Prevent Cell Death Research Articles

Poorly Differentiated Hepatocellular Carcinoma Cells Avoid Apoptosis by Interacting with T Cells via CD40–CD40 Ligand Linkage

Hepatocellular carcinoma (HCC) is associated with elevated soluble CD40 levels in our previous study. Here we aimed to investigate CD40's role in liver tumor progression. We examined CD40 levels in HCC patient tissues and various HCC cell lines, studying their interaction with CD4+T cells. RNA sequencing analysis was performed to explore the mechanisms of CD40 induction. Poorly differentiated HCC tumour tissues exhibited high membrane-bound CD40 (mCD40) expression, in contrast to non-tumour areas. Poorly differentiated HCC cell lines showed high expression of mCD40 with low CD40 promoter methylation which were opposite of well-differentiated ones. Solely modulating CD40 expression in HCC cells exerted no direct consequences on cell growth or appearance. Interestingly, HLFs co-cultured with activated (CD40L+) CD4+ T cells elevated CD40 levels and showed a modest 3.2% of dead cells, then increased to 10.9% underwent pre-neutralizing CD40 condition, while pre-blocking both CD40 and Integrin α5β1 concomitantly caused only 1.9% of cell death. RNA sequencing of co-cultured HLFs with activated CD4+ T cells revealed the upregulation of interferon (IFN) and immune response pathways. Elevated IFN-γ levels in the activated T cell media stimulated the JAK1/STAT3 pathway, resulting in increased CD40 expression in HLF. Collectively, CD40 expression in poorly differentiated HCC cells prevents cell death by interacting with CD40L in activated T cells. Targeting CD40 may represent a promising anticancer therapy.

Mitochondrial P-JNK target, SAB (SH3BP5), in regulation of cell death.

Cell death occurs in various circumstances, such as homeostasis, stress response, and defense, via specific pathways and mechanisms that are regulated by specific activator-induced signal transductions. Among them, Jun N-terminal kinases (JNKs) participate in various aspects, and the recent discovery of JNKs and mitochondrial protein SAB interaction in signal regulation of cell death completes our understanding of the mechanism of sustained activation of JNK (P-JNK), which leads to triggering of the machinery of cell death. This understanding will lead the investigators to discover the modulators facilitating or preventing cell death for therapeutic application in acute or chronic diseases and cancer. We discuss here the mechanism and modulators of the JNK-SAB-ROS activation loop, which is the core component of mitochondria-dependent cell death, specifically apoptosis and mitochondrial permeability transition (MPT)-driven necrosis, and which may also contribute to cell death mechanisms of ferroptosis and pyroptosis. The discussion here is based on the results and evidence discovered from liver disease models, but the JNK-SAB-ROS activation loop to sustain JNK activation is universally applicable to various disease models where mitochondria and reactive oxygen species contribute to the mechanism of disease.

KSRP improves pancreatic beta cell function and survival

Impaired insulin production and/or secretion by pancreatic beta cells can lead to high blood glucose levels and type 2 diabetes (T2D). Therefore, investigating new proteins involved in beta cell response to stress conditions could be useful in finding new targets for therapeutic approaches. KH-type splicing regulatory protein (KSRP) is a protein usually involved in gene expression due to its role in post-transcriptional regulation. Although there are studies describing the important role of KSRP in tissues closely related to glucose homeostasis, its effect on pancreatic beta cells has not been explored so far. Pancreatic islets from diet-induced obese mice (C57BL/6JUnib) were used to determine KSRP expression and we also performed in vitro experiments exposing INS-1E cells (pancreatic beta cell line) to different stressors (palmitate or cyclopiazonic acid—CPA) to induce cellular dysfunction. Here we show that KSRP expression is reduced in all the beta cell dysfunction models tested. In addition, when manipulated to knock down KSRP, beta cells exhibited increased death and impaired insulin secretion, whereas KSRP overexpression prevented cell death and increased insulin secretion. Taken together, our findings suggest that KSRP could be an important target to protect beta cells from impaired functioning and death.

Medicinal herbal remedies in neurodegenerative diseases: an update on antioxidant potential.

