Transition Metal Oxide-Decorated MXenes as Drugless Nanoarchitectonics for Enriched Nanocatalytic Chemodynamic Treatment.

Despite their unique characteristics, 2D MXenes with sole photothermal conversion ability are required to explore their superfluous abilities in biomedicine. The small-molecule-based chemotherapeutics suffer from various shortcomings of time-consuming and expensiveness concerning theoretical and performance (preclinical/clinical) checks. This study demonstrates the fabrication of Ti3C2 MXene nanosheets (TC-MX NSs) and subsequent decoration with transition metal oxides, that is, copper oxide (Cu2O/MX, CO-MX NCs) as drugless nanoarchitectonics for synergistic photothermal (PTT)-chemodynamic therapeutic (CDT) efficacies. Initially, the monolayer/few-layered TC-MX NSs are prepared using the chemical etching-assisted ultrasonic exfoliation method and then deposited with Cu2O nanoconstructs using the in situ reduction method. Further, the photothermal ablation under near-infrared (NIR)-II laser irradiation shows PTT effects of CO-MX NCs. The deposited Cu2O on TC-MX NSs facilitates the release of copper (Cu+) ions in the acidic microenvironment intracellularly for Fenton-like reaction-assisted CDT effects and enriched PTT effects synergistically. Mechanistically, these deadly free radicals intracellularly imbalance the glutathione (GSH) levels and result in mitochondrial dysfunction, inducing apoptosis of 4T1 cells. Finally, the in vivo investigations in BALB/c mice confirm the substantial ablation of breast carcinoma. Together, these findings demonstrate the potential synergistic PTT-CDT effects of the designed CO-MX NCs as drugless nanoarchitectonics against breast carcinoma.

Hybrid nanoarchitectonics of molybdenum dioxide (MoO2) and doxorubicin (DOX) for synergistic chemo-photothermal-based breast carcinoma therapy.

Cancer has emerged as one of the severe ailments due to the uncontrolled proliferation rate of cells, accounting for millions of deaths annually. Despite the availability of various treatment strategies, including surgical interventions, radiation, and chemotherapy, tremendous advancements in the past two decades of research have evidenced the generation of different nanotherapeutic designs toward providing synergistic therapy. In this study, we demonstrate the assembly of a versatile nanoplatform based on the hyaluronic acid (HA)-coated molybdenum dioxide (MoO2) assemblies to act against breast carcinoma. The hydrothermal approach-assisted MoO2 constructs are immobilized with doxorubicin (DOX) molecules on the surface. Further, these MoO2-DOX hybrids are encapsulated with the HA polymeric framework. Furthermore, the versatile nanocomposites of HA-coated MoO2-DOX hybrids are systematically characterized using various characterization techniques, and explored biocompatibility in the mouse fibroblasts (L929 cell line), as well as synergistic photothermal (808-nm laser irradiation for 10 min, 1 W/cm2) and chemotherapeutic properties against breast carcinoma (4T1 cells). Finally, the mechanistic views concerning the apoptosis rate are explored using the JC-1 assay to measure the intracellular mitochondrial membrane potential (MMP) levels. In conclusion, these findings indicated excellent photothermal and chemotherapeutic efficacies, exploring the enormous potential of MoO2 composites against breast cancer.

Overcoming Cancer Multi-drug Resistance (MDR): Reasons, mechanisms, nanotherapeutic solutions, and challenges.

Multi-drug resistance (MDR) in cancer cells, either intrinsic or acquired through various mechanisms, significantly hinders the therapeutic efficacy of drugs. Typically, the reduced therapeutic performance of various drugs is predominantly due to the inherent over expression of ATP-binding cassette (ABC) transporter proteins on the cell membrane, resulting in the deprived uptake of drugs, augmenting drug detoxification, and DNA repair. In addition to various physiological abnormalities and extensive blood flow, MDR cancer phenotypes exhibit improved apoptotic threshold and drug efflux efficiency. These severe consequences have substantially directed researchers in the fabrication of various advanced therapeutic strategies, such as co-delivery of drugs along with various generations of MDR inhibitors, augmented dosage regimens and frequency of administration, as well as combinatorial treatment options, among others. In this review, we emphasize different reasons and mechanisms responsible for MDR in cancer, including but not limited to the known drug efflux mechanisms mediated by permeability glycoprotein (P-gp) and other pumps, reduced drug uptake, altered DNA repair, and drug targets, among others. Further, an emphasis on specific cancers that share pathogenesis in executing MDR and effluxed drugs in common is provided. Then, the aspects related to various nanomaterials-based supramolecular programmable designs (organic- and inorganic-based materials), as well as physical approaches (light- and ultrasound-based therapies), are discussed, highlighting the unsolved issues and future advancements. Finally, we summarize the review with interesting perspectives and future trends, exploring further opportunities to overcome MDR.

