Reflex erection in the rat: reciprocal interplay between hemodynamic and somatic events.
Ontology highlight
ABSTRACT: Penile erection is a complex reflex under spinal control and modulated by the brain. The hemodynamic events under autonomic control and the perineal muscles somatic activity are interconnected during the reflex erection at the spinal level, however if the afferent feedback on the corpus cavernosum pressure during an erection affects the somatic activity (perineal muscles contractions) and vice versa is not known. This study was aimed to test this hypothesis using a rat model.Intracavernous pressure (ICP) and bulbocavernosus (BC) muscle EMG were recorded during reflex erections elicited with dorsal penile nerve (DNP) electrical stimulation in anaesthetized acutely spinalized SD rats with surgically (bilateral cavernous nerve section, CnX, n?=?8) and pharmacologically (trimetaphan infusion, TMPh, n?=?8) abolished pressor response, or with surgically (bilateral section of the motor branch of the pudendal nerve, PnX, n?=?7) and pharmacologically (1 mg/kg d-tubocurarine, n?=?8) blocked perineal muscles contractions, or with interrupted afferent input from the penis (bilateral crush of the dorsal penile nerve, DPnX, n?=?7). Control rats (n?=?8) received no intervention.Moderate positive correlations were found between net parameters of pressor and somatic activity during DNP-stimulation induced reflex erection in spinal rats, particularly the speed of pressor response development was positively correlated to EMG parameters. No changes of EMG activity were found in CnX rats, while the decrease of BC EMG in TMPh-treated males can be attributed to direct inhibitory action of TMPh on neuromuscular transmission. Pressor response latency was increased and ICP front slope decreased in dTK and PnX rats, indicating that perineal muscles contraction augment pressor response. DPN crush had little effect on ICP and EMG.Afferent input on the level of intracavernous pressure and the perineal muscles activity has minimal impact on, correspondingly, the somatic and the autonomic components of the reflex erection in spinal males, once the reflex has been initiated.
<h4>Background</h4>Penile erection is a complex reflex under spinal control and modulated by the brain. The hemodynamic events under autonomic control and the perineal muscles somatic activity are interconnected during the reflex erection at the spinal level, however if the afferent feedback on the corpus cavernosum pressure during an erection affects the somatic activity (perineal muscles contractions) and vice versa is not known. This study was aimed to test this hypothesis using a rat model.< ...[more]
Project description:Reflex cardiorespiratory alterations elicited after instillation of nociceptive agents intra-arterially (i.a) are termed as 'vasosensory reflex responses'. The present study was designed to evaluate such responses produced after i.a. instillation of histamine (1 mM; 10 mM; 100 mM) and to delineate the pathways i.e. the afferents and efferents mediating these responses. Blood pressure, electrocardiogram and respiratory excursions were recorded before and after injecting saline/histamine, in a local segment of femoral artery in urethane anesthetized rats. Paw edema and latencies of responses were also estimated. Separate groups of experiments were conducted to demonstrate the involvement of somatic nerves in mediating histamine-induced responses after ipsilateral femoral and sciatic nerve sectioning (+NX) and lignocaine pre-treatment (+Ligno). In addition, another set of experiments was performed after bilateral vagotomy (+VagX) and the responses after histamine instillation were studied. Histamine produced concentration-dependent hypotensive, bradycardiac, tachypnoeic and hyperventilatory responses of shorter latencies (2-7 s) favouring the neural mechanisms in eliciting the responses. Instillation of saline (time matched control) in a similar fashion produced no response, excluding the possibilities of ischemic/stretch effects. Paw edema was absent in both hind limbs indicating that the histamine did not reach the paws and did not spill out into the systemic circulation. +NX, +VagX, +Ligno attenuated histamine-induced cardiorespiratory responses significantly. These observations conclude that instillation of 10 mM of histamine produces optimal vasosensory reflex responses originating from the local vascular bed; afferents and efferents of which are mostly located in ipsilateral somatic and vagus nerves respectively.
