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1.
J Biol Chem ; : 100759, 2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-33965375

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19 global pandemic, utilizes the host receptor angiotensin-converting enzyme 2 (ACE2) for viral entry. However, other host factors might also play important roles in SARS-CoV-2 infection, providing new directions for antiviral treatments. GRP78 is a stress-inducible chaperone important for entry and infectivity for many viruses. Recent molecular docking analyses revealed putative interaction between GRP78 and the receptor binding domain (RBD) of the SARS-CoV-2 Spike protein (SARS-2-S). Here we report that GRP78 can form a complex with SARS-2-S and ACE2 on the surface and at the perinuclear region typical of the endoplasmic reticulum in VeroE6-ACE2 cells, and that the substrate binding domain of GRP78 is critical for this interaction. In vitro binding studies further confirmed that GRP78 can directly bind to the RBD of SARS-2-S and ACE2. To investigate the role of GRP78 in this complex, we knocked down GRP78 in VeroE6-ACE2 cells. Loss of GRP78 markedly reduced cell surface ACE2 expression and led to activation of markers of the unfolded protein response. Treatment of lung epithelial cells with a humanized monoclonal antibody (hMAb159) selected for its safe clinical profile in preclinical models, depleted cell surface GRP78 and reduced cell surface ACE2 expression, as well as SARS-2-S-driven viral entry and SARS-CoV-2 infection in vitro. Our data suggest that GRP78 is an important host auxiliary factor for SARS-CoV-2 entry and infection and a potential target to combat this novel pathogen and other viruses that utilize GRP78 in combination therapy.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33966163

RESUMO

The blast furnace casthouse is a typical heavy-polluting factory building of a steel enterprise. During the tapping process and the taphole opening, the dust concentration in the factory building's workroom can reach tens of thousands mg/m3. Over time, the air pollutants in the workplace can have unwanted consequences on employees' health. This paper selected a typical blast furnace tapping workshop. The flow, temperature, and soot concentration fields in the workshop are measured on site during tapping, and the distribution characteristics are obtained. The performance of the tapping smoke exhaust system is analyzed based on computational fluid dynamics. The findings are as follows: the concentration of PM2.5 in most of the work area was 80µg/m3, but the concentration reached 1mg/m3 near the slag ditch, which was heavy pollution. Because the opening and closing of doors and windows was unreasonable, it was difficult for the particulate matter to accumulate in the deep and middle of the plant discharge. The PMV of the worker's work area is about 3, and the waste heat removal efficiency is 4.2. Hence, this article's finding provides a scientific basis for optimizing the air distribution in the blast furnace cast house's workplace.

3.
Blood ; 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33971010

RESUMO

The mechanism underlying cell type-specific gene induction conferred by ubiquitous transcription factors as well as disruptions caused by their chimeric derivatives in leukemia is not well understood. Here we investigate whether RNAs coordinate with transcription factors to drive myeloid gene transcription. In an integrated genome-wide approach surveying for gene loci exhibiting concurrent RNA- and DNA-interactions with the broadly expressed transcription factor RUNX1, we identified the long noncoding RNA LOUP. This myeloid-specific and polyadenylated lncRNA induces myeloid differentiation and inhibits cell growth, acting as a transcriptional inducer of the myeloid master regulator PU.1. Mechanistically, LOUP recruits RUNX1 to both the PU.1 enhancer and the promoter, leading to the formation of an active chromatin loop. In t(8;21) acute myeloid leukemia, wherein RUNX1 is fused to ETO, the resulting oncogenic fusion protein RUNX1-ETO limits chromatin accessibility at the LOUP locus, causing inhibition of LOUP and PU.1 expression. These findings highlight the important role of the interplay between cell type-specific RNAs and transcription factors as well as their oncogenic derivatives in modulating lineage-gene activation and raise the possibility that RNA regulators of transcription factors represent alternative targets for therapeutic development.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33908140

