Gli1-mediated tumor cell-derived bFGF promotes tumor angiogenesis and pericyte coverage in non-small cell lung cancer.

BACKGROUND: Tumor angiogenesis inhibitors have been applied for non-small cell lung cancer (NSCLC) therapy. However, the drug resistance hinders their further development. Intercellular crosstalk between lung cancer cells and vascular cells was crucial for anti-angiogenenic resistance (AAD). However, the understanding of this crosstalk is still rudimentary. Our previous study showed that Glioma-associated oncogene 1 (Gli1) is a driver of NSCLC metastasis, but its role in lung cancer cell-vascular cell crosstalk remains unclear. METHODS: Conditioned medium (CM) from Gli1-overexpressing or Gli1-knockdown NSCLC cells was used to educate endothelia cells and pericytes, and the effects of these media on angiogenesis and the maturation of new blood vessels were evaluated via wound healing assays, Transwell migration and invasion assays, tube formation assays and 3D coculture assays. The xenograft model was conducted to establish the effect of Gli1 on tumor angiogenesis and growth. Angiogenic antibody microarray analysis, ELISA, luciferase reporte, chromatin immunoprecipitation (ChIP), bFGF protein stability and ubiquitination assay were performed to explore how Gli1 regulate bFGF expression. RESULTS: Gli1 overexpression in NSCLC cells enhanced the endothelial cell and pericyte motility required for angiogenesis required for angiogenesis. However, Gli1 knockout in NSCLC cells had opposite effect on this process. bFGF was critical for the enhancement effect on tumor angiogenesis. bFGF treatment reversed the Gli1 knockdown-mediated inhibition of angiogenesis. Mechanistically, Gli1 increased the bFGF protein level by promoting bFGF transcriptional activity and protein stability. Importantly, suppressing Gli1 with GANT-61 obviously inhibited angiogenesis. CONCLUSION: The Gli1-bFGF axis is crucial for the crosstalk between lung cancer cells and vascular cells. Targeting Gli1 is a potential therapeutic approach for NSCLC angiogenesis.

Activatable unsaturated liposomes increase lipid peroxide of cell membrane and inhibit tumor growth.

The cancer chemodynamic therapy based on the Fenton reaction has been attracting more and more attention. However, the performance of the Fenton reaction is restricted by the unsuitable physiological pH value and inadequate H2O2 content in the tumor microenvironment (TME). In this study, we proposed a novel method of inducing lipid peroxide (LPO) of the cancer cell membrane, whose performance is not limited by the pH value and H2O2 in the TME. The activatable LPO-inducing liposomes were constructed by encapsulating Fe3+-containing compound ferric ammonium citrate (FC) in the unsaturated soybean phospholipids (SPC). It was found that the FC could be reduced by the overexpressed glutathione (GSH) in the TME and produce iron redox couple. The Fe3+/Fe2+ mediated the peroxidation of the unsaturated SPC and induced the LPO in the cancer cells. Finally, LPO accumulation led to cancer cell death and tumor growth inhibition. Furthermore, the activatable liposomes did not damage healthy tissues because of the low GSH content in normal tissues and the GSH-triggered activation of the nanocarrier. Together, our findings revealed that FC-SPC-lipo displayed excellent anti-tumor performance and its therapeutic effects are less influenced by the TME, compared with the traditional ferroptosis.

"Two birds with one stone" strategy for the lung cancer therapy with bioinspired AIE aggregates.

Aggregation-induced emission luminogens (AIEgens) have emerged as novel phototherapeutic agents with high photostability and excellent performance to induce photodynamic and/or photothermal effects. In this study, a zwitterion-type NIR AIEgens C41H37N2O3S2 (named BITT) with biomimetic modification was utilized for lung cancer therapy. The tumor-associated macrophage (TAM)-specific peptide (CRV) was engineered into the lung cancer cell-derived exosomes. The CRV-engineered exosome membranes (CRV-EM) were obtained to camouflage the BITT nanoparticles (CEB), which targeted both lung cancer cells and TAMs through homotypic targeting and TAM-specific peptide, respectively. The camouflage with CRV-EM ameliorated the surface function of BITT nanoparticles, which facilitated the cellular uptake in both cell lines and induced significant cell death in the presence of laser irradiations in vitro and in vivo. CEB showed improved circulation lifetime and accumulations in the tumor tissues in vivo, which induced efficient photodynamic and photothermal therapy. In addition, CEB induced the tumor microenvironment remodeling as indicated by the increase of CD8 + and CD4 + T cells, as well as a decrease of M2 TAM and Myeloid-derived suppressor cells (MDSCs). Our work developed a novel style of bioinspired AIE aggregates, which could eliminate both lung cancer cells and TAMs, and remodel the tumor environments to achieve an efficient lung cancer therapy. To the best of our knowledge, we are the first to use this style of bioinspired AIE aggregates for photo-mediated immunotherapy in lung cancer therapy.

