Lycopene Promotes Osteogenesis and Reduces Adipogenesis through Regulating FoxO1/PPARγ Signaling in Ovariectomized Rats and Bone Marrow Mesenchymal Stem Cells.

Recent interest in preventing the development of osteoporosis has focused on the regulation of redox homeostasis. However, the action of lycopene (LYC), a strong natural antioxidant compound, on osteoporotic bone loss remains largely unknown. Here, we show that oral administration of LYC to OVX rats for 12 weeks reduced body weight gain, improved lipid metabolism, and preserved bone quality. In addition, LYC treatment inhibited ROS overgeneration in serum and bone marrow in OVX rats, and in BMSCs upon H2O2 stimulation, leading to inhibiting adipogenesis and promoting osteogenesis during bone remodeling. At the molecular level, LYC improved bone quality via an increase in the expressions of FoxO1 and Runx2 and a decrease in the expressions of PPARγ and C/EBPα in OVX rats and BMSCs. Collectively, these findings suggest that LYC attenuates osteoporotic bone loss through promoting osteogenesis and inhibiting adipogenesis via regulation of the FoxO1/PPARγ pathway driven by oxidative stress, presenting a novel strategy for osteoporosis management.

pH-responsive polyzwitterion covered nanocarriers for DNA delivery.

The success of gene therapy relies on gene nanocarriers to achieve therapeutic effects in vivo. Surface shielding of poly(ethylene glycol) (PEG), known as PEGylation, onto gene delivery carriers is a predominant strategy for extending blood circulation and improving therapeutic outcomes in vivo. Nevertheless, PEGylation frequently compromises the transfection efficiency by decreasing the interactions with the cellular membrane of the targeted cells, thereby preventing the cellular uptake and the subsequent endosomal escape. Herein, we developed a stepwise pH-responsive polyplex micelle for the plasmid DNA delivery with the surface covered by ethylenediamine-based polycarboxybetaines. This polyplex micelle switched its surface charge from neutral at pH 7.4 to positive at tumorous and endo-/lysosomal pH (i.e., pH 6.5 and 5.5, respectively), thus enhancing the cellular uptake and facilitating the endosomal escape toward efficient gene transfection. Additionally, the polyplex micelle demonstrated prolonged blood circulation as well as enhanced tumor accumulation, leading to highly effective tumor growth suppression by delivering an antiangiogenic gene. These results suggest the usefulness of a pH-responsive charge-switchable shell polymer on the surface of the polyplex micelle for the efficient nucleic acid delivery.

Green credit policy and the liquidity risks of heavily polluting enterprises.

As a kind of enterprises most affected by green policies-heavily polluting enterprises, whether the government's relevant policies can achieve its policy goals and what impact will be exerted on such enterprises is a critical issue. Based on the data of listed heavily polluting enterprises in China from 2007 to 2020, this paper uses the difference in differences model to test the impact of green credit policies on the liquidity risk of heavily polluting enterprises. The results show that the green credit policies intensify the liquidity risk of heavily polluting enterprises. Moreover, the green credit policies increase the financial and stock liquidity risks of heavily polluting enterprises by reducing the long-term debt ratio and information transparency. Green innovation and equity balance weaken the positive impact of green credit policies on the liquidity risk of heavily polluting enterprises. Heavily polluting enterprises can reduce the impact of green credit policies on their liquidity risk by increasing investment in green innovation and improving ownership structure.

Polymeric ligands comprising sulfur-containing amino acids for targeting tumor-associated amino acid transporters.

Various cancer cells overexpress L-type amino acid transporter 1 (LAT1) to take up a large number of neutral amino acids such as phenylalanine and methionine, and LAT1 transporter should be a promising target for cancer diagnosis and therapy. However, only a few studies reported drug delivery systems targeting LAT1 probably due to limited knowledge about the interaction between LAT1 and its substrate. Here, we developed polymers having methionine (Met)- or cysteine (Cys)-like structures on their side chains to examine their affinity with LAT1. While both the Met- and Cys-modified polymers exhibited efficient cellular uptake selectively in cancer cells, the Met-modified polymers exhibited higher cellular uptake efficiency in an LAT1-selective manner than the Cys-modified polymers. In the in vivo study, the intraperitoneally injected Met-modified polymers showed appreciable tumor-selective accumulation in the peritoneal dissemination model, and importantly, Met-modified polymers conjugated with photosensitizers exhibited significant therapeutic effects upon photoirradiation with reduced photochemical damage to normal organs. Our results may provide important knowledge about the polymer-LAT1 interaction, and the Met-modified polymers should offer a new concept for designing LAT1-targeting drug delivery systems.

Polymeric iron chelators for enhancing 5-aminolevulinic acid-induced photodynamic therapy.

