Self-Stimulated Photodynamic Nanoreactor in Combination with CXCR4 Antagonists for Antileukemia Therapy.

The treatment of acute myeloid leukemia (AML) remains unsatisfactory, owing to the absence of efficacious therapy regimens over decades. However, advances in molecular biology, including inhibiting the CXCR4/CXCL12 biological axis, have introduced novel therapeutic options for AML. Additionally, self-stimulated phototherapy can solve the poor light penetration from external sources, and it will overcome the limitation that traditional phototherapy cannot be applied to the treatment of AML. Herein, we designed and manufactured a self-stimulated photodynamic nanoreactor to enhance antileukemia efficacy and suppress leukemia recurrence and metastasis in AML mouse models. To fulfill our design, we utilized the CXCR4/CXCL12 biological axis and biomimetic cell membranes in conjunction with self-stimulated phototherapy. This nanoreactor possesses the capability to migrate into the bone marrow cavity, inhibit AML cells from infiltrating into the visceral organ, significantly enhance the antileukemia effect, and prolong the survival time of leukemic mice. Therefore, this nanoreactor has significant potential for achieving high success rates and low recurrence rates in leukemia treatment.

Microneedles loaded with cerium-manganese oxide nanoparticles for targeting macrophages in the treatment of rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a prevalent inflammatory autoimmune disease characterised by persistent inflammation and joint damage with elevated levels of reactive oxygen species (ROS). Current treatment modalities for RA have significant limitations, including poor bioavailability, severe side effects, and inadequate targeting of inflamed joints. Herein, we synthesised cerium/manganese oxide nanoparticles (NPs) as efficient drug carriers with antioxidant and catalytic-like functions that can eliminate ROS to facilitate the polarization of macrophages phenotype from M1 to M2 and alleviate inflammation. Methotrexate (MTX), a first-line RA medication, was loaded into the NPs, which were further modified with bovine serum albumin (BSA) and integrated into dissolving hyaluronic acid-based microneedles (MNs) for transdermal delivery. RESULT: This innovative approach significantly enhanced drug delivery efficiency, reduced RA inflammation, and successfully modulated macrophage polarization toward an anti-inflammatory phenotype. CONCLUSION: This research not only presents a promising drug delivery strategy for RA but also contributes broadly to the field of immune disease treatment by offering an advanced approach for macrophage phenotypic reprogramming.

A cardiomyocyte-based biosensing platform for dynamic and quantitative investigation of excessive autophagy.

Autophagy is an important physiological phenomenon in eukaryotes that helps maintain the cellular homeostasis. Autophagy is involved in the development of various cardiovascular diseases, affecting the maintenance of cardiac function and disease prognosis. Physiological levels of autophagy serve as a defense mechanism for cardiomyocytes against environmental stimuli, but an overabundance of autophagy may contribute to the development of cardiovascular diseases. However, conventional biological methods are difficult to monitor the autophagy process in a dynamic and chronic manner. Here, we developed a cardiomyocyte-based biosensing platform that records electrophysiological evolutions in action potentials to reflect the degree of autophagy. Different concentrations of rapamycin-mediated autophagy were administrated in the culture environment to simulate the autophagy model. Moreover, the 3-methyladenine (3-MA)-mediated autophagy inhibition was also investigated the protection on the autophagy. The recorded action potentials can precisely reflect different degrees of autophagy. Our study confirms the possibility of visualizing and characterizing the process of cardiomyocyte autophagy using cardiomyocyte-based biosensing platform, allowing to monitor the whole autophagy process in a non-invasive, real-time, and continuous way. We believe it will pave a promising avenue to precisely study the autophagy-related cardiovascular diseases.

Ubiquitin-specific proteases: From biological functions to potential therapeutic applications in gastric cancer.

