Inhibit Tumor Metastasis Research Articles

Antimetastatic Activity of Apoptolidin A by Upregulation of N-Myc Downstream-Regulated Gene 1 Expression in Human Colorectal Cancer Cells.

Colorectal cancer (CRC) is one of the most prevalent tumors with high metastatic potential; consequently, finding new drug candidates that suppress tumor metastasis is essential. Apoptolidin A is a macrocyclic lactone produced by Amycolatopsis sp. DW02G. It exhibits significant cytotoxicity against several cancer cell lines, but its effects on CRC cells remain unknown. Therefore, the present study investigated the antiproliferative and antimetastatic activities of apoptolidin A and its underlying molecular mechanisms in CRC cells. Apoptolidin A effectively inhibited CRC cell growth and colony formation. The induction of G0/G1 phase cell cycle arrest was associated with the downregulation of cyclin D1 and CDK4/6 expression. Long-term exposure to apoptolidin A also induced apoptosis as confirmed by the downregulation and upregulation of Bcl-2 and Bax expression, respectively. Moreover, apoptolidin A effectively upregulated the suppressed expression of N-Myc downstream-regulated gene 1 (NDRG1), a tumor suppressor gene, in a concentration-dependent manner in CRC cells. The antimetastatic potential of apoptolidin A was also correlated with the expression of epithelial-mesenchymal transition (EMT) biomarkers, including the upregulation of E-cadherin and downregulation of N-cadherin, vimentin, snail, and MMP9 in CRC cells. These findings suggest that apoptolidin A exerts antiproliferative and antimetastatic activities by regulating the NDRG1-activated EMT pathway in CRC cells.

CircNEIL3 inhibits tumor metastasis through recruiting the E3 ubiquitin ligase Nedd4L to degrade YBX1.

Distant metastasis is a major contributor to cancer-related mortality. However, the role of circRNAs in this process remains unclear. Herein, we profiled the circRNA expression in a cohort of 68 colorectal carcinoma (CRC) primary tumors and their paired liver metastatic lesions. By overlapping with the TGFβ-responsive circRNAs, circNEIL3 (hsa_circ_0001460) was identified as a TGFβ-repressive and metastasis-related circRNA. Functionally, circNEIL3 effectively inhibited tumor metastasis in both and invivoand invivo models of various cancer types. Mechanistically, circNEIL3 exerts its metastasis-repressive function through its direct interaction with oncogenic protein, Y-box-binding protein 1 (YBX1), which consequently promotes the Nedd4L-mediated proteasomal degradation of YBX1. Importantly, circNEIL3 expression was negatively correlated to YBX1 protein level and metastatic tendency in CRC patient samples. Collectively, our findings indicate the YBX1-dependent antimetastatic function of circNEIL3 and highlight the potential of circNEIL3 as a biomarker and therapeutic option in cancer treatment.

A multichannel Ca2+ nanomodulator amplifies exogenous and endogenous calcium overload for efficient antitumor and antimetastasis therapy

Calcium overload–based antitumor therapy via disruption of Ca2+ homeostasis has attracted significant attention, although the efficient elevation of calcium overload is extremely challenging. We designed an exogenous and endogenous Ca2+ multichannel nanomodulator (Lipo CaO2–TA–Fe3+/PArg). The material comprises tannic acid (TA) and Fe3+ assembled with calcium peroxide (CaO2) (CaO2–TA–Fe3+) and polyarginine (PArg) incorporated into a pH-responsive liposome. Upon internalization by the tumor cell, lysosomal acidity triggers TA and Fe3+ dissociation, stimulating CaO2 disintegration to self-supply Ca2+ and hydrogen peroxide (H2O2). The dissociated TA reduced Fe3+ to Fe2+, which reacted with H2O2 by the Fenton reaction, yielding self-circulating oxidative hydroxyl radicals (•OH). Most important, •OH oxidizes PArg for sustained nitric oxide (NO) production. The Lipo CaO2–TA–Fe3+/PArg nanomodulator amplified calcium overload via multiple channels: self-supplied exogenous Ca2+, •OH-opened Ca2+ influx channel (TRPA1), and closed outflux pump (PMCA4), and NO opened the ryanodine receptors (RyRs) on endoplasmic reticulum (ER) calcium stores. Amplification of calcium overload activated mitochondrial-mediated apoptosis pathways and resulted in 81.33% tumor inhibition in vivo. It also induced Calpain1 protease-inhibited depolymerization of action cytoskeleton, thereby inhibiting tumor metastasis. This exogenous and endogenous multichannel Ca2+ nanomodulator amplifies calcium overload and holds great promise for efficient ion interference-based antitumor and anti-metastasis therapy.

