Integration of caveolin-mediated cytosolic delivery and enzyme-responsive releasing of squalenoyl nanoparticles enhance the anti-cancer efficacy of chidamide in pancreatic cancer.

We explored the potential of overcoming the dense interstitial barrier in pancreatic cancer treatment by enhancing the uptake of hydrophilic chemotherapeutic drugs. In this study, we synthesized the squalenoyl-chidamide prodrug (SQ-CHI), linking lipophilic squalene (SQ) with the hydrophilic antitumor drug chidamide (CHI) through a trypsin-responsive bond. Self-assembled nanoparticles with sigma receptor-bound aminoethyl anisamide (AEAA) modification, forming AEAA-PEG-SQ-CHI NPs (A-C NPs, size 116.6 ± 0.4 nm), and reference nanoparticles without AEAA modification, forming mPEG-SQ-CHI NPs (M-C NPs, size 88.3 ± 0.3 nm), were prepared. A-C NPs exhibited significantly higher in vitro CHI release (74.7 %) in 0.5 % trypsin medium compared to release (20.2 %) in medium without trypsin. In vitro cell uptake assays revealed 3.6 and 2.3times higher permeation of A-C NPs into tumorspheres of PSN-1/HPSC or CFPAC-1/HPSC, respectively, compared to M-C NPs. Following intraperitoneal administration to subcutaneous tumor-bearing nude mice, the A-C NPs group demonstrated significant anti-pancreatic cancer efficacy, inducing cancer cell apoptosis and inhibiting proliferation in vivo. Mechanistic studies revealed that AEAA surface modification on nanoparticles promoted intracellular uptake through caveolin-mediated endocytosis. This nanoparticle system presents a novel therapeutic approach for pancreatic cancer treatment, offering a delivery strategy to enhance efficacy through improved tumor permeation, trypsin-responsive drug release, and specific cell surface receptor-mediated intracellular uptake.

Albumin conjugation promotes arsenic trioxide transport through alkaline phosphatase-associated transcytosis in MUC4 wildtype pancreatic cancer cells.

Pancreatic cancer (PC) has a poor prognosis due to chemotherapy resistance and unfavorable drug transportation. Albumin conjugates are commonly used as drug carriers to overcome these obstacles. However, membrane-bound glycoprotein mucin 4 (MUC4) has emerged as a promising biomarker among the genetic mutations affecting albumin conjugates therapeutic window. Human serum albumin-conjugated arsenic trioxide (HSA-ATO) has shown potential in treating solid tumors but is limited in PC therapy due to unclear targets and mechanisms. This study investigated the transport mechanisms and therapeutic efficacy of HSA-ATO in PC cells with different MUC4 mutation statuses. Results revealed improved penetration of ATO into PC tumors through conjugated with HSA. However, MUC4 mutation significantly affected treatment sensitivity and HSA-ATO uptake both in vitro and in vivo. Mutant MUC4 cells exhibited over ten times higher IC50 for HSA-ATO and approximately half the uptake compared to wildtype cells. Further research demonstrated that ALPL activation by HSA-ATO enhanced transcytosis in wildtype MUC4 PC cells but not in mutant MUC4 cells, leading to impaired uptake and weaker antitumor effects. Reprogramming the transport process holds potential for enhancing albumin conjugate efficacy in PC patients with different MUC4 mutation statuses, paving the way for stratified treatment using these delivery vehicles.

Structural Characterization and Tumor Microvascular Inhibition Activity of Total Polysaccharide from Trametes sanguinea Lloyd.

Trametes sanguinea Lloyd total polysaccharide (TsLTP), was obtained by water extraction and ethanol precipitation from T. sanguinea. The structural characterization of TsLTP was elucidated mutually by TsL1 and TsL2, whose mass ratio is 1: 4. TsL1 is mainly composed of mannose, glucose, galactose, and fucose, and consist of T-Linked-Fucp, T-Linked-Manp, T-Linked-Galp, 1,4-Linked-Manp, 1,4-Linked-Glcp, 1,6-Linked-Manp, 1,6-Linked-Galp, 1,3,4-Linked-Glcp, 1,4,6-Linked-Glcp and 1,3,6-Linked-Glcp, with a molar ratio of 2.1: 1.7: 1.4: 1.0: 3.6: 2.0: 8.6: 1.3: 2.2: 1.2, while TsL2 mainly comprise of glucose and consist of T-Linked-Glcp, 1,3-Linked-Glcp, 1,4-Linked-Glcp and 1,4,6-Linked-Glcp, with a molar ratio of 1.0: 2.1: 7.6: 1.4. TsLTP exhibited strong inhibitory effects on the migration, invasion, and tube formation of human umbilical vein endothelial cells (iHUVECs) and chick embryo chorioallantoic membrane (CAM) angiogenesis, whereas no inhibitory activity on human TNBC cell lines. Taken together, our study suggests that TsLTP possesses a significant inhibition of tumor microvascular activity both in vitro and in vivo. The study of TsLTP with novel monosaccharide composition and tumor microvascular inhibitory activity might be a beneficial attempt for application of polysaccharide from the genus Trametes in tumor therapy.

