Stress Signaling Pathways Research Articles

Biosynthesized Selenium Nanoparticles as an Effective Tool to Combat Soil Metal Stresses in Rice (Oryza sativa L.).

Nanotechnology has demonstrated significant potential to improve agricultural production and increase crop tolerance to abiotic stress including exposure to heavy metals. The present study investigated the mechanisms by which aloe vera extract gel-biosynthesized (AVGE) selenium nanoparticles (Se NPs) alleviated cadmium (Cd)-induced toxicity to rice (Oryza sativa L.). AVGE Se NPs, chemically synthesized bare Se NPs, and NaSeO3 as an ionic control were applied to Cd-stressed rice seedlings via root exposure in both hydroponic and soil systems. Upon exposure to AVGE Se NPs at 15 mg Se/L, the fresh root biomass was significantly increased by 100.7% and 19.5% as compared to Cd control and conventional bare Se NPs. Transcriptional analyses highlighted that AVGE Se NPs activated stress signaling and defense related pathways, including glutathione metabolism, phenylpropanoid biosynthesis and plant hormone signal transduction. Specifically, exposure to AVGE Se NPs upregulated the expression of genes associated with the gibberellic acid (GA) biosynthesis by and 4.79- and 3.29-fold as compared to the Cd-alone treatment and the untreated control, respectively. Importantly, AVGE Se NPs restored the composition of the endophyte community and recruit of beneficial species under Cd exposure; the relative abundance of Azospirillum was significantly increased in roots, shoots, and the rhizosphere soil by 0.73-, 4.58- and 0.37-fold, respectively, relative to the Cd-alone treatment. Collectively, these findings highlight the significant potential of AVGE Se NPs to enhance plant growth and to minimize the Cd-induced toxicity in rice and provide a promising nanoenabled strategy to enhance food safety upon crop cultivation in contaminated agricultural soils.

Roles of MDA-LDL/OX-LDL/LOX-1 and TNF-α/TLR4/NF-κB Signaling Pathways in Myocardial Damage by Implantations of Cardiac Pacemakers in Elderly Patients.

Permanent pacemakers are an established treatment for sick sinus syndrome and high-grade atrioventricular block. Permanent cardiac pacemaker implantations may damage the myocardium. This study evaluated markers of myocardial injury, oxidative stress and inflammation in elderly patients with permanent pacemaker implantations. Various markers were measured at 1, 2, 3 and 4 months after permanent pacemaker implantations in elderly patients. The levels of high-sensitivity troponin T (hsTnT), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), malondialdehyde-modified low-density lipoprotein (MDA-LDL), oxidized low-density lipoprotein (OX-LDL), tumour necrosis factor-α (TNF-α), toll-like receptor 4 (TLR4) and nuclear factor-kappa B (NF-κB) were increased in 2-month group compared with control and 1- month groups (P<0.001), and were further increased at 4-month group compared with 2- and 3- month groups after pacemaker implantations (P<0.001). Patients with dual-chamber pacemakers had higher levels of hsTnT, LOX-1, MDA-LDL, OX-LDL, TNF-α, TLR4 and NF-κB than patients with single chamber pacemakers (P<0.001). Patients who underwent the pacemakers with the active fixation leads had raised levels of hsTnT, LOX-1, MDA-LDL, OX-LDL, TNF-α, TLR4 and NF-κB compared patients with pacemakers using the passive fixation leads (P<0.001). Myocardial blood flows in 3-month and 4-month groups were lower than 1-month and 2-month groups (P<0.001). Levels of hsTnT, LOX-1, MDA-LDL, OX-LDL, TNF-α, TLR4 and NF-κB were elevated in elderly patients with permanent pacemaker implantations and the activations of oxidative stress and pro-inflammatory signalling pathways may be associated with myocardial damages and ischemia after pacemaker implantations in elderly patients.

TXNDC5 Plays a Crucial Role in Regulating Endoplasmic Reticulum Activity through Different ER Stress Signaling Pathways in Hepatic Cells.

