Liver-brain inflammation axis

It is becoming increasingly evident that peripheral organ-centered inflammatory diseases, including chronic inflammatory liver diseases, are associated with changes in central neural transmission that result in alterations in behavior. These behavioral changes include sickness behaviors, such as fatigue, cognitive dysfunction, mood disorders, and sleep disturbances. While such behaviors have a significant impact on quality of life, the changes within the brain and the communication pathways between the liver and the brain that give rise to changes in central neural activity are not fully understood. Traditionally, neural and humoral communication pathways have been described, with the three cytokines TNFα, IL-1β, and IL-6 receiving the most attention in mediating communication between the periphery and the brain, in the setting of peripheral inflammation. However, more recently, we described an immune-mediated communication pathway in experimentally induced liver inflammation whereby, in response to activation of resident immune cells in the brain (i.e., the microglia), peripheral circulating monocytes transmigrate into the brain, leading to development of sickness behaviors. These signaling pathways drive changes in behavior by altering central neurotransmitter systems. Specifically, changes in serotonergic and corticotropin-releasing hormone neurotransmission have been demonstrated and implicated in liver inflammation-associated sickness behaviors. Understanding how the liver communicates with the brain in the setting of chronic inflammatory liver diseases will help delineate novel therapeutic targets that can reduce the burden of symptoms in patients with liver disease.     

微生物-肠-脑轴的研究进展

肠道微生物群能够调节宿主肠道稳态,同时参与调节宿主神经系统功能和行为。肠道菌群失调可能导致宿主神经系统功能障碍,从而引发神经退行性疾病。因此,研究微生物在肠?脑轴中发挥的作用及其机制,靶向调控肠道微生物菌群结构和功能,将为神经系统疾病的诊断与治疗提供新的手段。近年来,有关肠道微生物与机体神经系统间的互作研究受到了广泛关注,然而其具体的调控机制还未明晰。因此,本文综述了肠道微生物对宿主神经健康的调节作用,以及肠道微生物与宿主间的互作在调节神经功能、行为的潜力等研究进展,为更好地了解肠道微生物在调控宿主神经系统功能和行为的作用机制提供参考。     

Ezh2 regulates anteroposterior axis specification and proximodistal axis elongation in the developing limb

Specification and determination (commitment) of positional identities precedes overt pattern formation during development. In the limb bud, it is clear that the anteroposterior axis is specified at a very early stage and is prepatterned by the mutually antagonistic interaction between Gli3 and Hand2. There is also evidence that the proximodistal axis is specified early and determined progressively. Little is known about upstream regulators of these processes or how epigenetic modifiers influence axis formation. Using conditional mutagenesis at different time points, we show that the histone methyltransferase Ezh2 is an upstream regulator of anteroposterior prepattern at an early stage. Mutants exhibit posteriorised limb bud identity. During later limb bud stages, Ezh2 is essential for cell survival and proximodistal segment elongation. Ezh2 maintains the late phase of Hox gene expression and cell transposition experiments suggest that it regulates the plasticity with which cells respond to instructive positional cues.     

Cytokines and the hypothalamic-pituitary-adrenal axis

After administration of the cytokines interleukin 1 (IL1), tumor necrosis factor (TNF), interleukin 2 and interleukin 6 to laboratory animals or humans, plasma levels of glucocorticoids are elevated. This effect is mediated by activation of the hypothalamic-pituitary unit. IL1 and TNF inhibit aldosterone production by rat adrenocortical cells in vitro and stimulate renin release by rat renal cortical cells. Administration of IL1 or TNF in rats suppresses hypothalamic-pituitary-thyroid function, whereas IL1 acts at the level of the brain and the gonads to interfere with gonadotropin and sex steroid secretion.

During stimulation of the immune system (e.g. during infectious diseases), peculiar alterations in hormone secretion occur (hypercortisolism, hyperreninemic hypoaldosteronism, euthyroid sick syndrome, hypogonadism). The role of cytokines in these alterations remains to be established.     

