Cell Death Signaling Pathways Research Articles

PD02-08 ESR1+ LUMINAL EPITHELIAL CELLS DRIVE THE PROSTATE GROWTH AND SURVIVAL IN THE ABSENCE OF SRD5A2

You have accessJournal of UrologyCME1 Apr 2023PD02-08 ESR1+ LUMINAL EPITHELIAL CELLS DRIVE THE PROSTATE GROWTH AND SURVIVAL IN THE ABSENCE OF SRD5A2 Christina Sharkey, Xingbo Long, Ra'ad Al-Faouri, Aria F. Olumi, and Zongwei Wang Christina SharkeyChristina Sharkey More articles by this author , Xingbo LongXingbo Long More articles by this author , Ra'ad Al-FaouriRa'ad Al-Faouri More articles by this author , Aria F. OlumiAria F. Olumi More articles by this author , and Zongwei WangZongwei Wang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003219.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Steroid 5α reductase 2 (SRD5A2) is the predominant enzyme responsible for prostatic development and growth. 5α reductase inhibitors (5ARI) are the only class of benign prostate hyperplasia-related medications that reduce prostate size. However, why the patients respond variably to 5ARI therapies is still largely unknown. We previously demonstrated that 30% of adult human prostatic tissues do not express the SRD5A2 gene and protein via epigenetic modifications. We established a SRD5A2 null (Srd5a2-/-) mouse model and through single cell RNA sequencing, we identified LE2, a sub-cell population of ESR1+ luminal epithelial that is upregulated in Srd5a2-/- mice. Our goal in this study is to characterize the spatial expression of LE2 markers and its functional phenotype when SRD5A2 is absent. METHODS: Homozygous Srd5a2-/- mice and littermate control heterozygous SRD5A2+/- mice were generated and differentially expressed gene profiles of LE2 were obtained from single-cell RNA sequencing (scRNA seq). Spatial expression of LE2 markers was evaluated by RNA fluorescence in-situ hybridization (RNA-FISH). Cell proliferation was detected by Ki67 and BrdU staining. The Cell Death and ER signaling pathways were evaluated with RT2 PCR profiler arrays (84 genes per array) and downstream signaling pathways were analyzed by western blot. Prostate biopsies from the clinical trial of 5ARI for Medical Therapy of Prostatic Symptoms (MTOPS) were used for immunohistochemistry. RESULTS: The prostate weight of Srd5a2-/- mice was significantly decreased compared to Srd5a2+/- littermate control mice (p<0.001). The prostate cell proliferation was suppressed in Srd5a2-/- mice (p=0.05). The cell death signaling akt1, caspase 7, caspase 9, and ER target genes cyp1a1 and vegfa were downregulated (p<0.05). On the other hand, in the anterior lobe of prostate of Srd5a2-/- mice, the cell proliferation was higher than that in control. scRNA seq showed that ESR1 was expressed mainly in the prostate anterior lobe and the number of ESR1+ LE2 cells was significantly increased upon SRD5A2 absence. This was confirmed by RNA-FISH using the probes of LE2 cell markers ESR1 and PVT1. Co-staining of LE2 cell markers ESR1 and PKCa in prostate biopsies of MTOPS further confirmed the existence of an equivalent LE2 cell population in the human prostate with BPH. CONCLUSIONS: Our data demonstrate that LE2, the subpopulation of prostate cells may play an important role in alternative pathways for prostate growth and survival in absence of SRD5A2 and androgen deprivation. Understanding the underlying androgen-independent pathways contributing to prostate growth can help identify novel therapeutic targets for the management of prostatic diseases. Source of Funding: NIH/R01 DK124502 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e71 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christina Sharkey More articles by this author Xingbo Long More articles by this author Ra'ad Al-Faouri More articles by this author Aria F. Olumi More articles by this author Zongwei Wang More articles by this author Expand All Advertisement PDF downloadLoading ...