RESUMO

This work reported the rational design of single-atom metal-insulator-semiconductor (SMIS) heterojunctions based on earth-abundant Sn-doped hematite nanorods (SF NRs) for high-rate, efficient CO 2 -to-syngas conversion and unveiled the details of dielectric field-assisted hole-tunneling dynamics at the SMIS heterojunctions. The results showed that the RuO x -Al 2 O 3 -Sn-Fe 2 O 3 photoanode (SMIS-3), which was prepared by a combined methodology of atomic deposition of 3.0 nm thick Al 2 O 3 overlayer with chemical grafting of atomically-dispersed RuO x hole-collectors, gives an incident photon-to-current conversion efficiency of 52.0% under 370 nm light irradiation in 0.1 M neutral phosphate buffer solution at 1.2 V vs Ag/AgCl, >5-fold larger than that of the bare SF NRs photoanode. The characterization results clearly indicated that the dielectric field mediated the charge dynamics at the Al 2 O 3 /SF NRs interface. The accumulation of long-lived holes on the surface of the SF NRs photoabsorber facilitates the fast tunneling transfer of hot holes to atomically-dispersed RuO x species, accelerating the O 2 -evolving reaction kinetics in the photoreaction compartment of PV-coupled artificial photosynthetic cells. Accordingly, a maximal CO-evolution rate of 265.3 mmol•g -1 •h -1 was achieved by integration of double SIMS-3 photoanodes with a single-atom Ni-doped graphene CO 2 -reduction-catalyst cathode, and an impressive overall quantum efficiency of 5.7% was recorded under 450 nm light irradiation.

5.
Biol Trace Elem Res ; 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33851329

RESUMO

As a highly toxic heavy metal, chromium has caused a certain threat to public health and livestock breeding in recent years. In poultry, as one of our most commonly consumed meat product, its health issues will seriously threaten the safety of human life. As previous studies have confirmed, when cells are stimulated by the external environment, mitochondria, as an organelle that provides energy to the cells, can cause damage and autophagy. The purpose of this study is to confirm whether Cr(VI) can cause mitophagy in cock heart. We first randomly divided 32 cocks into four groups to explore the mechanism of this effect. The cocks were then separately exposed to four different dose levels, namely, the control level and 10, 30, and 50 mg/kg levels, via daily oral intake into the body through mixed feeding for 45 days. After 45 days, we sampled and detected pathological changes and the levels of inflammatory factors (IL-6, TNF-α, and IFN-γ), mitochondrial membrane potential (MMP), adenosine triphosphatases (ATPases), and mitophagy-related proteins (LC3, p62/SQTM1, TOMM20, and Parkin). We found that IL-6, TNF-α, IFN-γ, and LC3II contents increased with the increase in Cr(VI) concentration. However, MMP, ATPases, p62/SQTM1, and TOMM20 levels decreased with the increase in Cr(VI) concentration. At the same time, Cr(VI) exposure caused heart tissue damages and Parkin translocation. In conclusion, our results proved that inflammatory damage, mitochondrial function damage, and mitophagy in cock heart tissues were dependent on Cr(VI) concentration.

