Magnetic two-dimensional nanocomposites for multimodal antitumor therapy: a recent review.

Magnetic two-dimensional nanocomposites (M2D NCs) that synergistically combine magnetic nanomedicine and 2D nanomaterials have emerged in multimodal antitumor therapy, attracting great interest in materials science and biomedical engineering. This review provides a summary of the recent advances of M2D NCs and their multimodal antitumor applications. We first introduce the design and fabrication of M2D NCs, followed by discussing new types of M2D NCs that have been recently reported. Then, a detailed analysis and discussions about the different types of M2D NCs are presented based on the structural categories of 2D NMs, including 2D graphene, transition metal dichalcogenides (TMDs), transition metal carbides/nitrides/carbonitrides (MXenes), black phosphorus (BP), layered double hydroxides (LDHs), metal organic frameworks (MOFs), covalent organic frameworks (COFs) and other 2D nanomaterials. In particular, we focus on the synthesis strategies, magnetic or optical responsive performance, and the versatile antitumor applications, which include magnetic hyperthermia therapy (MHT), photothermal therapy (PTT), photodynamic therapy (PDT), drug delivery, immunotherapy and multimodal imaging. We conclude the review by proposing future developments with an emphasis on the mass production and biodegradation mechanism of the M2D NCs. This work is expected to provide a comprehensive overview to researchers and engineers who are interested in such a research field and promote the clinical translation of M2D NCs in practical applications.

Enhanced nitrogen and phosphorus removal by a novel ecological floating bed integrated with three-dimensional biofilm electrode system.

The ecological floating bed (EFB) has been used extensively for the purification of eutrophication water. However, the traditional EFB (T-EFB) often exhibits a decline in nitrogen and phosphorus removal because of the limited adsorption capacity of fillers and inadequate electron donors. In the present study, a series of electrolysis-ecological floating beds (EC-EFBs) were constructed to investigate the decontamination performance of conventional pollutants. EC-EFB outperformed T-EFB in terms of nitrogen and phosphorus removal. Its removal efficiency of total nitrogen and total phosphorus was 20.51-32.95% and 45.06-96.20%, which were higher than that in T-EFB.. Moreover, the plants in EC-EFB demonstrated higher metabolic activity than those in T-EFB. Under the electrolysis condition of 0.51 mA/cm2 for 24 h, the malondialdehyde content and superoxide dismutase activity in EC-EFB were 6.08 nmol/g and 22.61 U/g, which were significantly lower compared to T-EFB (38.65 nmol/g and 26.13 U/g). And the soluble protein content of plant leaves increased from 3.31 mg/g to 5.72 mg/g in EC-EFB. Microbial analysis revealed that electrolysis could significantly change the microbial community and facilitate the proliferation of nitrogen-functional microbes, such as Thermomonas, Hydrogenophaga, Deinococcus, and Zoogloea. It is important to highlight that the hydrogen evolution reaction at the cathode area facilitated phosphorus removal in EC-EFB, thereby inhibiting phosphorus leaching. This study provides a promising and innovative technology for the purification of eutrophic water.

Pharmacokinetics, anti-rheumatoid arthritis activity, and active ingredient contents of Eucommia ulmoides Oliv.

Eucommia ulmoides Oliv. is a deciduous tree which contains various chemical ingredients. The main objective was to document the active chemical ingredients of Eucommia ulmoides Oliv. and their metabolic profiles in vivo, with a view to providing an experimental and theoretical basis for clarifying the mechanisms underlying the pharmacological activity of Eucommia ulmoides Oliv. against rheumatoid arthritis. Eight main active constituents of Eucommia ulmoides Oliv. bark (pinoresinol glucopyranoside, aucubin, geniposidic acid, geniposide, genipin, chlorogenic acid, quercetin and betulinic acid) were quantified using high-performance liquid chromatography (HPLC). This paper additionally identified and characterized prototype metabolites via ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) combined with the Human Metabolome Database (HMDB) and literature comparisons. Ultra pressure liquid chromatography-mass spectrometry/ mass spectrometry (UPLC-MS/MS) was subsequently employed to quantify these components in blood over time and evaluate their pharmacokinetic characteristics. The anti-rheumatoid arthritis effects of genipin, pinoresinol glucopyranoside and their combinations were assessed using in vitro cellular assays. We identified and characterized a total of 53 ingredients from Eucommia ulmoides Oliv. bark and plasma samples, among which 20 were confirmed as prototype metabolites. Meanwhile, this paper derived and analyzed the metabolic cleavage pathway of 8 index ingredients. Six of these compounds displayed rapid entry into blood, with high plasma exposure and fast elimination rates. Data from the in vitro cellular assay showed that aucubin, pinoresinol glucopyranoside, genipin, and combinations of these compounds effectively inhibit MH7A cell proliferation, reduce NO release, and decrease inflammatory factor levels.

