Structurally diverse analgesic diterpenoids from the flowers of Rhododendron molle.

Thirteen diterpenoids (1-13), classified into four structurally diverse carbon skeletons, including 1,5-seco-kalmane (1 and 6), grayanane (2-11), kalmane (12), and rhodomollane (13), were isolated from the flowers extract of Rhododendron molle. Among them, rhodomollinols A - E (1-5) were five new diterpenoids and their structures were elucidated by extensive spectroscopic methods including HRESIMS, UV, IR, 1D and 2D NMR, as well as quantum ECD calculations. Rhodomollinol A (1) is the first representative of a 6-deoxy-1,5-seco-kalmane diterpenoid. The abnormal NMR phenomenon of the presence of only 9 carbon resonances instead of 20 carbons in the 13C NMR spectrum of 1 was observed and elucidated by the quantum NMR calculations. All diterpenoids 1-13 showed significant analgesic activities in an acetic acid-induced writhing model. It's the first time to report the analgesic activity of a rhodomollane-type diterpenoid. At a dose of 1.0 mg/kg, diterpenoids 1-3, 6, 8, 9, and 12 reduced the writhe numbers with inhibition rates over 50%, and 9 exhibited stronger analgesic activity with a writhe inhibition rate of 89.7% than that of the positive control morphine. Importantly, even at the lowest dose of 0.04 mg/kg, rhodomollinols A (1) and B (2), rhodomollein X (7), and 2-O-methylrhodojaponin VI (9) still showed more potent analgesic effects than morphine with the writhe inhibition rates of 51.8%, 48.0%, 61.7%, and 60.0%, respectively. A preliminary structure-activity relationship might provide some clues to design potential analgesics on the basis of structurally diverse Ericaceae diterpenoids.

Discovery of highly functionalized grayanane diterpenoids from the flowers of Rhododendron molle as potent analgesics.

A systematical investigation on the chemical constituents of the flowers of Rhododendron molle (Ericaceae) led to the isolation and characterization of thirty-eight highly functionalized grayanane diterpenoids (1-38), including twelve novel analogues molleblossomins A-L (1-12). Their structures were elucidated by comprehensive methods, including 1D and 2D NMR analysis, calculated ECD, 13C NMR calculations with DP4+ probability analysis, and single crystal X-ray diffraction. Molleblossomins A (1), B (2), and E (5) are the first representatives of 2ß,3ß:9ß,10ß-diepoxygrayanane, 2,3-epoxygrayan-9(11)-ene, and 5,9-epoxygrayan-1(10),2(3)-diene diterpenoids, respectively. Molleblossomins G (7) and H (8) represent the first examples of 1,3-dioxolane-grayanane conjugates furnished with the acetaldehyde and 4-hydroxylbenzylidene acetal moieties, respectively. All grayanane diterpenoids 1-38 were screened for their analgesic activities in the acetic acid-induced writhing model, and all of them exhibited significant analgesic activities. Diterpenoids 6, 13, 14, 17, 20, and 25 showed more potent analgesic effects than morphine at a lower dose of 0.2 mg/kg, with the inhibition rates of 51.4%, 68.2%, 94.1%, 66.9%, 97.7%, and 60.0%, respectively. More importantly, even at the lowest dose of 0.04 mg/kg, rhodomollein X (14), rhodojaponin VI (20), and rhodojaponin VII (22) still significantly reduced the number of writhes in the acetic acid-induced pain model with the percentages of 61.7%, 85.8%, and 64.6%, respectively. The structure-activity relationship was summarized and might provide some hints to design novel analgesics based on the functionalized grayanane diterpenoids.

