Physiological Homeostasis Research Articles

Crosstalk between non-coding RNA and apoptotic signaling in diabetic nephropathy.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in diabetes mellitus. It is also a significant contributor to cardiovascular morbidity and mortality in diabetic patients Thereby, Innovative therapeutic approaches are needed to retard the initiation and advancement of DN. Hyperglycemia can induce apoptosis, a regulated form of cell death, in multiple renal cell types, such as podocytes, mesangial cells, and proximal tubule epithelial cells, ultimately contributing to the pathogenesis of DN. Recent genome-wide investigations have revealed the widespread transcription of the human genome, resulting in the production of numerous regulatory non-protein-coding RNAs (ncRNAs), including microRNAs (miRNAs) and diverse categories of long non-coding RNAs (lncRNAs). They play a critical role in preserving physiological homeostasis, while their dysregulation has been implicated in a broad spectrum of disorders, including DN. Considering the established association between apoptotic processes and the expression of ncRNAs in DN, a thorough understanding of their intricate interplay is essential. Therefore, the current work thoroughly analyzes the intricate interplay among miRNAs, lncRNAs, and circular RNAs in the context of apoptosis within the pathogenesis of DN. Additionally, in the final section, we demonstrated that ncRNA-mediated modulation of apoptosis can be achieved through stem cell-derived exosomes and herbal medicines, presenting potential avenues for the treatment of DN.

Abstract PR013: A vagal sensory-to-sympathetic axis restrains anti-tumor immunity

Abstract Solid tumors are innervated by distinct branches of the peripheral nervous system, and increased tumor innervation has been associated with poor cancer outcomes. However, it remains unexplored whether different types of nerves function together to sense and respond to a tumor, and how neural networks shape cancer immunity. As a major interoceptive system, vagal nerves sense a large variety of body signals and are critical for maintaining physiological homeostasis of visceral organs including the lung. While distinct vagal sensory neuron (VSN) subtypes have been identified to differently regulate pulmonary functions, it is unknown whether these VSNs interact with lung tumors and how they influence cancer progression. Here, we uncover that sensory nerves act through the sympathetic circuit to restrain anti-cancer immunity. Mechanistically, our data suggest that lung tumors hijack the vagal interoceptive system to activate sympathetic efferent nerves in the tumor microenvironment (TME), which in turn drive immune suppression via β2-adrenergic signaling in alveolar macrophages. Our key findings include: By applying anterograde labeling, tissue-clearing and 3D imaging to genetically engineered mouse models, we found that lung adenocarcinoma is richly innervated by vagal sensory nerves. We also showed that neurotrophic factors produced by cancer cells directly promote vagal sensory innervation. Furthermore, scRNA-seq analysis revealed tumor-induced transcriptional reprogramming of lung-innervating VSNs. Using multiple genetic tools to selectively label and deplete different VSN subtypes, we found that Npy2r + /Trpv1 + VSNs but not P2ry1 + VSNs innervate lung tumors and control lung cancer progression by inhibiting anti- cancer immunity. At the organism level, we demonstrated that vagal NPY2R/TRPV1 neurons inhibit anti-cancer immunity via the sympathetic axis. Depletion of vagal NPY2R/TRPV1 neurons resulted in reduced sympathetic nerve activity and a decreased norepinephrine level in the lung TME, whereas pharmacological activation of the sympathetic pathway suppressed the anti-tumor immune responses and restored tumor growth in mice lacking Npy2r + /Trpv1 + VSNs. At the molecular and cellular level, we identified that the vagal-to-sympathetic axis predominantly functions through β2-adrenergic signaling in alveolar macrophages (AMs) to drive immune suppression. AM depletion or selective deletion of β2-adrenergic receptor (ADRB2) in AMs derepressed the anti-tumor immunity and abolished the tumor-inhibiting effect of Npy2r + /Trpv1 + VSN ablation. Taken together, our study establishes an essential role of the sensory-to-sympathetic circuit in controlling cancer immunosurveillance, supporting the notion that the functional integration of sensory and sympathetic nerves systemically regulates anti- cancer immunity. Translationally, our findings from the preclinical model suggest that targeted disruption of the vagal sensory-to-sympathetic axis may provide new treatments for visceral organ cancers by enhancing anti-tumor immunity. Citation Format: Haohan Wei, Chuyue Yu, Bo Hu, Xing Zeng, Hiroshi Ichise, Ronald N. Germain, Rui Chang, Chengcheng Jin. A vagal sensory-to-sympathetic axis restrains anti-tumor immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr PR013.

