Publications by authors named "Mi Zhang"

323 Publications

Cytotoxic indole alkaloids and polyketides produced by a marine-derived fungus DS720.

Front Microbiol 2022 22;13:959754. Epub 2022 Jul 22.

Department of Thyroid and Breast Surgery, Northern Jiangsu People's Hospital, Yangzhou, China.

Marine-derived microorganisms possess the unique metabolic pathways to produce structurally novel secondary metabolites with potent biological activities. In this study, bioactivity-guided isolation of the marine deep-sea-derived fungus DS720 led to the characterization of four indole alkaloids (compounds -) and four polyketides (compounds -), such as two new indoles, flavonoids A () and B () with a C-6 reversed prenylation, and a new azaphilone, flaviazaphilone A (). Their chemical structures were unambiguously established by an extensive interpretation of spectroscopic data, such as 1D/2D NMR and HRESIMS data. The absolute configurations of the new compound were solved by comparing the experimental and calculated Electronic Circular Dichroism (ECD) spectra. Since sufficient amount of flavonoids A () was obtained, was subjected to a large-scale cytotoxic activity screening against 20 different human tumor cell lines. The results revealed that showed broad-spectrum cytotoxicities against HeLa, 5637, CAL-62, PATU8988T, A-375, and A-673 cell lines, with the inhibition rates of more than 90%. This study indicated that the newly discovered indole alkaloid may possess certain potential for the development of lead compounds in the future.
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http://dx.doi.org/10.3389/fmicb.2022.959754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9355579PMC
July 2022

Human umbilical cord mesenchymal stem cells for psoriasis: a phase 1/2a, single-arm study.

Signal Transduct Target Ther 2022 Aug 5;7(1):263. Epub 2022 Aug 5.

The Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China.

Psoriasis is a common, chronic immune-mediated systemic disease that had no effective and durable treatment. Mesenchymal stem cells (MSCs) have immunomodulatory properties. Therefore, we performed a phase 1/2a, single-arm clinical trial to evaluate the safety and efficacy of human umbilical cord-derived MSCs (UMSCs) in the treatment of psoriasis and to preliminarily explore the possible mechanisms. Seventeen patients with psoriasis were enrolled and received UMSC infusions. Adverse events, laboratory parameters, PASI, and PGA were analyzed. We did not observe obvious side effects during the treatment and 6-month follow-up. A total of 47.1% (8/17) of the psoriasis patients had at least 40% improvement in the PASI score, and 17.6% (3/17) had no sign of disease or minimal disease based on the PGA score. And the efficiency was 25% (2/8) for males and 66.7% (6/9) for females. After UMSC transplantation (UMSCT), the frequencies of Tregs and CD4 memory T cells were significantly increased, and the frequencies of T helper (Th) 17 and CD4 naive T cells were significantly decreased in peripheral blood (PB) of psoriasis patients. And all responders showed significant increases in Tregs and CD4 memory T cells, and significant decreases in Th17 cells and serum IL-17 level after UMSCT. And baseline level of Tregs in responders were significantly lower than those in nonresponders. In conclusion, allogeneic UMSCT is safe and partially effective in psoriasis patients, and level of Tregs may be used as a potent biomarker to predict the clinical efficacy of UMSCT. Trial registration Clinical Trials NCT03765957.
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http://dx.doi.org/10.1038/s41392-022-01059-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9352692PMC
August 2022

A Novel Polysaccharide From and Its Protective Effect Against Myocardial Injury.

Front Nutr 2022 14;9:961182. Epub 2022 Jul 14.

School of Basic Medical Sciences, Qingdao University, Qingdao, China.

We isolated and purified a novel polysaccharide from the root of , namely, polysaccharide (CVP) and confirmed its structure and molecular weight. Furthermore, experiment, CVP's protective effect against myocardial ischemia-reperfusion (I/R) injury in mice was evidenced by significantly reducing I/R-induced myocardial infarction (MI) size, decreasing the secretion of heart damage biomarkers, and improving cardiac function. Then, the myocardial anoxia/reoxygenation (A/R) injury model was established to mimic reperfusion injury. Noticeably, ferroptosis was the major death manner for A/R-damaged H9c2 cells. Meanwhile, CVP significantly inhibited ferroptosis by decreasing intracellular Fe level, enhancing GPX4 expression, and suppressing lipid peroxidation to confront A/R injury. In conclusion, CVP, with a clear structure, ameliorated I/R injury by inhibiting ferroptosis.
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http://dx.doi.org/10.3389/fnut.2022.961182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9330552PMC
July 2022

Effects of proteins on emulsion stability: The role of proteins at the oil-water interface.

Food Chem 2022 Jul 18;397:133726. Epub 2022 Jul 18.

State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China. Electronic address:

To obtain a stable protein-added emulsion system, researchers have focused on the design of the oil-water interface. This review discussed the updated details of protein adsorption behavior at the oil-water interface. We evaluated methods of monitoring interfacial proteins as well as their strengths and limitations. Based on the effects of structure on protein adsorption, we summarized the contribution of pre-changing methods to adsorption. In addition, the interaction of proteins and other surface-active molecules at the interface had been emphasized. Results showed that protein adsorption is affected by conformation, oil polarity and aqueous environments. The monitoring of interfacial proteins through spectroscopic properties in actual emulsion systems is an emerging trend. Pre-changing could improve the protein adsorption and the purpose of pre-changing of proteins is similar. In the interaction with other surface-active molecules, co-adsorption is desirable. By co-adsorption, the respective advantages can be exploited to obtain a more stable emulsion system.
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http://dx.doi.org/10.1016/j.foodchem.2022.133726DOI Listing
July 2022

lncKRT16P6 promotes tongue squamous cell carcinoma progression by sponging miR‑3180 and regulating GATAD2A expression.

Int J Oncol 2022 Sep 29;61(3). Epub 2022 Jul 29.

School and Hospital of Stomatology, Fujian Medical University, Fuzhou, Fujian 350002, P.R. China.

