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Signal transduction of apoptosis. Two major pathways of apoptosis exist in mammalian cells. Left, the extrinsic cell death pathway is mediated by a subgroup of the TNF receptor superfamily called the death receptors (CD95, TRAIL-R1/2, and TNF-R1). Receptor-mediated cell death is initiated by the recruitment of adapter proteins, like FADD, via the DD, which then bind to the death effector domain-containing caspase-8 or-10. Formation of this DISC results in the activation of caspase-8, which then directly cleaves and activates caspase-3,-6, or-7, the executioner enzymes of apoptosis. Right, in the mitochondrial or intrinsic pathway, which is initiated by multiple forms of cellular stress, proapoptotic Bcl-2 family members Bax and Bak translocate to the mitochondria. The BH3-only protein Bid activates Bax and Bak to mediate the release of cytochrome c in the cytosol. This triggers the assembly of the apoptosome (Apaf-1 and caspase-9) and subsequent activation of caspase-3 and cell death. IAPs bind directly to caspases and inhibit their enzymatic activity. The inhibitory function of IAPs is countered by the SMAC.
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Apoptosis, the major form of cellular suicide, is central to various physiological processes and the maintenance of homeostasis in multicellular organisms. Presumably, even more important is a causative or contributing role of apoptosis to various human diseases. These include situations with unwanted cell accumulation (cancer) and failure to eradi...
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... 2003;Fuentes-Prior and Salvesen, 2004). The subset of caspases that cleave selected substrates to produce the typical alteration changes associated with apoptosis are known as executioner caspases, which in mammals are caspases-3, -6, and -7. Executioner caspases are activated by apical initiator caspases, in- cluding caspase-8, -9, and -10 ( Fig. ...
Citations
... Cell death is triggered by actions affecting the cell and can be broadly classified into necrosis, autophagy, and apoptosis [41]. Triggering apoptosis is a potential therapeutic strategy in cancer, as it is a form of programmed cell death that efficiently removes cells with DNA damage or damage during development [42]. We confirmed cell death caused by 24-h 1-NP treatment in HaCaT cells. ...
Solar UVB irradiation cause skin photoaging by inducing the high expression of matrix metalloproteinase (MMPs) to inhibit the expression of Type1 procollagen synthesis. 1-Kestose, a natural trisaccharide, has been indicated to show a cytoprotective role in UVB radiation-induced-HaCaT cells. However, few studies have confirmed the anti-aging effects. In the present study, we evaluated the anti-photoaging and pathological mechanism of 1-kestose using Human keratinocytes (HaCaT) cells. The results found that 1-kestose pretreatment remarkably reduced UVB-generated reactive oxygen species (ROS) accumulation in HaCaT cells. 1-Kestose suppressed UVB radiation-induced MMPs expressions by blocking MAPK/AP-1 and NF-κB p65 translocation. 1-Kestose pretreatment increased Type 1 procollagen gene expression levels by activating TGF-β/Smad signaling pathway. Taken together, our results demonstrate that 1-kestose may serve as a potent natural trisaccharide for inflammation and photoaging prevention.
... With more understanding of cell death mechanisms, several biochemical features, such as DNA fragmentation, membrane alterations, and caspase activity, have been exploited to detect dying and dead cells. However, these approaches require fixation and staining of tissues, which limits the possibility of time-course evaluation [4]. To visualize the pharmacodynamics and the apoptosis response, scientists have designed live-cell staining probes such as peptide-tailored gold nanoclusters and recombinant substrate proteins [5,6]. ...
Conventional techniques for in vitro cancer drug screening require labor-intensive formalin fixation, paraffin embedding, and dye staining of tumor tissues at fixed endpoints. This way of assessment discards the valuable pharmacodynamic information in live cells over time. Here, we found endogenous lipofuscin-like auto-fluorescence acutely accumulated in the cell death process. Its unique red autofluorescence could report the apoptosis without labeling and continuously monitor the treatment responses in 3D tumor-culture models. Lifetime imaging of lipofuscin-like red autofluorescence could further distinguish necrosis from apoptosis of cells. Moreover, this endogenous fluorescent marker could visualize the apoptosis in live zebrafish embryos during development. Overall, this study validates that lipofuscin-like autofluorophore is a generic cell death marker. Its characteristic autofluorescence could label-free predict the efficacy of anti-cancer drugs in organoids or animal models.
... [2] Deregulation of apoptosisregulating genes has been linked to pathogenesis and cancer progression in disorders such as cancer. [3] Drugs that restore normal apoptotic pathways have the potential to effectively treat malignancies that rely on apoptotic system abnormalities to survive. [4,5] As a result, the search for chemicals that might induce apoptosis in tumor cells is of tremendous interest in the development of new cancer medicines. ...
