Stress Signaling Research Articles

LED therapy modulates M1/M2 macrophage phenotypes and mitigates dystrophic features in treadmill-trained mdx mice.

The mdx mouse phenotype, aggravated by chronic exercise on a treadmill, makes this murine model more reliable for the study of Duchenne muscular dystrophy (DMD) and allows the efficacy of therapeutic interventions to be evaluated. This study aims to investigate the effects of photobiomodulation by light-emitting diode (LED) therapy on functional, biochemical and morphological parameters in treadmill-trained adult mdx animals. Mdx mice were trained for 30min of treadmill running at a speed of 12m/min, twice a week for 4weeks. The LED therapy (850nm) was applied twice a week to the quadriceps muscle throughout the treadmill running period. LED therapy improved behavioral activity (open field) and muscle function (grip strength and four limb hanging test). Functional benefits correlated with reduced muscle damage; a decrease in the inflammatory process; modulation of the regenerative muscular process and calcium signalling pathways; and a decrease in oxidative stress markers. The striking finding of this work is that LED therapy leads to a shift from the M1 to M2 macrophage phenotype in the treadmill-trained mdx mice, enhancing tissue repair and mitigating the dystrophic features. Our data also imply that the beneficial effects of LED therapy in the dystrophic muscle correlate with the interplay between calcium, oxidative stress and inflammation signalling pathways. Together, these results suggest that photobiomodulation could be a potential adjuvant therapy for dystrophinopathies.

TROP2 promotes the proliferation of triple-negative breast cancer cells via calcium ion-dependent ER stress signaling pathway.

To explore the molecular mechanisms of tumor-associated calcium signal transduction factor 2 (TROP2) affecting the occurrence and development of triple-negative breast cancer (TNBC). The TCGA database, immunohistochemical staining, and qRT-PCR were used to analyze the expression of TROP2 in TNBC tissues and cells. The protein expressions of TROP2 and inositol 1,4,5-trisphosphate receptor (IP3R) after TROP2 knockdown were detected by western blot (WB). Cell proliferation was detected by CCK8 and colony formation assay, Annexin V-APC/PI flow cytometry was used to detect apoptosis, and intracellular calcium ion (Ca2+) was detected by flow cytometry with Fura 2-AM fluorescent probe. Finally, the morphological changes of the endoplasmic reticulum (ER) were observed by transmission electron microscopy, and the expression of ER stress (ERS)-related proteins was detected by WB and immunofluorescence staining. TROP2 was up-regulated in TNBC tumor tissues and cells. Silencing TROP2 decreased the proliferation rate and clone formation number, and increased the apoptosis rate and the Ca2+ level in TNBC cells. These phenomena were reversed after the addition of 2-APB. In addition, after TROP2 knockdown, the expressions of IP3R and ERS-related proteins were up-regulated, the ER was cystic dilated, and ERS was activated. And the addition of 2-APB significantly inhibited the activation of ERS induced by TROP2 knockdown. TROP2 regulated the proliferation and apoptosis of TNBC cells through a Ca2+-dependent ERS signaling pathway.

Conserved cysteine-switches for redox sensing operate in the cyclin-dependent kinase inhibitor p21(CIP/KIP) protein family

