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This review seeks to elucidate the therapeutic potential of tumor necrosis factor receptor 1 (TNFR1) and enhance our comprehension of its role in disease mechanisms. As a critical cell-surface receptor, TNFR1 regulates key signaling pathways, such as nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK), which are associated with pro-inflammatory responses and cell death. The intricate regulatory mechanisms of TNFR1 signaling and its involvement in various diseases, including inflammatory disorders, infectious diseases, cancer, and metabolic syndromes, have attracted increasing scholarly attention. Given the potential risks associated with targeting tumor necrosis factor-alpha (TNF-α), selective inhibition of the TNFR1 signaling pathway has been proposed as a promising strategy to reduce side effects and enhance therapeutic efficacy. This review emphasizes the emerging field of targeted therapies aimed at selectively modulating TNFR1 activity, identifying promising therapeutic strategies that exploit TNFR1 as a drug target through an evaluation of current clinical trials and preclinical studies. In conclusion, this study contributes novel insights into the biological functions of TNFR1 and presents potential therapeutic strategies for clinical application, thereby having substantial scientific and clinical significance. [ABSTRACT FROM AUTHOR]

Objectives: Parkinson's disease (PD) is a complex neurodegenerative disease with unclear pathogenesis. Some recent studies have shown that there is a close relationship between PD and ferroptosis. We aimed to identify the ferroptosis-related genes (FRGs) and construct competing endogenous RNA (ceRNA) networks to further assess the pathogenesis of PD. Methods: Expression of 97 substantia nigra (SN) samples were obtained and intersected with FRGs. Bioinformatics analysis, including the gene set enrichment analysis (GSEA), consensus cluster analysis, weight gene co-expression network analysis (WGCNA), and machine learning algorithms, were employed to assess the feasible differentially expressed genes (DEGs). Characteristic signature genes were used to create novel diagnostic models and construct competing endogenous RNA (ceRNA) regulatory network for PD, which were further verified by in vitro experiments and single-cell RNA sequencing (scRNA-seq). Results: A total of 453 DEGs were identified and 11 FRGs were selected. We sorted the entire PD cohort into two subtypes based on the FRGs and obtained 67 hub genes. According to the five machine algorithms, 4 features (S100A2, GNGT1, NEUROD4, FCN2) were screened and used to create a PD diagnostic model. Corresponding miRNAs and lncRNAs were predicted to construct a ceRNA network. The scRNA-seq and experimental results showed that the signature model had a certain diagnostic effect and lncRNA NEAT1 might regulate the progression of ferroptosis in PD via the NEAT1/miR-26b-5p/S100A2 axis. Conclusion: The diagnostic signatures based on the four FRGs had certain diagnostic and individual effects. NEAT1/miR-26b-5p/S100A2 axis is associated with ferroptosis in the pathogenesis of PD. Our findings provide new solutions for treating PD. [ABSTRACT FROM AUTHOR]

Ischemia-reperfusion injuries (IRI) across various organs and tissues, along with sepsis, significantly contribute to the progression of critical illnesses. These conditions disrupt the balance of inflammatory mediators and signaling pathways, resulting in impaired physiological functions in human tissues and organs. Ferroptosis, a distinct form of programmed cell death, plays a pivotal role in regulating tissue damage and modulating inflammatory responses, thereby influencing the onset and progression of severe illnesses. Recent studies highlight that pharmacological agents targeting ferroptosis-related proteins can effectively mitigate oxidative stress caused by IRI in multiple organs, alleviating associated symptoms. This manuscript delves into the mechanisms and signaling pathways underlying ferroptosis, its role in critical illnesses, and its therapeutic potential in mitigating disease progression. We aim to offer a novel perspective for advancing clinical treatments for critical illnesses. [ABSTRACT FROM AUTHOR]

Ferroptosis is a non-apoptotic form of regulated cell death characterized by iron accumulation and uncontrolled lipid peroxidation, leading to plasma membrane rupture and intracellular content release. Cancer immunotherapy, especially immune checkpoint inhibitors (ICIs) targeting PD-1 and PD-L1, has been considered a breakthrough in cancer treatment, achieving encouraging clinical anti-tumor effects in a variety of cancers. However, tumor immune evasion is indispensable to immunotherapy failure. The mechanisms of tumor immune evasion are quite complex, and its occurrence is inseparable from the ferroptosis in tumor microenvironment (TME). Thus, a comprehensive understanding of the role of ferroptosis in tumor immune evasion is crucial to enhance the efficacy of immunotherapy. In this review, we provide an overview of the recent advancements in understanding ferroptosis in cancer, covering molecular mechanisms and interactions with the TME. We also summarize the potential applications of ferroptosis induction in immunotherapy, as well as ferroptosis inhibition for cancer treatment in various conditions. We finally discuss ferroptosis as a double-edged sword, including the current challenges and future directions regarding its potential for cancer treatment. [ABSTRACT FROM AUTHOR]

