G‐quadruplexes (G4s) are prevalent in oncogenes and are potential antitumor drug targets. However, binding selectivity of compounds to G4s still faces challenges. Herein, we report a platinum(II) ...complex (Pt1), whose affinity to G4‐DNA is activated by adaptive binding and selectivity controlled by binding kinetics. The resolved structure of Pt1/VEGF‐G4 (a promoter G4) shows that Pt1 matches 3′‐G‐tetrad of VEGF‐G4 through Cl−‐dissociation and loop rearrangement of VEGF‐G4. Binding rate constants are determined by coordination bond breakage/formation, correlating fully with affinities. The selective rate‐determining binding step, Cl−‐dissociation upon G4‐binding, is 2–3 orders of magnitude higher than dsDNA. Pt1 potently targets G4 in living cells, effectively represses VEGF expression, and inhibits vascular growth in zebrafish. We show adaptive G4‐binding activation and controlled by kinetics, providing a complementary design principle for compounds targeting G4 or similar biomolecules.
A PtII compound was synthesized and adaptively bound G‐quadruplex DNA through kinetic control. The solution structure of the complex was solved. It was further proved that the compound can target G‐quadruplex in living cells, repress VEGF expression in cancer cells and inhibit blood vessels growth in zebrafish.
Abstract Mitochondria-targeted compounds represent a promising approach to target tumors selectively and overcome resistance to current anticancer therapies. In this work, three cyclometalated ...iridium(III) complexes ( 1 – 3 ) containing bis- N -heterocyclic carbene (NHC) ligands have been explored as theranostic and photodynamic agents targeting mitochondria. These complexes display rich photophysical properties, which greatly facilitates the study of their intracellular fate. All three complexes are more cytotoxic than cisplatin against the cancer cells screened. 1 – 3 can penetrate into human cervical carcinoma (HeLa) cells quickly and efficiently, and they can carry out theranostic functions by simultaneously inducing and monitoring the morphological changes in mitochondria. Mechanism studies show that these complexes exert their anticancer efficacy by initiating a cascade of events related to mitochondrial dysfunction. Additionally, they display up to 3 orders of magnitude higher cytotoxicity upon irradiation at 365 nm, which is so far the highest photocytotoxic responses reported for iridium complexes.
Sorafenib is the only approved first line systemic therapy for advanced hepatocellular carcinoma (HCC) in the last decade. Tumour resistance to sorafenib has been of major obstacles to improve HCC ...patient survival.
We polarised THP-1 cells to M1 and M2 macrophages, performed various in vitro assays and developed sorafenib-resistant xenograft models to investigate the role of tumour-associated macrophages (TAM)-secreted molecules in HCC resistance to the targeted therapy.
We demonstrated M2, but not M1, macrophages not only promote proliferation, colony formation and migration of hepatoma cells but also significantly confer tumour resistance to sorafenib via sustaining tumour growth and metastasis by secreting hepatocyte growth factor (HGF). HGF activates HGF/c-Met, ERK1/2/MAPK and PI3K/AKT pathways in tumour cells. Tumour-associated M2 macrophages were accumulated in sorafenib-resistance tumours more than in sorafenib-sensitive tumours in vivo and produced abundant HGF. HGF chemoattracts more macrophages migrated from surrounding area, regulates the distribution of M2 macrophages and increases hepatoma resistance to sorafenib in a feed-forward manner.
Our results provide new insights into the mechanisms of sorafenib resistance in HCC and rationale for developing new trials by combining sorafenib with a potent HGF inhibitor such as cabozantinib to improve the first line systemic therapeutic efficacy.
