Pathological Stress Research Articles

Antioxidant and Prooxidant Nanozymes: From Cellular Redox Regulation to Next‐Generation Therapeutics

AbstractNanozymes, nanomaterials with enzyme‐mimicking activity, have attracted tremendous interest in recent years owing to their ability to replace natural enzymes in various biomedical applications, such as biosensing, therapeutics, drug delivery, and bioimaging. In particular, the nanozymes capable of regulating the cellular redox status by mimicking the antioxidant enzymes in mammalian cells are of great therapeutic significance in oxidative‐stress‐mediated disorders. As the distinction of physiological oxidative stress (oxidative eustress) and pathological oxidative stress (oxidative distress) occurs at a fine borderline, it is a great challenge to design nanozymes that can differentially sense the two extremes in cells, tissues and organs and mediate appropriate redox chemical reactions. In this Review, we summarize the advances in the development of redox‐active nanozymes and their biomedical applications. We primarily highlight the therapeutic significance of the antioxidant and prooxidant nanozymes in various disease model systems, such as cancer, neurodegeneration, and cardiovascular diseases. The future perspectives of this emerging area of research and the challenges associated with the biomedical applications of nanozymes are described.

Sirtuin-3-Mediated Cellular Metabolism Links Cardiovascular Remodeling with Hypertension.

Hypertension can cause structural and functional abnormalities in the cardiovascular system, which can be attributed to both hemodynamic and nonhemodynamic factors. These alterations are linked with metabolic changes and are induced by pathological stressors. Sirtuins are enzymes that act as stress sensors and regulate metabolic adaptation by deacetylating proteins. Among them, mitochondrial SIRT3 performs a crucial role in maintaining metabolic homeostasis. Evidence from experimental and clinical studies has shown that hypertension-induced decreases in SIRT3 activity can lead to cellular metabolism reprogramming and, subsequently, increased susceptibility to endothelial dysfunction, myocardial hypertrophy, myocardial fibrosis, and heart failure. This review presents recent research advances in SIRT3-mediated metabolic adaptation in hypertensive cardiovascular remodeling.

Glutamine inhibits inflammation, oxidative stress, and apoptosis and ameliorates hyperoxic lung injury.

Glutamine (Gln) is the most widely acting and abundant amino acid in the body and has anti-inflammatory properties, regulates body metabolism, and improves immune function. However, the mechanism of Gln's effect on hyperoxic lung injury in neonatal rats is unclear. Therefore, this work focused on examining Gln's function in lung injury of newborn rats mediated by hyperoxia and the underlying mechanism. We examined body mass and ratio of wet-to-dry lung tissue weights of neonatal rats. Hematoxylin and eosin (HE) staining was performed to examine histopathological alterations of lung tissues. In addition, enzyme-linked immunoassay (ELISA) was conducted to measure pro-inflammatory cytokine levels within bronchoalveolar lavage fluid (BALF). Apoptosis of lung tissues was observed using TUNEL assay. Western blotting was performed for detecting endoplasmic reticulum stress (ERS)-associated protein levels. The results showed that Gln promoted body weight gain, significantly reduced pathological damage and oxidative stress in lung tissue, and improved lung function in neonatal rats. Gln reduced pro-inflammatory cytokine release as well as inflammatory cell production in BALF and inhibited apoptosis in lung tissue cells. Furthermore, we found that Gln could downregulate ERS-associated protein levels (GRP78, Caspase-12, CHOP) and inhibit c-Jun N-terminal kinase (JNK) and inositol-requiring enzyme 1 alpha (IRE1α) phosphorylation. These results in an animal model of bronchopulmonary dysplasia (BPD) suggest that Gln may have a therapeutic effect on BPD by reducing lung inflammation, oxidative stress, and apoptosis and improving lung function; its mechanism of action may be related to the inhibition of the IRE1α/JNK pathway.