Short-Term Flow Velocity Stress on the Behavioral, Physiological, and Biochemical Responses of the Large Yellow Croaker (Larimichthys crocea)

Flow velocity is a key environmental factor that affects the behavioral strategies and physiological homeostasis of fish. To study the effects of flow velocity on the behavioral changes and blood physiology of the yellow croaker, the behavioral patterns of yellow croakers in response to flow velocity stress were obtained by analyzing changes in tail wagging frequency and amplitude. Differences in blood glucose, lactate, and cortisol were compared to determine their appropriate flow rate ranges. The juvenile stage of the large yellow croaker is crucial, as environmental changes can affect the physiology of fish. Therefore, juvenile yellow croakers were selected as the experimental subjects for this study. Twenty-four healthy and uniformly sized large yellow croakers with body weights of (90.26 ± 9.91) g and body lengths of (19.91 ± 0.69) cm were randomly assigned to one control group and three experimental groups, with five fish in each group. The experimental group was set with three flow rates, namely 1 bl/s (20 cm/s), 2 bl/s (40 cm/s), and 3 bl/s (60 cm/s), with a flow rate stress duration of 1 h. The results showed that: (1) Under different flow velocities, the fish exhibited different tail wagging patterns. At low flow velocities, their tail fins exhibited a “C”-shaped swing, while at high flow velocities, their bodies exhibited an “S”-shaped swing. (2) Oscillation frequency and amplitude both increased with increasing flow velocity. At a flow velocity of 2 bl/s, the oscillation frequency significantly increased. When the flow velocity reached 3 bl/s, the oscillation amplitude significantly increased (p < 0.05). (3) Blood physiology showed significant changes with increased flow rate, and blood glucose content continuously decreased with increased flow rate, significantly decreasing at a flow rate of 2 bl/s (p < 0.05). Lactic acid and cortisol both increased with increasing flow rate, and significantly increased at a flow rate of 3 bl/s (p < 0.05). In summary, under high-flow velocity stress, significant changes occurred in the behavior and physiology of large yellow croakers, which were consistent with physiological changes in the blood. A flow rate higher than 2 bl/s can lead to intense swimming behavior, decreased blood sugar concentration, and increased lactate accumulation and stress levels. Therefore, the short-term tolerance of yellow croakers is 2 bl/s, and a flow rate of 1 bl/s is more suitable.

Astrocyte aquaporin mediates a tonic water efflux maintaining brain homeostasis.

Brain water homeostasis not only provides a physical protection, but also determines the diffusion of chemical molecules key for information processing and metabolic stability. As a major type of glia in brain parenchyma, astrocytes are the dominant cell type expressing aquaporin water channel. How astrocyte aquaporin contributes to brain water homeostasis in basal physiology remains to be understood. We report that astrocyte aquaporin 4 (AQP4) mediates a tonic water efflux in basal conditions. Acute inhibition of astrocyte AQP4 leads to intracellular water accumulation as optically resolved by fluorescence-translated imaging in acute brain slices, and in vivo by fiber photometry in mobile mice. We then show that aquaporin-mediated constant water efflux maintains astrocyte volume and osmotic equilibrium, astrocyte and neuron Ca2+ signaling, and extracellular space remodeling during optogenetically induced cortical spreading depression. Using diffusion-weighted magnetic resonance imaging (DW-MRI), we observed that in vivo inhibition of AQP4 water efflux heterogeneously disturbs brain water homeostasis in a region-dependent manner. Our data suggest that astrocyte aquaporin, though bidirectional in nature, mediates a tonic water outflow to sustain cellular and environmental equilibrium in brain parenchyma.