Summary
Gut microbiota can influence the aging process and may modulate aging‐related changes in cognitive function. Trimethylamine‐N‐oxide (TMAO), a metabolite of intestinal flora, has been shown to ...be closely associated with cardiovascular disease and other diseases. However, the relationship between TMAO and aging, especially brain aging, has not been fully elucidated. To explore the relationship between TMAO and brain aging, we analysed the plasma levels of TMAO in both humans and mice and administered exogenous TMAO to 24‐week‐old senescence‐accelerated prone mouse strain 8 (SAMP8) and age‐matched senescence‐accelerated mouse resistant 1 (SAMR1) mice for 16 weeks. We found that the plasma levels of TMAO increased in both the elderly and the aged mice. Compared with SAMR1‐control mice, SAMP8‐control mice exhibited a brain aging phenotype characterized by more senescent cells in the hippocampal CA3 region and cognitive dysfunction. Surprisingly, TMAO treatment increased the number of senescent cells, which were primarily neurons, and enhanced the mitochondrial impairments and superoxide production. Moreover, we observed that TMAO treatment increased synaptic damage and reduced the expression levels of synaptic plasticity‐related proteins by inhibiting the mTOR signalling pathway, which induces and aggravates aging‐related cognitive dysfunction in SAMR1 and SAMP8 mice, respectively. Our findings suggested that TMAO could induce brain aging and age‐related cognitive dysfunction in SAMR1 mice and aggravate the cerebral aging process of SAMP8 mice, which might provide new insight into the effects of intestinal microbiota on the brain aging process and help to delay senescence by regulating intestinal flora metabolites.
The thermal conductivity of hollow glass bead (HGB)-filled polypropylene (PP) composites was estimated using the thermal conductivity equation of inorganic hollow microsphere-filled polymer ...composites published in the previous paper. The estimations were compared with the measured data of the PP composites filled with two kinds of HGB with different size (the mean diameter was respectively 35μm and 70μm). The results showed that the predictions of the thermal conductivity were in good agreement with the measured data except to individual data points. Furthermore, both the estimated and measured thermal conductivity decreased roughly linearly with increasing the HGB volume fraction when the HGB volume fraction was less than 20%; the influence of the particle diameter on the thermal conductivity was insignificant.
•Folin–Ciocalteu method is found affected by addition order of sodium carbonate.•Effects of phenolic calibrations based classic method were investigated.•Phenolic levels are different between prior ...and late basification by GAE.•The performance of modified Folin–Ciocalteu method was validated.
The Folin–Ciocalteu method is widely applied for the determination of the total phenolic contents in natural products. This method is significantly affected by the addition of sodium carbonate. The currently applied Folin–Ciocalteu methods may have been modified without any validation in the quantitative standards and the order of processes. In this study, serial experiments were performed to investigate the effect of phenolic calibrations based on the classic Folin–Ciocalteu method. Esterification condensations were observed in the assays with prior basification for gallic acid and catechin used as quantitative standards. The phenolic contents obtained in the samples differed depending on when basification occurred compared with the gallic acid calibration. The bias of the classic Folin–Ciocalteu method derived from cross-linkage of molecules was first defined in this study. The performance of the Folin–Ciocalteu method is optimised and validated again.
Ruthenium complexes are promising photosensitizers (PSs), but their clinical applications have many limitations. Here, a multifunctional nano‐platform PDA‐Pt‐CD@RuFc formed by platinum‐decorated and ...cyclodextrin (CD)‐modified polydopamine (PDA) nanoparticles (NPs) loaded with a ferrocene‐appended ruthenium complex (RuFc) is reported. The NPs can successfully deliver RuFc to the tumor sites. The release of RuFc from the NPs can be triggered by low pH, photothermal heating, and H2O2. The combined photodynamic and photothermal therapy (PDT‐PTT) mediated by PDA‐Pt‐CD@RuFc NPs can overcome the hypoxic environment of tumors from several aspects. First, the platinum NPs can catalyze H2O2 to produce O2. Second, vasodilation caused by photothermal heating can sustain the oxygen supplement. Third, PDT exerted by RuFc can also occur through the non‐oxygen‐dependent Fenton reaction. Due to the presence of PDA, platinum NPs, and RuFc, the nanosystem can be used in multimodal imaging including photothermal, photoacoustic, and computed tomography imaging. The NPs can be excited by the near‐infrared two‐photon light source. Moreover, the combined treatment can improve the tumor microenvironments to obtain an optimized combined therapeutic effect. In summary, this study presents a tumor‐microenvironment‐adaptive strategy to optimize the potential of ruthenium complexes as PSs from multiple aspects.
