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A facile and efficient strategy was established for the construction of RC-529 and its derivatives. Four conjugates of RC-529 derivatives with Tn antigen were synthesized and all elicited strong and T cell-dependent immune responses in mice without requiring external adjuvants. In addition, all antisera induced by these conjugates could specifically recognize, bind to and kill Tn-overexpressing cancer cells. Thus, RC-529 shows promise as a useful platform for the development of new vaccine carriers with self-adjuvanting properties for the treatment of cancer. Moreover, preliminary structure-activity relationship analysis provides convincing support for further optimization of, and additional investigation into, RC-529.

In tumor cells, p53 is always inactivated due to the mutation or deletion of TP53 gene or inhibited by the overexpressed MDM2. Small-molecule induced restoring of p53 function by blocking MDM2-p53 protein-protein interactions has been highly pursued as an attractive therapeutic strategy for cancer therapy. To date, a large number of small-molecule inhibitors have been identified based on the compact and well-defined MDM2-p53 interactions, of which SAR405838, MK-8242, DS-3032b, NVP-CGM097, RG7112, HDM201, RG7388, ALRN-6924 and AMG 232 are undergoing clinical assessment at different phases for cancer therapy. This review is focused on the discovery and development of piperidinone-based MDM2-p53 inhibitors for cancer therapy, including the identification of hit compounds, hit-to-lead optimizations, binding models of ligands in the active site of MDM2, metabolic studies, and preclinical data of advanced piperidinone-based MDM2-p53 inhibitors. Additionally, acquired resistance of MDM2 inhibitors and potential toxicity toward normal tissues are briefly discussed.

Brief episodes of ischaemia and reperfusion render the heart resistant to subsequent prolonged ischaemic insult, termed ischaemic preconditioning. Here, we hypothesized that transient non-ischaemic stress by hypertrophic stimulation would induce endogenous cardioprotective signalling and enhance cardiac resistance to subsequent ischaemic damage. Transient transverse aortic constriction (TAC) or Ang-Ⅱ treatment was performed for 3–7 days in male mice and then withdrawn for several days by either aortic debanding or discontinuing Ang-Ⅱ treatment, followed by subsequent exposure to regional myocardial ischaemia by in situ coronary artery ligation. Following ischaemia/reperfusion (I/R) injury, myocardial infarct size and apoptosis were markedly reduced and contractile function was significantly improved in the TAC preconditioning group compared with that in the control group. Similar results were observed in mice receiving Ang-Ⅱ infusion. Mechanistically, TAC preconditioning enhanced ALDH2 activity, promoted AMPK activation and improved mitochondrial energy metabolism by increasing myocardial OXPHOS complex expression, elevating the mitochondrial ATP content and improving viable myocardium glucose uptake. Moreover, TAC preconditioning significantly mitigated I/R-induced myocardial iNOS/gp91phox activation, inhibited endoplasmic reticulum stress and ameliorated mitochondrial impairment. Using a pharmacological approach to inhibit AMPK signalling in the presence or absence of preconditioning, we demonstrated AMPK-dependent protective mechanisms of TAC preconditioning against I/R injury. Furthermore, treatment with adenovirus-encoded ALDH2 partially emulated the actions of hypertrophic preconditioning, as evidenced by improved mitochondrial metabolism, inhibited oxidative stress-induced mitochondrial damage and attenuated cell death through an AMPK-dependent mechanism, whereas genetic ablation of ALDH2 abrogated the aforementioned actions of TAC preconditioning. The present study demonstrates that preconditioning with hypertrophic stress protects the heart from I/R injury via mechanisms that improve mitochondrial metabolism, reduce oxidative/nitrative stress and inhibit apoptosis. ALDH2 is obligatorily required for the development of cardiac hypertrophic preconditioning and acts as the mediator of this process., Highlights • Hypertrophic preconditioning is a novel cardioprotective strategy against cardiac I/R injury. • Hypertrophic preconditioning improves mitochondrial metabolism, reduces oxidative and inhibits cardiomyocyte apoptosis. • ALDH2 is required for the development of cardiac hypertrophic preconditioning and acts as the mediator of this process.

