柳氮磺胺吡啶、甲硝唑、云南白药联合灌肠治疗溃疡性结肠炎疗效观察

目的：探讨柳氮磺胺吡啶（SASP）、甲硝唑和云南白药联合灌肠治疗溃疡性结肠炎的疗效。方法：将85例活动性溃疡性结肠炎患者随机分为两组,灌肠治疗组45例,采用联合灌肠治疗,每晚1次,保留1h,持续2周后口服SASP及甲硝唑维持治疗22周,口服对照组40例,予SASP加甲硝唑口服12周后,SASP剂量减半再持续12周,6个月疗程结束后复查疗效。结果：灌肠治疗组治愈率为93．3％（42／45例）有效率为100．0％（45／45例）,口服对照组则分别为47．5％（19／40例）和75．0％（30／40例）,两组治愈率和有效率比较差异有显著性意义（P＜0．01）。结论：柳氮磺胺吡啶及甲硝唑联合云南白药灌肠治疗溃疡性结肠炎疗效显著,且无明显毒副作用。     

Probiotic bacteria as modulators of cellular senescence: emerging concepts and opportunities

ABSTRACT

Probiotic bacteria are increasingly gaining importance in human nutrition owing to their multifaceted health beneficial effects. Studies have also shown that probiotic supplementation is useful in mitigating age-associated oxi-inflammatory stress, immunosenescence, and gut dysbiosis thereby promoting health and longevity. However, our current understanding of the process of aging suggests a strong interrelationship between the accumulation of senescent cells and the development of aging phenotype, including the predisposition to age-related disorders. The present review studies the documented pro-longevity effects of probiotics and highlights how these beneficial attributes of probiotics could be related to the mitigation of cellular senescence. We present a perspective that to fully understand and comprehend the anti-aging characteristics of probiotic bacteria; it is imperative that probiotics or their synbiotic amalgamation with plant polyphenols, be studied under the purview of cellular senescence, that may ultimately help devise probiotic-based anti-senescence strategies.     

p53 and rapamycin are additive

Mechanistic target of rapamycin (mTOR) is a kinase found in a complex (mTORC1) that enables macromolecular synthesis and cell growth and is implicated in cancer etiology. The rapamycin-FK506 binding protein 12 (FKBP12) complex allosterically inhibits mTORC1. In response to stress, p53 inhibits mTORC1 through a separate pathway involving cell signaling and amino acid sensing. Thus, these different mechanisms could be additive. Here we show that p53 improved the ability of rapamycin to: 1) extend mouse life span, 2) suppress ionizing radiation (IR)-induced senescence-associated secretory phenotype (SASP) and 3) increase the levels of amino acids and citric acid in mouse embryonic stem (ES) cells. This additive effect could have implications for cancer treatment since rapamycin and p53 are anti-oncogenic.     

Dissecting primary and secondary senescence to enable new senotherapeutic strategies

Cellular senescence is a state of stable cell cycle arrest that is known to be elicited in response to different stresses or forms of damage. Senescence limits the replication of old, damaged, and precancerous cells in the short-term but is implicated in diseases and debilities of aging due to loss of regenerative reserve and secretion of a complex combination of factors called the senescence-associated secretory phenotype (SASP). More recently, investigators have discovered that senescent cells induced by these methods (what we term “primary senescent cells”) are also capable of inducing other non-senescent cells to undergo senescence — a phenomenon we call “secondary senescence.” Secondary senescence has been demonstrated to occur via two broad types of mechanisms. First, factors in the SASP have been shown to be involved in spreading senescence; we call this phenomenon “paracrine senescence.” Second, primary senescent cells can induce senescence via an additional group of mechanisms involving cell-to-cell contacts of different types; we term this phenomenon “juxtacrine senescence.” “Secondary senescence” in our definition is thus the overarching term for both paracrine and juxtacrine senescence together. By allowing cells that are inherently small in number and incapable of replication to increase in number and possibly spread to anatomically distant locations, secondary senescence allows an initially small number of senescent cells to contribute further to age-related pathologies. We propose that understanding how primary and secondary senescent cells differ from each other and the mechanisms of their spread will enable the development of new rejuvenation therapies to target different senescent cell populations and interrupt their spread, extending human health- and potentially lifespan.     

DNA polymerase kappa counteracts inflammation-induced mutagenesis in multiple organs of mice

In vitro studies indicate that DNA polymerase kappa (Polκ) is able to accurately and efficiently perform DNA synthesis using templates containing various types of DNA damage, including benzo[a]pyrene (BP)-induced N²-deoxyguanosine adducts. In this study, we examined sensitivity of inactivated Polk knock-in (Polk^−/−) mice to BP carcinogenicity in the colon by administering an oral dose of BP plus dextran sulfate sodium (DSS), an inflammation causing promoter of carcinogenesis. Although colon cancer was successfully induced by BP plus DSS, there was no significant difference in tumor incidence or multiplicity between Polk^−/− and Polk^+/+ mice. Malignant lymphoma was induced in thymus by the treatment only in Polk^−/− mice, but it lacked statistical significance. Mutant frequencies (MFs) in the gpt reporter gene were strongly enhanced in colon; almost to the same extent in both types of mice. Micronucleus formation in bone marrow at the high dose of BP and DNA adducts in colon and lung was not significantly different between two types of mice. Surprisingly, however, Polk^−/− mice exhibited significantly higher MFs in colon and lung than did Polk^+/+ mice when they were treated with DSS alone. The most prominent mutation induced by DSS treatment was G:C to C:G transversion, whose specific MF in proximal colon was 30 times higher in Polk^−/− than in Polk^+/+ mice. DSS alone did not enhance MF at all in Polk^+/+ mice. The results indicate that Polκ does not suppress BP-induced mutagenesis and carcinogenesis in the colon, but counteracts inflammation-induced mutagenesis in multiple organs. Environ. Mol. Mutagen. 60:320–330, 2019. © 2019 Wiley Periodicals, Inc.     

Autophagy inhibition switches low-dose camptothecin-induced premature senescence to apoptosis in human colorectal cancer cells

Recently, several studies indicated that senescent tumor cells are resistant to apoptosis in chemotherapy. They may return to cell cycle, thus act as stumbling blocks in anticancer treatments. In the present study, we found that, in human colorectal cancer cells, low-dose camptothecin (CPT) simultaneously induced autophagy and premature senescence through AMPK-TSC2-mTOR pathway and ATM-Chk2-p53-p21 pathway respectively. What's important is the suppression of autophagy substantially increased apoptosis and greatly attenuated senescence possibly by blocking p53/p21 pathway, which suggests that autophagy plays an indispensable role in sustaining cell senescence caused by low-dose CPT. The combination of low-dose CPT and autophagy inhibitor, a way to lead senescent cells to die, would be potentially valuable in cancer therapy.