Tongue squamous cell carcinoma (TSCC) is characterized by a poor prognosis and its 5‑year overall survival rate has not improved significantly. However, the precise molecular mechanisms underlying TSCC remain largely unknown. Through RNA screening, the present study identified a novel long noncoding RNA (lncRNA), keratin 16 pseudogene 6 (lncKRT16P6), which was upregulated in TSCC tissues and cell lines and associated with TSCC tumor stage and differentiation grade. Inhibition of lncKRT16P6 expression reduced TSCC cell migration, invasion and proliferation. lncKRT16P6 sponged microRNA (miR)‑3180 and upregulated GATA zinc finger domain containing 2A (GATAD2A) expression. miR‑3180 inhibition reversed the lncKRT16P6 depletion‑induced attenuation of TSCC malignancy and GATAD2A depletion reversed the miR‑3180 silencing‑induced enhancement of TSCC malignancy. In summary, the present study revealed a potential competitive endogenous RNA (ceRNA) regulatory pathway in which lncKRT16P6 modulates GATAD2A expression by binding miR‑3180, ultimately promoting tumorigenesis and metastasis in TSCC. Therefore, lncKRT16P6 may be used as a prognostic biomarker and therapeutic target for clinical intervention in TSCC.
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http://dx.doi.org/10.3892/ijo.2022.5401DOI Listing
September 2022

miR-143-3p Inhibits Aberrant Tau Phosphorylation and Amyloidogenic Processing of APP by Directly Targeting DAPK1 in Alzheimer's Disease.

Int J Mol Sci 2022 Jul 20;23(14). Epub 2022 Jul 20.

Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China.

The neuropathology of Alzheimer's disease (AD) is characterized by intracellular aggregation of hyperphosphorylated tau and extracellular accumulation of beta-amyloid (Aβ). Death-associated protein kinase 1 (DAPK1), as a novel therapeutic target, shows promise for the treatment of human AD, but the regulatory mechanisms of DAPK1 expression in AD remain unclear. In this study, we identified miR-143-3p as a promising candidate for targeting DAPK1. miR-143-3p directly bound to the 3' untranslated region of human DAPK1 mRNA and inhibited its translation. miR-143-3p decreased tau phosphorylation and promoted neurite outgrowth and microtubule assembly. Moreover, miR-143-3p attenuated amyloid precursor protein (APP) phosphorylation and reduced the generation of Aβ40 and Aβ42. Furthermore, restoring DAPK1 expression with miR-143-3p antagonized the effects of miR-143-3p in attenuating tau hyperphosphorylation and Aβ production. In addition, the miR-143-3p levels were downregulated and correlated inversely with the expression of DAPK1 in the hippocampus of AD patients. Our results suggest that miR-143-3p might play critical roles in regulating both aberrant tau phosphorylation and amyloidogenic processing of APP by targeting DAPK1 and thus offer a potential novel therapeutic strategy for AD.
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http://dx.doi.org/10.3390/ijms23147992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9317260PMC
July 2022

The repression of oncoprotein SET by the tumor suppressor p53 reveals a p53-SET-PP2A feedback loop for cancer therapy.

Sci China Life Sci 2022 Jul 21. Epub 2022 Jul 21.

State Key Laboratory of Medical Molecular Biology & Department of Medical Genetics, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100005, China.

The oncoprotein SET is frequently overexpressed in many types of tumors and contributes to malignant initiation and progression through multiple mechanisms, including the hijacking of the tumor suppressors p53 and PP2A. Targeting aberrant SET represents a promising strategy for cancer intervention. However, the mechanism by which endogenous SET is regulated in cancer cells remains largely unknown. Here, we identified the tumor suppressor p53 as a key regulator that transcriptionally repressed the expression of SET in both normal and cancer cells. In addition, p53 stimulated PP2A phosphatase activity via p53-mediated transcriptional repression of SET, whereby SET-mediated inhibition of PP2A was alleviated. Moreover, targeting the interaction between SET and PP2A catalytic subunit (PP2Ac) with FTY720 enhanced stress-induced p53 activation via PP2A-mediated dephosphorylation of p53 on threonine 55 (Thr55). Therefore, our findings uncovered a previously unknown p53-SET-PP2A regulatory feedback loop. To functionally potentiate this feedback loop, we designed a combined therapeutic strategy by simultaneously administrating a p53 activator and SET antagonist in cancer cells and observed a dramatic synergistic effect on tumor suppression. Our study reveals mechanistic insight into the regulation of the oncoprotein SET and raises a potential strategy for cancer therapy by stimulating the p53-SET-PP2A feedback loop.
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http://dx.doi.org/10.1007/s11427-021-2123-8DOI Listing
July 2022

Characterization of Field-Evolved Resistance to Afidopyropen, a Novel Insecticidal Toxin Developed from Microbial Secondary Metabolites, in .

Toxins (Basel) 2022 Jul 1;14(7). Epub 2022 Jul 1.

Institute of Plant Protection, Beijing Academy of Agriculture and Forestry Sciences, Beijing 100097, China.

Afidopyropen, a newly identified chemical, is a derivative of pyripyropene A, which is produced by the filamentous fungus . It is a promising novel pesticide applied against whiteflies in agriculture. In this study, the reversion and selection, cross-resistance patterns, synergistic effects, and fitness costs of afidopyropen resistance were studied in a field-developed resistant population of . Compared to a reference MED-S strain, the field-developed resistant Haidian (HD) population showed 36.5-fold resistance to afidopyropen. Significant reversion of resistance to afidopyropen was found in the HD population when it was kept with no selective pressure of the insecticide. The HD-Afi strain, developed from the HD population with afidopyropen pressure, developed 104.3-fold resistance to afidopyropen and significant cross-resistance to sulfoxaflor. Piperonyl butoxide (PBO) largely inhibited afidopyropen resistance in the HD-Afi strain, which indicates that P450 monooxygenase could be involved in the resistance. Significant fitness costs associated with afidopyropen resistance were observed in HD-Afi. This study indicates that a rotation of afidopyropen with other chemical control agents could be useful for impeding afidopyropen resistance in . In addition, we expanded upon the understanding of resistance to afidopyropen, offering evidence suggesting the importance of devising better strategies for the management of whiteflies.
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http://dx.doi.org/10.3390/toxins14070453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9320511PMC
July 2022

Effect of Different Membranes on Vertical Bone Regeneration: A Systematic Review and Network Meta-Analysis.

Biomed Res Int 2022 14;2022:7742687. Epub 2022 Jul 14.