Acteoside exerts immunomodulatory effects on dendritic cells via aryl hydrocarbon receptor activation and ameliorates Th2-mediated allergic asthma by inducing Foxp3+ regulatory T cells.

Dendritic cells (DCs) are professional antigen-presenting cells that play a key role in directing T-cell responses and are involved in the pathogenesis of allergic asthma. Acteoside, an active phenylethanoid glycoside, is widely distributed in many medicinal plants. Herein, we explored the immunomodulatory effects of acteoside on bone marrow-derived DCs in vitro, and further investigated the immunosuppressive ability of acteoside to manipulate T helper type 2 (Th2)-mediated allergic asthma in mice. Following lipopolysaccharide activation, 50 µM of acteoside significantly reduced the production of proinflammatory mediators, including interleukin (IL)-12 and tumor necrosis factor (TNF)-α, whereas it enhanced secretion of the anti-inflammatory cytokine, IL-10, by DCs. However, these effects of acteoside on DCs were reversed by pretreatment with CH223191, an aryl hydrocarbon receptor (AhR) antagonist. Additionally, coculture of acteoside-treated DCs with CD4+ T cells promoted the generation of forkhead box P3-positive (Foxp3+) regulatory T cells (Tregs) via AhR activation. Using a murine asthma model, our results demonstrated that oral administration of 50 mg/kg of acteoside decreased levels of Th2-type cytokines, such as IL-4, IL-5, and IL-13, whereas the level of IL-10 and the frequency of CD4+Foxp3+ Tregs were augmented. Moreover, acteoside treatment markedly inhibited the elevated serum level of ovalbumin-specific immunoglobulin E, attenuated the development of airway hyperresponsiveness, and reduced inflammatory cell counts in bronchoalveolar lavage fluid. Additionally, histological results reveled that acteoside ameliorated pulmonary inflammation in asthmatic mice. Taken together, these results indicated that acteoside exhibits immunomodulatory effects on DCs and plays an anti-inflammatory role in the treatment of allergic asthma.

[Case series analysis of Professor Wang Qi's prescriptions for oligoasthenospermia].

OBJECTIVE: To conduct a case series analysis on Professor Wang Qi's prescriptions for oligoasthenospermia and a preliminary discussion on the clinical application of the pathogenesis theory of "kidney deficiency with dampness, heat, stasis, toxin and parasites" so as to provide some reference for the diagnosis and treatment of oligoasthenospermia by traditional Chinese medicine (TCM). METHODS: We selected 13 representative cases of oligoasthenospermia treated by Professor Wang Qi, analyzed the basic conditions of the patients, changes of the disease and prescriptions used, and investigated the treatment of oligoasthenospermia in view of Professor Wang Qi's TCM theory on andrology. RESULTS: Excellent therapeutic effect was achieved in 7, indefinite effect in 5 and no effect in 1 of the 13 cases. Totally 38 prescriptions were employed in the treatment, of which Bajitian was used in 30, Tusizi in 27, Gouqizi in 25, Sangshen in 25, Shuizhi in 24 and Danggui in 22. The drugs used in the treatment of 10 or more patients included Bajitian in 12, Sangshen in 11, Shuizhi in 11, Tusizi in 10 and Gouqizi in 10 cases. CONCLUSIONS: Professor Wang Qi's prescriptions are effective for the treatment of oligoasthenospermia and the pathogenesis theory of "kidney deficiency with dampness, heat, stasis, toxin and parasites" is valuable in guiding the clinical diagnosis and treatment in traditional Chinese medicine.

[Academician Wang Qi's medication rules for oligoasthenozoospermia: An analysis based on the Traditional Chinese Medicine Inheritance Auxiliary Platform].