It has been widely documented that medicinal herbal remedies are effective, have fewer side effects than conventional medicine, and have a synergistic effect on health collaborations in the fight against complicated diseases. Traditional treatments for neurological problems in ancient times sometimes involved the use of herbal remedies and conventional methods from East Asian countries including India, Japan, China, and Korea. We collected and reviewed studies on plant-derived neuroprotective drugs and tested them in neurotoxic models. Basic research, preclinical and clinical transgene research can benefit from in silico, in vitro, and in vivo investigations. Research, summaries of the extracts, fractions, and herbal ingredients were compiled from popular scientific databases, which were then examined according to origin and bioactivity. Given the complex and varied causes of neurodegeneration, it may be beneficial to focus on multiple mechanisms of action and a neuroprotection approach. This approach aims to prevent cell death and restore function to damaged neurons, offering promising strategies for preventing and treating neurodegenerative diseases. Neurodegenerative illnesses can potentially be treated with natural compounds that have been identified as neuroprotective agents. To gain deeper insights into the neuropharmacological mechanisms underlying the neuroprotective and therapeutic properties of naturally occurring antioxidant phytochemical compounds in diverse neurodegenerative diseases, this study aims to comprehensively review such compounds, focusing on their modulation of apoptotic markers such as caspase, Bax, Bcl-2, and proinflammatory markers. In addition, we delve into a range of efficacies of antioxidant phytochemical compounds as neuroprotective agents in animal models. They reduce the oxidative stress of the brain and have been shown to have anti-apoptotic effects. Many researches have demonstrated that plant extracts or bioactive compounds can fight neurodegenerative disorders. Herbal medications may offer neurodegenerative disease patients' new treatments. This may be a cheaper and more culturally appropriate alternative to standard drugs for millions of people with age-related NDDs.

THE EFFECT OF NEUROTRANSMITTERS ON PROGRAMMED CELL DEATH AND FORMATION OF REACTIVE OXYGEN SPECIES IN THE EPIDERMIS OF PEA LEAVES

Neurotransmitters are found not only in animals, but also in other living organisms, including plants. They are found in other living organisms, including plants. However, the data on the functions of these compounds in the plant world are far from being comprehensive. In particular, the issue concerning their impact on plant cell death still awaits further research. In the present work, the effects of neurotransmitters on programmed cell death and the formation of reactive oxygen species (ROS) in plants were tested. Programmed cell death was estimated from the destruction of cell nuclei, and ROS was determined using 2ʹ,7ʹ-dichlorofluorescein. Dopamine, norepinephrine, serotonin, histamine, acetylcholine and its synthetic analog acetylthiocholine were used. The catecholamines dopamine and norepinephrine at concentrations of 0.01-1 mM suppressed the destruction of guard cell nuclei in the epidermis of pea leaves, which was caused by KCN. Serotonin and acetylcholine at a concentration of 1-3 mM, on the contrary, increased the destruction of nuclei that was induced by KCN. Histamine and acetylthiocholine had no effect on KCN-dependent destruction of nuclei at concentrations of 0.01-3 mM. Acetylthiocholine at a concentration of 3 mM, in contrast to natural neurotransmitters, caused the destruction of guard cell nuclei in the absence of KCN. Dopamine, norepinephrine, and serotonin reduced the formation of ROS in the epidermis of pea leaves, which was induced by menadione. Histamine, acetylcholine and acetylthiocholine did not have a similar effect. The results demonstrate that dopamine, norepinephrine and serotonin have antioxidant properties in plants. In addition, dopamine and norepinephrine can prevent cell death.

Neutral Sphingomyelinase 2 Inhibition Limits Hepatic Steatosis and Inflammation.

