Cancer and the Metaorganism.

SUMMARY: Pathogenic shifts in the gut microbiota are part of the "ecological" alterations that accompany tumor progression and compromise immunosurveillance. The future management of health and disease including cancer will rely on the diagnosis of such shifts and their therapeutic correction by general or personalized strategies, hence restoring metaorganismal homeostasis.

Xbp1 promotes odontoblastic differentiation through modulating mitochondrial homeostasis.

Odontoblast differentiation depends on the orderly recruitment of transcriptional factors (TFs) in the transcriptional regulatory network. The depletion of crucial TFs disturbs dynamic alteration of the chromatin landscape and gene expression profile, leading to developmental defects. Our previous studies have revealed that the basic leucine zipper (bZIP) TF family is crucial in odontoblastic differentiation, but the function of bZIP TF family member XBP1 is still unknown. Here, we showed the stage-specific expression patterns of the spliced form Xbp1s during tooth development. Elevated Xbp1 expression and nuclear translocation of XBP1S in mesenchymal stem cells (MSCs) were induced by differentiation medium in vitro. Diminution of Xbp1 expression impaired the odontogenic differentiation potential of MSCs. The further integration of ATAC-seq and RNA-seq identified Hspa9 as a direct downstream target, an essential mitochondrial chaperonin gene that modulated mitochondrial homeostasis. The amelioration of mitochondrial dysfunction rescued the impaired odontogenic differentiation potential of MSCs caused by the diminution of Xbp1. Furthermore, the overexpression of Hspa9 rescued Xbp1-deficient defects in odontoblastic differentiation. Our study illustrates the crucial role of Xbp1 in odontoblastic differentiation via modulating mitochondrial homeostasis and brings evidence to the therapy of mitochondrial diseases caused by genetic defects.

Zinc and manganese homeostasis closely interact in mammalian cells.

Understanding the homeostatic interactions among essential trace metals is important for explaining their roles in cellular systems. Recent studies in vertebrates suggest that cellular Mn metabolism is related to Zn metabolism in multifarious cellular processes. However, the underlying mechanism remains unclear. In this study, we examined the changes in the expression of proteins involved in cellular Zn and/or Mn homeostatic control and measured the Mn as well as Zn contents and Zn enzyme activities to elucidate the effects of Mn and Zn homeostasis on each other. Mn treatment decreased the expression of the Zn homeostatic proteins metallothionein (MT) and ZNT1 and reduced Zn enzyme activities, which were attributed to the decreased Zn content. Moreover, loss of Mn efflux transport protein decreased MT and ZNT1 expression and Zn enzyme activity without changing extracellular Mn content. This reduction was not observed when supplementing with the same Cu concentrations and in cells lacking Cu efflux proteins. Furthermore, cellular Zn homeostasis was oppositely regulated in cells expressing Zn and Mn importer ZIP8, depending on whether Zn or Mn concentration was elevated in the extracellular milieu. Our results provide novel insights into the intricate interactions between Mn and Zn homeostasis in mammalian cells and facilitate our understanding of the physiopathology of Mn, which may lead to the development of treatment strategies for Mn-related diseases in the future.

Systematic HOIP interactome profiling reveals critical roles of linear ubiquitination in tissue homeostasis.

Linear ubiquitination catalyzed by HOIL-1-interacting protein (HOIP), the key component of the linear ubiquitination assembly complex, plays fundamental roles in tissue homeostasis by executing domain-specific regulatory functions. However, a proteome-wide analysis of the domain-specific interactome of HOIP across tissues is lacking. Here, we present a comprehensive mass spectrometry-based interactome profiling of four HOIP domains in nine mouse tissues. The interaction dataset provides a high-quality HOIP interactome resource with an average of approximately 90 interactors for each bait per tissue. HOIP tissue interactome presents a systematic understanding of linear ubiquitination functions in each tissue and also shows associations of tissue functions to genetic diseases. HOIP domain interactome characterizes a set of previously undefined linear ubiquitinated substrates and elucidates the cross-talk among HOIP domains in physiological and pathological processes. Moreover, we show that linear ubiquitination of Integrin-linked protein kinase (ILK) decreases focal adhesion formation and promotes the detachment of Shigella flexneri-infected cells. Meanwhile, Hoip deficiency decreases the linear ubiquitination of Smad ubiquitination regulatory factor 1 (SMURF1) and enhances its E3 activity, finally causing a reduced bone mass phenotype in mice. Overall, our work expands the knowledge of HOIP-interacting proteins and provides a platform for further discovery of linear ubiquitination functions in tissue homeostasis.