Project description:Effective patient prognosis necessitates identification of novel tumor promoting drivers of gastric cancer (GC) which contribute to worsened conditions by analysing TCGA-gastric adenocarcinoma dataset. Small leucine-rich proteoglycans, asporin (ASPN) and decorin (DCN), play overlapping roles in development and diseases; however, the mechanisms underlying their interplay remain elusive. Here, we investigated the complex interplay of asporin, decorin and their interaction with TGFβ in GC tumor and corresponding normal tissues. The mRNA levels, protein expressions and cellular localizations of ASPN and DCN were analyzed using real-time PCR, western blot and immunohistochemistry, respectively. The protein-protein interaction was predicted by in-silico interaction analysis and validated by co-immunoprecipitation assay. The correlations between ASPN and EMT proteins, VEGF and collagen were achieved using western blot analysis. A significant increase in expression of ASPN in tumor tissue vs. normal tissue was observed in both TCGA and our patient cohort. DCN, an effective inhibitor of the TGFβ pathway, was negatively correlated with stages of GC. Co-immunoprecipitation demonstrated that DCN binds with TGFβ, in normal gastric epithelium, whereas in GC, ASPN preferentially binds TGFβ. Possible activation of the canonical TGFβ pathway by phosphorylation of SMAD2 in tumor tissues suggests its role as an intracellular tumor promoter. Furthermore, tissues expressing ASPN showed unregulated EMT signalling. Our study uncovers ASPN as a GC-promoting gene and DCN as tumor suppressor, suggesting that ASPN can act as a prognostic marker in GC. For the first time, we describe the physical interaction of TGFβ with ASPN in GC and DCN with TGFβ in GC and normal gastric epithelium respectively. This study suggests that prevention of ASPN-TGFβ interaction or overexpression of DCN could serve as promising therapeutic strategies for GC patients.
Project description:Targeting nuclear factor-kappa B (NF-κB) represents a highly viable strategy against chemoresistance in cancers as well as cell death. Ubiquitination, including linear ubiquitination mediated by the linear ubiquitin chain assembly complex (LUBAC), is emerging as a crucial mechanism of overactivated NF-κB signaling. Ovarian tumor family deubiquitinase OTULIN is the only linear linkage-specific deubiquitinase; however, the molecular mechanisms of how it counteracts LUBAC-mediated NF-κB activation have been largely unknown. Here, we identify Lys64/66 of OTULIN for linear ubiquitination facilitated in a LUBAC-dependent manner as a necessary event required for OTULIN-LUBAC interaction under unstressed conditions, which becomes deubiquitinated by OTULIN itself in response to genotoxic stress. Furthermore, this self-deubiquitination of OTULIN occurs intermolecularly, mediated by OTULIN dimerization, resulting in the subsequent dissociation of OTULIN from the LUBAC complex and NF-κB overactivation. Oxidative stress induces OTULIN dimerization via cysteine-mediated covalent disulfide bonds. Our study reveals that the status of the physical interaction between OTULIN and LUBAC is a crucial determining factor for the genotoxic NF-κB signaling, as measured by cell survival and proliferation, while OTULIN loss of function resulting from its dimerization and deubiquitination leads to a dissociation of OTULIN from the LUBAC complex. Of note, similar molecular mechanisms apply to the inflammatory NF-κB signaling in response to tumor necrosis factor α. Hence, a fuller understanding of the detailed molecular mechanisms underlying the disruption of the OTULIN-LUBAC interaction will be instrumental for developing future therapeutic strategies against cancer chemoresistance and necroptotic processes pertinent to numerous human diseases.
Project description:We studied the relationship between somatosensory evoked potentials (SEP) recorded with scalp electroencephalography (EEG) and hemoglobin responses recorded non-invasively with diffuse optical imaging (DOI) during parametrically varied electrical forepaw stimulation in rats. Using these macroscopic techniques we verified that the hemodynamic response is not linearly coupled to the somatosensory evoked potentials, and that a power or threshold law best describes the coupling between SEP and the hemoglobin response, in agreement with the results of most invasive studies. We decompose the SEP response in three components (P1, N1, and P2) to determine which best predicts the hemoglobin response. We found that N1 and P2 predict the hemoglobin response significantly better than P1 and the input stimuli (S). Previous electrophysiology studies reported in the literature show that P1 originates in layer IV directly from thalamocortical afferents, while N1 and P2 originate in layers I and II and reflect the majority of local cortico-cortical interactions. Our results suggest that the evoked hemoglobin response is driven by the cortical synaptic activity and not by direct thalamic input. The N1 and P2 components, and not P1, need to be considered to correctly interpret neurovascular coupling.
Project description:The thyroid hormone-inactivating (TH-inactivating) enzyme type 3 iodothyronine deiodinase (D3) is an oncofetal protein that is rarely expressed in adult life but has been shown to be reactivated in the context of proliferation and neoplasms. D3 terminates TH action within the tumor microenvironment, thereby enhancing cancer cell proliferation. However, the pathological role of D3 and the contribution of TH metabolism in cancer have yet to be fully explored. Here, we describe a reciprocal regulation between TH action and the cancer-associated microRNA-21 (miR21) in basal cell carcinoma (BCC) skin tumors. We found that, besides being negatively regulated by TH at the transcriptional level, miR21 attenuates the TH signal by increasing D3 levels. The ability of miR21 to positively regulate D3 was mediated by the tumor suppressor gene GRHL3, a hitherto unrecognized D3 transcriptional inhibitor. Finally, in a BCC mouse model, keratinocyte-specific D3 depletion markedly reduced tumor growth. Together, our results establish TH action as a critical hub of multiple oncogenic pathways and provide functional and mechanistic evidence of the involvement of TH metabolism in BCC tumorigenesis. Moreover, our results identify a miR21/GRHL3/D3 axis that reduces TH in the tumor microenvironment and has potential to be targeted as a therapeutic approach to BCC.
