Construction of PEGylated chlorin e6@CuS-Pt theranostic nanoplatforms for nanozymes-enhanced photodynamic-photothermal therapy.

Multifunctional nanoagents with photodynamic therapy (PDT) and photothermal therapy (PTT) functions have shown great promise for cancer treatment, while the design and synthesis of efficient nanoagents remain a challenge. To realize nanozyme-enhanced PDT-PTT combined therapy, herein we have synthesized the Ce6@CuS-Pt/PEG nanoplatforms as a model of efficient nanoagents. Hollow CuS nanospheres with an average diameter of âˆ¼ 200 nm are first synthesized through vulcanization using Cu2O as the precursor. Subsequently, CuS nanospheres are surface-decorated with Pt nanoparticles (NPs) as nanozyme via an in-situ reduction route, followed by modifying the DSPE-PEG5000 and loading the photosensitizer Chlorin e6 (Ce6). The obtained Ce6@CuS-Pt/PEG NPs exhibit high photothermal conversion efficiency (43.08%), good singlet oxygen (1O2) generation ability, and good physiological stability. In addition, Ce6@CuS-Pt/PEG NPs show good catalytic performance due to the presence of Pt nanozyme, which can effectively convert H2O2 to O2 and significantly enhance the production of cytotoxic 1O2. When Ce6@CuS-Pt/PEG NPs dispersion is injected into mice, the tumors can be wholly suppressed owing to nanozyme-enhanced PDT-PTT combined therapy, providing better therapeutic effects compared to single-mode phototherapy. Thus, the present Ce6@CuS-Pt/PEG NPs can act as an efficient multifunctional nanoplatform for tumor therapy.

Probiotic intervention benefits multiple neural behaviors in older adults with mild cognitive impairment.

Probiotic supplements were shown to improve cognitive function in Alzheimer's disease (AD) patients. However, it is still unclear whether this applies to older individuals with mild cognitive impairment (MCI). We aimed to explore the effects of probiotic supplementation on multiple neural behaviors in older adults with MCI. Forty-two MCI patients (age > 60 years) were randomly divided into two groups and consumed either probiotics (n=21) or placebo (n=21) for 12 weeks. Various scale scores, gut microbiota measures and serological indicators were recorded pre- and posttreatment. After 12 weeks of intervention, cognitive function and sleep quality were improved in the probiotic group compared with those in the control group, and the underlying mechanisms were associated with changes in the intestinal microbiota. In conclusion, our study demonstrated that probiotic treatment enhanced cognitive function and sleep quality in older MCI patients, thus providing important insights into the clinical prevention and treatment of MCI.

Nanoscale Hf-hematoporphyrin frameworks for synergetic sonodynamic/radiation therapy of deep-seated tumors.

Most of tumors are located in deep-depth of animals, and the therapy of deep-seated tumors remains a severe challenge due to the performance reduction of promising technologies including phototherapy. To solve the problem, herein we have developed a hafnium-hemoporfin frameworks (HfHFs) as multifunctional theranostic nanoplatforms for synergetic sonodynamic therapy (SDT) and radiation therapy (RT) of deep-seated tumors. HfHFs are constructed by a sonication-assisted assembly route with hematoporphyrin monomethyl ether (HMME) sonosensitizer molecules as bridging linkers and Hf4+ as metal nodes. The resulting HfHFs sample is composed of spherical nanoparticles with size of 90-130 nm, and then surface-modified with DSPE-PEG to improve the water-dispersity. Under ultrasound (US) irradiation, HMME ligands in HfHFs can be motivated to produce singlet oxygen (1O2) due to sonodynamic effect. When the HfHFs sample is exposed by X-ray, the high atomic-number Hf4+ in the HfHFs can effectively absorb X-ray to increase RT effect by producing hydroxyl radicals (•OH). When HfHFs dispersion is intravenously injected in the tumor-bearing mice, the tumor can be monitored by CT imaging. Moreover, the deep-seated tumors coated by tissue barriers can be suppressed effectively by the synergistic SDT and RT, which is better than that of SDT or RT alone. Therefore, HfHFs can be employed as a novel nanoagent for the SDT-RT of deep-seated tumors.

