Elevated Stress Research Articles

Impact of Oxidative Stress and Neuroinflammation on Sarco/Endoplasmic Reticulum Ca2+-ATPase 2b Downregulation and Endoplasmic Reticulum Stress in Temporal Lobe Epilepsy.

Epilepsy is one of the most common neurological disorders. Calcium dysregulation and neuroinflammation are essential and common mechanisms in epileptogenesis. Sarco/endoplasmic reticulum (ER) Ca2+-ATPase 2b (SERCA2b), a crucial calcium regulatory pump, plays pathological roles in various calcium dysregulation-related diseases. However, the link between SERCA2b and neuroinflammation in epilepsy remains undetermined. This study aimed to establish the relationship between SERCA2b, oxidative stress, and neuroinflammation in epilepsy to elucidate the underlying molecular mechanism in epileptogenesis. Neuroinflammation and oxidative stress were induced in N2a cells using lipopolysaccharide (LPS) and hydrogen peroxide (H2O2). However, experimental temporal lobe epilepsy (TLE) was induced in mice using pilocarpine. Further, effects of oxidative stress and neuroinflammation on SERCA2b and ER stress markers were assessed at protein and mRNA levels. Calcium imaging was employed to determine intracellular calcium levels. SERCA2b expression significantly decreased after LPS, H2O2, and pilocarpine exposure at both mRNA and protein levels, mediated by upregulating neuroinflammation. This downregulation of SERCA2b was associated with increased production of reactive oxygen species and elevated intracellular calcium levels, leading to elevated ER stress markers. Our findings highlight a link between oxidative stress, neuroinflammation and SERCA2b in TLE. The results suggest that targeting SERCA2b could restore calcium homeostasis and ER stress processes, potentially providing a therapeutic option for TLE. This study underscores the importance of SERCA2b in the pathophysiology of epilepsy and its potential as a therapeutic target.

REVISION The Impact of Work Hours and Cultural Expectations on Mental Health in Japan

This study examines the relationship between Japan's work culture and the mental health of its workers, focusing on stress, anxiety, and depression caused by long working hours and high productivity demands. Japan’s work culture, which emphasizes loyalty to the company and endurance, has contributed to a significant rise in mental health issues. Despite efforts by the government and companies to reduce overtime and provide mental health support, the policies implemented so far have proven insufficient in addressing the root causes of workplace stress. This research incorporates in-depth interviews, surveys, and case studies from workers across both private and public sectors. The findings indicate a strong correlation between long working hours and elevated stress levels, with workers in the private sector, younger employees, and women experiencing higher levels of anxiety and stress. Policies like flexible work hours, mental health programs, and reduced overtime showed positive impacts on well-being, but their inconsistent implementation limits their effectiveness. The study concludes that policies must go beyond reducing working hours and incorporate structural changes in workplace culture. Future research should investigate the long-term effects of these reforms, explore sector-specific mental health needs, and consider gendered aspects of work-related stress.

Psychological stress and influence factors in elderly patients with mild coronary heart disease: a longitudinal follow-up study in Shanghai, China.

Effective health management is crucial for elderly patients with coronary heart disease (CHD). This study applied a Psycho-Cardiology model to CHD management, aiming to assess psychological stress among patients with mild CHD and identify potential influencing factors to provide substantiating evidence. This longitudinal study was based on a 9-year follow-up program of a community population in Shanghai, China. A total of 44,552 elderly people were included, with the average age being 74.9 (±10.35) years, and the proportion of female participants being 56.5%. To evaluate and compare the effect of the disease, individuals were categorized into four groups based on their medical records from the past 6 months, these being (I) a CHD with other chronic diseases group, (II) a CHD only group, (III) non-CHD patients with one (or more) chronic disease group, and (IV) non-patient group. Demographic characteristics, sleep quality and health status of each participants were collected using the Unified Needs Assessment Form for Elderly Care Questionnaire. A multivariate logistic regression was used for statistic analysis. Demographic characteristics differed significantly between the three chronic disease groups (Groups I, II and III) and the non-patient group. Participants in the CHD group reported poorer sleep quality, worse health status, and a more rapid health decline when compared to those with other chronic diseases. Factors such as age, gender, education level, disease duration, and family support were identified as potential influences on the self-reported subjective sleep quality in patients with mild CHD. While age, education level, living status and family support were potential factors influencing the self-assessed health status in participants without CHD (Groups III and IV). Patients with mild CHD may experience lower subjective sleep quality, health status scores, and a faster health-sleep decline, indicating elevated psychological stress. Higher education levels offer a protective effect against this stress, highlighting the importance of psycho-emotional interventions and educational strategies. Additionally, it is important to prioritize early intervention for newly diagnosed cases to aid in illness acceptance. These findings provide crucial insights for managing patients with mild CHD and inform the efficient allocation of healthcare resources.

