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Nature Communications Jan 2024Clinical efficacy of intranasal administration of oxytocin is increasingly explored in autism spectrum disorder, but to date, the biological effects of chronic... (Randomized Controlled Trial)
Randomized Controlled Trial
Clinical efficacy of intranasal administration of oxytocin is increasingly explored in autism spectrum disorder, but to date, the biological effects of chronic administration regimes on endogenous oxytocinergic function are largely unknown. Here exploratory biological assessments from a completed randomized, placebo-controlled trial showed that children with autism (n = 79, 16 females) receiving intranasal oxytocin for four weeks (12 IU, twice daily) displayed significantly higher salivary oxytocin levels 24 hours after the last oxytocin nasal spray administration, but no longer at a four-week follow up session. Regarding salivary oxytocin receptor gene (OXTR) epigenetics (DNA-methylation), oxytocin-induced reductions in OXTR DNA-methylation were observed, suggesting a facilitation of oxytocin receptor expression in the oxytocin compared to the placebo group. Notably, heightened oxytocin levels post-treatment were significantly associated with reduced OXTR DNA-methylation and improved feelings of secure attachment. These findings indicate that four weeks of chronic oxytocin administration stimulated the endogenous oxytocinergic system in children with autism.
Topics: Child; Female; Humans; Oxytocin; Autistic Disorder; Receptors, Oxytocin; Autism Spectrum Disorder; Administration, Intranasal; DNA
PubMed: 38167302
DOI: 10.1038/s41467-023-44334-4 -
Sheng Li Xue Bao : [Acta Physiologica... Feb 2024Prostaglandin E (PGE2) is an important lipid molecule derived from arachidonic acid, which regulates a variety of physiological and pathological activities. Based on the... (Review)
Review
Prostaglandin E (PGE2) is an important lipid molecule derived from arachidonic acid, which regulates a variety of physiological and pathological activities. Based on the inhibition of inflammatory PGE production, non-steroidal anti-inflammatory drugs (NSAIDs) are considered as the most commonly used drugs to treat inflammatory diseases and to relieve fever and pain symptoms. PGE mediates its functions via four different G protein-coupled receptors, named EP1-EP4. Though the limited distribution and low PGE affinity of EP1, it plays important roles in the maintenance of many physiological functions and homeostasis. Moreover, EP1 is widely involved in the inflammatory response, pain perception and multisystem pathological function regulation. In this review, we will briefly summarize the recent advances on the physiological and pathophysiological function of EP1 and its targeted drugs development.
Topics: Humans; Arachidonic Acid; Dinoprostone; Homeostasis; Pain
PubMed: 38444136
DOI: No ID Found -
Scientific Reports Nov 2023Tumor-associated inflammation plays a vital role in cancer progression. Among the various stromal cells, cancer-associated fibroblasts are promising targets for cancer...
Tumor-associated inflammation plays a vital role in cancer progression. Among the various stromal cells, cancer-associated fibroblasts are promising targets for cancer therapy. Several reports have indicated potent anti-inflammatory effects attributed to Curcumin. This study aimed to investigate whether inhibiting the inflammatory function of cancer-associated fibroblasts (CAFs) with Curcumin can restore anticancer immune responses. CAFs were isolated from breast cancer tissues, treated with Curcumin, and co-cultured with patients' PBMCs to evaluate gene expression and cytokine production alterations. Blood and breast tumor tissue samples were obtained from 12 breast cancer patients with stage II/III invasive ductal carcinoma. Fibroblast Activation Protein (FAP) + CAFs were extracted from tumor tissue, treated with 10 μM Curcumin, and co-cultured with corresponding PBMCs. The expression of smooth muscle actin-alpha (α-SMA), Cyclooxygenase-2(COX-2), production of PGE2, and immune cell cytokines were evaluated using Real-Time PCR and ELISA, respectively. Analyzes showed that treatment with Curcumin decreased the expression of genes α-SMA and COX-2 and the production of PGE2 in CAFs. In PBMCs co-cultured with Curcumin-treated CAFs, the expression of FoxP3 decreased along with the production of TGF-β, IL-10, and IL-4. An increase in IFN-γ production was observed that followed by increased T-bet expression. According to our results, Curcumin could reprogram the pro-tumor phenotype of CAFs and increase the anti-tumor phenotype in PBMCs. Thus, CAFs, as a component of the tumor microenvironment, are a suitable target for combination immunotherapies of breast cancer.