Bone marrow-thymus axis in senescence

This presentation offers a brief review of the bone marrow-thymus axis in senescence, a putative model for thymocyte differentiation, and recent results of our work on the status of pre-thymic stem cells in aged mice. The data presented here provide further evidence for a thymus endocrine influence on the bone marrow stem cells, specifically lymphocyte precursors. It has been postulated that the thymic hormones may act on lymphocyte precursors in the bone marrow and that the loss of thymic factors during senescence may be a contributing factor to the decreased cellular immune function. This study used Haar's in vitro model to investigate the bone marrow-thymus axis in aged mice. Erythroid-depleted bone-marrow cells from 3-month- and 24-month-old CBA (Thy 1.2) mice were placed in the upper half of a blind-well chamber with thymus supernatant in the lower half. Experimental cells were treated with thymus supernatant for 1 hr prior to migration. This study confirmed that pre-thymic stem cells in aged bone marrow are deficient in their ability to migrate to the thymus supernatant. It also revealed that treatment of the old bone marrow with thymus supernatant, made from neonatal thymus cultures, could dramatically improve the thymus migrating ability of the aged bone-marrow stem cells.     

Bombesin and the brain-gut axis

Bombesin is the first peptide shown to act in the brain to influence gastric function and the most potent peptide to inhibit acid secretion when injected into the cerebrospinal fluid (CSF) in rats and dogs. Bombesin responsive sites include specific hypothalamic nuclei (paraventricular nucleus, preoptic area and anterior hypothalamus), the dorsal vagal complex as well as spinal sites at T9-T10. The antisecretory effect of central bombesin encompasses a variety of endocrine/paracrine (gastrin, histamine) or neuronal stimulants. Bombesin into the CSF induces an integrated gastric response (increase in bicarbonate, and mucus, inhibition of acid, pepsin, vagally mediated contractions) enhancing the resistance of the mucosa to injury through autonomic pathways. The physiological significance of central action of bombesin on gastric function is still to be unraveled.     

A basophil-neuronal axis promotes itch

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Androgen axis in prostate cancer

Endocrine therapy for advanced prostate cancer is based on androgen ablation or blockade of the androgen receptor (AR). AR action in prostate cancer has been investigated in a number of cell lines, their derivatives, and transgenic animals. AR expression is heterogenous in prostate cancer in vivo; it could be detected in most primary tumors and their metastases. However, some cells lack the AR because of epigenetic changes in the gene promoter. AR expression increases after chronic androgen ablation in vitro. In several xenografts, AR upregulation is the most consistent change identified during progression towards therapy resistance. In contrast, the AR pathway may be by-passed during chronic treatment with a nonsteroidal anti-androgen. AR sensitivity in prostate cancer increases as a result of activation of the Ras/mitogen-activated protein kinase pathway. One of the major difficulties in endocrine therapy for prostate cancer is acquisition of agonistic properties of AR antagonists observed in the presence of mutated AR. Enhancement of AR function by associated coactivator proteins has been extensively investigated. Cofactors SRC-1, RAC3, p300/CBP, TIF-2, and Tip60 are upregulated in advanced prostate cancer. Most studies on ligand-independent activation of the AR are focused on Her-2/neu and interleukin-6 (IL-6). On the basis of studies that showed overexpression and activation of the AR in advanced prostate cancer, it was suggested that novel therapies that reduce AR expression will provide a benefit to patients. There is experimental evidence showing that prostate tumor growth in vitro and in vivo is inhibited following administration of chemopreventive drugs or antisense oligonucleotides that downregulate AR mRNA and protein expression.     

动物宿主——肠道微生物代谢轴研究进展

肠道中栖息着数量庞大且复杂多样的微生物菌群,在维持宿主肠道微环境稳态中发挥重要作用。微生物菌群可以利用宿主肠道的营养素,发酵产生代谢产物,与宿主机体形成宿主—微生物代谢轴(host-microbe metabolic axis)。该代谢轴既能影响营养素吸收和能量代谢,又可调控宿主各项生理过程。本文主要阐述宿主-肠道微生物代谢轴的概念、肠-肝轴、肠-脑轴、肠道微生物与宿主肠道代谢轴的互作以及对机体健康的影响。     

Coupling segmentation to axis formation

A characteristic feature of the vertebrate body is its segmentation along the anteroposterior axis, as illustrated by the repetition of vertebrae that form the vertebral column. The vertebrae and their associated muscles derive from metameric structures of mesodermal origin, the somites. The segmentation of the body is established by somitogenesis, during which somites form sequentially in a rhythmic fashion from the presomitic mesoderm. This review highlights recent findings that show how dynamic gradients of morphogens and retinoic acid, coupled to a molecular oscillator, drive the formation of somites and link somitogenesis to the elongation of the anteroposterior axis.     

