scholarly journals Stingless Bee Propolis: New Insights for Anticancer Drugs

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Jaqueline Ferreira Campos ◽  
Helder Freitas dos Santos ◽  
Thaliny Bonamigo ◽  
Nelson Luís de Campos Domingues ◽  
Kely de Picoli Souza ◽  
...  
Keyword(s):  
Cell Death ◽  
Anticancer Drugs ◽  
Stingless Bees ◽  
Scientific Basis ◽  
Stingless Bee ◽  
Parp Cleavage ◽  
Interacting Protein ◽  
Antitumor Potential ◽  
The Rich ◽  
Prevention Of Cancer

Natural products are important sources of biomolecules possessing antitumor activity and can be used as anticancer drug prototypes. The rich biodiversity of tropical and subtropical regions of the world provides considerable bioprospecting potential, including the potential of propolis produced by stingless bee species. Investigations of the potential of these products are extremely important, not only for providing a scientific basis for their use as adjuvants for existing drug therapies but also as a source of new and potent anticancer drugs. In this context, this article organizes the main studies describing the anticancer potential of propolis from different species of stingless bees with an emphasis on the chemical compounds, mechanisms of action, and cell death profiles. These mechanisms include apoptotic events; modulation of BAX, BAD, BCL2-L1 (BCL-2 like 1), and BCL-2; depolarization of the mitochondrial membrane; increased caspase-3 activity; poly (ADP-ribose) polymerase (PARP) cleavage; and cell death induction by necroptosis via receptor interacting protein kinase 1 (RIPK1) activation. Additionally, the correlation between compounds with antioxidant and anti-inflammatory potential is demonstrated that help in the prevention of cancer development. In summary, we highlight the important antitumor potential of propolis from stingless bees, but further preclinical and clinical trials are needed to explore the selectivity, efficacy, and safety of propolis.

scholarly journals Interplay between Endoplasmic Reticular Stress and Survivin in Colonic Epithelial Cells

Cells ◽  
2018 ◽  
Vol 7 (10) ◽  
pp. 171 ◽  
Author(s):  
Rohit Gundamaraju ◽  
Ravichandra Vemuri ◽  
Wai Chin Chong ◽  
Stephen Myers ◽  
Shaghayegh Norouzi ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Inflammatory Markers ◽  
Caspase 3 ◽  
Annexin V ◽  
Parp Cleavage ◽  
Cellular Survival ◽  
Unfolded Protein ◽  
Proliferative Assay ◽  
The Unfolded Protein Response

Sustained endoplasmic reticular stress (ERS) is implicated in aggressive metastasis of cancer cells and increased tumor cell proliferation. Cancer cells activate the unfolded protein response (UPR), which aids in cellular survival and adaptation to harsh conditions. Inhibition of apoptosis, in contrast, is a mechanism adopted by cancer cells with the help of the inhibitor of an apoptosis (IAP) class of proteins such as Survivin to evade cell death and gain a proliferative advantage. In this study, we aimed to reveal the interrelation between ERS and Survivin. We initially verified the expression of Survivin in Winnie (a mouse model of chronic ERS) colon tissues by using immunohistochemistry (IHC) and immunofluorescence (IF) in comparison with wild type Blk6 mice. Additionally, we isolated the goblet cells and determined the expression of Survivin by IF and protein validation. Tunicamycin was utilized at a concentration of 10 µg/mL to induce ERS in the LS174T cell line and the gene expression of the ERS markers was measured. This was followed by determination of inflammatory cytokines. Inhibition of ERS was carried out by 4Phenyl Butyric acid (4PBA) at a concentration of 10 mM to assess whether there was a reciprocation effect. The downstream cell death assays including caspase 3/7, Annexin V, and poly(ADP-ribose) polymerase (PARP) cleavage were evaluated in the presence of ERS and absence of ERS, which was followed by a proliferative assay (EdU click) with and without ERS. Correspondingly, we inhibited Survivin by YM155 at a concentration of 100 nM and observed the succeeding ERS markers and inflammatory markers. We also verified the caspase 3/7 assay. Our results demonstrate that ERS inhibition not only significantly reduced the UPR genes (Grp78, ATF6, PERKandXBP1) along with Survivin but also downregulated the inflammatory markers such as IL8, IL4, and IL6, which suggests a positive correlation between ERS and the inhibition of apoptosis. Furthermore, we provided evidence that ERS inhibition promoted apoptosis in LS174T cells and shortened the proliferation rate. Moreover, Survivin inhibition by YM155 led to a comparable effect as that of ERS inhibition, which includes attenuation of ERS genes and inflammatory markers as well as the promotion of programmed cell death via the caspase 3/7 pathway. Together, our results propose the interrelation between ERS and inhibition of apoptosis assigning a molecular and therapeutic target for cancer treatment.

