Fluorescent hyaluronic acid nanoprodrug: A tumor-activated autophagy inhibitor for synergistic cancer therapy.

Autophagy is a process that eliminates damaged cells and malfunctioning organelles via lysosomes, which is closely linked to cancer. Primaquine (PQ) was reported to impede autophagy flow by preventing autophagosomes from fusing with lysosomes at the late stage of autophagy. It will lead to cellular metabolic collapse and programmed cell death. Excessive or extended autophagy enhances the efficacy of chemotherapeutic drugs in cancer prevention. The utilization of autophagy inhibition in conjunction with chemotherapy has become a prevalent and reliable approach for the safe and efficient treatment of cancer. In this work, an acid-sensitive nanoprodrug (O@PD) targeting CD44 receptors was produced using Schiff-base linkages or electrostatic interactions from oxidized hyaluronic acid (OHA), PQ, and doxorubicin (DOX). The CD44-targeting prodrug system in triple-negative breast cancer (TNBC) cells was designed to selectively release DOX and PQ into the acidic tumor microenvironment and cellular endosomes. DOX was employed to investigate the cellular uptake and ex-vivo drug distribution of O@PD nanoprodrugs. PQ-induced autophagy suppression combined with DOX has a synergistic fatal impact in TNBC. O@PD nanoprodrugs demonstrated robust anticancer efficacy as well as excellent biological safety, making them suitable for clinical use.

Rhein kills Actinobacillus pleuropneumoniae, reduces biofilm formation, and effectively treats bacterial lung infections in mice.

Background. Actinobacillus pleuropneumoniae, a member of the Pasteurellaceae family, is known for its highly infectious nature and is the primary causative agent of infectious pleuropneumonia in pigs. This disease poses a considerable threat to the global pig industry and leads to substantial economic losses due to reduced productivity, increased mortality rates, and the need for extensive veterinary care and treatment. Due to the emergence of multi-drug-resistant strains, Chinese herbal medicine is considered one of the best alternatives to antibiotics due to its unique mechanism of action and other properties. As a type of Chinese herbal medicine, Rhein has the advantages of a wide antibacterial spectrum and is less likely to develop drug resistance, which can perfectly solve the limitations of current antibacterial treatments.Methods. The killing effect of Rhein on A. pleuropneumoniae was detected by fluorescence quantification of differential expression changes of key genes, and scanning electron microscopy was used to observe the changes in A. pleuropneumoniae status after Rhein treatment. Establishing a mouse model to observe the treatment of Rhein after A. pleuropneumoniae infection.Results. Here, in this study, we found that Rhein had a good killing effect on A. pleuropneumoniae and that the MIC was 25 µg ml-1. After 3 h of action, Rhein (4×MIC) completely kills A. pleuropneumoniae and Rhein has good stability. In addition, the treatment with Rhein (1×MIC) significantly reduced the formation of bacterial biofilms. Therapeutic evaluation in a murine model showed that Rhein protects mice from A. pleuropneumoniae and relieves lung inflammation. Quantitative RT-PCR (Quantitative reverse transcription polymerase chain reaction is a molecular biology technique that combines both reverse transcription and polymerase chain reaction methods to quantitatively detect the amount of a specific RNA molecule) results showed that Rhein treatment significantly downregulated the expression of the IL-18 (Interleukin refers to a class of cytokines produced by white blood cells), TNF-α, p65 and p38 genes. Along with the downregulation of genes such as IL-18, it means that Rhein has an inhibitory effect on the expression of these genes, thereby reducing the activation of inflammatory cells and the production of inflammatory mediators. This helps reduce inflammation and protects tissue from further damage.Conclusions. This study reports the activity of Rhein against A. pleuropneumoniae and its mechanism, and reveals the ability of Rhein to treat A. pleuropneumoniae infection in mice, laying the foundation for the development of new drugs for bacterial infections.

Crop Contamination and Human Exposure to Per- and Polyfluoroalkyl Substances around a Fluorochemical Industrial Park in China.

