Persistent Stress Research Articles

Musculoskeletal imaging of senescence.

Senescent cells play a vital role in the pathogenesis of musculoskeletal (MSK) diseases, such as chronic inflammatory joint disorders, rheumatoid arthritis (RA), and osteoarthritis (OA). Cellular senescence in articular joints represents a response of local cells to persistent stress that leads to cell-cycle arrest and enhanced production of inflammatory cytokines, which in turn perpetuates joint damage and leads to significant morbidities in afflicted patients. It has been recently discovered that clearance of senescent cells by novel "senolytic" therapies can attenuate the chronic inflammatory microenvironment of RA and OA, preventing further disease progression and supporting healing processes. To identify patients who might benefit from these new senolytic therapies and monitor therapy response, there is an unmet need to identify and map senescent cells in articular joints and related musculoskeletal tissues. To fill this gap, new imaging biomarkers are being developed to detect and characterize senescent cells in human joints and musculoskeletal tissues. This review article will provide an overview of these efforts. New imaging biomarkers for senescence cells are expected to significantly improve the specificity of state-of-the-art imaging technologies for diagnosing musculoskeletal disorders.

Helicobacter pylori secretory Proteins-Induced oxidative stress and its role in NLRP3 inflammasome activation

Helicobacter pylori-associated stomach infection is a leading cause of gastric ulcer and related cancer. H. pylori modulates the functions of infiltrated immune cells to survive the killing by reactive oxygen and nitrogen species (ROS and RNS) produced by these cells. Uncontrolled immune responses further produce excess ROS and RNS which lead to mucosal damage. The persistent oxidative stress is a major cause of gastric cancer. H. pylori regulates nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs), nitric oxide synthase 2 (NOS2), and polyamines to control ROS and RNS release through lesser-known mechanisms. ROS and RNS produced by these pathways differentiate macrophages and T cells from protective to inflammatory phenotype. Pathogens-associated molecular patterns (PAMPs) induced ROS activates nuclear oligomerization domain (NOD), leucine rich repeats (LRR) and pyrin domain-containing protein 3 (NLRP3) inflammasome for the release of pro-inflammatory cytokines. This study evaluates the role of H. pylori secreted concentrated proteins (HPSCP) related oxidative stress role in NLRP3 inflammasome activation and macrophage differentiation. To perceive the role of ROS/RNS, THP-1 and AGS cells were treated with 10 μM diphenyleneiodonium (DPI), 50 μM salicyl hydroxamic acid (SHX), 5 μM Carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP), which are specific inhibitors of NADPH oxidase (NOX), Myeloperoxidase (MPO), and mitochondrial oxidative phosphorylation respectively. Cells were also treated with 10 μM of NOS2 inhibitor l-NMMA and 10 μM of N-acetyl cysteine (NAC), a free radical scavenger·H2O2 (100 μM) treated and untreated cells were used as positive controls and negative control respectively. The expression of gp91phox (NOX2), NOS2, NLRP3, CD86 and CD163 was analyzed through fluorescent microscopy. THP-1 macrophages growth was unaffected whereas the gastric epithelial AGS cells proliferated in response to higher concentration of HPSCP. ROS and myeloperoxidase (MPO) level increased in THP-1 cells and nitric oxide (NO) and lipid peroxidation significantly decreased in AGS cells. gp91phox expression was unchanged, whereas NOS2 and NLRP3 downregulated in response to HPSCP, but increased after inhibition of NO, ROS and MPO in THP-1 cells. HPSCP upregulated the expression of M1 and M2 macrophage markers, CD86 and CD163 respectively, which was decreased after the inhibition of ROS.This study concludes that there are multiple pathways which are generating ROS during H. pylori infection which further regulates other cellular processes. NO is closely associated with MPO and inhibition of NLRP3 inflammasome. The low levels of NO and MPO regulates gastrointestinal tract homeostasis and overcomes the inflammatory response of NLRP3. The ROS also plays crucial role in macrophage polarization hence alter the immune responses duing H. pylori pathogenesis.

Development, piloting and evaluation of an app-supported psychosocial prevention intervention to strengthen participation in working life: a study protocol of a mixed-methods approach

IntroductionRates of incapacity to work due to mental disorders have increased in many European countries. The consequences of persistent stress can impact individuals’ physical and psychological well-being and gradually develop...

