Paeoniflorin Coordinates Macrophage Polarization and Mitigates Liver Inflammation and Fibrogenesis by Targeting the NF-[Formula: see text]B/HIF-1α Pathway in CCl4-Induced Liver Fibrosis.

Liver fibrosis is a disease largely driven by resident and recruited macrophages. The phenotypic switch of hepatic macrophages can be achieved by chemo-attractants and cytokines. During a screening of plants traditionally used to treat liver diseases in China, paeoniflorin was identified as a potential drug that affects the polarization of macrophages. The aim of this study was to evaluate the therapeutic effects of paeoniflorin in an animal model of liver fibrosis and explore its underlying mechanisms. Liver fibrosis was induced in Wistar rats via an intraperitoneal injection of CCl4. In addition, the RAW264.7 macrophages were cultured in the presence of CoCl2 to simulate a hypoxic microenvironment of fibrotic livers in vitro. The modeled rats were treated daily with either paeoniflorin (100, 150, and 200[Formula: see text]mg/kg) or YC-1 (2[Formula: see text]mg/kg) for 8 weeks. Hepatic function, inflammation and fibrosis, activation of hepatic stellate cells (HSC), and extracellular matrix (ECM) deposition were assessed in the in vivo and in vitro models. The expression levels of M1 and M2 macrophage markers and the NF-[Formula: see text]B/HIF-1[Formula: see text] pathway factors were measured using standard assays. Paeoniflorin significantly alleviated hepatic inflammation and fibrosis, as well as hepatocyte necrosis in the CCl4-induced fibrosis model. Furthermore, paeoniflorin also inhibited HSC activation and reduced ECM deposition both in vivo and in vitro. Mechanistically, paeoniflorin restrained M1 macrophage polarization and induced M2 polarization in the fibrotic liver tissues as well as in the RAW264.7 cells grown under hypoxic conditions by inactivating the NF-[Formula: see text]B/HIF-1[Formula: see text] signaling pathway. In conclusion, paeoniflorin exerts its anti-inflammatory and anti-fibrotic effects in the liver by coordinating macrophage polarization through the NF-[Formula: see text]B/HIF-1[Formula: see text] pathway.

The Efficacy of Volumetric Modulated Arc Therapy Combined With Chemotherapy, Brachytherapy, and Local Hyperthermia on Patients with Locally Advanced Cervical Cancer: A Retrospective Study.

OBJECTIVE: To evaluate the clinical outcomes of volumetric modulated arc therapy (VMAT) followed by brachytherapy (BT), combined with chemotherapy, and local hyperthermia (HT) on locally advanced cervical cancer (LACC). METHODS: In total, 40 patients with FIGO stage IB1-IVB cervical cancer from January 2016 to December 2018 were selectively enrolled in this study. All patients were treated with VMAT (50.4 Gy/1.8 Gy/28 f) concurrent with cisplatin-based chemotherapy (40 mg/m2, q1w, 6 cycles) and local HT (40.5-41°C for 60 min, BIW). BT (30-36 y/5-6 f, 2 f/w) was conducted after VMAT. Objective response rate (ORR), local control (LC) time, LC rate, progression-free survival (PFS) rate, cancer-specific survival (CSS) rate, overall survival (OS), median time to tumor progression and treatment-related toxicity were evaluated. RESULTS: The median follow-up time was 31 months (8-48). The ORR was 100% at 3 months after treatment and 92.1% at 6 months, respectively. The 1-year, 2-year, and 3-year LC rates were 87.4%, 81.9%, and 70.9%, respectively. The average LC time was 31.50 ± 1.89 months (95% CI 27.79-35.21). The 1-year, 2-year, and 3-year PFS rates were 75.85%, 61.2%, and 51.3%, respectively, while the median PFS was 27.07 months. The 1-year, 2-year, and 3-year OS rates were 95%, 84%, and 79.6%, respectively. In total, 12(30%) patients had grade 3/4 bone marrow suppression. One patient had grade 4 leukopenia. In total, 17 patients had grade 1/2 bone marrow suppression. Two patients had grade 3 nausea and grade 3 vomiting reaction, respectively. No grade 3/4 proctitis and bladder reaction were observed. In the late period of treatment, 1 patient had a rectal hemorrhage. In total, 13 patients had vaginal stenosis. CONCLUSION: VMAT concurrent with chemotherapy, BT, and local HT had a favorable short-term efficacy and acceptable toxicity on cervical cancer, which was an alternative option for LACC.