In Situ Reprogramming of Tumor-Associated Macrophages with Internally and Externally Engineered Exosomes.

The reprogramming of tumor-associated macrophages (TAMs) has emerged as an efficient strategy for immunotherapy. However, most of the approaches did not allow the in situ reprogramming of TAM because their low efficiency, non-specificity, or potential side effects. Herein, we produced exosomes with the clustered regularly interspaced short palindromic repeats interference (CRISPRi) internally engineered and the TAM specific peptide externally engineered onto the exosome membrane. The internally and externally engineered exosomes (IEEE, also named as I3E) allowed the selective homing to tumor tissue and targeted to M2-like TAMs, which nearly repressed the expression of PI-3 kinase gamma (PI3Kγ) completely, and induced the TAMs polarizing to M1 both in vitro and in vivo. The polarized M1 macrophages awakened the "hot" tumor-immunity, causing the increase of T lymphocyte infiltration and the decrease of myeloid-derived suppressor cells, and inhibiting the tumor growth significantly. I3E reprogramed TAMs in situ precisely and efficiently.

Gli1 promotes epithelial-mesenchymal transition and metastasis of non-small cell lung carcinoma by regulating snail transcriptional activity and stability.

Metastasis is crucial for the mortality of non-small cell lung carcinoma (NSCLC) patients. The epithelial-mesenchymal transition (EMT) plays a critical role in regulating tumor metastasis. Glioma-associated oncogene 1 (Gli1) is aberrantly active in a series of tumor tissues. However, the molecular regulatory relationships between Gli1 and NSCLC metastasis have not yet been identified. Herein, we reported Gli1 promoted NSCLC metastasis. High Gli1 expression was associated with poor survival of NSCLC patients. Ectopic expression of Gli1 in low metastatic A549 and NCI-H460 cells enhanced their migration, invasion abilities and facilitated EMT process, whereas knock-down of Gli1 in high metastatic NCI-H1299 and NCI-H1703 cells showed an opposite effect. Notably, Gli1 overexpression accelerated the lung and liver metastasis of NSCLC in the intravenously injected metastasis model. Further research showed that Gli1 positively regulated Snail expression by binding to its promoter and enhancing its protein stability, thereby facilitating the migration, invasion and EMT of NSCLC. In addition, administration of GANT-61, a Gli1 inhibitor, obviously suppressed the metastasis of NSCLC. Collectively, our study reveals that Gli1 is a critical regulator for NSCLC metastasis and suggests that targeting Gli1 is a prospective therapy strategy for metastatic NSCLC.

Artificial stem cells mediated inflammation-tropic delivery of antiviral drugs for pneumonia treatment.

BACKGROUND: Cytomegalovirus (CMV) pneumonia is a major cause of morbidity and mortality in immunodeficiency individuals, including transplant recipients and Acquired Immune Deficiency Syndrome patients. Antiviral drugs ganciclovir (GCV) and phosphonoformate (PFA) are first-line agents for pneumonia caused by herpesvirus infection. However, the therapy suffers from various limitations such as low efficiency, drug resistance, toxicity, and lack of specificity. METHODS: The antiviral drugs GCV and PFA were loaded into the pH-responsive nanoparticles fabricated by poly(lactic-co-glycolic acid) (PLGA) and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and further coated with cell membranes derived from bone marrow mesenchymal stem cells to form artificial stem cells, namely MPDGP. We evaluated the viral suppression effects of MPDGP in vitro and in vivo. RESULTS: MPDGP showed significant inflammation tropism and efficient suppression of viral replication and virus infection-associated inflammation in the CMV-induced pneumonia model. The synergistic effects of the combination of viral DNA elongation inhibitor GCV and viral DNA polymerase inhibitor PFA on suppressing the inflammation efficiently. CONCLUSION: The present study develops a novel therapeutic intervention using artificial stem cells to deliver antiviral drugs at inflammatory sites, which shows great potential for the targeted treatment of pneumonia. To our best knowledge, we are the first to fabricate this kind of artificial stem cell to deliver antiviral drugs for pneumonia treatment.

