Modulatory Action Research Articles

Endogenous nitric oxide derived from NOS I or II in thoracic spinal cord exerts opposing tonic modulation on sympathetic vasomotor tone via disparate mechanisms in anesthetized rats.

The sympathetic preganglionic neurons (SPN) in the thoracic spinal cord regulate vasomotor tone via norepinephrine released from sympathetic terminals and adrenal medulla. We assessed the hypothesis that nitric oxide synthase I (NOS I)- and NOS II-derived nitric oxide (NO) in the thoracic spinal cord differentially modulate sympathetic outflow and that the adrenal medulla may be involved in those modulatory actions. In Sprague-Dawley rats, NOS I immunoreactivity was distributed primarily in the perikaryon, proximal dendrites, or axons of SPN, and small clusters of NOS II immunoreactivity impinged mainly on the circumference of SPN. Intrathecal administration of 7-nitroindazole (7-NI), a specific NOS I antagonist, into the thoracic spinal cord significantly reduced arterial pressure, heart rate, and basal or baroreflex-mediated sympathetic vasomotor tone. On the other hand, intrathecal application of S-methylisothiourea (SMT), a specific NOS II antagonist, elevated arterial pressure with a transient reduction of heart rate, induced a surge of plasma norepinephrine, and reduced baroreflex-mediated but not basal sympathetic vasomotor tone. Bilateral adrenalectomy significantly exacerbated the cardiovascular responses to 7-NI but antagonized those to SMT. We conclude that both NOS I and NOS II are present in the thoracic spinal cord and are tonically active under physiological conditions. Furthermore, the endogenous NO generated by NOS I-containing SPN exerts a tonic excitatory action on vasomotor tone mediated by norepinephrine released from the adrenal medulla and sympathetic nerve terminals. On the other hand, NO derived from NOS II exerts a tonic inhibitory action on sympathetic outflow from the SPN that targets primarily the blood vessels.

Pain management in knee arthroplasty: an overview

Perioperative pain management after knee arthroplasty has undergone a conceptual revolution in the last decade. Along with other exciting innovations, including minimally invasive techniques, computer-assisted procedures and a significant stride in tribology, understanding pain modulation and drug action at a molecular level is recognized as the game changer in arthroplasty surgeries. While most patients usually recover and experience pain relief within 3 mo after TKA, about 20% (10–34%) of the patients are left with an unfavorable long-term pain outcome. Fifty-two percent of patients report moderate pain and 16% report severe pain at rest 30 days after TKA, while pain at movement affects as much as 78% of the patients. Inability to adequately control postoperative pain causes undue suffering, inability to participate in fast-track rehabilitation programs, sleep disturbance (44% patients first 3 nights), delayed discharge, and the development of persistent postsurgical pain. The goal of this review article is to give an overview of the fundamental concept of surgical pain, the molecular mechanism of action of different drugs, evolution of the concept of preventive analgesia, and state of the art for current pain management. When combined and standardized, these factors allow arthroplasty surgeons to offer outpatient arthroplasty procedures.

Editorial: Frontiers in Synaptic Plasticity: Dendritic Spines, Circuitries and Behavior.

Editorial: Frontiers in Synaptic Plasticity: Dendritic Spines, Circuitries and Behavior.

Crossed Module Actions on Continuous Trace C*-Algebras

We lift an action of a torus $\mathbb{T}^n$ on the spectrum of a continuous trace algebra to an action of a certain crossed module of Lie groups that is an extension of $\mathbb{R}^n$. We compute equivariant Brauer and Picard groups for this crossed module and describe the obstruction to the existence of an action of $\mathbb{R}^n$ in our framework.