Non-alcoholic fatty liver disease (NAFLD) is manifested by hepatic steatosis, insulin resistance, hepatocyte death, and systemic inflammation. Obesity induces steatosis and chronic inflammation in the liver. However, the precise mechanism underlying hepatic steatosis in the setting of obesity remains unclear. Here, we report studies that address this question. After 14 weeks on a high-fat diet (HFD) with high sucrose, C57BL/6 mice revealed a phenotype of liver steatosis. Transcriptional profiling analysis of the liver tissues was performed using RNA sequencing (RNA-seq). Our RNA-seq data revealed 692 differentially expressed genes involved in processes of lipid metabolism, oxidative stress, immune responses, and cell proliferation. Notably, the gene encoding neutral sphingomyelinase, SMPD3, was predominantly upregulated in the liver tissues of the mice displaying a phenotype of steatosis. Moreover, nSMase2 activity was elevated in these tissues of the liver. Pharmacological and genetic inhibition of nSMase2 prevented intracellular lipid accumulation and TNFα-induced inflammation in in-vitro HepG2-steatosis cellular model. Furthermore, nSMase2 inhibition ameliorates oxidative damage by rescuing PPARα and preventing cell death associated with high glucose/oleic acid-induced fat accumulation in HepG2 cells. Collectively, our findings highlight the prominent role of nSMase2 in hepatic steatosis, which could serve as a potential therapeutic target for NAFLD and other hepatic steatosis-linked disorders.

Lycopene prevents cell death in NRK-52E cells by inhibition of high glucose-activated DNA damage and apoptotic, autophagic, and necrotic pathways.

This study aims to investigate the effects of lycopene on apoptotic, autophagic, and necrotic pathways, oxidative status, and DNA damage in diabetic nephropathy at the molecular level. The sample of the study includes seven groups: lycopene (L), high glucose (G), high glucose + lycopene (GL), and control (C) groups tested at 12 and 24 h. The expression levels of genes in oxidative, apoptotic, autophagic, and necrotic cell death pathways are determined by reverse transcription-quantitative polymerase chain reaction analysis. The comet assay method is used for the analysis of DNA damage. It is observed that adding lycopene to high glucose for protective purposes reduces the expression of genes related to apoptosis, autophagy, and necrosis, as well as the DNA damage index, compared to cells given high glucose alone. Lycopene can be a safe and effective alternative agent.

The dysregulated autophagy in osteoarthritis: Revisiting molecular profile

The risk factors of osteoarthritis (OA) are different and obesity, lifestyle, inflammation, cell death mechanisms and diabetes mellitus are among them. The changes in the biological mechanisms are considered as main regulators of OA pathogenesis. The dysregulation of autophagy is observed in different human diseases. During the pathogenesis of OA, the autophagy levels (induction or inhibition) change. The supportive and pro-survival function of autophagy can retard the progression of OA. The protective autophagy prevents the cartilage degeneration. Moreover, autophagy demonstrates interactions with cell death mechanisms and through inhibition of apoptosis and necroptosis, it improves OA. The non-coding RNA molecules can regulate autophagy and through direct and indirect control of autophagy, they dually delay/increase OA pathogenesis. The mitochondrial integrity can be regulated by autophagy to alleviate OA. Furthermore, therapeutic compounds, especially phytochemicals, stimulate protective autophagy in chondrocytes to prevent cell death. The protective autophagy has ability of reducing inflammation and oxidative damage, as two key players in the pathogenesis of OA.

Oligodendrocyte Maturation Alters the Cell Death Mechanisms That Cause Demyelination.

Myelinating oligodendrocytes die in human disease and early in aging. Despite this, the mechanisms that underly oligodendrocyte death are not resolved and it is also not clear whether these mechanisms change as oligodendrocyte lineage cells are undergoing differentiation and maturation. Here, we used a combination of intravital imaging, single-cell ablation, and cuprizone-mediated demyelination, in both female and male mice, to discover that oligodendrocyte maturation dictates the dynamics and mechanisms of cell death. After single-cell phototoxic damage, oligodendrocyte precursor cells underwent programmed cell death within hours, differentiating oligodendrocytes died over several days, while mature oligodendrocytes took weeks to die. Importantly cells at each maturation stage all eventually died but did so with drastically different temporal dynamics and morphological features. Consistent with this, cuprizone treatment initiated a caspase-3-dependent form of rapid cell death in differentiating oligodendrocytes, while mature oligodendrocytes never activated this executioner caspase. Instead, mature oligodendrocytes exhibited delayed cell death which was marked by DNA damage and disruption in poly-ADP-ribose subcellular localization. Thus, oligodendrocyte maturation plays a key role in determining the mechanism of death a cell undergoes in response to the same insult. This means that oligodendrocyte maturation is important to consider when designing strategies for preventing cell death and preserving myelin while also enhancing the survival of new oligodendrocytes in demyelinating conditions.

