Factors affecting the number of bacteria in saliva and oral care methods for the recovery of bacteria in contaminated saliva after brushing: a randomized controlled trial.

BACKGROUND: Oral care is important in preventing aspiration pneumonia in older adults. However, it is not clear what kind of oral care can reduce the number of bacteria in saliva. The purposes of this study are to clarify whether there is a relationship between plaque amounts and salivary bacterial counts, and how bacteria dispersed into the oral cavity by brushing can be reduced. METHODS: First, saliva samples were collected from 10 healthy adult volunteers after 30 h of unbrushing and after thorough brushing, and the total bacterial count was determined by real-time PCR. Next, 40 older adults attending an outpatient dental clinic were randomly assigned into two groups: a wiping group (20 patients) and a mouthwashing group (20 patients). Saliva was collected before and after brushing, and after wiping in the wiping group and after mouthwashing in the mouthwashing group, and the total bacterial count was quantified by real-time PCR. RESULTS: In a study of volunteers, there was no association between plaque amounts and salivary bacterial counts. In a study of older adult patients, salivary bacterial counts were significantly higher in patients with higher oral hygiene index and fewer remaining teeth. Brushing increased salivary bacterial counts. Wiping did not significantly reduce the number of bacteria, while mouthwash returned the increased number of bacteria after brushing to the pre-brushing level. CONCLUSIONS: There is no direct relationship between the amount of plaque and the number of bacteria in saliva. Brushing disperses bacteria into the oral cavity, resulting in a marked increase in the number of bacteria in saliva. Wiping does not collect the dispersed bacteria, and it seems essential to rinse the mouth after brushing. TRIAL REGISTRATION: UMIN000045854.

Plectin promotes tumor formation by B16 mouse melanoma cells via regulation of Rous sarcoma oncogene activity.

BACKGROUND: Melanoma is a malignant tumor characterized by high proliferation and aggressive metastasis. To address the molecular mechanisms of the proto-oncogene, Rous sarcoma oncogene (Src), which is highly activated and promotes cell proliferation, migration, adhesion, and metastasis in melanoma. Plectin, a cytoskeletal protein, has recently been identified as a Src-binding protein that regulates Src activity in osteoclasts. Plectin is a candidate biomarker of certain tumors because of its high expression and the target of anti-tumor reagents such as ruthenium pyridinecarbothioamide. The molecular mechanisms by which plectin affects melanoma is still unclear. In this study, we examined the role of plectin in melanoma tumor formation. METHODS: We used CRISPR/Cas9 gene editing to knock-out plectin in B16 mouse melanoma cells. Protein levels of plectin and Src activity were examined by western blotting analysis. In vivo tumor formation was assessed by subcutaneous injection of B16 cells into nude mice and histological analysis performed after 2 weeks by Hematoxylin-Eosin (H&E) staining. Cell proliferation was evaluated by direct cell count, cell counting kit-8 assays, cyclin D1 mRNA expression and Ki-67 immunostaining. Cell aggregation and adhesion were examined by spheroid formation, dispase-based dissociation assay and cell adhesion assays. RESULTS: In in vivo tumor formation assays, depletion of plectin resulted in low-density tumors with large intercellular spaces. In vitro experiments revealed that plectin-deficient B16 cells exhibit reduced cell proliferation and reduced cell-to-cell adhesion. Since Src activity is reduced in plectin-deficient melanomas, we examined the relationship between plectin and Src signaling. Src overexpression in plectin knockout B16 cells rescued cell proliferation and improved cell-to-cell adhesion and cell to extracellular matrix adhesion. CONCLUSION: These results suggest that plectin plays critical roles in tumor formation by promoting cell proliferation and cell-to-cell adhesion through Src signaling activity in melanoma cells.

Dental needs in palliative care and problems in dental hygienist education: survey study of palliative care ward homepage, university syllabus, and academic conference abstracts.