Objective: The observational association between blood metabolites and asthma has been extensively studied. However, it is still unclear whether this association is causal. In this study, we aimed to investigate the causal relationship between blood metabolites and asthma using a bidirectional Mendelian randomization (MR) analysis. Additionally, we aimed to explore the potential mechanisms underlying this relationship. Methods: The study design involved the use of genetic instruments as instrumental variables (IVs) to fulfill the assumptions of MR analysis. The data on 1,091 metabolites and 309 metabolite ratios were obtained from the Canadian Longitudinal Study on Aging (CLSA), while the data on asthma were obtained from the Integrative Epidemiology Unit (IEU) Open GWAS Project. Utilizing the inverse variance-weighted (IVW) method as the primary MR analysis approach, sensitivity tests were conducted to assess the reliability of the findings, which involved employing Cochran's Q and the MR-Egger intercept. Furthermore, Bayesian weighted MR was used to further test the robustness of the results. Additionally, pathway analysis was conducted to explore the metabolic explanations underlying asthma. Result: In our study, a comprehensive MR Analysis identified 10 metabolites and 6 metabolite ratios significantly associated with the development of asthma (FDR < 0.05). The metabolites included glycerophosphocholines(GPCs), glycerophosphoethanolamines(GPEs), and an unknown metabolite. Of these, 1-arachidonoyl-GPC, 1-myristoyl-2-arachidonoyl-GPC, 1-palmitoyl-2-arachidonoyl-GPC, and 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPC were associated with an increased risk of asthma, whereas 1,2-dilinoleoyl-GPC, 1-palmitoyl-2-linoleoyl-GPC, 1,2-dilinoleoyl-GPE, 1 − oleoyl − 2 − linoleoyl − GPE, 1-palmitoyl-2-linoleoyl-GPE, and X-21470 were found to have a protective effect. No heterogeneity and pleiotropy were observed in the significant metabolites (p > 0.05), and each metabolite exhibited a consistent effect direction across all five methods. BWMR analysis results confirmed the significance and direction of effects across exposures, except for Cholesterol to linoleoyl-arachidonoyl-glycerol ratio(p = 0.673). Pathway analysis suggests that glycerophospholipid metabolism may potentially be a mechanism underlying the development of asthma. Conclusion: Our MR findings suggest that the identified metabolites and pathways can serve as biomarkers for clinical asthma screening and prevention, while also providing new insights for future mechanistic exploration and drug target selection. [ABSTRACT FROM AUTHOR]

The complex interplay between ferroptosis and efferocytosis in cancer has attracted significant interest recently. Efferocytosis, the process of eliminating apoptotic cells, is essential for preserving tissue homeostasis and reducing inflammation. However, dysregulation of efferocytosis can have profound effects on cancer. Apoptotic cells accumulate because of impaired efferocytosis, which triggers chronic inflammation and the release of pro-inflammatory chemicals. Surprisingly, accumulating evidence suggests that dysregulation of ferroptosis- a form of controlled cell death characterized by lipid peroxidation and the buildup iron-dependent reactive oxygen species (ROS)-can influence efferocytic activities within the tumor microenvironment. Dysfunctional iron metabolism and increased lipid peroxidation, are associated with ferroptosis, resulting in inadequate apoptotic cell clearance. Conversely, apoptotic cells can activate ferroptotic pathways, increasing oxidative stress and inducing cell death in cancer cells. This reciprocal interaction emphasizes the complex relationship between efferocytosis and ferroptosis in cancer biology. Understanding and managing the delicate balance between cell clearance and cell death pathways holds significant therapeutic potential in cancer treatment. Targeting the efferocytosis and ferroptosis pathways may offer new opportunities for improving tumor clearance, reducing inflammation, and sensitizing cancer cells to therapeutic interventions. Further research into the interaction between efferocytosis and ferroptosis in cancer will provide valuable insights for the development of novel therapies aimed at restoring tissue homeostasis and improving patient outcomes. [ABSTRACT FROM AUTHOR]

Herein, we synthesized novel 4-methyl coumarin-incorporated heterocyclic azo dyes, and structures were confirmed by analytical and spectroscopic approaches. Computational studies were performed using the DFT method with a B3LYP/ 6–31 G (d, p) basis set used to explore the molecular geometry, Mullikan atomic charges, global reactive descriptors, MEP, and RDG. Nonlinear optical (NLO) analysis revealed that the first-order hyperpolarizability of 1d was 18 times greater than that of urea. Natural bond orbital (NBO) analysis showed that all the compounds had greater stability due to internal charge transfer. Solvatochromic behavior was analyzed using UV–Vis spectroscopy, and the absorbance was observed in the range of 380–445 nm. The electrochemical behavior was determined by cyclic voltammetry, which exhibited two reduction peaks and was used to calculate the energy of the molecules (EHOMO-ELUMO). The antimicrobial activity was studied against different pathogens Viz., E. coli, S. aureus, and A. flavus, and the results showed that the compounds had good antimicrobial efficacy. "Furthermore, in silico molecular docking results revealed that compounds 1b and 1a have good binding site energies against the target enzymes DNA gyrase and O-methyltransferase, respectively". [ABSTRACT FROM AUTHOR]

Boron, essential for plant growth, necessitates precise regulation due to its potential toxicity. This regulation is achieved by borate transporters (BORs), which are homologous to the SLC4 family. The Arabidopsis thaliana Bor1 (AtBor1) transporter from clade I undergoes slow regulation through degradation and translational suppression, but its potential for fast regulation via direct activity modulation was unclear. Here, we combine cryo-electron microscopy, mutagenesis, and functional characterization to study AtBor1, revealing high-resolution structures of the dimer in one inactive and three active states. Our findings show that AtBor1 is regulated by two distinct mechanisms: an autoinhibitory domain at the carboxyl terminus obstructs the substrate pathway via conserved salt bridges, and phosphorylation of Thr410 allows interaction with a positively charged pocket at the cytosolic face, essential for borate transport. These results elucidate the molecular basis of AtBor1's activity regulation and highlight its role in fast boron level regulation in plants. Boron is essential for plant growth, and its transport is tightly regulated. Here, the authors present structures of the borate transporter AtBor1 in both inactive and active states, revealing how its C-terminal domain mediates autoinhibition. [ABSTRACT FROM AUTHOR]