A Novel Dye-Sensitized Solar Cell Structure Based on Metal Photoanode without FTO/ITO.

Traditional dye-sensitized solar cells (DSSC) use FTO/ITO containing expensive rare elements as electrodes, which are difficult to meet the requirements of flexibility. A new type of flexible DSSC structure with all-metal electrodes without rare elements is proposed in this paper. Firstly, a light-receiving layer was prepared outside the metal photoanode with small holes to realize the continuous oxidation-reduction reaction in the electrolyte; Secondly, the processing technology of the porous titanium dioxide (TiO2) film was analyzed. By testing the J-V characteristics, it was found that the performance is better when the heating rate is slow. Finally, the effects of different electrode material combinations were compared through experiments. Our results imply that in the case of all stainless-steel electrodes, the open-circuit voltage can reach 0.73 V, and in the case of a titanium photoanode, the photoelectric conversion efficiency can reach 3.86%.

Synthesis of highly active enzyme-metal nanohybrids and uncovering the design rules.

Nanobiohybrid CAL-B/MNPs were synthesized through enzyme in situ reduction of metal ions, including noble and non-noble metals. Lipase CAL-B acted as multifunctional reagents (reducing and supporting agents). The hybrid catalysts were systematically characterized by HRTEM, EDX, MALDI-TOF-MS, and XPS analysis, confirming that highly dispersed 3-5 nm nanoparticles were evenly dispersed on lipase matrix without agglomeration. The mechanism of CAL-B reducing metal ions was investigated, revealing that AGLFFSSKDL in the amino acid sequence of CAL-B from 111 to 128 formed a stable spatial structure through hydrogen bonding, which was the key factor for enzyme in situ reduction of metal ions into highly dispersed nanoparticles.

Anticancer activity of polymeric nanoparticles containing linoleic acid-SN38 (LA-SN38) conjugate in a murine model of colorectal cancer.

Biodegradable polymeric nanoparticles (NPs) have been used frequently as nanocarriers for anticancer drugs. Linoleic acid conjugated SN38 (LA-SN38)-loaded NPs (EBNPs) were developed using biodegradable poly (ethylene oxide)-poly (butylene oxide) (PEO-PBO) diblock copolymer by titration hydration method without using a toxic organic solvent. The EBNPs had high drug loading efficiency and entrapment efficiency for LA-SN38, at 7.53% and 93.55%, respectively. The polydispersity index (PDI) and average diameter were 0.173 ±â€¯0.019 and 226.1 ±â€¯1.2 nm, respectively. The transmission electron microscope (TEM) image presented that the NPs were homogeneous in size and had spherical structures. In vitro study showed the release behavior of EBNPs was slow and sustained. Furthermore, cytotoxicity and apoptosis assay proved that EBNPs were more effective in growth inhibition of human colon cancer cells. Cell uptake experiments further demonstrated that EBNPs could avoid the phagocytosis by macrophages and promote the uptake by cancer cells. In vivo, EBNPs had prolonged blood circulation time and tumor selectivity in biodistribution. The tumor inhibitory rate of EBNPs was higher compared to SNPs group and CPT-11group (P < 0.01), and the drug did not show significant systemic toxicity at the tested dose. These results indicated that EBNPs are a promising candidate for delivery of LA-SN38 to treat colorectal cancer.

Urinary biomarker evaluation for early detection of gentamycin-induced acute kidney injury.

