Cell Signaling Research Articles

Unraveling the AKT/ERK cascade and its role in Parkinson disease.

Parkinson disease represents a significant and growing burden on global healthcare systems, necessitating a deeper understanding of their underlying molecular mechanisms for the development of effective treatments. The AKT and ERK pathways play crucial roles in the disease, influencing multiple cellular pathways that support neuronal survival. Researchers have made notable progress in uncovering how these pathways are controlled by upstream kinases and how their downstream effects contribute to cell signalling. However, as we delve deeper into their intricacies, we encounter increasing complexity, compounded by the convergence of multiple signalling pathways. Many of their targets overlap with those of other kinases, and they not only affect specific substrates but also influence entire signalling networks. This review explores the intricate interplay of the AKT/ERK pathways with several other signalling cascades, including oxidative stress, endoplasmic reticulum stress, calcium homeostasis, inflammation, and autophagy, in the context of Parkinson disease. We discuss how dysregulation of these pathways contributes to disease progression and neuronal dysfunction, highlighting potential therapeutic targets for intervention. By elucidating the complex network of interactions between the AKT/ERK pathways and other signalling cascades, this review aims to provide insights into the pathogenesis of Parkinson disease and describe the development of novel therapeutic strategies.

Antipruritic effect of ursolic acid through MRGPRX2/MrgprB2-dependent inhibition of mast cell degranulation and reduced TSLP production

Ursolic acid (UA), a pentacyclic triterpene, exhibits diverse pharmacological effects, including potential treatment for allergic diseases. It downregulates thymic stromal lymphopoietin (TSLP) and disrupts mast cell signaling pathways. However, the exact molecular mechanism by which UA interferes with mast cell action remains unclear. Therefore, the current study aimed to uncover molecular entities underlying the effect of UA on mast cells and its potential antipruritic effect, specifically investigating its modulation of key molecules such as TRPV4, PAR2, and MRGPRX2, which are involved in TSLP regulation and sensation.Calcium imaging experiments revealed that UA pretreatment significantly suppressed MRGPRX2 activation (and its mouse orthologue MrgprB2), a G protein-coupled receptor predominantly expressed in mast cells. Molecular docking predictions suggested potential interactions between UA and MRGPRX2/MrgprB2. UA pretreatment also reduced mast cell degranulation through MRGPRX2 and MrgprB2-dependent mechanisms. In a dry skin mouse model, UA administration decreased tryptase and TSLP production in the skin, and diminished TSLP response in the sensory neurons. While PAR2 and TRPV4 activation enhances TSLP production, UA did not inhibit their activity. Notably, UA attenuated compound 48/80-induced scratching behaviors in mice and suppressed spontaneous scratching in a dry skin model.The present study confirms the effective inhibition of UA on MRGPRX2/MrgprB2, leading to reduced mast cell degranulation and suppressed scratching behaviors. These findings highlight the potential of UA as an antipruritic agent for managing various allergy- or itch-related conditions.

A comprehensive view on the fisetin impact on colorectal cancer in animal models: Focusing on cellular and molecular mechanisms.