Deubiquitination, a post-translational modification regulated by deubiquitinases, is essential for cancer initiation and progression. Ubiquitin-specific proteases (USPs) are essential elements of the deubiquitinase family, and are overexpressed in gastric cancer (GC). Through the regulation of several signaling pathways, such as Wnt/ß-Catenin and nuclear factor-κB signaling, and the promotion of the expression of deubiquitination- and stabilization-associated proteins, USPs promote the proliferation, metastasis, invasion, and epithelial-mesenchymal transition of GC. In addition, the expression of USPs is closely related to clinicopathological features, patient prognosis, and chemotherapy resistance. USPs therefore could be used as prognostic biomarkers. USP targeting small molecule inhibitors have demonstrated strong anticancer activity. However, they have not yet been tested in the clinic. This article provides an overview of the latest fundamental research on USPs in GC, aiming to enhance the understanding of how USPs contribute to GC progression, and identifying possible targets for GC treatment to improve patient survival.

Zinc as a potential regulator of the BCR-ABL oncogene in chronic myelocytic leukemia cells.

BACKGROUND: Generally, decreased zinc in the serum of tumor patients but increased zinc in tumor cells can be observed. However, the role of zinc homeostasis in myeloid leukemia remains elusive. BCR-ABL is essential for the initiation, maintenance, and progression of chronic myelocytic leukemia (CML). We are currently investigating the association between zinc homeostasis and CML. METHODS: Genes involved in zinc homeostasis were examined using three GEO datasets. Western blotting and qPCR were used to investigate the effects of zinc depletion on BCR-ABL expression. Furthermore, the effect of TPEN on BCR-ABL promoter activity was determined using the dual-luciferase reporter assay. MRNA stability and protein stability of BCR-ABL were assessed using actinomycin D and cycloheximide. RESULTS: Transcriptome data mining revealed that zinc homeostasis-related genes were associated with CML progression and drug resistance. Several zinc homeostasis genes were affected by TPEN. Additionally, we found that zinc depletion by TPEN decreased BCR-ABL mRNA stability and transcriptional activity in K562 CML cells. Zinc supplementation and sodium nitroprusside treatment reversed BCR-ABL downregulation by TPEN, suggesting zinc- and nitric oxide-dependent mechanisms. CONCLUSION: Our in vitro findings may help to understand the role of zinc homeostasis in BCR-ABL regulation and thus highlight the importance of zinc homeostasis in CML.

Triple-Negative or Close-to-Triple-Negative Breast Cancer Presenting as a Thick-Walled Cystic Lesion.

Clinical and pathologic characteristics of the invasive ductal carcinoma (IDC) presenting as a thick-walled breast cyst are little known. Three female patients were included in this report. A palpable, nontender breast lump was found in all cases. While mammography showed a hyperdense mass, ultrasonography demonstrated a thick-walled cystic mass. Magnetic resonance imaging clearly showed the cystic breast lesions with ring-like or irregular rim enhancement. A grade III IDC was confirmed in all cases. All IDCs but one were estrogen receptor negative, progesterone receptor negative, and human epidermal growth factor receptor 2 negative, with merely weak progesterone receptor positivity (5%) in one case. All cases underwent surgical management first and postoperative chemotherapy. Breast malignancy presenting as a thick-walled cystic mass could be a highly aggressive IDC, even triple-negative breast cancer. It is imperative for breast cancer-related practitioners to identify the potentially malignant cystic lesions timely and adopt appropriate management.

Dual Responsive Magnetic Drug Delivery Nanomicelles with Tumor Targeting for Enhanced Cancer Chemo/Magnetothermal Synergistic Therapy.