Sexual Assault-Related Interactions and Social Reactions in the Initial Months Following Assault: A Daily Diary Study.

Most sexual assault survivors disclose to informal supporters and receive both negative and positive social reactions. Converging evidence suggests that the first months after sexual assault are a period of increased support-seeking that may be uniquely important to survivors' recovery, especially among survivors at risk of chronic post-traumatic stress and alcohol misuse. However, no research has examined when and how often survivors talk about their assault and what social reactions they receive during this time. As such, the goal of this study was to characterize the day-to-day assault-related interactions and social reactions received by a high-risk group of survivors during the first months following sexual assault. Adult female survivors of past-10-week sexual assault with elevated assault-related post-traumatic stress and alcohol use (N = 41) completed a baseline assessment and daily diaries over 21 days as part of a larger mHealth clinical trial. Results demonstrated that assault-related interactions occurred on an average of 24.4% of days (range: 1-14 days), were more likely to occur earlier in the daily dairy period, and decreased in frequency over time. Across days, most survivors (75%) received both positive and negative reactions in these interactions, whereas fewer (20%) received only positive reactions and no one received only negative reactions. These findings suggest that survivors commonly have assault-related interactions with their supporters in the initial aftermath of the assault and that receiving both positive and negative social reactions is typical. Findings could inform future early interventions aiming to improve supporter reactions and better support survivors' recovery.

Nimotuzumab and irinotecan synergistically induce ROS-mediated apoptosis by endoplasmic reticulum stress and mitochondrial-mediated pathway in cervical cancer.

Irinotecan (CPT-11), a chemotherapeutic agent used to treat several types of cancer, induces cytotoxic effects on healthy cells. The epidermal growth factor receptor (EGFR) plays a crucial role in various forms of cancer. Nimotuzumab (NmAb), a monoclonal antibody that targets the EGFR, is utilized in some countries to treat malignancies that have an overexpression of EGFR. Yet, there is a lack of literature on the potential anticancer properties of the CPT-11 and NmAb combination on in vitro human cervical cancer cells. This study investigates the apoptosis mode of the CPT-11 and NmAb combination on cervical HeLa cancer cells. The Annexin V/propidium iodide staining examination demonstrated that the combination of CPT-11 and NmAb resulted in a decrease in the number of viable cells and more potent induction of cell apoptosis than the effects of CPT-11 or NmAb alone in HeLa cells. Furthermore, the combined treatment resulted in elevated levels of reactive oxygen species (ROS) and Ca2+ compared to the treatment with CPT-11 or NmAb alone. Cells that were pretreated with N-acetyl-l-cysteine, a substance that scavenges ROS, and then treated with CPT-11, NmAb, or a combination of CPT-11 and NmAb exhibited higher numbers of viable cells compared to those treated with CPT-11 or NmAb alone. The combination of CPT-11 and NmAb resulted in significantly higher caspase-3, -8, and -9 activity levels than CPT-11 or NmAb alone, as measured by flow cytometer assay. The combination of CPT-11 and NmAb in HeLa cells resulted in elevated endoplasmic reticulum stress-, mitochondria-, and caspase-mediated proteins compared to treatment with CPT-11 or NmAb alone. According to these observations, NmAb enhances the effectiveness of CPT-11 in fighting cancer by stimulating cell death in the HeLa cells. Therefore, NmAb has the potential to improve the efficacy of CPT-11 as a future cervical cancer treatment in humans.

Chloroquine-induced proinsulin misfolding in the endoplasmic reticulum underlies the attenuation of mature insulin synthesis.