Baicalin inhibits hepatocellular carcinoma cell growth and metastasis by suppressing ROCK1 signaling.

Hepatocellular carcinoma (HCC) is a common malignancy affecting many people worldwide. Baicalin is a flavonoid extracted from the dried root of Scutellaria baicalensis Georgi. It can effectively inhibit the occurrence and development of HCC. Nonetheless, the mechanism through which Baicalin inhibits HCC growth and metastasis remain unknown. This work discovered that Baicalin inhibited HCC cell proliferation, invasion, metastasis while inducing cell cycle arrest at the G0/G1 phase and apoptosis. In vivo HCC xenograft results indicated that Baicalin inhibited HCC growth. Western blotting analysis indicated that Baicalin suppressed the expressions of ROCK1, p-GSK-3ß, and ß-catenin, whereas it up-regulated the expressions of GSK-3ß and p-ß-catenin. Baicalin also reduced the expressions of Bcl-2, C-myc, Cyclin D1, MMP-9, and VEGFA, while increasing the expression of Bax. Molecular docking revealed that Baicalin docked in the binding site of the ROCK1 agonist, with a binding energy of -9 kcal/mol between the two. In addition, lentivirus-mediated suppression of ROCK1 expression improved the inhibitory effect of Baicalin on the proliferation, invasion, and metastasis of HCC and the expression of proteins associated with ROCK1/GSK-3ß/ß-catenin signaling pathway. Moreover, restoring ROCK1 expression decreased the anti-HCC efficacy of Baicalin. These findings suggest that Baicalin may decrease HCC proliferation and metastasis by suppressing ROCK1/GSK-3ß/ß-catenin signaling.

SNS alleviates depression-like behaviors in CUMS mice by regluating dendritic spines via NCOA4-mediated ferritinophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Depression is one of the most common mood disturbances worldwide. The Si-ni-san formula (SNS) is a famous classic Traditional Chinese Medicine (TCM) widely used to treat depression for thousands of years in clinics. However, the mechanism underlying the therapeutic effect of SNS in improving depression-like behaviors following chronic unpredictable mild stress (CUMS) remains unknown. AIM OF THE STUDY: This study aimed to investigate whether SNS alleviates depression-like behaviors in CUMS mice by regulating dendritic spines via NCOA4-mediated ferritinophagy in vitro and in vivo. STUDY DESIGN AND METHODS: In vivo, mice were exposed to CUMS for 42 days, and SNS (4.9, 9.8, 19.6 g/kg/d), fluoxetine (10 mg/kg/d), 3-methyladenine (3-MA) (30 mg/kg/d), rapamycin(1 mg/kg/d), and deferoxamine (DFO) (200 mg/kg/d) were conducted once daily during the last 3 weeks of the CUMS procedure. In vitro, a depressive model was established by culture of SH-SY5Y cells with corticosterone, followed by treatment with different concentrations of freeze-dried SNS (0.001, 0.01, 0.1 mg/mL) and rapamycin (10 nM), NCOA4-overexpression, Si-NCOA4. After the behavioral test (open-field test (OFT), sucrose preference test (SPT), forced swimming test (FST) and tail suspension test (TST), dendritic spines, GluR2 protein expression, iron concentration, and ferritinophagy-related protein levels (P62, FTH, NCOA4, LC3-II/LC3-I) were tested in vitro and in vivo using immunohistochemistry, golgi staining, immunofluorescence, and Western blot assays. Finally, HEK-293T cells were transfected by si-NCOA4 or GluR2-and NCOA4-overexpression plasmid and treated with corticosterone(100 µM), freeze-dried SNS(0.01 mg/mL), rapamycin(25 nM), and 3-MA(5 mM). The binding amount of GluR2, NCOA4, and LC3 was assessed by the co-immunoprecipitation (CO-IP) assay. RESULTS: 3-MA, SNS, and DFO promoted depressive-like behaviors in CUMS mice during OFT, SPT, FST and TST, improved the amount of the total, thin, mushroom spine density and enhanced GluR2 protein expression in the hippocampus. Meanwhile, treatment with SNS decreased iron concentrations and inhibited NCOA4-mediated ferritinophagy activation in vitro and in vivo. Importantly, 3-MA and SNS could prevent the binding of GluR2, NCOA4 and LC3 in corticosterone-treated HEK-293T, and rapamycin reversed this phenomenon after treatment with SNS. CONCLUSION: SNS alleviates depression-like behaviors in CUMS mice by regulating dendritic spines via NCOA4-mediated ferritinophagy.