Introduction: Stimulus-responsive nanocarrier systems are promising in cancer treatment. They improve drug stability and facilitate controlled drug release. However, single-responsive nanocarriers still face insufficient tumor targeting and low efficacy. Methods: In this study, we synthesized folate-modified DSPE-PEOz nanomicelles with PEG chains and loaded them with magnetic iron particles and doxorubicin (DOX). Folic acid (FA) was employed as a ligand to target cancer cells actively. The nanomicelles are biocompatible and acid-sensitive drug carriers. Magnetic field-responsive nanoparticles enable moderately controlled magnetothermal therapy of tumors regardless of tumor location. The pH/magnetic field dual-responsive nanomicelles shed their PEG layer in response to tumor tissue acidity and react to magnetic fields through magnetothermal effects. Results: In vitro and in vivo experiments demonstrated that the nanomicelles could efficiently target cancer cells, release drugs in response to pH changes, and enhance drug uptake through magnetothermal effects. Discussion: The dual-responsive magnetic nanomicelles are expected to enhance the anti-cancer efficacy of chemo/magnetothermal synergistic therapy.

Multi-omics study identifies that PICK1 deficiency causes male infertility by inhibiting vesicle trafficking in Sertoli cells.

BACKGROUND: Infertility affects approximately 10-15% of reproductive-age men worldwide, and genetic causes play a role in one-third of cases. As a Bin-Amphiphysin-Rvs (BAR) domain protein, protein interacting with C-kinase 1 (PICK1) deficiency could lead to impairment of acrosome maturation. However, its effects on auxiliary germ cells such as Sertoli cells are unknown. PURPOSE: The present work was aimed to use multi-omics analysis to research the effects of PICK1 deficiency on Sertoli cells and to identify effective biomarkers to distinguish fertile males from infertile males caused by PICK1 deficiency. METHODS: Whole-exome sequencing (WES) was performed on 20 infertility patients with oligozoospermia to identify pathogenic PICK1 mutations. Multi-omics analysis of a PICK1 knockout (KO) mouse model was utilized to identify pathogenic mechanism. Animal and cell function experiments of Sertoli cell-specific PICK1 KO mouse were performed to verify the functional impairment of Sertoli cells. RESULTS: Two loss-of-function deletion mutations c.358delA and c.364delA in PICK1 resulting in transcription loss of BAR functional domain were identified in infertility patients with a specific decrease in serum inhibin B, indicating functional impairment of Sertoli cells. Multi-omics analysis of PICK1 KO mouse illustrated that targeted genes of differentially expressed microRNAs and mRNAs are significantly enriched in the negative regulatory role in the vesicle trafficking pathway, while metabolomics analysis showed that the metabolism of amino acids, lipids, cofactors, vitamins, and endocrine factors changed. The phenotype of PICK1 KO mouse showed a reduction in testis volume, a decreased number of mature spermatozoa and impaired secretory function of Sertoli cells. In vitro experiments confirmed that the expression of growth factors secreted by Sertoli cells in PICK1 conditional KO mouse such as Bone morphogenetic protein 4 (BMP4) and Fibroblast growth factor 2 (FGF2) were decreased. CONCLUSIONS: Our study attributed male infertility caused by PICK1 deficiency to impaired vesicle-related secretory function of Sertoli cells and identified a variety of significant candidate biomarkers for male infertility induced by PICK1 deficiency.

The Saccharomyces cerevisiae acetyltransferase Gcn5 exerts antagonistic pleiotropic effects on chronological ageing.

Compared to replicative lifespan, epigenetic regulation of chronological lifespan (CLS) is less well understood in yeast. Here, by screening all the viable mutants of histone acetyltransferase (HAT) and histone deacetylase (HDAC), we demonstrate that Gcn5, functioning in the HAT module of the SAGA/SLIK complex, exhibits an epistatic relationship with the HDAC Hda1 to control the expression of starvation-induced stress response and respiratory cell growth. Surprisingly, the gcn5Δ mutants lose their colony-forming potential early in the stationary phase but display a longer maximum CLS than their WT counterparts, suggesting the contradictory roles of Gcn5 in lifespan regulation. Integrative analyses of the transcriptome, metabolome and ChIP assays reveal that Gcn5 is necessary for the activation of two regulons upon glucose starvation: the Msn2/4-/Gis1-dependent stress response and the Cat8-/Adr1-mediated metabolic reprogramming, to enable pro-longevity characteristics, including redox homeostasis, stress resistance and maximal storage of carbohydrates. The activation of Cat8-/Adr1-dependent regulon also promotes the pyruvate dehydrogenase (PDH) bypass, leading to acetyl-CoA synthesis, global and targeted H3K9 acetylation. Global H3K9 acetylation levels mediated by Gcn5 and Hda1 during the transition into stationary phase are positively correlated with senescent cell populations accumulated in the aged cell cultures. These data suggest that Gcn5 lies in the centre of a feed-forward loop between histone acetylation and starvation-induced gene expression, enabling stress resistance and homeostasis but also promoting chronological ageing concomitantly.