The cell cycle is a tightly regulated, dynamic process controlled by multiple checkpoints. When the prevention of cell cycle progression is needed, key effectors such as members of the p21 (CIP/KIP) inhibit cyclin-dependent kinases (CDKs). It is accepted that p21 does not sense DNA damage and that stress signals affect p21 indirectly. A plethora of DNA damaging events activate the tumor suppressor p53, which in turn transcriptionally activates p21, steeply changing its levels to reach CDK inhibition. The levels of p21 are also controlled by phosphorylation and ubiquitination events, which are relevant as they modulate p21 activity, localization, and stability. Intriguingly, here we report the first evidence of the direct control of p21 cell proliferation inhibition by DNA damaging signals. Specifically, we have identified a redox regulating mechanism that controls p21 capacity to reduce cell proliferation. Using the human p21 protein, we identified two cysteine-switches that independently regulate its cyclin-binding and linker (LH) modules respectively. Additionally, we provide a mechanistic explanation of how reactive cysteines embedded in unstructured regions of intrinsically disordered proteins respond to ROS without the guidance of protein structure, contributing to a vastly unexplored area of research. Cellular experiments utilizing p21KID mutants that disrupt disulfide-based switches demonstrate their impact on the capacity of p21 to inhibit cell cycle progression, thus highlighting the functional relevance of our findings. Furthermore, our investigation reveals that reactive cysteine residues are highly conserved across the Kinase Inhibitory Domain (KID) sequences of p21 proteins from higher eukaryotes, and the p27 and p57 human paralogs. We propose that the presence of conserved regulatory cysteines within the KIDs of p21 family members from multiple taxa provides those proteins with the capability for directly sensing ROS, enabling the direct regulation of cyclin kinase activity by ROS levels.

Perfluorooctane sulfonate causes damage to L-02 cells via Wnt/β-catenin signal path and endoplasmic reticulum stress pathway.

Perfluorooctane sulfonate (PFOS) is one of the most widely used perfluorinated compounds, and as an environmental endocrine disruptor and environmental persistent pollutant, the threat of PFOS to human health is of increasing concern. Exposure to PFOS has been shown to be closely associated with liver disease, but the intrinsic molecular targets and mechanisms of PFOS-induced liver damage are not well understood. This study was conducted to explore whether the Wnt/β-Catenin signaling pathway and the endoplasmic reticulum stress signaling pathway are involved in damage of PFOS to the liver. In this study, we used the CCK-8 method to detect cell viability, a microscope and DAPI staining to observe cell morphology, flow cytometry to detect cell ROS and apoptosis levels; and Western blot to detect the expressions of proteins in the WNT/β-Catenin, endoplasmic reticulum stress and apoptosis-related pathways. We found that PFOS activated WNT/β-Catenin and endoplasmic reticulum stress-related pathways in L-02 cells and could lead to the development of oxidative stress and apoptosis. Our findings showed that PFOS could cause damage to L-02 cells, and the WNT/β-Catenin signaling and endoplasmic reticulum stress pathways were involved in the changes caused by PFOS to L-02 cells, which provided a new theoretical basis for studying the hepatotoxicity and mechanism of PFOS. PFOS can lead to increased intracellular ROS levels, causing oxidative stress, endoplasmic reticulum stress and activation of the WNT/β-catenin signaling pathway. Our experimental results showed that PFOS can cause damage to L-02 cells, and the WNT/β-Catenin signaling pathway and endoplasmic reticulum stress pathway are involved in the process of damage caused by PFOS to L-02 cells.

Targeting Endoplasmic Reticulum Stress by Natural and Chemical Compounds Ameliorates Cisplatin-Induced Nephrotoxicity: A Review.

Cisplatin is a chemotherapeutic that dose-dependently causes renal complications such as decreased kidney function and acute kidney injury. The endoplasmic reticulum (ER) is responsible for calcium homeostasis and protein folding and plays a major part in cisplatin's nephrotoxicity. The current article reviews how chemical and natural compounds modulate cisplatin-induced apoptosis, autophagy, and inflammation by inhibiting ER stress signaling pathways. The available evidence indicates that natural compounds (Achyranthes aspera water-soluble extract, morin hydrate, fucoidan, isoliquiritigenin, leonurine, epigallocatechin-3-gallate, grape seed proanthocyanidin, and ginseng polysaccharide) and chemicals (Sal003, NSC228155, TUG891, dorsomorphin (compound C), HC-030031, dexmedetomidine, and recombinant human erythropoietin (rHuEpo)) can alleviate cisplatin nephrotoxicity by suppression of ER stress signaling pathways including IRE1α/ASK1/JNK, PERK-eIF2α-ATF4, and ATF6, as well as PI3K/AKT signaling pathway. Since ER and related signaling pathways are important in cisplatin nephrotoxicity, agents that can inhibit the abovementioned signaling pathways may hold promise in alleviating this untoward adverse effect.

