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1.
J Cell Physiol ; 2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33452710

RESUMO

While mesenchymal stem cells (MSCs) have been widely used to repair radiation-induced bone damage, the molecular mechanism underlying the effects of MSCs in the maintenance of bone homeostasis under radiation stress remains largely unknown. In this study, the role and mechanisms of R-spondin 1 (Rspo1)-leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) axis on the initiation of self-defense of bone mesenchymal stem cells (BMSCs) and maintenance of bone homeostasis under radiation stress were investigated. Interestingly, radiation increased levels of Rspo1 and LGR4 in BMSCs. siRNA knockdown of Rspo1 or LGR4 aggravated radiation-induced impairment of self-renewal ability and osteogenic differentiation potential of BMSCs. However, exogenous Rspo1 significantly attenuated radiation-induced depletion of BMSCs, and promoted the lineage shift towards osteoblasts. This alteration was associated with the reversal of mammalian target of rapamycin (mTOR) activation and autophagy decrement. Pharmacological and genetic blockade of autophagy attenuated the radio-protective effects of Rspo1, rendering BMSCs more vulnerable to radiation-induced injury. Then bone radiation injury was induced in C57BL6J mice to further determine the radio-protective effects of Rspo1. In mice, administration of Rspo1 recombinant protein alleviated radiation-induced bone loss. Our results uncover that Rspo1-LGR4-mTOR-autophagy axis are key mechanisms by which BMSCs initiate self-defense against radiation and maintain bone homeostasis. Targeting Rspo1-LGR4 may provide a novel strategy for the intervention of radiation-induced bone damage.

2.
Nat Prod Res ; : 1-7, 2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33356576

RESUMO

A new diterpenoid with an unusual capnosane skeleton, sinuhumilol A (1), alone with twelve known diverse compounds (2-13), were isolated from the South China Sea soft coral Sinularia humilis. Their structures and stereochemistry were elucidated by extensive spectroscopic analysis, quantum chemical calculations, and/or by the comparison of the spectroscopic data with those reported in the literature. In bioassay, compound 11 exhibited interesting specific cytotoxicity against the human colon adenocarcinoma cell line HT-29 with IC50 value of 12.5 µM.

3.
Front Cell Dev Biol ; 8: 580070, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33178694

RESUMO

Mesenchymal stem cells (MSCs) are pivotal to tissue homeostasis, repair, and regeneration due to their potential for self-renewal, multilineage differentiation, and immune modulation. Mitochondria are highly dynamic organelles that maintain their morphology via continuous fission and fusion, also known as mitochondrial dynamics. MSCs undergo specific mitochondrial dynamics during proliferation, migration, differentiation, apoptosis, or aging. Emerging evidence suggests that mitochondrial dynamics are key contributors to stem cell fate determination. The coordination of mitochondrial fission and fusion is crucial for cellular function and stress responses, while abnormal fission and/or fusion causes MSC dysfunction. This review focuses on the role of mitochondrial dynamics in MSC commitment under physiological and stress conditions. We highlight mechanistic insights into modulating mitochondrial dynamics and mitochondrial strategies for stem cell-based regenerative medicine. These findings shed light on the contribution of mitochondrial dynamics to MSC fate and MSC-based tissue repair.

4.
Onco Targets Ther ; 13: 11019-11029, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33149616

RESUMO

Background: Oral squamous cell carcinoma (OSCC), the most common epithelial malignant neoplasm in the head and neck, characterizes with local infiltration and metastasis of lymph nodes. The five-year survival rate of OSCC remains low despite the advances in clinical methods. Thus, it is necessary to develop a new effective therapeutic scheme for OSCC. Our previous results showed that metformin and 4SC-202 synergistically promoted the intrinsic apoptosis of OSCC in vitro and in vivo, but the effects on invasion and migration remained unclear. Methods: Human OSCC cell lines HSC6 and CAL33 were cultured with metformin (16 mM) or/and 4SC-202 (0.4 µM) for 72 h. STAT3 inhibitor S31-201 was applied at concentration of 60 µM for 48 h. Wound-healing assays and transwell assays were used to determine the invasion and migration ability of OSCC. qRT-PCR and Western blot were performed to detect mRNA levels and protein levels. Results: Metformin or/and 4SC-202 suppressed the migration and invasion of OSCC cells. Importantly, the expression of TWIST1 was suppressed by metformin and 4SC-202, while the invasion and migration inhibitory effects of metformin and 4SC-202 were countered by the overexpression of TWIST1. In addition, the phosphorylation level of STAT3 decreased after the administration of metformin or/and 4SC-202. Furthermore, inhibition of STAT3 by S31-201 suppressed the expression of TWIST1 and led to a decline in migration and invasion of OSCC, while overexpression of TWIST1 attenuated these effects. Conclusion: Metformin and 4SC-202 suppressed the invasion and migration of OSCC through inhibition of STAT3/TWIST1, and this scheme can serve as a novel therapeutic strategy for OSCC.