Dual single guide RNAs-mediating deletion of mature myostatin peptide results in concomitant muscle fibre hyperplasia and adipocyte hypotrophy in pigs.

Myostatin (MSTN) is a major gene target for skeletal muscle overgrowth in animals. We hypothesized that deletion of the entire mature peptide encoded by MSTN in pigs would knock out its bioactive form and accordingly stimulate skeletal muscle overgrowth. Thus, we engineered two pairs of single-guide RNAs (sgRNAs) to target exons 1 and 3 of MSTN in primary fetal fibroblasts of Taoyuan black pigs. We found that sgRNAs targeting exon 3, which encodes the mature peptide, had higher biallelic null mutation efficiency than those targeting exon 1. Somatic cell nuclear transfer was conducted using the exon 3 mutation cells as donor cells to generate five cloned MSTN null piglets (MSTN-/-). Growth testing revealed that both the growth rate and average daily weight gain of MST-/- pigs were greater than those of wild-type (MSTN+/+) pigs. Slaughter data demonstrated that the lean ratio of MSTN-/- pigs was 11.3% higher (P < 0.01) while the back-fat thickness was 17.33% lower (P < 0.01) than those of MSTN+/+ pigs. Haematoxylin-eosin staining indicated that the increased leanness of MSTN-/- pigs resulted from muscle fibre hyperplasia rather than hypertrophy.HE staining showed markedly decreased adipocyte size in MSTN-/- pigs. We also critically examined the off-target and random integration by resequencing, which showed that the founder MSTN-/- pigs contained no non-target mutations or exogenous plasmid elements. This study is the first to report the successful knock out of the mature MSTN peptide using dual sgRNA-mediated deletion, leading to the most prominent alteration of meat production traits in pigs published thus far. This new strategy is expected to have a wide impact on genetic improvements in food animals.

CILP2: A prognostic biomarker associated with immune infiltration in colorectal cancer.

The function played by cartilage intermediate layer protein 2 (CILP2) between colorectal cancer (CRC) progression and immune response remains unclear, especially with respect to immune cell infiltration and checkpoints. Materials and Methods: We examined CILP2 expression in The Cancer Genome Atlas (TCGA) COAD-READ cohort and analyzed its relationship with clinicopathological features, mutations, survival, and immunity. Gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway analysis, and gene set enrichment analyses (GSEA) were performed to determine CILP2 related pathways. To further investigate the results of TCGA analysis, validation was performed using CRC cell lines, fresh pathological tissues, and a CRC tissue microarray (TMA). Results: In both TCGA and TMA cohorts, CILP2 expression was increased in CRC tissues and was associated with patient T stage (T3 and T4), N stage (N1), pathological stage (III and IV), and overall survival. Immune cell infiltration and checkpoint analysis revealed that CILP2 expression is highly correlated with multiple immune marker genes, including PD-1. In addition, results of enrichment analysis indicated that CILP2 related genes was mainly enriched in extracellular matrix related functions. Conclusion: Elevated CILP2 expression is associated with adverse CRC clinical features and immune cells, it has potential as a biomarker detrimental to CRC survival.

Truncating PICK1 Variant Identified in Azoospermia Affected Mitochondrial Dysfunction in Knockout Mice.

