[Mechanism of total saponins of Panax japonicus against liver injury induced by acetaminophen in mice based on ERK/NF-κB/COX-2 signaling pathway].

This study investigated the effects and mechanisms of total saponins of Panax japonicus(TSPJ) against liver injury induced by acetaminophen(APAP). Male Kunming mice were randomly divided into a blank control group, TSPJ group(200 mg·kg~(-1), ig), model group, APAP+ TSPJ low-dose group(50 mg·kg~(-1), ig), APAP+ TSPJ medium-dose group(100 mg·kg~(-1), ig), APAP+ TSPJ high-dose group(200 mg·kg~(-1), ig), and APAP+ N-acetyl-L-cysteine group(200 mg·kg~(-1), ip). The administration group received the corresponding medications via ig or ip once a day for 14 consecutive days. After the last administration for one hour, except for the blank control group and TSPJ group, all groups of mice were given 500 mg·kg~(-1) APAP by gavage. After 24 hours, mouse serum and liver tissue were collected for serum alanine aminotransferase(ALT), aspartate aminotransferase(AST), reactive oxygen species(ROS), tumor necrosis factor alpha(TNF-α), interleukin-1 beta(IL-1ß), cyclooxygenase-2(COX-2), IL-6, IL-4, IL-10, as well as lactate dehydrogenase(LDH), glutathione(GSH), superoxide dismutase(SOD), catalase(CAT), total antioxidant capacity(T-AOC), malondialdehyde(MDA), and myeloperoxidase(MPO) liver tissue. Hematoxylin-eosin staining was used to observe the morphological changes of liver tissue. The mRNA expression levels of lymphocyte antigen 6G(Ly6G), galectin 3(Mac-2), TNF-α, IL-1ß, COX-2, IL-6, IL-4, and IL-10 in liver tissue were determined by quantitative real-time polymerase chain reaction(PCR). Western blot was utilized to detect the protein expression levels of Ly6G, Mac-2, extracellular regulated protein kinases(ERK), phosphorylated extracellular regulated protein kinases(p-ERK), COX-2, inhibitor of nuclear factor κB protein α(IκBα), phosphorylated inhibitor of nuclear factor κB protein α(p-IκBα), and nuclear factor-κB subunit p65(NF-κB p65) in cytosol and nucleus in liver tissue. The results manifested that TSPJ dramatically reduced liver coefficient, serum ALT, AST, ROS, TNF-α, IL-1ß, IL-6, and COX-2 levels, LDH, MPO, and MDA contents in liver tissue, and mRNA expressions of TNF-α, IL-1ß, and IL-6 in APAP-induced liver injury mice. It prominently elevated serum IL-4 and IL-10 levels, GSH, CAT, SOD, and T-AOC contents, and mRNA expressions of IL-4 and IL-10 in liver tissue, improved the degree of liver pathological damage, and suppressed neutrophil infiltration and macrophage recruitment in liver tissue. In addition, TSPJ lessened the mRNA and protein expressions of neutrophil marker Ly6G, macrophage marker Mac-2, and COX-2 in liver tissue, protein expressions of p-ERK, p-IκBα, and NF-κB p65 in nuclear, and p-ERK/ERK and p-IκBα/p-IκBα ratios and hoisted protein expression of NF-κB p65 in cytosol. These results suggest that TSPJ has a significant protective effect on APAP-induced liver injury in mice, and it can alleviate APAP-induced oxidative damage and inflammatory response. Its mechanism may be related to suppressing ERK/NF-κB/COX-2 signaling pathway activation, thus inhibiting inflammatory cell infiltration, cytokine production, and liver cell damage.

Urolithin B Attenuates Cerebral Ischemia-reperfusion Injury by Modulating Nrf2-regulated Anti-oxidation in Rats.

