Women with endometriosis have higher comorbidities: Analysis of domestic data in Taiwan

AbstractEndometriosis, defined by the presence of viable extrauterine endometrial glands and stroma, can grow or bleed cyclically, and possesses characteristics including a destructive, invasive, and metastatic nature. Since endometriosis may result in pelvic inflammation, adhesion, chronic pain, and infertility, and can progress to biologically malignant tumors, it is a long-term major health issue in women of reproductive age. In this review, we analyze the Taiwan domestic research addressing associations between endometriosis and other diseases. Concerning malignant tumors, we identified four studies on the links between endometriosis and ovarian cancer, one on breast cancer, two on endometrial cancer, one on colorectal cancer, and one on other malignancies, as well as one on associations between endometriosis and irritable bowel syndrome, one on links with migraine headache, three on links with pelvic inflammatory diseases, four on links with infertility, four on links with obesity, four on links with chronic liver disease, four on links with rheumatoid arthritis, four on links with chronic renal disease, five on links with diabetes mellitus, and five on links with cardiovascular diseases (hypertension, hyperlipidemia, etc.). The data available to date support that women with endometriosis might be at risk of some chronic illnesses and certain malignancies, although we consider the evidence for some comorbidities to be of low quality, for example, the association between colon cancer and adenomyosis/endometriosis. We still believe that the risk of comorbidity might be higher in women with endometriosis than that we supposed before. More research is needed to determine whether women with endometriosis are really at risk of these comorbidities

Toward the Understanding of the Metabolic Regulation of Sirtuins

The ability to sense and respond to fluctuations in environmental nutrient levels is a requisite for life. Therefore, multiple nutrient sensing mechanisms are developed though evolution. Silent information regulator 2 (Sir2) proteins, or sirtuins, are highly conserved nicotinamide adenine dinucleotide (NAD+) dependent protein deacetylases. Their dependence on NAD+ links their activity to cellular metabolic status to serve as critical intracellular nutrient sensors. There are seven sirtuins in mammals and these proteins may mediate some of the benefits of caloric restriction by modulating energy metabolism, genomic stability and stress resistance. However, the molecular mechanisms by which sirtuins exert their physiological or pathological influences are not fully understood. The aim of this dissertation work was to gain molecular insights into this knowledge by studying the two aspects of biology: chronic inflammation-induced insulin resistance, and mitochondrial unfolded protein response (mtUPR).Chronic low-grade inflammation has been shown to contribute to the pathophysiology of many diseases, such as atherosclerosis, diabetes, Alzheimer’s disease, Parkinson’s disease, and cancer. In addition, SIRT2, a cytosol localized sirtuin, has been reported to suppress inflammation in multiple inflammation-inducing mouse models. Based on these findings, we investigated whether SIRT2 suppresses chronic inflammation through regulating inflammasome activity. We found that SIRT2 specifically inhibits the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in macrophages by directly deacetylating NLRP3. We confirmed that NLRP3 acetylation enhances its inflammasome function by mutating the deacetylated lysine residues to mimic the constitutively deacetylated state. Under conditions of aging and overnutrition, two prominent risk factors associated with insulin resistance, SIRT2 ablation in mice leads to increased systematic chronic inflammation and insulin resistance. These results establish a novel regulation of the NLRP3 inflammasome by SIRT2, and identify a nodal control point at the interface of nutrient sensing and innate immunity.Perturbation of mitochondrial protein homeostasis (proteostasis), also known as mitochondrial protein folding stress (mtPFS), activates the mtUPR, a retrograde signaling pathway leading to transcriptional upregulation of mitochondrial chaperones, repression of translation, and stress relief. The mtUPR is a nascent cellular pathway: the molecular components and physiological relevance of which are not well understood. Our lab has previously shown that SIRT7, a nucleus localized sirtuin, alleviates the mtPFS. Here we set up the experimental system of mtUPR by treating the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) in HEK293T and Hela cells. We found that CDDO treatment leads to mitochondrial aggregation to a focus nearby the nucleus, and widespread increased electron density in the mitochondrial matrix under electron microscopy. We are going to analyze whether genetic manipulation of SIRT7 will also change these two newly identified mtPFS markers. In addition, we demonstrated global transcriptional downregulation of genes encoded by mitochondrial DNA in response to mtPFS, which can potentially relieve the stress and serve as a novel branch of mtUPR. These results not only broaden the understanding of inflammasome regulations and inflammasome-related diseases, but also provides important insights into detailed molecular mechanisms of mtUPR. Further, from the therapeutic standpoints, these findings also open novel avenues to treat diseases characteristic of chronic inflammation or mitochondrial dysfunction