High-resolution temporal transcriptomic profiling of the distal convoluted tubule identifies an early adaptive response to furosemide

The distal convoluted tubule (DCT) undergoes hypertrophy and hyperplasia to increase salt absorption in response to physiologic and pathological stresses, and has been implicated in the development of loop-diuretic resistance. However, the molecular mechanisms underlying DCT remodeling are unknown. We investigated progressive changes in the transcriptome of the early DCT (DCT1) in a time series (12, 24, 48, and 96 hours) after the administration of furosemide to identify initiating gene regulatory pathways. For high-resolution coverage, RNAseq was performed on isolated DCT1 segments, identified using a DCT1-specific Cre-driven fluorescent protein, tdTomato. An average of 17 million sequences were read per sample, providing genome-wide coverage of the DCT transcriptome (15499 genes). Sequence reads aligned on the mouse transcripts were quantified using Salmon, and differential gene expression analysis was performed using edgeR. All samples were enriched with known DCT-specific genes and lacked other nephron segment specific markers, indicating uniform purification of DCT tubules. Pathway and pattern clustering analysis of the time-resolved DCT transcriptome profiles revealed the early-induced genes were highly enriched in gene sets associated with cell cycle progression and cell proliferation. Meta-analysis of transcription factor binding enrichment at promoters of the early-induced genes revealed enrichment of genomic binding sites of Hypoxia-inducible factor 1 (HIF-1) signaling components (HIF1A, STAT3, RELA) across the early-induced gene promoters. Immunoblot analysis in kidney cortical tissues confirmed rapid activation of the HIF-1 signaling components following furosemide treatment. In summary, a core transcriptional regulatory axis in the DCT is activated rapidly after loop-diuretic treatment to drive a program of cell proliferation in the DCT. The results identify HIF1 signaling as a proximal pathway in the initiation of proliferative DCT remodeling. NIDDK, LeDucq Foundation This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

EFFECT OF EXOSOMES DERIVED FROM BONE MARROW MESENCHYMAL STEM CELLS ON PROGRAMMED CELL DEATH IN BLAST-INDUCED LUNG INJURY IN RATS.

Blast lung injuries (BLIs) are frequent because of industrial accidents and terrorist groups. Bone marrow mesenchymal stem cells (BMSCs) and exosomes derived from BMSCs (BMSCs-Exo) have become a hot topic in modern biology because of their significance in damage healing, immune regulation, and gene therapy. The aim of this study is to investigate the effect of BMSCs and BMSCs-Exo on BLI in rats caused by gas explosion. Here, BMSCs and BMSCs-Exo were transplanted into BLI rats via tail vein and then evaluated pathological alterations, oxidative stress, apoptosis, autophagy, and pyroptosis in the lung tissue. Through histopathology and changes in malondialdehyde (MDA) and superoxide dismutase (SOD) contents, we discovered that oxidative stress and inflammatory infiltration in the lungs were significantly reduced by BMSCs and BMSCs-Exo. After treatment with BMSCs and BMSCs-Exo, apoptosis-related proteins, such as cleaved caspase-3 and Bax, were significantly decreased, and the ratio of Bcl-2/Bax was significantly increased; the level of pyroptosis-associated proteins, including NLRP3, GSDMD-N, cleaved caspase-1, IL-1β, and IL-18, were decreased; autophagy-related proteins, beclin-1 and LC3, were downregulated while P62 was upregulated; the number of autophagosomes was decreased. In summary, BMSCs and BMSCs-Exo attenuate BLI caused by gas explosion, which may be associated with apoptosis, aberrant autophagy, and pyroptosis.

The locus coeruleus input to the rostral ventromedial medulla mediates stress-induced colorectal visceral pain

