Protein Imbalance Research Articles

FGF21 inhibits ferroptosis caused by mitochondrial damage to promote the repair of peripheral nerve injury.

Ferroptosis is a new type of cell death characterized by lipid peroxidation and iron dependency, representing an emerging disease regulation mechanism. The limited understanding of ferroptosis in peripheral nerve injury (PNI) complicates the management of such injuries. Mitochondrial dysfunction, which contributes to ferroptosis, further exacerbates the challenges of peripheral nerve repair. In this study, we established an in vitro model of Schwann cells model treated with TBHP and an in vivo sciatic nerve crush injury model in rats. These models were used to investigate the effects of fibroblast growth factor 21 (FGF21) on PNI, both in vitro and in vivo, and to explore the potential mechanisms linking injury-induced ferroptosis and mitochondrial dysfunction. Our findings reveal that PNI triggers abnormal accumulation of lipid reactive oxygen species (ROS) and inactivates mitochondrial respiratory chain complex III, leading to mitochondrial dysfunction. This dysfunction catalyzes the oxidation of excessive polyunsaturated fatty acids, resulting in antioxidant imbalance and loss of ferroptosis suppressor protein 1 (FSP1), which drives lipid peroxidation. Additionally, irregular iron metabolism, defective mitophagy, and other factors contribute to the induction of ferroptosis. Importantly, we found that FGF21 attenuates the abnormal accumulation of lipid ROS, restores mitochondrial function, and suppresses ferroptosis, thus promoting PNI repair. Notably, glutathione peroxidase 4 (GPX4), a downstream target of nuclear factor E2-related factor 2 (Nrf2), and the ERK/Nrf2 pathway are involved in the regulation of ferroptosis by FGF21. FGF21 promotes peripheral nerve repair by inhibiting ferroptosis caused by mitochondrial dysfunction. Therefore, targeting mitochondria and ferroptosis represents a promising therapeutic strategy for effective PNI repair.

Lipid and protein imbalances in muscle of a FAR1-patient with a heterozygous de novo variant.

Lipid and protein imbalances in muscle of a FAR1-patient with a heterozygous de novo variant.

Choline Metabolites Reverse Differentially the Habituation Deficit and Elevated Memory of Tau Null Drosophila.

Impaired neuronal plasticity and cognitive decline are cardinal features of Alzheimer's disease and related Tauopathies. Aberrantly modified Tau protein and neurotransmitter imbalance, predominantly involving acetylcholine, have been linked to these symptoms. In Drosophila, we have shown that dTau loss specifically enhances associative long-term olfactory memory, impairs foot shock habituation, and deregulates proteins involved in the regulation of neurotransmitter levels, particularly acetylcholine. Interestingly, upon choline treatment, the habituation and memory performance of mutants are restored to that of control flies. Based on these surprising results, we decided to use our well-established genetic model to understand how habituation deficits and memory performance correlate with different aspects of choline physiology as an essential component of the neurotransmitter acetylcholine, the lipid phosphatidylcholine, and the osmoregulator betaine. The results revealed that the two observed phenotypes are reversed by different choline metabolites, implying that they are governed by different underlying mechanisms. This work can contribute to a broader knowledge about the physiologic function of Tau, which may be translated into understanding the mechanisms of Tauopathies.

Efficacy of Laurus nobilis L. for Tight Junction Protein Imbalance in Leaky Gut Syndrome.

Laurus nobilis L. (LNL) belongs to the evergreen Lauraceae family. It is native to the Mediterranean and widely distributed in the southern United States, Europe, and the Middle East. LNL is rich in active ingredients of the sesquiterpene lactone series and has been reported to have antioxidant, anti-inflammatory, and anticancer effects. And parthenolide, known as a sesquiterpene lactone-based compound, inhibits the activation of lipopolysaccharide-binding protein (LBP), which is a major trigger for leaky gut syndrome. However, the effectiveness of LNL in improving the state of increased intestinal permeability has not yet been reported. Therefore, we demonstrated the efficacy of LNL, which is known to be rich in parthenolide, in improving intestinal permeability induced by IL-13. We investigated the improvement in permeability and analyzed major tight junction proteins (TJs), permeability-related mechanisms, weight and disease activity indices, and corresponding cytokine mechanisms. LNL maintained TJs homeostasis and clinical improvement by reducing increased claudin-2 through the inhibition of IL-13/STAT6 activation in TJ-damaged conditions. These results are expected to be effective in preventing leaky gut syndrome through the TJ balance and to further improve intestinal-related diseases, such as inflammatory bowel disease.