BACKGROUND: Although end-of-life patients have a variety of oral-related symptoms, the involvement of dentists and dental hygienists in the palliative care teams is limited. This study investigates the current state of palliative care education in universities that train dentists and dental hygienists and the need for dentistry in the clinical setting of palliative medicine in Japan. METHODS: First, we investigated the involvement of dentistry in hospitals with palliative care units from a website. The number of reports on palliative care presented by dental hygienists at academic conferences around 2016, when the public medical insurance system in Japan covered oral care for patients with terminal illnesses, were examined. We also surveyed the syllabuses of the university that trained nurses, dentists, and dental hygienists to determine their education regarding palliative care. RESULTS: Of the 376 hospitals with palliative care units, 176 (46.8%) had dentistry in the hospital. Additionally, 321 hospitals (85.4%), which included those without dentistry, responded that they provided oral care by dentists and dental hygienists in the palliative care unit. There were only two presentations on palliative care in the annual meetings of the two major academic societies by dental hygienists between 2012 and 2016. However, this number increased rapidly to 47 between 2017 and 2020. The syllabus surveys showed that, compared to nursing universities, universities that trained dentists or dental hygienists had lesser education in palliative care. Furthermore, education in the universities that trained dental hygienists was mostly related to the oral care of patients with terminal illnesses, while the physical and mental conditions of end-of-life patients were not well educated. CONCLUSION: Considering that society requires the involvement of dental hygienists in the field of palliative care, it is necessary to enhance basic and clinical education of palliative care in universities that train dentists and dental hygienists to provide good oral care to patients with terminal illnesses and contribute to improving their quality of life.

Leucine rich α-2 glycoprotein is a potential urinary biomarker for renal tubular injury.

Recent evidence suggests that renal tubular injury plays a key role in deterioration of renal function in both chronic kidney disease (CKD) and acute kidney injury (AKI). Since commonly used biochemical indicators such as GFR, serum creatinine, blood urea nitrogen and creatinine clearance are inappropriate for detecting alteration in renal tubules, biomarkers reflecting renal tubular injury have been extensively explored. Our research group identified leucine rich α-2 glycoprotein (LRG) as a novel serum biomarker for various inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. In inflammatory diseases, LRG expression is up-regulated at the site of inflammation, in accordance with the induction of LRG in many cell types by various inflammatory cytokines. Recently, urinary LRG was reported as a possible biomarker for several renal diseases, but the mechanism of LRG excretion in urine is still unclear. In this study, by analyzing a mouse albumin (ALB) overload model that is commonly used to study proteinuria-induced renal tubular injury, we provided evidence that urinary LRG is produced in renal tubular epithelial cells by interleukin-1ß (IL-1ß) that is released during proteinuria-induced renal damage. In this model, urinary LRG became detectable after ALB overload. In kidney, mRNA expression of LRG together with that of NACHT LRR and PYD domains-containing protein 3 (NLRP3) and IL-1ß was significantly up-regulated in ALB-overloaded mice, compared to PBS-treated mice. By pathological analysis of kidney, LRG was detected in the injured proximal tubules, distal tubules and collecting ducts in ALB-overloaded mice. Accordingly, in vitro stimulation of mouse renal cortical tubular epithelial cells with excessive ALB led to LRG mRNA up-regulation and its protein secretion, which was effectively blocked by IL-1 receptor antagonist. These results suggest that urinary LRG could be applied to a biomarker detecting renal tubular injury in various renal diseases.

A case of scleredema adultorum successfully treated with narrow-band ultraviolet B phototherapy.

Scleredema adultorum, also known as scleredema of Buschke, is a rare connective tissue disease with unknown etiology, which is characterized by diffuse skin induration of face, neck, upper chest, back, shoulders and arms. Although there is no established treatment for this disease, the efficacy of phototherapy has been reported. We herein describe a case of scleredema adultorum successfully treated with narrow-band ultraviolet B and discuss a potential mechanism explaining its efficacy for fibrotic skin diseases.

