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Despite standard treatment for non-small cell lung cancer (NSCLC) being surgical resection, cancer recurrence and complications, such as induction of malignant pleural effusion (MPE) and significant postoperative pain, usually result in treatment failure. In this study, an alginate-based hybrid hydrogel (SOG) is developed that can be injected into the resection surface of the lungs during surgery. Briefly, endoplasmic reticulum-modified liposomes (MSLs) pre-loaded with the signal transducer and activator of transcription 3 (STAT3) small interfering RNA and lidocaine hydrochloride are encapsulated in SOG. Once applied, MSLs strongly downregulated STAT3 expression in the tumor microenvironment, resulting in the apoptosis of lung cancer cells and polarization of tumor-associated macrophages towards the M1-like phenotype. Meanwhile, the release of lidocaine hydrochloride (LID) was beneficial for pain relief and natural killer cell activation. Our data demonstrated MSL@LID@SOG not only efficiently inhibited tumor growth but also potently improved the quality of life, including reduced MPE volume and pain relief in orthotopic NSCLC mouse models, even with a single administration. MSL@LID@SOG shows potential for comprehensive clinical management upon tumor resection in NSCLC, and may alter the treatment paradigms for other cancers.

Abstract Immune checkpoint inhibitors (ICIs) have shown remarkable success in cancer treatment. However, in cancer patients without sufficient antitumor immunity, numerous data indicate that blocking the negative signals elicited by immune checkpoints is ineffective. Drugs that stimulate immune activation‐related pathways are emerging as another route for improving immunotherapy. In addition, the development of nanotechnology presents a promising platform for tissue and cell type‐specific delivery and improved uptake of immunomodulatory agents, ultimately leading to enhanced cancer immunotherapy and reduced side effects. In this review, we summarize and discuss the latest developments in nanoparticles (NPs) for cancer immuno‐oncology therapy with a focus on lipid‐based NPs (lipid‐NPs), including the characteristics and advantages of various types. Using the agonists targeting stimulation of the interferon genes (STING) transmembrane protein as an exemplar, we review the potential of various lipid‐NPs to augment STING agonist therapy. Furthermore, we present recent findings and underlying mechanisms on how STING pathway activation fosters antitumor immunity and regulates the tumor microenvironment and provide a summary of the distinct STING agonists in preclinical studies and clinical trials. Ultimately, we conduct a critical assessment of the obstacles and future directions in the utilization of lipid‐NPs to enhance cancer immunotherapy.

Abstract Photodynamic therapy (PDT) has shown impressive therapeutic effects on various types of cancers by reactive oxygen species (ROS) generation and induction of immune responses. However, under certain conditions, the immune responses induced by PDT are not always sufficient to eradicate the remaining tumor cells. On the other hand, the photosensitizer indocyanine green (ICG) can mediate PDT under near-infrared (NIR) illumination, thereby enhancing the penetration depth of the excitation light into the tumor. We found that ICG is rapidly taken up in vitro by colorectal MC38 and CT26 tumor cells and it promotes PDT-mediated cell-killing effects. Our results furthermore revealed that ICG induces immunogenic cell death (ICD), as dendritic cells (DCs) were found to engulf ICG-PDT-treated tumor cells and undergo phenotypic maturation. ICG accumulated in tumors 2 h after administration, as measured by fluorescence and photoacoustic imaging. Considering the advantages of ICG as a photosensitizer, we sought to design a therapy that combines PDT and immune checkpoint blockade to maximize tumor control. To this end, a 25% thermosensitive polymer 407 hydrogel was included as a co-delivery platform for this treatment scheme. NIR-PDT under 808 nm irradiation in combination with cytotoxic T-lymphocyte-associated protein 4 (CTLA4)/programmed death-ligand 1 (PD-L1) checkpoint blockade prolonged survival rate of colorectal tumor-bearing mice by inducing a series of immune responses, like the phagocytosis of tumor debris by macrophages and DCs, and induction of acute inflammation, leukocyte infiltration, maturation and activation of DCs. Altogether, our work presents a NIR-triggered PDT strategy in combination with immune checkpoint blockade. Compared to a single treatment, the combination treatment increased efficiency to inhibit solid tumor growth and improved the survival rate of tumor-bearing mice.

