No abstract

DNA alkylating agents generally kill tumor cells by covalently binding with DNA to form interstrand or intrastrand cross-links. However, in the case of cisplatin, only a few DNA adducts (<1%) are highly toxic irreparable interstrand cross-links. Furthermore, cisplatin is rapidly detoxified by high levels of intracellular thiols such as glutathione (GSH). Since the discovery of its mechanism of action, people have been looking for ways to directly and efficiently remove intracellular GSH and increase interstrand cross-links to improve drug efficacy and overcome resistance, but there has been little breakthrough. Herein, we hypothesized that the anticancer efficiency of cisplatin can be enhanced through iodo-thiol click chemistry mediated GSH depletion and increased formation of DNA interstrand cross-links via mild hyperthermia triggered by near-infrared (NIR) light. This was achieved by preparing an amphiphilic polymer with platinum(IV) (Pt(IV)) prodrugs and pendant iodine atoms (iodides). The polymer was further used to encapsulate IR780 and assembled into Pt−I−IR780 nanoparticles. Induction of mild hyperthermia (43 °C) at the tumor site by NIR light irradiation had three effects: (1) it accelerated the GSH-mediated reduction of Pt(IV) in the polymer main chain to platinum(II) (Pt(II)); (2) it boosted the iodo-thiol substitution click reaction between GSH and iodide, thereby attenuating the GSH-mediated detoxification of cisplatin; (3) it increased the proportion of highly toxic and irreparable Pt-DNA interstrand cross-links. Therefore, we find that mild hyperthermia induced via NIR irradiation can enhance the killing of cancer cells and reduce the tumor burden, thus delivering efficient chemotherapy.

Background Gamma-glutamyl transferase (GGT) has been shown to be involved in the pathogenesis of both coronary artery disease (CAD) and liver disease, and it has been reported that the GGT-to-platelet ratio (GPR) is an independent predictor for adverse outcomes from liver fibrosis and hepatic carcinoma. However, the relation between the GPR and adverse outcomes in CAD patients after percutaneous coronary intervention (PCI) has not been investigated. Methods A total of 5,636 patients enrolled in Clinical Outcomes and Risk Factors of Patients with Coronary Heart Disease after PCI, a retrospective cohort study, from January 2008 to December 2016, were divided into two groups according to GPR (GPR < 0.12, n = 2,769 and GPR ≥ 0.12, n = 2,867). The primary outcome was long-term mortality including all-cause mortality (ACM) and cardiac mortality (CM) after PCI. The average follow-up time was 35.9 ± 22.6 months. Results We found that there were significant differences between the two groups in the incidences of ACM (p = 0.011), CM (p = 0.001), major adverse cardiovascular events (MACEs, p < 0.024), major adverse cardiovascular and cerebrovascular events (MACCEs, p = 0.014) and bleeding events (p = 0.003). Multivariate Cox regression analyses showed that GPR was an independent predictor for ACM (hazard ratio [HR]: 1.536 [95% confidence interval [CI]:1.162–2.032], p = 0.003), CM (HR: 1.763 [95% CI: 1.283–2.424], p < 0.001), MACCEs (HR: 1.269 [95% CI: 1.066–1.511], p = 0.007) and MACEs (HR: 1.308 [95% CI: 1.089–1.570], p = 0.004) in stable CAD patients but that it was an independent predictor for only the incidence of bleeding events (HR: 3.104 [95% CI: 1.680–5.736], p < 0.001) in acute coronary syndrome (ACS) patients. Conclusion This study indicates that GPR is an independent and novel predictor of adverse long-term outcomes in CAD patients who underwent PCI.

