Inflammatory Tissue Destruction Research Articles

Investigation of Effects of Local Vitamin C Application on Inflammatory Response and Periodontal Tissue Destruction in Rat Periodontitis Model

Background: The present study aims to evaluate the effect of local vitamin C application on inflammatory response and periodontal tissue destruction in rats with experimental periodontitis.
 Methods: A total of 21 animals, 7 rats in each group, were used in the study: 1- Non-ligation (NL), 2-experimental periodontitis (EP), and 3- local vitamin C (VtC) groups. Experimental periodontitis was induced in EP and VtC group rats. After 11 days, the ligature was removed. 50 mL of saline solution and vitamin C were injected locally into the vestibule sulcus of the EP and VtC group rats, respectively. After the rats were sacrificed, blood and gingival tissue samples were taken. TNF-α levels were analyzed biochemically in serum and 8-OHdG and MMP-8 were analyzed immunohistochemically in gingival tissue. The mandibular specimens were histologically evaluated for bone destruction and attachment loss.
 Results: The numeric density of 8-OHdG and MMP-8 immunopositive cells were found to be statistically significantly lower in the Vtc group than in the EP group. Vitamin C administration significantly reduced attachment loss and bone loss in the VtC group as compared to the EP group. However, there was no significant difference in serum TNF-α level in the VtC group compared to the EP group.
 Conclusions: Local application of vitamin C may reduce inflammation-related bone destruction by supporting the inflammatory response with the antioxidant activity of vitamin C and contributing to the resolution of inflammation with its potential immunomodulatory effect. Vitamin C may be a therapeutic agent that can be used in the treatment of periodontitis.

Kinin receptors regulate skeletal muscle regeneration: differential effects for B1 and B2 receptors.

After traumatic skeletal muscle injury, muscle healing is often incomplete and produces extensive fibrosis. Bradykinin (BK) reduces fibrosis in renal and cardiac damage models through the B2 receptor. The B1 receptor expression is induced by damage, and blocking of the kallikrein-kinin system seems to affect the progression of muscular dystrophy. We hypothesized that both kinin B1 and B2 receptors could play a differential role after traumatic muscle injury, and the lack of the B1 receptor could produce more cellular and molecular substrates for myogenesis and fewer substrates for fibrosis, leading to better muscle healing. To test this hypothesis, tibialis anterior muscles of kinin receptor knockout animals were subjected to traumatic injury. Myogenesis, angiogenesis, fibrosis, and muscle functioning were evaluated. Injured B1KO mice showed a faster healing progression of the injured area with a larger amount of central nucleated fiber post-injury when compared to control mice. In addition, they exhibited higher neovasculogenic capacity, maintaining optimal tissue perfusion for the post-injury phase; had higher amounts of myogenic markers with less inflammatory infiltrate and tissue destruction. This was followed by higher amounts of SMAD7 and lower amounts of p-SMAD2/3, which resulted in less fibrosis. In contrast, B2KO and B1B2KO mice showed more severe tissue destruction and excessive fibrosis. B1KO animals had better results in post-injury functional tests compared to control animals. We demonstrate that injured skeletal muscle tissues have a better repair capacity with less fibrosis in the presence of B2 receptor and absence of B1 receptor, including better performances in functional tests.

Wedelolactone Promotes the Chondrogenic Differentiation of Mesenchymal Stem Cells by Suppressing EZH2.

Osteoarthritis (OA) is a degenerative disease that leads to the progressive destruction of articular cartilage. Current clinical therapeutic strategies are moderately effective at relieving OA-associated pain but cannot induce chondrocyte differentiation or achieve cartilage regeneration. We investigated the ability of wedelolactone, a biologically active natural product that occurs in Eclipta alba (false daisy), to promote chondrogenic differentiation. Real-time reverse transcription-polymerase chain reaction, immunohistochemical staining, and immunofluorescence staining assays were used to evaluate the effects of wedelolactone on the chondrogenic differentiation of mesenchymal stem cells (MSCs). RNA sequencing, microRNA (miRNA) sequencing, and isobaric tags for relative and absolute quantitation analyses were performed to explore the mechanism by which wedelolactone promotes the chondrogenic differentiation of MSCs. We found that wedelolactone facilitates the chondrogenic differentiation of human induced pluripotent stem cell-derived MSCs and rat bone-marrow MSCs. Moreover, the forkhead box O (FOXO) signaling pathway was upregulated by wedelolactone during chondrogenic differentiation, and a FOXO1 inhibitor attenuated the effect of wedelolactone on chondrocyte differentiation. We determined that wedelolactone reduces enhancer of zeste homolog 2 (EZH2)-mediated histone H3 lysine 27 trimethylation of the promoter region of FOXO1 to upregulate its transcription. Additionally, we found that wedelolactone represses miR-1271-5p expression, and that miR-1271-5p post-transcriptionally suppresses the expression of FOXO1 that is dependent on the binding of miR-1271-5p to the FOXO1 3'-untranscribed region. These results indicate that wedelolactone suppresses the activity of EZH2 to facilitate the chondrogenic differentiation of MSCs by activating the FOXO1 signaling pathway. Wedelolactone may therefore improve cartilage regeneration in diseases characterized by inflammatory tissue destruction, such as OA.