Flavonoids, including fisetin, have been linked to a reduced risk of colorectal cancer (CRC) and have potential therapeutic applications for the condition. Fisetin, a natural flavonoid found in various fruits and vegetables, has shown promise in managing CRC due to its diverse biological activities. It has been found to influence key cell signaling pathways related to inflammation, angiogenesis, apoptosis, and transcription factors. The results of this study demonstrate that fisetin induces colon cancer cell apoptosis through multiple mechanisms. It impacts the p53 pathway, leading to increased levels of p53 and decreased levels of murine double minute 2, contributing to apoptosis induction. Fisetin also triggers the release of important components in the apoptotic process, such as second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI and cytochrome c. Furthermore, fisetin inhibits the cyclooxygenase-2 and wingless-related integration site (Wnt)/epidermal growth factor receptor/nuclear factor kappa B signaling pathways, reducing Wnt target gene expression and hindering colony formation. It achieves this by regulating the activities of cyclin-dependent kinase 2 and cyclin-dependent kinase 4, reducing retinoblastoma protein phosphorylation, decreasing cyclin E levels, and increasing p21 levels, ultimately influencing E2 promoter binding factor 1 and cell division cycle 2 (CDC2) protein levels. Additionally, fisetin exhibits various effects on CRC cells, including inhibiting the phosphorylation of Y-box binding protein 1 and ribosomal S6 kinase, promoting the phosphorylation of extracellular signal-regulated kinase 1/2, and disrupting the repair process of DNA double-strand breaks. Moreover, fisetin serves as an adjunct therapy for the prevention and treatment of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA)-mutant CRC, resulting in a reduction in phosphatidylinositol-3 kinase (PI3K) expression, Ak strain transforming phosphorylation, mTOR activity, and downstream target proteins in CRC cells with a PIK3CA mutation. These findings highlight the multifaceted potential of fisetin in managing CRC and position it as a promising candidate for future therapy development.

The influence of metabolic disorders on adaptive immunity.

The immune system plays a crucial role in protecting the body from invading pathogens and maintaining tissue homoeostasis. Maintaining homoeostatic lipid metabolism is an important aspect of efficient immune cell function and when disrupted immune cell function is impaired. There are numerous metabolic diseases whereby systemic lipid metabolism and cellular function is impaired. In the context of metabolic disorders, chronic inflammation is suggested to be a major contributor to disease progression. A major contributor to tissue dysfunction in metabolic disease is ectopic lipid deposition, which is generally caused by diet and genetic factors. Thus, we propose the idea, that similar to tissue and organ damage in metabolic disorders, excessive accumulation of lipid in immune cells promotes a dysfunctional immune system (beyond the classical foam cell) and contributes to disease pathology. Herein, we review the evidence that lipid accumulation through diet can modulate the production and function of immune cells by altering cellular lipid content. This can impact immune cell signalling, activation, migration, and death, ultimately affecting key aspects of the immune system such as neutralising pathogens, antigen presentation, effector cell activation and resolving inflammation.

Transient frequency preference responses in cell signaling systems

Ligand–receptor systems, covalent modification cycles, and transcriptional networks are the fundamental components of cell signaling and gene expression systems. While their behavior in reaching a steady-state regime under step-like stimulation is well understood, their response under repetitive stimulation, particularly at early time stages is poorly characterized. Yet, early-stage responses to external inputs are arguably as informative as late-stage ones. In simple systems, a periodic stimulation elicits an initial transient response, followed by periodic behavior. Transient responses are relevant when the stimulation has a limited time span, or when the stimulated component’s timescale is slow as compared to the timescales of the downstream processes, in which case the latter processes may be capturing only those transients. In this study, we analyze the frequency response of simple motifs at different time stages. We use dose-conserved pulsatile input signals and consider different metrics versus frequency curves. We show that in ligand–receptor systems, there is a frequency preference response in some specific metrics during the transient stages, which is not present in the periodic regime. We suggest this is a general system-level mechanism that cells may use to filter input signals that have consequences for higher order circuits. In addition, we evaluate how the described behavior in isolated motifs is reflected in similar types of responses in cascades and pathways of which they are a part. Our studies suggest that transient frequency preferences are important dynamic features of cell signaling and gene expression systems, which have been overlooked.

HIV infection is associated with compromised tumor microenvironment adaptive immune reactivity in Hodgkin lymphoma

