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1.
J Biochem Mol Toxicol ; : e22473, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32048404

RESUMO

γ-Aminobutyrate (GABA) is commonly used as a food supplement and a health care product by young females, due to its positive roles in relieving stress, alleviating anxiety, and improving sleep. However, its recommended daily dose in different products varies widely. Besides, it is unknown whether, and how, GABA consumption during early pregnancy influences pregnancy establishment. In this study, we found that when pregnant mice were treated with a high (12.5 mg/g) dose of GABA (orally) during preimplantation, there was a reduction in the number of implantation sites on day 5 of pregnancy. Also, among these unimplanted embryos, most exhibited morphological degeneration and developmental retardation, and only a few of them developed into blastocysts but could not implant into the uterus. Moreover, the expression of uterine receptivity-related factors-LIF, E-cadherin, and HOXA10-were all downregulated, while the number of uterine glands was reduced in the high GABA dose group. Finally, in vitro results demonstrated that GABA (ranging from 10 to 50 µg/µL) markedly inhibited preimplantation embryo development in a dose-response manner. However, this inhibitory effect was not observed when the embryos were pretreated with 40 µΜ 2-hydroxysaclofen, a GABAB antagonist, indicating that GABA exerts its inhibitory effects via its B-type receptor. Our results suggest that exposure to certain GABA concentrations, during early pregnancy, can impair preimplantation embryo development via its B-type receptor, and endometrial receptivity, which greatly disturbs early embryo implantation in mice. These findings could raise concerns about GABA consumption during the early stages of pregnancy.

2.
Mol Divers ; 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-32076911

RESUMO

A series of dibenzodiazepine 2-position derivatives, bearing N-methylpiperazine at the C-11 position, were prepared by using a concise approach. Their inhibitory activities of tumor cell proliferation in vitro were tested in five cell lines, including breast cancer cell BCAP37, gastric cancer cell SGC7901, liver cancer cell HepG2, cervical cancer cell HeLa and acute promyelocytic leukemia cell HL-60. Several compounds showed efficient tumor activity with IC50 values down to 0.30 µM. These compounds are expected to be a new class of potential anticancer lead compounds.

3.
Molecules ; 25(2)2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31963527

RESUMO

Aromatic heterocycles are ubiquitous building blocks in bioactive natural products, pharmaceutical and agrochemical industries. Accordingly, the carborane-fused heterocycles would be potential candidates in drug discovery, nanomaterials, metallacarboranes, as well as photoluminescent materials. In recent years, the transition metal catalyzed B-H activation has been proved to be an effective protocol for selective functionalization of B-H bond of o-carboranes, which has been further extended for the synthesis of polyhedral borane cluster-fused heterocycles via cascade B-H functionalization/annulation process. This article summarizes the recent progress in construction of polyhedral borane cluster-fused heterocycles via B-H activation.

4.
Cell Death Dis ; 11(1): 73, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996668

RESUMO

Our preliminary work has revealed that vitamin D receptor (VDR) activation is protective against cisplatin induced acute kidney injury (AKI). Ferroptosis was recently reported to be involved in AKI. Here in this study, we investigated the internal relation between ferroptosis and the protective effect of VDR in cisplatin induced AKI. By using ferroptosis inhibitor ferrostatin-1 and measurement of ferroptotic cell death phenotype in both in vivo and in vitro cisplatin induced AKI model, we observed the decreased blood urea nitrogen, creatinine, and tissue injury by ferrostatin-1, hence validated the essential involvement of ferroptosis in cisplatin induced AKI. VDR agonist paricalcitol could both functionally and histologically attenuate cisplatin induced AKI by decreasing lipid peroxidation (featured phenotype of ferroptosis), biomarker 4-hydroxynonenal (4HNE), and malondialdehyde (MDA), while reversing glutathione peroxidase 4 (GPX4, key regulator of ferroptosis) downregulation. VDR knockout mouse exhibited much more ferroptotic cell death and worsen kidney injury than wild type mice. And VDR deficiency remarkably decreased the expression of GPX4 under cisplatin stress in both in vivo and in vitro, further luciferase reporter gene assay showed that GPX4 were target gene of transcription factor VDR. In addition, in vitro study showed that GPX4 inhibition by siRNA largely abolished the protective effect of paricalcitol against cisplatin induced tubular cell injury. Besides, pretreatment of paricalcitol could also alleviated Erastin (an inducer of ferroptosis) induced cell death in HK-2 cell. These data suggested that ferroptosis plays an important role in cisplatin induced AKI. VDR activation can protect against cisplatin induced renal injury by inhibiting ferroptosis partly via trans-regulation of GPX4.

