Saroclazines A–C,thio-diketopiperazines from mangrove-derived fungi <Emphasis Type="Italic">Sarocladium kiliense</Emphasis> HDN11-84

Three new diketopiperazine derivatives (DKPs), saroclazines A–C (1–3) along with three known DKPs (4–6) were isolated from mangrove-derived fungi Sarocladium kiliense HDN11-84. Saroclazines A–B (1 and 2) possessed a free amide structure, which was first found in sulfur-containing aromatic DKPs. Their structures were elucidated by NMR, HRESIMS and X-ray. The cytotoxic activity of new compounds (1–3) was tested against HeLa cell lines, among which compound 2 showed an IC₅₀ value of 4.2 µM.     

Diethylstilbestrol impaired oogenesis of yellow catfish juveniles through disrupting hypothalamic–pituitary–gonadal axis and germ cell development

Diethylstilbestrol (DES), a non‐steroidal estrogen, has been found to cause altered germ cell development and disordered ovarian development in fish females. However, the mechanisms that might be involved are poorly understood. In this study, female juveniles of yellow catfish (Pelteobagrus fulvidraco) (120 days post‐hatching) were exposed to two doses (10 and 100 ng l^?1) of DES for 28 days. After the endpoint of exposure, decreased ovary weight and gonadosomatic index, as well as various ovarian impairments were observed in response to DES. Besides, DES elevated the mRNA levels of vitellogenin 1 (vtg 1) and estrogen receptor 1 (esr 1) in liver and decreased 17β‐estradiol level in plasma. Correspondingly, suppressed mRNA levels of the key genes in the hypothalamic–pituitary–gonadal axis (such as cyp19a1b, gnrh‐II, fshβ and lhβ in brain and fshr, lhr and cyp19a1a in ovary) after DES exposure were also observed. The declined level of plasma 17β‐estradiol and altered gene expressions of genes in the hypothalamic–pituitary–gonadal axis were thus supposed to be closely related to the disrupted oogenesis in DES‐treated fish. Analyses further demonstrated that, higher concentration of DES elevated the expression ratio of bax/bcl‐2, indicating the enhanced apoptosis occurred in ovary. Moreover, DES upregulated the expressions of genes involved in proliferation (cyclin d1 and pcna), meiotic entry (cyp26a1 and scp3) and meiotic maintenance (dmc1), resulting in arrested oogenesis in catfish. The present study greatly extended our understanding on the mechanisms underlying of reproductive toxicity of DES on fish oogenesis.     

Dehydroascorbic Acid and pGPMA Dual Modified pH-Sensitive Polymeric Micelles for Target Treatment of Liver Cancer

In clinical therapy, the poor prognosis of hepatocellular carcinoma (HCC) is mainly attributed to the failure of chemotherapeutical agents to accumulate in tumor as well as lack of potency of tumor penetration. In this work, we developed actively tumor-targeting micelles with pH-sensitive linker as a novel nanocarrier for HCC therapy. These micelles comprised biodegradable poly(ethylene glycol)-poly(aspartate) polymers, in which paclitaxel can be covalently conjugated to pAsp via an acid-labile acetal bond to form pH-responsive structures. In vitro drug release studies showed that these structures were stable in physiological condition, whereas collapsed once internalized into cells due to the mildly acidic environment in endo/lysosomes, resulting in facilitated intracellular paclitaxel release. In addition, dehydroascorbic acid and guanidinopropyl methacrylamide polymers were decorated on the surface of micelles to achieve specific tumor accumulation and tumor penetration. Cellular uptake and in vivo imaging studies proved that these micelles had remarkable targeting property toward hepatocarcinoma cells and tumor. Enhanced anti-HCC efficacy of the micelles was also confirmed both in vitro and in vivo. Therefore, this micellar system may be a potential platform of chemotherapeutics delivery for HCC therapy.     

Population Pharmacokinetics and Dosing Simulations of Ceftazidime in Chinese Neonates

An accurate dosage determination is required in neonates when antibiotics are used. The adult data cannot be simply extrapolated to the pediatric population due to significant individual differences. We aimed to identify factors impacting ceftazidime exposure in neonates and to provide drug dosing guidance to clinicians. Forty-three neonates aged less than 60 days with proven or suspected infections were enrolled in this study. After intravenous administration, blood samples were collected, and plasma ceftazidime concentration was determined using a HPLC method. Pharmacokinetic data were fitted using a nonlinear mixed-effects model approach. One-compartmental model could nicely characterize the ceftazidime in vivo behavior. The covariate test found that the postmenstrual age (day) was strongly associated with systemic drug clearance (L/h), and the effect of body weight (kg) was identified as the covariate on distribution volume (L). Compared with the base model, the addition of covariates improved the goodness-of-fit of the final model. Model validation (bootstrap, visual predictive check, and prediction-corrected visual predictive check) suggested a robust and reliable pharmacokinetic model was developed. Personalized dosage regimens were provided based on model simulations. The intravenous dose should be adjusted according to postmenstrual age, body weight, and minimum inhibitory concentration.