Associations of Parity With Change in Global Cognition and Incident Cognitive Impairment in Older Women.

Background: The evidence of the association between parity and risk of mild cognitive impairment (MCI) or dementia is mixed, and the relationship between parity and longitudinal cognitive changes is less clear. We investigated these issues in a large population of older women who were carefully monitored for development of MCI and probable dementia. Methods: Using the Women's Health Initiative Memory Study, 7,100 postmenopausal women (mean age 70.1 ± 3.8 years) with information on baseline parity (defined as the number of term pregnancies), measures of global cognition (Modified Mini-Mental State Examination score) from 1996-2007, and cognitive impairment (centrally adjudicated diagnoses of MCI and dementia) from 1996-2016 were included. Multivariable linear mixed-effects models were used to analyze the rate of changes in global cognition. Cox regression models were used to evaluate the risk of MCI/dementia across parity groups. Results: Over an average of 10.5 years, 465 new cases of MCI/dementia were identified. Compared with nulliparous women, those with a parity of 1-3 and ≥4 had a lower MCI/dementia risk. The HRs were 0.75 (0.56-0.99) and 0.71 (0.53-0.96), respectively (P < 0.01). Similarly, a parity of 1-3 and ≥4 was related to slower cognitive decline (ß = 0.164, 0.292, respectively, P < 0.05). Conclusion: Higher parity attenuated the future risk for MCI/dementia and slowed the rates of cognitive decline in elderly women. Future studies are needed to determine how parity affects late-life cognitive function in women.

Long non-coding RNA potassium voltage-gated channel subfamily Q member 1 overlapping transcript 1 regulates the proliferation and osteogenic differentiation of human periodontal ligament stem cells by targeting miR-24-3p.

OBJECTIVES: This study aims to explore the effect and molecular mechanism of long non-coding RNA (lncRNA) potassium voltage-gated channel subfamily Q member 1 overlapping transcript 1 (KCNQ1OT1) on proliferation and osteogenic differentiation in human periodontal ligament stem cells (hPDLSCs). METHODS: The hPDLSCs of normal periodontal tissues were isolated and cultured. The mineralized solution induced the osteoblast differentiation of hPDLSCs. The down-regulation of lncRNA KCNQ1OT1, the overexpression of anti-miR-24-3p on the proliferation and the levels of osteocalcin (OCN), osteopontin (OPN) and alkaline phosphatase (ALP) of hPDLSCs were investigated. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the levels of lncRNA KCNQ1OT1, miR-24-3p, OCN, OPN, and ALP. Methyl thiazolyl tetrazolium (MTT) method was used to detect cell viability and activity. Cell proliferation was evaluated by MTT. Western blot was used to detect protein expression. The targeted relationship between lncRNA KCNQ1OT1 and miR-24-3p was detected by double-luciferase experiment. RESULTS: The expression level of lncRNA KCNQ1OT1 increased, and that of miR-24-3p decreased during the osteogenesis of hPDLSCs (P<0.05). The down-regulation of lncRNA KCNQ1OT1 inhibited cell proliferation and reduced the mRNA and protein expression levels of OCN, OPN, and ALP (P<0.05). LncRNA KCNQ1OT1 targeted and regulated miR-24-3p. The overexpression of miR-24-3p inhibited cell proliferation and reduced the mRNA and protein expression levels of OCN, OPN, and ALP (P<0.05). Inhibition of miR-24-3p reversed the effect of the down-regulation of lncRNA KCNQ1OT1 on cell proliferation and mRNA and protein expression levels of OCN, OPN, and ALP (P<0.05). CONCLUSIONS: Down-regulation of lncRNA KCNQ1OT1 inhibited the proliferation and osteogenic differentiation of hPDLSCs by targeting the up-regulated expression of miR-24-3p.

Berberine augments ATP-induced inflammasome activation in macrophages by enhancing AMPK signaling.