Exploring the effect of the Uyghur medicine Munziq Balgam on a collagen-induced arthritis rat model by UPLC-MS/MS-based metabolomics approach.

Munziq Balgam (MBm) is a classic preparation of a traditional Uyghur medicine used for many years to treat abnormal body fluid diseases. The formula, as an in-hospital preparation, has already been used in the Hospital of Xinjiang Traditional Uyghur Medicine to treat rheumatoid arthritis (RA) with significant clinical effects. This study intends to reveal the intervention effect of MBm on collagen-induced arthritis (CIA) rats, discover the potential biomarkers with efficacy, and explore the mechanisms of metabolic regulation by using metabolomics method. Sprague Dawley (SD) rats were randomly divided into five groups: blank group, CIA model group, Munziq Balgam nomal-dosage, Munziq Balgam high-dosage group and control group. Body weight, paw swelling, arthritis index, immune indices and histopathological experiments were carried out. Plasma from rats were detected by UPLC-MS/MS. Metabolomics of plasma was performed to analyze metabolic profiles, potential biomarkers, and metabolic pathways of MBm for CIA rats. The main metabolic result of Uyghur medicine MBm was compared with that of Zhuang medicine Longzuantongbi granules (LZTBG) to explore the characteristics of two ethnic medicines from different regions for RA. MBm could significantly alleviate symptoms of CIA rats by relieving arthritis symptoms on paw redness and swelling, inflammatory cell infiltration, synovial hyperplasia, pannus, cartilage and bone tissue destruction, as well as inhibiting the expression of IL-1β, IL-6, TNF-α, UA and ALP. Linoleic acid, alpha-linolenic acid, pantothenate and CoA biosynthesis, achidonic acid, gycerophospholipid, sphingolipid metabolism, primary bile acid biosynthesis, porphyrin and chlorophyll metabolism and fatty acid degradation served as the main nine pathways of the interventional effect of MBm on CIA rats. Twenty-three different metabolites were screened out and strongly associated with the indicator makes of RA. Eight potential efficacy-related biomarkers were finally discovered in metabolic pathway network (phosphatidylcholine, bilirubin, sphinganine 1-phosphate, phytosphingosine, SM (d18:1/16:0), pantothenic acid, l-palmitoylcarnitine, chenodeoxycholate). Three metabolites (chenodeoxycholate, hyodeoxycholic acid and O-palmitoleoylcarnitine) were changed in both the metabolic study of MBm and LZTBG intervention effects on CIA rats. Additionally, MBm and LZTBG shared the same 6 metabolic pathways including linoleic acid, alpha-linolenic acid, pantothenate and CoA biosynthesis, achidonic acid, gycerophospholipid, and primary bile acid biosynthesis. The study suggested that MBm may effectively alleviate RA by regulating inflammation, immunity-related pathways and multiple targets. Metabolomics analysis showed that MBm (Xinjiang, the north of China) and LZTBG (Guangxi, the south of China), two ethnic medicines from different regions in China, share common metabolites and pathways but also have distinct differences in their interventions for RA.

Composition of subgingival microbiota associated with periodontitis and diagnosis of malignancy-a cross-sectional study.

Periodontitis is one of the world's most prevalent infectious conditions, affecting between 25 and 40% of the adult population. It is a consequence of the complex interactions between periodontal pathogens and their products, which trigger the host inflammatory response, chronic inflammation, and tissue destruction. Chronic systemic low-grade inflammation is involved in numerous diseases, and it is also known that long-lasting inflammation and chronic infections predispose one to cancer. Here, we characterized and compared the subgingival microbiota associated with periodontitis and diagnosis of malignancy in a longitudinal 10-year follow-up study. The study was conducted on 50 patients with periodontitis and 40 periodontally healthy individuals. The recorded clinical oral health parameters were periodontal attachment loss (AL), bleeding on probing (BOP), gingival index (GI), probing depth (PD), and plaque index (PI). Subgingival plaque was collected from each participant, from which DNA was extracted, and 16S rRNA gene amplicon sequencing performed. Cancer diagnoses data were collected between the years 2008-2018 from the Swedish Cancer Registry. The participants were categorized based on having cancer at the time of sample collection (CSC), having developed cancer later (DCL), and controls without any cancer. The most abundant phyla across all 90 samples were Actinobacteria, Proteobacteria, Firmicutes, Bacteroidetes, and Fusobacteria. At the genus level, Treponema, Fretibacterium, and Prevotella were significantly more abundant in samples of periodontitis patients compared to non-periodontitis individuals. With regard to samples of cancer patients, Corynebacterium and Streptococcus were more abundant in the CSC group; Prevotella were more abundant in the DCL group; and Rothia, Neisseria, and Capnocytophaga were more abundant in the control group. In the CSC group, we also found that the presence of periodontal inflammation, in terms of BOP, GI, and PLI, significantly correlated with species belonging to the genera Prevotella, Treponema, and Mycoplasma. Our results revealed that several subgingival genera were differentially enriched among the studied groups. These findings underscore the need for further research to fully understand the role that oral pathogens may play in the development of cancer.

