Polydopamine nanoparticles coated with a metal-polyphenol network for enhanced photothermal/chemodynamic cancer combination therapy.

Polydopamine nanoparticles (PDA NPs) are commonly used for photothermal therapy (PTT) of cancer because of their good biocompatibility and photothermal conversion capability. However, it is difficult to achieve a good tumor inhibition effect with a single PTT of PDA. Therefore, in this work, we prepared a combined anticancer nanosystem for enhanced chemodynamic therapy (CDT)/PTT by coating PDAs with an (-)-epigallocatechin gallate (EGCG)/iron (Fe) metal-polyphenol network (MPN). The MPN shell of this nanosystem named EGCG@PDA is degraded by the weakly acidic environment intracellular, releasing EGCG and Fe3+. EGCG inhibits the expression of heat shock proteins (HSPs) in cancer cells, thus eliminating their thermal protection against cancer cells for enhanced PTT. Meanwhile, the reductive EGCG can also reduce Fe3+ to Fe2+, to catalyze the decomposition of overexpressed hydrogen peroxide (H2O2) in cancer cells to generate strong oxidative hydroxyl radicals (OH), i.e., catalyzing the Fenton reaction, for CDT. After the Fenton reaction, the re-oxidized Fe ions can be reduced again by EGCG and reused to catalyze the Fenton reaction, which can achieve enhanced CDT. Both in vitro and in vivo studies have shown that EGCG@PDA has low dark toxicity and good anticancer effects. It is expected to be used for precision cancer therapy.

Small-size Ti3C2Tx MXene nanosheets coated with metal-polyphenol nanodots for enhanced cancer photothermal therapy and anti-inflammation.

As a controllable, simple method with few side effects, near-infrared (NIR) light-based photothermal therapy (PTT) has been proven an effective cancer therapeutic approach. However, PTT-induced inflammation is a potential negative factor. And the overexpressed heat shock proteins (HSPs) by cancer cells can protect them from hyperthermia during PTT. In this work, small-size Ti3C2Tx MXene nanosheets with high photothermal conversion efficiency in the region of NIR, high cargo loading capability and good free radical scavenging capability were chosen for cancer PTT and anti-inflammation. And (-)-epigallocatechin gallate (EGCG) was applied to form EGCG/Fe metal-polyphenol nanodots on the nanosheets. EGCG being released in acid cancer cells could reduce the expression of HSPs and could be used for anti-inflammation. As a result, the complex nanosheets named MXene@EGCG could achieve enhanced cancer PTT and be anti-inflammatory. Both in vitro and in vivo studies proved the good photothermal ability of MXene@EGCG and demonstrated that it could inhibit the expression of HSPs in tumor cells and relieve PTT-induced inflammation. Therefore, the nanosheets show good results in tumor ablation with a low level of inflammation, which provides another possibility for cancer therapy. STATEMENT OF SIGNIFICANCE: Photothermal therapy (PTT)-induced inflammation plays an essential role in some important stages of tumor development and is unfavorable for cancer treatment. And hyperthermia leads to the overexpression of heat shock proteins (HSPs) in cancer cells, which limits the therapeutic effect of PTT. Therefore, we coated small-size Ti3C2Tx MXene nanosheets with (-)-epigallocatechin gallate (EGCG)/Fe metal-polyphenol nanodots and named them as MXene@EGCG. This system shows a good photothermal conversion efficiency at 808 nm. And it can release EGCG in cancer cells to inhibit the expression of HSPs, thus achieving an enhanced cancer PTT. Both MXene and EGCG can also diminish the PTT-trigged inflammation. Both in vitro and in vivo studies prove the good anti-cancer PTT effect and anti-inflammation capability of MXene@EGCG.

Network Pharmacology and Mechanism Studies of the Protective Effect of Ginseng against Alzheimer's Disease Based on Aß Pathogenesis.

Alzheimer's disease (AD) is a critical neurodegenerative disease that manifests as progressive intellectual decline and is pathologically characterized by a progressive loss of neurons in the brain. Despite extensive research on this topic, the pathogenesis of AD is not fully understood, while the beta-amyloid (Aß) hypothesis remains the dominant one and only a few symptomatic drugs are approved for the treatment of AD. Ginseng has been widely reported as an effective herbal medicine for the treatment of neurodegenerative diseases such as dementia. Therefore, we explore the protective effects of ginseng in AD by a network pharmacological approach based on the pathogenesis of Aß. Twenty-one major ginsenosides are screened based on ultraperformance liquid chromatography-mass spectrometry/mass spectrometry (HPLC-MS/MS) data. Among them, MAPK8, MAPK9, BACE1, FLT1, CDK2, and CCR5 are the core targets. By molecular docking and validation with the in vitro cell model APPswe-SH-SY5Y, we find that ginsenosides Rg3 and Ro have good neuroprotective effects and can reduce the expression of Aß 1 - 42 in APPswe-SH-SY5Y. Finally, through RT-qPCR experiment, we find that ginsenoside Rg3 targeted MAPK8, FLT1, and CCR5, while ginsenoside Ro targeted MAPK8, MAPK9, FLT1, and CCR5 for its potential anti-AD efficacy.