Project description:The low bioavailability of nutrients, especially nitrogen (N) and phosphorus (P), is one of the most limiting factors for crop production. In this study, under N- and P-free nutrient solution (-N-P), nodulating white lupin plants developed some nodules and analogous cluster root structures characterized by different morphological, physiological, and molecular responses than those observed upon single nutrient deficiency (strong acidification of external media, a better nutritional status than -N+P and +N-P plants). The multi-elemental analysis highlighted that the concentrations of nutrients in white lupin plants were mainly affected by P availability. Gene-expression analyses provided evidence of interconnections between N and P nutritional pathways that are active to promote N and P balance in plants. The root exudome was mainly characterized by N availability in nutrient solution, and, in particular, the absence of N and P in the nutrient solution triggered a high release of phenolic compounds, nucleosides monophosphate and saponines by roots. These morphological, physiological, and molecular responses result from a close interplay between N and P nutritional pathways. They contribute to the good development of nodulating white lupin plants when grown on N- and P-free media. This study provides evidence that limited N and P availability in the nutrient solution can promote white lupin-Bradyrhizobium symbiosis, which is favourable for the sustainability of legume production.
Project description:Cancers are complex ecosystems composed of malignant cells embedded in an intricate microenvironment made of different non-transformed cell types and extracellular matrix (ECM) components. The tumor microenvironment is governed by constantly evolving cell-cell and cell-ECM interactions, which are now recognized as key actors in the genesis, progression and treatment of cancer lesions. The ECM is composed of a multitude of fibrous proteins, matricellular-associated proteins, and proteoglycans. This complex structure plays critical roles in cancer progression: it functions as the scaffold for tissues organization and provides biochemical and biomechanical signals that regulate key cancer hallmarks including cell growth, survival, migration, differentiation, angiogenesis, and immune response. Cells sense the biochemical and mechanical properties of the ECM through specialized transmembrane receptors that include integrins, discoidin domain receptors, and syndecans. Advanced stages of several carcinomas are characterized by a desmoplastic reaction characterized by an extensive deposition of fibrillar collagens in the microenvironment. This compact network of fibrillar collagens promotes cancer progression and metastasis, and is associated with low survival rates for cancer patients. In this review, we highlight how fibrillar collagens and their corresponding integrin receptors are modulated during cancer progression. We describe how the deposition and alignment of collagen fibers influence the tumor microenvironment and how fibrillar collagen-binding integrins expressed by cancer and stromal cells critically contribute in cancer hallmarks.
Project description:While many studies use parental socioeconomic status and health to predict children's health, this study examines the interplay over time between child and maternal health across childhood and adolescence. Using data from women in the National Longitudinal Study of Youth 1979 cohort and their children (N = 2,225), autoregressive cross-lagged models demonstrate a reciprocal relationship between child activity limitations and maternal health limitations in direct effects of child activity limitations on maternal health limitations two years later and vice versa-net of a range of health-relevant time-varying and time-invariant covariates. Furthermore, there are indirect effects of child activity limitations on subsequent maternal health limitations and indirect effects of maternal health limitations on subsequent child activity limitations via intervening health statuses. This study examines how the interplay between child and maternal health unfolds over time and describes how these interdependent statuses jointly experience health disadvantages.
Project description:Brassinosteroids (BRs) are steroid hormones that are essential for plant growth. Responses to these hormones are mediated by transcription factors of the bri1-EMS suppressor 1/brassinazole resistant 1 subfamily, and BRs activate these factors by impairing their inhibitory phosphorylation by GSK3/shaggy-like kinases. Here we show that BRs induce nuclear compartmentalization of CESTA (CES), a basic helix-loop-helix transcription factor that regulates BR responses, and reveal that this process is regulated by CES SUMOylation. We demonstrate that CES contains an extended SUMOylation motif, and that SUMOylation of this motif is antagonized by phosphorylation to control CES subnuclear localization. Moreover, we provide evidence that phosphorylation regulates CES transcriptional activity and protein turnover by the proteasome. A coordinated modification model is proposed in which, in a BR-deficient situation, CES is phosphorylated to activate target gene transcription and enable further posttranslational modification that controls CES protein stability and nuclear dynamics.