5.
Bioorg Med Chem Lett ; 31: 127710, 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33246105

RESUMO

A library of new 2-substituted pyrrolo[1,2-b]pyridazine derivatives were rapidly assembled and identified as PARP inhibitors. Structure-activity relationship for this class of inhibitor resulted in the discovery of most potent compounds 15a and 15b that exhibited about 29- and 5- fold selective activity against PARP-1 over PARP-2 respectively. The antiproliferative activity of the as-prepared compounds were demonstrated by further celluar assay in BRCA2-deficient V-C8 and BRCA1-deficient MDA-MB-436 cell lines, displaying that compound 15b could robustly reduce the corresponding cell proliferation and growth with CC50s of 340 and 106 nM respectively. The PK property of 15b was also investigated here.

6.
Inorg Chem ; 59(23): 17276-17281, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33231077

RESUMO

A biocompatible Y(III)-based metal-organic framework [Y4(TATB)2]·(DMF)3.5·(H2O) (ZJU-16, H3TATB= 4,4',4''-(1,3,5-triazine-2,4,6-triyl) tribenzoic acid) was synthesized, and it was adopted to load Mn2+ for chemodynamic therapy. Meanwhile, ibuprofen sodium (IBUNa), an anti-inflammatory drug, was introduced to increase the amount of Mn2+ (about 5.66 wt %) due to the low loading capacity of Mn2+. Mn&IBUNa@ZJU-16 which was loaded by Mn2+ and IBUNa exhibited significant effects of chemodynamic therapy and excellent inhibition of the 4T1 tumor cell growth, implying its long-term prospects in chemodynamic therapy and its possibility in bimodal cancer therapy.

7.
Biomed Pharmacother ; 133: 110906, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33190037

RESUMO

Oral squamous cell carcinoma (OSCC) is the major cause of morbidity and mortality in head and neck cancer patients worldwide. This malignant disease is challenging to treat because of the lack of effective curative strategies and the high incidence of recurrence. This study aimed to investigate the efficacy of a single and dual approach targeting ribosome biogenesis and protein translation to treat OSCC associated with the copy number variation (CNV) of ribosomal DNA (rDNA). Here, we found that primary OSCC tumors frequently exhibited a partial loss of 45S rDNA copy number and demonstrated a high susceptibility to CX5461 (a selective inhibitor of RNA polymerase I) and the coadministration of CX5461 and INK128 (a potent inhibitor of mTORC1/2). Combined treatment displayed the promising synergistic effects that induced cell apoptosis and reactive oxygen species (ROS) generation, and inhibited cell growth and proliferation. Moreover, INK128 compromised NHEJ-DNA repair pathway to reinforce the antitumor activity of CX5461. In vivo, the cotreatment synergistically suppressed tumor growth, triggered apoptosis and strikingly extended the survival time of tumor-bearing mice. Additionally, treatment with the individual compounds and coadministration appeared to reduce the incidence of enlarged inguinal lymph nodes. Our study supports that the combination of CX5461 and INK128 is a novel and efficacious therapeutic strategy that can combat this cancer and that 45S rDNA may serve as a useful indicator to predict the efficacy of this cotreatment.