Bushen-Yizhi formula (BSYZ), a traditional Chinese medicine formula consisting of six herbs has been reported to possess a neuroprotective effect. The present study aimed to investigate the effects of BSYZ on learning and memory abilities, as well as oxidative stress and neuronal apoptosis in the hippocampus of scopolamine (SCOP)-induced senescence in mice, in order to reveal whether BSYZ is a potential therapeutic agent for Alzheimer’s disease (AD). A high-performance liquid chromatography (HPLC) fingerprint was applied to provide a chemical profile of BSYZ. Extracts of BSYZ were orally administered to mice with SCOP-induced memory impairment for two weeks. The learning and memory abilities were determined by the Morris water maze test. The oxidant stress-related indices, such as activity of superoxide dismutase (SOD) and levels of glutathione (GSH) and malondialdehyde (MDA) were examined in hippocampus of SCOP-treated mice. The cell death ratio was assessed by TUNEL staining, while apoptotic-related proteins including Bcl-2 and Bax were determined by immunofluorescent staining and western blot analysis. Caspase-3 was determined by western blot analysis. Consequently, a chromatographic condition, which was conducted at 35°C with a flow rate of 0.8 ml/min on the Gemini C18 column with mobile phase of acetonitrile and water-phosphoric acid (100:0.1, v/v), was established to yield common fingerprint chromatography under 203 nm with a similarity index of 0.986 within 10 batches of BSYZ samples. BSYZ at a dose of 2.92 g/kg significantly improved the cognitive ability, restored the abnormal activity of SOD and increased the levels of MDA and GSH induced by SCOP. Moreover, the neural apoptosis in the hippocampus of SCOP-treated mice was reversed by BSYZ by regulating the expression of Bcl-2, Bax and caspase-3. The results demonstrated that BSYZ had neuroprotective effects in SCOP-induced senescence in mice by ameliorating oxidative stress and neuronal apoptosis in the brain, supporting its potential in AD treatment.

Aims A number of studies have attempted to demonstrate the benefits associated with personalized antiplatelet therapy guided by platelet function testing, which has led to disappointing findings. In this study, we used a new platelet function test to guide antiplatelet therapy in stable coronary artery disease (CAD) patients after percutaneous coronary intervention (PCI). Methods and results In the present randomized controlled trial, a total of 2237 patients with stable CAD undergoing PCI were randomly chosen to be administered personalized antiplatelet therapy (personalized group; n = 1123) or standard antiplatelet treatment (standard group; n = 1114). The patients in the standard therapy group, without detecting the platelet aggregation rate, were administered a 75 mg/day clopidogrel maintenance dosage plus 100 mg/day of aspirin for at least 6 months after the procedure. For the patients in the personalized therapy group, the antiplatelet strategy was performed according to the maximum aggregation rate (MAR), determined using a novel platelet analyser, PL-12. If MAR &gt; 55%, 90 mg ticagrelor was administered twice daily plus 100 mg/day of aspirin after PCI. If MAR ≤55%, 75 mg/day clopidogrel plus 100 mg/day of aspirin was administered after PCI. The primary endpoint was net clinical adverse events, which were a composite of cardiac death, myocardial infarction, stroke, stent thrombosis, urgent revascularization, and bleeding [Bleeding Academic Research Consortium (BARC) definitions, Type 2, 3, or 5], in the 180-day period after randomization. The primary endpoint was reached in 58 patients in the personalized group, compared with 85 patients in the standard group [5.1% vs. 7.5%, hazard ratio (HR) 0.678, 95% confidence interval (CI) 0.486–0.947, P = 0.023], on intention-to-treat analysis. We also found that the net clinical adverse events (including ischaemic and bleeding events) were significantly reduced in the personalized group at 30 days after PCI compared to the standard group (1.5% vs. 3.0%, HR 0.510, 95% CI 0.284–0.915, P = 0.020). We did not find a significant difference in major bleeding events at either the 30-day (0.5% vs. 0.3%, P = 0.322) or the 180-day follow-up (2.1% vs. 1.6%, P = 0.364) between the two groups. Conclusion The present study suggests that personalized antiplatelet therapy according to MAR can significantly improve the net clinical benefit 180 days after PCI.