Multifunctional Doxorubicin@Hollow-Cu9S8 nanoplatforms for Photothermally-Augmented Chemodynamic-Chemo therapy.

Multimodal therapy has attracted increasing interests in tumor treatment due to its high anti-cancer efficacy, and the key is to develop multifunctional nanoagents. The classic multifunctional nanoagents are made up of expensive and complex components, leading to limited practical applications. To solve these problems, we have developed the polyethylene glycol (PEG) coated hollow Cu9S8 nanoparticles (H-Cu9S8/PEG NPs), whose H-Cu9S8 component exhibits the photothermal effect for near-infrared (NIR) photothermal therapy (PTT), the Fenton-like catalytic activity for chemodynamic therapy (CDT), and the drug-loading capacity for chemotherapy. The H-Cu9S8/PEG NPs with a diameter of âˆ¼ 100 nm have been synthesized by sulfurizing cuprous oxide (Cu2O) nanoparticles through "Kirkendall effect", and they exhibit high photothermal conversion efficiency of 40.9%. Meanwhile, the H-Cu9S8/PEG NPs are capable of a Fenton-like reaction, which can be augmented by 2 times under the NIR irradiation. The hollow structure gives the H-Cu9S8/PEG high doxorubicin (DOX) loading capacity (21.1%), and then the DOX release can be further improved by pH and photothermal effect. When the DOX@H-Cu9S8/PEG dispersions are injected into the tumor-bearing mice, the tumor growth can be efficiently inhibited due to the synergistic effect of photothermally-augmented CDT-chemo therapy. Therefore, the DOX@H-Cu9S8/PEG can serve as a multifunctional nanoplatform for photothermally-augmented CDT-chemo treatment of malignant tumors.

Short Guanidinium-Functionalized Poly(2-oxazoline)s Displaying Potent Therapeutic Efficacy on Drug-Resistant Fungal Infections.

New antifungals are urgently needed to combat invasive fungal infections, due to limited types of available antifungal drugs and frequently encountered side effects, as well as the quick emergence of drug-resistance. We previously developed amine-pendent poly(2-oxazoline)s (POXs) as synthetic mimics of host defense peptides (HDPs) to have antibacterial properties, but with poor antifungal activity. Hereby, we report the finding of short guanidinium-pendent POXs, inspired by cell-penetrating peptides, as synthetic mimics of HDPs to display potent antifungal activity, superior mammalian cells versus fungi selectivity, and strong therapeutic efficacy in treating local and systemic fungal infections. Moreover, the unique antifungal mechanism of fungal cell membrane penetration and organelle disruption explains the insusceptibility of POXs to antifungal resistance. The easy synthesis and structural diversity of POXs imply their potential as a class of promising antifungal agents.

Coupling metal organic frameworks with molybdenum disulfide nanoflakes for targeted cancer theranostics.

The superior properties of metal organic frameworks (MOF) can provide great opportunities for merging functional nanoparticles to construct smart and versatile cancer theranostic agents. In this study, on the basis of non-mesoporous nanoparticles (molybdenum disulfide, MoS2), the structure of the MOF shell layer with an adjustable structure can be constructed through the natural coordination interaction between polydopamine (PDA) and iron ion, and the tumor cell target ligand was modified on the surface of the nanocomposite after loading the anticancer drug doxorubicin hydrochloride (DOX) to form a multifunctional cancer theranostics nanoplatform (DOX@MoS2-PMA). Benefiting from the excellent properties of MoS2 and MOF, the favorable photothermal properties and pH/near-infrared (NIR) laser-triggered DOX release behavior of composite nanoparticles were demonstrated. Its well-defined nanostructure, adequate colloidal stability, and satisfactory biocompatibility were further evidenced. Furthermore, the selective tumor cell targeting ability of DOX@MoS2-PMA can improve the cellular uptake efficacy and the photothermal-chemotherapy combination therapy can significantly enhance the killing effect on cancer cells both in vitro and in vivo. In addition, fluorescence imaging results show that nanoparticles can efficiently accumulate inside tumors. The photoacoustic (PA) and magnetic resonance (MR) imaging capabilities derived from different components of nanoparticles can perform better imaging effects. To the best of our knowledge, this is the first attempt to merge the performance of MoS2 with MOF for PA/MR dual-modality imaging-guided photothermal-chemotherapy combination therapy. Our work presented herein proves that MOF can be combined with non-mesoporous nanoparticles and exhibits excellent performance, thus opening a new avenue for endowing non-mesoporous nanoparticles with an efficient drug loading capacity and practical applications of MOFs in nanomedicine.

