Elafibranor emerged as a potential chemotherapeutic drug for non-muscle invasive bladder cancer.

Intravesical infusion of chemotherapeutics is highly recommended by several clinical guidelines for treating nonmuscle invasive bladder cancer (NMIBC). However, cytotoxic chemotherapeutics can cause a series of side effects, which greatly limits their application. Herein, a starvation therapy strategy was proposed, and elafibranor (ELA) was validated as a safe chemotherapeutic for NMIBC. The results showed that 20 µM ELA was sufficient to inhibit the proliferation and migration of bladder cancer cells and increase the level of intracellular reactive oxygen species (ROS). Furthermore, 2 mg/kg ELA treatment blocked the growth of primary tumors in an immunodeficient model by inhibiting proliferation and inducing apoptosis and improved the survival time of immunocompetent model mice. ELA treatment up to 10 mg/kg met the general safety requirements. We also established a patient-derived conditional reprogramming cell (CRC) model to assess the clinical translational potential of ELA. The antitumor effect and antitumor specificity of ELA treatment were confirmed. This work not only identified a promising chemotherapeutic for NMIBC but also provided a potential methodological system for drug discovery.

Local Delivery of Glabridin by Biomolecular Microneedle to Accelerate Infected Wound Healing.

Applying antibacterial polymers and pro-regenerative small molecules are two individual strategies for accelerating wound healing. However, integrating those two unique approaches into one therapeutic platform that meets clinical requirements is still a challenge. Herein, a series of antibacterial gelatin methacrylate (GelMA)/ε-polylysine (ε-PL) composite hydrogels (termed as GP-n HGs, n = 0, 10, 20, and 30, respectively) are innovatively fabricated by ultraviolet light (UV) crosslinking. The GP-n HGs are proved to be broad-spectrum antibacterial and biocompatible. Among those GP-n HGs, the GP-20 HG is selectively processed into microneedle following a mold-casting method. Then, the glabridin is loaded into those needles to produce composite microneedle termed GP-20@Gla MN. An S. aureus-infected full-thickness defect model in rats is created to evaluate the wound-healing effect of GP-20@Gla MN. Furthermore, an RNA sequencing assay is performed to explore the possible molecular mechanisms of glabridin in promoting tissue regeneration, and many positive routes are summarized. This work is of significant novelty in fulfilling complex clinical needs by simultaneously optimizing the advanced microneedles' chemical compositions and physical structures. This work will provide a promising therapeutic platform for treating infected and chronic wounds.

Validation of the Chinese version of PedsQL™ brain tumor module.

Background: The study introduced the Pediatric Quality of Life Inventory™ (PedsQL™) brain tumor module for the first time in China. Further, the Chinese version of the PedsQL™ brain tumor module was developed and its feasibility, reliability, and validity were investigated. Methods: A total 129 cases completed the assessment. Feasibility was evaluated according to the percentage of missing items and the time required to complete the questionnaire. Internal consistency, retest reliability, and split-half reliability were tested to confirm reliability. We evaluated validity by testing content validity, construct validity, and criterion-related validity. The consistency between the child-self and parent-proxy reports was analyzed by calculating the correlation coefficient (r value) between them. Results: The Cronbach's alpha values for all subscales were above 0.7 and many subscales scored more than 0.9. The intra-class correlation coefficients of retest reliability were higher than 0.9. The split-half reliability scores for all subscales were higher than 0.6. The factor-item correlations ranged between 0.575-0.922 in the child report and 0.492-0.949 in the parent report. Exploratory factor analyses produced five factors corresponding to each subscale in the child report and six factors in the parent report. Conclusion: The feasibility, reliability, and validity of the Chinese PedsQL™ brain tumor module were ascertained through this study. This module can be used to effectively monitor children with brain tumors and conduct descriptive or exploratory studies to determine the risk factors affecting their quality of life. This would help develop a new basis for formulating measures to improve patient prognosis and quality of life.