Ferroptosis participated in inhaled polystyrene nanoplastics-induced liver injury and fibrosis

The emerging contaminant nanoplastics (NPs) have received considerable attention. Due to their tiny size and unique colloidal properties, NPs could more easily enter the body and cross biological barriers with inhalation exposure. While NPs-induced hepatotoxicity has been reported, the hepatic impact of inhaled NPs was still unknown. To close this gap, a 40 nm polystyrene NPs (PS-NPs) inhalation exposure mice model was developed to explore the hepatotoxicity during acute (1 week), subacute (4 weeks), and subchronic period (12 weeks), with four exposure doses (0, 16, 40, and 100 μg/day). Results showed that inhaled PS-NPs caused a remarkable increase of ALT, AST, and ALP with a decrease of CHE, indicating liver dysfunction. Various histological abnormalities and significantly higher levels of inflammation in a dose- and time-dependent manner were observed. Moreover, after 4 weeks and 12 weeks of exposure, Masson staining and upregulated expression of TGF-β, α-SMA, and Col1a1 identified that inhaled PS-NPs exposure triggered the progression of liver fibrosis with the exposure time prolonged. From the mechanistic perspective, transcriptome analysis revealed that ferroptosis was involved in PS-NPs-induced liver hepatotoxicity, and key features of ferroptosis were detected, including persistent oxidative stress, iron overload, increased LPO, mitochondria damage, and the expression changes of GPX4, TFRC, and Ferritin. And in vitro and in vivo recovery tests showed that ferroptosis inhibitor Fer-1 treatment alleviated liver injury and fibrosis. The above results confirmed the critical role of ferroptosis in PS-NPs-induced hepatotoxicity. Furthermore, to better conclude our findings and understand the mechanistic causality within it, an adverse outcome pathway (AOP) framework was established. In total, this present study conducted the first experimental assessment of inhalation exposure to PS-NPs on the liver, identified that continuous inhaled PS-NPs could cause liver injury and fibrosis, and PS-NPs- ferroptosis provided a novel mechanistic explanation.

Hybrid gelatin-ascorbyl phosphate scaffolds accelerate diabetic wound healing via ROS scavenging, angiogenesis and collagen remodeling

Skin wound healing, particularly diabetic wound healing, is challenging in clinical management. Impaired wound healing is associated with persistent oxidative stress, altered inflammatory responses, unsatisfactory angiogenesis and epithelialization. Magnesium ascorbyl phosphate (MAP), which is an ascorbic acid derivative and active ingredient in cosmetics, has been reported to scavenge reactive oxygen species (ROS), and is considered a potential therapeutic agent for diabetic wounds. Herein, we report a hybrid gelatin-MAP scaffolds that can reduces oxidative stress damage, enhances angiogenesis and collagen remodeling to accelerate diabetic wound repair. Preliminary insights based on network pharmacology indicate that MAP may accelerate wound repair through multiple biological pathways, including extracellular matrix remodeling and anti-apoptosis. In vitro studies showed that the hybrid hydrogel scaffold had suitable mechanical properties, excellent biocompatibility and bioactivity. Further animal experiments demonstrated that the hydrogel accelerated full-thickness wound repair in diabetic mice (repair rate MAP vs Control=91.791±3.306 % vs 62.962±6.758 %) through antioxidant, neuroangiogenesis, collagen remodeling, and up-regulated the expression of the related factors COL-1, CD31, VEGF, and CGRP. Overall, we developed a bioactive hybrid hydrogel encapsulating MAP that synergistically promotes diabetic wound repair through multiple biological effects. This potentially integrated therapeutic scaffold may enrich future surgical approaches for treating diabetic wounds.