The pathogenesis of non-alcoholic fatty liver disease (NAFLD) is influenced by a number of variables, including endoplasmic reticulum stress (ER). Thioredoxin domain-containing 5 (TXNDC5) is a member of the protein disulfide isomerase family and acts as an endoplasmic reticulum (ER) chaperone. Nevertheless, the function of TXNDC5 in hepatocytes under ER stress remains largely uncharacterized. In order to identify the role of TXNDC5 in hepatic wild-type (WT) and TXNDC5-deficient (KO) AML12 cell lines, tunicamycin, palmitic acid, and thapsigargin were employed as stressors. Cell viability, mRNA, protein levels, and mRNA splicing were then assayed. The protein expression results of prominent ER stress markers indicated that the ERN1 and EIF2AK3 proteins were downregulated, while the HSPA5 protein was upregulated. Furthermore, the ATF6 protein demonstrated no significant alterations in the absence of TXNDC5 at the protein level. The knockout of TXNDC5 has been demonstrated to increase cellular ROS production and its activity is required to maintain normal mitochondrial function during tunicamycin-induced ER stress. Tunicamycin has been observed to disrupt the protein levels of HSPA5, ERN1, and EIF2AK3 in TXNDC5-deficient cells. However, palmitic acid has been observed to disrupt the protein levels of ATF6, HSPA5, and EIF2AK3. In conclusion, TXNDC5 can selectively activate distinct ER stress pathways via HSPA5, contingent on the origin of ER stress. Conversely, the absence of TXNDC5 can disrupt the EIF2AK3 cascade.

Docosahexaenoic acid ameliorates autistic‐like behaviors by inhibiting oxidative stress and inflammatory response in neonatal maternal separation rats

AbstractAutism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder characterized by impaired social interactions and communication, repetitive, or stereotyped behavior. Docosahexaenoic acid (DHA), an essential polyunsaturated fatty acid, has been demonstrated to exert anti‐oxidative stress and anti‐inflammatory properties, while also promoting myelin development and neural differentiation and development. However, it remains uncertain whether DHA can ameliorate autistic‐like behaviors, and if so, the underlying mechanisms are still unclear. Here, we established a neonatal maternal separation (NMS) rat model and treated it with DHA (80 mg/kg/day, i.p.). The results showed DHA treatment significantly alleviated autism‐like behaviors in the NMS rats during their juvenile period. Subsequently, we employed network pharmacology analysis and molecular docking methods to screen potential targets of DHA in ASD therapy. Through Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Wikipedia enrichment analysis, we identified anti‐oxidative stress, anti‐inflammatory and JNK signaling pathway that might be associated with DHA‐mediated improvement of autistic‐like behaviors. Furthermore, western blotting assays showed DHA significantly downregulated the expression levels of p‐JNK and c‐JUN, while upregulating the expression levels of NRF2, HO‐1, SOD1, and CAT. In addition, enzyme‐linked immunosorbent assay results showed DHA effectively reduced the production of pro‐inflammatory factors, such as TNF‐α, IL‐6, and IL‐1β. Collectively, our study predicted and validated that DHA exhibits the potential to improve autistic‐like behaviors induced by NMS in rats by suppressing JNK activation and inhibiting oxidative stress and inflammatory response. These findings suggest that DHA may be a potential therapeutic agent for the treatment of ASD.

Protective roles of thrombomodulin in cisplatin-induced nephrotoxicity through the inhibition of oxidative and endoplasmic reticulum stress

Cisplatin is an effective chemotherapeutic agent widely used for the treatment of various solid tumors. However, cisplatin has an important limitation in its use; currently, there is no method to ameliorate cisplatin-induced acute kidney injury (AKI). Thrombomodulin (TM) is well known not only for its role as a cofactor in the clinically important natural anticoagulation pathway but also for its anti-inflammatory properties. Here, we investigated the effects of TM in cisplatin-induced AKI. In mice intraperitoneally injected with 15 mg/kg cisplatin, TM (10 mg/kg) or PBS was administered intravenously at 24 h after cisplatin injection. TM significantly attenuated cisplatin-induced nephrotoxicity with the suppressed elevation of blood urea nitrogen and serum creatinine, and reduced histological damages. Actually, TM treatment significantly alleviated oxidative stress-induced apoptosis by reducing reactive oxygen species (ROS) levels in cisplatin-treated renal proximal tubular epithelial cells (RPTECs) in vitro. Furthermore, TM clarified cisplatin-induced apoptosis by reducing caspase-3 levels. In addition, TM attenuated the endoplasmic reticulum (ER) stress signaling pathway in both renal tissues and RPTECs to protect the kidneys from cisplatin-induced AKI. These findings suggest that TM is a potential protectant against cisplatin-induced nephrotoxicity through suppressing ROS generation and ER stress in response to cisplatin.

