Development of a Microheater with a Large Heating Area and Low Thermal Stress in the Heating Area.

In this paper, a microheater that can absorb thermal stress and has a large heating area is demonstrated by optimizing the structure and process of the microheater. Four symmetrically distributed elongated support beam structures were machined around the microheater via deep silicon etching. This design efficiently mitigates the deformation of the heated region caused by thermal expansion and enhances the structural stability of the microheater. The updated microheater no longer converts the work area into a thin film; instead, it creates a stable heating platform that can uniformly heat a work area measuring 10 × 10 mm2. The microheater is verified to have high temperature uniformity and structural stability in finite element simulation. Finally, thorough investigations of electrical-thermal-structural characterization were conducted. The test findings show that the new microheater can achieve 350 °C with a power consumption of 6 W and a thermal reaction time of 22 s. A scan of its whole plane reveals that the surface of the working area of the new microheater is flat and does not distort in response to variations in temperature, offering good structural stability.

Biopolymers for Hygroscopic Material Development.

The effective management of atmospheric water will create huge value for mankind. Diversified and sustainable biopolymers that are derived from organisms provide rich building blocks for various hygroscopic materials. Here, a comprehensive review of recent advances in developing biopolymers for hygroscopic materials is provided. It is begun with a brief introduction of species diversity and the processes of obtaining various biopolymer materials from organisms. The fabrication of hygroscopic materials is then illustrated, with a specific focus on the use of biopolymer-derived materials as substrates to produce composites and the use of biopolymers as building blocks to fabricate composite gels. Next, the representative applications of biopolymer-derived hygroscopic materials for dehumidification, atmospheric water harvesting, and power generation are systematically presented. An outlook on future challenges and key issues worthy of attention are finally provided.

Fluoride exposure confers NRF2 activation in hepatocyte through both canonical and non-canonical signaling pathways.

Due to the high abundance in the Earth's crust and industrial application, fluoride is widely present in our living environment. However, excessive fluoride exposure causes toxicity in different organs. As the most important detoxification and excretion organ, liver is more easily involved in fluoride toxicity than other organs, and oxidative stress is considered as the key mechanism related with fluoride hepatotoxicity. In this study, we mainly investigated the role of nuclear factor erythroid-derived 2-like 2 (NRF2, a core transcription factor in oxidative stress) in fluoride exposure-induced hepatotoxicity as well as the related mechanism. Herein, liver cells (BNL CL.2) were treated with fluoride in different concentrations. The hepatotoxicity and NRF2 signaling pathway were analyzed respectively. Our results indicated that excessive fluoride (over 1 mM) resulted in obvious toxicity in hepatocyte and activated NRF2 and NRF2 target genes. The increased ROS generation after fluoride exposure suppressed KEAP1-induced NRF2 ubiquitylation and degradation. Meanwhile, fluoride exposure also led to blockage of autophagic flux and upregulation of p62, which contributed to activation of NRF2 via competitive binding with KEAP1. Both pharmaceutical activation and genetic activation of NRF2 accelerated fluoride exposure-induced hepatotoxicity. Thus, the upregulation of NRF2 in hepatocyte after fluoride exposure can be regarded as a cellular self-defense, and NRF2-KEAP1 system could be a novel molecular target against fluoride exposure-induced hepatotoxicity.

A Positive Feedback Loop of lncRNA HOXD-AS2 and SMYD3 Facilitates Hepatocellular Carcinoma Progression via the MEK/ERK Pathway.