Nitric oxide acts upstream of indole-3-acetic acid in ameliorating arsenate stress in tomato seedlings

After their discovery, nitric oxide (NO) and indole-3-acetic acid (IAA) have been reported as game-changing cellular messengers for reducing abiotic stresses in plants. But, information regarding their shared signaling in regulating metal stress is still unclear. Herein, we have investigated about the joint role of NO and IAA in mitigation of arsenate [As(V)] toxicity in tomato seedlings. Arsenate being a toxic metalloid increases the NPQ level and cell death while decreasing the biomass accumulation, photosynthetic pigments, chlorophyll a fluorescence, endogenous NO content in tomato seedlings. However, application of IAA or SNP to the As(V) stressed seedlings improved growth together with less accumulation of arsenic and thus, preventing cell death. Interestingly, addition of c-PTIO, {2-(4-carboxyphenyl)-4, 4, 5, 5-tetramethylimidazoline-1-oxyl-3-oxide, a scavenger of NO} and 2, 3, 5-triidobenzoic acid (TIBA, an inhibitor of polar auxin transport) further increased cell death and inhibited activity of GST, leading to As(V) toxicity. However, addition of IAA to SNP and TIBA treated seedlings reversed the effect of TIBA resulting into decreased As(V) toxicity. These findings demonstrate that IAA plays a crucial and advantageous function in NO-mediated reduction of As(V) toxicity in seedlings of tomato. Overall, this study concluded that IAA might be acting as a downstream signal for NO-mediated reduction of As(V) toxicity in tomato seedlings.

Butylated Hydroxytoluene (BHT) Protects SH-SY5Y Neuroblastoma Cells from Ferroptotic Cell Death: Insights from In Vitro and In Vivo Studies.

Ferroptosis is a special kind of programmed cell death that has been implicated in the pathogenesis of a large number of human diseases. It involves dysregulated intracellular iron metabolism and uncontrolled lipid peroxidation, which together initiate intracellular ferroptotic signalling pathways leading to cellular suicide. Pharmacological interference with ferroptotic signal transduction may prevent cell death, and thus patients suffering from ferroptosis-related diseases may benefit from such treatment. Butylated hydroxytoluene (BHT) is an effective anti-oxidant that is frequently used in oil chemistry and in cosmetics to prevent free-radical-mediated lipid peroxidation. Since it functions as a radical scavenger, it has previously been reported to interfere with ferroptotic signalling. Here, we show that BHT prevents RSL3- and ML162-induced ferroptotic cell death in cultured human neuroblastoma cells (SH-SY5Y) in a dose-dependent manner. It prevents the RSL3-induced oxidation of membrane lipids and normalises the RSL3-induced inhibition of the intracellular catalytic activity of glutathione peroxidase 4. The systemic application of BHT in a rat Alzheimer's disease model prevented the upregulation of the expression of ferroptosis-related genes. Taken together, these data indicate that BHT interferes with ferroptotic signalling in cultured neuroblastoma cells and may prevent ferroptotic cell death in an animal Alzheimer's disease model.

A58 UTILIZATION OF HYPOXIA-TOLERANT ORGANISMS AS A MODEL IN THE STUDY OF ISCHEMIC-REPERFUSION INJURY IN TRANSPLANT HEPATOLOGY