The Conversationalist Club, School of Stomatology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China.

This study is aimed at performing a systematic review and a network meta-analysis of the effects of several membranes on vertical bone regeneration and clinical complications in guided bone regeneration (GBR) or guided tissue regeneration (GTR). We compared the effects of the following membranes: high-density polytetrafluoroethylene (d-PTFE), expanded polytetrafluoroethylene (e-PTFE), crosslinked collagen membrane (CCM), noncrosslinked collagen membrane (CM), titanium mesh (TM), titanium mesh plus noncrosslinked (TM + CM), titanium mesh plus crosslinked (TM + CCM), titanium-reinforced d-PTFE, titanium-reinforced e-PTFE, polylactic acid (PLA), polyethylene glycol (PEG), and polylactic acid 910 (PLA910). Using the PICOS principles to help determine inclusion criteria, articles are collected using PubMed, Web of Science, and other databases. Assess the risk of deviation and the quality of evidence using the Cochrane Evaluation Manual, and GRADE. 27 articles were finally included. 19 articles were included in a network meta-analysis with vertical bone increment as an outcome measure. The network meta-analysis includes network diagrams, paired-comparison forest diagrams, funnel diagrams, surface under the cumulative ranking curve (SUCRA) diagrams, and sensitivity analysis diagrams. SUCRA indicated that titanium-reinforced d-PTFE exhibited the highest vertical bone increment effect. Meanwhile, we analyzed the complications of 19 studies and found that soft tissue injury and membrane exposure were the most common complications.
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http://dx.doi.org/10.1155/2022/7742687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9303140PMC
July 2022

Covalent-Bonding Oxidation Group and Titanium Cluster to Synthesize a Porous Crystalline Catalyst for Selective Photo-Oxidation Biomass Valorization.

Angew Chem Int Ed Engl 2022 Jul 18:e202209289. Epub 2022 Jul 18.

School of Chemistry, South China Normal University, Guangzhou, 510006, P. R. China.

The selective photo-oxidation of biomass-derived 5-hydroxymethylfurfural (HMF) to 2,5-furandicarboxylic acid (FDCA) is important due to its substitute-role in polyester-fabrication. Here, a titanium-cluster based metal-covalent organic framework nanosheet has been synthesized through the covalent-coupling between Ti -NH and benzotrithiophene tricarbaldehyde (BTT). The integration of them endows the nanosheet with a visible-light-adsorption region, effective electron-hole separation-efficiency and suitable photo-oxidation ability. Specifically, its photo-selectivity for HMF-to-FDCA can be >95 % with ≈100 % conversion, which is more than 2, 5, and 10 times higher than MOF-901 (43 %), Ti -NH (19 %) and under-darkness (9 %), respectively. Notably, an O -based mechanism is proposed and the vital roles of Ti -NH and BTT are verified by DFT calculations. This work might facilitate the exploration of porous-crystalline-catalysts for selective biomass-valorization.
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http://dx.doi.org/10.1002/anie.202209289DOI Listing
July 2022

Evaluating the effects of air pollution control policies in China using a difference-in-differences approach.

Sci Total Environ 2022 Jul 13;845:157333. Epub 2022 Jul 13.

Institute of Geographic Sciences and Natural Resources Research, Chinese Academy of Sciences, Beijing 100101, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China.

Air pollution has caused wide concern in China, and many governance policies and plans have been implemented in recent years. Based on counterfactual quasi-natural experiments, we analyzed the implementation effects of autumn and winter air pollution control policies in the Jing-Jin-Ji region and surrounding areas using a difference-in-differences (DID) model. The control group was selected based on geographical and meteorological factors, and we analyzed the impact of the policies on six pollutants. The results show that the policies reduced air pollution overall, but not every pollutant. Due to the policy contribution, the concentrations of PM and PM in autumn and winter from 2017 to 2018 decreased by 6.9 % and 8.5 %, respectively. The numerical value of PM, PM, CO, and AQI in 2018-2019 decreased by 18.2 %, 7.2 %, 13.9 %, and 8.8 %, respectively. The role in the reduction of O, SO, and NO was not obvious. This work provides a research paradigm for evaluating the effects of atmospheric environment policy which can be applied to other studies and provide references for formulating additional policies.
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http://dx.doi.org/10.1016/j.scitotenv.2022.157333DOI Listing
July 2022

Carpel-specific downregulation of GhCKXs in cotton significantly enhances seed and fiber yield.

J Exp Bot 2022 Jul 6. Epub 2022 Jul 6.

Biotechnology Research Center, Southwest University, No. 2 Tiansheng Road, Beibei, Chongqing, 400715, P. R. China.

Cytokinin is considered to be an important driver of seed yield. To increase the yield of cotton while avoiding the negative consequences caused by constitutive overproduction of cytokinin, we carpel-specifically downregulated cytokinin oxidase/dehydrogenase (CKX), a key negative regulator of cytokinin levels, in transgenic cotton. The carpel-specific downregulation of CKXs significantly enhanced cytokinin levels in the carpels. The elevated cytokinin promoted the expression of carpel- and ovule-development associated genes, GhSTK2, GhAG1, and GhSHP, boosting ovule formation and thus producing more seeds in the ovary. Field experiments showed that the carpel-specific increase of cytokinin significantly increased both seed yield and fiber yield of cotton, without resulting in detrimental phenotypes. Our study details the regulatory mechanism of cytokinin signaling for seed development, and provides an effective and feasible strategy for the yield improvement of seed crops.
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http://dx.doi.org/10.1093/jxb/erac303DOI Listing
July 2022

Research on performance and dynamic competency evaluation of bid evaluation experts based on weight interval number.

PLoS One 2022 1;17(7):e0269467. Epub 2022 Jul 1.

Faculty of Civil Engineering and Mechanics, Kunming University of Science and Technology, Kunming, Yunnan Province, China.

Purpose/significance: In the past many years, some scholars have studied bid evaluation experts, such as the behavior of bid evaluation experts. However, previous research ignores the performance and competency of bid evaluation experts, so this paper aims to provide a theoretical basis for incentive and constraint mechanism and hierarchical or dynamic management of bid evaluation experts by implementing performance and dynamic competency evaluation of bid evaluation experts.

