apoptosis and abolished the beneficial role of T3 in neuronal survival. KLF9 mediates, in part, the neuronal protective role of T3. T3 treatment reduces hypoxic damage, although pathways that reduce DNA methylation and apoptosis, remains to be elucidated.

opencc-zeroJan 2024View details →

Data from: A novel triptolide analog downregulates NF-kB and induces mitochondrial apoptosis pathways in human pancreatic cancer

Pancreatic cancer is the seventh leading cause of cancer-related death worldwide, and despite advancements in disease management, the 5-year survival rate stands at only 12%. Triptolides have potent anti-tumor activity against different types of cancers, including pancreatic cancer, however poor solubility and toxicity limit their translation into clinical use. We synthesized a novel pro-drug of triptolide, (E)-19-[(1'-benzoyloxy-1'-phenyl)-methylidene]-Triptolide (CK21), which was formulated into an emulsion for in vitro and in vivo testing in rats and mice, and using human pancreatic cancer cell lines and patient-derived pancreatic tumor organoids. A time-course transcriptomic profiling of tumor organoids treated with CK21 in vitro was conducted to define its mechanism of action, as well as transcriptomic profiling at a single time point post-CK21 administration in vivo. Intravenous administration of emulsified CK21 resulted in the stable release of triptolide, and potent anti-proliferative effects on human pancreatic cancer cell lines and patient-derived pancreatic tumor organoids in vitro, and with minimal toxicity in vivo. Time course transcriptomic profiling of tumor organoids treated with CK21 in vitro revealed <10 differentially expressed genes (DEGs) at 3 h and ~8,000 DEGs at 12 h. Overall inhibition of general RNA transcription was observed, and Ingenuity pathway analysis together with functional cellular assays confirmed inhibition of the NF-κB pathway, increased oxidative phosphorylation and mitochondrial dysfunction, leading ultimately to increased reactive oxygen species (ROS) production, reduced B-cell-lymphoma protein 2 (BCL2) expression, and mitochondrial-mediated tumor cell apoptosis. CK21 is a novel pro-drug of triptolide that exerts potent anti-proliferative effects on human pancreatic tumors by inhibiting the NF-κB pathway, leading ultimately to mitochondrial-mediated tumor cell apoptosis.

opencc-by-4.0Feb 2022View details →

Data for Chromatin compaction precedes apoptosis in developing neurons by Rose et al.

Data for Chromatin compaction precedes apoptosis in developing neurons by Rose et al.

opencc-by-4.0May 2024View details →

Effect of gedunin on cell proliferation and apoptosis impact in skin melanoma cells A431 via PI3K/JNK signaling pathway

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Fig. 5 in Cytotoxicity of methanolic extract of Swertia petiolata against gastric cancer cell line SNU-5 is via induction of apoptosis ⁎

Fig. 5. Mitochondrial membrane potential (MMP %) of SNU-5 cells treated with indicated concentration of methanolic extract of plant for 48 h. The S. petiolata methanolic extracttreated SNU5 cells showed induction of MMP loss in a dose dependent manner.

Fig. 2. SNU5 in Cytotoxicity of methanolic extract of Swertia petiolata against gastric cancer cell line SNU-5 is via induction of apoptosis ⁎

Fig. 2. SNU5 cells were treated with indicated concentrations of methanolic extract of S. petiolata for 48 h and cells were prolonged for clonogenic assay for 21 days. The extract-treated SNU5 cells showed decrease in the percentage of colony formation as compared to control in a dose-dependent manner.

Fig. 1. SNU5 in Cytotoxicity of methanolic extract of Swertia petiolata against gastric cancer cell line SNU-5 is via induction of apoptosis ⁎

Fig. 1. SNU5 cells were treated with indicated concentration of methanolic extract of S. petiolata for 48 h. The extract-treated SNU5 cells showed nuclear condensation and marked fragmented in a dose dependent manner.

Fig. 3 in Cytotoxicity of methanolic extract of Swertia petiolata against gastric cancer cell line SNU-5 is via induction of apoptosis ⁎

Fig. 3. Cells were treated with different concentrations (a) control (b) 50 (c) 100 and (d) 150 μg/ml of extract for 48 h wherein apoptosis enhanced in a dose dependent manner as shown by flow cytometer using Annexin V/PI.

Fig. 4 in Cytotoxicity of methanolic extract of Swertia petiolata against gastric cancer cell line SNU-5 is via induction of apoptosis ⁎

Fig. 4. Production of ROS (%) SNU-5 cells treated with indicated concentration of methanolic extract of plant for 48 h. The S. petiolata methanolic extract-treated SNU5 cells showed the production of reactive oxygen species generated in a dose dependent manner.