The aging reproductive neuroendocrine axis

It is well known that the reproductive system is one of the first biological systems to show age-related decline. While depletion of ovarian follicles clearly relates to the end of reproductive function in females, evidence is accumulating that a hypothalamic defect is critical in the transition from cyclicity to acyclicity. This minireview attempts to present a concise review on aging of the female reproductive neuroendocrine axis and provide thought-provoking analysis and insights into potential future directions for this field. Evidence will be reviewed, which shows that a defect in pulsatile and surge gonadotropin hormone-releasing hormone (GnRH) secretion exists in normal cycling middle-aged female rats, which is thought to explain the significantly attenuated pulsatile and surge luteinizing hormone (LH) secretion at middle-age. Evidence is also presented, which supports the age-related defect in GnRH secretion as being due to a reduced activation of GnRH neurons. Along these lines, stimulation of GnRH secretion by the major excitatory transmitter glutamate is shown to be significantly attenuated in middle-aged proestrous rats. Corresponding age-related defects in other major excitatory regulatory factors, such as catecholamines, neuropeptide Y, and astrocytes, have also been demonstrated. Age-related changes in hypothalamic concentrations of neurotransmitter receptors, steroid receptors, and circulating steroid hormone levels are also reviewed, and discussion is presented on the complex interrelationships of the hypothalamus-pituitary-ovarian (HPO) axis during aging, with attention to how a defect in one level of the axis can induce defects in other levels, and thereby potentiate the dysfunction of the entire HPO axis.     

The pituitary-thyroid axis in acromegaly

The pituitary-thyroid axis of 12 acromegalic patients was evaluated by measurement of the serum concentrations (total and free) of thyroxine (T4), triiodothyronine (T3) and reverse T3 (rT3) and thyrotropin (TSH), growth hormone (GH) and prolactin (PRL) before and after iv stimulation with thyrotropin releasing hormone (TRH). Using an ultrasensitive method of TSH measurement (IRMA) basal serum TSH levels of the patients (0.76, 0.07-1.90 mIU/l) were found slightly, but significantly (P less than 0.01), lower than in 40 healthy controls (1.40, 0.41-2.50 mIU/l). The total T4 levels (TT4) were also reduced (84, 69-106 nmol/l vs 100, 72-156 nmol/l, P less than 0.01) and significantly correlated (P less than 0.02, R = 0.69) to the TSH response to TRH, suggesting a slight central hypothyroidism. The acromegalics had, however, normal serum levels of TT3 (1.79, 1.23-2.52 nmol/l vs 1.74, 0.78-2.84 nmol/l, P greater than 0.10), but significantly decreased levels of TrT3 (0.173, 0.077-0.430 nmol/l vs 0.368, 0.154-0.584 nmol/l, P less than 0.01) compared to the controls. The serum concentration of the free iodothyronines (FT4, FT3, FrT3) showed similar differences between acromegalics and normal controls. All the acromegalics showed a rise of serum TSH, GH and PRL after TRH. Positive correlation (P less than 0.05, R = 0.59) was found between the TSH and GH responses, but not between these two parameters and the PRL response to TRH. These findings may be explained by the existence of a central suppression of the TSH and GH secretion in acromegalic subjects, possibly exerted by somatostatin. Euthyroidism might be maintained by an increased extrathyroidal conversion of T4 to T3.     