9.
Artigo em Inglês | MEDLINE | ID: mdl-33220161

RESUMO

Acute dietary salt intake may cause an elevation in blood pressure (BP). The study aimed to assess the acute effect of saline loading on BP in subjects with different levels of salt intake. This study is based on the baseline survey of systemic epidemiology of salt sensitivity study. The sodium excretion in the 24-hour urine was calculated for estimating the level of salt intake. Subjects were performed an acute oral saline loading test (1 L), and data of 2019 participants were included for analyses. Multivariate linear regression and stratified analyses were performed to identify associations between 24-hour urinary sodium (24hUNa) with BP changes. Due to saline loading, systolic BP (SBP), pulse pressure, and urinary sodium concentration were significantly increased, while diastolic BP, heart rate, and urinary potassium concentration were significantly decreased. The SBP increments were more significant in subjects with lower salt intake, normotensives, elders, males, smokers, and drinkers. There was a significant linear negative dose-response association between SBP increment with 24hUNa (ß = -0.901, 95% CI: -1.253, -0.548), especially in lower salt intake individuals (ß = -1.297, 95% CI: -2.338, -0.205) and hypertensive patients (ß = -1.502, 95% CI: -2.037, -0.967). After excluding patients who received antidiabetic or antihypertensive medicines, the effects of negative associations weakened but remained significantly. In conclusion, acute salt loading leads to an increment in SBP, and the increased SBP was negatively related with 24hUNa. This study indicated avoiding acute salt loading was important for escaping acute BP changes, especially in lower salt intake populations.

10.
Chem Commun (Camb) ; 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33244547

RESUMO

A new avenue for fabricating ultra-high specific surface area (SSA) carbons with hierarchical porous and excellent energy storage ability is achieved from the biomass-waste of pitaya peel with the pre-treating process by ethanol and KOH to optimize the microstructure and porosity, displaying excellent supercapacitance in different electrolytes.

11.
Light Sci Appl ; 9: 166, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33024554

RESUMO

Optical nanoantennas can convert propagating light to local fields. The local-field responses can be engineered to exhibit nontrivial features in spatial, spectral and temporal domains, where local-field interferences play a key role. Here, we design nearly fully controllable local-field interferences in the nanogap of a nanoantenna, and experimentally demonstrate that in the nanogap, the spectral dispersion of the local-field response can exhibit tuneable Fano lineshapes with nearly vanishing Fano dips. A single quantum dot is precisely positioned in the nanogap to probe the spectral dispersions of the local-field responses. By controlling the excitation polarization, the asymmetry parameter q of the probed Fano lineshapes can be tuned from negative to positive values, and correspondingly, the Fano dips can be tuned across a broad spectral range. Notably, at the Fano dips, the local-field intensity is strongly suppressed by up to ~50-fold, implying that the hot spot in the nanogap can be turned into a cold spot. The results may inspire diverse designs of local-field responses with novel spatial distributions, spectral dispersions and temporal dynamics, and expand the available toolbox for nanoscopy, spectroscopy, nano-optical quantum control and nanolithography.

12.
Nat Prod Bioprospect ; 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33083968

RESUMO

A phytochemical investigation of the EtOH extract of the flowers of Lagerstroemia indica L. led to the isolation and characterization of a new pyrrole alkaloid, named lagerindicine (1), along with four known compounds (2-5). Their structures were elucidated by the detailed spectroscopic analysis and comparison with literature data, whereas the structure, in particularly, the absolute configuration (AC) of 1, was firmly determined by total synthesis. All the isolates were evaluated for their cytotoxic effects against human colon cancer cell (HCT-116), and compound 3 exhibited weak cytotoxicity with IC50 value of 28.4 µM.

13.
Cell Death Dis ; 11(10): 925, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33116117

RESUMO

CDK4/6 inhibitors show promising antitumor activity in a variety of solid tumors; however, their role in head and neck squamous cell carcinoma (HNSCC) requires further investigation. The senescence-associated secretory phenotype (SASP) induced by CDK4/6 inhibitors has dual effects on cancer treatment. The need to address the SASP is a serious challenge in the clinical application of CDK4/6 inhibitors. We investigated whether metformin can act as a senostatic drug to modulate the SASP and enhance the anticancer efficacy of CDK4/6 inhibitors in HNSCC. In this study, the efficacy of a combination of the CDK4/6 inhibitor LY2835219 and metformin in HNSCC was investigated in in vitro assays, an HSC6 xenograft model, and a patient-derived xenograft model. Senescence-associated ß-galactosidase staining, antibody array, sphere-forming assay, and in vivo tumorigenesis assay were used to detect the impacts of metformin on the senescence and SASP induced by LY2835219. We found that LY2835219 combined with metformin synergistically inhibited HNSCC by inducing cell cycle arrest in vitro and in vivo. Metformin significantly modulated the profiles of the SASP elicited by LY2835219 by inhibiting the mTOR and stat3 pathways. The LY2835219-induced SASP resulted in upregulation of cancer stemness, while this phenomenon can be attenuated when combined with metformin. Furthermore, results showed that the stemness inhibition by metformin was associated with blockade of the IL6-stat3 axis. Survival analysis demonstrated that overexpression of IL6 and stemness markers was associated with poor survival in HNSCC patients, indicating that including metformin to target these proteins might improve patient prognosis. Collectively, our data suggest that metformin can act as a senostatic drug to enhance the anticancer efficacy of CDK4/6 inhibitors by reprogramming the profiles of the SASP.

