Ferropsis cell death can cause complications that may be difficult to detect and quantify: autophagy role and possible therapeutics

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Cell Death ◽  
Side Effects ◽  
Animal Studies ◽  
The Novel ◽  
Small Molecule Probes ◽  
Cellular Assays ◽  
Radical Trapping ◽  
Protein Thiols ◽  
Limited Applicability ◽  
Near Future

It is possible to understand both the processes of ferroptosis and how this type of cell death will be harnessed in the near future. The novel ferroposis-based therapies will also be created and evaluated using various biomarkers. Selenium and vitamin E have been shown to support some types of cancer in several studies. Such environmental factors should be accounted for while exploring ferroaptosis's duties. The effect of these modifications will be dictated by the cellular and environmental context in which they are created. It is critical to determine whether the inhibitor can act as a lipophilic radical-trapping antioxidant and prevent ferroPTosis independently of the enzyme under investigation, as several studies with lipoxygenases have shown.Using pharmacological approaches to evaluate ferropsosis can have potential side effects that are difficult to measure. Using small-molecule probes may be investigated using small-molecules probes. It's essential to utilize a biochemical test or a pharmacodynamic marker of target inhibition when employing RSL3 to inhibit GPX4, or when using erastin to inhibit the system xc–cystine/glutamate antiporter, or by using an Xc–Cystine/Glutamate/Glutamic antiporter inhibitor, or an erast inhibitor, to inhibit Gpx4, GSH, and other types of protein thiols, such as GSH and protein thiola. Many tiny molecules that are potent and selective probes in cellular assays have limited applicability in animal studies. RSL3, a poor solubility, is useful only in instances when an injection is made directly into tissues or tumors. Interfering with iron to modulate ferroptosis has far-reaching ramifications. Findings obtained with iron chelators only should be interpreted with caution as depleting iron can have other side effects other than ferroPTosis suppression.

Aiming at Ideal Therapeutics-MOPr/DOPr or MOPr-DOPr Heteromertargeting Ligand

2020 ◽  
Vol 20 (31) ◽  
pp. 2843-2851 ◽  
Author(s):  
Wakako Fujita
Keyword(s):  
Side Effects ◽  
Opioid Receptor ◽  
Delta Opioid Receptor ◽  
The Novel ◽  
Pharmacological Effects ◽  
Opioid Use ◽  
Mu Opioid ◽  
Chronic Opioid Use ◽  
Near Future

Background and Objective: The recent alarming reports related to “opioid crisis” necessitate the development of safer and effective analgesics without unwanted side effects. Thus, there needs to be an alternative target or strategy for the development of drugs for the treatment of opioid use/abuse. As one of the novel targets, in these two decades, ligands targeting opioid receptor “heteromerization” including mu-opioid receptor (MOPr)-delta opioid receptor (DOPr) heteromer have been proposed and the pharmacological advancement of reduced side effects has been broadly accepted and well recognized. In this review, some of the ligands targeting both MOPr and DOPr or MOPr-DOPr heteromers are introduced especially focusing on their pharmacological effects in vivo. Conclusion: It has been found that most of those ligands possess potent antinociceptive activity (as much as or higher than that of morphine) with reduced side effects such as tolerance. In addition, some of them are also able to reduce or prevent physiological withdrawal symptoms observed under chronic opioid use. Importantly, there are an increasing number of evidence that show changes in heteromer expression in various pathological animal models and these strongly argue for targeting heteromers for the development of the next generation of pain medication in the near future.

A Compact Embodiment of Pluralities and Denial of Origins: Atwood’s The Year of The Flood

2016 ◽  
Vol 1 (3) ◽  
pp. 141
Author(s):  
Rana Sağıroğlu
Keyword(s):  
Science Fiction ◽  
21St Century ◽  
Social Order ◽  
Margaret Atwood ◽  
Rapid Change ◽  
The Novel ◽  
The World ◽  
Narrative Techniques ◽  
Why Questions ◽  
Near Future

Margaret Atwood, one of the most spectacular authors of postmodern movement, achieved to unite debatable and in demand critical points of 21st century such as science fiction, postmodernism and ecocriticism in the novel The Year of The Flood written in 2009. The novel could be regarded as an ecocritical manifesto and a dystopic mirror against today’s degenerated world, tending to a superficial base to keep the already order in use, by moving away from the fundamental solution of all humanity: nature. Although Atwood does not want her works to be called science fiction, it is obvious that science fiction plays an introductory role and gives the novel a ground explaining all ‘why’ questions of the novel. However, Atwood is not unjust while claiming that her works are not science fiction because of the inevitable rapid change of 21st century world becoming addicted to technology, especially Internet. It is easily observed by the reader that what she fictionalises throughout the novel is quite close to possibility, and the world may witness in the near future what she creates in the novel as science fiction. Additionally, postmodernism serves to the novel as the answerer of ‘how’ questions: How the world embraces pluralities, how heterogeneous social order is needed, and how impossible to run the world by dichotomies of patriarchal social order anymore. And lastly, ecocriticism gives the answers of ‘why’ questions of the novel: Why humanity is in chaos, why humanity has organized the world according to its own needs as if there were no living creatures apart from humanity. Therefore, The Year of The Flood meets the reader as a compact embodiment of science fiction, postmodernism and ecocriticism not only with its theme, but also with its narrative techniques.