5.
PLoS One ; 15(1): e0227924, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31951629

RESUMO

INTRODUCTION: Previous studies have provided equivocal evidence of antidepressant use on subsequent cognitive impairment; this could be due to inconsistent modeling approaches. Our goals are methodological and clinical. We evaluate the impact of statistical modeling approaches on the associations between antidepressant use and risk of Mild Cognitive Impairment (MCI) in older adults with depression. METHODS: 716 participants were enrolled. Our primary analysis employed a time-dependent Cox proportional hazards model. We also implemented two fixed-covariate proportional hazards models-one based on having ever used antidepressants during follow-up, and the other restricted to baseline use only. RESULTS: Treating antidepressant use as a time-varying covariate, we found no significant association with incident MCI (HR = 0.92, 95% CI: 0.70, 1.20). In contrast, when antidepressant use was treated as a fixed covariate, we observed a significant association between having ever used antidepressants and lower risk of MCI (HR = 0.40, 95% CI: 0.28, 0.56). However, in the baseline-use only model, the association was non-significant (HR = 0.84, 95% CI: 0.60, 1.17). DISCUSSION: Our results were dependent upon statistical models and suggest that antidepressant use should be modeled as a time-varying covariate. Using a robust time-dependent analysis, antidepressant use was not significantly associated with incident MCI among cognitively normal persons with depression.

6.
Mol Cancer ; 19(1): 1, 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31901224

RESUMO

Hepatocellular carcinoma (HCC) is the most commonmalignancy. Exsome plays a significant role in the elucidation of signal transduction pathways between hepatoma cells, angiogenesis and early diagnosis of HCC. Exosomes are small vesicular structures that mediate interaction between different types of cells, and contain a variety of components (including DNA, RNA, and proteins). Numerous studies have shown that these substances in exosomes are involved in growth, metastasis and angiogenesis in liver cancer, and then inhibited the growth of liver cancer by blocking the signaling pathway of liver cancer cells. In addition, the exosomal substances could also be used as markers for screening early liver cancer. In this review, we summarized to reveal the significance of exosomes in the occurrence, development, diagnosis and treatment of HCC, which in turn might help us to further elucidate the mechanism of exosomes in HCC, and promote the use of exosomes in the clinical diagnosis and treatment of HCC.

7.
Nat Commun ; 11(1): 284, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941941

RESUMO

The sp2 nature of graphene endows the hexagonal lattice with very high theoretical stiffness, strength and resilience, all well-documented. However, the ultimate stretchability of graphene has not yet been demonstrated due to the difficulties in experimental design. Here, directly performing in situ tensile tests in a scanning electron microscope after developing a protocol for sample transfer, shaping and straining, we report the elastic properties and stretchability of free-standing single-crystalline monolayer graphene grown by chemical vapor deposition. The measured Young's modulus is close to 1 TPa, aligning well with the theoretical value, while the representative engineering tensile strength reaches ~50-60 GPa with sample-wide elastic strain up to ~6%. Our findings demonstrate that single-crystalline monolayer graphene can indeed display near ideal mechanical performance, even in a large area with edge defects, as well as resilience and mechanical robustness that allows for flexible electronics and mechatronics applications.