Unlike physiological stress, which carries survival value, pathological stress is widespread in modern society and acts as a main risk factor for visceral pain. As the main stress-responsive nucleus in the brain, the locus coeruleus (LC) has been previously shown to drive pain alleviation through direct descending projections to the spinal cord, but whether and how the LC mediates pathological stress-induced visceral pain remains unclear. Here, we identified a direct circuit projection from LC noradrenergic neurons to the rostral ventromedial medulla (RVM), an integral relay of the central descending pain modulation system. Furthermore, the chemogenetic activation of the LC-RVM circuit was found to significantly induce colorectal visceral hyperalgesia and anxiety-related psychiatric disorders in naïve mice. In a dextran sulfate sodium (DSS)-induced visceral pain model, the mice also presented colorectal visceral hypersensitivity and anxiety-related psychiatric disorders, which were associated with increased activity of the LC-RVM circuit; LC-RVM circuit inhibition markedly alleviated these symptoms. Furthermore, the chronic restraint stress (CRS) model precipitates anxiety-related psychiatric disorders and induces colorectal visceral hyperalgesia, which is referred to as pathological stress-induced hyperalgesia, and inhibiting the LC-RVM circuit attenuates the severity of colorectal visceral pain. Overall, the present study clearly demonstrated that the LC-RVM circuit could be critical for the comorbidity of colorectal visceral pain and stress-related psychiatric disorders. Both visceral inflammation and psychological stress can activate LC noradrenergic neurons, which promote the severity of colorectal visceral hyperalgesia through this LC-RVM circuit.

Enhanced Mitochondria-SR Tethering Triggers Adaptive Cardiac Muscle Remodeling.

Cardiac contractile function requires high energy from mitochondria, and Ca2+ from the sarcoplasmic reticulum (SR). Via local Ca2+ transfer at close mitochondria-SR contacts, cardiac excitation feedforward regulates mitochondrial ATP production to match surges in demand (excitation-bioenergetics coupling). However, pathological stresses may cause mitochondrial Ca2+ overload, excessive reactive oxygen species production and permeability transition, risking homeostatic collapse and myocyte loss. Excitation-bioenergetics coupling involves mitochondria-SR tethers but the role of tethering in cardiac physiology/pathology is debated. Endogenous tether proteins are multifunctional; therefore, nonselective targets to scrutinize interorganelle linkage. Here, we assessed the physiological/pathological relevance of selective chronic enhancement of cardiac mitochondria-SR tethering. We introduced to mice a cardiac muscle-specific engineered tether (linker) transgene with a fluorescent protein core and deployed 2D/3D electron microscopy, biochemical approaches, fluorescence imaging, in vivo and ex vivo cardiac performance monitoring and stress challenges to characterize the linker phenotype. Expressed in the mature cardiomyocytes, the linker expanded and tightened individual mitochondria-junctional SR contacts; but also evoked a marked remodeling with large dense mitochondrial clusters that excluded dyads. Yet, excitation-bioenergetics coupling remained well-preserved, likely due to more longitudinal mitochondria-dyad contacts and nanotunnelling between mitochondria exposed to junctional SR and those sealed away from junctional SR. Remarkably, the linker decreased female vulnerability to acute massive β-adrenergic stress. It also reduced myocyte death and mitochondrial calcium-overload-associated myocardial impairment in ex vivo ischemia/reperfusion injury. We propose that mitochondria-SR/endoplasmic reticulum contacts operate at a structural optimum. Although acute changes in tethering may cause dysfunction, upon chronic enhancement of contacts from early life, adaptive remodeling of the organelles shifts the system to a new, stable structural optimum. This remodeling balances the individually enhanced mitochondrion-junctional SR crosstalk and excitation-bioenergetics coupling, by increasing the connected mitochondrial pool and, presumably, Ca2+/reactive oxygen species capacity, which then improves the resilience to stresses associated with dysregulated hyperactive Ca2+ signaling.

Successful treatment of a severe Takotsubo syndrome case complicated by liver abscess

The main manifestations of Takotsubo syndrome (TTS) are a spherical expansion of the left ventricle or near the apex and decreased systolic function. TTS is mostly thought to be induced by emotional stress, and the induction of TTS by severe infection is not often reported. A 72-year-old female patient with liver abscess reported herein was admitted due to repeated fever with a history of hypertension and impaired glucose tolerance. Her severe infection caused TTS, and her blood pressure dropped to 80/40 mmHg. IABP treatment was performed immediately and continued for 10 days, and comprehensive medication was administered. Based on her disease course and her smooth recovery, general insights and learnings may be: Adding to mental and other pathological stress reaction, serious infections from pathogenic microorganism could be of great important causation of stress reaction leading to TTS, while basic diseases such as coronary heart disease, hypertension, and diabetes were be of promoting factors; In addition to effective drug therapies for TTS, the importance of the timely using of IABP should be emphasized.