Apigenin suppresses tumor angiogenesis and growth via inhibiting HIF-1α expression in non-small cell lung carcinoma.

Tumor angiogenesis inhibitors such as Bevacizumab, Ramucirumab and Endostar have been applied to the therapy of non-small cell lung carcinoma (NSCLC) patients, especially for lung adenocarcinoma (LUAD). However, several safe concerns such as neutropenia, febrile neutropenia and hypertension pulmonary hemorrhage limit their further development. And they often showed poor efficacy and serious side effect for lung squamous cell carcinoma (LUSC) patient. Thus, identification of effective and safe tumor angiogenesis inhibitor for NSCLC therapy is warranted. Apigenin is a bioflavonoid with potential anti-tumor effect and perfect safety, but its effect on tumor angiogenesis and underlying mechanism are still unclear. Herein, we found that apigenin not merely suppressed endothelial cells related motilities but also reduced pericyte coverage. Further research showed that apigenin had strong suppressive activity against HIF-1α expression and its downstream VEGF-A/VEGFR2 and PDGF-BB/PDGFßR signaling pathway. Apigenin also reduced microvessel density and pericyte coverage on the xengraft model of NCI-H1299 cells, leading to suppression of tumor growth. Moreover, apigenein showed perfect anti-angiogenic effect in xengraft model of LUSC cell NCI-H1703 cells, indicating it may be developed into a potential angiogenesis inhibitor for LUSC patient. Collectively, our study provides new insights into the anti-tumor mechanism of apigenin and suggests that apigenin is a safe and effective angiogenesis inhibitor for NSCLC therapy.

Promoter methylation-regulated miR-148a-3p inhibits lung adenocarcinoma (LUAD) progression by targeting MAP3K9.

Lung adenocarcinoma (LUAD) characterized by high metastasis and mortality is the leading subtype of non-small cell lung cancer. Evidence shows that some microRNAs (miRNAs) may act as oncogenes or tumor suppressor genes, leading to malignant tumor occurrence and progression. To better understand the molecular mechanism associated with miRNA methylation in LUAD progression and clinical outcomes, we investigated the correlation between miR-148a-3p methylation and the clinical features of LUAD. In the LUAD cell lines and tumor tissues from patients, miR-148a-3p was found to be significantly downregulated, while the methylation of miR-148a-3p promoter was notably increased. Importantly, miR-148a-3p hypermethylation was closely associated with lymph node metastasis. We demonstrated that mitogen-activated protein (MAP) kinase kinase kinase 9 (MAP3K9) was the target of miR-148a-3p and that MAP3K9 levels were significantly increased in both LUAD cell lines and clinical tumor tissues. In A549 and NCI-H1299 cells, overexpression of miR-148a-3p or silencing MAP3K9 significantly inhibited cell growth, migration, invasion and cytoskeleton reorganization accompanied by suppressing the epithelial-mesenchymal transition. In a nude mouse xenograft assay we found that tumor growth was effectively inhibited by miR-148a-3p overexpression. Taken together, the promoter methylation-associated decrease in miR-148a-3p could lead to lung cancer metastasis by targeting MAP3K9. This study suggests that miR-148a-3p and MAP3K9 may act as novel therapeutic targets for the treatment of LUAD and have potential clinical applications.

Artificial exosomes mediated spatiotemporal-resolved and targeted delivery of epigenetic inhibitors.