SUMOylation of annexin A6 retards cell migration and tumor growth by suppressing RHOU/AKT1–involved EMT in hepatocellular carcinoma

BackgroundThe protein annexin A6 (AnxA6) is involved in numerous membrane-related biological processes including cell migration and invasion by interacting with other proteins. The dysfunction of AnxA6, including protein expression abundance change and imbalance of post-translational modification, is tightly related to multiple cancers. Herein we focus on the biological function of AnxA6 SUMOylation in hepatocellular carcinoma (HCC) progression.MethodsThe modification sites of AnxA6 SUMOylation were identified by LC-MS/MS and amino acid site mutation. AnxA6 expression was assessed by immunohistochemistry and immunofluorescence. HCC cells were induced into the epithelial-mesenchymal transition (EMT)-featured cells by 100 ng/mL 12-O-tetradecanoylphorbol-13-acetate exposure. The ability of cell migration was evaluated under AnxA6 overexpression by transwell assay. The SUMO1 modified AnxA6 proteins were enriched from total cellular proteins by immunoprecipitation with anti-SUMO1 antibody, then the SUMOylated AnxA6 was detected by Western blot using anti-AnxA6 antibody. The nude mouse xenograft and orthotopic hepatoma models were established to determine HCC growth and tumorigenicity in vivo. The HCC patient’s overall survival versus AnxA6 expression level was evaluated by the Kaplan–Meier method.ResultsLys579 is a major SUMO1 modification site of AnxA6 in HCC cells, and SUMOylation protects AnxA6 from degradation via the ubiquitin-proteasome pathway. Compared to the wild-type AnxA6, its SUMO site mutant AnxA6K579R leads to disassociation of the binding of AnxA6 with RHOU, subsequently RHOU-mediated p-AKT1ser473 is upregulated to facilitate cell migration and EMT progression in HCC. Moreover, the SENP1 deSUMOylates AnxA6, and AnxA6 expression is negatively correlated with SENP1 protein expression level in HCC tissues, and a high gene expression ratio of ANXA6/SENP1 indicates a poor overall survival of patients.ConclusionsAnxA6 deSUMOylation contributes to HCC progression and EMT phenotype, and the combination of AnxA6 and SENP1 is a better tumor biomarker for diagnosis of HCC grade malignancy and prognosis.

Diterpenoid honatisine overcomes temozolomide resistance in glioblastoma by inducing mitonuclear protein imbalance through disruption of TFAM-mediated mtDNA transcription

BackgroundGlioblastoma (GBM) represents as the most formidable intracranial malignancy. The systematic exploration of natural compounds for their potential applications in GBM therapy has emerged as a pivotal and fruitful avenue of research. PurposeIn the present study, a panel of 96 diterpenoids was systematically evaluated as a repository of potential antitumour agents. The primary objective was to discern their potency in overcoming resistance to temozolomide (TMZ). Through an extensive screening process, honatisine, a heptacyclic diterpenoid alkaloid, emerged as the most robust candidate. Notably, honatisine exhibited remarkable efficacy in patient-derived primary and recurrent GBM strains. Subsequently, we subjected this compound to comprehensive scrutiny, encompassing GBM cultured spheres, GBM organoids (GBOs), TMZ-resistant GBM cell lines, and orthotopic xenograft mouse models of GBM cells. ResultsOur investigative efforts delved into the mechanistic underpinnings of honatisine's impact. It was discerned that honatisine prompted mitonuclear protein imbalance and elicited the mitochondrial unfolded protein response (UPRmt). This effect was mediated through the selective depletion of mitochondrial DNA (mtDNA)-encoded subunits, with a particular emphasis on the diminution of mitochondrial transcription factor A (TFAM). The ultimate outcome was the instigation of deleterious mitochondrial dysfunction, culminating in apoptosis. Molecular docking and surface plasmon resonance (SPR) experiments validated honatisine's binding affinity to TFAM within its HMG-box B domain. This binding may promote phosphorylation of TFAM and obstruct the interaction of TFAM bound to heavy strand promoter 1 (HSP1), thereby enhancing Lon-mediated TFAM degradation. Finally, in vivo experiments confirmed honatisine's antiglioma properties. Our comprehensive toxicological assessments underscored its mild toxicity profile, emphasizing the necessity for a thorough evaluation of honatisine as a novel antiglioma agent. ConclusionIn summary, our data provide new insights into the therapeutic mechanisms underlying honatisine's selective inducetion of apoptosis and its ability to overcome chemotherapy resistance in GBM. These actions are mediated through the disruption of mitochondrial proteostasis and function, achieved by the inhibition of TFAM-mediated mtDNA transcription. This study highlights honatisine's potential as a promising agent for glioblastoma therapy, underscoring the need for further exploration and investigation.

