Computational analysis of curcumin-mediated alleviation of inflammation in periodontitis patients with experimental validation in mice.

AIM: Using network pharmacology and experimental validation to explore the therapeutic efficacy and mechanism of curcumin (Cur) in periodontitis treatment. MATERIALS AND METHODS: Network pharmacology was utilized to predict target gene interactions of Cur-Periodontitis. Molecular docking was used to investigate the binding affinity of Cur for the predicted targets. A mouse model with ligature-induced periodontitis (LIP) was used to verify the therapeutic effect of Cur. Microcomputed tomography (micro-CT) was used to evaluate alveolar bone resorption, while western blotting, haematoxylin-eosin staining and immunohistochemistry were used to analyse the change in immunopathology. SYTOX Green staining was used to assess the in vitro effect of Cur in a mouse bone marrow-isolated neutrophil model exposed to lipopolysaccharide. RESULTS: Network pharmacology identified 114 potential target genes. Enrichment analysis showed that Cur can modulate the production of neutrophil extracellular traps (NETs). Molecular docking experiments suggested that Cur effectively binds to neutrophil elastase (ELANE), peptidylarginine deiminase 4 (PAD4) and cathepsin G, three enzymes involved in NETs. In LIP mice, Cur alleviated alveolar bone resorption and reduced the expression of ELANE and PAD4 in a time-dependent but dose-independent manner. Cur can directly inhibit NET formation in the cell model. CONCLUSIONS: Our research suggested that Cur may alleviate experimental periodontitis by inhibiting NET formation.

Low-dose naltrexone's utility for non-cancer centralized pain conditions: a scoping review.

BACKGROUND: At low doses, naltrexone (LDN) has been shown to modulate inflammation through the interruption of microglial cell activation within the central nervous system. One of the most likely contributors to centralized pain is changes in microglial cell processing. Therefore, it has been postulated that LDN can be used to manage patients with pain resulting from central sensitization due to this relationship. This scoping review aims to synthesize the relevant study data for LDN as a novel treatment strategy for various centralized pain conditions. METHODS: A comprehensive literature search was conducted in PubMed, Embase, and Google Scholar, guided by the Scale for Assessment of Narrative Review Articles (SANRA) criteria. RESULTS: Forty-seven studies related to centralized pain conditions were identified. Many of the studies were case reports/series and narrative reviews, but a few randomized control trials have been conducted. Overall, the body of evidence revealed improvement in patient-reported pain severity and in outcomes related to hyperalgesia, physical function, quality of life, and sleep. Variability in dosing paradigms and the time to patient response was present in the reviewed studies. CONCLUSIONS: Evidence synthesized for this scoping review supports the ongoing use of LDN for the treatment of refractory pain in various centralized chronic pain conditions. Upon review of the currently available published studies, it is apparent that further high-quality, well-powered randomized control trials need to be conducted to establish efficacy, standardization for dosing, and response times. In summary, LDN continues to offer promising results in the management of pain and other distressing symptoms in patients with chronic centralized pain conditions.

Preliminary Evaluation of Wound Healing Potential of Leonurus japonicus Houtt. Extracts.

Leonurus japonicus Houtt. is a medicinal plant popular in Brazil as "rubim", used in local folk medicine for several applications as an anti-inflammatory, antioxidant, analgesic, and antimicrobial phytomedicine. The traditional use for wound healing is related; however, few studies have evaluated the wound healing activity. Thus, this study aimed to analyse the popular indication of the hydroalcoholic and aqueous extracts of L. japonicus aerial parts in a rat wound healing model. The initial chemical characterization was performed using flavonoid quantification and complemented with mass spectroscopy/chemometrics analysis. The wound's lesion contraction and tissue regeneration (histological study stained with hematoxylin-eosin and picrosirius) were determined. Hydroalcoholic and aqueous extracts presented high flavonoid content, and mass spectrometry analysis of the extracts demonstrated the presence of compounds with a mass between 100-650, reinforcing the presence of polyphenolic constituents. The extracts of L. japonicus improve various wound healing phases, like inflammatory modulation, wound contraction, and collagen synthesis, resulting in faster healing in rats. These effects could be related to the extracts' polyphenolic compounds.