The endothelin axis in cancer

The endothelin axis, comprising endothelins and their receptors, has recently emerged as relevant player in tumor growth and metastasis by regulating mitogenesis, cell survival, angiogenesis, bone remodeling, stimulation of nociceptor receptor, tumor-infiltrating immune cells, epithelial-to-mesenchymal transition, invasion and metastatic dissemination. Endothelin-1 participates in the growth and progression of a variety of tumors such as prostatic, ovarian, renal, pulmonary, colorectal, cervical, breast, bladder, endometrial carcinomas, Kaposi's sarcoma, brain tumors, melanoma, and bone metastases. This review highlights key signaling pathways activated by endothelin-1 axis in cancer, since the understanding the full spectrum activated by endothelin-1 is critical for the optimal design of targeted therapies. Preliminary experimental and clinical data demonstrate that interfering with endothelin receptor by using endothelin-1 receptor antagonists alone and in combination with cytotoxic drugs or molecular inhibitors could represent a new mechanism-based antitumor strategy.     

LKB1-AMPK axis revisited

The LKB1 tumor suppressor encodes a serine-threonine kinase whose substrates control cell metabolism, polarity, and motility. LKB1 is a major mediator of the cellular response to energy stress via activation of the master regulator of energy homeostasis, AMPK. While mutational inactivation of LKB1 promotes the development of many types of epithelial cancer, a recent report in Nature by Jeon et al. demonstrates that the LKB1-AMPK pathway can also have an unexpected positive role in tumorigenesis, acting to maintain metabolic homeostasis and attenuate oxidative stress thereby supporting the survival of cancer cells.Normal mammalian cells possess adaptive mechanisms that enable coupling of nutrient availability with demand via integrated control of growth and metabolism. The widespread deregulation of these processes is now recognized as a prominent hallmark of all cancers. A key nutrient sensor in normal and cancer cells is the LKB1-AMPK axis, which is critical for maintenance of metabolic homeostasis¹. In response to energy stress (and resulting increase in AMP:ATP ratio), LKB1 phosphorylates AMPK, which in turn phosphorylates numerous substrates controlling diverse metabolic processes, with the net effect of shifting the balance from anabolic to catabolic function and thereby restoring cellular ATP levels. LKB1 is an established tumor suppressor that is mutationally inactivated in a wide variety of epithelial cancers and promotes tumorigenesis when deleted in mouse models. While the underlying mechanisms for LKB1-mediated tumor suppression are not fully defined, the key role of AMPK in inactivating mTOR is thought to contribute to this process^1,2.An interesting paradox given this function as a tumor suppressor emerges from the observations that LKB1 or AMPK deletion renders primary cells resistant to transformation by overexpressed oncogenes and causes decreased viability of both cancer cell lines and primary cells under energy stress conditions^3,4,5,6,7,8. The significance of the survival function of the LKB1-AMPK axis in cancer pathogenesis and the associated molecular mechanisms are the main focus of a recent report by Jeon et al.⁹.In this study, the authors utilized the A549 lung cancer cell line, which exhibits homozygous inactivating mutations of endogenous LKB1, as a model to study LKB1-AMPK-dependent survival under energy stress. Reintroduction of LKB1 resulted in the expected activation of AMPK and improved cell survival upon glucose deprivation. This effect was independent of mTOR or p53 inactivation, insofar as rapamycin treatment or p53 dominant-negative coexpression did not affect the starvation-induced cell death in A549 vector-transduced (i.e., control) cells.Glucose starvation inhibits the pentose phosphate pathway (PPP), which is an important mechanism for NADPH production and consequent H₂O₂ detoxification (Figure 1). To survive in this setting, cells require compensatory NADPH generation, produced by other biochemical pathways. The authors hypothesized that a requirement for LKB1 in this adaptive NAPDH production may underlie its survival function in glucose-deprived cells. Consistent with this hypothesis, they showed that treatment with N-acetylcysteine or catalase, both antioxidants, inhibited starvation-induced death of both LKB1- and AMPK-deficient (A549/HeLa and MEFs, respectively) cells. In