Anti-inflammatory activity of d-pinitol possibly through inhibiting COX-2 enzyme: in vivo and in silico studies.

Introduction: D-pinitol, a naturally occurring inositol, has diverse biological activities like antioxidant, antimicrobial and anticancer activities. This study aimed to evaluate anti-inflammatory effect of d-pinitol in a chick model. Additionally, in silico studies were performed to evaluate the molecular interactions with cyclooxygenase-2 (COX-2). Methods: The tested groups received d-pinitol (12.5, 25, and 50 mg/kg) and the standard drugs celecoxib and ketoprofen (42 mg/kg) via oral gavage prior to formalin injection. Then, the number of licks was counted for the first 10 min, and the paw edema diameter was measured at 60, 90, and 120 min. Results and Discussion: The d-pinitol groups significantly (p < 0.05) reduced the number of paw licks and paw edema diameters, compared to negative control. When d-pinitol was combined with celecoxib, it reduced inflammatory parameters more effectively than the individual groups. The in silico study showed a promising binding capacity of d-pinitol with COX-2. Taken together, d-pinitol exerted anti-inflammatory effects in a dose-dependent manner, possibly through COX-2 interaction pathway.

Rehabilitation of Ectodermal Dysplasia Using CAD/CAM Mandibular Complete Denture and Maxillary Overdenture: A Clinical Report.

Ectodermal dysplasia is a genetic disorder characterized by the abnormal development of two or more ectodermally driven structures, leading to various clinical manifestations such as sparse hair, dry skin, and hypodontia or anodontia. The absence of teeth significantly impacts the quality of life for individuals affected by this condition. This article presents a clinical case report of a patient with ectodermal dysplasia who underwent full mouth rehabilitation using computer-aided design/computer-aided manufacturing (CAD/CAM) technology to fabricate a mandibular complete denture and a maxillary overdenture.

Bioactivity and molecular docking of lactones isolated from Centaurea pseudosinaica Czerep.

Two cytotoxic sesquiterpene lactones, 17-epichlorohyssopifolin A (1) and chlorjanerin (2), and a monoterpene lactone, loliolide (3) were isolated from Centaurea pseudosinaica. The cytotoxicity of the total extract and terpenoids 1-3 were evaluated against three human cancer cells (HepG2, PC-3, and HT-29), along with the human normal primary epidermal keratinocytes (HEKa) cells. With IC50 values ranging between 0.6 ± 0.04 and 5.0 ± 0.61 µg/mL against HepG2; 0.2 ± 0.01 and 11.9 ± 1.31 µg/mL against PC-3, and 0.04 ± 0.013 and 8.9 ± 0.97 µg/mL against HT-29, the total extract, and lactones 1-3 demonstrated cytotoxic effects. Compound 1 displayed the strongest impact on all cancer cells and a slightly safe effect on the normal cells HEKa. Compound 1 caused accumulation of HepG2 and HT-29 cells in G1 phase as displayed cell cycle analysis. On the other hand, the cell distributions were increased in the S phase in PC-3 cells. Furthermore, 1 caused apoptosis in PC-3 and HePG2 cells with 91.50%, and 79.72 %, respectively. A higher fraction of necrotic cells was observed in HT-29 cells amounting to 23.60%. These results suggested that the promising cytotoxicity exhibited by 1 is brought by the apoptosis induction in the cancer cells, which were evaluated. As the compounds showed antiproliferative effect against the HT-29 cells, the docking simulation was performed aiming at determining how they would interact with the EGFR enzyme, whose PDB: 4I23 is considered one of the two distinct wild types of EGFR enzymes. The antibacterial activity results revealed that 3 showed the most remarkable antibacterial effects, especially against the examined Gram-positive bacteria. The total extract exhibited potent activity against all examined bacteria. The total extract showed a potent antifungal effect against two Candida and two Aspergillus pathogens. The antioxidant activity revealed the potency of the total extract and 3 as antioxidant candidates. The obtained results refer to the importance of Centaurea pseudosinaica as a source of potent antiproliferative agents and the whole plant as an antipathogenic and antioxidant agent.

