Activation Of Adaptive Responses Research Articles

From pain to tumor immunity: influence of peripheral sensory neurons in cancer.

The nervous and immune systems are the primary sensory interfaces of the body, allowing it to recognize, process, and respond to various stimuli from both the external and internal environment. These systems work in concert through various mechanisms of neuro-immune crosstalk to detect threats, provide defense against pathogens, and maintain or restore homeostasis, but can also contribute to the development of diseases. Among peripheral sensory neurons (PSNs), nociceptive PSNs are of particular interest. They possess a remarkable capability to detect noxious stimuli in the periphery and transmit this information to the brain, resulting in the perception of pain and the activation of adaptive responses. Pain is an early symptom of cancer, often leading to its diagnosis, but it is also a major source of distress for patients as the disease progresses. In this review, we aim to provide an overview of the mechanisms within tumors that are likely to induce cancer pain, exploring a range of factors from etiological elements to cellular and molecular mediators. In addition to transmitting sensory information to the central nervous system, PSNs are also capable, when activated, to produce and release neuropeptides (e.g., CGRP and SP) from their peripheral terminals. These neuropeptides have been shown to modulate immunity in cases of inflammation, infection, and cancer. PSNs, often found within solid tumors, are likely to play a significant role in the tumor microenvironment, potentially influencing both tumor growth and anti-tumor immune responses. In this review, we discuss the current state of knowledge about the degree of sensory innervation in tumors. We also seek to understand whether and how PSNs may influence the tumor growth and associated anti-tumor immunity in different mouse models of cancer. Finally, we discuss the extent to which the tumor is able to influence the development and functions of the PSNs that innervate it.

Overview of Yersinia pestis Metallophores: Yersiniabactin and Yersinopine.

The pathogenic anaerobic bacteria Yersinia pestis (Y. pestis), which is well known as the plague causative agent, has the ability to escape or inhibit innate immune system responses, which can result in host death even before the activation of adaptive responses. Bites from infected fleas in nature transmit Y. pestis between mammalian hosts causing bubonic plague. It was recognized that a host's ability to retain iron is essential in fighting invading pathogens. To proliferate during infection, Y. pestis, like most bacteria, has various iron transporters that enable it to acquire iron from its hosts. The siderophore-dependent iron transport system was found to be crucial for the pathogenesis of this bacterium. Siderophores are low-molecular-weight metabolites with a high affinity for Fe3+. These compounds are produced in the surrounding environment to chelate iron. The siderophore secreted by Y. pestis is yersiniabactin (Ybt). Another metallophore produced by this bacterium, yersinopine, is of the opine type and shows similarities with both staphylopine and pseudopaline produced by Staphylococcus aureus and Pseudomonas aeruginosa, respectively. This paper sheds light on the most important aspects of the two Y. pestis metallophores as well as aerobactin a siderophore no longer secreted by this bacterium due to frameshift mutation in its genome.

Conjugated linoleic acid downregulates Alzheimer's hallmarks in aluminum mouse model through an Nrf2-mediated adaptive response and increases brain glucose transporter levels.

Mitochondrial dysfunction, oxidative stress, inflammation and glucose dysmetabolism are pathological signs of Alzheimer's disease (AD). Dietary aluminum (Al) overload is often used to induce AD in rodents and trigger the onset of oxidative-stress hallmarks resembling those of the human disease. The Nuclear factor erythroid 2-related factor 2 (Nrf2), owing to its key role in redox homeostasis, mitochondrial function and inflammation, is a promising drug target for neurological disorders, but only a few data are available on its modulatory effects on glucose transporter expression levels. While it has been found that the protective effect of Conjugated linoleic acid (CLA) occurs through the activation of an Nrf2-mediated adaptive response, its beneficial effect on the considered pathological signs in the Al-induced model has not been established yet. Thirty-five male BalbC mice were divided into 5 groups: two Al-intoxicated groups were treated for 5 weeks with low or high Al doses (8 or 100mg/kg/day in drinking water, respectively; L or H). Two groups of animals, orally supplemented with CLA (600mg/kgbw/day) for 7 weeks (2 preliminary weeks plus the 5-week treatment with Al; CLA+L, CLA+H) were used to investigate its protective effect, while untreated mice were used as control (Cntr). We provide evidence that mitochondrial dysfunction, Nrf2 alteration, inflammation and Acetylcholinesterase (AChE) hyperactivation can occur even from L exposure. Interestingly, animal pre-treatment with an allometric CLA dose led to significant downregulation of the toxic effects elicited by L or H, likely through the activation of an adaptive response. In conclusion, CLA ability to increase the level of glucose transporters - along with its antioxidant and anti-inflammatory effect - expands the therapeutic targets of these molecules and comes out as an intriguing suitable candidate for the treatment of multifactorial disease.