Asymptomatic hyperuricemia (AH) is an early stage of gout. Emerging evidence shows that the intestinal microbiota is related to gout. However, the relationship between AH and the intestinal microbiota is poorly understood. Therefore, the aim of the current study was to explore the possible correlation between AH and intestinal flora. We compared the intestinal microbial communities of AH (45 cases) and healthy subjects (45 cases) by 16S rRNA gene sequencing and clustering analysis on the incorporated population. Intestinal-type clustering can be divided into two groups, and significant differences in the proportion of AH are found among different bowel types. Alpha diversity indices were higher in the AH group than in the control group, and beta diversity indices also showed significant differences. A total of 19 genera were found different between the AH group and the control group. Compared with the control group, some probiotics are increased in the AH population. Two groups were ranked by importance of bacteria. We found the different bacteria partially coincided with the important bacteria, and the joint diagnosis level of the important bacteria was good. Conclusion: There were significant differences in the composition of intestinal biota between AH patients and healthy subjects. Some probiotics increased in AH.

Background The aim of this study was to assess the prognostic value of red blood cell distribution width (RDW) in patients with coronary artery disease undergoing percutaneous coronary intervention (PCI). Methods A retrospective cohort study (CORFCHD-PCI, [Identifier: ChiCTR-INR-16010153]) of 6050 patients who were hospitalized with a diagnosis of coronary artery disease (CAD) and treated with PCI from January 2008 to December 2016 were enrolled in the study. The primary outcome was long-term mortality after PCI. Clinical follow-up data of participating patients were obtained during an outpatient examination 35.9 ± 22.6 months after PCI. Demographic and clinical data and admission laboratory parameters were recorded, and patients were categorized into two groups according to RDW level (high group ≥13.1%; low group < 13.1%). Results Multivariate Cox regression analysis revealed RDW as an independent prognosis factor for cardiac death. The incidence of cardiac death increased 1.33 times in patients in the high RDW group (HR, 1.331; 95% CI, 1.009–1.755, P = 0.043). Kaplan–Meier survival analysis suggested that patients with high RDW tended to have an increased accumulated risk of cardiac death. However, we did not found significant differences in the incidence of long-term mortality (adjusted HR = 1.203[0.941–1.537], P = 0.140), MACCE (adjusted HR = 1.128[0.979–1.301], P = 0.096), MACE (adjusted HR = 1.155[0.994–1.341], P = 0.059), stroke, bleeding events or readmission between the two groups. Conclusion The baseline level of RDW is an independent predictor for cardiac death in post-PCI CAD patients.

This study explored the curative effect and underlying mechanisms of a traditional Chinese medicine compound prescription, Bushen-Yizhi formula (BSYZ), in ibotenic acid (IBO)-induced rats. Morris water maze and novel object recognition tests showed that BSYZ significantly improved spatial and object memory. Brain immunohistochemistry staining showed that BSYZ significantly up-regulated expression of choline acetyltransferase (ChAT) and nerve growth factor (NGF) in the hippocampus and cortex. The protein tyrosine kinase high-affinity receptor TrkA was slightly increased in the hippocampus and cortex, and significantly enhanced in the nucleus basalis of Meynert (NBM) after BSYZ intervention. The immunoreactivity of the p75 low-affinity receptor in BSYZ-treated rats was significantly strengthened in the cortex. Similar expression trends of nerve growth factor (NGF), TrkA, and p75 mRNA were observed in the hippocampus and cortex. Additionally, BSYZ reversed IBO-induced disorders of acetylcholine (ACh) levels, ChAT, and cholinesterase (ChE) in the cortex, which was consistent with the changes in mRNA levels of ChAT and acetylcholinesterase (AChE). Expression of ChAT and AChE proteins and mRNA in the hippocampus was up-regulated, whereas the apoptosis-relative protein cleaved caspase-3 was decreased after administration of BSYZ. Moreover, changes in cell death were confirmed by histological morphology. Thus, the results indicated that the BSYZ formula could ameliorate memory impairments in IBO-induced rats, and it exerted its therapeutic action probably by modulating cholinergic pathways, NGF signaling, and anti-apoptosis. Overall, it is suggested that the BSYZ formula might be a potential therapeutic approach for the treatment of Alzheimer's disease (AD) and other cholinergic impairment-related diseases.