[Liver cancer treatment with mitochondrial homeostasis].

Systemic treatment, including molecular targeted therapy, immunotherapy, and chemotherapy, is an important means of achieving long-term survival in patients with intermediate-and advanced-stage liver cancer. However, some patients are insensitive to treatment and even develop drug resistance. Mitochondria are the center of cellular energy metabolism and, at the same time, are the priority targets for systemic therapy. Mitochondrial homeostasis plays an important role in the treatment of liver cancer. The relationship between the two advances is elucidated so as to provide better ideas for the clinical treatment of liver cancer.

Immune tolerance and the prevention of autoimmune diseases essentially depend on thymic tissue homeostasis.

The intricate balance of immune reactions towards invading pathogens and immune tolerance towards self is pivotal in preventing autoimmune diseases, with the thymus playing a central role in establishing and maintaining this equilibrium. The induction of central immune tolerance in the thymus involves the elimination of self-reactive T cells, a mechanism essential for averting autoimmunity. Disruption of the thymic T cell selection mechanisms can lead to the development of autoimmune diseases. In the dynamic microenvironment of the thymus, T cell migration and interactions with thymic stromal cells are critical for the selection processes that ensure self-tolerance. Thymic epithelial cells are particularly significant in this context, presenting self-antigens and inducing the negative selection of autoreactive T cells. Further, the synergistic roles of thymic fibroblasts, B cells, and dendritic cells in antigen presentation, selection and the development of regulatory T cells are pivotal in maintaining immune responses tightly regulated. This review article collates these insights, offering a comprehensive examination of the multifaceted role of thymic tissue homeostasis in the establishment of immune tolerance and its implications in the prevention of autoimmune diseases. Additionally, the developmental pathways of the thymus are explored, highlighting how genetic aberrations can disrupt thymic architecture and function, leading to autoimmune conditions. The impact of infections on immune tolerance is another critical area, with pathogens potentially triggering autoimmunity by altering thymic homeostasis. Overall, this review underscores the integral role of thymic tissue homeostasis in the prevention of autoimmune diseases, discussing insights into potential therapeutic strategies and examining putative avenues for future research on developing thymic-based therapies in treating and preventing autoimmune conditions.

A single-cell atlas of lung homeostasis reveals dynamic changes during development and aging.

Aging is a global challenge, marked in the lungs by function decline and structural disorders, which affects the health of the elderly population. To explore anti-aging strategies, we develop a dynamic atlas covering 45 cell types in human lungs, spanning from embryonic development to aging. We aim to apply the discoveries of lung's development to address aging-related issues. We observe that both epithelial and immune cells undergo a process of acquisition and loss of essential function as they transition from development to aging. During aging, we identify cellular phenotypic alternations that result in reduced pulmonary compliance and compromised immune homeostasis. Furthermore, we find a distinctive expression pattern of the ferritin light chain (FTL) gene, which increases during development but decreases in various types of lung cells during the aging process.

Aldicarb disturbed bile acid, steroid hormone and oxylipin homeostasis in C57BL/6 J mice.

