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Excessive production of transforming growth factor β1 (TGF-β1) in activated hepatic stellate cells (aHSCs) promotes liver fibrosis by activating the TGF-β1/Smad signaling pathway. Thus, specifically inhibiting the pro-fibrotic activity of TGF-β1 in aHSCs is an ideal strategy for treating liver fibrosis. Overexpression of platelet-derived growth factor β receptor (PDGFβR) has been demonstrated on the surface of aHSCs relative to normal cells in liver fibrosis. Interferon-gamma peptidomimetic (mIFNγ) and truncated TGF-β receptor type II (tTβRII) inhibit the TGF-β1/Smad signaling pathway by different mechanisms. In this study, we designed a chimeric protein by the conjugation of (1) mIFNγ and tTβRII coupled via plasma protease-cleavable linker sequences (FNPKTP) to (2) PDGFβR-recognizing peptide (BiPPB), namely BiPPB-mIFNγ-tTβRII. This novel protein BiPPB-mIFNγ-tTβRII was effectively prepared using Escherichia coli expression system. The active components BiPPB-mIFNγ and tTβRII were slowly released from BiPPB-mIFNγ-tTβRII by hydrolysis using the plasma protease thrombin in vitro. Moreover, BiPPB-mIFNγ-tTβRII highly targeted to fibrotic liver tissues, markedly ameliorated liver morphology and fibrotic responses in chronic liver fibrosis mice by both inhibiting the phosphorylation of Smad2/3 and inducing the expression of Smad7. Meanwhile, BiPPB-mIFNγ-tTβRII markedly reduced the deposition of collagen fibrils and expression of fibrosis-related proteins in acute liver fibrosis mice. Furthermore, BiPPB-mIFNγ-tTβRII showed a good safety performance in both liver fibrosis mice. Taken together, BiPPB-mIFNγ-tTβRII improved the in vivo anti-liver fibrotic activity due to its high fibrotic liver-targeting potential and the dual inhibition of the TGF-β1/Smad signaling pathway, which may be a potential candidate for targeting therapy on liver fibrosis. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis is a remodeling process of the cardiac interstitium, characterized by abnormal metabolism of the extracellular matrix, excessive accumulation of collagen fibers, and scar tissue hyperplasia. Persistent activation and transdifferentiation into myofibroblasts of cardiac fibroblasts promote the progression of fibrosis. Transforming growth factor-β1 (TGF-β1) is a pivotal factor in cardiac fibrosis. Latency-associated peptide (LAP) is essential for activating TGF-β1 and its binding to the receptor. Thus, interference with TGF-β1 and the signaling pathways using LAP may attenuate cardiac fibrosis. Recombinant full-length and truncated LAP were previously constructed, expressed, and purified. Their effects on cardiac fibrosis were investigated in isoproterenol (ISO)-induced cardiac fibroblasts (CFs) and C57BL/6 mice. The study showed that LAP and tLAP inhibited ISO-induced CF activation, inflammation, and fibrosis, improved cardiac function, and alleviated myocardial injury in ISO-induced mice. LAP and tLAP alleviated the histopathological alterations and inhibited the elevated expression of inflammatory and fibrosis-related markers in cardiac tissue. In addition, LAP and tLAP decreased the ISO-induced elevated expression of TGF-β, αvβ3, αvβ5, p-Smad2, and p-Smad3. The study indicated that LAP and tLAP attenuated ISO-induced cardiac fibrosis via suppressing TGF-β/Smad pathway. This study may provide a potential approach to alleviate cardiac fibrosis. Key points: • LAP and tLAP inhibited ISO-induced CF activation, inflammation, and fibrosis. • LAP and tLAP improved cardiac function and alleviated myocardial injury, inflammation, and fibrosis in ISO-induced mice. • LAP and tLAP attenuated cardiac fibrosis via suppressing TGF-β/Smad pathway. [ABSTRACT FROM AUTHOR]

