Construction of a gene model related to the prognosis of patients with gastric cancer receiving immunotherapy and exploration of COX7A1 gene function.

BACKGROUND: GC is a highly heterogeneous tumor with different responses to immunotherapy, and the positive response depends on the unique interaction between the tumor and the tumor microenvironment (TME). However, the currently available methods for prognostic prediction are not satisfactory. Therefore, this study aims to construct a novel model that integrates relevant gene sets to predict the clinical efficacy of immunotherapy and the prognosis of GC patients based on machine learning. METHODS: Seven GC datasets were collected from the Gene Expression Omnibus (GEO) database, The Cancer Genome Atlas (TCGA) database and literature sources. Based on the immunotherapy cohort, we first obtained a list of immunotherapy related genes through differential expression analysis. Then, Cox regression analysis was applied to divide these genes with prognostic significancy into protective and risky types. Then, the Single Sample Gene Set Enrichment Analysis (ssGSEA) algorithm was used to score the two categories of gene sets separately, and the scores differences between the two gene sets were used as the basis for constructing the prognostic model. Subsequently, Weighted Correlation Network Analysis (WGCNA) and Cytoscape were applied to further screen the gene sets of the constructed model, and finally COX7A1 was selected for the exploration and prediction of the relationship between the clinical efficacy of immunotherapy for GC. The correlation between COX7A1 and immune cell infiltration, drug sensitivity scoring, and immunohistochemical staining were performed to initially understand the potential role of COX7A1 in the development and progression of GC. Finally, the differential expression of COX7A1 was verified in those GC patients receiving immunotherapy. RESULTS: First, 47 protective genes and 408 risky genes were obtained, and the ssGSEA algorithm was applied for model construction, showing good prognostic discrimination ability. In addition, the patients with high model scores showed higher TMB and MSI levels, and lower tumor heterogeneity scores. Then, it is found that the COX7A1 expressions in GC tissues were significantly lower than those in their corresponding paracancerous tissues. Meanwhile, the patients with high COX7A1 expression showed higher probability of cancer invasion, worse clinical efficacy of immunotherapy, worse overall survival (OS) and worse disease-free survival (DFS). CONCLUSIONS: The ssGSEA score we constructed can serve as a biomarker for GC patients and provide important guidance for individualized treatment. In addition, the COX7A1 gene can accurately distinguish the prognosis of GC patients and predict the clinical efficacy of immunotherapy for GC patients.

DNA Demethylation of Promoter Region Facilitates Atoh-1-Induced Interleukin-19 Expression Activation in Bone Marrow Monocytes of Old Mice.

With increasing age, there is a notable increase in the differentiation of bone marrow-derived mononuclear cells (BMMs) into osteoclasts, accompanied by a concurrent rise in both osteoclast quantity and activity. This escalation in osteoclastic activity accelerates bone resorption, which in turn contributes to age-related bone loss and metabolic bone disorders, notably osteoporosis. Our study confirms that elevated IL-19 expression promotes aging-induced bone loss in aged mice and sheds light on the regulatory mechanisms upstream of IL-19 expression and secretion. Primarily, it is the methylation status of the IL-19 gene's promoter region that impacts Atonal BHLH Transcription Factor 1 (Atoh1)'s ability to bind to the promoter. We found that this specific mechanism involves reduced expression and binding affinity of Dnmt1 to the IL-19 promoter region. The findings of our study suggest that targeting IL-19 could be a potential strategy for managing bone loss-related conditions and enhance the current understanding of how DNA methylation levels contribute to age-related bone loss.

Efficient intracellular and in vivo delivery of toxin proteins by a ROS-responsive polymer for cancer therapy.