Assessment of myocardial bridging and the pericoronary fat attenuation index on coronary computed tomography angiography: predicting coronary artery disease risk

BackgroundThe fat attenuation index (FAI) is a radiological parameter that represents pericoronary adipose tissue (PCAT) inflammation, along with myocardial bridging (MB), which leads to pathological shear stress in the coronary vessels; both are associated with coronary atherosclerosis. In the present study, we assessed the predictive value of FAI values and MB parameters through coronary computed tomography angiography (CCTA) for predicting the risk of coronary atherosclerosis and vulnerable plaque in patients with MB.MethodsWe included 428 patients who underwent CCTA and were diagnosed with MB. FAI values, MB parameters, and high-risk coronary plaque (HRP) characteristics were recorded. The subjects were classified into two groups (A and B) according to the absence or presence of coronary plaque in the segment proximal to the MB. Group B was further divided into Groups B1 (HRP-positive) and B2 (HRP-negative) according to the HRP characteristic classification method. The differences among the groups were analysed. Multiple logistic regression analysis was performed to determine the independent correlation between FAI values and MB parameters and coronary atherosclerosis and vulnerable plaque risk.ResultsCompared to the subjects in Group A, those in Group B presented greater MB lengths, MB depths and muscle index values, more severe MB systolic stenosis and higher FAIlesion values (all P < 0.05). In multivariate logistic analysis, age (OR 1.076, P < 0.001), MB systolic stenosis (OR 1.102, P < 0.001) and FAIlesion values (OR 1.502, P < 0.001) were independent risk factors for the occurrence of coronary atherosclerosis. Compared to subjects in Group B2, those in Group B1 presented greater MB lengths and higher FAI values (both P < 0.05). However, only the FAIlesion value was an independent factor for predicting HRP (OR 1.641, P < 0.001).ConclusionIn patients with MB, MB systolic stenosis was associated with coronary plaque occurrence in the segment proximal to the MB. The FAI value was not only closely related to coronary atherosclerosis occurrence but also associated with plaque vulnerability. FAI values may provide more significant value in the prediction of coronary atherosclerosis than MB parameters in CCTA.

Penthorum chinense Pursh compound flavonoids supplementation alleviates Aflatoxin B1-induced liver injury via modulation of intestinal barrier and gut microbiota in broiler

Aflatoxin B1 (AFB1) is a commonly occurring toxicant in animal and human diets, leading to hazardous effects on health. AFB1 is known to be a hepato-toxicant, and the intestinal barrier may play a crucial role in reversing AFB1-induced liver injury. This study aimed to optimize the extraction conditions of Penthorum chinense Pursh Compound Flavonoids (PCPCF) by the response surface method with a Box-Behnken design and investigate the effects of PCPCF on AFB1-induced liver injury in broilers. A total of 164 one-day-old broilers were divided into seven groups, including Control, PCPCF (400 mg PCPCF/kg feed), AFB1 (3 mg AFB1/kg feed), and YCHT (Yin-Chen-Hao-Tang extract, 3 mg AFB1 +10 mL YCHT/kg feed) and low, medium, and high dose groups (PCPCF at 3 mg AFB1 +200, 400, 600 mg respectively). Samples of serum, liver, duodenum, and cecum contents were collected at 14th and 28th days for further analysis. The results showed that the maximum extraction rate of PCPCF was 8.15 %. PCPCF was rich in rutin, quercetin, liquiritin and kaempferol, and significantly inhibited the growth of Aspergillus flavus. The addition of PCPCF improved the growth performance of AFB1-injury broilers, modulated liver function, and increased serum immunoglobulin levels. PCPCF also alleviated liver pathological and oxidative stress damages caused by AFB1 and decreased AFB1-DNA and AFB1-lysine content in the liver. Furthermore, PCPCF supplementation ameliorated intestinal pathological damage, improved intestinal permeability of duodenum in the AFB1-induced broilers, and repaired the intestinal mucosal and mechanical barrier associated with the Notch signaling pathway. Meanwhile, PCPCF improved the intestinal flora structure of AFB1-damaged broilers and increased the abundance of beneficial bacteria. In conclusion, PCPCF ameliorated the adverse effects of AFB1 on growth performance and alleviated liver damage by repairing the intestinal barrier and improving intestinal health of broiler chicken.