Photodynamic therapy (PDT), which combines light and oxygen with a photosensitizer to induce reactive oxygen species (ROS)-mediated killing of primary tumor cells, benefits from non-invasive properties and its negligible toxicity to surrounding healthy tissues. In this study, we have shown that the second-generation photosensitizer FOSCAN can be internalized by tumor cells and effectively induce tumor cell death when exposed to laser irradiation in vitro. In addition, these dying tumor cells can be phagocytosed by dendritic cells and lead to their activation and maturation as assessed by in vitro co-culture models. While PDT induces immunogenic tumor cell apoptosis, its application for the treatment of tumors located in deep tissues and advanced malignancies has been limited. In this study, we demonstrate that hepatitis B core virus-like particles (HBc VLPs) can serve as a vaccine to enhance PDT-induced anti-cancer immunity by priming humoral immune responses and inducing CD8+ T cell responses. The combination of PDT and HBc VLPs increased the survival rate of MC-38 tumor-bearing mice to 55%, compared to 33% in PDT alone and no tumor-free mice in vaccine alone. Moreover, the combination effectively prevented tumor recurrence in vivo through enhanced immune memory T cells after therapy. Therefore, as both are clinically approved techniques, this combination provides a promising strategy for cancer therapy.

Bone defects are a major threat to human health, and heterotopic bone provides advantages that other materials do not provide in the treatment of bone defects. MPEG-PCL microspheres loaded with bone morphogenetic protein-2 (BMP-2/MPEG-PCL-MS) are an emerging means of culturing heterotopic bone. However, the effect of such microspheres on the quality of heterotopic bone osteogenesis has rarely been studied. The performance of heterotopic bone as a bone repair material has also rarely been reported. To explore the effect of microspheres on heterotopic bone osteogenesis and to explore the performance of heterotopic bone in bone repair, we designed compression tests, nanoindentation tests, and a finite element (FE) simulation. The effects of microspheres on the quality of heterotopic bone osteogenesis and performance of heterotopic bone as a bone repair material were evaluated from the mechanical properties, material properties, and FE simulation. The results demonstrate that eight-week heterotopic bone using microspheres has suitable mechanical and material properties, performs well in bone repair FE simulation, and can meet the material requirements of bone repair. Hence, this heterotopic bone as bone repair material has promising potential for clinical applications, and provides a good strategy for combination between tissue engineering and pharmaceutical science.

Cancer immunotherapy has shown remarkable progress in recent years. Nanocarriers, such as liposomes, have favorable advantages with the potential to further improve cancer immunotherapy and even stronger immune responses by improving cell type-specific delivery and enhancing drug efficacy. Liposomes can offer solutions to common problems faced by several cancer immunotherapies, including the following: (1) Vaccination: Liposomes can improve the delivery of antigens and other stimulatory molecules to antigen-presenting cells or T cells; (2) Tumor normalization: Liposomes can deliver drugs selectively to the tumor microenvironment to overcome the immune-suppressive state; (3) Rewiring of tumor signaling: Liposomes can be used for the delivery of specific drugs to specific cell types to correct or modulate pathways to facilitate better anti-tumor immune responses; (4) Combinational therapy: Liposomes are ideal vehicles for the simultaneous delivery of drugs to be combined with other therapies, including chemotherapy, radiotherapy, and phototherapy. In this review, different liposomal systems specifically developed for immunomodulation in cancer are summarized and discussed.