OBJECTIVE: The protein interacting with C kinase 1 (PICK1) plays a critical role in vesicle trafficking, and its deficiency in sperm cells results in abnormal vesicle trafficking from Golgi to acrosome, which eventually disrupts acrosome formation and leads to male infertility. METHODS: An azoospermia sample was filtered, and the laboratory detection and clinical phenotype indicated typical azoospermia in the patient. We sequenced all of the exons in the PICK1 gene and found that there was a novel homozygous variant in the PICK1 gene, c.364delA (p.Lys122SerfsX8), and this protein structure truncating variant seriously affected the biological function. Then we constructed a PICK1 knockout mouse model using clustered regularly interspaced short palindromic repeat cutting technology (CRISPRc). RESULTS: The sperm from PICK1 knockout mice showed acrosome and nucleus abnormalities, as well as dysfunctional mitochondrial sheath formation. Both the total sperm and motility sperm counts were decreased in the PICK1 knockout mice compared to wild-type mice. Moreover, the mitochondrial dysfunction was verified in the mice. These defects in the male PICK1 knockout mice may have eventually led to complete infertility. CONCLUSION: The c.364delA novel variant in the PICK1 gene associated with clinical infertility, and pathogenic variants in the PICK1 may cause azoospermia or asthenospermia by impairing mitochondrial function in both mice and humans.

Renewable biohydrogen production from Clostridium sp. LQ25 using different forms of ferric as electron acceptor.

Clostridium sp. LQ25 was cultured in different forms of ferric (ferric citrate and ferric hydroxide) as electron acceptors to investigate growth, ferric reduction, hydrogen production, fermentation products and fermentation process. The growth of the strain LQ25 detected by protein was 82.8 ± 2.1 mg/L and 73.5 ± 1.7 mg/L using ferric citrate and ferric hydroxide as electron acceptors, which was 33.3 % and 18.4 % higher than without ferric, respectively. The accumulation concentration of Fe(II) was 9.0 ± 0.6 mg/L and 5.0 ± 0.2 mg/L when using ferric citrate and ferric hydroxide as electron acceptors, and ferric citrate was 1.8-fold higher than ferric hydroxide, which indicated that the ability of ferric reduction was higher using ferric citrate as electron acceptor. The hydrogen production of strain LQ25 was 238.0 ± 1.0 mmol/mol glucose and 113.0 ± 1.3 mmol/mol glucose under condition of ferric citrate and ferric hydroxide as electron acceptors, which was 2.6 and 1.2-fold higher than without ferric, respectively. The growth and hydrogen production of strain LQ25 was promoted by using ferric as electron acceptor, while the fermentation type of strain did not change and was always butyrate type. The differential expression of the genes of strain LQ25 was significant when using ferric as electron acceptor, mainly in NADH and PFL pathway. This study provided preliminary evidence for hydrogen production by Clostridium sp. LQ25 in the presence of electron acceptor.

Activated Natural Killer Cells-Dependent Dendritic Cells Recruitment and Maturation by Responsive Nanogels for Targeting Pancreatic Cancer Immunotherapy.

Although enormous success has been obtained for dendritic cells (DCs)-mediated antigen-specific T cells anticancer immunotherapy in the clinic, it still faces major challenging problems: insufficient DCs in tumor tissue and low response rate for tumor cells lacking antigen expression, especially in low immunogenic tumors such as pancreatic cancer. Here, these challenges are tackled through tumor microenvironment responsive nanogels with prominent tumor-targeting capability by Panc02 cell membranes coating and inhibition of tumor-derived prostaglandin E2 (PGE2), aimed at improving natural killer (NK) cells activation and inducing activated NK cells-dependent DCs recruitment. The engineered nanogels can on-demand release acetaminophen to inhibit PGE2 secretion, thus promoting the activity of NK cells for non-antigen-specific tumor elimination. Furthermore, activated NK cells can secrete chemokines as CC motif chemokine ligand 5 and X-C motif chemokine ligand 1 to recruit immature DCs, and then promote DCs maturation and induce antigen-dependent CD8+ T cells proliferation for enhancing antigen-specific immunotherapy. Notably, these responsive nanogels show excellent therapeutic effect on Panc02 pancreatic tumor growth and postsurgical recurrence, especially combination of the programmed cell death-ligand 1 checkpoint-blockade immunotherapy. Therefore, this study provides a simple strategy for enhancing low immunogenic tumors immunotherapy through an antigen-independent way and antigen-dependent way synergetically.

