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A 5.5-y-old intact male cynomolgus macaque (Macaca fasicularis) presented with inappetence and weight loss 57 d after heterotopic heart and thymus transplantation while receiving an immunosuppressant regimen consisting of tacrolimus, mycophenolate mofetil, and methylprednisolone to prevent graft rejection. A serum chemistry panel, a glycated hemoglobin test, and urinalysis performed at presentation revealed elevated blood glucose and glycated hemoglobin (HbA1c) levels (727 mg/dL and 10.1%, respectively), glucosuria, and ketonuria. Diabetes mellitus was diagnosed, and insulin therapy was initiated immediately. The macaque was weaned off the immunosuppressive therapy as his clinical condition improved and stabilized. Approximately 74 d after discontinuation of the immunosuppressants, the blood glucose normalized, and the insulin therapy was stopped. The animal''s blood glucose and HbA1c values have remained within normal limits since this time. We suspect that our macaque experienced new-onset diabetes mellitus after transplantation, a condition that is commonly observed in human transplant patients but not well described in NHP. To our knowledge, this report represents the first documented case of new-onset diabetes mellitus after transplantation in a cynomolgus macaque.Abbreviations: NODAT, new-onset diabetes mellitus after transplantationNew-onset diabetes mellitus after transplantation (NODAT, formerly known as posttransplantation diabetes mellitus) is an important consequence of solid-organ transplantation in humans.7-10,15,17,19,21,25-28,31,33,34,37,38,42 A variety of risk factors have been identified including increased age, sex (male prevalence), elevated pretransplant fasting plasma glucose levels, and immunosuppressive therapy.7-10,15,17,19,21,25-28,31,33,34,37,38,42 The relationship between calcineurin inhibitors, such as tacrolimus and cyclosporin, and the development of NODAT is widely recognized in human medicine.7-10,15,17,19,21,25-28,31,33,34,37,38,42 Cynomolgus macaques (Macaca fasicularis) are a commonly used NHP model in organ transplantation research. Cases of natural and induced diabetes of cynomolgus monkeys have been described in the literature;14,43,45 however, NODAT in a macaque model of solid-organ transplantation has not been reported previously to our knowledge. 相似文献
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Joshua A Kramer Audra M Hachey Lynn M Wachtman Keith G Mansfield 《Comparative medicine》2009,59(2):174-179
Giardia intestinalis is a common protozoan parasite that can infect many laboratory animal primates, although its role as a contributor to the induction of gastrointestinal disease remains unclear. This study sought to investigate the prevalence of Giardia in a colony of common marmosets by using a Giardia antigen-capture assay and to address the possible eradication of this infection by using tinidazole, an antiprotozoal similar to metronidazole but requiring fewer doses. Among 31 colony marmosets, 13 (42%) were positive for Giardia. Two doses of oral tinidazole eliminated the infection in all animals. Repeat testing of the 13 Giardia-positive monkeys 1 y later showed that 11 remained negative and that treated animals had a significant increase in weight at 1 y. Giardia antigen is common in common marmoset feces, and treatment using oral tinidazole is possible and highly effective.Giardia intestinalis is a common zoonotic protozoan parasite causing diarrhea in humans and animals worldwide. Infection usually results from contact with the feces of an infected host or drinking water contaminated with Giardia cysts. As few as 10 cysts are necessary for infection in human subjects.36 Giardia causes both an acute disease and a chronic asymptomatic state. The most common clinical signs of acute disease are diarrhea, flatulence, foul stool, and abdominal cramps. In addition, Giardia has been implicated as a cause of cognitive impairment and stunted growth in infected children in developing countries.1,2,29Giardiasis has previously been reported to occur in a variety of laboratory primates, including several species of neotropical monkeys such as marmosets and squirrel monkeys.13,20,28 Such infections may pose a zoonotic risk to animal handlers and potentially affect colony health. Common marmosets (Callithrix jacchus) frequently manifest chronic wasting and inflammatory bowel disease known as ‘wasting marmoset syndrome.’ The etiology of the intestinal disease is unknown, but marmosets often present clinically with skeletal muscle atrophy, marked weight loss, alopecia, and a history of intermittent diarrhea.5,11,16,21,35 Likely no single infectious agent or nutritional deficiency causes the clinical spectrum, but rather a combination of factors result in antigenic stimulation of the intestinal tract resulting in the chronic disease. The presence of Giardia cannot be ruled out as a cofactor.Several studies have compared various diagnostic tools for detection of Giardia in fecal specimens. Multiple fecal tests for Giardial colonization are available, including antigen-detection enzyme immunoassays, immunochromatographic strips, and microscopy of wet-mounted stool after fecal flotation.9,24,37,38 Enzyme immunoassays are a rapid and precise tool for detecting Giardia in fecal specimens; test sensitivities and specificities have approached 100% in several studies.9,22,24,37 In addition, these studies have indicated that repeat stool sampling on different days may increase the yield of testing, because organisms are variably shed.9,14,36 The specific recommendation is to test 3 samples on alternate days or 3 samples within a 10-d span.38Treatment options for Giardia infection are varied and include metronidazole, albendazole, quinacrine, furazolidone, and several other nitroimidazoles including tinidazole, secnidazole, ornidazole, and nimorazole.15 The most common treatment choice in veterinary medicine is metronidazole; however, this drug requires 5 to 8 d of treatment and ensuring animal compliance is difficult.27 Several of metronidazole''s structural analogues, including tinidazole, are used as a single dose in the treatment of Giardiasis in humans with high cure rates (approximately 90%) and low complications.3,8,10,26,39In this study we examined the use of a commercially available antigen-capture assay to diagnose Giardiasis in a large breeding colony of common marmosets. To address possible eradication of the infection, we describe the safe use and efficacy of tinidazole as a new treatment option in this species. 相似文献
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O Maximyuk V Khmyz C-J Lindskog V Vukojevi? T Ivanova I Bazov K F Hauser G Bakalkin O Krishtal 《Cell death & disease》2015,6(3):e1683
Neuropeptides induce signal transduction across the plasma membrane by acting through cell-surface receptors. The dynorphins, endogenous ligands for opioid receptors, are an exception; they also produce non-receptor-mediated effects causing pain and neurodegeneration. To understand non-receptor mechanism(s), we examined interactions of dynorphins with plasma membrane. Using fluorescence correlation spectroscopy and patch-clamp electrophysiology, we demonstrate that dynorphins accumulate in the membrane and induce a continuum of transient increases in ionic conductance. This phenomenon is consistent with stochastic formation of giant (~2.7 nm estimated diameter) unstructured non-ion-selective membrane pores. The potency of dynorphins to porate the plasma membrane correlates with their pathogenic effects in cellular and animal models. Membrane poration by dynorphins may represent a mechanism of pathological signal transduction. Persistent neuronal excitation by this mechanism may lead to profound neuropathological alterations, including neurodegeneration and cell death.Neuropeptides are the largest and most diverse family of neurotransmitters. They are released from axon terminals and dendrites, diffuse to pre- or postsynaptic neuronal structures and activate membrane G-protein-coupled receptors. Prodynorphin (PDYN)-derived opioid peptides including dynorphin A (Dyn A), dynorphin B (Dyn B) and big dynorphin (Big Dyn) consisting of Dyn A and Dyn B are endogenous ligands for the κ-opioid receptor. Acting through this receptor, dynorphins regulate processing of pain and emotions, memory acquisition and modulate reward induced by addictive substances.1, 2, 3, 4 Furthermore, dynorphins may produce robust cellular and behavioral effects that are not mediated through opioid receptors.