Theranostic Lipid Nanoparticles for Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is a common urological malignancy and represents a leading threat to healthcare. Recent years have seen a series of progresses in the early diagnosis and management of RCC. Theranostic lipid nanoparticles (LNPs) are increasingly becoming one of the focuses in this field, because of their suitability for tumor targeting and multimodal therapy. LNPs can be precisely fabricated with desirable chemical compositions and biomedical properties, which closely match the physiological characteristics and clinical needs of RCC. Herein, a comprehensive review of theranostic LNPs is presented, emphasizing the generic tool nature of LNPs in developing advanced micro-nano biomaterials. It begins with a brief overview of the compositions and formation mechanism of LNPs, followed with an introduction to kidney-targeting approaches, such as passive, active, and stimulus responsive targeting. With examples provided, a series of modification strategies for enhancing the tumor targeting and functionality of LNPs are discussed. Thereafter, research advances on applications of these LNPs for RCC including bioimaging, liquid biopsy, drug delivery, physical therapy, and gene therapy are summarized and discussed from an interdisciplinary perspective. The final part highlights the milestone achievements of translation medicine, current challenges as well as future development directions of LNPs for the diagnosis and treatment of RCC.

Emerging Bioprinting for Wound Healing.

Bioprinting has attracted much attention due to its suitability for fabricating biomedical devices. In particular, bioprinting has become one of the growing centers in the field of wound healing, with various types of bioprinted devices being developed, including 3D scaffolds, microneedle patches, and flexible electronics. Bioprinted devices can be designed with specific biostructures and biofunctions that closely match the shape of wound sites and accelerate the regeneration of skin through various approaches. Herein, a comprehensive review of the bioprinting of smart wound dressings is presented, emphasizing the crucial effect of bioprinting in determining biostructures and biofunctions. The review begins with an overview of bioprinting techniques and bioprinted devices, followed with an in-depth discussion of polymer-based inks, modification strategies, additive ingredients, properties, and applications. The strategies for the modification of bioprinted devices are divided into seven categories, including chemical synthesis of novel inks, physical blending, coaxial bioprinting, multimaterial bioprinting, physical absorption, chemical immobilization, and hybridization with living cells, and examples are presented. Thereafter, the frontiers of bioprinting and wound healing, including 4D bioprinting, artificial intelligence-assisted bioprinting, and in situ bioprinting, are discussed from a perspective of interdisciplinary sciences. Finally, the current challenges and future prospects in this field are highlighted.

Double-network cellulose-based hybrid hydrogels with favourable biocompatibility and antibacterial activity for wound healing.

Bacterial infections are among the leading causes of delayed wound healing. At present, a series of antibacterial materials, such as antibiotics, antimicrobial peptides (AMPs), metals and metal oxides (MMOs), have been used to fabricate antibacterial wound dressings. However, their translational potential is limited owing to their poor biocompatibility. ε-Polylysine (ε-PL) is a natural macromolecule with excellent biocompatibility and broad-spectrum antibacterial activity. Herein, ε-PL was incorporated into a cellulose/γ-polyglutamic acid (γ-PGA) composite hydrogel to form a novel double-network hydrogel termed as CGLH. The elastic modulus of CGLH increased from 0.097 ± 0.015 MPa to 0.441 ± 0.096 MPa, and the equilibrium swelling ratio increased from 382.7 ± 24.3 % to 611.2 ± 8.6 %. Several preclinical models were used to investigate the translational potential of this hydrogel. CGLH exhibited good biocompatibility and antibacterial activity, which promoted the healing of infected and critical-size wounds within 12 days. CGLH had positive effects on collagen synthesis, vascularization and cell proliferation. As a result, this study not only provided an effective alternative for wound healing but also proposed a double-network strategy for creating biocompatible and antibacterial biomaterials.

Engineering a Phosphoketolase Pathway to Supplement Cytosolic Acetyl-CoA in Aspergillus niger Enables a Significant Increase in Citric Acid Production.