BACKGROUND: Malignant tumor is usually associated with epigenetic dysregulation, such as overexpression of histone deacetylase (HDAC), thus HDAC has emerged as a therapeutic target for cancer. Histone deacetylase inhibitor has been approved for clinical use to treat hematological cancers. However, the low solubility, short circulation lifetime, and high cytotoxicity partially limited their applications in solid tumor. METHODS: The upconversion nanoparticles (UC) modified with mesoporous silica (SUC) was used to load an HDACI, suberoylanilide hydroxamic acid (SAHA), and further camouflaged with M1 macrophage-derived exosome membranes (EMS). EMS was characterized in size and compositions. We also analyzed the epigenetic regulation induced by EMS. Furthermore, we evaluate the biodistribution and in vivo tumor inhibition after the systemic administration of EMS. RESULTS: This novel style spatiotemporal-resolved drug delivery system, EMS showed a high loading efficiency of SAHA. EMS could be taken up by lung cancer cells and lead to efficient epigenetic inhibition. We found that the integrin α4ß1 on M1-EM, was crucial for the homing of EMS to tumor tissues for the first time. In tumor-bearing mice, EMS showed spatiotemporal-resolved properties and facilitated the drug accumulation in the tumors, which induced superior anti-tumor effects. CONCLUSION: This novel style of spatiotemporal-resolved nanoparticles can be used as a theranostic platform for lung cancer therapy.

Epigenetic inhibition assisted chemotherapeutic treatment of lung cancer based on artificial exosomes.

We adopted a novel strategy by combining histone deacetylase (HDAC) inhibitors with traditional chemotherapeutics to treat solid tumors. However, chemotherapeutics often have a narrow therapeutic index and need multiple administrations with undesired side effects that lead to the intolerance. To reduce the non-specificity of chemotherapeutics, targeted therapy was introduced to restrict such agents in the tumor with minimum effects on other tissues. We developed bioinspired artificial exosomes (AE), which enabled to deliver chemotherapeutics to the tumors effectively after systemic administration. AE were produced by incorporating membrane proteins from cancer cells into phospholipid liposomes that mimicked the plasma membrane. The synthesized AE were used for the delivery of broad-spectrum chemotherapeutic doxorubicin (DOX) and vorinostat (SAHA), an epigenetic inhibitor. The combination of DOX and SAHA showed synergistic effects on suppressing non-small cell lung cancer cells and xenograft tumors without apparent adverse effects. AE facilitated the delivery of drugs to tumor tissue and extended the retention time of drugs within tumors. Taken together, these studies suggest that the bioengineered artificial exosomes may serve as novel delivery strategy for chemotherapeutics to treat non-small cell lung cancer.

The Antibacterial Effects of Supermolecular Nano-Carriers by Combination of Silver and Photodynamic Therapy.

The over-use of antibiotics has promoted multidrug resistance and decreased the efficacy of antibiotic therapy. Thus, it is still in great need to develop efficient treatment strategies to combat the bacteria infection. The antimicrobial photodynamic therapy (aPDT) and silver nanoparticles have been emerged as effective antibacterial methods. However, the silver therapy may induce serious damages to human cells at high concentrations and, the bare silver nanoparticles may rapidly aggregate, which would reduce the antibacterial efficacy. The encapsulation of sliver by nano-carrier is a promising way to avoid its aggregation and facilitates the co-delivery of drugs for combination therapy, which does not require high concentration of sliver to exert antibacterial efficacy. This work constructed a self-assembled supermolecular nano-carrier consisting of the photosensitizers (PSs), the anti-inflammatory agent and silver. The synthesized supermolecular nano-carrier produced reactive oxygen species (ROS) under the exposure of 620-nm laser. It exhibited satisfying biocompatibility in L02 cells. And, this nano-carrier showed excellent antibacterial efficacy in Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) as indicated by bacterial growth and colony formation. Its antibacterial performance is further validated by the bacteria morphology through the scanning electron microscope (SEM), showing severely damaged structures of bacteria. To summary, the supermolecular nano-carrier TCPP-MTX-Ag-NP combining the therapeutic effects of ROS and silver may serve as a novel strategy of treatment for bacterial infection.

Triptolide suppresses the growth and metastasis of non-small cell lung cancer by inhibiting ß-catenin-mediated epithelial-mesenchymal transition.