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 As evident from pharmacological, morphological, genetic and human neuropathological studies, these effects are generally pathological, including cell death, neurodegeneration, neurological dysfunctions and chronic pain. Big Dyn is the most active pathogenic peptide, which is about 10- to 100-fold more potent than Dyn A, whereas Dyn B does not produce non-opioid effects.16, 17, 22, 25 Big Dyn enhances activity of acid-sensing ion channel-1a (ASIC1a) and potentiates ASIC1a-mediated cell death in nanomolar concentrations30, 31 and, when administered intrathecally, induces characteristic nociceptive behavior at femtomolar doses.17, 22 Inhibition of endogenous Big Dyn degradation results in pathological pain, whereas prodynorphin (Pdyn) knockout mice do not maintain neuropathic pain.22, 32 Big Dyn differs from its constituents Dyn A and Dyn B in its unique pattern of non-opioid memory-enhancing, locomotor- and anxiolytic-like effects.25Pathological role of dynorphins is emphasized by the identification of PDYN missense mutations that cause profound neurodegeneration in the human brain underlying the SCA23 (spinocerebellar ataxia type 23), a very rare dominantly inherited neurodegenerative disorder.27, 33 Most PDYN mutations are located in the Big Dyn domain, demonstrating its critical role in neurodegeneration. PDYN mutations result in marked elevation in dynorphin levels and increase in its pathogenic non-opioid activity.27, 34 Dominant-negative pathogenic effects of dynorphins are not produced through opioid receptors.ASIC1a, glutamate NMDA (N-methyl-d-aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)/kainate ion channels, and melanocortin and bradykinin B2 receptors have all been implicated as non-opioid dynorphin targets.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 30, 31, 35, 36 Multiplicity of these targets and their association with the cellular membrane suggest that their activation is a secondary event triggered by a primary interaction of dynorphins with the membrane. Dynorphins are among the most basic neuropeptides.37, 38 The basic nature is also a general property of anti-microbial peptides (AMPs) and amyloid peptides that act by inducing membrane perturbations, altering membrane curvature and causing pore formation that disrupts membrane-associated processes including ion fluxes across the membrane.39 The similarity between dynorphins and these two peptide groups in overall charge and size suggests a similar mode of their interactions with membranes.In this study, we dissect the interactions of dynorphins with the cell membrane, the primary event in their non-receptor actions. Using fluorescence imaging, correlation spectroscopy and patch-clamp techniques, we demonstrate that dynorphin peptides accumulate in the plasma membrane in live cells and cause a profound transient increase in cell membrane conductance. Membrane poration by endogenous neuropeptides may represent a novel mechanism of signal transduction in the brain. This mechanism may underlie effects of dynorphins under pathological conditions including chronic pain and tissue injury. 相似文献
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Q Xia Q Hu H Wang H Yang F Gao H Ren D Chen C Fu L Zheng X Zhen Z Ying G Wang 《Cell death & disease》2015,6(3):e1702
Neuroinflammation is a striking hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Previous studies have shown the contribution of glial cells such as astrocytes in TDP-43-linked ALS. However, the role of microglia in TDP-43-mediated motor neuron degeneration remains poorly understood. In this study, we show that depletion of TDP-43 in microglia, but not in astrocytes, strikingly upregulates cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production through the activation of MAPK/ERK signaling and initiates neurotoxicity. Moreover, we find that administration of celecoxib, a specific COX-2 inhibitor, greatly diminishes the neurotoxicity triggered by TDP-43-depleted microglia. Taken together, our results reveal a previously unrecognized non-cell-autonomous mechanism in TDP-43-mediated neurodegeneration, identifying COX-2-PGE2 as the molecular events of microglia- but not astrocyte-initiated neurotoxicity and identifying celecoxib as a novel potential therapy for TDP-43-linked ALS and possibly other types of ALS.Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the degeneration of motor neurons in the brain and spinal cord.1 Most cases of ALS are sporadic, but 10% are familial. Familial ALS cases are associated with mutations in genes such as Cu/Zn superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TARDBP) and, most recently discovered, C9orf72. Currently, most available information obtained from ALS research is based on the study of SOD1, but new studies focusing on TARDBP and C9orf72 have come to the forefront of ALS research.1, 2 The discovery of the central role of the protein TDP-43, encoded by TARDBP, in ALS was a breakthrough in ALS research.3, 4, 5 Although pathogenic mutations of TDP-43 are genetically rare, abnormal TDP-43 function is thought to be associated with the majority of ALS cases.1 TDP-43 was identified as a key component of the ubiquitin-positive inclusions in most ALS patients and also in other neurodegenerative diseases such as frontotemporal lobar degeneration,6, 7 Alzheimer''s disease (AD)8, 9 and Parkinson''s disease (PD).10, 11 TDP-43 is a multifunctional RNA binding protein, and loss-of-function of TDP-43 has been increasingly recognized as a key contributor in TDP-43-mediated pathogenesis.5, 12, 13, 14Neuroinflammation, a striking and common hallmark involved in many neurodegenerative diseases, including ALS, is characterized by extensive activation of glial cells including microglia, astrocytes and oligodendrocytes.15, 16 Although numerous studies have focused on the intrinsic properties of motor neurons in ALS, a large amount of evidence showed that glial cells, such as astrocytes and microglia, could have critical roles in SOD1-mediated motor neuron degeneration and ALS progression,17, 18, 19, 20, 21, 22 indicating the importance of non-cell-autonomous toxicity in SOD1-mediated ALS pathogenesis.Very interestingly, a vital insight of neuroinflammation research in ALS was generated by the evidence that both the mRNA and protein levels of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2) are upregulated in both transgenic mouse models and in human postmortem brain and spinal cord.23, 24, 25, 26, 27, 28, 29 The role of COX-2 neurotoxicity in ALS and other neurodegenerative disorders has been well explored.30, 31, 32 One of the key downstream products of COX-2, prostaglandin E2 (PGE2), can directly mediate COX-2 neurotoxicity both in vitro and in vivo.33, 34, 35, 36, 37 The levels of COX-2 expression and PGE2 production are controlled by multiple cell signaling pathways, including the mitogen-activated protein kinase (MAPK)/ERK pathway,38, 39, 40 and they have been found to be increased in neurodegenerative diseases including AD, PD and ALS.25, 28, 32, 41, 42, 43, 44, 45, 46 Importantly, COX-2 inhibitors such as celecoxib exhibited significant neuroprotective effects and prolonged survival or delayed disease onset in a SOD1-ALS transgenic mouse model through the downregulation of PGE2 release.28Most recent studies have tried to elucidate the role of glial cells in neurotoxicity using TDP-43-ALS models, which are considered to be helpful for better understanding the disease mechanisms.47, 48, 49, 50, 51 Although the contribution of glial cells to TDP-43-mediated motor neuron degeneration is now well supported, this model does not fully suggest an astrocyte-based non-cell autonomous mechanism. For example, recent studies have shown that TDP-43-mutant astrocytes do not affect the survival of motor neurons,50, 51 indicating a previously unrecognized non-cell autonomous TDP-43 proteinopathy that associates with cell types other than astrocytes.Given that the role of glial cell types other than astrocytes in TDP-43-mediated neuroinflammation is still not fully understood, we aim to compare the contribution of microglia and astrocytes to neurotoxicity in a TDP-43 loss-of-function model. Here, we show that TDP-43 has a dominant role in promoting COX-2-PGE2 production through the MAPK/ERK pathway in primary cultured microglia, but not in primary cultured astrocytes. Our study suggests that overproduction of PGE2 in microglia is a novel molecular mechanism underlying neurotoxicity in TDP-43-linked ALS. Moreover, our data identify celecoxib as a new potential effective treatment of TDP-43-linked ALS and possibly other types of ALS. 相似文献
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R Visconti R Della Monica L Palazzo F D'Alessio M Raia S Improta M R Villa L Del Vecchio D Grieco 《Cell death and differentiation》2015,22(9):1551-1560