OBJECTIVE: To analyze the medication rules for oligoasthenozoospermia (OAZ) observed by Wang Qi, an academician, master of Traditional Chinese Medicine (TCM) and initiator of andrology in TCM. METHODS: We collected the outpatient cases of OAZ treated by Wang Qi and established a database of clinical medical records using the TCM Inheritance Auxiliary Platform. Employing the integrated rule-based system for analysis of the software, we modified the mutual information method, complex system entropy clustering analysis and other data mining methods, and summarized the medication rules Wang Qi followed in the treatment of OAZ. RESULTS: A total of 134 prescriptions made by Wang Qi for the treatment of OAZ were collected, involving 110 TCM drugs, which are mainly neutral and warm in nature and taste sweet and mostly act through the liver and kidney meridians. The core formula ingredients of the prescriptions included Morinda officinalis, Cuscuta chinensis, Lycium barbarum, Mulberry, Angelica sinensis, Astragalus mongholicus and Fish Maw, and most frequently Morinda officinalis, Cuscuta chinensis, Lycium barbarum and Mulberry. CONCLUSIONS: Wang Qi holds that kidney deficiency, dampness-heat, blood stasis and toxin are the main pathogenic factors for OAZ. The basic treatment of OAZ is to invigorate the kidney and replenish the essence, and meanwhile activate blood circulation, dissipate stasis and eliminate dampness-heat.

[Huatan Qushi Decoction improves lipid metabolism and semen quality in obese rats with oligoasthenozoospermia: Effects and mechanisms].

OBJECTIVE: To explore the regulatory effect of Huatan Qushi Decoction (HTQSD) on lipid metabolism and semen quality in obese rats with oligoasthenozoospermia (OA) and its underlying mechanisms. METHODS: Ninety-six 8-week-old male Wistar rats were randomly divided into six groups of equal number: blank control, OA model control, Wuzi Yanzong Pills (WZYZP), and high-, medium- and low-dose HTQSD, the blank controls fed with a normal diet and the others with a high-fat diet, all for 8 weeks. Meanwhile, the rats in the blank control and OA model control groups were treated intragastrically with normal saline, those in the WZYZP group with WZYZP at 1.07 g/kg, and those in the high-, medium- and low-dose HTQSD groups with HTQSD at 26.25, 13.125 and 6.5625 g/kg, respectively. The body weights of the animals were obtained at 1, 4 and 8 weeks of modeling and intervention, the levels of serum TG, TC, HDL-C and LDL-C, the liver and testis indexes and semen quality detected at 4 and 8 weeks, and the expression of HO-1 mRNA determined at 8 weeks. RESULTS: At 8 weeks of modeling and intervention, the rats in the model control group, compared with the blank controls, showed significant increases in the body weight (ï¼»523.1 ± 25.54ï¼½ vs ï¼»451.50 ± 27.53ï¼½ g, P < 0.01) and levels of serum TG (ï¼»8.58 ± 0.39ï¼½ vs ï¼»2.18 ± 0.28ï¼½ nmol/L, P < 0.001), TC (ï¼»4.41 ± 1.44ï¼½ vs ï¼»1.68 ± 0.18ï¼½ nmol/L, P < 0.01) and LDL-C (ï¼»2.06 ± 0.17ï¼½ vs ï¼»0.48 ± 0.57ï¼½ nmol/L,P<0.01), but decreases in the level of serum HDL-C (ï¼»27.92 ± 0.40ï¼½ vs ï¼»57.47 ± 1.52ï¼½ nmol/L,P < 0.01), sperm motility (ï¼»11.31 ± 4.87ï¼½% vs ï¼»39.66 ± 2.77ï¼½%, P < 0.01), sperm concentration (ï¼»31.07 ± 10.52ï¼½ vs ï¼»65.37 ± 6.30ï¼½ ×106/ml, P < 0.01) and the expression of HO-1 mRNA (0.16 ± 0.03 vs 1.06 ± 0.20, P < 0.01). The rats in the medium-dose HTQSD group, in comparison with the model controls, exhibited remarkable decreases in the body weight (ï¼»445.13 ± 34.19ï¼½ vs ï¼»523.1 ± 25.54ï¼½ g, P < 0.01) and levels of serum TG (ï¼»2.05 ± 0.27ï¼½ vs ï¼»8.58 ± 0.39ï¼½ nmol/L,P < 0.01), TC (ï¼»1.63 ± 0.21ï¼½ vs ï¼»4.41 ± 1.44ï¼½ nmol/L,P < 0.01) and LDL-C (0.45 ± 0.07) vs ï¼»2.06 ± 0.17ï¼½ nmol/L, P < 0.01), but increases in the level of serum HDL-C (ï¼»48.35 ± 3.63ï¼½ vs ï¼»27.92 ± 0.40ï¼½ nmol/L, P < 0.01), sperm motility (ï¼»32.84 ± 6.22ï¼½% vs ï¼»11.31 ± 4.877ï¼½%, P < 0.01) and sperm concentration (ï¼»46.90 ± 6.39ï¼½ vs ï¼»31.07 ± 10.52ï¼½ ×106/ml, P < 0.05), and the low-dose HTQSD group showed a significantly up-regulated expression of HO-1 mRNA (0.76 ± 0.13 vs 0.16±0.03, P < 0.01). CONCLUSIONS: HTQSD can regulate the blood lipid level and improve semen quality in obese rats with oligoasthenozoospermia by promoting serum anti-oxidation and reducing oxidative stress.