Purpose: HOX cluster-embedded long noncoding RNAs (HOX-lncRNAs) have been shown to be tightly related to hepatocellular carcinoma (HCC). However, the potential biological roles and underlying molecular mechanism of HOX-lncRNAs in HCC largely remains to be elucidated. Methods: The expression signature of eighteen HOX-lncRNAs in HCC cell lines were measured by qRT-PCR. HOXD-AS2 expression and its clinical significance in HCC was investigated by bioinformatics analysis utilizing the TCGA data. Subcellular localization of HOXD-AS2 in HCC cells was observed by RNA-FISH. Loss­of­function experiments in vitro and in vivo were conducted to probe the roles of HOXD-AS2 in HCC. Potential HOXD-AS2-controlled genes and signaling pathways were revealed by RNA-seq. Rescue experiments were performed to validate that SMYD3 mediates HOXD-AS2 promoting HCC progression. The positive feedback loop of HOXD-AS2 and SMYD3 was identified by luciferase reporter assay and ChIP-qPCR. Results: HOXD-AS2 was dramatically elevated in HCC, and its up-regulation exhibited a positive association with aggressive clinical features (T stage, pathologic stage, histologic grade, AFP level, and vascular invasion) and unfavorable prognosis of HCC patients. HOXD-AS2 was distributed both in the nucleus and the cytoplasm of HCC cells. Knockdown of HOXD-AS2 restrained the proliferation, migration, invasion of HCC cells in vitro, as well as tumor growth in subcutaneous mouse model. Transcriptome analysis demonstrated that SMYD3 expression and activity of MEK/ERK pathway were impaired by silencing HOXD-AS2 in HCC cells. Rescue experiments revealed that SMYD3 as downstream target mediated oncogenic functions of HOXD-AS2 in HCC cells through altering the expression of cyclin B1, cyclin E1, MMP2 as well as the activity of MEK/ERK pathway. Additionally, HOXD-AS2 was uncovered to be positively regulated at transcriptional level by its downstream gene of SMYD3. Conclusion: HOXD-AS2, a novel oncogenic HOX-lncRNA, facilitates HCC progression by forming a positive feedback loop with SMYD3 and activating the MEK/ERK pathway.

Liquiritigenin Confers Liver Protection by Enhancing NRF2 Signaling through Both Canonical and Non-canonical Signaling Pathways.

Oxidative stress plays a critical role in drug-induced liver injury. In recent years, liquiritigenin (LQ), a natural flavonoid distributed in Glycyrrhizae Radix et Rhizoma (Gan Cao), shows protective effects against oxidative hepatotoxicity. However, the underlying mechanism remains unclear. In this study, we mainly investigated the role of NRF2, a core transcription factor in oxidative stress, in LQ-induced hepatoprotection. Our results indicated that the function of LQ to eliminate reactive oxygen species in liver cells was dependent on NRF2 activation. Both a canonical signaling pathway and a non-canonical signaling pathway are involved in LQ-induced NRF2 activation. LQ induced NRF2 activation in a KEAP1-C151-dependent manner partially. Meanwhile, LQ led to the blockage of autophagic flux and upregulation of p62, which competitively bound with KEAP1 and conferred NRF2 activation in a KEAP1-C151-independent manner. Totally, our study reveals a novel molecular mechanism underlying the hepatoprotection of LQ, providing a new insight into the pathogenesis and therapeutic strategy of oxidative liver injury.

miR-3,178 contributes to the therapeutic action of baicalein against hepatocellular carcinoma cells via modulating HDAC10.

Hepatocellular carcinoma (HCC) is the most common type of hepatic malignancies with high mortality and poor prognosis. Baicalein, one of the major and bioactive flavonoids isolated from Scutellaria baicalensis Georgi, which is reported to have anti-proliferation effect in varying cancers, including HCC, whose underlying molecular mechanism is still largely unknown. In this study, we found that baicalein significantly inhibited proliferation and colony formation, blocked cell cycle, and promoted apoptosis in HCC cells MHCC-97H and SMMC-7721 in vitro and reduced tumor volume and weight in vivo. Increased microRNA (miR)-3,178 levels and decreased histone deacetylase 10 (HDAC10) expression were found in cells treated with baicalein and in patients' HCC tissues. HDAC10 was identified as a target gene of miR-3,178 by luciferase activity and western blot. Both baicalein treatment and overexpression of miR-3,178 could downregulate HDAC10 protein expression and inactivated AKT, MDM2/p53/Bcl2/Bax and FoxO3α/p27/CDK2/Cyclin E1 signal pathways. Not only that, knockdown of miR-3,178 could partly abolish the effects of baicalein and the restoration of HDAC10 could abated miR-3,178-mediated role in HCC cells. Collectively, baicalein inhibits cell viability, blocks cell cycle, and induces apoptosis in HCC cells by regulating the miR-3,178/HDAC10 pathway. This finding indicated that baicalein might be promising for treatment of HCC.