MDB-72. BREFELDIN A (BFA) INDUCES CD133 PROTEOLYTIC PROCESSING IN MEDULLOBLASTOMA STEM CELLS (MBSCS)

Abstract BACKGROUND Medulloblastoma (MB) is a malignant brain tumor occurring in children, characterized by elevated resistance to conventional chemotherapy. Medulloblastoma stem cells (MBSCs) represent a fraction of the tumor cell population which has been associated with poor prognosis and refractoriness to conventional therapies. CD133 (Prominin 1, PROM1) is a transmembrane protein serving as a cancer stem cell marker associated with cancer progression. Brefeldin A (BFA) is an antibiotic disrupting the Golgi apparatus, thus triggering Endoplasmic reticulum (ER) stress signaling pathways. BFA cancer-inhibitory properties have been already described in cancer of different tissue origin. However, the effects of BFA on MBCSs have not been investigated yet. Thus, the aim of this study was to characterize the response of MBSCs to BFA and the effects induced by BFA on CD133. METHODS Human group 3 MB (G3MB) cell lines were grown in stem selective medium (B27™) and treated with 0.3 uM BFA for 24h before collection. Apoptosis, clonogenicity and CD133 expression were evaluated. CD133 was immunoprecipitated and the corresponding bands were excised and analyzed by nanoLC-MS/MS. Raw data were processed using PEAKS XPro. RESULTS Our results show that BFA-treated cells induced the overexpression of a CD133 isoform that was missing the N-terminus region. Moreover, we found a downregulation of CD133 activated intracellular signalling together with a reduced exposition on cell membrane. CONCLUSIONS We report here for the first time, a N-terminus proteolytic processing of CD133, potentially associated to the cell trafficking effects induced by BFA. Finally, this study suggests a proof of principle for the design of novel molecules with similar structures and mechanism of action of BFA.

Novel insights into the GCN2 pathway and its targeting. Therapeutic value in cancer and lessons from lung fibrosis development.

Defining the mechanisms that allow cells to adapt to environmental stress is critical for understanding the progression of chronic diseases and identifying relevant drug targets. Among these, activation of the pathway controlled by the eIF2-alpha kinase GCN2 is critical for translational and metabolic reprogramming of the cell in response to various metabolic, proteotoxic, and ribosomal stressors. However, its role has frequently been investigated through the lens of a stress pathway signaling via the eIF2α-activating transcription factor 4 (ATF4) downstream axis, while recent advances in the field have revealed that the GCN2 pathway is more complex than previously thought. Indeed, this kinase can be activated through a variety of mechanisms, phosphorylate substrates other than eIF2α, and regulate cell proliferation in a steady state. This review presents recent findings regarding the fundamental mechanisms underlying GCN2 signaling and function, as well as the development of drugs that modulate its activity. Furthermore, by comparing the literature on GCN2's antagonistic roles in two challenging pathologies, cancer and pulmonary diseases, the benefits, and drawbacks of GCN2 targeting, particularly inhibition, are discussed.

Unraveling Differences in Molecular Mechanisms and Immunological Contrasts between Squamous Cell Carcinoma and Adenocarcinoma of the Cervix.