Topics: Humans; Female; Breast Neoplasms; Cancer-Associated Fibroblasts; Curcumin; Cyclooxygenase 2; Dinoprostone; Fibroblasts; Inflammation; Cell Line, Tumor; Tumor Microenvironment
PubMed: 38008819
DOI: 10.1038/s41598-023-48073-w -
Translational Psychiatry Jan 2024Non-suicidal self-injury (NSSI) is a transdiagnostic psychiatric symptom with high prevalence and relevance in child and adolescent psychiatry. Therefore, it is of great...
Non-suicidal self-injury (NSSI) is a transdiagnostic psychiatric symptom with high prevalence and relevance in child and adolescent psychiatry. Therefore, it is of great interest to identify a biological phenotype associated with NSSI. The aim of the present study was to cross-sectionally investigate patterns of biological markers underlying NSSI and associated psychopathology in a sample of female patients and healthy controls. Comprehensive clinical data, saliva and blood samples, heart rate variability and pain sensitivity, were collected in n = 149 patients with NSSI and n = 40 healthy participants. Using machine-based learning, we tested the extent to which oxytocin, dehydroepiandrosterone (DHEA), beta-endorphin, free triiodothyronine (fT3), leukocytes, heart rate variability and pain sensitivity were able to classify participants regarding their clinical outcomes in NSSI, depression and borderline personality disorder symptomatology. We evaluated the predictive performance of several models (linear and logistic regression, elastic net regression, random forests, gradient boosted trees) using repeated cross-validation. With NSSI as an outcome variable, both logistic regression and machine learning models showed moderate predictive performance (Area under the Receiver Operating Characteristic Curve between 0.67 and 0.69). Predictors with the highest predictive power were low oxytocin (OR = 0.55; p = 0.002), low pain sensitivity (OR = 1.15; p = 0.021), and high leukocytes (OR = 1.67; p = 0.015). For the psychopathological outcome variables, i.e., depression and borderline personality disorder symptomatology, models including the biological variables performed not better than the null model. A combination of hormonal and inflammatory markers, as well as pain sensitivity, were able to discriminate between participants with and without NSSI disorder. Based on this dataset, however, complex machine learning models were not able to detect non-linear patterns of associations between the biological markers. These findings need replication and future research will reveal the extent to which the respective biomarkers are useful for longitudinal prediction of clinical outcomes or treatment response.
Topics: Child; Humans; Adolescent; Oxytocin; Phenotype; Pain Threshold; Machine Learning; Self-Injurious Behavior; Biomarkers
PubMed: 38267430
DOI: 10.1038/s41398-024-02776-4 -
EBioMedicine Nov 2023Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis and it is characterized by predominant pro-tumor Th2-type inflammation. T follicular helper (Tfh) cells...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis and it is characterized by predominant pro-tumor Th2-type inflammation. T follicular helper (Tfh) cells are relevant immunoregulators in cancer, and often correlate with better survival. How the Th2-skewed microenvironment in PDAC modulates the differentiation of Tfh cells and their immunoregulatory function is unknown.
METHODS
We carried out high-dimensional flow cytometry and T-cell receptor- and RNA-sequencing, as well as bioinformatics, immunohistochemistry and in vitro mechanistic studies.