Inflammatory diseases, including psoriasis, atherosclerosis, rheumatoid arthritis, and ulcerative colitis, are characterized by persistent inflammation. Moreover, the existing treatments for inflammatory diseases only provide temporary relief by controlling symptoms, and treatments of unstable and expensive. Therefore, new therapeutic solutions are urgently needed to address the underlying causes or symptoms of inflammatory diseases. Inflammation frequently coincides with a high level of (reactive oxygen species) ROS activation, serving as a fundamental element in numerous physiological and pathological phenotypes that can result in serious harm to the organism. Given its pivotal role in inflammation, oxidative stress, and ferroptosis, ROS represents a focal node for investigating the (nuclear factor E2-related factor 2) Nrf2 pathway and ferroptosis, both of which are intricately linked to ROS. Ferroptosis is mainly triggered by oxidative stress and involves iron-dependent lipid peroxidation. The transcription factor Nrf2 targets several genes within the ferroptosis pathway. Recent studies have shown that Nrf2 plays a significant role in three key ferroptosis-related routes, including the synthesis and metabolism of glutathione/glutathione peroxidase 4, iron metabolism, and lipid processes. As a result, ferroptosis-related treatments for inflammatory diseases have attracted much attention. Moreover, drugs targeting Nrf2 can be used to manage inflammatory conditions. This review aimed to assess ferroptosis regulation mechanism and the role of Nrf2 in ferroptosis inhibition. Therefore, this review article may provide the basis for more research regarding the treatment of inflammatory diseases through Nrf2-inhibited ferroptosis. [ABSTRACT FROM AUTHOR]

Ferroptosis, a unique type of regulated cell death plays a vital role in inhibiting tumour malignancy and has presented new opportunities for treatment of therapy in hepatocellular carcinoma. Accumulating studies indicate that epigenetic modifications by non-coding RNAs, including microRNAs, long noncoding RNAs, and circular RNAs, can determine cancer cell vulnerability to ferroptosis in HCC. The present review first summarize the updated core molecular mechanisms of ferroptosis. We then provide a concised overview of epigenetic modification of ferroptosis in HCC. Finally, we review the recent progress in understanding of the ncRNA-mediated regulated mechanisms on ferroptosis in HCC. The review will promote our understanding of the ncRNA-mediated epigenetic regulatory mechanisms modulating ferroptosis in malignancy of HCC, highlighting a novel strategies for treatment of HCC through targeting ncRNA-ferroptosis axis. [ABSTRACT FROM AUTHOR]

Efflux-mediated β-lactam resistance is a major public health concern, reducing the effectiveness of β-lactam antibiotics against many bacteria. Structural analyses show the efflux protein TolC in Gram-negative bacteria acts as a channel for antibiotics, impacting bacterial susceptibility and virulence. This study examines β-lactam drug efflux mediated by TolC using experimental and computational methods. Molecular dynamics simulations of drug-free TolC reveal essential movements and key residues involved in TolC opening. A whole-gene-saturation mutagenesis assay, mutating each TolC residue and measuring fitness effects under β-lactam selection, is performed. Here we show the TolC-mediated efflux of three antibiotics: oxacillin, piperacillin, and carbenicillin. Steered molecular dynamics simulations identify general and drug-specific efflux mechanisms, revealing key positions at TolC's periplasmic entry affecting efflux motions. Our findings provide insights into TolC's structural dynamics, aiding the design of new antibiotics to overcome bacterial efflux mechanisms. Modelling and deep mutational scanning of TolC provide insights for designing β-lactams to evade resistance, by outlining how efflux is fine-tuned for efficiency via transient hydrogen bonds with antibiotics and how allostery impacts exit site motions. [ABSTRACT FROM AUTHOR]

The development of drug resistance remains a major challenge in cancer treatment. Ferroptosis, a unique type of regulated cell death, plays a pivotal role in inhibiting tumour growth, presenting new opportunities in treating chemotherapeutic resistance. Accumulating studies indicate that epigenetic modifications by non-coding RNAs (ncRNA) can determine cancer cell vulnerability to ferroptosis. In this review, we first summarize the role of chemotherapeutic resistance in cancer growth/development. Then, we summarize the core molecular mechanisms of ferroptosis, its upstream epigenetic regulation, and its downstream effects on chemotherapeutic resistance. Finally, we review recent advances in understanding how ncRNAs regulate ferroptosis and from such modulate chemotherapeutic resistance. This review aims to enhance general understanding of the ncRNA-mediated epigenetic regulatory mechanisms which modulate ferroptosis, highlighting the ncRNA-ferroptosis axis as a key druggable target in overcoming chemotherapeutic resistance. [ABSTRACT FROM AUTHOR]