The effects of a small amount of fluoroethylene carbonate (C 3 H 3 FO 3 or FEC) on the electrochemical performance of lithium-rich layered oxide cathode Li 1.16 [Mn 0.75 Ni 0.25 ] 0.84 O 2 have been focused herein. When 1 vol.% or 2 vol.% FEC was introduced into the electrolyte, cycling performance and rate capability of Li 1.16 [Mn 0.75 Ni 0.25 ] 0.84 O 2 have been improved, and the initial irreversible capacity (C irr ) loss has been lessened by suppressing the parasitic side reactions between cathode and electrolyte. However, excess FEC (5% in volume) will lead to the decreased lithium transference number (t Li+ ), large concentration polarization and the reduced discharge capacity especially at high current. DFT calculations indicate that FEC enhances the anti-oxidation ability of the electrolyte system, and the preferential accumulation and reaction of FEC near cathode during charging due to the strong coordination between FEC and PF 6 − anion. The results from electrochemical impedance spectroscopy (EIS), X-ray photoelectron spectroscopy (XPS) and differential scanning calorimetry (DSC) measures indicate that a more stable SEI film has been formed on the cathode surface with FEC as additive, which leads to the suppression of the electrolyte aggressive decomposition and the enhancement of thermal stability.

Li 1.375 Ni 0.25 Mn 0.75 O 2+ γ exhibits an obviously enhanced electrochemical performance after AlF 3 surface modification, including the high initial discharge capacities of 276.8 mA h g − 1 and high coulombic efficiency of 93.6%. The results from powder X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), inductively coupled plasma (ICP) and galvanostatical test confirm that its electrochemical improvement can be mainly attributed to the appearance of spinel-like structure on the surface of the layered material induced by AlF 3 -modified. Moreover, the reduced charge transfer resistance ( R ct ) during cycling contributes to a better cycle stability of AlF 3 -modified Li 1.375 Ni 0.25 Mn 0.75 O 2+ γ .

Li1+x(Ni0.37Mn0.63)1−xO2 (x = 0.123, 0.111, 0.086, 0.070, 0.031) cathode materials were synthesized via coprecipitation of carbonates and the samples with long lifespan for lithium ion batteries were obtained through adjusting the content of lithium. Their crystal structure and electrochemical performance were characterized by means of powder X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), inductive coupled plasma (ICP), galvanostatic charge/discharge test and electrochemical impedance spectrum (EIS). The XRD data show that the materials can be indexed as a single α-NaFeO2 phase except the sample with x = 0.031. The FESEM results indicate that the primary particles size increase with an increase of x value and the secondary particles retain the spherical morphology. The as-prepared sample with x = 0.086 delivers the largest discharge capacity of 232.1 mAh g−1 and a high initial efficiency of 81.8% at 0.2 C in the potential range of 2.5–4.7 V. Moreover, the better cycle performances are obtained for samples with x = 0.123 and 0.111, and the capacity retentions are up to 89 and 81% of the first discharge capacity at 0.5 C after 500 cycles, respectively.

Dexmedetomidine (Dex) has been demonstrated to provide neuroprotection against ischemia/reperfusion (I/R) injury. However, the exact mechanism of this protection remains unknown. Here, we explored the neuroprotective effect of Dex in rats exposed to cerebral I/R-induced by middle cerebral artery occlusion (MCAO) and the role of phosphatidylinositol 3-kinase (PI3K)/Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), and glycogen synthase kinase-3β (GSK-3β) in this protective action. Adult male Sprague-Dawley rats were subjected to MCAO for 90 min followed by reperfusion for 24h and Dex (15 μg/kg, i.v.) was administered immediately after the onset of MCAO. The neurological deficit score, cerebral infarct volume, brain edema, and neuron survival were evaluated at 24h of reperfusion. The effect of Dex on p-Akt, p-ERK1/2 and p-GSK-3β expression in the ischemic hemisphere was assayed by Western blot. Treatment of rats exposed to I/R with Dex caused not only marked reduction in the neurological deficit score, cerebral infarct volume, and brain edema (P