Due to their significant environmental impact, there has been a gradual restriction of the production and utilization of legacy per- and polyfluoroalkyl substances (PFAS), leading to continuous development and adoption of novel alternatives. To effectively identify the potential environmental risks from crop consumption, the levels of 25 PFAS, including fourteen perfluoroalkyl acids (PFAAs), two precursor substances and nine novel alternatives, in agricultural soils and edible parts of various crops around a fluoride industrial park (FIP) in Changshu city, China, were measured. The concentration of ΣPFAS in the edible parts of all crops ranged from 11.64 to 299.5 ng/g, with perfluorobutanoic acid (PFBA) being the dominant compound, accounting for an average of 71% of ΣPFAS. The precursor substance, N-methylperfluoro-octanesulfonamidoacetic acid (N-MeFOSAA), was detected in all crop samples. Different types of crops showed distinguishing accumulation profiles for the PFAS. Solanaceae and leafy vegetables showed higher levels of PFAS contamination, with the highest ΣPFAS concentrations reaching 190.91 and 175.29 ng/g, respectively. The highest ΣAlternative was detected in leafy vegetables at 15.21 ng/g. The levels of human exposure to PFAS through crop consumption for various aged groups were also evaluated. The maximum exposure to PFOA for urban toddlers reached 109.8% of the standard value set by the European Food Safety Authority (EFSA). In addition, short-chained PFAAs and novel alternatives may pose potential risks to human health via crop consumption.

Wearable EMI Shielding Composite Films with Integrated Optimization of Electrical Safety, Biosafety and Thermal Safety.

Biomaterial-based flexible electromagnetic interference (EMI) shielding composite films are desirable in many applications of wearable electronic devices. However, much research focuses on improving the EMI shielding performance of materials, while optimizing the comprehensive safety of wearable EMI shielding materials has been neglected. Herein, wearable cellulose nanofiber@boron nitride nanosheet/silver nanowire/bacterial cellulose (CNF@BNNS/AgNW/BC) EMI shielding composite films with sandwich structure are fabricated via a simple sequential vacuum filtration method. For the first time, the electrical safety, biosafety, and thermal safety of EMI shielding materials are optimized integratedly. Since both sides of the sandwich structure contain CNF and BC electrical insulation layers, the CNF@BNNS/AgNW/BC composite films exhibit excellent electrical safety. Furthermore, benefiting from the AgNW conductive networks in the middle layer, the CNF@BNNS/AgNW/BC exhibit excellent EMI shielding effectiveness of 49.95 dB and ultra-fast response Joule heating performance. More importantly, the antibacterial property of AgNW ensures the biosafety of the composite films. Meanwhile, the AgNW and the CNF@BNNS layers synergistically enhance the thermal conductivity of the CNF@BNNS/AgNW/BC composite film, reaching a high value of 8.85 W m‒1 K‒1, which significantly enhances its thermal safety when used in miniaturized electronic device. This work offers new ideas for fabricating biomaterial-based EMI shielding composite films with high comprehensive safety.

Investigation on the Energy-Absorbing Properties of Bionic Spider Web Structure.

In recent years, spider webs have received significant attention due to their exceptional mechanical properties, including strength, toughness, elasticity, and robustness. Among these spider webs, the orb web is a prevalent type. An orb web's main framework consists of radial and spiral threads, with elastic and sticky threads used to capture prey. This paper proposes a bionic orb web model to investigate the energy-absorbing properties of a bionic spider web structure. The model considers structural parameters such as radial line length, radial line cross-sectional diameter, number of spiral lines, spiral spacing, and spiral cross-sectional diameter. These parameters are evaluated to assess the energy absorption capability of the bionic spider web structure. Simulation results reveal that the impact of the radial line length and spiral cross-sectional diameter on the energy absorption of the spider web is more significant compared to the radial line cross-sectional diameter, the number of spiral lines, and spiral spacing. Specifically, within a radial line length range of 60-80 mm, the total absorbed energy of a spider web is inversely proportional to the radial line length of the web. Moreover, the number of spiral lines and spiral spacing of the spider web, when within the range of 6-10 turns and 4-5.5 mm, respectively, are proportional to the total energy absorbed. A regression equation is derived to predict the optimal combination of structural parameters for maximum energy absorption. The optimal parameters are determined as follows: radial line length of 63.48 mm, radial line cross-sectional diameter of 0.46 mm, ten spiral lines, spiral spacing of 5.39 mm, and spiral cross-sectional diameter of 0.48 mm.