Cellular quality control systems sense and mediate homeostatic responses to prevent the buildup of aberrant macromolecules, which arise from errors during biosynthesis, damage by environmental insults, or imbalances in enzymatic and metabolic activity. Lipids are structurally diverse macromolecules that have many important cellular functions, ranging from structural roles in membranes to functions as signaling and energy-storage molecules. As with other macromolecules, lipids can be damaged (e.g., oxidized), and cells require quality control systems to ensure that nonfunctional and potentially toxic lipids do not accumulate. Ferroptosis is a form of cell death that results from the failure of lipid quality control and the consequent accumulation of oxidatively damaged phospholipids. In this review, we describe a framework for lipid quality control, using ferroptosis as an illustrative example to highlight concepts related to lipid damage, membrane remodeling, and suppression or detoxification of lipid damage via preemptive and damage-repair lipid quality control pathways. [ABSTRACT FROM AUTHOR]

ASCT2 is an obligate exchanger of neutral amino acids, contributing to cellular amino acid homeostasis. ASCT2 belongs to the same family (SLC1) as Excitatory Amino Acid Transporters (EAATs) that concentrate glutamate in the cytosol. The mechanism that makes ASCT2 an exchanger rather than a concentrator remains enigmatic. Here, we employ cryo-electron microscopy and molecular dynamics simulations to elucidate the structural basis of the exchange mechanism of ASCT2. We establish that ASCT2 binds three Na+ ions per transported substrate and visits a state that likely acts as checkpoint in preventing Na+ ion leakage, both features shared with EAATs. However, in contrast to EAATs, ASCT2 retains one Na+ ion even under Na+-depleted conditions. We demonstrate that ASCT2 cannot undergo the structural transition in TM7 that is essential for the concentrative transport cycle of EAATs. This structural rigidity and the high-affinity Na+ binding site effectively confine ASCT2 to an exchange mode. ASCT2 is a Na+-dependent obligatory amino acid exchanger. Here, the authors untangle the structural basis of the exchange mechanism in ASCT2, revealing that structural rigidity and a high-affinity Na+ binding site effectively confine ASCT2 to an exchange mode. [ABSTRACT FROM AUTHOR]

The mechanism of selectivity in ion channels is still an open question in biology. Recent studies suggest that the selectivity filter may exhibit quantum coherence, which could help explain how ions are selected and conducted. However, environmental noise causes decoherence and loss of quantum effects. It is hoped that the effect of classical noise on ion channels can be modeled using the framework provided by quantum decoherence theory. In this paper, the behavior of the ion channel system was simulated using two models: the Spin–Boson model and the stochastic Hamiltonian model under classical noise. Additionally, using a different approach, the system's evolution was modeled as a two-level Spin–Boson model with tunneling, interacting with a bath of harmonic oscillators, based on decoherence theory. We investigated under what conditions the decoherence model approaches and deviates from the noise model. Specifically, we examined Gaussian noise and Ornstein-Uhlenbeck noise in our model. Gaussian noise shows a very good agreement with the decoherence model. By examining the results, it was found that the Spin–Boson model at a high hopping rate of potassium ions can simulate the behavior of the system in the classical noise approach for Gaussian noise. [ABSTRACT FROM AUTHOR]

Background: Routine coagulation tests are not widely accepted diagnostic criteria of trauma-induced hypercoagulopathy (TIH) due to insensitivity. Lymphatic vessels drain approximately 10% of the interstitial fluid into the lymphatic system and form lymph. Subjective: The purpose of this study was to identify the potential lymph biomarkers for TIH. Methods: Eighteen male Sprague-Dawley rats were randomly assigned to the sham (non-fractured rats with sham surgery and vehicle treatment), the VEH (fractured rats with vehicle treatment) and the CLO (fractured rats with clopidogrel treatment) group. Thoracic duct lymph was obtained to perform proteomics and untargeted metabolomics. Results: A total of 1207 proteins and 16,695 metabolites were identified. The top 5 GO terms of lymph proteomics indicated that oxidative stress and innate immunity were closely associated with TIH and antithrombotic therapy. The top 5 GO terms of lymph metabolomics showed that homocystine and lysophosphatidylcholine were the differential expressed metabolites (DEMs) between the sham and VEH groups, while cholic acid, docosahexaenoic acid, N1-Methyl-2-pyridone-5-carboxamide, isoleucine and testosterone are the DEMs between the VEH and CLO group. Conclusions: This study presents the first proteomic and metabolomic profiling of lymph after TIH and antithrombotic therapy, and predicts the possible lymph biomarkers for TIH. [ABSTRACT FROM AUTHOR]

The involvement of cell death in acute kidney injury (AKI) is linked to multiple factors including energy depletion, electrolyte imbalance, reactive oxygen species, inflammation, mitochondrial dysfunction, and activation of several cell death pathway components. Since our review in 2003, discussing the relative contributions of apoptosis and necrosis, several other forms of cell death have been identified and are shown to contribute to AKI. Currently, these various forms of cell death can be fundamentally divided into accidental cell death and regulated or programmed cell death based on functional aspects. Several death initiator and effector molecules switch molecules that may act as signaling components triggering either death or protective mechanisms or alternate cell death pathways have been identified as part of the machinery. Intriguingly, several of these cell death pathways share components and signaling pathways suggesting complementary or compensatory functions. Thus, defining the cross talk between distinct cell death pathways and identifying the unique molecular effectors for each type of cell death may be required to develop novel strategies to prevent cell death. Furthermore, depending on the multiple forms of cell death simultaneously induced in different AKI settings, strategies for combination therapies that block multiple cell death pathways need to be developed to completely prevent injury, cell death, and renal function. This review highlights the various cell death pathways, cross talk, and interactions between different cell death modalities in AKI. [ABSTRACT FROM AUTHOR]

