ABSTRACT
Mildewed tobacco leaves seriously impact on cigarette product quality and pose a health risk to person. However, early moldy tobacco leaves are hardly found by naked eyes in the workshop. In this work, we self-assemble AuAg nanoalloys on silicon wafers to construct Si/AuAg chips. The headspace-surface enhanced Raman scattering (SERS) protocol is developed to monitor volatile 1,2-dichloro-3-methoxybenzene (2,3-DCA) and 2,4,6-trichloroanisole (2,4,6-TCA) released from postharvest tobacco. Consequently, the visualization of the SERS peak at 1592 cm-1 assigned to ν(CC) after headspace collection for 10 min and the SERS intensity ratio of 1054 and 1035 cm-1 from 2,3-DCA and 2,4,6-TCA less than 0.5 could be used as indicators to predict early moldy tobacco. Additionally, with headspace collection time prolonging to 2 h, a SERS band at 682 cm-1 due to ν(CCl) of 2,4,6-TCA occurs, confirming the mildew of leaves. The headspace-SERS protocol paves a path for rapid and on-site inspection of the quality of tobacco leaves and cigarettes during storage with a portable Raman system.
ABSTRACT
Efficient global optimization is a widely used method for optimizing expensive black-box functions. In this paper, we study the worst-case oracle complexity of the efficient global optimization problem. In contrast to existing kernel-specific results, we derive a unified lower bound for the oracle complexity of efficient global optimization in terms of the metric entropy of a ball in its corresponding reproducing kernel Hilbert space. Moreover, we show that this lower bound nearly matches the upper bound attained by non-adaptive search algorithms, for the commonly used squared exponential kernel and the Matérn kernel with a large smoothness parameter ν. This matching is up to a replacement of d/2 by d and a logarithmic term logRϵ, where d is the dimension of input space, R is the upper bound for the norm of the unknown black-box function, and ϵ is the desired accuracy. That is to say, our lower bound is nearly optimal for these kernels.
ABSTRACT
Bazi Bushen (BZBS), a traditional Chinese medicine (TCM), has demonstrated therapeutic efficacy in testicular dysfunction within D-galactose and NaNO2 mouse models. This study aimed to ascertain if BZBS could also mitigate the decline in testicular function associated with natural aging. Therefore, male aged mice were employed to evaluate the preventive effects of BZBS on male reproductive aging. This was achieved by assessing sex hormone production, testicular histomorphology, and spermatogenesis. Relative to the untreated aged control group, BZBS administration elevated the levels of sex hormones and spermatocyte populations and preserved normal testicular structure in aged mice. Notably, spermatogenesis was maintained. Further analyses, including malondialdehyde (MDA) assays and real-time PCR, indicated that BZBS diminished testicular oxidative stress and the inflammatory burden. Corroborating these findings, mice treated with BZBS exhibited reductions in the populations of senescent and apoptotic cells within the seminiferous tubules, suggesting alleviated cellular damage. In contrast, we observed that rapamycin, a drug known for its longevity benefits, induced excessive testicular apoptosis and did not decrease lipid peroxidation. Collectively, our results highlight BZBS's promising clinical potential in counteracting male reproductive aging, underlining its mechanisms of action.