Topological Design of a Hinger Bracket Based on Additive Manufacturing.

Topology optimization technology is often used in the design of lightweight structures under the condition that mechanical performance should be guaranteed, but a topology-optimized structure is often complicated and difficult to process using traditional machining technology. In this study, the topology optimization method, with a volume constraint and the minimization of structural flexibility, is applied to the lightweight design of a hinge bracket for civil aircraft. A mechanical performance analysis is conducted using numerical simulations to obtain the stress and deformation of the hinge bracket before and after topology optimization. The numerical simulation results show that the topology-optimized hinge bracket has good mechanical properties, and its weight was reduced by 28% compared with the original design of the model. In addition, the hinge bracket samples before and after topology optimization are prepared with additive manufacturing technology and mechanical performance tests are conducted using a universal mechanical testing machine. The test results show that the topology-optimized hinge bracket can satisfy the mechanical performance requirements of a hinge bracket at a weight loss ratio of 28%.

Antimicrobial Peptide MPX with Broad-Spectrum Bactericidal Activity Promotes Proper Abscess Formation and Relieves Skin Inflammation.

Bacteria have developed antibiotic resistance during the large-scale use of antibiotics, and multidrug-resistant strains are common. The development of new antibiotics or antibiotic substitutes has become an important challenge for humankind. MPX is a 14 amino acid peptide belonging to the MP antimicrobial peptide family. In this study, the antibacterial spectrum of the antimicrobial peptide MPX was first tested. The antimicrobial peptide MPX was tested for antimicrobial activity against the gram-positive bacterium S. aureus ATCC 25923, the gram-negative bacteria E. coli ATCC 25922 and Salmonella enterica serovar Typhimurium CVCC541, and the fungus Candida albicans ATCC 90029. The results showed that MPX had good antibacterial activity against the above four strains, especially against E. coli, for which the MIC was as low as 15.625 µg/mL. The study on the bactericidal mechanism of the antimicrobial peptide revealed that MPX can destroy the integrity of the cell membrane, increase membrane permeability, and change the electromotive force of the membrane, thereby allowing the contents to leak out and mediating bacterial death. A mouse acute infection model was used to evaluate the therapeutic effect of MPX after acute infection of subcutaneous tissue by S. aureus. The study showed that MPX could promote tissue repair in S. aureus infection and alleviate lung damage caused by S. aureus. In addition, skin H&E staining showed that MPX treatment facilitated the formation of appropriate abscesses at the subcutaneous infection site and facilitated the clearance of bacteria by the skin immune system. The above results show that MPX has good antibacterial activity and broad-spectrum antibacterial potential and can effectively prevent the invasion of subcutaneous tissue by S. aureus, providing new ideas and directions for the immunotherapy of bacterial infections.

Self-cleaning and regenerable nano zero-valent iron modified PCN-224 heterojunction for photo-enhanced radioactive waste reduction.

The expansion of large-scale nuclear power causes a substantial volume of radioactive wastewater containing uranium to be released into the environment. Because of uranium's toxicity and bioaccumulation, it is critical to develop the efficient and sustainable materials for selective removal of uranium (VI). Herein, a regenerable anti-biofouling nano zero-valent iron doped porphyrinic zirconium metal-organic framework (NZVI@PCN-224) heterojunction system was successfully fabricated. Due to the Schottky-junction effect at the NZVI/MOF interface, the NZVI nanomaterial immobilized on PCN-224 could improve interfacial electron transfer and separation efficiency, and enhance entire reduction of highly soluble U(VI) to less soluble U(IV), involving photocatalytic reduction and chemical reduction. Meanwhile, the photocatalytic effect also prompts the NZVI@PCN-224 to produce more biotoxic reactive oxygen species (ROS), resulting in high anti-microbial and anti-algae activities. Under dark conditions, NZVI@PCN-224 with a large specific surface area could provide sufficient oxo atoms as the uranium binding sites and show the highest uranium-adsorbing capability of 57.94 mg/g at pH 4.0. After eight adsorption-desorption cycles, NZVI@PCN-224 still retained a high uranium adsorption capacity of 47.98 mg/g and elimination efficiency (91.72%). This sorption/reduction/anti-biofouling synergistic strategy of combining chelation, chemical reduction and photocatalytic performance inspires new insights for highly efficient treatment of liquid radioactive waste.