Design, Synthesis and Antitumor Activity of FAK/PLK1 Dual Inhibitors with Quinazolinone as the Skeleton

Febrifugine is a kind of quinazolinone compound with high biological activity from a Chinese herb called Chang Shan (Dichroa febrifuga). Febrifugine and its derivatives possess extensive biological activities, some of which exhibited anti-tumor activities as FAK inhibitors. However, they are not very effective at inhibiting tumor metastasis, perhaps because tumors gain energy through compensatory activation of other signaling pathways that promote cell migration and invasion. Therefore, seventeen novel febrifugine derivatives with quinazolinone skeleton were designed, synthesized and acted as potential FAK/PLK1 dual inhibitors. These compounds were determined by 1 H-NMR, 13 C-NMR and MS. Most of the compounds exhibited good inhibitory activity against cancer cell lines by computer-assisted screening, antitumor activity test and FAK/PLK1 inhibitory activity test, wherein compound 3b was screened as a high-efficiency lead compound.

DNA Nanoclusters Combined with One-Shot Radiotherapy Augment Cancer Immunotherapy Efficiency.

Immunotherapy shows immense promise for improving cancer treatment. Combining immunotherapy with radiotherapy provides a conspicuous advantage due to its enhanced abscopal effect. However, established immune tolerance mechanisms in the tumor microenvironment can hamper the generation of a sufficient abscopal effect. Herein, a type of DNA nanocluster (DNAnc) that is self-assembled by a CpG-ODNs-loaded Y-shaped double-stranded DNA vector based on the unique complementary base-pairing rules is designed. The unique structure of DNAnc makes it load more than ≈8125.5 ± 822.5 copies of CpG ODNs within one single nanostructure, which effectively increases resistance to nuclease degradation and elevates the efficiency of repolarizing macrophages to an M1-like phenotype. Mechanistic studies reveal that more DNAncs are endocytosed by macrophages in the cancer tissue and repolarized macrophages to elicit a robust abscopal effect with the accumulation of macrophages induced by radiotherapy, generating potent, long-term, and durable antitumor immunity for the inhibition of tumor metastasis and the prevention of tumor recurrence, which provides a novel strategy to boost cancer immunotherapy.

Ultrasound-Induced Piezocatalysis Triggered NO Generation for Enhanced Hypoxic Tumor Therapy.

Conventional NO gas generation based on l-arginine (l-Arg) is usually dependent on H2O2 and O2, both of which are very limited within the tumor microenvironment, thus greatly limiting l-Arg's therapeutic effect. Herein, a novel nanoplatform for efficiently triggering NO production based on ultrasound-induced piezocatalysis was developed, which was fabricated by coating amphiphilic poly-l-arginine (DSPE-PEG2000-Arg, DPA) on the piezoelectric material of barium titanate (BTO). The resulting BTO@DPA nanoparticles can efficiently generate H2O2, 1O2, and O2 via ultrasound-induced piezocatalysis based on BTO and oxidize the surface arginine to produce NO, which can even further interact with the reactive oxygen species (ROS) to produce more reactive peroxynitrite, thus inducing serious tumor cell apoptosis both in hypoxia and normoxia. After intravenous injection, BTO@DPA accumulated well at the tumor tissue at 4 h postinjection; later, ultrasound irradiation on the tumor not only achieved the best tumor inhibition rate of ∼70% but also completely inhibited tumor metastasis to the lungs via the alleviation of tumor hypoxia. Such a strategy was not dependent on the tumor microenvironment and can be well controlled by ultrasound irradiation, providing a simple and efficient therapy paradigm for hypoxic tumor.