FINDINGS
We identified Tfh1-, Tfh2-, and Tfh17-like cell clusters in the blood, tumors and tumor-draining lymph-nodes (TDLNs) of chemo-naïve PDAC patients and showed that high percentages of Tfh2 cells within the tumor tissue and TDLNs correlated with reduced patient survival. Moreover, only Tfh2 cells were highly activated and were reduced in frequency in patients who responded to neoadjuvant chemotherapy. RNA-sequencing analysis of immunoglobulin expression showed that tumor and TDLN samples expressed all immunoglobulin (IGH) isotypes apart from IGHE. Consistent with these findings, Tfh2 cells differentiated in vitro by tumor microenvironment-conditioned dendritic cells promoted the production of anti-inflammatory IgG4 antibodies by co-cultured B cells, dependent on IL-13. Moreover, unexpectedly, Tfh2 cells inhibited the secretion of pro-inflammatory IgE, dependent on prostaglandin E.
INTERPRETATION
Our results indicate that in PDAC, highly activated pro-tumor Tfh2 favor anti-inflammatory IgG4 production, while inhibit pro-inflammatory IgE. Thus, targeting the circuits that drive Tfh2 cells, in combination with chemotherapy, may re-establish beneficial anti-tumor Tfh-B cell interactions and facilitate more effective treatment.
FUNDING
Research grants from the Italian Association for Cancer Research (AIRC) IG-19119 to MPP and the AIRC Special Program in Metastatic disease: the key unmet need in oncology, 5 per Mille no. 22737 to CB, MF, CD, MR and MPP; the ERA-NET EuroNanoMed III (a collaborative european grant financed by the Italian Ministry of Health, Italy) project PANIPAC (JTC2018/041) to MPP; the Fondazione Valsecchi to SC.
Topics: Humans; Immunoglobulin G; Dinoprostone; Pancreatic Neoplasms; Immunoglobulin E; Anti-Inflammatory Agents; RNA; Tumor Microenvironment
PubMed: 37776595
DOI: 10.1016/j.ebiom.2023.104819 -
Cell Communication and Signaling : CCS Apr 2024VEGFR2 (Vascular endothelial growth factor receptor 2) is a central regulator of placental angiogenesis. The study of the VEGFR2 proteome of chorionic villi at term...
VEGFR2 (Vascular endothelial growth factor receptor 2) is a central regulator of placental angiogenesis. The study of the VEGFR2 proteome of chorionic villi at term revealed its partners MDMX (Double minute 4 protein) and PICALM (Phosphatidylinositol-binding clathrin assembly protein). Subsequently, the oxytocin receptor (OT-R) and vasopressin V1aR receptor were detected in MDMX and PICALM immunoprecipitations. Immunogold electron microscopy showed VEGFR2 on endothelial cell (EC) nuclei, mitochondria, and Hofbauer cells (HC), tissue-resident macrophages of the placenta. MDMX, PICALM, and V1aR were located on EC plasma membranes, nuclei, and HC nuclei. Unexpectedly, PICALM and OT-R were detected on EC projections into the fetal lumen and OT-R on 20-150 nm clusters therein, prompting the hypothesis that placental exosomes transport OT-R to the fetus and across the blood-brain barrier. Insights on gestational complications were gained by univariable and multivariable regression analyses associating preeclampsia with lower MDMX protein levels in membrane extracts of chorionic villi, and lower MDMX, PICALM, OT-R, and V1aR with spontaneous vaginal deliveries compared to cesarean deliveries before the onset of labor. We found select associations between higher MDMX, PICALM, OT-R protein levels and either gravidity, diabetes, BMI, maternal age, or neonatal weight, and correlations only between PICALM-OT-R (p < 2.7 × 10), PICALM-V1aR (p < 0.006), and OT-R-V1aR (p < 0.001). These results offer for exploration new partnerships in metabolic networks, tissue-resident immunity, and labor, notably for HC that predominantly express MDMX.
Topics: Female; Humans; Infant, Newborn; Pregnancy; Diabetes Mellitus; Gravidity; Oxytocin; Placenta; Pre-Eclampsia; Proteomics; Receptors, Oxytocin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2
PubMed: 38594674
DOI: 10.1186/s12964-024-01567-0 -
Brain and Behavior Dec 2023Posttraumatic stress disorder (PTSD) is a complex and heterogeneous mental health condition that can develop after exposure to a traumatic event. Clinical trials have... (Review)
Review
BACKGROUND
Posttraumatic stress disorder (PTSD) is a complex and heterogeneous mental health condition that can develop after exposure to a traumatic event. Clinical trials have used alternative pharmacological agents to treat PTSD, but their associated neural correlates remain unclear. The present systematic review aims to summarize the changes in brain function associated with the use of these alternative pharmacological agents in PTSD.