AbstractThe impact of HIV infection on the tumor microenvironment (TME) of classic Hodgkin lymphoma (cHL), one of the most common comorbidities after HIV infection, is not well understood. Here, we have used multiplexed immunofluorescence and spatial transcriptomic analysis to dissect the impact of viral infections (Epstein-Barr virus [EBV] and HIV/EBV) on cHL TME. HIV−EBV+ cHL TME was characterized by higher cell densities of CD8high T cells coexpressing inhibitory receptors (PD-1 and TIGIT), macrophage subsets, and an in situ inflammatory molecular profile associated with increased expression of T-cell receptor (TCR) and B-cell receptor cell signaling pathways than HIV−EBV− cHL TME. Compared with HIV−EBV+, HIV+EBV+ cHL TME was characterized by significantly less CD8high T cells coexpressing PD-1 and TIGIT, a profile concomitant with significantly increased cell densities of CD155high neoplastic cells. Significant downregulation of in situ TCR signaling and upregulation of extracellular matrix reorganization pathways were found in HIV+EBV+ cHL TME, in line with an altered topological organization of CXCL13 and heparan sulfate, an extracellular matrix glycosaminoglycan. Our data reveal the complexity of the cellular and molecular composition of cHL TME in the presence of viral infections, with possible implications for combinatorial immunotherapies. Furthermore, the data suggest specific molecular targets and pathways for further investigation that could improve our understanding of possible mechanistic links between HIV and lymphomagenesis.

The Impact of PAD4-dependent Neutrophil Extracellular Trap Formation on the Early Development of Intestinal Fibrosis in Crohn's Disease.

During early phases of inflammation, activated neutrophils extrude neutrophil extracellular traps (NETs) in a PAD4-dependent manner, aggravating tissue injury and remodelling. In this study, we investigated the potential pro-fibrotic properties and signalling of NETs in Crohn's disease (CD). NETs and activated fibroblasts were labelled on resected ileum from CD patients by multiplex immunofluorescence staining. NETs-treated human primary intestinal fibroblasts were analysed by bulk RNA-sequencing to uncover cell signalling pathways, and by high-throughput imaging to assess collagen production and migratory activity. Consequentially, TLR2/NF-kB pathway was evaluated by transfection of CCD-18Co fibroblasts with NF-kB-luciferase reporter plasmid, incorporating C29 to block TLR2 signalling. A chronic DSS mouse model was used to define the specific role of PAD4 deletion in neutrophils (MRP8-Cre, Pad4fl/fl). Immunofluorescence showed spatial co-localisation of NETs and activated fibroblasts in ileal ulcerations of CD patients. Transcriptomic analysis revealed upregulation of pro-fibrotic genes and activation of TLR-signalling pathways in NETs-treated fibroblasts. NETs treatment induced fibroblast proliferation, diminished migratory capability, and increased collagen release. Transfection experiments indicated a substantial increase in NF-kB expression with NETs, whereas C29 led to decreased expression and release of collagen. In line, a significantly reduction in collagen content was observed in the colon of MRP8-Cre, Pad4fl/fl mice subjected to chronic DSS colitis. NETs potentially serve as an initial stimulus for pathological activation of fibroblasts within the intestine via the TLR2/NF-kB pathway. Given their early involvement in inflammation, inhibition of PAD4 might offer a strategy to modulate both inflammation and fibrogenesis in CD.

MicroRNA miR-27a-5p reduces intestinal inflammation induced by Clostridioides difficile flagella by regulating the NF-κB signaling pathway.

Clostridioides difficile is a major cause of nosocomial post-antibiotic infections, often resulting in severe inflammation and watery diarrhea. Previous studies have highlighted the role of C. difficile flagellin FliC in activating the TLR5 receptor and triggering NF-κB cell signaling, leading to the release of pro-inflammatory cytokines. However, the microRNAs (miRNAs) mediated regulatory mechanisms underlying the FliC-induced inflammatory response remain unclear. miRNA expression levels were analyzed in Caco-2 intestinal epithelial cells following FliC stimulation, infection with the epidemic C. difficile R20291 strain, or its unflagellated mutant by RT-qPCR. Chemical inhibitors were used to block NF-κB signaling, and their impact on miR-27a-5p expression was assessed. Knockdown and overexpression experiments with miRNA inhibitor and mimic were conducted to elucidate miR-27a-5p's functional role in FliC-induced inflammatory responses. Additionally, a mouse model of C. difficile infection was treated with miR-27a-5p to evaluate its therapeutic potential in vivo. miR-27a-5p showed significant FliC-dependent overexpression in Caco-2 cells. Inhibition of NF-κB signaling suppressed miR-27a-5p overexpression. Knockdown of miR-27a-5p increased NF-κB activation and TNF-α and IL-8 cytokine production, while its overexpression had the opposite effect. Moreover, miR-27a-5p was overexpressed in the caeca of C. difficile-infected mice, correlating with intestinal IL-8 levels. Treatment of infected mice with miR-27a-5p mimic reduced disease severity and intestinal inflammation. miR-27a-5p plays a crucial role in regulating C. difficile-induced inflammation, suggesting its potential as a therapeutic target for controlling severe infection. These findings offer valuable insights into potential therapeutic strategies for managing C. difficile infection and associated inflammatory complications.