Tea polyphenol carrier-enhanced dexamethasone nanomedicines for inflammation-targeted treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by synovial inflammation, cartilage damage and bone erosion. In the progression of RA, the inflammatory mediators including ROS, NO, TNF-α, and IL-6 play important roles in the aggravation of inflammation. Hence, reducing the generation and release of inflammatory mediators is of great importance. However, the high dose and frequent administration of clinical anti-inflammatory drugs such as glucocorticoids (GCs) usually lead to severe side effects. The development of nanotechnology provides a promising strategy to overcome these issues. Here, polyphenol-based nanoparticles with inherent anti-oxidative and anti-inflammatory activities were developed and used as a kind of nanocarrier to deliver dexamethasone (Dex). The in vitro experiments confirmed that the nanoparticles and drugs could act synergistically for suppressing inflammatory mediators in the LPS/INF-γ-induced inflammatory cell model. After intravenous administration, the Dex-loaded nanoparticles with good biosafety showed effective accumulation in inflamed joints and improved therapeutic efficacy by inducing anesis of synovial inflammation and cartilage destruction over free Dex in a collagen-induced arthritis (CIA) mouse model. The results demonstrated that polyphenol-based nanoparticles with therapeutic functions may serve as an innovative platform to synergize with chemotherapeutic agents for enhanced treatment of inflammatory diseases.

Tunable Stress Relaxing Biomimetic Matrices: Hyaluronan/Hydroxyapatite Hybridization Mediates Assembly of Collagen Fibrils.

The alluring correlations of cellular behaviors with viscoelastic extracellular matrices have driven increasing endeavors directed toward the understanding of mechanical cues on cell growth and differentiation via preparing biomimetic scaffolds/gels with viscoelastic controllability. Indeed, systematic investigations, especially into calcium phosphate-containing biomimetics, are relatively rare. Here, oxidized hyaluronic acid/hydroxyapatite hybrids (OHAHs) were synthesized by hyaluronan-mediated biomimetic mineralization with confined ion diffusion and subsequent oxidization treatment. The collagen self-assembly was applied to fabricate tunable stress relaxing fibrillar matrices in the presence of OHAHs in which the incorporated hyaluronic acid with aldehyde groups acted to improve the component compatibility as well as to supplement the molecular interactions with the occurrence of a Schiff-base reaction. With the addition of varying OHAH contents, the self-assembly behavior of collagen was altered, and the obtained collagen-hybrid (CH) matrices presented a heterogeneous fibrillar structure interspersed with OHAHs, characterized by large fibrillar bundles coexisting with small fibrils. The OHAHs improved the hydrogel stability of pure collagen, and according to rheological and nanoindentation measurements, CH matrices also exhibited tunable stress relaxation rates, following an OHAH concentration-dependent fashion. The proliferation and spreading of MC3T3-E1 cells cultured onto such CH matrices were further found to increase with the stress relaxing rate of the matrices. The present study showed that the introduction of hydroxyapatite incorporated with active hyaluronic acid during collagen reconstitution was a simple and effective strategy to realize the preparation of tunable stress relaxing biomimetic matrices potentially used for further appraising the regulation of mechanical cues on cell behaviors.

The Effect of Warm Acupuncture on EOS, IgE, Inflammatory Factors, and T Lymphocyte Subsets in Patients with Allergic Rhinitis of Lung Qi Deficiency and Cold-Type.

Objective: The purpose of this study was to investigate the effects of warming needle therapy on eosinophils, specific immunoglobulin E (IgE), inflammatory factors, and T lymphocyte subsets in patients with lung qi deficiency and cold-type allergic rhinitis (AR). Methods: A total of 155 patients with lung qi deficiency and cold-type AR from May 2021 to December 2022 were randomly divided into a study group of 76 cases and a control group of 79 cases. The control group received medication (chlorpheniramine and fluticasone), and the study group received medication combined with warming needle therapy. The efficacy, TCM syndrome score, eosinophils, IgE, inflammatory factors (interleukin-6 (IL-6), IL-8, and tumor necrosis factor-alpha (TNF-α)), T lymphocyte subsets (CD3+, CD4+, and CD8+), and rhinoconjunctivitis quality of life questionnaire (RQLQ) scores were evaluated after 2 weeks of treatment. Results: The total effective rate in the study group was 92.11%, which was higher than that in the control group (77.22%) (P < .05). The TCM syndrome scores of the study group were lower than those of the control group after 1 and 2 weeks of treatment (P < .05). The positive rate of eosinophils in the study group was lower than that in the control group after 1 week (47.37% vs. 64.56%, P < .05) and after 2 weeks (21.05% vs. 37.97%, P < .05) of treatment. The serum levels of specific IgE, IL-6, IL-8, and TNF-α in the study group were lower than those in the control group after 1 and 2 weeks of treatment (P < .05). The peripheral blood levels of CD3+ and CD4+ were higher and the peripheral blood level of CD8+ was lower in the study group than in the control group after 1 and 2 weeks of treatment (P < .05). The RQLQ scores of the study group were lower than those of the control group after 1 and 2 weeks of treatment (P < .05). Conclusion: Warming needle therapy can effectively improve the clinical symptoms of patients with lung qi deficiency and cold-type AR, reduce inflammation, and enhance immune function.