Common molecular and pathophysiological underpinnings of delirium and Alzheimer’s disease: molecular signatures and therapeutic indications

BackgroundDelirium and Alzheimer's disease (AD) are common causes of cognitive dysfunction among older adults. These neurodegenerative diseases share a common and complex relationship, and can occur individually or concurrently, increasing the chance of permanent mental dysfunction. However, the common molecular pathophysiology, key proteomic biomarkers, and functional pathways are largely unknown, whereby delirium is superimposed on AD and dementia.MethodsWe employed an integrated bioinformatics and system biology analysis approach to decipher such common key proteomic signatures, pathophysiological links between delirium and AD by analyzing the gene expression data of AD-affected human brain samples and comparing them with delirium-associated proteins. The present study identified the common drug target hub-proteins examining the protein–protein interaction (PPI) and gene regulatory network analysis. The functional enrichment and pathway analysis was conducted to reveal the common pathophysiological relationship. Finally, the molecular docking and dynamic simulation was used to computationally identify and validate the potential drug target and repurposable drugs for delirium and AD.ResultsWe detected 99 shared differentially expressed genes (sDEGs) associated with AD and delirium. The sDEGs-set enrichment analysis detected the transmission across chemical synapses, neurodegeneration pathways, neuroinflammation and glutamatergic signaling pathway, oxidative stress, and BDNF signaling pathway as the most significant signaling pathways shared by delirium and AD. The disease-sDEGs interaction analysis highlighted the other disease risk factors with delirium and AD development and progression. Among the sDEGs of delirium and AD, the top 10 hub-proteins including ALB, APP, BDNF, CREB1, DLG4, GAD1, GAD2, GFAP, GRIN2B and GRIN2A were found by the PPI network analysis. Based on the maximum molecular docking binding affinities and molecular dynamic simulation (100 ns) results, the ALB and GAD2 were found as prominent drug target proteins when tacrine and donepezil were identified as potential drug candidates for delirium and AD.ConclusionThe study outlined the common key biomolecules and biological pathways shared by delirium and AD. The computationally reported potential drug molecules need a deeper investigation including clinical trials to validate their effectiveness. The outcomes from this study will help to understand the typical pathophysiological relationship between delirium and AD and flag future therapeutic development research for delirium.

Tubeimoside-I, an inhibitor of HSPD1, enhances cytotoxicity of oxaliplatin by activating ER stress and MAPK signaling pathways in colorectal cancer

Ethnopharmacological relevanceTubeimoside-I (TBM) promotes various cancer cell death by increasing the reactive oxygen species (ROS) production. However, the specific molecular mechanisms of TBM and its impact on oxaliplatin-mediated anti-CRC activity are not yet fully understood. Aim of the studyTo elucidate the therapeutic effect and underlying molecular mechanism of TBM on oxaliplatin-mediated anti-CRC activity. Materials and methods3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), colony formation, wound healing assays and flow cytometry were conducted to investigate the changes in cell phenotypes and ROS generation. Real-time quantitative PCR (qRT-PCR) and western blotting were performed to detect the expressions of related mRNA and proteins. Finally, mouse xenograft models demonstrated that synergistic anti-tumor effects of combined treatment with TBM and oxaliplatin. ResultsThe synergistic enhancement of the anti-tumor effects of oxaliplatin in colon cancer cells by TBM involved in the regulation of ROS-mediated endoplasmic reticulum (ER) stress, C-jun-amino-terminal kinase (JNK), and p38 MAPK signaling pathways. Mechanistically, TBM increased ROS generation in colon cancer cells by inhibiting heat shock protein 60 (HSPD1) expression. Knocking down HSPD1 increased TBM-induced antitumor activity and ROS generation in colon cancer cells. The mouse xenograft tumor models further validated that the combination therapy exhibited stronger anti-tumor effects than monotherapy alone. ConclusionsCombined therapy with TBM and oxaliplatin might be an effective therapeutic strategy for some CRC patients.