The isoquinoline alkaloid berberine possesses many pharmacological activities including antibacterial infection. Although the direct bactericidal effect of berberine has been documented, its influence on the antibacterial functions of macrophages is largely unknown. As inflammasome activation in macrophages is important for the defense against bacterial infection, we aimed to investigate the influence of berberine on inflammasome activation in murine macrophages. Our results showed that berberine significantly increased ATP-induced inflammasome activation as reflected by enhanced pyroptosis as well as increased release of caspase-1p10 and mature interleukin-1ß (IL-1ß) in macrophages. Such effects of berberine could be suppressed by AMP-activated protein kinase (AMPK) inhibitor compound C or by knockdown of AMPKα expression, indicating the involvement of AMPK signaling in this process. In line with increased IL-1ß release, the ability of macrophages to kill engulfed bacteria was also intensified by berberine. This was corroborated by the in vivo finding that the peritoneal live bacterial load was decreased by berberine treatment. Moreover, berberine administration significantly improved survival of bacterial infected mice, concomitant with increased IL-1ß levels and elevated neutrophil recruitment in the peritoneal cavity. Collectively, these data suggested that berberine could enhance bacterial killing by augmenting inflammasome activation in macrophages through AMPK signaling.

ATP-Induced Inflammasome Activation and Pyroptosis Is Regulated by AMP-Activated Protein Kinase in Macrophages.

Adenosine triphosphate (ATP) is released by bacteria and host cells during bacterial infection as well as sterile tissue injury, acting as an inducer of inflammasome activation. Previous studies have shown that ATP treatment leads to AMP-activated protein kinase (AMPK) activation. However, it is unclear whether AMPK signaling has been involved in the regulation of ATP-induced inflammasome activation and subsequent pyroptosis. In this study, we aimed to investigate this issue in lipopolysaccharide-activated murine macrophages. Our results showed that AMPK signaling was activated in murine macrophages upon ATP treatment, which was accompanied by inflammasome activation and pyroptosis as evidenced by rapid cell membrane rupture as well as mature interleukin (IL)-1ß and active caspase-1p10 release. The ATP-induced inflammasome activation and pyroptosis were markedly suppressed by an AMPK inhibitor compound C or small-interfering RNA-mediated knockdown of AMPKα, but could be greatly enhanced by metformin (a well-known AMPK agonist). Importantly, metformin administration increased the mortality of mice with bacterial sepsis, which was likely because metformin treatment enhanced the systemic inflammasome activation as indicated by elevated serum and hepatic IL-1ß levels. Collectively, these data indicated that the AMPK signaling positively regulated ATP-induced inflammasome activation and pyroptosis in macrophages, highlighting the possibility of AMPK-targeting therapies for inflammatory diseases involving inflammasome activation.

Piperine Suppresses Pyroptosis and Interleukin-1ß Release upon ATP Triggering and Bacterial Infection.

Piperine is a phytochemical present in black pepper (Piper nigrum Linn) and other related herbs, possessing a wide array of pharmacological activities including anti-inflammatory effects. Previously, we demonstrated that piperine has therapeutic effects on bacterial sepsis in mice, but the underlying mechanism has not been fully elucidated. In this study, we aimed to investigate the influences of piperine on pyroptosis in murine macrophages. The results showed that piperine dose-dependently inhibited ATP-induced pyroptosis, thereby suppressing interleukin-1ß (IL-1ß) or high mobility group box-1 protein (HMGB1) release in LPS-primed bone marrow-derived macrophages and J774A.1 cells. Accompanying this, ATP-induced AMP-activated protein kinase (AMPK) activation was greatly suppressed by piperine, whereas AMPK agonist metformin counteracted piperine's inhibitory effects on pyroptosis. Moreover, piperine administration greatly reduced both peritoneal and serum IL-1ß levels in the mouse model intraperitoneally infected with Escherichia coli, suggestive of suppressing systemic inflammation and pyroptosis. Our data indicated that piperine could protect macrophages from pyroptosis and reduced IL-1ß and HMGB1 release by suppressing ATP-induced AMPK activation, suggesting that piperine may become a potential therapeutic agent against bacterial sepsis.

Antiviral anthraquinones and azaphilones produced by an endophytic fungus Nigrospora sp. from Aconitum carmichaeli.