Method/process: Firstly, the evaluation index system of performance and dynamic competency of bid evaluation experts is preliminarily constructed by referring to relevant literature, and then the constructed evaluation index was modified and improved by consulting relevant stakeholders' experts. Secondly, considering the hesitation and consistency of expert weighting, the calculation method of expert weight coefficient and index score interval number is improved. Based on the theory of weight interval number, the corresponding mathematical optimization model is constructed to calculate the index weight according to the purpose of performance judgment and dynamic competency clustering of bid evaluation experts. Finally, the data of performance and dynamic competency of bid evaluation experts is obtained by questionnaire survey, and the empirical analysis was carried out by simulating the bid evaluation experts consistent with the actual situation.

Results/conclusion: After improving the calculation method of index score interval number, and then calculating index weight interval number through index score interval number, the length of index weight interval number can be decreased and the calculation accuracy of index weight interval number can be increased. In addition, the index weight calculated by the constructed mathematical optimization model can make the intra-class discrimination smaller and the inter-class discrimination larger. Finally, some suggestions are also provided for the management of bid evaluation experts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0269467PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9249197PMC
July 2022

Salvianolic acid A promotes mitochondrial biogenesis and function via regulating the AMPK/PGC-1α signaling pathway in HUVECs.

Exp Ther Med 2022 Jul 1;24(1):485. Epub 2022 Jun 1.

Department of Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China.

Mitochondrial dysregulation is an important pathology that leads to endothelial dysfunction, and the occurrence and development of cardiovascular diseases. Salvianolic acid A (SAA) has been demonstrated to be effective in the treatment of vascular complications of type 2 diabetes mellitus. Limited information has been reported on the effects of SAA on mitochondrial function in endothelial cells. In the present study, the effects of SAA on mitochondrial biogenesis and the related underlying mechanisms were investigated in human umbilical vein endothelial cells (HUVECs). Mitotracker red staining and transmission electron microscopy were used to evaluate the effect of SAA on mitochondrial quality. The effect of SAA treatment on mitochondrial DNA/nuclear DNA ratio of HUVECs was detected by real-time quantitative PCR. Western blot was used to determine the protein expression levels of complex III and Complex IV of mitochondrial oxidative phosphorylation subunit, and ATP production was determined by ATP test kit. Real-time quantitative PCR and Western blot were used to determine the effects of SAA on the expression of peroxisome proliferator-activated receptor γ coactivator (PGC-1α) and its target genes nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM) proteins and genes. Finally, in the presence of 5'AMP-activated protein kinase (AMPK) specific inhibitors, the expression of PGC-1α, NRF1 and TFAM proteins and the phosphorylation levels of AMPK and Acetyl CoA Carboxylase (ACC) were detected by Western blot or real-time quantitative PCR. The results showed that SAA treatment significantly promoted mitochondrial biogenesis and enhanced mitochondrial function of HUVECs. SAA significantly increased the expression levels of PGC-1α and its target genes NRF1 and (TFAM), a key regulator of mitochondrial biogenesis in HUVECs. These enhancements were accompanied by significantly increased phosphorylation of AMPK and ACC, and were significantly inhibited by specific AMPK inhibitors. These results suggest that SAA may promote mitochondrial biogenesis in endothelial cells by activating the AMPK-mediated PGC-1α/TFAM signaling pathway. These data provide new insights into the mechanism of action of SAA in treating diabetic vascular complications.
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http://dx.doi.org/10.3892/etm.2022.11412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9214604PMC
July 2022

A mechanistic investigation of the effect of dispersion phase protein type on the physicochemical stability of water-in-oil emulsions.

Food Res Int 2022 Jul 26;157:111293. Epub 2022 Apr 26.

State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi 214122, China. Electronic address:

In this study, effects of two animal-based and two plant-based proteins on the stability of W/O emulsions were evaluated. On physical stability, turbiscan stability index values showed that the trend of protein-added emulsion followed the order: whey protein isolate (WPI) < sodium caseinate (CAS) < pea protein isolation (PPI) < chickpea protein isolation (CPI). On chemical stability, the inhibition of lipid oxidation followed the order: CPI < CAS < WPI < PPI. The particle size, zeta potential, ability to increase emulsion viscosity and interfacial adsorption of proteins affected the emulsion physical stability. Among the effects of chemical stability, antioxidant properties, physical barrier effects and transition metal ion binding capacity were crucial for lipid oxidation. In improving the stability of W/O emulsions, we found great potential of CPI and PPI for the future combined application of both and to improve the stability of W/O emulsions.
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http://dx.doi.org/10.1016/j.foodres.2022.111293DOI Listing
July 2022

Blocking ERK-DAPK1 Axis Attenuates Glutamate Excitotoxicity in Epilepsy.

Int J Mol Sci 2022 Jun 7;23(12). Epub 2022 Jun 7.

Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China.

Glutamate excitotoxicity induces neuronal cell death during epileptic seizures. Death-associated protein kinase 1 (DAPK1) expression is highly increased in the brains of epilepsy patients; however, the underlying mechanisms by which DAPK1 influences neuronal injury and its therapeutic effect on glutamate excitotoxicity have not been determined. We assessed multiple electroencephalograms and seizure grades and performed biochemical and cell death analyses with cellular and animal models. We applied small molecules and peptides and knocked out and mutated genes to evaluate the therapeutic efficacy of kainic acid (KA), an analog of glutamate-induced neuronal damage. KA administration increased DAPK1 activity by promoting its phosphorylation by activated extracellular signal-regulated kinase (ERK). DAPK1 activation increased seizure severity and neuronal cell death in mice. Selective ERK antagonist treatment, DAPK1 gene ablation, and uncoupling of DAPK1 and ERK peptides led to potent anti-seizure and anti-apoptotic effects in vitro and in vivo. Moreover, a DAPK1 phosphorylation-deficient mutant alleviated glutamate-induced neuronal apoptosis. These results provide novel insight into the pathogenesis of epilepsy and indicate that targeting DAPK1 may be a potential therapeutic strategy for treating epilepsy.
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http://dx.doi.org/10.3390/ijms23126370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9223430PMC
June 2022

Occlusal Disharmony-A Potential Factor Promoting Depression in a Rat Model.

Brain Sci 2022 Jun 7;12(6). Epub 2022 Jun 7.