A mitochondria-targeted coenzyme Q peptoid induces superoxide dismutase and alleviates salinity stress in plant cells

Salinity is a serious challenge to global agriculture and threatens human food security. Plant cells can respond to salt stress either by activation of adaptive responses, or by programmed cell death. The mechanisms deciding the respective response are far from understood, but seem to depend on the degree, to which mitochondria can maintain oxidative homeostasis. Using plant PeptoQ, a Trojan Peptoid, as vehicle, it is possible to transport a coenzyme Q10 (CoQ10) derivative into plant mitochondria. We show that salinity stress in tobacco BY-2 cells (Nicotiana tabacum L. cv Bright Yellow-2) can be mitigated by pretreatment with plant PeptoQ with respect to numerous aspects including proliferation, expansion, redox homeostasis, and programmed cell death. We tested the salinity response for transcripts from nine salt-stress related-genes representing different adaptive responses. While most did not show any significant response, the salt response of the transcription factor NtNAC, probably involved in mitochondrial retrograde signaling, was significantly modulated by the plant PeptoQ. Most strikingly, transcripts for the mitochondrial, Mn-dependent Superoxide Dismutase were rapidly and drastically upregulated in presence of the peptoid, and this response was disappearing in presence of salt. The same pattern, albeit at lower amplitude, was seen for the sodium exporter SOS1. The findings are discussed by a model, where plant PeptoQ modulates retrograde signalling to the nucleus leading to a strong expression of mitochondrial SOD, what renders mitochondria more resilient to perturbations of oxidative balance, such that cells escape salt induced cell death and remain viable.

COVID-19 and Cushing's syndrome: recommendations for a special population with endogenous glucocorticoid excess

COVID-19 and Cushing's syndrome: recommendations for a special population with endogenous glucocorticoid excess

Developmental and transcriptomic features characterize defects of silk gland growth and silk production in silkworm naked pupa mutant

The silkworm Bombyx mori is a well-characterized model organism for studying the silk gland development and silk production process. Using positional cloning and gene sequencing, we have previously reported that a truncated fibroin heavy chain was responsible for silkworm naked pupa (Nd) mutant. However, the mechanisms by which the mutant FibH causes developmental defects and secretion-deficiency of the silk gland remain to be fully elucidated. Here, silk gland's developmental features, histomorphology, and transcriptome analyses were used to characterize changes in its structure and gene expression patterns between Nd mutant and WT/Dazao. Whole larval stage investigation showed that Nd-PSG undergoes an arrested/delayed development, which eventually resulted in a gland degeneration. By using section staining and transmission electron microscope, a blockade in intracellular vesicle transport from endoplasmic reticulum to Golgi apparatus (secretion-deficiency) and an increased number of autophagosomes and lysosomes were found in Nd-PSG's cytoplasm. Next, by using RNA sequencing and comparative transcriptomic analysis, 2178 differentially expressed genes were identified between Nd-PSG and WT-PSG, among which most of the DEGs associated with cellular stress responses (autophagy, ubiquitin-proteasome system, and heat shock response) were significantly up-regulated in Nd-PSG, suggesting that mutant FibH perturbed cellular homeostasis and resulted in an activation of adaptive responses in PSG cells. These findings reveal the molecular mechanism of the Naked pupa (Nd) mutation and provide insights into silk gland development as well as silk protein production in silkworm Bombyx mori.

Impact of delipidated estrous sheep serum supplementation on in vitro maturation, cryotolerance and endoplasmic reticulum stress gene expression of sheep oocytes.

High lipid content of oocytes and embryos in domestic animals is one of the well-known factors associated with poor cryosurvival. Herein, we wanted to determine whether the use of delipidated estrous sheep serum during in vitro maturation (IVM) of ovine oocytes reduces the cytoplasmic lipid droplets content and improves embryo development and cryotolerance after vitrification. Cumulus oocytes complexes (COCs) were matured in vitro for 24 h in medium supplemented with whole or delipidated estrous sheep serum prior to vitrification. Neutral lipid present in lipid droplets of COCs, cleavage rate, embryo development rate on Day 6 and Day 8, and hatching rate on Day 8, were compared among experimental groups. Endoplasmic reticulum stress genes were evaluated in in vitro matured COCs under different lipid conditions prior to vitrification. The lipid droplets’ content (mean fluorescence intensity) of oocytes cultured with IVM media supplemented with delipidated serum was lower than COCs matured with whole serum (7.6 ± 1.7 vs. 22.8 ± 5.0 arbitrary units, respectively; P< 0.05). Despite IVM treatment, oocytes subjected to vitrification showed impaired competence compared with the non-vitrified groups (P<0.05). No significant differences in embryo production were observed in non-vitrified COCs after maturation in delipidated or whole serum (33.4±4.9 vs 31.9 ±4.2). COCs matured in delipidated serum and subjected to vitrification showed increased expression of ATF4, ATF6, GRP78, and CHOP10 genes (ER stress markers). Collectively, our results demonstrate that although supplementation of IVM medium with delipidated estrous sheep serum reduces the presence of cytoplasmic lipid droplets in oocytes after maturation, oocyte cryotolerance is not improved. Notably, the expression of genes associated with the unfolded protein response (UPR) was increased in COCs, with fewer lipid droplets subjected to vitrification, suggesting that oocyte cryopreservation is associated with ER stress and activation of adaptive responses.