Astrocyte aquaporin mediates a tonic water efflux maintaining brain homeostasis

Brain water homeostasis not only provides a physical protection, but also determines the diffusion of chemical molecules key for information processing and metabolic stability. As a major type of glia in brain parenchyma, astrocytes are the dominant cell type expressing aquaporin water channel. How astrocyte aquaporin contributes to brain water homeostasis in basal physiology remains to be understood. We report that astrocyte aquaporin 4 (AQP4) mediates a tonic water efflux in basal conditions. Acute inhibition of astrocyte AQP4 leads to intracellular water accumulation as optically resolved by fluorescence-translated imaging in acute brain slices, and in vivo by fiber photometry in mobile mice. We then show that aquaporin-mediated constant water efflux maintains astrocyte volume and osmotic equilibrium, astrocyte and neuron Ca2+ signaling, and extracellular space remodeling during optogenetically induced cortical spreading depression. Using diffusion-weighted magnetic resonance imaging (DW-MRI), we observed that in vivo inhibition of AQP4 water efflux heterogeneously disturbs brain water homeostasis in a region-dependent manner. Our data suggest that astrocyte aquaporin, though bidirectional in nature, mediates a tonic water outflow to sustain cellular and environmental equilibrium in brain parenchyma.

Unraveling the bidirectional relationship between muscle inflammation and satellite cells activity: influencing factors and insights.

Inflammation stands as a vital and innate function of the immune system, essential for maintaining physiological homeostasis. Its role in skeletal muscle regeneration is pivotal, with the activation of satellite cells (SCs) driving the repair and generation of new myofibers. However, the relationship between inflammation and SCs is intricate, influenced by various factors. Muscle injury and repair prompt significant infiltration of immune cells, particularly macrophages, into the muscle tissue. The interplay of cytokines and chemokines from diverse cell types, including immune cells, fibroadipogenic progenitors, and SCs, further shapes the inflammation-SCs dynamic. While some studies suggest heightened inflammation associates with reduced SC activity and increased fibro- or adipogenesis, others indicate an inflammatory stimulus benefits SC function. Yet, the existing literature struggles to delineate clearly between the stimulatory and inhibitory effects of inflammation on SCs and muscle regeneration. This paper comprehensively reviews studies exploring the impact of pharmacological agents, dietary interventions, genetic factors, and exercise regimes on the interplay between inflammation and SC activity.

Copper oxide nanoparticles induce non-alcoholic fatty liver disease by disrupting bile acid homeostasis and perturbing the intestinal microbial homeostasis

The wide application of copper oxide nanoparticles (CuO NPs) in various fields such as medicine, food, agriculture, and animal husbandry can result in direct or indirect oral exposure of CuO NPs to the human body. Therefore, the research on the biosafety of CuO NPs is crucially important. However, previous research mainly concentrated on CuO NPs-induced oxidative stress, rather than the dysregulation of metabolic homeostasis. Our current finding indicates that CuO NPs can enter the systemic circulation and accumulate in the liver by being adopted by the colon and disrupting the intestinal barrier. Subsequently, CuO NPs can impair bile acid (BA) homeostasis through increased reabsorption of bile acids (BAs), ultimately leading to non-alcoholic fatty liver disease (NAFLD). Additionally, the direct stimulation from CuO NPs, damage to the gut barrier, and disruption of BA homeostasis can also disrupt microbial homeostasis in the intestines, including alterations in the composition and biological functions of gut microbiota, thereby triggering NAFLD. These findings deepen our understanding of the biosafety of CuO NPs and provide evidence for their role in disrupting physiological homeostasis.

VEGF-Virus Interactions: Pathogenic Mechanisms and Therapeutic Applications.

Many types of viruses directly or indirectly target the vascular endothelial growth factor (VEGF) system, which is a central regulator of vasculogenesis and angiogenesis in physiological homeostasis, causing diverse pathologies. Other viruses have been developed into effective therapeutic tools for VEGF modulation in conditions such as cancer and eye diseases. Some viruses may alter the levels of VEGF in the pathogenesis of respiratory syndromes, or they may encode VEGF-like factors, promoting vascular disruption and angiogenesis to enable viruses' systemic spread. Oncogenic viruses may express interactive factors that perturb VEGF's functional levels or downstream signaling, which increases the neovascularization and metastasis of tumors. Furthermore, many viruses are being developed as therapeutic vectors for vascular pathologies in clinical trials. Major examples are those viral vectors that inhibit the role of VEGF in the neovascularization required for cancer progression; this is achieved through the induction of immune responses, by exposing specific peptides that block signaling or by expressing anti-VEGF and anti-VEGF receptor-neutralizing antibodies. Other viruses have been engineered into effective pro- or anti-angiogenesis multitarget vectors for neovascular eye diseases, paving the way for therapies with improved safety and minimal side effects. This article critically reviews the large body of literature on these issues, highlighting those contributions that describe the molecular mechanisms, thus expanding our understanding of the VEGF-virus interactions in disease and therapy. This could facilitate the clinical use of therapeutic virus vectors in precision medicine for the VEGF system.

