Transient Mild Photothermia Improves Therapeutic Performance of Oral Nanomedicines with Enhanced Accumulation in the Colitis Mucosa.

The treatment outcomes of oral medications against ulcerative colitis (UC) have long been restricted by low drug accumulation in the colitis mucosa and subsequent unsatisfactory therapeutic efficacy. Here, high-performance pluronic F127 (P127)-modified gold shell (AuS)-polymeric core nanotherapeutics loading with curcumin (CUR) is constructed. Under near-infrared irradiation, the resultant P127-AuS@CURs generate transient mild photothermia (TMP; ≈42 °C, 10 min), which facilitates their penetration through colonic mucus and favors multiple cellular processes, including cell internalization, lysosomal escape, and controlled CUR release. This strategy relieves intracellular oxidative stress, improves wound healing, and reduces immune responses by polarizing the proinflammatory M1-type macrophages to the anti-inflammatory M2-type. Upon oral administration of hydrogel-encapsulating P127-AuS@CURs plus intestinal intralumen TMP, their therapeutic effects against acute and chronic UC are demonstrated to be superior to those of a widely used clinical drug, dexamethasone. The treatment of P127-AuS@CURs (+ TMP) elevates the proportions of beneficial bacteria (e.g., Lactobacillus and Lachnospiraceae), whose metabolites can also mitigate colitis symptoms by regulating genes associated with antioxidation, anti-inflammation, and wound healing. Overall, the intestinal intralumen TMP offers a promising approach to enhance the therapeutic outcomes of noninvasive medicines against UC.

Dual-driven nanomotors enable tumor penetration and hypoxia alleviation for calcium overload-photo-immunotherapy against colorectal cancer.

The treatment efficacies of conventional medications against colorectal cancer (CRC) are restricted by a low penetrative, hypoxic, and immunosuppressive tumor microenvironment. To address these restrictions, we developed an innovative antitumor platform that employs calcium overload-phototherapy using mitochondrial N770-conjugated mesoporous silica nanoparticles loaded with CaO2 (CaO2-N770@MSNs). A loading level of 14.0 wt% for CaO2-N770@MSNs was measured, constituting an adequate therapeutic dosage. With the combination of oxygen generated from CaO2 and hyperthermia under near-infrared irradiation, CaO2-N770@MSNs penetrated through the dense mucus, accumulated in the colorectal tumor tissues, and inhibited tumor cell growth through endoplasmic reticulum stress and mitochondrial damage. The combination of calcium overload and phototherapy revealed high therapeutic efficacy against orthotopic colorectal tumors, alleviated the immunosuppressive microenvironment, elevated the abundance of beneficial microorganisms (e.g., Lactobacillaceae and Lachnospiraceae), and decreased harmful microorganisms (e.g., Bacteroidaceae and Muribaculaceae). Moreover, together with immune checkpoint blocker (αPD-L1), these nanoparticles showed an ability to eradicate both orthotopic and distant tumors, while potentiating systemic antitumor immunity. This treatment platform (CaO2-N770@MSNs plus αPD-L1) open a new horizon of synergistic treatment against hypoxic CRC with high killing power and safety.

[Effects of acupuncture on hemorrhagic transformation and motor function in stroke patients after intravenous thrombolysis with rt-PA: a prospective cohort study].

OBJECTIVE: To observe the effects of the Xingnao Kaiqiao (regaining consciousness and opening orifices) acupuncture on hemorrhagic transformation and limb motor function after intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) in stroke patients. METHODS: A total of 130 stroke patients after rt-PA thrombolytic were divided into an acupuncture group (58 cases, 1 case dropped off) and a non-acupuncture group (72 cases, 7 cases dropped off) according to whether they received acupuncture treatment. Propensity score matching (PSM) was used to match each group, with 38 patients in each group. The patients in the non-acupuncture group received rt-PA thrombolytic therapy and western medical basic treatment. In addition to the basic treatment, the patients in the acupuncture group received Xingnao Kaiqiao acupuncture at Shuigou (GV 26), bilateral Neiguan (PC 6), and ipsilateral Sanyinjiao (SP 6), Chize (LU 5), once a day for 14 days. The incidence of hemorrhagic transformation within 30 days after onset was compared between the two groups. The Fugl-Meyer assessment (FMA) score and activities of daily living (ADL) score were observed at baseline and 30 days, 6 months, 1 year after onset in the two groups. The disability rate at 6 months and 1 year after onset was recorded, and safety was evaluated in both groups. RESULTS: The incidence of hemorrhagic transformation in the acupuncture group was 5.3% (2/38), which was lower than 21.1% (8/38) in the non-acupuncture group (P<0.05). At 30 days, 6 month, and 1 year after onset, the FMA and ADL scores of both groups were higher than those at baseline (P<0.01), and the scores in the acupuncture group were higher than those in the non-acupuncture group (P<0.01). The disability rate in the acupuncture group at 1 year after onset was 10.5% (4/38), which was lower than 28.9% (11/38) in the non-acupuncture group (P<0.05). There was no significant difference in the incidence of adverse events between the two groups (P>0.05). CONCLUSION: The Xingnao Kaiqiao acupuncture method could reduce the incidence of hemorrhagic transformation in stroke patients after intravenous thrombolysis with rt-PA, improve their motor function and daily living ability, and reduce the long-term disability rate.