Chloroquine (CQ), initially introduced for the clinical treatment of malaria, has subsequently been found to exhibit beneficial effects in combating diabetes mellitus. The anti-hyperglycemic properties of chloroquine may be attributed to its anti-inflammatory response and its ability to activate the insulin signaling pathway. However, both animal and clinical studies have yielded mixed results. Moreover, the impact of chloroquine on pancreatic β-cells, the key player of glycemic control, was not known. To fill this knowledge gap, we investigated the effects of chloroquine on pancreatic β-cell functions. Our findings revealed that while chloroquine did not alter proinsulin expression, it interfered with the conversion of proinsulin to insulin, resulting in reduced insulin levels. Using multiple independent approaches, we further showed that chloroquine disrupted proinsulin oxidative folding in the endoplasmic reticulum (ER) and impaired proinsulin trafficking from ER to Golgi, leading to ER stress and decreased insulin production. Notably, the elevated ER stress observed in chloroquine-treated β-cells was reversed upon knockout of insulin genes, indicating that chloroquine-induced β-cell ER stress primarily through the accumulation of misfolded proinsulin, rather than directly affecting ER homeostasis. Further investigation into the mechanisms underlying chloroquine-induced proinsulin misfolding revealed that the accumulation of misfolded proinsulin was not caused by autophagy inhibition or the alkaline pH of chloroquine. Instead, it was primarily due to the disruption of the interaction between proinsulin and protein disulfide isomerase (PDI). Our findings unveiled new mechanisms of chloroquine treatment and raised important safety considerations regarding the use of chloroquine in diabetes treatment.

Exploring stress and depressive symptoms in pregnancy and the IL-1β, IL-6, and C-reactive protein pathway: Looking for possible biomarker targets.

Individuals undergo significant stress throughout pregnancy and are at high risk for depressive symptoms. Elevated stress and depressive symptoms are associated with inflammatory processes and adverse maternal-infant outcomes. However, the biological processes associated with psychosocial outcomes and the maternal immune system remain unclear. As such, we aimed to examine associations among perceived stress, depressive symptoms, salivary IL-1β, IL-6, and CRP levels, and hair and salivary cortisol levels during the second and third trimesters of pregnancy. We conducted an ancillary study consisting of 37 pregnant individuals. Participants collected salivary samples and measures of perceived stress and depression at 17-19 weeks, 25-27 weeks, and 32-34 weeks gestation. We collected a one-time hair sample between 36 and 40 weeks. Provided salivary samples were used to detect changes in cortisol, IL-1β, IL-6, and CRP levels. Hair was used to detect changes in cortisol levels throughout pregnancy. Elevated levels of perceived stress and depressive symptoms are associated with increased salivary CRP levels, respectively (p=0.0142, p=0.0008). Salivary and hair cortisol increased significantly throughout the second and third trimesters of pregnancy (p=0.0004 and p<0.0001). We also observed variations in IL-6 during pregnancy (p=0.029) and significant increases between 25 and 27 weeks (p=0.016). Salivary samples may provide a non-invasive measurement of alterations in cytokine and cortisol levels in pregnant individuals reporting elevated stress and depressive symptoms. These may be candidate biomarkers for mechanistic study possibly aiding providers in early detection of deleterious immunological processes which could result in adverse maternal-infant outcomes.

Microstructural and Micromechanical Evolution of Olivine Aggregates During Transient Creep

AbstractTo examine the microstructural evolution that occurs during transient creep, we deformed samples of polycrystalline olivine to different strains that spanned the initial transient deformation. Two sets of samples with different initial grain sizes of 5 μm and 20 μm were deformed in torsion at T = 1,523 K, P = 300 MPa, and a constant shear strain rate of 1.5 × 10−4 s−1, during which both sets of samples experienced strain hardening. We characterized the microstructures at the end of each experiment using high‐angular resolution electron backscatter diffraction (HR‐EBSD) and dislocation decoration. In the coarse‐grained samples, dislocation density increased from 1.5 × 1011 m−2 to 3.6 × 1012 m−2 with strain. Although the same final dislocation density was reached in the fine‐grained samples, it did not vary significantly at small strains, potentially due to concurrent grain growth during deformation. In both sets of samples, HR‐EBSD analysis revealed that intragranular stress heterogeneity increased in magnitude with strain and that elevated stresses are associated with regions of high geometrically necessary dislocation density. Further analysis of the stresses and their probability distributions indicate that the stresses are imparted by dislocations and cause long‐range elastic interactions among them. These characteristics indicate that dislocation interactions were the primary cause of strain hardening during transient creep in our samples. A comparison of the results to the predictions of three recent models reveals that the models do not correctly predict the evolution in stress and dislocation density with strain in our experiments due to a lack of previous such data in their calibrations.