Salivary cortisol, dehydroepiandrosterone, and chromogranin A levels in patients with gingivitis and periodontitis and a novel biomarker for psychological stress.

This study aimed to investigate the neuroendocrine responses based on cortisol, dehydroepiandrosterone (DHEA), cortisol/DHEA ratio, and chromogranin A levels, which reflect the activity of the hypothalamic-pituitary-adrenal axis, according to the presence or absence of psychological stress in patients with gingivitis and periodontitis compared to that in healthy controls. In total, 117 patients (60 women, mean age: 36.29 ± 19.03 years) participated in this case-control study, comprising 32 healthy controls, 49 patients with gingivitis, and 36 patients with periodontitis. We investigated the presence of psychological stress and salivary characteristics, and analyzed the stress-related biomarkers of cortisol, DHEA, cortisol/DHEA ratio, and chromogranin A in the stimulated saliva. Salivary cortisol and chromogranin A levels increased with the severity of periodontal disease; their levels were the highest in the periodontitis group and were significantly higher in the following descending order: periodontitis, gingivitis, and healthy control groups (all values of p < 0.001). Additionally, the DHEA levels and cortisol/DHEA ratio were higher in the periodontitis group than those in the healthy control group (all values of p < 0.001). A multivariate logistic regression analysis revealed that the factors predicting above-average cortisol levels were periodontitis (odds ratio [OR] = 256.829; p < 0.001), women (OR = 6.365; p = 0.004), and psychological stress (OR = 6.036; p = 0.007); those predicting above-average cortisol/DHEA ratios were periodontitis (OR = 11.436; p < 0.001), psychological stress (OR = 3.977; p = 0.003), and women (OR = 2.890; p = 0.026). Thus, periodontitis and psychological stress were significant and strong predictors of above-average cortisol levels and cortisol/DHEA ratios. In the gingivitis group, salivary cortisol levels (r = 0.381, p = 0.007) and cortisol/DHEA ratios (r = 0.479, p < 0.001) were correlated with the presence of psychological stress. In the periodontitis group, increased cortisol/DHEA ratios (r = 0.412, p = 0.013) and lowered salivary buffer capacities (r = -0.334, p = 0.047) were correlated with the presence of psychological stress. Periodontitis is a multifactorial disease resulting in inflammatory tissue destruction, which differs from gingivitis and a healthy state. Differences in stress-related neuroendocrine markers were revealed based on the severity of periodontal disease. The biomarkers that could be classified according to disease severity were salivary cortisol and chromogranin A levels. Above-average cortisol levels and cortisol/DHEA ratios are significant predictors of psychological stress in patients with gingivitis and periodontitis.

Who is in the driver's seat? Parvimonas micra: An understudied pathobiont at the crossroads of dysbiotic disease and cancer.

Recent advances in our understanding of microbiome composition at sites of inflammatory dysbiosis have triggered a substantial interest in a variety of historically understudied bacteria, especially among fastidious obligate anaerobes. A plethora of new evidence suggests that these microbes play outsized roles in establishing synergistic polymicrobial infections at many different sites in the human body. Parvimonas micra is a prime example of such an organism. Despite being almost completely uncharacterized at the genetic level, it is one of the few species commonly detected in abundance at multiple mucosal sites experiencing either chronic or acute inflammatory diseases, and more recently, it has been proposed as a discriminating biomarker for multiple types of malignancies. In the absence of disease, P. micra is commonly found in low abundance, typically residing within the oral cavity and gastrointestinal tract. P. micra exhibits the typical features of an inflammophilic organism, meaning its growth actually benefits from active inflammation and inflammatory tissue destruction. In this mini-review, we will describe our current understanding of this underappreciated but ubiquitous pathobiont, specifically focusing upon the role of P. micra in polymicrobial inflammatory dysbiosis and cancer as well as the key emerging questions regarding its pathobiology. Through this timely work, we highlight Parvimonas micra as a significant driver of disease and discuss its unique position at the crossroads of dysbiosis and cancer.

Creating an atlas of the bone microenvironment during oral inflammatory-related bone disease using single-cell profiling.