Ferroptosis, an iron-dependent form of cell death characterized by uncontrolled lipid peroxidation, is governed by molecular networks involving diverse molecules and organelles. Since its recognition as a non-apoptotic cell death pathway in 2012, ferroptosis has emerged as a crucial mechanism in numerous physiological and pathological contexts, leading to significant therapeutic advancements across a wide range of diseases. This review summarizes the fundamental molecular mechanisms and regulatory pathways underlying ferroptosis, including both GPX4-dependent and -independent antioxidant mechanisms. Additionally, we examine the involvement of ferroptosis in various pathological conditions, including cancer, neurodegenerative diseases, sepsis, ischemia–reperfusion injury, autoimmune disorders, and metabolic disorders. Specifically, we explore the role of ferroptosis in response to chemotherapy, radiotherapy, immunotherapy, nanotherapy, and targeted therapy. Furthermore, we discuss pharmacological strategies for modulating ferroptosis and potential biomarkers for monitoring this process. Lastly, we elucidate the interplay between ferroptosis and other forms of regulated cell death. Such insights hold promise for advancing our understanding of ferroptosis in the context of human health and disease. [ABSTRACT FROM AUTHOR]

Autophagy is a protective mechanism through which cells degrade and recycle proteins and organelles to maintain cellular homeostasis and integrity. An accumulating body of evidence underscores the significant impact of dysregulated autophagy on podocyte injury in chronic kidney disease (CKD). In this review, we provide a comprehensive overview of the diverse types of autophagy and their regulation in cellular homeostasis, with a specific emphasis on podocytes. Furthermore, we discuss recent findings that focus on the functional role of different types of autophagy during podocyte injury in chronic kidney disease. The intricate interplay between different types of autophagy and podocyte health requires further research, which is critical for understanding the pathogenesis of CKD and developing targeted therapeutic interventions. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with increasing prevalence worldwide. NAFLD could develop from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), NASH-related fibrosis, cirrhosis, and even hepatocellular carcinoma. However, the mechanism of NAFLD development has not yet been fully defined. Recently, emerging evidence shows that the dysregulated iron metabolism marked by elevated serum ferritin, and ferroptosis are involved in the NAFLD. Understanding iron metabolism and ferroptosis can shed light on the mechanisms of NAFLD development. Here, we summarized studies on iron metabolism and the ferroptosis process involved in NAFLD development to highlight potential medications and therapies for treating NAFLD. [ABSTRACT FROM AUTHOR]

Ferroptosis is a type of regulated cell death characterized by iron accumulation and uncontrolled lipid peroxidation, leading to plasma membrane rupture and intracellular content release. Originally investigated as a targeted therapy for cancer cells carrying oncogenic RAS mutations, ferroptosis induction now exhibits potential to complement chemotherapy, immunotherapy, and radiotherapy in various cancer types. However, it can lead to side effects, including immune cell death, bone marrow impairment, liver and kidney damage, cachexia (severe weight loss and muscle wasting), and secondary tumorigenesis. In this review, we discuss the advantages and offer an overview of the diverse range of documented side effects. Furthermore, we examine the underlying mechanisms and explore potential strategies for side effect mitigation. [ABSTRACT FROM AUTHOR]

Ferroptosis is a novel mechanism of programmed cell death, characterized by intracellular iron overload, intensified lipid peroxidation, and abnormal accumulation of reactive oxygen species, which ultimately resulting in cell membrane impairment and demise. Research has revealed that cancer cells exhibit a greater demand for iron compared to normal cells, indicating a potential susceptibility of cancer cells to ferroptosis. Stomach and colorectal cancers are common gastrointestinal malignancies, and their elevated occurrence and mortality rates render them a global health concern. Despite significant advancements in medical treatments, certain unfavorable consequences and drug resistance persist. Consequently, directing attention towards the phenomenon of ferroptosis in gastric and colorectal cancers holds promise for enhancing therapeutic efficacy. This review aims to elucidate the intricate cellular metabolism associated with ferroptosis, encompassing lipid and amino acid metabolism, as well as iron metabolic processes. Furthermore, the significance of ferroptosis in the context of gastric and colorectal cancer is thoroughly examined and discussed. [ABSTRACT FROM AUTHOR]

The control of biological cell death is essential for the body's appropriate growth. The resistance of cells to the apoptotic process presents a new difficulty in the treatment of cancer. To combat cancer cells, researchers are working to find new apoptotic pathways and components to activate. One of the processes of regulated cell death (RCD) is referred to as ferroptosis marked by a decline in the activity of lipid glutathione peroxidase 4 (GPX4) after the buildup of reactive oxygen species (ROS). Since lipid peroxidation is a crucial component of ferroptosis and is required for its start, numerous medicines have been studied, particularly for the treatment of cancer. In this context, autophagy is an additional form of RCD that can govern ferroptosis through shared signaling pathways/factors involved in both mechanisms. In this review, we will explore the molecular mechanisms underlying ferroptosis and its association with autophagy, to gain fresh insights into their interplay in cancer advancement, and the potential of natural products for its treatment. [ABSTRACT FROM AUTHOR]