DIMINISHED HAND GRIP STRENGTH AND CIRRHOSIS: PREVALENCE AND ASSOCIATED FACTORS.

Sarcopenia is a syndrome characterized by progressive and generalized loss of muscle mass and strength, observed to varying degrees in patients with various chronic conditions. In cirrhotic patients, it reflects protein-energy malnutrition due to metabolic protein imbalance and is associated with worsened prognosis and reduced post-liver transplantation survival. To evaluate the epidemiological distribution of diminished hand grip (HG) strength in cirrhotic patients at an outpatient clinic of Santa Casa de Misericórdia in Vitória-ES, Brazil, seeking its association with liver function and cirrhosis complications. Cross-sectional, epidemiological, and single-center study. A questionnaire was administered to patients and HG strength was measured using a dynamometer, with three interval measures taken for 3 seconds each. The study's total population was 64 cirrhotic patients, with a mean age of 58 years and alcohol as the most prevalent etiology. Reduced HG strength was defined based on two reference values: using cutoff point 1, reduced HG strength was identified in 33 patients (51.6%); according to cutoff point 2, 23 (35.9%) had reduced HG strength. The study showed that, among the parameters observed, there was an association between the female gender and diminished HG strength in both cutoff points. Additionally, it was noted that patients with a score of 15 or more on the Model for End-Stage Liver Disease (MELD) had decreased HG strength at cutoff point 2. The study showed no association between decreased HG strength and the occurrence of cirrhosis complications in the population studied. In our study, we obtained a diminished HG strength variation of 35-52%, which was related to higher MELD scores, suggesting an association with worse clinical outcomes. Therefore, the presence of reduced muscle strength in cirrhotic patients may be linked to prognostic factors and should be valued as clinical data in the management of these patients.

Reduced Mitochondrial Protein Translation Promotes Cardiomyocyte Proliferation and Heart Regeneration.

The importance of mitochondria in normal heart function are well recognized and recent studies have implicated changes in mitochondrial metabolism with some forms of heart disease. Previous studies demonstrated that knockdown of the mitochondrial ribosomal protein S5 (MRPS5) by small interfering RNA (siRNA) inhibits mitochondrial translation and thereby causes a mitonuclear protein imbalance. Therefore, we decided to examine the effects of MRPS5 loss and the role of these processes on cardiomyocyte proliferation. We deleted a single allele of MRPS5 in mice and used left anterior descending coronary artery ligation surgery to induce myocardial damage in these animals. We examined cardiomyocyte proliferation and cardiac regeneration both in vivo and in vitro. Doxycycline treatment was used to inhibit protein translation. Heart function in mice was assessed by echocardiography. Quantitative real-time polymerase chain reaction and RNA sequencing were used to assess changes in transcription and chromatin immunoprecipitation (ChIP) and BioChIP were used to assess chromatin effects. Protein levels were assessed by Western blotting and cell proliferation or death by histology and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays. Adeno-associated virus was used to overexpress genes. The luciferase reporter assay was used to assess promoter activity. Mitochondrial oxygen consumption rate, ATP levels, and reactive oxygen species were also analyzed. We determined that deletion of a single allele of MRPS5 in mice results in elevated cardiomyocyte proliferation and cardiac regeneration; this observation correlates with improved cardiac function after induction of myocardial infarction. We identified ATF4 (activating transcription factor 4) as a key regulator of the mitochondrial stress response in cardiomyocytes from Mrps5+/- mice; furthermore, ATF4 regulates Knl1 (kinetochore scaffold 1) leading to an increase in cytokinesis during cardiomyocyte proliferation. The increased cardiomyocyte proliferation observed in Mrps5+/- mice was attenuated when one allele of Atf4 was deleted genetically (Mrps5+/-/Atf4+/-), resulting in the loss in the capacity for cardiac regeneration. Either MRPS5 inhibition (or as we also demonstrate, doxycycline treatment) activate a conserved regulatory mechanism that increases the proliferation of human induced pluripotent stem cell-derived cardiomyocytes. These data highlight a critical role for MRPS5/ATF4 in cardiomyocytes and an exciting new avenue of study for therapies to treat myocardial injury.