Citric acid is widely used in the food, chemical and pharmaceutical industries. Aspergillus niger is the workhorse used for citric acid production in industry. A canonical citrate biosynthesis that occurred in mitochondria was well established; however, some research suggested that the cytosolic citrate biosynthesis pathway may play a role in this chemical production. Here, the roles of cytosolic phosphoketolase (PK), acetate kinase (ACK) and acetyl-CoA synthetase (ACS) in citrate biosynthesis were investigated by gene deletion and complementation in A. niger. The results indicated that PK, ACK and ACS were important for cytosolic acetyl-CoA accumulation and had significant effects on citric acid biosynthesis. Subsequently, the functions of variant PKs and phosphotransacetylase (PTA) were evaluated, and their efficiencies were determined. Finally, an efficient PK-PTA pathway was reconstructed in A. niger S469 with Ca-PK from Clostridium acetobutylicum and Ts-PTA from Thermoanaerobacterium saccharolyticum. The resultant strain showed an increase of 96.4% and 88% in the citrate titer and yield, respectively, compared with the parent strain in the bioreactor fermentation. These findings indicate that the cytosolic citrate biosynthesis pathway is important for citric acid biosynthesis, and increasing the cytosolic acetyl-CoA level can significantly enhance citric acid production.

Designing Low Tortuosity Electrodes through Pattern Optimization for Fast-Charging.

The development of fast-charging technologies is crucial for expediting the progress and promotion of electric vehicles. In addition to innovative material exploration, reduction in the tortuosity of electrodes is a favored strategy to enhance the fast-charging capability of lithium-ion batteries by optimizing the ion-transfer kinetics. To realize the industrialization of low-tortuosity electrodes, a facile, cost-effective, highly controlled, and high-output continuous additive manufacturing roll-to-roll screen printing technology is proposed to render customized vertical channels within electrodes. Extremely precise vertical channels are fabricated by applying the as-developed inks, using LiNi0.6 Mn0.2 Co0.2 O2 as the cathode material. Additionally, the relationship between the electrochemical properties and architecture of the channels, including the pattern, channel diameter, and edge distance between channels, is revealed. The optimized screen-printed electrode exhibited a seven-fold higher charge capacity (72 mAh g-1 ) at a current rate of 6 C and superior stability compared with that of the conventional bar-coated electrode (10 mAh g-1 , 6 C) at a mass loading of 10 mg cm-2 . This roll-to-roll additive manufacturing can potentially be applied to various active materials printing to reduce electrode tortuosity and enable fast charging in battery manufacturing.

Biochar raw material selection and application in the food chain: A review.

As one of the largest carbon emitters, China promises to achieve carbon emissions neutrality by 2060. Various industries are developing businesses to reduce carbon emissions. As an important greenhouse gas emissions scenario, the reduction of carbon emissions in the food chain can be achieved by preparing the wastes into biochar. The food chain, as one of the sources of biochar, consists of production, processing and consumption, in which many wastes can be transferred into biochar. However, few studies use the food chain as the system to sort out the raw materials of biochar. A systematic review of the food chain application in serving as raw materials for biochar is helpful for further application of such technique, providing supportive information for the development of biochar preparation and wastes treating. In addition, there are many pollution sources in the food production process, such as agricultural contaminated soil and wastewater from livestock and aquatic, that can be treated on-site to achieve the goal of treating wastes with wastes within the food chain. This study focuses on waste resource utilization and pollution remediation in the food chain, summarizing the sources of biochar in the food chain and analyzing the feasibility of using waste in food chain to treat contaminated sites in the food chain and discussing the impacts of the greenhouse gas emissions. This review provides a reference for the resource utilization of waste and pollution reduction in the food chain.

Downregulation of microRNA-124-3p promotes subventricular zone neural stem cell activation by enhancing the function of BDNF downstream pathways after traumatic brain injury in adult rats.

AIMS: In this study, the effect of intracerebral ventricle injection with a miR-124-3p agomir or antagomir on prognosis and on subventricular zone (SVZ) neural stem cells (NSCs) in adult rats with moderate traumatic brain injury (TBI) was investigated. METHODS: Model rats with moderate controlled cortical impact (CCI) were established and verified as described previously. The dynamic changes in miR-124-3p and the status of NSCs in the SVZ were analyzed. To evaluate the effect of lateral ventricle injection with miR-124-3p analogs and inhibitors after TBI, modified neurological severity scores (mNSSs) and rotarod tests were used to assess motor function prognosis. The variation in SVZ NSC marker expression was also explored. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of predicted miR-124-3p targets was performed to infer miR-124-3p functions, and miR-124-3p effects on pivotal predicted targets were further explored. RESULTS: Administration of miR-124 inhibitors enhanced SVZ NSC proliferation and improved the motor function of TBI rats. Functional analysis of miR-124 targets revealed high correlations between miR-124 and neurotrophin signaling pathways, especially the TrkB downstream pathway. PI3K, Akt3, and Ras were found to be crucial miR-124 targets and to be involved in most predicted functional pathways. Interference with miR-124 expression in the lateral ventricle affected the PI3K/Akt3 and Ras pathways in the SVZ, and miR-124 inhibitors intensified the potency of brain-derived neurotrophic factor (BDNF) in SVZ NSC proliferation after TBI. CONCLUSION: Disrupting miR-124 expression through lateral ventricle injection has beneficial effects on neuroregeneration and TBI prognosis. Moreover, the combined use of BDNF and miR-124 inhibitors might lead to better outcomes in TBI than BDNF treatment alone.