To grant faithful chromosome segregation, the spindle assembly checkpoint (SAC) delays mitosis exit until mitotic spindle assembly. An exceedingly prolonged mitosis, however, promotes cell death and by this means antimicrotubule cancer drugs (AMCDs), that impair spindle assembly, are believed to kill cancer cells. Despite malformed spindles, cancer cells can, however, slip through SAC, exit mitosis prematurely and resist killing. We show here that the Fcp1 phosphatase and Wee1, the cyclin B-dependent kinase (cdk) 1 inhibitory kinase, play a role for this slippage/resistance mechanism. During AMCD-induced prolonged mitosis, Fcp1-dependent Wee1 reactivation lowered cdk1 activity, weakening SAC-dependent mitotic arrest and leading to mitosis exit and survival. Conversely, genetic or chemical Wee1 inhibition strengthened the SAC, further extended mitosis, reduced antiapoptotic protein Mcl-1 to a minimum and potentiated killing in several, AMCD-treated cancer cell lines and primary human adult lymphoblastic leukemia cells. Thus, the Fcp1-Wee1-Cdk1 (FWC) axis affects SAC robustness and AMCDs sensitivity.The spindle assembly checkpoint (SAC) delays mitosis exit to coordinate anaphase onset with spindle assembly. To this end, SAC inhibits the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C) to prevent degradation of the anaphase inhibitor securin and cyclin B, the major mitotic cyclin B-dependent kinase 1 (cdk1) activator, until spindle assembly.1 However, by yet poorly understood mechanisms, exceedingly prolonging mitosis translates into cell death induction.2, 3, 4, 5, 6, 7 Although mechanistic details are still missing on how activation of cell death pathways is linked to mitosis duration, prolongation of mitosis appears crucial for the ability of antimicrotubule cancer drugs (AMCDs) to kill cancer cells.2, 3, 4, 5, 6, 7 These drugs, targeting microtubules, impede mitotic spindle assembly and delay mitosis exit by chronically activating the SAC. Use of these drugs is limited, however, by toxicity and resistance. A major mechanism for resistance is believed to reside in the ability of cancer cells to slip through the SAC and exit mitosis prematurely despite malformed spindles, thus resisting killing by limiting mitosis duration.2, 3, 4, 5, 6, 7 Under the AMCD treatment, cells either die in mitosis or exit mitosis, slipping through the SAC, without or abnormally dividing.2, 3, 4 Cells that exit mitosis either die at later stages or survive and stop dividing or proliferate, giving rise to resistance.2, 3, 4 Apart from a role for p53, what dictates cell fate is still unknown; however, it appears that the longer mitosis is protracted, the higher the chances for cell death pathway activation are.2, 3, 4, 5, 6, 7Although SAC is not required per se for killing,6 preventing SAC adaptation should improve the efficacy of AMCD by increasing mitosis duration.2, 3, 4, 5, 6, 7 Therefore, further understanding of the mechanisms by which cells override SAC may help to improve the current AMCD therapy. Several kinases are known to activate and sustain SAC, and cdk1 itself appears to be of primary relevance.1, 8, 9 By studying mitosis exit and SAC resolution, we recently reported a role for the Fcp1 phosphatase to bring about cdk1 inactivation.10, 11 Among Fcp1 targets, we identified cyclin degradation pathway components, such as Cdc20, an APC/C co-activator, USP44, a deubiquitinating enzyme, and Wee1.10, 11 Wee1 is a crucial kinase that controls the G2 phase by performing inhibitory phosphorylation of cdk1 at tyr-15 (Y15-cdk1). Wee1 is also in a feedback relationship with cdk1 itself that, in turn, can phosphorylate and inhibit Wee1 in an autoamplification loop to promote the G2-to-M phase transition.12 At mitosis exit, Fcp1 dephosphorylated Wee1 at threonine 239, a cdk1-dependent inhibitory phosphorylation, to dampen down the cdk1 autoamplification loop, and Cdc20 and USP44, to promote APC/C-dependent cyclin B degradation.10, 11, 12 In this study we analysed the Fcp1 relevance in SAC adaptation and AMCD sensitivity. 相似文献
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Elaine N Videan Christopher B Heward Kajal Chowdhury John Plummer Yali Su Richard G Cutler 《Comparative medicine》2009,59(3):287-296
In the oxidative stress hypothesis of aging, the aging process is the result of cumulative damage by reactive oxygen species. Humans and chimpanzees are remarkably similar; but humans live twice as long as chimpanzees and therefore are believed to age at a slower rate. The purpose of this study was to compare biomarkers for cardiovascular disease, oxidative stress, and aging between male chimpanzees and humans. Compared with men, male chimpanzees were at increased risk for cardiovascular disease because of their significantly higher levels of fibrinogen, IGF1, insulin, lipoprotein a, and large high-density lipoproteins. Chimpanzees showed increased oxidative stress, measured as significantly higher levels of 5-hydroxymethyl-2-deoxyuridine and 8-iso-prostaglandin F2α, a higher peroxidizability index, and higher levels of the prooxidants ceruloplasmin and copper. In addition, chimpanzees had decreased levels of antioxidants, including α- and β-carotene, β-cryptoxanthin, lycopene, and tocopherols, as well as decreased levels of the cardiovascular protection factors albumin and bilirubin. As predicted by the oxidative stress hypothesis of aging, male chimpanzees exhibit higher levels of oxidative stress and a much higher risk for cardiovascular disease, particularly cardiomyopathy, compared with men of equivalent age. Given these results, we hypothesize that the longer lifespan of humans is at least in part the result of greater antioxidant capacity and lower risk of cardiovascular disease associated with lower oxidative stress.Abbreviations: 5OHmU, 5-hydroxymethyl-2-deoxyuridine; 8isoPGF2α, 8-iso-prostaglandin F2α; HDL, high-density lipoprotein; IGF1, insulin-like growth factor 1; LDL, low-density lipoprotein; ROS, reactive oxygen speciesAging is characterized as a progressive reduction in the capacity to withstand the stresses of everyday life and a corresponding increase in risk of mortality. According to the oxidative stress hypothesis of aging, much of the aging process can be accounted for as the result of cumulative damage produced by reactive oxygen species (ROS).6,21,28,41,97 Endogenous oxygen radicals (that is, ROS) are generated as a byproduct of normal metabolic reactions in the body and subsequently can cause extensive damage to proteins, lipids, and DNA.6,41 Various prooxidant elements, in particular free transition metals, can catalyze these destructive reactions.6 The damage caused by ROS can be counteracted by antioxidant defense systems, but the imbalance between production of ROS and antioxidant defenses, over time, leads to oxidative stress and may contribute to the rate of aging.28,97Oxidative stress has been linked to several age-related diseases including neurodegenerative diseases, ophthalmologic diseases, cancer, and cardiovascular disease.21,28,97 Of these, cardiovascular disease remains the leading cause of adult death in the United States and Europe.71 In terms of cardiovascular disease, oxidative stress has been linked to atherosclerosis, hypertension, cardiomyopathy, and chronic heart failure in humans.55,78,84 Increases in oxidant catalysts (prooxidants)—such as copper, iron, and cadmium—have been associated with hypertension, coronary artery disease, atherosclerosis, and sudden cardiac death.98,102,106 Finally, both endogenous and exogenous antioxidants have been linked to decreased risk of cardiovascular disease, although the mechanisms behind this relationship are unclear.11,52,53 However, the oxidative stress hypothesis of aging aims to explain not only the mechanism of aging and age-related diseases (such as cardiovascular disease) in humans but also the differences between aging rates and the manifestations of age-related diseases across species.The differences in antioxidant and ROS levels between animals and humans offer promise for increasing our understanding of human aging. Additional evidence supporting the oxidative stress hypothesis of aging has come from comparative studies linking differences in aging rates across taxa with both antioxidant and ROS levels.4,17-21,58,71,86,105 In mammals, maximum lifespan potential is positively correlated with both serum and tissue antioxidant levels.17,18,21,71,105 Research has consistently demonstrated that the rate of oxidative damage varies across species and is negatively correlated with maximum lifespan potential.4,19,20,58,71,86 However, few studies involved detailed comparisons of hypothesized biochemical indicators of aging and oxidative stress between humans and animals.6 This type of interspecies comparison has great potential for directly testing the oxidative stress hypothesis of aging.Much evolutionary and genetic evidence supports remarkable similarity between humans and chimpanzees.95,100 Despite this similarity, humans have a lifespan of almost twice that of chimpanzees.3,16,47 Most comparative primate aging research has focused on the use of a macaque model,62,81,88 and several biochemical markers of age-related diseases have been identified in both humans and macaque monkeys.9,22,28,81,93,97 Several other species of monkeys have also been used in research addressing oxidative stress, antioxidant defenses, and maximum lifespan potential.18,21,58,105 However, no study to date has examined biochemical indicators of oxidative stress and aging in chimpanzees and humans as a test of the oxidative stress hypothesis for aging. The purpose of this study is to compare biochemical markers for cardiovascular disease, oxidative stress, and aging directly between male chimpanzees and humans. Given the oxidative stress hypothesis for aging and the known role of oxidative stress in cardiovascular disease, we predict that chimpanzees will show higher levels of cardiovascular risk and oxidative stress than humans. 相似文献