6.
Huan Jing Ke Xue ; 42(5): 2121-2132, 2021 May 08.
Artigo em Chinês | MEDLINE | ID: mdl-33884781

RESUMO

In order to study the pollution characteristics and causes of winter haze pollution in Beijing, a typical PM2.5 pollution process in Beijing in December 2019 was used as the analysis object using aerosol vertical detection data, boundary layer meteorological field and near-ground turbulence data, and the difference in haze. The characteristics of the pollution stage and the evolution of the physical and chemical characteristics of the boundary layer were comprehensively analyzed. The results showed that ① the pollution process in Beijing during the observation period lasted 5 d and experienced two generations and eliminations. The maximum hourly PM2.5 concentration was 220 µg·m-3 and the time exceeding the severe pollution standard was 64 h, thereby accounting for 53% of the total time. ② The aerosol optical properties and meteorological field observation data showed that the pollution originated from the regional transmission of aerosols and water vapor on the surface of the southwest urban agglomeration in Beijing, which accounted for 48% of the total pollution transmission, followed by a stable high-altitude situation and ground pressure field configuration. The near-surface layer maintained weak southerly winds (wind speed: 1-2 m·s-1), a strong inversion temperature close to the ground ï¼»0.8 K·(100 m)-1ï¼½, high humidity (relative humidity above 80%), and other unfavorable diffusion weather conditions, thereby promoting the accumulation of pollutants and the conversion of moisture absorption. Superimposing local pollution emissions were the main reasons for the maintenance of haze days. In addition, the near-ground extinction coefficient increased from 0.070 km-1 to 5.954 km-1, and the depolarization ratio decreased from 0.05 to 0.02 during the two pollution generation and disappearance processes, thereby indicating that the spherical characteristics of aerosols gradually became significant as the pollution increased. ③ The analysis of the turbulence observation data showed that the characteristic quantities of different pollution stages were significantly different and negatively correlated with the pollutant concentration. Before the occurrence of heavy pollution, the turbulence statistics (turbulence intensity, friction velocity, and turbulent kinetic energy) suddenly decreased from high values (the hourly variation rate was 77%, thereby far exceeding the daily fluctuation of 33%), and the turbulence intensity responded first. During the pollution accumulation stage, the friction velocity (0.04-0.21 m·s-1), turbulence intensity (average: 0.678 m2·s-2), and turbulence energy (average: 0.643 m2·s-2) were maintained at a low level, and the bottom atmosphere had a poor mixing and diffusion ability, which is important for continuous pollution accumulation. Four hours before the end of the pollution event, the turbulence intensity again showed a sharp increase (increment of more than one order of magnitude); thus, the turbulence intensity can be used as a predictive indicator of the occurrence and end of a heavy pollution event, and the response time is the same as the continuous turbulence intensity after the turbulence peak. In addition, the sensible heat fluxes on sunny days and haze days were both transported from the ground to the atmosphere, and showed clear daily single-peak changes. The sensible heat flux on haze days (20 W·m-2) was smaller than that on sunny days (60 W·m-2). The latent heat flux was approximately 0 W·m-2 in the whole process. ④ There was a feedback effect between the meteorological conditions of the pollution layer and the boundary layer. On the one hand, unfavorable diffusion of the meteorological conditions was conducive to the accumulation of pollution. On the other hand, the aerosol layer and water vapor cooling effect that accumulated near the ground were worse than the night cooling radiation on the inversion layer The contribution was greater, thereby further inhibiting the development of turbulent motion and ultimately resulting in increased pollution.

7.
J Nanobiotechnology ; 19(1): 98, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33827604

RESUMO

BACKGROUND: Nano-Fenton reactors as novel strategy to selectively convert hydrogen peroxide (H2O2) into active hydroxyl radicals in tumor microenvironment for cancer therapy had attracted much attention. However, side effects and low efficiency remain the main drawbacks for cancer precise therapy. RESULTS: Here, ruthenium-loaded palmitoyl ascorbate (PA)-modified mesoporous silica (Ru@SiO2-PA) was successfully fabricated and characterized. The results indicated that Ru@SiO2-PA under pH6.0 environment displayed enhanced growth inhibition against human cancer cells than that of pH7.4, which indicated the super selectivity between cancer cells and normal cells. Ru@SiO2-PA also induced enhanced cancer cells apoptosis, followed by caspase-3 activation and cytochrome-c release. Mechanism investigation revealed that Ru@SiO2-PA caused enhanced generation of superoxide anion, which subsequently triggered DNA damage and dysfunction of MAPKs and PI3K/AKT pathways. Moreover, Ru@SiO2-PA effectively inhibited tumor spheroids and tumor xenografts growth in vivo by induction of apoptosis. The real-time imaging by monitoring Ru fluorescence in vitro and in vivo revealed that Ru@SiO2-PA mainly accumulated in cell nucleus and tumor xenografts. Importantly, Ru@SiO2-PA showed no side effects in vivo, predicting the safety and potential application in clinic. CONCLUSIONS: Our findings validated the rational design that Ru@SiO2-PA can act as novel tumor microenvironment-response nano-Fenton reactors for cancer precise therapy.

8.
Plant Biol (Stuttg) ; 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33721388

RESUMO

Global warming results in high temperature stress (HTS), which presents severe challenges for the worldwide modern agricultural production and will have significant impacts on the yield and quality of crops. Accumulation of photosynthetic products, activities of the sucrose-starch metabolism related enzymes, phytohormone levels and metabolic profiling using LC-MS were analysed in the flag leaves and/or the in the developing grains treated with HTS during the grain filling stage of an indica-rice. HTS induced significant yield loss, and caused grain quality reduction with less amylose contents. HTS reduced photosynthetic product accumulation in flag leaves and less starch accumulation in the developing grains, compared to that under normal temperatures. The activities of sucrose-starch metabolism related enzymes were dis-regulated in developing grains grown under HT. Moreover, phytohormone homeostasis in the flag leaves and developing grains was also dramatically disturbed by HT. Metabolic profiling detected many metabolites had remarkably different relative fold abundances at different timepoints in the developing grains under HT versus those under normal temperatures, these metabolites enriched in different HTS-responding pathways. The changed phytohormone ratio and auxin levels might associate with the reduced photosynthetic product and its translocation, and ultimately reduced starch accumulation in the developing grains. The detected metabolites might play different roles in responding to the influence of HTS in developing grains at different development stages. These results provide theoretical reference and the basis for regulation of rice production with higher quality and yields when grown under HT.