Haemophilus parainfluenzae is a Gram-negative opportunist pathogen within the mucus of the nose and mouth without significant symptoms and has an ability to cause various infections ranging from ear, eye, and sinus to pneumonia. A concerning development is the increasing resistance of H. parainfluenzae to beta-lactam antibiotics, with the potential to cause dental infections or abscesses. The principal objective of this investigation is to utilize bioinformatics and immuno-informatic methodologies in the development of a candidate multi-epitope Vaccine. The investigation focuses on identifying potential epitopes for both B cells (B lymphocytes) and T cells (helper T lymphocytes and cytotoxic T lymphocytes) based on high non-toxic and nonallergenic characteristics. The selection process involves identifying human leukocyte antigen alleles demonstrating strong associations with recognized antigenic and overlapping epitopes. Notably, the chosen alleles aim to provide coverage for 90% of the global population. Multi-epitope constructs were designed by using suitable linker sequences. To enhance the immunological potential, an adjuvant sequence was incorporated using the EAAAK linker. The final vaccine construct, comprising 344 amino acids, was achieved after the addition of adjuvants and linkers. This multi-epitope Vaccine demonstrates notable antigenicity and possesses favorable physiochemical characteristics. The three-dimensional conformation underwent modeling and refinement, validated through in-silico methods. Additionally, a protein-protein molecular docking analysis was conducted to predict effective binding poses between the multi-epitope Vaccine and the Toll-like receptor 4 protein. The Molecular Dynamics (MD) investigation of the docked TLR4-vaccine complex demonstrated consistent stability over the simulation period, primarily attributed to electrostatic energy. The docked complex displayed minimal deformation and enhanced rigidity in the motion of residues during the dynamic simulation. Furthermore, codon translational optimization and computational cloning was performed to ensure the reliability and proper expression of the multi-Epitope Vaccine. It is crucial to emphasize that despite these computational validations, experimental research in the laboratory is imperative to demonstrate the immunogenicity and protective efficacy of the developed vaccine. This would involve practical assessments to ascertain the real-world effectiveness of the multi-epitope Vaccine. [ABSTRACT FROM AUTHOR]

Background: Sepsis-associated encephalopathy (SAE) refers to the widespread impairment of brain function caused by noncentral nervous system infection mediated by sepsis. Lipid peroxidation-induced ferroptosis contributes to the occurrence and course of SAE. This study aimed to investigate the relationship between neuronal injury and lipid peroxidation-induced ferroptosis in SAE. Methods: Baseline data were collected from pediatric patients upon admission, and the expression levels of various markers related to lipid peroxidation and ferroptosis were monitored in the serum and peripheral blood mononuclear cells (PBMCs) of patients with SAE as well as SAE model mice. The hippocampal phosphatidylethanolamine-binding protein (PEBP)-1/15-lysine oxidase (LOX)/ glutathione peroxidase 4 (GPX4) pathway was assessed for its role on the inhibitory effect of ferroptosis in SAE treatment. Results: The results showed elevated levels of S100 calcium-binding protein beta (S-100β), glial fibrillary acidic protein, and malondialdehyde in the serum of SAE patients, while superoxide dismutase levels were reduced. Furthermore, analysis of PBMCs revealed increased transcription levels of PEBP1, LOX, and long-chain fatty acyl-CoA synthetase family member 4 (ACSL4) in SAE patients, while the transcription levels of GPX4 and cystine/glutamate transporter xCT (SLC7A11) were decreased. In comparison to the control group, the SAE mice exhibited increased expression of S-100β and neuron-specific enolase (NSE) in the hippocampus, whereas the expression of S-100β and NSE were reduced in deferoxamine (DFO) mice. Additionally, iron accumulation was observed in the hippocampus of SAE mice, while the iron ion levels were reduced in the DFO mice. Inhibition of ferroptosis alleviated the mitochondrial damage (as assessed by transmission electron microscopy, hippocampal mitochondrial ATP detection, and the JC-1 polymer-to-monomer ratio in the hippocampus) and the oxidative stress response induced by SAE as well as attenuated neuroinflammatory reactions. Further investigations revealed that the mechanism underlying the inhibitory effect of ferroptosis in SAE treatment is associated with the hippocampal PEBP-1/15-LOX/GPX4 pathway. Conclusion: These results offer potential therapeutic targets for the management of neuronal injury in SAE and valuable insights into the potential mechanisms of ferroptosis in neurological disorders. [ABSTRACT FROM AUTHOR]

Fused heterocyclic core-based molecules have high-performing advantages; however, non-fused heterocyclic materials deserve to be studied because of their facile synthetic routes and tunability in optoelectronic properties. In this work, we reported five molecules, namely, D1, D2, D3, D4, and D5 containing imidazolyl–thienyl–imidazolyl-based core, and four peripheral TPA donor units substituted with five acceptors A1, A2, A3, A4, and A5 by thiophene spacer were simulated for theoretical investigation of photovoltaic properties using reference R molecule as a model. For the optimization of geometry and forecasting important electronic parameters, computations with density functional theory-based B3LYP functional and 6-31G (d, p) basis set in both gas and THF were carried out. The calculations include frontier molecular orbital (FMO) energies, band gap energies, density of state (DOS), transition density matrix (TDM), reorganizational energies of hole and electron, molecular electrostatic potential (MEP), open-circuit voltage (Voc), and power conversion efficiencies (PCE). The results show that this molecular engineering of non-fused rings endows these molecules with interesting features, including the shift in absorption, change in frontier orbital energies, and decrease in reorganizational energies and elevating device efficiencies PCE = 7.44% when compared with reference R = 1.35%. The molecular strategy of these new molecules give us the possibility that these simple structured, and easy to chemically modified non-fused rings can be used as building blocks in OSCs and PSCs. [ABSTRACT FROM AUTHOR]