Proteomic identification of heterogeneous nuclear ribonucleoprotein K as a novel cold-associated autoantigen in patients with secondary Raynaud's phenomenon.

OBJECTIVE: The aim of this study was to identify cold-associated autoantibodies in patients with RP secondary to CTDs. METHODS: Indirect immunofluorescence staining was performed on non-permeabilized cold-stimulated normal human dermal microvascular endothelial cells (dHMVECs), using patients' sera. Cold-induced alterations in cell surface proteomes were analysed by isobaric tag for relative and absolute quantitation (iTRAQ) analysis. Serological proteome analysis (SERPA) was applied to screen cold-associated autoantigens. The prevalence of the candidate autoantibody was determined by ELISA in 290 patients with RP secondary to CTDs (SSc, SLE or MCTD), 10 patients with primary RP and 27 healthy controls. RESULTS: Enhanced cell surface immunoreactivity was detected in cold-stimulated dHMVECs when incubated with sera from patients with secondary RP. By iTRAQ analysis, many proteins, including heterogeneous nuclear ribonucleoprotein K (hnRNP-K), were found to be increased on the cell surface of dHMVECs after cold stimulation. By the SERPA approach, hnRNP-K was identified as a candidate autoantigen in patients with secondary RP. Cold-induced translocation of hnRNP-K to the cell surface was confirmed by immunoblotting and flow cytometry. By ELISA analysis, patients with secondary RP show a significantly higher prevalence of anti-hnRNP-K autoantibody (30.0%, 61/203) than patients without RP (9.2%, 8/87, P = 0.0001), patients with primary RP (0%, 0/10, P = 0.0314) or healthy controls (0%, 0/27, P = 0.0001). CONCLUSION: By comprehensive proteomics, we identified hnRNP-K as a novel cold-associated autoantigen in patients with secondary RP. Anti-hnRNP-K autoantibody may potentially serve as a biomarker for RP secondary to various CTDs.

Brushing Methods for Patients Unable to Use a Mouthwash: A Preliminary Study of the Effects of Moisturizing Gel and Povidone-Iodine in Healthy Volunteers.

INTRODUCTION:  Brushing older adults or intubated patients who are unable to rinse can transmit bacteria from dental plaque into the oral cavity and increase the risk of aspiration pneumonia. Therefore, this study examined brushing methods to prevent the spread of bacteria in the oral cavity.  Methods: Three types of brushing methods were performed on five volunteers by dental hygienists (water group: brushing with toothbrush bristles soaked in water; gel group: brushing with a moisturizing gel placed on the toothbrush; PV-I group: brushing with toothbrush bristles dipped in povidone-iodine). Neither group spat out the saliva or gargled during brushing but brushed while wiping the water/gel/PV-I solution with a sponge brush. The same five volunteers served as subjects for the three methods. Saliva was collected before and after brushing, and the number of colonies was determined using bacterial culture.  Results: The water group demonstrated a significantly increased number of bacteria in the saliva owing to the spread of bacteria from the dental plaque. The gel group prevented the spread of the bacteria. The PV-I group showed a significant decrease in the number of bacteria in the saliva after brushing. CONCLUSIONS:  Brushing with toothbrush bristles dipped in a povidone-iodine solution is recommended for intubated or older adult patients who cannot gargle.

Preoperative and Postoperative Salivary Bacterial Counts in Infants Undergoing Cardiac Surgery: A Prospective Observational Study.