Ischemia-reperfusion (IR) induces a wide range of irreversible injuries. Cerebral IR injury (IRI) refers to additional brain tissue damage that occurs after blood flow is restored following cerebral ischemia. Currently, no established methods exist for treating IRI. Oxidative stress is recognized as a primary mechanism initiating IRI and a crucial focal target for its treatment. Urolithin B, a metabolite derived from ellagitannins, antioxidant polyphenols, has demonstrated protective effects against oxidative stress in various disease conditions. However, the precise mechanism underlying UB's effect on IRI remains unclear. In our current investigation, we assessed UB's ability to mitigate neurological functional impairment induced by IR using a neurological deficit score. Additionally, we examined cerebral infarction following UB administration through TTC staining and neuron Nissl staining. UB's inhibition of neuronal apoptosis was demonstrated through the TUNEL assay and Caspase-3 measurement. Additionally, we examined UB's effect on oxidative stress levels by analyzing malondialdehyde (MDA) concentration, superoxide dismutase (SOD) activity, and immunohistochemistry analysis of inducible nitric oxide synthase (iNOS) and 8-hydroxyl-2'-deoxyguanosine (8-OHdG). Notably, UB demonstrated a reduction in oxidative stress levels. Mechanistically, UB was found to stimulate the Nrf2/HO-1 signaling pathway, as evidenced by the significant reduction in UB's neuroprotective effects upon administration of ATRA, an Nrf2 inhibitor. In summary, UB effectively inhibits oxidative stress induced by IR through the activation of the Nrf2/HO-1 signaling pathway. These findings suggest that UB holds promise as a therapeutic agent for the treatment of IRI.

miR-1180 Targets FXYD5 to Regulate Pancreatic Cancer Cells Migration and Invasion.

Pancreatic cancer is a fatal malignancy typically diagnosed in older males and has an aggressive progression. The function of the miR-1180/FXYD5 axis in pancreatic cancer malignant behaviors was investigated. 20 pairs of pancreatic cancer and adjacent normal tissue samples were harvested from pancreatic cancer patients, and qRT-PCR, IHC, and western blot assays were performed, respectively, to detect the mRNA expression and protein levels of miR-1180 or FXYD5. Transwell and scratch assays were conducted to detect the migratory and invasive ability of pancreatic cancer cells; a Dual-luciferase reporter assay was employed to validate miR-1180 targeting FXYD5. miR-1180 targeting FXYD5 to regulate the migratory and invasive ability of pancreatic cancer cells was validated in mouse xenograft tumor models. FXYD5 expression was increased in pancreatic cancer tissue samples than in adjacent normal tissue samples (P < 0.01), and FXYD5 expression exhibited a positive correlation with the migratory and invasive ability of pancreatic cancer cells. miR-1180 targeted FXYD5 and negatively regulated FXYD5. Restoring miR-1180 expression could inhibit the migratory and invasive ability of pancreatic cancer cells (P < 0.01), and this effect could potentially be alleviated by FXYD5 overexpression. The miR-1180/FXYD5 axis positively regulated E-cadherin and negatively regulated MMP2 and MMP9 expression levels. In vivo findings demonstrated that miR-1180 overexpression inhibited tumor growth and lung metastasis (P < 0.05), while FXYD5 overexpression promoted tumor growth and lung metastasis (P < 0.05). In conclusion, the miR-1180 /FXYD5 axis could be involved in pancreatic cancer metastasis through the regulation of EMT and extracellular matrix degradation.

Tumor Metabolism-Rewriting Nanomedicines for Cancer Immunotherapy.

Cancer immunotherapy has become an established therapeutic paradigm in oncologic therapy, but its therapeutic efficacy remains unsatisfactory in the majority of cancer patients. Accumulating evidence demonstrates that the metabolically hostile tumor microenvironment (TME), characterized by acidity, deprivation of oxygen and nutrients, and accumulation of immunosuppressive metabolites, promotes the dysfunction of tumor-infiltrating immune cells (TIICs) and thereby compromises the effectiveness of immunotherapy. This indicates the potential role of tumor metabolic intervention in the reinvigoration of antitumor immunity. With the merits of multiple drug codelivery, cell and organelle-specific targeting, controlled drug release, and multimodal therapy, tumor metabolism-rewriting nanomedicines have recently emerged as an attractive strategy to strengthen antitumor immune responses. This review summarizes the current progress in the development of multifunctional tumor metabolism-rewriting nanomedicines for evoking antitumor immunity. A special focus is placed on how these nanomedicines reinvigorate innate or adaptive antitumor immunity by regulating glucose metabolism, amino acid metabolism, lipid metabolism, and nucleotide metabolism at the tumor site. Finally, the prospects and challenges in this emerging field are discussed.