9.
Int Immunopharmacol ; 95: 107480, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33676148

RESUMO

Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist, which can regulate inflammatory responses. However, whether DEX interferes with the inflammation resolving remains unclear. Here, we reported the effects of DEX on zymosan-induced generalized inflammation in mice during resolution. Mice were administered intraperitoneally with DEX after the initiation of sepsis. The resolution interval (Ri), a vital resolution indice, decreased from twelve hours to eight hours after the administration of DEX. The induction of peritoneal pro-inflammatory interleukin [IL] - 1ß and tumour necrosis factor-α (TNF-α) appeared to be inhibited. Of interest, the anti-inflammatory transforming growth factor-ß1 (TGF-ß1) but not IL-10 levels were up-regulated at twenty-four hours in the DEX group along with 1.0 mg/mice zymosan A (ZyA) treatment. The expression levels of multiple genes related to protective immune processes and clearance functions were detected and revealed the same trends. DEX markedly increased the F4/80+Ly6G+ macrophage population. Additionally, the adequate apoptotic neutrophil clearance from injury after DEX installation could be reverse by opsonization or co-instillation of TGF-ß1 neutralizing antibody in vivo, promoting the inflammation-resolution programs. In conclusion, DEX post-treatment, via the increase of F4/80+Ly6G+ macrophages, provokes further secretion of TGF-ß1, leading to the attenuated cytokine storm and accelerated inflammation resolving.

10.
ACS Nano ; 15(4): 6645-6657, 2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33787219

RESUMO

The synthesis of stimuli-responsive hybrid structures composed of drug-loaded UiO-66 metal-organic framework nanoparticles, NMOFs, locked by DNA tetrahedra gates is presented. The hybrid systems combine the high loading capacity of drugs in the porous NMOFs and the effective cell permeation properties of the DNA tetrahedra. The nucleic acid-functionalized UiO-66 NMOFs are loaded with drugs (doxorubicin, DOX, or camptothecin, CPT) or with dyes as drug models (Rhodamine 6G or fluorescein) and used to prepare stimuli-responsive carriers. In this study, two different stimuli-responsive NMOFs are presented. One system introduces the drug-loaded NMOFs locked by pH-responsive DNA tetrahedra. At acidic pH values, the gating tetrahedra are dissociated from the NMOFs through the formation of i-motif structures, resulting in the unlocking of the NMOFs and the release of the drugs. In addition, the tetrahedra gates are modified with AS1411 aptamer tethers, and these target the drug-loaded NMOFs to nucleolin receptors overexpressed in certain malignant cells. A second system involves the preparation of NMOFs loaded with drugs/dyes and gated by the microRNA (miRNA)-responsive tetrahedra (miRNA-21 or miRNA-155). In the presence of miRNAs, the dissociation of miRNA-responsive tetrahedra from the NMOFs leads to the unlocking of the NMOFs and the release of the loads. Further developments of the miRNA-responsive tetrahedra-gated hybrid carriers include the following. (i) By appropriate engineering of the miRNA gating units, the exonuclease III (Exo III)-amplified unlocking of the carriers, through the regeneration of the miRNA triggers, and the enhanced release of the loaded drugs are demonstrated. (ii) By applying mixtures of miRNA-21-responsive DNA tetrahedra-gated DOX-loaded NMOFs and miRNA-155-responsive DNA tetrahedra-gated CPT-loaded NMOFs, the multiplexed miRNA-21/miRNA-155-dictated release of the drugs is demonstrated. As compared to the analog DNA duplex-modified NMOFs, DNA tetrahedra-gated, drug-loaded NMOFs permeation into malignant MDA-MB-231 breast cancer cells presents more effective cell permeation. Effective and selective cytotoxicity toward the malignant cells, as compared to nonmalignant epithelial MCF-10A breast cells, is demonstrated due to the acidic pH, present in cancer cells, or the miRNA-21, present in MDA-MB-231 malignant cells.