This study aims to refine our understanding of the inherent heterogeneity in cervical cancer by exploring differential gene expression profiles, immune cell infiltration dynamics, and implicated signaling pathways in the two predominant histological types of cervix carcinoma, Squamous Cell Carcinoma (SCC) and Adenocarcinoma (ADC). Targeted gene expression data that were previously generated from samples of primary cervical cancer were re-analyzed. The samples were grouped based on their histopathology, comparing SCC to ADC. Each tumor in the study was confirmed to be high risk human papilloma virus (hrHPV) positive. A total of 21 cervical cancer samples were included, with 11 cases of SCC and 10 of ADC. Data analysis revealed a total of 26 differentially expressed genes, with 19 genes being overexpressed in SCC compared to ADC (Benjamini-Hochberg (BH)-adjusted p-value < 0.05). Importantly, the immune checkpoint markers CD274 and CTLA4 demonstrated significantly higher expression in SCC compared to ADC. In addition, SCC showed a higher infiltration of immune cells, including B and T cells, and cytotoxic cells. Higher activation of a variety of pathways was found in SCC samples including cytotoxicity, interferon signaling, metabolic stress, lymphoid compartment, hypoxia, PI3k-AKT, hedgehog signaling and Notch signaling pathways. Our findings show distinctive gene expression patterns, signaling pathway activations, and trends in immune cell infiltration between SCC and ADC in cervical cancer. This study underscores the heterogeneity within primary cervical cancer, emphasizing the potential benefits of subdividing these tumours based on histological and molecular differences.

Taohong Siwu decoction alleviates cognitive impairment by suppressing endoplasmic reticulum stress and apoptosis signaling pathway in vascular dementia rats

Ethnopharmacological relevanceTaohong Siwu Decoction (TSD), a classic traditional Chinese medicine formula, is used for the treatment of vascular diseases, including vascular dementia (VD). However, the mechanisms remain unclear. Aim of studyThis study aimed to investigate whether TSD has a positive effect on cognitive impairment in VD rats and to confirm that the mechanism of action is related to the Endoplasmic Reticulum stress (ERs) and cell apoptosis signaling pathway. Materials and methodsA total of 40 male adult Sprague-Dawley rats were divided into four groups: sham-operated group (Sham), the two-vessel occlusion group (2VO), the 2VO treated with 4.5 g/kg/d TSD group (2VO + TSD-L), the 2VO treated with 13.5 g/kg/d TSD group (2VO + TSD-H). The rats underwent either 2VO surgery or sham surgery. Postoperative TSD treatment was given for 4 consecutive weeks. Behavioral tests were initiated at the end of gastrulation. Open-field test (OFT) was used to detect the activity level. The New Object Recognition test (NOR) was used to test long-term memory. The Morris water maze (MWM) test was used to examine the foundation of spatial learning and memory. As a final step, the hippocampus was taken for molecular testing. The protein levels of GRP78 (Bip), p-PERK, PERK, IRE1α, p-IRE1α, ATF6, eIF2α, p-eIF2α, ATF4, XBP1, Bcl-2 and Bax were determined by Western blot. Immunofluorescence visualizes molecular expression. ResultsIn the OFT, residence time in the central area was significantly longer in both TSD treatment groups compared to the 2VO group. In the NOR, the recognition index was obviously elevated in both TSD treatment groups. The 2VO group had a significantly longer escape latency and fewer times in crossing the location of the platform compared with the Sham group in MWM. TSD treatment reversed this notion. Pathologically, staining observations confirmed that TSD inhibited hippocampal neuronal loss and alleviated the abnormal reduction of the Nissl body. In parallel, TUNEL staining illustrated that TSD decelerated neuronal apoptosis. Western Blot demonstrated that TSD reduces the expression of ERs and apoptotic proteins. ConclusionIn this study, the significant ameliorative effect on cognitive impairment of TSD has been determined by comparing the behavioral data of the 4 groups of rats. Furthermore, it was confirmed that this effect of TSD was achieved by suppressing the ERs-mediated apoptosis signaling pathway.

Genome-wide identification and phylogenetic and expression pattern analyses of EPF/EPFL family genes in the Rye (Secale cereale L.)

Rye (Secale cereale L.) is one of the major cereal crop species in the Triticeae family and is known to be most tolerant to diverse abiotic stresses, such as cold, heat, osmotic, and salt stress. The EPIDERMAL PATTERNING FACTOR (EPF) and EPF-LIKE (EPFL) families of small secreted peptides act to regulate many aspects of plant growth and development; however, their functions are not widely characterized in rye. In this study, we identified 12 ScEPF/EPFL genes, which can be divided into six groups and are evenly distributed on six rye chromosomes. Further examination of the gene structure and protein conservation motifs of EPF/EPFL family members demonstrated the high conservation of the ScEPF/EPFL sequence. Interactions between ScEPF/EPFL proteins and promoters containing hormone- and stress-responsive cis-acting elements suggest that the regulation of ScEPF/EPFL expression is complex. Expression profiling analyses revealed that ScEPF/EPFL genes exhibited tissue-specific expression patterns. Notably, ScEPFL1,ScEPFL7, ScEPFL9, and ScEPFL10 displayed significantly higher expression levels in spikelets compared to other tissues. Moreover, fluorescence quantification experiments demonstrated that these genes exhibited distinct expression patterns in response to various stress conditions, suggesting that each gene plays a unique role in stress signaling pathways. Our research findings provide a solid basis for further investigation into the functions of ScEPF/EPFLs. Furthermore, these genes can serve as potential candidates for breeding stress-resistant rye varieties and improving production yields.