Jujuboside B suppresses angiogenesis and tumor growth via blocking VEGFR2 signaling pathway.

Jujuboside B (JuB), one of the main active triterpenoid saponins from the traditional Chinese medicine Ziziphus jujuba, possesses a wide range of pharmacological activities. However, it is unknown whether JuB can inhibit tumor angiogenesis, a crucial step in solid tumor growth. In this study, we found that JuB significantly inhibited the proliferation, migration, and tube formation of human umbilical vein endothelial cells in a dose-dependent manner. JuB also suppressed angiogenesis in chick embryo chorioallantoic membranes and Matrigel plugs. Moreover, through angiogenesis inhibition, JuB delayed the growth of human HCT-15 colorectal cancer xenograft in mice. Western blot assay demonstrated that JuB inhibited the phosphorylation of VEGFR2 and its key downstream protein kinases, such as Akt, FAK, Src, and PLCγ1. In conclusion, the antiangiogenic potency and molecular mechanism of JuB are revealed for the first time, indicating that this triterpene saponin may be further explored as a potential drug candidate or lead compound for antiangiogenic cancer therapy.

Identification and Quantification of 5-Methylcytosine and 5-Hydroxymethylcytosine on Random DNA Sequences by a Nanoconfined Electrochemiluminescence Platform.

5-Methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are two of the most abundant epigenetic marks in mammalian genomes, and it has been proven that these dual epigenetic marks give a more accurate prediction of recurrence and survival in cancer than the individual mark. However, due to the similar structure and low expression of 5mC and 5hmC, it is challenging to distinguish and quantify the two methylation modifications. Herein, we employed the ten-eleven translocation family dioxygenases (TET) to convert 5mC to 5hmC via a specific labeling process, which realized the identification of the two marks based on a nanoconfined electrochemiluminescence (ECL) platform combined with the amplification strategy of a recombinase polymerase amplification (RPA)-assisted CRISPR/Cas13a system. Benefiting from the TET-mediated conversion strategy, a highly consistent labeling pathway was developed for identifying dual epigenetic marks on random sequence, which reduced the system error effectively. The ECL platform was established via preparing a carbonized polymer dot embedded SiO2 nanonetwork (CPDs@SiO2), which exhibited higher ECL efficiencies and more stable ECL performance compared to those of the scattered emitters due to the nanoconfinement-enhanced ECL effect. The proposed bioanalysis strategy could be employed for the identification and quantification of 5mC and 5hmC in the range from 100 aM to 100 pM, respectively, which provides a promising tool for early diagnosis of diseases associated with abnormal methylation.

Delayed-onset adenosine deaminase deficiency with a novel synonymous mutation and a case series from China.

BACKGROUND: Adenosine deaminase (ADA) is a key enzyme in the purine salvage pathway. Genetic defects of the ADA gene can cause a subtype of severe combined immunodeficiency. To date, few Chinese cases have been reported. METHODS: We retrospectively reviewed the medical records of patients diagnosed with ADA deficiency in Beijing Children's Hospital and summarized the previously published ADA deficiency cases from China in the literature. RESULTS: Nine patients were identified with two novel mutations (W272X and Q202 =). Early-onset infection, thymic abnormalities and failure to thrive were the most common manifestations of Chinese ADA-deficient patients. The ADA genotype has a major effect on the clinical phenotype. Notably, a novel synonymous mutation (c.606G>A, p.Q202=) was identified in a delayed-onset patient, which affected pre-mRNA splicing leading to a frameshift and premature truncation of the protein. Furthermore, the patient showed γδT cells expansion with an increased effect or phenotype, which may be associated with the delayed onset of disease. In addition, we reported cerebral aneurysm and intracranial artery stenosis for the first time in ADA deficiency. Five patients died with a median age of four months, while two patients received stem cell transplantation and are alive. CONCLUSIONS: This study described the first case series of Chinese ADA-deficient patients. Early-onset infection, thymic abnormalities and failure to thrive were the most common manifestations in our patients. We identified a synonymous mutation that affected pre-mRNA splicing in the ADA gene, which had never been reported in ADA deficiency. Furthermore, we reported cerebral aneurysm in a delayed-onset patient for the first time. Further study is warranted to investigate the underlying mechanisms.