MicroRNA­210 negatively regulates the radiosensitivity of nasopharyngeal carcinoma cells.

Radiotherapy is one of the primary methods of treatment of malignant tumors, however, resistance to radiation is a major problem. The reasons for the radioresistance are still poorly understood. However, it is generally accepted that microRNAs (miRNAs or miRs) can regulate the radiosensitivity of tumors. The present study therefore aimed to identify specific miRNAs and their effects on radioresistant cells. More specifically, the aim was to investigate specific miRNAs and their effects on radioresistant tumor cells. The radioresistant tumor cells (CNE­2R) were established using a dose gradient method, and the miRNA expression profiles of CNE­2R cells and the parental cells (CNE­2) were determined. The expression of miR­210 in CNE­2R cells was significantly higher than in CNE­2 cells. CNE­2R cells were transfected with LV­hsa­miR­210­inhibitor, and CNE­2 cells were transfected with LV­hsa­miR­210. The expression of miR­210 was confirmed by reverse transcription quantitative­polymerase chain reaction. The percentages of CNE­2R­miR­210­inhibitor and CNE­2 cells in the G2/M phase were higher than in the CNE­2R and CNE­2­miR­210 cells, and the percentages of cells in S phase were lower than in the CNE­2R and CNE­2­miR­210 cells. Following 4 Gy of radiation, CNE­2R­miR­210­inhibitor and CNE­2 cells, which express low levels of miR­210, had a higher apoptosis rate than CNE­2R and CNE­2­miR­210 cells. Following 4, 8 and 12 Gy of radiation, cell viability and survival fraction of CNE­2R­miR­210­inhibitor cells were lower than those of CNE­2R and CNE­2­miR­210 cells, and similar to those of CNE­2 cells. Together, these findings strongly suggest that miR­210 negatively regulates the radiosensitivity of tumor cells, and may therefore have therapeutic potential for the treatment of radiation resistance.

Anti-ABCG2 scFv antibody of lung adenocarcinoma increases chemosensitivity and induces apoptosis through the activation of mitochondrial pathway.

ABCG2 is a multidrug resistance efflux pump expressed in many diverse tumors. The overexpression of ABCG2 is associated with resistance to a wide variety of anticancer agents, providing a noticeable setback to successful cancer therapy. Therapies targeting ABCG2 may therefore be a promising candidate for reversal of chemoresistance. The anti-ABCG2 single-chain variable fragment (scFv) antibody was constructed by phage display peptide library technology. Immunoblotting, ELISA and immunocytochemistry were used to evaluate the soluble expression and immunoreactivity of the scFv. The effects of scFv on cell function and chemosensitization were confirmed by colony formation, cell migration and CCK-8 assays. Flow cytometry was used to analyse the cell cycle and apoptosis. Radioimmunoimaging and nude mouse tumorigenicity assays were taken to determine the biodistribution and antitumor capacity of the scFv antibody. We have successfully screened out the candidate scFv antibody with an apparent molecular weight of 34 kDa. The scFv demonstrated favourable binding ability to lung adenocarcinoma cells and ABCG2 antigen, and the radioactivity was specifically aggregated at the tumor location. Furthermore, the internalized scFv resulted in antibody-mediated downregulation of ABCG2, proliferation inhibition, apoptosis and cisplatin (DDP) sensitivity. The anti-ABCG2 scFv antibody possesses good tumoraffin and antitumor activity and may therefore be an effective therapeutic agent for lung adenocarcinoma that is dependent on ABCG2 for drug resistance and survival.