Microbiome and the inflammatory pathway in peri-implant health and disease with an updated review on treatment strategies.

Crestal bone preservation around the dental implant for aesthetic and functional success is widely researched and documented over a decade. Several etiological factors were put forth for crestal bone loss; of which biofilm plays a major role. Biofilm is formed by the colonization of wide spectra of bacteria inhabited around dental implants. Bacterial adherence affects the regulators of bone growth and an early intervention preserves the peri-implant bone. Primary modes of therapy stated in early literature were either prevention or treatment of infection caused by biofilm. This narrative review overviews the microbiome during different stages of peri-implant health, the mechanism of bone destruction, and the expression of the biomarkers at each stage. Microbial contamination and the associated biomarkers varied depending on the stage of peri-implant infection. The comprehensive review helps in formulating a research plan, both in diagnostics and treatment aspects in improving peri-implant health.

Advanced application of stimuli-responsive drug delivery system for inflammatory arthritis treatment.

Inflammatory arthritis is a major cause of disability in the elderly. This condition causes joint pain, loss of function, and deterioration of quality of life, mainly due to osteoarthritis (OA) and rheumatoid arthritis (RA). Currently, available treatment options for inflammatory arthritis include anti-inflammatory medications administered via oral, topical, or intra-articular routes, surgery, and physical rehabilitation. Novel alternative approaches to managing inflammatory arthritis, so far, remain the grand challenge owing to catastrophic financial burden and insignificant therapeutic benefit. In the view of non-targeted systemic cytotoxicity and limited bioavailability of drug therapies, a major concern is to establish stimuli-responsive drug delivery systems using nanomaterials with on-off switching potential for biomedical applications. This review summarizes the advanced applications of triggerable nanomaterials dependent on various internal stimuli (including reduction-oxidation (redox), pH, and enzymes) and external stimuli (including temperature, ultrasound (US), magnetic, photo, voltage, and mechanical friction). The review also explores the progress and challenges with the use of stimuli-responsive nanomaterials to manage inflammatory arthritis based on pathological changes, including cartilage degeneration, synovitis, and subchondral bone destruction. Exposure to appropriate stimuli induced by such histopathological alterations can trigger the release of therapeutic medications, imperative in the joint-targeted treatment of inflammatory arthritis.

Urinary Exosomal Tissue TIMP and Angiopoietin-1 Are Preoperative Novel Biomarkers of Well-Differentiated Thyroid Cancer.

Finding non-invasive and sensitive biomarkers for early screening of high-risk patients remains important in clinical practice. A higher concentration of urine exosomal thyroglobulin protein was found in late-stage patients with thyroid carcinoma compared to those with early stage in our previous study. This prospective study aims to find new prognostic biomarkers before surgery for decision-making with this platform. We enrolled patients newly diagnosed with papillary and follicular cancer from 2017 to 2018. Preoperative urine samples were collected and the exosomal proteins were analyzed. The association of the concentration of urine exosomal proteins with lymph node metastasis and MACIS score (metastasis, age, completeness of resection, invasion, and size) was analyzed with multiple logistic regression. In total, 21 patients were included, with a mean age of 51.29 ± 10.29 years and a majority of female patients (85.71%). The concentration of urine exosomal TIMP (tissue inhibitor of metalloproteinase) was significantly higher in patients with lymph node metastasis (p = 0.01). Multiple logistic regression analysis showed association of urine exosomal TIMP (adjusted odds ratio (aOR): 3.09, 95% confidence interval (CI): 0.99-9.6, p = 0.052), angiopoietin-1 (aOR: 2.24, 95% CI: 0.97-5.15, p = 0.058) with lymph node metastasis. However, no association was noted between MACIS score and various urine exosomal protein candidates. Preoperative urine exosomal data could suggest certain peptides having the potential as prognostic indicators for screening patients with high-risk before surgery. Further study with a large cohort and long follow-up is needed to identify the application of urine exosomal proteins on prognostic prediction.

Matrix Metalloproteinases in Human Decidualized Endometrial Stromal Cells.

Cyclic changes, such as growth, decidualization, shedding, and regeneration, in the human endometrium are regulated by the reciprocal action of female hormones, such as estradiol (E2), and progesterone (P4). Matrix metalloproteases (MMPs) and tissue inhibitors of MMPs (TIMPs) control the invasion of extravillous trophoblast cells after implantation. Several MMPs and TIMPs function in the decidua and endometrial stromal cells (ESCs). Here, we aimed to systematically investigate the changes in MMPs and TIMPs associated with ESC decidualization. We evaluated the expression of 23 MMPs, four TIMPs, and four anti-sense non-coding RNAs from MMP loci. Primary ESC cultures treated with E2 + medroxyprogesterone acetate (MPA), a potent P4 receptor agonist, showed significant down-regulation of MMP3, MMP10, MMP11, MMP12, MMP20, and MMP27 in decidualized ESCs, as assessed by quantitative reverse transcription PCR. Further, MMP15 and MMP19 were significantly upregulated in decidualized ESCs. siRNA-mediated silencing of Heart and Neural Crest Derivatives Expressed 2 (HAND2), a master transcriptional regulator in ESC decidualization, significantly increased MMP15 expression in untreated human ESCs. These results collectively indicate the importance of MMP15 and MMP19 in ESC decidualization and highlight the role of HAND2 in repressing MMP15 transcription, thereby regulating decidualization.