Targeting ER Stress with Saikosaponin A to Overcome Resistance under Radiation in Gastric Cancer Cells

Saikosaponin A is a triterpene saponin and a potentially bioactive compound derived from Bupleurum falcatum L. However, the molecular mechanisms and effects of saikosaponin A in gastric cancer remain unknown. In the present study, I evaluated the effects of saikosaponin A on cell death and endoplasmic reticulum stress via calcium and reactive oxygen species release. Targeting reactive oxygen species with diphenyleneiodonium and N-acetylcysteine inhibited cell death and protein kinase RNA-like ER kinase signaling pathway by down-regulating Nox4 and inducing glucose-regulated protein 78 exosomes. Furthermore, saikosaponin A caused a synergistic inhibitory effect of the epithelial mesenchymal transition phenomenon, indicating the reversible phenotype modulation by epithelial cells under radiation exposure in radiation-resistant gastric cancer cells. These results suggest that saikosaponin A-mediated calcium and reactive oxygen species-induced endoplasmic reticulum stress overcome radio-resistance and induce cell death under radiation in gastric cancer cells. Therefore, saikosaponin A in combination with radiation may be a potential strategy for gastric cancer therapy.

Tumor Necrosis Factor-Alpha/Tumor Necrosis Factor-Alpha Receptor 1 Signaling Pathway Leads to Thymocytes' Cell Death by Necroptosis in a Mouse Model of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is characterized by an increased proliferation and loss of differentiation of hematopoietic myeloid progenitors or precursors. Studies performed in AML-affected patients revealed a T cell deficiency characterized by a reduced thymic output and peripheral functional abnormalities. To assess for the thymus function during AML, we used an AML mouse model and showed a drastic thymic atrophy. We observed a massive loss among double (CD4+CD8+- DP) and single positive (CD4+/8+- SP) thymocytes. We assessed for the expression of different actors of cell death signalling pathways by RT-qPCR or Western blotting. When comparing leukemic to control mice, there was a significant increase in the expression of Mlkl gene, phosphorylated MLKL and RIPK3 proteins, and tumor necrosis factor (TNF)-alpha receptors 1 on DP and SP thymocytes. These findings revealed a necroptosis cell death which was also observed in vitro when using cultured wild-type thymocytes and recombinant TNF-alpha protein. Thus, we demonstrated that TNF-alpha plays a deleterious role in thymic function during AML by contributing to extensive thymocytes' death.

Different Ways to Die: Cell Death Pathways and Their Association With Spinal Cord Injury.

Cell death is a systematic/nonsystematic process of cessation of normal morphology and functional properties of the cell to replace and recycle old cells with new also promoting inflammation in some cases. It is a complicated process comprising multiple pathways. Some are well-explored, and others have just begun to be. The research on appropriate control of cell death pathways after acute and chronic damage of neuronal cells is being widely researched today due to the lack of regeneration and recovering potential of a neuronal cell after sustaining damage and the inability to control the direction of neuronal growth. In the progression and onset of various neurological diseases, impairments in programmed cell death signaling processes, like necroptosis, apoptosis, ferroptosis, pyroptosis, and pathways directly or indirectly linked, like autophagy as in nonprogrammed necrosis, are observed. Spinal cord injury (SCI) involves the temporary or permanent disruption of motor activities due to the death of a neuronal and glial cell in the spinal cord accompanied by axonal degeneration. Recent years have seen a significant increase in research on the intricate biochemical interactions that occur after a SCI. Different cell death pathways may significantly impact the subsequent damage processes that lead to the eventual neurological deficiency after an injury to the spinal cord. A better knowledge of the molecular basis of the involved cell death pathways might help enhance neuronal and glial survival and neurological deficits, promoting a curative path for SCI.

Transcriptome Analysis of Retinal and Choroidal Pathologies in Aged BALB/c Mice Following Systemic Neonatal Murine Cytomegalovirus Infection.

Our previous studies have shown that systemic neonatal murine cytomegalovirus (MCMV) infection of BALB/c mice spread to the eye with subsequent establishment of latency in choroid/RPE. In this study, RNA sequencing (RNA-Seq) analysis was used to determine the molecular genetic changes and pathways affected by ocular MCMV latency. MCMV (50 pfu per mouse) or medium as control were injected intra-peritoneally (i.p.) into BALB/c mice at <3 days after birth. At 18 months post injection, the mice were euthanized, and the eyes were collected and prepared for RNA-Seq. Compared to three uninfected control eyes, we identified 321 differentially expressed genes (DEGs) in six infected eyes. Using the QIAGEN Ingenuity Pathway Analysis (QIAGEN IPA), we identified 17 affected canonical pathways, 10 of which function in neuroretinal signaling, with the majority of DEGs being downregulated, while 7 pathways function in upregulated immune/inflammatory responses. Retinal and epithelial cell death pathways involving both apoptosis and necroptosis were also activated. MCMV ocular latency is associated with upregulation of immune and inflammatory responses and downregulation of multiple neuroretinal signaling pathways. Cell death signaling pathways are also activated and contribute to the degeneration of photoreceptors, RPE, and choroidal capillaries.