Rational design of efficient cytosolic protein delivery carriers holds enormous promise for biotherapeutics development. Several delivery systems have been developed during the past decades, while tailoring the balance between extracellular protein binding and intracellular cargo release is still challenging. In this study, we synthesized a series of oxygen-sensitive reactive polymers, rich in boron, by radical polymerization and post-modification for cytosolic protein delivery in vitro and in vivo. The introduction of boronate building blocks into the polymer scaffold significantly enhanced its protein binding affinity, and the polymer/protein complexes with high stability were obtained by tailoring the molecular ratios between the boronate ligands and the amine groups. The lead material screened from the polymer library exhibited efficient protein delivery efficacy that can release cargo proteins in cytosol in a reactive oxygen species responsive manner, which enables intracellular delivery of proteins with maintained bioactivity. In addition, the polymer-based nanoformulations efficiently delivered saporin, a toxin protein, into osteosarcoma cells and tumor tissues, and exhibited high therapeutic efficacy in an osteosarcoma mouse model. The synthesized polymer in this study can be developed as a promising nanocarrier for cytosolic delivery of protein therapeutics to treat a variety of diseases.

Benzaldehyde-tethered fluorous tags for cytosolic delivery of bioactive peptides.

Development of intracellular delivery systems for bioactive peptides remains challenging. Herein, we report a facile strategy to address this issue by conjugating peptides with benzaldehyde-tethered fluorous tags to generate dynamic peptide amphiphiles via a hydrazone bond for efficient cytosolic delivery. Those dynamic peptide fluoroamphiphiles could self-assemble into nanoparticles that readily cross the cell membrane. Using this strategy, several bioactive peptides were efficiently internalized by cancer cells and released into the cytosol to exert their biological functions, which showed much higher efficacies than non-fluorous lipids and cell penetrating peptide decorated peptides. Moreover, the fluorous tagged proapoptotic peptide was able to efficiently inhibit tumor growth in vivo. This report provides a new family of fluorous tags based on benzaldehyde for efficient cytosolic peptide delivery.

Recent Advances in Poly(α-L-glutamic acid)-Based Nanomaterials for Drug Delivery.

Poly(α-L-glutamic acid) (PGA) is a class of synthetic polypeptides composed of the monomeric unit α-L-glutamic acid. Owing to their biocompatibility, biodegradability, and non-immunogenicity, PGA-based nanomaterials have been elaborately designed for drug delivery systems. Relevant studies including the latest research results on PGA-based nanomaterials for drug delivery have been discussed in this work. The following related topics are summarized as: (1) a brief description of the synthetic strategies of PGAs; (2) an elaborated presentation of the evolving applications of PGA in the areas of drug delivery, including the rational design, precise fabrication, and biological evaluation; (3) a profound discussion on the further development of PGA-based nanomaterials in drug delivery. In summary, the unique structures and superior properties enables PGA-based nanomaterials to represent as an enormous potential in biomaterials-related drug delivery areas.

Effects of inorganic and organic selenium sources on the growth performance of broilers in China: A meta-analysis.

This study aims to investigate the effects of different selenium (Se) sources on the growth performance of Chinese broilers and provide a scientific rationale for adding Se additives to broiler feed. Relevant studies that meet standard inclusion criteria were identified and extracted from China National Knowledge Infrastructure and Wanfang and Chinese Scientific Journal (VIP) databases. A total of 9 studies with 539 subjects were included. A meta-analysis was performed with STATA15.0 to estimate the combined standardized mean difference (SMD) with a 95% confidence interval (95% CI). Heterogeneity test of articles was examined by Q-test, and the results showed that P values of feed conversion ratio, average daily gain (ADG), and average daily intake were all less than 0.05, suggesting a strong heterogeneity among the selected literature. Therefore, the random effect model is selected to calculate the SMD of the three indexes. The combined SMDs (95% CI) of feed:gain, ADG, and average daily feed intake (ADFI) were -0.39 (-1.03, 0.25), 0.26 (-0.29, 0.81), and -1.45 (-3.09, 0.20), respectively, and the P values were all less than 0.05. This study shows that the absolute differences in the growth performance (feed:gain, ADG, and ADFI) of broilers fed with either organic or inorganic Se supplements at the same dose were quite small. The P values of Egger's test were 0.770, 0.089, and 0.426, respectively, for the above indexes, showing no significant publication bias. Sensitivity analysis ensured the stability and reliability of the results. In summary, the effects of organic and inorganic Se in feed on the growth performance of broilers are statistically equal.

A two-dimensional photonic crystal hydrogel biosensor for colorimetric detection of penicillin G and penicillinase inhibitors.