Mounting evidence has shown that the gut microbiota plays a key role in human health. The homeostasis of the gut microbiota could be affected by many factors, including environmental chemicals. Aldicarb is a carbamate insecticide used to control a variety of insects and nematode pests in agriculture. Aldicarb is highly toxic and its wide existence has become a global public health concern. In our previous study, we have demonstrated that aldicarb disturbed the gut microbial community structure and composition. However, the impacts of aldicarb on gut microbiota-derived metabolites, bile acids, remain elusive. In present study, we performed targeted metabolomics analysis to explore the effects of aldicarb exposure on bile acids, as well as steroid hormones and oxylipins in the serum, feces and liver of C57BL/6 J mice. Our results showed that aldicarb exposure disturbed the level of various bile acids, steroid hormones and oxylipins in the serum and feces of C57BL/6 J mice. In the liver, the level of cortisol was decreased, meanwhile 15,16-dihydroxyoctadeca-9,12-dienoic acid was increased in aldicarb-treated mice. Metagenomic sequencing analysis showed that the relative abundance of a bile salt hydrolase, choloylglycine hydrolase (EC:3.5.1.24) and a sulfatase enzyme involved in steroid hormone metabolism, arylsulfatase, was significantly increased by aldicarb exposure. Furthermore, correlations were found between gut microbiota and various serum metabolites. The results from this study are helpful to improve the understanding of the impact of carbamate insecticides on host and microbial metabolism.

Transcriptional and metabolic profiling of sulfur starvation response in two monocots.

BACKGROUND: Sulfur (S) is a mineral nutrient essential for plant growth and development, which is incorporated into diverse molecules fundamental for primary and secondary metabolism, plant defense, signaling, and maintaining cellular homeostasis. Although, S starvation response is well documented in the dicot model Arabidopsis thaliana, it is not clear if the same transcriptional networks control the response also in the monocots. RESULTS: We performed series of physiological, expression, and metabolite analyses in two model monocot species, one representing the C3 plants, Oryza sativa cv. kitaake, and second representing the C4 plants, Setaria viridis. Our comprehensive transcriptomic analysis revealed twice as many differentially expressed genes (DEGs) in S. viridis than in O. sativa under S-deficiency, consistent with a greater loss of sulfur and S-containing metabolites under these conditions. Surprisingly, most of the DEGs and enriched gene ontology terms were species-specific, with an intersect of only 58 common DEGs. The transcriptional networks were different in roots and shoots of both species, in particular no genes were down-regulated by S-deficiency in the roots of both species. CONCLUSIONS: Our analysis shows that S-deficiency seems to have different physiological consequences in the two monocot species and their nutrient homeostasis might be under distinct control mechanisms.

Sensory neurons: An integrated component of innate immunity.

The sensory nervous system possesses the ability to integrate exogenous threats and endogenous signals to mediate downstream effector functions. Sensory neurons have been shown to activate or suppress host defense and immunity against pathogens, depending on the tissue and disease state. Through this lens, pro- and anti-inflammatory neuroimmune effector functions can be interpreted as evolutionary adaptations by host or pathogen. Here, we discuss recent and impactful examples of neuroimmune circuitry that regulate tissue homeostasis, autoinflammation, and host defense. Apparently paradoxical or conflicting reports in the literature also highlight the complexity of neuroimmune interactions that may depend on tissue- and microbe-specific cues. These findings expand our understanding of the nuanced mechanisms and the greater context of sensory neurons in innate immunity.

The response of Dual-leucine zipper kinase (DLK) to nocodazole: Evidence for a homeostatic cytoskeletal repair mechanism.

Genetic and pharmacological perturbation of the cytoskeleton enhances the regenerative potential of neurons. This response requires Dual-leucine Zipper Kinase (DLK), a neuronal stress sensor that is a central regulator of axon regeneration and degeneration. The damage and repair aspects of this response are reminiscent of other cellular homeostatic systems, suggesting that a cytoskeletal homeostatic response exists. In this study, we propose a framework for understanding DLK mediated neuronal cytoskeletal homeostasis. We demonstrate that low dose nocodazole treatment activates DLK signaling. Activation of DLK signaling results in a DLK-dependent transcriptional signature, which we identify through RNA-seq. This signature includes genes likely to attenuate DLK signaling while simultaneously inducing actin regulating genes. We identify alterations to the cytoskeleton including actin-based morphological changes to the axon. These results are consistent with the model that cytoskeletal disruption in the neuron induces a DLK-dependent homeostatic mechanism, which we term the Cytoskeletal Stress Response (CSR) pathway.

Approaches for studying human macrophages.