[Bioinformatic analysis of immune correlation and prognostic value of SERPINs in glioma].

Objective To investigate the expression of serine protease inhibitors (SERPINs) and immune infiltration in gliomas and identify their relationship with the prognosis. Methods By using R and several bioinformatics analysis databases, the expression of 35 genes of Serpins in glioma tissues from TCGA were collected and analyzed; In GEPIA, genes with significant differences were selected for survival analysis and genes with the most prognostic value were chosen for further analysis. To probe the correlation between SERPIN and tumor immunity, gene expression in pan-cancer, cells cluster enrichment in tumor tissue, and the correlation between macrophage infiltration and SERPIN expression were analyzed, via TIMER and TISCH. Results The expression of SERPIN in glioma changed, showing a significant correlation with glioma grade and prognosis. SERPINE2 and SERPINH1 were significantly correlated with the prognosis of patients with high-grade glioma, and may involve in the immune regulation within the tumor immune microenvironment through different pathways with immune cells. Conclusion The expression of SERPINs are closely related to the clinical prognosis and immunity in glioma, among which SERPINE2 and SERPINH1 are the key genes with significant effect.

Clinical and Epidemiological Study of Intracranial Tumors in Children and Identification of Diagnostic Biomarkers for the Most Common Tumor Subtype and Their Relationship with the Immune Microenvironment Through Bioinformatics Analysis.

Brain tumors are the second most common pediatric malignancy and have poor prognosis. Understanding the pathogenesis of tumors at the molecular level is essential for clinical treatment. We conducted a retrospective study on the epidemiology of brain tumors in children based on clinical data obtained from a neurosurgical center. After identifying the most prevalent tumor subtype, we identified new potential diagnostic biomarkers through bioinformatics analysis of the public database. All children (0-15 years) with brain tumors diagnosed histopathologically between 2010 and 2020 at the Department of Neurosurgery, Xijing Hospital, were reviewed retrospectively for age distribution, sex predilection, native location, tumor location, symptoms, and histological grade, and identified the most common tumor subtypes. Two datasets (GSE44971 and GSE44684) were downloaded from the Gene Expression Omnibus database, whereas the GSE44971 dataset was used to screen the differentially expressed genes between normal and tumor samples. Gene ontology, disease ontology, and gene set enrichment analysis enrichment analyses were performed to investigate the underlying mechanisms of differentially expressed genes in the tumor. Combined with methylation data in the GSE44684 dataset, we further analyzed the correlation between methylation and gene expression levels. Two algorithms, LASSO and SVM-RFE, were used to select the hub genes of the tumor. The diagnostic value of the hub genes was assessed using the receiver operating characteristic (ROC) curve. Finally, we further evaluated the relationship between the hub gene and the tumor microenvironment and immune gene sets. Overall, 650 children from 18 provinces in China were included in this study. The male-to-female ratio was 1.41:1, and the number of patients reached a peak in the 10-15-year-old group (41.4%).The most common symptoms we encountered in our institute were headache and dizziness 250 (28.2%), and nausea and vomiting 228 (25.7%). The predominant location is supratentorial, with a supratentorial to infratentorial ratio of 1.74:1. Low-grade tumors (WHO I/II) constituted 60.9% of all cases and were predominant in every age group. According to basic classification, the most common tumor subtype is pilocytic astrocytoma (PA). A total of 3264 differentially expressed genes were identified in the GSE44971 dataset, which are mainly involved in the process of neural signal transduction, immunity, and some diseases. Correlation analysis indicated that the expression of 45 differentially expressed genes was negatively correlated with promoter DNA methylation. Next, we acquired five hub genes (NCKAP1L, GPR37L1, CSPG4, PPFIA4, and C8orf46) from the 45 differentially expressed genes by intersecting the LASSO and SVM-RFE models. The ROC analysis revealed that the five hub genes had good diagnostic value for patients with PA (AUC > 0.99). Furthermore, the expression of NCKAP1L was negatively correlated with immune, stromal, and estimated scores, and positively correlated with immune gene sets. This study, based on the data analysis of intracranial tumors in children in a single center over the past 10 years, reflected the clinical and epidemiological characteristics of intracranial tumors in children in Northwest China to a certain extent. PA is considered the most common subtype of intracranial tumors in children. Through bioinformatics analysis, we suggested that NCKAP1L, GPR37L1, CSPG4, PPFIA4, and C8orf46 are potential biomarkers for the diagnosis of PA.