Periplocin inhibits hepatocellular carcinoma progression and reduces the recruitment of MDSCs through AKT/NF-κB pathway.

AIMS: We aimed to evaluate the effect of periplocin on inhibiting hepatocellular carcinoma (HCC) and further determine its mechanisms. MAIN METHODS: Cytotoxic activity of periplocin against HCC cells was tested by CCK-8 and colony formation assays. The antitumor effects of periplocin were evaluated in human HCC SK-HEP-1 xenograft and murine HCC Hepa 1-6 allograft mouse models. Flow cytometry was used to measure cell cycle distribution, apopotosis, and the number of myeloid-derived suppressor cells (MDSCs). Hoechst 33258 dye was applied to observe the nuclear morphology. Network pharmacology was performed to predict possible signaling pathways. Drug affinity responsive target stability assay (DARTS) was used to evaluate AKT binding of periplocin. Western blotting, immunohistochemistry, and immunofluorescence were used to examine the protein expression levels. KEY FINDING: Periplocin inhibited cell viability with IC50 values from 50 nM to 300 nM in human HCC cells. Periplocin disrupted cell cycle distribution and promoted cell apoptosis. Moreover, AKT was predicted as the target of periplocin by network pharmacology, which was confirmed by that AKT/NF-κB signaling was inhibited in periplocin-treated HCC cells. Periplocin also inhibited the expression of CXCL1 and CXCL3, leading to decreased accumulation of MDSCs in HCC tumors. SIGNIFICANCE: These findings reveal the function of periplocin in inhibiting HCC progression by G2/M arrest, apoptosis and suppression of MDSCs accumulation through blockade of the AKT/NF-κB pathway. Our study further suggests that periplocin has the potential to be developed as an effective therapeutic agent for HCC.

Analysis of the typing of adenovirus and its clinical characteristics in children with acute respiratory tract infection.

BACKGROUND: The purpose of this study was to investigate the typing of adenovirus (AdV) infection in children hospitalized with acute respiratory tract infection (ARTI) and its clinical characteristics. METHODS: Samples from 7832 hospitalized children with ARTIs from January 2021 to June 2022 were tested by multiplex PCR for AdV. AdV hex neighborhood genes were amplified and sequenced for typing by nested PCR. RESULTS: Three hundred twenty-eight cases were positive for AdV with rate of 4.48% (328/7832). No statistical difference in the rate of AdV detection was observed in different ages (P > 0.05). Among the 328 cases, 305 cases underwent amplification and sequence determination of AdV five-neighborhood, six-neighborhood and fibronectin genes. Only 237 cases were sequenced successfully for all 3 genetic fragments. The typing results of 231 cases with 3 genes were consistent, with 49.78% (115/231) of type 3, 41.56% (96/231) of type 7 and 8.66% (20/231) of other types identified. The main clinical symptoms in 231 children hospitalized with ARTI who were AdV positive were cough, sputum not easily coughable, Wheezing or shortness of breath and fever. Clinical diagnoses of 231 cases included: acute bronchitis 3.03% (7/231), capillary bronchitis 16.45% (38/231), pneumonia (mild/severe) 76.62% (177/231) (68.40% (158/231) in mild and 8.23% (19/231) in severe cases), bronchial asthma combined with pulmonary infection 3.46% (8/231). Higher percentage of shortness of breath, multilobar infiltration, and pleural effusion were found in type 7. Calcitoninogen in type 7 were significantly higher than those of type 3 and other types, and the white blood cell count was lower than those of type 3 and other types, and the difference was statistically significant (P < 0.05). CONCLUSION: AdV type 3 and 7 were frequently found in hospitalized children with acute lower respiratory tract involvement. AdV type 7 seems to be associated with more severe outcome.

Performing robot-assisted pylorus and vagus nerve-preserving gastrectomy for early gastric cancer: A case series of initial experience.