Multi-Targeted and On-Demand Non-Coding RNA Regulation Nanoplatform against Metastasis and Recurrence of Triple-Negative Breast Cancer.

Dysregulation of microRNAs (miRs) is the hallmark of triple-negative breast cancer (TNBC), which is closely involved with itsgrowth, metastasis, and recurrence. Dysregulated miRs are promising targets for TNBC therapy, however, targeted and accurate regulation of multiple disordered miRs in tumors is still a great challenge. Here, a multi-targeting and on-demand non-coding RNA regulation nanoplatform (MTOR) is reported to precisely regulate disordered miRs, leading to dramatical suppression of TNBC growth, metastasis, and recurrence. With the assistance of long blood circulation, ligands of urokinase-type plasminogen activator peptide and hyaluronan located in multi-functional shells enable MTOR to actively target TNBC cells and breast cancer stem cell-like cells (BrCSCs). After entering TNBC cells and BrCSCs, MTOR is subjected to lysosomal hyaluronidase-induced shell detachment, leading to an explosion of the TAT-enriched core, thereby enhancing nuclear targeting. Subsequently, MTOR could precisely and simultaneously downregulate microRNA-21 expression and upregulate microRNA-205 expression in TNBC. In subcutaneous xenograft, orthotopic xenograft, pulmonary metastasis, and recurrence TNBC mouse models, MTOR shows remarkably synergetic effects on the inhibition of tumor growth, metastasis, and recurrence due to its on-demand regulation of disordered miRs. This MTOR system opens a new avenue for on-demand regulation of disordered miRs against growth, metastasis, and recurrence of TNBC.

H2O2 responsive CO gas release platform with CA IX-Targeting for inhibiting tumor growth and metastasis

Carbon monoxide (CO) gas therapy has emerged as a highly promising anti-tumor strategy. However, targeting delivery and controlled intratumoral release of CO still have unsatisfactory outcomes. Herein, we constructed a novel CO therapeutic platform consisting of a carbonic anhydrase IX (CA IX) inhibitor (CAI) and intelligent responsive CO-releasing molecules (CORMs). The formed platform coupled with CAI can actively target CA IX overexpressed tumor cells to achieve targeted delivery of CORMs. After reaching the tumor site and being internalized by tumor cells, CORMs can be activated by the endogenous H2O2, realizing the light induced excited-state intramolecular proton transfer (ESIPT) effect and spatiotemporal controllable release of CO. Next, CAI can prevent tumor metastasis by inhibiting CA IX to alleviate the acidic tumor extracellular environment, while the generated CO can also achieve tumor metastasis inhibition by inhibiting vascular endothelial growth factor (VEGF). In vitro and in vivo experiments indicate that the constructed CO gas therapeutic platform can significantly inhibit tumor growth and metastasis, which provides a new direction for tumor gas therapy.

Investigation on protein dimerization and evaluation of medicine effects by single molecule force spectroscopy