Macrophages are vital tissue components involved in organogenesis, maintaining homeostasis, and responses to disease. Mouse models have significantly improved our understanding of macrophages. Further investigations into the characteristics and development of human macrophages are crucial, considering the substantial anatomical and physiological distinctions between mice and humans. Despite challenges in human macrophage research, recent studies are shedding light on the ontogeny and function of human macrophages. In this opinion, we propose combinations of cutting-edge approaches to examine the diversity, development, niche, and function of human tissue-resident macrophages. These methodologies can facilitate our exploration of human macrophages more efficiently, ideally providing new therapeutic avenues for macrophage-relevant disorders.

Plant growth-promoting rhizobacteria Pseudomonas aeruginosa HG28-5 improves salt tolerance by regulating Na+/K+ homeostasis and ABA signaling pathway in tomato.

Salinity stress badly restricts the growth, yield and quality of vegetable crops. Plant growth-promoting rhizobacteria (PGPR) is a friendly and effective mean to enhance plant growth and salt tolerance. However, information on the regulatory mechanism of PGPR on vegetable crops in response to salt stress is still incomplete. Here, we screened a novel salt-tolerant PGPR strain Pseudomonas aeruginosa HG28-5 by evaluating the tomatoes growth performance, chlorophyll fluorescence index, and relative electrolyte leakage (REL) under normal and salinity conditions. Results showed that HG28-5 colonization improved seedling growth parameters by increasing the plant height (23.7%), stem diameter (14.6%), fresh and dry weight in the shoot (60.3%, 91.1%) and root (70.1%, 92.5%), compared to salt-stressed plants without colonization. Likewise, HG28-5 increased levels of maximum photochemical efficiency of PSII (Fv/Fm) (99.3%), the antioxidant enzyme activities as superoxide dismutase (SOD, 85.5%), peroxidase (POD, 35.2%), catalase (CAT, 20.6%), and reduced the REL (48.2%), MDA content (41.3%) and ROS accumulation in leaves of WT tomatoes under salt stress in comparison with the plants treated with NaCl alone. Importantly, Na+ content of HG28-5 colonized salt-stressed WT plants were decreased by15.5% in the leaves and 26.6% in the roots in the corresponding non-colonized salt-stressed plants, which may be attributed to the higher K+ concentration and SOS1, SOS2, HKT1;2, NHX1 transcript levels in leaves of colonized plants under saline condition. Interestingly, increased abscisic acid (ABA) content and upregulation of ABA pathway genes (ABA synthesis-related genes NCED1, NCED2, NCED4, NECD6 and signal genes ABF4, ABI5, and AREB) were observed in HG28-5 inoculated salt-stressed WT plants. ABA-deficient mutant (not) with NCED1 deficiency abolishes the effect of HG28-5 on alleviating salt stress in tomato, as exhibited by the substantial rise of REL and ROS accumulation and sharp drop of Fv/Fm in the leaves of not mutant plants. Notably, HG28-5 colonization enhances tomatoes fruit yield by 54.9% and 52.4% under normal and saline water irrigation, respectively. Overall, our study shows that HG28-5 colonization can significantly enhance salt tolerance and improved fruit yield by a variety of plant protection mechanism, including reducing oxidative stress, regulating plant growth, Na+/K+ homeostasis and ABA signaling pathways in tomato. The findings not only deepen our understanding of PGPR regulation plant growth and salt tolerance but also allow us to apply HG28-5 as a microbial fertilizer for agricultural production in high-salinity areas.

Immune Homeostasis: A Novel Example of Teamwork.

All living organisms must maintain homeostasis to survive, reproduce, and pass their traits on to the next generation. If homeostasis is not maintained, it can result in various diseases and ultimately lead to death. Physiologists have coined the term "homeostasis" to describe this process. With the emergence of immunology as a separate branch of medicine, the concept of immune homeostasis has been introduced. Maintaining immune homeostasis is crucial to support overall homeostasis through different immunological and non-immunological routes. Any changes in the immune system can lead to chronic inflammatory or autoimmune diseases, immunodeficiency diseases, frequent infections, and cancers. Ongoing scientific advances are exploring new avenues in immunology and immune homeostasis maintenance. This chapter introduces the concept of immune homeostasis and its maintenance through different mechanisms.

Posttranscriptional Events Orchestrate Immune Homeostasis of CD8+ T Cells.