Synergic Effects of Berberine and Curcumin on Improving Cognitive Function in an Alzheimer's Disease Mouse Model.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, and no effective therapies have been found to prevent or cure AD to date. Berberine and curcumin are extracts from traditional Chinese herbs that have a long history of clinical benefits for AD. Here, using a transgenic AD mouse model, we found that the combined berberine and curcumin treatment had a much better effect on improving the cognitive function of mice than the single-drug treatment, suggesting synergic effects of the combined berberine and curcumin treatment. In addition, we found that the combined berberine and curcumin treatment had significant synergic effects on reducing soluble amyloid-ß-peptide(1-42) production. Furthermore, the combination treatment also had remarkable synergic effects on decreasing inflammatory responses and oxidative stress in both the cortex and hippocampus of AD mice. We also found that the combination treatment performed much better than the single drugs in reducing the APP and BACE1 levels and increasing AMPKα phosphorylation and cell autophagy, which might be the underlying mechanism of the synergic effects. Taken together, the result of this study reveal the synergic effects and potential underlying mechanisms of the combined berberine and curcumin treatment in improving the symptoms of AD in mice. This study sheds light on a new strategy for exploring new phytotherapies for AD and also emphasizes that more research should focus on the synergic effects of herbal drugs in the future.

Synthesis of Bi2WO6-x nanodots with oxygen vacancies as an all-in-one nanoagent for simultaneous CT/IR imaging and photothermal/photodynamic therapy of tumors.

All-in-one nanoagents with a single-component and all-required functions have attracted increasing attention for the imaging-guided therapy of tumors, but the design and preparation of such nanoagents remain a challenge. Herein, we report the introduction of oxygen vacancies to traditional semiconductors with heavy-metal elements for tuning photoabsorption in the near infrared (NIR) region, by using Bi2WO6 (band-gap: ∼2.7 eV) as a model. Bi2WO6-x nanodots with sizes of ∼3 or ∼8 nm have been prepared by a facile coprecipitation-solvothermal method assisted by citric acid (CA, 0.1-1.5 g) as the reduction agent. CA confers the removal of O atoms from the [Bi2O2]2+ layer during the solvothermal process, resulting in the formation of plenty of oxygen vacancies in the Bi2WO6-x crystal. As a result, NIR photoabsorption of Bi2WO6-x nanodots can be remarkably enhanced with the increase of the CA amount from 0 to 1.0 g. Under irradiation of a single-wavelength (808 nm, 1.0 W cm-2) NIR laser, black Bi2WO6-x-CA1.0 nanodots can not only efficiently produce a sufficient amount of heat with a photothermal conversion efficiency of 45.1% for photothermal therapy, but also generate singlet oxygen (1O2) for photodynamic therapy. Furthermore, due to the presence of heavy-metal (Bi and W) elements, Bi2WO6-x-CA1.0 nanodots have high X-ray attenuation ability for CT imaging. After the Bi2WO6-x-CA1.0 nanodot dispersion is injected into the tumor-bearing mice, the tumor can be imaged by using CT and an IR thermal camera. After irradiation with a single-wavelength (808 nm, 1.0 W cm-2, 10 min) NIR laser, the tumor can be completely suppressed by the synergic photothermal and photodynamic effects of Bi2WO6-x-CA1.0 nanodots, without recurrence and treatment-induced toxicity. Therefore, Bi2WO6-x nanodots have great potential as a novel all-in-one nanoagent for the imaging and phototherapy of tumors.