Reactive oxygen species and caspase activation mediate silica-induced apoptosis in alveolar macrophages

2001 ◽  
Vol 280 (1) ◽  
pp. L10-L17 ◽  
Author(s):  
Han-Ming Shen ◽  
Zhuo Zhang ◽  
Qi-Feng Zhang ◽  
Choon-Nam Ong
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Alveolar Macrophages ◽  
Caspase 3 ◽  
Reactive Oxygen ◽  
Parp Cleavage ◽  
Oxygen Species ◽  
Caspase Activation ◽  
Caspase 9 ◽  
Induced Apoptosis

Alveolar macrophages (AMs) are the principal target cells of silica and occupy a key position in the pathogenesis of silica-related diseases. Silica has been found to induce apoptosis in AMs, whereas its underlying mechanisms involving the initiation and execution of apoptosis are largely unknown. The main objective of the present study was to examine the form of cell death caused by silica and the mechanisms involved. Silica-induced apoptosis in AMs was evaluated by terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling assay and cell cycle/DNA content analysis. The elevated level of reactive oxygen species (ROS), caspase-9 and caspase-3 activation, and poly(ADP-ribose) polymerase (PARP) cleavage in silica-treated AMs were also determined. The results showed that there was a temporal pattern of apoptotic events in silica-treated AMs, starting with ROS formation and followed by caspase-9 and caspase-3 activation, PARP cleavage, and DNA fragmentation. Silica-induced apoptosis was significantly attenuated by a caspase-3 inhibitor, N-acetyl-Asp-Glu-Val-Asp aldehyde, and ebselen, a potent antioxidant. These findings suggest that apoptosis is an important form of cell death caused by silica exposure in which the elevated ROS level that results from silica exposure may act as an initiator, leading to caspase activation and PARP cleavage to execute the apoptotic process.

scholarly journals MLKL forms disulfide bond-dependent amyloid-like polymers to induce necroptosis

2017 ◽  
Vol 114 (36) ◽  
pp. E7450-E7459 ◽  
Author(s):  
Shuzhen Liu ◽  
Hua Liu ◽  
Andrea Johnston ◽  
Sarah Hanna-Addams ◽  
Eduardo Reynoso ◽  
...  
Keyword(s):  
Cell Death ◽  
Disulfide Bond ◽  
Kinase Domain ◽  
Proteinase K ◽  
Interacting Protein ◽  
Tnf Α ◽  
Mouse Cells ◽  
Red Dye ◽  
Necessary And Sufficient ◽  
Human And Mouse

Mixed-lineage kinase domain-like protein (MLKL) is essential for TNF-α–induced necroptosis. How MLKL promotes cell death is still under debate. Here we report that MLKL forms SDS-resistant, disulfide bond-dependent polymers during necroptosis in both human and mouse cells. MLKL polymers are independent of receptor-interacting protein kinase 1 and 3 (RIPK1/RIPK3) fibers. Large MLKL polymers are more than 2 million Da and are resistant to proteinase K digestion. MLKL polymers are fibers 5 nm in diameter under electron microscopy. Furthermore, the recombinant N-terminal domain of MLKL forms amyloid-like fibers and binds Congo red dye. MLKL mutants that cannot form polymers also fail to induce necroptosis efficiently. Finally, the compound necrosulfonamide conjugates cysteine 86 of human MLKL and blocks MLKL polymer formation and subsequent cell death. These results demonstrate that disulfide bond-dependent, amyloid-like MLKL polymers are necessary and sufficient to induce necroptosis.

scholarly journals Analysis of programmed cell death in mouse fetal oocytes

Reproduction ◽  
2007 ◽  
Vol 134 (2) ◽  
pp. 241-252 ◽  
Author(s):  
A M Lobascio ◽  
F G Klinger ◽  
M L Scaldaferri ◽  
D Farini ◽  
M De Felici
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Specific Inhibitor ◽  
Annexin V ◽  
Death Process ◽  
Parp Cleavage ◽  
Tunel Staining ◽  
Calpain Inhibitor ◽  
Dna Ladder ◽  
Caspase 2