Changes in physiochemical properties and in vitro digestion of corn starch prepared with heat-moisture treatment.

To investigate the effect of heat-moisture treatment (HMT) on the physiochemical properties and in vitro digestibility of corn starch, the pasting behavior, viscoelasticity, thermal properties, long/short range structure, morphology and in vitro digestion of corn starch treated with different HMT conditions (HMT-20, 25, 30, 35 and 40 %) were characterized. Results indicated that after HMT, the pasting and disintegration behaviors of corn starch were affected and correlated with the moisture content. The dynamic viscoelasticity of corn starch was changed, and when glassy conditions were reached, the elastic properties decreased with increasing moisture while the viscous properties increased, especially for the HMT-40 %. The thermal stability of starch was improved by HMT, although the enthalpy of pasting (ΔH) was reduced. Additionally, the HMT processing also promoted the conversion of RDS to SDS and/or RS (SDS and RS increased to 39.80 % and 31.68 % for HMT-40 %, respectively), which might attribute to the rearrangement of free starch molecules. The present work provides a potential approach to make functional starches with healthy properties.

NIR-II imaging-guided photothermal cancer therapy combined with enhanced immunogenic death.

Photothermal therapy has a remarkable effect on the destruction of tumors. It kills tumor cells by photothermal ablation and induces immunogenic cell death by activating the immune response in tumor tissues. However, inhibition of the tumor immune microenvironment suppresses PTT-induced body-specific anti-tumor immunity. In this study, we designed the GdOF@PDA-HA-R837-hydrogel complex to achieve NIR-II imaging-guided photothermal ablation and enhanced immune response. Due to the doping of Yb and Er elements and the presence of a polydopamine coating, the synthesized nanoparticles enable NIR-II and photoacoustic imaging of tumor tissues, which will help in the integration of multimodal tumor imaging for diagnosis and treatment. Polydopamine is used as a photothermal agent and drug carrier because of its excellent photothermal ability and high drug loading capacity under 808 nm near infrared light. Hyaluronic acid can bind to specific receptors on the surface of cancer cells, allowing nanoparticles to aggregate around the tumor, thus enhancing the targeting ability of nanoparticles. In addition, imiquimod (R837) has been used as an immune response modulator to enhance the immunotherapeutic effect. The presence of a hydrogel enhanced the retention effect of nanoparticles in the tumor. We demonstrate that the combination of photothermal therapy with immune adjuvants effectively induces ICD, which in turn stimulates the activation of specific anti-tumor immunity and enhances the effect of photothermal therapy in vivo.

Iridoid from Eucommia ulmoides Oliv. Exerts Antiarthritis Effects by Inhibiting the JAK2/STAT3 Signaling Pathway In Vivo and In Vitro.

The purpose of this study was to investigate the anti-inflammatory effects of EU-Idd both in vivo and in vitro. In vivo, we used the collagen-induced arthritis (CIA) rat model to investigate the efficacy of EU-Idd on rheumatoid arthritis. Hematoxylin-eosin staining and Safranin O-fast green staining were used to evaluate the pathological status of the ankle joints in CIA rats. Micro-CT scanning was used to investigate bone erosion of the ankle joints. In vitro, the effect of EU-Idd on Th17 cell differentiation was identified by flow cytometry. TRAP staining was used to detect osteoclast cells. HFLS-RA model cells, induced by tumor necrosis factor-α(TNF-α), were used to evaluate the anti-inflammatory effects of EU-Idd while the levels of related inflammatory cytokines and JAK2/STAT3 proteins were detected by RT-qPCR and western blotting. EU-Idd alleviated joint inflammation in CIA rats and exerted protective effects on the ankle joints. EU-Idd also prevented the differentiation of CD4+ T cells into Th17 cells, reduced the number of osteoclasts, and improved the expression levels of bone metabolism-related proteins including OPG and RANKL. Moreover, EU-Idd inhibited the invasion and migration of HFLS-RA cells and downregulated the expression of related inflammatory cytokine genes and the protein expression levels of p-JAK2 and p-STAT3, both in vivo and in vitro. EU-Idd exerts anti-inflammatory and osteoprotective effects by regulating the JAK2/STAT3 pathway in rheumatoid arthritis. These results are beneficial to excavate new pharmaceutical ingredients for rheumatoid arthritis from iridoid.