Monitoring the dimerization state of the mesenchymal-epithelial transition factor (Met) was essential for in-depth understanding of the tumor signal transduction network. At present, the dimerization activation pathway of Met protein was mainly studied at the macro level, while the research at the single molecule level was far from comprehensive. Herein, the dimerization activation of Met protein's extracellular domain induced by ligand hepatocyte growth factor (HGF) was dynamically studied by single-molecule force spectroscopy. Met protein was immobilized on a biomimetic lipid membrane for ensuring its physiological environment, and then the Met dimers were recognized by bivalent probe which was formed by two Met-binding aptamers. Then the dimeric state of Met protein could be distinguished from monomeric state of Met protein through some parameters, (such as unimodal ratio, bimodal ratio and separation work). The unimodal indicates the occurrence of single molecule binding event, and the bimodal represents the occurrence of double binding event (also represents the presence of Met dimer). Before HGF treatment, most of the Met protein on the lipid membrane was still in the form of monomer, so the unimodal ratio in the force curve was larger (78.8 ± 5.2%), and the bimodal ratio was smaller (17.0 ± 4.1%). After HGF treatment, the unimodal ratio decreased to 54.0 ± 7.4%, and the bimodal ratio increased to 43.2 ± 7.3%. It was due to the formation of dimers after the binding of Met protein on the fluidity lipid membrane with HGF. In addition, the average separation work increased to about 2 times after HGF treatment. Given that studies of Met protein dimerization inhibitors have contributed to the development of more potent and safe inhibitors to significantly inhibit tumor metastasis, the effects of different medicines (including anticoagulant medicines, different antibiotics and anti-cancer medicines) on the dimerization activation of Met protein were then explored by the platform described above. The results showed that anticoagulant medicines heparin and its analogs can significantly inhibit HGF-mediated Met protein activation, while different antibiotics and anticancer medicines had no significant effect on the dimerization of Met protein. This work provided a platform for studying protein dimerization as well as for screening Met protein dimerization inhibitors at the single-molecule level.

Synergistic effect of docetaxel and gambogic acid on bone metastasis of lung cancer

Gambogic acid (GA) as an active compound isolated from Gamboge, have been investigated for many years and proved to be a promising natural anticancer agent for clinical treatment. This study aimed to investigate the inhibitory effect of docetaxel (DTX) combined with gambogic acid on bone metastasis of lung cancer. The anti-proliferation effect of the combination of DTX and GA on Lewis lung cancer (LLC) cells was determined by MTT assays. The anticancer effect of the combination of DTX and GA on bone metastasis of lung cancer in vivo was explored. Evaluation of the efficacy of drug therapy was performed by comparing the degree of bone destruction and the pathological section of bone tissue of the treated mice with that of the control mice. In vitro cytotoxicity, cell migration, and osteoclast-induced formation assay showed that GA enhanced the therapeutic effect of DTX in Lewis lung cancer cell with a synergistic effect. In an orthotopic mouse model of bone metastasis, the average survival of the DTX+GA combination group (32.61d±1.06 d) was significantly increased compared with that of the DTX group (25.75 d±0.67 d) or GA group (23.99 d±0.58 d), *P<0.01. The combination of DTX and GA has synergistic effect and resulted in more effective inhibition of tumor metastasis, providing a strong preclinical rationale for the clinical development of the DTX+GA combination for treating bone metastasis of lung cancer.

A bispecific glycopeptide spatiotemporally regulates tumor microenvironment for inhibiting bladder cancer recurrence.

Up to 75% of bladder cancer patients suffer from recurrence due to postoperative tumor implantation. However, clinically used Bacillus Calmette-Guerin (BCG) treatment failed to inhibit the recurrence. Here, we report a bispecific glycopeptide (bsGP) that simultaneously targets CD206 on tumor-associated macrophages (TAMs) and CXCR4 on tumor cells. bsGP repolarizes protumoral M2-like TAMs to antitumor M1-like that mediated cytotoxicity and T cell recruitment. Meanwhile, bsGP is cleaved by the MMP-2 enzyme to form nanostructure for the long-term inhibition of CXCR4 downstream signaling, resulting in reduced tumor metastasis and promoted T cell infiltration. In orthotopic bladder tumor models, bsGP reduced the postoperative recurrence rate to 22%. In parallel, the recurrence rates of 89 and 78% were treated by doxycycline and BCG used in clinic, respectively. Mechanistic studies reveal that bsGP reduces the matrix microenvironment barrier, increasing the spatially redirected CD8+ T cells to tumor cells. We envision that bis-targeting CD206 and CXCR4 may pave the way to inhibit tumor metastasis and recurrence.