addition, metabolic analysis of the glucose-starved A549 cells revealed that the ratios of NADP/NADPH and oxidized glutathione/reduced glutathione (GSSG/GSH) were maintained in LKB1-transduced cells, whereas both ratios were increased in the vector-transduced cells. Since NAPDH is mainly utilized to reduce GSSG to its GSH form, which is in turn used to detoxify cells from H₂O₂ through the function of glutathione peroxidase, these results reveal that the LKB1-AMPK axis has a central role in suppressing oxidative stress (Figure 1).Open in a separate windowFigure 1AMPK is phosphorylated and activated by LKB1 in response to an increasing cellular AMP:ATP ratio (which reflects a decrease in energy supply). AMPK in turn phosphorylates and inactivates ACC1/2, promoting a shift from fatty acid synthesis (FAS) to fatty acid oxidation (FAO). FAS depletes NADPH that is required for H₂O₂ detoxification. FAO, by contrast, produces metabolites that are used by the TCA cycle, resulting in increased NADPH and enhanced cell survival. This pathway may only be transiently activated in glucose-deprived cells since ATP, produced by the coupling the TCA cycle with oxidative phosphorylation (OXPHOS), will eventually inhibit AMPK. In addition to the role of the LKB1-AMPK pathway in facilitating tumor cell survival, LKB1 is a context-specific tumor suppressor, which acts to control cell polarity and restrict cell growth via mTOR inactivation and induction of other AMPK-related kinases.Upon glucose starvation and consequent loss of PPP function, the major contributor to NADPH generation is mitochondrial metabolism whose activity is maintained by fatty acid oxidation in this context. The rate-limiting enzyme in catabolism of fatty acids is carnitine palmitoyltransferase 1 (CPT1). Under normal conditions, CPT1 is inhibited by the malonyl-CoA produced by acetyl-CoA carboxylase alpha (ACC1) and acetyl-CoA carboxylase beta (ACC2). These two enzymes are subject to inhibition by phosphorylation by AMPK¹⁰. Therefore, the authors hypothesized that LKB1-AMPK may control the levels of NADPH by inhibiting ACC1 and ACC2. Targeted knockdown studies revealed that ACC2 inactivation was sufficient to restore NADP/NADPH and GSSG/GSH ratios and to rescue cell death in glucose-starved A549 cells. These findings were extended by a set of experiments using the constitutively active ACC2 (S212A) mutant, the fatty acid synthase (FAS) inhibitor C75, the ACC inhibitor TOFA, malate supplement, buthionine sulphoximine (which depletes GSH), and nicotinamide, that together support the hypothesis that survival under glucose starvation is dependent on the inactivation of ACC2 (and ACC1 in some cell types) by AMPK-regulated phosphorylation.Matrix detachment impairs cell viability in part due to induction of energy stress, leading to NADPH depletion and increased H₂O₂ levels. The authors found that the LKB1-AMPK axis also plays a pro-survival role in this setting. LKB1-null cells have reduced viability and impaired growth under anchorage-independent conditions, due mainly to decreased NADPH levels and subsequent oxidative stress.Cancer cells need to activate survival mechanisms to cope with energy stress and matrix detachment during tumor progression. Thus, the authors speculated that the LKB1-AMPK-ACC1/2-NADPH pathway might play an important role in promoting tumor growth. Correspondingly, NAC treatment or shRNA-mediated knockdown of ACC1/2 increased anchorage-independent growth of A549 cells in soft agar, and ACC1/2 knockdown enhanced tumorigenicity in xenograft studies. Moreover, similar effects were seen using RAS V12-transformed AMPKα^−/− MEF cells with concurrent ACC1/2 knockdown, consistent with LKB1 and AMPK acting in a common pathway to promote tumorigenesis.The results described above were obtained mainly in the setting of ectopically restoring LKB1 in LKB1-deficient cancer cells. An important question that is raised by these findings is whether cancers that arise with an intact LKB1-AMPK axis require this pathway for sustained tumorigenesis. To address this issue, the authors examined the impact of knockdown of either LKB1 or AMPKα1 in MCF7 breast cancer cells. These manipulations reduced xenograft tumor formation, as did overexpression of the constitutively active, phosphorylation-deficient mutants ACC mutant (ACC1-S79A or ACC2-S212A). Collectively, these observations indicate that activation of AMPK and consequent inactivation of ACC1/2 by endogenous AMPK is an important