Oral inflammatory diseases such as apical periodontitis are common bacterial infectious diseases that may affect the periapical alveolar bone tissues. A protective process occurs simultaneously with the inflammatory tissue destruction, in which mesenchymal stem cells (MSCs) play a primary role. However, a systematic and precise description of the cellular and molecular composition of the microenvironment of bone affected by inflammation is lacking. In this study, we created a single-cell atlas of cell populations that compose alveolar bone in healthy and inflammatory disease states. We investigated changes in expression frequency and patterns related to apical periodontitis, as well as the interactions between MSCs and immunocytes. Our results highlight an enhanced self-supporting network and osteogenic potential within MSCs during apical periodontitis-associated inflammation. MSCs not only differentiated toward osteoblast lineage cells but also expressed higher levels of osteogenic-related markers, including Sparc and Col1a1. This was confirmed by lineage tracing in transgenic mouse models and human samples from oral inflammatory-related alveolar bone lesions. In summary, the current study provides an in-depth description of the microenvironment of MSCs and immunocytes in both healthy and disease states. We also identified key apical periodontitis-associated MSC subclusters and their biomarkers, which could further our understanding of the protective process and the underlying mechanisms of oral inflammatory-related bone disease. Taken together, these results enhance our understanding of heterogeneity and cellular interactions of alveolar bone cells under pathogenic and inflammatory conditions. We provide these data as a tool for investigators not only to better appreciate the repertoire of progenitors that are stress responsive but importantly to help design new therapeutic targets to restore bone lesions caused by apical periodontitis and other inflammatory-related bone diseases.

The antimicrobial peptide LK2(6)A(L) exhibits anti-inflammatory activity by binding to the myeloid differentiation 2 domain and protects against LPS-induced acute lung injury in mice

Acute lung injury (ALI) is a life-threatening disease that is generally attributable to an uncontrolled inflammatory response in the lung, but there is a lack of effective treatments. At present, regulating the inflammatory response has become an important strategy for treating ALI. In the present study, LK2(6)A(L), a peptide derived from the natural antimicrobial peptide temporin-1CEa, inhibited lipopolysaccharide (LPS)-induced expression of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and NO in RAW264.7 cells. Herein, the anti-inflammatory mechanism of LK2(6)A(L) was investigated. The RNA-sequencing (RNA-seq) results showed that LK2(6)A(L) significantly inhibited the TLR4-mediated NF-κB and MAPK signaling pathways in LPS-induced RAW264.7 cells. The results of co-immunoprecipitation (Co-IP), pull-down experiment, confocal laser scanning microscopy, and surface plasmon resonance (SPR) suggested that MD2 was the direct target of LK2(6)A(L). Chemical inhibition of MD2 and its knockdown abolished the anti-inflammatory effect of LK2(6)A(L). Molecular dynamic simulation indicated that LK2(6)A(L) could bind to the active domain of the MD2 hydrophobic pocket via six hydrogen bonds. The truncated peptides were designed based on analysis of the molecular docking of LK2(6)A(L) to MD2. The truncated peptide IS-7 showed strong affinity to MD2 and a remarkable inhibitory effect on pro-inflammatory factors that was comparable to the effect of LK2(6)A(L). Finally, LK2(6)A(L) and IS-7 relieved inflammatory symptoms and lung tissue destruction in the ALI mouse model. Overall, our study suggested that LK2(6)A(L) showed promising anti-inflammatory activity by targeting MD2, and the amino acid domain 7–13 was an important area that binds with MD2 and also an anti-inflammatory active region. LK2(6)A(L) and IS-7 may be potential new treatments for ALI and other acute inflammatory diseases.

Intragraft B Cells, Just Not Like the Others.