Massage therapy can effectively relieve cancer pain: A meta-analysis.

BACKGROUND: To critically evaluate the effects of massage therapy on cancer pain. METHODS: Nine Chinese and English databases (PubMed, Cochrane Library, Embase, SCOPUS, Web of Science core, China Biomedical Literature Database, China National Knowledge Infrastructure, Wanfang, and VIP) were systematically searched from the inception of databases to November 2022 for randomized controlled trials. According to Cochrane Collaboration, 2 reviewers independently assessed the risk of bias and extracted data from the included studies. All analyses were performed with Review Manager 5.4. RESULTS: Thirteen randomized controlled trials were included in the meta-analysis, containing 1000 patients (498 in the massage therapy group and 502 in the control group). Massage therapy could significantly relieve cancer pain in patients (standardized mean difference = -1.16, 95% confidence interval [-1.39, -0.93], P < .00001), especially those in the perioperative period and those with hematological malignancies. Foot reflexology and hand acupressure had a moderate effect on cancer pain relief, with hand acupressure being more effective. Massage duration of 10 to 30 minutes and a program length of ≥1 week had a better effect and could significantly relieve pain. The occurrence of adverse events was reported in 4 of the 13 studies, all of which were no adverse events. CONCLUSIONS: Massage therapy can be used as a complementary alternative therapy to relieve cancer pain in patients with hematological malignancies, breast cancer, and cancers of the digestive system. It is suggested that chemotherapy patients use foot reflexology, and perioperative period patients use hand acupressure. A massage duration of 10 to 30 minutes and a program length of ≥1 week is recommended to achieve better effects.

Adsorption of Different Ionic Types of Polyacrylamide on Montmorillonite Surface: Insight from QCM-D and Molecular Dynamic Simulation.

This study investigates the interaction between montmorillonite and polyacrylamide (PAM) with different ionic types using quartz crystal microbalance with dissipation monitoring (QCM-D) and molecular dynamics (MD) simulations. The goal was to understand the effect of ionicity and ionic type on polymer deposition on montmorillonite surfaces. The results of the QCM-D analysis showed that a decrease in pH led to an increase in the adsorption of montmorillonite on the alumina surface. The ranking of adsorption mass on alumina and pre-adsorbed montmorillonite alumina surfaces was found to be cationic polyacrylamide (CPAM) > polyacrylamide (NPAM) > anionic polyacrylamide (APAM). The study also found that CPAM had the strongest bridging effect on montmorillonite nanoparticles, followed by NPAM, while APAM had a negligible bridging effect. The MD simulations showed that ionicity had a significant influence on the adsorption of polyacrylamides. The cationic functional group N(CH3)3+ had the strongest attraction interaction with the montmorillonite surface, followed by the hydrogen bonding interaction of the amide functional group CONH2, and the anionic functional group COO- had a repulsive interaction. The results suggest that at high ionicity levels, CPAM can be adsorbed on the montmorillonite surface, while at low ionicity levels, APAM may still be adsorbed with a strong coordination trend.

Long-term intensive management reduced the soil quality of a Carya dabieshanensis forest.