In-vivo Hepatoprotective Evaluation of Sicyos edulis on Wistar Albino Rats

The liver is known for synthesising enzymes, metabolism, and excretion of drugs and food. However, during biological processes, the abnormality occurs in the liver, which becomes a significant global health burden in humans, characterised by loss of synthetic function, breakdown of blood, irregular vitamin K, and localised, permanent changes to parenchymal cells. The study was designed to research the Phytochemical and biological screening of Sicyos edulis leaf for hepatoprotective activity on laboratory animals using paracetamol and methotrexate model for acute incidence. The study evaluated liver toxicity in healthy Wistar albino rats using two in vivo models. Each study group consists of six animals. In the first model, paracetamol p.o. for seven days. Similarly, in the second model, methotrexate was administered (single dose treatment) to animals with 20mg/kg, b.w., p.o. Both models were challenged with methanolic extract of Sicyos edulis leaf (MESEL) of doses 100mg/kg (low) and 200 mg/kg (high) p.o. for seven days, respectively. On day 8th, the blood samples were collected from the tail vein and analysed for various biochemical parameters. MESEL successfully restored the elevated serum biomarker levels in our study. The decrease in aspartate aminotransferase was observed by removing toxic metabolites, the reduction in alanine aminotransferase was due to an increase in ATP synthesis in mitochondria, thereby modulating the balance of liver energy metabolism, and the decrease in alkaline phosphates is due to tissue regeneration, an increase in total protein denotes the restoration of protein imbalance from acute liver injury. At different concentrations, all these effects strengthen the liver, regulate body metabolism, and ultimately inhibit further liver cell damage in favour of their regeneration. Our study also evidences the protective action of MESEL in rats against the Paracetamol and methotrexate model. The study reveals hepatocyte regeneration followed by hepatic restoration in pre-clinical settings. Keywords: Acute liver disease, Sicyos edulis, Silymarin, Methotrexate, Liver enzymes

Nutrition, frailty assessment, and interventions for the liver transplant candidate.

Nutrition, frailty assessment, and interventions for the liver transplant candidate.

Icariin alleviates autistic-like behavior, hippocampal inflammation and vGlut1 expression in adult BTBR mice

Autism spectrum disorder (ASD) is a complicated, heterogeneous disorder characterized by social interaction deficits and repetitive stereotypical behaviors. Neuroinflammation and synaptic protein dysregulation have been implicated in ASD pathogenesis. Icariin (ICA) has proven to exert neuroprotective function through anti-inflammatory function. Therefore, this study aimed to clarify the effects of ICA treatment on autism-like behavioral deficits in BTBR mice and whether these changes were related to modifications in the hippocampal inflammation and the balance of excitatory/inhibitory synapses. ICA supplementation (80 mg/kg, once daily for ten days, i.g.) ameliorated social deficits, repetitive stereotypical behaviors, and short-term memory deficit without affecting locomotor activity or anxiety-like behaviors of BTBR mice. Furthermore, ICA treatment inhibited neuroinflammation via decreasing microglia number and the soma size in the CA1 region of the hippocampus, as well as the protein levels of proinflammatory cytokines in the hippocampus of BTBR mice. In addition, ICA treatment also rescued excitatory-inhibitory synaptic protein imbalance by inhibiting the increased vGlut1 level without affecting the vGAT level in the BTBR mouse hippocampus. Collectively, the observed results indicate that ICA treatment alleviates ASD-like features, mitigates disturbed balance of excitatory-inhibitory synaptic protein, and inhibits hippocampal inflammation in BTBR mice, and may represent a novel promising drug for ASD treatment.