B-cell infiltrates are found in most human transplants during rejection. Despite years of research, however, their role and exact contribution to the rejection process are still enigmatic. As a first step toward cracking this vexing puzzle, investigators have begun characterizing the phenotype and specificity of these infiltrating cells. In recent years, a few characteristics have emerged from studies conducted primarily with human kidney and heart transplant specimens.1,2 In a study published in this issue, Zheng and colleagues used a fully allogeneic Balb/c into B6 kidney transplant model to address some of these questions (see Zhang et al3 in this issue). Aside from its technical prowess—try transplanting a mouse kidney in your spare time—the experimental model appears clinically relevant because it recapitulates most features of antibody-mediated rejection and T cell–mediated rejection such as donor-specific antibodies, T- and B-cell infiltrates in the graft interstitium, glomerulitis, and C4d deposition in structures resembling peritubular capillaries. Allografts are lost within 1 mo with a median survival time of 21 d. Using μMT mice as recipients decreased the severity of rejection, indicating that B cells were involved in the rejection mechanism. Remarkably, CD4+ T-cell infiltrates were unchanged in these mice, suggesting that B-cell deficiency did not overtly impact the development of T cell–mediated rejection. The authors took advantage of the model to further characterize the graft-infiltrating B cells. Some features had already been observed in human B cells; others are novel and point to an unrecognized function of these cells. Among the common characteristics between mice and men is the fact that infiltrates include a higher proportion of memory cells. This had previously been reported for human kidney and heart transplants.1,2,4,5 Another striking similarity noted between intragraft B cells found in this model and in humans is their peculiar transcriptomic signature, including the expression of genes attributed to innate-like B cells such as Ahnak.1 In contrast, a number of differences were also noticeable. In particular, the fact that graft B cells predominantly express germline-encoded immunoglobulin genes and show only a low level of clonal expansion is perplexing and in disagreement with the past analysis of human kidney and heart transplant infiltrates.1,6,7 This discrepancy could result from short time, only 20 d, between transplant and rejection compared to months or years in human allograft recipients. Another apparent difference comes from the reactivity of these cells. Mouse-switched intragraft B cells appear enriched for allospecific cells, although this is more questionable in humans.1,2,8-10 The authors then investigated the functional properties of intragraft B cells and especially their capacity to promote the proliferation of CD4+ T cells. This part of the study is particularly interesting because it represents one of the first attempts to determine the function of intragraft B cells presumably associated with their innate-like profile. Results revealed a decreased ability to expand CD4 T cells when compared to lymph node (LN) B cells. Moreover, using Foxp3IRES−GFPmice, a model familiar to this research group, Zheng et al showed that intragraft B cells stimulate Tfh cells in a different manner than LN B cells, resulting in reduced proliferation and diminished cytokine secretion with the exception of granulocyte-macrophage colony-stimulating factors. Notwithstanding its inherent limitations, this experimental model offers invaluable insights into kidney graft-infiltrating B cells at the time of active rejection. For one, their contribution to the inflammatory reaction and tissue destruction is now substantiated. Two, and likely the most important observation corroborating previous findings in humans, intragraft B cells appear to be different from LN B cells in their molecular phenotype, especially through the expression of genes associated with an innate-like profile. Moreover, we learn from the present study that intragraft B cells also differ from LN B cells in their ability to interact with Tfh cells. These characteristics are definitely worth noting and raise additional questions. Are intragraft innate-like B cells related to conventional CD5+ B1 B cells? Are they enriched in autoreactive or polyreactive clones as suggested by their innate-like phenotype as documented for human intragraft B cells?1,2 More relevant to patient care, would removing these cells therapeutically correct ongoing rejection? These important questions can now be addressed using a relevant model like the one described by Zheng et al.

Flare-up of mucocutaneous leishmaniasis following infliximab discontinuation and antiparasitic therapy in a patient with juvenile idiopathic arthritis.

A 25-year-old patient had been treated for 4 years with infliximab for JIA. He was admitted for nodular and erythematosquamous lesions of the face and ears that had been evolving for 1 year (Fig. 1A). A skin biopsy with PCR allowed the diagnosis of Leishmania infantum mucocutaneous leishmaniasis (MCL). There was no visceral involvement. The patient lived in the south of France and had not travelled to another endemic area. Infliximab was discontinued and, 10 weeks after the last infusion, treatment with liposomal amphotericin-B 18 mg/kg was initiated. On the third day of treatment, he had a sudden but transient worsening of the lesions (Fig. 1B). One month later, he had complete response to the disease and infliximab was reintroduced (Fig. 1C). No recurrence occurred at a 6-month follow-up. TNFα mediates immune control of Leishmania infection but is also responsible for induced tissue damage. About 50 cases of MCL/cutaneous leishmaniasis have been reported in patients with anti-TNFα in the Mediterranean basin [1]. We report the first case of paradoxical worsening of MCL, which could be explained in two ways: immune restoration following anti-TNFα discontinuation, leading to inflammatory tissue destruction, as has been described in HIV-infected patients with leishmaniasis after highly active antiretroviral therapy (HAART) introduction [2]; and/or a ‘pseudo-Herxheimer’ type reaction related to Leishmania lysis.

Experiences of a Single Center in One Hundred Ninety-Four Adult Patients With Langerhans Cell Histiocytosis.