Biejiajian pill inhibits progression of hepatocellular carcinoma by downregulating PDGFRß signaling in cancer-associated fibroblasts.

ETHNOPHARMACOLOGICAL RELEVANCE: Biejiajian pill (BJJP) is a canonical formula that is clinically used to treat chronic liver disease, especially to decrease the incidence of hepatocellular carcinoma (HCC). However, the mechanisms underlying the prevention of HCC progression by BJJP remain unclear. AIM OF THE STUDY: This study aimed to determine whether BJJP inhibits HCC progression by downregulating platelet-derived growth factor receptor beta (PDGFRß) signaling in cancer-associated fibroblasts (CAFs) in a mouse model of diethylnitrosamine (DEN)/carbon tetrachloride (CCl4)-induced HCC. MATERIALS AND METHODS: C57BL/6 male mice were intraperitoneally injected with DEN 2 weeks after birth, followed by repeated injections of CCl4 weekly from 6 weeks of age onwards, to recapitulate features of HCC. At week 14, BJJP was orally administered to mice. The effects of BJJP on HCC progression were evaluated using histology, immunohistochemistry, and serum biochemical marker levels. Transcriptome analysis, molecular docking, quantitative real-time PCR, and Western blot were used to study the genes targeted by BJJP and the associated signaling pathway. The effects of BJJP on PDGFRß signaling in CAFs and the underlying mechanism were demonstrated. RESULTS: BJJP treatment significantly suppressed carcinogenesis and cancer progression, and it ameliorated liver inflammation in mice with HCC. A total of 176 genes, including PDGFRß, were significantly downregulated after BJJP treatment and five components of BJJP with high binding affinity to PDGFRß were identified. BJJP inhibited the phosphorylation of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), and glycogen synthase kinase 3 beta (GSK3ß) by suppressing PDGFRß expression in CAFs, and it also downregulated the expression of the downstream proteins hepatocyte growth factor (HGF) and vascular endothelial growth factor A (VEGF-A). Furthermore, BJJP-containing serum consistently reduced PDGFRß, HGF, and VEGF-A expression levels in HSC-derived CAFs in vitro. Importantly, PDGF-BB induced PDGFRß activation in CAFs and both BJJP and sunitinib (a kinase inhibitor) inhibited PDGF-BB/PDGFRß signaling. CONCLUSION: BJJP inhibits the progression of HCC through suppressing VEGF-A and HGF expression in CAFs by downregulating PDGFRß signaling.

Is vitamin D deficiency a risk factor for all-cause mortality and rehospitalization in heart failure patients?: A systematic review and meta-analysis.

OBJECTIVE: The association of low 25-hydroxyvitamin D level with mortality and rehospitalization remains inconsistent in patients with heart failure. This systematic review and meta-analysis aimed to evaluate the value of blood 25-hydroxyvitamin D level in predicting all-cause mortality and hospitalization in heart failure patients. METHODS: Two reviewers independently search the articles indexed in PubMed and Embase databases until November 30, 2021. Only the prospective or retrospective cohort studies evaluating the association of blood 25-hydroxyvitamin D level with all-cause mortality and rehospitalization in heart failure patients were selected. The predictive value of 25-hydroxyvitamin D level was summarized by pooling multivariable adjusted risk estimates for the bottom versus reference top 25-hydroxyvitamin D level. RESULTS: Seven studies with a total of 5941 patients with heart failure were identified. The pooled adjusted risk ratio (RR) of all-cause mortality was 1.37 (95% confidence interval [CI] 1.13-1.66), with significant heterogeneity (I2 = 70.5%; P = 0.002). However, there was no clear association between low 25-hydroxyvitamin D level and all-cause rehospitalization risk (RR 1.38; 95% CI 0.87-2.19). CONCLUSIONS: Low blood level of 25-hydroxyvitamin D may be an independent risk factor for all-cause mortality in patients with heart failure. Serum 25-hydroxyvitamin D level may provide prognostic information in heart failure patients. Additional randomized controlled trials are required to explore whether treatment of 25-hydroxyvitamin D deficiency by supplementation of vitamin D can improve survival in heart failure patients.

