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Drug resistance is one of the major obstacles in the drug therapy of cancers. Efforts in this area in pre-clinical research have focused on developing novel platforms to evaluate and decrease drug resistance. In this paper, inspired by the structure of hives where swarms live and breed, we propose porous hydrogel arrays with a uniform pore structure for the generation of hepatoma cell spheroids and the investigation of drug resistance. The porous hydrogel arrays were fabricated using polyethylene glycol diacrylate (PEGDA) hydrogel to negatively replicate a well-designed template. Benefiting from the elaborate processing of the template, the prepared porous hydrogel arrays possessed a uniform pore structure. Due to their anti-adhesion properties and the excellent biocompatibility of the PEGDA hydrogel, the hepatoma cells could form well-defined and uniform hepatoma cell spheroids in the porous hydrogel arrays. We found that the resistant hepatoma cell spheroids showed more significant Lenvatinib resistance and a migratory phenotype compared with a two-dimensional (2D) cell culture, which reveals the reason for the failure of most 2D cell-selected drugs for in vivo applications. These features give such porous hydrogel arrays promising application prospects in the investigation of tumor cell spheroid culture and in vitro drug resistance.

Salivary extracellular vesicles (EVs), as novel functional carriers and potential biomarkers, are usually obtained by ultracentrifugation (UC) and polyethylene glycol (PEG)-based precipitation methods. However, salivary EVs obtained by these two methods have not been systematically compared. Here, we perform an in-depth analysis on EVs isolated by these two methods using proteomics. Both methods obtain EVs ranging from 40 to 210 nm, with the PEG method resulting in a wider size distribution. PEG-separated products were irregularly shaped and aggregated, while UC-separated ones were monodispersed and teacup-shaped. Additionally, the expression of EV-specific markers was higher in UC-separated EVs. Using tandem mass spectrometry proteomics, we identified and quantified 1217 kinds of saliva exosomal proteins and 361 kinds of differential proteins, showing that UC can isolate more EV-related proteins. These results offer some guidance for EV separating and provide potential direction for the use of EVs in non-invasive diagnosis.

Acute pancreatitis (AP) is a highly fatal acute inflammation and is often accompanied by multiple organ dysfunction syndrome (MODS). The liver, one of the most vulnerable extrapancreatic organs in AP, is the major organ involved in the evolution of the disease and correlates strongly with the occurrence of MODS. However, the etiology of pancreatitis-associated liver injury (PALI) has not been clarified and currently lacks an effective treatment. 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) is a cell permeable nucleoside with pleiotropic effects on anti-inflammatory and antioxidant stress that binds with adenosine monophosphate protein kinase (AMPK) and induces AMPK activation. However, the role of AICAR in PALI remains elusive. Here, we show that activation of AMPK by AICAR, a direct AMPK agonist, significantly ameliorates sodium taurocholate-induced PALI in rats, whereas treatment of PALI rats with the AMPK antagonist Compound C profoundly exacerbates the degree of liver injury, suggesting that hepatic AMPK activation exerts an essential protective role in PALI. Mechanistically, AICAR induces AMPK activation, which in turn activates nuclear factor erythroid 2-related factor 2(Nrf2) -regulated hepatic antioxidant capacity and inhibits NLRP3 inflammasome-mediated pyrolysis, protecting rats from sodium taurocholate-induced PALI. In addition, Nrf2 deficiency strikingly weakens the beneficial effects of AICAR on alleviation of liver injury, oxidative stress and NLRP3 inflammasome activation in L-arginine-induced PALI mice. Thus, AICAR protects against PALI in rodents by triggering AMPK, which is mediated at least in part by Nrf2-modulated antioxidant effects and NLRP3 inflammasome activation.

A film with an elaborate microstructure and multifunctions is urgently needed in wound healing. Here, we present a multiactive encapsulated inverse opal film with a monitorable delivery system for chronic wound healing. The inverse opal film is prepared by using poly(lactic-co-glycolic acid) to negatively replicate a colloidal crystal template, which presents a high specific surface area and interconnected nanopores. It could be imparted with a potent antibacterial effect and promote angiogenesis by loading the vascular endothelial growth factor into the nanopores and encapsulating by chitosan. In addition, it is demonstrated that the structure color change of the film could intuitively reflect the drug release progress from the nanopores, which made the film a real-time drug monitoring system. In the affected wound model, the properties of the multifunctional film in promoting wound healing are certified by the faster healing speed, more granulation tissue, less inflammation, and even a distribution of new blood vessels and collagen. These results indicate that the resultant multifunctional film has a practical application value in clinical wound care.