HBO Alleviates Neural Stem Cell Pyroptosis via lncRNA-H19/miR-423-5p/NLRP3 Axis and Improves Neurogenesis after Oxygen Glucose Deprivation.

Due to the limited neurogenesis capacity, there has been a big challenge in better recovery from neurological dysfunction caused by stroke for a long time. Neural stem cell (NSC) programmed death is one of the unfavorable factors for neural regeneration after stroke. The types of death such as apoptosis and necroptosis have been deeply investigated while the pyroptosis of NSCs is not quite understood. Although it is well accepted that hyperbaric oxygen (HBO) alleviates the oxygen-glucose deprivation (OGD) injury after stroke and reduces programmed death of NSCs, whether NSC pyroptosis is involved in this process is still unknown. Therefore, this study is aimed at studying the potential effect of HBO treatment on NSC pyroptosis following OGD exposure, as well as its influence on NSC proliferation and differentiation in vitro. The results revealed that OGD increased NOD-like receptor protein 3 (NLRP3) expression to induce the pyroptotic death of NSCs, which was rescued by HBO treatment. And the upregulated lncRNA-H19 functioned as a molecular sponge of miR-423-5p to target NLRP3 for NSC pyroptosis following OGD. Most importantly, it was confirmed that HBO exerted protection of NSCs against pyroptosis by inhibiting lncRNA-H19/miR-423-5p/NLRP3 axis. Moreover, HBO restraint of lncRNA-H19-associated pyroptosis benefited the proliferation and neuronal differentiation of NSCs. It was concluded that HBO attenuated NSC pyroptosis via lncRNA-H19/miR-423-5p/NLRP3 axis and enhanced neurogenesis following OGD. The findings provide new insight into NSC programmed death and enlighten therapeutic strategy after stroke.

Identification of key methylation differentially expressed genes in posterior fossa ependymoma based on epigenomic and transcriptome analysis.

BACKGROUND: Posterior fossa ependymoma (EPN-PF) can be classified into Group A posterior fossa ependymoma (EPN-PFA) and Group B posterior fossa ependymoma (EPN-PFB) according to DNA CpG island methylation profile status and gene expression. EPN-PFA usually occurs in children younger than 5 years and has a poor prognosis. METHODS: Using epigenome and transcriptome microarray data, a multi-component weighted gene co-expression network analysis (WGCNA) was used to systematically identify the hub genes of EPN-PF. We downloaded two microarray datasets (GSE66354 and GSE114523) from the Gene Expression Omnibus (GEO) database. The Limma R package was used to identify differentially expressed genes (DEGs), and ChAMP R was used to analyze the differential methylation genes (DMGs) between EPN-PFA and EPN-PFB. GO and KEGG enrichment analyses were performed using the Metascape database. RESULTS: GO analysis showed that enriched genes were significantly enriched in the extracellular matrix organization, adaptive immune response, membrane raft, focal adhesion, NF-kappa B pathway, and axon guidance, as suggested by KEGG analysis. Through WGCNA, we found that MEblue had a significant correlation with EPN-PF (R = 0.69, P = 1 × 10-08) and selected the 180 hub genes in the blue module. By comparing the DEGs, DMGs, and hub genes in the co-expression network, we identified five hypermethylated, lower expressed genes in EPN-PFA (ATP4B, CCDC151, DMKN, SCN4B, and TUBA4B), and three of them were confirmed by IHC. CONCLUSION: ssGSEA and GSVA analysis indicated that these five hub genes could lead to poor prognosis by inducing hypoxia, PI3K-Akt-mTOR, and TNFα-NFKB pathways. Further study of these dysmethylated hub genes in EPN-PF and the pathways they participate in may provides new ideas for EPN-PF treatment.