Abstract Background Ischemic-reperfusion injury (IRI) is a barrier to successful liver transplantation. This complex process is initiated by an episode of hypoxia and decreased adenosine triphosphate (ATP) production. Mammalian hepatocytes are susceptible to prolonged hypoxia and may experience irreversible damage with ATP depletion. Yet, facultative anaerobes have developed physiological hepatoprotective strategies to tolerate hypoxic stress. The painted turtle (Chrysemys picta belli) and the common goldfish (Carassius auratus) are able to survive under severe hypoxia for weeks to months. Aims Introducing hypoxia-tolerant organisms as a suitable animal model for studying IRI in transplant hepatology. Methods A comprehensive search of PubMed, OVID, CINAHL, and Cochrane databases up to May 2023 was conducted to identify all studies reporting experimental evidence and hepatoprotective pathways in hypoxia-tolerant organisms (HTOs). Each article was qualitatively assessed. The primary focus was on cell death, intracellular ion gradient, mitochondrial function, and reactive oxygen species (ROS) with hypoxia and IRI. Results HTOs have increased glycogen storage with a greater ATP yield from anaerobic metabolism (glycolysis). Approximately 15-30% of liver mass in HTOs is composed of glycogen which is massive compared to 5-6% in mammals. Turtle isolated hepatocytes can tolerate 10 hours of anoxia by reducing cellular metabolic demand by 90% through decreased protein synthesis and ion channel activity. Goldfish hepatocytes can tolerate 6 hours of anoxia via similar strategies. In mammals, mitochondria undergo depolarization, Ca2+ efflux, cellular swelling, and apoptosis with anoxia. Yet, a depolarized mitochondrial membrane potential is regulated to provide cellular protection in HTOs. The ability to preserve mitochondrial function and electrochemical gradients with oxygen lack is an important contributor to cellular survival. Even in mammalian hepatocytes, if the mitochondrial integrity is maintained, cells are better able to tolerate ischemic insults. Finally, formation of radicals with reperfusion leads to hepatocyte apoptosis and necrosis in the mammalian model. Meanwhile, regulated ROS levels in turtles and goldfish cells, prevent cell death and IRI. Conclusions IRI is of significant interest in transplant hepatology. Although extremely valuable, the traditional mammalian models are vulnerable to hypoxia. Meanwhile, HTOs have undergone years of adaptation with thousands of genes dedicated to hypoxia tolerance. Utilizing these organisms can provide a broader understanding of IRI and avoid irreversible tissue damage in transplant hepatology. Funding Agencies CIHR

Diabetic Cardiomyopathy and Cell Death: Focus on Metal-Mediated Cell Death.

Cardiac myocyte death is an essential initiator of the pathogenesis and progression of various etiological cardiomyopathies, including diabetic cardiomyopathy (DCM), a disease that has been reported since 1972. Cardiac cell death has been detected in the hearts of patients with diabetes and in animal models, and the role of cell death in the pathogenesis of DCM has been extensively investigated. The first review by the authors, specifically focusing on "Cell death and diabetic cardiomyopathy," was published in the journal, Cardiovascular Toxicology in 2003. Over the past two decades, studies investigating the role of cardiac cell death in the pathogenesis of DCM have gained significant attention, resulting in the discovery of several new kinds of cell death involving different mechanisms, including apoptosis, necroptosis, pyroptosis, autophagy, ferroptosis, and cuproptosis. After the 20th anniversary of the review published in 2003, we now provide an update with a focus on the potential role of metal-mediated cell death, ferroptosis, and cuproptosis in the development of DCM in compliance with this special issue. The intent of our review is to further stimulate work in the field to advance the body of knowledge and continue to drive efforts to develop more advanced therapeutic approaches to prevent cell death, particularly metal-dependent cell death, and, ultimately, to reduce or prevent the development of DCM.

Advances in lung ischemia/reperfusion injury: unraveling the role of innate immunity.

Lung ischemia/reperfusion injury (LIRI) is a common occurrence in clinical practice and represents a significant complication following pulmonary transplantation and various diseases. At the core of pulmonary ischemia/reperfusion injury lies sterile inflammation, where the innate immune response plays a pivotal role. This review aims to investigate recent advancements in comprehending the role of innate immunity in LIRI. A computer-based online search was performed using the PubMed database and Web of Science database for published articles concerning lung ischemia/reperfusion injury, cell death, damage-associated molecular pattern molecules (DAMPs), innate immune cells, innate immunity, inflammation. During the process of lung ischemia/reperfusion, cellular injury even death can occur. When cells are injured or undergo cell death, endogenous ligands known as DAMPs are released. These molecules can be recognized and bound by pattern recognition receptors (PRRs), leading to the recruitment and activation of innate immune cells. Subsequently, a cascade of inflammatory responses is triggered, ultimately exacerbating pulmonary injury. These steps are complex and interrelated rather than being in a linear relationship. In recent years, significant progress has been made in understanding the immunological mechanisms of LIRI, involving novel types of cell death, the ability of receptors other than PRRs to recognize DAMPs, and a more detailed mechanism of action of innate immune cells in ischemia/reperfusion injury (IRI), laying the groundwork for the development of novel diagnostic and therapeutic approaches. Various immune components of the innate immune system play critical roles in lung injury after ischemia/reperfusion. Preventing cell death and the release of DAMPs, interrupting DAMPs receptor interactions, disrupting intracellular inflammatory signaling pathways, and minimizing immune cell recruitment are essential for lung protection in LIRI.