A simple penicillinase functionalized two-dimensional photonic crystal hydrogel (2DPPCH) biosensor was developed for colorimetric detection of penicillin G and penicillinase inhibitors. The penicillinase can specifically recognize penicillin G and catalyze it to produce penicilloic acid, which decreases the pH of the hydrogel microenvironment and shrinks the pH-sensitive hydrogel. The particle spacing decrease of the 2D photonic crystal array induced by the hydrogel shrinkage further causes a blue-shift in the diffraction wavelength. While the hydrolysis reaction is repressed upon treatment with clavulanate potassium (a kind of penicillinase inhibitor), no significant change in the diffraction wavelength is found. The detection of targets can be achieved by measuring the Debye diffraction ring diameter or observing the structural color change in the visible region. The lowest detectable concentrations for penicillin G and clavulanate potassium are 1 µM and 0.1 µM, respectively. Moreover, the 2DPPCH is proved to exhibit high selectivity and an excellent regeneration property, and it shows satisfactory performance for penicillin G analysis in real water samples.

Carrier-Free Platinum Nanomedicine for Targeted Cancer Therapy.

Numerous nanomedicines have been developed to improve the efficiency and safety of conventional anticancer drugs; however, the complexities in carrier materials and functional integration make it challenging to promote these candidates for clinical translation. In this study, a facile method to prepare carrier-free anticancer nanodrug with inherent bone targeting and osteoclastogenesis inhibition capabilities is reported. Phytic acid, a naturally occurring and nontoxic product, is reacted with cisplatin to form uniform nanoparticles of different sizes. The prepared nanoparticles possess high drug loading and pH-responsive drug release behaviors. Phytic acid in the nanomedicine ensures high bone targeting and osteoclastogenesis inhibition, and the released platinum drugs triggered by tumor extracellular acidity eradicate tumor cells. The nanomedicine around 100 nm shows high anticancer activity and much reduced side effects in a subcutaneous breast cancer model when compared with cisplatin. In addition, it shows high accumulation at osteolytic lesions, and efficiently inhibits tumor growth and tumor-associated osteolysis in a bone metastatic breast cancer model. Here, a facile and efficient strategy to prepare carrier-free nanomedicines with high anticancer drug loading, inherent bone targeting, and osteoclast inhibitory activities for cancer therapy is provided.

Bifunctional and Bioreducible Dendrimer Bearing a Fluoroalkyl Tail for Efficient Protein Delivery Both In Vitro and In Vivo.

Rational design of stimuli-responsive polymers for cytosolic protein delivery with robust efficiency is of great importance but remains a challenging task. Here, we reported a bioreducible and amphiphilic dendrimer bearing a fluoroalkyl tail for this purpose. The fluorolipid was conjugated to the focal point of a cysteamine-cored polyamidoamine dendrimer via disulfide bond, while phenylboronic acid moieties were decorated on dendrimer surface for efficient protein binding. The yielding polymer showed high protein binding capability and complex stability and could efficiently release the cargo proteins in a glutathione-responsive manner. The designed polymer was effective in the delivery of various membrane-impermeable proteins into living cells with reserved bioactivities. In addition, the polymer efficiently delivered a toxin protein saporin into 4T1 breast cancer cells and inhibited the tumor growth in vivo after intravenous injection. The developed polymer in this study is a promising vector for the delivery of membrane-impermeable proteins to treat various diseases.

S,S-Tetrazine-Based Hydrogels with Visible Light Cleavable Properties for On-Demand Anticancer Drug Delivery.

Photocleavable hydrogels are of great importance in the field of controlled drug delivery, stem cell fate regulation, surface patterning, and intelligent devices. However, the development of novel photocleavable gel systems by visible light is usually met with challenges such as the lack of efficient and tunable photocleavable groups and reactions. Herein, we reported the facile fabrication of a new type of photocleavable hydrogels by the direct gelation of 4-arm thiol-terminated polyethylene glycol with 3,6-dichloro-1,2,4,5-tetrazine via the formation of S,S-tetrazine linkages. The prepared hydrogels underwent efficient degradation upon irradiation by ultraviolet or green light, and the degradation kinetics could be significantly promoted by hydrogen peroxide. Correspondingly, the hydrogels loaded with calcium peroxide microparticles or glucose oxidase/catalase enzymes enabled the precise and efficient in vivo photocontrol of gel degradation and drug release for cancer treatment. This work offers a promising and facile strategy towards the fabrication of visible light cleavable hydrogels with tunable and on-demand drug release properties.