Classification of maxillectomy in edentulous arch defects, algorithm, concept, and proposal classifications: A review.

OBJECTIVES: Aramany's classification of postsurgical maxillectomy defects was introduced for partially edentulous situations, and has been widely used for education and effective communication among practitioners. Numerous classifications of maxillofacial defects, based on surgical procedure, resultant defects, or prosthodontist's perspective after rehabilitation, exist in the literature. However, no single classification has incorporated all these factors. The purpose of this review was to highlight the classification systems and describe a pragmatic classification series for edentulous maxillary arch defects (maxillectomy) by applying the Aramany classification criteria, to enhance treatment outcomes and communication among practitioners. MATERIAL AND METHODS: An electronic search of the literature published in English was conducted using the PubMed/MEDLINE and Google Scholar database. Keywords used were "maxillectomy classification" AND "surgical resection," "maxillectomy classification" AND "complete edentulous." In addition, a manual search was also performed followed the same criteria in the following journals: Journal of Prosthetic Dentistry and Journal of Prosthodontics. RESULTS: Several classification systems for partial dentition were found in terms of size, location, dentition, and extension of the defect (isolated or communication defects). The findings revealed a variety of maxillectomy defect classifications for partially dentate, considering surgical factors and rehabilitation. However, no study or classification system exist for the edentulous arch defects. CONCLUSIONS: Different classification systems for maxillectomy defects exist in the literature, only for partially dentate patients. To the authors best knowledge, no classification system for completely edentulous maxillary arch defects have been proposed till date. A simple classification system with clear characteristics for edentulous maxillectomy dental arch defects has been proposed. This classification was modeled after Aramany classification for easier memorization and application.

Serum-Based lncRNA ANRIL, TUG1, UCA1, and HIT Expressions in Breast Cancer Patients.

Breast cancer is a heterogeneous disease and is the most common and prevalent form of malignancy diagnosed in women. lncRNAs are found to be frequently dysregulated in cancer, and its expression plays a critical role in tumorigenesis. The study included 100 histopathologically confirmed, newly diagnosed untreated patients of invasive ductal carcinoma (IDC) of breast cancer patients and 100 healthy subjects. After blood collection, the serum was separated and total RNA was extracted, cDNA was synthesized using 100 ng of total RNA, and lncRNA (ANRIL, TUG1, UCA1, and HIT) expression was analyzed. Increased ANRIL (3.83-fold), TUG1 (7.64-fold), UCA1 (7.82-fold), and HIT (3.31-fold) expressions were observed in breast cancer patients compared to healthy controls. Relative expression of lncRNAs UCA-1 (p = 0.010) and HIT-1 (p < 0.0001) was significantly elevated in patients with advanced breast cancer stage compared to those with early-stage disease. While lncRNA TUG-1 expression was found to be higher in patients with early-stage tumors than those with advanced-stage tumors (p = 0.06), lncRNA ANRIL showed increased expression in patients with PR positive status (p = 0.04). However, we found a significant difference in lncRNA HIT expression in HER-2 positive breast cancer patients compared to HER-2 negative breast cancer patients (p = 0.005). An increase in the expression of serum lncRNAs ANRIL (p < 0.0001), UCA-1 (p = 0.004), and HIT (p < 0.0001) was observed in the distant organ metastatic breast cancer patients. In the ROC curve concerning lymph node involvement, the sensitivity and specificity of lncRNA HIT were 68% and 58%, respectively (p value = 0.007). In the ROC curve w.r.t. stages of disease, the sensitivity and specificity of lncRNA HIT were 80% and 50%, respectively (p value < 0.0001). Better sensitivity and specificity were observed for lncRNA HIT (sensitivity 91% and specificity 78%; p value < 0.0001) and ANRIL (sensitivity 70% and specificity 60%; p value < 0.0001) w.r.t distant organ metastases.

IL-17-induced inflammation modulates the mPGES-1/PPAR-γ pathway in monocytes/macrophages.