Screening and verification of CYP3A4 inhibitors from Bushen-Yizhi formula to enhance the bioavailability of osthole in rat plasma.

ETHNOPHARMACOLOGICAL RELEVANCE: With the features of multiple-components and targets as well as multifunction, traditional Chinese medicine (TCM) has been widely used in the prevention and treatment of various diseases for a long time. During the application of TCM, the researches about bioavailability enhancement of the bioactive constituents in formula are flourishing. Bushen-Yizhi formula (BSYZ), a TCM prescription with osthole (OST) as one of the main bioactive ingredients, have been widely used to treat kidney deficiency, mental retardation and Alzheimer's disease. However, the underlying biological mechanism and compound-enzyme interaction mediated bioavailability enhancement of OST are still not clearly illuminated. AIM OF THE STUDY: The aim of this study is to explore the material basis and molecular mechanism from BSYZ in the bioavailability enhancement of OST. Screening the potential CYP3A4 inhibitors using theoretical prediction and then verifying them in vitro, and pharmacokinetics study of OST in rat plasma under co-administrated of screened CYP3A4 inhibitors and BSYZ were also scarcely reported. MATERIALS AND METHODS: Screening of CYP3A4 inhibitors from BSYZ was performed with molecular docking simulation from systems pharmacology database. The screened compounds were verified by using P450-Glo Screening Systems. A multiple reaction monitoring (MRM) mass spectrometry method was established for OST quantification. Male Sprague-Dawley rats divided into four groups and six rats in each group were employed in the pharmacokinetics study of OST. The administrated conditions were group I, OST (20 mg/kg); group II, BSYZ (containing OST 1 mg/mL, at the dose of 20 mg/kg OST in BSYZ); group III, co-administration of ketoconazole (Ket, 75 mg/kg) and OST (20 mg/kg); group IV, co-administration of CYP3A4 inhibitor (10 mg/kg) and OST (20 mg/kg). They were determined by using HPLC-MS/MS (MRM) and statistical analysis was performed using student's t-test with p < 0.05 as the level of significance. RESULTS: 21 potential CYP3A4 inhibitors were screened from BSYZ compounds library. From the results of verification in vitro, we found 4 compounds with better CYP3A4 inhibition efficiency including Oleic acid, 1,2,3,4,6-O-Pentagalloylglucose, Rutin, and Schisantherin B. Under further verification, Schisantherin B exhibited the best inhibitory effect on CYP3A4 (IC50 = 0.339 µM), and even better than the clinically used drug (Ket) at the concentration of 5 µM. In the study of pharmacokinetics, the area under the curve (AUC, ng/L*h) of OST after oral administration of BSYZ, Ket and Schisantherin B (2196.23 ± 581.33, 462.90 ± 92.30 and 1053.03 ± 263.62, respectively) were significantly higher than that of pure OST treatment (227.89 ± 107.90, p < 0.01). CONCLUSIONS: Schisantherin B, a profoundly effective CYP3A4 inhibitor screened from BSYZ antagonized the metabolism of CYP3A4 on OST via activity inhibition, therefore significantly enhanced the bioavailability of OST in rat plasma. The results of this study will be helpful to explain the rationality of the compatibility in TCM formula, and also to develop new TCM formula with more reasonable drug compatibility.

Insights into oral bioavailability enhancement of therapeutic herbal constituents by cytochrome P450 3A inhibition.

Herbal plants typically have complex compositions and diverse mechanisms. Among them, bioactive constituents with relatively high exposure in vivo are likely to exhibit therapeutic efficacy. On the other hand, their bioavailability may be influenced by the synergistic effects of different bioactive components. Cytochrome P450 3A (CYP3A) is one of the most abundant CYP enzymes, responsible for the metabolism of 50% of approved drugs. In recent years, many therapeutic herbal constituents have been identified as CYP3A substrates. It is more evident that CYP3A inhibition derived from the herbal formula plays a critical role in improving the oral bioavailability of therapeutic constituents. CYP3A inhibition may be the mechanism of the synergism of herbal formula. In this review, we explored the multiplicity of CYP3A, summarized herbal monomers with CYP3A inhibitory effects, and evaluated herb-mediated CYP3A inhibition, thereby providing new insights into the mechanisms of CYP3A inhibition-mediated oral herb bioavailability.

