Narrative Review of the Complex Interaction between Pain and Trauma in Children: A Focus on Biological Memory, Preclinical Data, and Epigenetic Processes

The incidence and collective impact of early adverse experiences, trauma, and pain continue to increase. This underscores the urgent need for translational efforts between clinical and preclinical research to better understand the underlying mechanisms and develop effective therapeutic approaches. As our understanding of these issues improves from studies in children and adolescents, we can create more precise preclinical models and ultimately translate our findings back to clinical practice. A multidisciplinary approach is essential for addressing the complex and wide-ranging effects of these experiences on individuals and society. This narrative review aims to (1) define pain and trauma experiences in childhood and adolescents, (2) discuss the relationship between pain and trauma, (3) consider the role of biological memory, (4) decipher the relationship between pain and trauma using preclinical data, and (5) examine the role of the environment by introducing the importance of epigenetic processes. The ultimate scope is to better understand the wide-ranging effects of trauma, abuse, and chronic pain on children and adolescents, how they occur, and how to prevent or mitigate their effects and develop effective treatment strategies that address both the underlying causes and the associated physiological and psychological effects

Periarticular histiocytic sarcoma with heart metastasis in a cat

A 4-year-old intact female domestic short-haired cat was referred for recommendations about adjuvant medical treatment 1 month after left forelimb amputation due to periarticular histiocytic sarcoma (HS). At presentation, physical abnormalities were limited to enlarged ipsilateral superficial cervical and axillary lymph nodes. Routine blood analysis, abdominal ultrasound, and thoracic radiology were unremarkable. The cat initially received lomustine without any adverse events. Four weeks later, the cat developed severe acute respiratory distress. Results of thoracic radiographs and transthoracic echocardiographic analysis were suggestive of pulmonary and heart metastasis. Due to the cat's poor clinical condition and prognosis, the owner elected euthanasia, and a necropsy was performed. Based on gross pathology, histopathology, and immunohistochemistry, an HS with nodal, renal, pulmonary, and heart (right auricular and right ventricular) metastases was diagnosed. This case represents the first description of HS with a heart metastasis in a cat, providing further insight into the clinical course and metastatic behavior of this rare malignant neoplasm. Clinicians should be aware of this site of metastasis and consider HS in the list of differential diagnoses for secondary heart tumors in cats

Effect of Cromoglycate on Gas Changes, During Bronchial Challenge by UNCDW in Children with Asthma

Eighteen asthmatic children were challenged with ultrasonically nebulized cold distilled water (UNCDW). Blood gas composition was monitored transcutaneously (tcpO2 and tcpCO2) during and after the challenge. Assuming as basal the response to this UNCDW test, nine children (Group A) were then chosen at random to inhale cromoglycate by aerosol delivery for 8 days. Nine children (Group B), acting as a control, inhaled saline for 8 days. At the end of this therapy, each child repeated the UNCDW test. Statistical analysis with t-test for paired data was used to compare the results of each child to both tests. Mean basal tcpO2 and tcpCO2 were all within the expected normal range. In all children, both mean tcpO2 and tcpCO2 were reduced during and after UNCDW inhalation. Mean tcpCO2 values during the challenge were significantly (p < 0.001) lower than the corresponding steady state 2 rain after the UNCDW challenge, with a mean drop of −7% (2.1 S.D.). Mean tcpO2 values remained significantly decreased (p < 0.001) from the fifth mitt of the UNCDW challenge to the end of the observation period, with a mean drop of −20% (15.5 S.D.). After treatment with cromoglycate (Group A), the mean tcpCO2 values during UNCDW did not change significantly from those ofsteady state conditions: −0.8% (0.5 S.D.); whereas mean tcpO2 values decreased by −4% (4.9 S.D.). The control children treated with saline (Group B) showed mean tcpCO2 and tcpO2 values which were significantly different (p < 0.001) from those of the steady state conditions: mean drop of tcpCO2, −6% (4.2 S.D.); mean drop of tcpO2, −20% (4.7 S.D.). In conclusion, it emerges that: UNCDW induces nonspecific broncho-constriction in asthmatic children with a typical drop of tcpCO2 and tcpO2; the treatment with cromoglycate normalizes the time course of tcpCO2 (hyper-reactivity) and reduces dramatically the drop of tcpO2 time course (hyper-responsivity) during and after the UNCDW test

LPS-Induced Garcia Effect and Its Pharmacological Regulation Mediated by Acetylsalicylic Acid: Behavioral and Transcriptional Evidence