Amaranthus retroflexus L. and Chenopodium glaucum L. are two widely distributed destructive weeds. Their strong adaptability and massive seed production make them the hardest weeds to deal with. This present study intended to investigate the effect of leachate from Eupatorium adenophorum on the growth of these weeds and explore the potential to develop an environmental friendly strategy to use the leach- ate to control the weeds. Seeds of A. retroflexus L. and C. glaucum L. were soaked in solutions containing 0%, 0.6%, 1.25%, 2.5%, and 5% leachate from E. adenophorum leaves. A. retroflexus and C. glaucum seedlings grown in pots were sprayed with leachate solutions in the same concentration range. The effects of these leachate solutions on membrane permeability and germination of seeds, and growth and physiological characteristics of the seedlings were investigated. The highest concentration of leachate (5%) caused significant damage to the cell membrane of seeds of both weed species, whereas lower concentrations (0.6%) promoted repair of the membrane system, as reflected by higher and lower than control in relative conductivity (RC), respec- tively. Different concentrations of leachate showed distinct allelopathic inhibitory effects on the two weed species; lower concentrations showed weak inhibitory or even positive effects, whereas higher con- centrations showed stronger inhibitory effects. Higher concentrations of leachate (2.5% and 5%) delayed germination and significantly decreased the emergence rate of the seeds, survival rate, and dry matter accumulation of the seedlings. When treated by 5% leachate, the emergence date of A. retroflexus was delayed by 3.6 d, emergence rate of the seeds and survival rate was 69.1% and 70.6% of the control, respectively, seedling dry matter was 48.6% less than the control; In the case of C. glaucum, the emergence date was delayed by 2.7 d, emergence rate of the seeds and survival rate was 45.1% and 58.6% of the con- trol, respectively, seedling dry matter was 44.7% less than the control. There were significant interactions among the different concentrations of leachate and the length of treatment period with respect to activ- ities of antioxidant enzymes, malondialdehyde (MDA) contents, and chlorophyll contents. Seedlings trea- ted with 0.6%, 1.25%, or 2.5% leachate solution for 24-72 h showed increased superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) activities. When seedlings were treated with leachate solu- tions for 96 h, antioxidant enzyme activities and chlorophyll content decreased in A. retroflexus, but only CAT activity decreased in C. glaucum. When seedlings of the two weed species were treated with 5% leachate solution, CAT activity and chlorophyll content decreased and MDA content gradually increased with longer treatment times (from 24 to 96 h). The two weed species showed different allelopathic responses to E. adenophorum; A. retroflexus was more sensitive than C. glaucum. Based on the investigation, it could be speculated that the delayed germination and low germination rate of the weeds after treatment by leachate could be due to the fact that leachate damaged the membrane sys- tem of the seeds. By delaying germination, lowering the germination rate of the weeds and inhibiting seed- ling growth, leachate from E. adenophorum could provide an effective way of controlling the weeds.

Previous studies have reported that female gender confers cardioprotection against ischemia/reperfusion (I/R) injury, partly because estrogen activates phosphatidylinositol-3-kinase/Akt (PI3K/Akt) pathway. We have previously proven that cardioprotection of sevoflurane postconditioning is mediated by PI3K/Akt pathway in male rats. The purpose of the present study was to determine whether the cardioprotection of sevoflurane postconditioning is influenced by gender, and the role of PI3K/Akt pathway in such gender difference.Isolated hearts from 2-mo-old male and female SD rats were subjected to ischemia for 40 min and reperfusion for 2 h in the Langendorff apparatus, and were randomly assigned to the following groups: no ischemia/reperfusion (CON), ischemia/reperfusion (I/R), I/R+sevoflurane postconditioning (I/R+SPC), I/R+100 nM wortmannin (I/R+WOR), and I/R+SPC+WOR. Postconditioning was performed with administration of 3.0% sevoflurane at the first 10 min of reperfusion. Left ventricular developed pressure (LVDP), left ventricular end-diastolic pressure (LVEDP), and myocardial lactate dehydrogenase (LDH) release were measured. Infarct size was detected by riphenyltetrazolium chloride staining. The protein expression of total Akt (t-Akt) and phosphorylated Akt (Ser(473)) (p-Akt) were determined by Western blot.The I/R group showed lower LVDP and higher LVEDP than CON group in the same gender during reperfusion period. The LDH release and infarct size were smaller in the female I/R group (P0.05 versus male I/R group). Sevoflurane postconditioning markedly improved left ventricular function and decreased LDH, infarct size in the male I/R+SPC group (P0.05 versus male I/R group) but not in the female I/R+SPC group. Wortmannin abolished the cardioprotection of sevoflurane postconditioning in the male I/R+SPC+Wort group (P0.05 versus male I/R+SPC group), and markedly increased the infarct size and LVEDP and decreased LVDP in female rats. The t-Akt protein expression was no significant difference in all groups. The ratio of p-Akt/t-Akt expression in the male CON group was a little lower than that in the female CON group, but there was no statistical significance. In male rats, the ratio of p-Akt/t-Akt was no difference between CON and I/R group, but it was higher in I/R+SPC group than that in I/R group (P0.05). In female rats, the level of p-Akt was markedly increased by I/R, which was markedly higher than that in male I/R group (P0.05). However, p-Akt was not different between I/R and I/R+SPC groups. Wortmannin decreased the p-Akt expression in both male and female rats.It is concluded that female rat hearts showed greater resistance to I/R injury, and sevoflurane postconditioning developed cardioprotection in male rats but not in female rats. The PI3K/Akt pathway may be involved in the cardioprotection by both sevoflurane postconditioning and gender.