Biological valorization of lignin to flavonoids.

Lignin is the most affluent natural aromatic biopolymer on the earth, which is the promising renewable source for valuable products to promote the sustainability of biorefinery. Flavonoids are a class of plant polyphenolic secondary metabolites containing the benzene ring structure with various biological activities, which are largely applied in health food, pharmaceutical, and medical fields. Due to the aromatic similarity, microbial conversion of lignin derived aromatics to flavonoids could facilitate flavonoid biosynthesis and promote the lignin valorization. This review thereby prospects a novel valorization route of lignin to high-value natural products and demonstrates the potential advantages of microbial bioconversion of lignin to flavonoids. The biodegradation of lignin polymers is summarized to identify aromatic monomers as momentous precursors for flavonoid synthesis. The biosynthesis pathways of flavonoids in both plants and strains are introduced and compared. After that, the key branch points and important intermediates are clearly discussed in the biosynthesis pathways of flavonoids. Moreover, the most significant enzyme reactions including Claisen condensation, cyclization and hydroxylation are demonstrated in the biosynthesis pathways of flavonoids. Finally, current challenges and potential future strategies are also discussed for transforming lignin into various flavonoids. The holistic microbial conversion routes of lignin to flavonoids could make a sustainable production of flavonoids and improve the feasibility of lignin valorization.

Electroacupuncture regulates microglia polarization via lncRNA-mediated hippo pathway after ischemic stroke.

Microglia polarization and microglia-mediated inflammation play a crucial role in the development of ischaemic brain injury. Electroacupuncture (EA) has the function of anti-inflammatory, which has been thoroughly validated and utilized to treat ischemic brain damage. The fundamental mechanism by which EA alleviates ischemic brain damage by decreasing microglia polarization and microglia-mediated inflammation, however, remains unknown. In the current study, the activation of microglia and inflammatory cytokines was analyzed to confirm the anti-inflammatory function of EA in middle cerebral artery occlusion (MCAO) rats. Whole-transcriptome sequencing was used to examine the differentially expressed lncRNAs in the control, MCAO, and MCAO +EA groups. Our findings demonstrated that EA treatment reduced microglia activation and inflammatory cytokine production. In addition, there are 44 lncRNAs were found significantly different in three groups, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of the predicted targets of these lncRNAs suggested that the Hippo pathway may contribute to the development of ischaemic brain injury and to the anti-inflammatory function of EA. Moreover, our data showed that lncRNA TCONS_00022826 (Lnc826) was upregulated in MCAO group, whereas blocked by EA treatment. Furthermore, in vitro OGD cell model data showed that Lnc826 promoted M1 polarization of microglia by regulating the Hippo pathway. Our data suggested that regulating microglia polarization via Lnc826-mediated hippo pathway is a possible mechanism of the EA treatment on ischemic brain injury.

Chirality-Dependent Tumor Phototherapy Using Amino Acid-Engineered Chiral Phosphorene.

Phosphorene, also known as black phosphorus nanosheet (BPNS), has been investigated as a nanoagent for tumor therapy. However, promoting its intracellular accumulation while preventing the cytoplasmic decomposition remains challenging. Herein, for the first time, we propose a chiral BPNS designed through surface engineering based on amino acids with high biocompatibility and an abundant source for application in chirality-dependent tumor phototherapy based on its intracellular metabolism. The advantage of using cysteine (Cys) over other amino acids was that its d, l, or dl-form could efficiently work as the chirality inducer to modify the BPNS through electrostatic interaction and prevent alterations in the intrinsic properties of the BPNS. In particular, d-Cys-BPNS displayed an approximately threefold cytotoxic effect on tumor cells compared with l-Cys-BPNS, demonstrating a chirality-dependent therapy behavior. d-Cys-BPNS not only promoted high intracellular content but also showed resistance to cytoplasmic decomposition. Cys-engineered BPNS also demonstrated chirality-dependent phototherapy effects on tumor-bearing mice, in proximity to the results in vitro. Chiral engineering is expected to open new avenues that could promote the use of BPNS in tumor phototherapy and boost chiral nanomedicine.