Objectives Hypericin is a polycyclic aromatic naphthodianthrone that occurs naturally. It is also an active ingredient in some species of the genus Hypericum. Emerging evidence suggests that hypericin has attracted great attention as a potential anticancer drug and exhibits remarkable antiproliferative effect upon irradiation on various tumour cells. This paper aims to summarise the anticancer effect and molecular mechanisms modulated by hypericin-medicated photodynamic therapy and its potential role in the cancer treatment. Key findings Hypericin-medicated photodynamic therapy could inhibit the proliferation of various tumour cells including bladder, colon, breast, cervical, glioma, leukaemia, hepatic, melanoma, lymphoma and lung cancers. The effect is primarily mediated by p38 mitogen-activated protein kinase (MAPK), JNK, PI3K, CCAAT-enhancer-binding protein homologous protein (CHOP)/TRIB3/Akt/mTOR, TRAIL/TRAIL-receptor, c-Met and Ephrin-Eph, the mitochondria and extrinsic signalling pathways. Furthermore, hypericin-medicated photodynamic therapy in conjunction with chemotherapeutic agents or targeted therapies is more effective in inhibiting the growth of tumour cells. Summary During the past few decades, the anticancer properties of photoactivated hypericin have been extensively investigated. Hypericin-medicated photodynamic therapy can modulate a variety of proteins and genes and exhibit a great potential to be used as a therapeutic agent for various types of cancer. [ABSTRACT FROM AUTHOR]

Chickpea isoflavones have diverse pharmacological activities but with low water solubility and bioavailability. In this work, the isoflavone content in chickpeas was first increased by germination, and then the bioaccessibility and bioavailability of isoflavones in chickpea sprout extracts (CSE) were enhanced using β-cyclodextrin (β-CD) inclusion techniques. Firstly, the total content of isoflavones was increased by 182 times through sprouting, and isoflavones were presented mostly in the germ and radicle. Then, the chickpea sprout extract/β-cyclodextrin (CSE/β-CD) inclusion complex was prepared and characterized. The in vitro test showed that the cumulative release of two isoflavones, formononetin (FMN) and biochanin A (BCA), in the CSE/β-CD was significantly increased in a simulated digestive fluid. The in vivo rat pharmacokinetics demonstrated that the inclusion of FMN and BCA by β-CD effectively increased their bioavailability in rat plasma and tissues, especially in the liver. The study provides a feasible strategy for improving the bioavailability of isoflavones from chickpeas and is also beneficial to the utilization of other legume resources.

XYY-CP1106, a candidate compound synthesized from a hybrid of hydroxypyridinone and coumarin, has been shown to be remarkably effective in treating Alzheimer’s disease. A simple, rapid and accurate high-performance liquid chromatography coupled with the triple quadrupole mass spectrometer (LC-MS/MS) method was established in this study to elucidate the pharmacokinetics of XYY-CP1106 after oral and intravenous administration in rats. XYY-CP1106 was shown to be rapidly absorbed into the blood (Tmax, 0.57–0.93 h) and then eliminated slowly (T1/2, 8.26–10.06 h). Oral bioavailability of XYY-CP1106 was (10.70 ± 1.72)%. XYY-CP1106 could pass through the blood–brain barrier with a high content of (500.52 ± 260.12) ng/g at 2 h in brain tissue. The excretion results showed that XYY-CP1106 was mainly excreted through feces, with an average total excretion rate of (31.14 ± 0.05)% in 72 h. In conclusion, the absorption, distribution and excretion of XYY-CP1106 in rats provided a theoretical basis for subsequent preclinical studies.

Alzheimer’s disease (AD) is a typical progressive neurodegenerative disorder, and with multiple possible pathogenesis. Among them, coumarin derivatives could be used as potential drugs as monoamine oxidase-B (MAO-B) inhibitors. Our lab has designed and synthesized coumarin derivatives based on MAO-B. In this study, we used nuclear magnetic resonance (NMR)-based metabolomics to accelerate the pharmacodynamic evaluation of candidate drugs for coumarin derivative research and development. We detailed alterations in the metabolic profiles of nerve cells with various coumarin derivatives. In total, we identified 58 metabolites and calculated their relative concentrations in U251 cells. In the meantime, the outcomes of multivariate statistical analysis showed that when twelve coumarin compounds were treated with U251cells, the metabolic phenotypes were distinct. In the treatment of different coumarin derivatives, there several metabolic pathways changed, including aminoacyl-tRNA biosynthesis, D-glutamine and D-glutamate metabolism, glycine, serine and threonine metabolism, taurine and hypotaurine metabolism, arginine biosynthesis, alanine, aspartate and glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, glutathione metabolism and valine, leucine and isoleucine biosynthesis. Our work documented how our coumarin derivatives affected the metabolic phenotype of nerve cells in vitro. We believe that these NMR-based metabolomics might accelerate the process of drug research in vitro and in vivo.