The Arabidopsis E3 ubiquitin ligase DOA10A promotes localization of abscisic acid (ABA) receptors to the membrane through mono-ubiquitination in ABA signaling.

The endoplasmic reticulum-associated degradation (ERAD) system eliminates misfolded and short-lived proteins to maintain physiological homeostasis in the cell. We have previously reported that ERAD is involved in salt tolerance in Arabidopsis. Given the central role of the phytohormone abscisic acid (ABA) in plant stress responses, we sought to identify potential intersections between the ABA and the ERAD pathways in plant stress response. By screening for the ABA response of a wide array of ERAD mutants, we isolated a gain-of-function mutant, doa10a-1, which conferred ABA hypersensitivity to seedlings. Genetic and biochemical assays showed that DOA10A is a functional E3 ubiquitin ligase which, by acting in concert with specific E2 enzymes, mediates mono-ubiquitination of the ABA receptor, followed by their relocalization to the plasma membrane. This in turn leads to enhanced ABA perception. In summary, we report here the identification of a novel RING-type E3 ligase, DOA10A, which regulates ABA perception by affecting the localization and the activity of ABA receptors through their mono-ubiquitination.

Immunometabolism: signaling pathways, homeostasis, and therapeutic targets.

Immunometabolism plays a central role in sustaining immune system functionality and preserving physiological homeostasis within the organism. During the differentiation and activation, immune cells undergo metabolic reprogramming mediated by complex signaling pathways. Immune cells maintain homeostasis and are influenced by metabolic microenvironmental cues. A series of immunometabolic enzymes modulate immune cell function by metabolizing nutrients and accumulating metabolic products. These enzymes reverse immune cells' differentiation, disrupt intracellular signaling pathways, and regulate immune responses, thereby influencing disease progression. The huge population of immune metabolic enzymes, the ubiquity, and the complexity of metabolic regulation have kept the immune metabolic mechanisms related to many diseases from being discovered, and what has been revealed so far is only the tip of the iceberg. This review comprehensively summarized the immune metabolic enzymes' role in multiple immune cells such as T cells, macrophages, natural killer cells, and dendritic cells. By classifying and dissecting the immunometabolism mechanisms and the implications in diseases, summarizing and analyzing advancements in research and clinical applications of the inhibitors targeting these enzymes, this review is intended to provide a new perspective concerning immune metabolic enzymes for understanding the immune system, and offer novel insight into future therapeutic interventions.

Effects of Nitrite Stress on the Antioxidant, Immunity, Energy Metabolism, and Microbial Community Status in the Intestine of Litopenaeus vannamei

Nitrite is the main environmental pollutant that endangers shrimp culture. Intestinal health is essential for the disease resistance of shrimp. In this study, Litopenaeus vannamei shrimps were separately exposed to 1 and 5 mg/L of nitrite stress for 48 h, and then the variations in intestinal health were investigated from the aspects of histology, antioxidant, immunity, energy metabolism, and microbial community status. The results showed that nitrite stress damaged intestinal mucosa, and 5 mg/L of nitrite induced more obvious physiological changes than 1 mg/L. Specifically, the relative expression levels of antioxidant (ROMO1, Nrf2, SOD, GPx, and HSP70), ER stress (Bip and XBP1), immunity (proPO, Crus, ALF, and Lys), inflammation (JNK and TNF-α), and apoptosis (Casp-3 and Casp-9) genes were increased. Additionally, intestinal energy metabolism was activated by inducing glucose metabolism (HK, PK, PDH, and LDH), lipid metabolism (AMPK and FAS), tricarboxylic acid cycle (MDH, CS, IDH, SDH, and FH), and electron transfer chain (NDH, CytC, COI, CCO, and AtpH) gene transcription. Further, the homeostasis of intestinal microbiota composition was also disturbed, especially the abundance of some beneficial genera (Clostridium sensu stricto 1, Faecalibacterium, Romboutsia, and Ruminococcaceae UCG-010). These results reveal that nitrite stress could damage the intestinal health of L. vannamei by destroying mucosal integrity, inducing oxidation and ER stress, interfering with physiological homeostasis and energy metabolism, and disrupting the microbial community.