Evaluation of antioxidative, analgesic and anti-inflammatory activities of methanolic extract of Myrica nagi leaves - an animal model approach

Myrica nagi (family Myricaceae) is commonly known as Kathphal (Hindi) and Bayberry (English) and it has a long history of usage in traditional medicine. It is popular actinorhizal plant for its symbiotic relationship with Frankia. This study was taken in force to estimate the analgesic, anti-inflammatory and anti-oxidative activities of methanolic extract of Myrica nagi (MMN) in an animal model. Anti-oxidative property of MMN was assessed by free radical scavenging assay (DPPH method). The acute toxicity test of methanolic extract of MMN revealed that the median lethal dose (LD50) was found to be 2080 mg/kg body weight in mice. The anti-inflammatory property was evaluated by carrageenan-induced acute inflammation in rats by measuring rat paw volume at different time intervals and toxicological analysis using mice. The analgesic effect was measured in Wistar rats using the acetic acid-induced writhing test and MMN at 200 mg/kg BW showed 54.56 % inhibition of writhing. MMN showed higher anti-oxidant activity in DPPH assays as compared to standard. High dose of MMN showed a significant reduction (21.71 %) in inflammation after 4 h of treatment, which was comparable to diclofenac (10 mg/kg BW; 32.75 %)-treated group. Significant reduction (p < 0.05) in the levels of inflammatory cytokine (IL-1β and TNF-α) markers were also observed in serum of MMN-treated animals as compared to control. Taken together, the phenolic compounds of MMN may serve as potential herbal drug for amelioration of acute inflammation due to their modulatory action on free radicals.

Role of Vitamin D in Hospitalized Children With Lower Tract Acute Respiratory Infections.

Vitamin D is known to have modulatory actions in the immune system. Its influence on the severity of lower tract acute respiratory infections (LT-ARIs) is unclear. The aim of the present study was to evaluate the role of vitamin D on LT-ARI in paediatric patients. Children admitted to hospital with LT-ARI were prospectively recruited through the GENDRES network (March 2009-May 2013). The 25-hydroxyvitamin D (25-OHD) levels were measured by immunoassay. The severity of the illness was evaluated according to clinical scales, length of hospital stay, ventilatory requirements, and pediatric intensive care unit admission. A total of 347 patients with a median (interquartile range) age of 8.4 (2.6-21.1) months were included. The mean (SD) 25-OHD levels in our series were 27.1 (11.3) ng/mL. In this study, a cutoff value of ≥30 ng/mL was considered optimal vitamin status. Patients with 25-OHD levels <20 ng/mL were at a higher risk of showing severe signs of respiratory difficulties (OR 5.065, 95% confidence interval 1.998-12.842; P = 0.001) than patients with normal values, and had a 117% higher risk of oxygen necessity and 217% higher risk of ventilatory requirement than those patients with normal values. An inverse correlation was found between 25-OHD levels and the severity in the evaluated scales. 25-OHD levels did not influence PICU admission rate or length of hospital stay. 25-OHD levels of children admitted because of a LT-ARI are <30 ng/mL. Lower levels of 25-OHD were found to be correlated with severity of the disease. The possible role of abnormal 25-OHD levels as a facilitator or consequence of the infection needs further evaluation.

Abstract P2-03-02: Modulatory action of melatonin and miR-17 on ROCK-1 in breast cancer metastasis model