A new hydroanthraquinone derivative, 6-O-demethyl-4-dehydroxyaltersolanol A (1), and two new azaphilones, 8,11-didehydrochermesinone B (6) and (7S)-7-hydroxy-3,7-dimethyl-isochromene-6,8-dione (8), along with five known analogues (2-5 and 7), were isolated from the culture broth of Nigrospora sp. YE3033, an endophytic fungus obtained from Aconitum carmichaeli. Their structures were elucidated on the basis of spectroscopic analyses. Biological activity test indicated that compounds 1-3, and 7 exhibited the inhibitory effects on influenza viral strain of A/Puerto Rico/8/34 (H1N1) with the IC50 values of 2.59, 8.35, 7.82, and 0.80µg/mL, respectively, while the low cytotoxicity of 7 with the CC50 value of 184.75µg/mL, displaying a promising potential of 7 in the development of anti-influenza A virus drugs.

A new dimeric anthraquinone from endophytic Talaromyces sp. YE3016.

A new unsymmetrical dimeric anthraquinone, 3-demethyl-3-(2-hydroxypropyl)-skyrin (1) was isolated from the solid-state fermentation extract of an endophytic fungal strain Talaromyces sp. YE 3016, together with five known compounds, skyrin (2), oxyskyrin (3), emodin (4), 1,3,6-trihydroxy-8-methyl-anthraquinone (5) and ergosterol (6). The structure of the new compound was elucidated on the basis of spectroscopic analysis. Compounds 1-3 exhibited moderate cytotoxic activities against MCF-7 cell line.

Chemotherapeutic agent CPT-11 eliminates peritoneal resident macrophages by inducing apoptosis.

CPT-11 (Irinotecan) is a first-line chemotherapeutic agent in clinic, but it may induce side effects including diarrhea and enteritis in patients. The underlying mechanism of CPT-11's intestinal toxicity is unclear. Peritoneal resident macrophages have been reported to be important for the maintenance of intestinal homeostasis. In this study, we evaluated the cytotoxic effects of CPT-11 on mouse peritoneal resident macrophages. CPT-11 was administered intraperitoneally to mice and their peritoneal exudate cells were isolated for evaluation. CPT-11 treatment strikingly decreased the ratio of F4/80(hi)MHCII(low) large peritoneal macrophages (LPMs), which are regarded as prenatally-originated peritoneal resident macrophages. Consistent with this, the transcription factor GATA6 specifically expressed in LPMs was barely detectable in the macrophages from CPT-11-treated mice, indicative of elimination of LPMs. Such elimination of LPMs was at least partly due to CPT-induced apoptosis in macrophages, because inhibition of apoptosis by caspase-3 inhibitor z-DEVD-fmk significantly diminished the loss of GATA6(+) LPMs. As GATA6 is a transcription factor that controls expression of multiple genes regulating peritoneal B-1 cell development and translocation, elimination of GATA6(+) LPMs led to a great reduction in B-1 cells in the peritoneal cavity after CPT-11 treatment. These results indicated that CPT-11-induced apoptosis contributed to the elimination of peritoneal resident macrophages, which might in turn impair the function of peritoneal B-1 cells in maintaining intestinal homeostasis. Our findings may at least partly explain why CPT-11 treatment in cancer patients induces diarrhea and enteritis, which may provide a novel avenue to prevent such side effects.

2-Amino-4-(2-chloro-phen-yl)-6-(naph-thalen-1-yl)pyridine-3-carbonitrile.

In the title compound, C(22)H(14)ClN(3), prepared by a one-pot reaction under microwave irradiation, the dihedral angles between the central pyridine ring and the pendant naphthyl and chloro-benzene ring systems are 49.2 (2) and 58.2 (3)°, respectively. In the crystal, inversion dimers linked by pairs of N-H⋯N hydrogen bonds generate R(2) (2)(8) loops. The pyridine N atom is the acceptor.

2-Chloro-N-[3-cyano-1-(3,4-dichloro-phen-yl)-1H-pyrazol-5-yl]acetamide.

In the title compound, C(12)H(7)Cl(3)N(4)O, the dihedral angle between the pyrazole and benzene rings is 35.6 (3)°. In the crystal, mol-ecules are linked by N-H⋯O hydrogen bonds generating C(4) chains propagating in [100].