METHODS
Clinical trials using functional magnetic resonance imaging, either at rest or during the performance of tasks, were included if they compared the effects of alternative pharmacological agents between PTSD patients and either trauma-exposed controls or never-exposed healthy controls.
RESULTS
Sixteen studies were included, of which 11 used intranasal oxytocin, 2 used hydrocortisone, and 3 used delta-9-tetrahydrocannabinol (THC). Oxytocin administration was associated with the normalization of functional connectivity between the ventromedial prefrontal cortex and amygdala as well as enhanced the function of brain regions specifically involved in emotion processing (e.g., amygdala), working memory (e.g., dorsolateral prefrontal cortex), and reward (e.g., putamen). Hydrocortisone did not influence brain function at rest or during the performance of an autobiographical memory task, whereas THC was associated with the reduction of the amygdala and increased medial prefrontal cortex activation.
CONCLUSIONS
This systematic review identified preliminary evidence for normalizing brain function after the use of alternative pharmacological agents. Importantly, sex-specific differences were noted, in particular when using oxytocin, that will require further investigation.
Topics: Female; Humans; Male; Brain; Emotions; Hydrocortisone; Magnetic Resonance Imaging; Oxytocin; Stress Disorders, Post-Traumatic; Clinical Trials as Topic
PubMed: 37864378
DOI: 10.1002/brb3.3292 -
Sheng Li Xue Bao : [Acta Physiologica... Apr 2024Chronic liver disease (CLD) is a major global health burden in terms of growing morbidity and mortality. Although many conditions can cause CLD, leading to cirrhosis and... (Review)
Review
Chronic liver disease (CLD) is a major global health burden in terms of growing morbidity and mortality. Although many conditions can cause CLD, leading to cirrhosis and hepatocellular carcinoma (HCC), viral hepatitis, drug-induced liver injury (DILI), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are the most common culprits. Prostaglandin E (PGE), produced in the liver, is an important lipid mediator derived from the ω-6 polyunsaturated fatty acid, arachidonic acid, and plays a critical role in hepatic homeostasis. The physiological effects of PGE are mediated through four classes of E-type prostaglandin (EP) receptors, namely EP1, EP2, EP3 and EP4. In recent years, an increasing number of studies has been done to clarify the effects of PGE and EP receptors in regulating liver function and the pathogenesis of CLD to create a new potential clinical impact. In this review, we overview the biosynthesis and regulation of PGE and discuss the role of its synthesizing enzymes and receptors in the maintenance of normal liver function and the development and progress of CLD. We also discuss the potential of the PGE-EP receptors system in treating CLD with various etiologies.
Topics: Humans; Dinoprostone; Receptors, Prostaglandin E; Liver Diseases; Chronic Disease; Animals; Liver; Liver Diseases, Alcoholic; Non-alcoholic Fatty Liver Disease
PubMed: 38658381
DOI: No ID Found -
BMC Complementary Medicine and Therapies Sep 2023We reported a gastric anti-ulcerogenic effect of the Nigella sativa (L.)-derived herbal melanin (HM) using rat models. However, the molecular mechanisms underlying this...