Sustained Exposure to High‐Sucrose Diet Triggers Endoplasmic Reticulum Stress in Hippocampus and Anticipates Cognitive and Motor Impairments in Adults Rats

BackgroundMetabolic syndrome (MS)‐related conditions promotes endoplasmic reticulum stress (ERS) in order to control their deleterious effects through activation of adaptive responses known as Unfolded Protein Response (UPR). However, under chronic stress, UPR can evolve to apoptotic pathways. Previously, we have shown that MS induced by high‐sucrose diet triggers the ERS and apoptotic pathways in hippocampus and lead to motor and behavioral impairments in young rats.AimsIn the present study we sought to investigate if sustained exposure to such diet is capable to intensify those metabolic disturbances and anticipate neurological impairments in adult rats.MethodsThus, weaned Wistar rats were divided in two groups: the control group (CTR, n=7), fed with a standard chow; and obese group (HSD, n=7), fed with high‐sucrose diet (25% sucrose). Both groups were followed for 6 months and evaluated for MS development; serum redox profile; and hippocampal gene and protein expressions of UPR sensors (IRE1α, PERK and ATF6), chaperones (GRP78, GRP94, PDI, calnexin and calreticulin), neural plasticity marker (BDNF), antioxidant defense (NRF2), senescence (P53 and P21) and apoptosis (BCL2, CHOP and PARP‐1). Furthermore, cognitive, behavioral and motor functions were also assessed, through Morris water maze, open field and rotarod test, respectively. For aging control, 20 month‐old rats (OLD, n=7) fed with standard chow were included as an aging control for gene/protein expressions and neurological assessments.ResultsThe exposure to high‐sucrose diet was capable to induce MS with marked weight gain, central obesity, dysglicemia in both fasting and fed states, hypertriglyceridemia and high free fatty acids, fat storage in liver, glucose intolerance, hyperinsulinemia and peripheral as well as hepatic insulin resistance. The redox profile assessment showed higher lipid peroxidation with increased serum MDA levels and higher SOD activity in HSD as compared to CTR, but catalase was unchanged. UPR sensors gene expression was reduced in both HSD and OLD groups. All chaperones evaluated presented decreased gene expression, but only GRP78 and GRP94 also presented a decreased protein expression. BDNF expression was reduced in HSD (FC 0.3) and OLD groups, but NRF2 did not present any difference. As expected, the senescence markers were increased in OLD group, but only P21 was increased in HSD (FC 1.8). Assessment of apoptotic pathways showed decreased expression of BCL2 and increased gene and protein expression of CHOP. Assessment of PARP‐1 protein expression suggested the presence of calpain, a necrosis marker. Neurological evaluation demonstrated motor deficit, anxiogenic behavior and cognitive impairments (learning and spatial memory) in HSD.ConclusionsIn to to, our data support that sustained exposure to high‐sucrose diet promotes metabolic disturbances, which disrupt hippocampus homeostasis and lead to cognitive and motor impairments in 6‐months old rats.Support or Funding InformationFundação de Amparo à Pesquisa e ao Desenvolvimento Científico e Tecnológico do Maranhão – FAPEMA and rede INCT Redoxoma

Dual function of CD70 in viral infection: modulator of early cytokine responses and activator of adaptive responses.

The role of the TNF family member CD70 in adaptive T cell responses has been intensively studied, but its function in innate responses is still under investigation. In this study, we show that CD70 inhibits the early innate response to murine CMV (MCMV) but is essential for the optimal generation of virus-specific CD8 T cells. CD70(-/-) mice reacted to MCMV infection with a robust type I IFN and proinflammatory cytokine response. This response was sufficient for initial control of MCMV, although at later time points, CD70(-/-) mice became more susceptible to MCMV infection. The heightened cytokine response during the early phase of MCMV infection in CD70(-/-) mice was paralleled by a reduction in regulatory T cells (Treg). Treg from naive CD70(-/-) mice were not as efficient at suppressing T cell proliferation compared with Treg from naive wild-type mice, and depletion of Treg during MCMV infection in Foxp3-diphtheria toxin receptor mice or in wild-type mice recapitulated the phenotype observed in CD70(-/-) mice. Our study demonstrates that although CD70 is required for the activation of the antiviral adaptive response, it has a regulatory role in early cytokine responses to viruses such as MCMV, possibly through maintenance of Treg survival and function.