Effects of the Antimicrobial Peptide Mastoparan X on the Performance, Permeability and Microbiota Populations of Broiler Chickens.

Restrictions on antibiotics are driving the search for alternative feed additives to promote gastrointestinal health and development in broiler chicken production. Proteins including antimicrobial peptides can potentially be applied as alternatives to antibiotics and are one of the most promising alternatives. We investigated whether the addition of MPX to the diet affects the production performance, immune function and the intestinal flora of the caecal contents of broiler chickens. One hundred one-day-old chickens were randomly divided into two groups: control (basal diet) and MPX (20 mg/kg) added to the basal diet. The results indicated that dietary supplementation with MPX improved the performance and immune organ index, decreased the feed conversion ratio, increased the villus length, maintained the normal intestinal morphology and reduced the IL-6 and LITNF mRNA expression levels of inflammation-related genes. In addition, MPX increased the mRNA expression of the digestive enzymes FABP2 and SLC2A5/GLUT5 and the tight junction proteins ZO-1, Claudin-1, Occludin, JAM-2 and MUC2, maintained the intestinal permeability and regulated the intestinal morphology. Moreover, MPX increased the CAT, HMOX1 and SOD1 mRNA expression levels of the antioxidant genes. Furthermore, a 16S rRNA microflora analysis indicated that the abundance of Lactobacillus and Lactococcus in the cecum was increased after addition of MPX at 14 d and 28 d. This study explored the feasibility of using antimicrobial peptides as novel feed additives for broiler chickens and provides a theoretical basis for their application in livestock.

Industrial water consumption forecasting based on combined CEEMD-ARIMA model for Henan province, central chain: A case study.

Industrial water consumption is a major component of the total regional water consumption. Accurate and scientific prediction of industrial water consumption is an essential guide to the rational use of natural resources. In this paper, we proposed a combined model of CEEMD (collective empirical modal decomposition) and ARIMA (autoregressive integrated moving average) for forecasting industrial water consumption to establish an accurate and efficient forecasting model, because of the poor generalization ability of most current industrial water consumption forecasting models. The influencing factors of industrial water consumption are complex, and the data are non-stationary. "Decomposition-prediction-reconstruction" is one of the significant methods for forecasting time series data, and the data decomposition has a suppressive influence on the modal mixing problem in the EMD decomposition procedure. Based on the smoothing ability of CEEMD for non-smooth signals and the better adaptation of the autoregressive moving average prediction model (ARIMA), a combined CEEMD-ARIMA model was established for industrial water consumption forecasting. This study was conducted for industrial water consumption in Henan Province in central China. The results suggest the combined CEEMD-ARIMA model has a favorable forecasting effect, with an average relative percentage error of 1.96%, and mean square error (MSE) of 0.35, a Nash efficiency coefficient (NSE) of 0.95, a prediction pass rate of 100%, and a better prediction accuracy than the ARIMA model and the combined EEMD-ARIMA model. It provides an effective prediction method for the prediction of industrial water consumption and has good application prospects.

The Antimicrobial Peptide MPX Can Kill Staphylococcus aureus, Reduce Biofilm Formation, and Effectively Treat Bacterial Skin Infections in Mice.

Staphylococcus aureus is a common pathogen that can cause pneumonia and a variety of skin diseases. Skin injuries have a high risk of colonization by S. aureus, which increases morbidity and mortality. Due to the emergence of multidrug-resistant strains, antimicrobial peptides are considered to be among the best alternatives to antibiotics due to their unique mechanism of action and other characteristics. MPX is an antibacterial peptide extracted from wasp venom that has antibacterial activity against a variety of bacteria. This study revealed that MPX has good bactericidal activity against S. aureus and that its minimum inhibitory concentration (MIC) is 0.08 µM. MPX (4×MIC) can kill 99.9% of bacteria within 1 h, and MPX has good stability. The research on the bactericidal mechanism found that MPX could destroy the membrane integrity, increase the membrane permeability, change the membrane electromotive force, and cause cellular content leakage, resulting in bactericidal activity. Results from a mouse scratch model experiment results show that MPX can inhibit colonization by S. aureus, which reduces the wound size, decreases inflammation, and promotes wound healing. This study reports the activity of MPX against S. aureus and its mechanism and reveals the ability of MPX to treat S. aureus infection in mice, laying the foundation for the development of new drugs for bacterial infections.