5-Aminolevulinic acid (5-ALA) is an amino acid that can be metabolized into a photosensitizer, protoporphyrin IX (PpIX) selectively in a tumor cell, permitting minimally invasive photodynamic diagnosis/therapy. However, some malignant tumor cells have excess intracellular labile iron and facilitate the conversion of PpIX into heme, which compromises the therapeutic potency of 5-ALA. Here, we examined the potential of chelation of such unfavorable intratumoral labile iron in photodynamic therapy (PDT) with 5-ALA hydrochloride, using polymeric iron chelators that we recently developed. The polymeric iron chelator efficiently inactivated the intracellular labile iron in cultured cancer cells and importantly enhanced the accumulation of PpIX, thereby improving the cytotoxicity upon photoirradiation. Even in in vivo study with subcutaneous tumor models, the polymeric iron chelator augmented the intratumoral accumulation of PpIX and the PDT effect. This study suggests that our polymeric iron chelator could be a tool for boosting the effect of 5-ALA-induced PDT by modulating tumor microenvironment.

Cancerous pH-responsive polycarboxybetaine-coated lipid nanoparticle for smart delivery of siRNA against subcutaneous tumor model in mice.

Lipid nanoparticles (LNPs) have been commonly used as a vehicle for nucleic acids, such as small interfering RNA (siRNA); the surface modification of LNPs is one of the determinants of their delivery efficiency especially in systemic administration. However, the applications of siRNA-encapsulated LNPs are limited due to a lack effective systems to deliver to solid tumors. Here, we report a smart surface modification using a charge-switchable ethylenediamine-based polycarboxybetaine for enhancing tumor accumulation via interaction with anionic tumorous tissue constituents due to selective switching to cationic charge in response to cancerous acidic pH. Our polycarboxybetaine-modified LNP could enhance cellular uptake in cancerous pH, resulting in facilitated endosomal escape and gene knockdown efficiency. After systemic administration, the polycarboxybetaine-modified LNP accomplished high tumor accumulation in SKOV3-luc and CT 26 subcutaneous tumor models. The siPLK-1-encapsulated LNP thereby accomplished significant tumor growth inhibition. This study demonstrates a promising potential of the pH-responsive polycarboxybetaine as a material for modifying the surface of LNPs for efficient nucleic acid delivery.

Polymeric Iron Chelators Enhancing Pro-Oxidant Antitumor Efficacy of Vitamin C by Inhibiting the Extracellular Fenton Reaction.

Intravenously injected high-dose vitamin C (VC) induces extracellular H2O2, which can penetrate into the tumor cells and suppress tumor growth. However, extracellular labile iron ions in the tumor decompose H2O2 via the Fenton reaction, limiting the therapeutic effect. In this regard, we recently developed a polymeric iron chelator that can inactivate the intratumoral labile iron ions. Here, we examined the effect of our polymeric iron chelator on the high-dose VC therapy in in vitro and in vivo. In the in vitro study, the polymeric iron chelator could inactivate the extracellular labile iron ions and prevent the unfavorable decomposition of VC-induced H2O2, augmenting pro-oxidative damage to DNA and inducing apoptosis in cultured cancer cells. Even in the in vivo study, the polymeric iron chelator significantly improved the antitumor effect of VC in subcutaneous DLD-1 and CT26 tumors in mice, while conventional iron chelators could not. This work indicates the importance of modulating tumor-associated iron ions in the high-dose VC therapy and should contribute to a better understanding of its mechanism.

Potential urinary monitoring of the enhanced permeability and retention effect using MMP-2-responsive poly(ethylene glycol) derivatives.

The enhanced permeability and retention (EPR) effect is fundamental to tumor-targeted drug delivery using nanoparticles. However, recent studies reported heterogeneity of the EPR effect, and companion diagnostics are considered to be key to predicting and optimizing the benefits of the EPR effect. Here, as a new material to simply endow the function of companion diagnostics to nanoparticles, we designed a poly(ethylene glycol) (PEG) derivative conjugated with low molecular fluorescent dye through synthetic substrate linker that can be cleaved in response to MMP-2, which is overexpressed in tumor extracellular matrix. Upon tumor accumulation, the low molecular fluorescent dye is released from the PEG and quickly excreted to urine, thereby reporting its tumor accumulation level as a fluorescent signal in the urine. In this study, this urinary reporter was conjugated with albumin, and the functionalized albumin exhibited efficient accumulation in various tumors. Importantly, the functionalized albumin exhibited significantly higher excretion of the fluorescent dye in the urine in mice with tumors compared with those without tumors. The PEG derivatives proposed in this study may be a promising tool to predict the EPR effect in individual cancer patients.

Systemically Applicable Glutamine-Functionalized Polymer Exerting Multivalent Interaction with Tumors Overexpressing ASCT2.

Transporter ASCT2, which predominantly imports glutamine (Gln), is overexpressed in a variety of cancer cells, and targeting ASCT2 is expected to be a promising approach for tumor diagnosis and therapy. In this work, we designed a series of glutamine-modified poly(l-lysine) (PLys(Gln)) homopolymers and PEG-PLys(Gln) block copolymers and investigated their tumor-targeting abilities. With increasing degree of polymerization in the PLys(Gln) homopolymers, their cellular uptake was gradually enhanced through multivalent interactions with ASCT2. The performance of PEG-PLys(Gln) in blood circulation and tumor accumulation could be controlled by tuning of the molecular weight of PEG. Our results highlight the utility of molecular recognition in ASCT2/PLys(Gln) for tumor targeting through systemic administration.