INTRODUCTION: Postoperative pneumonia may develop in infants after cardiac surgery; however, only a few reports are available on perioperative oral bacteria in infants. This study aimed to examine preoperative and postoperative salivary bacterial counts in infants undergoing cardiac surgery. MATERIALS AND METHODS: The number of bacteria in the saliva of 105 infants (average age: 20 months) who underwent surgery for congenital heart disease was determined by culturing before and after surgery. Factors associated with changes in the bacterial count were further examined. Patients received systemic antimicrobials for an average of four days immediately before surgery. RESULTS: Postoperative salivary bacterial counts were higher in older patients, who had erupting teeth and had longer surgical times. The average number of colonies before surgery was 104.53 CFU/mL; on the day after surgery, this number significantly decreased to 103.68 CFU/mL. The rate of reduction was especially high in infants without tooth eruption. The total number of bacterial colonies in saliva decreased after surgery, most likely because of the use of systemically administered antibiotics, and the rate of decrease was particularly high in infants without tooth eruptions. CONCLUSION: This study examined the preoperative and postoperative salivary bacterial counts in infants undergoing cardiac surgery. In the future, we would like to further examine bacterial flora and the effects of perioperative oral care. This study provides insights into the development of new strategies for preventing and treating surgical site infections and pneumonia in children.

Comparison of the Efficacy of Three Types of Disinfectants Approved for Oral Use in Japan in Reducing the Bacterial Count of Tongue Coating: A Randomised-Controlled Study.

PURPOSE: Tongue coating is one of the primary causes of halitosis and some diseases such as aspiration pneumonia. However, to date, an effective method for reducing the bacterial count of tongue coating has not been established. We conducted a randomised-controlled study to compare the efficacy of three types of disinfectants approved for oral use in Japan in reducing the bacterial count of tongue coating. MATERIALS AND METHODS: Thirty-two participants were randomly assigned to the following four groups according to the solution used: 1. benzethonium chloride; 2. povidone iodine; 3. hydrogen peroxide; 4. tap water (control group). Tongue cleaning with the three test disinfectants and water was performed using a toothbrush, and the bacterial count on the tongue dorsum before and after tongue cleaning was measured using the Rapid Oral Bacteria Quantification System. RESULTS: The bacterial count decreased statistically significantly after tongue brushing using povidone iodine and hydrogen peroxide solutions (both p = 0.012), but not after brushing using 0.2% benzethonium chloride and tap water. CONCLUSION: Tongue brushing with povidone iodine or hydrogen peroxide was the most effective method for reducing the bacterial count of tongue coating.

Transducin-like enhancer of split 3 regulates proliferation of melanoma cells via histone deacetylase activity.

Melanoma, one of the most aggressive neoplasms, is characterized by rapid cell proliferation. Transducin-like Enhancer of Split (TLE) is an important regulator of cell proliferation via Histone deacetylase (HDAC) recruitment. Given that HDAC activity is associated with melanoma progression, we examined the relationship between TLE3, a TLE family member, and melanoma. TLE3 expression was increased during the progression of human patient melanoma (p < 0.05). Overexpression of Tle3 in B16 murine melanoma cells led to an increase in cell proliferation (p < 0.01) as well as the number of cyclinD1-positive cells. in vivo injection of mice with B16 cells overexpressing Tle3 resulted in larger tumor formation than in mice injected with control cells (p < 0.05). In contrast, siRNA-mediated knockdown of Tle3 in B16 cells or TLE3 in HMV-II human melanoma cells decreased proliferation (p < 0.01). Treatment of B16 cells with trichostatin A (2.5 µM), a class I and II HDAC inhibitor, prevented the effect s of Tle3 on proliferation. In conclusion, these data indicate that Tle3 is required, at least in part, for proliferation in the B16 mouse melanoma model.

New onset or transition of disease state of psoriatic arthritis during treatment with ustekinumab: A single-center retrospective study.