A Novel In Situ Method for Simultaneously and Selectively Measuring AsIII, SbIII, and SeIV in Freshwater and Soils.

Anthropogenic and climatic perturbations redistribute arsenic (As), antimony (Sb), and selenium (Se) within the environment. The speciation characteristics of these elements determine their behavior and biogeochemical cycling, but these redox-sensitive species are challenging to capture, with few methods able to harmonize measurements across the whole plant-soil-ecosystem continuum. In this study, we developed a novel diffusive gradient in thin films (DGT) method based on aminopropyl and mercaptopropyl bi-functionalized mesoporous silica spheres (AMBS) to achieve in-situ, simultaneous, and selective quantification of AsIII, SbIII, and SeIV, three typical/toxic but difficult to measure inorganic species. When used for environmental monitoring within a river catchment, AMBS-DGT exhibited stable/accurate predictions of these species despite varying water chemistries (ionic strength 0.01-200 mmol L-1 NO3-, pH 5-9 for AsIII and SbIII, and pH 5-7.5 for SeIV). Furthermore, river deployments also showed that time-averaged species concentrations by AMBS-DGT were reproducible compared with high-frequency sampling and measurement by high performance liquid chromatography coupled with inductively coupled plasma mass spectroscopy. When AMBS-DGT was used for sub-mm scale chemical imaging of soil solute fluxes, the method resolved concomitant redox-constrained spatial patterns of AsIII, SbIII, and SeIV associated with root O2 penetration within anaerobic soil. Improved capabilities for measurement of compartment interfaces and microniche features are critical alongside the measurement of larger-scale hydrological processes that dictate the fine-scale effects, with the AMBS-DGT achieving this for AsIII, SbIII, and SeIV.

Engineering naphthalimide-cyanine integrated near-infrared dye into ROS-responsive nanohybrids for tumor PDT/PTT/chemotherapy.

Photodynamic (PDT) and photothermal therapies (PTT) are emerging treatments for tumour ablation. Organic dyes such as porphyrin, chlorin, phthalocyanine, boron-dipyrromethene and cyanine are the clinically or preclinically used photosensitizer or photothermal agents. Development of structurally diverse near-infrared dyes with long absorption wavelength is of great significance for PDT and PTT. Herein, we report a novel near-infrared dye ML880 with naphthalimide modified cyanine skeleton. The introduction of naphthalimide moiety results in stronger electron delocalization and larger redshift in emission compared with IR820. Furthermore, ML880 is co-loaded with chemotherapeutic drug into ROS-responsive mesoporous organosilica (RMON) to construct nanomedicine NBD&ML@RMON, which exhibits remarkable tumor inhibition effects through PDT/PTT/chemotherapy in vivo.

Validation and Assessment of Diffusive Gradients in Thin-Films (DGT) Technique for Measuring Nutrients in Taihu Lake Water with Algae Bloom.

DGT (diffusive gradients in thin films) technique has been developed for measuring nitrogen in freshwaters and applied to assess the bioavailability of phosphorus in soils/sediments. These two elements are the main nutrients causing algae bloom, but DGT has never been used in the field water conditions with algae bloom. In our study, a pair of DGT devices were used in comparison with grab sampling to characterize the performance of this technique to measure labile NO3-N, NH4-N, and PO4-P concentrations in algae-cultivated Taihu Lake water. The results showed that DGT measurement was highly affected by algae bloom and the environmental conditions using the current assemblies, especially for NH4-N measurement. For in situ measurement of nutrients in the real environment, an improvement to the DGT technique is required. The comprehensive assessment of the level of eutrophication needs to consider a variety of environmental factors rather than just the concentration of nutrients.

