PTEN inhibition enhances sensitivity of ovarian cancer cells to the poly (ADP-ribose) polymerase inhibitor by suppressing the MRE11-RAD50-NBN complex.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPis) can effectively treat ovarian cancer patients with defective homologous recombination (HR). Loss or dysfunction of PTEN, a typical tumour suppressor, impairs double-strand break (DSB) repair. Hence, we explored the possibility of inhibiting PTEN to induce HR deficiency (HRD) for PARPi application. METHODS: Functional studies using PTEN inhibitor VO-OHpic and PARPi olaparib were performed to explore the molecular mechanisms in vitro and in vivo. RESULTS: In this study, the combination of VO-OHpic with olaparib exhibited synergistic inhibitory effects on ovarian cancer cells was demonstrated. Furthermore, VO-OHpic was shown to enhance DSBs by reducing nuclear expression of PTEN and inhibiting HR repair through the modulation of MRE11-RAD50-NBN (MRN) complex, critical for DSB repair. TCGA and GTEx analysis revealed a strong correlation between PTEN and MRN in ovarian cancer. Mechanistic studies indicated that VO-OHpic reduced expression of MRN, likely by decreasing PTEN/E2F1-mediated transcription. Moreover, PTEN-knockdown inhibited expression of MRN, increased sensitivities to olaparib, and induced DSBs. In vivo experiments showed that the combination of VO-OHpic with olaparib exhibited enhanced inhibitory effects on tumour growth. CONCLUSIONS: Collectively, this study highlights the potential of PTEN inhibitors in combination therapy with PARPis to create HRD for HRD-negative ovarian cancers.

C-S-Selective Stille-Coupling Enables Stereodefined Alkene Synthesis.

A palladium-catalyzed highly C-S-selective Stille cross-coupling between aryl thianthrenium salts and tri- or tetrasubstituted alkenyl stannanes is described. Herein, critical challenges including site- and chemoselectivity control are well addressed through C-H thianthrenation and C-S alkenylation, thereby providing an expedient access to stereodefined tri- and tetrasubstituted alkenes in a stereoretentive fashion. Indeed, the palladium-catalyzed Stille-alkenylation of poly(pseudo)halogenated arenes displays privileged capability to differentiate C-S over C-I, C-Br, C-Cl bonds, as well as oxygen-based triflates (C-OTf), tosylates (C-OTs), carbamates and sulfamates under mild reaction conditions. Sequential and multiple cross-couplings via selective C-X functionalization should be widely applicable for increasing functional molecular complexity. Modular installation of stereospecific alkene motifs into pharmaceuticals illustrated the synthetic application of the present protocol in drug discovery.

A Purposefully Designed pH/GSH-Responsive MnFe-Based Metal-Organic Frameworks as Cascade Nanoreactor for Enhanced Chemo-Chemodynamic-Starvation Synergistic Therapy.

Metal-organic frameworks (MOFs) have emerged as promising novel therapeutics for treating malignancies due to their tunable porosity, biocompatibility, and modularity to functionalize with various chemotherapeutics drugs. However, the design and synthesis of dual-stimuli responsive MOFs for controlled drug release in tumor microenvironments are vitally essential but still challenging. Meanwhile, the catalytic effect of metal ions selection and ratio optimization in MOFs for enhanced chemodynamic therapy (CDT) is relatively unexplored. Herein, a series of MnFe-based MOFs with pH/glutathione (GSH)-sensitivity are synthesized and then combined with gold nanoparticles (Au NPs) and cisplatin prodrugs (DSCP) as a cascade nanoreactor (SMnFeCGH) for chemo-chemodynamic-starvation synergistic therapy. H+ and GSH can specifically activate the optimal SMnFeCGH nanoparticles in cancer cells to release Mn2+/4+ /Fe2+/3+ , Au NPs, and DSCP rapidly. The optimal ratio of Mn/Fe shows excellent H2 O2 decomposition efficiency for accelerating CDT. Au NPs can cut off the energy supply to cancer cells for starvation therapy and strengthen CDT by providing large amounts of H2 O2 . Then H2 O2 is catalyzed by Mn2+ /Fe2+ to generate highly toxic •OH with the depletion of GSH. Meanwhile, the reduced DSCP accelerates cancer cell regression for chemotherapy. The ultrasensitivity cascade nanoreactor can enhance the anticancer therapeutic effect by combining chemotherapy, CDT, and starvation therapy.

miR-155 Modulates Cockroach Allergen- and Oxidative Stress-Induced Cyclooxygenase-2 in Asthma.