Subject(s)
Aging , Drugs, Chinese Herbal , Oxidative Stress , Spermatogenesis , Testis , Animals , Male , Mice , Aging/drug effects , Drugs, Chinese Herbal/pharmacology , Testis/drug effects , Testis/metabolism , Oxidative Stress/drug effects , Spermatogenesis/drug effects , Reproduction/drug effects , Apoptosis/drug effects , Humans , Malondialdehyde/metabolism , Gonadal Steroid Hormones/metabolismABSTRACT
BACKGROUND: Chronic inflammation and metabolic dysfunction are key features of systemic aging, closely associated with the development and progression of age-related metabolic diseases. Bazi Bushen (BZBS), a traditional Chinese medicine used to alleviate frailty, delays biological aging by modulating DNA methylation levels. However, the precise mechanism of its anti-aging effect remains unclear. In this study, we developed the Energy Expenditure Aging Index (EEAI) to estimate biological age. By integrating the EEAI with transcriptome analysis, we aimed to explore the impact of BZBS on age-related metabolic dysregulation and inflammation in naturally aging mice. METHODS: We conducted indirect calorimetry analysis on five groups of mice with different ages and utilized the data to construct EEAI. 12 -month-old C57BL/6 J mice were treated with BZBS or ß-Nicotinamide Mononucleotide (NMN) for 8 months. Micro-CT, Oil Red O staining, indirect calorimetry, RNA sequencing, bioinformatics analysis, and qRT-PCR were performed to investigate the regulatory effects of BZBS on energy metabolism, glycolipid metabolism, and inflammaging. RESULTS: The results revealed that BZBS treatment effectively reversed the age-related decline in energy expenditure and enhanced overall metabolism, as indicated by the aging index of energy expenditure derived from energy metabolism parameters across various ages. Subsequent investigations showed that BZBS reduced age-induced visceral fat accumulation and hepatic lipid droplet aggregation. Transcriptomic analysis of perirenal fat and liver indicated that BZBS effectively enhanced lipid metabolism pathways, such as the PPAR signaling pathway, fatty acid oxidation, and cholesterol metabolism, and improved glycolysis and mitochondrial respiration. Additionally, there was a significant improvement in inhibiting the inflammation-related arachidonic acid-linoleic acid metabolism pathway and restraining the IL-17 and TNF inflammatory pathways activated via senescence associated secretory phenotype (SASP). CONCLUSIONS: BZBS has the potential to alleviate inflammation in metabolic organs of naturally aged mice and maintain metabolic homeostasis. This study presents novel clinical therapeutic approaches for the prevention and treatment of age-related metabolic diseases.
ABSTRACT
Collision of a replication fork with a DNA nick is thought to generate a one-ended break, fostering genomic instability. Collision of the opposing converging fork with the nick could, in principle, form a second DNA end, enabling conservative repair by homologous recombination (HR). To study mechanisms of nickase-induced HR, we developed the Flp recombinase "step arrest" nickase in mammalian cells. Flp-nickase-induced HR entails two-ended, BRCA2/RAD51-dependent short tract gene conversion (STGC), BRCA2/RAD51-independent long tract gene conversion, and discoordinated two-ended invasions. HR induced by a replication-independent break and by the Flp-nickase differ in their dependence on BRCA1 . To determine the origin of the second DNA end during Flp-nickase-induced STGC, we blocked the opposing fork using a site-specific Tus/ Ter replication fork barrier. Flp-nickase-induced STGC remained robust and two-ended. Thus, collision of a single replication fork with a Flp-nick can trigger two-ended HR, possibly reflecting replicative bypass of lagging strand nicks. This response may limit genomic instability during replication of a nicked DNA template.
ABSTRACT
We design a p-aminothiophenol (pATP) modified Au/ITO chip to determine nitrite ions in lake water by a ratiometric surface-enhanced Raman scattering (SERS) method based on nitrite ions triggering the transformation of pATP to p,p'-dimercaptoazobenzene (DMAB). Intriguingly, by using the SERS peak (at 1008 cm-1) from benzoic ring deforming as an internal standard instead of the traditional peak at 1080 cm-1, the detection sensitivity of the method was improved 10 times.
ABSTRACT
Hydrogen peroxide (H2O2) residue in foodstuffs will bring great harm to human health. We immobilize the composite of the reduced polyaniline (PANIR) modified gold nanoparticles on the surface of ITO (ITO/AuNPs/PANIR) to develop surface-enhanced Raman scattering (SERS) sensor for H2O2.detection. The principle is that PANIR is oxidized by H2O2 to generate a new SERS peak at 1460 cm-1 for realizing quantitative analysis of H2O2. Fe2+-Fenton reaction is introduced to catalytically react with H2O2 to hydroxyl radical, which speeds up the oxidation of PANIR. Before SERS detection, acidic treatment could guarantee the reduced state of PANIR in composite. Limit of detection of ITO/AuNPs/PANIR-based SERS assay for H2O2 is down to 1.78 × 10-12 mol/L and a good linear relationship from 1 × 10-10 to 3.16 × 10-7 mol/L is achieved. Furthermore, the SERS sensor could be regenerated by acidic treatment. As a scenario, the renewable SERS sensor is utilized to monitor H2O2 residues in food and environmental samples.