A multifunctional nanocomposite for ruthenium‐based photosensitizers that can successfully adapt to and remodel tumor microenvironments is developed. The release of the photosensitizer can be triggered by low pH, photothermal heating, and H2O2. The as‐fabricated nanoparticles can accumulate in tumor tissues and show great potential for combined therapy with multimodal imaging capacities.
Enhanced reactive oxygen species (ROS) at the beginning of reperfusion activated signal transducer and activator of transcription 3 (STAT3) in intermittent hypobaric hypoxia (IHH)-afforded ...cardioprotection against ischemia/reperfusion (I/R). However, its mechanism remains largely unknown. This study aimed to investigate the role and the downstream of STAT3 in exogenous enhanced post-ischemic ROS-induced cardioprotection using the model of moderate hydrogen peroxide postconditioning (H
2
O
2
PoC) mimicking endogenous ROS in IHH. Moderate H
2
O
2
PoC not only improved the post-ischemic myocardial contractile recovery and reduced the infarct size in isolated rat I/R hearts, but also alleviated mitochondrial calcium overload and ameliorated Ca
2+
transients, cell contraction, and mitochondrial membrane potential in rat I/R cardiomyocytes. However, the cardioprotective effects of moderate H
2
O
2
PoC were abrogated by Janus kinase 2 (JAK2)/STAT3 inhibitor AG490 in rat hearts as well as adenovirus-delivered short hairpin RNA specific for STAT3 and the opener of mitochondrial calcium uniporter (MCU) spermine in rat cardiomyocytes. Notably, the moderate H
2
O
2
PoC-afforded cardioprotection abrogated by spermine could be rescued by STAT3 over-expression with adenovirus in rat I/R cardiomyocytes. Besides, moderate H
2
O
2
PoC enhanced mitochondrial STAT3 expression during I/R. A co-localization/interaction of STAT3 or phospho-STAT3
ser727
and MCU was observed in rat cardiomyocytes with moderate H
2
O
2
PoC at 5 and 30 min of reperfusion but not in rat I/R cardiomyocytes. Further, STAT3 interacted with the N-terminal domain (NTD) of MCU in rat cardiomyocytes with moderate H
2
O
2
PoC. These findings indicated that post-ischemic moderate ROS activate STAT3 against cardiac I/R by inhibiting MCU opening via its interaction with the NTD of MCU to alleviate mitochondrial calcium overload.
A novel nitrogen doped hybrid material composed of in situ‐formed graphene natively grown on hierarchical ordered porous carbon is prepared, which successfully combines the advantages of both ...materials, such as high surface area, high mass transfer, and high conductivity. The outstanding structural properties of the resultant material render it an excellent metal‐free catalyst for electrochemical oxygen reduction.
In this paper, 100 nm-thick zinc oxide (ZnO) films were deposited as a seed layer on Corning glass substrates via a radio frequency (RF) magnetron sputtering technique, and vertical well-aligned ...Fe-doped ZnO (FZO) nanorod (NR) arrays were then grown on the seed layer-coated substrates via a low-temperature solution method. FZO NR arrays were annealed at 600 °C and characterized by using field emission scanning microscopy (FE-SEM) and X-ray diffraction spectrum (XRD) analysis. FZO NRs grew along the preferred (002) orientation with good crystal quality and hexagonal wurtzite structure. The main ultraviolet (UV) peak of 378 nm exhibited a red-shifted phenomenon with Fe-doping by photoluminescence (PL) emission. Furthermore, FZO photodetectors (PDs) based on metal–semiconductor–metal (MSM) structure were successfully manufactured through a photolithography procedure for UV detection. Results revealed that compared with pure ZnO NRs, FZO NRs exhibited a remarkable photosensitivity for UV PD applications and a fast rise/decay time. The sensitivities of prepared pure ZnO and FZO PDs were 43.1, and 471.1 for a 3 V applied bias and 380 nm UV illumination, respectively.
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