School and Hospital of Stomatology, Fujian Medical University, Fuzhou 350004, China.

Objectives: Patients with occlusal disharmony (OD) may be susceptible to depression. The hypothalamus-pituitary-adrenal axis, 5-HT and 5HTR in the prefrontal cortex (PFC), amygdala, and hippocampus are involved in the modulation of emotion and depression. This study investigated whether OD affects the HPA axis and 5-HT system and, subsequently, produces depression-like behaviors in rats.

Materials And Methods: OD was produced by removing 0.5 and 0.25 mm of hard tissue from the cusps of the maxillary molars in randomly selected sides of Sprague-Dawley rats. CUS involved exposure to 2 different stressors per day for 35 days. OD-, CUS-, and OD + CUS-treated groups and an untreated control group were compared in terms of behavior, endocrine status and brain histology.

Results: There were significant differences among the four groups in the behavior tests ( < 0.05), especially in the sucrose preference test, where there was a significant decrease in the OD group compared to the control group. ACTH and CORT concentrations were significantly higher in the OD + CUS group than the control group ( < 0.05). Expression of GR and 5-HTR in the PFC, amygdala and hippocampal CA1 was significantly higher in the OD, CUS and OD + CUS groups than the control group ( < 0.05).

Conclusion: OD promotes depression-like behaviors through peripheral and central pathways via the HPA axis, GR and 5-HT system.
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http://dx.doi.org/10.3390/brainsci12060747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9221239PMC
June 2022

Temporal Changes of Fish Diversity and Driver Factors in a National Nature Reserve, China.

Animals (Basel) 2022 Jun 14;12(12). Epub 2022 Jun 14.

School of Life Sciences, Nanchang University, Nanchang 330031, China.

Freshwater-fish diversity declined rapidly due to multiple anthropogenic disturbances. The loss of fish diversity often manifested itself in taxonomic homogenization over time. Knowledge of multi-faceted diversity (i.e., species, functional, and phylogenetic diversity) perspectives is important for biodiversity assessment and conservation planning. Here, we analyzed the change of the species diversity and phylogenetic diversity of fish in 2008 and 2021 as well as explored the driver factors of the biodiversity patterns in the Lushan National Nature Reserve. The results showed that the species diversity and phylogenetic diversity of fish have declined from 2008 to 2021, with five species lost over time. We found an overall homogenization trend in the fish fauna of the study area, with a 4% increase in taxonomic similarity among the rivers. Additionally, we found that community structure of fish was significantly different among the rivers, and environmental filtering was the main contributor to the phylogenetic diversity of fish in 2008 and 2021. This study provides new insight into the patterns and drivers of fish-biodiversity change in the broader Yangtze River basin and informs management efforts.
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http://dx.doi.org/10.3390/ani12121544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9219462PMC
June 2022

[Effects of chamber characteristics on CO and CH flux at the water-air interface measured by the chamber method].

Ying Yong Sheng Tai Xue Bao 2022 Jun;33(6):1563-1571

Yale-NUIST Center on Atmospheric Environment, Nanjing University of Information Science & Technology, Nanjing 210044, China.

The chamber method is widely used to measure CO and CH flux in inland water. However, the designs of chamber used in various studies are different and lack unified standards, which would affect the observation results. To clarify the impacts of chamber characteristics, including light transmittance, air pressure difference inside and outside the chamber, and gas mixing degree in the chamber, on CO and CH flux measurements at the water-air interface, we compared the effects of transparent/opaque chamber, the chamber with/without air pressure equalizing device and fan on CO and CH flux measurements in the aquaculture pond, based on the multi-channel closed dynamic chamber system. The results showed that, during the daytime in summer, compared with the transparent chamber which could measure the actual CO flux, when CO was emitted from the pond, the opaque chamber overestimated the CO flux by 90%; when CO was absorbed by the pond, the opaque chamber underestimated the CO flux by 50%. The CH diffusion flux measured by the opaque chamber was 40% lower than that measured by the transparent chamber. There was no significant difference between CO and CH flux measured by the chamber with and without air pressure equalizing device. CO flux observed by the chamber without fan had poor representativeness, being 20% higher than that observed by the chamber with fan. Moreover, CH flux emitted through different pathways could not be distinguished using the chamber without fan. Therefore, when the chamber method was used to observe the CO and CH flux at the water-air interface, the chamber shall be transparent and be installed with fan.
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http://dx.doi.org/10.13287/j.1001-9332.202206.019DOI Listing
June 2022

Autophagy Induced by Muscarinic Acetylcholine Receptor 1 Mediates Migration and Invasion Targeting Atg5 via AMPK/mTOR Pathway in Prostate Cancer.

J Oncol 2022 9;2022:6523195. Epub 2022 Jun 9.

Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, China.

Increasing numbers of researchers discovered the expression of muscarinic acetylcholine receptor 1 in human cancers, while its function in human prostate cancer is still unclear. Our present study focused on CHRM1 to clarify its role in mediating autophagy in prostate cancer. We used immunohistochemistry, western blotting, and immunofluorescence experiments to observe the expression of muscarinic acetylcholine receptor 1 both in nude mice with subcutaneous tumors and in prostate cancer cells. The autophagy was observed through transmission electron microscopy, western blotting, quantitative real-time PCR, and immunofluorescence. After that, we used lentivirus to establish CHRM1 and Atg5 knockdown models. Then, the migration and invasion abilities after knocking down muscarinic acetylcholine receptor 1 and Atg5 were detected by transwell assays. In addition, the AMPK/mTOR pathway-related targets were detected by western blotting. We found that muscarinic acetylcholine receptor 1 was abundantly expressed both in vitro and in vivo in prostate cancer. The overexpression of muscarinic acetylcholine receptor 1 positively regulated migration and invasion in tumor cells as well as the activation of autophagy. Muscarinic acetylcholine receptor 1 was highly correlated with Atg5 and activated the AMPK/mTOR signaling pathway. Downregulation of Atg5 inhibited cell autophagy in prostate cancer cells and the migration and invasion of prostate cancer cells. Meanwhile, abnormal expressions of AMPK/mTOR pathway-related proteins were found. In conclusion, the present findings indicated that muscarinic acetylcholine receptor 1 is highly expressed in prostate cancer cells and promotes cell invasion and migration of prostate cancer. Autophagy is activated in prostate cancer cells and the activation of muscarinic acetylcholine receptor 1 positively regulates autophagy in prostate cancer cells. Moreover, muscarinic acetylcholine receptor 1 induces autophagy-mediated cell migration and invasion by targeting Atg5 in prostate cancer cells via AMPK/mTOR pathway, which uncovered that regulating muscarinic acetylcholine receptor 1, identified in this study, can be a promising solution for treating prostate cancer.
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http://dx.doi.org/10.1155/2022/6523195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9203210PMC
June 2022

An unprecedented ergostane with a 6/6/5 tricyclic 13(14 → 8)abeo-8,14-seco skeleton from Talaromyces adpressus.