Systematic analysis of the cuprotosis in tumor microenvironment and prognosis of gastric cancer

Cuprotosis is a new programmed cell death related to cancer. However, the characteristics of cuprotosis in gastric cancer (GC) remain unknown. Ten cuprotosis molecules from 1544 GC patients were used to identify three GC molecular genotypes. Cluster A was characterized by the best clinical outcome and was significantly enriched in metabolic signaling pathways. Cluster B exhibited elevated immune activation, high immune stroma scores and was significantly enriched in tumor immune signaling pathways. Cluster C was characterized by severe immunosuppression and poor response to immunotherapy. Notably, the citrate cycle, cell cycle, and p53 signaling pathways were enriched in the differentially expressed genes among the three subtypes, which were critical signaling pathways for cell death. We also developed a cuprotosis signature risk score that could accurately predict the survival, immunity, and subtype of GC. This study presents a systematic analysis of cuprotosis molecules and provides new immunotherapeutic targets for GC patients.

Cell Death Pathways: The Variable Mechanisms Underlying Fine Particulate Matter-Induced Cytotoxicity.

Recently, the advent of health risks due to the cytotoxicity of fine particulate matter (FPM) is concerning. Numerous studies have reported abundant data elucidating the FPM-induced cell death pathways. However, several challenges and knowledge gaps are still confronted nowadays. On one hand, the undefined components of FPM (such as heavy metals, polycyclic aromatic hydrocarbons, and pathogens) are all responsible for detrimental effects, thus rendering it difficult to delineate the specific roles of these copollutants. On the other hand, owing to the crosstalk and interplay among different cell death signaling pathways, precisely determining the threats and risks posed by FPM is difficult. Herein, we recapitulate the current knowledge gaps present in the recent studies regarding FPM-induced cell death, and propose future research directions for policy-making to prevent FPM-induced diseases and improve knowledge concerning the adverse outcome pathways and public health risks of FPM.

Bioinformatic analysis of biological pathways in coronary heart disease and Alzheimer’s disease

Aim. Using bioinformatic tools, to perform a pathway enrichment analysis in Alzheimer’s disease and coronary heart disease (CHD).Materials and methods. Genes contributing to susceptibility to CHD and Alzheimer’s disease were obtained from the public database DisGeNET (Database of Gene – Disease Associations). A pathway enrichment analysis was performed in the ClueGO Cytoscape plug-in (version 3.6.0) using hypergeometric distribution and the KEGG and Reactome databases.Results. The identified genes contributing to susceptibility to Alzheimer’s disease and CHD are included in 69 common signaling pathways, grouped into the following subgroups: cell death signaling pathways (1); signaling pathways regulating immune responses (2); signaling pathways responsible for fatty acid metabolism (3); signaling pathways involved in the functioning of the nervous system (4), cardiovascular system (5), and endocrine system (6).Conclusion. Following the performed analysis, we identified possible associations between processes involving genetic factors and their products in CHD and Alzheimer’s disease. In particular, we assumed that susceptibility genes involved in the implementation of these pathways regulate apoptosis, production of inflammatory cytokines and chemokines, lipid metabolism, β-amyloid formation, and angiogenesis.

Pyroptosis in neutrophils: Multimodal integration of inflammasome and regulated cell death signaling pathways.

Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation of plasma membrane (PM) macropores composed of gasdermin-family (GSDM) proteins. It facilitates two major functions in innate immunity: (i) elimination of intracellular replicative niches for pathogenic bacteria; and (ii) non-classical secretion of IL-1 family cytokines that amplify host-beneficial inflammatory responses to microbial infection or tissue damage. Physiological roles for gasdermin D (GSDMD) in pyroptosis and IL-1β release during inflammasome signaling have been extensively characterized in macrophages. This involves cleavage of GSDMD by caspase-1 to generate GSDMD macropores that mediate IL-1β efflux and progression to pyroptotic lysis. Neutrophils, which rapidly accumulate in large numbers at sites of tissue infection or damage, become the predominant local source of IL-1β in coordination with their potent microbiocidal capacity. Similar to macrophages, neutrophils express GSDMD and utilize the same spectrum of diverse inflammasome platforms for caspase-1-mediated cleavage of GSDMD. Distinct from macrophages, neutrophils possess a remarkable capacity to resist progression to GSDMD-dependent pyroptotic lysis to preserve their viability for efficient microbial killing while maintaining GSDMD-dependent mechanisms for export of bioactive IL-1β. Rather, neutrophils employ cell-specific mechanisms to conditionally engage GSDMD-mediated pyroptosis in response to bacterial pathogens that use neutrophils as replicative niches. GSDMD and pyroptosis have also been mechanistically linked to induction of NETosis, a signature neutrophil pathway that expels decondensed nuclear DNA into extracellular compartments for immobilization and killing of microbial pathogens. This review summarizes a rapidly growing number of recent studies that have produced new insights, unexpected mechanistic nuances, and some controversies regarding the regulation of, and roles for, neutrophil inflammasomes, pyroptosis, and GSDMs in diverse innate immune responses.