Biejiajian Pill Promotes the Infiltration of CD8+ T Cells in Hepatocellular Carcinoma by Regulating the Expression of CCL5.

Tumor-infiltrating CD8+T lymphocytes are mostly associated with a favorable prognosis in numerous cancers, including hepatocellular carcinoma (HCC). Biejiajian Pill (BJJP) is a common type of traditional Chinese medicine that is widely used in the treatment of HCC in China. Previous studies showed that BJJP suppressed the growth of HCC cells both in vivo and in vitro, by exerting direct cytotoxic effects on tumor cells. The present study demonstrated that in addition to direct cytotoxicity, BJJP inhibits the growth of tumor cells by promoting the infiltration of CD8+T cells into the tumor in H22-bearing mice. Mechanistically, chemokine ligand 5 (CCL5) was identified as one of the most highly expressed chemokines by tumor cells in vivo after treatment with BJJP. Additionally, CCL5 was knocked down in H22 cells and the results showed that knockdown of the gene significantly impaired the infiltration of CD8+T cells in vivo. Furthermore, the effects of BJJP on human HCC cell lines were assessed in vitro. Similarly, cells treated with BJJP had higher expression of CCL5 mRNA, which was consistent with increased levels of CCL5 protein in human tumor cells. These findings provide new insights into the anticancer effects of BJJP, which regulated the expression of CCL5 and the infiltration of CD8+T cells. The results, therefore, suggest that BJJP has great potential application in clinical practice.

Second near-infrared photothermal-amplified immunotherapy using photoactivatable composite nanostimulators.

BACKGROUND: The construction of a nanoimmune controlled-release system that spatiotemporally recognizes tumor lesions and stimulates the immune system response step by step is one of the most potent cancer treatment strategies for improving the sensitivity of immunotherapy response. RESULTS: Here, a composite nanostimulator (CNS) was constructed for the release of second near-infrared (NIR-II) photothermal-mediated immune agents, thereby achieving spatiotemporally controllable photothermal-synergized immunotherapy. CNS nanoparticles comprise thermosensitive liposomes as an outer shell and are internally loaded with a NIR-II photothermal agent, copper sulfide (CuS), toll-like receptor-9 (TLR-9) agonist, cytosine-phospho-guanine oligodeoxynucleotides, and programmed death-ligand 1 (PD-L1) inhibitors (JQ1). Following NIR-II photoirradiation, CuS enabled the rapid elevation of localized temperature, achieving tumor ablation and induction of immunogenic cell death (ICD) as well as disruption of the lipid shell, enabling the precise release of two immune-therapeutical drugs in the tumor region. Combining ICD, TLR-9 stimulation, and inhibited expression of PD-L1 allows the subsequent enhancement of dendritic cell maturation and increases infiltration of cytotoxic T lymphocytes, facilitating regional antitumor immune responses. CONCLUSION: CNS nanoparticle-mediated photothermal-synergized immunotherapy efficiently suppressed the growth of primary and distant tumors in two mouse models and prevented pulmonary metastasis. This study thus provides a novel sight into photo-controllably safe and efficient immunotherapy.

Pyridoxine regulates hair follicle development via the PI3K/Akt, Wnt and Notch signalling pathways in rex rabbits.