Bioorg Chem 2022 Jun 13;127:105943. Epub 2022 Jun 13.

Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address:

Talasterone A (1), an unprecedented 6/6/5 tricyclic 13(14 → 8)abeo-8,14-seco-ergostane steroid, together with two known congeners dankasterone B (2) and (14β,22E)-9,14-dihydroxyergosta-4,7,22-triene-3,6-dione (3), were characterized from Talaromyces adpressus. The structure of 1 with absolute configuration was elucidated based on NMR spectroscopic data and ECD calculation. Compound 2 belongs to a class of unconventional 13(14 → 8)abeo-ergostanes, which have been renewed via the 1,2-migration of C-13-C-14 bond to C-8. In addition, compound 1 represents the first example of ergostane with a tricyclic 13(14 → 8)abeo-8,14-seco-ergostane skeleton. The proposed biosynthetic pathway was established with the support of the coisolation of the known congeners from the producing organism. It is especially noteworthy that compound 1 exhibited potent anti-inflammatory activity with an IC value of 8.73 ± 0.66 μM, inhibiting the NF-κB pathway and thus reducing the production of proinflammatory cytokines.
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http://dx.doi.org/10.1016/j.bioorg.2022.105943DOI Listing
June 2022

Deep Grouping Analysis of the Altered Cervical Canal Microbiota in Intrauterine Adhesion Patients.

Reprod Sci 2022 Jun 16. Epub 2022 Jun 16.

Nanjing Maternal and Child Health Medical Institute, Women's Hospital of Nanjing Medical University (Nanjing Maternity and Child Health Care Hospital), Nanjing, China.

To deeply analyze the alterations of cervical canal microbiota in intrauterine adhesion (IUA) patients and microbiota's relation to intrauterine adhesion (IUA) severity, we prospectively enrolled 23 consecutive patients diagnosed with mild-to-severe IUA and 8 women with infertility, 3 women with submucous myomas, or 8 women with endometrial polyps, but without IUA, as non_IUA subjects. For deep grouping analysis, these enrolled women were divided into six groups, two groups, and four groups respectively. Cervical mucus was drawn from the cervical canal of each participant. The bacterial composition was identified by 16S rDNA high-throughput sequencing. For analysis of six groups, mild IUA patients had similar cervical canal microbiota diversity and composition with submucous myomas patients. Compared with mild IUA participants, patients with moderate or severe IUA had a significantly lower diversity of bacteria and higher load of Firmicutes. For analysis of two groups, IUA patients had a significantly lower diversity of bacteria and higher load of Firmicutes than non_IUA subjects. KEGG pathway function analysis showed that metabolic pathways, biosynthesis of secondary metabolites, and microbial metabolism in diverse environments were mostly enriched for these cervical canal microbiota in all enrolled patients. The severity of IUA was associated with the altered abundance of phylum Firmicutes/Acinetobacteria or genus Lactobacillus/Gardnerella in the cervical canal. Higher bacterial load but less diversity in the cervical canal may be related with the severity of IUA. The function of these cervical canal microbiota were mostly involved in metabolic pathways.
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http://dx.doi.org/10.1007/s43032-022-01006-wDOI Listing
June 2022

Anti-HIV Tigliane-Type Diterpenoids from the Aerial Parts of .

J Nat Prod 2022 06 14;85(6):1658-1664. Epub 2022 Jun 14.

School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang110016, People's Republic of China.

Tigliane-type diterpenoids have attracted much attention in drug discovery since they have been reported to exhibit remarkable biological effects, such as tumor-promoting, antineoplastic, and anti-HIV activities. In continuing our efforts to discover novel biologically important diterpenoids from species, was investigated phytochemically for the first time. As a result, four new (-) and one known () tigliane-type diterpenoid were isolated, and their structures were elucidated by spectroscopic data analysis. Tiglianes (-) showed potent anti-HIV activity against HIV-1 infection of MT4 lymphocytes with IC values of 1.1-65.4 nM.
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http://dx.doi.org/10.1021/acs.jnatprod.1c01195DOI Listing
June 2022

Intrinsically Bioactive Manganese-Eumelanin Nanocomposites Mediated Antioxidation and Anti-Neuroinflammation for Targeted Theranostics of Traumatic Brain Injury.

Adv Healthc Mater 2022 Jun 13:e2200517. Epub 2022 Jun 13.

Department of Nuclear Medicine, Daping Hospital, Army Medical University, Chongqing, 400042, China.

Overproduced reactive oxygen species and the induced oxidative stress and neuroinflammation often result in secondary injury, which is associated with unfavorable prognosis in traumatic brain injury (TBI). Unfortunately, current medications cannot effectively ameliorate the secondary injury at traumatic sites. Here, it is reported that intrinsically bioactive multifunctional nanocomposites (ANG-MnEMNPs-Cur, AMEC) mediate antioxidation and anti-neuroinflammation for targeted TBI theranostics, which are engineered by loading the neuroprotective agent curcumin on angiopep-2 functionalized and manganese doped eumelanin-like nanoparticles. After intravenous delivery, efficient AMEC accumulation is observed in lesions of TBI mice models established by controlled cortical impact method, evidenced by T -T magnetic resonance and photoacoustic dual-modal imaging. Therapeutically, AMEC effectively alleviates neuroinflammation, protects blood-brain barrier integrity, relieves brain edema, reduces brain tissue loss, and improves the cognition of TBI mice. Mechanistically, following the penetration into the traumatic tissues via angiopep-2 mediated targeting effect, the efficacy of AMEC is synergistically improved by combined functional moieties of curcumin and eumelanin. This is achieved by the alleviation of oxidative stress, inhibition of neuroinflammation via M1-to-M2 macrophage reprogramming, and promotion of neuronal regeneration. The as-developed AMEC with well-defined mechanisms of action may represent a promising targeted theranostics strategy for TBI and other neuroinflammation-associated intracranial diseases.
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http://dx.doi.org/10.1002/adhm.202200517DOI Listing
June 2022

Oxygen-Generating Hydrogels Overcome Tumor Hypoxia to Enhance Photodynamic/Gas Synergistic Therapy.