Novel pathogenesis of post-traumatic stress disorder studied in transgenic mice

Posttraumatic stress disorder (PTSD) is very common after exposure to trauma, mental stress or violence. Because objective biological markers for PTSD are lacking, exactly diagnosing PTSD is a challenge for clinical psychologists. In-depth research on the pathogenesis of PTSD is a key for solving this problem. In this work, we used male Thy1-YFP transgenic mice, in which neurons are fluorescently labeled, to research the effects of PTSD on neurons in vivo. We initially discovered that pathological stress associated with PTSD increased the activation of glycogen synthesis kinase-beta (GSK-3β) in neurons and induced the translocation of the transcription factor forkhead box-class O3a (FoxO3a) from the cytoplasm to the nucleus, which decreased the expression of uncoupling protein 2 (UCP2) and increased mitochondrial production of reactive oxygen species (ROS) to trigger neuronal apoptosis in the prefrontal cortex (PFC). Furthermore, the PTSD model mice showed increased freezing and anxiety-like behaviors and more severe decrease of memory and exploratory behavior. Additionally, leptin attenuated neuronal apoptosis by increasing the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which further elevated the expression of UCP2 and inhibited the mitochondrial production of ROS induced by PTSD, thus reducing neuronal apoptosis and ameliorating PTSD-related behaviors. Our study is expected to promote the exploration of PTSD-related pathogenesis in neural cells and the clinical effectiveness of leptin for PTSD.

The Wave Sign Correlates with the Posterior Horn Medial Meniscus (PHMM) Tear in the Anterior Cruciate Ligament (ACL) Deficient Knee.

A posterior horn medial meniscus (PHMM) tear subjects the knee to pathological stresses, especially in the setting of a deficient anterior cruciate ligament (ACL). These PHMM tears have to be surgically addressed, however they remain a diagnostic challenge. Hence, this study aims to evaluate the wave sign as an arthroscopic diagnostic aid for the PHMM tear which may be occult. This is a retrospective study of 61 consecutive patients (62 ACL-deficient knees) who underwent arthroscopic primary ACL reconstruction between September 2017 and August 2018. We defined PHMM tears as tears located in the posterior one-third of the medial meniscus. Root tears and ramp lesions were included in our analysis. The arthroscopic findings were recorded after a comprehensive arthroscopic survey. In the sample of ACL-deficient knees, 44 (71.0%) had a concomitant medial meniscus tear. The most common location for the tear was in the posterior horn (81.8%). There were seven occult PHMM tears, not described by the radiologist or identified by the operating surgeon on the pre-operative magnetic resonance imaging. The wave sign was identified in 10 (16.1%) knees, all confirming the presence of the PHMM tear. A positive correlation was found between the presence of the wave sign and the PHMM tear. The wave sign has a statistically significant but weak positive correlation with the presence of the PHMM. We view the wave sign as a valuable arthroscopic cue to rule-in the presence of the PHMM tear in the ACL-deficient knee.

Adjunctive Integrated Stress Response Inhibition Accelerates Tuberculosis Clearance in Mice.