The disease-specific accumulation of pathological proteins has long been the major focus of research in neurodegenerative diseases (ND), including Alzheimer's disease (AD) and related dementias (RD), but the recent identification of a multitude of genetic risk factors for ND in immune-associated genes highlights the importance of immune processes in disease pathogenesis and progression. Studies in animal models have characterized the local immune response to disease-specific proteins in AD and ADRD, but due to the complexity of disease processes and the co-existence of multiple protein pathologies in human donor brains, the precise role of immune processes in ND is far from understood. To better characterize the interplay between different extracellular and intracellular protein pathologies and the brain's intrinsic immune system in ND, we set out to comprehensively profile the local immune response in postmortem brain samples of individuals with "pure" beta-Amyloid and tau pathology (AD), "pure" α-Synuclein pathology in Lewy body diseases (LBD), as well as cases with Alzheimer's disease neuropathological changes (ADNC) and Lewy body pathology (MIX). Combining immunohistochemical profiling of microglia and digital image analysis, along with deep immunophenotyping using gene expression profiling on the NanoString nCounter® platform and digital spatial profiling on the NanoString GeoMx® platform we identified a robust immune activation signature in AD brain samples. This signature is maintained in persons with mixed pathologies, irrespective of co-existence of AD pathology and Lewy body (LB) pathology, while LBD brain samples with "pure" LB pathology exhibit an attenuated and distinct immune signature. Our studies highlight disease- and brain region-specific immune response profiles to intracellular and extracellular protein pathologies and further underscore the complexity of neuroimmune interactions in ND. [ABSTRACT FROM AUTHOR]

Ferroptosis, a type of cell death involving iron and lipid peroxidation, has been found to be closely associated with the development of many diseases. Mitochondria are vital components of eukaryotic cells, serving important functions in energy production, cellular metabolism, and apoptosis regulation. Presently, the precise relationship between mitochondria and ferroptosis remains unclear. In this study, we aim to systematically elucidate the mechanisms via which mitochondria regulate ferroptosis from multiple perspectives to provide novel insights into mitochondrial functions in ferroptosis. Additionally, we present a comprehensive overview of how mitochondria contribute to ferroptosis in different conditions, including cancer, cardiovascular disease, inflammatory disease, mitochondrial DNA depletion syndrome, and novel coronavirus pneumonia. Gaining a comprehensive understanding of the involvement of mitochondria in ferroptosis could lead to more effective approaches for both basic cell biology studies and medical treatments. [ABSTRACT FROM AUTHOR]

Tripartite motif 21 (TRIM21) is an E3 ubiquitin ligase that shows great promise for protein degradation through ubiquitination. Here, ultrasmall chiral gold nanoparticles (D- or L-NPs) modified by D- or L-glutathione ligands were fabricated. After conjugated with an NLR family pyrin domain-containing protein 3 (NLRP3) antibody (D-NP-aNLRP3 or L-NP-aNLRP3), D-NP-aNLRP3 showed effective delivery efficiency of the antibody into microglia and prevented Aβ-mediated microglia senescence, and p16ink4a, a marker of senescence, in the microglia was reduced by 90.3% ± 7.8% while L-NP-aNLRP3 decreased by 48.01% ± 3.1%. Mechanistic investigations revealed that the D-NP-aNLRP3 ((1.5 ± 0.3) × 107 M−1) exhibited sixteen-fold larger binding affinity to transmembrane glycoprotein SLC3A2 than L-type ((9.5 ± 2.7) × 105 M−1), which led to a high efficiency of antibody delivery and TRIM21-dependent NLRP3 degradation. Notably, the blood-brain barrier (BBB)-crossing ability of chiral NP-aNLRP3 as well as NLRP3 degradation was demonstrated in vivo. The APP/PS1 Alzheimer's disease (AD) model mice experiments exhibited a reduction of 89.7% ± 6.8% for the NLRP3 protein and 84.2 ± 7.5% for p16ink4a following the intravenous administration of D-NP-aNLRP3 once a week for 60 days. Furthermore, the levels of the AD markers Aβ and phosphorylated-Tau in the brains were reduced by 86.2% ± 8.2% and 81.6% ± 9.1%; these were 2.1-fold and 1.9-fold higher than those treated with L-NP-aNLRP3, respectively. The studies provide a method to rescue AD-like pathologies and prevent senescence. [ABSTRACT FROM AUTHOR]

Sarcoma is a malignant tumor that originates from mesenchymal tissue. The common treatment for sarcoma is surgery supplemented with radiotherapy and chemotherapy. However, patients have a 5-year survival rate of only approximately 60%, and sarcoma cells are highly resistant to chemotherapy. Ferroptosis is an iron-dependent nonapoptotic type of regulated programmed cell death that is closely related to the pathophysiological processes underlying tumorigenesis, neurological diseases and other conditions. Moreover, ferroptosis is mediated via multiple regulatory pathways that may be targets for disease therapy. Recent studies have shown that the induction of ferroptosis is an effective way to kill sarcoma cells and reduce their resistance to chemotherapeutic drugs. Moreover, ferroptosis-related genes are related to the immune system, and their expression can be used to predict sarcoma prognosis. In this review, we describe the molecular mechanism underlying ferroptosis in detail, systematically summarize recent research progress with respect to ferroptosis application as a sarcoma treatment in various contexts, and point out gaps in the theoretical research on ferroptosis, challenges to its clinical application, potential resolutions of these challenges to promote ferroptosis as an efficient, reliable and novel method of clinical sarcoma treatment. [ABSTRACT FROM AUTHOR]