Cascaded Amplifier Nanoreactor for Efficient Photodynamic Therapy.

Photodynamic therapy (PDT) utilizes reactive oxygen species (ROS) to treat established diseases and has attracted growing attention in the field of cancer therapy. However, in a tumor microenvironment (TME), the inherent hypoxia and high level of antioxidants severely hamper the efficacy of ROS generation. Here, we describe a cascaded amplifier nanoreactor based on self-assembled nanofusiforms for persistent oxygenation to amplify ROS levels. The nanofusiform assembly is capable of photothermal and photodynamic treatment and regulation of redox oxidation stress by antioxidant depletion to prevent ROS tolerance. The Pt nanozyme decoration of the nanofusiform enables efficient oxygen supplements via Pt nanozyme-catalyzed decomposition of H2O2 overexpressed in TME and generation of O2. Furthermore, the temperature elevation resulted from the photothermal effect of the nanofusiform increases the catalase-like catalytic activity of the Pt nanozyme for boosted oxygen generation. Thus, such a triple cascade strategy using nanozyme-based nanofusiforms amplifies the ROS level by continuous oxygenation, enhancing the efficacy of PDT in vitro and in vivo. Meanwhile, an in vivo multi-modal imaging including near-infrared fluorescence imaging, photothermal imaging, and magnetic resonance imaging achieves precise tumor diagnosis. The rationally designed nanofusiform acts as an efficient ROS amplifier through multidimension strengthening of continuous oxygenation, providing a potential smart nanodrug for cancer therapy.

Treating Immunologically Cold Tumors by Precise Cancer Photoimmunotherapy with an Extendable Nanoplatform.

Although immunotherapy has merged as an ideal cancer therapeutic strategy for preventing tumor growth and recurrence, effective approaches to treat immunologically cold tumors are still lacking. Herein, we reported a practical and extendable nanoplatform (HA/ZIF-8@ICG@IMQ) that facilely integrated various therapeutics and functions for boosting host antitumor immunity to treat immunologically cold tumors. The tumor-targeted and microenvironment-responsive HA/ZIF-8@ICG@IMQ facilitated the tumor-specific accumulation and release of photothermal agents and immune adjuvants. With near-infrared irradiation, the designed nanoparticles effectively enhanced the infiltration of cytotoxic T lymphocytes and helper T cells and effectively blocked the growth of primary and distant tumors. Moreover, the smart therapeutic could effectively prevent tumor rechallenge and recurrence with a long-term host immunological memory response. This method shows an effective immunologically cold tumor treatment using extendable nanotherapeutics and may have reference significance for clinical cancer therapy.

Multifunctional siRNA-Laden Hybrid Nanoplatform for Noninvasive PA/IR Dual-Modal Imaging-Guided Enhanced Photogenetherapy.

Small interfering RNA (siRNA)-induced gene therapy has been recognized as a promising avenue for effective cancer treatment, while easy enzymatic degradation, poor transfection efficiency, nonspecific biodistribution, and uncontrolled release hinder its extensive clinical applications. Zeolitic imidazolate frameworks-8 (ZIF-8) have emerged as promising drug carriers without an in-depth exploration in programmable siRNA delivery. Herein, we report a multifunctional PDAs-ZIF-8 (PZ) nanoplatform for delivering siRNA with combined photothermal therapy (PTT) and gene therapy (GT) via the noninvasive guidance of photoacoustic (PA)/near-infrared (IR) dual-modal imaging. The ingenious PZ nanocarriers mediated the tumor-specific accumulation of therapeutic siRNA without undesired degradation and preleakage. The pH-responsive ZIF-8 decomposed in an acidic tumor microenvironment that was accompanied by the release of siRNA payloads for cleaving target mRNA in gene silencing therapy. Meanwhile, the polydopamine nanoparticles (PDAs) could simultaneously serve as a powerful noninvasive PA/IR imaging contrast agent and versatile photothermal agent for diagnosis-guided photogenetherapy. The systematic in vitro and in vivo experimental explorations demonstrated that our PDAs-siRNA-ZIF-8 (PSZ) could greatly enhance the therapeutic efficiency as compared with the corresponding PTT or GT monotherapy. This work holds great potential to advance the development of more intelligent diagnosis and therapeutic strategies, thus supplying promising smart nanomedicines in the near future.