Fluoroalkylation promotes cytosolic peptide delivery.

Cytosolic delivery of peptides remains a challenging task owing to their susceptibility to enzymatic degradation and the existence of multiple intracellular barriers. Here, we report a new strategy to address these issues by decoration of a fluorous tag on the terminal of cargo peptides. The fluorous-tagged peptides were assembled into nanostructures, efficiently internalized by cells via several endocytic pathways and released into the cytosol after endosomal escape. They were relatively stable against enzymatic degradation and showed much higher efficiency than nonfluorinated analogs and cell penetrant peptide-conjugated ones. The proposed strategy also efficiently delivered a proapoptotic peptide into specific sites in the cells and restored the function of cargo peptide after cytosolic delivery. The fluorous-tagged proapoptotic peptide efficiently inhibited tumor growth in vivo. This study provides an efficient fluorination strategy to promote the cytosolic delivery of peptides.

A responsive photonic crystal film sensor for the ultrasensitive detection of uranyl ions.

As an effective nuclear energy resource, uranium plays an important role in industry and energy but the wastes of uranium also cause radioactive contamination, which is harmful to the environment and the human body. Herein, a responsive photonic crystal (PC) film sensor for the ultrasensitive and label-free detection of uranyl ions (UO22+) has been proposed, which is easy to construct and does not need to be combined with a hydrogel. The PC film is not pH-sensitive because it is obtained by the self-assembly of methyl methacrylate-acrylonitrile co-polymeric nanospheres (PMMA-AN). These nanospheres were modified with amidoxime groups, which have a good coordination ability with UO22+. The bindings between nanospheres and UO22+ change the refractive index and disturb the face-centered cubic structure of the film, which leads to a decrease in the diffraction peak intensity of the PC film. The sensor works in the concentration range of 10 pM to 100 µM for UO22+ determination and the decreased intensities of the diffraction peaks are linearly correlated with the logarithm of UO22+ concentration in the range from 1 nM to 100 µM. Moreover, the sensor shows good selectivity for UO22+ and can also perform the determination of UO22+ in a real sample. The responsive PC film sensor shows great potential in the label-free and ultrasensitive detection of UO22+.

An elastic gel consisting of natural polyphenol and pluronic for simultaneous dura sealing and treatment of spinal cord injury.

Dura injury can be intractable during neurosurgical operations. Dural sealant is effective for aiding dura repair and diminishing postoperative complications. However, a more optimal dural sealant is still clinically required. On the other hand, spinal cord injury (SCI) is a common comorbidity of the dural injury. Exception for surgical decompression, other clinically approved treatment for SCI is still limited. In this study, an elastic gel consisting of natural polyphenol tannic acid (TA) and pluronic F-127 (PF127) was prepared by a facile strategy. Comparing with traditional fibrin glue, the prepared TA-PF127 gel exhibited much higher bonding strength and sealing effect both in vitro and in vivo, and thus effectively prevented postoperative cerebral spinal fluid leakage. Based on a mice severe SCI model of spinal cord transection, the sealing and antioxidant property of TA-PF127 gel effectively decreased the reactive oxygen species production, inhibited neural cells apoptosis and inflammatory response, promoted glial scar formation and restrained lesion zone, maintained neurons and dramatically promoted neurological function recovery of mice after SCI. Due to the simple and biocompatible components in the gel, TA-PF127 has a promising potential to become a novel dural sealant for simultaneous dura sealing and SCI treatment in clinical neurosurgical operations.

Amplification of oxidative stress via intracellular ROS production and antioxidant consumption by two natural drug-encapsulated nanoagents for efficient anticancer therapy.