14.
Neoplasia ; 22(11): 617-629, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33045527

RESUMO

Protein arginine methyltransferase 5 (PRMT5) is an important type II arginine methyltransferase that can play roles in cancers in a highly tissue-specific manner, but its role in the carcinogenesis and metastasis of head and neck squamous cell carcinoma (HNSCC) remains unclear. Here, we detected PRMT5 expression in HNSCC tissues and performed series of in vivo and in vitro assays to investigate the function and mechanism of PRMT5 in HNSCC. We found that PRMT5 was overexpressed in dysplastic and cancer tissues, and associated with lymph node metastasis and worse patient survival. PRMT5 knockdown repressed the malignant phenotype of HNSCC cells in vitro and in vivo. PRMT5 specific inhibitor blocked the formation of precancerous lesion and HNSCC in 4NQO-induced tongue carcinogenesis model, prevented lymph node metastasis in tongue orthotopic xenograft model and inhibited cancer development in subcutaneous xenograft model and Patient-Derived tumor Xenograft (PDX) model. Mechanistically, PRMT5-catalyzed H3R2me2s promotes the enrichment of H3K4me3 in the Twist1 promoter region by recruiting WDR5, and subsequently activates the transcription of Twist1. The rescue experiments indicated that overexpressed Twist1 abrogated the inhibition of cell invasion induced by PRMT5 inhibitor. In summary, this study elucidates that PRMT5 inhibition could reduce H3K4me3-mediated Twist1 transcription and retard the carcinogenesis and metastasis of HNSCC.

15.
Food Funct ; 11(10): 9129-9143, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33026011

RESUMO

Herein, a sturgeon skin gelatine film combined with esculin and ferric citrate was developed as an edible food packaging material to prevent Enterococcus faecalis (E. faecalis) contamination. E. faecalis is able to hydrolyse esculin in the film, and then the hydrolysed product, esculetin, combines with ferric citrate to form a brown-black phenol iron complex. This phenomenon can be observed easily after 48 h of contamination under visible light, and it can be determined under 365 nm ultraviolet light with high sensitivity. With the addition of esculin and ferric citrate, the film showed better mechanical properties and water vapour permeability than those of the unmodified gelatine. When an increased amount of esculin was added, an increase in thermal stability, antioxidant activity, and antioxidant stability of the film was observed. These physicochemical characteristics are beneficial for developing a packaging material for food storage that mitigates foodborne illness caused by E. faecalis.

16.
Int J Mol Sci ; 21(20)2020 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-33050591

RESUMO

Autotetraploid rice is a useful rice germplasm for polyploid rice breeding. However, low fertility limits its commercial production. A neo-tetraploid rice with high fertility was developed from the progenies of crossing between autotetraploid lines by our research group. Our previous study showed that a myeloblastosis (MYB) transcription factor, MOF1, might be associated with the pollen development in tetraploid rice. However, little information is available about its role in pollen development in tetraploid rice. Here, we identified a new haplotype of MOF1 from neo-tetraploid rice and marked it as MOF1a. Transcriptome and qRT-PCR analysis demonstrated that MOF1a highly expressed in anthers, and displayed differential expression in neo-tetraploid rice compared to tetraploid rice line with low pollen fertility. The mutant (mof1a) of MOF1a, which was generated by CRISPR/Cas9 knockout in neo-tetraploid rice, showed low pollen fertility, and also exhibited abnormal tapetum and middle layer development, and defective chromosome behaviors during meiosis. A total of 13 tapetal related genes were found to be up-regulated in meiotic anthers of MOF1a compared with wild type plants by RNA-seq analysis, including CYP703A3, PTC1, and OsABCG26, which had been demonstrated to affect tapetal development. Moreover, 335 meiosis-related genes displayed differential expression patterns at same stage, including nine important meiosis-related genes, such as metallothionein OsMT1a. These results demonstrated that MOF1a plays an important role in pollen development and provides a foundation for understanding the molecular mechanism underlying MOF1a in reproduction of tetraploid rice.