Niche Cells Crosstalk In Neuroinflammation After Traumatic Brain Injury.

Traumatic brain injury (TBI) is recognized as the disease with high morbidity and disability around world in spite of the work ongoing in neural protection. Due to heterogeneity among the patients, it's still hard to acquire satisfying achievements in clinic. Neuroinflammation, which exists since primary injury occurs, with elusive duality, appear to be of significance from recovery of injury to neurogenesis. In recent years, studied have revealed that communication in neurogenic niche is more than "cell to cell" communication, and study on NSCs represent it as central role in the progress of neural regeneration. Hence, the neuroinflammation-affecting crosstalk after TBI, and clarifying definitive role of NSCs in the course of regeneration is a promising subject for researchers, for its great potential in overcoming the frustrating status quo in clinic, promoting welfare of TBI patient.

Microstructure and Low-Cycle Fatigue Behavior of Al-9Si-4Cu-0.4Mg-0.3Sc Alloy with Different Casting States.

The low-cycle fatigue behavior of Al-9Si-4Cu-0.4Mg-0.3Sc alloy with different casting states was investigated by performing low-cycle fatigue tests and by means of observations and analysis with a scanning electron microscope (SEM) and a transmission electron microscope (TEM). It was found that the metal-mold cast and die-cast Al-9Si-4Cu-0.4Mg-0.3Sc alloys exhibited the cyclic stress response of strain hardening under all imposed total strain amplitudes. The cyclic deformation resistance and fatigue life of the metal-mold cast Al-9Si-4Cu-0.4Mg-0.3Sc alloy were lower than those of the die-cast Al-9Si-4Cu-0.4Mg-0.3Sc alloy. The plastic strain and elastic strain amplitudes of the metal-mold cast and die-cast Al-9Si-4Cu-0.4Mg-0.3Sc alloys were linearly related to the number of reversals to failure, which obeyed the Coffin-Manson and Basquin formulas, respectively. The results of TEM observation revealed that at all imposed total strain amplitudes, the cyclic deformation mechanisms of the metal-mold cast and die-cast Al-9Si-4Cu-0.4Mg-0.3Sc alloys were planar slip and wavy slip at the lower and higher strain amplitudes, respectively.

Co-administration of combretastatin A4 nanoparticles and sorafenib for systemic therapy of hepatocellular carcinoma.

Effective systemic therapy is highly desired for the treatment of hepatocellular carcinoma (HCC). In this study, a combination of nanoparticles of poly(L-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4 sodium salt (CA4-NPs) plus sorafenib is developed for the cooperative systemic treatment of HCC. The CA4-NPs leads to the disruption of established tumor blood vessels and extensive tumor necrosis, however, inducing increased expression of VEGF-A and angiogenesis. Sorafenib reduces the VEGF-A induced angiogenesis and further inhibits tumor proliferation, cooperating with the CA4-NPs. A significant decrease in tumor volume and prolonged survival time are observed in the combination group of CA4-NPs plus sorafenib compared with CA4-NPs or sorafenib monotherapy in subcutaneous and orthotopic H22 hepatic tumor models. Seventy-one percent of the mice are alive without residual tumor at 96 days post tumor inoculation for the subcutaneous models treated with CA4-NPs 30 or 35 mg·kg-1 plus sorafenib 30 mg·kg-1. Our findings suggest that co-administration of sorafenib and CA4-NPs possesses significant antitumor efficacy for HCC treatment. STATEMENT OF SIGNIFICANCE: Effective systemic therapy is highly desired for the treatment of hepatocellular carcinoma (HCC). Herein, we demonstrate that a combination of nanoparticles of poly(L-glutamic acid)-graft-methoxy poly(ethylene glycol)/combretastatin A4 sodium salt (CA4-NPs) plus sorafenib is a promising synergistic approach for systemic treatment of HCC. The CA4-NPs leads to the disruption of established tumor blood vessels and extensive tumor necrosis, however, inducing increased expression of VEGF-A and angiogenesis. Sorafenib reduces the VEGF-A induced angiogenesis and further inhibits tumor proliferation, cooperating with the CA4-NPs.