Modulation of Cell Death Pathways for Cellular Protection and Anti-Tumoral Activity: The Role of Thymus spp. Extracts and Their Bioactive Molecules.

Natural products used for their health-promoting properties have accompanied the evolution of humanity. Nowadays, as an effort to scientifically validate the health-promoting effects described by traditional medicine, an ever-growing number of bioactivities are being described for natural products and the phytochemicals that constitute them. Among them, medicinal plants and more specifically the Thymus genus spp., arise as products already present in the diet and with high acceptance, that are a source of phytochemicals with high pharmacological value. Phenolic acids, flavonoid glycoside derivatives, and terpenoids from Thymus spp. have been described for their ability to modulate cell death and survival pathways, much-valued bioactivities in the pharmaceutical industry, that continually sought-after new formulations to prevent undesired cell death or to control cell proliferation. Among these, wound treatment, protection from endogenous/exogenous toxic molecules, or the induction of selective cell death, such as the search for new anti-tumoral agents, arise as main objectives. This review summarizes and discusses studies on Thymus spp., as well as on compounds present in their extracts, with regard to their health-promoting effects involving the modulation of cell death or survival signaling pathways. In addition, studies regarding the main bioactive molecules and their cellular molecular targets were also reviewed. Concerning cell survival and proliferation, Thymus spp. present themselves as an option for new formulations designed for wound healing and protection against chemicals-induced toxicity. However, Thymus spp. extracts and some of their compounds regulate cell death, presenting anti-tumoral activity. Therefore Thymus spp. is a rich source of compounds with nutraceutical and pharmaceutical value.

GSDMD deficiency ameliorates hyperoxia-induced BPD and ROP in neonatal mice

Bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) are among the most common morbidities affecting extremely premature infants who receive oxygen therapy. Many clinical studies indicate that BPD is associated with advanced ROP. However, the mechanistic link between hyperoxia, BPD, and ROP remains to be explored. Gasdermin D (GSDMD) is a key executor of inflammasome-induced pyroptosis and inflammation. Inhibition of GSDMD has been shown to attenuate hyperoxia-induced BPD and brain injury in neonatal mice. The objective of this study was to further define the mechanistic roles of GSDMD in the pathogenesis of hyperoxia-induced BPD and ROP in mouse models. Here we show that global GSDMD knockout (GSDMD-KO) protects against hyperoxia-induced BPD by reducing macrophage infiltration, improving alveolarization and vascular development, and decreasing cell death. In addition, GSDMD deficiency prevented hyperoxia-induced ROP by reducing vasoobliteration and neovascularization, improving thinning of multiple retinal tissue layers, and decreasing microglial activation. RNA sequencing analyses of lungs and retinas showed that similar genes, including those from inflammatory, cell death, tissue remodeling, and tissue and vascular developmental signaling pathways, were induced by hyperoxia and impacted by GSDMD-KO in both models. These data highlight the importance of GSDMD in the pathogenesis of BPD and ROP and suggest that targeting GSDMD may be beneficial in preventing and treating BPD and ROP in premature infants.

Polymolecular botanical drug of Orthosiphon stamineus extract (C5OSEW5050ESA) as a complementary therapy to overcome gemcitabine resistance in pancreatic cancer cells.