The acyl-CoA thioesterase (ACOT) family catalyses the hydrolysis of acyl-CoA thioesters to their corresponding non-esterified fatty acid and coenzyme A (CoA). Increasing evidence suggests that cancer cells generally have altered lipid metabolism in different aspects. However, the roles of the ACOT family in cancer, especially in pancreatic ductal carcinoma (PDAC), are largely unknown. In the present study, we mined data to determine the clinical significance of all eleven ACOT genes among nine major solid tumour types from TCGA database and found that the expression of ACOT4 in PDAC was negatively correlated with patient survival, establishing ACOT4 as a potential biomarker of PDAC. Depletion of ACOT4 attenuated the proliferation and tumour formation of PDAC cells. Using mass spectrometry, HSPA1A was found to associate with ACOT4. Furthermore, we found that phosphorylation of ACOT4 at S392 by AKT decreased the binding of ACOT4 to HSPA1A, resulting in ACOT4 accumulation. The ACOT4 elevation promotes pancreatic tumourigenesis by producing excessive CoA to support tumour cell metabolism. Thus, our study expands the relationship between AKT signalling and lipid metabolism and establishes a functional role of ACOT4 in PDAC.

Exosomes secreted by most cells possese many biological functions and arouse great interest in biomedical research. However, the effective and convenient methods for the capture of exosomes from clinical samples or cultured cells is still scarce. In this work, we developed novel magnetic graphene oxide nanoparticles (MGONs) for the efficient capture of exosomes, in which Fe3O4@SiO2 magnetic nanoparticles (NPs) were decorated with GO through dopamine. CD63 aptamers were attached to the surface of MGONs, which could recognize and bound to CD63 on the exosome membrane. The number of exosomes adsorbed onto the MGONs surface was 1.5 times that attached to the Fe3O4@SiO2 surface. The capture rate of exosomes reached as high as 89.4% within 15 minutes at room temperature. Moreover, exosomes can be effectively enriched and isolated under external magnetic field and the capture process did not affect their morphological structure and biological functions. Through hybridizing with a FAM-labelled single-stranded DNA probe, the concentration of captured exosomes could also be recorded by measuring the fluorescence intensity, and the limit of detection of this system reached 2.4×107 particles/ml. These aptamer-decorated MGONs also showed potential in high-effieient capture of exosomes using cancer patients samples, which demonstrated that the resultant MGONs had significant practical values in early disease diagnosis and the related clinical applications.

Integrating magnetic oxide thin films without restriction of substrates is crucial for their applications in electronic and spintronic devices. Here the water-soluble Sr3Al2O6 (SAO) layer is employed as the sacrificial layer to transfer the millimeter-size single-crystal Fe3O4 films from SrTiO3 (STO) to silicon and flexible PET substrates. Structural characterizations indicate that the transferred films have the same epitaxial quality with the as-grown films. The hysteresis loops measurements of flexible Fe3O4/PET samples show a deceasing magnetic anisotropy under both of convex and concave deformations. Such tunable magnetic anisotropy is confirmed by fitting the angular dependence of ferromagnetic resonance (FMR) fields. These results provide a damage-free way to fabricate single-crystal spinel ferrites films on the selected substrates for flexible spintronic devices.

Increasing evidences have suggested that natural killer (NK) cells in the tumor microenvironment are involved in the regulation of cancer development. However, the potential biological roles and regulatory mechanisms of NK cells in pancreatic cancer (PC) remain unclear. Co-culture system of NK cells with PC cells is used to test the ability of cancer cell proliferation, migration and invasion both in vitro and in vivo. And tail vein intravenous transfer was used to test metastasis in vivo. Meanwhile, extracellular vesicles (EVs) were separated and examined. Furthermore, reporter assay and Biotin-RNA pull down assay were performed to verify the interaction between molecules. NK cells can inhibit the malignant transformation of co-cultured PC cells both in vivo and in vitro, which requires miR-3607-3p. miR-3607-3p is found enriched in the EVs of NK cells and transmitted to PC cells, and low level of miR-3607-3p predicts poor prognosis in PC patients. It can also inhibit proliferation, migration and invasion of PC cells in vitro. Importantly, IL-26 is found to be a direct target of miR-3607-3p in PC cells. miR-3607-3p enriched in EVs derived from NK cells can inhibit the malignant transformation of PC probably through directly targeting of IL-26.