Exposure to cockroach allergen is a strong risk factor for developing asthma. Asthma has been associated with allergen-induced airway epithelial damage and heightened oxidant stress. In this study, we investigated cockroach allergen-induced oxidative stress in airway epithelium and its underlying mechanisms. We found that cockroach extract (CRE) could induce reactive oxygen species (ROS) production, particularly mitochondrial-derived ROS, in human bronchial epithelial cells. We then used the RT2 Profiler PCR array and identified that cyclooxygenase-2 (COX-2) was the most significantly upregulated gene related to CRE-induced oxidative stress. miR-155, predicted to target COX-2, was increased in CRE-treated human bronchial epithelial cells, and was showed to regulate COX-2 expression. Moreover, miR-155 can bind COX-2, induce COX-2 reporter activity, and maintain mRNA stability. Furthermore, CRE-treated miR-155-/- mice showed reduced levels of ROS and COX-2 expression in lung tissues and PGE2 in bronchoalveolar lavage fluid compared with wild-type mice. These miR-155-/- mice also showed reduced lung inflammation and Th2/Th17 cytokines. In contrast, when miR-155-/- mice were transfected with adeno-associated virus carrying miR-155, the phenotypic changes in CRE-treated miR-155-/- mice were remarkably reversed, including ROS, COX-2 expression, lung inflammation, and Th2/Th17 cytokines. Importantly, plasma miR-155 levels were elevated in severe asthmatics when compared with nonasthmatics or mild-to-moderate asthmatics. These increased plasma miR-155 levels were also observed in asthmatics with cockroach allergy compared with those without cockroach allergy. Collectively, these findings suggest that COX-2 is a major gene related to cockroach allergen-induced oxidative stress and highlight a novel role of miR-155 in regulating the ROS-COX-2 axis in asthma.

Bombyx mori Rad23 (BmRad23) contributes to the repair of UV-damaged BmNPV.

Baculoviruses have been developed as long-term and environmentally friendly biopesticides. However, solar ultraviolet radiation can reduce the activity of baculovirus. Radiation sensitive 23 (Rad23) can recognize DNA damage and is involved with nucleotide excision repair (NER). In the current study, BmRad23 was accumulated mainly within the nucleus. Host cell reactivation (HCR) assays have shown that BmRad23 significantly facilitated the expression of UV-damaged mCherry reporter gene. Reverse transcription quantitative PCR (RT-qPCR) result showed that the mRNA expression level of BmRad23 was increased in (Bombyx mori nuclear polyhedrovirus, BmNPV) BmNPV-infected BmN cells. However, the expression of BmRad23 was increased significantly when BmNPV budded viruses (BVs) or BmN cells were irradiated with UV light. Overexpression of BmRad23 promoted the mRNA levels of two UV-induced DNA damage repair genes which were from Bombyx mori and BmNPV, respectively. Meanwhile, the overexpression of BmRad23 in BmN cells was conducive to the proliferation of BmNPV and UV-damaged BmNPV. The recombinant BmNPV BVs expressing BmRad23 showed stronger resistance to UV radiation than the control virus. In conclusion, the results revealed that BmRad23 contributed to the proliferation of BmNPV and the repair of UV-damaged BmNPV, which would provide a reference for the development of efficient baculovirus pesticides against UV radiation.

Liposome-based codelivery of celecoxib and doxorubicin hydrochloride as a synergistic dual-drug delivery system for enhancing the anticancer effect.