Drug-induced acute kidney injury is a serious problem in drug development and clinical treatment. Thus, highly efficient and non-invasive urinary biomarkers are required to control and prevent drug-induced acute kidney injury. Expanding on a previous study, we evaluated 9 novel urinary biomarkers in beagles, which were treated with gentamycin at a dose of 40 mg/kg for 12 consecutive days. N-acetyl-ß-D-glucosaminidase was detected with high sensitivity and specificity at the early stage of renal injury (Area under the ROC cure (AUC) = 0.929, 95%CI: 0.722-0.995, P < 0.05 vs. serum creatinine and blood urea nitrogen). More importantly, the results indicated that albumin and trefoil factor-3 were significantly increased 6 days after gentamycin injection (compared with the control group, both P < 0.05). Receiver operator characteristics analysis showed that the diagnostic value of these two biomarkers were both high (both AUCs=1.000; both 95% CI: 0.832-1.000; albumin or trefoil factor-3 vs. serum creatinine or blood urea nitrogen, both P < 0.05). Moreover, albumin and trefoil factor-3 levels were highly correlated to the degree of kidney injury (both Pearson's r > 0.8, P < 0.05). Our data indicate that albumin and trefoil factor-3 may have value in the early diagnosis of kidney injury in non-rodent species and may thus inspire the preclinical use of urinary biomarkers in drug-induced acute kidney injury.

Cerium oxide nanoparticles induce cytotoxicity in human hepatoma SMMC-7721 cells via oxidative stress and the activation of MAPK signaling pathways.

BACKGROUND: Lanthanide cerium oxide (CeO2) nanoparticles have extensive applications in industrial fields, and concerns regarding their potential toxicity in humans and their environmental impact have increased. We investigated the underlying molecular mechanisms by which CeO2 nanoparticles induce toxicity in human hepatoma SMMC-7721 cells. RESULTS: Our results demonstrated that CeO2 nanoparticles reduced viability, caused dramatic morphological damage, and induced apoptosis in SMMC-7721 cells. CeO2 nanoparticles significantly increased the production of reactive oxygen species (ROS) and malondialdehyde (MDA), and significantly reduced the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-px) and catalase (CAT). The phosphorylation levels of ERK1/2, JNK and p38 MAPK were significantly elevated after treatment with CeO2 nanoparticles. Pretreatment with the antioxidant N-acetyl-cysteine (NAC): reduced the induction of ROS and MDA by CeO2 nanoparticles; recovered the activity of SOD, GSH-px and CAT; reduced the phosphorylation levels of ERK1/2, JNK and p38; and attenuated CeO2 nanoparticles-induced damage and apoptosis in SMMC-7721 cells. CONCLUSIONS: Our data demonstrated that CeO2 nanoparticles induced damage and apoptosis in human SMMC-7721 cells via oxidative stress and the activation of MAPK signaling pathways.

Taguchi approach for anti-heat stress prescription compatibility in mice spleen lymphocytes in vitro.

Heat stress (HS) may induce immunosuppression as well as inhibit the proliferation of lymphocytes. This study evaluated the effects on immune function of our prescription on splenic lymphocytes under HS as well as its compatibility. The effects of four herbal extracts from Agastache rugosa, Atractylodes lancea, Cortex Phellodendri, and Gypsum Fibrosum on heat treated splenic lymphocytes were investigated and the compatibility of the prescription was also explored by using the Taguchi method. This study revealed changes in proliferation by traditional Chinese medicines of splenic lymphocytes after HS. Proliferation in the HS group was significantly lower than the control group. Under HS, the effects of higher concentrations of Agastache rugosa (100 and 200 µg/mL), Atractylodes lancea (100 and 200 µg/mL), Cortex Phellodendri (50 and 100 µg/mL) and Gypsum Fibrosum (100 and 200 µg/mL) caused a significant increase on ConA/LPS-induced proliferation of lymphocytes than lower concentrations. We, therefore, conclude that the prescription of traditional Chinese medicines may recover splenic lymphocytes from the immunosuppression induced by HS. The Taguchi design, which allows rapid and high efficiency for the selection of the best conditions for our prescription on HS-treated splenic lymphocytes, demonstrated that Agastache rugosa (200 µg/mL), Atractylodes lancea (200 µg/mL), Cortex Phellodendri (100 µg/mL) and Gypsum Fibrosum (100 µg/mL) were the optimal conditions for the prescription. The validation experiment confirmed that our composition in optimum extraction conditions enhanced effects on ConA or LPS-stimulated lymphocytes under HS. The results showed that the Taguchi optimization approach is a suitable method for optimization of the composition of prescription.

Enhancement of Astragalus polysaccharide on the immune responses in pigs inoculated with foot-and-mouth disease virus vaccine.