Understanding the Reaction Processes in Li-Ion Batteries By Voltage Relaxation Analysis

The open circuit voltage (OCV) transient observed after current interruption is a very useful electrochemical signal providing crucial information about a Li-ion battery (LIB), including its state of charge and health, and kinetics of internal processes. Generally, OCV transient is divided into immediate and long-term relaxations, which are probably related to current-dependent kinetic processes and changes in the instantaneous thermodynamic state, respectively. Previous studies have attempted to analyze the pulse and relaxation voltages of LIBs under Li concentration gradients in both the electrolyte and electrode, with much success. Nevertheless, they have been limited in understanding what is really happening inside the cell in detail. This was mainly due to the fact that the experiments were performed on full cells with overlapping anode and cathode signals, which hindered the interpretation of detailed internal reactions, and for the same reason, only unsystematic phenomenological interpretations were possible. So it is necessary to separate relaxation signals from the anode and cathode for more accurate analysis. Even in a half-cell, where the signal contribution of the Li counter electrode (CE) to the overall cell signal is believed to be very small, the degree of potential relaxation attributable to the CE might be non-negligible due to the concentration change of active ions around the electrode. Therefore, in order to fully understand the electrochemical characteristics of the working electrode (WE), a precise analysis of the voltage relaxation of a single electrode is required.In this study, various test cells, including three-electrode half-cells and full cell, and a voltage-controllable symmetrical cell, were fabricated to analyze the pulse and relaxation process in order to further understand the reaction kinetics of the battery. In particular, we aimed to distinguish the detailed processes and to understand the overvoltage evolution during battery operation. For this purpose, Ni-rich layered oxide and graphite were used as the cathode and anode, respectively. Li metal was adopted as the CE and RE in both the half-cell and three-electrode cells. In the two- and three-electrode cathode half-cell experiments, it was confirmed that the overpotential contribution of Li CE in half-cells was one-third to half of total overpotential in specific operating conditions. Considering the relatively fast redox reaction rate of Li, this result strongly implies that a concentration overpotential due to the CE can play a critical role in OCV relaxation. In other words, a typical test cell structure where the opposing areas of WE and CE are similar, total cell overpotential is greatly affected by CE. Supporting this argument, a cell designed with a large CE area and abundant electrolyte showed the very small contribution of CE. In experiments with two- and three-electrode anode half-cells, the contribution of Li CE was similar to that of the cathode half-cell. Next, to investigate the change in the effect of Li CE on the overall overpotential as the cell degrades under repeated cycles, the OCV relaxation with cycles was analyzed for the test cells used above. The analysis revealed an obvious cycle dependence of the long-term OCV relaxation signal, which was confirmed to be largely an effect of Li CE. To investigate the unexpected voltage behavior of Li, Li symmetric cells were configured to obtain voltage curves over time with cycling. From the analysis results, it is proposed that the voltage curve variation is mainly due to different local reaction resistances and highly tortuous surface morphology of the Li surface.In conclusion, the overpotential of Li CE had a large impact on total overpotential in the commonly used two-electrode half-cells, which may cause errors in voltage curve interpretation. Under these circumstances, we further investigated whether the systematic and thorough analysis of the OCV relaxation could reliably separate the cathode and anode overpotential signals in the full cell, as well as the detailed reaction signals at each electrode. To this end, we performed an overpotential analysis using two- and three-electrode cells, as well as a voltage-controllable symmetrical cell, cross-validating the results with those obtained in the half-cell experiments above and electrochemical impedance spectroscopy. In this presentation, we will show how to derive the overpotential contribution of the cathode and anode, and the detailed reaction processes from the short- and long-term OCV relaxation curves obtained from a full-cell. Furthermore, we will discuss the reliability of the separated signals and possible future work to improve their accuracy.