Maintaining immune homeostasis is instrumental for host health. Immune cells, such as T cells, are instrumental for the eradication of pathogenic bacteria, fungi and viruses. Furthermore, T cells also play a major role in the fight against cancer. Through the formation of immunological memory, a pool of antigen-experienced T cells remains in the body to rapidly protect the host upon reinfection or retransformation. In order to perform their protective function, T cells produce cytolytic molecules, such as granzymes and perforin, and cytokines such as interferon γ and tumor necrosis factor α. Recently, it has become evident that posttranscriptional regulatory events dictate the kinetics and magnitude of cytokine production by murine and human CD8+ T cells. Here, the recent literature regarding the role posttranscriptional regulation plays in maintaining immune homeostasis of antigen-experienced CD8+ T cells is reviewed.

Immune Homeostasis Maintenance Through Advanced Immune Therapeutics to Target Atherosclerosis.

Atherosclerosis remains the leading cause of coronary heart disease (CHD) with enormous health and societal tolls. Traditional drug development approaches have been focused on small molecule-based compounds that aim to lower plasma lipids and reduce systemic inflammation, two primary causes of atherosclerosis. However, despite the widely available lipid-lowering and anti-inflammatory small compounds and biologic agents, CHD prevalence still remains high. Based on recent advances revealing disrupted immune homeostasis during atherosclerosis pathogenesis, novel strategies aimed at rejuvenating immune homeostasis with engineered immune leukocytes are being developed. This chapter aims to assess basic and translational efforts on these emerging strategies for the effective development of atherosclerosis treatment, as well as key challenges in this important translational field.

T Cell Subsets and Immune Homeostasis.

T cells are a heterogeneous group of cells that can be classified into different subtypes according to different classification methods. The body's immune system has a highly complex and effective regulatory network that allows for the relative stability of immune system function. Maintaining proper T cell homeostasis is essential for promoting protective immunity and limiting autoimmunity and tumor formation. Among the T cell family members, more and more T cell subsets have gradually been characterized. In this chapter, we summarize the functions of some key T cell subsets and their impact on immune homeostasis.

Mitochondrial control of lymphocyte homeostasis.

Mitochondria play a multitude of essential roles within mammalian cells, and understanding how they control immunity is an emerging area of study. Lymphocytes, as integral cellular components of the adaptive immune system, rely on mitochondria for their function, and mitochondria can dynamically instruct their differentiation and activation by undergoing rapid and profound remodelling. Energy homeostasis and ATP production are often considered the primary functions of mitochondria in immune cells; however, their importance extends across a spectrum of other molecular processes, including regulation of redox balance, signalling pathways, and biosynthesis. In this review, we explore the dynamic landscape of mitochondrial homeostasis in T and B cells, and discuss how mitochondrial disorders compromise adaptive immunity.

An interaction graph approach to gain new insights into mechanisms that modulate cerebrovascular tone.

Mechanisms to modulate cerebrovascular tone are numerous, interconnected, and spatially dependent, increasing the complexity of experimental study design, interpretation of action-effect pathways, and mechanistic modelling. This difficulty is exacerbated when there is an incomplete understanding of these pathways. We propose interaction graphs to break down this complexity, while still maintaining a holistic view of mechanisms to modulate cerebrovascular tone. These graphs highlight the competing processes of neurovascular coupling, cerebral autoregulation, and cerebral reactivity. Subsequent analysis of these interaction graphs provides new insights and suggest potential directions for research on neurovascular coupling, modelling, and dementia.

Headaches Attributed to Disorders of Homeostasis.

Headaches attributed to disorders of homeostasis include those different headache types associated with metabolic and systemic diseases. These are headache disorders occurring in temporal relation to a disorder of homeostasis including hypoxia, high altitude, airplane travel, diving, sleep apnea, dialysis, autonomic dysreflexia, hypothyroidism, fasting, cardiac cephalalgia, hypertension and other hypertensive disorders like pheochromocytoma, hypertensive crisis, and encephalopathy, as well as preeclampsia or eclampsia. The proposed mechanism behind the causation of these headache subtypes including diagnostic criteria, evaluation, treatment, and overall management will be discussed.