BackgroundLangerhans cell histiocytosis (LCH) is a rare inflammatory myeloid neoplasia belonging to the group of histiocytoses. Inflammatory tissue destruction with fibrosis can result in dysfunction in any organ. Our evaluation aimed to collect information on characteristics, courses, and therapeutic options of this rare disease pattern in adult patients with conclusions on prognostic factors and follow-up management.MethodsThe medical records of 194 adult patients with histologically confirmed LCH were evaluated in this retrospective study. Patients were treated at the Protestant Clinics in Gelsenkirchen from 2000 to 2014 and St. Franziskus-Hospital in Cologne until 2020.ResultsThe median age of onset was 38 years (18 to 79 years). In 65.5% of patients, only one organ was primarily involved, and in 34.5% of cases, multiple organs were involved. The skeleton, lungs, and skin were most commonly affected. In 15.5% of patients, pituitary insufficiency existed years before or at the time of diagnosis. The follow-up time of patients from the time of histologic diagnosis ranged from 6 to 408 months (median 49 months). Four patients died from sequelae of their underlying histiocytic disease. Irreversible late sequelae due to disease or therapy were detectable in 34% of patients. In 25.3% of the patients, the course of the disease could be controlled initially, but with the proviso of no smoking in case of lung involvement. Specific therapeutic measures such as surgery for solitary osteolysis, radiotherapy of osseous and cerebral manifestations, immunotherapy especially for lung and skin involvement, and chemotherapy for multisystem disease were primarily required in 74.7% of patients. As a result, 27.3% of all patients reached the nonactive stage. Of these, 26.4% had reactivation during the follow-up period. Of the remaining patients with continued active disease, 51.1% showed disease progression during follow-up.ConclusionsStandardized diagnostics are required to capture the clinical picture. Due to the variable course, it is often sufficient to initially control with obligatory smoking cessation in case of pulmonary involvement. Follow-up examinations should be predominantly symptom-oriented with attention to possible late sequelae.

Effect of melatonin supplementation on the gingival health and lipid profiles in obese periodontitis patients

Background: Obesity increases the host’s susceptibility by modulating the immune and inflammatory systems in a manner that predisposes to inflammatory tissue destruction and leaves an individual at greater risk of periodontitis. Melatonin is a pineal secretory product involved in numerous actions, such as regulation of internal biological clocks and energy metabolism, and it functions as an antioxidant and anti-inflammatory agent. There exists a substantial amount of evidence supporting the beneficial effect of melatonin supplementation on obesity and its complications. Aim of the study: To investigate the effects of systemic melatonin intake on periodontal health status and lipid profiles in obese periodontitis patients. Subjects and methods: Subjects included in the study were distributed into the following groups: Group I, 20 subjects with normal weight and healthy periodontium (controls) not subjected to any treatment. Group II: 30 obese periodontitis patients subjected to scaling and root planing (SRP) only. Group III: 30 obese periodontitis patients subjected to SRP and supplemented with 5mg melatonin tablets for 1 month. Study groups subjected to estimation of plaque index (PLI), bleeding on probing (BOP), cholesterol (chol), triglycerides (TG), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) at baseline and after 4 weeks recall visit. Results: Regarding the clinical parameters, the second visit exhibited decreasing in all parameters in both study groups except BOP score 0 were it increased significantly. Regarding lipid profiles, the second visit showed decreasing in all profiles except HDL where it increased in both study groups with a significant difference. All correlations between lipid profiles in recall visit in both study groups exhibited a positive significant correlation between chol and TG, chol and LDL, LDL and TG in group III. In group II all results exhibited a positive significant correlation, whereas the only strong negative correlation was found between chol and HDL, HDL and LDL. Conclusion: Daily supplementation with 5mg melatonin tab significantly improved periodontal health and reduced chol, TG, LDL with increasing HDL.

Investigation of the relationship between periodontal and systemic inflammation in children with Sickle Cell Disease: A case- control study.

Periodontal diseases are chronic inflammatory diseases and tissue destruction increases with oxidative stress in periodontal tissues. Periodontal diseases are associated with systemic diseases such as diabetes, cardio-vascular diseases and rheumatoid arthritis by means of systemic inflammation. Sickle cell disease (SCD) is a chronic inflammatory disease in which vaso-occlusive crisis and endothelial dysfunction are present. It is not known whether the chronic systemic inflammation seen in SCD affect periodontal tissues. The aim of this study was to investigate the relationship between periodontal and systemic inflammation in children with SCD. Forty-three children with SCD and 43 healthy children were included in the study. Physical, dental and periodontal statuses were examined, blood and saliva samples were taken. Levels of pro-inflammatory and oxidative stress mediators in serum and saliva were evaluated. The periodontal findings of the groups were similar. The majority of the subjects in both groups had gingival inflammation. In SCD group, significantly higher serum high sensitive C-reactive protein (Hs-CRP), interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, total oxidant status (TOS), nitric oxide (NO) and salivary IL-6 were observed (p<0.05). There were positive correlations between salivary IL-6 levels and serum Hs-CRP levels (r=0.303, p<0.05). In addition; it was determined that salivary IL-6, TNF-α and NO levels were increased 3-6 times in children with a history of painful crisis or acute chest syndrome compared to children who had never had a painful crisis or acute chest syndrome. Although, observed oral health status was similar in both groups, salivary cytokine levels were increased in children with SCD. The higher salivary cytokine levels may be associated with chronic systemic inflammation and vaso-occlusion observed in children with SCD.

The Immune Response to Respiratory Viruses: From Start to Memory.