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A Fauster M Rebsamen K V M Huber J W Bigenzahn A Stukalov C-H Lardeau S Scorzoni M Bruckner M Gridling K Parapatics J Colinge K L Bennett S Kubicek S Krautwald A Linkermann G Superti-Furga 《Cell death & disease》2015,6(5):e1767
Necroptosis is a form of regulated necrotic cell death mediated by receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3. Necroptotic cell death contributes to the pathophysiology of several disorders involving tissue damage, including myocardial infarction, stroke and ischemia-reperfusion injury. However, no inhibitors of necroptosis are currently in clinical use. Here we performed a phenotypic screen for small-molecule inhibitors of tumor necrosis factor-alpha (TNF-α)-induced necroptosis in Fas-associated protein with death domain (FADD)-deficient Jurkat cells using a representative panel of Food and Drug Administration (FDA)-approved drugs. We identified two anti-cancer agents, ponatinib and pazopanib, as submicromolar inhibitors of necroptosis. Both compounds inhibited necroptotic cell death induced by various cell death receptor ligands in human cells, while not protecting from apoptosis. Ponatinib and pazopanib abrogated phosphorylation of mixed lineage kinase domain-like protein (MLKL) upon TNF-α-induced necroptosis, indicating that both agents target a component upstream of MLKL. An unbiased chemical proteomic approach determined the cellular target spectrum of ponatinib, revealing key members of the necroptosis signaling pathway. We validated RIPK1, RIPK3 and transforming growth factor-β-activated kinase 1 (TAK1) as novel, direct targets of ponatinib by using competitive binding, cellular thermal shift and recombinant kinase assays. Ponatinib inhibited both RIPK1 and RIPK3, while pazopanib preferentially targeted RIPK1. The identification of the FDA-approved drugs ponatinib and pazopanib as cellular inhibitors of necroptosis highlights them as potentially interesting for the treatment of pathologies caused or aggravated by necroptotic cell death.Programmed cell death has a crucial role in a variety of biological processes ranging from normal tissue development to diverse pathological conditions.1, 2 Necroptosis is a form of regulated cell death that has been shown to occur during pathogen infection or sterile injury-induced inflammation in conditions where apoptosis signaling is compromised.3, 4, 5, 6 Given that many viruses have developed strategies to circumvent apoptotic cell death, necroptosis constitutes an important, pro-inflammatory back-up mechanism that limits viral spread in vivo.7, 8, 9 In contrast, in the context of sterile inflammation, necroptotic cell death contributes to disease pathology, outlining potential benefits of therapeutic intervention.10 Necroptosis can be initiated by death receptors of the tumor necrosis factor (TNF) superfamily,11 Toll-like receptor 3 (TLR3),12 TLR4,13 DNA-dependent activator of IFN-regulatory factors14 or interferon receptors.15 Downstream signaling is subsequently conveyed via RIPK116 or TIR-domain-containing adapter-inducing interferon-β,8, 17 and converges on RIPK3-mediated13, 18, 19, 20 activation of MLKL.21 Phosphorylated MLKL triggers membrane rupture,22, 23, 24, 25, 26 releasing pro-inflammatory cellular contents to the extracellular space.27 Studies using the RIPK1 inhibitor necrostatin-1 (Nec-1) 28 or RIPK3-deficient mice have established a role for necroptosis in the pathophysiology of pancreatitis,19 artherosclerosis,29 retinal cell death,30 ischemic organ damage and ischemia-reperfusion injury in both the kidney31 and the heart.32 Moreover, allografts from RIPK3-deficient mice are better protected from rejection, suggesting necroptosis inhibition as a therapeutic option to improve transplant outcome.33 Besides Nec-1, several tool compounds inhibiting different pathway members have been described,12, 16, 21, 34, 35 however, no inhibitors of necroptosis are available for clinical use so far.2, 10 In this study we screened a library of FDA approved drugs for the precise purpose of identifying already existing and generally safe chemical agents that could be used as necroptosis inhibitors. We identified the two structurally distinct kinase inhibitors pazopanib and ponatinib as potent blockers of necroptosis targeting the key enzymes RIPK1/3. 相似文献
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Jianzhong Xu Xiuli Wang C Brian Toney Jesse Seamon Quanjun Cui 《Comparative medicine》2010,60(4):295-299
The purpose of this study was to conduct a comprehensive evaluation of the vascular supply to the femoral head, including the vessels that give rise to the terminal perfusing branches. Using a casting agent, we highlighted the anatomy of the external iliac and ischiatic arteries with their associated branches after anatomic dissection of 24 hips from 12 Leghorn chickens. We confirmed published findings regarding perfusion of the femoral head and identified 3 previously undescribed arterial branches to this structure. The first branch (the acetabular branch of the femoralis artery) was supplied by the femoralis artery and directly perfused the acetabulum and femoral head. The second branch (the lateral retinacular artery) was a tributary of the femoralis artery that directly supplied the femoral head. Finally, we found that the middle femoral nutrient artery supplies a previously undescribed ascending intraosseous branch (the ascending branch of the middle femoral nutrient artery) that perfuses the femoral head. Precise understanding of the major vascular branches to the femoral head would allow for complete or selective ligation of its blood supply and enable the creation of a reproducible bipedal model of femoral head osteonecrosis.Like humans, chickens are bipedal animals that rely on the hip joint to absorb the majority of the body''s weight. This anatomy, in concert with their high activity level, makes chickens an attractive model for the study of osteonecrosis of the femoral head in humans. The vast majority of animal research on osteonecrosis of the femoral head has been performed on quadrupedal animals,3,4,10,19,25,26,28,29,31,36,37,41,51,52 thus limiting its application to bipedal species because most quadruped models fail to progress to end-stage mechanical collapse similar to that in humans.6Avascular necrosis is the death of bone that occurs from ischemia due to disruption of the vascular supply to bone through direct or indirect mechanisms.38 Avascular necrosis should be differentiated from the broader term of osteonecrosis, which refers to bone death in general.32 Causes of femoral head osteonecrosis include direct and indirect disruption of vascular supply (traumatic injury, intravascular coagulation, extrinsic compression) as well as changes in cellular differentiation and cellular apoptosis.4,7,12,15,17,18,24,30-32,38,49,50 Accordingly, causes of osteonecrosis are both traumatic and nontraumatic.16,31,32The arterial anatomy in the chicken hindlimb has been outlined by several authors.20,22,27,35,42,44,45 Briefly, the external iliac and ischiatic artery arise from the abdominal aorta to provide blood supply to the chicken hind limb. The external iliac artery has 2 main branches—the femoralis and femoral circumflex arteries—that distribute blood to the chicken hindlimb. The ischiatic artery provides 3 main branches: the trochanteric artery, superior femoral nutrient artery, and middle femoral nutrient artery. Although the terminal vascular supply to the femoral head of Leghorn and Broiler chickens has been described,46,47 the origin of these terminal arteries with reference to the ischiatic and femoralis arteries and their respective branches has not been addressed. The current study will describe the blood vessels that feed these terminal branches to the chicken femoral head. 相似文献
12.