Combination therapy with conventional chemotherapeutic drugs strongly demonstrates a good approach to reduce cytotoxicity, resistance, and the dose of the potent anticancer drugs. The purpose of this research was to design and characterize liposome incorporating celecoxib (CEL) and doxorubicin hydrochloride (DOX) and investigate the anti-tumor efficacy of this combination on different tumor cells. A simple comparison study had been performed for liposomes formulation using thin-film hydration method and pH-gradient method. HSPC-incorporated liposomes were chosen for encapsulation of both CEL and DOX. The formulations showed small particle size and polydispersity index with high encapsulation efficiency. DOX/CEL liposomes displayed the strongest cytotoxicity against B16 and MGC80-3 cells in comparison to the corresponding drug solutions. By incorporation of both agents, a significant reduction in IC50 from 0.927 to 0.198 µg/ml and from 0.81 to 0.535 µg/ml against B16 cells and MGC80-3 cells, respectively, was observed. CEL also significantly improved the intracellular retention and accumulation of DOX in vitro. Our data suggest that the developed liposomal formulation proved to be the most effective formulative strategy as a dual drug delivery system for incorporation of both doxorubicin HCL and CEL and could be considered a useful tool for enhancing the therapeutic efficacy of the anticancer drug.

Roles of MYC-targeting long non-coding RNA MINCR in cell cycle regulation and apoptosis in non-small cell lung Cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer death in the world, and has a relatively low survival rate. Long non-coding RNAs (lncRNAs) have been demonstrated to modulate cancer progression through a variety of molecular mechanisms. We sought to investigate the role and potential mechanism of MYC-induced long non-coding RNA (MINCR) in NSCLC. METHODS: Expression levels of MINCR was first identified using The Cancer Genome Atlas (TCGA), further confirmed with specimens from 29 NSCLC patients and three cell lines using qRT-PCR. Overexpression and knockdown of MINCR were performed in NSCLC cell lines through MINCR overexpression vectors and synthesized siRNAs, respectively. The roles of MINCR in NSCLC cell lines, such as cell proliferation, cell cycle arrest, and apoptosis, were identified by MTT, flow cytometry, and Western blot. The modulation of MINCR-regulated genes, including c-Myc and its downstream effectors, as well as apoptosis-associated genes, was analyzed using Western blot. RESULTS: MINCR expression was increased in NSCLC patients from TCGA datasets, and was also significantly increased in our collected specimens from NSCLC patients and NSCLC cell lines. Knocking down of MINCR greatly inhibited the growth of NSCLC cell lines PC9 and A549. In addition, silencing of MINCR induced cell cycle arrest and apoptosis. Furthermore, silencing of MINCR reduced the expression levels of oncogene c-Myc and its downstream cyclin A, cyclin D, CD4, and CDK2, as well as apoptosis-associated Bcl-2, while significantly increased the expression levels of cleaved PARP-1. In the meantime, overexpression of MINCR remarkably enhanced cell proliferation of PC9 cells and activated c-Myc and its downstream effectors. CONCLUSION: MINCR exerted inhibitory effects on the cell cycle arrest and apoptosis of NSCLC cells by activating c-Myc and its downstream effectors, suggesting that this lncRNA could be used as a potential therapeutic target for the treatment of NSCLC.

BmNPV infection correlates with the enhancement of the resistance of Bombyx mori cells to UV radiation.

At present, the effect of ultraviolet (UV) radiation on the interaction between Bombyx mori nucleopolyhedrovirus (BmNPV) and host remains unclear. In the current study, UV treatment significantly reduced the activity of BmNPV budded viruses (BVs), and UV-damaged BmN cells were not conducive to BmNPV proliferation. BmNPV infection significantly reduced the viability of host cells, but increased the viability of high-dose UV-treated host cells. Furthermore, the quantitative reverse-transcription PCR (qPCR) results suggested that BmNPV and Bombyx mori might mutually use the same DNA repair proteins for repairing UV-induced damage and BmNPV infection promote the ability of host cells to repair UV-induced damage.

Baculovirus-Encoded MicroRNAs: A Brief Overview and Future Prospects.

MicroRNAs (miRNAs) are a class of non-coding RNAs with ∼22 nucleotides, which are able to regulate various biological processes, including the viral life cycle and host-pathogen interactions. Long primary transcripts (pri-miRNAs) are initially transcribed in nucleus, and subsequently processed by Dicer in cytoplasm to generate mature miRNAs. Baculoviruses consist of large, enveloped, insect-pathogenic viruses with a double-stranded circular DNA genome. Recent studies suggest that baculoviruses encode some miRNAs to manipulate expression regulation of host genes, whereas host modulate viral gene expression via miRNAs to limit viral infection. In the review, we will focus on the biogenesis and functions of miRNAs and the interactions between baculoviruses, insect, and miRNAs. It will be helpful to delve into the related mechanisms of BmNPV-encoded miRNAs that contribute to infection and pathogenesis.