TRIM7 modulates NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells.

OBJECTIVE: Glioblastoma is one of the most common intracranial malignant tumors with an unfavorable prognosis, and iron metabolism as well as ferroptosis are implicated in the pathogenesis of glioblastoma. The present study aims to decipher the role and mechanisms of tripartite motif-containing protein 7 (TRIM7) in ferroptosis and glioblastoma progression. METHODS: Stable TRIM7-deficient or overexpressing human glioblastoma cells were generated with lentiviral vectors, and cell survival, lipid peroxidation and iron metabolism were evaluated. Immunoprecipitation, protein degradation and ubiquitination assays were performed to demonstrate the regulation of TRIM7 on its candidate proteins. RESULTS: TRIM7 expression was elevated in human glioblastoma cells and tissues. TRIM7 silence suppressed growth and induced death, while TRIM7 overexpression facilitated growth and inhibited death of human glioblastoma cells. Meanwhile, TRIM7-silenced cells exhibited increased iron accumulation, lipid peroxidation and ferroptosis, which were significantly reduced by TRIM7 overexpression. Mechanistically, TRIM7 directly bound to and ubiquitinated nuclear receptor coactivator 4 (NCOA4) using K48-linked chains, thereby reducing NCOA4-mediated ferritinophagy and ferroptosis of human glioblastoma cells. Moreover, we found that TRIM7 deletion sensitized human glioblastoma cells to temozolomide therapy. CONCLUSION: We for the first time demonstrate that TRIM7 modulates NCOA4-mediated ferritinophagy and ferroptosis in glioblastoma cells, and our findings provide a novel insight into the progression and treatment for human glioblastoma.

PARP inhibitors diminish DNA damage repair for the enhancement of tumor photodynamic therapy.

Pancreatic cancer is a lethal malignancy and only around 4% of patients will live 5 years post-diagnosis. Photodynamic therapy (PDT) is a promising strategy for treating malignant tumors because of its high selectivity. Through the colocalization of light, oxygen and photosensitizer, a large number of reactive oxygen species (ROS) are generated under excitation at a specific wavelength of a laser, which can induce DNA damage and destroy cancer cells. However, the repair mechanism of cell will repair part of the damaged DNA, which could reduce the efficiency of PDT. The poly (ADP-Ribose) polymerase (PARP) plays a wide and multifaceted role in the cellular response to DNA damage, with growing evidence for participation in multiple pathways of DNA damage repair and genome maintenance. Cells require PARP to resolve single-strand DNA breaks (SSBs) induced by chemotherapy agents. Its inhibition is thought to result in the accumulation of damage in DNA, which may eventually lead to cell death. The combination therapy of PDT and PARP inhibitors may benefit patients. In this study, we design and synthesize a zeolitic imidazolate framework-8 (ZIF-8) to co-deliver DNA damaging agent Chlorin e6 (Ce6) and PARP inhibitor Olaparib (Ola). Ce6 and Ola demonstrate strong synergistic actions, providing a novel approach for the treatment of pancreatic cancer.

lncRNAs Functioned as ceRNA to Sponge miR-15a-5p Affects the Prognosis of Pancreatic Adenocarcinoma and Correlates With Tumor Immune Infiltration.