Abstract Breast cancer is the most common cancer in women is often associated with high morbidity and mortality rates, with great financial impact on health system. Besides, the disease is characterized by the high rates of metastasis, which worsen significantly the prognosis. This process is associated with two regulatory molecules, microRNAs (miR), specially miR-17, and ROCK-1, which overexpression has been associated to tumor growth and metastasis. In contrast, melatonin has shown oncostatic and anti-metastatic properties by reducing the cell ability to migrate and invade the tissue, besides the inhibition of cell proliferation. The aim of this study was to investigate the effect of melatonin to modulate miR-17 and ROCK-1, a possible candidate gene to miR-17 target in metastatic breast cancer cell line, MDA-MB-231. To determine the effect of melatonin to modulate miR-17 and ROCK-1, MDA-MB-231 cells were treated with melatonin and anti-miR-17-5p. ROCK-1 and miR-17 gene expression were accessed by real time PCR and ROCK-1 protein expression verified by immunocytochemistry and western blotting. Migration and invasion assay was performed to verify the action of melatonin and anti-miR-17-5p to inhibit these processes. In the in vivo study, was developed pulmonary metastasis model followed for six weeks, the tumor induction was continued for 4 weeks, and treatment with anti-miR-17-5p inhibitor for two more weeks. At the end of treatment, animals were euthanized, the lungs removed and used for analysis of miR-17-5p and Let-7c (positive control) and ROCK-1 gene expression. ROCK-1 protein was analyzed by immunohistochemistry. MiR17-5p inhibition managed directly modulate gene and protein expression of ROCK-1 in MDA-MB-231 cells, as well, the gene expression of MYC. In additional, the migration and invasion were decreased after melatonin and anti-miR-17-5p treatment. To validate the findings of the study in vitro with miR-17, was used for lung metastasis model in athymic nude mice. According to our findings, normal animals without metastasis (negative control) had lower levels of miR-17 compared to animals with metastasis and without treatment (positive control). In contrast, animals with metastasis who received anti-miR17-5p treatment, interestingly also had low miR-17 levels compared to positive control animals. Furthermore, it was observed fewer metastases and a reduction in ROCK-1 protein expression in these treated animals compared to positive control animals. Our results demonstrated that miR-17-5p inhibition can modulate ROCK-1 gene and protein in MDA-MB-231 cells and decreasing the number of lung metastases in treated animals. Furthermore, melatonin can act as a synergic mechanism to decrease migration and invasion on metastasis processes mediated by ROCK-1. Citation Format: Borin TF, Pongeluppi RI, Gelaleti GB, Leonel C, Moschetta MG, Ferreira LC, Zuccari DAPdC. Modulatory action of melatonin and miR-17 on ROCK-1 in breast cancer metastasis model. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-03-02.

Syntaxin-3 Binds and Regulates Both R- and L-Type Calcium Channels in Insulin-Secreting INS-1 832/13 Cells.

Syntaxin (Syn)-1A mediates exocytosis of predocked insulin-containing secretory granules (SGs) during first-phase glucose-stimulated insulin secretion (GSIS) in part via its interaction with plasma membrane (PM)-bound L-type voltage-gated calcium channels (Cav). In contrast, Syn-3 mediates exocytosis of newcomer SGs that accounts for second-phase GSIS. We now hypothesize that the newcomer SG Syn-3 preferentially binds and modulates R-type Cav opening, which was postulated to mediate second-phase GSIS. Indeed, glucose-stimulation of pancreatic islet β-cell line INS-1 induced a predominant increase in interaction between Syn-3 and Cavα1 pore-forming subunits of R-type Cav2.3 and to lesser extent L-type Cavs, while confirming the preferential interactions between Syn-1A with L-type (Cav1.2, Cav1.3) Cavs. Consistently, direct binding studies employing heterologous HEK cells confirmed that Syn-3 preferentially binds Cav2.3, whereas Syn-1A prefers L-type Cavs. We then used siRNA knockdown (KD) of Syn-3 in INS-1 to study the endogenous modulatory actions of Syn-3 on Cav channels. Syn-3 KD enhanced Ca2+ currents by 46% attributed mostly to R- and L-type Cavs. Interestingly, while the transmembrane domain of Syn-1A is the putative functional domain modulating Cav activity, it is the cytoplasmic domain of Syn-3 that appears to modulate Cav activity. We conclude that Syn-3 may mimic Syn-1A in the ability to bind and modulate Cavs, but preferring Cav2.3 to perhaps participate in triggering fusion of newcomer insulin SGs during second-phase GSIS.

Pre-emptive analgesia and its supraspinal mechanisms: enhanced descending inhibition and decreased descending facilitation by dexmedetomidine.