8.
Nutrients ; 12(1)2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31936037

RESUMO

Hyperlipidemia is associated with metabolic disorders, but the detailed mechanisms and related interventions remain largely unclear. As a functional food in Asian diets, Herba houttuyniae has been reported to have beneficial effects on health. The present research was to investigate the protective effects of Herba houttuyniae aqueous extract (HAE) on hyperlipidemia-induced liver and heart impairments and its potential mechanisms. Male C57BL/6J mice were administered with 200 or 400 mg/kg/day HAE for 9 days, followed by intraperitoneal injection with 0.5 g/kg poloxamer 407 to induce acute hyperlipidemia. HAE treatment significantly attenuated excessive serum lipids and tissue damage markers, prevented hepatic lipid deposition, improved cardiac remodeling, and ameliorated hepatic and cardiac oxidative stress induced by hyperlipidemia. More importantly, NF-E2 related factor (Nrf2)-mediated antioxidant and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)-mediated mitochondrial biogenesis pathways as well as mitochondrial complex activities were downregulated in the hyperlipidemic mouse livers and hearts, which may be attributable to the loss of adenosine monophosphate (AMP)-activated protein kinase (AMPK) activity: all of these changes were reversed by HAE supplementation. Our findings link the AMPK/PGC-1α/Nrf2 cascade to hyperlipidemia-induced liver and heart impairments and demonstrate the protective effect of HAE as an AMPK activator in the prevention of hyperlipidemia-related diseases.

9.
Eye Vis (Lond) ; 6: 38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31819893

RESUMO

Background: Keratoconus (KC) is a common corneal condition with an unknown gender predominance. Although numerous studies have investigated the genetic component of KC, no specific genes have yet been attributed to the condition. We recently reported posterior segment changes occurring in the eyes of KC patients. However, it is not clear whether these changes are part of KC pathogenesis or reflect changes in anatomical features of the eye manifested by changes at the cornea. Given retinal changes represent the main characteristics observed in age-related macular degeneration (AMD) and that pleiotropy has been demonstrated between different eye diseases, we wished to assess if known AMD associated genes were also associated with KC. Methods: A total of 248 KC subjects and 366 non-KC (control) subjects were recruited from public and private clinics in Melbourne for this analysis. Nineteen single nucleotide polymorphisms (SNPs) previously associated with AMD, including rs10490924 (ARMS2/HTRA1), rs10737680 (CFH), rs13278062 (TNFRSF10A), rs1864163 (CETP), rs2230199 (C3), rs3130783 (IER3/DDR1), rs334353 (TGFBR1), rs3812111 (COL10A1), rs429608 (C2/CFB), rs4420638 (APOE), rs4698775 (CFI), rs5749482 (TIMP3), rs6795735 (ADAMTS9), rs8017304 (RAD51B), rs8135665 (SLC16A8), rs920915 (LIPC), rs943080 (VEGFA), rs9542236 (B3GALTL) and rs13081855 (COL8A1/FILIP1L), were genotyped in this cohort. Logistic regression was applied to evaluate the association between these SNPs and KC on both genders together, as well as each gender separately. Linear regression was also applied to assess the association between SNPs and corneal curvature. Bonferroni correction was applied to adjust for multiple testing. Results: Genotyping data were available for 18 SNPs. The SNP, rs6795735 (ADAMTS9) was significantly associated with KC (p = 3.5 × 10- 4) when both genders were assessed, whereas rs5749482 (TIMP3) was only associated in males (p = 7.7 × 10- 4) following Bonferroni multiple correction. However, when the covariates of age and gender were included, the associations became non-significant. In addition, none of the SNPs appeared significant for corneal curvature. Conclusions: Our study suggested a potential association of rs6795735 in the ADAMTS9 gene and rs5749482 in the TIMP3 gene in KC and that different associations may be gender specific. Overall, SNPs initially identified as associated with AMD following multiple correction may be further impacted by other factors such as age or gender and further studies are needed to resolve this issue.

10.
Oxid Med Cell Longev ; 2019: 8010614, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781351

RESUMO

Acute kidney injury (AKI) is a heterogeneous group of critical disease conditions with high incidence and mortality. Vasoconstriction, oxidative stress, apoptosis, and inflammation are generally thought to be the main pathogenic mechanisms of AKI. Ferroptosis is a type of iron-dependent nonapoptotic cell death characterized by membrane lipid peroxide accumulation and polyunsaturated fatty acid consumption, and it plays essential roles in many diseases, including cancers and neurologic diseases. Recent studies have revealed an emerging role of ferroptosis in the pathophysiological processes of AKI. Here, in the present review, we summarized the most recent discoveries on the role of ferroptosis in the pathogenesis of AKI as well as its therapeutic potential in AKI.