The evaluation of soil quality can provide new insights into the sustainable management of forests. This study investigated the effects of three types of forest management intensities (non-management (CK), extensive management (EM), and intensive management (IM)), and five management durations (0, 3, 8, 15, and 20 years) on the soil quality of a Carya dabieshanensis forest. Further, minimum data sets (MDS) and optimized minimum data sets (OMDS) were established to evaluate the soil quality index (SQI). A total of 20 soil indicators representing its physical, chemical, and biological properties were measured for the 0-30 cm layer. Using one-way ANOVA and principal component analysis (PCA), the total data set (TDS), the minimum data set (MDS), and optimized minimum data set (OMDS) were established. The MDS and OMDS contained three (alkali hydrolyzed nitrogen (AN), soil microbial biomass nitrogen (SMBN), and pH) and four (total phosphorus (TP), soil organic carbon (SOC), AN, and bulk density (BD)) soil indicators, respectively. The SQI derived from the OMDS and TDS exhibited a stronger correlation (r = 0.94, p < 0.01), which was suitable for evaluating the soil quality of the C. dabieshanensis forest. The evaluation results revealed that the soil quality was highest during the early stage of intensive management (IM-3), and the SQI of each soil layer was 0.81 ± 0.13, 0.47 ± 0.11, and 0.38 ± 0.07, respectively. With extended management times, the degree of soil acidification increased, and the nutrient content decreased. Compared with the untreated forest land the soil pH, SOC, and TP decreased by 2.64-6.24%, 29.43-33.04%, and 43.63-47.27%, respectively, following 20 years of management, while the SQI of each soil layer decreased to 0.35 ± 0.09, 0.16 ± 0.02 and 0.12 ± 0.06, respectively. In contrast to extensive management, the soil quality deteriorated more rapidly under longer management and intensive supervision. The OMDS established in this study provides a reference for the assessment of soil quality in C. dabieshanensis forests. In addition, it is suggested that the managers of C. dabieshanensis forests should implement measures such as increasing the amount of P-rich organic fertilizer and restoring vegetation to increase soil nutrient resources for the gradual restoration of soil quality.

Long-term phosphorus addition alleviates CO2 and N2O emissions via altering soil microbial functions in secondary rather primary tropical forests.

Tropical forests, where the soils are nitrogen (N) rich but phosphorus (P) poor, have a disproportionate influence on global carbon (C) and N cycling. While N deposition substantially alters soil C and N retention in tropical forests, whether P input can alleviate these N-induced effects by regulating soil microbial functions remains unclear. We investigated soil microbial taxonomy and functional traits in response to 10-year independent and interactive effects of N and P additions in a primary and a secondary tropical forest in Hainan Island. In the primary forest, N addition boosted oligotrophic bacteria and phosphatase and enriched genes responsible for C-, P-mineralization, nitrification and denitrification, suggesting aggravated P limitation while N excess. This might stimulate P excavation via organic matter mineralization, and enhance N losses, thereby increasing soil CO2 and N2O emissions by 86% and 110%, respectively. Phosphorus and NP additions elevated C-mining enzymes activity mainly due to intensified C limitation, causing 82% increase in CO2 emission. In secondary forest, P and NP additions reduced phosphatase activity, enriched fungal copiotrophs and increased microbial biomass, suggesting removal of nutrient deficiencies and stimulation of fungal growth. Meanwhile, soil CO2 emission decreased by 25% and N2O emission declined by 52-82% due to alleviated P acquisition from organic matter decomposition and increased microbial C and N immobilization. Overall, N addition accelerates most microbial processes for C and N release in tropical forests. Long-term P addition increases C and N retention via reducing soil CO2 and N2O emissions in the secondary but not primary forest because of strong C limitation to microbial N immobilization. Further, the seasonal and annual variations in CO2 and N2O emissions should be considered in future studies to test the generalization of these findings and predict and model dynamics in greenhouse gas emissions and C and N cycling.

Long-term nitrogen and phosphorus fertilization reveals that phosphorus limitation shapes the microbial community composition and functions in tropical montane forest soil.

Microorganisms govern soil nutrient cycling. It is therefore critical to understand their responses to human-induced increases in N and P inputs. We investigated microbial community composition, biomass, functional gene abundance, and enzyme activities in response to 10-year N and P addition in a primary tropical montane forest, and we explored the drivers behind these effects. Fungi were more sensitive to nutrient addition than bacteria, and the fungal community shift was mainly driven by P availability. N addition aggravated P limitation, to which microbes responded by increasing the abundance of P cycling functional genes and phosphatase activity. In contrast, P addition alleviated P deficiency, and thus P cycling functional gene abundance and phosphatase activity decreased. The shift of microbial community composition, changes in functional genes involved in P cycling, and phosphatase activity were mainly driven by P addition, which also induced the alteration of soil stoichiometry (C/P and N/P). Eliminating P deficiency through fertilization accelerated C cycling by increasing the activity of C degradation enzymes. The abundances of C and P functional genes were positively correlated, indicating the intensive coupling of C and P cycling in P-limited forest soil. In summary, a long-term fertilization experiment demonstrated that soil microorganisms could adapt to induced environmental changes in soil nutrient stoichiometry, not only through shifts of microbial community composition and functional gene abundances, but also through the regulation of enzyme production. The response of the microbial community to N and P imbalance and effects of the microbial community on soil nutrient cycling should be incorporated into the ecosystem biogeochemical model.