We report a short-term culture system that allowsto define novel characteristic of programmed cell death (PCD) in fetal oocytes and to underscore newaspects of this process. Mouse fetal oocytes culturedin conditions allowingmeiotic prophase I progression underwent apoptotic degeneration waves as revealed by TUNEL staining. TEM observations revealed recurrent atypical apoptotic morphologies characterized by the absence of chromatin margination and nuclear fragmentation; oocytes with autophagic and necrotic features were also observed. Further characterization of oocyte death evidenced DNA ladder, Annexin V binding, PARP cleavage, and usually caspase activation (namely caspase-2). In the aim to modulate the oocyte death process, we found that the addition to the culture medium of the pancaspase inhibitors Z-VAD orcaspase-2-specific inhibitor Z-VDVAD resulted in a partial and transient prevention of this process. Oocyte death was significantly reduced by the antioxidant agent NAC and partly prevented by KL and IGF-I growth factors. Finally, oocyte apoptosis was reduced by calpain inhibitor I and increased by rapamycin after prolonged culture.These results support the notion that fetal oocytes undergo degeneration mostly by apoptosis. This process is, however, often morphologically atypical and encompasses other forms of cell death including caspase-independent apoptosis and autophagia. The observation that oocyte death occurs mainly at certain stages of meiosis and can only be attenuated by typical anti-apoptotic treatments favors the notion that it is controlled at least in part by stage-specific oocyte-autonomous meiotic checkpoints and when activated is little amenable to inhibition being the oocyte able to switch back and forth among different death pathways.

scholarly journals Physicochemical characteristics and sensory profile of honey samples from stingless bees (Apidae: Meliponinae) submitted to a dehumidification process

2009 ◽  
Vol 81 (1) ◽  
pp. 143-149 ◽  
Author(s):  
Carlos A.L. Carvalho ◽  
Geni S. Sodré ◽  
Antonio A.O. Fonseca ◽  
Rogério M.O. Alves ◽  
Bruno A. Souza ◽  
...  
Keyword(s):  
Electric Conductivity ◽  
Stingless Bees ◽  
Reducing Sugars ◽  
Physicochemical Characteristics ◽  
Stingless Bee ◽  
Sensory Characteristics ◽  
Sensory Profile ◽  
Diastatic Activity ◽  
Sensory Evaluations

This study was conducted to evaluate the effect of a dehumidification process on the physicochemical and sensory characteristics of stingless-bee honey. Melipona scutellaris and M. quadrifasciata honey samples were submitted to a dehumidification process and to physicochemical (reducing sugars, apparent sucrose, moisture, diastatic activity, hydroxymethylfurfural, ash, pH, acidity, and electric conductivity) and sensory evaluations (fluidity, color, aroma, crystallization,flavor,and acceptability). The results indicated that the dehumidification process does not interfere with honey quality and acceptability.

scholarly journals Inhibition of Caspases Inhibits the Release of Apoptotic Bodies: Bcl-2 Inhibits the Initiation of Formation of Apoptotic Bodies in Chemotherapeutic Agent-induced Apoptosis

1999 ◽  
Vol 145 (1) ◽  
pp. 99-108 ◽  
Author(s):  
Jiandi Zhang ◽  
Mary C. Reedy ◽  
Yusuf A. Hannun ◽  
Lina M. Obeid
Keyword(s):  
Cell Death ◽  
Chemotherapeutic Agent ◽  
Chromatin Condensation ◽  
Membrane Lipid ◽  
Lymphoid Cells ◽  
Parp Cleavage ◽  
Apoptotic Bodies ◽  
Normal Morphology ◽  
Release Assay ◽  
Induced Apoptosis

During apoptosis, the cell actively dismantles itself and reduces cell size by the formation and pinching off of portions of cytoplasm and nucleus as “apoptotic bodies.” We have combined our previously established quantitative assay relating the amount of release of [3H]-membrane lipid to the degree of apoptosis with electron microscopy (EM) at a series of timepoints to study apoptosis of lymphoid cells exposed to vincristine or etoposide. We find that the [3H]-membrane lipid release assay correlates well with EM studies showing the formation and release of apoptotic bodies and cell death, and both processes are regulated in parallel by inducers or inhibitors of apoptosis. Overexpression of Bcl-2 or inhibition of caspases by DEVD inhibited equally well the activation of caspases as indicated by PARP cleavage. They also inhibited [3H]-membrane lipid release and release of apoptotic bodies. EM showed that cells overexpressing Bcl-2 displayed near-normal morphology and viability in response to vincristine or etoposide. In contrast, DEVD did not prevent cell death. Although DEVD inhibited the chromatin condensation, PARP cleavage, release of apoptotic bodies, and release of labeled lipid, DEVD-treated cells showed accumulation of heterogeneous vesicles trapped in the condensed cytoplasm. These results suggest that inhibition of caspases arrested the maturation and release of apoptotic bodies. Our results also imply that Bcl-2 regulates processes in addition to caspase activation.