Tuning the NIR photoabsorption of CuWO4-x nanodots with oxygen vacancies for CT imaging guided photothermal therapy of tumors.

A traditional CuWO4 semiconductor (Eg = 2.25 eV) shows photoabsorption in the visible range with an edge at ∼550 nm, limiting its application in near-infrared (NIR) laser-induced photothermal ablation therapy (PAT). To tune the NIR photoabsorption of CuWO4, we report a trisodium citrate-induced strategy for generating oxygen vacancies. CuWO4 and CuWO4-x nanoparticles are prepared by a facile coprecipitation-solvothermal method in the absence or presence of trisodium citrate (0.2-0.5 g) as the reducing agent. Without trisodium citrate, CuWO4 consists of aggregated particles, and its dispersion has a typical yellow-green color without NIR photoabsorption. With the addition of trisodium citrate from 0.2 to 0.5 g, CuWO4-x samples are composed of monodisperse nanodots with increased sizes from ∼2 to ∼6 nm, and the color of these dispersions becomes darker with increased NIR photoabsorption, that is, from 0.178 to 0.685 at 808 nm. As a result, the aqueous dispersion of CuWO4-x-0.5 nanodots prepared with 0.5 g trisodium citrate exhibits a high photothermal efficiency of 47.6% under 808 nm laser irradiation. Simultaneously, CuWO4-x-0.5 nanodots have high X-ray attenuation as a CT imaging agent due to the presence of a heavy metal element (W). When the CuWO4-x-0.5 dispersion is injected into the tumors of mice, the tumors can be observed by CT and thermal imaging. After 808 nm laser irradiation (1.0 W cm-2, 10 min), cancer cells in vivo can be efficiently ablated by the photothermal effects of CuWO4-x, without obvious toxicity and side effects. Therefore, CuWO4-x can act as a novel all-in-one agent for CT imaging-guided photothermal therapy of tumors.

Vitamin D ameliorates impaired wound healing in streptozotocin-induced diabetic mice by suppressing NF-κB-mediated inflammatory genes.

Diabetic wounds are characterized by delayed wound healing due to persistent inflammation and excessive production of reactive oxygen species. Vitamin D, which is well acknowledged to enhance intestinal calcium absorption and increase in plasma calcium level, has recently been shown to display beneficial effects in various vascular diseases by promoting angiogenesis and inhibiting inflammatory responses. However, the role of Vitamin D in diabetic wound healing is still unclear. In the present study, we investigated the role of Vitamin D in cutaneous wound healing in streptozotocin (STZ)-induced diabetic mice. Four weeks after injection of STZ, a full thickness excisional wound was created with a 6-mm diameter sterile biopsy punch on the dorsum of the mice. Vitamin D was given consecutively for 14 days by intraperitoneal injection. Vitamin D supplementation significantly accelerated wound healing in diabetic mice and improved the healing quality as assessed by measuring the wound closure rate and histomorphometric analyses. By monitoring the level of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin (IL) 6 (IL-6), IL-1ß) in the wounds, reduced inflammatory response was found in VD treatment group. Furthermore, nuclear factor κB (NF-κB) pathway was found to be involved in the process of diabetic wound healing by assessing the relative proteins in diabetic wounds. Vitamin D supplementation obviously suppressed NF-κB pathway activation. These results demonstrated that Vitamin D improves impaired wound healing in STZ-induced diabetic mice through suppressing NF-κB-mediated inflammatory gene expression.

Tripterine treatment improves endothelial progenitor cell function via integrin-linked kinase.