Using cross-linked hyaluronic acid gel to prevent postoperative lumbar epidural space adhesion: in vitro and in vivo studies.

PURPOSE: Hyaluronic acid prevents tissue adhesion after different surgeries. Physical barriers and inflammatory regulation have been suggested to be involved in the mechanism of these clinical effects. However, the molecular mechanism by which hyaluronic acid prevents epidural adhesion has not yet been reported. METHODS: In the current in vivo studies, we investigated cross-linked hyaluronic acid gel in the regulation of scar gene expression, the accumulation of fibroblasts in scar tissue, and the prevention of epidural adhesion. The effect of cross-linked hyaluronic acid gel on the secretion of inflammatory factors was observed in vitro. In addition, to ensure the accuracy and reliability of the in vivo gene expression results, we used a cell model to detect the target genes in vitro. RESULTS: The expression levels of TGFß1 and COL1A1 mRNA were decreased in the cross-linked hyaluronic acid gel-treated group, and the protein expression of levels TGFß1 and COL1A1 were also reduced, as detected by Western blotting in vitro and in vivo (P < 0.05). Histomorphometry results demonstrated that the number of fibroblasts in the experimental group was significantly lower than that in the control group 2 weeks postoperatively. Micro-CT scans showed that the cross-linked hyaluronic acid gel could reduce adhesion in the epidural space after laminectomy. Additionally, the cross-linked hyaluronic acid gel could inhibit IL-6 secretion. CONCLUSIONS: These results indicate that cross-linked hyaluronic acid gel can prevent epidural adhesion by inhibiting inflammatory factors, such as IL-6, and downregulating TGFß1 and COL1A1 mRNA expression. These slides can be retrieved under Electronic Supplementary Material.

A Single Dose of Local Injection of Adipose Stem Cells Promotes Ectopic Cartilage Regeneration In Vivo by Modulating Inflammatory Response and Enhancing Cartilage Extracellular Matrix Synthesis in a Porcine Model.

BACKGROUND: Uncontrollable inflammatory response following ectopic engineered cartilage implantation is devastating to the aesthetic and functional outcomes of the recipients. Adipose stem cells (ASCs) have a good immunomodulatory capacity via a paracrine mechanism. However, works of literature are scarce regarding ASC modulation in ectopic engineered cartilage regeneration in vivo. This study aims to explore how ASCs modulate the inflammatory response after engineered cartilage implantation and affect the implants in a nonchondrogenic milieu in large immunocompetent animals. METHODS: Porcine engineered elastic cartilages were cultured in vitro for 3 weeks with chondrocyte cell sheeting technology and then assigned into two groups: ASCs and Control (saline injection). All samples (n= 6 per group) were autologously implanted into different subcutaneous pockets, and a single dose of ASCs was injected at three points around the implant. All samples were harvested after 2 weeks in vivo for analysis. RESULTS: In the examination of inflammation, we observed reduced inflammatory cell infiltration and improved M2 macrophage polarization in the implanted engineered cartilage with ASC injection compared to the control. There were also enhanced anti-inflammatory cytokines and reduced proinflammatory cytokines inside and adjacent to the implants, while in serum, there were no significant differences. In the examination of the cartilage quality, there were significant increases in cartilage extracellular matrix and chondrogenic factors, and the elastic cartilage phenotype was maintained compared to control. CONCLUSION: This study finds that a single dose of ASCs can promote ectopic cartilage regeneration by modulating inflammation and enhancing cartilage matrix synthesis in a porcine model.

The Emerging Biological Functions of Exosomes from Dental Tissue-Derived Mesenchymal Stem Cells.