COX7A1 enhances the sensitivity of human NSCLC cells to cystine deprivation-induced ferroptosis via regulating mitochondrial metabolism.

COX7A1, a subunit of cytochrome c oxidase, holds an important position in the super-assembly which integrates into multi-unit heteromeric complexes peripherally in the mitochondrial electron transport chain (ETC). Recently, some studies indicated the significant potential of COX7A1 in cancer metabolism and therapy. However, the underlying metabolic process and therapy mechanism remain unclear. In this study, COX7A1-overexpressed cell line was established via lentivirus transduction. The relationship between COX7A1 and ferroptosis, a novel form of cell death driven by iron-dependent lipid peroxidation, was further analyzed in different human non-small-cell lung carcinoma (NSCLC) cells respectively. Our results showed that COX7A1 increased the sensitivity of NSCLC cells to the ferroptosis induced by cysteine deprivation via enhancing the tricarboxylic acid (TCA) cycle and the activity of complex IV in mitochondrial ETC. Meanwhile, COX7A1 suppressed mitochondrial dynamics as well as mitochondrial biogenesis and mitophagy through blocking autophagic flux. The autophagy activator, rapamycin, relieved the autophagic blockage and further strengthened the sensitivity to cysteine deprivation-induced ferroptosis of NSCLC cells in vitro and in vivo. Taken together, our data indicate the close association of COX7A1 with cysteine deprivation-induced ferroptosis, and provide a novel insight into the therapy mode against human NSCLC.

Correction: Wang et al. Polycyclic Polyprenylated Acylphloroglucinol Derivatives from Hypericum acmosepalum. Molecules 2019, 24, 50.

The authors wish to make the following correction to their paper [...].

iMyoblasts for ex vivo and in vivo investigations of human myogenesis and disease modeling.

Skeletal muscle myoblasts (iMyoblasts) were generated from human induced pluripotent stem cells (iPSCs) using an efficient and reliable transgene-free induction and stem cell selection protocol. Immunofluorescence, flow cytometry, qPCR, digital RNA expression profiling, and scRNA-Seq studies identify iMyoblasts as a PAX3+/MYOD1+ skeletal myogenic lineage with a fetal-like transcriptome signature, distinct from adult muscle biopsy myoblasts (bMyoblasts) and iPSC-induced muscle progenitors. iMyoblasts can be stably propagated for >12 passages or 30 population doublings while retaining their dual commitment for myotube differentiation and regeneration of reserve cells. iMyoblasts also efficiently xenoengrafted into irradiated and injured mouse muscle where they undergo differentiation and fetal-adult MYH isoform switching, demonstrating their regulatory plasticity for adult muscle maturation in response to signals in the host muscle. Xenograft muscle retains PAX3+ muscle progenitors and can regenerate human muscle in response to secondary injury. As models of disease, iMyoblasts from individuals with Facioscapulohumeral Muscular Dystrophy revealed a previously unknown epigenetic regulatory mechanism controlling developmental expression of the pathological DUX4 gene. iMyoblasts from Limb-Girdle Muscular Dystrophy R7 and R9 and Walker Warburg Syndrome patients modeled their molecular disease pathologies and were responsive to small molecule and gene editing therapeutics. These findings establish the utility of iMyoblasts for ex vivo and in vivo investigations of human myogenesis and disease pathogenesis and for the development of muscle stem cell therapeutics.

Muscular dystrophies are a group of inherited genetic diseases characterised by progressive muscle weakness. They lead to disability or even death, and no cure exists against these conditions. Advances in genome sequencing have identified many mutations that underly muscular dystrophies, opening the door to new therapies that could repair incorrect genes or rebuild damaged muscles. However, testing these ideas requires better ways to recreate human muscular dystrophy in the laboratory. One strategy for modelling muscular dystrophy involves coaxing skin or other cells from an individual into becoming 'induced pluripotent stem cells'; these can then mature to form almost any adult cell in the body, including muscles. However, this approach does not usually create myoblasts, the 'precursor' cells that specifically mature into muscle during development. This limits investigations into how disease-causing mutations impact muscle formation early on. As a response, Guo et al. developed a two-step protocol of muscle maturation followed by stem cell growth selection to isolate and grow 'induced myoblasts' from induced pluripotent stem cells taken from healthy volunteers and muscular dystrophy patients. These induced myoblasts can both make more of themselves and become muscle, allowing Guo et al. to model three different types of muscular dystrophy. These myoblasts also behave as stem cells when grafted inside adult mouse muscles: some formed human muscle tissue while others remained as precursor cells, which could then respond to muscle injury and start repair. The induced myoblasts developed by Guo et al. will enable scientists to investigate the impacts of different mutations on muscle tissue and to better test treatments. They could also be used as part of regenerative medicine therapies, to restore muscle cells in patients.