Gemcitabine remains the cornerstone of pancreatic cancer treatment, despite exhibiting a modest effect on patient survival due to the development of drug resistance. Nuvastatic™ polymolecular botanical drug Orthosiphon stamineus (O.stamineus) is a folklore Asian herbal medicine that is used for the treatment of a variety of ailments. However, little is known about the mechanism of actions of the Nuvastatic™ polymolecular botanical drug of O.stamineus as a complementary therapy in resistant pancreatic cancer. It is postulated that the proprietary O.stamineus extract formulation (ID: C5EOSEW5050ESA) in Nuvastatic™ may sensitise resistant pancreatic cancer cells to gemcitabine. This study was conducted to assess the cytotoxic activity and synergistic effects of C5EOSEW5050ESA in gemcitabine-resistant pancreatic cancer cells. The effects of C5EOSEW5050ESA treatment on cell viability, multidrug-resistant genes, epithelial-mesenchymal transition, cellular senescence, cell death, and Notch signalling pathway were evaluated in gemcitabine-resistant Panc-1cells. C5EOSEW5050ESA sensitised gemcitabine resistant cells towards C5EOSEW5050ESA-gemcitabine combination treatment by reducing the expression of multidrug-resistant genes and epithelial-mesenchymal transition markers in gemcitabine-resistant cells compared to the control group, possibly through the inhibition of Notch signalling. This study provides valuable insight into using C5EOSEW5050ESA as a potential complementary treatment for resistant pancreatic cancer.

Protective effect of Guanxin Danshen formula on myocardial ischemiareperfusion injury in rats

Myocardial ischemia/reperfusion injury (MIRI) leads to myocardial tissue necrosis, which will increase the size of myocardial infarction. The study examined the protective effect and mechanism of the Guanxin Danshen formula (GXDSF) on MIRI in rats. MIRI model was performed in rats; rat H9C2 cardiomyocytes were hypoxia-reoxygenated to establish a cell injury model. The GXDSF significantly reduced myocardial ischemia area, reduced myocardial structural injury, decreased the levels of interleukin (IL-1β, IL-6) in serum, decreased the activity of myocardial enzymes, increased the activity of superoxide dismutase (SOD), and reduced glutathione in rats with MIRI. The GXDSF can reduce the expression of nucleotide- binding oligomerization domain, leucine-rich repeat and pyrin domain containing nod-like receptor family protein 3 (NLRP3), IL-1β, caspase-1, and gasdermin D (GSDMD) in myocardial tissue cells. Salvianolic acid B and notoginsenoside R1 protected H9C2 cardiomyocytes from hypoxia and reoxygenation injury and reduced the levels of tumor necrosis factor α (TNF-α) and IL-6 in the cell supernatant, decreasing the NLRP3, IL-18, IL-1β, caspase-1, and GSDMD expression in H9C2 cardiomyocytes. GXDSF can reduce the myocardial infarction area and alleviate the damage to myocardial structure in rats with MIRI, which may be related to the regulation of the NLRP3. GXDSF reduces MIRI in rat myocardial infarction injury, improves structural damage in myocardial ischemia injury, and reduces myocardial tissue inflammation and oxidative stress by lowering inflammatory factors and controlling focal cell death signaling pathways.

De Novo Class of Momordicoside with Potent and Selective Tumor Cell Growth Inhibitory Activity as Pyruvate Kinase Muscle Isozyme 2 and Anti-apoptotic Myeloid Leukemia 1 Inhibitors

The difficulty in treating cancer resides in targeting abnormal proliferation while protecting normal proliferation, necessitating a thorough comprehension of the normal and malignant mechanisms that promote cell growth and proliferation. Targeting cell death signaling pathways such as glycolytic and mitochondrial apoptosis is the hallmark of many cancers, the aim of which this research is ready to evaluate. Atomistic molecular dynamics simulation of top hits after molecular docking and ADMET profiling of the ligands were performed for main protease-hit complexes. Docking scores of ligands used against PKM2 range from –9.36 to –12.1 kcal/mol, wherein momordicoside-F2 had the highest score (2.1 kcal/mol), performing better than the FDA-approved drug benserazide. Likewise, the scores ranged between –8.51 and –12.05 kcal/mol for Anti-apoptotic Myeloid Leukemia 1 (MCL-1), with momordicoside-F1 being the highest-ranked compound. The RMSD plots depicted stable trajectories with consistent and minor fluctuations implying that the protein (PKM2 and MCL1) backbone underwent minor structural perturbations. In addition, several significant peaks of increased fluctuations were also observed, indicating their increased interaction potential, implying that the ligands could adapt well in the protein's binding pocket. The SASA analysis results show that the ligands retained inside their shallow binding pocket. The phylogenetic tree obtained implies the likelihood of recurring results of the in silico profiling. Conclusively, this research unveils that Mormordicoside F1 shows good stability with MCL-1, likewise, momordicoside-F2 against PKM2. These hits can be a better re-purposing option.