This study was conducted to evaluate the effect of pyridoxine on the development of hair follicles in Rex rabbits and the underlying molecular mechanism. Two hundred 3-month-old Rex rabbits were randomly divided into 5 groups and fed diets supplemented with 0, 5, 10, 20, or 40 mg/kg pyridoxine. The hair follicle density on the dorsal skin and the gene and protein expression levels of components of the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB or Akt), Wnt, Notch and bone morphogenetic protein (BMP) signalling pathways were measured. In addition, free hair follicles were isolated from Rex rabbits and cultured with pyridoxine in vitro to measure hair shaft growth. Furthermore, dermal papilla cells (DPC) were isolated from the skin of Rex rabbits and cultured with pyridoxine in vitro to measure the gene and protein expression levels of components of the PI3K/Akt, Wnt, Notch and BMP signalling pathways. The results showed that the addition of dietary pyridoxine significantly increased the total follicle density, secondary follicle density, and secondary-to-primary ratio (S/P, P < 0.05), that the growth ratio of hair stems was promoted by pyridoxine in basic culture medium, and that the growth length of tentacle hair follicles cultured in the pyridoxine group was longer than that in the control group (P < 0.05). In addition, pyridoxine changed the DPC cycle progression and promoted cell proliferation, and appropriate concentrations of pyridoxine (10 and 20 µmol/L) significantly inhibited cell apoptosis (P < 0.05). Pyridoxine significantly affected the gene expression of components of the PI3K/Akt, Wnt and Notch signalling pathways in the skin and DPC of Rex rabbits (P < 0.05), increased the levels of phosphorylated catenin beta 1 (CTNNB1) and Akt, and decreased the level of phosphorylated glycogen synthase kinase 3 beta (GSK-3ß) (P < 0.05). Therefore, the molecular mechanism by which pyridoxine promotes hair follicle density in Rex rabbits probably occurs through activation of the PI3K/Akt, Wnt and Notch signalling pathways, prolonging hair follicle growth and delaying the onset of telogen.

Radioactive Iodine-125 in Tumor Therapy: Advances and Future Directions.

Radioactive iodine-125 (I-125) is the most widely used radioactive sealed source for interstitial permanent brachytherapy (BT). BT has the exceptional ability to deliver extremely high doses that external beam radiotherapy (EBRT) could never achieve within treated lesions, with the added benefit that doses drop off rapidly outside the target lesion by minimizing the exposure of uninvolved surrounding normal tissue. Spurred by multiple biological and technological advances, BT application has experienced substantial alteration over the past few decades. The procedure of I-125 radioactive seed implantation evolved from ultrasound guidance to computed tomography guidance. Compellingly, the creative introduction of 3D-printed individual templates, BT treatment planning systems, and artificial intelligence navigator systems remarkably increased the accuracy of I-125 BT and individualized I-125 ablative radiotherapy. Of note, utilizing I-125 to treat carcinoma in hollow cavity organs was enabled by the utility of self-expandable metal stents (SEMSs). Initially, I-125 BT was only used in the treatment of rare tumors. However, an increasing number of clinical trials upheld the efficacy and safety of I-125 BT in almost all tumors. Therefore, this study aims to summarize the recent advances of I-125 BT in cancer therapy, which cover experimental research to clinical investigations, including the development of novel techniques. This review also raises unanswered questions that may prompt future clinical trials and experimental work.

Combining Multiple High-Resolution In Situ Techniques to Understand Phosphorous Availability Around Rice Roots.

Resolving chemical/biological drivers of P behavior around lowland/flooded rice roots remains a challenge because of the heterogeneity of the plant-soil interactions, compounded by sampling and analytical constraints. High-spatial-resolution (sub-mm) visualization enables these processes to be isolated, characterized, and deciphered. Here, three advanced soil imaging systems, diffusive gradients in thin-film technique coupled with laser ablation-ICPMS (DGT-LA-ICPMS), O2 planar optode, and soil zymography, were integrated. This trio of approaches was then applied to a rice life cycle study to quantify solute-P supply, through two dimensions, in situ, and low-disturbance high-resolution (HR) chemical imaging. This allowed mechanisms of P release to be delineated by O2, Fe, and phosphatase activity mapping at the same scale. HR-DGT revealed P depletion around both living and dead rice roots but with highly spatially variable Fe/P ratios (∼0.2-12.0) which aligned with changing redox conditions and root activities. Partnering of HR-DGT and soil zymography revealed concurrent P depletion and phosphatase hotspots in the rhizosphere and detritusphere zones (Mantel: 0.610-0.810, p < 0.01). This close affinity between these responses (Pearson correlation: -0.265 to -0.660, p < 0.01) cross-validates the measurements and reaffirms that P depletion stimulates phosphatase activity and Porg mineralization. The µ-scale biogeochemical landscape of rice rhizospheres and detritusphere, as documented here, needs greater consideration when implementing interventions to improve sustainable P nutrition.

Sinisan Protects Primary Hippocampal Neurons Against Corticosterone by Inhibiting Autophagy via the PI3K/Akt/mTOR Pathway.