[Effects of triterpenoid and iridoid of Eucommiae Cortex on collagen-induced arthritis in rats].

The ethyl acetate fraction of ethanol extract of Eucommiae Cortex can effectively inhibit joint inflammation and bone destruction in rats with collagen-induced arthritis(CIA) and has a potential therapeutic effect on rheumatoid arthritis. The triterpenoid(EU-Tid) and iridoid(EU-Idd) of Eucommiae Cortex are derivatives isolated from the ethyl acetate fraction of the ethanol extract of Eucommiae Cortex, and it is not clear whether they have inhibitory effects on joint inflammation and bone erosion in CIA rats. Therefore, based on the CIA model, the effects of EU-Tid, EU-Idd, and their combination(EU-TP) on arthritis in rats were observed, and the material basis of Eucommiae Cortex against arthritis was further clarified. The samples were collected two and four weeks after administration to observe the pathological changes in different stages of arthritis in CIA rats. For the rats in the model control group, with the prolongation of the disease course, the paw volume and arthritis score increased and histopathological lesions aggravated. Compared with the model control group, the drug administration groups showed reduced paw volumes and arthritis scores, and improved joint lesions and cartilage destruction. Additionally, the mRNA expression levels of tumor necrosis factor-α(TNF-α), interleukin-17(IL-17), and interleukin-23(IL-23) in the spleen were down-regulated in the drug administration groups. EU-TP and EU-Tid at concentrations of 160 and 320 µg·mL~(-1) could significantly inhibit the proliferation of human fibroblast-like synoviocytes-RA(HFLS-RA) and nitric oxide(NO) release in the supernatant of RAW264.7 cells induced by lipopolysaccharide(LPS) at the concentration range of 10-80 µg·mL~(-1) in vitro. EU-Idd had no effect on the proliferation of HFLS-RA but could reduce the NO release at concentrations of 40 and 80 µg·mL~(-1). The results indicated that the terpenoids of Eucommiae Cortex had great potential in the treatment of rheumatoid arthritis.

Disease Markers and Therapeutic Targets for Rheumatoid Arthritis Identified by Integrating Bioinformatics Analysis with Virtual Screening of Traditional Chinese Medicine.

OBJECTIVE: The aim of this study was to identify potentially important Rheumatoid arthritis (RA) targets related to immune cells based on bioinformatics analysis, and to identify small molecules of traditional Chinese medicine (TCM) associated with these targets that have potential therapeutic effects on RA. METHODS: Gene expression profile data related to RA were downloaded from the Gene Expression Omnibus (GSE55235, GSE55457, and GSE77298), and datasets were merged by the batch effect removal method. The RA key gene set was identified by protein-protein interaction network analysis and machine learning-based feature extraction. Furthermore, immune cell infiltration analysis was carried out on all DEGs to obtain key RA markers related to immune cells. Batch molecular docking of key RA markers was performed on our previously compiled dataset of small molecules in TCM using AutoDock Vina. Moreover, in vitro experiments were performed to examine the inhibitory effect of screened compounds on the synovial cells of an RA rat model. RESULTS: The PPI network and feature extraction with machine learning classifiers identified eight common key RA genes: MYH11, CFP, LY96, IGJ, LPL, CD48, RAC2, and CSK. RAC2 was significantly correlated with the infiltration and expression of five immune cells, with significant differences in these immune cells in the normal and RA samples. Molecular docking and in vitro experiments also showed that sanguinarine, sesamin, and honokiol could effectively inhibit the proliferation of RA rat synovial cells, also could all effectively inhibit the secretion of TNF-α and IL-1ß in synovial cells, and had a certain inhibitory effect on expression of the target protein RAC2. CONCLUSIONS: The core gene set of RA was screened from a new perspective, revealing biomarkers related to immune cell infiltration. Using molecular docking, we screened out TCM small molecules for the treatment of RA, providing methods and technical support for the treatment of RA with TCM.

A Randomized, Open-Label, Multicenter, Phase 3 Study of High-Dose Vitamin C Plus FOLFOX ± Bevacizumab versus FOLFOX ± Bevacizumab in Unresectable Untreated Metastatic Colorectal Cancer (VITALITY Study).