Vitrimerization: Converting Thermoset Polymers into Vitrimers.

Thermoset polymers with permanently cross-linked networks have outstanding mechanical properties and solvent resistance, but they cannot be reprocessed or recycled. On the other hand, vitrimers with covalent adaptable networks can be recycled. Here we provide a simple and practical method coined as "vitrimerization" to convert the permanent cross-linked thermosets into vitrimer polymers without depolymerization. The vitrimerized thermosets exhibit comparable mechanical properties and solvent resistance with the original ones. This method allows recycling and reusing the unrecyclable thermoset polymers with minimum loss in mechanical properties and enables closed-loop recycling of thermosets with the least environmental impact.

Changes and Diurnal Variation of Visual Quality after Orthokeratology in Myopic Children.

PURPOSE: To assess the changes and the diurnal variation of visual quality after orthokeratology in myopic children. METHODS: Forty-four eyes of 22 subjects with a mean age of 10.55 ± 1.53 years (8 to 14 years) were enrolled in this prospective study. Their spherical equivalent ranged from -1.25 to -4.25 diopters (D) and astigmatism was less than 1.00 D. Parameters including corneal curvature, ocular objective scatter index (OSI), the modulation transfer function (MTF), root mean square of ocular and corneal wavefront aberrations, and contrast sensitivity function (CSF) were measured before and at two time points during the same day after 1 month of orthokeratology. RESULTS: After orthokeratology, uncorrected visual acuity (UCVA) and spherical equivalent were significantly improved from baseline (P < 0.001), and their diurnal variation was not significant (P=0.083, 0.568). OSI increased from 0.29 ± 0.15 to 0.65 ± 0.31 (P < 0.001). MTF decreased significantly (P < 0.01). Corneal curvature and ocular total aberration decreased (P < 0.001), while the ocular and corneal higher-order aberration increased significantly (P < 0.01). The CSF under photopic condition decreased at 3 cpd (P=0.006) and increased at 18 cpd (P=0.012). The diurnal variation of CSF at 18 cpd under mesopic and high glare conditions and at 12 cpd under photopic condition was significant (P=0.002, 0.01, 0.017). CONCLUSIONS: Orthokeratology can effectively improve UCVA and high spatial frequency CSF by decreasing the low-order aberrations. However, MTF and CSF at low spatial frequency decreased because of the increase of intraocular scattering and high-order aberrations. Meanwhile, CSF at high spatial frequency fluctuates significantly at two times during the same day after 1 month orthokeratology.

Covalent self-assembled nanoparticles with pH-dependent enhanced tumor retention and drug release for improving tumor therapeutic efficiency.

Developing a smart drug delivery system with enhanced tumor retention at the tumor site, and rapid intracellular drug release promises to improve the therapeutic index and mitigate side effects. To this end, covalent phenylboronic acid (PBA)-based self-assembly nanoparticles (BNPs) consisting of pH-responsive cores and detachable poloxamer 188 shells were constructed for loading doxorubicin (DOX) in a simple process. The poloxamer 188 coating could be easily detached when the breakage of the borate ester bonds in the external nanocores was initially triggered in the tumor extracellular weak acid environment. The concealed PBA was subsequently exposed and could react with sialic acids (SA), which are overexpressed on tumor cells, and this enhanced the tumor retention effect of the fresh nanoparticle as well as facilitating the cellular uptake after removing the protective layers. Furthermore, owing to the existence of pH-responsive esters, the uptaken fresh nanoparticles could rapidly release DOX in the acidic tumor environment, which resulted in an enhanced therapeutic efficiency in vitro and in vivo. In summary, this pH dependent behaviour of DOX/BNPs provided new insights for enhanced chemotherapeutic treatment in cancer.

Multifunctional nanoplatform for enhanced photodynamic cancer therapy and magnetic resonance imaging.

Co-delivery of photosensitizers and synergistic agents by one single nanoplatform is interesting for enhancing photodynamic therapy (PDT) of cancer. Here, a multifunctional nanoplatform for enhanced photodynamic therapy and magnetic resonance imaging of cancer was constructed. The poly (lactide-co-glycolide) (PLGA) nanoparticles (NPs) loaded with hematoporphyrin monomethyl ether (HMME) were coated with multifunctional manganese dioxide (MnO2) shells, which were designed as PLGA/HMME@MnO2 NPs. Once the NPs were effectively taken up by tumor cells, the intracellular H2O2 was catalysed by the MnO2 shells to generate O2. Meanwhile, the higher glutathione (GSH) promoted the degradation of MnO2 into Mn2+ ions with the ability of magnetic resonance (MR) imaging. After the degradation of outer layer, the release of photosensitizer was promoted. Under irradiation, the released HMME produced cytotoxic reactive oxygen species (ROS) to damage the tumor cells when the O2 was generated in the hypoxic tumor site. Furthermore, the decreased GSH level further inhibited the consumption of the produced ROS, which greatly enhanced the PDT efficacy. Therefore, this study suggested that this multifunctional system has the potential for enhanced photodynamic therapy and magnetic resonance imaging.