A hydrogel-enabled cascade amplification of radiosensitization and immune activation for cancer radiotherapy

Hypofractionated radiotherapy (HRT) is a promising approach for tumor treatment, owing to its straightforward elimination of tumor cells and stimulation of immunogenic cell death. However, clinical application of HRT is hindered by the inherent radio-resistance and inadequate immune activation. Herein, an injectable hydrogel platform was reported, enabling a cascade amplification of radiosensitization and immune activation to potentiate HRT. The hydrogel with encapsulated TLR7/8 agonist R848 is in situ constructed in tumor via L-norvaline-based polymer (LNP, a gelator). During HRT, the released L-norvaline from LNP suppresses L-arginine consumption through arginase 1 (ARG1) pathway, sparing adequate L-arginine that was used for radiosensitizer nitric oxide (NO) production by inducible NO synthase (iNOS). Meanwhile, R848 repolarizes tumor-associated macrophages (TAMs) from M2 type with rich ARG1 to M1 type with rich iNOS, reinforcing NO production and disrupting M2-type TAMs-induced radio-resistance and immunosuppression. Therefore, the hydrogel demonstrates a cascade regulation of radio-sensitization and immune activation, achieving powerful inhibition of tumor growth and tumor metastasis. This hydrogel provides a novel approach to potentiate HRT, holding great promise in clinical application.

Engineered bacteria combined with doxorubicin nanoparticles suppress angiogenesis and metastasis in murine melanoma models.

Methods capable of distributing antitumour therapeutics uniformly throughout an entire tumour and that can suppress metastasis at the same time, would be of great significance in improving cancer treatment. Bacteria-mediated synergistic therapies have been explored for better specificity, temporal and spatial controllability, as well for providing regulation of the immune microenvironment, in order to provide improved cancer treatment. To achieve this goal, here we developed an engineered bacteria delivery system (GDOX@HSEc) using synthetic biology and interfacial chemistry technologies. The engineered bacteria were concurrently modified to express heparin sulfatase 1 (HSulf-1) inside (HSEc), to attach doxorubicin-loaded glycogen nanoparticles (GDOX NPs) on their surface. Here we demonstrate that HSEc can actively target and colonise tumour sites resulting in HSulf-1 overexpression, thereby suppressing angiogenesis and metastasis. Simultaneously, the GDOX NPs were able to penetrate into tumour cells, leading to intracellular DNA damage. Our results confirmed that a combination of biotherapy and chemotherapy using GDOX@HSEc resulted in significant melanoma suppression in murine models, with reduced side effects. This study provides a powerful platform for the simultaneous delivery of biomacromolecules and chemotherapeutic drugs to tumours, representing an innovative strategy potentially more effective in treating solid tumours. STATEMENT OF SIGNIFICANCE: An original engineered bacteria-based system (GDOX@HSEc) was developed using synthetic biology and interfacial chemistry technologies to concurrently produce naturally occurring heparin sulfatase 1 (HSulf-1) inside and anchor doxorubicin-loaded glycogen nanoparticles on the surface. GDOX@HSEc allowed for combined local delivery of chemotherapeutic agents along with the enzymes and immunostimulatory bacterial adjuvants, which resulted in a synergistic action in the inhibition of tumour growth and metastasis. The study provides a potential therapeutic approach that allows therapeutic agents to be distributed in a spatiotemporally controllable manner in tumours for combinatorial enhanced therapy.

Tumor Microenvironment Regulation and Cancer Targeting Therapy Based on Nanoparticles.