Cancer cells are commonly characterized by high cellular oxidative stress and thus have poor tolerance to oxidative insults. In this study, we developed a nano-formulation to elevate the level of reactive oxygen species (ROS) in cancer cells via promoting ROS production as well as weakening cellular anti-oxidizing systems. The nanoagent was fabricated by encapsulating two natural product molecules, cinnamaldehyde (CA) and diallyl trisulfide (DATS), in PLGA-PEG copolymer formulated nanoparticles. CA promotes ROS generation in cancer cells and DATS depletes cellular glutathione. CA and DATS exhibited a synergistic effect in amplifying the ROS levels in cancer cells and further in their combined killing of cancer cells. The in vivo experiments revealed that the CA and DATS-encapsulated nanoagent suppressed tumors more efficiently as compared with the single drug-loaded ones, and the tumor-targeted delivery further enhanced the therapeutic efficacy. This study suggests that the combined enhancement of oxidative stress by CA and DATS could be a promising strategy for cancer therapy.

Off-on switching of enzyme activity by near-infrared light-induced photothermal phase transition of nanohybrids.

The off-on manipulation of enzyme activity is a challenging task. We report a new strategy for reversible off-on control of enzyme activity by near-infrared light. Enzymes acting on macromolecular substrates are embedded with an ultrasmall platinum nanoparticle and decorated with thermoresponsive copolymers, which exhibit upper critical solution temperature (UCST) behavior. The polymer-enzyme nanohybrids form microscale aggregates in solution below the UCST to prevent macromolecular substrates from approaching the enzymes and thus inhibit the enzyme activity, and they disassemble above the UCST to reactivate the enzyme. Upon near-infrared irradiation, platinum nanoparticles inside the enzymes generate heat through a photothermal effect to cause phase transition of the copolymers. Therefore, we can reversibly switch off and on the activities of three enzymes acting on polysaccharide, protein, and plasmid. The enzyme activities are increased by up to 61-fold after laser irradiation. This study provides a facile and efficient method for off-on control of enzyme activity.

Albumin-Encapsulated Platinum Nanoparticles for Targeted Photothermal Treatment of Glioma.

Brain tumors are hard to cure due to the life-threatening impact on the vital function areas of brain plus the blood-brain barrier caused poor drug delivery to brain. In this study, we utilized the human serum albumin (HSA) as a template to synthesize ultrasmall platinum nanoparticle for targeted photothermal treatment of glioma. The HSA-encapsulated platinum nanoparticle (HSA-Pt) possessed uniform size and shape, and represented excellent photothermal effect. As an endogenous protein in blood, HSA endowed HSA-Pt great biocompatibility and prolonged blood circulation time. In a subcutaneous model, HSA-Pt accumulated more in tumors than the control nanoparticle due to its long circulation time, resulting in more efficient photothermal regression of tumors. Furthermore, in an orthotropic glioma model, HSA-Pt was able to penetrate the blood-brain barrier and target to glioma, and the tumors were significantly suppressed by photothermal therapy. This study suggests HSA-Pt associated targeted photothermal therapy can be used for the treatment of brain tumors.

Ozone disinfection of chlorine-resistant bacteria in drinking water.

The wide application of chlorine disinfectant for drinking water treatment has led to the appearance of chlorine-resistant bacteria, which pose a severe threat to public health. This study was performed to explore the physiological-biochemical characteristics and environmental influence (pH, temperature, and turbidity) of seven strains of chlorine-resistant bacteria isolated from drinking water. Ozone disinfection was used to investigate the inactivation effect of bacteria and spores. The DNA concentration and cell surface structure variations of typical chlorine-resistant spores (Bacillus cereus spores) were also analysed by real-time qPCR, flow cytometry, and scanning electron microscopy to determine their inactivation mechanisms. The ozone resistance of bacteria (Aeromonas jandaei < Vogesella perlucida < Pelomonas < Bacillus cereus < Aeromonas sobria) was lower than that of spores (Bacillus alvei < Lysinibacillus fusiformis < Bacillus cereus) at an ozone concentration of 1.5 mg/L. More than 99.9% of Bacillus cereus spores were inactivated by increasing ozone concentration and treatment duration. Moreover, the DNA content of Bacillus cereus spores decreased sharply, but approximately 1/4 of the target genes remained. The spore structure exhibited shrinkage and folding after ozone treatment. Both cell structures and gene fragments were damaged by ozone disinfection. These results showed that ozone disinfection is a promising method for inactivating chlorine-resistant bacteria and spores in drinking water.