Welfare and performance benefits of shade provision during summer for feedlot cattle in a temperate climatic zone.

There is increasing interest from cattle lot-feeders in the use of shade to mitigate the effects of a potential heat stress event, though it is unclear whether the reported benefits of shade in previous studies conducted in more high-risk heat stress zones are pertinent in cooler temperate zones. The objectives of this study were to measure the welfare and performance benefits of shade provision for lot-fed cattle at a commercial feedlot located in a mild heat-stress risk zone in Western Australia. Six blocks of black Angus (Bos taurus) steers were inducted into the feedlot over six time-windows across a southern hemisphere summer, with 80 cattle per block housed in a partially shaded pen (providing 3.125 m2 of shade per animal) and 80 in an unshaded pen. Parameters assessed in 960 cattle over the first 70 days in the feedlot included weight gain, feed intake, and physiological and behavioral indices of overall health and welfare. Over the months of October through to May in which the experiment was conducted, shaded cattle demonstrated a modest 0.13kg overall increase in average daily gain across the 70-day feedlot period (P = 0.13). There was no difference in dry matter intake between any block or treatment. The physiological and behavioral markers of health and welfare revealed that, even during to hottest times of the experiment, the cattle were quite able to thermoregulate, via increased panting and seeking shade (if available), to maintain physiological homeostasis. In addition, we measured the effect of heat stress and shade provision on the affective state of the cattle. Qualitative behavioral assessment was used to indicate that the cattle in the 'no stress' temperature humidity index (THI) category and the shaded cattle in the 'moderate stress' THI category displayed the most positive demeanor (P < 0.05), being described as more 'settled and sociable', while the unshaded cattle in the 'moderate stress' THI category and all cattle in the 'severe stress' THI category were described as more 'agitated/anxious' (P < 0.05). Overall, the findings from the present study suggest that there are definite welfare and modest performance benefits associated with providing cattle with shade in summer in a feedlot situated in a temperate climatic zone.

Branched-chain amino acid metabolism: Pathophysiological mechanism and therapeutic intervention in metabolic diseases.

Branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential for maintaining physiological functions and metabolic homeostasis. However, chronic elevation of BCAAs causes metabolic diseases such as obesity, type 2 diabetes (T2D), and metabolic-associated fatty liver disease (MAFLD). Adipose tissue, skeletal muscle, and the liver are the three major metabolic tissues not only responsible for controlling glucose, lipid, and energy balance but also for maintaining BCAA homeostasis. Under obese and diabetic conditions, different pathogenic factors like pro-inflammatory cytokines, lipotoxicity, and reduction of adiponectin and peroxisome proliferator-activated receptors γ (PPARγ) disrupt BCAA metabolism, leading to excessive accumulation of BCAAs and their downstream metabolites in metabolic tissues and circulation. Mechanistically, BCAAs and/or their downstream metabolites, such as branched-chain ketoacids (BCKAs) and 3-hydroxyisobutyrate (3-HIB), impair insulin signaling, inhibit adipogenesis, induce inflammatory responses, and cause lipotoxicity in the metabolic tissues, resulting in multiple metabolic disorders. In this review, we summarize the latest studies on the metabolic regulation of BCAA homeostasis by the three major metabolic tissues-adipose tissue, skeletal muscle, and liver-and how dysregulated BCAA metabolism affects glucose, lipid, and energy balance in these active metabolic tissues. We also summarize therapeutic approaches to restore normal BCAA metabolism as a treatment for metabolic diseases.

Autophagy deficiency exacerbated hypoxia-reoxygenation induced inflammation and cell death via a mitochondrial DNA/STING/IRF3 pathway

AimsAutophagy is an important cellular process for maintaining physiological homeostasis and is known to protect against cardiovascular diseases including ischemia reperfusion (I/R) injury. The underlying mechanisms behind its protection require further characterization. Materials and methodsAtg7 knock out (AKO) mice were generated and subjected to I/R injury, complemented by Atg7 KO in a H9c2 cardiomyoblast cellular model ± hypoxia-reoxygenation. Subsequently, in both models, inflammation and cell death were studied. Key findingsWe confirmed that Atg7 KO led to autophagy, including mitophagy, deficiency. Upon H/R, Atg7 KO cells exhibited increased cell death compared to WT cells. Notably, we found that autophagy deficiency increased stress-induced mitochondrial fission, release of mitochondrial DNA, and sterile inflammation, namely activation of a STING/IRF3 axis leading to elevated interferon-α. Following I/R injury, AKO mice showed elevated cell death which correlated with a gene expression profile indicative of decreased anti-inflammatory responses. SignificanceAutophagy deficiency in the cardiomyocyte setting results in detrimental effects during I/R injury in mice or H/R injury in cells, mediated in part via mtDNA/IRF3/STING pathway. As such, modulation of this pathway may yield novel and promising therapeutics to treat or prevent I/R injury.