BACKGROUND AND PURPOSE: Recent biochemical and pharmacological studies have reported that in several tissues and cell types, microsomal PGE2 synthase (mPGES) and PPAR-γ expression are modulated by a variety of inflammatory factors and stimuli. Considering that very little is known about the biological effects promoted by IL-17 in the context of mPGES-1/PPAR-γ modulation, we sought to investigate the contribution of this unique cytokine on this integrated pathway during the onset of inflammation. EXPERIMENTAL APPROACH: We evaluated effects of PF 9184 (mPGES-1 inhibitor) and troglitazone (PPAR-γ agonist) in vitro, using the mouse macrophage cell line J774A.1. In vivo, the dorsal air pouch model in CD1 mice was used, and inflammatory infiltrates were analysed by flow cytometry. Locally produced cyto-chemokines and PGs were assessed using elisa assays. Western blots were also employed to determine the activity of various enzymes involved in downstream signalling pathways. KEY RESULTS: PF 9184 and troglitazone, in a time- and dose-dependent manner, modulated leukocyte infiltration, myeloperoxidase activity, and the expression of COX-2/mPGES-1, NF-кB/IкB-α, and mPTGDS-1/PPAR-γ, induced by IL-17. Moreover, both PF 9184 and troglitazone modulated PG (PGE2 , PGD2 , and PGJ2 ) production, the expression of different pro-inflammatory cyto-chemokines, and the recruitment of inflammatory monocytes, in response to IL-17. CONCLUSIONS AND IMPLICATIONS: Our data suggest that IL-17 may constitute a specific modulator of inflammatory monocytes during later phases of the inflammatory response. The results of this study show, for the first time, that the IL-17/mPGES-1/PPAR-γ pathway could represent a potential therapeutic target for inflammatory-based and immune-mediated diseases. LINKED ARTICLES: This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc.

Paracetamol poisoning induces acute liver injury in rats: inhibition of miR-155/cd45 axis-mediated antioxidant depletion and hepatotoxicity using quercetin and resveratrol / La intoxicación por paracetamol induce daño hepático agudo en ratas: inhibición de la depleción de antioxidantes mediado por el eje miR-155/cd45 y hepatotoxicidad usando quercetina y resveratrol

SUMMARY: Ingestion of an overdose of paracetamol (also called acetaminophen, or APAP) induces hepatotoxicity that can lead to liver failure. The link between the pro-inflammatory microRNA-155 (miR-155) and leukocyte infiltration (CD45) in APAP- antioxidant depletion and liver toxicity with and without the natural polyphenolic compounds, quercetin (QUR) plus resveratrol (RES) has not been previously studied. Therefore, acute hepatic injury was induced in rats by 2 g/kg APAP (single dose, orally) and another group started QUR (50 mg/kg) plus RES (30 mg/kg) treatment one week prior to APAP ingestion. Animals were culled 24 hours post the paracetamol treatment. APAP overdose induced hepatic and blood levels of miR-155 expression, CD45 (leukocyte common antigen) immunostaining, degenerated hepatocytes, and hepatic injury enzymes; alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which were markedly decreased by QUR+RES. Whereas, APAP intoxication ameliorated liver tissue levels of the antioxidants, glutathione peroxidase and superoxide dismutase that were augmented by QUR+RES. Moreover, a significant (p<0.05) correlation between miR-155/CD45 axis and liver tissue injury was observed. These findings show that paracetamol intoxication augments miR- 155/CD45 axis-mediated modulation of antioxidants and liver injury in rats, and is protected by QUR+RES.