Engineered fabrication of EGCG-UV absorber conjugated nano-assemblies for antioxidative sunscreens with broad-band absorption.

Applying sunscreen is a common, convenient, and effective measure to protect skin from ultraviolet (UV) damage, but most of UV absorbers in the present commercially available sunscreens are accompanied with the insufficiencies in terms of efficacy and biosafety. The use of nanotechnology to combine conventional UV absorbers with biocompatible natural products is a feasible strategy to combat these deficiencies. Herein, a simple, green and engineering preparation of broad-band sunscreens was demonstrated by the molecular assembly of a UV absorber aminobenzoic acid (ABA) and polyphenol extracted from green tea (EGCG). Spherical and negatively-charged EGCG/ABA nanoparticles (EA NPs) were simply synthesized with a wide range of particle size from 54.6 to 715.1 nm. These NPs had the satisfactory biocompatibility and antioxidative activity, and could protect fibroblasts from oxidative-stress damage. The formulations containing 10 wt% EA NPs further exhibited broad-spectrum UV absorption and lower UV transmittance than commercial sunscreens. It is believed that this study would spur the utilization of natural reproducible sources for developing biosafe sunscreens with strong anti-UV capability. Indeed, this simple nanotechnology aimed at tackling the biosafe risk of conventional UV absorbers provides a feasible solution strategy with green tea extracts.

[Warming-needle moxibustion with different lengths of moxa stick for asthenospermia with kidney deficiency and liver depression: a randomized controlled trial].

OBJECTIVE: To explore the clinical effect of warming-needle moxibustion with different lengths of moxa stick for asthenospermia with kidney deficiency and liver depression. METHODS: A total of 240 patients with asthenospermia of kidney deficiency and liver depression were randomly divided into a 4-cm group (moxibustion with 4-cm moxa stick, 60 cases, 3 cases dropped off), a 3-cm group (moxibustion with 3-cm moxa stick, 60 cases, 4 cases dropped off), a 2-cm group (moxibustion with 2-cm moxa stick, 60 cases, 2 cases dropped off) and an acupuncture group (60 cases, 3 cases dropped off). All patients were treated with warming-needle moxibustion with different lengths of moxa stick or conventicnal acupuncture at Zhongwan (CV 12), Guanyuan (CV 4), Zhongji (CV 3), Guilai (ST 29), Yaoyangguan (GV 3), Guanyuanshu (BL 26), etc., once a day, five times a week; 4-week treatment was taken as one course, a total of two courses of treatment were given. The semen routine indexes, seminal plasma biochemical indexes, sex hormone levels and TCM syndrome score were compared before and after treatment among the 4 groups. RESULTS: After treatment, the sperm density, sperm viability, ratio of grade A sperm, ratio of grade A and B sperm, seminal plasma fructose and neutral α-glucosidase were higher than those before treatment (P<0.05, P<0.01), and the sperm deformity rates were lower than those before treatment in the 4-cm group and the 3-cm group (P<0.01, P<0.05). The ratio of grade A sperm, ratio of grade A and B sperm, seminal plasma fructose and neutral α-glucosidase in the 4-cm group were higher than the other three groups (P<0.05, P<0.01), and the sperm deformity rate was lower than the other three groups (P<0.05). After treatment, except for dizziness and tinnitus score, each-domain score and total scores of TCM syndrome scale in the 4-cm group and the 3-cm group were lower than those before treatment (P<0.01, P<0.05). The each-domain score of depression, weak waist and knees, low sexual function and total score in the 4-cm group were lower than those in the other three groups (P<0.05, P<0.01). The total effective rate was 87.7% (50/57) in the 4-cm group, which was higher than 78.6% (44/56) in the 3-cm group, 77.6% (45/58) in the 2-cm group and 70.2% (40/57) in the acupuncture group (P<0.05, P<0.01). CONCLUSION: The warming-needle moxibustion with 4-cm moxa stick could effectively improve quality and motility of sperm and clinical symptoms in patients with asthenospermia of kidney deficiency and liver depression, which is superior to moxibustion with 3-cm, 2-cm moxa sticks and conventional acupuncture.