11.
BMC Womens Health ; 21(1): 99, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33676505

RESUMO

BACKGROUND: The present study aims to use two different kinds of filling materials, oxidized regenerated cellulose and gelatin sponge, to repair defects of breast-conserving surgery due to breast cancer, and compare the clinical efficacy, cosmetic effect and complication rate among groups. METHODS: A total of 125 patients, who had breast -conserving surgery due to breast cancer, were enrolled into the present study. Postoperative efficacy was assessed by a doctor and patient, according to the Harvard/NSABP/RTOG Breast Cosmetic Grading Scale. RESULTS: Among these patients, 41 patients received conventional breast-conserving surgery, and 84 patients received breast-conserving surgery plus filling implantation (41 patients in the oxidized regenerated cellulose group and 43 patients in the gelatin sponge group). All patients had small to medium sized breasts (cup size A and B). The average weight of tumor tissues was 56.61 ± 11.57 g in the conventional breast-conserving surgery group, 58.41 ± 8.53 g in the oxidized regenerated cellulose group, and 58.77 ± 9.90 g in the gelatin sponge group. The difference in pathological factors, average operation time, length of stay and local infection rate was not statistically significant among the three groups. 18 patients in the oxidized regenerated cellulose group and 15 patients in the gelatin sponge group were evaluated to have a good cosmetic effect by the surgeon and patient, while 12 patients in the conventional breast-conserving surgery group were evaluated to be have good cosmetic effect by the surgeon and patient. The cosmetic effects in the oxidized regenerated cellulose group and gelatin sponge group were comparable, and these were superior to those in the conventional breast-conserving surgery group. CONCLUSION: The use of oxidized regenerated cellulose and gelatin sponge is a feasible approach for defect repair after breast-conserving surgery.

12.
Medicine (Baltimore) ; 100(12): e25017, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33761657

RESUMO

ABSTRACT: Overweight and obesity may be associated with poor clinical outcome, including chronic kidney disease (CKD). However, whether body mass index (BMI), waist-to-hip ratio (WHR), and waist circumference (WC) are related to CKD is yet to be elucidated.A total of 7593 adults were divided into 4 groups based on the estimated glomerular filtration rate (eGFR) quartile. The eGFR was calculated with the CKD Epidemiology Collaboration. Multiple linear regression analyzed the association between eGFR and WHR, BMI, and WC. Logistic regression analysis determined whether the CKD patients were associated with WHR, BMI, and WC after adjusting for other variables.The mean age of the cohort was 72.34 ±â€Š7.30 years. Multiple linear regression analysis showed that WC (P = .006) was associated with eGFR, although adjusted by lifestyle factor and biochemical indicators. The individuals in the underweight, overweight, and obese groups had significantly lower eGFR value than those in the healthy weight group in moderate CKD. The eGFR in the overweight group with WHR ≤0.894 was higher than in the healthy weight group with WHR >0.894 group (P = .036). Overweight with WHR ≤0.894 group had a longer WC with a pronounced increase in the hip circumference. Logistic regression analysis showed that the WC (OR = 1.362, P < .001) and BMI (OR = 1.227, P = .031) were independent risk factors for moderate CKD patients. Each standard deviation (SD) of high BMI and WC level was associated with 23.0% and 17.3% higher odds of moderate CKD (OR = 1.230, P = .017 and OR = 1.173, P = .021, respectively).WC is an independent risk factor for eGFR. Combined BMI and WC are important factors that would predict moderate CKD patients.


Assuntos
Índice de Massa Corporal , Insuficiência Renal Crônica/diagnóstico , Circunferência da Cintura , Relação Cintura-Quadril , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Taxa de Filtração Glomerular , Humanos , Estilo de Vida , Modelos Logísticos , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Sobrepeso/fisiopatologia , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Magreza/fisiopatologia , Adulto Jovem
13.
Zhongguo Zhong Yao Za Zhi ; 46(6): 1311-1331, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33787127