survival mechanism in cancer (Figure 1).These conclusions are of particular note considering the established role of LKB1 in tumor suppression. This tumor suppressive function may involve the ability of the LKB1-AMPK pathway to promote mTOR inactivation by TSC2 and raptor phosphorylation^1,2, as well as functions of other members of the family of AMPK-related kinases. Since mTOR activation is a common feature of cancer and a driver of many tumor types, it may seem counterintuitive to assign a tumorigenic role in one of its major inhibitors. Another layer of complexity stems from the fact that AMPK activation is unlikely to be sustained for prolonged period of time. Fatty acid oxidation, activated by AMPK during glucose starvation, will feed into the TCA-oxidative phosphorylation cycles, in turn leading to ATP production and AMP:ATP ratio decrease, followed by AMPK inactivation (Figure 1). To reconcile these two opposing functions of AMPK, the authors suggest that this negative feedback loop is a reflection of the temporal manner of AMPK activation that, at physiological levels, is essential for the survival of the tumor cells during energy stress (starvation or matrix detachment) but it is quickly followed by inactivation. According to this model, use of LKB1 or AMPK inhibitors in acute regimens could prove beneficial for cancer therapy by sensitizing cells to energy stress. Moreover, the acute nature of the treatment could potentially cause metabolic stress, sensitizing cells to other chemotherapy regiments. Sustained inactivation of the LKB1-AMPK pathway on the other hand, could result in long-term stress, promote rewiring of intracellular metabolic processes, and tip the balance towards increased proliferation due to activation of mTOR and other pathways.Based on these results, a major question is raised: How do LKB1-deficient tumors bypass the normal requirement for the LKB1-AMPK axis in energy stress response? Presumably, LKB1 inactivation must occur in the context of specific cooperating molecular alterations that enable cell survival despite these impairments in metabolic homeostasis, thereby allowing the pro-tumorigenic consequences of LKB1 loss to take hold. One potential escape route could involve alternative, LKB1-independent mechanisms for AMPK activation such as induction of CAMK2 or a hexokinase-dependent pathway¹, but other pathways could be equally important. Further studies will likely uncover additional adaptive processes permitting cell survival under metabolic stress in the absence of LKB1. Metabolic profiling of LKB1 null tumors could provide a glimpse of these alternative pathways, opening the way for new targeted therapeutic strategies. Moreover, cancer genome sequencing efforts are likely to reveal specific complementation groups of mutations that coexist with LKB1 mutations in different cancer types or are mutually exclusive, reflecting molecular pathways that synergize with LKB1 deficiency. Additionally, other important AMPK-independent functions of LKB1 should also be brought into focus. In this regard, AMPKα1/2 are constituents of a 14-member family of kinases that are phosphorylated and activated by LKB1 and that broadly include regulators of epithelial cell polarity as well as metabolism. Disruption of polarity, as altered metabolism, is a hallmark of epithelial cancer progression¹¹, and the relative roles of these processes downstream of LKB1 in growth control is an area of active investigation. Indeed, inactivation of LKB1 produces dramatic invasive and migratory phenotypes in different cancer models^12,13,14. The findings of Jeon et al.⁹ may thus presage that the LKB1-AMPK axis is only a minor component of the LKB1 tumor suppressor program compared to its functions in metabolic adaptation and cell survival.Long-term use of metformin, in the treatment of Type II diabetes, has been shown to reduce tumor incidence and sensitizes multiple cancer cell types to chemotherapy¹. Furthermore, LKB1 controls hepatic glucose metabolism and the therapeutic effects of metformin. A recent study that revealed that AMPK is activated by salicylate also suggests that this mechanism is, at least partly, responsible for the cancer-protective effects of aspirin¹⁵. On the other hand, inhibition of LKB1-AMPK sensitizes cancer cells to energy stress-induced apoptosis. Therefore, the results presented by Jeon et al.⁹ suggest that targeting the LKB1-AMPK axis in cancer should be done with caution and with attention to specific contexts.