Ustekinumab (UST) is a treatment option for psoriatic arthritis (PsA), but recent observations indicate that some psoriatic patients may experience new onset of PsA or worsening of pre-existent PsA. We retrospectively analyzed all cases of psoriasis vulgaris (PsV) and PsA treated with UST in our facility between 2011 and 2015. PsA developed in eight out of 179 PsV patients, mostly later than 8 months after initiation of UST. It was generally not severe, and none had received tumor necrosis factor (TNF)-α inhibitors previously, indicating that the possibility of unmasking pre-existing subclinical arthritis is minimal. The eruptions were well controlled at the time of the onset of arthritis in most cases. Interestingly, those who developed arthritis showed a significantly lower body mass index. Regarding pre-existing PsA, nine PsA patients received UST, and at least partial improvement of PsA could be achieved in two out of three bio-naive and three out of six bio-switched patients from TNF-α inhibitors. PsA was largely more refractory to UST than the eruptions. Altogether, our present study is in agreement with the notion that UST may be less efficient than TNF-α inhibitors for PsA. While UST cannot fully prevent new development of PsA, it is unlikely that UST increases the risk of new onset of PsA as a paradoxical adverse reaction.

Neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and mean platelet volume in Japanese patients with psoriasis and psoriatic arthritis: Response to therapy with biologics.

Recent studies indicate the presence of systemic inflammation in psoriatic patients, and this inflammatory status is significantly associated with a range of comorbidities. The aim of this study was to evaluate the clinical significance of novel inflammatory biomarkers, neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and mean platelet volume (MPV) in Japanese patients with plaque-type psoriasis (PsV) and psoriatic arthritis (PsA). One hundred and eighty-six patients with PsV and 50 patients with PsA treated with biologics, including infliximab, adalimumab and ustekinumab, were retrospectively analyzed before and after treatment. At baseline, NLR and PLR, as well as C-reactive protein (CRP), were significantly higher in PsA patients than those in PsV patients, and a significant correlation was found between NLR and PLR. In PsV patients, the NLR-high and PLR-high subgroups exhibited significantly higher Psoriasis Area and Severity Index scores compared with the NLR-low and PLR-low subgroups, respectively, and the NLR-high subgroup also showed higher CRP levels. MPV value was negatively associated with the presence of arthritis, but its association with inflammation was less clear than that of NLR or PLR. After treatment of the patients with biologics for up to 12 months, NLR and PLR decreased promptly in parallel with a decrease of CRP, irrespective of the type of biologics used. Altogether, these results indicate that both NLR and PLR may be useful markers to evaluate systemic inflammation in psoriatic patients. They may serve as simple, convenient and cost-effective biomarkers to monitor the disease course after systemic therapy.

Leucine-rich alpha 2 glycoprotein promotes Th17 differentiation and collagen-induced arthritis in mice through enhancement of TGF-ß-Smad2 signaling in naïve helper T cells.

BACKGROUND: Leucine-rich alpha 2 glycoprotein (LRG) has been identified as a serum protein elevated in patients with active rheumatoid arthritis (RA). Although the function of LRG is ill-defined, LRG binds with transforming growth factor (TGF)-ß and enhances Smad2 phosphorylation. Considering that the imbalance between T helper 17 (Th17) cells and regulatory T cells (Treg) plays important roles in the pathogenesis of RA, LRG may affect arthritic pathology by enhancing the TGF-ß-Smad2 pathway that is pivotal for both Treg and Th17 differentiation. The purpose of this study was to explore the contribution of LRG to the pathogenesis of arthritis, with a focus on the role of LRG in T cell differentiation. METHODS: The differentiation of CD4 T cells and the development of collagen-induced arthritis (CIA) were examined in wild-type mice and LRG knockout (KO) mice. To examine the influence of LRG on T cell differentiation, naïve CD4 T cells were isolated from LRG KO mice and cultured under Treg- or Th17-polarization condition in the absence or presence of recombinant LRG. RESULTS: In the CIA model, LRG deficiency led to ameliorated arthritis and reduced Th17 differentiation with no influence on Treg differentiation. By addition of recombinant LRG, the expression of IL-6 receptor (IL-6R) was enhanced through TGF-ß-Smad2 signaling. In LRG KO mice, the IL-6R expression and IL-6-STAT3 signaling was attenuated in naïve CD4 T cells, compared to wild-type mice. CONCLUSIONS: Our findings suggest that LRG upregulates IL-6R expression in naïve CD4 T cells by the enhancement of TGF-ß-smad2 pathway and promote Th17 differentiation and arthritis development.