The changes in active components in mulberry leaves harvested in different months and their antioxidant activities were investigated. Ultra-high-performance liquid chromatography–tandem quadrupole time-of-flight mass spectrometry (UPLC–Q-TOF-MS) with multivariate statistical tools was used to investigate the chemical constituents in the extracts of mulberry leaves. The results indicated that mulberry leaves were rich in phenolic acids, flavonoids, organic acids, and fatty acid derivatives. In addition, 25 different compounds were identified in the different batches of mulberry leaves. The 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity was measured to evaluate the in vitro antioxidant activities of mulberry leaves. Among the four batches, batch A, harvested in December, exhibited the strongest DPPH radical-scavenging activity, while batch B, harvested in March, showed the weakest activity. This was related to the total phenolic content in the mulberry leaves of each batch. The optimal harvest time of mulberry leaves greatly influences the bioactivity and bioavailability of the plant.

Paris polyphylla var. chinensis (Franch.) Hara is a perennial herb belonging to the Trilliaceae family. Ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC/Q–TOF MS) was used to detect the composition of different fractions of Paris polyphylla var. chinensis leaves. Meanwhile, the extracts of different fractions were evaluated for their cytotoxic activities against four selected human cancer cell lines and one human normal epithelial cell line based on the MTT assay method. Multivariate statistical analysis was performed to screen differential compounds and to analyze the distributions between different fractions. Finally, more than 60 compounds were obtained and identified from the different fractions of Paris polyphylla var. chinensis leaves, and the chloroform and n−butanol extracts showed significant cytotoxic effects on these four cancer cells. Several compounds were preliminarily identified from different fractions, including 36 steroidal saponins, 11 flavonoids, 10 ceramides, 8 lipids, 6 organic acids, and 8 other compounds. Various compounds were screened out as different chemical components of different fractions, which were considered as a potential substance basis for the cytotoxicity of Paris polyphylla var. chinensis leaves.

Pomaces of sea buckthorn berry were usually side-products during the processing of juice. Due to a lack of an economical and effective extraction method, it was typically recognized as waste. For the purpose of resource utilization, the mechanochemical-assisted extraction (MCAE) method was applied to develop an ecofriendly extraction method and product with better pharmacology activity. The parameters were investigated through response surface methodology (RSM) design experiments. The processing conditions were optimized as follows: amount of Na2CO3 40%, ball-to-material rate 29:1 g/g, milling speed 410 rpm, milling time 24 min, extraction temperature 25 °C, extraction time 20 min and the solid-to-solution ratio 1:10 g/mL. Under these conditions, the yields of flavonoids from sea buckthorn pomaces were 26.82 ± 0.53 mg/g, which corresponds to an increase of 2 times in comparison with that extracted by the heat reflux extraction method. Meanwhile, the hepatoprotective activity of sea buckthorn pomaces extracts was studied by the liver injury induced by ip injection of tetracycline. Biochemical and histopathological studies showed that biomarkers in serum and liver of nonalcoholic fatty liver disease (NAFLD) mice were significantly ameliorated when sea buckthorn flavonoids extracted by MCAE were used. Altogether, these results demonstrate that, as a green and efficient extraction, MCAE treatment could increase the extraction yield of sea buckthorn flavonoids, meanwhile it could exhibit significant activity of improving liver function. This research provided a new way to use pomaces of sea buckthorn as a functional food. It also has great value on the comprehensive utilization of nature’s resources.

Ellagic acid is a phenolic compound that exhibits both antimutagenic and anticarcinogenic activity in a wide range of assays in vitro and in vivo. It occurs naturally in some foods such as raspberries, strawberries, grapes, and black currants. In this study, a valid and reliable method based on mechanochemical-assisted extraction (MCAE) and macroporous adsorption resin was developed to extract and prepare ellagic acid from Phyllanthus urinaria L. (PUL). The MCAE parameters, acidolysis, and macroporous adsorption resin conditions were investigated. The key MCAE parameters were optimized as follows: the milling time was 5 min, the ball mill speed was 100 rpm, and the ball mill filling rate was 20.9%. Sulfuric acid with a concentration of 0.552 mol/L was applied for the acidolysis with the optimized acidolysis time of 30 min and acidolysis temperature of 40 °C. Additionally, the XDA-8D macroporous resin was chosen for the purification work. Both the static and dynamic adsorption tests were carried out. Under the optimized conditions, the yield of ellagic acid was 10.2 mg/g, and the content was over 97%. This research provided a rapid and efficient method for the preparation of ellagic acid from the cheaply and easily obtained PUL. Meanwhile, it is relatively low-cost work that can provide a technical basis for the comprehensive utilization of PUL.