Despite numerous advances in tuberculosis (TB) drug development, long treatment durations have led to the emergence of multidrug resistance, which poses a major hurdle to global TB control. Shortening treatment time therefore remains a top priority. Host-directed therapies that promote bacterial clearance and/or lung health may improve the efficacy and treatment duration of tuberculosis antibiotics. We recently discovered that inhibition of the integrated stress response, which is abnormally activated in tuberculosis and associated with necrotic granuloma formation, reduced bacterial numbers and lung inflammation in mice. Here, we evaluated the impact of the integrated stress response (ISR) inhibitor ISRIB, administered as an adjunct to standard tuberculosis antibiotics, on bacterial clearance, relapse, and lung pathology in a mouse model of tuberculosis. Throughout the course of treatment, ISRIB robustly lowered bacterial burdens compared to the burdens with standard TB therapy alone and accelerated the time to sterility in mice, as demonstrated by significantly reduced relapse rates after 4 months of treatment. In addition, mice receiving adjunctive ISRIB tended to have reduced lung necrosis and inflammation. Together, our findings identify the ISR pathway as a promising therapeutic target with the potential to shorten TB treatment durations and improve lung health. IMPORTANCE Necrosis of lung lesions is a hallmark of tuberculosis (TB) that promotes bacterial growth, dissemination, and transmission. This process is driven by the persistent hyperactivation of the integrated stress response (ISR) pathway. Here, we show that adjunctive ISR inhibition during standard antibiotic therapy accelerates bacterial clearance and reduces immunopathology in a clinically relevant mouse model of TB, suggesting that host-directed therapies that de-escalate these pathological stress responses may shorten TB treatment durations. Our findings present an important conceptual advance toward overcoming the challenge of improving TB therapy and lowering the global burden of disease.

Nonadult vertebral maturation in Late Holocene hunter‐gatherers from Patagonia (Salitroso Lake, Argentina)

AbstractBioarchaeological research of bone growth patterns provides information on the health status and disease of past populations. Recent studies have pointed out the potential of metric analysis of nonadult vertebrae as indicators of stress during different stages of ontogeny, highlighting that most vertebral measurements present low sexual dimorphism, a stable and known pattern of growth and give useful information even in incomplete spines. The aims of this paper are first, to construct a vertebral growth profile for nonadults of a skeletal series of Patagonian Late Holocene hunter‐gatherers from Salitroso Lake (SAC); second, to compare it to the ones obtained in other archaeological and modern populations with different stress experiences; and third, building on this, to assess whether individuals with evidence of stress experienced in early development demonstrate different patterns in vertebral growth than those without. Two spinal dimensions are used: vertebral body height (VBH) and transverse diameter of the neural canal (TDNC) in a sample of 23 nonadult skeletons with ages previously estimated from dental and bone indicators. The vertebral dimensions of 20 adults between 18 and 35 years of age were also measured as reference information. Results show that the growth of the VBH is steady over the years and reaches adulthood size by approximately 16 years of age whereas TDNC dimensions do not experience marked fluctuations in size throughout life and adult dimensions are reached at approximately 4 years of age as expected. The vertebral growth pattern observed in SAC is similar to that obtained in other archaeological samples from very different settings but experiencing relatively high nutritional or pathological stress in early stages of life. However, it is markedly different, and systematically smaller, to the 20th century sample pattern, probably responding to a secular trend in the modern population with a more stable access to resources and medical treatment. Finally, SAC individuals with systemic stress markers do not tend to exhibit smaller vertebral dimensions than those without them.

Spermidine reduced neuropathic pain in chronic constriction injury-induced peripheral neuropathy in rats.

Neuropathic pain is one of the most critical types of chronic pain despite the increasing advances in medical science. Spermidine (SPD) is a natural polyamine that has wide roles in several cellular processes inducing autophagy and reducing oxidative stress. This study aimed to investigate the effects of SPD on oxidative stress markers and pain threshold in the neuropathic rat model of chronic constriction injury (CCI) model. Eighteen adult male rats were divided into three groups: sham, CCI and CCI+SPD. After induction of neuropathy via CCI model in the CCI and CCI+SPD groups, SPD (1 mg/kg/day, orally) was administered to the CCI+SPD group for 3weeks. The behavioral tests (von Frey, hot plate) were done four times during the experiment. At the end of the study, electrophysiological tests, the H & E staining, and oxidative stress assay of the prefrontal cortex (PFC), spinal cord, and sciatic nerve were performed. The threshold of pain in hot plate and von Frey tests was significantly lower in the CCI group than in the sham group, which was reversed by SPD treatment in the CCI+ SPD group. In addition, nerve conduction was considerably lower in the CCI group than in the sham and CCI+SPD groups (P< 0.01, P< 0.05, respectively). The CCI group showed neuronal degeneration and fibrosis in the different tissues in the H & E assay; elevated tissues level of nitrite, decreased levels of superoxide dismutase (SOD), glutathione (GPx), and catalase were also observed. However, SPD treatment modulated the pathological changes and oxidative stress biomarkers. In conclusion, SPD showed beneficial effects in decreasing neuropathic pains. SPD treatment reduced oxidative stress and improved histopathological changes and behavioral tests in the CCI-induced neuropathic pain in in vivo model.