Role of Oxidative Stress Signaling, Nrf2, on Survival and Stemness of Human Adipose-Derived Stem Cells Exposed to X-rays, Protons and Carbon Ions.

Some cancers have a poor prognosis and often lead to local recurrence because they are resistant to available treatments, e.g., glioblastoma. Attempts have been made to increase the sensitivity of resistant tumors by targeting pathways involved in the resistance and combining it, for example, with radiotherapy (RT). We have previously reported that treating glioblastoma stem cells with an Nrf2 inhibitor increases their radiosensitivity. Unfortunately, the application of drugs can also affect normal cells. In the present study, we aim to investigate the role of the Nrf2 pathway in the survival and differentiation of normal human adipose-derived stem cells (ADSCs) exposed to radiation. We treated ADSCs with an Nrf2 inhibitor and then exposed them to X-rays, protons or carbon ions. All three radiation qualities are used to treat cancer. The survival and differentiation abilities of the surviving ADSCs were studied. We found that the enhancing effect of Nrf2 inhibition on cell survival levels was radiation-quality-dependent (X-rays > proton > carbon ions). Furthermore, our results indicate that Nrf2 inhibition reduces stem cell differentiation by 35% and 28% for adipogenesis and osteogenesis, respectively, using all applied radiation qualities. Interestingly, the results show that the cells that survive proton and carbon ion irradiations have an increased ability, compared with X-rays, to differentiate into osteogenesis and adipogenesis lineages. Therefore, we can conclude that the use of carbon ions or protons can affect the stemness of irradiated ADSCs at lower levels than X-rays and is thus more beneficial for long-time cancer survivors, such as pediatric patients.

Pemphigus vulgaris autoantibodies induce an ER stress response.

Desmosomes are intercellular junctions that mediate cell-cell adhesion and are essential for maintaining tissue integrity. Pemphigus vulgaris (PV) is an autoimmune epidermal blistering disease caused by autoantibodies (IgG) targeting desmoglein 3 (Dsg3), a desmosomal cadherin. PV autoantibodies cause desmosome disassembly and loss of cell-cell adhesion, but the molecular signaling pathways that regulate these processes are not fully understood. Using high-resolution time-lapse imaging of live keratinocytes, we found that ER tubules make frequent and persistent contacts with internalizing Dsg3 puncta in keratinocytes treated with PV patient IgG. Biochemical experiments demonstrated that PV IgG activated ER stress signaling pathways, including both IRE1⍺ and PERK pathways, in cultured keratinocytes. Further, ER stress transcripts were upregulated in PV patient skin. Pharmacological inhibition of ER stress protected against PV IgG-induced desmosome disruption and loss of keratinocyte cell-cell adhesion, suggesting that ER stress may be an important pathomechanism and therapeutically targetable pathway for PV treatment. These data support a model in which desmosome adhesion is integrated with ER function to serve as a cell adhesion stress sensor that is activated in blistering skin disease.