Non-small cell lung cancer (NSCLC) is characterized by a high incidence of metastasis and poor survival. As epithelial-mesenchymal transition (EMT) is well recognized as a major factor initiating tumor metastasis, developing EMT inhibitor could be a feasible treatment for metastatic NSCLC. Recent studies show that triptolide isolated from Tripterygium wilfordii Hook F attenuated the migration and invasion of breast cancer, colon carcinoma, and ovarian cancer cells, and EMT played important roles in this process. In the present study we investigated the effect of triptolide on the migration and invasion of NSCLC cell lines. We showed that triptolide (0.5, 1.0, 2.0 nM) concentration-dependently inhibited the migration and invasion of NCI-H1299 cells. Triptolide treatment concentration-dependently suppressed EMT in NCI-H1299 cells, evidenced by significantly elevated E-cadherin expression and reduced expression of ZEB1, vimentin, and slug. Furthermore, triptolide treatment suppressed ß-catenin expression in NCI-H1299 and NCI-H460 cells, overexpression of ß-catenin antagonized triptolide-caused inhibition on EMT, whereas knockout of ß-catenin enhanced the inhibitory effect of triptolide on EMT. Administration of triptolide (0.75, 1.5 mg/kg per day, ip, every 2 days) for 18 days in NCI-H1299 xenograft mice dose-dependently suppressed the tumor growth, restrained EMT, and decreased lung metastasis, as evidence by significantly decreased expression of mesenchymal markers, increased expression of epithelial markers as well as reduced number of pulmonary lung metastatic foci. These results demonstrate that triptolide suppresses NSCLC metastasis by targeting EMT via reducing ß-catenin expression. Our study implies that triptolide may be developed as a potential agent for the therapy of NSCLC metastasis.

Doxorubicin-loaded hydrogen peroxide self-providing copper nanodots for combination of chemotherapy and acid-induced chemodynamic therapy against breast cancer.

In recent years, chemodynamic therapy (CDT) has gained increasing interest in cancer treatment. In contrast to photodynamic therapy and sonodynamic therapy, extrinsic excitations such as laser or ultrasound are not required in CDT. As a result, the CDT performance is not limited by the penetration depth of the external irritation. However, CDT relies heavily on hydrogen peroxide (H2O2) in the tumour microenvironment (TME). Insufficient H2O2 in the TME limits the CDT performance, and the most reported methods to produce H2O2 in the TME are dependent on oxygen supply, which is restricted by the hypoxic TME. In this study, H2O2 self-providing copper nanodots were proposed, and the drug doxorubicin (DOX) was successfully loaded to construct DOX-nanodots. Our results showed that the nanodots produced H2O2 in the weakly acidic TME due to the peroxo group and further generated the most active hydroxyl radical (OH) through the Fenton-like reaction. This process was pH-dependent and did not occur in a neutral environment. In addition to OH, the nanodots also produced singlet oxygen (1O2) and superoxide anions (O2-) in the cancer cells. The copper nanodots performed promising CDT against breast cancer in vitro and in vivo, with enhanced cell apoptosis and decreased cell proliferation. The combination of chemotherapy and CDT using DOX-nanodots further improved the therapeutic effects. The treatments showed good biocompatibility with no obvious toxicity in major tissues, possibly due to the specific OH generation in the weakly acidic TME. In summary, the H2O2 self-providing copper nanodots in combination with DOX showed promising cancer-curing effects due to the oxygen-independent and tumour-specific production of reactive oxygen species and the cooperation of chemotherapy.

High-Performance Dual Combination Therapy for Cancer Treatment with Hybrid Membrane-Camouflaged Mesoporous Silica Gold Nanorods.

Conventional chemotherapy usually induces significant side effects due to its inability to discriminate between cancer and normal cells. Moreover, the efficacy of cancer elimination is still unsatisfied. Here, we fabricated a nanocomposite enabling high-performance dual combination therapy (chemo/photothermal therapy). This style of novel nanocomposites was constructed with doxorubicin (DOX)-loaded mesoporous silica gold (MSG) nanorods, which were further camouflaged with hybrid membranes derived from HeLa cells and red blood cells (HRMSGD). The hybrid membrane-camouflaged structure showed enhanced circulation lifetime and cell line-specific delivery of chemotherapeutics both in vitro and in vivo. The dual combination therapy by HRMSGD showed an unattainable therapeutic effect, compared with a single treatment, and inhibited tumor growth significantly. Furthermore, the nanoplatforms were photoacoustic-responsive, which showed real-time and noninvasive tracking capability. The present study established nanoplatforms with hybrid cell membrane-camouflaged multifunctional gold nanorods, which realized the combination of homotypic targeting, noninvasive tracking, chemotherapy, and photothermal therapy. To the best of our knowledge, this is the first study to use a natural membrane to camouflage mesoporous silica-modified gold nanorods, which opened a new avenue for cancer treatment.