Although we have made remarkable achievements in cancer awareness and medical technology, there are still tremendous increases in cancer incidence and mortality. However, most anti-tumor strategies, including immunotherapy, show low efficiency in clinical application. More and more evidence suggest that this low efficacy may be closely related to the immunosuppression of the tumor microenvironment (TME). The TME plays a significant role in tumorigenesis, development, and metastasis. Therefore, it is necessary to regulate the TME during antitumor therapy. Several strategies are developing to regulate the TME as inhibiting tumor angiogenesis, reversing tumor associated macrophage (TAM) phenotype, removing T cell immunosuppression, and so on. Among them, nanotechnology shows great potential for delivering regulators into TME, which further enhance the antitumor therapy efficacy. Properly designed nanomaterials can carry regulators and/or therapeutic agents to eligible locations or cells to trigger specific immune response and further kill tumor cells. Specifically, the designed nanoparticles could not only directly reverse the primary TME immunosuppression, but also induce effective systemic immune response, which would prevent niche formation before metastasis and inhibit tumor recurrence. In this review, we summarized the development of nanoparticles (NPs) for anti-cancer therapy, TME regulation, and tumor metastasis inhibition. We also discussed the prospect and potential of nanocarriers for cancer therapy.

The metabolite alpha-ketoglutarate: a novel target of gasdermin C-dependent pyroptosis.

The metabolite alpha-ketoglutarate: a novel target of gasdermin C-dependent pyroptosis.

Naringenin and Hesperidin as Promising Alternatives for Prevention and Co-Adjuvant Therapy for Breast Cancer.

Citrus (genus Citrus L.) fruits are essential sources of bioactive compounds with antioxidant properties, such as flavonoids. These polyphenolic compounds are divided into subclasses, in which flavanones are the most prominent. Among them, naringenin and hesperidin are emerging compounds with anticancer potential, especially for breast cancer (BC). Several mechanisms have been proposed, including the modulation of epigenetics, estrogen signaling, induction of cell death via regulation of apoptotic signaling pathways, and inhibition of tumor invasion and metastasis. However, this information is sparse in the literature and needs to be brought together to provide an overview of how naringenin and hesperidin can serve as therapeutic tools for drug development and as a successful co-adjuvant strategy against BC. This review detailed such mechanisms in this context and highlighted how naringenin and hesperidin could interfere in BC carcinogenesis and be helpful as potential alternative therapeutic sources for breast cancer treatment.

Matthew effect photoimmunotheranostics enabled by proton-driven nanoconverter

The construction of novel photothermal agents (PTAs) with near-infrared (NIR) light-responsive capacity that can differentiate normal and abnormal tissues bidirectionally to minimize adverse effects of photothermal therapy (PTT) is of great importance yet a huge challenge. We are developing “Matthew Effect Photoimmunotheranostics (MEP)”, demonstrated using an intelligent proton-driven enhanced nanoconverter (PEN) with self-refueling capacity by a facile polymerization method to form biocompatible photothermal agent polyaniline (PANI) with glucose oxidase (GOx) as the enhancer. PEN accumulates in the tumor region selectively after intravenous injection and GOx depletes glucose to re-establish the tumor microenvironment towards energy shortage and acidity aggravation, suppressing the expression of heat shock proteins to disturb the thermoresistance mechanism of tumor cells and promoting the proton-driven conversion of PANI to activated state synergistically. Strikingly, the PEN can differentiate normal and cancerous tissues bidirectionally with an “OFF-ON-OFF” mode to minimize adverse effects due to the enormous difference in glucose consumption between normal cells and tumor cells. PEN-mediated hyperthermia can induce immunogenic cell death. Under photoacoustic imaging and NIR-II light irradiation, PEN achieves tumor elimination with high specificity with synergistic mild hyperthermia/immune response by MEP. PEN-induced adaptive antitumor immunity is effective for eliminating distant tumors and suppressing tumor metastasis and recurrence.

Mechanisms of Antitumor Invasion and Metastasis of the Marine Fungal Derivative Epi-Aszonalenin A in HT1080 Cells