RESUMO

Kudzu plants in the subfamily sphenoideae of Leguminosae are commonly used herbs in China, Japan, Korea, India and Thailand, with a long history of medicinal use. They are recorded in Chinese Pharmacopoeia, Japanese Pharmacopeia, Korea Pharmacopeia, Ayurveda Pharmacopoeia of India and Flora of Thailand. There are 15-20 species of Pueraria in the world, including 7 species and 2 varieties in China. At present, there are 6 species with medicinal value, such as Pueraria lobata and P. thomsonii. The main chemical components of the genus are isoflavones, flavonoids, terpenes, steroids, coumarins, puerarin glycosides and benzopyrans. A total of 240 compounds have been isolated and identified from this genus, and their pharmacological effects mainly include improvement of the cardiovascular system, antioxidant, hypoglycemic, antipyretic, anti-inflammatory, anti-alcoholic and estrogen-like effects. In this study, chemical constituents and pharmacological activities of Pueraria at home and abroad were systematically summarized, in order to provide references for the material basis, quality control and further development of Pueraria genus.


Assuntos
Isoflavonas , Pueraria , China , Isoflavonas/farmacologia , Japão , Raízes de Plantas , República da Coreia , Tailândia
14.
Mol Hum Reprod ; 27(3)2021 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-33599278

RESUMO

Human zygotes are difficult to obtain for research because of limited resources and ethical debates. Corrected human tripronuclear (ch3PN) zygotes obtained by removal of the extra pronucleus from abnormally fertilized tripronuclear (3PN) zygotes are considered an alternative resource for basic scientific research. In the present study, eight-cell and blastocyst formation efficiency were significantly lower in both 3PN and ch3PN embryos than in normal fertilized (2PN) embryos, while histone H3 lysine 9 trimethylation (H3K9me3) levels were much higher. It was speculated that the aberrant H3K9me3 level detected in ch3PN embryos may be related to low developmental competence. Microinjection of 1000 ng/µl lysine-specific demethylase 4A (KDM4A) mRNA effectively reduced the H3K9me3 level and significantly increased the developmental competence of ch3PN embryos. The quality of ch3PN zygotes improved as the grading criteria, cell number and pluripotent expression significantly increased in response to KDM4A mRNA injection. Developmental genes related to zygotic genome activation (ZGA) were also upregulated. These results indicate that KDM4A activates the transcription of the ZGA program by enhancing the expression of related genes, promoting epigenetic modifications and regulating the developmental potential of ch3PN embryos. The present study will facilitate future studies of ch3PN embryos and could provide additional options for infertile couples.

15.
Clin Cancer Res ; 27(8): 2352-2366, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33542077

RESUMO

PURPOSE: Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors (NAMPTi) are currently in development, but may be limited as single-agent therapy due to compound-specific toxicity and cancer metabolic plasticity allowing resistance development. To potentially lower the doses of NAMPTis required for therapeutic benefit against acute myeloid leukemia (AML), we performed a genome-wide CRISPRi screen to identify rational disease-specific partners for a novel NAMPTi, KPT-9274. EXPERIMENTAL DESIGN: Cell lines and primary cells were analyzed for cell viability, self-renewal, and responses at RNA and protein levels with loss-of-function approaches and pharmacologic treatments. In vivo efficacy of combination therapy was evaluated with a xenograft model. RESULTS: We identified two histone deacetylases (HDAC), HDAC8 and SIRT6, whose knockout conferred synthetic lethality with KPT-9274 in AML. Furthermore, HDAC8-specific inhibitor, PCI-34051, or clinical class I HDAC inhibitor, AR-42, in combination with KPT-9274, synergistically decreased the survival of AML cells in a dose-dependent manner. AR-42/KPT-9274 cotreatment attenuated colony-forming potentials of patient cells while sparing healthy hematopoietic cells. Importantly, combined therapy demonstrated promising in vivo efficacy compared with KPT-9274 or AR-42 monotherapy. Mechanistically, genetic inhibition of SIRT6 potentiated the effect of KPT-9274 on PARP-1 suppression by abolishing mono-ADP ribosylation. AR-42/KPT-9274 cotreatment resulted in synergistic attenuation of homologous recombination and nonhomologous end joining pathways in cell lines and leukemia-initiating cells. CONCLUSIONS: Our findings provide evidence that HDAC8 inhibition- or shSIRT6-induced DNA repair deficiencies are potently synergistic with NAMPT targeting, with minimal toxicity toward normal cells, providing a rationale for a novel-novel combination-based treatment for AML.