Objective: Corticosterone causes significant neurotoxicity in primary hippocampal neurons which is associated with depression. Dysfunctional autophagy is implicated in cognitive impairment and depressive-like behavior. The traditional Chinese medicine Sinisan (SNS) is highly effective in clinical treatment of depression. However, the molecular mechanisms underlying therapeutic effects of SNS are unknown. Purpose: The aim of this study was to elucidate the protective effect of SNS and the underlying mechanisms against corticosterone-induced neuronal damage. Study Design: The effects of serum derived from rats containing SNS (or untreated controls) on the expression of autophagy-related molecules in primary rat hippocampal neurons exposed to different concentrations of corticosterone for different intervals were explored. Methods: CCK-8 assay, LDH assay were used to analyze cell viability and LDH activity. Western blot, qRT-PCR, and immunofluorescence assays were used to determine protein and mRNA expression levels of molecules such as LC3, p62, Beclin1, ULK1, PI3K, p-PI3K, Akt p-Akt, mTOR, p-mTOR, p70S6, p-p70S6, 4ebp1 and p-4ebp1. Results: Corticosterone induced a dose- and time-dependent reduction in cellular viability. Moreover, corticosterone (100-400 µM) treatment for 24 h increased LC3-II/LC3-I protein ratio, increased Beclin1 and ULK1 protein expression levels, and decreased p62, PI3K, p-PI3K, p-Akt, p-mTOR, p-p70S6, and p-4ebp1 protein expression levels. Notably, SNS-containing serum reversed corticosterone-induced reduction of neuronal viability, and increased p62, PI3K, p-Akt, p-mTOR, p-p70S6, and p-4ebp1 protein and mRNA expression levels. In addition, SNS-containing serum decreased LC3-II/LC3-I protein ratio, and downregulated Beclin1, and ULK1 protein and mRNA expression in primary hippocampal neurons. Conclusion: SNS protects primary hippocampal neurons against corticosterone-induced neurotoxicity by preventing excessive autophagy through activation of PI3K/AKT/mTOR pathway.

Biejiajian Pill Inhibits Carcinogenesis and Metastasis via the Akt/GSK-3ß/Snail Signaling Pathway in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is among the most usual cancers globally. In China, Biejiajian pill (BJJP), Traditional Chinese Medicine clinical prescription, is broadly utilized for the prevention and therapy of HCC. However, the mechanisms by which BJJP exerts its effects on the prevention of tumor invasion and metastasis are still largely unknown. In this study, in vitro multiple hepatic cancer cell lines and an in vivo xenograft mice model were used to validate the preventive effects and molecular mechanisms of BJJP in HCC. We established that BJJP significantly repressed the proliferation, metastasis and infiltration of HCC cells. Furthermore, BJJP remarkably suppressed HCC cell migration, as well as invasion via epithelial-mesenchymal transition (EMT) by modulating Snail expression, which was associated with the repression of Akt/GSK-3ß/Snail signaling axis activation. In vivo HCC xenograft results indicated that BJJP delayed HCC development and efficiently inhibited lung metastasis. Taken together, BJJP was shown to be an effective therapeutic agent against HCC through repression of the Akt/GSK-3ß/Snail signaling cascade and EMT.

Polymer-based hydrogels with local drug release for cancer immunotherapy.

Immunotherapy that boosts the body's immune system to treat local and distant metastatic tumors has offered a new treatment option for cancer. However, cancer immunotherapy via systemic administration of immunotherapeutic agents often has two major issues of limited immune responses and potential immune-related adverse events in the clinic. Hydrogels, a class of three-dimensional network biomaterials with unique porous structures can achieve local delivery of drugs into tumors to trigger the antitumor immunity, resulting in amplified immunotherapy at lower dosages. In this review, we summarize the recent development of polymer-based hydrogels as drug release systems for local delivery of various immunotherapeutic agents for cancer immunotherapy. The constructions of polymer-based hydrogels and their local delivery of various drugs in tumors to achieve sole immunotherapy, and chemotherapy-, and phototherapy-combinational immunotherapy are introduced. Furthermore, a brief conclusion is given and existing challenges and further perspectives of polymer-based hydrogels for cancer immunotherapy are discussed.