Application of improved seasonal GM(1,1) model based on HP filter for runoff prediction in Xiangjiang River.

Runoff forecasting is essential for the reasonable use of regional water resources, flood prevention, and mitigation, as well as the development of ecological civilization. Runoff is influenced by the intersection of many factors, and the change process is extremely complex, showing significant stochasticity, nonlinearity, and heterogeneity, making traditional prediction models less adaptable. The Hodrick-Prescott filter (HP filter) is a well-established signal separation method. The traditional GM(1,1) model is capable of portraying the growth trend of the time series but cannot capture the periodic characteristics of the time series. Therefore, a novel coupled prediction model-HPF-GM(1,1) model is proposed in this study and applied to the runoff prediction of the Zhuzhou section of Xiangjiang River in Hunan Province. This model enables to separate seasonal factors from non-seasonal factors in the runoff time series, and introduce seasonal factors based on the traditional GM(1,1) model, which solves the challenge that the traditional GM(1,1) model is unable to predict seasonal time series. The results show that the HPF-GM(1,1) model has a mean relative error of 4.82%, a root mean square error of 7.44, and a Nash efficiency coefficient of 0.93, which is better than the traditional GM(1,1) model, the DGGM(1,1) model and the SGM(1,1) model of prediction accuracy. Obviously, the HP filter provides a new approach to data pre-processing of runoff series and the proposed HPF-GM(1,1)-coupled model extends new ideas for nonlinear runoff prediction.

Assessment of the value of ecosystem services in water sources of the South-North Water Diversion Central Project: the case of Dengzhou City, Henan Province.

Dengzhou City is the first ecological water recharge city after the commissioning of the South-North Water Diversion Project. A study on the ecological service value of Dengzhou City and its evolutionary characteristics can provide a theoretical basis for the water supply security of the Central Line Project and regional ecological environmental protection. Based on the ecosystem service value equivalent factor method, GIS, ENVI and GeoSOS-FLUS software were used to monetize the ecosystem service values of Dengzhou City in 2007, 2011, 2014, 2015 and 2020; analyze the spatial and temporal change characteristics under its land use change conditions and predict the regional ecosystem service values of Dengzhou City in 2025. The results show that since the completion and commissioning of the South-North Water Transfer Central Project in 2014, the value of ecosystem services in Dengzhou City has rapidly increased from US$3.792 billion to US$4.612 billion, and in 2025, the value of ecosystem services in Dengzhou City is expected to reach US$4.8 billion.

The Antimicrobial Peptide Mastoparan X Protects Against Enterohemorrhagic Escherichia coli O157:H7 Infection, Inhibits Inflammation, and Enhances the Intestinal Epithelial Barrier.

Escherichia coli can cause intestinal diseases in humans and livestock, destroy the intestinal barrier, exacerbate systemic inflammation, and seriously threaten human health and animal husbandry development. The aim of this study was to investigate whether the antimicrobial peptide mastoparan X (MPX) was effective against E. coli infection. BALB/c mice infected with E. coli by intraperitoneal injection, which represents a sepsis model. In this study, MPX exhibited no toxicity in IPEC-J2 cells and notably suppressed the levels of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), myeloperoxidase (MPO), and lactate dehydrogenase (LDH) released by E. coli. In addition, MPX improved the expression of ZO-1, occludin, and claudin and enhanced the wound healing of IPEC-J2 cells. The therapeutic effect of MPX was evaluated in a murine model, revealing that it protected mice from lethal E. coli infection. Furthermore, MPX increased the length of villi and reduced the infiltration of inflammatory cells into the jejunum. SEM and TEM analyses showed that MPX effectively ameliorated the jejunum damage caused by E. coli and increased the number and length of microvilli. In addition, MPX decreased the expression of IL-2, IL-6, TNF-α, p-p38, and p-p65 in the jejunum and colon. Moreover, MPX increased the expression of ZO-1, occludin, and MUC2 in the jejunum and colon, improved the function of the intestinal barrier, and promoted the absorption of nutrients. This study suggests that MPX is an effective therapeutic agent for E. coli infection and other intestinal diseases, laying the foundation for the development of new drugs for bacterial infections.