scholarly journals An outline of SARS-CoV-2 pathogenesis and the complement cascade of immune system

2021 ◽  
Vol 45 (1) ◽  
Author(s):  
Padmalochan Hembram
Keyword(s):  
Immune System ◽  
Dark Side ◽  
Main Body ◽  
The Novel ◽  
Transmission Chain ◽  
The World ◽  
Therapeutic Molecules ◽  
Rapid Transmission ◽  
Novel Coronavirus ◽  
Near Future

Abstract Background Coronavirus disease 19 is a viral infection caused by a novel coronavirus, SARS-CoV-2. It was first notified in Wuhan, China, is now spread into numerous part of the world. Thus, the world needs urgent support and encouragement to develop a vaccine or antiviral treatments to combat the atrocious outbreak. Main body of the abstract The origin of this virus is yet unknown; however, rapid transmission from human-to-human “Anthroponosis” has widely confirmed. The world is witnessing a continuous hike in SARS-CoV-2 infection. In light of the outbreak of coronavirus disease 19, we have aimed to highlight the basic and vital information about the novel coronavirus. We provide an overview of SARS-CoV-2 transmission, timeline and its pathophysiological properties which would be an aid for the development of therapeutic molecules and antiviral drugs. Immune system plays a crucial role in virus infection in order to control but may have dark side when becomes uncontrollable. The host and SARS-CoV-2 interaction describe how the virus exploits host machinery and how overactive host immune response can cause disease severity also addressed in this review. Short conclusion Safe and effective vaccines may be the game-changing tools, but in the near future wearing mask, washing hands at regular intervals, avoiding crowed, maintaining physical distancing and hygienic surrounding, must be good practices to reduce and break the transmission chain. Still, research is ongoing not only on how vaccines protect against disease, but also against infection and transmission.

scholarly journals Kinase Inhibitors of DNA-PK, ATM and ATR in Combination with Ionizing Radiation Can Increase Tumor Cell Death in HNSCC Cells While Sparing Normal Tissue Cells

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 925
Author(s):  
Eva-Maria Faulhaber ◽  
Tina Jost ◽  
Julia Symank ◽  
Julian Scheper ◽  
Felix Bürkel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Side Effects ◽  
Ionizing Radiation ◽  
Cell Lines ◽  
Normal Tissue ◽  
Kinase Inhibitors ◽  
Induced Response ◽  
Tumor Control ◽  
Tumor Cell Death

(1) Kinase inhibitors (KI) targeting components of the DNA damage repair pathway are a promising new type of drug. Combining them with ionizing radiation therapy (IR), which is commonly used for treatment of head and neck tumors, could improve tumor control, but could also increase negative side effects on surrounding normal tissue. (2) The effect of KI of the DDR (ATMi: AZD0156; ATRi: VE-822, dual DNA-PKi/mTORi: CC-115) in combination with IR on HPV-positive and HPV-negative HNSCC and healthy skin cells was analyzed. Cell death and cell cycle arrest were determined using flow cytometry. Additionally, clonogenic survival and migration were analyzed. (3) Studied HNSCC cell lines reacted differently to DDRi. An increase in cell death for all of the malignant cells could be observed when combining IR and KI. Healthy fibroblasts were not affected by simultaneous treatment. Migration was partially impaired. Influence on the cell cycle varied between the cell lines and inhibitors; (4) In conclusion, a combination of DDRi with IR could be feasible for patients with HNSCC. Side effects on healthy cells are expected to be limited to normal radiation-induced response. Formation of metastases could be decreased because cell migration is impaired partially. The treatment outcome for HPV-negative tumors tends to be improved by combined treatment.

scholarly journals Targeting AKT/mTOR and Bcl-2 for Autophagic and Apoptosis Cell Death in Lung Cancer: Novel Activity of a Polyphenol Compound

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 534
Author(s):  
Sucharat Tungsukruthai ◽  
Onrapak Reamtong ◽  
Sittiruk Roytrakul ◽  
Suchada Sukrong ◽  
Chanida Vinayanwattikun ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Cancer Cells ◽  
Proteomic Analysis ◽  
Interaction Analysis ◽  
Time Dependent ◽  
The Novel ◽  
Protein Protein Interaction ◽  
Autophagy Induction ◽  
Acidic Vesicle