Pancreatic adenocarcinoma (PAAD) is one of the most common malignant tumors with poor prognosis worldwide. Mounting evidence suggests that the expression of lncRNAs and the infiltration of immune cells have prognostic value for patients with PAAD. We used Gene Expression Omnibus (GEO) database and identified six genes (COL1A2, ITGA2, ITGB6, LAMA3, LAMB3, and LAMC2) that could affect the survival rate of pancreatic adenocarcinoma patients. Based on a series of in silico analyses for reverse prediction of target genes associated with the prognosis of PAAD, a ceRNA network of mRNA (COL1A2, ITGA2, LAMA3, LAMB3, and LAMC2)-microRNA (miR-15a-5p)-long non-coding RNA (LINC00511, LINC01578, PVT1, and TNFRSF14-AS1) was constructed. We used the algorithm "CIBERSORT" to assess the proportion of immune cells and found three overall survival (OS)-associated immune cells (monocytes, M1 macrophages, and resting mast cell). Moreover, the OS-associated gene level was significantly positively associated with immune checkpoint expression and biomarkers of immune cells. In summary, our results clarified that ncRNA-mediated upregulation of OS-associated genes and tumor-infiltration immune cells (monocytes, M1 macrophages M1, and resting mast cell resting) correlated with poor prognosis in PAAD.

Progresses and Prospects of Neuroprotective Agents-Loaded Nanoparticles and Biomimetic Material in Ischemic Stroke.

Ischemic stroke remains the leading cause of death and disability, while the main mechanisms of dominant neurological damage in stroke contain excitotoxicity, oxidative stress, and inflammation. The clinical application of many neuroprotective agents is limited mainly due to their inability to cross the blood-brain barrier (BBB), short half-life and low bioavailability. These disadvantages can be better eliminated/reduced by nanoparticle as the carrier of these drugs. This review expounded the currently hot researched nanomedicines from the perspective of the mechanism of ischemic stroke. In addition, this review describes the bionic nanomedicine delivery strategies containing cells, cell membrane vesicles and exosomes that can effectively avoid the risk of clearance by the reticuloendothelial system. The potential challenges and application prospect for clinical translation of these delivery platforms were also discussed.

Cancer cell membrane-coated nanogels as a redox/pH dual-responsive drug carrier for tumor-targeted therapy.

Nanocarriers have shown great advantages in increasing the efficiency of drug delivery and reducing drug side effects. However, their lack of targeting and on-demand drug release abilities will seriously limit their clinical application. Herein, we report tumor cell membrane coated nanogels (NGs) with redox/pH dual-responsive behavior for enhanced tumor chemotherapy. The cell membrane coating improves the tumor targeting efficiency, and stimuli-responsive drug release enhances the therapeutic effects. These NGs are well dispersed in PBS with an average size of 109.1 ± 5.2 nm and a narrow polydispersity index of 0.12. Both in vitro and in vivo studies indicate that these NGs can responsively release the therapeutic drug DOX under acidic conditions or high GSH concentrations and effectively inhibit tumor growth. Based on the results, this nanogel shows promise as a platform for tumor-targeted chemotherapy for future clinical translation.

Protein interacting with C-kinase 1 is involved in epithelial-mesenchymal transformation and suppresses progress of gastric cancer.

Protein interacting with C-kinase 1 (PICK1) is a 415-aa multidomain scaffold protein encoded by the PICK1 gene. Accumulating evidence suggests that PICK1 is involved in the progression of cancer. However, the role of PICK1 in gastric cancer (GC) remains largely unknown. Using integrated analysis of publicly available GC transcriptome data from the Gene Expression Omnibus (GEO) database and immunohistochemistry analysis of samples obtained from clinical GC patients, we found that PICK1 expression was significantly down-regulated in gastric tumor tissues in comparison with adjacent normal tissues. Our analyses also revealed that decreased expression of PICK1 conferred a disadvantage on overall survival time in GC patients. Additionally, PICK1 expression showed a strong association with the epithelial-mesenchymal transition (EMT) pathway, and PICK1 might represent a functional bridge for EMT. Moreover, PICK1 expression was significantly decreased in the EMT subtype of GC and was negatively correlated with the expression of fibronectin 1 (FN1) and myosin light chain 9 (MYL9) mRNAs. Thus, our study provides evidence that PICK1 is a promising biomarker for the molecular etiology of GC.