PURPOSE: To compare the efficacy and safety of high-dose vitamin C plus FOLFOX ± bevacizumab versus FOLFOX ± bevacizumab as first-line treatment in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Between 2017 and 2019, histologically confirmed patients with mCRC (n = 442) with normal glucose-6-phosphate dehydrogenase status and no prior treatment for metastatic disease were randomized (1:1) into a control (FOLFOX ± bevacizumab) and an experimental [high-dose vitamin C (1.5 g/kg/d, intravenously for 3 hours from D1 to D3) plus FOLFOX ± bevacizumab] group. Randomization was based on the primary tumor location and bevacizumab prescription. RESULTS: The progression-free survival (PFS) of the experimental group was not superior to the control group [median PFS, 8.6 vs. 8.3 months; HR, 0.86; 95% confidence interval (CI), 0.70-1.05; P = 0.1]. The objective response rate (ORR) and overall survival (OS) of the experimental and control groups were similar (ORR, 44.3% vs. 42.1%; P = 0.9; median OS, 20.7 vs. 19.7 months; P = 0.7). Grade 3 or higher treatment-related adverse events occurred in 33.5% and 30.3% of patients in the experimental and control groups, respectively. In prespecified subgroup analyses, patients with RAS mutation had significantly longer PFS (median PFS, 9.2 vs. 7.8 months; HR, 0.67; 95% CI, 0.50-0.91; P = 0.01) with vitamin C added to chemotherapy than with chemotherapy only. CONCLUSIONS: High-dose vitamin C plus chemotherapy failed to show superior PFS compared with chemotherapy in patients with mCRC as first-line treatment but may be beneficial in patients with mCRC harboring RAS mutation.

Neobavaisoflavone inhibits antitumor immunosuppression via myeloid-derived suppressor cells.

Neobavaisoflavone (Neo), as a traditional Chinese medicine, is the active ingredient in the herb Psoralea corylifolial and has antitumor activity. Myeloid-derived suppressor cells (MDSCs), which are a heterogeneous population of haematopoietic cells of the myeloid lineage, have been reported to be closely related to the pathogenesis of tumour progression, but whether Neo can regulate MDSC expansion and function remains unclear. Here, we found that Neo could inhibit the expansion and suppressive function of MDSCs by targeting STAT3. Importantly, Neo inhibited the growth of 4T1 and LLC tumours in vivo, as well as lung metastasis of 4T1 tumours in vivo. Furthermore, we identified MDSCs as the direct targets by which Neo attenuated tumour progression. In addition, Neo notably enhanced anti-PD-1 efficacy in anti-PD-1-insensitive 4T1 tumours. Therefore, our study sheds light on the development of Neobased therapeutic strategies against cancer.

HKUST-1 nano metal-organic frameworks combined with ZnGa2O4:Cr3+ near-infrared persistent luminescence nanoparticles for in vivo imaging and tumor chemodynamic and photothermal synergic therapy.

The multifunctional theranostic nanoplatform based on the combination of persistent luminescent nanoparticles (PLNPs) and metal-organic frameworks (MOFs) has both in vivo imaging and tumor therapeutic drug-loading functions, providing a new strategy for accurate and effective tumor diagnosis and treatment. Herein, the near-infrared (NIR) PLNP SiO2@Zn1.05Ga1.9O4:Cr was combined with HKUST-1 MOFs to form a core-shell structure theranostic nanoplatform which possessed the triple function of autofluorescence-free NIR PersL bioimaging, tumor chemodynamic therapy (CDT), and tumor photothermal therapy (PTT). Also, the photothermal conversion efficiency reached 58.7%, which is superior to the reported nano metal-organic framework (NMOF) photothermal reagents. We demonstrated that the nanoplatform could enter the tumors of mice within 0.5 h and could be target-activated by H2O2 and H2S in the tumor cells, resulting in effective PTT and CDT synergistic treatment. Tumor-bearing mice experiments showed that the tumor could be completely cured without harming normal tissue. This theranostic nanoplatform may provide a promising strategy showing imaging, PTT, and CDT synergistic treatment tri-mode for clinical cancer therapy.

Computation-Based Discovery of Potential Targets for Rheumatoid Arthritis and Related Molecular Screening and Mechanism Analysis of Traditional Chinese Medicine.