The Pleiotropic Role of Extracellular ATP in Myocardial Remodelling

Myocardial remodelling is a molecular, cellular, and interstitial adaptation of the heart in response to altered environmental demands. The heart undergoes reversible physiological remodelling in response to changes in mechanical loading or irreversible pathological remodelling induced by neurohumoral factors and chronic stress, leading to heart failure. Adenosine triphosphate (ATP) is one of the potent mediators in cardiovascular signalling that act on the ligand-gated (P2X) and G-protein-coupled (P2Y) purinoceptors via the autocrine or paracrine manners. These activations mediate numerous intracellular communications by modulating the production of other messengers, including calcium, growth factors, cytokines, and nitric oxide. ATP is known to play a pleiotropic role in cardiovascular pathophysiology, making it a reliable biomarker for cardiac protection. This review outlines the sources of ATP released under physiological and pathological stress and its cell-specific mechanism of action. We further highlight a series of cardiovascular cell-to-cell communications of extracellular ATP signalling cascades in cardiac remodelling, which can be seen in hypertension, ischemia/reperfusion injury, fibrosis, hypertrophy, and atrophy. Finally, we summarize current pharmacological intervention using the ATP network as a target for cardiac protection. A better understanding of ATP communication in myocardial remodelling could be worthwhile for future drug development and repurposing and the management of cardiovascular diseases.

Neuronal stress granules as dynamic microcompartments: current concepts and open questions.

Stress granules are cytosolic, membraneless RNA-protein complexes that form in the cytosol in response to various stressors. Stress granules form through a process termed liquid-liquid phase separation, which increases the local concentration of RNA and protein within the granules, creates dynamic sorting stations for mRNAs and associated proteins, and modulates the availability of mRNA for protein translation. We introduce the concept that neuronal stress granules act as dynamic cytosolic microcompartments in which their components differentially cycle in and out, monitoring the cellular environment. We discuss that neuronal stress granules have distinctive features and contain substructures in which individual components interact transiently. We describe that neuronal stress granules modulate protein expression at multiple levels and affect the proteoform profile of the cytoskeletal protein tau. We argue that a better knowledge of the regulation of stress granule dynamics in neurons and the modulation of their material state is necessary to understand their function during physiological and pathological stress responses. Finally, we delineate approaches to determine the behavior and regulation of critical stress granule organizers and the physical state of stress granules in living neurons.

UFL1, a UFMylation E3 ligase, plays a crucial role in multiple cellular stress responses.

The UFM1 conjugation system(UFMylation)is a novel type of ubiquitin-like system that plays an indispensable role in maintaining cell homeostasis under various cellular stress. Similar to ubiquitination, UFMylation consists of a three-step enzymatic reaction with E1-like enzymes ubiquitin-like modifier activating enzyme5 (UBA5), E2-like enzymes ubiquitin-fold modifier-conjugating enzyme 1(UFC1), and E3-like ligase UFM1-specific ligase 1 (UFL1). As the only identified E3 ligase, UFL1 is responsible for specific binding and modification of the substrates to mediate numerous hormone signaling pathways and endocrine regulation under different physiological or pathological stress, such as ER stress, genotoxic stress, oncogenic stress, and inflammation. Further elucidation of the UFL1 working mechanism in multiple cellular stress responses is essential for revealing the disease pathogenesis and providing novel potential therapeutic targets. In this short review, we summarize the recent advances in novel UFL1 functions and shed light on the potential challenges ahead, thus hopefully providing a better understanding of UFMylation-mediated cellular stress.

Combining three independent pathological stressors induces a heart failure with preserved ejection fraction phenotype.