Tea leaf-derived exosome-like nanotherapeutics retard breast tumor growth by pro-apoptosis and microbiota modulation.

While several artificial nanodrugs have been approved for clinical treatment of breast tumor, their long-term applications are restricted by unsatisfactory therapeutic outcomes, side reactions and high costs. Conversely, edible plant-derived natural nanotherapeutics (NTs) are source-widespread and cost-effective, which have been shown remarkably effective in disease treatment. Herein, we extracted and purified exosome-like NTs from tea leaves (TLNTs), which had an average diameter of 166.9 nm and a negative-charged surface of - 28.8 mV. These TLNTs contained an adequate slew of functional components such as lipids, proteins and pharmacologically active molecules. In vitro studies indicated that TLNTs were effectively internalized by breast tumor cells (4T1 cells) and caused a 2.5-fold increase in the amount of intracellular reactive oxygen species (ROS) after incubation for 8 h. The high levels of ROS triggered mitochondrial damages and arrested cell cycles, resulting in the apoptosis of tumor cells. The mouse experiments revealed that TLNTs achieved good therapeutic effects against breast tumors regardless of intravenous injection and oral administration through direct pro-apoptosis and microbiota modulation. Strikingly, the intravenous injection of TLNTs, not oral administration, yielded obvious hepatorenal toxicity and immune activation. These findings collectively demonstrate that TLNTs can be developed as a promising oral therapeutic platform for the treatment of breast cancer.

Silver and copper-oxide nanoparticles prepared with GA3 induced defense in rice plants and caused mortalities to the brown planthopper, Nilaparvata lugens (Stål).

BACKGROUND: Nanoparticles have been employed as nanopesticides for pest control in agriculture. However, the harmful effects of their chemical synthesis on human and environmental health have resulted in increased use of green synthetic approaches, including the use of plant extracts. The brown planthopper, Nilaparvata lugens (Stål) (BPH), is a severe pest of rice plants (Oryza sativa L.), especially in Asia. It is usually controlled chemically but has developed resistance against many insecticides. RESULTS: In this study, we synthesized metallic silver (Ag-NPs) and copper-oxide (CuO-NPs) nanoparticles using the exogenous phytohormone, gibberellic acid (GA3), as a reducing agent. We then sprayed them separately on rice plants and BPH together and evaluated their effects on the plants and insects. SEM and TEM images showed that the synthesis was successful, indicated by the sizes (25-60 nm), uniform shape and spherical and cubical structures of Ag-NPs, as well as by the rugby sheet-like of CuO-NPs with lateral sizes of 150-340 nm and thickness of 30-70 nm. Independent applications of the nanoparticles and GA3 on rice plants induced different volatile profiles, of which the highest number emitted was under Ag-NPs, including the highest emission of linalool. Transcriptome analysis showed that Ag-NPs-treated rice plants showed different transcriptome profiles compared to the control, 24 h after treatment, including the upregulation of the linalool synthase gene, genes of plants transcription factors such as WRKY, bHLH and NAC and other genes involved in plant defense responses. In all treatments, the mortality rate of BPH increased with an increase in NPs concentrations over time but was prominent under Ag-NPs treatment. The LC50 values for Ag-NPs and CuO-NPs decreased with an increase in time. Also, the nanoparticles increased the activities of protective enzymes (POD, SOD and CAT), inhibited that of detoxification enzymes (A-CHE, ACP and AKP), and reduced total protein concentrations in the BPH. CONCLUSIONS: These results show that synthesizing nanoparticles using phytohormones may be a safer and environmentally friendly option, which also holds promise for controlling the BPH in rice production.

Tumor-Microenvironment-Activatable Nanoreactor Based on a Polyprodrug for Multimodal-Imaging-Medicated Enhanced Cancer Chemo/Phototherapy.