Tissue-Specific Loss of DARS2 Activates Stress Responses Independently of Respiratory Chain Deficiency in the Heart

Adaptive stress responses activated upon mitochondrial dysfunction are assumed to arise in order to counteract respiratory chain deficiency. Here, we demonstrate that loss of DARS2 (mitochondrial aspartyl-tRNA synthetase) leads to the activation of various stress responses in a tissue-specific manner independently of respiratory chain deficiency. DARS2 depletion in heart and skeletal muscle leads to the severe deregulation of mitochondrial protein synthesis followed by a strong respiratory chain deficit in both tissues, yet the activation of adaptive responses is observed predominantly in cardiomyocytes. We show that the impairment of mitochondrial proteostasis in the heart activates the expression of mitokine FGF21, which acts as a signal for cell-autonomous and systemic metabolic changes. Conversely, skeletal muscle has an intrinsic mechanism relying on the slow turnover of mitochondrial transcripts and higher proteostatic buffering capacity. Our results show that mitochondrial dysfunction is sensed independently of respiratory chain deficiency, questioning the current view on the role of stress responses in mitochondrial diseases.

Exploiting the Good Guys: Th1 Antiviral &amp; Antitumor Human &amp; Mouse NKT Cells

Toll-like receptor 2 (TLR2) signaling from TLR2/1 or TLR2/ 6 complexes, in response to peptidoglycan (PGN)-embedded lipoproteins and glycopolymers, is a primary step in the activation of adaptive responses against Staphylococcus aureus and other Gram-positive bacteria. Recent studies from our laboratory have shown that PGN from S. aureus can also down-regulate human T cell activation through a TLR2dependent, IL-10-mediated mechanism (Chau et al, Nature Medicine 2009; 15: 641). The molecular basis of the plasticity of TLR2-dependent signaling is unknown. Here we show that the down-regulatory effect of TLR2 signaling on adaptive T cell responses is operational when human monocytes and monocyte-derived macrophages (MΦ), but not monocytederived dendritic cells (DCs), are the primary antigenpresenting cells (APCs). Such a modulatory capacity of MΦs correlated with significantly higher levels of surface TLR2 on MΦs than on DCs, with surface levels of TLR1 and TLR6 being similar in these APCs. Differential availability of TLR2 signaling complexes correlated with functional polarization of these APCs into IL-10-producing or IL-12-producing cells in response to staphylococcal PGN. The IL-10 response triggered by TLR2/1 and TLR2/6 agonists did not require the TLR accessory molecules CD14 and CD36, and was dependent on the activation of the PI3K/Akt pathway. Our results illustrate that S. aureus can exploit an inherent plasticity of TLR2dependent signaling to modulate the host response. This may explain the different outcomes of the interaction between S. aureus and humans, which range from commensalism to pathogenicity (i.e., local infection, sepsis, toxic shock).

Adaptive response: Part II. Further modeling for dose rate and time influences

Purpose: For adaptive response (AR) behavior, to model and analyze the dose rate dependence of AR. To examine and to model the influence of time interval between primer and challenge dose on the magnitude of radioprotection.Method and materials: Microdosimetry is used to examine effects of rate of critical volume specific energy depositions on activation of AR and induction of deleterious damage. The dose rate dependent adaptive response data, Shadley and Wiencke and Shadley et al. on AR fading, are analyzed.Results: We obtain good agreement with observed AR behavior. The 4 – 6 hour activation time for AR is from time necessary for the accumulation of enzymatic resources from the increased radioprotective capability for the recognition and repair of deleterious DNA damage and perhaps resources for reduction of RSO. The Shadley and Wiencke data, for the low 1.0 cGy primer dose, is as a result of a minimum rate of specific energy depositions (hits) for adaptive response to become operative and become fully activated. Increased deleterious damage with increased dose rate for a high 50 cGy primer dose is from a reduction in dose rate sparing as the rate approaches acute exposure.Conclusions: The microdosimetric model substantiates the prior observations in Part I that only several radiation-induced charged particle cell nucleus traversals are sufficient to activate adaptive response. Further however we find here that a minimum dose rate threshold is necessary. The model shows promise to provide insight into adaptive response time and dose rate behavior.