Epi-aszonalenin A (EAA) is an alkaloid that is isolated and purified from the secondary metabolites of coral symbiotic fungi and has been shown to have good atherosclerotic intervention activity and anti-angiogenic activity in our previous studies. In the present study, antiangiogenic activity was used as a basis of an intensive study of its mechanism of action against tumor metastasis and invasion. Invasive metastatic pairs are a hallmark of malignancy, and the dissemination of tumor cells is the most dangerous process in the development of tumors. The results of cell wound healing and the Transwell chamber assay showed that EAA interfered well with PMA-induced migration and invasion of HT1080 cells. Western blot and the ELISA assay showed that EAA decreased MMPs and vascular endothelial growth factor (VEGF) activity and inhibited the expression of N-cadherin and hypoxia-inducible factor-1α (HIF-1α) by regulating the phosphorylation of downstream mitogen-activated protein kinase (MAPK), PI3K/AKT, and NF-κB pathways. Simultaneous molecular docking results revealed that the mimic coupling between the EAA and MMP-2/-9 molecules formed a stable interaction. The results of this study provide a research basis for the inhibition of tumor metastasis by EAA, and together with previous studies, confirm the potential pharmacology and drug potential for this class of compound for application in angiogenesis-related diseases and further improve the availability of coral symbiotic fungi.

Effects of Kisspeptin on the reproductive function in the Dabry’s sturgeon (Acipenser dabrynus)

Kisspeptin, a kind of neuropeptide, is involved in various physiological processes such as tumor metastasis inhibition and reproductive regulation due to its ability to interact with Kisspeptin receptor-Kissr. In teleost, Kisspeptin/Kissr system stimulates the hypothalamus-pituitary–gonadal axis (HPG axis), which is crucial for the reproductive regulation. Compared to one Kisspeptin protein Kiss1 was existed in mammals, two Kisspeptin were identified in sturgeon species, including Kiss1 and Kiss2, with specific receptors of Kissr1 and Kissr2, respectively. However, few reports described the effects of the two isoforms of Kisspeptin on the reproductive regulation in sturgeon. The core peptides of Kiss1 and Kiss2 (Kiss1-10 and Kiss2-10) of Dabry’s sturgeon were successfully synthesized to explore the functional influence of Kisspeptin on the sturgeon HPG axis in the present study. The present findings suggested that intraperitoneal injection of Kiss1-10 and Kiss2-10 could significantly up-regulate the mRNA expression of Gnrh、Fsh and Lh in the hypothalamus and pituitary and the content of Lh protein in the serum. Assays of Kisspeptin-treated cells demonstrated that Kiss1-10 and Kiss2-10 can significantly promote the expression of Gnrh in hypothalamus cells and Lh and Fsh in pituitary cells of Dabry’s sturgeon, indicating their direct-acting effect on pituitary cells and regulatory function on the reproductive development of sturgeon. This study described the reproductive function of the Kisspeptin in the Dabry’s sturgeon for the first time, and provided supportive reference for the development of high-efficiency ripening technologies of artificially breeding sturgeon.

Enhancing the Management of Metastatic Tumors by Robust Co-Delivery of 5-Fluorouracil/MicroRNA-10b Inhibitor Using EGFR-Targeted Nanovehicles.

Invasion and metastasis are the leading causes of death of patients with CRC. 5-Fluorouracil is widely used in clinic practice as the basic chemotherapy drug for CRC. However, it is inefficient in inhibiting tumor metastasis. MicroRNA-10b is uninvolved in regulating the growth of primary tumors; however, it could induce early tumor metastases and is a key regulator of chemotherapeutic resistance to 5-FU. A multifunctional nanovehicle that can carry small molecule drugs not only through the hydrophobic pockets of conjugated β-cyclodextrin but also through electrostatic interaction between the conjugated peptides and siRNA to target functional genes is previously developed. In this study, a nanovehicle, named GCD, with epithelium growth factor receptor (EGFR)-targeted characteristics to simultaneously deliver chemotherapeutic and nucleotide drugs to distinct targets in CRC, is employed. These data show that co-delivery of 5-FU and anti-miR-10b can be effectively applied to targeted therapy of EGFR-overexpressed CRC, particularly inhibiting the metastasis of CRC. Furthermore, the therapeutic effect of this combination on tumor xenograft models derived from patients with CRC is evaluated. Taken together, this study may provide insights into the inhibition of tumor growth and metastasis simultaneously.