This study is aimed at screening potential therapeutic ingredients in traditional Chinese medicine (TCM) and identifying the key rheumatoid arthritis (RA) targets using computational simulations. Data for TCM-active ingredients with clear pharmacological effects were collected. Absorption, distribution, metabolism, excretion, and toxicity were evaluated. Potential RA targets were identified using the Gene Expression Omnibus (GEO) database, protein-protein interaction network, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and potential TCM ingredients using AutoDock Vina. To examine the mechanisms underlying small molecules, target prediction, Gene Ontology, KEGG, and network modeling analyses were conducted; the effects were verified in rat synovial cells using cell proliferation assay. The activities of tumor necrosis factor TNF-α and IL-1ß and alterations in cellular target protein levels were detected by ELISA and Western blotting, respectively. In total, data for 432 TCM active ingredients with clear pharmacological effects were obtained. Five critical RA-related genes were identified; CCL5 and CXCL10 were selected for molecular docking. Target prediction and network-based proximity analysis showed that dioscin could modulate 22 known RA clinical targets. Dioscin, asiaticoside, and ginsenoside Re could effectively inhibit in vitro cell proliferation and secretion of TNF-α and IL-1ß in RA rat synovial cells. Using bioinformatics and computer-aided drug design, the potential small anti-RA molecules and their mechanisms of action were comprehensively identified. Dioscin could significantly inhibit proliferation and induce apoptosis in RA rat synovial cells by reducing TNF-α and IL-1ß secretion and inhibiting abnormal CCL5, CXCL10, CXCR2, and IL2 expression.

Anti-inflammatory effects of aucubin in cellular and animal models of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. It is known that aucubin (AU) exerts anti-inflammatory activity, but its effects and mechanisms in RA are unclear. This study investigated the anti-inflammatory effects and mechanisms of AU in vivo and in vitro. Human fibroblast-like synoviocyte cells from patients with RA (HFLS-RA), RAW264.7 cells, and MC3T3-E1 cells were used to evaluate the effects of AU on migration, invasion, apoptosis, osteoclast differentiation and production. Immunofluorescence was used to observe nuclear translocation of nuclear factor (NF)-κB, the double luciferase reporter gene method was used to observe NF-κB-p65 activity in AU-treated MC3T3-E1 cells. RT-qPCR was used to measure expression of bone metabolism and inflammation-related genes, and western blot was used to measure bone metabolism and NF-κB protein expression levels. Collagen-induced arthritis (CIA) rat model was used for pharmacodynamics study. Arthritis indexes were measured in the ankle and knee, histological staining and Micro-computed tomography were performed on the ankle joints. Also, inflammatory factor gene expression and the levels of NF-κB-related proteins were detected as in vitro. AU effectively inhibited HFLS-RA cell migration and invasion, promoted apoptosis, and inhibited RAW264.7 cell differentiation into osteoclasts, as well as inhibited NF-κB-p65 activity in MC3T3-E1 cells. Notably, AU significantly reduced the gene expression levels of three cell-related inflammatory factors and bone metabolism factors, effectively inhibited the expression of p-Iκκα ß, p-IκBα, and p-p65 proteins. In vivo, AU relieved joint inflammation, reduced related inflammatory factors, and inhibited NF-κB signaling. It could be used to treat RA-related synovial inflammation and bone destruction through the NF-κB pathway.

Novel Glutathione Activated Smart Probe for Photoacoustic Imaging, Photothermal Therapy, and Safe Postsurgery Treatment.

Preventing tumor recurrence is the most important target for cancer treatment. However, the current effective and advanced technology relies on the use of near-infrared region (NIR), and the equipment of NIR-I and NIR-II fluorescence imaging technique-based fluorescent-guided surgery is expensive and complicated to operate. Here, we report a safe and effective strategy of an organic-inorganic hybrid gold nanoparticle-based novel smart probe (Au@PDA-ss-PEGm NPs) which is appropriate for photoacoustic imaging (PAI) and plasmonic photothermal therapy (PPTT) of tumors in vivo. After intravenous injection, the probe would be transported to the tumor to penetrate the cellular membrane. Then the disulfide bond on the probe surface would be broken with the help of a high concentration of glutathione in the tumor cell. The remaining Au@PDA NPs would aggregate to form plasmonic nanoclusters and exhibit a notable plasmon coupling enhanced photothermal (PCEPT) effect. Besides, the results further proved its good biosafety and pharmacokinetic characteristics in vivo and, more important, a short time exposure under 808 nm laser after surgical removal of the tumor, which would be effective to prevent tumor recurrence and bring dawn to the high-efficiency treatment of tumors.