16.
Colloids Surf B Biointerfaces ; 201: 111627, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33639510

RESUMO

As a first-line tuberculostatic drug, isoniazid (INH) plays effective and irreplaceable role in prevention and treatment of tuberculosis. In this work, a rapid and simple signal-on fluorescence approach is established for INH assay by employing a platform composed of silver nanoclusters (AgNCs) and MnO2 nanosheets. In the proposed sensing system, strong red fluorescence of poly (methacrylic acid)-stabilized AgNCs can be greatly quenched after they attach to the surfaces of MnO2 nanosheets. With the addition of INH, MnO2 nanosheets are reduced to Mn2+ and subsequently release the AgNCs, which leads to obvious fluorescence recovery again. Based on this mechanism, highly sensitive detection of INH in the range of 0.8-200 µM is realized (detection limit: 476 nM). The present strategy shows remarkable advantages including simplicity, rapidness, high sensitivity and wide detectable range. This method is also practical and comparable to high-performance liquid chromatography, which can be applied to detect INH in human urine and serum samples as well as pharmaceutical products.

17.
Eur J Drug Metab Pharmacokinet ; 46(2): 265-275, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33576936

RESUMO

BACKGROUND AND OBJECTIVE: At present, the deficiency of ß-cell function is progressive in patients with type 2 diabetes mellitus. Exenatide cannot only control blood glucose well, but also promotes the regeneration and proliferation of islet ß-cells and improves the function of ß cells. However, it needs to be given twice a day, and there are many adverse reactions such as nausea. PEGylated exenatide (study code: PB-119) needs to be administered only once a week. The purpose of this experiment was to evaluate the safety, pharmacokinetics and pharmacodynamics of an escalating dose regimen of subcutaneous PEGylated exenatide injections in healthy subjects. METHODS: Twelve healthy young adult subjects in each group received once-weekly subcutaneous injections of 165 µg, 330 µg, and 660 µg PEGylated exenatide for 6 weeks. Plasma drug concentration was determined in venous blood collected across selected time points. Safety and tolerability were evaluated by monitoring adverse events, laboratory parameters, and electrocardiogram. Blood glucose, insulin,  glucagon and C peptide were monitored at different time points to evaluate the pharmacodynamics of PEGylated exenatide. RESULTS: A total of 11, 10, and 12 subjects completed the study in 165 µg, 330 µg, and 660 µg dose groups, respectively. After 6 consecutive weeks of administration, the t1/2 in the 165 µg, 330 µg, and 660 µg dose groups was 55.67 ± 11.03 h, 56.99 ± 21.37 h, and 54.81 ± 13.87 h, respectively. The Cavg was 4.22 ± 0.78 ng/ml, 6.03 ± 1.43 ng/ml, and 10.50 ± 3.06 ng/ml, respectively. AUCss was 708.59 ± 131.87 h•ng/ml, 1012.63 ± 240.79 h•ng/ml, and 1763.81 ± 514.50 h•ng/ml, respectively. The accumulation index was 1.15 ± 0.07, 1.17 ± 0.11, and 1.14 ± 0.07. The CLss/F was 241.25 ± 51.13 ml/h, 341.53 ± 73.62 ml/h, and 450.06 ± 313.76 ml/h, respectively. A total of 10 of 36 (27.78%) subjects in the three dose groups developed specific antibodies after consecutive subcutaneous injections of PEGylated exenatide. The Cavg and Cmax were higher than those of antibody-negative subjects. Furthermore, in antibody-positive subjects, CLss/F, t1/2, AUCτ, accumulation index, MRT(0-inf) and other parameters were lower than those of antibody-negative subjects. In the 165 µg dose group, two subjects (16.67%) experienced 4 adverse events. In the 330 µg dose group, no subjects reported adverse events. In the 660 µg dose group, 8 subjects (66.67%) reported 16 adverse events, which were mostly gastrointestinal. There were no significant changes in the pharmacodynamic parameters except the glucagon level at day 36 in the 660 µg dose group, the 2h postprandial insulin and C peptide levels at day 36 and day 50 in the 165 µg dose group compared with baseline (- 1 day). CONCLUSION: A once-weekly subcutaneous injection of 165 µg and 330 µg PEGylated exenatide is safe. No significant effects on blood glucose or pancreatic hormone levels were observed in the subjects within these dose groups. The pharmacokinetic parameters of PEGylated exenatide may be affected by immunogenicity. CLINICAL TRIALS REGISTRATION: The study is registered at clinicaltrials.gov (No. NCT03062774).