Multi-Omics Analysis Reveals the Toxicity of Polyvinyl Chloride Microplastics toward BEAS-2B Cells.

Polyvinyl chloride microplastics (PVC-MPs) are microplastic pollutants widely present in the environment, but their potential risks to human lung health and underlying toxicity mechanisms remain unknown. In this study, we systematically analyzed the effects of PVC-MPs on the transcriptome and metabolome of BEAS-2B cells using high-throughput RNA sequencing and untargeted metabolomics technologies. The results showed that exposure to PVC-MPs significantly reduced the viability of BEAS-2B cells, leading to the differential expression of 530 genes and 3768 metabolites. Further bioinformatics analyses showed that PVC-MP exposure influenced the expression of genes associated with fluid shear stress, the MAPK and TGF-β signaling pathways, and the levels of metabolites associated with amino acid metabolism. In particular, integrated pathway analysis showed that lipid metabolic pathways (including glycerophospholipid metabolism, glycerolipid metabolism, and sphingolipid metabolism) were significantly perturbed in BEAS-2B cells following PVC-MPs exposure. This study provides new insights and targets for a deeper understanding of the toxicity mechanism of PVC-MPs and for the prevention and treatment of PVC-MP-associated lung diseases.

Targeting the Ferroptosis and Endoplasmic Reticulum Stress Signaling Pathways by CBX7 in Myocardial Ischemia/reperfusion Injury.

Ferroptosis and endoplasmic reticulum stress (ERS) are common events in the process of myocardial ischemia/reperfusion injury (IRI). The suppression of chromobox7 (CBX7) has been reported to protect against ischemia/reperfusion injury, This research is purposed to expose the impacts and mechanism of CBX7 in myocardial IRI. CBX7 expression was detected using RT-qPCR and western blotting analysis. CCK-8 assay detected cell viability. Inflammatory response and oxidative stress were detected by ELISA, DCFH-DA probe and related assay kits. Flow cytometry analysis and caspase3 activity assay were used to detect cell apoptosis. C11-BODIPY 581/591 staining and ferro-orange staining were used to detect lipid reactive oxygen species (ROS) and Fe2+ level, respectively. Western blotting was used to detect the expression of proteins associated with apoptosis, ferroptosis and ERS. In the hypoxia/reoxygenation (H/R) model of rat cardiomyocytes H9c2, CBX7 was highly expressed. CBX7 interference significantly protected against inflammatory response, oxidative stress, apoptosis, ferroptosis and ERS induced by H/R in H9c2 cells. Moreover, after the pretreatment with ferroptosis activator erastin or ERS agonist Tunicamycin (TM), the protective effects of CBX7 knockdown on the inflammation, oxidative stress and apoptosis in H/R-induced H9c2 cells was partially abolished. To summarize, CBX7 down-regulation may exert anti-ferroptosis and anti-ERS activities to alleviate H/R-stimulated myocardial injury.

Genome-wide identification, classification and expression analysis of the heat shock transcription factor family in Garlic (Allium sativum L.)