Identification of POU4F1 as a novel prognostic biomarker and therapeutic target in esophageal squamous cell carcinoma

BackgroundEsophageal cancer is a significant global health concern, ranking seventh in incidence and sixth in mortality. It encompasses two pathological types: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma, with ESCC being more prevalent globally and associated with higher mortality rates. The POU (Pit-Oct-Unc) domain family transcription factors, comprising 15 members, play important roles in embryonic development and organ formation. Aberrant expression of POUs has been observed in several human cancers, influencing cell proliferation, tumor invasion, and drug resistance. However, their specific role in ESCC remains unknown.MethodsWe analyzed TCGA and GEO databases to assess POUs expression in ESCC tissues. Kaplan-Meier and ROC analyses were used to evaluate the prognostic value of POUs. Gene Set Enrichment Analysis and Protein-Protein interaction network were used to explore the potential pathway. Functional assays (Cell Counting Kit-8, EdU Staining assay, and cloning formation assay) and mechanism analyses (RNA-seq, flow cytometry, and Western blot) were conducted to determine the effects of POU4F1 knockdown on ESCC cell phenotypes and signaling pathways.ResultsPOU4F1 and POU6F2 were upregulated in various cancer tissues, including ESCC, compared to normal tissues. POU4F1 expression was significantly correlated with patient survival and superior to previous models (AUC = 0.776). Knockdown of POU4F1 inhibited ESCC cell proliferation and affected cell cycle, autophagy, and DNA damage pathways in ESCC cells.ConclusionPOU4F1 is a novel and promising prognostic and therapeutic target for ESCC patients, providing insights into potential treatment strategies.

Deciphering the effect of a Cu(II)-hydrazone complex on intracellular cell signalling pathways in a human osteosarcoma 2D and 3D models.

New therapeutic strategies for osteosarcoma (OS) have demonstrated the potential efficacy of copper compounds as anticancer drugs and as a substitute for the often used platinum compounds. OS is a type of bone cancer, primarily affecting young adults and children..The main objective of this work is to discover the molecular targets and cellular pathways related to the antitumor properties of a Cu(II)-hydrazone toward human OS 2D and 3D systems. Cell viability study using MG-63 cells was evaluated in OS monolayer and spheroids. CuHL significantly reduced cell viability in OS models (IC50 2D: 2.6 ± 0.3 µM; IC50 3D: 9.9 ± 1.4 µM) (p<0.001). Also, CuHL inhibits cell proliferation and it induces cells to apoptosis. The main mechanism of action found for CuHL are the interaction with DNA, genotoxicity, the ROS generation and the proteasome activity inhibition. Besides, 67 differentially expressed proteins were found using proteomic approaches. Of those 67 proteins, 40 were found overexpressed and 27 underexpressed. The response to stress and to unfolded protein, as well as ATP synthesis were the most affected biological process among upregulated proteins, whilst proteins related to DNA replication and redox homeostasis were downregulated.

Enhancement of response learning in male rats with intrastriatal infusions of a BDNF - TrkB agonist, 7,8-dihydroxyflavone.