MicroRNA-Gene Interactions Impacted by Toxic Metal(oid)s during EMT and Carcinogenesis.

Chronic environmental exposure to toxic metal(loid)s significantly contributes to human cancer development and progression. It is estimated that approximately 90% of cancer deaths are a result of metastasis of malignant cells, which is initiated by epithelial-mesenchymal transition (EMT) during early carcinogenesis. EMT is regulated by many families of genes and microRNAs (miRNAs) that control signaling pathways for cell survival, death, and/or differentiation. Recent mechanistic studies have shown that toxic metal(loid)s alter the expression of miRNAs responsible for regulating the expression of genes involved in EMT. Altered miRNA expressions have the potential to be biomarkers for predicting survival and responses to treatment in cancers. Significantly, miRNAs can be developed as therapeutic targets for cancer patients in the clinic. In this mini review, we summarize key findings from recent studies that highlight chemical-miRNA-gene interactions leading to the perturbation of EMT after exposure to toxic metal(loid)s including arsenic, cadmium, nickel, and chromium.

Vitamin D3 and Ischemic Stroke: A Narrative Review.

Ischemic stroke is one of the major causes of death and permanent disability worldwide. The only efficient treatment to date is anticoagulant therapy and thrombectomy, which enable restitution of blood flow to ischemic tissues. Numerous promising neuroprotectants have failed in clinical trials. Given the complex pathomechanism of stroke, a multitarget pharmacotherapy seems a more rational approach in stroke prevention and treatment than drugs acting on single molecular targets. Recently, vitamin D3 has emerged as a potential treatment adjunct for ischemic stroke, as it interferes with the key prosurvival pathways and shows neuroprotective, anti-inflammatory, regenerative and anti-aging properties in both neuronal and vascular tissue. Moreover, the stimulatory effect of vitamin D3 on brain-derived neurotrophic factor (BDNF) signaling and neuroplasticity may play a role not only in the recovery of neurological functions, but also in ameliorating post-stroke depression and anxiety. This narrative review presents advances in research on the biochemical mechanisms of stroke-related brain damage, and the genomic and non-genomic effects of vitamin D3 which may interfere with diverse cell death signaling pathways. Next, we discuss the results of in vitro and in vivo experimental studies on the neuroprotective potential of 1alpha,25-dihydroxyvitamin D3 (calcitriol) in brain ischemia models. Finally, the outcomes of clinical trials on vitamin D3 efficiency in ischemic stroke patients are briefly reviewed. Despite the mixed results of the clinical trials, it appears that vitamin D3 still holds promise in preventing or ameliorating neurological and psychiatric consequences of ischemic stroke and certainly deserves further study.

Pathomechanisms of non-coding RNAs and hub genes related to the oxidative stress in diabetic complications

Cytokine storms, oxidative stress, and hyperglycemia can enhance the risk of type 2 diabetes (T2D). Moreover, T2D may change the functional and structural heart. However, some signaling pathways, such as insulin resistance, dyslipidemia, and hyperglycemia, can play in T2D, and various pathomechanics and pathophysiology involved in T2D are not understood. Moreover, it is well documented that the non-coding RNAs are potentially pivotal molecules in oxidative stress, inflammation, and cell death signaling pathways. Hence, long non-coding RNAs (lncRNAs) and microRNAs may have vital roles in oxidative stress, inflammation, metabolism, T2D, and cardiovascular systems. Non-coding RNAs can target hub gene networks and suppress or trigger various cascades. Furthermore, lifestyle is the other factor that may affect the prevalence of T2D. A sedentary lifestyle and excessive sitting can enhance inflammation, oxidative stress, and hyperglycemia. Here, we attempt to comprehend the role of hub genes, non-coding RNAs, and unhealthy lifestyles on the pathomechanics and pathophysiology of diabetic vascular complications.

Different modalities of host cell death and their impact on Mycobacterium tuberculosis infection.