BACKGROUND: Pylorus and vagus nerve-preserving gastrectomy (PPG) is a function-preserving surgery for early gastric cancer (GC) that has gained considerable interest in the recent years. The operative technique performed using the Da Vinci Xi robot system is considered ideal for open and laparoscopic surgery. AIM: To introduce Da Vinci Xi robot-assisted PPG (RAPPG)-based operative procedure and technical points as well as report the initial experience based on the clinical pathology data of eight cases of early GC. METHODS: Da Vinci Xi robot-assisted pylorus and vagus nerve-preserving gastrectomy (RAPPG) was performed for 11 consecutive patients with middle GC from December 2020 to July 2021. Outcome measures were postoperative morbidity, operative time, blood loss, number of lymph nodes harvested, postoperative hospital stay, time to first flatus, time to diet, and resection margins. RESULTS: Eight of the 11 patients who were pathologically diagnosed with early GC were enrolled in a retrospective study to assess the feasibility and safety of RAPPG. The mean operative time, mean blood loss, mean number of lymph nodes harvested, length of preserved pylorus canal, distal margin, and proximal margin were 330.63 ± 47.24 min, 57.50 ± 37.70 mL, 18.63 ± 10.57, 3.63 ± 0.88 cm, 3.50 ± 1.31 cm, and 3.63 ± 1.19 cm, respectively. None of the cases required conversion to laparotomy. Postoperative complications occurred in two (25.0%) patients. Postoperative complications were hyperamylasemia and gastric stasis in one case and incision infection in the other. Time to first flatus was 3.75 ± 2.49 d after the operation, and postoperative hospital stay was 10.13 ± 4.55 d. CONCLUSION: The core technique in the Da Vinci Xi RAPPG is lymph node dissection and the anatomic method of the nerve. Robotic surgical procedures are feasible and safe. With the progress of surgical technology, optimization of medical insurance structure, and emergence of evidence-based medicine, automated surgery systems will have a broad application in clinical treatment.

Metaplastic breast cancer with chondrosarcomatous differentiation combined with concurrent bilateral breast cancer: A case report.

BACKGROUND: Metaplastic breast carcinoma (MBC) is a rare subtype of invasive breast cancer comprising malignant epithelial and mesenchymal cells. Compared with other invasive breast cancers, MBC is not only histologically distinctly heterogeneous but also has a rapid and aggressive growth pattern, which leads to a significant risk of recurrence and mortality. CASE SUMMARY: In this study, we report the case of a patient with a large left breast mass diagnosed with bilateral invasive ductal carcinoma in both breasts after a preoperative core needle aspiration biopsy of the bilateral breast mass. The patient received neoadjuvant chemotherapy and underwent bilateral breast modified radical mastectomy. Postoperative pathology suggested carcinosarcoma with predominantly chondrosarcoma in the left breast and invasive ductal carcinoma (luminal B) in the right breast. As the patient did not achieve complete pathological remission after six cycles of neoadjuvant chemotherapy, we administered six months of intensive capecitabine treatment. Then the patient was switched to continuous treatment with endocrine therapy using letrozole + goserelin, and the patient is currently in stable condition. However, as MBC of the breast is concurrently diagnosed with chondrosarcoma differentiation, our case is sporadic. CONCLUSION: Given the variety of immunohistochemical types of bilateral breast cancer, achieving effective chemotherapy should be a key research focus.

Light-Triggered Efficient Sequential Drug Delivery of Biomimetic Nanosystem for Multimodal Chemo-, Antiangiogenic, and Anti-MDSC Therapy in Melanoma.

In view of the multiple pathological hallmarks of tumors, nanosystems for the sequential delivery of various drugs whose targets are separately located inside and outside tumor cells are desired for improved cancer therapy. However, current sequential delivery is mainly achieved through enzyme- or acid-dependent degradation of the nanocarrier, which would be influenced by the heterogeneous tumor microenvironment, and unloading efficiency of the drug acting on the target outside tumor cells is usually unsatisfactory. Here, a light-triggered sequential delivery strategy based on a liposomal formulation of doxorubicin (DOX)-loaded small-sized polymeric nanoparticles (DOX-NP) and free sunitinib in the aqueous cavity, is developed. The liposomal membrane is doped with photosensitizer porphyrin-phospholipid (PoP) and hybridized with red blood cell membrane to confer biomimetic features. Near-infrared light-induced membrane permeabilization triggers the "ultrafast" and "thorough" release of sunitinib (100% release in 5 min) for antiangiogenic therapy and also myeloid-derived suppressor cell (MDSC) inhibition to reverse the immunosuppressive tumor environment. Subsequently, the small-sized DOX-NP liberated from the liposomes is more easily uptaken by tumor cells for improved immunogenic chemotherapy. RNA sequencing and immune-related assay indicates therapeutic immune enhancement. This light-triggered sequential delivery strategy demonstrates the potency in cancer multimodal therapy against multiple targets in different spatial positions in tumor microenvironment.