Near-infrared photoresponsive drug delivery nanosystems for cancer photo-chemotherapy.

Drug delivery systems (DDSs) based on nanomaterials have shown a promise for cancer chemotherapy; however, it remains a great challenge to localize on-demand release of anticancer drugs in tumor tissues to improve therapeutic effects and minimize the side effects. In this regard, photoresponsive DDSs that employ light as an external stimulus can offer a precise spatiotemporal control of drug release at desired sites of interest. Most photoresponsive DDSs are only responsive to ultraviolet-visible light that shows phototoxicity and/or shallow tissue penetration depth, and thereby their applications are greatly restricted. To address these issues, near-infrared (NIR) photoresponsive DDSs have been developed. In this review, the development of NIR photoresponsive DDSs in last several years for cancer photo-chemotherapy are summarized. They can achieve on-demand release of drugs into tumors of living animals through photothermal, photodynamic, and photoconversion mechanisms, affording obviously amplified therapeutic effects in synergy with phototherapy. Finally, the existing challenges and further perspectives on the development of NIR photoresponsive DDSs and their clinical translation are discussed.

Near-infrared photothermal liposomal nanoantagonists for amplified cancer photodynamic therapy.

Photodynamic therapy (PDT) has been demonstrated to be a promising strategy for the treatment of cancer, while its therapeutic efficacy is often compromised due to excessive concentrations of glutathione (GSH) as a reactive oxygen species (ROS) scavenger in cancer cells. Herein, we report the development of near-infrared (NIR) photothermal liposomal nanoantagonists (PLNAs) for amplified PDT through through the reduction of intracellular GSH biosynthesis. Such PLNAs were constructed via encapsulating a photosensitizer, indocyanine green (ICG) and a GSH synthesis antagonist, l-buthionine sulfoximine (BSO) into a thermal responsive liposome. Under NIR laser irradiation at 808 nm, PLNAs generate mild heat via a ICG-mediated photothermal conversion effect, which leads to the destruction of thermal responsive liposomes for a controlled release of BSO in a tumor microenvironment, ultimately reducing GSH levels. This amplifies intracellular oxidative stresses and thus synergizes with PDT to afford an enhanced therapeutic efficacy. Both in vitro and in vivo data verify that PLNA-mediated phototherapy has an at least 2-fold higher efficacy in killing cancer cells and inhibiting tumor growth compared to sole PDT. This study thus demonstrates a NIR photothermal drug delivery nanosystem for amplified photomedicine.

Efficacy and safety of CT-guided 125I seed implantation as a salvage treatment for locally recurrent head and neck soft tissue sarcoma after surgery and external beam radiotherapy: A 12-year study at a single institution.

OBJECTIVES: The objective of this study was to evaluate the efficacy and safety of CT-guided radioactive 125I seed implantation as a salvage treatment for locally recurrent head and neck soft tissue sarcoma (HNSTS) after surgery and external beam radiotherapy. METHODS AND MATERIALS: From December 2006 to February 2018, 25 patients with locally recurrent HNSTS after surgery and external beam radiotherapy were enrolled. All the patients successfully underwent CT-guided 125I seed implantation. The primary end points included the objective response rate (ORR) and local progression-free survival (LPFS). The secondary end points were survival (OS) and safety profiles. RESULTS: After 125I seed implantation, the ORR was 76.0%. The 1-, 3-, and 5-year LPFS rates were 65.6%, 34.4%, and 22.9%, respectively, with the median LPFS of 16.0 months. The 1-, 3-, and 5-year OS rates were 70.8%, 46.6%, and 34.0%, respectively, with the median OS of 28.0 months. Furthermore, univariate analyses showed that the recurrent T stage and histological grade were prognostic factors of LPFS, whereas only the histological grade was a predictor of OS. The major adverse events were skin/mucosal toxicities, which were generally of lower grade (≤Grade 2) and were well tolerated. CONCLUSIONS: Radioactive 125I seed implantation could be an effective and safe alternative treatment for locally recurrent HNSTS after failure of surgery and radiotherapy. Recurrent T stage and histological grade were the main factors influencing the efficacy.