Acetamiprid (ACE) and imidacloprid (IMI) are two major members in the family of neonicotinoid pesticides, which are synthesized with a higher selectivity to insects. The present study determined and compared in vitro effects of ACE, IMI and nicotine on mammalian reproduction by using an integrated testing strategy for reproductive toxicology, which covered sperm quality, sperm penetration into oocytes and preimplantation embryonic development. Direct chemical exposure (500 µM or 5 mM) on spermatozoa during capacitation was performed, and in vitro fertilization (IVF) process, zygotes and 2-cell embryos were respectively incubated with chemical-supplemented medium until blastocyst formation to evaluate the reproductive toxicity of these chemicals and monitor the stages mainly affected. Generally, treatment of 500 µM or 5 mM chemicals for 30 min did not change sperm motility and DNA integrity significantly but the fertilization ability in in vitro fertilization (IVF) process, indicating that IVF process could detect and distinguish subtle effect of spermatozoa exposed to different chemicals. Culture experiment in the presence of chemicals in medium showed that fertilization process and zygotes are adversely affected by direct exposure of chemicals (P<0.05), in an order of nicotine>IMI>ACE, whereas developmental progression of 2-cell stage embryos was similar to controls (P>0.05). These findings unveiled the hazardous effects of neonicotinoid pesticides exposure on mammalian sperm fertilization ability as well as embryonic development, raising the concerns that neonicotinoid pesticides may pose reproductive risks on human reproductive health, especially in professional populations.
Small‐leaved Kuding tea (SLKDT; Ligustrum robustum) is a traditional Chinese tea. We systematically investigated the effect of SLKDT extract on obesity. SLKDT‐controlled weight gain in mice fed a high‐fat diet. Tissue specimen results showed that the SLKDT extract alleviated liver damage and fat accumulation. Meanwhile, SLKDT extract improved dyslipidemia by decreasing total cholesterol, triglycerides, and low‐density lipoprotein cholesterol levels and increasing high‐density lipoprotein cholesterol levels. Furthermore, SLKDT extract reduced alanine aminotransferase, alkaline phosphatase, and aspartate transaminase levels in the serum and liver tissues; decreased inflammatory cytokines, including interleukin (IL)‐1β, tumor necrosis factor‐α, interferon‐γ, and IL‐6; and increased the anti‐inflammatory cytokines, IL‐4 and IL‐10. The quantitative PCR results showed that SLKDT extract upregulated the mRNA expressions of peroxisome proliferator‐activated receptor (PPAR)‐α, lipoprotein lipase, carnitine palmitoyltransferase 1, and cholesterol 7 alpha hydroxylase and downregulated PPAR‐γ and CCAAT/enhancer‐binding protein‐alpha mRNA expressions in the obese mouse livers to reduce adipocyte differentiation and fat accumulation, promote fat oxidation, and improve dyslipidemia, thereby inhibiting the immune response and alleviating liver injury. SLKDT shows a potential for preventing obesity and regulating obesity‐related syndrome, so it is possible to be further developed as a novel treatment for fighting obesity.
Human cathepsin K, a cysteine proteinase of the papain family, has been recognized as a potential drug target for the treatment of osteoporosis. The predominant expression of cathepsin K in osteoclasts has rendered the enzyme into a major target for the development of novel antiresorptive drugs. Now, we report the pharmacological properties of OST-4077 [furan-2-carboxylic acid (1-{1-[4-fluoro-2-(2-oxo-pyrrolidin-1-yl)-phenyl]-3-oxo-piperidin-4-ylcarbamoyl}-cyclohexyl)-amide] as a novel selective cathepsin K inhibitor. Human and rat cathepsin K were inhibited in vitro by OST-4077 with the IC 50 values of 11 and 427 nM, respectively. OST-4077 suppressed bone resorption induced by rabbit osteoclasts (IC 50 , 37 nM) but did not affect bone mineralization or cellular alkaline phosphatase activity in MC3T3-E1 cells. Parathyroid hormone-induced bone resorption was inhibited in a dosedependent manner in thyroparathyroidectomized rats gavaged with a single dose of OST-4077 (ED 50 , 69 mg/kg). When given orally twice daily for 4 weeks to 3-month-old ovariectomized (OVX) rats, OST-4077 dose-dependently prevented bone loss, as monitored by bone densitometry, ash content, and urinary excretion of deoxypyridinoline. No change in serum osteocalcin in the OVX rats by OST-4077 suggested that bone formation might not be affected by the agent. In summary, OST-4077 selectively inhibited bone resorbing activities of osteoclasts and prevented bone loss induced by estrogen deficiency but did not affect bone formation.
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