BackgroundThe heat shock transcription factor (HSF) plays a crucial role in the regulatory network by coordinating responses to heat stress as well as other stress signaling pathways. Despite extensive studies on HSF functions in various plant species, our understanding of this gene family in garlic, an important crop with nutritional and medicinal value, remains limited. In this study, we conducted a comprehensive investigation of the entire garlic genome to elucidate the characteristics of the AsHSF gene family.ResultsIn this study, we identified a total of 17 AsHSF transcription factors. Phylogenetic analysis classified these transcription factors into three subfamilies: Class A (9 members), Class B (6 members), and Class C (2 members). Each subfamily was characterized by shared gene structures and conserved motifs. The evolutionary features of the AsHSF genes were investigated through a comprehensive analysis of chromosome location, conserved protein motifs, and gene duplication events. These findings suggested that the evolution of AsHSF genes is likely driven by both tandem and segmental duplication events. Moreover, the nucleotide diversity of the AsHSF genes decreased by only 0.0002% from wild garlic to local garlic, indicating a slight genetic bottleneck experienced by this gene family during domestication. Furthermore, the analysis of cis-acting elements in the promoters of AsHSF genes indicated their crucial roles in plant growth, development, and stress responses. qRT-PCR analysis, co-expression analysis, and protein interaction prediction collectively highlighted the significance of Asa6G04911. Subsequent experimental investigations using yeast two-hybridization and yeast induction experiments confirmed its interaction with HSP70/90, reinforcing its significance in heat stress.ConclusionsThis study is the first to unravel and analyze the AsHSF genes in garlic, thereby opening up new avenues for understanding their functions. The insights gained from this research provide a valuable resource for future investigations, particularly in the functional analysis of AsHSF genes.

Treponema pallidum recombinant protein Tp0768 enhances the ability of HUVECs to promote neutrophil chemotaxis through the TLR2/ER stress signaling pathway.

Neutrophils are essential cells involved in inflammation. However, the specific mechanism of neutrophil chemotaxis induced by Treponema pallidum remains unknown. In this study, human umbilical vein endothelial cells (HUVECs) were utilized as target cells to investigate the expression levels of chemokines when stimulated with different concentrations of Tp0768 (also known as TpN44.5 or TmpA, a T. pallidum infection dependent antigen). The results indicated that Tp0768 treatment enhanced neutrophil chemotaxis in HUVECs, which was closely associated with the expression levels of CXCL1, CXCL2, and CXCL8 (also known as interleukin-8). At the same time, the results show that the Toll-like receptor 2 (TLR2) signaling pathway is activated and that endoplasmic reticulum (ER) stress occurs. Furthermore, the findings revealed that the use of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and immunoglobulin-regulated enhancer 1 (IRE1) inhibitors reduced the expression levels of CXCL1, CXCL2, and CXCL8. Additionally, inhibiting TLR2 significantly decreased the expression levels of ER stress-related proteins (PERK and IRE1), CXCL1, CXCL2, and CXCL8. Consequently, neutrophil chemotaxis was significantly inhibited after treatment with TLR2, PERK, and IRE1 inhibitors. These findings shed light on the role of Tp0768 in enhancing neutrophil chemotaxis in endothelial cells, providing a foundation for further exploration of syphilis pathogenesis and offering a new direction for the diagnosis and treatment of T. pallidum infection.

Intranasal Administration of Apelin-13 Ameliorates Cognitive Deficit in Streptozotocin-Induced Alzheimer's Disease Model via Enhancement of Nrf2-HO1 Pathways.

The discovery of novel diagnostic methods and therapies for Alzheimer's disease (AD) faces significant challenges. Previous research has shed light on the neuroprotective properties of Apelin-13 in neurodegenerative disorders. However, elucidating the mechanism underlying its efficacy in combating AD-related nerve injury is imperative. In this study, we aimed to investigate Apelin-13's mechanism of action in an in vivo model of AD induced by streptozocin (STZ). We utilized an STZ-induced nerve injury model of AD in mice to investigate the effects of Apelin-13 administration. Apelin-13 was administered intranasally, and cognitive impairment was assessed using standardized behavioral tests, primarily, behavioral assessment, histological analysis, and biochemical assays, in order to evaluate synaptic plasticity and oxidative stress signaling pathways. Our findings indicate that intranasal administration of Apelin-13 ameliorated cognitive impairment in the STZ-induced AD model. Furthermore, we observed that this effect was potentially mediated by the enhancement of synaptic plasticity and the attenuation of oxidative stress signaling pathways. The results of this study suggest that intranasal administration of Apelin-13 holds promise as a therapeutic strategy for preventing neurodegenerative diseases such as AD. By improving synaptic plasticity and mitigating oxidative stress, Apelin-13 may offer a novel approach to neuroprotection in AD and related conditions.