Impact of Alcohol on Vestibular Function in Relation to the Legal Limit of 0.25 Mg/L Breath Alcohol Concentration

The aim of this study was to investigate the effect of alcohol on sacculocollic and vestibulo-ocular reflex systems , when the breath alcohol concentration (BrAC) is close to the legal limit of 0.25 mg/l. Twenty healthy male volunteers underwent vestibular evoked myogenic potential and caloric coupled with visual suppression tests. These tests were conducted prior to imbibing alcohol at a dosage of 0.5 g/kg to achieve a peak BrAC of around 0.25 mg/l. Once the peak BrAC was reached, these tests were performed again. Predosing and postdosing analytical results were compared, as were those with BrAC levels 6 0.25 mg/l and = 0.25 mg/l was significantly less than that with BrAC <0.25 mg/l. Likewise, the visual suppression index decreased considerably after alcohol ingestion. In conclusion, from the perspective of vestibular function, the 0.25-mg/l BrAC limit gains clinical significance, because the vestibulo-ocular reflex performance deteriorates further, when the BrAC exceeds 0.25 mg/l. However, impaired performance of sacculocollic reflex and vestibulocerebellar interaction has occurred, when the BrAC was <0.25 mg/l , suggesting that a lower legal threshold is appropriate. Copyright (C) 2007 S. Karger AG, Basel

All-Cause Mortality in Patients with Type 2 Diabetes in Association with Achieved Hemoglobin A(1c), Systolic Blood Pressure, and Low-Density Lipoprotein Cholesterol Levels

Background: To identify the ranges of hemoglobin A(1c) (HbA1c), systolic blood pressure (SBP), and low-density lipoprotein cholesterol (LDL-C) levels which are associated with the lowest all-cause mortality. ;Methods: A retrospective cohort of 12,643 type 2 diabetic patients (aged &gt;= 18 years) were generated from 2002 to 2010, in Far-Eastern Memorial Hospital, New Taipei city, Taiwan. Patients were identified to include any outpatient diabetes diagnosis (ICD-9: 250), and drug prescriptions that included any oral hypoglycemic agents or insulin prescribed during the 6 months following their first outpatient visit for diabetes. HbA1c, SBP, and LDL-C levels were assessed by the mean value of all available data, from index date to death or censor date. Deaths were ascertained by matching patient records with the Taiwan National Register of Deaths. ;Results: Our results showed general U-shaped associations, where the lowest hazard ratios occurred at HbA1c 7.0-8.0%, SBP 130-140 mmHg, and LDL-C 100-130 mg/dL. The risk of mortality gradually increases if the patient's mean HbA1c, SBP, or LDL-C during the follow-up period was higher or lower than these ranges. In comparison to the whole population, the adjusted hazard ratio (95% CI) for patients with HbA1c 7.0-8.0%, SBP 130-140 mmHg, and LDL-C 100-130 mg/dL were 0.69 (0.62-0.77), 0.80 (0.72-0.90), and 0.68 (0.61-0.75), respectively. ;Conclusions: In our type 2 diabetic cohort, the patients with HbA1c 7.0-8.0%, SBP 130-140 mmHg, or LDL-C 100-130 mg/dL had the lowest all-cause mortality. Additional research is needed to confirm these associations and to further investigate their detailed mechanisms