Mannose receptor modulates macrophage polarization and allergic inflammation through miR-511-3p.

BACKGROUND: Mannose receptor (MRC1/CD206) has been suggested to mediate allergic sensitization and asthma to multiple glycoallergens, including cockroach allergens. OBJECTIVE: We sought to determine the existence of a protective mechanism through which MRC1 limits allergic inflammation through its intronic miR-511-3p. METHODS: We examined MRC1-mediated cockroach allergen uptake by lung macrophages and lung inflammation using C57BL/6 wild-type (WT) and Mrc1-/- mice. The role of miR-511-3p in macrophage polarization and cockroach allergen-induced lung inflammation in mice transfected with adeno-associated virus (AAV)-miR-511-3p (AAV-cytomegalovirus-miR-511-3p-enhanced green fluorescent protein) was analyzed. Gene profiling of macrophages with or without miR-511-3p overexpression was also performed. RESULTS: Mrc1-/- lung macrophages showed a significant reduction in cockroach allergen uptake compared with WT mice, and Mrc1-/- mice had an exacerbated lung inflammation with increased levels of cockroach allergen-specific IgE and TH2/TH17 cytokines in a cockroach allergen-induced mouse model compared with WT mice. Macrophages from Mrc1-/- mice showed significantly reduced levels of miR-511-3 and an M1 phenotype, whereas overexpression of miR-511-3p rendered macrophages to exhibit a M2 phenotype. Furthermore, mice transfected with AAV-miR-511-3p showed a significant reduction in cockroach allergen-induced inflammation. Profiling of macrophages with or without miR-511-3p overexpression identified 729 differentially expressed genes, wherein expression of prostaglandin D2 synthase (Ptgds) and its product PGD2 were significantly downregulated by miR-511-3p. Ptgds showed a robust binding to miR-511-3p, which might contribute to the protective effect of miR-511-3p. Plasma levels of miR-511-3p were significantly lower in human asthmatic patients compared with nonasthmatic subjects. CONCLUSION: These studies support a critical but previously unrecognized role of MRC1 and miR-511-3p in protection against allergen-induced lung inflammation.

Proteomic response of the rat liver in differential swimming modes.

Moderate exercise helps improve competition results, providing a balanced muscle tone and biochemical activity, whereas excessive training disrupts the balance between training and recovery, causes harm to the organism, and leads to overtraining syndrome (OTS). To explore the mechanisms of different protein expressions during training and acquisition of immunity, we used proteomic analyses to investigate the differences of liver-protein expressions between 2 swimming modes. Sprague-Dawley rats were randomly divided into control (CT), fatigue training (FT), and exhaustive training (ET) groups, and liver tissues from each group were subjected to 2-dimensional electrophoresis (2DE). A total of 4518 protein spots were detected in 9 replicates, and 45 protein spots exhibited a >2-fold difference in expression (P < .05), 31 of which was successfully identified by mass spectrometry. SERPINA3K expression decreased markedly during 2 stages from CT â†’ FT and FT â†’ ET, while DDT, RHOT1, and RBP4 decreased significantly only from CT â†’ ET but not from the former 2 stages. By contrast, KRT8, PCBD1, KRT18, PRDX1, and ACY1A showed significant >2-fold increase in expression in either the CT â†’ FT or FT â†’ ET stages. Bioinformatic analyses showed that among the identified proteins, 30.2%, 54.18%, and 15.62% were involved in biological processes, molecular functions, and cell composition, respectively. Notably, PCBD1, PRDX1, and PPP1CB were involved in redox processes, while PPP1CB was only expressed in the FT group. RGN, PSMB9, and AGT, commonly recognized as oxidative stress biomarkers, may involve in regulating homeostasis in the locomotor mode and may provide diagnostic criteria for the occurrence and prevention of exercise-induced fatigue and OTS.

Aryl Hydrocarbon Receptor Protects Lungs from Cockroach Allergen-Induced Inflammation by Modulating Mesenchymal Stem Cells.