The IAPEN INDIA Association for Parenteral and Enteral Nutrition Chennai Declaration on the Fundamental Right to Nutritional Care of Patients Under Treatment

Malnutrition can be defined as a state of nutrition in which a deficiency or excess or imbalance of energy, protein, and other nutrients cause measurable adverse effects on body tissues, eventually affecting the quality of life and clinical outcome. Malnutrition is associated with many adverse outcomes both in the community as well as in clinical settings; including a suppressed immune system, impaired wound healing, muscle wasting, extended periods of hospital stay, and increased mortality. Undetected malnutrition not only enhances the risk of adverse complications for patients but impacts negatively with an increase in health care costs. This can be prevented if protocol prioritized attention is given to their nutritional care. Achievement of good nutrition is important and is a must in overall healthcare, hence, all stakeholders should be updated regarding the management of malnutrition and challenges encountered. It’s time we start, mobilize everyone and engage governments, policymakers, gain national and global cooperation to address the issue of malnutrition in healthcare settings. The objective of this specialist declaration is to provide evidence-based recommendations for the proper management of malnutrition by a multi-parametric approach starting with the screening of all patients by trained healthcare professionals with easy-to-use validated screening tools. Nutrition screening is the first step towards identifying patients at risk and requiring intervention at the earliest. Only a few accredited hospitals have nutrition screening at the time of reporting as a protocol. The timing of recognizing the presence of malnutrition or at-risk is of paramount importance to reverse the deteriorating nutritional status before the patient becomes cachectic. Keywords: Nutrition care, Malnutrition, Prevention, Clinical nutrition, Human right to nutrition care, Screening, Assessment, Dietitian

Role of mitophagy in the hallmarks of aging.

Aging, subjected to scientific scrutiny, is extensively defined as a time-dependent decline in functions that involves the majority of organisms. The time-dependent accretion of cellular lesions is generally a universal trigger of aging, while mitochondrial dysfunction is a sign of aging. Dysfunctional mitochondria are identified and removed by mitophagy, a selective form of macroautophagy. Increased mitochondrial damage resulting from reduced biogenesis and clearance may promote the aging process. The primary purpose of this paper is to illustrate in detail the effects of mitophagy on aging and emphasize the associations between mitophagy and other signs of aging, including dietary restriction, telomere shortening, epigenetic alterations, and protein imbalance. The evidence regarding the effects of these elements on aging is still limited. And although the understanding of relationship between mitophagy and aging has been long-awaited, to analyze details of such a relationship remains the main challenge in aging studies.

Dietary cobalt oxide nanoparticles alleviate aging through activation of mitochondrial UPR in Caenorhabditis elegans.

Mitochondrial unfolded protein response (UPRmt), which is a mitochondrial proteostasis pathway, orchestrates an adaptive reprogramming for metabolism homeostasis and organismal longevity. Similar to other defense systems, compromised UPRmt is a feature of several age-related diseases. Here we report that dimercapto succinic acid (DMSA)-modified cobalt oxide nanoparticles (Co3O4 NPs), which have received wide-spread attention in biomedical fields, is a promising UPRmt activator and, more importantly, provides a gate for extending healthy lifespan. Methods: UPRmt activation by Co3O4 NPs was tested in transgenetic Caenorhabditis elegans (C. elegans) specifically expressing UPRmt reporter Phsp-6::GFP, and the underlying mechanism was further validated by mitochondrial morphology, mtDNA/nDNA, metabolism-related genes' expression, mitonuclear protein imbalance, oyxgen assumption and ATP level in C. elegans. Then therapeutic response aganist senescence was monitored by lifespan analysis, lipofusin contents, MDA contents, Fe accumulation, pharyngeal locomotion performance as well as athletic ability (head thrashes and body bends) at different developmental stages of C. elegans. RNAi towards ubl-5 or atfs-1 in UPRmt pathway was applied to clarify the role of UPRmt in Co3O4 NPs -mediated anti-aging effects. Finally, the effect of Co3O4 NPs on mitochondrial homeostasis and D-galactose-induced cell viability decline in mammalian cells were studied. Results: Co3O4 NPs was revealed as a bona fide activator of the UPRmt signaling pathway, through fine-tuning mitochondrial dynamics and inducing a stoichiometric imbalance between OXPHOS subunits encoded by mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) at early life stage of C. elegans. Phenotypically, Co3O4 NPs treatment protect C. elegans from external stresses. More importantly, dietary low level of Co3O4 NPs effectively extend lifespan and alleviate aging-related physiological and functional decline of worms, demonstrating its potential roles in delaying aging. While the protective effect exerted by Co3O4 NPs was compromised in line with atfs-1 or ubl-5 RNAi treatment. Further studies verified the conservation of Co3O4 NPs in activating UPRmt and exerting protective effects in mammalian cells. Conclusions: The results reveal beneficial effects of Co3O4 NPs on mitochondrial metabolic control, thus presenting their potential efficacy in anti-aging care.