MiR-3663-3p participates in the anti-hepatocellular carcinoma proliferation activity of baicalein by targeting SH3GL1 and negatively regulating EGFR/ERK/NF-κB signaling.

Baicalein is a purified flavonoid that exhibits anticancer effects in hepatocellular carcinoma (HCC). However, its underlying molecular mechanisms remain largely unclear. In this study, we found that baicalein inhibited HCC cell growth, induced apoptosis, and blocked cell cycle arrest at the S phase in vitro, as well as reduced HCC tumor volume and weight in vivo. Quantitative reverse transcriptase-PCR (qRT-PCR) results suggested that miR-3663-3p was downregulated in HCC tissues. After baicalein treatment, miR-3663-3p expression was upregulated in HCC cells. Transfection of miR-3663-3p suppressed HCC cell proliferation and colony formation, increased the proportion of apoptotic cells in vitro, and reduced the volume and weight of tumors in vivo. The results of dual-luciferase reporter assay showed that miR-3663-3p could directly bind to the 3'-UTR of SH3GL1. SH3GL1 overexpression partly reduced the growth-inhibiting effect of miR-3663-3p. Both baicalein treatment and miR-3663-3p overexpression downregulated the expression of SH3GL1 and inactivated the Erk1/2, p-NF-κB/p65, and EGFR signaling pathways. Overall, our data suggest that baicalein may act as a novel HCC suppressor, and that the miR-3663-3p/SH3GL1/EGFR/ERK/NF-κB pathway plays a vital role in HCC progression. Thus, baicalein treatment or miR-3663-3p induction may be a promising strategy for HCC therapy.

Two new polycyclic polyprenylated acylphloroglucinols derivatives from Hypericum acmosepalum.

Polycyclic polyprenylated acylphloroglucinols (PPAPs) were mainly obtained from the plants of Hypericum genus of Guttiferae family, and possessed intriguing chemical structures and appealing biological activities. Two new PPAPs derivatives, hyperacmosin C (1) and hyperacmosin D (2) were isolated from H. acmosepalum. Their structures were established by NMR, HREIMS, and experimental electronic circular dichroism spectra. Besides, compound 1 showed significant hepatoprotective activity at 10 µM against paracetamol-induced HepG2 cell damage and compound 2 could moderately increase the relative glucose consumption.

[Expression and significance of myeloid-derived suppressor cells-associated chemokine MIP-1γ and its receptor CCR1 in the spleen of hepatoma H22-bearing mice].

Objective To study the expression and significance of myeloid-derived suppressor cell (MDSC)-associated chemokines in the spleen of hepatoma H22-bearing mice. Methods The percentage of splenic MDSCs was examined by flow cytometry. Splenic MDSCs were sorted using flow cytometry and co-cultured with activated splenocytes, and then the level of IFN-γ in the supernatant of co-cultured cells was assayed by ELISA. The murine orthotopic hepatoma model was established. The differential cytokine expression in the spleens of normal and tumor-bearing mice was assayed by protein chip, and splenic MDSC-associated chemokines were verified using ELISA. The chemokine receptors on splenic MDSCs were also detected by flow cytometry. Results The percentage of splenic MDSCs was markedly raised in the tumor-bearing mice, and splenic MDSCs exhibited immune-inhibitory function. Ten up-regulated cytokines and nine down-regulated ones were found out using protein chip. Among the up-regulated cytokines, 5 cytokines were chemokines, namely B lymphocyte chemoattractant (BLC), chemokine (C-X-C motif) ligand 16 (CXCL16), macrophage/monocyte chemotactic protein-5 (MCP-5), macrophage inflammatory protein 1γ (MIP-1γ) and MIP-2. The level of splenic MDSC-associated chemokine MIP-1γ significantly increased in the spleen of tumor-bearing mice, and its receptor CCR1 was also expressed on the cell surface of splenic MDSCs. Conclusion Splenic MDSC-associated chemokine MIP-1γ and its receptor CCR1 were obtained by protein chip, and they might be associated with the accumulation of splenic MDSCs in hepatoma H22-bearing mice.