In the central nervous system (CNS), hyperglycemia leads to neuronal damage and cognitive decline. Recent research has focused on revealing alterations in the brain in hyperglycemia and finding therapeutic solutions for alleviating the hyperglycemia-induced cognitive dysfunction. Adiponectin is a protein hormone with a major regulatory role in diabetes and obesity; however, its role in the CNS has not been studied yet. Although the presence of adiponectin receptors has been reported in the CNS, adiponectin receptor-mediated signaling in the CNS has not been investigated. In the present study, we investigated adiponectin receptor (AdipoR)-mediated signaling in vivo using a high-fat diet and in vitro using neural stem cells (NSCs). We showed that AdipoR1 protects cell damage and synaptic dysfunction in the mouse brain in hyperglycemia. At high glucose concentrations in vitro, AdipoR1 regulated the survival of NSCs through the p53/p21 pathway and the proliferation- and differentiation-related factors of NSCs via tailless (TLX). Hence, we suggest that further investigations are necessary to understand the cerebral AdipoR1-mediated signaling in hyperglycemic conditions, because the modulation of AdipoR1 might alleviate hyperglycemia-induced neuropathogenesis.Adiponectin secreted by the adipose tissue1, 2 exists in either a full-length or globular form.3, 4, 5, 6 Adiponectin can cross the blood–brain barrier, and various forms of adiponectin are found in the cerebrospinal fluid.7, 8, 9, 10, 11 Adiponectin exerts its effect by binding to the adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2)12, 13 that have different affinities for the various circulating adiponectins.12, 14, 15, 16, 17 Several studies reported that both receptor subtypes are expressed in the central nervous system (CNS).7, 12, 18 As adiponectin modulates insulin sensitivity and inflammation,19 its deficiency induces insulin resistance and glucose intolerance in animals fed a high-fat diet (HFD).19, 20, 21 In addition, adiponectin can ameliorate the glucose homeostasis and increase insulin sensitivity.22, 23, 24 Adiponectin, which is the most well-known adipokine, acts mainly as an anti-inflammatory regulator,25, 26 and is associated with the onset of neurological disorders.27 In addition, a recent study reported that adiponectin promotes the proliferation of hippocampal neural stem cells (NSCs).28 Considering that adiponectin acts by binding to the adiponectin receptors, investigation of the adiponectin receptor-mediated signaling in the brain is crucial to understand the cerebral effects of adiponectin and the underlying cellular mechanisms.The prevalence of type II diabetes mellitus (DM2) and Alzheimer''s disease increases with aging.29 According to a cross-sectional study, in people with DM2, the risk of dementia is 2.5 times higher than that in the normal population.30, 31 A study performed between 1980 and 2002 suggested that an elevated blood glucose level is associated with a greater risk for dementia in elderly patients with DM2.32 In addition, according to a 9-year-long longitudinal cohort study, the risk of developing Alzheimer''s disease was 65% higher in people with diabetes than in control subjects.33 A community-based cohort study also reported that higher plasma glucose concentrations are associated with an increased risk for dementia, because the higher glucose level has detrimental effects on the brain.31 High blood glucose level causes mitochondria-dependent apoptosis,34, 35, 36 and aggravates diverse neurological functions.37, 38 Inflammation and oxidative stress, which are commonly observed in people with diabetes, inhibit neurogenesis.39, 40, 41 Similarly, neurogenesis is decreased in mice and rats with genetically induced type I diabetes.42, 43 In addition, diabetic rodents have a decreased proliferation rate of neural progenitors.43, 44 Furthermore, several studies suggested that an HFD leads to neuroinflammation, the impairment of synaptic plasticity, and cognitive decline.45, 46Here, we investigated whether AdipoR1-mediated signaling is associated with cell death in the brain of mice on a HFD, and whether high glucose level modifies the proliferation and differentiation capacity of NSCs in vitro. Our study provides novel findings about the role of AdipoR1-mediated signaling in hyperglycemia-induced neuropathogenesis. 相似文献
13.
X-N Wu Z-H Yang X-K Wang Y Zhang H Wan Y Song X Chen J Shao J Han 《Cell death and differentiation》2014,21(11):1709-1720
Necroptosis is mediated by a signaling complex called necrosome, containing receptor-interacting protein (RIP)1, RIP3, and mixed-lineage kinase domain-like (MLKL). It is known that RIP1 and RIP3 form heterodimeric filamentous scaffold in necrosomes through their RIP homotypic interaction motif (RHIM) domain-mediated oligomerization, but the signaling events based on this scaffold has not been fully addressed. By using inducible dimer systems we found that RIP1–RIP1 interaction is dispensable for necroptosis; RIP1–RIP3 interaction is required for necroptosis signaling, but there is no necroptosis if no additional RIP3 protein is recruited to the RIP1–RIP3 heterodimer, and the interaction with RIP1 promotes the RIP3 to recruit other RIP3; RIP3–RIP3 interaction is required for necroptosis and RIP3–RIP3 dimerization is sufficient to induce necroptosis; and RIP3 dimer-induced necroptosis requires MLKL. We further show that RIP3 oligomer is not more potent than RIP3 dimer in triggering necroptosis, suggesting that RIP3 homo-interaction in the complex, rather than whether RIP3 has formed homo polymer, is important for necroptosis. RIP3 dimerization leads to RIP3 intramolecule autophosphorylation, which is required for the recruitment of MLKL. Interestingly, phosphorylation of one of RIP3 in the dimer is sufficient to induce necroptosis. As RIP1–RIP3 heterodimer itself cannot induce necroptosis, the RIP1–RIP3 heterodimeric amyloid fibril is unlikely to directly propagate necroptosis. We propose that the signaling events after the RIP1–RIP3 amyloid complex assembly are the recruitment of free RIP3 by the RIP3 in the amyloid scaffold followed by autophosphorylation of RIP3 and subsequent recruitment of MLKL by RIP3 to execute necroptosis.Necroptosis is a type of programmed necrosis characterized by necrotic morphological changes, including cellular organelle swelling, cell membrane rupture,1, 2, 3 and dependence of receptor-interacting protein (RIP)14 and RIP3.5, 6, 7 Physiological function of necroptosis has been illustrated in host defense,8, 9, 10, 11 inflammation,12, 13, 14, 15, 16 tissue injury,10, 17, 18 and development.19, 20, 21Necroptosis can be induced by a number of different extracellular stimuli such as tumor necrosis factor (TNF). TNF stimulation leads to formation of TNF receptor 1 (TNFR1) signaling complex (named complex I), and complex II containing RIP1, TRADD, FAS-associated protein with a death domain (FADD), and caspase-8, of which the activation initiates apoptosis. If cells have high level of RIP3, RIP1 recruits RIP3 to form necrosome containing FADD,22, 23, 24 caspase-8, RIP1, and RIP3, and the cells undergo necroptosis.25, 26 Caspase-8 and FADD negatively regulates necroptosis,27, 28, 29, 30 because RIP1, RIP3, and CYLD are potential substrates of caspase-8.31, 32, 33, 34 Necrosome also suppresses apoptosis but the underlying mechanism has not been described yet. Mixed-lineage kinase domain-like (MLKL) is downstream of RIP3,35, 36 and phosphorylation of MLKL is required for necroptosis.37, 38, 39, 40, 41, 42Apoptosis inducing complex (complex II) and necrosome are both supramolecular complexes.43, 44, 45 A recent study showed that RIP1 and RIP3 form amyloidal fibrils through their RIP homotypic interaction motif46 (RHIM)-mediated polymerization, and suggested that amyloidal structure is essential for necroptosis signaling.47 The RIP1–RIP3 heterodimeric amyloid complex is believed to function as a scaffold that brings signaling proteins into proximity to permit their activation. However, RIP1 and RIP3 also can each form fibrils on their own RHIM domains in vitro. It is unclear how the homo- and hetero-interactions are coordinated and organized on the amyloid scaffold to execute their functions in necroptosis. Here, we used inducible dimerization systems to study the roles of RIP1–RIP1, RIP1–RIP3, and RIP3–RIP3 interactions in necroptosis signaling. Our data suggested that it is the RIP1–RIP3 interaction in the RIP1–RIP3 heterodimeric amyloid complex that empowers to recruit other free RIP3; homodimerization of RIP3 triggers its autophosphorylation and only the phosphorylated RIP3 can recruit MLKL to execute necroptosis. 相似文献
14.