We reported a gastric anti-ulcerogenic effect of the Nigella sativa (L.)-derived herbal melanin (HM) using rat models. However, the molecular mechanisms underlying this HM gastroprotective effect remain unknown. Cyclooxygenase-2 (COX-2)-catalyzed prostaglandin E2 (PGE2) and toll-like receptor 4 (TLR4)-mediated interleukin-6 (IL-6) production and secretion play major roles in gastric mucosal protection. In the current study, the human gastric carcinoma epithelial cell line AGS was used as a model to investigate the effect of HM on TLR4, COX-2, glycoprotein mucin 4 protein and gene expression using immuno-cyto-fluorescence staining, Western blot technology, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Gastroprotective markers PGE2 and IL-6 production and secretion were also assessed using an enzyme-linked immunosorbent assay (ELISA). Bacterial lipopolysaccharides (LPS), well-known inducers of TLR4, COX-2, PGE2 and IL-6 expression, were used as a positive control. We showed that HM upregulated its main receptor TLR4 gene and protein expression in AGS cells. HM increased, in a dose- and time-dependent manner, the secretion of PGE2 and the expression of COX-2 mRNA and protein, which was detected in the nucleus, cytoplasm and predominantly at the intercellular junctions of the AGS cells. In addition, HM enhanced IL-6 production and secretion, and upregulated the mucin 4 gene expression, the hallmarks of gastroprotection. To check whether HM-induced PGE2 and IL-6 through TLR4 signaling and COX-2 generated, AGS cells were pre-treated with a TLR4 signaling inhibitor TAK242 and the COX-2 inhibitor NS-398. A loss of the stimulatory effects of HM on COX-2, PGE2 and IL-6 production and secretion was observed in TAK242 and NS-398-pre-treated AGS cells, confirming the role of TLR4 signaling and COX-2 generated in the HM gastroprotective effects. In conclusion, our results showed that HM enhances TLR4/COX-2-mediated secretion of gastroprotective markers PGE2 and IL-6, and upregulates mucin 4 gene expression in the human gastric epithelial cell line AGS, which may contribute to the promising beneficial gastroprotective effect of HM for human gastric prevention and treatment.
Topics: Humans; Animals; Rats; Stomach Neoplasms; Melanins; Cyclooxygenase 2; Dinoprostone; Toll-Like Receptor 4; Interleukin-6; Mucin-4
PubMed: 37658354
DOI: 10.1186/s12906-023-04124-3 -
Biology of Reproduction Sep 2023Cyclic regression of the ovarian corpus luteum, the endocrine gland responsible for progesterone production, involves rapid matrix remodeling. Despite fibroblasts in...
Cyclic regression of the ovarian corpus luteum, the endocrine gland responsible for progesterone production, involves rapid matrix remodeling. Despite fibroblasts in other systems being known for producing and maintaining extracellular matrix, little is known about fibroblasts in the functional or regressing corpus luteum. Vast transcriptomic changes occur in the regressing corpus luteum, among which are reduced levels of vascular endothelial growth factor A (VEGFA) and increased expression of fibroblast growth factor 2 (FGF2) after 4 and 12 h of induced regression, when progesterone is declining and the microvasculature is destabilizing. We hypothesized that FGF2 activates luteal fibroblasts. Analysis of transcriptomic changes during induced luteal regression revealed elevations in markers of fibroblast activation and fibrosis, including fibroblast activation protein (FAP), serpin family E member 1 (SERPINE1), and secreted phosphoprotein 1 (SPP1). To test our hypothesis, we treated bovine luteal fibroblasts with FGF2 to measure downstream signaling, type 1 collagen production, and proliferation. We observed rapid and robust phosphorylation of various signaling pathways involved in proliferation, such as ERK, AKT, and STAT1. From our longer-term treatments, we determined that FGF2 has a concentration-dependent collagen-inducing effect, and that FGF2 acts as a mitogen for luteal fibroblasts. FGF2-induced proliferation was greatly blunted by inhibition of AKT or STAT1 signaling. Our results suggest that luteal fibroblasts are responsive to factors that are released by the regressing bovine corpus luteum, an insight into the contribution of fibroblasts to the microenvironment in the regressing corpus luteum.
Topics: Animals; Cattle; Female; Cell Proliferation; Collagen; Corpus Luteum; Dinoprost; Fibroblast Growth Factor 2; Fibroblasts; Luteolysis; Progesterone; Proto-Oncogene Proteins c-akt; Vascular Endothelial Growth Factor A
PubMed: 37283496
DOI: 10.1093/biolre/ioad065