A nano-innate immune system activator for cancer therapy in a 4T1 tumor-bearing mouse model.

BACKGROUND: Harnessing the immune system to fight cancer has led to prominent clinical successes. Strategies to stimulate innate immune effectors are attracting considerable interest in cancer therapy. Here, through conjugating multivalent Fc fragments onto the surface of mesoporous silica nanoparticles (MSN), we developed a nanoparticle-based innate immune system activator (NISA) for breast cancer immunotherapy. METHODS: NISA was prepared through conjugating mouse IgG3 Fc to MSN surface. Then, long-chain PEG5000, which was used to shield Fc to confer nanoparticle colloidal stability, was linked to the MSN surface via matrix metalloprotease-2 (MMP-2)-cleavable peptide (GPLGIAGQC). The activation of multiple components of innate immune system, including complement and the innate cells (macrophages and dendritic cells) and the associated anticancer effect were investigated. RESULTS: Fc fragments of NISA can be exposed through hydrolysis of long-chain PEG5000 by highly expressed MMP-2 in tumor microenvironment. Then, effective stimulation and activation of multiple components of innate immune system, including complement, macrophages, and dendritic cells were obtained, leading to efficient antitumor effect in 4T1 breast cancer cells and orthotopic breast tumor model in mice. CONCLUSIONS: The antitumor potency conferred by NISA highlights the significance of stimulating multiple innate immune elements in cancer immunotherapy.

Saikosaponin A, a Triterpene Saponin, Suppresses Angiogenesis and Tumor Growth by Blocking VEGFR2-Mediated Signaling Pathway.

Saikosaponin A (SSA), a main triterpenoid saponin component from Radix Bupleurum, has been revealed to have a variety of pharmacological activities. However, whether SSA can inhibit angiogenesis, a key step in solid tumor progression, remains unknown. In this study, we demonstrated that SSA could powerfully suppress the proliferation, migration, and tube formation of human umbilical vein endothelial cells. SSA also significantly inhibited angiogenesis in the models of the chick embryo chorioallantoic membrane and Matrigel plugs. Moreover, SSA was found to inhibit tumor growth in both orthotopic 4T1 breast cancer and subcutaneous HCT-15 colorectal tumor by the inhibition of tumor angiogenesis. Western blot assay indicated the antiangiogenic mechanism of SSA in the suppression of the protein phosphorylation of VEGFR2 and the downstream protein kinase including PLCγ1, FAK, Src, and Akt. In summary, SSA can suppress angiogenesis and tumor growth by blocking the VEGFR2-mediated signaling pathway.

Endothelium-specific depletion of LRP1 improves glucose homeostasis through inducing osteocalcin.

The vascular endothelium is present within metabolic organs and actively regulates energy metabolism. Here we show osteocalcin, recognized as a bone-secreted metabolic hormone, is expressed in mouse primary endothelial cells isolated from heart, lung and liver. In human osteocalcin promoter-driven green fluorescent protein transgenic mice, green fluorescent protein signals are enriched in endothelial cells lining aorta, small vessels and capillaries and abundant in aorta, skeletal muscle and eye of adult mice. The depletion of lipoprotein receptor-related protein 1 induces osteocalcin through a Forkhead box O -dependent pathway in endothelial cells. Whereas depletion of osteocalcin abolishes the glucose-lowering effect of low-density lipoprotein receptor-related protein 1 depletion, osteocalcin treatment normalizes hyperglycemia in multiple mouse models. Mechanistically, osteocalcin receptor-G protein-coupled receptor family C group 6 member A and insulin-like-growth-factor-1 receptor are in the same complex with osteocalcin and required for osteocalcin-promoted insulin signaling pathway. Therefore, our results reveal an endocrine/paracrine role of endothelial cells in regulating insulin sensitivity, which may have therapeutic implications in treating diabetes and insulin resistance through manipulating vascular endothelium.