Heart failure (HF) with preserved ejection fraction (HFpEF) is defined as HF with an ejection fraction (EF) ≥ 50% and elevated cardiac diastolic filling pressures. The underlying causes of HFpEF are multifactorial and not well-defined. A transgenic mouse with low levels of cardiomyocyte (CM)-specific inducible Cavβ2a expression (β2a-Tg mice) showed increased cytosolic CM Ca2+, and modest levels of CM hypertrophy, and fibrosis. This study aimed to determine if β2a-Tg mice develop an HFpEF phenotype when challenged with two additional stressors, high-fat diet (HFD) and Nω-nitro-l-arginine methyl ester (l-NAME, LN). Four-month-old wild-type (WT) and β2a-Tg mice were given either normal chow (WT-N, β2a-N) or HFD and/or l-NAME (WT-HFD, WT-LN, WT-HFD-LN, β2a-HFD, β2a-LN, and β2a-HFD-LN). Some animals were treated with the histone deacetylase (HDAC) (hypertrophy regulators) inhibitor suberoylanilide hydroxamic acid (SAHA) (β2a-HFD-LN-SAHA). Echocardiography was performed monthly. After 4 mo of treatment, terminal studies were performed including invasive hemodynamics and organs weight measurements. Cardiac tissue was collected. Four months of HFD plus l-NAME treatment did not induce a profound HFpEF phenotype in FVB WT mice. β2a-HFD-LN (3-Hit) mice developed features of HFpEF, including increased atrial natriuretic peptide (ANP) levels, preserved EF, diastolic dysfunction, robust CM hypertrophy, increased M2-macrophage population, and myocardial fibrosis. SAHA reduced the HFpEF phenotype in the 3-Hit mouse model, by attenuating these effects. The 3-Hit mouse model induced a reliable HFpEF phenotype with CM hypertrophy, cardiac fibrosis, and increased M2-macrophage population. This model could be used for identifying and preclinical testing of novel therapeutic strategies.NEW & NOTEWORTHY Our study shows that three independent pathological stressors (increased Ca2+ influx, high-fat diet, and l-NAME) together produce a profound HFpEF phenotype. The primary mechanisms include HDAC-dependent-CM hypertrophy, necrosis, increased M2-macrophage population, fibroblast activation, and myocardial fibrosis. A role for HDAC activation in the HFpEF phenotype was shown in studies with SAHA treatment, which prevented the severe HFpEF phenotype. This "3-Hit" mouse model could be helpful in identifying novel therapeutic strategies to treat HFpEF.

Quasi-causal associations between chronotype and post-traumatic stress disorder symptoms: A twin study

ObjectiveThe evening (“night owl”) chronotype is associated with greater severity and lifetime prevalence of post-traumatic stress disorder (PTSD) symptoms compared to morning or intermediate chronotypes. This twin study investigated the gene-environment relationships between chronotype, recent PTSD symptoms, and lifetime intrusive symptoms. MethodsWe used the reduced Horne-Östberg Morningness-Eveningness Questionnaire (rMEQ) to assess chronotype in a sample of 3777 same-sex adult twin pairs raised together (70.4% monozygotic, 29.6% dizygotic) in the community-based Washington State Twin Registry. PTSD symptoms were reported on the Impact of Events Scale (IES) and a single item for lifetime experience of intrusive symptoms after a stressful or traumatic event. ResultsGenetic influences accounted for 50% of chronotype variance, 30% of IES score variance, and 14% of lifetime intrusive symptom variance. Bivariate twin models showed a phenotypic association (bp) between evening chronotype and more severe PTSD symptoms (bp = −0.16, SE = 0.02, p < .001) that remained significant even after adjusting for shared genetic and environmental influences (bp = −0.10, SE = 0.04, p = .009), as well as age, sex, and self-reported sleep duration (bp = −0.11, SE = 0.04, p = .004). An association was found between evening chronotype and lifetime intrusive symptoms (bp = −0.11, SE = 0.03, p < .001) that was no longer significant after adjusting for shared genetic and environmental influences (bp = 0.04, SE = 0.06, p = .558). ConclusionsOur results suggest a “quasi-causal” relationship between evening chronotype and PTSD symptoms that is not purely attributable to genetic or shared environmental factors. Evening chronotype may increase vulnerability to pathologic stress responses in the setting of circadian misalignment, providing potential avenues of prevention and treatment using chronobiological strategies.