25-Hydroxycholesterol attenuates tumor necrosis factor alpha-induced blood-brain barrier breakdown in vitro

Intracellular cholesterol metabolism is regulated by the SREBP-2 and LXR signaling pathways. The effects of inflammation on these molecular mechanisms remain poorly studied, especially at the blood-brain barrier (BBB) level. Tumor necrosis factor α (TNFα) is a proinflammatory cytokine associated with BBB dysfunction. Therefore, the aim of our study was to investigate the effects of TNFα on BBB cholesterol metabolism, focusing on its underlying signaling pathways. Using a human in vitro BBB model composed of human brain-like endothelial cells (hBLECs) and brain pericytes (HBPs), we observed that TNFα increases BBB permeability by degrading the tight junction protein CLAUDIN-5 and activating stress signaling pathways in both cell types. TNFα also promotes cholesterol release and decreases cholesterol accumulation and APOE secretion. In hBLECs, the expression of SREBP-2 targets (LDLR and HMGCR) is increased, while ABCA1 expression is decreased. In HBPs, only LDLR and ABCA1 expression is increased. TNFα treatment also induces 25-hydroxycholesterol (25-HC) production, a cholesterol metabolite involved in the immune response and intracellular cholesterol metabolism. 25-HC pretreatment attenuates TNFα-induced BBB leakage and partially alleviates the effects of TNFα on ABCA1, LDLR, and HMGCR expression. Overall, our results suggest that TNFα favors cholesterol efflux via an LXR/ABCA1-independent mechanism at the BBB, while it activates the SREBP-2 pathway. Treatment with 25-HC partially reversed the effect of TNFα on the LXR/SREBP-2 pathways. Our study provides novel perspectives for better understanding cerebrovascular signaling events linked to BBB dysfunction and cholesterol metabolism in neuroinflammatory diseases.

TUDCA inhibits EV71 replication by regulating ER stress signaling pathway and suppressing autophagy

Tauroursodeoxycholic acid (TUDCA) is a naturally occurring hydrophilic bile acid that alleviates endoplasmic reticulum (ER) stress and inhibits apoptosis, thereby protecting cells. Previous studies have shown that enterovirus 71 (EV71) infection modulates ER stress and induces autophagy to assist viral replication. This study observed the effects of TUDCA pretreatment on HeLa and Vero cells infected with EV71, finding that TUDCA inhibits EV71 replication in TUDCA pretreated HeLa and Vero cells in a dose-dependent manner. We found that TUDCA pretreatment inhibited EV71 replication by regulating three branches of UPR, that is up-regulated ATF6, down-regulated both PERK and IRE1. The results also indicated that autophagy which is downstream of UPR, was inhibited either. The results indicate that TUDCA inhibits EV71 replication by regulating UPR sensor proteins and autophagy following ER stress.

The Therapeutic Mechanisms of Honey in Mitigating Toxicity from Anticancer Chemotherapy Toxicity: A Review.

Within the domain of conventional oncochemotherapeutics, anticancer chemotherapy (AC) has emerged as a potent strategy for the treatment of cancers. AC is the mainstay strategy for solid and non-solid cancer treatment. Its mechanistic action targets the blockage of DNA transcription and the dysregulation of cell cycle machinery in cancer cells, leading to the activation of death pathways. However, the attendant side effect of toxicity inflicted by AC on healthy tissues presents a formidable challenge. The crucial culprit in the AC side effect of toxicity is unknown, although oxidative stress, mitochondrial impairment, inflammatory cascades, autophagy dysregulation, apoptosis, and certain aberrant signaling have been implicated. Honey is a natural bee product with significant health benefits and pharmacological properties. Interestingly, the literature reports that honey may proffer a protection mechanism for delicate tissue/organs against the side effect of toxicity from AC. Thus, this review delves into the prospective role of honey as an alleviator of the AC side effect of toxicity; it provides an elucidation of the mechanisms of AC toxicity and honey's molecular mechanisms of mitigation. The review endeavors to unravel the specific molecular cascades by which honey orchestrates its mitigating effects, with the overarching objective of refining its application as an adjuvant natural product. Honey supplementation prevents AC toxicity via the inhibition of oxidative stress, NF-κB-mediated inflammation, and caspase-dependent apoptosis cascades. Although there is a need for increased mechanistic studies, honey is a natural product that could mitigate the various toxicities induced by AC.