Computational analysis of bevacizumab binding with protein receptors for its potential anticancer activity

Breast cancer poses a significant global challenge, prompting researchers to explore novel approaches for potential treatments. In this study, we investigated the binding free energy (ΔG) of bevacizumab, an anti-cancer therapy targeting angiogenesis through the inhibition of vascular endothelial growth factor (VEGF), with various proto-oncogenes including CDK4, EGFR, frizzled, IGFR, OmoMYC, and KIT. Our in-silico investigation revealed that hydrogen bonding is pivotal in inducing conformational changes within the DNA structure, impeding its replication and preventing cell death. Molecular docking results revealed the presence of crucial hydrogen bonds and supported the formation of stable bevacizumab complexes. The molecular docking scores for the tested complexes were CDK4 (Score = −7.2 kcal/mol), EGFR (Score = −8.5 kcal/mol), frizzled (Score = −6.9 kcal/mol), IGFR (Score = −7.8 kcal/mol), KIT (Score = −6.5 kcal/mol), and MYC (Score = −8.3 kcal/mol). The binding mode demonstrated vital hydrogen bonds correlated with the observed energy gap. Notably, the calculated binding free energies of the tested compounds are as follows: CDK4 (ΔG = 24275.195 ± 6411.293 kJ/mol), EGFR (ΔG = 363273.625 ± 8731.466 kJ/mol), frizzled (ΔG = 181751.990 ± 28438.515 kJ/mol), IGFR (ΔG = 162414.725 ± 10728.367 kJ/mol), KIT (ΔG = 40162.585 ± 4331.017 kJ/mol), and MYC (ΔG = 434783.463 ± 53989.676 kJ/mol). Furthermore, through extensive 100 ns MD simulations, we observed the formation of a stable bevacizumab complex structure. The simulations confirmed the stability of the bevacizumab complex with the proto-oncogenes. The results of this study highlight the potential of bevacizumab complex as a promising candidate for anticancer treatment. The identification of hydrogen bonding, along with the calculated binding free energies and molecular docking scores, provides valuable insights into the molecular interactions and stability of the bevacizumab complexes. These findings and the extensive MD simulations open new avenues for future research and development of bevacizumab as a targeted therapy for breast cancer and other related malignancies. Communicated by Ramaswamy H. Sarma

Impaired Expression of Humanin during Adrenocortical Carcinoma.

The discovery of mitochondria-derived peptides (MDPs) has provided a new perspective on mitochondrial function. MDPs encoded by mitochondrial DNA (mtDNA) can act as hormone-like peptides, influencing cell survival and proliferation. Among these peptides, humanin has been identified as a crucial factor for maintaining cell survival and preventing cell death under various conditions. Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy that results from adrenal hormone dysfunction. This study aimed to investigate humanin expression in the adrenal tissue and serum of patients with ACC. For the first time, our study revealed significant reduction in the mRNA expression of humanin in patients with ACC compared to healthy controls. However, no significant changes were observed in the serum humanin levels. Interestingly, we identified a positive correlation between patient age and serum humanin levels and a negative correlation between tumor size and LDL levels. While the impaired expression of humanin in patients with ACC may be attributed to mitochondrial dysfunction, an alternative explanation could be related to diminished mitochondrial copy number. Further investigations are warranted to elucidate the intricate relationship among humanin, mitochondrial function, and ACC pathology.

Development of a mouse model expressing a bifunctional glutathione-synthesizing enzyme to study glutathione limitation in vivo