Histology, fatty acid composition, antioxidant and glycolipid metabolism, and transcriptome analyses of the acute cold stress response in Phoxinus lagowskii

Water temperature is a crucial environmental factor that significantly affects the physiological and biochemical processes of fish. Due to the occurrence of cold events in aquaculture, it is imperative to investigate how fish respond to cold stress. This study aims to uncover the mechanisms responds to acute cold stress by conducting a comprehensive analysis of the histomorphology, glycolipid metabolic and antioxidant enzymes, fatty acid composition and transcriptome at three temperatures (16 °C, 10 °C and 4 °C) in Phoxinus lagowskii. Our results showed that cold stress not damaged muscle microstructure but caused autophagy (at 10 °C). In addition, serum glucose (Glu) and triglycerides (TG) increased during cold stress. The activities of reactive oxygen species (ROS), superoxide dismutase (SOD), catalase (CAT), fructose phosphokinase (PFK), hexokinase (HK), pyruvate kinase (PK), and malondialdehyde (MDA) content in muscle were measured and analyzed. During cold stress, superoxide dismutase and catalase activities increased, reactive oxygen species content decreased. No significant difference in Glutathione peroxidase (GPx) activity, malondialdehyde and total cholesterol (T-CHO) contents among groups. Phosphokinase and pyruvate kinase activities decreased, and HK activity increased during cold stress. Our study resulted in the identification of a total of 25,400 genes, with 2524 genes showing differential expression across different temperature treatments. Furthermore, KEGG pathway indicated that some pathways upregulated during light cold stress (at 10 °C, including autophagy, and AMP-activated protein kinase (AMPK) signaling pathway. Additionally, circadian rhythm is among the most enriched pathways in genes up-regulated during severe cold stress (at 4 °C). Our findings offer valuable insights into how cold-water fish respond to cold stress.

Sargassum seaweed extract regulates physio-molecular patterns in Sesamum indicum L. towards better growth and Macrophomina tolerance

Seaweed extracts have gained significant attention in agriculture as they contain biologically active components that promote plant growth, increase productivity and stress signalling pathways for disease tolerance. The present study, reveal the positive effect of Sargassum tenerrimum extract on Sesamum indicum L. at both vegetative and reproductive stages towards enhancing tolerance against charcoal rot disease caused by Macrophomina phaseolina. The application of S. tenerrimum extract alone and in combination with Macrophomina enhanced the plant's growth and yield. In both stages, the S. tenerrimum extract alone and in combination with Macrophomina resulted in increased membrane stability index, photosynthetic pigments and osmolytes as compared to control and Macrophomina treatment. Significant decrease in the accumulation of reactive oxygen species was observed in combined treatment as compared to Macrophomina treatment alone in both the stages with both sprays. Antioxidative enzymes exhibited higher accumulation in S. tenerrimum extract treatment and in combination during both sprays at both stages. The improved yield was observed with the applications of S. tenerrimum extract at both stages. Consequently, this study highlights the beneficial role of S. tenerrimum extract in managing diseases in S. indicum by modulating physio-biochemical pathways for improved growth and yield.

SIRT1 exerts protective effects by inhibiting endoplasmic reticulum stress and NF-κB signaling pathways.

Silent information regulator two homolog 1 (SIRT1), an NAD + -dependent histone deacetylase, plays a pivotal regulatory role in a myriad of physiological processes. A growing body of evidence suggests that SIRT1 can exert protective effects in metabolic disorders and neurodegenerative diseases by inhibiting endoplasmic reticulum (ER) stress and the nuclear factor-κB (NF-κB) inflammatory signaling pathway. This review systematically elucidates the molecular mechanisms and biological significance of SIRT1 in regulating ER stress and the NF-κB pathway. On one hand, SIRT1 can deacetylate key molecules in the ER stress pathway, such as glucose-regulated protein 78 (GRP78), X-box binding protein 1 (XBP1), PKR-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6), thereby alleviating ER stress. On the other hand, SIRT1 can directly or indirectly remove the acetylation modification of the NF-κB p65 subunit, inhibiting its transcriptional activity and thus attenuating inflammatory responses. Through these mechanisms, SIRT1 can ameliorate insulin resistance in metabolic diseases, exert cardioprotective effects in ischemia-reperfusion injury, and reduce neuronal damage in neurodegenerative diseases. However, it is important to note that while these findings are promising, the complex nature of the biological systems involved warrants further investigation to fully unravel the intricacies of SIRT1's regulatory mechanisms. Nevertheless, understanding the regulatory mechanisms of SIRT1 on ER stress and the NF-κB pathway is of great significance for expanding our knowledge of the pathogenesis of related diseases and exploring new preventive and therapeutic strategies targeting SIRT1.