Molecular alteration of the proteasome contributes to AD-like pathology in the brain of HFD-STZ diabetic rats.

Diabetes-related cognitive impairment has been shown in diverse epidemiological investigations and lab-based studies, although the underlying pathological mechanisms remain unclear. Unbalanced protein homeostasis may contribute to cognitive decline by inducing abnormal protein aggregation in the diabetic brain. This study aimed to determine possible changes in the proteasome, which is an important pathway involved in abnormal protein degradation. To this end, we examined potential alterations of proteasomal subunits and hydrolytic activity in the brain of diabetic rats fed with high-fat diet combined with small doses of streptozotocin (STZ). Furthermore, lactacystin were used to inhibit proteasomal activity in vivo and typical Alzheimer's disease (AD)-like pathologies were detected, including amyloid-beta, tau phosphorylation, and oxidative protein changes. Our results showed that proteasomal activity increased in the brains of diabetic rats compared to age-matched control rats. After proteasome inhibition, the levels of tau phosphorylation and protein oxidative modification significantly increased; however, no changes were detected in the pathway involved in amyloid production. These results indicated that changes in protein homeostasis balance in diabetes play a role in some typical AD-like changes, especially in oxidative protein degradation, providing evidence that prevention of diabetes-induced protein imbalance may be a potential therapeutic target.

Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras

Epigenetic mediation through bromodomain and extraterminal (BET) proteins have progressively translated protein imbalance into effective cancer treatment. Perturbation of druggable BET proteins through proteolysis-targeting chimeras (PROTACs) has recently contributed to the discovery of effective therapeutics. Unfortunately, precise and microenvironment-activatable BET protein degradation content with promising tumor selectivity and pharmacological suitability remains elusive. Here, we present an enzyme-derived clicking PROTACs (ENCTACs) capable of orthogonally cross-linking two disparate small-molecule warhead ligands that recognize BET bromodomain-containing protein 4 (BRD4) protein and E3 ligase within tumors only upon hypoxia-induced activation of nitroreductase enzyme. This localized formation of heterobifunctional degraders promotes specific down-regulation of BRD4, which subsequently alters expression of epigenetic targets and, therefore, allows precise modulation of hypoxic signaling in live cells, zebrafish, and living mice with solid tumors. Our activation-feedback system demonstrates compelling superiorities and may enable the PROTAC technology with more flexible practicality and druggable potency for precision medicine in the near future.

Mitochondrial proteotoxic stresses activate abscisic acid signaling in plants

The mitochondrial proteome is composed of both mitochondrial DNA (mtDNA)-encoded and nuclear DNA (nuDNA)-encoded proteins. The mitonuclear protein imbalance leads to the occurrence of mitochondrial proteotoxic stresses. As a response to the mitochondrial proteotoxic stress, mitochondrial unfolded protein response (UPRmt) is induced in cells to restore the mitochondrial functions. Although UPRmt has been extensively studied in animals, much less is known about the mechanisms of UPRmt signaling in plants. We report here that a DNA intercalating agent, ethidium bromide (EtBr) triggers UPRmt in Arabidopsis thaliana, with characteristic features similar to those caused by the mitochondrial translation inhibitor doxycycline (Dox). EtBr/Dox treatments activate abscisic acid (ABA) signaling. Then ABA promotes the expression of UPRmt genes, like alternative oxidase 1a (AOX1a). A key regulator of ABA signaling, ABA insensitive 5 (ABI5) directly binds to the promoter of AOX1a, which enhances AOX1a gene transcription. Our study reveals a link between ABA and UPRmt in plants.