Biomedical research has long strived to improve our understanding of the immune response to respiratory viral infections, an effort that has become all the more important as we live through the consequences of a pandemic. The disease course of these infections is shaped in large part by the actions of various cells of the innate and adaptive immune systems. While these cells are crucial in clearing viral pathogens and establishing long-term immunity, their effector mechanisms may also escalate into excessive, tissue-destructive inflammation detrimental to the host. In this review, we describe the breadth of the immune response to infection with respiratory viruses such as influenza and respiratory syncytial virus. Throughout, we focus on the host rather than the pathogen and try to describe shared patterns in the host response to different viruses. We start with the local cells of the airways, onto the recruitment and activation of innate and adaptive immune cells, followed by the establishment of local and systemic memory cells key in protection against reinfection. We end by exploring how respiratory viral infections can predispose to bacterial superinfection.

Discovery of anti-inflammatory physiological peptides that promote tissue repair by reinforcing epithelial barrier formation.

Epithelial barriers that prevent dehydration and pathogen invasion are established by tight junctions (TJs), and their disruption leads to various inflammatory diseases and tissue destruction. However, a therapeutic strategy to overcome TJ disruption in diseases has not been established because of the lack of clinically applicable TJ-inducing molecules. Here, we found TJ-inducing peptides (JIPs) in mice and humans that corresponded to 35 to 42 residue peptides of the C terminus of alpha 1-antitrypsin (A1AT), an acute-phase anti-inflammatory protein. JIPs were inserted into the plasma membrane of epithelial cells, which promoted TJ formation by directly activating the heterotrimeric G protein G13. In a mouse intestinal epithelial injury model established by dextran sodium sulfate, mouse or human JIP administration restored TJ integrity and strongly prevented colitis. Our study has revealed TJ-inducing anti-inflammatory physiological peptides that play a critical role in tissue repair and proposes a previously unidentified therapeutic strategy for TJ-disrupted diseases.

Community-acquired methicillin-resistant Staphylococcus aureus provoked cytokine storm causing severe infection on BALB/c mice

Methicillin-resistant Staphylococcus aureus (MRSA) has become the most important pathogen of hospital-acquired (HA) or community-acquired (CA) infections. However, it is unclear of the cytokines responsible for pathological hyper-inflammation in sepsis related cytokine storm for MRSA infection. In this study, we selected typical HA-MRSA strain (YNSA163: ST239-t030-SCCmecⅢ) and two CA-MRSA isolates (YNSA7: ST59-t439-SCCmecⅣa and YNSA53: ST59-t437-SCCmecⅤb) from our previous research, infected on BALB/c mice, and analyzed the cytokine storm patterns during infection process. The animal experiments revealed the most serious lethal effect on BALB/c mice caused by YNSA7 strain infection, followed by YNSA53, and no BALB/c mice died for YNSA163 infection. Histopathological analyses revealed that lung was the most seriously damaged organs, followed by spleen and kidney, especially for CA-MRSA infection. The severe inflammatory reactions, tissue destruction, and massive exudation of inflammatory mediators and cells could be identified in CA-MRSA strains infected mice. Interleukin-6 (IL-6) and IL-10 were both highly expressed in spleen and lung of YNSA7 and YNSA53 dead cases compared with YNSA53 survived and YNSA163 cases, which demonstrated cytokine storm pattern for CA-MRSA strains infection. The results of IL-6 intervention experiment verified that the enhanced IL-6 secretion was responsible for the host lethality of YNSA7 infection. RNA-sequencing results among three MRSA isolates indicated most of the differentially expressed genes referred to cellular process, metabolism and genetic information processing of bacteria. Specifically, clpP, chp chemotaxis inhibit, fnbB, pathogencity island protein and virulence associated protein E were highly expressed in YNSA7 strain. In general, CA-MRSA strains provoked cytokine storm on BALB/c mice led to severe infection and lethality, the up-regulated of some virulence genes might play important role in pathogenesis.

Comparison of virulence-related determinants between the ST59-t437 and ST239-t030 genotypes of methicillin-resistant\xa0Staphylococcus aureus