[Clinical effect and safety of filiform-fire needle in treatment of peripheral facial paralysis: a Meta-analysis].

OBJECTIVE: To systematically evaluate the clinical effect and safety of filiform-fire needle in the treatment of peripheral facial paralysis at different stages. METHODS: Articles of the randomized controlled clinical trials (RCTs) about filiform fire needle treatment of peripheral facial paralysis published from the inception of the databases of CNKI, Wanfang, VIP, SinoMed, PubMed, Embase and Cochrane Library to December 20th, 2021 were retrieved first. The Cochrane Handbook 5.1 system was used to extract data and evaluate the quality (risk of bias) of the included papers. The overall effective rate, cure rate, Sunnybrook facial nerve function score, facial disability index scale, physical and social function score and related adverse reactions were used as the outcome indicators. The RevMan5.3 software was used for heterogeneity test and Meta-analysis was performed on papers with little clinical heterogeneity. RESULTS: A total of eligible 9 RCTs were included, involving 519 patients. The results of Meta-analysis showed that: compared with the conventional acupuncture therapy, the filiform fire needle in the treatment of peripheral facial paralysis had significant advantages in raising the overall effective rate (RR=1.14, 95%CIï¼»1.07,1.21ï¼½, P<0.000 1) and cure rate (RR=1.59, 95%CIï¼»1.29,1.97ï¼½, P<0.000 1),and in improving Sunnybrook facial neurological function score (MD=17.85, 95%CIï¼»15.72,19.97ï¼½, P<0.000 01), physical function score of facial disability index scale (MD=4.16, 95%CIï¼»3.15,5.16ï¼½, P<0.000 01) and social function score (MD=2.47, 95%CIï¼»1.53,3.41ï¼½, P<0.000 01). Safety analysis showed that there was no obvious adverse reaction during the filiform fire needle therapy, and the patients' tolerance to pain had no statistical difference relevant to the conventional acupuncture treatment (P>0.05). CONCLUSION: Filiform fire needle is superior to conventional acupuncture in the treatment of facial paralysis in all stages, but its reliability is limited due to fewer high-quality literature with scientific and rigorous methods and trial designs. Therefore, more large-sample and high-quality RCT studies are warranted for further verification.

Acetylshikonin induces autophagy-dependent apoptosis through the key LKB1-AMPK and PI3K/Akt-regulated mTOR signalling pathways in HL-60 cells.

Acetylshikonin (ASK) is a natural naphthoquinone derivative of traditional Chinese medicine Lithospermum erythrorhyzon. It has been reported that ASK has bactericidal, anti-inflammatory and antitumour effects. However, whether ASK induces apoptosis and autophagy in acute myeloid leukaemia (AML) cells and the underlying mechanism are still unclear. Here, we explored the roles of apoptosis and autophagy in ASK-induced cell death and the potential molecular mechanisms in human AML HL-60 cells. The results demonstrated that ASK remarkably inhibited the cell proliferation, viability and induced apoptosis in HL-60 cells through the mitochondrial pathway, and ASK promoted cell cycle arrest in the S-phase. In addition, the increased formation of autophagosomes, the turnover from light chain 3B (LC3B) I to LC3B II and decrease of P62 suggested the induction of autophagy by ASK. Furthermore, ASK significantly decreased PI3K, phospho-Akt and p-p70S6K expression, while enhanced phospho-AMP-activated protein kinase (AMPK) and phospho-liver kinase B1(LKB1) expression. The suppression of ASK-induced the conversion from LC3B I to LC3B II caused by the application of inhibitors of AMPK (compound C) demonstrated that ASK-induced autophagy depends on the LKB1/AMPK pathway. These data suggested that the autophagy induced by ASK were dependent on the activation of LKB1/AMPK signalling and suppression of PI3K/Akt/mTOR pathways. The cleavage of the apoptosis-related markers caspase-3 and caspase-9 and the activity of caspase-3 induced by ASK were markedly reduced by inhibitor of AMPK (compound C), an autophagy inhibitor 3-methyladenine (3-MA) and another autophagy inhibitor chloroquine (CQ). Taken together, our data reveal that ASK-induced HL-60 cell apoptosis is dependent on the activation of autophagy via the LKB1/AMPK and PI3K/Akt-regulated mTOR signalling pathways.