Laparoscopic sigmoid colectomy with primary anastomosis for experimental modeling in the nonhuman primate.

Laparoscopic colon surgery is performed frequently in the clinical setting for a multitude of reasons including cancer, infection, and autoimmune disease. As a result, extensive research has been conducted in relation to clinical outcomes after surgery, but more recently, in relation to the impact of surgery and other patient factors on physiologic homeostasis including the host microbiome. Despite this, experimental surgical models for laparoscopic colon surgery are scarce in the literature with most studies utilizing rodents. While rodent studies provide valuable insights into basic mechanistic processes, the translation of novel therapeutic approaches to clinical practice often requires the use of large animal models. In exploring the intricate systems biology linking surgery and medicine, sophisticated models such as nonhuman primates (NHPs) play a pivotal role. By closely resembling human anatomical, physiological, and behavioral characteristics, NHPs facilitate the development and refinement of complex surgical techniques and peri-operative practices. Furthermore, they enable longitudinal studies that comprehensively assess both immediate and long-term outcomes. The availability and utilization of multiple robust models enhance the validity of surgical research, leading to more successful translation to human clinical practice. Here we describe our technique for performing a laparoscopic sigmoid colectomy with a primary anastomosis in an NHP. The entire procedure was well tolerated without significant ventilation or hemodynamic issue. To our knowledge, this represents the first laparoscopic sigmoid colectomy with primary anastomosis performed in an NHP. Furthermore, this demonstrates the feasibility of the technique and provides a relevant, preclinical model for the study of surgical colon disease. Although the surgical colectomy model in NHPs closely resembles the clinical scenario, it is crucial to recognize that a 'model' inherently comes with limitations. The intended use of any model should be carefully evaluated concerning the target patient population with the consideration of potential disparities in anatomy, physiology, environmental factors, and disease to properly interpret results. This model provides an opportunity to study mechanisms, from a systems biology perspective, underlying both innovative surgical treatments and their effects on diseases such as colon cancer, as well as benign conditions like inflammatory bowel disease, diverticulitis, and anastomotic leak, offering high predictive value.

Oxidative state is associated with migration distance, but not traits linked to flight energetics

Flight can be highly energy demanding, but its efficiency depends largely on flight style, wing shape and wing loading, and a range of morphological and lifestyle adaptations that can modify the cost of sustained flight. Such behavioural and morphological adaptations can also influence the physiological costs associated with migration. For instance, during intense flight and catabolism of reserves, lipid damage induced by pro‐oxidants increases, and to keep oxidative physiological homeostasis under control, the antioxidant machinery can be upregulated. Studies on the oxidative physiology of endurance flight have produced contradictory results, making generalization difficult, especially because multispecies studies are missing. Therefore, to explore the oxidative cost of flight and migration, we used samples collected during the breeding season from 113 European bird species and explored the associations of measures of antioxidant capacity (total antioxidant status, uric acid and glutathione concentration) and oxidative damage of lipids (malondialdehyde) with variables reflecting flight energetics (year‐round or specifically during migration) using a phylogenetic framework. We found that none of the traits predicting year‐round flight energy expenditure (flight style, wing morphology and flight muscle morphology) explained any measures of oxidative state. Our results suggest that birds endure their everyday flight exercise without or with low oxidative cost. However, oxidative damage to lipids and one component of the endogenous antioxidant system (uric acid), measured after the end of spring migration on breeding adult birds, increased with migration distance. Our results suggest that migration could have oxidative consequences that might be carried over to subsequent life‐history stages (breeding).