Enhancement effect of Ni on the mechanical and thermodynamic properties of Au-xNi (x = 0.5,1.0,1.5,2.0,2.5,3.0) alloy: a first-principles study

Abstract Au-17.5Ni is a high-performance solder extensively utilized in the assembly of satellites, aircraft engines, and ceramic components, owing to its exceptional high-temperature properties. However, its inherent brittleness renders it susceptible to defects such as fractures, cracking, and delamination during the manufacturing of welding wires and foils. To mitigate these challenges, this study employs first-principles calculations to investigate the structural stability, mechanical properties, and thermal behavior of the primary phase in the Au-17.5Ni alloy, with a particular focus on the Au-rich phase, a solid solution of Ni in Au. The results indicate that the Au-2.0Ni composition exhibits the highest plasticity, characterized by a Pugh’s ratio (B/G) of 7.671 and a hardness value of 0.643 GPa, representing a 31.76% increase compared to pure Au. These improvements significantly enhance the processing performance of the Au-17.5Ni alloy. Moreover, the constant pressure specific heat capacity (Cp) of Au-xNi alloys exceeds that of pure Au and increases with higher Ni content. At 800 K, the Au-3.0Ni alloy exhibits the highest Cp at 31.179 J mol−1·K−1, indicating improved high-temperature stability. Additionally, the thermal expansion coefficients for Au-1.0Ni, Au-2.0Ni, and Au-3.0Ni increase by 13.037%, 22.858%, and 38.097%, respectively, which may lead to elevated thermal stresses in welded joints. Consequently, maintaining the Ni content in the Au-rich phase of the Au-17.5Ni solder below 2.0 wt% can significantly enhance solder processability, ultimately improving the yield of welding wires and foils.

Induction of GPX4-regulated ferroptotic stress promotes epithelial-to-mesenchymal transition in renal tubule cells induced by PM2.5

Increasing evidence links exposure to fine particulate matter (PM2.5) with an elevated risk of kidney disease. In this study, we investigated the effect of PM2.5 exposure on human proximal tubular epithelial (HK−2) cells and found that it elevated ferroptotic stress markers, including increased iron, reactive oxygen species (ROS), and malondialdehyde (MDA), along with reducing glutathione (GSH) levels. PM2.5 promotes the epithelial-to-mesenchymal transition (EMT) in these cells, which is associated with the loss of epithelial morphology, lowered expression of E-cadherin, and elevated expression of α-smooth muscle actin (α-SMA). Notably, a reduction in PM2.5-induced EMT characteristics was observed using either a ferroptosis-specific inhibitor (Fer-1) or a mitochondrial ROS scavenger (Mito-Tempo). Moreover, Fer-1 effectively counteracted ferroptotic stress and restored glutathione peroxidase 4 (GPX4) expression in PM2.5-exposed cells, which may explain its efficacy in inhibiting EMT induced by PM2.5. In contrast, GPX4 knockdown exacerbated EMT features in PM2.5-treated cells. Further studies showed that GPX4 overexpression alleviated EMT markers in mouse tubular cells following PM2.5 exposure, indicating the role of GPX4 in reducing ferroptotic stress and may prevent tubular injury caused by PM2.5 exposure. Our study highlights that PM2.5 may induce GPX4-regulated ferroptotic stress in tubular cells, potentially triggering the EMT process and contributing to kidney injury.