Novel series of heterocycliccompounds pairing hybrids pyrazole, naphthalene and pyrazoline/thiazoldinemoieties were synthesized. The starting compounds pyrazolyl hydrazinecarbothioamidewere synthesized by the reaction of the 4‐formyl pyrazole derivatives with thiosemicarbazide to afford the substituted carbothioamide in good yields. The carbothioamideswere used as starting materials for synthesis of a variety of pyrazolylhydrazinylthiazole derivativesandpyrazolylhydrazonothiazolidin derivatives. The structures of the newly synthesized compounds were deduced depending on their spectrum data and elemental analysis. The cytotoxicity of the selected compounds was screened in vitro against three human breast cancer cell lines. The four compounds showed a gradual decrease in cell viability and theonly compound thiazolidin‐4‐one10b showed IC5010.16, 8.25 and 4.88 μM against the above cell lines, respectively. Thus, it was selected for further in vitro biological investigations. The Structure‐activity relationship for these compounds was interpreted in terms of molecular docking.
... Apoptosis defects can lead to tumors and other cell death disorders, whereas excessive activation can lead to cytopenic diseases. Apoptosis includes two classic pathways that eventually activate the caspase cascade: the external (death receptor pathway) and the internal pathway (mitochondrial pathway) [112]. Apoptotic pathways may respond differently to different GNE mutations [111]. ...
GNE myopathy is a hereditary muscle disorder characterized by muscle atrophy and weakness initially involving the lower distal extremities. The treatment of GNE myopathy mainly focuses on a sialic acid deficiency caused by a mutation in the GNE gene, but it has not achieved the expected effect. The main pathological features of GNE myopathy are myofiber atrophy and rimmed vacuoles, including accumulation of amyloid β, which is mainly found in atrophic muscle fibers. Although the role of amyloid β and other misfolded proteins on the nervous system has been widely recognized, the cause and process of the formation of amyloid β in the pathological process of GNE myopathy are unclear. In addition, amyloid β has been reported to be linked to quality control mechanisms of proteins, such as molecular chaperones, the ubiquitin–proteasome system, and the autophagy-lysosome system. Herein, we summarize the possible reasons for amyloid β deposition and illustrate amyloid β-mediated events in the cells and their role in muscle atrophy in GNE myopathy. This review represents an overview of amyloid β and GNE myopathy that could help identify a potential mechanism and thereby a plausible therapeutic for the disease.
... Cell death is triggered by actions affecting the cell and can be broadly classified into necrosis, autophagy, and apoptosis [41]. Triggering apoptosis is a potential therapeutic strategy in cancer, as it is a form of programmed cell death that efficiently removes cells with DNA damage or damage during development [42]. We confirmed cell death caused by 24-h 1-NP treatment in HaCaT cells. ...
The skin, which is the largest organ of the human body, is in direct contact with pollutants in the surrounding atmosphere. Meanwhile, 1-nitropyrene (1-NP), the most abundant nitro-polycyclic aromatic hydrocarbon found in particulate matter, is known to have carcinogenic effects; however, studies on its toxicity in human and canine skin are still needed. In this study, we investigated 1-NPinduced apoptosis and inflammatory pathways in HaCaT cells. In addition, we also measured the cytoprotective effect of methyl gallate (MG), which is widely distributed in medicinal and edible plants and is well known for its anti-inflammatory and antioxidant properties. MG inhibited 1-NPinduced cell death and apoptosis pathways, including the cleavage of PARP and activation of caspase-3, -7, and -9. MG also suppressed 1-NP-induced COX-2 expression and phosphorylation of mitogen-activated protein kinases (MAPKs) and MAPK kinases (MAPKKs). Our findings suggest that 1-NP induces skin toxicity in human and canine through apoptosis and inflammatory responses, and moreover, that this can be prevented by treatment with MG.
... Apoptosis is a key component in development and aging, but it is also the mechanism of death followed in various neurodegenerative and autoimmune diseases [81][82][83]. Previously, many of these diseases were associated with other causes. Glaucoma, for example, was attributed to elevated intraocular pressure. ...
The retina is part of the central nervous system, its analysis may provide an idea of the health and functionality, not only of the retina, but also of the entire central nervous system, as has been shown in Alzheimer’s or Parkinson’s diseases. Within the retina, the ganglion cells (RGC) are the neurons in charge of processing and sending light information to higher brain centers. Diverse insults and pathological states cause degeneration of RGC, leading to irreversible blindness or impaired vision. RGCs are the measurable endpoints in current research into experimental therapies and diagnosis in multiple ocular pathologies, like glaucoma. RGC subtype classifications are based on morphological, functional, genetical, and immunohistochemical aspects. Although great efforts are being made, there is still no classification accepted by consensus. Moreover, it has been observed that each RGC subtype has a different susceptibility to injury. Characterizing these subtypes together with cell death pathway identification will help to understand the degenerative process in the different injury and pathological models, and therefore prevent it. Here we review the known RGC subtypes, as well as the diagnostic techniques, probes, and biomarkers for programmed and unprogrammed cell death in RGC.