Effects of foliar spraying with melatonin and chitosan Nano-encapsulated melatonin on tomato (Lycopersicon esculentum L. cv. Falcato) plants under salinity stress

Melatonin has been found to be crucial in the growth and development of plants under stress conditions. In this study, the effects of melatonin and nano melatonin regarding the growth and development of tomato plants, along with their photosynthetic pigment, phenol, and antioxidant activity, were investigated under saline conditions. The study was conducted using a completely randomized design with three replications, and the applied treatments were salt stress and foliar spraying of melatonin at a concentration of 0 (control), melatonin (Mel), and nano capsule-melatonin (Nano-Mel) at 500 µM. Salinity treatments included application of sodium chloride with two concentration of 0 mM NaCl (S1) and 50 mM NaCl (S2). Under saline conditions, Mel and Nano-Mel increased both shoot and root fresh and dry weights, improved relative water content (RWC), and enhanced antioxidant activity and phenolic content. Salinity elevated leaf ABA content, unaffected by Mel or Nano-Mel. Chlorophyll fluorescence and SPAD values demonstrated resilience to salinity with Mel and Nano-Mel applications. Nano-Mel notably mitigated Na + accumulation in leaves under salinity, helping maintain K + homeostasis. Proline levels rise due to salinity but decreased with Mel and Nano-Mel treatments. Electrolyte leakage (EL) increased under salinity but is significantly reduced by Mel, indicating enhanced membrane stability. The findings reveal that salinity stress significantly reduced plasma membrane intrinsic protein (PIP) expression in roots and leaves, whereas Mel and Nano-Mel treatments enhance PIP expression, particularly in roots. The study concludes that Mel and Nano-Mel effectively alleviate salinity-induced stress, promoting growth and maintaining physiological homeostasis in tomato plants.

Physiological and behavioral variation by urbanization and climate in an urban-tolerant toad

The distribution of a species is best understood by examining the organism-environment interaction. Climate and anthropogenic habitat degradation, including urbanization, are salient features of the environment that can limit species distributions, especially for ectotherms. Comparative studies of the capacity of individuals to cope with rapid environmental change can help us understand the future success or failure of local populations or even the species. Studies of the glucocorticoid stress response are commonly used to understand how species cope with environmental stressors. Glucocorticoids modulate many aspects of physiological homeostasis including changes in energetic allocation and behavior. In a time of global amphibian decline the Gulf Coast Toad (Incilius nebulifer) is increasing its distribution and abundance. To understand how this species deals with thermal and urban stressors, we studied glucocorticoid regulation, hop performance, and lipid storage in I. nebulifer juveniles across nine populations that differed in average annual temperature and level of imperviousness (as an indication of urbanization). We measured corticosterone release rates at baseline, during agitation stress, and during recovery; then measured locomotor performance and whole-body lipids. We tested if I. nebulifer in hotter temperatures and more urbanized habitats exhibits elevated baseline corticosterone levels and either a reduced corticosterone stress response (“stress resistance” hypothesis) or quick post-stress recovery by negative feedback (“on again, off again” hypothesis). We also tested whether they exhibit reduced fat stores and decreased locomotor performance as costs of dealing with thermal and urban stressors. We found that I. nebulifer showed elevated baseline and agitation (stressed-induced) corticosterone release rates, and higher lipid storage with increasing urbanization. Climate had quadratic effects on these traits, such that populations living at the lowest and highest temperatures had the lowest corticosterone release rates and lipid stores, and the highest hop performance was observed in the least urbanized site at the warmest climate. Additionally, the rate of glucocorticoid recovery after agitation (negative feedback) decreased with increasing temperature and increased with increasing urbanization. These results indicate that I. nebulifer follows the “on again, off again” hypothesis in an adaptive pattern, which may help them cope with environmental change in terms of urbanization and climatic differences.

Intracellular Iron Deficiency and Abnormal Metabolism, Not Ferroptosis, Contributes to Homocysteine-Induced Vascular Endothelial Cell Death.