3D bioprinting of Salvianolic acid B-sodium alginate-gelatin skin scaffolds promotes diabetic wound repair via antioxidant, anti-inflammatory, and proangiogenic effects

In patients with diabetic wounds, wound healing is impaired due to the presence of persistent oxidative stress, an altered inflammatory response, and impaired angiogenesis and epithelization. Salvianolic acid B (SAB), which is derived from the Chinese medicinal plant Salvia miltiorrhiza, has been found to exhibit antioxidant, anti-inflammatory, and proangiogenic effects. Previous studies have used 3D bioprinting technology incorporating sodium alginate (SA) and gelatin (Gel) as basic biomaterials to successfully produce artificial skin. In the current study, 3D bioprinting technology was used to incorporate SAB into SA-Gel to form a novel SAB-SA-Gel composite porous scaffold. The morphological characteristics, physicochemical characteristics, biocompatibility, and SAB release profile of the SAB-SA-Gel scaffolds were evaluated in vitro. In addition, the antioxidant, anti-inflammatory, and proangiogenic abilities of the SAB-SA-Gel scaffolds were evaluated in cells and in a rat model. Analysis demonstrated that 1.0 wt% (the percentage of SAB in the total weight of the solution containing SA and Gel) SAB-SA-Gel scaffolds had strong antioxidant, anti-inflammatory, and proangiogenic properties both in cells and in the rat model. The 1.0% SAB-SA-Gel scaffold reduced the expression of tumor necrosis factor-α, interleukin-6, and interluekin-1β and increased the expression of transforming growth factor-β. In addition, this scaffold removed excessive reactive oxygen species by increasing the expression of superoxide dismutase, thereby protecting fibroblasts from injury. The scaffold increased the expression of vascular endothelial growth factor and platelet/endothelial cell adhesion molecule-1, accelerated granulation tissue regeneration and collagen deposition, and promoted wound healing. These findings suggest that this innovative scaffold may have promise as a simple and efficient approach to managing diabetic wound repair.

Protective Factors of Burnout: Resilience and Mindfulness

The aim of present research is to study the combined effects of two variables, namely, mindfulness and resilience on one outcome measure, namely, Burnout as well as investigating the relative contribution of mindfulness and resilience to reduce Burnout among college students. Individuals face persistent stress and demands in their personal and professional lives and remain at a constant risk of Burnout due to academic work, pressure and high competition. Burnout affects the mental health and performance of young adults. Mindfulness and Resilience have been recognized as protective factors against Burnout and helps to cope with the stress associated with it. The study composed a sample of 74 individuals (Male=34, Female=40) using The Five Facet Mindfulness Questionnaire (FFMQ-15), Brief Resilience Scale (BRS) and Oldenburg Burnout Inventory (OLBI-S). Quantitative research design has been used and Regression analysis found significant predictors (Mindfulness and Resilience) of Burnout. The obtained results for regression analysis, the F= 11.081, p<0.001 values indicates that the concerned factors have significant impact on Burnout and the R2 value found 0.238 which depicts 23.8% of the total variance for Burnout. It concluded that increased Mindfulness and Resilience among college students leads to lower feelings of Burnout. Interventions, trainings, workshops and counseling become necessary in educational perspectives to provide the coping strategies with the negative outcomes of Burnout through practices of Mindfulness and Resilience.

Bioinspired Tumor Calcification-Guided Early Diagnosis and Eradication of Hepatocellular Carcinoma.

Tumor calcification is found to be associated with the benign prognostic, and which shows considerable promise as a somewhat predictive index of the tumor response clinically. However, calcification is still a missing area in clinical cancer treatment. A specific strategy is proposed for inducing tumor calcification through the synergy of calcium peroxide (CaO2)-based microspheres and transcatheter arterial embolization for the treatment of hepatocellular carcinoma (HCC). The persistent calcium stress in situ specifically leads to powerful tumor calcioptosis, resulting in diffuse calcification and a high-density shadow on computed tomography that enables clear localization of the in vivo tumor site and partial delineation of tumormargins in an orthotopic HCC rabbit model. This osmotic calcification can facilitate tumor clinical diagnosis, which is of great significance in differentiating tumor response during early follow-up periods. Proteome and phosphoproteome analysis identify that calreticulin (CALR) is a crucial target protein involved in tumor calcioptosis. Further fluorescence molecular imaging analysis also indicates that CALR can be used as a prodromal marker of calcification to predict tumor response at an earlier stage in different preclinical rodent models. These findings suggest that upregulated CALR in association with tumor calcification, which may be broadly useful for quick visualization of tumor response.

Persistent and De Novo Stress Urinary Incontinence After Minimally Invasive Sacrocolpopexy.