Enhanced Immunostimulatory Activity of a Cytosine-Phosphate-Guanosine Immunomodulator by the Assembly of Polymer DNA Wires and Spheres.

Unmethylated cytosine-phosphate-guanosine (CpG) oligodeoxynucleotides are immunostimulatory nucleic acids wildly utilized as adjuvants or for vaccines to treat diseases. However, there is a lack of simple and efficient vectors for CpG oligodeoxynucleotide delivery with long-lasting immune stimulation. Herein, self-assembled polymer wires consisting of CpG motifs by hybridization chain reaction were constructed with excellent biocompatibility and immunostimulatory activity. The designed polymer DNA wires acted as programmable multivalent immunoadjuvants and triggered immune response, stimulated pro-inflammatory cytokine secretion, and induced the apoptosis of cancer cells. More strikingly, polymer nanospheres assembled from the polymer DNA wires and cationic poly-l-lysine further improved cellular uptake and continuously stimulate the lysosomal Toll-like receptor 9 of immune cells, thereby remarkably enhancing the activation of immune cells. These results demonstrated that self-assembled polymer DNA nanoassemblies with multivalent CpG could trigger strong immune response and further induce cancer cell death.

An intelligent ZIF-8-gated polydopamine nanoplatform for in vivo cooperatively enhanced combination phototherapy.

The extreme complexity and heterogeneity of fatal tumors requires the development of combination phototherapy considering the limited therapeutic efficiency of conventional monomodal photodynamic therapy (PDT) or photothermal therapy (PTT). However, tumor-specific drug administration and the accompanying hypoxia-restrained PDT present the main obstacles for executing an efficient combination phototherapy. Developing a highly biocompatible, tumor-specific, near infrared absorbing, and oxygen (O2)-evolving multifunctional nanoplatform is thus crucial for an effective PDT-based combination therapy. In this contribution, a multifunctional ZIF-8-gated polydopamine nanoparticle (PDA) carrier was synthesized for simultaneously delivering a photosensitizer and a catalase (CAT) into tumor cells, thus realizing a cooperatively enhanced combination photodynamic and photothermal therapy, as systematically demonstrated in vitro and in vivo. The ZIF-8 gatekeeper facilitates the simultaneous and effective delivery of these functional payloads, and the subsequent tumor acidic pH-stimulated drug release. This leads to a significant improvement of combination efficacy by ameliorating tumor hypoxic conditions since the CAT-mediated self-sufficient O2 generation could substantially promote an efficient PDT operation. In addition, this nanoplatform can effectively convert near infrared photoradiation into heat, resulting in thermally induced elimination of cancerous cells. As an intelligent multi-mode therapeutic nanosystem, this inorganic/organic hybrid nanosystem showed great potential for accurate cancer diagnosis and immediate therapy.

Stimuli-responsive multifunctional metal-organic framework nanoparticles for enhanced chemo-photothermal therapy.

Construction of stimuli-responsive multifunctional nanoparticles is critical for nanotherapeutic delivery. Though metal-organic frameworks (MOFs) have been emerged as promising delivery vehicles, the therapeutic efficacy of MOFs in cancer treatment is limited by the lack of a general approach for the preparation of stimuli-responsive multifunctional MOFs. We show that the combination of a versatile coating material polydopamine with MOFs enables facile integration of different functional therapeutics, obtaining stimuli-responsive multifunctional MOFs with extensive photothermal efficiency and outstanding capability to abrogate tumors by chemo-photothermal therapy. Exemplary MOFs including ZIF-8, UiO-66, and MIL-101 were utilized to prepare stimuli-responsive multifunctional MOFs to illustrate the generality of the strategy. This approach enables targeted drug delivery and stimuli-responsive release of multi-therapeutics and allows combination therapy with excellent in vitro and in vivo antitumor activity. Taking into account the diversity of MOFs and different functional molecules, this work provides flexible access to programmable MOF nanoparticles for specific biological applications.

Versatile Catalytic Deoxyribozyme Vehicles for Multimodal Imaging-Guided Efficient Gene Regulation and Photothermal Therapy.