Glutathione (GSH) is a highly abundant tripeptide thiol that performs diverse protective and biosynthetic functions in cells. While changes in GSH availability are associated with inborn errors of metabolism, cancer and neurodegenerative disorders, studying the limiting role of GSH in physiology and disease has been challenging due to its tight regulation. To address this, we generated cell and mouse models that express a bifunctional glutathione-synthesizing enzyme from Streptococcus thermophilus (GshF), which possesses both glutamate-cysteine ligase and glutathione synthase activities. GshF expression allows efficient production of GSH in the cytosol and mitochondria and prevents cell death in response to GSH depletion, but not ferroptosis induction, indicating that GSH is not a limiting factor under lipid peroxidation. CRISPR screens using engineered enzymes further revealed genes required for cell proliferation under cellular and mitochondrial GSH depletion. Among these, we identified the glutamate-cysteine ligase modifier subunit, Gclm, as a requirement for cellular sensitivity to buthionine sulfoximne, a glutathione synthesis inhibitor. Finally, GshF expression in mice is embryonically lethal but sustains postnatal viability when restricted to adulthood. Overall, our work identifies a conditional mouse model to investigate the limiting role of GSH in physiology and disease.

IKKε and TBK1 prevent RIPK1 dependent and independent inflammation.

TBK1 and IKKε regulate multiple cellular processes including anti-viral type-I interferon responses, metabolism and TNF receptor signaling. However, the relative contributions and potentially redundant functions of IKKε and TBK1 in cell death, inflammation and tissue homeostasis remain poorly understood. Here we show that IKKε compensates for the loss of TBK1 kinase activity to prevent RIPK1-dependent and -independent inflammation in mice. Combined inhibition of IKKε and TBK1 kinase activities caused embryonic lethality that was rescued by heterozygous expression of kinase-inactive RIPK1. Adult mice expressing kinase-inactive versions of IKKε and TBK1 developed systemic inflammation that was induced by both RIPK1-dependent and -independent mechanisms. Combined inhibition of IKKε and TBK1 kinase activities in myeloid cells induced RIPK1-dependent cell death and systemic inflammation mediated by IL-1 family cytokines. Tissue-specific studies showed that IKKε and TBK1 were required to prevent cell death and inflammation in the intestine but were dispensable for liver and skin homeostasis. Together, these findings revealed that IKKε and TBK1 exhibit tissue-specific functions that are important to prevent cell death and inflammation and maintain tissue homeostasis.

Medicinal potential of embelin and its nanoformulations: An update on the molecular mechanism and various applications.

Natural herbs have garnered significant research recently as their components target multiple disease signaling pathways, making them highly potential for various disease prevention and treatment. Embelin, a naturally occurring benzoquinone isolated from Embelia ribes, has shown promising biological activities such as antitumor, antidiabetic, anti-oxidant, and antimicrobial. Various mechanisms have been reported, including monitoring genes that synchronize the cell cycle, up-regulating multiple anti-oxidant enzymes, suppressing genes that prevent cell death, influencing transcription factors, and preventing inflammatory biomarkers. However, the hydrophobic nature of embelin leads to poor absorption and limits its therapeutic potential. This review highlights a wide range of nanocarriers used as delivery systems for embelin, including polymeric nanoparticles, liposomes, nanostructured lipid carriers, micelles, nanoemulsion, and metallic nanoparticles. These embelin nanomedicine formulations have been developed in preclinical studies as a possible treatment for many disorders and characterized using various in vitro, ex vivo, and in vivo models.

Nrf2 in human cancers: biological significance and therapeutic potential.

The nuclear factor-erythroid 2-related factor 2 (Nrf2) is able to control the redox balance in the cells responding to oxidative damage and other stress signals. The Nrf2 upregulation can elevate the levels of antioxidant enzymes to support against damage and death. In spite of protective function of Nrf2 in the physiological conditions, the stimulation of Nrf2 in the cancer has been in favour of tumorigenesis. Since the dysregulation of molecular pathways and mutations/deletions are common in tumors, Nrf2 can be a promising therapeutic target. The Nrf2 overexpression can prevent cell death in tumor and by increasing the survival rate of cancer cells, ensures the carcinogenesis. Moreover, the induction of Nrf2 can promote the invasion and metastasis of tumor cells. The Nrf2 upregulation stimulates EMT to increase cancer metastasis. Furthermore, regarding the protective function of Nrf2, its stimulation triggers chemoresistance. The natural products can regulate Nrf2 in the cancer therapy and reverse drug resistance. Moreover, nanostructures can specifically target Nrf2 signaling in cancer therapy. The current review discusses the potential function of Nrf2 in the proliferation, metastasis and drug resistance. Then, the capacity of natural products and nanostructures for suppressing Nrf2-mediated cancer progression is discussed.