Data on stress urinary incontinence (SUI) after minimally invasive sacrocolpopexy (SCP) with or without midurethral sling placement are limited. The aim of the study was to determine the incidence of SUI after minimally invasive sacrocolpopexy. This was a secondary analysis of 2 randomized clinical trials of participants undergoing SCP. Participants completed symptom assessment and urodynamic testing. Participants underwent SCP with or without midurethral sling placement. Preoperatively, participants were defined as having symptomatic SUI, occult SUI, or no SUI. Participants completed the Pelvic Floor Distress Inventory-20 at 6 and 12 months postoperatively and were categorized as having persistent SUI in the setting of symptomatic or occult SUI or de novo SUI. Eighty-one participants were included. Sixty-one participants met inclusion criteria for the persistent SUI analysis: 42 participants with symptomatic SUI and 19 participants with occult SUI. There were 20 participants in the de novo SUI group. The overall incidence of persistent SUI was 26.2% (95% confidence interval [CI], 15.8%-39.1%) with 33.3% (95% CI, 19.6%-49.6%) of symptomatic and 10.5% (95% CI, 1.5%-33.1%) of occult participants. Bothersome symptoms were defined as "moderately" or "quite a bit" bothered postoperatively. Of participants with symptomatic SUI, 14.3% participants were bothered and no participants underwent retreatment. No patient with occult SUI was bothered; however, 1 patient underwent retreatment. The incidence of de novo SUI was 45% (95% CI, 23.1%-68.5%). No patient in the de novo SUI group was bothered or underwent SUI treatment. Approximately 1 in 4 participants reported persistent SUI. Almost 50% reported de novo SUI. However, few participants were bothered or underwent treatment.

Near-infrared light-activatable, analgesic nanocomposite delivery system for comprehensive therapy of diabetic wounds in rats

Impaired angiogenesis, bacterial infection, persistent severe pain, exacerbated inflammation, and oxidative stress injury are intractable problems in the treatment of chronic diabetic ulcer wounds. A strategy that effectively targets all these issues has proven challenging. Herein, an in-situ sprayable nanoparticle-gel composite comprising platinum clusters (Pt) loaded-mesoporous polydopamine (MPDA) nanoparticle and QX-314-loaded fibrin gel (Pt@MPDA/QX314@Fibrin) was developed for diabetic wound analgesia and therapy. The composite shows good local analgesic effect of QX-314 mediated by near-infrared light (NIR) activation of transient receptor potential vanilloid 1 (TRPV1) channel, as well as multifunctional therapeutic effects of rapid hemostasis, anti-inflammation, antioxidation, and antibacterial properties that benefit the fast-healing of diabetic wounds. Furthermore, it demonstrates that the composite, with good biodegradability and biosafety, significantly relieved wound pain by inhibiting the expression of c-Fos in the dorsal root ganglion and the activation of glial cells in the spinal cord dorsal horn. Consequently, our designed sprayable Pt@MPDA/QX314@Fibrin composite with good biocompatibility, NIR activation of TRPV1 channel-mediated QX-314 local wound analgesia and comprehensive treatments, is promising for chronic diabetic wound therapy.

Coastal environmental changes after the Saemangeum seawall construction

The coastal environment in the Saemangeum area has experienced persistent physical stresses owing to the irregular operation of the sluice gates and related artificial disturbances since seawall construction, which has led to restricted freshwater-seawater circulation. To understand the impacts of stress, we performed long-term (1999-2022, 24 years) in situ measurements of relevant biotic and abiotic parameters and employed the random forest (RF) technique to determine the phytoplankton community response to environmental disturbance. Specifically, we estimated chlorophyll-a (Chl-a) concentrations using an RF model based on various environmental factors such as sea surface temperature (SST), sea surface salinity (SSS), dissolved oxygen saturation (DO), dissolved inorganic nitrogen (DIN), and dissolved inorganic phosphorus (DIP) as input variables. From the RF analysis, each environmental factor contributed to variation in Chl-a concentration as follows: SSS (42.91%), SST (17.88%), DIP (14.38%), DIN (13.36%), and DO (11.48%). In addition, we performed sensitivity experiments by altering the salinity, which was revealed to be the most influential environmental parameter. As a result, Chl-a concentration increased by approximately 1.79 times in lower salinity conditions (from 7 to 27 psu) compared to the normal salinity conditions prior to the seawall construction (from 12 to 32 psu) in both areas, including the inside and outside the seawall. More importantly, lower salinity conditions stimulated dinoflagellate blooms, that is, red tides, implying that restricted freshwater-seawater circulation could worsen coastal ecosystems. Thus, this study contributes to understanding the impacts of environmental changes caused by sluice gate manipulation on marine ecosystems, such as phytoplankton community dynamics. Moreover, this study recommends an ecologically suitable operation scheme for Saemangeum sluice gates to ensure a healthy coastal ecosystem.