scholarly journals Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production

Blood ◽  
2012 ◽  
Vol 119 (10) ◽  
pp. 2368-2375 ◽  
Author(s):  
Guilherme B. Fortes ◽  
Leticia S. Alves ◽  
Rosane de Oliveira ◽  
Fabianno F. Dutra ◽  
Danielle Rodrigues ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Critical Role ◽  
Membrane Integrity ◽  
Iron Chelation ◽  
Heme Oxygenase 1 ◽  
Cytotoxic Effects ◽  
Interacting Protein ◽  
Free Heme ◽  
Necrosis Factor

Abstract Diseases that cause hemolysis or myonecrosis lead to the leakage of large amounts of heme proteins. Free heme has proinflammatory and cytotoxic effects. Heme induces TLR4-dependent production of tumor necrosis factor (TNF), whereas heme cytotoxicity has been attributed to its ability to intercalate into cell membranes and cause oxidative stress. We show that heme caused early macrophage death characterized by the loss of plasma membrane integrity and morphologic features resembling necrosis. Heme-induced cell death required TNFR1 and TLR4/MyD88-dependent TNF production. Addition of TNF to Tlr4−/− or to Myd88−/− macrophages restored heme-induced cell death. The use of necrostatin-1, a selective inhibitor of receptor-interacting protein 1 (RIP1, also known as RIPK1), or cells deficient in Rip1 or Rip3 revealed a critical role for RIP proteins in heme-induced cell death. Serum, antioxidants, iron chelation, or inhibition of c-Jun N-terminal kinase (JNK) ameliorated heme-induced oxidative burst and blocked macrophage cell death. Macrophages from heme oxygenase-1 deficient mice (Hmox1−/−) had increased oxidative stress and were more sensitive to heme. Taken together, these results revealed that heme induces macrophage necrosis through 2 synergistic mechanisms: TLR4/Myd88-dependent expression of TNF and TLR4-independent generation of ROS.

scholarly journals Agrochemical synergism imposes higher risk to Neotropical bees than to honeybees

2017 ◽  
Vol 4 (1) ◽  
pp. 160866 ◽  
Author(s):  
Hudson V. V. Tomé ◽  
Gabryele S. Ramos ◽  
Micaele F. Araújo ◽  
Weyder C. Santana ◽  
Gil R. Santos ◽  
...  
Keyword(s):  
Apis Mellifera ◽  
Stingless Bees ◽  
Synergistic Effects ◽  
Stingless Bee ◽  
Key Factors ◽  
Thiophanate Methyl ◽  
Africanized Honeybee ◽  
Modes Of Action ◽  
Population Numbers

Bees are key pollinators whose population numbers are declining, in part, owing to the effects of different stressors such as insecticides and fungicides. We have analysed the susceptibility of the Africanized honeybee, Apis mellifera , and the stingless bee, Partamona helleri, to commercial formulations of the insecticides deltamethrin and imidacloprid. The toxicity of fungicides based on thiophanate-methyl and chlorothalonil were investigated individually and in combination, and with the insecticides. Results showed that stingless bees were more susceptible to insecticides than honeybees. The commercial fungicides thiophanate-methyl or chlorothalonil caused low mortality, regardless of concentration; however, their combination was as toxic as imidacloprid to both species, and over 400-fold more toxic than deltamethrin for A. mellifera . There were highly synergistic effects on mortality caused by interactions in the mixture of imidacloprid and the fungicides thiophanate-methyl, chlorothalonil and the combined fungicide formulation in A. mellifera, and also to a lesser extent in P. helleri . By contrast, mixtures of the deltamethrin and the combined fungicide formulation induced high synergy in P. helleri , but had little effect on the mortality of A. mellifera . Differences in physiology and modes of action of agrochemicals are discussed as key factors underlying the differences in susceptibility to agrochemicals.

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