ACS Appl Mater Interfaces 2022 Jun 10;14(24):27551-27563. Epub 2022 Jun 10.

Centre for Diseases Prevention and Control of Eastern Theater, Nanjing 210002, China.

Hypoxic environment is a bottleneck of photodynamic therapy (PDT) in tumor treatment, as oxygen is the critical substrate for photosensitivity reaction. Herein, a sustained oxygen supply system based on cerium nanoparticles and hydrogel (GHCAC) was explored for enhanced synergistic PDT and gas therapy. Ceria nanoparticles were prepared as a drug carrier by self-assembly mediated by hyaluronic acid (HA), a targeting for CD44 on cervical cancer cells, followed by photosensitizer and l-arginine (l-Arg) loading. Then, the GHCAC system was developed by incorporating a prepared nanocarrier (HCePA) and O-evolving agent calcium peroxide (CaO) into the hydrogel (Gel) developed by a poloxamer. Gel in the system could moderately infiltrate HO to react with CaO and generate sustained oxygen using the catalase-like activity of HCePA. The system could efficiently alleviate hypoxia in tumor environments for up to 7 days, meeting the "once injection, repeat irradiation" strategy and enhanced PDT efficacy. Besides, the generated singlet oxygen (O) in the PDT process could also oxidize l-Arg into high concentrations of nitric oxide for synergistic gas therapy. The developed oxygen supplied and drug delivery Gel system is a new strategy for synergistic PDT/gas therapy to overcome cervical cancer.
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http://dx.doi.org/10.1021/acsami.2c02949DOI Listing
June 2022

Morroniside, a novel GATA3 binding molecule, inhibits hepatic stellate cells activation by enhancing lysosomal acid lipase expression.

Phytomedicine 2022 Aug 24;103:154199. Epub 2022 May 24.

International Institute for Translational Chinese Medicine, School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, 510006, China; Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China. Electronic address:

Background: Liver fibrosis can be easily developed into irreversible liver cirrhosis or even liver cancer. Lysosomal acid lipase (LAL), encoded by the lipase A (Lipa) gene, is a critical enzyme involved in liver fibrosis development. Morroniside, an iridoid glycoside isolated from Cornus officinalis Sieb. et Zucc., exerts hepatic protective effects. However, the mechanism of action underling the anti-liver fibrosis effects of morroniside have not been fully elucidated.

Purpose: To explore whether Lipa served as a biomarker for liver fibrosis and investigate the anti-liver fibrosis effects of morroniside and the underlying action mechanism in liver fibrosis cell models.

Methods: LAL expression was examined in the liver tissues of CCl and high-fat diet (HFD)-induced liver fibrosis animal models. α-smooth muscle actin (α-SMA) level, collagen and GATA family expressions were analyzed by Real-time PCR and Western blot. Putative transcription factor binding sites in the DNA sequences of Lipa was identified by PROMO-ALGGEN v8.3 online software and ENCODE ChIP-Seq Significance Tool. MD simulation was performed to explore the protein-ligand interaction.

Results: We found that the expression of hepatic LAL is lower in the liver fibrosis animal models than the control models. The reduced LAL expression is associated with HSCs activation, suggesting LAL is novel liver fibrosis biomarker. More importantly, our data showed that morroniside exerts anti-liver fibrosis effects in vitro. Mechanistic studies reveal that it binds to the hydrophobic sites of GATA3 and also reduces GATA3 expression, which increases LAL expression.

Conclusions: This study, for the first time, suggests LAL is a novel biomarker for liver fibrosis. Besides, morroniside exerts its anti-liver fibrosis effects by targeting GATA3 and LAL and hence inhibits HSC activation. These findings provide strong scientific evidence to support the development of morroniside as novel alternative or complementary therapeutics for liver injury prevention and treatment.
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http://dx.doi.org/10.1016/j.phymed.2022.154199DOI Listing
August 2022

Design, synthesis and bioactivity of novel naphthalimide-benzotriazole conjugates against A549 cells via targeting BCL2 G-quadruplex and inducing autophagy.

Life Sci 2022 May 18;302:120651. Epub 2022 May 18.

Lab of Chemical Biology and Molecular Drug Design, College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou, 310014, China; Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou, 310014, China. Electronic address:

Aims: In this study, a series of novel naphthalimide-benzotriazole conjugates (1a-3c) based on 1, 8-naphthalimide as a core skeleton, aiming at G-quadruplexes, were designed and synthesized, and their anti-cancer activity and mechanism were studied.

Materials And Methods: Using the CCK-8 assay, FRET melting, EMSA, CD, and molecular docking, intracellular assays, western blotting, immunofluorescence, and flow cytometry.

Key Findings: By the CCK-8 assay, it was found that the compound, 2-(3-(piperazin-1-yl)propyl)-6-(1H-benzo [d][1,2,3]triazol-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (3a), has better activity against A549 cells. Through extracellular assays, including FRET melting, EMSA, CD, and molecular docking, results showed that 3a selectively interacted with BCL2 G-quadruplex(es). Further studies by intracellular assays, including western blotting, immunofluorescence, flow cytometry, etc., verified that 3a mediated the death of A549 cells by two pathways: inhibition of the expression of the BCL2 gene, causing tumor cell apoptosis, and promotion of genetic instability, causing autophagy. This study suggests that the type of compounds, in particular, 3a, may be a potential molecule to explore for BCL2 G-quadruplex-targeted drugs against lung cancer.