Moderate Water Stress Impact on Yield Components of Greenhouse Tomatoes in Relation to Plant Water Status.

The scarcity of water resources affects tomato production. Deficit irrigation may optimize water management with only a low reduction in yield. Deficit irrigation scheduling based on applied water presented no clear conclusions. Water stress management based on plant water status, such as water potential, could improve the scheduling. The aim of this work was to evaluate the physiological and yield responses of different tomato cultivars to deficit irrigation. Three experiments were carried out in 2020 and 2022 at the University of Seville (Spain). "Cherry" and "chocolate Marmande" cultivars with an indeterminate growth pattern were grown in a greenhouse. Treatments were: Control (full irrigated) and Deficit. Deficit plants were irrigated based on water potential measurements. Moderate water stress did not significantly reduce the yield, although it affected other processes. Fruit size and total soluble solids were the most sensitive parameters to water stress. The latter increased only when persistent water stress was applied. However, truss development and fruit number were not affected by the level of water stress imposed. Such results suggest that moderate water stress, even in sensitive phenological stages such as flowering, would not reduce yield. Deficit irrigation scheduling based on plant water status will allow accurate management of water stress.

Calibration and verification of creep parameters for concrete

Concrete is a material which undergoes slow increasing deformation while subjected to persistent mechanical stress. This phenomenon is known as creep. In concrete material, creep occurs at all stress levels. Additional deformation of concrete structures at the end of their design working life caused by creep is usually two to three times of the immediate elastic deformation value, but might be even more in some cases. The value is dependent on many parameters, e.g. concrete grade, cement class, ambient environment relative humidity, geometry of the structure (drying surface of concrete in contact with air) and also the age of concrete at the time of loading. According to corresponding European standard, the effects of creep are evaluated using creep coefficient, and should be considered for verification of serviceability limit states, and if significant, also at ultimate limit states. In order to evaluate the creep effects in geometrically more complex structures, numerical finite element (FEM) analyses might be conducted. In commercially available software ANSYS, there is a library of several implicit creep equations, with several input parameters. These parameters need to be calibrated in order to match the assumptions of the creep effects over time in accordance with the corresponding European standard. In this study, calibration process of European standard concrete C35/45 parameters for selected implicit creep equation from ANSYS library is presented. The parameters are calibrated for two different ambient relative humidity (RH) levels, 78.8% and 90%, each for concrete loaded in 28 days (also 90 days for RH 78.8% and 50 days for RH 90%) after its casting, and suitable for finite element analysis of creep effects within the first year after loading of the concrete structure. The calibration process is split into two parts, analytical one conducted in table processor, where approximate estimations of suitable parameter values are determined. The second part consist of the subsequent optimization process in OptiSLang software, where the optimal parameter values are determined in order to achieve the best match between the time dependent Eurocode standard creep coefficient and the creep coefficient based on the results of one solid element uniaxial compression test in ANSYS finite element software. The obtained parameters are then verified on an analysis of a simply-supported concrete beam modelled of solid 3D finite elements. The values of selected creep equation parameters are summarized in the table, and might be used in the subsequent ongoing research.

Small molecules for impairing endoplasmic reticulum in cancer.