Targeting hypoxia for sensitization of tumors to apoptosis enhancement through supramolecular biohybrid bacteria.

Bacteria-driven drug-delivery systems have drawn considerable interests for their highly selective hypoxia-targeting and efficacy in tumor inhibition. For the first time, a supramolecular biohybrid bacterium (SA@HU) is constructed by coating attenuated Salmonella typhimurium (S. typhimurium ΔppGpp/Lux) with nanoassemblies. In addition, the host-guest inclusion complexes based on hydroxypropyl-ß-cyclodextrin (HPCD) and amantadine (AMA) was developed to encapsulate the natural antineoplastic product, ursolic acid (UA). It is found that the drug-carried coating layer has no significant impact on the antitumor activity or tumor-targeting capacity of bacteria. Significant restraint of tumor progression is achieved by SA@HU due to the synergy of cellular immune activation and apoptosis enhancement. Most importantly, intravenous delivery of UA by this biohybrid vector can cause tumor lysis, as the bacteria-attracting nutrients beneficial for preferential accumulation of bacteria in tumor. The mutual promotion of bacteria and UA may also contribute to a superior anticancer effect. Hence, the SA@HU-based biotic/abiotic supramolecular therapeutic system represents a novel strategy for combined chemo-bacterial therapy.

A Cascade-Targeting Nanocapsule for Enhanced Photothermal Tumor Therapy with Aid of Autophagy Inhibition.

Autophagy is a homeostatic lysosome-dependent metabolic process to eliminate damaged or dysfunctional cellular organelles, which is closely associated with tumor progression. Indocyanine green (ICG) can convert NIR light energy to localized heat for cancer cell and tissue ablation. However, the effect of autophagy modulation on ICG-mediated photothermal therapy remains unknown. In this study, it is found that primaquine (PQ) suppresses autophagy flux at a late stage through the impeding fusion of the autophagosome with the lysosome to form an autophagolysosome, leading to cell apoptosis or necrosis. This autophagosome-lysosome fusion inhibitory effect and the autophagosome accumulation are more evident in the photothermal therapy combined with autophagy inhibition. Motivated by this notable effect, a cascade-targeting nanocapsule (HCP) is constructed using an organic solvent-free strategy to coencapsulate PQ and ICG. By targeting the cluster designation 44 molecule and sequentially enhancing the cell-penetrating peptide-mediated endocytosis, the codelivery of PQ/ICG by HCP achieves selective recognition and reinforces the internalization by MCF-7 cells to exert a synergistic therapeutic effect on MCF-7 cells both in vitro and in vivo. The HCP system for the photothermal and autophagy inhibition combination therapy represents a novel strategy for the treatment of breast cancer.

Proteomic Analyses of Cysteine Redox in High-Fat-Fed and Fasted Mouse Livers: Implications for Liver Metabolic Homeostasis.

Intensive oxidative stress occurs during high-fat-diet-induced hepatic fat deposition, suggesting a critical role for redox signaling in liver metabolism. Intriguingly, evidence shows that fasting could also result in redox-profile changes largely through reduced oxidant or increased antioxidant levels. However, a comprehensive landscape of redox-modified hepatic substrates is lacking, thereby hindering our understanding of liver metabolic homeostasis. We employed a proteomic approach combining iodoacetyl tandem mass tag and nanoliquid chromatography tandem mass spectrometry to quantitatively probe the effects of high-fat feeding and fasting on in vivo redox-based cysteine modifications. Compared with control groups, ∼60% of cysteine residues exhibited downregulated oxidation ratios by fasting, whereas ∼94% of these ratios were upregulated by high-fat feeding. Importantly, in fasted livers, proteins exhibiting diminished cysteine oxidation were annotated in pathways associated with fatty acid metabolism, carbohydrate metabolism, insulin, peroxisome proliferator-activated receptors, and oxidative respiratory chain signaling, suggesting that fasting-induced redox changes targeted major metabolic pathways and consequently resulted in hepatic lipid accumulation.