Enhancement of learning and memory by cognitive and physical exercise may be mediated by brain-derived neurotrophic factor (BDNF) acting at tropomyosin receptor kinase B (TrkB). Upregulation of BDNF and systemic administration of a TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), enhance learning of several hippocampus-sensitive tasks in rodents. Although BDNF and 7,8-DHF enhance functions of other brain areas too, these effects have mainly targeted non-cognitive functions. One goal of the present study was to determine whether 7,8-DHF would act beyond the hippocampus to enhance cognitive functions sensitive to manipulations of the striatum. Here, we examined the effects of intrastriatal infusions of 7,8-DHF on learning a striatum-sensitive response maze and on phosphorylation of TrkB receptors in 3-month-old male Sprague Dawley rats. Most prior studies of BDNF and 7,8-DHF effects on learning and memory have administered the drugs for days to months before assessing effects on cognition. A second goal of the present study was to determine whether a single drug treatment near the time of training would effectively enhance learning. Moreover, 7,8-DHF is often tested for its ability to reverse impairments in learning and memory rather than to enhance these functions in the absence of impairments. Thus, a third goal of this experiment was to evaluate the efficacy of 7,8-DHF in enhancing learning in unimpaired rats. In untrained rats, intrastriatal infusions of 7,8-DHF resulted in phosphorylation of TrkB receptors, suggesting that 7,8-DHF acted as a TrkB agonist and BDNF mimic. The findings that a single, intra-striatal infusion of 7,8-DHF 20 min before training enhanced response learning in rats suggest that, in addition to its trophic effects, BDNF modulates learning and memory through receptor mediated cell signaling events.

Structure of a model lipid membrane oxidized by human 15-lipoxygenase-2

Enzyme-mediated lipid oxidation is an important regulatory event in cell signaling, with oxidized lipids being potent signaling molecules that can illicit dramatic changes in cell behavior. For example, peroxidation of an arachidonoyl poly-unsaturated fatty acid by the human enzyme 15-lipoxygenase-2 (15-LOX-2) has been associated with formation of atherosclerotic plaques. Previous work on synthetically oxidized membranes has shown that oxidized lipid tails will change their conformation to facilitate interactions between the peroxide group and the lipid headgroups. However, this phenomenon has not been directly observed for a lipid membrane that has undergone enzyme-catalyzed oxidation. In this study, we report on the structure of a model lipid membrane before and after oxidation by 15-LOX-2. A model lipid membrane monolayer at the air-liquid interface was constructed from 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (SAPC) in a Langmuir trough, and X-ray reflectivity measurements were conducted to determine the electron density profile of the system. Exposure to 15-LOX-2 caused a dramatic change in the SAPC structure, namely a blurred distinction between the lipid tail/head layers and shortening of the average lipid tail length by ∼3 Å. The electron density profile of the oxidized SAPC monolayer is similar to that of a synthetically oxidized substrate mimic. Overall, this reported observation of an enzymatically-oxidized membrane structure in situ is helping to bridge a gap in the literature between structural studies on synthetically oxidized membranes and cellular studies aiming to understand physiological responses.

T cell receptor clonotype in tumor microenvironment contributes to intratumoral signaling network in patients with colorectal cancer.

Single-cell RNA sequencing (scRNA-seq) has contributed to understanding cellular heterogeneity and immune profiling in cancer. The aim of the study was to investigate gene expression and immune profiling in colorectal cancer (CRC) using scRNA-seq. We analyzed single-cell gene expression and T cell receptor (TCR) sequences in 30 pairs of CRC and matched normal tissue. Intratumoral lymphocytes were measured with digital image analysis. CRC had more T cells, epithelial cells, and myeloid cells than normal colorectal tissue. CRCs with microsatellite instability had more abundant T cells than those without microsatellite instability. Immune cell compositions of CRC and normal colorectal tissue were inversely correlated. CD4 + or CD8 + proliferating T cells, CD4 + effector memory T cells, CD8 + naïve T cells, and regulatory T cells of CRC showed higher TCR clonal expansion. Tumor epithelial cells interacted with immune cells more strongly than normal. T cells, myeloid cells, and fibroblasts from CRCs of expanded T cell clonotypes showed increased expression of genes related to TNF and NFKB signaling and T cell activation. CRCs of expanded T cell clonotypes also showed stronger cellular interactions among immune cells, fibroblasts, and endothelial cells. Pro-inflammatory CXCL and TNF signaling were activated in CRCs of expanded T cell clonotype. In conclusion, scRNA-seq analysis revealed different immune cell compositions, differential gene expression, and diverse TCR clonotype dynamics in CRC. TCR clonality expansion is associated with immune activation through T cell signaling and chemokine signaling. Patients with CRCs of expanded clonotype can be promising candidates for immunotherapy.