11.
Opt Express ; 27(22): 31850-31863, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31684409

RESUMO

Fast and high-performance cavity ring-down spectrometer (CRDS) is highly desired to precisely extract spectral parameters. In this paper, we present our comb-assisted Pound-Drever-Hall (PDH) locked CRDS setup, aiming to retrieve molecular parameters. In the setup, a dynamic feedback is used to keep the tight PDH locking even under strong absorption in the spectral measurement. PDH light and probing light enter the ring-down cavity simultaneously under orthogonal polarization, which enables a fast acquisition of ring-down events without interrupting PDH locking. Ultra-stable cavity temperature is realized, which has an accuracy below 0.5 mK in 27 minutes. The optical frequency comb (OFC) system is developed to rapidly and automatically measure the frequency axis with a relatively wide beat-note range. The minimum detectable absorption coefficient and noise-equivalent absorption coefficient (NEA) are 7.6×10-12cm-1 and 5.3×10-12cm-1Hz-1/2, respectively. The spectrometer is implemented to measure CO2 transition and extract line parameters. The uncertainty for line position is evaluated to be 120 kHz. An accuracy of 0.31% for line intensity is beneficial to the precise determination of CO2 content for the purpose of environment protection and other applications.

12.
Org Lett ; 21(22): 9276-9279, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31686514

RESUMO

An efficient in situ Pd-NHC catalytic system for regioselective arylation of B(3,6)-H bonds of o-carborane has been developed for the first time. A series of symmetric and unsymmetric 3,6-diaryl-o-carboranes anchored with active groups have been synthesized with moderate to good yields under mild conditions. This work offers an efficient protocol for selective activation of B(3,6)-H bonds and has important value in design coupling reactions for selective functionalization of o-carboranes.

14.
Nat Commun ; 10(1): 5099, 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31704930

RESUMO

High strength and high ductility are often mutually exclusive properties for structural metallic materials. This is particularly important for aluminum (Al)-based alloys which are widely commercially employed. Here, we introduce a hierarchical nanostructured Al alloy with a structure of Al nanograins surrounded by nano-sized metallic glass (MG) shells. It achieves an ultrahigh yield strength of 1.2 GPa in tension (1.7 GPa in compression) along with 15% plasticity in tension (over 70% in compression). The nano-sized MG phase facilitates such ultrahigh strength by impeding dislocation gliding from one nanograin to another, while continuous generation-movement-annihilation of dislocations in the Al nanograins and the flow behavior of the nano-sized MG phase result in increased plasticity. This plastic deformation mechanism is also an efficient way to decrease grain size to sub-10 nm size for low melting temperature metals like Al, making this structural design one solution to the strength-plasticity trade-off.

15.
J Ethnopharmacol ; 251: 112332, 2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31669443

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Dahuang Zhechong pill (DHZCP) is a commonly used traditional Chinese medicine for the treatment of hepatocarcinoma. AIM OF THE STUDY: Previous studies have found that DHZCP can exert anti-hepatocarcinoma effects and reverse drug resistance by inhibiting energy metabolism. The goal of this study was to further explore the pharmacodynamic substances that inhibit energy metabolism. METHODS: The components of DHZCP absorbed into plasma were identified by UHPLC-Q-TOF-MS/MS. The Swiss and STITCH databases were used for target collection. The DAVID database was used for pathway enrichment analysis. Cytoscape software was used for network construction. The CCK-8 method detected cell viability. Chemiluminescence was used to detect ATP levels. RESULTS: A total of 89 components absorbed into plasma were identified by UHPLC-Q-TOF-MS/MS. Based on this, 24 potential pharmacodynamic substances were selected by network pharmacology. Among them, 11 components such as rhein can significantly inhibit ATP levels. CONCLUSIONS: Rhein, emodin, chrysophanol, hypoxanthine, baicalein, baicalin, wogonoside, acteoside, formononetin, isoliquiritigenin, and glycyrrhizic acid were the pharmacodynamic substances responsible for inhibition of energy metabolism of DHZCP.