Mycobacterium tuberculosis (Mtb) is the pathogen that causes tuberculosis (TB), a leading infectious disease of humans worldwide. One of the main histopathological hallmarks of TB is the formation of granulomas comprised of elaborately organized aggregates of immune cells containing the pathogen. Dissemination of Mtb from infected cells in the granulomas due to host and mycobacterial factors induces multiple cell death modalities in infected cells. Based on molecular mechanism, morphological characteristics, and signal dependency, there are two main categories of cell death: programmed and nonprogrammed. Programmed cell death (PCD), such as apoptosis and autophagy, is associated with a protective response to Mtb by keeping the bacteria encased within dead macrophages that can be readily phagocytosed by arriving in uninfected or neighboring cells. In contrast, non-PCD necrotic cell death favors the pathogen, resulting in bacterial release into the extracellular environment. Multiple types of cell death in the PCD category, including pyroptosis, necroptosis, ferroptosis, ETosis, parthanatos, and PANoptosis, may be involved in Mtb infection. Since PCD pathways are essential for host immunity to Mtb, therapeutic compounds targeting cell death signaling pathways have been experimentally tested for TB treatment. This review summarizes different modalities of Mtb-mediated host cell deaths, the molecular mechanisms underpinning host cell death during Mtb infection, and its potential implications for host immunity. In addition, targeting host cell death pathways as potential therapeutic and preventive approaches against Mtb infection is also discussed.

Cytoglobin Silencing Promotes Melanoma Malignancy but Sensitizes for Ferroptosis and Pyroptosis Therapy Response.

Despite recent advances in melanoma treatment, there are still patients that either do not respond or develop resistance. This unresponsiveness and/or acquired resistance to therapy could be explained by the fact that some melanoma cells reside in a dedifferentiated state. Interestingly, this dedifferentiated state is associated with greater sensitivity to ferroptosis, a lipid peroxidation-reliant, iron-dependent form of cell death. Cytoglobin (CYGB) is an iron hexacoordinated globin that is highly enriched in melanocytes and frequently downregulated during melanomagenesis. In this study, we investigated the potential effect of CYGB on the cellular sensitivity towards (1S, 3R)-RAS-selective lethal small molecule (RSL3)-mediated ferroptosis in the G361 melanoma cells with abundant endogenous expression. Our findings show that an increased basal ROS level and higher degree of lipid peroxidation upon RSL3 treatment contribute to the increased sensitivity of CYGB knockdown G361 cells to ferroptosis. Furthermore, transcriptome analysis demonstrates the enrichment of multiple cancer malignancy pathways upon CYGB knockdown, supporting a tumor-suppressive role for CYGB. Remarkably, CYGB knockdown also triggers activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and subsequent induction of pyroptosis target genes. Altogether, we show that silencing of CYGB expression modulates cancer therapy sensitivity via regulation of ferroptosis and pyroptosis cell death signaling pathways.

Lipid Nanoparticle Delivery of Fas Plasmid Restores Fas Expression to Suppress Melanoma Growth In Vivo.

Fas ligand (FasL), expressed on the surface of activated cytotoxic T lymphocytes (CTLs), is the physiological ligand for the cell surface death receptor, Fas. The Fas-FasL engagement initiates diverse signaling pathways, including the extrinsic cell death signaling pathway, which is one of the effector mechanisms that CTLs use to kill tumor cells. Emerging clinical and experimental data indicate that Fas is essential for the efficacy of CAR-Tcell immunotherapy. Furthermore, loss of Fas expression is a hallmark of human melanoma. We hypothesize that restoring Fas expression in tumor cells reverses human melanoma resistance to Tcell cytotoxicity. DNA hypermethylation, at the FAS promoter, down-regulates FAS expression and confers melanoma cell resistance to FasL-induced cell death. Forced expression of Fas in tumor cells overcomes melanoma resistance to FasL-induced cell death in vitro. Lipid nanoparticle-encapsulated mouse Fas-encoding plasmid therapy eliminates Fas+ tumor cells and suppresses established melanoma growth in immune-competent syngeneic mice. Similarly, lipid nanoparticle-encapsulated human FAS-encoding plasmid (hCOFAS01) therapy significantly increases Fas protein levels on tumor cells of human melanoma patient-derived xenograft (PDX) and suppresses the established human melanoma PDX growth in humanized NSG mice. In human melanoma patients, FasL is expressed in activated and exhausted Tcells, Fas mRNA level positively correlates with melanoma patient survival, and nivolumab immunotherapy increases FAS expression in tumor cells. Our data demonstrate that hCOFAS01 is an effective immunotherapeutic agent for human melanoma therapy with dual efficacy in increasing tumor cell FAS expression and in enhancing CTL tumor infiltration.