Starch metabolism in guard cells: At the intersection of environmental stimuli and stomatal movement.

Starch metabolism in guard cells plays a central role in regulating stomatal movement in response to light, elevated ambient CO2 and potentially other abiotic and biotic factors. Here, we discuss how various guard cell signal transduction pathways converge to promote rearrangements in guard cell starch metabolism for efficient stomatal responses, an essential physiological process that sustains plant productivity and stress tolerance. We suggest manipulation of guard cell starch dynamics as a previously overlooked strategy to improve stomatal behaviour under changing environmental conditions.

Nrf2 cell signaling pathway is responsible for the antioxidant effect of resveratrol in aging.

One of the markers of aging is oxidative stress, a condition characterized by an increase in free radicals concomitant with a reduction in antioxidant defenses. Within this, resveratrol is a compound that has been shown to act as a potent antioxidant. However, few studies highlight the cellular signaling pathways that are activated or inhibited during aging and that are responsible for this biological effect. To verify the antioxidant profile of resveratrol (5 μM) in leukocytes from donors in different age groups. The project was approved by the Ethics Committee. Individuals were divided into three groups: 20-39, 40-59, and 60-80 years old. After separating the leukocytes, assays were performed to evaluate the AMPK (AMP-activated protein kinase) and Nrf2 (erythroid nuclear factor 2-related factor 2) pathways. In addition, luciferase assay and enzyme-linked immunosorbent assay were performed to evaluate transcription factor activation and Nrf2 expression, respectively. The analysis between age and treatment was performed using Pearson correlation (*P < 0.05). There was a reduction in the antioxidant effect of resveratrol during the aging process. In leukocytes from donors over 60 years of age, the AMPK pathway was silenced. Nrf2 was active at all ages. There was an increase in the activation of the transcription factor and phosphorylated protein in all age groups. Nrf2 is an important biochemical mechanism responsible for the antioxidant effect of resveratrol. This effect diminishes with aging but is still observed. Geriatr Gerontol Int 2024; ••: ••-••.

GRB7 Plays a Vital Role in Promoting the Progression and Mediating Immune Evasion of Ovarian Cancer.

Despite breakthroughs in treatment, ovarian cancer (OC) remains one of the most lethal gynecological malignancies, with an increasing age-standardized mortality rate. This underscores an urgent need for novel biomarkers and therapeutic targets. Although growth factor receptor-bound protein 7 (GRB7) is implicated in cell signaling and tumorigenesis, its expression pattern and clinical implications in OC remain poorly characterized. To systematically investigate GRB7's expression in OC, our study utilized extensive datasets from TCGA, GTEx, CCLE, and GEO. The prognostic significance of GRB7 was evaluated by means of Kaplan-Meier and Cox regression analyses. Using a correlation analysis and gene set enrichment analysis, relationships between GRB7's expression and gene networks, immune cell infiltration and immunotherapy response were investigated. In vitro experiments were conducted to confirm GRB7's function in the biology of OC. Compared to normal tissues, OC tissues exhibited a substantial upregulation of GRB7. Reduced overall survival, disease-specific survival, and disease-free interval were all connected with high GRB7 mRNA levels. The network study demonstrated that GRB7 is involved in pathways relevant to the course of OC and has a positive connection with several key driver genes. Notably, GRB7's expression was linked to the infiltration of M2 macrophage and altered response to immunotherapy. Data from single-cell RNA sequencing data across multiple cancer types indicated GRB7's predominant expression in malignant cells. Moreover, OC cells with GRB7 deletion showed decreased proliferation and migration, as well as increased susceptibility to T cell-mediated cytotoxicity. With respect to OC, our results validated GRB7 as a viable prognostic biomarker and a promising therapeutic target, providing information about its function in tumorigenesis and immune modulation. GRB7's preferential expression in malignant cells highlights its significance in the biology of cancer and bolsters the possibility that it could be useful in enhancing the effectiveness of immunotherapy.