Bismuth chelate as a contrast agent for X-ray computed tomography.

BACKGROUNDS: Due to the unexpected side effects of the iodinated contrast agents, novel contrast agents for X-ray computed tomography (CT) imaging are urgently needed. Nanoparticles made by heavy metal elements are often employed, such as gold and bismuth. These nanoparticles have the advantages of long in vivo circulation time and tumor targeted ability. However, due to the long residence time in vivo, these nanoparticles may bring unexpected toxicity and, the preparation methods of these nanoparticles are complicated and time-consuming. METHODS: In this investigation, a small molecular bismuth chelate using diethylenetriaminepentaacetic acid (DPTA) as the chelating agent was proposed to be an ideal CT contrast agent. RESULTS: The preparation method is easy and cost-effective. Moreover, the bismuth agent show better CT imaging for kidney than iohexol in the aspect of improved CT values. Up to 500 µM, the bismuth agent show negligible toxicity to L02 cells and negligible hemolysis. And, the bismuth agent did not induce detectable morphology changes to the main organs of the mice after intravenously repeated administration at a high dose of 250 mg/kg. The pharmacokinetics of the bismuth agent follows the first-order elimination kinetics and, it has a short half-life time of 0.602 h. The rapid clearance from the body promised its excellent biocompatibility. CONCLUSIONS: This bismuth agent may serve as a potential candidate for developing novel contrast agent for CT imaging in clinical applications.

Identification of a novel tumor angiogenesis inhibitor targeting Shh/Gli1 signaling pathway in Non-small cell lung cancer.

Although angiogenesis inhibitors targeting VEGF/VEGFR2 have been applied for tumor therapy, the outcomes are still unsatisfactory. Thus, it is urgent to develop novel angiogenesis inhibitor for cancer therapy from new perspectives. Identification of novel angiogenesis inhibitor from natural products is believed to be one of most promising strategy. In this study, we showed that pristimerin, an active agent isolated from traditional Chinese herbal medicine Celastrus aculeatus Merr, was a novel tumor angiogenesis inhibitor that targeting sonic hedgehog (Shh)/glioma associated oncogene 1 (Gli1) signaling pathway in non-small cell lung cancer (NSCLC). We showed that pristimerin affected both the early- and late-stage of angiogenesis, suggesting by that pristimerin inhibited Shh-induced endothelial cells proliferation, migration, invasion as well as pericytes recruitment to the endothelial tubes, which is critical for the new blood vessel maturation. It also suppressed tube formation, vessel sprouts formation and neovascularization in chicken embryo chorioallantoic membrane (CAM). Moreover, it significantly decreased microvessel density (MVD) and pericyte coverage in NCI-H1299 xenografts, resulting in tumor growth inhibition. Further research revealed that pristimerin suppressed tumor angiogenesis by inhibiting the nucleus distribution of Gli1, leading to inactivation of Shh/Gli1 and its downstream signaling pathway. Taken together, our study showed that pristimerin was a promising novel anti-angiogenic agent for the NSCLC therapy and targeting Shh/Gli1 signaling pathway was an effective approach to suppress tumor angiogenesis.

Matrine Protects Against MCD-Induced Development of NASH via Upregulating HSP72 and Downregulating mTOR in a Manner Distinctive From Metformin.

The present study investigated the effects of matrine on non-alcoholic steatohepatitis (NASH) in mice induced by a methionine choline-deficient (MCD) diet and the mechanism involved. The study was performed in C57B/6J mice fed a MCD diet for 6 weeks to induce NASH with or without the treatment of matrine (100 mg/kg/day in diet). Metformin was used (250 mg/kg/day in diet) as a comparator for mechanistic investigation. Administration of matrine significantly reduced MCD-induced elevations in plasma ALT and AST but without changing body or liver fat content. Along with alleviating liver injury, matrine suppressed MCD-induced hepatic inflammation (indicated by TNFα, CD68, MCP-1, and NLRP3) and fibrosis (indicated by collagen 1, TGFß, Smad3, and sirius-red staining). In comparison, metformin treatment did not show any clear sign of effects on these parameters indicative of NASH. Further examination of the liver showed that matrine treatment rescued the suppressed HSP72 (a chaperon protein against cytotoxicity) and blocked the induction of mTOR (a key protein in a stress pathway). In keeping with the lack of the improvement of the NASH features, metformin did not show any significant effect against MCD-induced changes in HSP72 and mTOR. Matrine protects against MCD-induced development of NASH which is refractory to metformin treatment. Its anti-NASH effects involve enhancing HSP72 and downregulating mTOR but do not rely on amelioration of hepatosteatosis.