There are several limitations to the application of nanoparticles in the treatment of cancer, including their low drug loading, poor colloidal stability, insufficient tumor penetration, and uncontrolled release of the drug. Herein, gelatin/laponite (LP)/doxorubicin (GLD) nanoparticles are developed by crosslinking LP with gelatin for doxorubicin delivery. GLD shows high doxorubicin encapsulation efficacy (99%) and strong colloidal stability, as seen from the unchanged size over the past 21 days and reduced protein absorption by 48-fold compared with unmodified laponite/doxorubicin nanoparticles. When gelatin from 115 nm GLD reaches the tumor site, matrix metallopeptidase-2 (MMP-2) from the tumor environment breaks it down to release smaller 40 nm LP nanoparticles for effective tumor cell endocytosis. As demonstrated by superior penetration in both in vitro three-dimensional (3D) tumor spheroids (138-fold increase compared to the free drug) and in vivo tumor models. The intracellular low pH and MMP- 2 further cause doxorubicin release after endocytosis by tumor cells, leading to a higher inhibitory potential against cancer cells. The improved anticancer effectiveness and strong in vivo biocompatibility of GLD have been confirmed using a mouse tumor-bearing model. MMP-2/pH sequentially triggered anticancer drug delivery is made possible by the logical design of tumor-penetrating GLD, offering a useful method for anticancer therapy. [ABSTRACT FROM AUTHOR]

Truncated transforming growth factor β receptor type II (tTβRII) is a promising anti-liver fibrotic candidate because it serves as a trap for binding excessive TGF-β1 by means of competing with wild type TβRII (wtTβRII). However, the widespread application of tTβRII for the treatment of liver fibrosis has been limited by its poor fibrotic liver-homing capacity. Herein, we designed a novel tTβRII variant Z-tTβRII by fusing the platelet-derived growth factor β receptor (PDGFβR)-specific affibody ZPDGFβR to the N-terminus of tTβRII. The target protein Z-tTβRII was produced using Escherichia coli expression system. In vitro and in vivo studies showed that Z-tTβRII has a superior specific fibrotic liver-targeting potential via the engagement of PDGFβR-overexpressing activated hepatic stellate cells (aHSCs) in liver fibrosis. Moreover, Z-tTβRII significantly inhibited cell migration and invasion, and downregulated fibrosis- and TGF-β1/Smad pathway-related protein levels in TGF-β1-stimiluated HSC-T6 cells. Furthermore, Z-tTβRII remarkably ameliorated liver histopathology, mitigated the fibrosis responses and blocked TGF-β1/Smad signaling pathway in CCl4-induced liver fibrotic mice. More importantly, Z-tTβRII exhibits a higher fibrotic liver-targeting potential and stronger anti-fibrotic effects than either its parent tTβRII or former variant BiPPB-tTβRII (PDGFβR-binding peptide BiPPB modified tTβRII). In addition, Z-tTβRII shows no significant sign of potential side effects in other vital organs in liver fibrotic mice. Taken together, we conclude that Z-tTβRII with its a high fibrotic liver-homing potential, holds a superior anti-fibrotic activity in liver fibrosis in vitro and in vivo, which may be a potential candidate for targeted therapy for liver fibrosis. [ABSTRACT FROM AUTHOR]

Nanostructured silicon carbide (SiC) materials are expected to have bright prospect in application as high-performance electrode materials with excellent charge–discharge cycling stability. However, the exploration of SiC-based micro-supercapacitors (MSCs) still remains a grand challenge seriously hampered by low areal capacities and complicated multistep production process. Herein, we report that rationally designed SiC/C nanocomposite with hierarchical porous structure and improved electrical conductivity has been realized by a facile and rapid carbothermic reduction using silica sol and sucrose as silicon and carbon source. The amorphous carbon between SiC nanoparticles (NPs) contributes to enlarged surface areas and excellent conductivity, not only ensuring intimate contact between the electrolyte and the electrode but also providing an effective ion highway for electrolyte ions. As a result, MSCs based on SiC/C nanocomposite (Si/C mass ratio of 1:1.5) demonstrate an optimal specific areal capacitance of 11.8 mF cm−2 at 2 mV s−1, outstanding flexibility (104.5% retention of initial capacitance at 180° bending), and superior integration. Most notably, the capacitance remains at 97.3% of the initial value after 50000 charging/discharging cycles, superior to that of most advanced SiC-based MSCs ever reported. This work demonstrates an effective design for hierarchical porous SiC/C nanocomposite for energy storage, which gives significant inspirations on the exploration of high-performance SiC-based MSCs. [ABSTRACT FROM AUTHOR]