The Emerging Role of Herbal Medicines in Cancer by Interfering with Posttranslational Modifications.

Significance: Herbal medicines have a long history of comprehensive cancer treatment through various posttranslational modifications (PTMs). Recently, emerging evidence revealed that dysregulation of reactive oxygen species (ROS) and ROS-regulated signaling pathways influence cancer initiation, growth, and progression in a paradoxical role with either low levels or increasing levels of basal ROS. However, ROS-triggered modifications of target proteins in the face of ROS-mediated signal transduction are not fully understood in the anticancer therapies of herbal medicines. In this review, we briefly introduce the PTM-dependent regulations of herbal medicines, and then focus on the current ideals that targeting ROS-dependent PTMs via antioxidant and redox signaling pathways can provide a promising strategy in herbal-based anticancer effects. Recent Advances: Advanced development in highly sensitive mass spectrometry-based techniques has helped utilize ROS-triggered protein modifications in numerous cancers. Accumulating evidence has been achieved in laboratory to extensively ascertain the biological mechanism of herbal medicines targeting ROS in cancer therapy. Two general mechanisms underlining ROS-induced cell signaling include redox state and oxidative modification of target protein, indicating a new perspective to comprehend the intricate dialogues between herbal medicines and cancer cellular contexts. Critical Issues: Complex components of herbal medicines limit the benefits of herbal-based cancer therapies. In this review, we address that ROS-dependent PTMs add a layer of proteomic complexity to the cancer through altering the protein structure, expression, function, and localization. Elaborating ROS-triggered PTMs implicated in cell signaling, apoptosis, and transcriptional regulation function, and the possible cellular signaling, has provided important information about the contribution of many ROS targeting herbal therapies in anticancer effects. Continued optimization of proteomic strategies for PTM analysis in herbal medicines is also briefly discussed. Future Directions: Rigorous evaluations of herbal medicines and proteomic strategies are necessary to explore the aberrant regulation of ROS-triggered antioxidant and redox signaling contributing to the novel protein targets and herbal-associated pharmacological issues. These efforts will eventually help develop more herbal drugs as modern therapeutic agents.

The mechanism of ITGB4 in tumor migration and invasion.

Integrin β4 (ITGB4) is a transmembrane protein that functions as a mechanosensor, mediating the bidirectional exchange of information between the intracellular and extracellular matrices. ITGB4 plays a critical role in cell adhesion, migration, and signaling. Numerous studies have implicated ITGB4 as a key facilitator of tumor migration and invasion. This review provides a foundational description of the mechanisms by which ITGB4 regulates tumor migration and invasion through pathways involving focal adhesion kinase (FAK), protein kinase B (AKT), and matrix metalloproteinases (MMPs). These mechanisms encompass epithelial-mesenchymal transition (EMT), phosphorylation, and methylation of associated molecules. Additionally, this review explores the role of ITGB4 in the migration and invasion of prevalent clinical tumors, including those of the digestive system, breast, and prostate.

Contributions of T Cell Signaling for Wound Healing.

It has long been known that T cells participate in wound healing, however, it is still enigmatic about the landscape of the signaling derived from T cells in the process of wound healing. With the advantages of scRNA-seq, in combination of immunofluorescent imaging, we identified activated T cells, cytotoxic T cells (CTLs), exhausting T cells and Tregs existing in inflammation phase of wound healing. Further analysis revealed each T cell population possess distinguished signals contributed to wound healing, some are critical for improving the wound healing quality. Besides, this study discovered and validated the exhistance of exhausting T cells among the T cells accumulated in skin duing wound healing, and the molecular mechanism(s) and contribution of exhausting T cells to wound healing deserves extensive studies in the future.