WRKY transcription factor 40 from eggplant (Solanum melongena L.) regulates ABA and salt stress responses

Plants are affected by many environmental factors during their various stages of growth, among which salt stress is a key factor. WRKY transcription factors play important roles in the response to stress in plants. In this study, SmWRKY40 from eggplant (Solanum melongena L.) was found to belong to the subfamily of WRKY transcription factor group II, closely related to the evolution of wild tomato ScWRKY40 (Solanum chilense). The expression of SmWRKY40 could be induced by several abiotic stresses (drought, salt, and high temperature) and ABA to different degrees, with salt stress being the most significant. In Arabidopsis thaliana, the seed germination rate of SmWRKY40 overexpression seedlings was significantly higher than those of the wild type under high concentrations of NaCl and ABA, and root elongation of overexpression lines was also longer than wild type under NaCl treatments. SmWRKY40 overexpression lines were found to enhance Arabidopsis tolerance to salt with lower ROS, MDA, higher soluble protein, proline accumulation, and more active antioxidant enzymes. The expression level of genes related to stress and ABA signaling displayed significant differences in SmWRKY40 overexpression line than that of WT. These results indicate that SmWRKY40 regulates ABA and salt stress responses in Arabidopsis.

Exploring Oxidative Stress in Disease and Its Connection with Adenosine

Oxidative stress, characterized by an imbalance between the production of reactive oxygen species and the body’s antioxidant defenses, plays an important role in the pathogenesis of various health conditions, including cancer and neurological disorders. For example, excessive ROS can lead to mutations, genomic instability, and uncontrolled cell proliferation in cancer. In neurological disorders, oxidative stress contributes to neuronal damage, inflammation, and the progression of diseases such as Alzheimer’s and Parkinson’s diseases. Adenosine, a nucleoside involved in energy transfer and signal transduction, is crucial to maintaining cellular homeostasis. Its role extends to modulating oxidative stress. Adenosine receptors are implicated in various physiological processes and in the pathophysiology of diseases. The interplay between oxidative stress and adenosine signaling is complex and critical. Adenosine can modulate oxidative stress responses, providing therapeutic potential for conditions where oxidative stress is a key player. Understanding this connection opens up avenues for novel therapeutic strategies targeting adenosine receptors to mitigate oxidative damage.

Jumonji histone demethylases are therapeutic targets in small cell lung cancer

Small cell lung cancer (SCLC) is a recalcitrant cancer of neuroendocrine (NE) origin. Changes in therapeutic approaches against SCLC have been lacking over the decades. Here, we use preclinical models to identify a new therapeutic vulnerability in SCLC consisting of the targetable Jumonji lysine demethylase (KDM) family. We show that Jumonji demethylase inhibitors block malignant growth and that etoposide-resistant SCLC cell lines are particularly sensitive to Jumonji inhibition. Mechanistically, small molecule-mediated inhibition of Jumonji KDMs activates endoplasmic reticulum (ER) stress genes, upregulates ER stress signaling, and triggers apoptotic cell death. Furthermore, Jumonji inhibitors decrease protein levels of SCLC NE markers INSM1 and Secretogranin-3 and of driver transcription factors ASCL1 and NEUROD1. Genetic knockdown of KDM4A, a Jumonji demethylase highly expressed in SCLC and a known regulator of ER stress genes, induces ER stress response genes, decreases INSM1, Secretogranin-3, and NEUROD1 and inhibits proliferation of SCLC in vitro and in vivo. Lastly, we demonstrate that two different small molecule Jumonji KDM inhibitors (pan-inhibitor JIB-04 and KDM4 inhibitor SD70) block the growth of SCLC tumor xenografts in vivo. Our study highlights the translational potential of Jumonji KDM inhibitors against SCLC, a clinically feasible approach in light of recently opened clinical trials evaluating this drug class, and establishes KDM4A as a relevant target across SCLC subtypes.

Rice A20/AN1 protein, OsSAP10, confers water-deficit stress tolerance via proteasome pathway and positive regulation of ABA signaling in Arabidopsis.