Autophagic cell death (ACD) is an alternative death mechanism in resistant malignant cancer cells. In this study, we demonstrated how polyphenol stilbene compound PE5 exhibits potent ACD-promoting activity in lung cancer cells that may offer an opportunity for novel cancer treatment. Cell death caused by PE5 was found to be concomitant with dramatic autophagy induction, as indicated by acidic vesicle staining, autophagosome, and the LC3 conversion. We further confirmed that the main death induction caused by PE5 was via ACD, since the co-treatment with an autophagy inhibitor could reverse PE5-mediated cell death. Furthermore, the defined mechanism of action and upstream regulatory signals were identified using proteomic analysis. Time-dependent proteomic analysis showed that PE5 affected 2142 and 1996 proteins after 12 and 24 h of treatment, respectively. The crosstalk network comprising 128 proteins that control apoptosis and 25 proteins involved in autophagy was identified. Protein–protein interaction analysis further indicated that the induction of ACD was via AKT/mTOR and Bcl-2 suppression. Western blot analysis confirmed that the active forms of AKT, mTOR, and Bcl-2 were decreased in PE5-treated cells. Taken together, we demonstrated the novel mechanism of PE5 in shifting autophagy toward cell death induction by targeting AKT/mTOR and Bcl-2 suppression.

scholarly journals Potentially Curative Therapeutic Activity of NEO212, a Perillyl Alcohol-Temozolomide Conjugate, in Preclinical Cytarabine-Resistant Models of Acute Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3385
Author(s):  
Axel H. Schönthal ◽  
Steve Swenson ◽  
Radu O. Minea ◽  
Hye Na Kim ◽  
Heeyeon Cho ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Side Effects ◽  
Anticancer Activity ◽  
Myeloid Leukemia ◽  
Perillyl Alcohol ◽  
Therapeutic Activity ◽  
Acute Myeloid

Despite progress in the treatment of acute myeloid leukemia (AML), the clinical outcome remains suboptimal and many patients are still dying from this disease. First-line treatment consists of chemotherapy, which typically includes cytarabine (AraC), either alone or in combination with anthracyclines, but drug resistance can develop and significantly worsen prognosis. Better treatments are needed. We are developing a novel anticancer compound, NEO212, that was created by covalent conjugation of two different molecules with already established anticancer activity, the alkylating agent temozolomide (TMZ) and the natural monoterpene perillyl alcohol (POH). We investigated the anticancer activity of NEO212 in several in vitro and in vivo models of AML. Human HL60 and U937 AML cell lines, as well as different AraC-resistant AML cell lines, were treated with NEO212 and effects on cell proliferation, cell cycle, and cell death were investigated. Mice with implanted AraC-sensitive or AraC-resistant AML cells were dosed with oral NEO212, and animal survival was monitored. Our in vitro experiments show that treatment of cells with NEO212 results in growth inhibition via potent G2 arrest, which is followed by apoptotic cell death. Intriguingly, NEO212 was equally potent in highly AraC-resistant cells. In vivo, NEO212 treatment strikingly extended survival of AML mice and the majority of treated mice continued to thrive and survive without any signs of illness. At the same time, we were unable to detect toxic side effects of NEO212 treatment. All in all, the absence of side effects, combined with striking therapeutic activity even in an AraC-resistant context, suggests that NEO212 should be developed further toward clinical testing.

scholarly journals Calcium Signaling in Plant Programmed Cell Death

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1089
Author(s):  
Huimin Ren ◽  
Xiaohong Zhao ◽  
Wenjie Li ◽  
Jamshaid Hussain ◽  
Guoning Qi ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Abiotic Stresses ◽  
Animal Studies ◽  
Future Research ◽  
Significant Progress ◽  
Biotic And Abiotic Stresses ◽  
Stress Perception ◽  
The Past

Programmed cell death (PCD) is a process intended for the maintenance of cellular homeostasis by eliminating old, damaged, or unwanted cells. In plants, PCD takes place during developmental processes and in response to biotic and abiotic stresses. In contrast to the field of animal studies, PCD is not well understood in plants. Calcium (Ca2+) is a universal cell signaling entity and regulates numerous physiological activities across all the kingdoms of life. The cytosolic increase in Ca2+ is a prerequisite for the induction of PCD in plants. Although over the past years, we have witnessed significant progress in understanding the role of Ca2+ in the regulation of PCD, it is still unclear how the upstream stress perception leads to the Ca2+ elevation and how the signal is further propagated to result in the onset of PCD. In this review article, we discuss recent advancements in the field, and compare the role of Ca2+ signaling in PCD in biotic and abiotic stresses. Moreover, we discuss the upstream and downstream components of Ca2+ signaling and its crosstalk with other signaling pathways in PCD. The review is expected to provide new insights into the role of Ca2+ signaling in PCD and to identify gaps for future research efforts.

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