Metal Phenolic Network-Integrated Multistage Nanosystem for Enhanced Drug Delivery to Solid Tumors.

Metal-phenolic networks (MPNs) are an emerging class of supramolecular surface modifiers with potential use in various fields including drug delivery. Here, the development of a unique MPN-integrated core-satellite nanosystem (CS-NS) is reported. The "core" component of CS-NS comprises a liposome loaded with EDTA (a metal ion chelator) in the aqueous core and DiR (a near-infrared photothermal transducer) in the bilayer. The "satellite" component comprises mesoporous silica nanoparticles (MSNs) encapsulating doxorubicin and is coated with a Cu2+ -tannic acid MPN. Liposomes and MSNs self-assemble into the CS-NS through adhesion mediated by the MPN. When irradiated with an 808 nm laser, CS-NS liberated the entrapped EDTA, leading to Cu2+ chelation and subsequent disassembly of the core-satellite nanostructure. Photo-conversion from the large assembly to the small constituent particles proceeded within 5 min. Light-triggered CS-NS disassembly enhanced the carrier and cargo penetration and accumulation in tumor spheroids in vitro and in orthotopic murine mammary tumors in vivo. CS-NS is long circulating in the blood and conferred improved survival outcomes to tumor-bearing mice treated with light, compared to controls. These results demonstrate an MPN-integrated multistage nanosystem for improved solid tumor treatment.

SERS diagnosis of liver fibrosis in the early stage based on gold nanostar liver targeting tags.

In order to realize the accurate and early diagnosis of liver fibrosis, a long slow pathological process which may lead to cirrhosis or even liver cancer, liver targeting tags made up of gold nanostars and glycyrrhetinic acid are reported in this paper. Gold nanostars (GNSs) and GNS liver targeting tags (GLTTs) were injected into model mice with stage S1 liver fibrosis and normal mice via the tail vein respectively, then the SERS spectra were collected. GLTTs had a better detection effect on liver tissue than unmodified GNSs (12.85 times), and better detection reproducibility as well. Moreover, according to the MTT and survival analysis experiments, GLTTs also had better biocompatibility. Hence, the changes of 10 SERS signals and other substances in the early stage of liver fibrosis were analyzed at the molecular level, and the SERS characteristic peaks that could be used for the diagnosis of early liver fibrosis were screened out. Revealed by the experimental results, the GLTTs designed and prepared were applicable to the efficient SERS detection of early liver fibrosis in mice, and the strategy we have proposed might be a potential approach for the early diagnosis of this disease in clinics.

Autophagy Induced by a Novel Triazol Derivative Promotes Angiogenesis Through Decreasing Interferon-Inducible Protein 10 Level in Vascular Endothelial Cells.

ABSTRACT: Autophagy plays an important role in angiogenesis, whereas the mechanisms of vascular endothelial cell (VEC) autophagy associated with angiogenesis remain unclear. In this study, we identified a novel triazol derivative (JL025) that significantly promoted angiogenesis both in vitro and in vivo. Moreover, JL025 had no effects on cell proliferation but dramatically increased the autophagy level of VEC. The suppression of autophagy inhibited JL025-induced angiogenesis in vitro and in vivo, suggesting that JL025-induced angiogenesis was dependent on the enhanced autophagy. Mechanistic studies indicated that JL025-induced VEC autophagy was related to the Protein Kinase B/mTOR signaling pathway. Meanwhile, JL025 decreased the antiangiogenic chemokine interferon-inducible protein 10 (IP10) protein level in human VECs. Importantly, the suppression of autophagy inhibited JL025-induced decrease of IP10 protein level, indicating that autophagy mediated the degradation of IP10. Taken together, our findings provide new insights into the relationship of VEC autophagy with angiogenesis, and JL025 may have a therapeutic potential in related diseases.