Overexpression of rice A20/AN1 zinc-finger protein, OsSAP10, improves water-deficit stress tolerance in Arabidopsis via interactionwith multiple proteins. Stress-associated proteins (SAPs) constitute a class of A20/AN1 zinc-finger domain containing proteins and their genes are induced in response to multiple abiotic stresses. The role of certain SAP genes in conferring abiotic stress tolerance is well established, but their mechanism of action is poorly understood. To improve our understanding of SAP gene functions, OsSAP10, a stress-inducible rice gene, was chosen for the functional and molecular characterization. To elucidate its role in water-deficit stress (WDS) response, we aimed to functionally characterize its roles in transgenic Arabidopsis, overexpressing OsSAP10. OsSAP10 transgenics showed improved tolerance to water-deficit stress at seed germination, seedling and mature plant stages. At physiological and biochemical levels, OsSAP10 transgenics exhibited a higher survival rate, increased relative water content, high osmolyte accumulation (proline and soluble sugar), reduced water loss, low ROS production, low MDA content and protected yield loss under WDS relative to wild type (WT). Moreover, transgenics were hypersensitive to ABA treatment with enhanced ABA signaling and stress-responsive genes expression. The protein-protein interaction studies revealed that OsSAP10 interacts with proteins involved in proteasomal pathway, such as OsRAD23, polyubiquitin and with negative and positive regulators of stress signaling, i.e., OsMBP1.2, OsDRIP2, OsSCP and OsAMTR1. The A20 domain was found to be crucial for most interactions but insufficient for all interactions tested. Overall, our investigations suggest that OsSAP10 is an important candidate for improving water-deficit stress tolerance in plants, and positively regulates ABA and WDS signaling via protein-protein interactions and modulation of endogenous genes expression in ABA-dependent manner.

Tocilizumab unfolds colo-protective and immunomodulatory effect in experimentally induced ulcerative colitis via mitigating autophagy and ER stress signaling

Ulcerative colitis (UC) is an idiopathic, chronic, relapsing inflammatory bowel disease (IBD), characterized by chronic inflammation of the gastrointestinal tract. The pathophysiology of UC is complicated and involves several factors including immune, genetic, and environmental factors. Recently, a huge amount of research has concentrated on the role of interleukins including interleukin-6 (IL-6) in its pathophysiology. Thus, this study aims to examine the colo-protective and immunomodulatory effect of Tocilizumab (TCZ) in an experimental model of dextran sulfate sodium (DSS) induced UC. In the current study, we analyzed the inflammatory, immunomodulatory, apoptotic, autophagy, and endoplasmic reticulum (ER) stress markers and other clinical features including stool consistency, rectal bleeding, and edema markers in rats. Our results showed that induction of colitis caused bloody diarrhea and increased IL-6 levels. Treatment with TCZ significantly ameliorated DSS-induced injury via decreasing inflammatory markers of colon injury (IL-6), signal transducer and activator of transcription-3 (STAT-3), and C-reactive protein (CRP). Furthermore, TCZ attenuated the apoptotic marker (caspase-3), and down-regulated endoplasmic reticulum stress sensor proteins (inositol- requiring transmembrane kinase endonuclease-1 (IRE-1) and activated transcription factor-6 (ATF-6)) and autophagy proteins (autophagy-related 16-like protein 1 (ATG16L1) and nucleotide-binding oligomerization domain-containing protein-2 (NOD2)), as compared to DSS group. Altogether, the current data suggest TCZ to be a promising protective therapy against UC.Graphical

Novel flexible magnetoelastic biosensor based on PDMS/FeSiB/QD composite film for the detection of African swine fever virus P72 protein.