Switching of biologics in psoriasis: Reasons and results.

Efficacy and safety profiles of biologics have been established for moderate to severe psoriasis. However, inefficacy or adverse events sometimes require changing the treatment to other biologics. Here, we examine the effectiveness of this strategy. We retrospectively investigated cases requiring switching biologics. We enrolled 275 psoriatic patients treated with biologics between January 2010 and December 2014 in our hospital. Of these, 51 required a switch to another biologic. First-line therapies were infliximab (IFX, n = 26), adalimumab (ADA, n = 18) and ustekinumab (UST, n = 7), and second-line therapies were IFX (n = 5), ADA (n = 21) and UST (n = 25). Reasons for switching were inefficacy (n = 38), adverse events (n = 11) and others (n = 2). The details were primary failure (n = 15), secondary failure (n = 23) and infusion reactions (n = 8). In 49 patients who switched biologics due to inefficacy and adverse events, the mean Psoriasis Area and Severity Index (PASI) score at week 16 was 4.3 for first-line therapies and 2.9 for second-line therapies (P < 0.05). Switching to a second biologic therapy to address the first's inefficacy or adverse events often results in significant improvement in moderate to severe psoriasis.

Leucine-rich α-2 glycoprotein promotes lung fibrosis by modulating TGF-ß signaling in fibroblasts.

TGF-ß has an important role in fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Detailed analysis of TGF-ß signaling in pulmonary fibrosis at the molecular level is needed to identify novel therapeutic targets. Recently, leucine-rich alpha-2 glycoprotein (LRG) was reported to function as a modulator of TGF-ß signaling in angiogenesis and tumor progression. However, the involvement of LRG in fibrotic disorders, including IPF, has not yet been investigated. In this study, we investigated the role of LRG in fibrosis by analyzing LRG knockout (KO) mice with bleomycin-induced lung fibrosis, an animal model of pulmonary fibrosis. The amount of LRG in the lungs of wild-type (WT) mice was increased by bleomycin administration prior to fibrosis development. In LRG KO mice, lung fibrosis was significantly suppressed, as indicated by attenuated Masson's trichrome staining and lower collagen content than those in WT mice. Moreover, in the lungs of LRG KO mice, phosphorylation of Smad2 was reduced and expression of α-SMA was decreased relative to those in WT mice. In vitro experiments indicated that LRG enhanced the TGF-ß-induced phosphorylation of Smad2 and the expression of Serpine1 and Acta2, the downstream of Smad2, in fibroblasts. Although endoglin, an accessory TGF-ß receptor, is essential for LRG to promote TGF-ß signaling in endothelial cells during angiogenesis, we found that endoglin did not contribute to the ability of LRG to enhance Smad2 phosphorylation in fibroblasts. Taken together, our data suggest that LRG promotes lung fibrosis by modulating TGF-ß-induced Smad2 phosphorylation and activating profibrotic responses in fibroblasts.

Sputum Leucine-Rich Alpha-2 Glycoprotein as a Marker of Airway Inflammation in Asthma.