The Relationship Between Perceived Stress and Aggression Behavior Among Individuals with Major Depressive Disorder (MDD)

This study examines how perceived stress impacts aggression in individuals diagnosed with Major Depressive Disorder (MDD), specifically looking at the variations between genders. The study utilizes a quantitative questionnaire to investigate the correlation between stress and aggression, as well as the factors that exacerbate this relationship, including the reciprocal linking of stress and aggression. Perceived stress and aggression exhibited a substantial and advantageous correlation (r = 0.62, p &lt; 0.01), suggesting that an increase in aggression was linked to elevated stress levels. 78% of males and 58% of females admitted to frequently exhibiting aggression, while males reported engaging in aggressive behaviors more frequently than females. A reciprocal relationship was discovered, in which escalated aggression led to elevated stress levels and increased stress caused heightened aggression (r = 0.54, p &lt; 0.05), thereby establishing a detrimental feedback cycle. These results indicate that interventions aimed at reducing stress could be especially helpful in decreasing aggression in male MDD patients. This study enhances our comprehension of the dynamics between stress and aggression in MDD and highlights the significance of addressing these aspects in therapy.

Targeting Yes-Associated Protein (YAP) in Breast Cancer: In Silico Molecular Dynamics, Luminescence-Based InVitro, and InVivo Validation of Rauvolfia tetraphylla-Derived Inhibitors.

The study aims to elucidate the pharmacological mechanism of Rauvolfia tetraphylla against breast cancer through a comprehensive, multi-faceted approach. This includes molecular docking, molecular dynamics, and experimental validation. Initial screening via ADME analysis and network pharmacology identified key compounds and potential targets. Protein-protein interaction (PPI) network analysis pinpointed Yes-associated protein-1 (YAP) as a crucial target. Molecular docking revealed that three compounds-ajmaline, reserpine, and serpentine-exhibited strong binding affinities with YAP, with scores of -6.5 to -6.7 kcal/mol. Molecular dynamics simulations were conducted to assess the stability of these interactions further. Experimental validation showed R. tetraphylla inhibited breast cancer cell proliferation, with an IC50 of 348.69 μg/mL, while demonstrating cytoprotective effects on Vero cells (IC50: 1056.23 μg/mL). Migration assays indicated an 88.5% reduction in cell migration, and increased ROS levels signaled elevated stress in cancer cells. Apoptosis was confirmed by AO/EtBr staining. Invivo validation in a DMBA-induced mouse model confirmed significant tumor growth inhibition, supported by changes in YAP expression and histopathological analysis. These findings highlight R. tetraphylla as a promising therapeutic candidate against breast cancer, offering insights into its mechanisms and potential for future drug development and clinical applications.

Analyze the Effect of Steel Waste on Performance Characteristics of Concrete

This cross-sectional study investigates the immediate impact of occupational stress on short-term heart rate variability (HRV) and muscle strength among 200 construction workers in Chennai. The Perceived Stress Scale (PSS) was employed to assess stress levels, while HRV was measured using a portable ECG device, focusing on time-domain (RMSSD) and frequency-domain (HF Power) parameters. Muscle strength was evaluated using a MicroFET 2 dynamometer. Pearson correlation and multivariate regression analyses were applied to determine the associations between stress, HRV, and muscle strength, adjusting for confounding factors such as age, body mass index (BMI), and work duration. Results revealed a significant negative correlation between perceived stress and both HRV indices (RMSSD: r=-0.45, p&lt;0.01; HF Power: r=-0.50, p&lt;0.01) as well as muscle strength (r=-0.40, p&lt;0.01). Higher stress levels were associated with reduced HRV and diminished muscle strength. Regression analyses confirmed that stress independently predicted lower HRV (RMSSD: ?=-0.35, p&lt;0.01; HF Power: ?=-0.42, p&lt;0.01) and decreased muscle strength (?=-0.32, p&lt;0.01). These findings suggest that elevated stress negatively impacts both cardiovascular and muscular functioning, potentially increasing the health risks among construction workers. The study highlights the importance of implementing stress management interventions to improve both the physical well-being and productivity of workers in the construction industry.