2,6-Dichloro-N-(4-chloro-phen-yl)benzamide.

In the title compound, C(13)H(8)Cl(3)NO, the dihedral angle between the benzene rings is 63.2 (2)°. In the crystal, N-H⋯O hydrogen bonds link the mol-ecules into C(4) chains propagating in [001]. Weak aromatic π-π stacking also occurs [centroid-centroid separations = 3.759 (3) and 3.776 (3) Å].

[Effects of the treatment with different fluids on alveolar epithelium barrier in rats with acute lung injury].

OBJECTIVE: To observe the effects of different fluids on alveolar epithelium barrier in rats with acute lung injury (ALI). METHODS: Thirty-six Sprague-Dawley (SD) rats were randomly assigned into six groups with 6 rats in each group. ALI was induced by intravenous injection of lipopolysaccharide(LPS). Rats in all treatment groups were given different fluids and sacrificed after 4 hours. Evans blue dye (EBD) was injected via the femoral vein 30 minutes before death. Tracheobronchial tree was washed with normal saline (NS) after death, and broncho-alveolar lavage fluid (BALF) was collected. Leakage of EBD from blood into BALF (alveolar epithelial permeability) and wet/dry (W/D) ratio were measured. The mRNA expression of surfactant protein-C (SP-C) was assessed by reverse transcription-polymerase chain reaction (RT-PCR). Alveolar epithelium apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling (TUNEL). Lung injury was evaluated by Smith lung injury score. RESULTS: (1) Lung injury scores in LPS and NS groups were significantly higher than in control group (both P < 0.05). Compared with NS group, lung injury scores were significantly lower in 5% albumin (ALB) and 6% hydroxyethyl starch 130/0.4 (HES) groups (both P < 0.05), and there was no significant difference in 4% succinylated gelatin (GEL) group (P > 0.05). No significant difference was found among the latter three groups. (2) W/D ratio in LPS and NS groups were significantly higher than that in control group (both P < 0.05). Compared with NS group, W/D ratios were lower in ALB, HES and GEL groups (all P < 0.05). But it showed no significant difference among the latter three groups. (3) Alveolar epithelial permeability in LPS and NS groups were remarkably higher than that in control group (both P < 0.05). Compared with NS group, the alveolar epithelial permeability were significantly lower in ALB, HES and GEL groups (all P < 0.05). The alveolar epithelial permeability in the latter two groups were significant lower than that in ALB group (both P < 0.05) but higher than that of control group. (4) The SP-C mRNA expression in LPS, NS, ALB and GEL groups were lower than that in control and HES groups (all P < 0.05), but there was no difference between control and HES groups (P > 0.05). (5) Apoptosis index (AI) of alveolar epithelial cell in all the treatment groups were significantly higher than that in control group (all P < 0.05). Compared with NS group, AI were noticeably lower in ALB and HES groups (both P < 0.05). CONCLUSION: Compared with NS, colloid can probably improve the alveolar epithelial permeability and protect the barrier function.

[Effect of compound glycyrrhizin on peripheral T-lymphocyte subset in AIDS patients].

OBJECTIVE: To probe the effect and mechanism of Compound Glycyrrhizin in treating AIDS. METHODS: Forty AIDS patients were randomly divided into a treatment group and a control group, both treated with HAART. In addition, the former was given Compound Glycyrrhizin for 6 months, and the CD4+ T count and the expressions of CD8+ and HLA-DR on the surface of peripheral blood lymphocytes (PBL) were studied before and after the treatment. RESULTS: After 6 months of treatment, the expressions of CD8+ and CD38+ of PBL in the treatment group [(6.6 +/- 2.1)%] were found lower than in the control [(11.4 +/- 3.8)%] (t = 5.043, P < 0.01) and CD4+ T count [(243.6 +/- 91.2) x 10(6)/L vs (170.8 +/- 55.7) x 10(6)/L] rose more significantly (t = 3.045, P < 0.01). CONCLUSION: Compound Glycyrrhizin can lower the expression of active T-lymphocyte subset, inhibit HIV and help immune reconstitution.