Gregory W Salyards Uriel Blas-Machado Sasmita Mishra Stephen B Harvey Abigail M Butler 《Comparative medicine》2013,63(1):62-66
Spontaneous neoplasms in Mongolian gerbils have an incidence of 20% to 26.8%, but osteosarcomas occur at a much lower rate. Here we report a 1-y-old Mongolian gerbil with a spontaneous osteosarcoma at the level of the proximal tibia, with metastases to the pectoral muscles and lungs. Grossly, the tibial mass obliterated the tibia and adjacent muscles, and an axillary mass with a bloody, cavitary center expanded the pectoral muscles. Microscopically, the tibial mass was an infiltrative, osteoblastic mesenchymal neoplasm, and the axillary mass was an anaplastic mesenchymal neoplasm with hemorrhage. The lung contained multiple metastatic foci. Immunohistochemistry for osteonectin was strongly positive in the tibial, axillary, and pulmonary metastases. Although osteosarcoma is the most common primary malignant bone neoplasm that occurs spontaneously in all laboratory and domestic animal species and humans, it arises less frequently than does other neoplasms. The current case of spontaneous osteoblastic osteosarcoma of the proximal tibia and metastases to the pectoral muscles and lung in a Mongolian gerbil is similar in presentation, histology, and predilection site of both osteoblastic and telangiectatic osteosarcomas in humans. In addition, this case is an unusual manifestation of osteosarcoma in the appendicular skeleton of a Mongolian gerbil.Mongolian gerbils are used frequently in biologic research,1,2,4,9,10,12-14 particularly in oncogenic studies and filariasis research studying Brugia malayi.2 There have been several reports1,6,10,11,13-15 of spontaneous neoplasms, particularly in gerbils 2 y of age and older, typically occurring with the highest incidences in the skin, reproductive tract, and adrenal glands; however, neoplasms have also been reported in the thyroid, thymus, liver, kidney, pancreas, and bone.1,6,10,11,13-15 The incidence of spontaneous neoplasms occurring in the subfamily Gerbillinae ranges from 20% to 26.8%,1,6,10,11,13-15 depending on the study, age, and sex of the animals.With a lower incidence than those reported for other neoplasms, osteosarcomas in gerbils have been described in the ramus of the mandible and as an extraskeletal mass throughout the peritoneum.10,11 The usual age of onset for osteosarcomas in Mongolian gerbils is approximately 3 y (36 to 39 mo); however, no tumor type has been reported at less than 2 y of age in this species.10,11 Here we report a spontaneous osteosarcoma that occurred at the level of the proximal tibia, with metastases to the pectoral muscles and lung, in a 1-y-old Mongolian gerbil. 相似文献
15.
16.
Amelia C Jones James G Herndon Cynthia L Courtney Lynn Collura Joyce K Cohen 《Comparative medicine》2014,64(3):200-210
In 2008, clinical observations in our colony of sooty mangabeys (Cercocebus atys) suggested a high frequency of type 2 diabetes. Postmortem studies of diabetic animals revealed dense amyloid deposits in pancreatic islets. To investigate these findings, we screened our colony (97 male mangabeys; 99 female mangabeys) for the disease from 2008 to 2012. The overall prevalence of diabetes was 11% and of prediabetes was 7%, which is nearly double that reported for other primate species (less than 6%). Fructosamine and triglyceride levels were the best indicators of diabetes; total cholesterol and glycated hemoglobin were not associated with disease. Increasing age was a significant risk factor: prevalence increased from 0% in infants, juveniles, and young adults to 11% in adults and 19% in geriatric mangabeys. Sex, medroxyprogesterone acetate exposure, and SIV status were unrelated to disease. Weight was marginally higher in prediabetics, but body condition did not indicate obesity. Of the 49 mangabeys that were necropsied after clinical euthanasia or death from natural causes, 22 were diabetic; all 22 animals demonstrated pancreatic amyloid, and most had more than 75% of islets replaced with amyloid. We conclude that type 2 diabetes is more common in mangabeys than in other primate species. Diabetes in mangabeys has some unusual pathologic characteristics, including the absence of altered cholesterol levels and glycated hemoglobin but a robust association of pancreatic insular amyloidosis with clinical diabetes. Future research will examine the genetic basis of mangabey diabetes and evaluate additional diagnostic tools using imaging and serum markers.Abbreviations: HbA1c, glycated hemoglobin; MPA, medroxyprogesterone acetate; YNPRC, Yerkes National Primate Research CenterSooty mangabeys (Cercocebus atys) are Old World NHP that are native to West Africa. Historically their use in research has been limited to infectious disease studies, leprosy studies, and behavioral research.14,25 Over the past 20 to 30 y, they have been used in HIV–AIDS research. Mangabeys are natural hosts of SIVsmm, which is recognized as the origin of HIV2 infection in humans.7,8,30,36,42 SIV typically is nonpathogenic in mangabeys despite high levels of virus replication, which makes this species a unique and invaluable model in AIDS research.7,30,36,42 Our facility maintains a colony of approximately 200 sooty mangabeys. In 2008 clinical observations of relative hyperglycemia, glucosuria, and weight loss in our colony suggested that type 2 diabetes mellitus occurred at a relatively high frequency in this population. Spontaneous diabetes was found in 10% of the colony, and 5% of animals were prediabetic; this incidence is higher than that typically reported for other NHP species, such as cynomolgus macaques (less than 1% to 2%)22 and chimpanzees (less than 1%).37 The prevalence of spontaneous diabetes in humans is typically 8.3%.2,6,22,37 In addition, necropsies revealed that many affected animals had dense amyloid deposits in pancreatic islet cells. Insular amyloidosis was seen on histology, with a total replacement of islets by amyloid deposition in advanced diabetes. Advanced diabetes was determined by increased weight loss and severity of relative hyperglycemia. The increased clinical prevalence of diabetes in our mangabey colony prompted additional characterization of the clinicopathologic profile, risk factors, and prevalence of diabetes in our mangabey colony.The form of diabetes in this mangabey colony is characterized as type 2 diabetes mellitus, as they have hyperglycemia, hypertriglyceridemia, and islet amyloidosis. Type 2 diabetes mellitus is the most common of the 3 forms of diabetes, and has been documented in humans and NHP,22,31,37,55 including rhesus macaques (Macaca mulatta), cynomolgus macaques (Macaca fascicularis), Celebes crested macaques (Macaca nigra), bonnet macaques (Macaca radiate), pigtailed macaques (Macaca nemestrina), vervet monkeys (Chlorocebus pygerythrus), squirrel monkeys (Saimiri sciureus), chimpanzees (Pan troglodytes), and woolly monkeys (Lagothrix spp.).1,24,31,52,55 Type 2 diabetes is a chronic metabolic disorder in which insulin resistance occurs in liver, muscle, and adipose tissue. As type 2 diabetes progresses, it also can be characterized as a relative insulin deficiency.1,6,15,22,29,31,37,55 The initial clinical presentation of diabetes in humans and NHP includes polydipsia, polyuria, polyphagia, weight loss, and lethargy.1,6,22,27,31,37,55 Similar presentation was observed in our colony of diabetic mangabeys.Diagnostic criteria of diabetes in NHP species is similar to that for humans and is based on clinical symptoms and routine lab tests, including serum chemistry panel to evaluate persistent fasting hyperglycemia, hypertriglyceridemia, and hypercholesterolemia.2,6,11,16-18,21,22,29,31,37,48-50,52,55 Hypertriglyceridemia and hypercholesterolemia frequently are elevated due to diabetes and therefore are used as supportive diagnostic markers. In addition, the disease is characterized by transient hyperinsulinemia followed by insulin deficiency subsequent to glucose challenge. Urinalysis is used to evaluate glucosuria and ketonuria. These tests are not exclusive for diagnosing diabetes and can be inconsistent between species, thus making conclusive diagnosis challenging. For example, hyperglycemia can be a transient finding associated with recent food intake or stress associated with