Background/Objectives: Homocysteine (Hcy) and iron are factors co-related with the progression of cardiovascular diseases. The vascular endothelium is an important barrier for physiological homeostasis, and its impairment initiates cardiovascular injury. However, the mechanism underlying Hcy-caused vascular endothelial cell injury and the participation of iron are not fully elucidated. This study aims to investigate the Hcy-induced vascular endothelial injury and iron metabolism dysfunction as well as the underlying molecular mechanism. Methods: Human umbilical vein endothelial cells (HUVECs) were employed as the experimental model to examine the Hcy-induced endothelial injury and its underlying mechanism via various biochemical assays. Results: Hcy suppressed the cell viability and proliferation and caused cell death in a concentration-dependent manner. Hcy induced cell cycle arrest, apoptosis, and autophagy as well as impairment of intracellular energy metabolism. Hcy disrupted the intracellular antioxidant system and mitochondrial function by increasing intracellular ROS, MDA and mitochondrial content, and decreasing the SOD activity and mitochondrial membrane potential. Hcy significantly reduced the GSH-Px activity along with the accumulation of intracellular GSH in a concentration-dependent manner. Ferroptosis inhibitors, Ferrostatin-1 (Fer-1), and Deferoxamine (DFO) significantly decreased the Hcy-caused cytotoxicity accompanied by a reduction in dysregulated mitochondria content, but only DFO ameliorated the elevation of intracellular ROS, and neither Fer-1 nor DFO affected the Hcy-caused reduction in intracellular ATP. In addition, Hcy decreased the intracellular concentration of iron, and supplementing Hcy with various concentrations of Fe3+ increased the cell viability and decreased the LDH release in a concentration-dependent manner. Hcy dramatically decreased the mRNA expression level of transferrin receptor while increasing the mRNA expression levels of transferrin, ferritin light chain, ferritin heavy chain, ferroportin, and SLC7A11. Moreover, Hcy suppressed the protein expression of phospho-Akt, phospho-mTOR, Beclin-1, LC3A/B, Nrf2, HO-1, phospho-MEK1/2, phospho-ERK1/2, and Caspase-3 in concentration- and time-dependent manners. Conclusions: Hcy-induced vascular endothelial injury is likely to be associated with apoptosis and autophagy, but not ferroptosis. The key underlying mechanisms are involved in the disruption of the intracellular antioxidant system and iron metabolism via regulation of PI3K/Akt/mTOR, MAPKs, Nrf2/HO-1, and iron metabolism.

Exposure to Cyantraniliprole Adversely Impacts Fitness of Harmonia axyridis: Acute Toxicity and Sublethal Effects on Development, Fecundity and Antioxidant Responses.

Extensive utilization of pesticides and their persistent residues inadvertently pose threats to the effectiveness and fitness of biocontrol agents in agroecosystems. However, these ecological consequences are generally disregarded when executing integrated pest management strategies (IPM). Cyantraniliprole (CNAP) serves as a wide-spectrum diamide insecticide and its sublethal effects have been well characterized on multiple insect pests, whereas its impacts on beneficial natural enemies remain unfathomed. Herein we exposed Harmonia axyridis, a predacious generalist, to lethal and sublethal concentrations of CNAP via dipping treatment (egg stage) and topical applications (1st-instar stage + adult stage). The acute toxicity tests revealed that LC50 of CNAP were 90.11, 86.11 and 240.50 mg/L against embryos, 1st instar nymphs and female adults, respectively, with safety factors ranging from 1.14 to 5.34, suggesting its medium toxicity for H. axyridis and larval stage was the most susceptible. The embryonic, larval and pupal durations of coccinellids ecdysed from CNAP-treated eggs and 1st instars were all elongated under sublethal concentrations, of which LC30 triggered more pronounced and significant retardations relative to control. Besides, exposed coccinellids displayed substantially diminished pupal mass and pupation rate, most notably for insects molted from the 1st-instar stage upon CNAP sublethal treatments. With respect to reproductive performance, LC10 and LC30 of CNAP all significantly suppressed female fecundity, as evidenced by reduced vitellin content, a prolonged pre-oviposition period (POP), mitigated laid eggs and the egg hatching rate. Specifically, there existed positive correlations between vitellin level (Vn) and number of eggs deposited by per female, indicative of CNAP affecting fecundity by regulation of Vn. In addition, the antioxidant system was also profoundly disrupted by CNAP, with compromised POD activity at different concentrations over time and induced hormesis of SOD/CAT activities post LC10 exposure. Activities of SOD and TAC were enhanced to exert protective functions during the first 48 h, while defense collapsed at 72 h following LC30 treatments that depleted all enzymatic activities. We speculated that fitness trade-offs may occur between reproductive capacity and antioxidant defenses to sustain physiological homeostasis in response to CNAP stress. Collectively, this study evaluated the ecological risk of CNAP and unmasked its adverse implications for overall fitness of H. axyridis, which highlighted rational application of agrochemicals to conserve biocontrol agents when implementing IPM strategies for sustainable pest control.