Exosomes are one kind of small-cell extracellular membranous vesicles that can regulate intercellular communication and give rise to mediating the biological behaviors of cells, involving in tissue formation, repair, the modulation of inflammation, and nerve regeneration. The abundant kinds of cells can secret exosomes, among them, mesenchymal stem cells (MSCs) are very perfect cells for mass production of exosomes. Dental tissue-derived mesenchymal stem cells (DT-MSCs), including dental pulp stem cells, stem cells from exfoliated deciduous teeth, stem cells from apical papilla, stem cells from human periodontal ligament (PDLSCs), gingiva-derived mesenchymal stem cells, dental follicle stem cells, tooth germ stem cells, and alveolar bone-derived mesenchymal stem cells, are now known as a potent tool in the area of cell regeneration and therapy, more importantly, DT-MSCs can also release numerous types of exosomes, participating in the biological functions of cells. Hence, we briefly depict the characteristics of exosomes, give a detailed description of the biological functions and clinical application in some respects of exosomes from DT-MSCs through systematically reviewing the latest evidence, and provide a rationale for their use as tools for potential application in tissue engineering.

A Biomimetic Smart Nanoplatform as "Inflammation Scavenger" for Regenerative Therapy of Periodontal Tissue.

Introduction: The functional reconstruction of periodontal tissue defects remains a clinical challenge due to excessive and prolonged host response to various endogenous and exogenous pro-inflammatory stimuli. Thus, a biomimetic nanoplatform with the capability of modulating inflammatory response in a microenvironment-responsive manner is attractive for regenerative therapy of periodontal tissue. Methods: Herein, a facile and green design of engineered bone graft materials was developed by integrating a biomimetic apatite nanocomposite with a smart-release coating, which could realize inflammatory modulation by "on-demand" delivery of the anti-inflammatory agent through a pH-sensing mechanism. Results: In vitro and in vivo experiments demonstrated that this biocompatible nanoplatform could facilitate the clearance of reactive oxygen species in human periodontal ligament stem cells under inflammatory conditions via inhibiting the production of endogenous proinflammatory mediators, in turn contributing to the enhanced healing efficacy of periodontal tissue. Moreover, this system exhibited effective antimicrobial activity against common pathogenic bacteria in the oral cavity, which is beneficial for the elimination of exogenous pro-inflammatory factors from bacterial infection during healing of periodontal tissue. Conclusion: The proposed strategy provides a versatile apatite nanocomposite as a promising "inflammation scavenger" and propels the development of intelligent bone graft materials for periodontal and orthopedic applications.

The Impact of Activity-Based Interventions on Neuropathic Pain in Experimental Spinal Cord Injury.

Physical activity-based rehabilitative interventions represent the main treatment concept for people suffering from spinal cord injury (SCI). The role such interventions play in the relief of neuropathic pain (NP) states is emerging, along with underlying mechanisms resulting in SCI-induced NP (SCI-NP). Animal models have been used to investigate the benefits of activity-based interventions (ABI), such as treadmill training, wheel running, walking, swimming, and bipedal standing. These activity-based paradigms have been shown to modulate inflammatory-related alterations as well as induce functional and structural changes in the spinal cord gray matter circuitry correlated with pain behaviors. Thus far, the research available provides an incomplete picture of the cellular and molecular pathways involved in this beneficial effect. Continued research is essential for understanding how such interventions benefit SCI patients suffering from NP and allow the development of individualized rehabilitative therapies. This article reviews preclinical studies on this specific topic, goes over mechanisms involved in SCI-NP in relation to ABI, and then discusses the effectiveness of different activity-based paradigms as they relate to different forms, intensity, initiation times, and duration of ABI. This article also summarizes the mechanisms of respective interventions to ameliorate NP after SCI and provides suggestions for future research directions.

Traditional plant use during lactation and postpartum recovery: Infant development and maternal health roles.