restraint for blood sample collection or anesthetic access, whereas hypertriglyceridemia can be seen in obese animals and those with other metabolic diseases such as pancreatitis and hypothyroidism.1,22,37,55The typical clinical approach to the diagnosis of diabetes in NHP and other veterinary patients includes evaluation of fructosamine and glycated hemoglobin (HbA1c) levels and glucose tolerance testing. These tests are indices of glycemic control and are used in clinical settings primarily to assess prognosis and response to treatment; they are also useful for the initial diagnosis of diabetes when used in parallel with serum chemistry markers. Fructosamine and HbA1c can both provide information on long-term glycemic control, because fructosamine reflects average blood glucose levels over 2 to 3 wk whereas HbA1c reflects average blood glucose over 2 to 3 mo preceding blood collection. HbA1c is the primary test for diabetes in human medicine,6,31,35,37 whereas fructosamine is commonly used in veterinary medicine. Glucose tolerance testing provides an indirect measure of insulin sensitivity, but it is not frequently used clinically in NHP because of the requirement for prolonged physical restraint or sedation.1,21,22,26,27,34,37,55Prevention and management of diabetes in NHP and humans can be achieved by identifying potential risk factors, including age, weight, sex, genetics, hormone drug exposure, and viral status.1,6,15,22,29,31,37,42,55 Advanced age, obesity, sex, and genetics are associated with diabetes in some species of NHP and humans.1,6,15,22,29,31,37,55 In addition, exposure to drugs such as medroxyprogesterone acetate (MPA) is suspected to be linked to diabetes due to the hormonal effects of progesterone impacting glucoregulatory function.1,6,10,22,23,31,34,55 MPA exposure is of interest, because it is used regularly in our mangabey colony as both a contraceptive and as therapy for endometriosis. In addition, SIV status is being evaluated as a risk factor, because a portion of our colony is SIV positive. Although HIV is not thought to be associated with diabetes in people, SIV pathogenesis in mangabeys differs; therefore it was of interest to explore the possible association of SIV and diabetes in mangabeys.7,30,36,42 Pancreatic insular amyloidosis has been documented to be associated with type 2 diabetes in several species. Amyloidosis is a group of disorders that are caused by extracellular deposition of misfolded proteins that can result in impaired function of any organ.15,20,23,28,32,43,45,48,49 Because a high incidence of pancreatic insular amyloid was noted at necropsy, we sought to document the relationship with clinical diabetes in mangabeys.Spontaneous type 2 diabetes mellitus has been well documented in several species of NHP. Because the literature contains little information regarding the clinicopathologic features (the ‘profile’), risk factors, and prevalence of spontaneous diabetes mellitus in sooty mangabeys, the primary aims of the current study were 1) to determine whether elevated levels of fasting blood glucose, fructosamine, HbA1c, triglycerides, and total cholesterol levels are reliable diagnostic markers of type 2 diabetes mellitus in this NHP species; 2) to determine whether age, sex, MPA exposure, and SIV status influence the risk of diabetes; 3) to determine whether body weight influences diabetic status; 4) to evaluate the relationship between pancreatic amyloidosis and diabetes mellitus; and 5) to characterize the prevalence of diabetes mellitus in the mangabey population at our institution. To our knowledge, this report is the first to describe the natural occurrence of type 2 diabetes mellitus within a captive colony of sooty mangabeys. We hypothesized that blood glucose, fructosamine, HbA1c, triglyceride, and total cholesterol would be reliable diagnostic markers and that age, sex, and MPA exposure would influence the risk of diabetes in this species. 相似文献
17.
18.
S L Petersen T T Chen D A Lawrence S A Marsters F Gonzalvez A Ashkenazi 《Cell death and differentiation》2015,22(11):1846-1857
Tumor necrosis factor α (TNFα) triggers necroptotic cell death through an intracellular signaling complex containing receptor-interacting protein kinase (RIPK) 1 and RIPK3, called the necrosome. RIPK1 phosphorylates RIPK3, which phosphorylates the pseudokinase mixed lineage kinase-domain-like (MLKL)—driving its oligomerization and membrane-disrupting necroptotic activity. Here, we show that TNF receptor-associated factor 2 (TRAF2)—previously implicated in apoptosis suppression—also inhibits necroptotic signaling by TNFα. TRAF2 disruption in mouse fibroblasts augmented TNFα–driven necrosome formation and RIPK3-MLKL association, promoting necroptosis. TRAF2 constitutively associated with MLKL, whereas TNFα reversed this via cylindromatosis-dependent TRAF2 deubiquitination. Ectopic interaction of TRAF2 and MLKL required the C-terminal portion but not the N-terminal, RING, or CIM region of TRAF2. Induced TRAF2 knockout (KO) in adult mice caused rapid lethality, in conjunction with increased hepatic necrosome assembly. By contrast, TRAF2 KO on a RIPK3 KO background caused delayed mortality, in concert with elevated intestinal caspase-8 protein and activity. Combined injection of TNFR1-Fc, Fas-Fc and DR5-Fc decoys prevented death upon TRAF2 KO. However, Fas-Fc and DR5-Fc were ineffective, whereas TNFR1-Fc and interferon α receptor (IFNAR1)-Fc were partially protective against lethality upon combined TRAF2 and RIPK3 KO. These results identify TRAF2 as an important biological suppressor of necroptosis in vitro and in vivo.Apoptotic cell death is mediated by caspases and has distinct morphological features, including membrane blebbing, cell shrinkage and nuclear fragmentation.1, 2, 3, 4 In contrast, necroptotic cell death is caspase-independent and is characterized by loss of membrane integrity, cell swelling and implosion.1, 2, 5 Nevertheless, necroptosis is a highly regulated process, requiring activation of RIPK1 and RIPK3, which form the core necrosome complex.1, 2, 5 Necrosome assembly can be induced via specific death receptors or toll-like receptors, among other modules.6, 7, 8, 9 The activated necrosome engages MLKL by RIPK3-mediated phosphorylation.6, 10, 11 MLKL then oligomerizes and binds to membrane phospholipids, forming pores that cause necroptotic cell death.10, 12, 13, 14, 15 Unchecked necroptosis disrupts embryonic development in mice and contributes to several human diseases.7, 8, 16, 17, 18, 19, 20, 21, 22The apoptotic mediators FADD, caspase-8 and cFLIP suppress necroptosis.19, 20, 21, 23, 24 Elimination of any of these genes in mice causes embryonic lethality, subverted by additional deletion of RIPK3 or MLKL.19, 20, 21, 25 Necroptosis is also regulated at the level of RIPK1. Whereas TNFα engagement of TNFR1 leads to K63-linked ubiquitination of RIPK1 by cellular inhibitor of apoptosis proteins (cIAPs) to promote nuclear factor (NF)-κB activation,26 necroptosis requires suppression or reversal of this modification to allow RIPK1 autophosphorylation and consequent RIPK3 activation.2, 23, 27, 28 CYLD promotes necroptotic signaling by deubiquitinating RIPK1, augmenting its interaction with RIPK3.29 Conversely, caspase-8-mediated CYLD cleavage inhibits necroptosis.24TRAF2 recruits cIAPs to the TNFα-TNFR1 signaling complex, facilitating NF-κB activation.30, 31, 32, 33 TRAF2 also supports K48-linked ubiquitination and proteasomal degradation of death-receptor-activated caspase-8, curbing apoptosis.34
TRAF2 KO mice display embryonic lethality; some survive through birth but have severe developmental and immune deficiencies and die prematurely.35, 36 Conditional TRAF2 KO leads to rapid intestinal inflammation and mortality.37 Furthermore, hepatic TRAF2 depletion augments apoptosis activation via Fas/CD95.34 TRAF2 attenuates necroptosis induction in vitro by the death ligands Apo2L/TRAIL and Fas/CD95L.38 However, it remains unclear whether TRAF2 regulates TNFα-induced necroptosis—and if so—how. Our present findings reveal that TRAF2 inhibits TNFα necroptotic signaling. Furthermore, our results establish TRAF2 as a biologically important necroptosis suppressor in vitro and in vivo and provide initial insight into the mechanisms underlying this function. 相似文献
19.