17.
Front Oncol ; 10: 1740, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32984057

RESUMO

Background: Alternative splicing (AS) plays an essential role in tumorigenesis and progression. This study aimed to develop a novel prognostic model based on the AS events to obtain more accurate survival prediction and search for potential therapeutic targets in oral squamous cell carcinoma (OSCC). Methods: Seven types of AS events in 326 OSCC patients with RNA-seq were obtained from the TCGA SpliceSeq tool and the TCGA database. Cox analysis, the least absolute shrinkage and selection operator Cox regression and random forest were employed to establish prognostic models. Genomics of Drug Sensitivity in Cancer (GDSC) was adopted to estimate the possible drug sensiticity. Prognostic splicing factor (SF)-AS network was constructed by Cytoscape. Results: The final model included 12 AS events, showing satisfactory performance. The area under the curve for 3- and 5-year survival in the training cohort was 0.83 and 0.82, respectively while that in internal validation was 0.83 and 0.82 accordingly. The calibration curve also indicated a satisfactory agreement between the observation and the predictive values. Low-risk patients stratified by the final model presented higher sensitivity to three chemo drugs. Besides, the prognostic SF-AS regulatory network contained five key SFs and 62 AS events. Conclusions: We developed a powerful prognostic AS signature for OSCC and deepened the understanding of SF-AS network regulatory mechanisms. Low-risk patients tended to be more sensitive to the three chemo drugs while five key SFs including CELF2, TIA1, HNRNPC, HNRNPK, and SRSF9 were identified as potential prognostic biomarkers, which may offer new prospects for effective therapies of OSCC.

19.
Bioorg Chem ; 103: 104223, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32891002

RESUMO

Seven new cembrane-type diterpenes, lobophytolins C-I (3-9), and one new prenylated-guiane-type diterpene, lobophytolin J (10), along with six known related ones (1, 2, 11-14), have been isolated from the soft coral Lobophytum sp. collected off the Xisha Island in the South China Sea. Their structures were elucidated by extensive spectroscopic analysis and quantum mechanical (QM)-NMR methods. The absolute configuration of lobophytolin H (8) was determined by the application of the modified Mosher's method and chemical transformation. Lobophytolin D (4) exhibited promising cytotoxicities in in vitro bioassays against HT-29, Capan-1, A549, and SNU-398 human cancer cell lines with IC50 values of 4.52, 6.62, 5.17, and 6.15 µM, respectively.

20.
BMC Oral Health ; 20(1): 250, 2020 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-32894117

RESUMO

BACKGROUND: This study aims to compare the percentage of dentin removed, instrumentation efficacy, root canal filling and load at fracture between contracted endodontic cavities, and traditional endodontic cavities on root canal therapy in premolars. METHODS: Forty extracted intact human first premolars were imaged with micro-CT and randomly assigned to the contracted endodontic cavity (CEC) or traditional endodontic cavity (TEC) groups. CEC was prepared with the aid of a 3D-printed template, canals were prepared with a 0.04 taper M-Two rotary instrument, and cavities were restored with resin. Specimens were loaded to fracture in an Instron Universal Testing Machine after a fatigue phase. The data were analyzed by the independent samples T test and Mann-Whitney U test, appropriate post hoc tests. RESULTS: In the premolars tested in vitro, the percentage of dentin removed in the premolars with two dental roots in the CEC group (3.85% ± 0.42%) was significantly smaller (P < 0.05) than in the TEC group (4.94% ± 0.5%). The untouched canal wall (UCW) after instrumentation for TECs (16.43% ± 6.56%) was significantly lower (P < .05) than the UCW (24.42% ± 9.19%) for CECs in single-rooted premolars. No significant differences were observed in the increased canal volume and surface areas in premolars between the TEC and CEC groups (P > 0.05). CECs conserved coronal dentin in premolars with two dental roots but no impact on the instrument efficacy. There were no differences between the CEC groups and the TEC groups in the percentage of filling material and voids (P > 0.05). In addition, the mean load at failure of premolars did not significantly differ between the CEC and TEC groups and there was no significant difference in the type of fracture (P > 0.05). CONCLUSION: The results of this study suggest that CEC could not improve the fracture resistance of the endodontically treated premolars. The instrumentation efficacy and the percentage of filling material did not significantly differ between CECs and TECs in premolars.

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