Ferroptosis, a regulated cell death hallmarked by excessive lipid peroxidation, is implicated in various (patho)physiological contexts. During ferroptosis, lipid peroxidation leads to a diverse change in membrane properties and the dysre)gulation of ion homeostasis via the cation channels, ultimately resulting in plasma membrane rupture. This review illuminates cellular membrane dynamics and cation handling in ferroptosis regulation. [ABSTRACT FROM AUTHOR]

Molecular dynamics is a powerful tool that has been long used for the simulation of biomolecules. It complements experiments, by providing detailed information about individual atomic motions. But there is an essential and often overlooked assumption that, left unchecked, could invalidate any results from it: is the simulated trajectory long enough, so that the system has reached thermodynamic equilibrium, and the measured properties are converged? Previous studies showed mixed results in relation to this assumption. This has profound implications, as the resulting simulated trajectories may not be reliable in predicting equilibrium properties. Yet, this is precisely what most molecular dynamics studies do. So the question arises: are these studies even valid?Here, we present a thorough analysis of up to a hundred microseconds long trajectories, of several system with varying size, to probe the convergence of different structural, dynamical and cumulative properties, and elaborate on the relevance of the concept of equilibrium, and its physical and biological meaning. The results show that properties with the most biological interest tend to converge in multi-microsecond trajectories, although other properties–like transition rates to low probability conformations–may require more time. Molecular dynamics (MD) is a powerful tool for the simulation of proteins and other biomolecules, however, convergence and equilibrium in MD simulations remain underexplored. Here, the authors investigate long MD trajectories of several proteins and reveal that, although full convergence of all properties may not be reached, the most biologically interesting properties do, in fact, reach convergence during multi-microsecond simulation trajectories. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a global public safety issue that poses a threat to death, characterized by high fatality rates, severe injuries and low recovery rates. There is growing evidence that necroptosis regulates the pathophysiological processes of a variety of diseases, particularly those affecting the central nervous system. Thus, moderate necroptosis inhibition may be helpful in the management of TBI. Receptor-interacting protein kinase (RIP) 3 is a key mediator in the necroptosis, and its absence helps restore the microenvironment at the injured site and improve cognitive impairment after TBI. In this report, we review different domains of RIP3, multiple analyses of necroptosis, and associations between necroptosis and TBI, RIP3, RIP1, and mixed lineage kinase domain-like. Next, we elucidate the potential involvement of RIP3 in TBI and highlight how RIP3 deficiency enhances neuronal function. [ABSTRACT FROM AUTHOR]

Mitochondria are organelles with double-membrane structure of inner and outer membrane, which provides main energy support for cell growth and metabolism. Reactive oxygen species (ROS) mainly comes from mitochondrial and can cause irreversible damage to cells under oxidative stress. Thus, mitochondrial homeostasis is the basis for maintaining the normal physiological function of cells and mitophagy plays a pivotal role in the maintenance of mitochondrial homeostasis. At present, to enhance the sensitivity of cancer cells to radiotherapy and chemotherapy by regulating mitochondria has increasingly become a hot spot of cancer therapy. It is particularly important to study the effect of ionizing radiation (IR) on mitochondria and the role of mitophagy in the radiosensitivity of cancer cells. Most of the existing reviews have focused on mitophagy-related molecules or pathways and the impact of mitophagy on diseases. In this review, we mainly focus on discussing the relationship between mitophagy and radiosensitivity of cancer cells around mitochondria and IR. [ABSTRACT FROM AUTHOR]

Potassium (K+) channels play vital roles in various physiological functions, including regulating K+ flow in cell membranes, impacting nervous system signal transduction, neuronal firing, muscle contraction, neurotransmitters, and enzyme secretion. Their activation and switch‐off are directly linked to diseases like arrhythmias, atrial fibrillation, and pain etc. Although the experimental methods play important roles in the studying the structure and function of K+ channels, they are still some limitations to enclose the dynamic molecular processes and the corresponding mechanisms of conformational changes during ion transport, permeation, and gating control. Relatively, computational methods have obvious advantages in studying such problems compared with experimental methods. Recently, more and more three‐dimensional structures of K+ channels have been disclosed based on experimental methods and in silico prediction methods, which provide a good chance to study the molecular mechanism of conformational changes related to the functional regulations of K+ channels. Based on these structural details, molecular dynamics simulations together with related methods such as enhanced sampling and free energy calculations, have been widely used to reveal the conformational dynamics, ion conductance, ion channel gating, and ligand binding mechanisms. Additionally, the accessibility of structures also provides a large space for structure‐based drug design. This review mainly addresses the recent progress of computational methods in the structure, mechanism, and drug design of K+ channels. After summarizing the progress in these fields, we also give our opinion on the future direction in the area of K+ channel research combined with the cutting edge of computational methods. This article is categorized under:Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo MethodsStructure and Mechanism > Computational Biochemistry and BiophysicsData Science > Chemoinformatics [ABSTRACT FROM AUTHOR]