[The role of stem cell-derived exosomes in repairing myocardial injury].

At present, it is generally believed that the paracrine effect of stem cells in the repair of myocardial injury is one of the important ways for stem cell therapy. Exosomes are phospholipid bilayer-enclosed nanovesicles that secreted by cells under physiological and pathological conditions. Cargo loaded into exosomes including protein, lipids and nucleic acids can be delivered to recipient cells. Therefore, exosomes are recognized as important mediators for intercellular communication. It has been suggested that exosomes from stem cells (eg. embryonic stem cells, induced pluripotent stem cells, cardiac progenitor cells, mesenchymal stem cells and cardiosphere-derived cells) have protective effects against heart injury. In this review, we summarized recent research progresses on stem cell-derived exosomes in myocardial injury, including the therapeutic effects and mechanism.

Preconditioning lessens high fat induced metabolic syndrome along with markers of increased metabolic capacity in muscle and adipose tissue.

Postnatal overconsumption of fat is believed to increase the susceptibility to metabolic disease in the later life. Here we examined whether prior exposure to high fat (HF) in the adulthood may also accelerate the development of metabolic disorders in mice. Adult mice (12 weeks) were pre-exposed to two episodes of an HF diet each for 2 weeks followed by 2 weeks of washout with a low-fat diet. The mice were then fed the same HF diet for 6 weeks. Unexpectedly, prior exposures to HF diet significantly alleviated body weight gain, visceral adiposity and glucose/insulin intolerance during the period of last HF feeding. These protective effects were evident without changing calorie intake and were specific for HF, but not high fructose (HFru) diet. Following the HF prior exposures was increases in plasma fibroblast growth factor 21 (FGF21), the expressions of phospho-AMP-activated protein kinase (pAMPK), mitochondrial complex II and the expression of uncoupling protein (UCP) 3 in muscle and UCP1 and Sirtuin 1 (SIRT1) in adipose tissue. However, in the liver there was no significant change in pAMPK, SIRT1 expression or the capacity of glucose production. These findings indicated that, instead of exacerbating metabolic conditions, prior exposures to HF diet lead to the preconditioning against subsequent overload of HF, possibly involving FGF21-associated enhancement of markers for metabolic capacity in muscle and adipose tissue. This paradoxical phenomenon may offer a unique paradigm to identify factors and explore dietary ingredients with beneficial effects for the control of the metabolic syndrome in humans.

CuS Nanodot-Loaded Thermosensitive Hydrogel for Anticancer Photothermal Therapy.

The purpose of this research is to establish an injectable hydrogel encapsulating copper sulfide (CuS) nanodots for photothermal therapy against cancer. The CuS nanodots were prepared by one-pot synthesis, and the thermosensitive Pluronic F127 was used as the hydrogel matrix. The CuS nanodots and the hydrogel were characterized by morphous, particle size, serum stability, photothermal performance upon repeated 808 nm laser irradiation, and rheology features. The effects of the CuS nanodots and the hydrogel were evaluated qualitatively and quantitatively in 4T1 mouse breast cancer cells. The retention, photothermal efficacy, therapeutic effects, and systemic toxicity of the hydrogel were assessed in tumor bearing mouse model. The CuS nanodots with a diameter of about 8 nm exhibited satisfying serum stability, photoheat conversion ability, and repeated laser exposure stability. The hydrogel encapsulation did not negatively influence the above features of the photothermal agent. The nanodot-loaded hydrogel shows a phase transition at body temperature and, as a result, a long retention in vivo. The photothermal-agent-embedded hydrogel played a promising photothermal therapeutic effect in the tumor bearing mouse model with low systemic toxicity after peritumoral administration.