Negatively charged phospholipids accelerate the membrane fusion activity of the plant-specific insert domain of an aspartic protease.

Various plants use antimicrobial proteins/peptides to resist phytopathogens. In the potato, Solanum tuberosum, the plant-specific insert (PSI) domain of an aspartic protease performs this role by disrupting phytopathogen plasma membranes. However, the mechanism by which PSI selects target membranes has not been elucidated. Here, we studied PSI-induced membrane fusion, focusing on the effects of lipid composition on fusion efficiency. Membrane fusion by the PSI involves an intermediate state whereby adjacent liposomes share their bilayers. We found that increasing the concentration of negatively charged phosphatidylserine (PS) phospholipids substantially accelerated PSI-mediated membrane fusion. NMR data demonstrated that PS did not affect the binding between the PSI and liposomes but had seminal effects on the dynamics of PSI interaction with liposomes. In PS-free liposomes, the PSI underwent significant motion, which was suppressed on PS-contained liposomes. Molecular dynamics simulations showed that the PSI binds to PS-containing membranes with a dominant angle ranging from -31° to 30°, with respect to the bilayer, and is closer to the membrane surfaces. In contrast, PSI is mobile and exhibits multiple topological states on the surface of PS-free membranes. Taken together, our data suggested that PS lipids limit the motion of the anchored PSI, bringing it closer to the membrane surface and efficiently bridging different liposomes to accelerate fusion. As most phytopathogens have a higher content of negatively charged lipids as compared with host cells, these results indicate that the PSI selectively targets negatively charged lipids, which likely represents a way of distinguishing the pathogen from the host.

Arbuscular mycorrhizal colonization outcompetes root hairs in maize under low phosphorus availability.

BACKGROUND AND AIMS: An increase in root hair length and density and the development of arbuscular mycorrhiza symbiosis are two alternative strategies of most plants to increase the root-soil surface area under phosphorus (P) deficiency. Across many plant species, root hair length and mycorrhization density are inversely correlated. Root architecture, rooting density and physiology also differ between species. This study aims to understand the relationship among root hairs, arbuscular mycorrhizal fungi (AMF) colonization, plant growth, P acquisition and mycorrhizal-specific Pi transporter gene expression in maize. METHODS: Using nearly isogenic maize lines, the B73 wild type and the rth3 root hairless mutant, we quantified the effect of root hairs and AMF infection in a calcareous soil under P deficiency through a combined analysis of morphological, physiological and molecular factors. KEY RESULTS: Wild-type root hairs extended the rhizosphere for acid phosphatase activity by 0.5 mm compared with the rth3 hairless mutant, as measured by in situ zymography. Total root length of the wild type was longer than that of rth3 under P deficiency. Higher AMF colonization and mycorrhiza-induced phosphate transporter gene expression were identified in the mutant under P deficiency, but plant growth and P acquisition were similar between mutant and the wild type. The mycorrhizal dependency of maize was 33 % higher than the root hair dependency. CONCLUSIONS: The results identified larger mycorrhizal dependency than root hair dependency under P deficiency in maize. Root hairs and AMF inoculation are two alternative ways to increase Pi acquisition under P deficiency, but these two strategies compete with each other.

Preparation of Strong Antioxidative, Therapeutic Nanoparticles Based on Amino Acid-Induced Ultrafast Assembly of Tea Polyphenols.