ERN1 KNOCKDOWN AFFECTS THE EXPRESSION OF PDHA1, PDHB, PDHX, DLD, AND DLAT GENES AND MODIFIES THEIR HYPOXIC REGULATION

Aim. The purpose of this study was to investigate the role of ERN1 in the regulation of the expression of pyruvate dehydrogenase complex genes in U87MG glioma cells. Methods. We used qPCR analysis to study the role of hypoxia, caused by incubating cells in 0.5 mM dimethyloxalylglycine for 4 hours, in the expression of pyruvate dehydrogenase complex genes as well as its interaction with the ERN1 endoplasmic reticulum stress signaling pathway in U87 glioma cell culture. Three glioma cell culture lines were used in the study (control glioma cells, cells with complete blockade of the enzymatic activity of ERN1 protein, and cells with inactivation of endoribonuclease only). Results. It has been demonstrated that the expression level of most PHD genes decreases under hypoxic conditions in control glioma cells and cells with ERN1 blockade. Conclusions. It is important to note that the effect of hypoxia is gene-specific and dependent on the activity of ERN1 protein for some genes. It has also been demonstrated that different genes are regulated by different enzymatic activities of the ERN1 signaling protein. The PDHX and DLD genes are regulated by the protein kinase activity of ERN1, PDHA1 and PDHB proteins by the endoribonuclease of ERN1, and the DLAT gene is regulated by both enzymatic activities.

Oridonin promotes RSL3-induced ferroptosis in breast cancer cells by regulating the oxidative stress signaling pathway JNK/Nrf2/HO-1

The incidence and mortality of breast cancer, the most common malignant tumor among women in the world, are increasing year by year, which greatly threatens women's health. Ferroptosis is an iron and lipid reactive oxygen species (ROS)-dependent process, a novel form of cell death that is distinct from apoptosis and is closely related to the progression of breast cancer. Inducing the occurrence of ferroptosis in tumor cells can effectively block its malignant progress in vivo. Oridonin (ORI), the primary active ingredient extracted from the Chinese herbal medicine Rabdosia rubescens, has been shown to cause glutathione depletion and directly inhibit glutathione peroxidase 4 induced cell death by ferroptosis, but its mechanism of action in breast cancer remains inadequately elucidated. Therefore, we further investigated whether ORI could promote RSL3-induced ferroptosis in breast cancer cells by regulating the oxidative stress pathway JNK/Nrf2/HO-1. In our study, we assessed cell survival of RSL3 and ORI treatment by MTT assay, and found that co-treatment with RSL3 and ORI inhibited cell proliferation, as evidenced by the cloning assay. To investigate the ability of ORI to promote RSL3-induced ferroptosis in breast cancer cells, we measured levels of ROS, malondialdehyde, glutathione, superoxide dismutase, and Fe2+ content. Lipid peroxidation, ROS, and mitochondrial membrane potential levels induced by co-treatment of ORI with RSL3 were reversed by ferrostatin-1, further confirming that the cell death induced by RSL3 and ORI was ferroptosis rather than other programmed cell death modes. Moreover, RSL3 and ORI co-treatment regulated the JNK/Nrf2/HO-1 axis, as demonstrated by western blotting and target activator validation. Our results showed that ORI could enhance the inhibitory effect of RSL3 on breast cancer cells viability via the induction of ferroptosis. Mechanistically, it potentiated RSL3-induced ferroptosis in breast cancer cells by activating the JNK/Nrf2/HO-1 axis. This study provides a theoretical basis for the application of ORI based on the mechanism of ferroptosis, and provides potential natural drug candidates for cancer prevention and treatment.