Nutritional management of calves grazing wheat and small grain pasture

Small grain forages are a unique and economically important resource in the Southern Great Plains and in similar areas worldwide. Income is possible from both increasing value of stocker calves grazing during the fall and winter as well as the harvested grain. Wheat and other small grain species are used in this “dual purpose” production system if calves are removed from pastures at the first hollow stem development stage. As more producers have opted to forgo grain harvest in order to graze-out cropped acres, other small grains (oats, cereal rye, triticale, barley) and cool-season annuals (annual ryegrass) are often planted in mixtures. These alternative cool-season annuals and mixtures have similar protein and digestibility attributes to wheat pasture, so management and supplementation recommendations are similar. Risk factors of production include forage growth and climatic variation as well as the bloat provocative nature of the forage, which impacts performance, death losses and economics of the enterprise. Small grain forages are high in crude Protein (17 to 35% of DM) and are highly digestible (up to 85% IVOMD), which is adequate for potential average daily gains in excess of 2.5 lbs per day. However, these performance levels are often not achieved in practice. Growth performance is impacted by forage availability, mineral deficiencies and imbalances, energy and protein imbalances in the rumen, and bloat. This review focuses on the nutritional management of stocker calves grazing smallgrain forages to improve predictability of performance and maintain economic sustainability.

Interactions between endoplasmic reticulum stress and extracellular vesicles in multiple diseases.

Immune responses can severely perturb endoplasmic reticulum (ER) function. As a protein-folding factory and dynamic calcium storage compartment, the ER plays a pivotal role in resisting pathogens and in the development of autoimmune diseases and various other diseases, including cancer, cardiovascular, neurological, orthopedic, and liver-related diseases, metabolic disorders, etc. In recent years, an increasing number of studies have shown that extracellular vesicles (EVs) play important roles in these conditions, suggesting that cells carry out some physiological functions through EVs. The formation of EVs is dependent on the ER. ER stress, as a state of protein imbalance, is both a cause and consequence of disease. ER stress promotes the transmission of pathological messages to EVs, which are delivered to target cells and lead to disease development. Moreover, EVs can transmit pathological messages to healthy cells, causing ER stress. This paper reviews the biological functions of EVs in disease, as well as the mechanisms underlying interactions between ER stress and EVs in multiple diseases. In addition, the prospects of these interactions for disease treatment are described.

Heme oxygenase-1 protects against endotoxin-induced acute lung injury depends on NAD+-mediated mitonuclear communication through PGC1α/PPARγ signaling pathway.

Endotoxin-induced acute lung injury (ALI) is a challenging life-threatening disease for which no specific therapy exists. Mitochondrial dysfunction is corroborated as hallmarks in sepsis which commonly disrupt mitochondria-centered cellular communication networks, especially mitonuclear crosstalk, where the ubiquitous cofactor nicotinamide adenine dinucleotide (NAD+) is essential for mitonuclear communication. Heme oxygenase-1 (HO-1) is critical for maintaining mitochondrial dynamic equilibrium and regulating endoplasmic reticulum (ER) and Golgi stress to alleviating acute lung injury. However, it is unclear whether HO-1 regulates NAD+-mediated mitonuclear communication to exert the endogenous protection during endotoxin-induced ALI. In this study, we observed HO-1 attenuated endotoxin-induced ALI by regulated NAD+ levels and NAD+ affected the mitonuclear communication, including mitonuclear protein imbalance and UPRmt to alleviate lung damage. We also found the protective effect of HO-1 depended on NAD+ and NAD+-mediated mitonuclear communication. Furtherly, the inhibition of the PGC1α/PPARγ signaling exacerbates the septic lung injury by reducing NAD+ levels and repressing the mitonuclear protein imbalance and UPRmt. Altogether, our study certified that HO-1 ameliorated endotoxin-induced acute lung injury by regulating NAD+ and NAD+-mediated mitonuclear communications through PGC1α/PPARγ pathway. The present study provided complementary evidence for the cytoprotective effect of HO-1 as a potential target for preventing and attenuating of endotoxin-induced ALI.