Despite the clinical importance of pre-emptive analgesia, the mechanisms by which it attenuates pain associated with central sensitization are poorly understood. We find that fentanyl and the α2-adrenoceptor agonist dexmedetomidine (Dex) differ significantly in their modulatory actions on noxious mechanical and noxious heat-evoked nociception in vivo. Unlike fentanyl, Dex modified descending control of nociception by decreasing the threshold for descending inhibition and/or increasing the threshold for descending facilitation. Dex exhibited after-actions on activities of thalamus in prolongation of noxious heat-evoked paw withdrawal latency that persisted for at least 7 days. This study provides insight into the organization of thalamic modulation in pre-emptive analgesia. We investigated and compared the antinociceptive effects of intraperitoneal administration of fentanyl (2-60 μg kg(-1)) and dexmedetomidine (Dex, 1-10 μg kg(-1); a highly selective α2-adrenoceptor agonist) in the regulation of nociception assessed by measuring noxious paw withdrawal reflexes in rats. Fentanyl elevated noxious mechanical paw withdrawal threshold and prolonged paw withdrawal heat latency within 1-1.5 h (P < 0.05). Dex failed to affect the mechanical paw withdrawal threshold, yet significantly prolonged the paw withdrawal heat latency in a bi-phasic manner; a short transient 1-1.5 h period followed by a second, slowly developing increase in latency that persisted for at least 7 days (P < 0.05). Lesion of the dorsolateral funiculus (DLF) did not influence fentanyl-induced antinociceptive effects, indicating peripheral and spinal antinociceptive mechanisms. By contrast, the Dex-induced second, but not the first, phase of the prolonged paw withdrawal heat latency was significantly blocked by the lesion of either DLF or thalamic ventromedial (VM) nuclei, and was attenuated by intracerebral administration of either atipamezole (α2-adrenoceptor antagonist) or WAY-100635 (5-HT1A receptor antagonist) into the VM nuclei (P < 0.05). Upon intramuscular 5.8% saline-induced muscle nociception, pre-emptive injection of fentanyl enhanced mechanical hyperalgesia and blocked heat hypoalgesia, whereas Dex significantly prevented the occurrence of mechanical hyperalgesia and enhanced heat hypoalgesia. It is suggested that Dex, but not fentanyl, significantly enhances descending inhibition and/or decreases descending facilitation to modulate pain and nociception. The present study provides novel insight into thalamus-mediated mechanisms in pre-emptive analgesia.

Post-infectious irritable bowel syndrome (PI-IBS) after infection with Shiga-like toxin-producing Escherichia coli (STEC) O104:H4: A cohort study with prospective follow-up.

In May/June 2011, the new Shiga-like toxin-producing Escherichia coli (STEC) strain O104:H4 caused the severest outbreak ever recorded of hemorrhagic enterocolitis in 3842 patients in Germany. As bacterial enterocolitis is an established risk factor of subsequent irritable bowel syndrome (IBS), we aimed to estimate prevalence and incidence of post-infectious (PI)-IBS after six and 12 months in a cohort of STEC O104:H4 patients and to prospectively identify associated somatic and psychometric risk factors. A total of 389 patients were studied prospectively at baseline and at six and 12 months after STEC infection using STEC disease-related questionnaires and validated instruments for IBS (Rome III) and psychological factors. Frequencies and logistic regression models using multiple imputations were applied to assess predictor variables. Prevalence of IBS increased from 9.8% prior to STEC infection to 23.6% at six and 25.3% at 12 months after STEC infection. In patients without IBS symptoms prior to STEC infection, incidence of new IBS was 16.9%. Logistic regression models indicated higher somatization and anxiety scores as risk factors for, and mesalazine treatment during, STEC infection as the only significant protective factor against IBS. No other factor analyzed, including disease severity, showed an association. PI-IBS rates following this unusually severe STEC outbreak were similar to what has been observed after other infectious gastroenteritis outbreaks. Our findings suggest that mesalazine may have reduced the risk of subsequent PI-IBS. As altered mucosal immune activity is a pivotal pathogenic factor in PI-IBS, our observation of a potential protective effect of mesalazine might be explained by its known modulatory action on mucosal immunity, and may warrant further investigation.