Exposure to cockroach allergen leads to allergic sensitization and increased risk of developing asthma. Aryl hydrocarbon receptor (AhR), a receptor for many common environmental contaminants, can sense not only environmental pollutants but also microbial insults. Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the capacity to modulate immune responses. In this study, we investigated whether AhR can sense cockroach allergens and modulate allergen-induced lung inflammation through MSCs. We found that cockroach allergen-treated AhR-deficient (AhR(-/-)) mice showed exacerbation of lung inflammation when compared with wild-type (WT) mice. In contrast, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an AhR agonist, significantly suppressed allergen-induced mouse lung inflammation. MSCs were significantly reduced in cockroach allergen-challenged AhR(-/-) mice as compared with WT mice, but increased in cockroach allergen-challenged WT mice when treated with TCDD. Moreover, MSCs express AhR, and AhR signaling can be activated by cockroach allergen with increased expression of its downstream genes cyp1a1 and cyp1b1. Furthermore, we tracked the migration of i.v.-injected GFP(+) MSCs and found that cockroach allergen-challenged AhR(-/-) mice displayed less migration of MSCs to the lungs compared with WT. The AhR-mediated MSC migration was further verified by an in vitro Transwell migration assay. Epithelial conditioned medium prepared from cockroach extract-challenged epithelial cells significantly induced MSC migration, which was further enhanced by TCDD. The administration of MSCs significantly attenuated cockroach allergen-induced inflammation, which was abolished by TGF-ß1-neutralizing Ab. These results suggest that AhR plays an important role in protecting lungs from allergen-induced inflammation by modulating MSC recruitment and their immune-suppressive activity.

Evidence for the role of BmNPV Bm65 protein in the repair of ultraviolet-induced DNA damage.

It is unclear how, or to what extent, baculovirus DNA that has been damaged by ultraviolet (UV) light is repaired during infection and replication. In our previous study, expression of Bombyx mori nucleopolyhedrovirus (BmNPV) ORF Bm65, a homolog of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) ac79, correlated with decreased inactivation of virus by UV irradiation. In the current study, we accumulated more evidence pointing to a role for Bm65 in repair of UV-induced DNA damage. The localization of Bm65 was studied using enhanced green fluorescent protein (EGFP) fusion constructs expressed in BmN cells transfected with a Bm65 expression plasmid. The results indicate that Bm65-EGFP accumulates in the nucleus. A host cell reactivation assay showed that Bm65 significantly increased the expression of UV-damaged mCherry reporter gene. An assay measuring cyclobutane pyrimidine dimers (CPDs) in UV-irradiated BmN cells found that CPD quantity was decreased in cells transfected with a Bm65 expression plasmid. We also showed that after UVC treatment, the viability of Bm65-transfected cells was higher than that of egfp-transfected cells. These results suggest that Bm65 may be involved in the repair of baculovirus DNA that has been damaged by UV light.

Long Non-Coding RNAs in Hepatitis B Virus-Related Hepatocellular Carcinoma: Regulation, Functions, and Underlying Mechanisms.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer death in the world. Hepatitis B virus (HBV) and its X gene-encoded protein (HBx) play important roles in the progression of HCC. Although long non-coding RNAs (lncRNAs) cannot encode proteins, growing evidence indicates that they play essential roles in HCC progression, and contribute to cell proliferation, invasion and metastasis, autophagy, and apoptosis by targeting a large number of pivotal protein-coding genes, miRNAs, and signaling pathways. In this review, we briefly outline recent findings of differentially expressed lncRNAs in HBV-related HCC, with particular focus on several key lncRNAs, and discuss their regulation by HBV/HBx, their functions, and their underlying molecular mechanisms in the progression of HCC.

Optimization of Ultrasonic-Assisted Enzymatic Extraction Conditions for Improving Total Phenolic Content, Antioxidant and Antitumor Activities In Vitro from Trapa quadrispinosa Roxb. Residues.