OVERLOADING IN ELEMENTARY SCHOOL TEACHERS: A REVIEW

Teacher workload intensification in basic education is a critical issue impacting both teacher well-being and the quality of education. This literature review employs a systematic review methodology to synthesize findings from existing research on the causes and consequences of excessive workloads among teachers. The review identifies key contributors to workload intensification, including administrative responsibilities, lesson planning, student assessments, extracurricular duties, and broad curriculum requirements within limited timeframes. These factors detract from teachers' core instructional functions and contribute to elevated stress levels, burnout, and attrition. The analysis highlights "time poverty" as a significant barrier, limiting teachers' ability to engage in effective pedagogy and professional development. Additionally, the study reveals that excessive workloads undermine teachers' physical and mental health, leading to reduced motivation and job dissatisfaction. To address these challenges, proposed solutions include reducing class sizes, streamlining curricular requirements, and providing additional support staff. The review underscores the necessity of educational policy reforms that prioritize teacher well-being, support effective teaching practices, and foster sustainable work environments. By alleviating workload pressures, these reforms can enhance teacher retention, professional satisfaction, and ultimately, improve educational outcomes for students. This study contributes to ongoing discussions on optimizing teacher workload to ensure high-quality education systems.

Effect of elevated temperature and water stress on seed germination of the Himalayan medicinal herb Aconitum spicatum

Effect of elevated temperature and water stress on seed germination of the Himalayan medicinal herb <i>Aconitum spicatum</i>

Mechanical forces inducing oxaliplatin resistance in pancreatic cancer can be targeted by autophagy inhibition

Pancreatic cancer remains one of the most lethal malignancies, with limited treatment options and poor prognosis. A common characteristic among pancreatic cancer patients is the biomechanically altered tumor microenvironment (TME), which among others is responsible for the elevated mechanical stresses in the tumor interior. Although significant research has elucidated the effect of mechanical stress on cancer cell proliferation and migration, it has not yet been investigated how it could affect cancer cell drug sensitivity. Here, we demonstrated that mechanical stress triggers autophagy activation, correlated with increased resistance to oxaliplatin treatment in pancreatic cancer cells. Our results demonstrate that inhibition of autophagy using hydroxychloroquine (HCQ) enhanced the oxaliplatin-induced apoptotic cell death in pancreatic cancer cells exposed to mechanical stress. The combined treatment of HCQ with losartan, a known modulator of mechanical abnormalities in tumors, synergistically enhanced the therapeutic efficacy of oxaliplatin in murine pancreatic tumor models. Furthermore, our study revealed that the use of HCQ enhanced the efficacy of losartan to alleviate mechanical stress levels and restore blood vessel integrity beyond its role in autophagy modulation. These findings underscore the potential of co-targeting mechanical stresses and autophagy as a promising therapeutic strategy to overcome drug resistance and increase chemotherapy efficacy.

Mechanism of shear-enhanced rotating-disk microfiltration for separation of microbe/protein bio-suspension

Shear-enhanced dynamic filtration is a promising approach for separating fermented biological products. In this study, we aimed to investigate the separation of bovine serum albumin (BSA) and polymethyl methacrylate (PMMA) particles in a binary suspension using rotating-disk microfiltration. Type-R and Type-RB rotating-disk configurations were designed and compared using experimental data and simulated results. The effects of operating conditions, including rotational speed and filtration pressure, on filtration flux, resistance, and protein rejection, were analyzed. Because the filter membrane rejected all the PMMA particles, the primary source of filtration resistance in the PMMA/BSA suspension was the fouling cake. Although BSA rejection increased with higher filtration pressure, it decreased as the rotational speed increased. Computational fluid dynamics simulations were used to model the flow velocity and shear stress distributions within the rotating-disk dynamic microfiltration system. The results showed that Type-RB achieved a 55 % increase in flux compared to Type-R, owing to a significant reduction in cake resistance by approximately 46 %. A proportional relationship between the mean cake mass and the ratio of qs/τw under varying operating conditions was established using a force balance model. These findings suggest that elevated shear stress significantly enhances filtration performance, with Type-RB demonstrating superior effectiveness for bio-suspension separation.

Novel insights into cuproptosis inducers and inhibitors.