The effects of Astragalus polysaccharides (APS) on the immune response in pigs immunized with foot-and-mouth disease virus (FMDV) vaccine were investigated. Fifteen pigs were randomly divided into five groups. Four groups were vaccinated with a FMDV inactivated vaccine. Pigs in three experimental groups were administered varying doses of APS (APS1, 5mg/kg; APS2, 10mg/kg; APS3, 20mg/kg). The influence of APS on the number of CD3(+)CD4(-)CD8(+) cytotoxic T cells, CD3(+)CD4(+)CD8(+) T helper memory cells, and CD3(-)CD4(-)CD8(+) natural killer cells among peripheral blood lymphocytes (PBL) in the three APS groups were significant compared to the vaccine group. In vitro stimulation of PBL by Con A and LPS in APS groups induced a stronger proliferative response at 2 and 6 weeks post-inoculation (PI). APS markedly increased the titer of FMDV-specific antibody in a dose-dependent manner, and up-regulated mRNA expression of IFN-γ and IL-6. APS could potentially be used as an immunomodulator for a FMDV vaccine and provide better protection against FMDV.

Microarray analysis of gene expression profiles of rat small intestine in response to heat stress.

Ambient temperature is a critical factor that affects biological organisms in many ways. In this study, the authors investigated gene expression changes in rat small intestine in response to heat stress. Male Sprague-Dawley rats were randomly divided into control and heat-stressed groups. Both groups were housed at 25 °C, although the heat-stressed group was also subjected to 40 °C for 2 h each day for 10 successive days. Rats were sacrificed 1, 3, 6, and 10 days after heat treatment, and sections of their small intestine epithelial tissue were excised for morphological examination and microarray analyses. The rat rectal and body surface temperatures and serum cortisol levels were all significantly increased after heat treatment (p < 0.05). The jejuna were significantly damaged by 3 days after heat treatment began. Microarray analysis showed that 422 genes were differentially expressed, of which 290 genes were significantly upregulated and 132 genes were significantly downregulated. Subsequent bioinformatics analyses revealed that the differentially expressed genes were mainly related to stress, immune regulation, and metabolism processes. The bioinformatics analysis of the differentially expressed genes should be beneficial to further investigations on the underlying mechanisms involved in heat stress-induced damage in the small intestine.

Effect of heat stress on the porcine small intestine: a morphological and gene expression study.

With the presence of global warming, the occurrence of extreme heat is becoming more common, especially during the summer, increasing pig susceptibility to severe heat stress. The aim of the current study was to investigate changes in morphology and gene expression in the pig small intestine in response to heat stress. Forty eight Chinese experimental mini pigs (Sus scrofa) were subjected to 40 degrees C for 5h each day for 10 successive days. Pigs were euthanized at 1, 3, 6, and 10 days after heat treatment and sections of the small intestine epithelial tissue were excised for morphological examination and microarray analyses. After heat treatment, the pig rectal temperature, the body surface temperature and serum cortisol levels were all significantly increased. The duodenum and jejunum displayed significant damage, most severe after 3 days of treatment. Microarray analysis found 93 genes to be up-regulated and 110 genes to be down-regulated in response to heat stress. Subsequent bioinformatic analysis (including gene ontology and KEGG pathway analysis) revealed the genes altered in response to heat stress related to unfolded protein, regulation of translation initiation, regulation of cell proliferation, cell migration and antioxidant regulation. Heat stress caused significant damage to the pig small intestine and altered gene expression in the pig jejunum. The results of the bioinformatic analysis from the present study will be beneficial to further investigate the underlying mechanisms involved in heat stress-induced damage in the pig small intestine.

[Model study on CO2 removal by photobioreactor].

The key point of study on CO2 removal by microalgae cultured in a photobioreactor is to improve CO2 removal capability. In this paper, a model of air-lift photobioreactor was developed by combination of conditions including the velocity of flow, the degree of mixing, the gas-liquid mass transfer and the rate of photosynthesis, and two corresponding simplified methods, such as time discretization and lumped parameters were put forward. Using a method of lumped parameters, the model for simulation of time course of DO, pH in the column air-lift photobioreactor and prediction of CO2, O2 concentrations in the outlet gas under different CO2 concentration in the aeration gas was thoroughly discussed. Experimental data were also used to verify the model which could potentially be applied to rational design of the photobioreactor, high-density culture of microalgae and efficient removal of CO2.