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Irritable bowel syndrome (IBS) is a very common refractory disease. Its exact pathophysiological mechanism is still unclear. Despite the availability of plentiful drugs to control IBS, most patients do not respond well. Ginsenoside Rd is one of the major active components of Panax ginseng, which has been verified to produce various pharmacological actions. However, the role of ginsenoside Rd in modulating smooth muscle contractility is still undefined. The aim of this study is to investigate the effects of ginsenoside Rd on intestinal contractility and related mechanisms in IBS.

Reactive oxygen species (ROS) are involved in the signal transduction and cell defence in mammalian cells. However, excessive ROS derived under pathophysiological conditions are associated with the development of a wide range of diseases including cardiovascular, metabolic, neurodegenerative diseases and cancer. gp91phox -containing NADPH oxidase (Nox2) was found to be one of the primary enzymatic sources of ROS and p47phox is its key regulator. LMH001 was developed in this lab as an inhibitor of Nox2 targeting p47phox , but its chemical properties and preclinical pharmacokinetics and pharmacodynamics (PK/PD) have not been studied. At the same time, the role of p47phox and its signalling pathways under pathophysiological conditions remained unclear. Therefore, the overall aim of this study is to characterise the PK/PD properties of LMH001 and understand its mechanism in depth by knockout (KO) of p47phox in Angiotensin II (AngII)-induced oxidative stress and cardiac hypertrophy model. The plasma concentration of LMH001 showed a mono-exponential decline pattern with a t1/2 = 0.042 h and a clearance = 5682.63 mL/h/kg, and its effect in reducing AngII-stimulated H9C2 (a rat myoblast cell line) ROS production showed an IC50 = 124.00 �� 42.6 ng/ml. In the AngII-induced hypertrophic models, wild type (WT) mice displayed significantly raised systolic blood pressure (SBP) and induced cardiac hypertrophy after AngII-infusion. In contrast, p47phox KO mice only demonstrated a mild increase in SBP without hypertrophy. There was also phosphorylation of ERK1/2, p38 MAPK and MAPK kinase 3/6 (MKK3/6). Apoptosis was suggested by increased levels of ���H2AX and apoptosis signal-regulating kinase 1 (ASK1) phosphorylation. In conclusion, p47phox plays a crucial role in AngII-induced cardiac oxidative stress and hypertrophy. Its signalling through MKK3/6, p38MAPK and ERK1/2 phosphorylation are essential in ���H2AX and ASK1 phosphorylation and cardiomyocyte apoptosis. This study also provided vital information on the chemical properties, PK/PD, and pharmacological efficacy of LMH001. Its potential as a drug candidate for oxidative stress-related diseases was discussed, and future experiments on the development of LMH drugs were suggested.

Randomized, skewed caches (RSCs) such as CEASER-S have recently received much attention to defend against contention-based cache side channels. By randomizing and regularly changing the mapping(s) of addresses to cache sets, these techniques are designed to obfuscate the leakage of memory access patterns. However, new attack techniques, e.g., Prime+Prune+Probe, soon demonstrated the limits of RSCs as they allow attackers to more quickly learn which addresses contend in the cache and use this information to circumvent the randomization. To yet maintain side-channel resilience, RSCs must change the random mapping(s) more frequently with adverse effects on performance and implementation complexity. This work aims to make randomization-based approaches more robust to allow for reduced re-keying rates and presents Chameleon Cache. Chameleon Cache extends RSCs with a victim cache (VC) to decouple contention in the RSC from evictions observed by the user. The VC allows Chameleon Cache to make additional use of the multiple mappings RSCs provide to translate addresses to cache set indices: when a cache line is evicted from the RSC to the VC under one of its mappings, the VC automatically reinserts this evicted line back into the RSC by using a different mapping. As a result, the effects of previous RSC set contention are hidden and Chameleon Cache exhibits side-channel resistance and eviction patterns similar to fully associative caches with random replacement. We show that Chameleon Cache has performance overheads of < 1% and stress that VCs are more generically helpful to increase side-channel resistance and re-keying intervals of randomized caches., 12 pages, 9 figures, 6 algorithms, 1 table