Anticancer nanomedicine-based multimodal imaging and synergistic therapy hold great promise in cancer diagnosis and therapy owing to their abilities to improve therapeutic efficiency and reduce unnecessary side effects, producing promising clinical prospects. Herein, we integrated chemotherapeutic drug camptothecin (CPT) and near-infrared-absorbing new indocyanine green (IR820) into a single system by charge interaction and obtained a tumor-microenvironment-activatable PCPTSS/IR820 nanoreactor to perform thermal/fluorescence/photoacoustic-imaging-guided chemotherapy and photothermal therapy simultaneously. Specifically, the generated PCPTSS/IR820 showed an excellent therapeutic agent loading content and size stability, and the trials in vitro and in vivo suggested that the smart PCPTSS/IR820 could deeply permeate into tumor tissues due to its suitable micellar size. Upon near-infrared laser irradiation, the nanoreactor further produced a terrific synergism of chemo-photo treatment for cancer therapy. Therefore, the PCPTSS/IR820 polyprodrug-based nanoreactor holds outstanding promise for multimodal imaging and combined dual therapy.

Application of ceramsite and activated alumina balls as recyclable bulking agents for sludge composting.

Composting is a major sludge-treatment method and bulking agents are very important in sludge composting. In this study, ceramsite and activated alumina balls were chosen as recyclable bulking agents for sludge composting. Variations in the temperature, pH, electrical conductivity, organic matter, dissolved organic carbon, moisture content, and heavy metals were detected during composting with different bulking-agent treatments as well as differences in the germination index values. The results showed that both bulking agents could ensure the maturity of the compost; further, ceramsite treatment resulted in the best water removal efficiency. According to the sequential extraction procedure, both ceramsite and activated alumina balls could stabilize Cd but they also increased the mobility of Zn. After comparing the effects of different particle sizes of ceramsite on composting, 20 mm was determined to be the most optimal value. Additionally, the recovery rates of ceramsite and activated alumina balls were 96.9% and 99.9%, respectively.

Methotrexate-based amphiphilic prodrug nanoaggregates for co-administration of multiple therapeutics and synergistic cancer therapy.

The goal of nanomedicine is to seek strategies that are more efficient to address various limitations and challenges faced by conventional medicines, including lack of target specificity, poor bioavailability, premature degradability, and undesired side effects. Self-assembling drug amphiphiles represent a prospective nanomedicine for cancer therapy owing to their favorable route of administration and therapeutic efficiency compared with pristine drug counterparts. In this work, we report a class of self-deliverable prodrug amphiphiles consisting of the hydrophilic drug methotrexate (MTX) and the hydrophobic anticancer drugs camptothecin (CPT) and doxorubicin (DOX) for targeted and combinational chemotherapy. The disulfide bond and hydrazone bond, which are subject to stimuli-triggered bond cleavage, were introduced to link these therapeutic agents and form two prodrug amphiphiles, named as MTX-CPT and MTX-DOX, respectively, which could self-assemble into stable prodrug nanoaggregates (NAs) in aqueous media. MTX molecules in the prodrug NAs facilitated NA uptake into tumor cells with high expression of folic acid receptors (FRs). This systemic study provided clear evidence of the synergistic therapeutic effect by co-administrating dual prodrug NAs on various tumor cells in vitro and a xenograft tumor model in vivo. The obtained prodrug amphiphiles provide an efficient strategy for the design of multifunctional drug delivery systems and elaborate therapeutic nanoplatforms for cancer chemotherapy. STATEMENT OF SIGNIFICANCE: This work presents two kinds of prodrug amphiphiles that are carrier free and integrate targeted drug delivery, stimuli-triggered drug release, synergistic therapy, and theranostic function into a single system. Reduction/acid active prodrug amphiphiles can self-assemble into micellar nanoaggregates (NAs) at a very low critical aggregation concentration. These NAs exhibit superior stability in physiological environment and disassemble in the presence of tumor cells expressing folic acid receptors or the high glutathione or in low pH tumoral endosomal environment. The induced disassembly of prodrug NAs can "switch on" the inherent fluorescence of the internalized camptothecin or doxorubicin for the detection of tumor cells. Compared to a single type of prodrug NA, co-administration of dual prodrug combination can produce an evident synergistic therapeutic effect against various tumor cells in vitro and inhibit xenograft tumor growth in vivo. The methotrexate-based prodrug amphiphiles may provide a potential strategy for developing multifunctional nanoplatforms and delivery of multiple therapeutics in chemotherapy.