Ubiquitin-like protease 1 (Ulp1) of Saccharomyces cerevisiae emerges as a fundamental tool to obtain the natural N-terminal target protein by cleavage of the small ubiquitin-related modifier (SUMO) fusion protein. However, the costly commercial Ulp1 and its complicated procedures limit its application in the preparation of the target protein with natural N-terminal sequence. Here, we describe the preparation of bioactive codon-optimized recombinant truncated Ulp1 (Leu403-Lys621) (rtUlp1) of S. cerevisiae in Escherichia coli using only one-step with Ni-NTA affinity chromatograph, and the application of rtUlp1 to cleave the SUMO fusion protein by simply mixing the purified rtUlp1, SUMO fusion protein and DL-Dithiothreitol in Tris-HCl buffer. The optimal expression level of non-fusion protein rtUlp1 accounts for approximately 50 % of the total cellular protein and 36 % of the soluble form by addition of isopropyl β-D-l-thiogalactopyranoside at a final concentration of 0.4 mM at 18 °C for 20 h. The purification of target protein rtUlp1 was conducted by Ni-NTA affinity chromatography. The final yield of rtUlp1 was 45 mg/l in flask fermentation with a purity up to 95 %. Furthermore, the high purity of rtUlp1 could effectively cleave the SUMO-tTβRII fusion protein (SUMO gene fused to truncated transforming growth factor-beta receptor type II gene) with the above simplified approach, and the specific activity of the rtUlp1 reached up to 2.8 × 10 U/mg, which is comparable to the commercial Ulp1. The preparation and application strategy of the rtUlp1 with commonly available laboratory resources in this study will be convenient to the cleavage of the SUMO fusion protein to obtain the natural N-terminal target protein, which can be implemented in difficult-to-express protein functional analysis. [ABSTRACT FROM AUTHOR]

Hepatocyte growth factor (HGF) is an effective anti-fibrotic factor because of its bioactivity in inhibiting fibrosis-related proteins in the development of hepatic fibrosis. However, high-level production of bioactive mature form HGF is difficult because of its complex structure. Here, we report a non-fusion protein expression system to obtain truncated variant of N-terminal hairpin and first kringle domains of HGF (tvNK1) in Escherichia coli to determine its anti-fibrotic effects on hepatic stellate cells (HSCs). Under the selected conditions of cultivation and isopropyl-β-D-1-thiogalactopyranoside induction, the expression level of tvNK1 accounted for approximately 65 % of the total cellular protein and 50 % of fusion protein in the supernatant of whole cell lysates. The recombinant protein could be purified in one step with Ni-affinity chromatograph. Finally, about 65 mg recombinant tvNK1 was obtained from 1 l fermentation culture with no <95 % purity. In vitro, the final purified tvNK1 was shown to inhibit the proliferation of HSCs and decrease the mRNA and protein expression levels of fibrosis-related COL1A1 and α-smooth muscle actin genes. [ABSTRACT FROM AUTHOR]

With the highly competitive development of communication technologies, modern information manufactures place high importance on the ability to control the transmitted signal using easy miniaturization materials. A controlled and miniaturized optical information device is, therefore, vital for researchers in information and communication fields. Here we propose a controlled signal transport in a doubly clamped carbon nanotube system, where the transmitted signal can be controlled by another pump beam. Pump off results in the transmitted signal off, while pump on results in the transmitted signal on. The more pump, the more amplified output signal transmission. Analogous with traditional cavity optomechanical system, the role of optical cavity is played by a localized exciton in carbon nanotube while the role of the mechanical element is played by the nanotube vibrations, which enables the realization of an opto-transistor based on carbon nanotube. Since the signal amplification and attenuation have been observed in traditional optomechanical system, and the nanotube optomechanical system has been realized in laboratory, the proposed carbon nanotube opto-transistor could be implemented in current experiments and open the door to potential applications in modern optical networks and future quantum networks. [ABSTRACT FROM AUTHOR]