18.
Sci Rep ; 11(1): 1399, 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33446805

RESUMO

SHP2 is a ubiquitous tyrosine phosphatase involved in regulating both tumor and immune cell signaling. In this study, we discovered a novel immune modulatory function of SHP2. Targeting this protein with allosteric SHP2 inhibitors promoted anti-tumor immunity, including enhancing T cell cytotoxic function and immune-mediated tumor regression. Knockout of SHP2 using CRISPR/Cas9 gene editing showed that targeting SHP2 in cancer cells contributes to this immune response. Inhibition of SHP2 activity augmented tumor intrinsic IFNγ signaling resulting in enhanced chemoattractant cytokine release and cytotoxic T cell recruitment, as well as increased expression of MHC Class I and PD-L1 on the cancer cell surface. Furthermore, SHP2 inhibition diminished the differentiation and inhibitory function of immune suppressive myeloid cells in the tumor microenvironment. SHP2 inhibition enhanced responses to anti-PD-1 blockade in syngeneic mouse models. Overall, our study reveals novel functions of SHP2 in tumor immunity and proposes that targeting SHP2 is a promising strategy for cancer immunotherapy.

19.
Aging (Albany NY) ; 13(2): 2727-2749, 2020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33373318

RESUMO

Oxybenzone (OBZ), an ultraviolet light filter that is widely used in sunscreens and cosmetics, is an emerging contaminant found in humans and the environment. Recent studies have shown that OBZ has been detected in women's plasma, urine, and breast milk. However, the effects of OBZ exposure on oocyte meiosis have not been addressed. In this study, we investigated the detrimental effects of OBZ on oocyte maturation and the protective roles of melatonin (MT) in OBZ-exposed mouse models. Our in vitro and in vivo results showed that OBZ suppressed oocyte maturation, while MT attenuated the meiotic defects induced by OBZ. In addition, OBZ facilitated H3K4 demethylation by increasing the expression of the Kdm5 family of genes, elevating ROS levels, decreasing GSH, impairing mitochondrial quality, and disrupting spindle configuration in oocytes. However, MT treatment resulted in significant protection against OBZ-induced damage during oocyte maturation and improved oocyte quality. The mechanisms underlying the beneficial roles of MT involved reduction of oxidative stress, inhibition of apoptosis, restoration of abnormal spindle assembly and up-regulation of H3K4me3. Collectively, our results suggest that MT protects against defects induced by OBZ during mouse oocyte maturation in vitro and in vivo.

20.
Artigo em Inglês | MEDLINE | ID: mdl-33188514

RESUMO

In iron and steel industry, sintering process releases large amount and different kinds of pollutants. Most sintering plants had applied the dust removal system and the flue gas desulfurization (FGD) system for exhaust treatment in China. Previous studies of FGD systems were focused on the removal of air pollutants from coal-fired boiler, rather than in the iron ore sintering process. In this study, PM, heavy metals, and dioxins were sampled at a China typical sintering plant with both wet and semi-dry FGDs. The results showed that the PM removal efficiencies of the wet and semi-dry FGDs were 29.44% and 22.28%, respectively. The size distributions of PM were at the range of 0.7~4.7 µm in the inlet flue gases of both FGDs. The overall removal efficiencies of heavy metals were above 65%. In both outlet flue gases, Pb as the most elements accounted for 93.33% of total at the wet FGD, while Pb, Cr, and Zn accounted for 76.34% at the semi-dry FGD. The proportions of gaseous heavy metals in the inlets of both FGDs were improved than those in the outlets. Furthermore, the total emission amounts of dioxins in both inlets and outlets of the flue gases were 0.0385 ng-TEQ/m3 and 0.0248 ng-TEQ/m3 at the wet FGD and 0.0078 ng-TEQ/m3 and 0.0050 ng-TEQ/m3 at the semi-dry FGD, respectively. The overall removal efficiencies of dioxins were all above 35%. The polychlorinated dibenzofurans (PCDFs) ratio in the dioxins lightly increased from 84.46 to 88.80% through wet FGD, while it decreased from 80.83 to 44.35% in semi-dry FGD.

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