Artemisinin and artemisinin derivatives as anti-fibrotic therapeutics.

Fibrosis is a pathological reparative process that can occur in most organs and is responsible for nearly half of deaths in the developed world. Despite considerable research, few therapies have proven effective and been approved clinically for treatment of fibrosis. Artemisinin compounds are best known as antimalarial therapeutics, but they also demonstrate antiparasitic, antibacterial, anticancer, and anti-fibrotic effects. Here we summarize literature describing anti-fibrotic effects of artemisinin compounds in in vivo and in vitro models of tissue fibrosis, and we describe the likely mechanisms by which artemisinin compounds appear to inhibit cellular and tissue processes that lead to fibrosis. To consider alternative routes of administration of artemisinin for treatment of internal organ fibrosis, we also discuss the potential for more direct oral delivery of Artemisia plant material to enhance bioavailability and efficacy of artemisinin compared to administration of purified artemisinin drugs at comparable doses. It is our hope that greater understanding of the broad anti-fibrotic effects of artemisinin drugs will enable and promote their use as therapeutics for treatment of fibrotic diseases.

Combined obeticholic acid and apoptosis inhibitor treatment alleviates liver fibrosis.

Obeticholic acid (OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possibly due to the lower dosage to reduce the incidence of the side-effect of pruritus. Here we propose a combinatory therapeutic strategy of OCA and apoptosis inhibitor for combating against liver fibrosis. CCl4-injured mice, d-galactosamine/LPS (GalN/LPS)-treated mice and cycloheximide/TNFα (CHX/TNFα)-treated HepG2 cells were employed to assess the effects of OCA, or together with IDN-6556, an apoptosis inhibitor. OCA treatment significantly inhibited hepatic stellate cell (HSC) activation/proliferation and prevented fibrosis. Elevated bile acid (BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs. OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis. An enhanced anti-fibrotic effect was observed when OCA was co-administrated with IDN-6556. Our study demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs. The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.

Hepatitis C Virus-Induced Monocyte Differentiation Into Polarized M2 Macrophages Promotes Stellate Cell Activation via TGF-ß.

BACKGROUND & AIMS: Monocyte and macrophage (MΦ) activation contributes to the pathogenesis of chronic hepatitis C virus (HCV) infection. Disease pathogenesis is regulated by both liver-resident MΦs and monocytes recruited as precursors of MΦs into the damaged liver. Monocytes differentiate into M1 (classic/proinflammatory) or M2 (alternative/anti-inflammatory) polarized MΦs in response to tissue microenvironment. We hypothesized that HCV-infected hepatoma cells (infected with Japanese fulminant hepatitis-1 [Huh7.5/JFH-1]) induce monocyte differentiation into polarized MΦs. METHODS: Healthy human monocytes were co-cultured with Huh7.5/JFH-1 cells or cell-free virus for 7 days and analyzed for MΦ markers and cytokine levels. A similar analysis was performed on circulating monocytes and liver MΦs from HCV-infected patients and controls. RESULTS: Huh7.5/JFH-1 cells induced monocytes to differentiate into MΦs with increased expression of CD14 and CD68. HCV-MΦs showed M2 surface markers (CD206, CD163, and Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN)) and produced both proinflammatory and anti-inflammatory cytokines. HCV-induced early interleukin 1ß production promoted transforming growth factor (TGF)ß production and MΦ polarization to an M2 phenotype. TGF-ß secreted by M2-MΦ led to hepatic stellate cell activation indicated by increased expression of collagen, tissue inhibitor of metalloproteinase 1, and α-smooth muscle actin. In vivo, we observed a significant increase in M2 marker (CD206) expression on circulating monocytes and in the liver of chronic HCV-infected patients. Furthermore, we observed the presence of a unique collagen-expressing CD14+CD206+ monocyte population in HCV patients that correlated with liver fibrosis. CONCLUSIONS: We show an important role for HCV in induction of monocyte differentiation into MΦs with a mixed M1/M2 cytokine profile and M2 surface phenotype that promote stellate cell activation via TGF-ß. We also identified circulating monocytes expressing M2 marker and collagen in chronic HCV infection that can be explored as a biomarker.

Atheroprotective Effects of Tumor Necrosis Factor-Stimulated Gene-6.