Fiber-shaped supercapacitors are considered to be one of the most promising power source candidates in flexible electronics for their light weight, high flexibility and wearability. Here, inspired by natural silkworms spinning and their hierarchical fiber structure, we present a multi-channel co-flow microfluidic strategy for one-step spinning of multicomponent carbon nanotubes (CNTs) microfiber supercapacitors. By injecting polyurethane (PU) and CNTs dispersed solutions into the microfluidic channels respectively, microfibers with single or double CNTs cores and PU shells could be continuously generated. These microfibers were also with highly tailorable structures, shapes and sizes of their encapsulated multicomponent CNTs cores through varying parameters such as microfluidic chip designs, flow rates and channel sizes. We have demonstrated that the resultant CNTs microfibers showed good flexibility, stability and cycle life performance for energy storage capacity through various electrochemical tests. Meanwhile, the practical application of CNTs microfibers in powering LED lights has also been successfully studied. Thus, we believe that these fiber-shaped CNT supercapacitors would reveal important utility in electronic applications which requiring flexible electronic systems.

Tanshinone IIA (TSA) is a lipophilic diterpene purified from the Chinese herb Danshen, which exhibits potent antioxidant and anti-inflammatory properties. Effect of TSA remains largely uninvestigated on the osteogenic differentiation of bone marrow mesenchymal stem cells (BM-MSCs), which are widely used in cell-based therapy of bone diseases. In the present study, both ALP activity at day 7 and calcium content at day 24 were upregulated during the osteogenesis of mouse BM-MSCs treated with TSA (1 and 5 μM), demonstrating that it promoted the osteogenesis at both early and late stages. We found that TSA promoted osteogenesis and inhibited osteoclastogenesis, evident by RT-PCR analysis of osteogenic marker gene expressions. However, osteogenesis was inhibited by TSA at 20 μM. We further revealed that TSA (1 and 5 μM) upregulated BMP and Wnt signaling. Co-treatment with Wnt inhibitor DKK-1 or BMP inhibitor noggin significantly decreased the TSA-promoted osteogenesis, indicating that upregulation of BMP and Wnt signaling plays a significant role and contributes to the TSA-promoted osteogenesis. Of clinical interest, our study suggests TSA as a promising therapeutic strategy during implantation of BM-MSCs for a more effective treatment of bone diseases.

Malvidin is one of the most widespread anthocyanidins which exhibits significant antioxidant and anti-inflammatory activity. The aim of this paper is to investigate the effects of Malvidin on osteoarthritis (OA). We created an animal model of OA using Wistar rats administered by monosodium iodoacetate (MIA). Effects of Malvidin on hyperalgesia were evaluated by paw pressure tests and compression threshold test. Articular chondrocytes were isolated from the OA rats to detect the apoptotic chondrocytes using senescence-associated β-galactosidase (SA-β-gal) staining kit. The expression levels of pro-inflammatory cytokines and matrix metalloproteinase (MMPs) were assessed by western blot and qPCR. Luciferase assay was used to determine the impact of Malvidin on nuclear factor-kappa B (NF-κB) pathway. Malvidin treatment exhibited significant pain-relieving effects in OA rats and decreased the expression level of apoptotic marker SA-β-gal in chondrocytes. We found that the upregulated expressions of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and MMPs induced by MIA in cartilage tissues were significantly reversed by Malvidin. Furthermore, Malvidin inhibited NF-κB pathway via an NF-κB inhibitor (IκBα)-independent manner through suppressing p65 nuclear transportation in vitro. Our findings suggest that Malvidin significantly attenuates the OA-induced pain and inflammation by inhibiting NF-κB signaling pathway and suppressing pro-inflammatory cytokine expression and chondrocyte apoptosis.

Hepatic encephalopathy (HE) refers to a complex and reversible neuro-psychiatric syndrome that results from complications of acute or chronic hepatic failure, particularly alcoholic cirrhosis. It will lead to frequent life disruptions, poor quality of life and extensive use of health care resources. We conducted the review of several agents based on randomized controlled trials (RCTs) of high-quality Jadad scores (≥3) to provide effective information for clinical practice. Rifaximin appears at least to be as effective as conventional treatments, but not superior to them. L-Ornithine-L-aspartate appears to be a safe and effective treatment of chronic HE when compared with a placebo regime. Other treatments include non-absorbable disaccharides (NAD) and benzodiazepine receptor antagonists. In spite of the variability in the improvement of HE, NAD and non-absorbed antibiotics such as rifaximin offer a favorable benefit–risk ratio in the improvement of HE. Further RCTs with power calculation and a multi-centre approach with adequate population number are needed to resolve the heterogeneous results