... [9] The changes in normal cell cycle regulation and apoptosis-related genes can lead to cancer and are linked to cancer progression. [10] Certain drugs have proved to be cytotoxic by inducing an apoptotic pathway that could effectively treat cancers. [11] Around 20 million compounds were documented, of half were heterocyclic compounds. ...
Objective:
To evaluate the antiproliferative and apoptosis inducing activity of different sydnones on cancer cell lines and their interaction with cancer proteins by molecular docking studies.
Material and methods:
Antiproliferative activity was carried out by MTT assay and apoptosis inducing activity was performed by DAPI and Annexin V and propidium iodide staining. Molecular docking studies were performed using AutoDock Tools 1.5.6. Pharmacokinetics properties like ADME and toxicity were analysed by pkCSM web server.
Result:
In this study, four new sydnone compounds 3-(4-nonylbiphenyl-4'-yl) sydnone (MC-182), 3-(4-propylbiphenyl-4'-yl) sydnone (MC-454), 3-(4-hexylbiphenyl-4'-yl) sydnone (MC-433), and 3-(4-methylbiphenyl-4'-yl) sydnone (MC-431) were screened for antiproliferative and apoptotic effect against BT-474 (human breast cancer), HeLa (human cervical cancer) and Jurkat (human myeloid leukemia) Mostly, all the sydnone compounds exhibited decent antiproliferative effectiveness, but compound MC-431, MC-433, and MC-454 showed more antiproliferative activity (IC50 1.71, 10.09 and 2.87 μM against BT-474, Hela and Jurkat cell line, respectively). The changes of morphological characteristics of cancer cells determined by staining techniques indicate the apoptotic cell death. The molecular docking and interaction studies were carried out between sydnones with cancer proteins (epidermal growth factor domain receptor tyrosine kinase [EGF-TK], tumor necrosis factor-alpha [TNF-α] and Caspase3. Among all four sydnone molecules, two compounds MC-454 and MC-431 showed good binding energy with targeted proteins. Drug-like property was predicted by ADME toxicity study.
Conclusion:
The results indicate sydnone compounds were found to exhibit anticancer activity by inducing apoptosis. The molecular docking study of sydnones with cancer proteins showed a decent interaction affinity. The results of absorption, distribution, metabolism, excretion and toxicity studies by the Insilco approach also proved that MC-454 sydnone showed better In-Vivo administration. Thus, the current research work indicates that these sydnone compounds would be prospective in developing anticancer medicines.
... The changes in normal cell cycle regulation and also changes in apoptosis related genes can lead to cancer and associated to cancer progression [7,8]. Certain drugs proved to be cytotoxic by inducing apoptotic pathway that has the possible effective towards treating cancers [9]. ...
Sydnones have been a novel class of mesoionic compound due to versatility of their applications in various fields. Sydnone derivative have seen as an interesting structure grouped in the heterocyclic community, which is having regions of both positive and negative charges linked with a poly-heteroatomic system. This structural characteristic allows them to cross biological membranes and interact with biomolecules. Four sydnones namely 3-(4-decyloxybiphenyl-4′-yl) sydnone (MC-176), 3-(4-octyloxy-2,3-difluorobiphenyl-4′-yl) sydnone (MC-192), 3-(4-biphenyl-4′-yl) sydnone (MC-450) and 3-(4-butylbiphenyl-4′-yl) sydnone (MC-456) were evaluated for biophysical interactions between DNA and sydnones and antiproliferative activity. The UV-visible spectroscopic study indicates interaction between sydnone and dsDNA with a slight red and hypochromic shift in absorption spectra, which shows the intercalation mode of binding. The binding constant of DNA-Sydnone complexes were in the range from 1.4 × 104 M–1 to 7.1 × 104 M–1 for different sydnone compounds (MC-176, MC-192, MC-450, MC-456). FTIR spectra indicated that sydnone interaction with DNA occurs through base pairs and the phosphate backbone of the DNA. The cytotoxic and apoptotic effects of a sydnone derivatives on human cervical cancer (HeLa) and breast tumor (BT) 474 cancer cell lines were determined. The compounds possess antiproliferative activity in a concentration-dependent mode. The changes of morphological characteristic of cancer cells were determined by fluorescent staining techniques indicate the apoptotic cell death. The molecular docking studies of sydnone compounds with caspase 3 and EGF-TK showed better interactions (according to docking score) along with commercially available breast cancer drug molecule anastrozole. The docking score of sydnone molecules (MC-456, MC-450, MC-192 and MC-176) with EGF-TK enzyme were -6.44, -6.42, -5.46 and -4.53, respectively. The binding energy of anastrozole with EGF-TK was -6.41. As well Caspase 3 inhibition with sydnone compounds MC-456, MC-450, MC-192 and MC-176 were -6.09, -6.48, -5 and -3.49, respectively. The binding energy of anastrozole with caspase 3 was -6.24. All sydnone compounds were studied for ADME toxicity studies along with Lipinski rule of five to assess their drug likeness properties by in silico approach. MC-450 found to have good ADMET (absorption, distribution, metabolism, excretion and toxicology) properties among all the sydnone compounds. Thus, the present work indicates that these sydnone compounds would be a well prospective in developing anticancer medicines.