Tumor necrosis factor-stimulated gene-6 (TSG-6), an anti-inflammatory protein, was shown to be localized in the neointima of injury-induced rat arteries. However, the modulatory effect of TSG-6 on atherogenesis has not yet been reported. We aimed to evaluate the atheroprotective effects of TSG-6 on human endothelial cells (HECs), human monocyte-derived macrophages (HMDMs), human aortic smooth muscle cells (HASMCs) in vitro, and aortic lesions in apolipoprotein E-deficient mice, along with expression levels of TSG-6 in coronary lesions and plasma from patients with coronary artery disease (CAD). TSG-6 was abundantly expressed in HECs, HMDMs, and HASMCs in vitro. TSG-6 significantly suppressed cell proliferation and lipopolysaccharide-induced up-regulation of monocyte chemotactic protein-1, intercellular adhesion molecule-1, and vascular adhesion molecule-1 in HECs. TSG-6 significantly suppressed inflammatory M1 phenotype and suppressed oxidized low-density lipoprotein-induced foam cell formation associated with down-regulation of CD36 and acyl-CoA:cholesterol acyltransferase-1 in HMDMs. In HASMCs, TSG-6 significantly suppressed migration and proliferation, but increased collagen-1 and -3 expressions. Four-week infusion of TSG-6 into apolipoprotein E-deficient mice significantly retarded the development of aortic atherosclerotic lesions with decreased vascular inflammation, monocyte/macrophage, and SMC contents and increased collagen fibers. In addition, it decreased peritoneal M1 macrophages with down-regulation of inflammatory molecules and lowered plasma total cholesterol levels. In patients with CAD, plasma TSG-6 levels were significantly increased, and TSG-6 was highly expressed in the fibrous cap within coronary atherosclerotic plaques. These results suggest that TSG-6 contributes to the prevention and stability of atherosclerotic plaques. Thus, TSG-6 may serve as a novel therapeutic target for CAD.

DNA-PKcs plays role in cancer metastasis through regulation of secreted proteins involved in migration and invasion.

The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a major role in DNA damage signaling and repair and is also frequently overexpressed in tumor metastasis. We used isogenic cell lines expressing different levels of DNA-PKcs to investigate the role of DNA-PKcs in metastatic development. We found that DNA-PKcs participates in melanoma primary tumor and metastasis development by stimulating angiogenesis, migration and invasion. Comparison of conditioned medium content from DNA-PKcs-proficient and deficient cells reveals that DNA-PKcs controls secretion of at least 103 proteins (including 44 metastasis-associated with FBLN1, SERPINA3, MMP-8, HSPG2 and the inhibitors of matrix metalloproteinases, such as α-2M and TIMP-2). High throughput analysis of secretomes, proteomes and transcriptomes, indicate that DNA-PKcs regulates the secretion of 85 proteins without affecting their gene expression. Our data demonstrate that DNA-PKcs has a pro-metastatic activity via the modification of the tumor microenvironment. This study shows for the first time a direct link between DNA damage repair and cancer metastasis and highlights the importance of DNA-PKcs as a potential target for anti-metastatic treatment.

Discriminatory metabolic and inflammatory parameters in serum and omental adipose tissue of obese patients with different insulin sensitivity.

OBJECTIVE: Metabolically healthy obese phenotype is defined by high insulin sensitivity and lack of metabolic syndrome, parameters regulated by omental adipose tissue inflammation, ectopic fat deposition and adipose tissue dysfunction. Our study aimed to identify novel metabolic and inflammatory markers in serum and omental adipose tissue which characterize the "unhealthy" obese patients and distinguish them from obese patients with better metabolic profile. DESIGN: Cross-sectional study. PATIENTS: Subjects included 75 obese patients undergoing bariatric surgery at the Tel-Aviv Medical Center (mean age 43.9 ± 13.9, mean BMI 41 ± 8.4). The HOMA median value was used as a cut-off to differentiate between patients with better or worse insulin resistance. MEASUREMENTS: Demographic data, fasting serum insulin, glucose, bile acids, serum metabolic and inflammatory markers were obtained. During the bariatric surgery, omental adipose tissue was harvested and analyzed for metabolic and inflammatory markers using qRT-PCR. Logistic regressions were used to calculate odds ratio and 95% confidence interval for the prediction of the metabolic profile. RESULTS: Serum markers that were significantly higher among the obese with HOMA >6 were total bile acids. In the omental adipose tissue the inflammatory markers TNFα and ADAM17 were significantly higher among obese patients with HOMA >6. In multivariate analysis, the strongest predictor for insulin resistance was ADAM17 (OR = 1.82, 1.06-3.14, P = 0.031). CONCLUSIONS: The study highlighted the predictive value of serum bile acids in identifying obese patients at high risk. Secondly, omental adipose tissue ADAM17 was revealed as a novel and strongest independent predictor for higher insulin resistance in morbidly obese patients.