Nanoformulations offer the opportunity to overcome the shortcomings of drug molecules, such as low solubility, side effects, insufficient stability, etc., but in most of the current nanomedicines, nanocarriers as excipients do not directly participate in the therapy procedure. Accordingly, it is promising to develop the nanotherapeutics composed entirely of pharmaceutically active molecules. Tea polyphenols, especially epigallocatechin gallate (EGCG), are a kind of natural antioxidants with various biological and health beneficial effects and are extensively investigated as nutrients and anticancer drugs. Here, the size-tunable and highly active polyphenol nanoparticles were conveniently synthesized in water and could be massively produced with a simple facility. Compared to the previous strategies, either molecular assembly via oxidative coupling or combination with other biomacromolecules, the present preparation was conducted by the amino acid-triggered Mannish condensation reactions, thus permitting the flexible molecular design of various polyphenol nanoparticles by selecting different amino acids. This straightforward and ultrafast method actually opens up a novel means to make use of naturally reproducible polyphenols. Moreover, inheriting the salient properties of EGCG, these nanoparticles show strong antioxidation capacity, 10-fold higher than the extensively investigated polydopamine nanoparticles, and they are biosafe but have therapeutic effects, according to the in vitro and in vivo assessments of anticancer activity, which is promising for various biomedical purposes.

Time-staggered delivery of erlotinib and doxorubicin by gold nanocages with two smart polymers for reprogrammable release and synergistic with photothermal therapy.

Photochemotherapy is currently an effective anticancer therapy. Recently, it has been reported that cancer cells pretreated with epidermal growth factor receptor (EGFR) inhibitor erlotinib (Erl) can significantly synergize its apoptosis against the DNA damaging agent doxorubicin (Dox). As a result, we designed two gold nanocages (Au NCs) microcontainers covered with different smart polymer shell-PAA (pH responsive) and p (NIPAM-co-AM) (temperature responsive) containing Erl and Dox respectively. The acidic tumor microenvironment and NIR light irradiation can selectively activate the release of Erl and Dox. Time staggered release of Erl and Dox and photothermal therapy enhance the apoptotic signaling pathways, resulting in improved tumor cell killing in both MCF-7 (low EGFR expression) and A431 (very high EGFR expression) tumor cells, but more efficient in the latter. The photochemotherapy strategy controls the order and duration of drug exposure precisely in spatial and temporal, and significantly improves the therapeutic efficacy against high EGFR expressed tumors.

Differential photothermal and photodynamic performance behaviors of gold nanorods, nanoshells and nanocages under identical energy conditions.

Various gold (Au) nanostructures have shown promising near infrared (NIR) light-activated phototherapeutic effects; however, their reported photothermal or photodynamic performance behavior is usually inconsistent or even conflicted, dramatically limiting the improvement of phototherapeutic Au nanostructures. The potential reason for this uncertainty is mainly because the photoactivities of Au nanostructures are not evaluated under identical energy conditions. Herein, three Au nanostructures, Au nanorods (NRs), nanoshells (NSs), and nanocages (NCs), were prepared to provide the same localized surface plasmon resonance (LSPR) peaks at 808 nm. All these Au nanostructures (at the same optical density) could fully exert their photoactivities under the identical and optimal energy conditions of 808 nm laser irradiation. It was found that these Au nanostructures could induce similar levels of temperature elevation but different levels of reactive oxygen species (ROS) production, where Au NCs exhibited the highest ROS production, followed by Au NSs and NRs. In vitro and in vivo phototherapeutic assessments further supported that Au NCs could cause the most severe cell death and tumor growth regression. This means that the identical incident energy has different contributions to the photothermal and photodynamic performance of Au nanostructures, and the corner angle structures of Au NCs compared with NSs and NCs could more efficiently convert the photon energy into photodynamic properties. Altogether, Au NCs hold great potential for phototherapy due to their efficient energy utilization capability.

Resonance Energy Transfer-Promoted Photothermal and Photodynamic Performance of Gold-Copper Sulfide Yolk-Shell Nanoparticles for Chemophototherapy of Cancer.