17.
FASEB J ; 33(12): 14296-14306, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31645130

RESUMO

Growing evidence has suggested that autophagy-related protein 7 (ATG7) plays an important role in insulin signaling, but the mechanism of ATG7 in hepatic insulin sensitivity is not fully understood. The purpose of the present study is to clarify the underlying molecular mechanisms of ATG7 in obesity development. Serum and liver samples from mice fed a high fat diet (HFD) were evaluated for metabolic profile data and ATG expressions during obesity development. We found that compared with other ATGs, ATG7 expression increased earlier with lower hepatic insulin sensitivity in the 4-wk HFD-fed mice. For in vitro analyses, silencing ATG7 significantly up-regulated insulin-stimulated phosphorylation of protein kinase B (Akt) and down-regulated phosphatase and tension homolog deleted on chromosome ten (PTEN) in HepG2 cells. Replenishing PTEN to ATG7-silenced hepatocytes restored the phosphorylated Akt level. Furthermore, ATG7 silencing led to higher c-JUN expression, which transcriptionally reduced PTEN expression. These results reveal a novel mechanism by which ATG7 regulates Akt phosphorylation via the c-JUN/PTEN pathway at the early stage of HFD-induced metabolic disorder.-Zhao, D., Zhang, S., Wang, X., Gao, D., Liu, J., Cao, K., Chen, L., Liu, R., Liu, J., Long, J. ATG7 regulates hepatic Akt phosphorylation through the c-JUN/PTEN pathway in high fat diet-induced metabolic disorder.

18.
Sci Adv ; 5(9): eaaw6499, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31579820

RESUMO

RNA interference (RNAi) technology can specifically silence the expression of a target gene and has emerged as a promising therapeutic method to treat cancer. In the present study, we showed that natural halloysite nanotube (HNT)-assisted delivery of an active small interfering RNA (siRNA) targeting receptor-interacting protein kinase 4 ( RIPK4 ) efficiently silenced its expression to treat bladder cancer. The HNTs/siRNA complex increased the serum stability of the siRNA, increased its circulation lifetime in blood, and promoted the cellular uptake and tumor accumulation of the siRNA. The siRNA markedly down-regulated RIPK4 expression in bladder cancer cells and bladder tumors, thus inhibiting tumorigenesis and progression in three bladder tumor models (a subcutaneous model, an in situ bladder tumor model, and a lung metastasis model), with no adverse effects. Thus, we revealed a simple but effective method to inhibit bladder cancer using RIPK4 silencing, indicating a promising therapeutic method for bladder cancer.

19.
Nanotechnology ; 30(47): 475708, 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31507271

RESUMO

The excellent mechanical properties of single- and few-layer graphene have been well-quantified and evidenced by computational methods and local indentation measurements. However, there are less experimental reports on the in-plane mechanical properties of multilayer graphene sheets, despite many practical applications in flexible electronic and energy devices (e.g. graphene flexible electronic display, battery, and storage devices) are actually based on these thicker nanosheets. Here, in-plane fracture behaviors of multilayer graphene nanosheets with thicknesses between ∼10 and 300 nm (∼10-1000 layers) are characterized and quantified by in situ scanning electron microscopy and transmission electron microscopy under tensile loading. We found that, generally, the fracture strengths of graphene nanosheets decrease as the thickness (or layers) increases; however, the fracture strain of thinner graphene sheets is less than that of thicker sheets. The fracture process of the thicker nanosheets includes the initial flattened stage, the stable elastic stage, and the rapid fracture with brittle characteristics, while the thinner nanosheets show obvious delamination between the atomic layers at fracture. This work provides critical experimental insights into the tensile fracture behavior of multilayer two-dimensional materials and a better understanding on their realistic mechanical performance for potential flexible device and composite applications.

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