Sarcopenia as a potential risk factor for senile blepharoptosis: Nationwide Surveys (KNHANES 2008–2011)

Abstract As the world’s population is aging, sarcopenia is recognized as essential to assess people’s lifelong condition and do appropriate early intervention. Senile blepharoptosis is also a problem in old age deteriorating visual function and causing a cosmetic decline. We investigated the association between sarcopenia and the prevalence of senile blepharoptosis, using a nationwide representative survey in Korea. A total of 11,533 participants were recruited. We used the body mass index (BMI)- adjusted appendicular skeletal muscle (ASM) definition as the muscle mass index (MMI, ASM [kg] divided by BMI [kg/m2]). The association between blepharoptosis prevalence and MMI was analyzed using multivariate logistic regression. Sarcopenia, defined as the lowest MMI quintile group in both men and women, was also associated with the prevalence of blepharoptosis (ORs 1.92, 95% CI 1.17–2.16; p < 0.001). These associations remained statistically significant after adjusting for various factors related to blepharoptosis using multivariate analysis (ORs 1.18, 95% CI 1.04–1.34; p = 0.012). Moreover, MMI was found to have a proportional relationship with eyelid lifting force (levator function), which is closely related to the occurrence and severity of ptosis. Sarcopenia is related to the prevalence of senile blepharoptosis, and patients with lower MMI were more likely to have blepharoptosis. These results suggest that sarcopenia can affect visual function and aesthetics

Protein tyrosine phosphatase 1B as a therapeutic target for Graves' orbitopathy in an in vitro model.

Graves' orbitopathy (GO) is characterised in early stages by orbital fibroblast inflammation, which can be aggravated by oxidative stress and often leads to fibrosis. Protein tyrosine protein 1B (PTP1B) is a regulator of inflammation and a therapeutic target in diabetes. We investigated the role of PTP1B in the GO mechanism using orbital fibroblasts from GO and healthy non-GO subjects. After 24 hours of transfection with PTPN1 siRNA, the fibroblasts were exposed to interleukin (IL)-1β, cigarette smoke extract (CSE), H2O2, and transforming growth factor (TGF)-β stimulations. Inflammatory cytokines and fibrosis-related proteins were analysed using western blotting and/or enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) release was detected using an oxidant-sensitive fluorescent probe. IL-1β, tumor necrosis factor (TNF)-α, bovine thyroid stimulating hormone (bTSH), high-affinity human stimulatory monoclonal antibody of TSH receptor (M22), and insulin-like growth factor-1 (IGF-1) significantly increased PTP1B protein production in GO and non-GO fibroblasts. PTPN1 silencing significantly blocked IL-1β-induced inflammatory cytokine production, CSE- and H2O2-induced ROS synthesis, and TGF-β-induced expression of collagen Iα, α-smooth muscle actin (SMA), and fibronectin in GO fibroblasts. Silencing PTPN1 also decreased phosphorylation levels of Akt, p38, and c-Jun N-terminal kinase (JNK) and endoplasmic reticulum (ER)-stress response proteins in GO cells. PTP1B may be a potential therapeutic target of anti-inflammatory, anti-oxidant and anti-fibrotic treatment of GO

Implication of Leptin-Signaling Proteins and Epstein-Barr Virus in Gastric Carcinomas