Subject(s)
Gold , Metal Nanoparticles , Humans , Gold/chemistry , Hydrogen Peroxide , Metal Nanoparticles/chemistry , Spectrum Analysis, Raman , FoodABSTRACT
Particle counting serves as a pivotal constituent in diverse analytical domains, encompassing a broad spectrum of entities, ranging from blood cells and bacteria to viruses, droplets, bubbles, wear debris, and magnetic beads. Recent epochs have witnessed remarkable progressions in microfluidic chip technology, culminating in the proliferation and maturation of microfluidic chip-based particle counting methodologies. This paper undertakes a taxonomical elucidation of microfluidic chip-based particle counters based on the physical parameters they detect. These particle counters are classified into three categories: optical-based counters, electrical-based particle counters, and other counters. Within each category, subcategories are established to consider structural differences. Each type of counter is described not only in terms of its working principle but also the methods employed to enhance sensitivity and throughput. Additionally, an analysis of future trends related to each counter type is provided.
ABSTRACT
Bazi Bushen (BZBS), a traditional Chinese medicine, has been proven effective in the treatment of age-related disease in mouse models. However, whether its therapeutic effects are due to antiaging mechanism has not yet been explored. In the present study, we investigated the antiaging effects of BZBS in naturally aging mice by using behavioral tests, liver DNA methylome sequencing, methylation age estimation, and frailty index assessment. The methylome analysis revealed a decrease of mCpG levels in the aged mouse liver. BZBS treatment tended to restore age-associated methylation decline and prune the methylation pattern toward that of young mice. More importantly, BZBS significantly rejuvenated methylation age of the aged mice, which was computed by an upgraded DNA methylation clock. These results were consistent with enhanced memory and muscular endurance, as well as decreased frailty score and liver pathological changes. KEGG analysis together with aging-related database screening identified methylation-targeted pathways upon BZBS treatment, including oxidative stress, DNA repair, MAPK signaling, and inflammation. Upregulation of key effectors and their downstream effects on elevating Sod2 expression and diminishing DNA damage were further investigated. Finally, in vitro experiments with senescent HUVECs proved a direct effect of BZBS extracts on the regulation of methylation enzymes during cellular aging. In summary, our work has revealed for the first time the antiaging effects of BZBS by slowing the methylation aging. These results suggest that BZBS might have great potential to extend healthspan and also explored the mechanism of BZBS action in the treatment of age-related diseases.
Subject(s)
Epigenesis, Genetic , Frailty , Animals , Mice , Frailty/genetics , Aging/genetics , DNA Methylation , Cellular SenescenceABSTRACT
This paper proposes Attribute-Decomposed GAN (ADGAN) and its enhanced version (ADGAN++) for controllable image synthesis, which can produce realistic images with desired attributes provided in various source inputs. The core ideas of the proposed ADGAN and ADGAN++ are both to embed component attributes into the latent space as independent codes and thus achieve flexible and continuous control of attributes via mixing and interpolation operations in explicit style representations. The major difference between them is that ADGAN processes all component attributes simultaneously while ADGAN++ utilizes a serial encoding strategy. More specifically, ADGAN consists of two encoding pathways with style block connections and is capable of decomposing the original hard mapping into multiple more accessible subtasks. In the source pathway, component layouts are extracted via a semantic parser and the segmented components are fed into a shared global texture encoder to obtain decomposed latent codes. This strategy allows for the synthesis of more realistic output images and the automatic separation of un-annotated component attributes. Although the original ADGAN works in a delicate and efficient manner, intrinsically it fails to handle the semantic image synthesizing task when the number of attribute categories is huge. To address this problem, ADGAN++ employs the serial encoding of different component attributes to synthesize each part of the target real-world image, and adopts several residual blocks with segmentation guided instance normalization to assemble the synthesized component images and refine the original synthesis result. The two-stage ADGAN++ is designed to alleviate the massive computational costs required when synthesizing real-world images with numerous attributes while maintaining the disentanglement of different attributes to enable flexible control of arbitrary component attributes of the synthesized images. Experimental results demonstrate the proposed methods' superiority over the state of the art in pose transfer, face style transfer, and semantic image synthesis, as well as their effectiveness in the task of component attribute transfer. Our code and data are publicly available at https://github.com/menyifang/ADGAN.
ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Obesity is a critical threat to global health, and brown adipose tissue (BAT) is a potential target for the treatment of obesity and comorbidities. Xuezhikang Capsule (XZK), an extract of red yeast rice, has remarkable clinical efficacy and is widely used for the treatment of hyperlipidemia and coronary heart disease. However, its modulatory effect on BAT remains unknown. AIM OF THIS STUDY: The aim of this study was to investigate the protective mechanism of XZK in the obese spontaneously hypertensive rat (SHR) model by evaluating the regulatory effect of XZK on the BAT gene profile through transcriptome sequencing. MATERIALS AND METHODS: The SHRs were randomly divided into four groups: the standard chow diet (STD) group, the STD supplemented with 126 mg/kg of XZK group, the high-fat diet (HFD) group, and the HFD supplemented with 126 mg/kg of XZK group. All SHRs were fed for 18 weeks. The metabolic phenotypes, including body weight, fat mass, oral glucose tolerance test (OGTT), and serum glucose and lipid levels, was evaluated, and hematoxylin and eosin staining (H&E) staining was performed to evaluate the adipose tissue histopathological phenotype. Transcriptome sequencing was performed to determine the mechanism by which XZK improves the metabolic phenotype and the expression of key differential expression genes was verified by real-time quantitative polymerase chain reaction (qRT-PCR). RESULTS: XZK inhibited HFD-induced weight gain and adipose tissue remodeling in SHRs and prevented hypertrophy of epididymal adipocytes and maintained the brown fat phenotype. XZK intervention also improved glucose and lipid metabolism in SHRs, as suggested by a reduction in serum triglyceride (TG), low-density cholesterol (LDL-C), and fasting blood glucose (FBG) levels as well as increasing in serum high-density cholesterol (HDL-C) levels. Transcriptome sequencing analysis confirmed the regulatory effect of XZK on the gene expression profile of BAT, and the expression patterns of 45 genes were reversed by the XZK intervention. Additionally, the results of the transcriptome analysis of 10 genes that are important for brown fat function were in line with the results of qRT-PCR. CONCLUSIONS: XZK protected SHRs from HFD-induced obesity, inhibited fat accumulation and improved glucolipid metabolism. Additionally, the protective effect of XZK on the overall metabolism of obese SHRs might partly be related to its regulatory effect on the BAT gene expression profile. These findings might provide novel therapeutic strategies for obesity-related metabolic diseases in traditional Chinese medicine (TCM).