20.
Robert T Dauchy Aaron E Hoffman Melissa A Wren-Dail John P Hanifin Benjamin Warfield George C Brainard Shulin Xiang Lin Yuan Steven M Hill Victoria P Belancio Erin M Dauchy Kara Smith David E Blask 《Comparative medicine》2015,65(6):473-485
Light controls pineal melatonin production and temporally coordinates circadian rhythms of metabolism and physiology in normal and neoplastic tissues. We previously showed that peak circulating nocturnal melatonin levels were 7-fold higher after daytime spectral transmittance of white light through blue-tinted (compared with clear) rodent cages. Here, we tested the hypothesis that daytime blue-light amplification of nocturnal melatonin enhances the inhibition of metabolism, signaling activity, and growth of prostate cancer xenografts. Compared with male nude rats housed in clear cages under a 12:12-h light:dark cycle, rats in blue-tinted cages (with increased transmittance of 462–484 nm and decreased red light greater than 640 nm) evinced over 6-fold higher peak plasma melatonin levels at middark phase (time, 2400), whereas midlight-phase levels (1200) were low (less than 3 pg/mL) in both groups. Circadian rhythms of arterial plasma levels of linoleic acid, glucose, lactic acid, pO2, pCO2, insulin, leptin, and corticosterone were disrupted in rats in blue cages as compared with the corresponding entrained rhythms in clear-caged rats. After implantation with tissue-isolated PC3 human prostate cancer xenografts, tumor latency-to-onset of growth and growth rates were markedly delayed, and tumor cAMP levels, uptake–metabolism of linoleic acid, aerobic glycolysis (Warburg effect), and growth signaling activities were reduced in rats in blue compared with clear cages. These data show that the amplification of nighttime melatonin levels by exposing nude rats to blue light during the daytime significantly reduces human prostate cancer metabolic, signaling, and proliferative activities.Abbreviations: A-V, arterial–venous difference, ipRGC, intrinsically photosensitive retinal ganglion cell, LA, linoleic acid, 13-HODE, 13-hydroxyoctadecadienoic acid, TFA, total fatty acidsLight profoundly influences circadian, neuroendocrine, and neurobehavioral regulation in all mammals and is essential to life on our planet.2,15,28, 40 The light–dark cycle entrains the master biologic clock, located in the suprachiasmatic nucleus of the brain, in an intensity-, duration-, and wavelength-dependent manner.8-13 Photobiologic responses, including circadian rhythms of metabolism and physiology, are mediated by organic molecules called ‘chromophores,’ which are contained within a small subset of retinal cells, called the intrinsically sensitive retinal ganglion cells (ipRGC).16,29,31,36,41,49,53,59 In humans and rodents light quanta are detected by the chromophore melanopsin, which detects light quanta in principally the short-wavelength, blue-appearing portion of the spectrum (446 to 477 nm), and transmits its photic information via the retinohypothalamic tract to the ‘molecular clock’ of the suprachiasmatic nucleus. This region of the brain regulates the daily pineal gland production of the circadian neurohormone melatonin (N-acetyl-5-methoxytryptamine), which results in high levels produced at night and low levels during daytime.38,54 The daily, rhythmic melatonin signal provides temporal coordination of normal behavioral and physiologic functions including chronobiologic rhythms of locomotor activity,2 sleep-wake cycle,2,14 dietary and water intake,2,51 hormone secretion and metabolism.5,44,47,61 Alterations in light intensity, duration, and spectral quality at a given time of day,8-13,17,19-22,24,61 such as occurs in night-shift workers exposed to light at night,26,34,46,57 acutely suppresses endogenous melatonin levels in most mammalian species9,11,44,45,54,55 and may lead to various disease states, including metabolic syndrome5,61 and carcinogenesis.4-7,17,18Recent studies from our laboratory5,20,23-25,60,61 have demonstrated that relatively small changes in the spectral transmittance (color) of light passing through translucent amber (>590 nm), blue (>480 nm), and red-tinted (>640 nm) polycarbonate laboratory rodent cages, compared with standard polycarbonate clear cages (390 to 700 nm), during the light phase markedly influenced the normal nighttime melatonin signal and disrupted temporal coordination of metabolism and physiology.19,24,61 Most notable was our discovery that, in both male and female pigmented nude rats maintained in blue-tinted rodent cages, nighttime melatonin levels were as much as 7 times higher than normal nighttime peak levels in animals maintained in all other cage types.19 An earlier study in human subjects diagnosed with midwinter insomnia coupled with low nighttime melatonin levels demonstrated that daily exposure to intense morning bright polychromatic light therapy for up to one week resulted in a restoration of nocturnal melatonin levels to those of control subjects.35 In another study, exposure to blue-tinted (470 nm) LED light (100 lx) for approximately 20 min in the morning after 2 sleep-restricted (6 h) nights led to earlier onset of the melatonin surge at nighttime.30In the United States alone this year, approximately 240,000 men will be diagnosed with prostate cancer, and nearly 30,000 will die from this disease (National Cancer Institute; www.cancer.gov/). Epidemiologic studies have shown that night shift work, which involves circadian disruption, including nocturnal melatonin suppression, markedly increases prostate cancer risk in men.26,34,46,57,58 Both in vitro and in vivo studies have demonstrated that melatonin inhibits human prostate cancer growth, including that of androgen-receptor–negative, castration-resistant PC3 human prostate cancer cells.20,29,42,56 Cancer cells depend primarily on aerobic glycolysis (Warburg effect) over oxidative phosphorylation to meet their bioenergetic needs supporting biomass formation.5 The Warburg effect is characterized by increased cellular uptake of glucose and production of lactate despite an abundance of oxygen. Investigations have shown that signal transduction pathways that include AKT, MEK, NFκB, GS3Kβ, and PDK1 drive the Warburg effect.5,61 In addition, cancer cells rely on increased uptake of the ω6 fatty acid linoleic acid (LA), which is prevalent in the western diet.4-6 In most cancers, LA uptake occurs through a cAMP-dependent transport mechanism, and LA is metabolized to the mitogenic agent 13-hydroxyoctadecadienoic acid (13-HODE). In most tumors, 13-HODE plays an important role in enhancing downstream phosphorylation of ERK 1/2, AKT, and activation of the Warburg effect, thereby leading to increased cell proliferation and tumor growth.4-6 Melatonin, the principal neurohormone of the pineal gland and whose production is regulated by the suprachiasmatic nucleus,4,5 modulates processes of tumor initiation, progression, and growth in vivo.5 The circadian nocturnal melatonin signal not only inhibits LA uptake and metabolism, the Warburg effect in human cancer xenografts, and ultimately tumor growth, but it actually drives circadian rhythms in tumor metabolism, signal transduction activity, and cell proliferation. These effects are extinguished when melatonin production is suppressed by light exposure at night.5In the present investigation, we examined the hypothesis that the spectral transmittance (color) of short-wavelength (480 nm) bright light passing through blue-tinted standard laboratory rodent cages during the light phase not only amplifies the normal circadian nocturnal melatonin signal but also enhances the inhibition of the metabolism, signaling activity, and growth progression of human PC3 androgen-receptor–negative human prostate cancer xenografts in male nude rats. 相似文献