Hyperacmosins E-G, three new homoadamantane-type polyprenylated acylphloroglucinols from Hypericum acmosepalum.

Three new homoadamantane-type polyprenylated acylphloroglucinols, hyperacmosins E-G (1-3), with seven known compounds were isolated from the air-dried aerial parts of Hypericum asmosepalum. Their structures were determined by NMR, HRESIMS and experimental electronic circular dichroism (ECD) spectra. The hepatoprotective activity of these compounds were evaluated. Compounds 4 and 8 exhibited hepatoprotective activity against paracetamol-induced HepG2 cell damage.

Sandwiching Sulfur into the Dents Between N, O Co-Doped Graphene Layered Blocks with Strong Physicochemical Confinements for Stable and High-Rate Li-S Batteries.

The development of lithium-sulfur batteries (LSBs) is restricted by their poor cycle stability and rate performance due to the low conductivity of sulfur and severe shuttle effect. Herein, an N, O co-doped graphene layered block (NOGB) with many dents on the graphene sheets is designed as effective sulfur host for high-performance LSBs. The sulfur platelets are physically confined into the dents and closely contacted with the graphene scaffold, ensuring structural stability and high conductivity. The highly doped N and O atoms can prevent the shuttle effect of sulfur species by strong chemical adsorption. Moreover, the micropores on the graphene sheets enable fast Li+ transport through the blocks. As a result, the obtained NOGB/S composite with 76 wt% sulfur content shows a high capacity of 1413 mAh g-1 at 0.1 C, good rate performance of 433 mAh g-1 at 10 C, and remarkable stability with 526 mAh g-1 at after 1000 cycles at 1 C (average decay rate: 0.038% per cycle). Our design provides a comprehensive route for simultaneously improving the conductivity, ion transport kinetics, and preventing the shuttle effect in LSBs.

Ring1 promotes the transformation of hepatic progenitor cells into cancer stem cells through the Wnt/ß-catenin signaling pathway.

The proliferation of hepatic progenitor cells (HPCs) is observed in reactive conditions of the liver and primary liver cancers. Ring1 as a member of polycomb-group proteins which play vital roles in carcinogenesis and stem cell self-renewal was increased in HCC patients and promoted proliferation and survival of cancer cell by degrading p53. However, the mechanisms of Ring1 driving the progression of hepatocarcinogenesis have not been elucidated. In this study, forced expression Ring1 and Ring1 siRNA lentiviral vectors were utilized to stably overexpression and silence Ring1 in HPC cell line (WB-F344), respectively. Our finding indicated that overexpression of Ring1 in HPCs promoted colony formation, cell multiplication, and invasion in vitro, conversely depletion of Ring1 repressed the biological functions of HPCs relative to controls. The expression of ß-catenin was upregulated in the HPCs with overexpression of Ring1, and the correlation analysis also showed that ß-catenin and Ring1 had a significant correlation in the liver cancer tissues and adjacent tissues. The activation of the Wnt/ß-catenin signaling pathway significantly increased the expression of liver cancer stem cells related (LCSCs)-related molecular markers CD90 and EpCAM, which led to the transformation of HPCs into LCSCs. Most importantly, the injection of HPCs with overexpressed Ring1 into the subcutaneous of nude mice leads to the formation of poorly differentiated HCC neoplasm. Our findings elucidate that overexpression of Ring1 the activated Wnt/ß-catenin signaling pathway and drove the transformation of HPCs into cancer stem cell-like cells, suggesting Ring1 has extraordinary potential in early diagnosis of HCC.

Boscartins L-O: Cembrane-type diterpenoids from the gum resin of Boswellia sacra Flueck.