A Targeted and pH-Responsive Bortezomib Nanomedicine in the Treatment of Metastatic Bone Tumors.

Bortezomib is a boronate proteasome inhibitor widely used as an efficient anticancer drug; however, the clinical use of bortezomib is hampered by its adverse effects such as hematotoxicity and peripheral neuropathy, and low efficacy on solid tumors due to unfavorable pharmacokinetics and poor penetration in the solid tumors. In this study, we developed a tripeptide Arg-Gly-Asp (RGD)-targeted dendrimer conjugated with catechol and poly(ethylene glycol) groups for the targeted delivery of bortezomib to metastatic bone tumors. Bortezomib was loaded on the dendrimer via a boronate-catechol linkage with pH-responsive property, which plays an essential role in the control of bortezomib loading and release. The nontargeted bortezomib nanomedicine showed minimal cytotoxicity at pH 7.4, but significantly increased anticancer activity when cyclic RGD (cRGD) moieties were anchored on the dendrimer surface. The ligand cRGD enabled efficient internalization of the bortezomib complex by breast cancer cells such as MDA-MB-231 cells. The targeted nanomedicine efficiently depressed the progression of metastatic bone tumors and significantly inhibited the tumor-associated osteolysis in a model of bone tumors. This study provided an insight into the development of nanomedicine for metastatic bone tumors.

Foe to Friend: Supramolecular Nanomedicines Consisting of Natural Polyphenols and Bortezomib.

Bortezomib (BTZ) is a first-in-class boronate proteasome inhibitor used for cancer therapy, but its therapeutic efficacy is usually inhibited by dietary polyphenols due to boronate-catechol complexation. Benefiting from such dynamic covalent chemistry, herein we describe a novel class of supramolecular nanomedicines by rationally converting natural polyphenols from foe to friend through polyphenol-mediated BTZ assembly strategy. The simple conjugation of BTZ to catechol-containing natural polyphenols via boronate ester bond allows the facile formation of dynamic drug amphiphiles, with pH-dependent assembly/disassembly behaviors under different physiological conditions. Ferric ion was also incorporated into the supramolecular system via metal-phenolic coordination interaction to both introduce bioimaging function and facilitate stability of the supramolecular nanomedicines. Our investigation revealed that the supramolecular nanomedicine consisting of natural polyphenol, BTZ and ferric ion dramatically induced apoptosis on cancer cells and suppressed tumor growth in both subcutaneous and bone tumor models with limited adverse effects. Such natural polyphenol-mediated small drug assembly strategy enables the robust fabrication of supramolecular nanomedicines for efficient delivery and controlled release of BTZ in targeted tumor sites, which could be further employed in other types of boronic acid-containing supramolecular therapeutics toward a wide range of diseases.

Fluoropolymers for intracellular and in vivo protein delivery.

The design of efficient and universal carriers to transport proteins into cells is highly desirable in the development of biotherapeutics. However, intracellular protein delivery remains a major challenge owing to the multiple barriers in protein delivery process, such as protein encapsulation, endocytosis, endosomal escape and intracellular protein release. Recently, it was reported that fluorination on polymers is beneficial for their self-assembly and intracellular trafficking. We hypothesize the fluoropolymers can be used to encapsulate proteins and developed as a new class of carriers to break down the barriers during intracellular protein delivery. In this study, we successfully discovered an efficient and non-toxic polymer for protein delivery in a library of fluoropolymers. The lead material A6-2 in the library efficiently transported various proteins including bovine serum albumin, ß-galactosidase, saporin and a cyclic hendecapeptide into the cytosol of living cells with minimal cytotoxicity. More importantly, activities of delivered proteins and peptides were maintained after delivery. The A6-2/saporin complex was further coated with a hyaluronic acid shell, and the yielding nanoparticle efficiently suppressed tumor growth in a breast cancer model by targeted protein delivery. This study provides a new insight into the design of efficient and biocompatible polymers for protein delivery.