Antagonistic Effect of a Salivary Proline-Rich Peptide on the Cytosolic Ca2+ Mobilization Induced by Progesterone in Oral Squamous Cancer Cells.

A salivary proline-rich peptide of 1932 Da showed a dose-dependent antagonistic effect on the cytosolic Ca2+ mobilization induced by progesterone in a tongue squamous carcinoma cell line. Structure-activity studies showed that the activity of the peptide resides in the C-terminal region characterized by a proline stretch flanked by basic residues. Furthermore, lack of activity of the retro-inverso peptide analogue suggested the involvement of stereospecific recognition. Mass spectrometry-based shotgun analysis, combined with Western blotting tests and biochemical data obtained with the Progesterone Receptor Membrane Component 1 (PGRMC1) inhibitor AG205, showed strong evidence that p1932 performs its modulatory action through an interaction with the progesterone receptor PGRMC1, which is predominantly expressed in this cell line and, clearly, plays a role in progesterone induced Ca2+ response. Thus, our results point to p1932 as a modulator of the transduction signal pathway mediated by this protein and, given a well-established involvement of PGRMC1 in tumorigenesis, highlight a possible therapeutic potential of p1932 for the treatment of oral cancer.

Editorial: Crosstalk between the Osteogenic and Neurogenic Stem Cell Niches: How Far are They from Each Other?

Editorial: Crosstalk between the Osteogenic and Neurogenic Stem Cell Niches: How Far are They from Each Other?

The multi-facet aspects of cell sentience and their relevance for the integrative brain actions: role of membrane protein energy landscape.

Several ion channels can be randomly and spontaneously in an open state, allowing the exchange of ion fluxes between extracellular and intracellular environments. We propose that the random changes in the state of ion channels could be also due to proteins exploring their energy landscapes. Indeed, proteins can modify their steric conformation under the effects of the physicochemical parameters of the environments with which they are in contact, namely, the extracellular, intramembrane and intracellular environments. In particular, it is proposed that the random walk of proteins in their energy landscape is towards attractors that can favor the open or close condition of the ion channels and/or intrinsic activity of G-protein-coupled receptors. The main aspect of the present proposal is that some relevant physicochemical parameters of the environments (e.g. molecular composition, temperature, electrical fields) with which some signaling-involved plasma membrane proteins are in contact alter their conformations. In turn, these changes can modify their information handling via a modulatory action on their random walk towards suitable attractors of their energy landscape. Thus, spontaneous and/or signal-triggered electrical activities of neurons occur that can have emergent properties capable of influencing the integrative actions of brain networks. Against this background, Cook's hypothesis on 'cell sentience' is developed by proposing that physicochemical parameters of the environments with which the plasma-membrane proteins of complex cellular networks are in contact fulfill a fundamental role in their spontaneous and/or signal-triggered activity. Furthermore, it is proposed that a specialized organelle, the primary cilium, which is present in most cells (also neurons and astrocytes), could be of peculiar importance to pick up chemical signals such as ions and transmitters and to detect physical signals such as pressure waves, thermal gradients, and local field potentials.