Lymnaea stagnalis learns and remembers to avoid certain foods when their ingestion is followed by sickness. This rapid, taste-specific, and long-lasting aversion—known as the Garcia effect—can be formed by exposing snails to a novel taste and 1 h later injecting them with lipopolysaccharide (LPS). However, the exposure of snails to acetylsalicylic acid (ASA) for 1 h before the LPS injection, prevents both the LPS-induced sickness state and the Garcia effect. Here, we investigated novel aspects of this unique form of conditioned taste aversion and its pharmacological regulation. We first explored the transcriptional effects in the snails’ central nervous system induced by the injection with LPS (25 mg), the exposure to ASA (900 nM), as well as their combined presentation in untrained snails. Then, we investigated the behavioral and molecular mechanisms underlying the LPS-induced Garcia effect and its pharmacological regulation by ASA. LPS injection, both alone and during the Garcia effect procedure, upregulated the expression levels of immune- and stress-related targets. This upregulation was prevented by pre-exposure to ASA. While LPS alone did not affect the expression levels of neuroplasticity genes, its combination with the conditioning procedure resulted in their significant upregulation and memory formation for the Garcia effect

Dysregulation of NF–Y splicing drives metabolic rewiring and aggressiveness in colon cancer

NF-Y is an evolutionarily conserved transcription factor that binds specifically to the CCAAT elements of eukaryotic genes, most of which frequently deregulated in cancer. NF-YA, the regulatory subunit of the NF-Y complex, has two isoforms generated by alternative splicing, NF-YAl and NF-YAs, which differ in the transactivation domain. Transcriptomic data from The Cancer Genome Atlas (TCGA) database highlighted a significant increase in the expression of NF-YAs at the expense of NF-YAl in colorectal cancer (CRC), compared to healthy tissues. Despite this, high NF-YAl levels predict lower patients’ survival and distinguish the mesenchymal molecular subtype CMS4, which is characterized by the worst prognosis. Through the analysis of 3D cellular models, we demonstrated that altered expression of genes related to extracellular matrix and epithelial-mesenchymal transition sustains enhanced migratory and invasive behavior of NF-YAl-transduced cells. Moreover, the integration of metabolomics, bioenergetics and transcriptional analyses demonstrated a direct role for NFYAl in metabolic flexibility of cancer cells that adjust their metabolism in response to environmental changes to potentiate migration. The zebrafish xenograft model confirmed the metastatic potential triggered by NF-YAl in CRC cells. Altogether, our data highlight the transcriptional role of NF-YAl in CRC aggressiveness and suggest splice-switching strategies to hinder NF-YAl-induced metastatic dissemination

Preliminary assessment of the mucosal toxicity of tea tree (Melaleuca alternifolia) and rosemary (rosmarinus officinalis) essential oils on novel porcine uterus models

Antimicrobial resistance, an ever-growing global crisis, is strongly linked to the swine production industry. In previous studies, Melaleuca alternifolia and Rosmarinus officinalis essential oils have been evaluated for toxicity on porcine spermatozoa and for antimicrobial capabilities in artificial insemination doses, with the future perspective of their use as antibiotic alternatives. The aim of the present research was to develop and validate in vitro and ex vivo models of porcine uterine mucosa for the evaluation of mucosal toxicity of essential oils. The in vitro model assessed the toxicity of a wider range of concentrations of both essential oils (from 0.2 to 500 mg/mL) on sections of uterine tissue, while the ex vivo model was achieved by filling the uterine horns. The damage induced by the oils was assessed by Evans Blue (EB) permeability assay and histologically. The expression of ZO-1, a protein involved in the composition of tight junctions, was assessed through immunohistochemical and immunofluorescence analysis. The results showed that low concentrations (0.2\u20130.4 mg/mL) of both essential oils, already identified as non-spermicidal but still antimicrobial, did not alter the structure and permeability of the swine uterine mucosa. Overall, these findings strengthen the hypothesis of a safe use of essential oils in inseminating doses of boar to replace antibiotics

A Novel Perilla frutescens (L.) Britton Cell-Derived Phytocomplex Regulates Keratinocytes Inflammatory Cascade and Barrier Function and Preserves Vaginal Mucosal Integrity In Vivo

: In the last years, the medicinal plant Perilla frutescens (L.) Britton has gained scientific interest because leaf extracts, due to the presence of rosmarinic acid and other polyphenols, have shown anti-allergic and skin protective potential in pre-clinical studies. Nevertheless, the lack of standardized extracts has limited clinical applications to date. In this work, for the first time, a standardized phytocomplex of P. frutescens, enriched in rosmarinic acid and total polyphenols, was produced through innovative in vitro cell culture biotechnology and tested. The activity of perilla was evaluated in an in vitro inflammatory model of human keratinocytes (HaCaT) by monitoring tight junctions, filaggrin, and loricrin protein levels, the release of pro-inflammatory cytokines and JNK MAPK signaling. In a practical health care application, the perilla biotechnological phytocomplex was tested in a multilayer model of vaginal mucosa, and then, in a preliminary clinical observation to explore its capacity to preserve vaginal mucosal integrity in women in peri-menopause. In keratinocytes cells, perilla phytocomplex demonstrated to exert a marked activity in epidermis barrier maintenance and anti-inflammatory effects, preserving tight junction expression and downregulating cytokines release through targeting JNK activation. Furthermore, perilla showed positive effects in retaining vaginal mucosal integrity in the reconstructed vaginal mucosa model and in vivo tests. Overall, our data suggest that the biotechnological P. frutescens phytocomplex could represent an innovative ingredient for dermatological applications