Stems are the important residues of Trapa quadrispinosa Roxb., which are abundant in phenolic compounds. Ultrasonic-assisted enzymatic extraction (UAEE) is confirmed as a novel extraction technology with main advantages of enhancing extraction yield and physiological activities of the extracts from various plants. In this study, UAEE was applied to obtain the highest yield of phenolic content, strongest antioxidant, and antitumor activities and to optimize the extraction conditions using response surface methodology (RSM). The extracts from the stems of T. quadrispinosa were characterized by determination of their antioxidant activities through 2,2-azinobis(3-ethylbenzthiazoline)-6-sulfonic acid (ABTS), 1,1-Diphenyl-2-picrylhydrazxyl (DPPH) radical scavenging, total antioxidant capacity (TAC), ferric reducing antioxidant capacity (FRAC) methods and of their antitumor activity by MTT method. The selected key independent variables were cellulase concentration (X1: 1.5%-2.5%), extraction time (X2: 20-30 min) and extraction temperature (X3: 40-60 °C). The optimal extraction conditions for total phenolic content (TPC) value of the extracts were determined as 1.74% cellulase concentration, 25.5 min ultrasonic extraction time and 49.0 °C ultrasonic temperature. Under these conditions, the highest TPC value of 53.6 ± 2.2 mg Gallic acid equivalent (GAE)/g dry weight (DW) was obtained, which agreed well with the predicted value (52.596 mg GAE/g·DW. Furthermore, the extracts obtained from UAEE presented highest antioxidant activities through ABTS, DPPH, TAC and FRAC methods were of 1.54 ± 0.09 mmol Trolox equivalent (TE)/g·DW; 1.45 ± 0.07 mmol·TE/g·DW; 45.2 ± 2.2 mg·GAE/g·DW; 50.4 ± 2.6 µmol FeSO4 equivalent/g·DW and lowest IC50 values of 160.4 ± 11.6 µg/mL, 126.1 ± 10.8 µg/mL, and 178.3 ± 13.1 µg/mL against Hela, HepG-2 and U251 tumor cells, respectively. The results indicated that the UAEE was an efficient alternative to improve extraction yield and enhance the antioxidant and antitumor activities of the extracts. The phenolic extracts from the stems of T. quadrispinosa had significant antioxidant and antitumor activities, which could be used as a source of potential antioxidant and antitumor agents.

Overexpression of Bm65 correlates with reduced susceptibility to inactivation by UV light.

Ultraviolet (UV) light is one of the factors that causes baculovirus inactivation. However, little is known about the response of baculoviruses to UV light. In the present study, Bombyx mori nucleopolyhedrovirus (BmNPV) orf 65 (Bm65), the homolog of Autographa californica nucleopolyhedrovirus orf 79 (Ac79), a predicted endonuclease, was analyzed. Preliminary results indicated that Bm65 mainly accumulated within the nucleus and could improve the survival rate of Escherichia coli (E. coli) and BmNPV BVs after UV radiation, suggesting that Bm65 was involved in the repair of UV-induced DNA damage.

The L60V variation in hepatitis B virus core protein elicits new epitope-specific cytotoxic T lymphocytes and enhances viral replication.

Mutations in the core protein (HBc) of hepatitis B virus (HBV) are associated with aggressive hepatitis and advanced liver diseases in chronic hepatitis B (CHB). In this study, we identified the L60V variation in HBc that generates a new HLA-A2-restricted CD8(+) T cell epitope by screening an overlapping 9-mer peptide pool covering HBc and its variants. The nonameric epitope V60 was determined by structural and immunogenic analysis. The HBc L60V variation is correlated with hepatic necroinflammation and higher viral levels, and it may be associated with a poor prognosis in CHB patients. Immunization with the defined HBV epitope V60 peptide elicited specific cytotoxic T lymphocyte (CTL)-induced liver injury in HLA-A2(+) HBV transgenic mice. In addition, in vitro and in vivo experiments both demonstrated that the HBc L60V variation facilitates viral capsid assembly and increases HBV replication. These data suggest that the HBc L60V variation can impact both HBV replication and HBV-specific T cell responses. Therefore, our work provides further dissection of the impact of the HBc L60V variation, which orchestrates HBV replication, viral persistence, and immunopathogenesis during chronic viral infection.

Nanoparticle/Engineered Bacteria Based Triple-Strategy Delivery System for Enhanced Hepatocellular Carcinoma Cancer Therapy.