Nutrient Sensing and the Oxidative Stress Response

The simplicity and effectiveness of calorie restriction (CR) in lifespan and healthspan extension have fascinated generations searching for the Fountain of Youth. CR reduces levels of oxidative stress and damage, which have been postulated in the free radical theory of aging as a major cause of aging and diseases of aging. This reduction has long been viewed as a result of passive slowing of metabolism. Recent advances in nutrient sensing have provided molecular insights into the oxidative stress response and suggest that CR triggers an active defense program involving a cascade of molecular regulators to reduce oxidative stress. Physiological studies have provided strong support for oxidative stress in the development of aging-associated conditions and diseases but have also revealed the surprising requirement for oxidative stress to support normal physiological functions and, in some contexts, even slow aging and prevent the progression of cancer. Deciphering the molecular mechanisms and physiological implications of the oxidative stress response during CR will increase our understanding of the basic biology of aging and pave the way for the design of CR mimetics to improve healthspan

R1R2 peptide ameliorates pulmonary fibrosis in mice through fibrocyte migration and differentiation

<div><p>Circulating fibrocytes play a key role in the pathogenesis of pulmonary fibrosis. Fibrocytes are bone marrow-derived leukocytes, which enter the lungs in response to their chemoattractant CXCL12 and differentiate into fibroblasts or myofibroblasts, leading to excess deposition of the collagen-rich extracellular matrix. Matrix metalloproteinase (MMP)-9 and MMP-2, secreted by fibrocytes, degrade the subendothelial basement membrane and promote fibrocyte influx into the lungs. Here, we demonstrate that R1R2, a novel peptide derived from the bacterial adhesin SFS, attenuates pulmonary fibrosis by preventing the differentiation of fibrocytes into myofibroblasts and by reducing the invasion of fibrocytes through basement membrane-like proteins. Moreover, our findings reveal dual regulation of R1R2 on MMP-9 through reduced enzymatic activity on gelatin and increased cleavage of CXCL12. These data suggest that R1R2 has potent anti-fibrotic effects against pulmonary fibrosis.</p></div

R1R2 disables the proteolytic activity of MMP-9.

<p>(A) Equal amounts of R1R2, the scrambled peptide, or bovine serum albumin (BSA; 20 μg/mL) were coated onto 96-well plates; fibronectin (FN), collagen (Col), or phosphate-buffered saline (PBS) were added into the wells, and the interaction between the peptides was evaluated by measuring the absorbance at 405 nm. **** <i>P</i> < 0.0001, one-way analysis of variance (ANOVA) followed by a Bonferroni <i>t</i> test. (B) Biotinylated R1R2 or scrambled peptide (20 μg/mL) were added into 96-well plates coated with catalytic domain or full-length proteins (FLPs) of MMP-9 and MMP-2. Bound R1R2 and the scrambled peptide were quantified at 405 nm by using a solid-phase binding assay following the incubation of anti-biotin antibodies. **** <i>P</i> < 0.0001 by t-test. (C, D) Enzymatic activity levels of catalytic domain (C) or FLPs (D) of MMP-9 were determined using a fluorescence gelatinolytic assay in the presence of 10 times the molar ratio of R1R2 or the scrambled peptide. (E, F) Enzymatic activity of MMP-9 was evaluated using a fluorescence gelatinolytic assay in the presence of 300 μg/mL (0.9 μM) FN and 20 μM R1R2 or the scrambled peptide. (G, H) Enzymatic activity of catalytic domain (G) or FLPs (H) of MMP-2 was determined using a fluorescence gelatinolytic assay in the presence of 10 times the molar ratio of R1R2 or scrambled peptide. Data are expressed as the mean ± SD. * <i>P</i> < 0.05, ** <i>P</i> < 0.01, and *** <i>P</i> < 0.001 by <i>t</i> test.</p