Environmental risk factors for the development of oral squamous cell carcinoma in cats

Background: Risk factors for oral squamous cell carcinoma (OSCC) in cats are derived from a single study dated almost 20 years ago. The relationship between inflammation of oral tissues and OSCC is still unclear. Objectives: To investigate previously proposed and novel potential risk factors for OSCC development, including oral inflammatory diseases. Animals: Hundred cats with OSCC, 70 cats with chronic gingivostomatitis (CGS), 63 cats with periodontal disease (PD), and 500 controls. Methods: Prospective, observational case-control study. Cats with OSCC were compared with an age-matched control sample of client-owned cats and cats with CGS or PD. Owners of cats completed an anonymous questionnaire including demographic, environmental and lifestyle information. Results: On multivariable logistic regression, covariates significantly associated with an increased risk of OSCC were rural environment (OR: 1.77; 95% CI: 1.03-3.04; P&nbsp;=.04), outdoor access (OR: 1.68; 95% CI: 1.07-2.63; P&nbsp;=.02), environmental tobacco smoke (OR: 1.77; 95% CI: 1.05-3; P&nbsp;=.03), and petfood containing chemical additives (OR: 1.98; 95% CI: 1.04-3.76; P&nbsp;=.04). Risk factors shared with CGS and PD were outdoor access and petfood containing chemical additives, respectively. A history of oral inflammation was reported in 35% of cats with OSCC but did not emerge as a risk factor. Conclusions and Clinical Importance: The study proposes novel potential risk factors for OSCC in cats. Although a history of inflammatory oral disease was not significantly more frequent compared with random age-matched controls, OSCC shared several risk factors with CGS and PD

An Evolutionary Cancer Epigenetic Approach Revealed DNA Hypermethylation of Ultra-Conserved Non-Coding Elements in Squamous Cell Carcinoma of Different Mammalian Species

BACKGROUND: Ultra-conserved non-coding elements (UCNEs) are genomic sequences that exhibit &gt; 95% sequence identity between humans, mammals, birds, reptiles, and fish. Recent findings reported their functional role in cancer. The aim of this study was to evaluate the DNA methylation modifications of UNCEs in squamous cell carcinoma (SCC) from different mammal species. METHODS: Fifty SCCs from 26 humans, 17 cats, 3 dogs, 1 horse, 1 bovine, 1 badger, and 1 porcupine were investigated. Fourteen feline stomatitis and normal samples from 36 healthy human donors, 7 cats, 5 dogs, 5 horses, 2 bovines and 1 badger were collected as normal controls. Bisulfite next generation sequencing evaluated the DNA methylation level from seven UCNEs (uc.160, uc.283, uc.416, uc.339, uc.270, uc.299, and uc.328). RESULTS: 57/59 CpGs were significantly different according to the Kruskal-Wallis test (p &lt; 0.05) comparing normal samples with SCC. A common DNA hypermethylation pattern was observed in SCCs from all the species evaluated in this study, with an increasing trend of hypermethylation starting from normal mucosa, through stomatitis to SCC. CONCLUSIONS: Our findings indicate that UCNEs are hypermethylated in human SCC, and this behavior is also conserved among different species of mammals

FROM PRECLINICAL TO CLINICAL EVIDENCE: EXPLORING THE MULTIPLE PERSPECTIVES AND HEALING POWER OF BOSWELLIA SERRATA ROXB. EX COLEBR

Boswellia serrata Roxb. ex Colebr. is a species belonging to the Burseraceae family, typical of dry environments of the Indian region. The oil-gum-resin, obtained from the trunk and thick branches, is known in phytotherapy for the volatile fraction which contains up to 70% terpenes. The most important and characteristic constituents are represented by pentacyclic triterpenes, named boswellic acids. B. serrata is known for multiple beneficial effects, mainly correlated to anti-inflammatory activity. This review aims to provide a comprehensive overview on the activities and potential applications of B. serrata based on clinical and preclinical evidence. An up-to-date literature review of preclinical and clinical studies related to the applications of B. serrata preparations in different pathological conditions was conducted using the main databases of scientific literature. A body of evidence point out the role of B. serrata extracts and its active constituents in the treatment of several inflammatory diseases. In particular, clinical trials revealed its use as a topical remedy of skin diseases, such as eczema and psoriasis, and internally in the treatment of asthma, intestinal and osteoarticular inflammatory diseases. Preclinical findings highlighted the positive effects of B. serrata extracts in cardiovascular and neurodegenerative diseases, and in cancer. Finally, B. serrata finds application as a feed additive in veterinary use. Although some limitations must be overcome, such as poor bioavailability, evidence supports that B. serrata is a promising medicinal plant. Furthermore, the use of B. serrata appears to have a favorable toxicological profile, but caution may be necessary regarding potential botanical-drug interactions