Subject(s)
Drugs, Chinese Herbal , Obesity , Animals , Rats , Adipose Tissue, Brown/drug effects , Adipose Tissue, Brown/metabolism , Cholesterol , Diet, High-Fat , Glucose , Metabolic Diseases/prevention & control , Mice, Inbred C57BL , Obesity/complications , Obesity/drug therapy , Obesity/metabolism , Rats, Inbred SHR , Transcriptome , Drugs, Chinese Herbal/pharmacology , Disease Models, Animal , Humans , MiceABSTRACT
Purpose: The senescence-accelerated prone mouse 8 (SAMP8) is a widely used model for accelerating aging, especially in central aging. Mounting evidence indicates that the microbiota-gut-brain axis may be involved in the pathogenesis and progression of central aging-related diseases. This study aims to investigate whether Bazi Bushen capsule (BZBS) attenuates the deterioration of the intestinal function in the central aging animal model. Methods: In our study, the SAMP8 mice were randomly divided into the model group, the BZ-low group (0.5 g/kg/d BZBS), the BZ-high group (1 g/kg/d BZBS) and the RAPA group (2 mg/kg/d rapamycin). Age-matched SAMR1 mice were used as the control group. Next, cognitive function was detected through Nissl staining and two-photon microscopy. The gut microbiota composition of fecal samples was analyzed by 16S rRNA gene sequencing. The Ileum tissue morphology was observed by hematoxylin and eosin staining, and the intestinal barrier function was observed by immunofluorescence. The expression of senescence-associated secretory phenotype (SASP) factors, including P53, TNF-α, NF-κB, IL-4, IL-6, and IL-10 was measured by real-time quantitative PCR. Macrophage infiltration and the proliferation and differentiation of intestinal cells were assessed by immunohistochemistry. We also detected the inflammasome and pyroptosis levels in ileum tissue by western blotting. Results: BZBS improved the cognitive function and neuronal density of SAMP8 mice. BZBS also restored the intestinal villus structure and barrier function, which were damaged in SAMP8 mice. BZBS reduced the expression of SASP factors and the infiltration of macrophages in the ileum tissues, indicating a lower level of inflammation. BZBS enhanced the proliferation and differentiation of intestinal cells, which are essential for maintaining intestinal homeostasis. BZBS modulated the gut microbiota composition, by which BZBS inhibited the activation of inflammasomes and pyroptosis in the intestine. Conclusion: BZBS could restore the dysbiosis of the gut microbiota and prevent the deterioration of intestinal barrier function by inhibiting NLRP3 inflammasome-mediated pyroptosis. These results suggested that BZBS attenuated the cognitive aging of SAMP8 mice, at least partially, by targeting the microbiota-gut-brain axis.
ABSTRACT
Microhomology-mediated end joining (MMEJ) is a highly mutagenic pathway to repair double-strand breaks (DSBs). MMEJ was thought to be a backup pathway of homologous recombination (HR) and canonical nonhomologous end joining (C-NHEJ). However, it attracts more attention in cancer research due to its special function of microhomology in many different aspects of cancer. In particular, it is initiated with DNA end resection and upregulated in homologous recombination-deficient cancers. In this review, I summarize the following: (1) the recent findings and contributions of MMEJ to genome instability, including phenotypes relevant to MMEJ; (2) the interaction between MMEJ and other DNA repair pathways; (3) the proposed mechanistic model of MMEJ in DNA DSB repair and a new connection with microhomology-mediated break-induced replication (MMBIR); and (4) the potential clinical application by targeting MMEJ based on synthetic lethality for cancer therapy.
Subject(s)
DNA Breaks, Double-Stranded , DNA End-Joining Repair , Humans , DNA Repair/genetics , Homologous Recombination , Genomic Instability , DNA/metabolismABSTRACT
A specific surface-enhanced Raman scattering (SERS) assay for dopamine (DA) based on an azo derivatization reaction is proposed for the first time by preparation of p-aminothiophenol (PATP)-modified composite SERS substrate, composed of metal-organic framework (MIL-101) decorated with Au and Ag nanoparticles. As the result, the SERS method for detection of the azo reaction between PATP and DA exhibits superior sensitivity, selectivity, and stability. A reasonable linearity in the range 10-6 to 10-10 molâL-1 is achieved, and the limit of detection is 1.2 × 10-12 molâL-1. The reactive SERS assay is free from interference in complex physiological fluid. The feasibility of the proposed SERS method for the detection of DA levels in fetal bovine serum (FBS) samples and human serum samples is validated by HPLC-MS methods, displaying promising application potential in early disease diagnosis.