Interleukin-15 and cisplatin co-encapsulated thermosensitive polypeptide hydrogels for combined immuno-chemotherapy.

In situ-forming thermosensitive hydrogels based on poly(ethylene glycol)-poly(γ-ethyl-l-glutamate) diblock copolymers (mPEG-b-PELG) were prepared for the co-delivery of interleukin-15 (IL-15) and cisplatin (CDDP). The polypeptide-based hydrogels as local drug delivery carriers could reduce the systemic toxicity, degrade thoroughly within 3weeks after subcutaneous injection into rats and display an acceptable biocompatibility. When incubated with mouse melanoma B16 cells, only the CDDP-treated groups had significant effects on the S phase cell-cycle arrest in melanoma cells. After a single peritumoral injection of the hydrogel containing IL-15/CDDP in C57BL/6 mice inoculated with B16F0-RFP melanoma cells, the dual drug-loaded hydrogels displayed synergistic anticancer efficacy, which was resulted from a combination of CDDP-mediated S arrest and IL-15/CDDP-induced recovery of CD8+ T cell and NK cell populations to reduce immunosuppression and enhance antitumor immunity. Hence, the as-prepared thermosensitive polypeptide hydrogels for localized and sustained co-delivery of IL-15 and CDDP may have potential for efficient treatment of melanoma.

Synergistic therapeutic effects of Schiff's base cross-linked injectable hydrogels for local co-delivery of metformin and 5-fluorouracil in a mouse colon carcinoma model.

In situ formed hydrogels based on Schiff base reaction were formulated for the co-delivery of metformin (ME) and 5-fluorouracil (5FU). The reactive aldehyde-functionalized four-arm polyethylene glycol (PFA) was synthesized by end-capping of 4-arm PEG with 4-formylbenzoic acid (FA) and used as a cross-linking agent. The injectable hydrogels are designed through the quick gelation induced by the formation of covalent bonds via Schiff-base reaction of PFA with 4-arm poly (ethylene glycol)-b-poly (L-lysine) (PPLL). This formulation eliminated the need for metal catalysts and complicated processes in the preparation of in situ-forming hydrogels. In vitro degradation and drug release studies demonstrated that both ME and 5FU were released through PFA/PPLL hydrogels in a controlled and pH-dependent manner. When incubated with mouse colon adenocarcinoma cells (C26), the ME/5FU-incorporated PFA/PPLL hydrogels had synergistic inhibitory effects on the cell cycle progression and cell proliferation in colon cancer cells. After a single subcutaneous injection of the hydrogel containing ME/5FU beside the tumors of BALB/c mice inoculated with C26 cells, the dual-drug-loaded hydrogels displayed superior therapeutic activity resulted from a combination of p53-mediated G1 arrest and apoptosis in C26 cells. Hence, the Schiff's base cross-linked hydrogels containing ME and 5FU may have potential therapeutic applications in the treatments of colon cancer.

Oxidation of KCNB1 K(+) channels in central nervous system and beyond.

KCNB1, a voltage-gated potassium (K(+)) channel that conducts a major delayed rectifier current in the brain, pancreas and cardiovascular system is a key player in apoptotic programs associated with oxidative stress. As a result, this protein represents a bona fide drug target for limiting the toxic effects of oxygen radicals. Until recently the consensus view was that reactive oxygen species trigger a pro-apoptotic surge in KCNB1 current via phosphorylation and SNARE-dependent incorporation of KCNB1 channels into the plasma membrane. However, new evidence shows that KCNB1 can be modified by oxidants and that oxidized KCNB1 channels can directly activate pro-apoptotic signaling pathways. Hence, a more articulated picture of the pro-apoptotic role of KCNB1 is emerging in which the protein induces cell's death through distinct molecular mechanisms and activation of multiple pathways. In this review article we discuss the diverse functional, toxic and protective roles that KCNB1 channels play in the major organs where they are expressed.