... First-generation TRAIL therapeutics were well tolerated but revealed limited anti-tumor effects, which was mainly attributed to their biologic properties. Therefore, secondgeneration TRAIL-based molecules with improved antitumorigenic activity have been developed and were shown to exhibit an efficient therapeutic response when combined with sensitizing agents, such as small-molecule BCL-X L inhibitors or the proteasome inhibitor bortezomib [34][35][36]. ...
Hepatocellular carcinoma (HCC) represents a global health challenge with limited therapeutic options. Anti-angiogenic immune checkpoint inhibitor-based combination therapy has been introduced for progressed HCC, but improves survival only in a subset of HCC patients. Tyrosine-kinase inhibitors (TKI) such as sorafenib represent an alternative treatment option but have only modest efficacy. Using different HCC cell lines and HCC tissues from various patients reflecting HCC heterogeneity, we investigated whether the sorafenib response could be enhanced by combination with pro-apoptotic agents, such as TNF-related apoptosis-inducing ligand (TRAIL) or the BH3-mimetic ABT-737, which target the death receptor and mitochondrial pathway of apoptosis, respectively. We found that both agents could enhance sorafenib-induced cell death which was, however, dependent on specific BH3-only proteins. TRAIL augmented sorafenib-induced cell death only in NOXA-expressing HCC cells, whereas ABT-737 enhanced the sorafenib response also in NOXA-deficient cells. ABT-737, however, failed to augment sorafenib cytotoxicity in the absence of BIM, even when NOXA was strongly expressed. In the presence of NOXA, BIM-deficient HCC cells could be in turn strongly sensitized for cell death induction by the combination of sorafenib with TRAIL. Accordingly, HCC tissues sensitive to apoptosis induction by sorafenib and TRAIL revealed enhanced NOXA expression compared to HCC tissues resistant to this treatment combination. Thus, our results suggest that BH3-only protein expression determines the treatment response of HCC to different sorafenib-based drug combinations. Individual profiling of BH3-only protein expression might therefore assist patient stratification to certain TKI-based HCC therapies.
... It is reported that the most important strategy in the development of a medicine for cancer treatment is that normal cells should be damaged less due to the cytotoxic effects of chemotherapy [32] and the stipulation of cell deaths such as apoptosis [33], entosis [34], autophagy [35], anoikis [36,37] and necroptosis [38] plays an important role in cancer cells. The research of anticancer effects of natural products, the majority of which are made of plant extracts and/or compounds, involves research on animals and the determination of cytotoxic effects on cancer cell lines and the effects on the types of cell death prior to clinical studies [39,40]. ...
Purpose:
The present study aimed to research the cytotoxic effects of Colchicum baytopiorum extract on normal and cancerous cells and reveal the cell death mechanisms in cancerous cells triggered by this effect.
Methods:
Within this framework, the cells' index values obtained with an xCELLigence Real Time Cell Analysis DP device, selectivity index (SI), apoptotic index (AI) based on a DAPI application and time-related activities of caspase 3,7 and 9 with a spectrofluorometer were inspected. The expressions of apoptosis/autophagy/entosis/necroptosis/anoikis-related genes were researched with qRT-PCR.
Results:
It was determined that C. baytopiorum extract had displayed a high selectivity [(SI)=4], increased AI (p<0.01) and activation of caspases 3,7 and 9 (p<0.05). It was observed that the mRNA expressions of Atg12, Atg16, Atg5, Atg7, bad, bak, bax, bcl-xL, Beclin1, caspase3, FLIP, Puma, LC3, mcl-1, Bit1, Rho, RIP1, ROCK and TRAF2 genes in C-4 I cells to which the plant extract was applied had increased significantly in comparison with the control group (FC≥1.5). A lowering was detected in the mRNA levels of IAP, SRC kinase and TNF.
Conclusion:
Consequently, it was revealed that the plant extract used had increased the gene expressions in the autophagic cell death pathway in C-4 I cells along with apoptosis and thus, it could be a promising candidate for cervix carcinoma treatment.