Subject(s)
Metal Nanoparticles , Metal-Organic Frameworks , Aniline Compounds , Dopamine , Humans , Silver , Sulfhydryl CompoundsABSTRACT
PURPOSE: To evaluate longitudinal changes in subfoveal choroidal thickness (SFChT) among children receiving atropine 0.05%, 0.025%, or 0.01% over 2 years and their associations with treatment outcomes in myopia control. DESIGN: Double-blinded randomized controlled trial. METHODS: SFChT was measured at 4-month intervals using spectral domain optical coherence tomography. Cycloplegic spherical equivalent (SE), axial length (AL), best-corrected visual acuity, parental SE, outdoor time, near work diopter hours, and treatment compliance were also measured. RESULTS: 314 children were included with qualified choroidal data. The 2-year changes in SFChT from baseline were 21.15 ± 32.99 µm, 3.34 ± 25.30 µm, and -0.30 ± 27.15 µm for the atropine 0.05%, 0.025%, and 0.01% groups, respectively (P < .001). A concentration-dependent response was observed, with thicker choroids at higher atropine concentrations (ß = 0.89, P < .001). Mean SFChT thickness significantly increased at 4 months in the atropine 0.025% (P = .001) and 0.05% groups (P < .001) and then remained stable until the end of the second year (P > .05 for all groups). Over 2 years, an increase in SFChT was associated with slower SE progression (ß = 0.074, P < .001) and reduced AL elongation (ß = -0.045, P < .001). In the mediation analysis, 18.45% of the effect on SE progression from atropine 0.05% was mediated via its choroidal thickening. CONCLUSIONS: Low concentration atropine induced a choroidal thickening effect along a concentration-dependent response throughout the treatment period. The choroidal thickening was associated with a slower SE progression and AL elongation among all the treatment groups. Choroidal response can be used for assessment of long-term treatment outcomes and as a guide for concentration titrations of atropine.
Subject(s)
Atropine , Myopia , Atropine/therapeutic use , Axial Length, Eye , Child , Choroid , Humans , Myopia/diagnosis , Myopia/drug therapy , Refraction, Ocular , Tomography, Optical CoherenceABSTRACT
Retinoblastoma is the most common intraocular cancer in childhood. Loss of function in both copies of the RB1 gene is the causal mutation of retinoblastoma. Current treatment for retinoblastoma includes the use of chemotherapeutic agents, such as the DNA damaging agent etoposide, which is a topoisomerase II poison that mainly generates DNA double-strand breaks (DSBs) and genome instability. Unfaithful repairing of DSBs could lead to secondary cancers and serious side effects. Previously, we found that RB knocked-down mammalian cells depend on a highly mutagenic pathway, the micro-homology mediated end joining (MMEJ) pathway, to repair DSBs. Poly ADP ribose polymerase 1 (PARP1) is a major protein in promoting the MMEJ pathway. In this study, we explored the effects of olaparib, a PARP inhibitor, in killing retinoblastoma cells. Retinoblastoma cell line Y79 and primary retinoblastoma cells expressed the cone-rod homeobox protein (CRX), a photoreceptor-specific marker. No detectable RB expression was found in these cells. The co-treatment of olaparib and etoposide led to enhanced cell death in both the Y79 cells and the primary retinoblastoma cells. Our results demonstrated the killing effects in retinoblastoma cells by PARP inhibitor olaparib after inducing DNA double-strand breaks. The use of olaparib in combination with etoposide could improve the cell-killing effects. Thus, lower dosages of etoposide can be used to treat retinoblastoma, which would potentially lead to a lower level of DSBs and a relatively more stable genome.