Background: New treatment modalities for hepatocellular carcinoma (HCC) are desperately critically needed, given the lack of specificity, severe side effects, and drug resistance with single chemotherapy. Engineered bacteria can target and accumulate in tumor tissues, induce an immune response, and act as drug delivery vehicles. However, conventional bacterial therapy has limitations, such as drug loading capacity and difficult cargo release, resulting in inadequate therapeutic outcomes. Synthetic biotechnology can enhance the precision and efficacy of bacteria-based delivery systems. This enables the selective release of therapeutic payloads in vivo. Methods: In this study, we constructed a non-pathogenic Escherichia coli (E. coli) with a synchronized lysis circuit as both a drug/gene delivery vehicle and an in-situ (hepatitis B surface antigen) Ag (ASEc) producer. Polyethylene glycol (CHO-PEG2000-CHO)-poly(ethyleneimine) (PEI25k)-citraconic anhydride (CA)-doxorubicin (DOX) nanoparticles loaded with plasmid encoded human sulfatase 1 (hsulf-1) enzyme (PNPs) were anchored on the surface of ASEc (ASEc@PNPs). The composites were synthesized and characterized. The in vitro and in vivo anti-tumor effect of ASEc@PNPs was tested in HepG2 cell lines and a mouse subcutaneous tumor model. Results: The results demonstrated that upon intravenous injection into tumor-bearing mice, ASEc can actively target and colonise tumor sites. The lytic genes to achieve blast and concentrated release of Ag significantly increased cytokine secretion and the intratumoral infiltration of CD4/CD8+T cells, initiated a specific immune response. Simultaneously, the PNPs system releases hsulf-1 and DOX into the tumor cell resulting in rapid tumor regression and metastasis prevention. Conclusion: The novel drug delivery system significantly suppressed HCC in vivo with reduced side effects, indicating a potential strategy for clinical HCC therapy.

A Novel CaCu-Metal-Organic-Framework Based Multimodal Treatment Platform for Enhanced Synergistic Therapy of Hepatocellular Carcinoma.

Metal ions have attracted a lot of interest in antitumor therapy due to their unique mechanism of action. However, multiple death mechanisms associate with metal ions to synergistic antitumors have few studies mainly due to the serious challenges in designing and building metal-associated multimodal treatment platforms. Hence, a series of glutathione-activatable CaCu-based metal-organic-frameworks loaded with doxorubicin and ovalbumin are successfully designed and synthesized with an "all in one" strategy, which is modified by galactosamine-linked hyaluronic acid to prepare multimodal treatment platform (SCC/DOX@OVA-HG) for targeted delivery and synergistic antitumor therapy. SCC/DOX@OVA-HG can be rapidly degraded by the overexpressed glutathione and then releases the "cargoes" in the tumor microenvironment. The released Cu+ efficiently catalyzes H2O2 to produce highly toxic ROS for CDT, and the up-regulation of calcium ion concentration in tumor cells induced by the released Ca2+ enables calcium overload therapy, which synergically enhances the metal-related death pattern. Meanwhile, OVA combined with Ca2+/Cu2+ further activates macrophages into an M1-like phenotype to accelerate tumor cell death through immunotherapy. Besides, the released DOX can also insert into the DNA double helix for chemotherapy. Consequently, the developed SCC/DOX@OVA-HG reveals significantly improved antitumor efficacy through a multimodal synergistic therapy of chemotherapy, chemodynamic therapy, calcium overload, and immunotherapy.

Menin signaling and therapeutic targeting in breast cancer.

To date, mounting evidence have shown that patients with multiple endocrine neoplasia type 1 (MEN1) may face an increased risk for breast carcinogenesis. The product of the MEN1 gene, menin, was also indicated to be an important regulator in breast cancer signaling network. Menin directly interacts with MLL, EZH2, JunD, NF-κB, PPARγ, VDR, Smad3, ß-catenin and ERα to modulate gene transcriptions leading to cell proliferation inhibition. Moreover, interaction of menin-FANCD2 contributes to the enhancement of BRCA1-mediated DNA repair mechanism. Ectopic expression of menin causes Bax-, Bak- and Caspase-8-dependent apoptosis. However, despite numbers of menin inhibitors were exploited in other cancers, data on the usage of menin inhibitors in breast cancer treatment remain limited. In this review, we focused on the menin associated signaling pathways and gene transcription regulations, with the aim of elucidating its molecular mechanisms and of guiding the development of novel menin targeted drugs in breast cancer therapy.