Fig. 7 in Cytotoxicity of methanolic extract of Swertia petiolata against gastric cancer cell line SNU-5 is via induction of apoptosis ⁎

Fig. 7. Structures of the compounds tentatively identified from the methanolic extract of S. petiolata, (i) Chlorogenic acid (ii) p-Coumaric acid (iii) Ursolic acid (iv) Myrecetin 3-O- rahamnoside (v) Quercetin 3-arabinoside (vi) Kaempherol 3-O-glucoside (vii) Naringenin (viii) Genistein (ix) Isorhamnetin (x) Swerchirin.

opencc-zeroJun 2021View details →

A novel mitochondrial Kv1.3-caveolin axis controls cell survival and apoptosis

The voltage-gated potassium channel Kv1.3 plays an apparent dual physiological role by participating in activation and proliferation of leukocytes as well as promoting apoptosis in several types of tumor cells. Therefore, Kv1.3 is considered a potential pharmacological target for immunodeficiency and cancer. Different cellular locations of Kv1.3, at the plasma membrane or the mitochondria, could be responsible for such duality. While plasma membrane Kv1.3 facilitates proliferation, the mitochondrial channel modulates apoptotic signaling. Several molecular determinants of Kv1.3 drive the channel to the cell surface, but no information is available about its mitochondrial targeting. Caveolins, which are able to modulate cell survival, participate in the plasma membrane targeting of Kv1.3. The channel, via a caveolin-binding domain (CDB), associates with caveolin 1 (Cav1), which localizes Kv1.3 to lipid raft membrane microdomains. The aim of our study was to understand the role of such interactions not only for channel targeting but also for cell survival in mammalian cells. By using a caveolin association-deficient channel (Kv1.3 CDBless), we demonstrate here that while the Kv1.3-Cav1 interaction is responsible for the channel localization in the plasma membrane, a lack of such interaction accumulates Kv1.3 in the mitochondria. Kv1.3 CDBless severely affects mitochondrial physiology and cell survival, indicating that a functional link of Kv1.3 with Cav1 within the mitochondria modulates the pro-apoptotic effects of the channel. Therefore, the balance exerted by these two complementary mechanisms fine-tune the physiological role of Kv1.3 during cell survival or apoptosis. Our data highlight an unexpected role for the mitochondrial caveolin-Kv1.3 axis during cell survival and apoptosis.

opencc-by-4.0Oct 2021View details →

The lncRNA TUG1 regulates Smac/DIABLO expression by competitively inhibiting miR-29b and modulates the apoptosis of lens epithelial cells in age-related cataracts

As one of the first discovered lncRNAs, TUG1 has been reported to be widely expressed in a variety of tumours. It promotes cell proliferation, differentiation, apoptosis and migration. However, our understanding of its importance in cataracts is limited. This study aims to explore the mechanism by which TUG1 mediates the apoptosis of lens epithelial cells by regulating the miR-29b/Smac axis in age-related cataracts and to identify more strategies for the nonsurgical treatment of cataracts. In this experiment we found TUG1 and Smac were expressed at high levels in age-related cataract (ARC) samples and HLEB3 cells treated with H2O2, while miR-29b expression was decreased. In vitro cell-based experiments confirmed that the downregulation of TUG1 inhibits lens epithelial cell apoptosis. Mechanistically, Smac expression is negatively regulated by miR-29b. TUG1 competitively inhibits miR-29b expression and causes the release of more Smac. In addition, miR-29b reverses the effect of TUG1 on HLE-B3 cells. In conclusion, lncRNATUG1 increases Smac expression by competitively inhibiting miR-29b and promoting the apoptosis of lens epithelial cells in age-related cataracts. This mechanism is the cytological basis of ARC formation. Based on these results, the TUG1-miR29b-Smac axis may be a new molecular pathway to regulate the development of age-related cataracts.

Fig. 5 in Hyperelodiones A-C, monoterpenoid polyprenylated acylphoroglucinols from Hypericum elodeoides, induce cancer cells apoptosis by targeting RXRα

Fig. 5. The interaction between RXRα-LBD and compounds. After treated with compounds 1–3, the binding affinity of compound toward RXRα-LBD was measured via fluorescence quenching technology at 298 K.

Fig. 7 in Hyperelodiones A-C, monoterpenoid polyprenylated acylphoroglucinols from Hypericum elodeoides, induce cancer cells apoptosis by targeting RXRα

Fig. 7. Cytotoxic effects of compounds 1–3. HeLa and MCF-7 cells were exposed to various concentrations of compounds 1–3 (0, 3.125, 6.25, 12.5, 25, 50 μΜ). After 48 h, cytotoxic activities of compounds against cancer cells were measured by MTT assay. The values are the mean ± SD for four independent replicates.

Fig. 9 in Hyperelodiones A-C, monoterpenoid polyprenylated acylphoroglucinols from Hypericum elodeoides, induce cancer cells apoptosis by targeting RXRα

Fig. 9. Molecular docking of compounds 1–3 toward RXRα-LBD. (A) Docking of 1 to RXRα-LBD. (B) Docking of 2 to RXRα-LBD. (C) Docking of 3 to RXRα-LBD. (D) Binding site of 1 to the RXRα-LBD. (E) Binding site of 2 to the RXRα-LBD. (F) Binding site of 3 to the RXRα-LBD.

Fig. 6 in Hyperelodiones A-C, monoterpenoid polyprenylated acylphoroglucinols from Hypericum elodeoides, induce cancer cells apoptosis by targeting RXRα

Fig. 6. The RXRα transactivation effects of compounds. 293T cells were treated with different concentrations of new compounds (0, 12.5, 25 μΜ), the transactivation activities of reporter gene for RXRα were measured by dual-luciferase reporter gene assay. The values are the mean ± SD for four independent replicates (*p <0.05, **p <0.01, compared with cells treated with 9-cis-RA alone).

Fig. 8 in Hyperelodiones A-C, monoterpenoid polyprenylated acylphoroglucinols from Hypericum elodeoides, induce cancer cells apoptosis by targeting RXRα

Fig. 8. PARP cleavage induction by compound 3. HeLa cells and MCF-7 cells were treated with different concentrations of compound 3 (0, 10, 20, 30 μΜ) for 48 h. The level of cleaved PARP was analyzed by Western blot.