Catalytic deoxyribozyme has great potential for gene regulation, but the poor efficiency of the cleavage of mRNA and the lack of versatile DNAzyme vehicles remain big challenges for potent gene therapy. By the rational designing of a diverse vehicle of polydopamine-Mn2+ nanoparticles (MnPDA), we demonstrate that MnPDA has integrated functions as an effective DNAzyme delivery vector, a self-generation source of DNAzyme cofactor for catalytic mRNA cleavage, and an inherent therapeutic photothermal agent as well as contrast agent for photoacoustic and magnetic resonance imaging. Specifically, the DNAzyme-MnPDA nanosystem protects catalytic deoxyribozyme from degradation and enhances cellular uptake efficiency. In the presence of intracellular glutathione, the nanoparticles are able to in situ generate free Mn2+ as a cofactor of DNAzyme to effectively trigger the catalytic cleavage of mRNA for gene silencing. In addition, the nanosystem shows high photothermal conversion efficiency and excellent stability against photothermal processing and degradation in complex environments. Unlike previous DNAzyme delivery vehicles, this vehicle exhibits diverse functionalities for potent gene regulation, allowing multimodal imaging-guided synergetic gene regulation and photothermal therapy both in vitro and in vivo.

Nitrate reductase-mediated NO production enhances Cd accumulation in Panax notoginseng roots by affecting root cell wall properties.

Panax notoginseng (Burk) F. H. Chen is a traditional medicinal herb in China. However, the high capacity of its roots to accumulate cadmium (Cd) poses a potential risk to human health. Although there is some evidence for the involvement of nitric oxide (NO) in mediating Cd toxicity, the origin of Cd-induced NO and its function in plant responses to Cd remain unknown. In this study, we examined NO synthesis and its role in Cd accumulation in P. notoginseng roots. Cd-induced NO production was significantly decreased by application of the nitrate reductase inhibitor tungstate but not the nitric oxide synthase inhibitor L-NAME (N(G)-methyl-l-arginine acetate), indicating that nitrate reductase is the major contributor to Cd-induced NO production in P. notoginseng roots. Under conditions of Cd stress, sodium nitroprusside (SNP, an NO donor) increased Cd accumulation in root cell walls but decreased Cd translocation to the shoot. In contrast, the NO scavenger cPTIO (2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide) and tungstate both significantly decreased NO-increased Cd retention in root cell walls. The amounts of hemicellulose 1 and pectin, together with pectin methylesterase activity, were increased with the addition of SNP but were decreased by cPTIO and tungstate. Furthermore, increases or decreases in hemicellulose 1 and pectin contents as well as pectin methylesterase activity fit well with the increased or decreased retention of Cd in the cell walls of P. notoginseng roots. The results suggest that nitrate reductase-mediated NO production enhances Cd retention in P. notoginseng roots by modulating the properties of the cell wall.

Role of the plasma membrane H(+)-ATPase in the regulation of organic acid exudation under aluminum toxicity and phosphorus deficiency.

Aluminum (Al) toxicity and phosphorus (P) deficiency are 2 major limiting factors for plant growth and crop production in acidic soils. Organic acids exuded from roots have been generally regarded as a major resistance mechanism to Al toxicity and P deficiency. The exudation of organic acids is mediated by membrane-localized OA transporters, such as ALMT (Al-activated malate transporter) and MATE (multidrug and toxic compound extrusion). Beside on up-regulation expression of organic acids transporter gene, transcriptional, translational and post-translational regulation of the plasma membrane H(+)-ATPase are also involved in organic acid release process under Al toxicity and P deficiency. This mini-review summarizes the current knowledge about this field of study on the role of the plasma membrane H(+)-ATPase in organic acid exudation under Al toxicity and P deficiency conditions.

Burdock fructooligosaccharide induces fungal resistance in postharvest Kyoho grapes by activating the salicylic acid-dependent pathway and inhibiting browning.

Burdock fructooligosaccharide (BFO) is a natural elicitor from Arcitum lappa. The effects of BFO in controlling postharvest disease in grape, apple, banana, kiwi, citrus, strawberry, and pear were investigated. The disease index, decay percentage, and area under the disease progress curve indicated that BFO has general control effects on postharvest disease of fruits. Kyoho grapes were studied to elucidate the mechanism of BFO in boosting the resistance of grapes to Botrytis cinerea infection. BFO treatment induced upregulation of the npr1, pr1, pal, and sts genes, and inhibited the total phenol content decrease, which activated chitinase and ß-1,3-glucanase. These results indicated that the salicylic acid-dependent signalling pathway was induced. The delayed colour change and peroxidase and polyphenoloxidase activity suggested that BFO delayed grape browning. The reduced respiration rate, weight loss, and titratable acidity prolonged the shelf life of postharvest grapes. BFO is a promising elicitor in postharvest disease control.