RESUMEN: La ingestión de una sobredosis de paracetamol (también llamado acetaminofeno o APAP) induce hepatotoxicidad que puede provocar insuficiencia hepática. El vínculo entre el microARN-155 proinflamatorio (miR-155) y la infiltración de leucocitos (CD45) en el agotamiento de APAP- antioxidante y la toxicidad hepática con y sin los compuestos polifenólicos naturales, quercetina (QUR) más resveratrol (RES) no ha sido previamente investigado. En este estudio, se indujo daño hepático agudo en ratas con 2 g/kg de APAP (dosis única, por vía oral) y otro grupo comenzó el tratamiento con QUR (50 mg/ kg) más RES (30 mg/kg) una semana antes de la ingestión de APAP. Los animales se sacrificaron 24 horas después del tratamiento con paracetamol. La sobredosis de APAP indujo niveles hepáticos y sanguíneos de expresión de miR-155, inmunotinción de CD45 (antígeno leucocitario común), degeneración de los hepatocitos y daño hepático enzimático; alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST), disminuyeron notablemente con QUR+RES. Mientras que la intoxicación con APAP mejoró los niveles de antioxidantes, glutatión peroxidasa y superóxido dismutasa en el tejido hepático los que aumentaron con QUR+RES. Además, se observó una correlación significativa (p<0,05) entre el eje miR-155/CD45 y la lesión del tejido hepático. Estos hallazgos muestran que la intoxicación por paracetamol aumenta la modulación mediada por el eje miR-155/CD45 de los antioxidantes y la lesión hepática en ratas, y está protegida por QUR+RES.

Role of miRNA-495 and NRXN-1 and CNTN-1 mRNA Expression and Its Prognostic Importance in Breast Cancer Patients.

Breast cancer is a heterogeneous disease in which genetic factors are involved in disease worsening and higher mortality. Epidemiological and clinical research revealed that breast cancer incidence continues to rise. 100 histopathologically confirmed untreated newly diagnosed cases of invasive ductal carcinoma (IDC) of breast and 100 healthy subjects were involved and blood samples were collected in non-EDTA plain vials. Serum was separated by centrifugation, total RNA was extracted from serum, and cDNA synthesis was done to study the miRNA-495 and neurexin-1 (NRXN-1) and contactin 1 (CNTN-1) mRNA expression by QRT-PCR. The expression levels of miRNA-495, NRXN-1, and CNTN-1 were expressed in fold change. The present study observed decreased relative miRNA-495 expression (0.07-fold) while an increase in NRXN-1 (11.61-fold) and CNTN-1 (4.92-fold) was observed among breast cancer patients compared to healthy controls. A significant difference was observed in miRNA-495 expression with menopausal status (p=0.0001) and TNM stages (p=0.02). It was observed that NRXN-1 expression was significantly associated with menopausal status (p=0.03), lymph node involvement (p < 0.0001), estrogen receptor (ER) status (p=0.03), progesterone receptor (PR) status (p=0.005), TNM stages (p < 0.0001), and distant metastases (p < 0.0001). CNTN-1 expression was also found to be associated with lymph node involvement (p=0.01), PR status (p=0.03), HER2 status (p=0.04), TNM stages (p < 0.0001), and distant metastases (p < 0.0001). ROC suggested that NRXN-1 and CNTN-1 could be the important predictive marker for disease advancement and distant organ metastases. The study concluded that the decreased expression of miR-495 observed in breast cancer patients showed a negative correlation with NRXN-1 while the increased expression of NRXN-1 and CNTN-1 was linked with disease advancement and distant metastases and could be the important predictive marker for breast cancer patients.

Irritable Bowel Syndrome: Prevalence and Risk Factors in Jazan Region, Saudi Arabia.

Background The prevalence of irritable bowel syndrome (IBS) worldwide remains heterogeneous. In Saudi Arabia, there are insufficient studies on the prevalence of IBS among the general population, yet the prevalence of IBS in certain professional groups has been reported. This study was conducted to determine the prevalence of IBS and its associated risk factors in the Jazan Region of Saudi Arabia. Methods An online cross-sectional study was conducted from January to March 2020 in the Jazan Region of Saudi Arabia, using a multi-stage stratified sampling technique. The data were collected using a web-based validated Rome IV questionnaire. The Rome IV criteria are used to diagnose functional gut disorders, including IBS. Logistic regression analysis was used to determine the odds ratio (OR) with 95% confidence intervals (95% CI) for the selected risk factors. Results The survey included 1554 participants with an overall IBS prevalence of 16%. Women had a higher incidence of IBS than men (55.3% and 44.7%, respectively). IBS-mixed (32.66%) and constipation-predominant (32.25%) were the most common subtypes. In multiple regression analysis, female gender (OR = 1.503, p-value = 0.037), stress (OR = 2.386, p-value = 0.000), anxiety (OR = 1.943, p-value = 0.000), and tobacco smoking (OR = 2.093, p-value = 0.001) showed a statistically significant association with IBS. Conclusions The prevalence of IBS in the southwest region of Saudi Arabia is high. Female sex, tobacco smoking, stress, and anxiety are the major risk factors associated with IBS.