Cuproptosis is a new pattern of Cu-dependent cell death distinct from classic cell death pathways and characterized by aberrant lipoylated protein aggregation in TCA cycle, Fe-S cluster protein loss, HSP70 elevation, proteotoxic and oxidative stress aggravation. Previous studies on Cu homeostasis and Cu-induced cell death provide a great basis for the discovery of cuproptosis. It has gradually gathered enormous research interests and large progress has been achieved in revealing the metabolic pathways and key targets of cuproptosis, due to its role in mediating some genetic, neurodegenerative, cardiovascular and tumoral diseases. In terms of the key targets in cuproptosis metabolic pathways, they can be categorized into three types: oxidative stress, mitochondrial respiration, ubiquitin-proteasome system. And strategies for developing cuproptosis inducers and inhibitors involved in these targets have been continuously improved. Briefly, based on the essential cuproptosis targets and metabolic pathways, this paper classifies some relevant inducers and inhibitors including small molecule compounds, transcription factors and ncRNAs with the overview of principle, scientific and medical application, in order to provide reference for the cuproptosis study and target therapy in the future.

Multiple Myeloma Cells with Increased Proteasomal and ER Stress Are Hypersensitive to ATX-101, an Experimental Peptide Drug Targeting PCNA.

Objectives: To examine the regulatory role of PCNA in MM, we have targeted PCNA with the experimental drug ATX-101 in three commercial cell lines (JJN3, RPMI 1660, AMO) and seven in-house patient-derived cell lines with a more primary cell-like phenotype (TK9, 10, 12, 13, 14, 16 and 18) and measured the systemic molecular effects. Methods: We have used a multi-omics untargeted approach, measuring the gene expression (transcriptomics), a subproteomics approach measuring mainly signalling proteins and proteins in complex with these (signallomics) and quantitative metabolomics. These results are supplemented with traditional analysis, e.g., viability, Western and ELISA analysis. Results: The sensitivity of the cell lines to ATX-101 varied, including between three cell lines derived from the same patient at different times of disease. A trend towards increased sensitivity to ATX-101 during disease progression was detected. Although with different sensitivities, ATX-101 treatment resulted in numerous changes in signalling and metabolite pools in all cell lines. Transcriptomics and signallomics analysis of the TK cell lines revealed that elevated endogenous expression of ribosomal genes, elevated proteasomal and endoplasmic reticulum (ER) stress and low endogenous levels of NAD+ and NADH were associated with ATX-101 hypersensitivity. ATX-101 treatment further enhanced the ER stress, reduced primary metabolism and reduced the levels of the redox pair GSH/GSSG in sensitive cells. Signallome analysis suggested that eleven proteins (TPD52, TNFRS17/BCMA, LILRB4/ILT3, TSG101, ZNRF2, UPF3B, FADS2, C11orf38/SMAP, CGREF1, GAA, COG4) were activated only in the sensitive MM cell lines (TK13, 14 and 16 and JJN3), and not in nine other cancer cell lines or in primary monocytes. These proteins may therefore be biomarkers of cells with activated proteasomal and ER stress even though the gene expression levels of these proteins were not elevated. Interestingly, carfilzomib-resistant cells were at least as sensitive to ATX-101 as the wild-type cells, suggesting both low cross-resistance between ATX-101 and proteasome inhibitors and elevated proteasomal stress in carfilzomib-resistant cells. Conclusions: Our multi-omics approach revealed a vital role of PCNA in regulation of proteasomal and ER stress in MM.

Ascitic Shear Stress Activates GPCRs and Downregulates Mucin 15 to Promote OvarianCancer Malignancy.

The accumulation of ascites in patients with ovarian cancer increases their risk of transcoelomic metastasis. Although common routes of peritoneal dissemination are known to follow distinct paths of circulating ascites, the mechanisms that initiate these currents and subsequent fluid shear stresses are not well understood. Here, we developed a patient-based, boundary-driven computational fluid dynamics model to predict an upper range of fluid shear stress generated by the accumulation of ascites. We show that ovarian cancer cells exposed to ascitic shear stresses display heightened G protein-coupled receptor mechanosignaling and the induction of an epithelial to mesenchymal-like transition through p38α mitogen-activated protein kinase and mucin 15 modulation. These findings along with a shear-induced immunomodulatory secretome position elevated shear stress as a protumoural signal. Together, this study suggests inhibition of the Gαq protein and restriction of ascites accumulation as maintenance strategies for overcoming mechanotransduction-mediated metastasis within the peritoneal cavity.