Burdock (Arctium lappa L.) is one of the nutritional foods widely planted in many countries. Dried burdock root (BR) is available as a herbal tincture and tea in many Asian countries with good flavor and taste. In this study, the volatile components in dried BR were identified and the effects of different drying methods on the volatile components were investigated by HS-GC-MS method. A total of 49 compounds were identified. Different drying methods including hot-air drying (HD, at 50, 60, 70, and 80 °C), vacuum drying (VD, at 50, 60, 70, and 80 °C), sunlight drying (SD), natural drying (ND), and vacuum freeze drying (VFD) were evaluated by HS-GC-MS-based metabolomics method. Results showed that different drying methods produced different effects on the volatile compounds. It was observed that 2,3-pentanedione, 1-(1H-pyrrol-2-yl)-ethanone, furfural, and heptanal were detected at higher concentrations in HD 80 and VD 70. The traditional HD and SD methods produced more flavor substances than VFD. The BR treated by the VFD method could maintain the shape of the fresh BR pieces while HD50 and VD80 methods could maintain the color of fresh BR pieces. These findings could help better understand the flavor of the corresponding processed BR and provide a guide for the drying and processing of BR tea.

Background: Temperature is one of the main variables need to be regulated in cryogenic wind tunnel to realize the true flight Reynolds number. A new control methodology based on L1 output feedback adaptive control is deployed in the temperature control. Methods: This design is composed of three parts: linear quadratic Gaussian baseline control, L1 adaptive control and nonlinear feedforward control. A linear quadratic Gaussian controller is implemented as the baseline controller to provide the basic robustness of temperature control. A L1 output feedback adaptive controller with a modified piecewise constant adaptive law is deployed as an augmentation for the baseline controller to cancel the uncertainties within the actuator’s bandwidth. The modified adaptive law can guarantee better steady-state tracking performance compared with the standard adaptive law. A global nonlinear optimization process is carried out to obtain a suboptimal filter design for the L1 controller to maximize the performance index. The nonlinear feedforward control is to cancel the coupling effects in control of the tunnel. Results: With these design techniques, the augmented L1 adaptive controller improves the performance of the baseline controller in the presence of uncertainties of dynamics. The simulation results and analysis demonstrate the effectiveness of the proposed control architecture. Conclusion: The modification of adaptive law plus the global nonlinear optimization of the filter in the L1 adaptive control architecture helps the controller achieve good control performance and acceptable robustness for the temperature control over a wide range of operations.

Orthosiphon stamineus Benth. (OS) is a traditional folk medicine for the treatment of kidney stones and other urinary tract diseases. In this study, a rapid and sensitive Ultra high-performance liquid chromatography (UHPLC)-MS/MS approach was established and validated for the simultaneous quantification of nine bioactive components in rat plasma. The nine components from OS extract detected in rat plasma were danshensu, protocatechuic acid, caffeic acid, rosmarinic acid, salvianolic acid A, salvianolic acid B, cichoric acid, sinensetin and eupatorin. After liquid-liquid extraction with ethyl acetate, the plasma samples were subjected to a triple quadrupole mass spectrometer employing electrospray ionization (ESI) technique and operating in multiple reaction monitoring (MRM) with both positive and negative ion modes. The standard curves showed good linear regression (r > 0.9915) over the concentration range for the nine analytes. The inter-day and intra-day precision and accuracy were found to be within 15% of the nominal concentration. The recovery and stability of nine compounds were all demonstrated to be within acceptable limits. The approach was successfully applied to investigate the pharmacokinetic analysis of the nine bioactive components after oral administration of OS extract in rats.