Genotoxic potential of Cynanchum sarcomedium Meve &amp; Liede coupled with its modulatory action on oxidative-stress–mediatedgenotoxicity by hydrogen peroxide

The present study evaluated the genotoxic effect of aqueous extract of C. sarcomedium Meve and Liede and its protective role in chromosomal aberrations induced by 2% hydrogen peroxide (H2O2) on Allium cepa root meristem. Our results showed that the C. sarcomedium extract induced major chromosomal aberrations, viz., nuclear lesions, chromosome breaks, chromosome laggards, vagrance, stickiness, and bridges. These are irreversible in nature and indicate that the plant is a potent clastogen. Total chromosome aberrations were more frequent with increase in exposure time and concentrations of plant extract. For antigenotoxic screening, three different modes of treatment were used: pretreatment, posttreatment, and simultaneous treatment. The significant induction of a wide spectrum of chromosomal aberrations and the reduction in mitotic index effected by the aqueous extract reinforced the genotoxic potential of the plant. The modulatory effect of plant extract was expressed in terms of inhibition percentage and had an excellent effect in reversing chromosomal aberrations induced by H2O2. Dose-dependent results suggest the genotoxic and antigenotoxic effect of C. sarcomedium on onion root tips. These findings offer a useful basis for further investigations on C. sarcomedium, a shrub with a broad array of prospective therapeutic activities.

Modulatory Action by the Serotonergic System: Behavior and Neurophysiology in Drosophila melanogaster.

Serotonin modulates various physiological processes and behaviors. This study investigates the role of 5-HT in locomotion and feeding behaviors as well as in modulation of sensory-motor circuits. The 5-HT biosynthesis was dysregulated by feeding Drosophila larvae 5-HT, a 5-HT precursor, or an inhibitor of tryptophan hydroxylase during early stages of development. The effects of feeding fluoxetine, a selective serotonin reuptake inhibitor, during early second instars were also examined. 5-HT receptor subtypes were manipulated using RNA interference mediated knockdown and 5-HT receptor insertional mutations. Moreover, synaptic transmission at 5-HT neurons was blocked or enhanced in both larvae and adult flies. The results demonstrate that disruption of components within the 5-HT system significantly impairs locomotion and feeding behaviors in larvae. Acute activation of 5-HT neurons disrupts normal locomotion activity in adult flies. To determine which 5-HT receptor subtype modulates the evoked sensory-motor activity, pharmacological agents were used. In addition, the activity of 5-HT neurons was enhanced by expressing and activating TrpA1 channels or channelrhodopsin-2 while recording the evoked excitatory postsynaptic potentials (EPSPs) in muscle fibers. 5-HT2 receptor activation mediates a modulatory role in a sensory-motor circuit, and the activation of 5-HT neurons can suppress the neural circuit activity, while fluoxetine can significantly decrease the sensory-motor activity.

Chemical Characterization and Cytoprotective Effect of the Hydroethanol Extract from Annona coriacea Mart. (Araticum).

Introduction:Annona coriacea Mart. (araticum) is a widely distributed tree in the cerrado. Its value is attributed principally to the consumption of its fruit which possesses a large nutritive potential. The objective was to identify the chemical profile and evaluate the antimicrobial and cytoprotective activity of the hydroethanol extract of A. coriacea Mart. (HEAC) leaves against the toxicity of mercury chloride.Materials and Methods:The characterization of components was carried out using high-performance liquid chromatography (HPLC). The minimum inhibitory concentration (MIC) was determined by microdilution method in broth with strains of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. For evaluation of the modulatory and cytoprotective activity of aminoglycoside antibiotics (gentamicin and amikacin) and mercury chloride (HgCl2), the substances were associated with the HEAC at subinhibitory concentrations (MIC/8).Results and Discussion:The HPLC analysis revealed the presence of flavonoids such as Luteolin (1.84%) and Quercetin (1.19%) in elevated concentrations. The HEAC presented an MIC ≥512 μg/mL and significant antagonistic action in aminoglycosides modulation, and it also showed cytoprotective activity to S. aureus (significance P < 0.0001) and E. coli (significance P < 0.05) bacteria against the mercury chloride heavy metal with significance, this action being attributed to the chelating properties of the flavonoids found in the chemical identification.Conclusions:The results acquired in this study show that the HEAC presents cytoprotective activity over the tested strains in vitro and can also present antagonistic effect when associated with aminoglycosides, reinforcing the necessity of taking caution when combining natural and pharmaceutical products.SUMMARY The hydroalcoholic extract of A. coriacea Mart. presents in vitro cytoprotective activity against the toxic effect of Hg. Abbreviations Used: HPLC-DAD: High-performance liquid chromatography with a diode array detector; MIC: Minimum inhibitory concentration; DMSO: Dimethyl sulfoxide