Circulating long non-coding RNAs NKILA, NEAT1, MALAT1, and MIAT expression and their association in type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a multifactorial disorder that leads to alterations in gene regulation. Long non-coding RNAs (lncRNAs) have become a major research topic as they are involved in metabolic disorders. METHODS: This study included a total of 400 study subjects; 200 were subjects with T2DM and 200 were healthy subjects. Extracted RNA was used to synthesize cDNA by quantitative real time. Serum analysis was carried out to determine differences in biochemical parameters. Recorded data were used to evaluate associations with expression of lncRNAs NF-kappaB interacting lncRNA (NKILA), nuclear enriched abundant transcript 1 (NEAT1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and myocardial infarction-associated transcript (MIAT) in T2DM cases. RESULTS: Compared with healthy controls, patients with T2DM showed an overall increase in expression of lncRNAs NKILA, NEAT, MALAT1, and MIAT by 3.94-fold, 5.28-fold, 4.46-fold, and 6.35-fold, respectively. Among patients with T2DM, higher expression of lncRNA NKILA was associated with hypertension (p=0.001), smoking (p<0.0001), and alcoholism (p<0.0001). Altered NEAT1 expression was significantly associated with weight loss (p=0.04), fatigue (p=0.01), slow wound healing (p=0.002), blurred vision (p=0.008), loss of appetite (p=0.007), smoking (p<0.0001), and alcoholism (p<0.0001). Higher expression of lncRNA MALAT1 was significantly linked with weight loss (p=0.003), blurred vision (p=0.01), smoking (p<0.0001), and alcoholism (p<0.0001). Expression of lncRNA MIAT was associated with only blurred vision (p<0.0001), smoking (p<0.0001), and alcoholism (p<0.0001). Positive correlations of lncRNA NKILA with lncRNAs NEAT1 (r=0.42, p<0.0001), MALAT (r=0.36, p<0.0001) and MIAT (r=0.42, p<0.0001) were observed among patients with T2DM. Significant positive correlations of lncRNA NEAT with lncRNAs MALAT and MIAT were observed among patients with T2DM. A positive correlation between lncRNAs MALAT and MIAT was also observed among patients with T2DM. CONCLUSION: Increased circulating NKILA, NEAT1, MALAT, and MIAT expression in patients with T2DM, which is linked with poor patient outcomes and significantly linked with alcoholism and smoking, may influence the degree and severity of disease among patients with T2DM. These lncRNAs may contribute to the progression of T2DM disease or other related diabetes-related complications.

Assessment of Cell-Free Long Non-Coding RNA-H19 and miRNA-29a, miRNA-29b Expression and Severity of Diabetes.