The endoplasmic reticulum plays an important role in maintaining the protein homeostasis of cells as well as regulating Ca2+ storage. An increased load of unfolded proteins in the endoplasmic reticulum due to alterations in the cell's metabolic pathway leads to the activation of the unfolded protein response, also known as ER stress. ER stress plays a major role in maintaining the growth and survival of various cancer cells, but persistent ER stress can also lead to cell death and hence can be a therapeutic pathway in the treatment of cancer. In this review, we focus on different types of small molecules that impair different ER stress sensors, the protein degradation machinery, and chaperone proteins. We also review the metal complexes and other miscellaneous compounds inducing ER stress through multiple mechanisms. Finally, we discuss the challenges in this emerging area of research and the potential direction of research to overcome them towards next-generation ER-targeted cancer therapy.

Post-stress Social Interaction and 3-Cyano-N-(1,3-Diphenyl-1H-Pyrazol-5-yl) Benzamide Treatment Attenuate Depressive-like Behavior Induced by Repeated Social Defeat Stress

Persistent stress increases the probability for developing depression significantly thereafter. Repeated social defeat stress is a widely used model to investigate depressive-like behavior in preclinical models. Hence, the repeated social defeat stress model provided an ideal animal model, through which the hypotheses of prevention and treatment can be investigated. We have successfully induced depressive-like behavior for male C57BL/6J mice with this model. Here, we reported that certain level of during-stress social interactions with single female or multiple male peer(s) exerted a positive role in preventing the development of depressive-like behavior induced by repeated social defeat stress. Our data suggested that the stress-susceptible mice may benefit from positive social interaction, which reduces the chance for depressive-like behavior development. Since numerous studies indicate that the metabotropic glutamate receptor 5 (mGluR5) plays an important role in various cognitive functions, we further investigate the treatment effect of 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) on the depressive-like behavior induced by repeated social defeat stress. Most importantly, robust anti-depressant effects have been achieved through modulating the mGluR5 function. We found that single oral dose administration of CDPPB (20 mg/kg), to some extent, alleviated the social avoidance behaviors for the stress-susceptible mice. Our data implies that the CDPPB, a positive allosteric modulator of mGluR5, is a promising anti-depressant candidate with limited side effect.

The association between neuropsychiatric effects of substance use and occurrence of endoplasmic reticulum and unfolded protein response: A systematic review

IntroductionThis systematic review aimed to assess the association between neuropsychiatric effects of substance use and occurrence of ER stress and unfolded protein response (UPR) through comprehensive electronic search of existing literature and review of their findings. MethodsA comprehensive electronic literature search was carried out on research articles published between 1950 to July 2023 through major databases, such as Scopus, Web of Science, Google Scholar, PubMed, PsycINFO, EMBASE, Medline and Cochrane Library. ResultsA total of 21 research articles were selected for review, which were comprised of sixteen animal studies, four human studies and one study on postmortem human brain samples. The selected studies revealed that alcohol, methamphetamine, cocaine, opioid and kratom exposures contributed to neuropsychiatric effects: such as decline in learning and memory function, executive dysfunction, alcohol, methamphetamine, opioid, and kratom dependence. These effects were associated with activation and persistent of ER stress and UPR with elevation of BiP and CHOP expression and the direction of ER stress is progressing towards the PERK-eIF2α-ATF4-CHOP pathway and neuronal apoptosis and neurodegeneration at various regions of the brain. In addition, regular kratom use in humans also contributed to elevation of p-JNK expression, denoting progress of ER stress towards the IRE1-ASK1-JNK-p-JNK pathway which was linked to kratom use disorder. However, treatment with certain compounds or biological agents could reverse the activation of ER stress. ConclusionsThe neuropsychiatric effects of alcohol, methamphetamine, cocaine, opioid and kratom use may be associated with persistent ER stress and UPR.

Inositol hexaphosphate enhances chemotherapy by reversing senescence induced by persistently activated PERK and diphthamide modification of eEF2