Dihydroartemisinin increases gemcitabine therapeutic efficacy in ovarian cancer by inducing reactive oxygen species.

Ovarian cancer is the major cause of death in women gynecological malignancy and gemcitabine (GEM) is commonly used in related chemotherapy. However, more than 90% GEM is catalyzed into an inactive metabolite 2'-deoxy-2',2'-difluorouridine by stromal and cellular cytidine deaminase (CDA). Dihydroartemisinin (DHA), which possesses an intramolecular endoperoxide bridge, could be activated by heme or ferrous iron to produce reactive oxygen species (ROS). The excess ROS generation will excite expression of heme oxygenase-1 and suppress CDA expression. Under low CDA expression, the inactivation of GEM is decreased in turn to exert excellent therapeutic efficiency. Herein, we first studied the ROS generation by DHA in vitro with A2780 cells by means of flow cytometry and confocal laser scanning microscopy. Furthermore, cytotoxicity assay in vitro showed that DHA + GEM had synergistic effect, with molar ratio of DHA and GEM at 10. Eventually, in A2780 ovarian cancer xenograft tumor model, DHA + GEM exhibited significant antitumor efficiency with lower blood toxicity than GEM alone. Noteworthy, the combination treatment group completely eliminated the tumors on day 14.

Co-administration of genistein with doxorubicin-loaded polypeptide nanoparticles weakens the metastasis of malignant prostate cancer by amplifying oxidative damage.

Prostate cancer is a typical malignant disease with a high incidence and a poor prognosis. Doxorubicin hydrochloride (DOX·HCl) is one of the most effective agents in the treatment of prostate cancer, but severe side effects and metastasis after its treatment impose restrictions on its application. Herein, a combination of genistein (GEN) and doxorubicin-loaded polypeptide nanoparticles (DOX-NPs) is constructed for the treatment of prostate cancer. The DOX-NPs can reduce the side effects caused by free DOX·HCl and produce a relatively low level of intracellular reactive oxygen species (ROS)-induced oxidative damage, while GEN, an inhibitor of the oxidative DNA repair enzyme apurinic/apyrimidinic endonuclease1 (APE1), can further amplify the ROS-induced oxidative damage by downregulating the intracellular expression of APE1 and reducing oxidative DNA repair in the prostate cancer cells. Because high levels of ROS-induced oxidative damage can prevent the distant metastasis of tumor cells, the distant metastasis of malignant prostate cancer cells is significantly inhibited by the combination of genistein and DOX-NPs with amplified oxidative damage.

Bortezomib Increases the Cancer Therapeutic Efficacy of Poly(amino acid)-Doxorubicin.

Currently, chemotherapy is still a primary method to treat cancers. Doxorubicin is a regular chemotherapy drug, and a previous study indicated that mPEG5k-b-P(Glu10-r-Phe10)-doxorubicin is a more excellent nanodrug for cancer therapy, as it created a therapeutic advantage compared with free doxorubicin. Therefore, the efficacy of doxorubicin-resistant tumor treatment was investigated in this paper. While the cell viability and cell uptake results did not reflect an advantage of the nanodrug in drug-resistant tumors, comparison of the genetic expression of sensitive and resistant tumor cells highlighted NFκB. The proteasome inhibitor bortezomib, which is approved clinically and may influence the NFκB activity, was thus employed. The MTT assay and flow cytometry indicated that it could increase the therapeutic efficacy of poly(amino acid)-doxorubicin, and Western blot results showed that bortezomib and poly(amino acid)-doxorubicin can synergistically diminish NFκB expression. The synergism was confirmed through the orthotopic xenograft model in vivo. Thus, bortezomib can enhance the cancer therapeutic efficiency of poly(amino acid)-doxorubicin not only during the sensitive period but also during the resistant period. This makes the combination of bortezomib and poly(amino acid)-doxorubicin a potent strategy and guidance for the clinic.