<div><p>We investigated the clinicopathological implications of leptin-signaling proteins and Epstein-Barr virus (EBV)-infection status in gastric carcinomas. Immunohistochemistry for leptin signalling-related proteins (leptin, leptin-receptor, pSTAT3, ERK, pAkt, mTOR and HIF-1 alpha), and <i>in situ</i> hybridization for EBV-encoded small RNAs was performed in 343 cases of gastric carcinomas. The siRNA against leptin-receptor was transfected into three stomach cancer cell lines, and western blot for caspase 3 was performed. The TNM stage was a prognostic factor in all 343 patients, and was negatively correlated with expression of leptin, pSTAT3, ERK, pAkt, mTOR and HIF-1 alpha (<i>P</i> < 0.05). Leptin-receptor expression was correlated with poor survival in 207 patients of the advanced gastric cancer (AGC) subgroup, 139 of the Lauren diffuse group, and in 160 patients with lymph node metastasis (<i>P</i> < 0.05, respectively). Additionally, in stomach cancer cells, cleaved caspase 3 level increased by leptin-receptor inhibition, that is, apoptosis increased. Interestingly, EBV-positive AGC (n = 29) tended to show better survival of patients than EBV-negative AGC (n = 178) (<i>P</i> = 0.06). pAkt expression was related with a good survival of 32 patients (9%) in the EBV-positive subgroup, but was not an independent prognostic factor. Among, leptin signaling-related proteins, expressions of leptin-receptor and mTOR were different between EBV-positive subgroup and EBV-negative subgroup (<i>P</i> < 0.05, respectively). In conclusion, leptin-signaling proteins and EBV status show different significance on patient survival, according to subsets of gastric carcinomas. The leptin-receptor may predict poor patient prognosis in the AGC, Lauren diffuse and lymph node metastasis subgroups, while EBV-positive status can show a good prognosis in the AGC. Each leptin signaling-related protein may be differently involved in carcinogenesis of EBV-negative and EBV-positive subsets.</p></div

Antibodies used for immunohistochemical staining.

<p>Antibodies used for immunohistochemical staining.</p

Overview of clinicopathological features and immunohistochemical staining results.

<p>^a<i>P</i> < 0.05. EBV, Epstein-Barr virus.</p><p>Overview of clinicopathological features and immunohistochemical staining results.</p

Kaplan-Meier survival curves in each group of gastric carcinomas according to leptin-receptor expression status (A-D).

<p>(<b>A</b>) Advanced TNM stage was associated with poor survival of patients in all cases of gastric carcinoma (n = 343) (<i>P</i> < 0.001). (<b>B</b>) Leptin-receptor positivity was related with unfavorable survival outcome in the advanced gastric carcinoma subgroup (n = 207) (<i>P</i> = 0.015). (<b>C</b>) Leptin-receptor positivity was correlated with poor survival rate in the diffuse-type gastric carcinoma subgroup (n = 139) (<i>P</i> = 0.007). (<b>D</b>) Leptin-receptor positivity was compatible with lower survival rate in patients with lymph node metastasis (n = 160) (<i>P</i> = 0.023).</p

Effect of leptin-receptor inhibition in gastric carcinoma cells.

<p>Leptin-receptor in total cell lysate was inhibited by siRNA against leptin-receptor (50 μM). Cleaved caspase 3 (p11, p17 and p20 subunits) was remarkably increased in gastric carcinoma cell lines transfected with siRNA against leptin-receptor, comparing to each original cell line and each scrambled siRNA-treated cell line. The beta-actin was loading controls. ‘Si scramble’ means cells transfected with scrambled siRNA, and ‘Si Leptin-R,’ cells transfected with siRNA against leptin-receptor.</p

Representative immunohistochemical features of seven protein markers including proteins related to leptin signaling pathway (A-G) and <i>in situ</i> hybridization of Epstein-Barr virus encoded small RNAs (H).

<p>(<b>A</b>) Leptin shows cytoplasmic expression in cancer cells (x 400). (<b>B</b>) Leptin-receptor exhibits membranous staining in cancer cells (x 200). (<b>C</b>) pSTAT3 shows nuclear staining in cancer cells (x 400). (<b>D</b>) ERK has nuclear positivity in cancer cells (x 400). (<b>E</b>) pAkt shows cytoplasmic or nuclear staining in cancer cells (x 200). (<b>F</b>) mTOR has cytoplasmic positivity in cancer cells (x 200). (<b>G</b>) HIF-1 alpha has cytoplasmic or nuclear staining in cancer cells (x 400). (<b>H</b>) Most of the cancer cells show blue colored nuclear staining on <i>in situ</i> hybridization for Epstein-Barr virus (x 400).</p