Over the last two decades, the danger of sharing resources between programs has been repeatedly highlighted. Multiple side-channel attacks, which seek to exploit shared components for leaking information, have been devised, mostly targeting shared caching components. In response, the research community has proposed multiple cache designs that aim at curbing the source of side channels. With multiple competing designs, there is a need for assessing the level of security against side-channel attacks that each design offers. In this work we propose CacheFX, a flexible framework for assessing and evaluating the resilience of cache designs to side-channel attacks. CacheFX allows the evaluator to implement various cache designs, victims, and attackers, as well as to exercise them for assessing the leakage of information via the cache. To demonstrate the power of CacheFX, we implement multiple cache designs and replacement algorithms, and devise three evaluation metrics that measure different aspects of the caches:(1) the entropy induced by a memory access; (2) the complexity of building an eviction set; and (3) protection against cryptographic attacks. Our experiments highlight that different security metrics give different insights to designs, making a comprehensive analysis mandatory. For instance, while eviction-set building was fastest for randomized skewed caches, these caches featured lower eviction entropy and higher practical attack complexity. Our experiments show that all non-partitioned designs allow for effective cryptographic attacks. However, in state-of-the-art secure caches, eviction-based attacks are more difficult to mount than occupancy-based attacks, highlighting the need to consider the latter in cache design.

The primordial follicle pool established in early life determines the ovarian reserve in the female reproductive lifespan. Premature exhaustion of primordial follicles contributes to primary ovarian insufficiency (POI), that is dependent by the initial size of the primordial follicle pool and by the rate of its activation and depletion. AAI, a powerful nephrotoxin with carcinogenic potential, is present in the Aristolochiaceae species, which can release AAI into soil as a persistent pollutant. In order to assess the potential risk of Aristolochic Acid I (AAI) exposure on mammalian oogenesis, we uncovered its adverse effect on primordial folliculogenesis in the neonatal mouse ovary and its effect on female fertility in adulthood. Pregnant mice were orally administrated with doses of AAI without hepatic or renal toxicity during late-gestation. Ovaries from offspring of administered female displayed gross aberrations during primordial folliculogenesis. Also, unenclosed oocytes in germ-cell cysts showed increased DNA damage. Furthermore, several key factors, including NANOS3, SOX9, KLF4, that govern early gonad's differentiation were abnormally expressed in the exposed ovary, while the follicle formation was partially restored by knockdown of Nanos3 or sox9. In adulthood, these aberrations evolved into a significant reduction in offspring number and impaired ovarian reserve. Together, our results show that AAI influences primordial folliculogenesis and, importantly, affected female fertility. This study shows that administration of drugs herbs or consumption of vegetables that contain AAs during pregnancy may adversely influence the fertility of offspring.

Ceramic coatings were formed by micro-arc oxidation (MAO) on 6061aluminum alloy with and without a high temperature oxidation prefab film under a constant voltage. The effect of the high temperature oxidation prefab film on the initial stage of growth process of the MAO ceramic coatings was studied in this paper. The results showed that the prefab film decreased the arc starting voltage and the arc starting time of the micro-arc oxidation, and promoted the evolution processes of the micro-discharge and the surface morphology of the coating. The prefab film and electrolyte composition, especially element P, participated in the formation of the coatings. The growth process of the micro-arc oxidation ceramic coatings on specimens with the prefab film consists of four steps. The first step is the formation of grain type of oxide lumps, the second step is the spread of the lumps like little worms along the specimen surface, the third step is the formation of many network areas with a number of linear materials like little worms, and the fourth step is the development of network areas into a continuous layer. However, at the same period, the growth process of micro-arc oxidation ceramic coatings on the specimens without the prefab film consists of two steps. The first step is the formation of a little grain type of oxide lumps, and the second step is the increase of the number of grain type of oxide lumps and the expansion of the lumps like little worms in line along the surface of specimens.