Gold (Au) core@void@copper sulfide (CuS) shell (Au-CuS) yolk-shell nanoparticles (YSNPs) were prepared in the present study for potential chemo-, photothermal, and photodynamic combination therapy, so-called "chemophototherapy". The resonance energy transfer (RET) process was utilized in Au-CuS YSNPs to achieve both enhanced photothermal and photodynamic performance compared with those of CuS hollow nanoparticles (HNPs). A series of Au nanomaterials as cores that had different localized surface plasmon resonance (LSPR) absorption peaks at 520, 700, 808, 860, and 980 nm were embedded in CuS HNPs to screen the most effective Au-CuS YSNPs according to the RET process. Thermoresponsive polymer was fabricated on these YSNPs' surface to allow for controlled drug release. Au808-CuS and Au980-CuS YSNPs were found capable of inducing the largest temperature elevation and producing the most significant hydroxyl radicals under 808 and 980 nm laser irradiation, respectively, which could accordingly cause the most severe 4T1 cell injury through oxidative stress mechanism. Moreover, doxorubicin-loaded (Dox-loaded) P(NIPAM-co-AM)-coated Au980-CuS (p-Au980-CuS@Dox) YSNPs could more efficiently kill cells than unloaded particles upon 980 nm laser irradiation. After intravenous administration to 4T1 tumor-bearing mice, p-Au980-CuS YSNPs could significantly accumulate in the tumor and effectively inhibit the tumor growth after 980 nm laser irradiation, and p-Au980-CuS@Dox YSNPs could further potentiate the inhibition efficiency and exhibit excellent in vivo biocompatibility. Taken together, this study sheds light on the rational design of Au-CuS YSNPs to offer a promising candidate for chemophototherapy.

Size-controlled, colloidally stable and functional nanoparticles based on the molecular assembly of green tea polyphenols and keratins for cancer therapy.

While intelligent nanoparticles with therapeutic effects provide a resolving strategy for low drug loading efficacy, poor metabolism and elimination of current nanoparticulate drug delivery systems, precise preparation of colloidally stable but stimuli-responsive nanocarriers with size tunability is still a challenging task. Here, we develop a facile and sustainable method through the use of naturally reproducible green tea polyphenols and hair keratins to prepare biocompatible, colloidally stable, stimuli-responsive nanoparticles with therapeutic effects. The present strategy simply involves covalent interactions of tea catechins and keratins, giving rise to the molecular assembly of size-controlled nanoparticles (30-230 nm) which are long-term colloidally stable at physiological media but are disassembled under pathological conditions, ideally for targeted delivery of anticancer drugs. The cell experiments confirmed that these nanoparticles are bio-safe, have the inherent bioactivity of tea catechins, and that the drug-loaded nanoparticles yield a higher cancer cell inhibition rate than free drugs. In addition, the nanoparticles are found to improve the bioavailability of tea polyphenols, according to animal studies, which further demonstrates that the use of nanoparticles as drug carriers results in enhanced anticancer efficacy with negligible systemic toxicity. Given that large-scale preparation of size-controlled nanoparticles could already be easily achieved, the present study actually provides an innovative nanotechnological approach to make good use of green tea polyphenols with beneficial health effects, potentially for therapeutic and preventive purposes.

Functional nanoparticles of tea polyphenols for doxorubicin delivery in cancer treatment.

Nanoparticulate pharmaceutical drug delivery systems (NDDSs) are widely used to enhance the effectiveness and to decrease the side effects of chemotherapeutic drugs. Owing to the complex multistep synthesis process, expensive or not safe constituents, clinical applications of NDDSs have severely been constrained. Green tea polyphenols (TPs) are well recognized for their beneficial health effects, including anticancer activity. Herein, we reported the sole use of tea polyphenols to fabricate TP nanoparticles for chemo-drug delivery in cancer treatment. The TP nanoparticles (TP-NPs) with diameters of 100-130 nm, exhibited a high doxorubicin hydrochloride (DOX·HCl) loading capability. The DOX loaded TP-NPs (DOX@TP-NPs) were glutathione (GSH)- and pH-responsive for the release of DOX. In vitro cell experiments showed higher cancer cell inhibition rates of DOX@TP-NPs compared to the free drug on both HT-29 cells and HeLa cells, possibly due to induced accumulation of reactive oxygen species and decreasing mitochondrial membrane potential. Animal studies further confirmed that efficient accumulation and retention of DOX in the tumor site were achieved with the DOX@TP-NP formulation, resulting in enhanced anticancer efficacy with negligible systemic toxicity. The simply-prepared TP nanoparticles as functional nanocarriers for therapeutic agents are promising in cancer treatment.