BACKGROUND: Type 2 diabetes mellitus [T2DM] has been one of the common diseases and is characterized by increased blood glucose levels and suggested that cell-free non-coding RNAs and microRNAs (miRNAs) have been demonstrated to serve as important diagnostic/prognostic biomarkers in diabetes. MATERIALS/METHODS: The present study included clinically confirmed newly diagnosed 200 cases of T2DM and 200 healthy subjects, and all the parameters were taken care in diagnosis. Blood samples collected in plain vials were used for cell-free total RNA extraction and after that 100ng of total RNA was used to synthesize the cDNA for cell-free lncRNA H19, miRNA-29a, and miRNA-29b expression using quantitative real-time PCR method. Serum Biochemical parameters were analyzed after collection of the sample to observe the changes among T2DM cases and healthy controls. RESULTS: It was observed that type 2 diabetic patients had decreased [0.59 fold] lncRNA H19 expression while increased miRNA-29a [5.62 fold] and miRNA-29b [5.58 fold] expression. Decreased expression of lncRNA H19 was observed to be associated with gender [p=0.004], hypertension [p<0.0001], weight loss [p=0.02] and fatigue [p=0.02]. Increased miRNA29a expression was linked with hypertension [p<0.0001], alcoholism [p=0.04], and smoking [p<0.0001] as well as miRNA-29b expression was associated with hypertension [p=0.0001], weight loss [p=0.002], smoking [p=0.0002], alcoholism [p<0.0001]. Low [≤1 fold] and high [>1 fold] expression of lncRNA H19 expression was linked with miRNA-29a [p=0.005] and miRNA-29b [p<0.0001] expression. lncRNA H19 expression showed negative correlation with miRNA-29a expression [r= -27, p<0.0001] and miRNA-29b [r= -47, p<0.0001]. CONCLUSION: The present study concluded that lower lncRNA H19 expression, and increased miRNA-29b, a miRNA-29b expression associated with the severity of T2DM patients. Decreased lncRNA H19 expression, and increased miRNA-29b, miRNA-29b expression observed to be interrelated with clinicopathological findings of T2DM patients could involve in pathogenesis disease.

Metformin inhibits mTOR-HIF-1α axis and profibrogenic and inflammatory biomarkers in thioacetamide-induced hepatic tissue alterations.

The potential inhibitory effect of the antidiabetic and anti-inflammatory drug, metformin on thioacetamide (TAA)-induced hepatotoxicity associated with the inhibition of mammalian target of rapamycin (mTOR)-hypoxia-inducible factor-1α (HIF-1α) axis has not been investigated before. Therefore, we tested whether metformin can protect against liver injuries including fibrosis induced by TAA possibly via the downregulation of mTOR-HIF-1α axis and profibrogenic and inflammatory biomarkers. Rats either injected with TAA (200 mg/kg; twice a week for 8 weeks) before being killed after 10 weeks (model group) or were pretreated with metformin (200 mg/kg) daily for 2 weeks before TAA injections and continued receiving both agents until the end of the experiment, at Week 10 (protective group). Using light and electron microscopy examinations, we observed in the model group substantial damage to the hepatocytes and liver tissue such as collagen deposition, infiltration of inflammatory cells, and degenerative cellular changes with ballooned mitochondria that were substantially ameliorated by metformin. Metformin also significantly ( p < 0.05) inhibited TAA-induced HIF-1α, mTOR, the profibrogenic biomarker α-smooth muscle actin, tissue inhibitor of metalloproteinases-1, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), alanine aminotransferase (ALT) and aspartate aminotransferase in harvested liver homogenates and blood samples. In addition, a significant ( p < 0.01) positive correlation between hypoxia scoring (HIF-1α) and the serum levels of TNF-α ( r = 0.797), IL-6 ( r = 0.859), and ALT ( r = 0.760) was observed. We conclude that metformin protects against TAA-induced hepatic injuries in rats, which is associated with the inhibition of mTOR-HIF-1α axis and profibrogenic and inflammatory biomarkers; thus, may offer therapeutic potential in humans.

Mesenchymal stromal cell therapy for liver diseases.

The therapeutic potential of mesenchymal stromal cells (MSCs) in the treatment of liver fibrosis is predominantly based on their immunosuppressive properties, and their ability to secrete various trophic factors. This potential has been investigated in clinical and preclinical studies. Although the therapeutic mechanisms of MSC transplantation are still not fully characterised, accumulating evidence has revealed that various trophic factors secreted by MSCs play key therapeutic roles in regeneration by alleviating inflammation, apoptosis, and fibrosis as well as stimulating angiogenesis and tissue regeneration in damaged liver. In this review, we summarise the safety, efficacy, potential transplantation routes and therapeutic effects of MSCs in patients with liver fibrosis. We also discuss some of the key strategies to enhance the functionality of MSCs, which include sorting and/or priming with factors such as cytokines, as well as genetic engineering.