BackgroundMethicillin-resistant Staphylococcus aureus (MRSA) is an important pathogen for human infection. Hospital-acquired (HA) and community-acquired (CA) MRSA infections are serious clinical problems worldwide. In this study, we selected typical HA-MRSA strain and CA-MRSA isolates from our previous research and compared their phenotypic and pathogenic abilities both in vitro and in vivo.ResultsST59-t437-SCCmecIVa (YNSA7) and ST59-t437-SCCmecVb (YNSA53) belonged to two prevalent subclones of CA-MRSA, while ST239-t030-SCCmecIII (YNSA163) was an HA-MRSA epidemic clone in Southwest China. ST59-t437 strains demonstrated faster growth ability, higher survival rate resistance to human blood, and more toxin secretion levels and cytotoxicity than ST239-t030. The virulence and regulatory genes of hld, psm-α, RNAIII, agrA, and crtN were highly expressed on CA-MRSA isolates, especially the ST59-t437-SCCmecIVa subclone. However, the ST239-t030 strain had the strongest adhesion and biofilm ability among these MRSA bacteria. Animal experiments revealed the most serious lethal effect on BALB/c mice caused by the YNSA7 strain infection. The survival rates of BALB/c mice infected with the three MRSA strains were 16.7, 50.0 and 100.0% for YNSA7, YNSA53 and YNSA163, respectively. Histopathological analyses of infected animals indicated that the lungs were the most seriously damaged organs, especially for ST59-t437 MRSA. Severe inflammatory reactions, tissue destruction, and massive exudation of inflammatory mediators and cells could be identified in ST59-t437 strain-infected animals.ConclusionsIn general, ST59-t437 strains showed higher pathogenic ability than the ST239-t030 isolate, while ST239-t030 MRSA revealed the features prevalent in hospital settings, specifically for adhesion and biofilm ability.

Human Amniotic Mesenchymal Stem Cells Inhibit aGVHD by Regulating Balance of Treg and T Effector Cells.

BackgroundAcute graft versus host disease (aGVHD) remains a leading cause of transplant-related mortality following allogeneic haematopoietic cell transplantation (allo-HCT). Human amniotic mesenchymal stem cells (hAMSCs) are a novel mesenchymal stem cells (MSCs), which have stronger proliferation and immunomodulatory ability compared with bone marrow mesenchymal stem cells (BM-MSCs). Besides, as the amniotic membrane is often treated as medical waste after delivery, hAMSCs can be obtained conveniently and noninvasively. The aim of this study was to explore the therapeutic efficacy and underlying mechanisms of hAMSCs transplantation for the humanized aGVHD mouse model.MethodsWe established a humanized aGVHD mouse model by transplanting human peripheral blood mononuclear cells (PBMCs) into NOD-PrkdcscidIL2rγnull (NPG) mice, human amniotic membrane collected from discarded placenta of healthy pregnant women after delivery and hAMSCs were extracted from amniotic membrane and expanded in vitro. Mice were divided into untreated group (Control), aGVHD group (aGVHD), and hAMSCs treatment group (aGVHD+hAMSCs), the hAMSCs labeled with GFP were administered to aGVHD mice to explore the homing ability of hAMSCs. T effector and regulatory T cells (Tregs) levels and cytokines of each group in target organs were detected by flow cytometry and cytometric bead array (CBA), respectively.ResultsWe successfully established a humanized aGVHD mouse model using NPG mice. The hAMSCs have the ability to inhibit aGVHD in this mouse model through reduced villous blunting and lymphocyte infiltration of the gut while reducing inflammatory edema, tissue destruction and lymphocyte infiltration into the parenchyma of the liver and lung. hAMSCs suppressed CD3+CD4+ T and CD3+CD8+ T cell expression and increased the proportion of Tregs, and besides, hAMSCs can reduce the levels of IL-17A, INF-γ, and TNF in aGVHD target organs.ConclusionThe NPG murine environment was capable of activating human T cells to produce aGVHD pathology to mimic aGVHD as in humans. The hAMSCs controlled aGVHD by decreasing inflammatory cytokine secretion within target organs by modulating the balance of Tregs and T effector cells in humanized mice.

A phycocyanin derived eicosapeptide attenuates lung fibrosis development

Pulmonary fibrosis (PF) is a progressive respiratory disease. Phycocyanin derived eicosapeptide (PP20) is a novel peptide derived from active protein C-phycocyanin in Cyanobacteria. The aim of our study was to explore the anti-fibrotic activity of the PP20 and its underlying mechanism. Characteristic features of pulmonary fibrosis in oleic acid (OA)-induced mice and epithelial-mesenchymal transition (EMT) in TGF-β1-exposed A549 and HFL-1 cells with or without PP20 and the change of TGF-β/Smad and MAPK signaling pathways were examined. Smad and MAPK agonists were used to explore the role of TGF-β/Smad and MAPK signaling in TGF-β1- induced collagen I expression in A549 cells and α-SMA expression in HFL-1 cells when treated with PP20. Our results showed that PP20 significantly alleviated the inflammatory response and tissue destruction, inhibited EMT, restored the imbalance of TIMP-1/MMP-9 and reduced collagen fiber deposition. Moreover, PP20 inhibited TGF-β1-induced EMT and collagen I expression in A549 cells. PP20 could also inhibit the proliferation, and decrease TGF-β1-induced the expression of collagen I and transformation of fibroblasts into myofibroblasts in HFL-1 cells. Additionally, animal experiments and cell experiments combined with pathway agonists have shown that PP20 can negatively regulate TGF-β/Smad and MAPK pathways and show anti-fibrotic properties. PP20 may be a promising drug candidate for protection against pulmonary fibrosis.