Four undescribed cembrane-type diterpenoids, boscartins L-O, as well as five known compounds (1S, 3R, 11S, 12R, 7E)-1,12-epoxy-4-methylenecembr-7- ene- 3,11-diol, isoincensole oxide, incensole oxide, incensole acetate and incensole oxide acetate were isolated from the gum resin of Boswellia sacra Flueck. (Burseraceae). The structures of these compounds were elucidated by extensive 1D and 2D NMR spectroscopic and mass spectrometric analysis, as well as comparisons with known compounds. The absolute configurations of the known compound (1S, 3R, 7E, 11S, 12R)-1,12-epoxy-4-methylenecembr-7-ene-3,11-diol was unequivocally confirmed by single-crystal X-ray diffraction analysis with Cu Kα radiation. Incensole acetate exhibited significant hepatoprotective activity at 10 µM against paracetamol-induced HepG2 cell damage.

Hyperascyrins L - N, rare methylated polycyclic polyprenylated acylphloroglucinol derivatives from Hypericum ascyron.

Seven natural compounds, including new compounds hyperascyrins L-N (1-3) and four known compounds (4-7), were acquired from the aerial parts of Hypericum ascyron, that were all identified as methylated polycyclic polyprenylated acylphloroglucinol derivatives (mPPAPs). The structures of these compounds were established by NMR spectroscopy, experimental and calculated electronic circular dichroism (ECD) data. The neuroprotective activities and hepatoprotective activity of these compounds (10 µM) were evaluated. Compounds 1, 2 and 3 exhibited neuroprotection activity. Compounds 1 and 3 show hepatoprotective activity.

Polycyclic Polyprenylated Acylphloroglucinol Derivatives from Hypericum acmosepalum.

Hypericum acmosepalum belongs to the Hypericum genus of the Guttiferae family. The characteristic components in Hypericum are mainly a series of polycyclic polyprenylated acylphloroglucinols (PPAPs), flavonoids, and xanthones. Among them, the PPAPs have received much attention due to their novel structures and diverse pharmacological activities and have become hot spots in organic chemistry and medicinal chemistry. However, there are few reports about the chemical constituents of Hypericum acmosepalum at present, especially the PPAPs. This research is dedicated to the study of the air-dried aerial parts of Hypericum acmosepalum, which were extracted with 95% EtOH under reflux, then suspended and successively partitioned with petroleum ether and ethyl acetate. Five PPAP derivatives were obtained using various chromatographic techniques, and their structures were determined by NMR spectroscopic data, including two new phloroglucinol derivatives, hyperacmosin A (1) and hyperacmosin B (2). Those compounds were evaluated for their neuroprotective effect using two models.

Methylated Polycyclic Polyprenylated Acylphloroglucinol Derivatives from Hypericum ascyron.

Hyperascyrins A-H (1-11) and four known compounds (12-15) were acquired from the air-dried aerial parts of Hypericum ascyron and were all identified as methylated polycyclic polyprenylated acylphloroglucinol derivatives. Their structures were established by NMR spectroscopy, experimental and calculated electronic circular dichroism (ECD) data, and comparison with established compounds. Compounds 8 and 9 showed protection against paracetamol-induced HepG2 cell damage at 10 µM. The neuroprotective activities of all compounds (10 µM) were evaluated, and compounds 1 and 8 exhibited mild neuroprotection against glutamate-induced toxicity in SK-N-SH cells.

[Chemical constituents of Hypericum perforatum].

A chemical investigation on the aerial parts of Hypericum perforatum resulted in the isolation of a new phloroglucinol derivatives (1), and seven known compounds (2-8). The structures of the compounds were elucidated by means of spectroscopic methods (MS, IR, 1D NMR, and 2D NMR) as 3-methyl-4,6-di (3- methyl-2-butenyl)-3-(4-methyl-3-pentenyl)-2-(2-ethyl-1-oxobutyl)-cyclohexanone (1)，hyperforin (2)，(2R,3R,4S,6R)-3-methyl-4,6-di(3-methyl-2-butenyl)-2-(2-methyl-1-oxo-propyl)-3-(4-methyl-3-pentenyl)-cyclohexanone (3)，hyperscabrin B (4)，hyperscabrin C (5)，furohyperforin isomer 1 (6)，furoadhyperforin (7)，and furohyperforin (8). Compound 1 was a new compound, and compounds 3-5 were obtained from H. perforatum for the first time.