Biomimetic Nanomedicine Targeting Orchestrated Metabolism Coupled with Regulatory Factors to Disrupt the Metabolic Plasticity of Breast Cancer.

Targeting nutrient metabolism has been proposed as an effective therapeutic strategy to combat breast cancer because of its high nutrient requirements. However, metabolic plasticity enables breast cancer cells to survive under unfavorable starvation conditions. The key mammalian target regulators rapamycin (mTOR) and hypoxia-inducible-factor-1 (HIF-1) tightly link the dynamic metabolism of glutamine and glucose to maintain nutrient flux. Blocking nutrient flow also induces autophagy to recycle nutrients in the autophagosome, which exacerbates metastasis and tumor progression. Compared to other common cancers, breast cancer is even more dependent on mTOR and HIF-1 to orchestrate the metabolic network. Therefore, we develop a cascade-boosting integrated nanomedicine to reprogram complementary metabolism coupled with regulators in breast cancer. Glucose oxidase efficiently consumes glucose, while the delivery of rapamycin inside limits the metabolic flux of glutamine and uncouples the feedback regulation of mTOR and HIF-1. The hydroxyl radical generated in a cascade blocks the later phase of autophagy without nutrient recycling. This nanomedicine targeting orchestrated metabolism can disrupt the coordination of glucose, amino acids, nucleotides, lipids, and other metabolic pathways in breast cancer tissues, effectively improving the durable antitumor effect and prognosis of breast cancer. Overall, the cascade-boosting integrated system provides a viable strategy to address cellular plasticity and efficient enzyme delivery.

HELLP syndrome manifesting as abnormal fetal umbilical artery blood flow and rapidly worsening laboratory indexes: A case report.

RATIONALE: HELLP syndrome, a rare but serious obstetric complication, is often overdiagnosed due to its nonspecific symptoms and inappropriate clinical testing. PATIENT CONCERNS: A 30-year-old nulliparous pregnant Chinese woman at gestational age of 28+1 weeks was admitted to our hospital because Doppler ultrasonography at a local hospital had detected loss of fetal umbilical artery end-diastolic blood flow lasting 12 hours. On admission to our hospital, the patient showed elevated blood pressure (148/84 mm Hg), but blood pressure and laboratory indicators after admission were normal. However, the patient developed abdominal pain during hospitalization. INTERVENTIONS: Dexamethasone was given after admission to our hospital to promote fetal lung maturation, magnesium sulfate was given to protect fetal brain nerves, and maternal blood pressure was closely monitored. In addition, fetal umbilical artery blood flow was dynamically monitored. After three days in hospital with normal blood pressure, the patient developed abdominal pain accompanied by diarrhea. She was positive for Murphy's sign and laboratory tests showed no obvious abnormalities. Acute cholecystitis was suspected, but symptomatic and supportive treatment did not relieve abdominal pain and her blood pressure increased progressively to 212/130 mm Hg. Magnesium sulfate was given immediately to prevent spasm, and nitroglycerin was administered intravenously against hypertension. Liver enzymes, blood coagulation, and routine urinalysis were abnormal. The patient was diagnosed with HELLP syndrome, and an emergency cesarean section was performed. DIAGNOSIS: HELLP syndrome. OUTCOMES: After the cesarean section, platelet (PLT) count continuously decreased and transaminase and bilirubin levels continously increased. The newborn was transferred to the neonatal intensive care unit after birth and discharged at a corrected gestational age of 34 weeks. By postoperative day 6, laboratory indicators had returned to normal and the patient was discharged. LESSONS SUBSECTIONS: Our case highlights that HELLP syndrome is a serious complication, and it should be diagnosed carefully and not arbitrarily on the basis of some abnormal indicators and stable clinical manifestations. Accurate early identification, active monitoring and management are essential for improving prognosis and avoiding maternal or infant mortality.

Acute exposure to environmentally relevant concentrations of Chinese PFOS alternative F-53B induces oxidative stress in early developing zebrafish.

6:2 chlorinated polyfluorinated ether sulfonate (F-53B), a Chinese PFOS alternative, has recently been identified in the aquatic environment at concentrations similar to or higher than perfluorooctane sulfonate (PFOS). Although previous studies have shown that F-53B can trigger oxidative stress in fish, the underlying molecular mechanism is still largely unknown. In this study, zebrafish embryos were exposed to various concentrations of F-53B (0, 0.5, 20 and 200 µg/L) for 5 d to investigate oxidative stress responses and possible molecular mechanisms of action. Our results showed that F-53B accumulated in a concentration-dependent manner in zebrafish larvae. The contents of malondialdehyde (MDA) and reduced glutathione (GSH), as well as the activities, mRNA and protein levels of most of antioxidant enzyme genes involved in the phosphatidylinositol 3-kinase (PI3K)/Akt/Nrf2-ARE pathway were significantly reduced. Further in silico study indicated that F-53B binds tightly to PI3K, which may be related to the inhibition of Nrf2-regulated antioxidant functions by F-53B as a PI3K inhibitor. Combining in vivo and in silico studies, we elucidated the effects of F-53B on antioxidant system of zebrafish through the PI3K/Akt/Nrf2-ARE pathway, which increases our understanding of the molecular mechanism of F-53B on antioxidant responses in fish.

[Identification of glycosylphosphatidylinositol-anchored protein from Schistosoma japonicum].

OBJECTIVE: To identify glycosylphosphatidylinositol (GPI) anchored protein of Schistosoma japonicum. METHODS: Based on the gene sequence of Schistosoma mansoni GPI anchored protein Sm200 (GenBank Assess No: XM_002569560.1), bioinformatics analysis was performed to find out its homologous gene sequence in S. japonicum, then a selected partial coding sequence (SjGPIs, about 933 bp) from the homologous gene sequence were amplified, and cloned into PET-28a(+) vector. The recombinant plasmid pET-28a(+)SjGPIs were transformed into E. coli Top10 cells and induced with IPTG for protein expression. The recombinant protein SjGPIs was purified with Ni-NTA resin, and the purified recombinant SjGPIs protein was used as antigen to prepare antiserum in New Zealand rabbit. The antiserum was used to detect S. japonicum GPI-anchored protein. To identify a GPI-anchored protein, the detected protein were identified by phosphatidylinositol-specific phospholipase C (PI-PLC) digestion. White blood cells from S. japonicum-infected mice was examined whether they endocytosed GPI-anchored proteins by Western blotting. RESULTS: The homologous gene sequence of S. mansoni GPI Sm200 gene was found in S. japonicum genome. A 3 495 bp coding sequence was obtained, containing the complete C-terminal sequence. The selected gene sequence (SjGPIs) were amplified and the recombinant plasmid pET-28a(+)-SjGPIs was established. According to the analysis of C-terminal sequence, Western blotting and enzyme digestion of PI-PLC, a GPI-anchored protein was present in S. japonicum tegument (about 1M(r)200000), named SjGPI200. The protein was detected in white blood cells of infected mice. CONCLUSION: SjGPI200 protein exists in S. japonicum, and anchored to parasite tegument via GPI.