Significance: Our findings demonstrate that compound 3a as a BCL2 G-quadruplex ligand induces DNA damage, autophagy, and apoptosis in A549 cells. This study provides us with a type of lead compound as an anti-tumor drug.
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http://dx.doi.org/10.1016/j.lfs.2022.120651DOI Listing
May 2022

A Machine Learning Model Based on PET/CT Radiomics and Clinical Characteristics Predicts Tumor Immune Profiles in Non-Small Cell Lung Cancer: A Retrospective Multicohort Study.

Front Immunol 2022 29;13:859323. Epub 2022 Apr 29.

Department of Nuclear Medicine, Daping Hospital, Army Medical University, Chongqing, China.

Background: The tumor immune microenvironment (TIME) phenotypes have been reported to mainly impact the efficacy of immunotherapy. Given the increasing use of immunotherapy in cancers, knowing an individual's TIME phenotypes could be helpful in screening patients who are more likely to respond to immunotherapy. Our study intended to establish, validate, and apply a machine learning model to predict TIME profiles in non-small cell lung cancer (NSCLC) by using F-FDG PET/CT radiomics and clinical characteristics.

Methods: The RNA-seq data of 1145 NSCLC patients from The Cancer Genome Atlas (TCGA) cohort were analyzed. Then, 221 NSCLC patients from Daping Hospital (DPH) cohort receivedF-FDG PET/CT scans before treatment and CD8 expression of the tumor samples were tested. The Artificial Intelligence Kit software was used to extract radiomic features of PET/CT images and develop a radiomics signature. The models were established by radiomics, clinical features, and radiomics-clinical combination, respectively, the performance of which was calculated by receiver operating curves (ROCs) and compared by DeLong test. Moreover, based on radiomics score (Rad-score) and clinical features, a nomogram was established. Finally, we applied the combined model to evaluate TIME phenotypes of NSCLC patients in The Cancer Imaging Archive (TCIA) cohort (n = 39).

Results: TCGA data showed CD8 expression could represent the TIME profiles in NSCLC. In DPH cohort, PET/CT radiomics model outperformed CT model (AUC: 0.907 vs. 0.861, = 0.0314) to predict CD8 expression. Further, PET/CT radiomics-clinical combined model (AUC = 0.932) outperformed PET/CT radiomics model (AUC = 0.907, = 0.0326) or clinical model (AUC = 0.868, = 0.0036) to predict CD8 expression. In the TCIA cohort, the predicted CD8-high group had significantly higher immune scores and more activated immune pathways than the predicted CD8-low group ( = 0.0421).

Conclusion: Our study indicates that F-FDG PET/CT radiomics-clinical combined model could be a clinically practical method to non-invasively detect the tumor immune status in NSCLCs.
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http://dx.doi.org/10.3389/fimmu.2022.859323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9105942PMC
April 2022

Peptide PDHPS1 Inhibits Ovarian Cancer Growth through Disrupting YAP Signaling.

Mol Cancer Ther 2022 07;21(7):1160-1170

Department of Gynecology, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, Jiangsu, China.

The lives of patients with ovarian cancer are threatened largely due to metastasis and drug resistance. Endogenous peptides attract increasing attention in oncologic therapeutic area, a few antitumor peptides have been approved by the FDA for clinical use over the past decades. However, only few peptides or peptide-derived drugs with antiovarian cancer effects have been identified. Here we focused on the biological roles and mechanism of a peptide named PDHPS1 in ovarian cancer development. Our results indicated that PDHPS1 reduced the proliferation ability of ovarian cancer cells in vitro and inhibited the ovarian cancer growth in vivo. Peptide pull down and following mass spectrometry, Western blot and qRT-PCR revealed that PDHPS1 could bind to protein phosphatase 2 phosphatase activator (PTPA), an essential activator of protein phosphatase 2A (PP2A), which resulted in increase of phosphorylated YAP, further inactivated YAP, and suppressed the expression of its downstream target genes. Flow cytometry, cell membrane permeability test, and IHC staining study demonstrated that there were no observable side effects of PDHPS1 on normal ovarian epithelium and hepatorenal function. Besides, modification of membrane penetration could improve the physicochemical properties and biological activity of PDHPS1. In conclusion, our study demonstrated that the endogenous peptide PDHPS1 serves as an antitumor peptide to inhibit YAP signaling pathway though interacting with PTPA in ovarian cancer.
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http://dx.doi.org/10.1158/1535-7163.MCT-21-0848DOI Listing
July 2022

Melatonin ameliorates tau-related pathology via the miR-504-3p and CDK5 axis in Alzheimer's disease.

Transl Neurodegener 2022 05 9;11(1):27. Epub 2022 May 9.

Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, 350122, Fujian, China.

Background: Intracellular accumulation of the microtubule-associated protein tau and its hyperphosphorylated forms is a key neuropathological feature of Alzheimer's disease (AD). Melatonin has been shown to prevent tau hyperphosphorylation in cellular and animal models. However, the molecular mechanisms by which melatonin attenuates tau hyperphosphorylation and tau-related pathologies are not fully understood.

Methods: Immunofluorescence, immunoblotting analysis and thioflavin-S staining were employed to examine the effects of early and late treatment of melatonin on tau-related pathology in hTau mice, in which nonmutated human tau is overexpressed on a mouse tau knockout background. High-throughput microRNA (miRNA) sequencing, quantitative RT-PCR, luciferase reporter assay and immunoblotting analysis were performed to determine the molecular mechanism.

Results: We found that both early and late treatment of melatonin efficiently decreased the phosphorylation of soluble and insoluble tau at sites related to AD. Moreover, melatonin significantly reduced the number of neurofibrillary tangles (NFTs) and attenuated neuronal loss in the cortex and hippocampus. Furthermore, using miRNA microarray analysis, we found that miR-504-3p expression was upregulated by melatonin in the hTau mice. The administration of miR-504-3p mimics dramatically decreased tau phosphorylation by targeting p39, an activator of the well-known tau kinase cyclin-dependent kinase 5 (CDK5). Compared with miR-504-3p mimics alone, co-treatment with miR-504-3p mimics and p39 failed to reduce tau hyperphosphorylation.

Conclusions: Our results suggest for the first time that melatonin alleviates tau-related pathologies through upregulation of miR-504-3p expression by targeting the p39/CDK5 axis and provide novel insights into AD treatment strategies.
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http://dx.doi.org/10.1186/s40035-022-00302-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9082841PMC
May 2022
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