ETHNOPHARMACOLOGICAL RELEVANCE: Evidence of phytochemical roles in infant development and maternal recovery offers insights into beneficial functions of traditional plant use during lactation and the postpartum period. Ethnopharmacological research has relevance to global priorities on maternal and child health, to understanding origins and determinants of human self-medication, and for reconciling traditional postpartum practices and mainstream healthcare. AIM OF THE STUDY: Present emerging evidence, within evolutionary and socio-cultural contexts, on the role of maternal consumption on transfer of phytochemicals into breast milk with impacts on maternal and child health, and on infant development. Establish current state of knowledge and an ethnopharmacological research agenda that is attentive to cross-cultural and regional differences in postpartum plant use. MATERIALS AND METHODS: An extensive literature review using Medline, Scopus, and Web of Science focused on traditional and contemporary use and socio-cultural context, as well as physiological, pharmacological, toxicological, and behavioral activities of plants used medicinally by women during postpartum recovery and lactation. RESULTS: The most widely reported postpartum plants show antimicrobial, anti-inflammatory, immunological, and neurophysiological activities, with low toxicity. Phytochemicals transfer from maternal consumption into breast milk in physiological concentrations, while animal studies demonstrate immunomodulation and other actions of medicinal plants during lactation. Reporting on the use and diverse traditional knowledge of women about plants during the postpartum period is obscured by the marginal place of obstetric issues and by gender biases in ethnobotanical research. In many contemporary contexts use is prejudiced by precautionary risk warnings in health literature and practice that confound lactation with pregnancy. CONCLUSIONS: Although systematic investigation of postpartum plant use is lacking, known pharmacological activities support potential benefits on infant development and maternal health with immediate and long-term consequences in relation to allergic, inflammatory, autoimmune, and other diseases. An ethnopharmacological agenda focused on the perinatal period requires directed methodologies and a regional approach in relation to culturally-specific knowledge and practices, traditional plant use, and local health needs. Testing the hypothesis that phytochemicals transferred from medicinal plants into breast milk impact the human immune system and other aspects of infant development requires extended analysis of phytochemicals in human milk and infant lumen and plasma, as well as effects on gastrointestinal and milk microbiome.

Phase II trial of salvage therapy with trabectedin in metastatic pancreatic adenocarcinoma.

PURPOSE: No standard salvage chemotherapy has been identified for metastatic pancreatic adenocarcinoma (mPA), and there is an urgent need for active agents against this disease. This phase II trial explored the activity of trabectedin in mPA progressing after gemcitabine-based first-line chemotherapy. METHODS: Patients with gemcitabine-resistant disease received trabectedin 1.3 mg/m(2) as a 3-h intravenous continuous infusion every 3 weeks until disease progression or unacceptable toxicity or for a maximum of 6 months. The primary endpoint was progression-free survival rate at 6 months (PFS-6). Since trabectedin modulates the production of selected inflammatory mediators, this study also aimed to identify inflammatory biomarkers predictive for response to trabectedin. RESULTS: Between February 2011 and February 2012, 25 patients received trabectedin. PFS-6 was 4%, median PFS 1.9 months (range 0.8-7.4), and median overall survival 5.2 months (range 1.1-24.3). Grade >2 toxicity consisted of neutropenia in 44% of patients, febrile neutropenia and thrombocytopenia both in 12%, anemia in 8%, fatigue in 12%, and AST and ALT increase in 8 and 4%, respectively. Trabectedin was shown to modulate the production of inflammatory mediators, and at disease progression, levels of a subgroup of cytokines/chemokines were modified. Furthermore, tissue analysis identified 30 genes associated with better prognosis. CONCLUSIONS: Although it has shown some ability to modulate inflammatory process, single-agent trabectedin had no activity as salvage therapy for mPA.

Immuno-modulatory Effect of IFN-gamma in AMD and its Role as a Possible Target for Therapy.

Age-related macular degeneration (AMD) is a neurodegenerative disease characterized by retinal cell atrophy, and/or choroidal neovascularization in the macula and constitutes the most common cause of blindness among the elderly in industrialized countries. The management of AMD is constrained by our insufficient knowledge of its underlying mechanisms. Recent studies point towards an emerging involvement of interferon-gamma (IFN-γ), a soluble cytokine associated with innate and adaptive immunity. IFN-γ promotes proinflammatory responses by activating proinflammatory cytokines and chemokines, thereby recruiting immune cells such as macrophages and T cells. On the other hand, IFN-γ modulates inflammatory response by upregulating anti-inflammatory factors or inhibiting development of immune cells related to autoimmune response. The complex role of IFN-γ in AMD pathogenesis is intriguing and worth further investigation in terms of therapeutic development.