Oxaliplatin is an important initial chemotherapy benefiting advanced-stage colorectal cancer patients. Frustratingly, acquired oxaliplatin resistance always occurs after sequential chemotherapy with diverse antineoplastic drugs. Therefore, an exploration of the mechanism of oxaliplatin resistance formation in-depth is urgently needed. We generated oxaliplatin-resistant colorectal cancer models by four representative compounds, and RNA-seq revealed that oxaliplatin resistance was mainly the result of cells’ response to stimulus. Moreover, we proved persistent stimulus-induced endoplasmic reticulum stress (ERs) and associated cellular senescence were the core causes of oxaliplatin resistance. In addition, we screened diverse phytochemicals for ER inhibitors in silico, identifying inositol hexaphosphate (IP6), whose strong binding was confirmed by surface plasmon resonance. Finally, we confirmed the ability of IP6 to reverse colorectal cancer chemoresistance and investigated the mechanism of IP6 in the inhibition of diphthamide modification of eukaryotic elongation factor 2 (eEF2) and PERK activation. Our study demonstrated that oxaliplatin resistance contributed to cell senescence induced by persistently activated PERK and diphthamide modification of eEF2 levels, which were specifically reversed by combination therapy with IP6.

Transcriptomic profiling of Polycystic Kidney Disease identifies paracrine factors in the early cyst microenvironment

Initial cysts that are formed upon Pkd1 loss in mice impose persistent stress on surrounding tissue and trigger a cystic snowball effect, in which local aberrant PKD-related signaling increases the likelihood of new cyst formation, ultimately leading to accelerated disease progression. Although many pathways have been associated with PKD progression, the knowledge of early changes near initial cysts is limited. To perform an unbiased analysis of transcriptomic alterations in the cyst microenvironment, microdomains were collected from kidney sections of iKsp-Pkd1del mice with scattered Pkd1-deletion using Laser Capture Microdissection. These microdomains were defined as F4/80-low cystic, representing early alterations in the cyst microenvironment, F4/80-high cystic, with more advanced alterations, or non-cystic. RNA sequencing and differential gene expression analysis revealed 953 and 8088 dysregulated genes in the F4/80-low and F4/80-high cyst microenvironment, respectively, when compared to non-cystic microdomains. In the early cyst microenvironment, several injury-repair, growth, and tissue remodeling-related pathways were activated, accompanied by mild metabolic changes. In the more advanced F4/80-high microdomains, these pathways were potentiated and the metabolism was highly dysregulated. Upstream regulator analysis revealed a series of paracrine factors with increased activity in the early cyst microenvironment, including TNFSF12 and OSM. In line with the upstream regulator analysis, TWEAK and Oncostatin-M promoted cell proliferation and inflammatory gene expression in renal epithelial cells and fibroblasts in vitro. Collectively, our data provide an overview of molecular alterations that specifically occur in the cyst microenvironment and identify paracrine factors that may mediate early and advanced alterations in the cyst microenvironment.

Hsf1 and the molecular chaperone Hsp90 support a 'rewiring stress response' leading to an adaptive cell size increase in chronic stress.

Cells are exposed to a wide variety of internal and external stresses. Although many studies have focused on cellular responses to acute and severe stresses, little is known about how cellular systems adapt to sublethal chronic stresses. Using mammalian cells in culture, we discovered that they adapt to chronic mild stresses of up to two weeks, notably proteotoxic stresses such as heat, by increasing their size and translation, thereby scaling the amount of total protein. These adaptations render them more resilient to persistent and subsequent stresses. We demonstrate that Hsf1, well known for its role in acute stress responses, is required for the cell size increase, and that the molecular chaperone Hsp90 is essential for coupling the cell size increase to augmented translation. We term this translational reprogramming the 'rewiring stress response', and propose that this protective process of chronic stress adaptation contributes to the increase in size as cells get older, and that its failure promotes aging.

Hsf1 and the molecular chaperone Hsp90 support a ‘rewiring stress response’ leading to an adaptive cell size increase in chronic stress

Cells are exposed to a wide variety of internal and external stresses. Although many studies have focused on cellular responses to acute and severe stresses, little is known about how cellular systems adapt to sublethal chronic stresses. Using mammalian cells in culture, we discovered that they adapt to chronic mild stresses of up to two weeks, notably proteotoxic stresses such as heat, by increasing their size and translation, thereby scaling the amount of total protein. These adaptations render them more resilient to persistent and subsequent stresses. We demonstrate that Hsf1, well known for its role in acute stress responses, is required for the cell size increase, and that the molecular chaperone Hsp90 is essential for coupling the cell size increase to augmented translation. We term this translational reprogramming the ‘rewiring stress response’, and propose that this protective process of chronic stress adaptation contributes to the increase in size as cells get older, and that its failure promotes aging.