CHOICE OF SILVER DRUGS IN THERAPY OF RHINOSINUSITIS AT CHILDREN AGE

The article describes major etiological factors and mechanisms of rhinosinusitis, traditional approaches to therapy of rhinosinusitis in children. Special attention is given to mechanisms of intense antiseptic, antifungal and immune modulating action of silver. The article presents Protargol drug that can be prepared immediately before application. Due to the silver proteinate with antiseptic, anti-inflammatory and binding effects Protargol can be used for therapy of acute and chronic rhinosinusitis in children.

Pain Management in Knee Arthroplasty: An Overview

Perioperative pain management after knee arthroplasty has undergone a conceptual revolution in the last decade. Along with other exciting innovations, including minimally invasive techniques, computer-assisted procedures and a significant stride in tribology, understanding pain modulation and drug action at molecular level is recognized as the game changer in arthroplasty surgeries.

Effects of adrenomedullin on the expression of inflammatory cytokines and chemokines in oviducts from women with tubal ectopic pregnancy: an in-vitro experimental study

BackgroundThe occurrence of tubal ectopic pregnancy (tEP) is related to the inflammation of the oviduct. Recently, Adrenomedullin (ADM) was found highly expression in human oviduct. The current study is to investigate whether ADM have a modulatory action on inflammatory cytokines and chemokines in oviductal tissue from women with tubal ectopic pregnancy (tEP).MethodsOviductal isthmus samples were collected from women with tEP undergoing salpingectomy, and women undergoing hysterectomy for benign gynaecological conditions. The mRNA and protein levels of inflammatory cytokines/chemokines were assayed by PCR (n = 6 for tEP, n = 5 for controls) and protein microarray methods (n = 5 for both tEP and controls) respectively.ResultsSome of the inflammatory cytokines/chemokines were upregulated by ADM in oviducts from tEP patients at both mRNA and protein levels. Incubation of oviduct from tEP patients with ADM for 24 h down-regulated some of these cytokines/chemokines.ConclusionOur results suggest an additional mechanism whereby ADM insufficiency may increase the susceptibility to tEP through diminished anti-inflammatory activity. The actual impact of the relationship between ADM and inflammatory process on tubal implantation needs further exploration.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-015-0117-x) contains supplementary material, which is available to authorized users.

Melatonin enhancement of the radiosensitivity of human breast cancer cells is associated with the modulation of proteins involved in estrogen biosynthesis

Enhancing the radiosensitivity of cancer cells is one of the most important tasks in clinical radiobiology. Endocrine therapy and radiotherapy are two cancer treatment modalities which are often given together in patients with locally-advanced breast cancer and positive hormone-receptor status. Oncostatic actions of melatonin are relevant on estrogen-dependent mammary tumors. In the present study, we wanted to evaluate the effects of the combination of ionizing radiation and melatonin on proteins involved in estrogen biosynthesis in breast cancer cells. We demonstrated a role of melatonin in mediating the sensitization of human breast cancer cells to the ionizing radiation by decreasing around 50% the activity and expression of proteins involved in the synthesis of estrogens in these cells. Thus, melatonin pretreatment before radiation reduces the amount of active estrogens at cancer cell level. Melatonin 1 nM induced a 2-fold change in p53 expression as compared to radiation alone. The regulatory action of melatonin on p53 could be a link between melatonin and its modulatory action on the sensitivity of breast cancer cells to ionizing radiation. These findings may have implications for designing clinical trials using melatonin and radiotherapy.