African swine fever (ASF) is a highly contagious and severe hemorrhagic disease caused by the African swine fever virus (ASFV). The continuous spread of ASFV affects the safety of the global meat supply; therefore, the establishment of sensitive and specific detection methods for ASFV has become an important hot spot in food safety. Herein, we developed a flexible magnetoelastic (ME) biosensor based on PDMS/FeSiB/QDs composite films for the detection of ASFV P72 protein. Based on the high luminescence performance of CsPbBr3 quantum dots and the excellent magnetoelastic effect of FeSiB, flexible ME biosensors convert stress signals generated by antibody-antigen-specific binding into optical and electromagnetic signals. The nanostructures covalently linked by quantum dots and PDMS provide biomodification sites for ASFV P72 antibodies, simplifying the functionalization modification process compared to the case of conventional biosensors. The deformation of the PDMS film is amplified, and the conversion of surface stress signals to electrical signals is enhanced by exposing the biosensor to a uniform magnetic field. The experimental results proved that the flexible ME biosensor has a wide linear range of 10 ng mL-1-100 μg mL-1, and the detection limit is as low as 0.079 ng mL-1. Moreover, the flexible ME biosensor also shows good stability, sensitivity and specificity, confirming the potential for early disease screening.

Intrinsic Mechanism of CaCl2 Alleviation of H2O2 Inhibition of Pea Primary Root Gravitropism.

Normal root growth is essential for the plant uptake of soil nutrients and water. However, exogenous H2O2 inhibits the gravitropic growth of pea primary roots. It has been shown that CaCl2 application can alleviate H2O2 inhibition, but the exact alleviation mechanism is not clear. Therefore, the present study was carried out by combining the transcriptome and metabolome with a view to investigate in depth the mechanism of action of exogenous CaCl2 to alleviate the inhibition of pea primordial root gravitropism by H2O2. The results showed that the addition of CaCl2 (10 mmol·L-1) under H2O2 stress (150 mmol·L-1) significantly increased the H2O2 and starch content, decreased peroxidase (POD) activity, and reduced the accumulation of sugar metabolites and lignin in pea primary roots. Down-regulated genes regulating peroxidase, respiratory burst oxidase, and lignin synthesis up-regulated PGM1, a key gene for starch synthesis, and activated the calcium and phytohormone signaling pathways. In summary, 10 mmol·L-1 CaCl2 could alleviate H2O2 stress by modulating the oxidative stress response, signal transduction, and starch and lignin accumulation within pea primary roots, thereby promoting root gravitropism. This provides new insights into the mechanism by which CaCl2 promotes the gravitropism of pea primary roots under H2O2 treatment.

Divergent Processing of Cell Stress Signals as the Basis of Cancer Progression: Licensing NFκB on Chromatin.

Inflammation is activated by diverse triggers that induce the expression of cytokines and adhesion molecules, which permit a succession of molecules and cells to deliver stimuli and functions that help the immune system clear the primary cause of tissue damage, whether this is an infection, a tumor, or a trauma. During inflammation, short-term changes in the expression and secretion of strong mediators of inflammation occur, while long-term changes occur to specific groups of cells. Long-term changes include cellular transdifferentiation for some types of cells that need to regenerate damaged tissue, as well as death for specific immune cells that can be detrimental to tissue integrity if they remain active beyond the boundaries of essential function. The transcriptional regulator NFκB enables some of the fundamental gene expression changes during inflammation, as well as during tissue development. During recurrence of malignant disease, cell stress-induced alterations enable the growth of cancer cell clones that are substantially resistant to therapeutic intervention and to the immune system. A number of those alterations occur due to significant defects in feedback signal cascades that control the activity of NFκB. Specifically, cell stress contributes to feedback defects as it overrides modules that otherwise control inflammation to protect host tissue. NFκB is involved in both the suppression and promotion of cancer, and the key distinctive feature that determines its net effect remains unclear. This paper aims to provide a clear answer to at least one aspect of this question, namely the mechanism that enables a divergent response of cancer cells to critical inflammatory stimuli and to cell stress in general.