BACKGROUND: Asthma is a chronic inflammatory disease of airways, but an ideal biomarker that accurately reflects ongoing airway inflammation has not yet been established. The aim of this study was to examine the potential of sputum leucine-rich alpha-2 glycoprotein (LRG) as a new biomarker for airway inflammation in asthma. METHODS: We obtained induced sputum samples from patients with asthma (N = 64) and healthy volunteers (N = 22) and measured LRG concentration by sandwich enzyme-linked immunosorbent assay (ELISA). Ovalbumin (OVA)-induced asthma model mice were used to investigate the mechanism of LRG production during airway inflammation. The LRG concentrations in the bronchoalveolar lavage fluid (BALF) obtained from mice were determined by ELISA and mouse lung sections were stained with anti-LRG antibody and periodic acid-Schiff (PAS) reagent. RESULTS: Sputum LRG concentrations were significantly higher in patients with asthma than in healthy volunteers (p = 0.00686). Consistent with patients' data, BALF LRG levels in asthma model mice were significantly higher than in control mice (p = 0.00013). Immunohistochemistry of lung sections from asthma model mice revealed that LRG was intensely expressed in a subpopulation of bronchial epithelial cells, which corresponded with PAS-positive mucus producing cells. CONCLUSION: These findings suggest that sputum LRG is a promising biomarker of local inflammation in asthma.

Myeloid cell-derived LRG attenuates adverse cardiac remodelling after myocardial infarction.

AIMS: Leucine-rich α2-glycoprotein (LRG) is considered as a biomarker of the clinical activities of chronic inflammatory diseases, including heart failure. However, its pathophysiological roles in cardiac remodelling after myocardial infarction (MI) remain to be clarified. In this study, we have addressed functional roles of LRG in cardiac remodelling after MI. METHODS AND RESULTS: MI was generated by ligating the left coronary artery in mice. Real-time reverse transcription (RT)-PCR and immunoblot analyses revealed that the expressions of LRG transcript and protein were up-regulated in post-infarct myocardium. LRG protein was produced by heart-infiltrating myeloid cells, such as macrophages and neutrophils. To elucidate functional roles of LRG in cardiac remodelling, we generated MI in wild-type (WT) and LRG-deficient (LRG(-/-)) mice and found that LRG gene ablation aggravated myocardial fibrosis with cardiac dysfunction after MI. Immunohistochemical analyses with anti-CD31 antibody revealed that capillary density decreased at border zone in LRG(-/-) mice compared with WT mice. Consistently, the expression of apelin receptor was reduced in LRG(-/-) mice, implying that the impaired angiogenic activity is associated with adverse cardiac remodelling in LRG(-/-) mice. Moreover, LRG gene ablation suppressed the activation of smad1/5/8, a pro-angiogenic signalling pathway. Finally, the transplantation of WT bone marrow cells into LRG(-/-) mice attenuated cardiac fibrosis with functional improvement after MI, accompanied by restoration of capillary density compared with the bone marrow transplantation from LRG(-/-) mice. CONCLUSION: LRG, produced by heart-infiltrating myeloid cells, suppresses adverse cardiac remodelling after MI as a novel cardioprotective factor. LRG signalling could be a therapeutic target against cardiovascular diseases.

Leucine-rich α-2-glycoprotein promotes TGFß1-mediated growth suppression in the Lewis lung carcinoma cell lines.

Leucine-rich α2-glycoprotein (LRG) is an approximately 50-kDa glycoprotein that has been found to be elevated in the sera of patients with several types of cancer. LRG directly binds to transforming growth factor beta 1 (TGFß1) and modulates TGFß1 signaling in endothelial cells; however, the precise function of LRG in cancer remains unclear. This study aimed to investigate the role of LRG in cancer. Lewis lung carcinoma (LLC) cells hardly expressed LRG. The growth of LLC tumors allografted in the LRG knockout (KO) mice was significantly increased compared with wild-type (WT) mice. Conversely, overexpression of LRG significantly inhibited the growth of LLC tumors in WT mice. In the presence of LRG, TGFß1 significantly inhibited the proliferation of LLC cells and human hepatocellular carcinoma Hep3B cells in vitro by inducing apoptosis via the potent activation of smad2 and its downstream signaling pathway. Furthermore, administration of a TGFßR1 inhibitor (SB431542) significantly enhanced the growth of LLC tumors in WT mice compared with LRG KO mice via inhibition of apoptosis. We propose that LRG potentiates the effect of TGFß1 in cancer cells whose growth is suppressed in the presence of TGFß1.