BACKGROUND/AIMS: Atherosclerosis is associated with dysfunction of endothelial progenitor cells (EPCs). Tripterine, a chemical compound derived from the Chinese medicinal plant Tripterygium wilfordii Hook, displays anti-inflammatory properties in several animal models. We hypothesized that tripterine can improve EPC function and thus the efficiency of EPC transplantation. METHODS AND RESULTS: Tripterine preconditioning (2.5 µM, 4 h) improved EPC proliferation, tube formation, migration, and adhesion, and reduced apoptosis in cells cultured in ox-LDL (200 µg/ml). Tripterine restored integrin-linked kinase (ILK) levels downregulated by ox-LDL in EPCs, suggesting the involvement of the ILK/Akt pathway. Small interfering RNA-mediated depletion of ILK and dominant-negative ILK transduction inhibited the phosphorylation of the ILK downstream signaling targets protein kinase B/Akt and glycogen synthase kinase 3-beta (GSK-3ß), and reduced ß-catenin and cyclin D1 expression. In atherosclerotic mice injected with green fluorescent protein-labeled EPCs to evaluate EPC function, tripterine decreased aortic lesions and plaque deposition, and injection of tripterine-treated EPCs restored ILK levels. CONCLUSION: The present results suggest that tripterine improves vascular function in atherosclerosis by enhancing EPC function through a mechanism involving the ILK signaling pathway.

Green tea epigallocatechin-3-gallate (EGCG) promotes neural progenitor cell proliferation and sonic hedgehog pathway activation during adult hippocampal neurogenesis.

SCOPE: Adult hippocampal neurogenesis is a lifelong feature of brain plasticity that appears to be critically involved in adult brain function and neurological disease. Recent studies suggest that (-)-epigallocatechin-3-gallate (EGCG), which is the main polyphenolic constituent of green tea, may be used for the prevention and treatment of various neurodegenerative diseases. We hypothesized that EGCG promotes adult neurogenesis, which may be beneficial to hippocampus-dependent learning and memory. METHODS AND RESULTS: We show that EGCG treatment significantly increased the number of 5-bromo-2'-deoxyuridine (BrdU)-labeled cells in adult hippocampal neural progenitor cell (NPC) cultures and in the dentate gyrus of adult mice. Meanwhile, EGCG markedly improved spatial cognition in mice. These events are associated with the sonic hedgehog (Shh) signaling pathway. We observed that EGCG triggered a robust upregulation of Shh receptor (Patched) mRNA and protein expression in cultured NPCs as well as an upregulation of the downstream Shh transcriptional target Gli1. These changes were further confirmed in the hippocampus of mice administered EGCG. The blockage of the Shh signal with the pharmacological inhibitor cyclopamine attenuated EGCG-induced hippocampal neurogenesis. CONCLUSION: Our results provide strong evidence that EGCG enhances adult hippocampal neurogenesis.

Combination therapy with transarterial chemoembolization and interferon-alpha compared with transarterial chemoembolization alone for hepatitis B virus related unresectable hepatocellular carcinoma.

BACKGROUND AND AIMS: The present study was carried out to test the hypothesis that interferon-alpha (IFN-alpha) treatment would reduce or postpone the recurrence rate and improve the overall survival rate in patients after transarterial chemoembolization (TACE) treatment of hepatitis B virus (HBV) related unresectable hepatocellular carcinoma (HCC). METHODS: 216 patients with unresectable HBV-related HCC were randomized into a TACE group and a TACE-IFN group, each group had 108 patients. In the TACE-IFN group, patients received IFN-alpha1b at a dose of 3 million units (mu) three times a week by intramuscular injection one week after/before TACE treatment, for 48 weeks. RESULTS: The median disease-free survival in the TACE-IFN treatment group was 23.6 months (95% CI: 21.4-25.8) and 20.3 months (95% CI: 15.8-24.8) in the TACE group (P = 0.027). The disease free rate at 24 months in the TACE group was lower than in the TACE-IFN group (39.8% vs 59.3%, P = 0.004). The median overall survival was 29 months (95% CI: 27.5-32.1) in the TACE-IFN group and 26 months (95% CI: 20.1-31.9) in the TACE group (P = 0.003). The 2-year overall survival in the TACE-IFN group was higher than in the TACE group (72.2% vs 52.8%, P = 0.003). CONCLUSIONS: IFN-alpha treatment reduced recurrence and improved the survival of patients after TACE treatment of HBV-related HCC, with acceptable toxicities.