Subject(s)
DNA End-Joining Repair/drug effects , Phthalazines/pharmacology , Piperazines/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Recombinational DNA Repair/drug effects , Retinoblastoma Protein/deficiency , Retinoblastoma/genetics , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , DNA Breaks, Double-Stranded , Dose-Response Relationship, Drug , Etoposide/pharmacology , Humans , Retinoblastoma/metabolismABSTRACT
Abuse of tobramycin (TOB) causes a series of diseases. Therefore, the development of rapid and sensitive method for analyzing TOB in food products is necessary. In this work, aptamer modified SnO2/Bi2S3-based photoelectrochemical (PEC) sensor was developed for the determination of TOB in milk. Under optimal condition, a wide linear response for TOB from 5 to 50 nmol/L with a limit of detection of 4.28 nmol/L is reached. The possible detection mechanism is that TOB molecules are specifically captured by aptamer, increasing electron transfer resistance and declining the photocurrent. Thanks to the favorably matched energy level of SnO2, and Bi2S3, the PEC aptasensor exhibits high sensitivity, and with the aid of oxalate, the sensitivity of the sensor is further improved. Importantly, the stability of the PEC aptasensor is also satisfactory due to the calcination of SnO2/Bi2S3 at 450 °C.
Subject(s)
Aptamers, Nucleotide/metabolism , Biosensing Techniques/methods , Bismuth/chemistry , Limit of Detection , Milk/chemistry , Sulfides/chemistry , Tin Compounds/chemistry , Tobramycin/analysis , Animals , Electrochemical Techniques/methods , Electrochemistry , Food Analysis , Photochemical Processes , Tobramycin/metabolismABSTRACT
Inactivation of the retinoblastoma tumor suppressor gene (RB1) leads to genome instability, and can be detected in retinoblastoma and other cancers. One damaging effect is causing DNA double strand breaks (DSB), which, however, can be repaired by homologous recombination (HR), classical non-homologous end joining (C-NHEJ), and micro-homology mediated end joining (MMEJ). We aimed to study the mechanistic roles of RB in regulating multiple DSB repair pathways. Here we show that HR and C-NHEJ are decreased, but MMEJ is elevated in RB-depleted cells. After inducing DSB by camptothecin, RB co-localizes with CtIP, which regulates DSB end resection. RB depletion leads to less RPA and native BrdU foci, which implies less end resection. In RB-depleted cells, less CtIP foci, and a lack of phosphorylation on CtIP Thr847, are observed. According to the synthetic lethality principle, based on the altered DSB repair pathway choice, after inducing DSBs by camptothecin, RB depleted cells are more sensitive to co-treatment with camptothecin and MMEJ blocker poly-ADP ribose polymerase 1 (PARP1) inhibitor. We propose a model whereby RB can regulate DSB repair pathway choice by mediating the CtIP dependent DNA end resection. The use of PARP1 inhibitor could potentially improve treatment outcomes for RB-deficient cancers.
Subject(s)
DNA Breaks, Double-Stranded , DNA Repair , Retinoblastoma Protein/metabolism , Signal Transduction , DNA End-Joining Repair , Homologous Recombination , Humans , Phosphorylation , Poly (ADP-Ribose) Polymerase-1/antagonists & inhibitors , Poly (ADP-Ribose) Polymerase-1/metabolism , Retinoblastoma Protein/geneticsABSTRACT
In this work, an S hybrid nanosheet with multiple functions is synthesized by in situ modification of gold nanoparticles (AuNPs) onto two-dimensional (2D) metalloporphyrinic metal-organic framework (MOF) (Cu-tetra(4-carboxyphenyl)porphyrin chloride(Fe(III)), designated as AuNPs/Cu-TCPP(Fe). Cu-TCPP(Fe) nanosheets contribute peroxidase-like activity, and AuNPs have glucose oxidase (GOx) mimicking performance, which induce the cascade catalysis reactions to convert glucose into hydrogen peroxide (H2O2), and then, by using AuNP catalysis, H2O2 oxidizes the no Raman-active leucomalachite green (LMG) into the Raman-active malachite green (MG). Simultaneously, in the presence of AuNPs, sensitive and selective surface-enhanced Raman scattering (SERS) determination of glucose can be achieved. The bioenzyme-free SERS assay based on such AuNPs/Cu-TCPP(Fe) nanosheets is used for detection of glucose in saliva, showing good recovery from 96.9 to 100.8%. The work paves a new way to design a nanozyme-based SERS protocol for biomolecule analysis.
Subject(s)
Glucose/analysis , Metal Nanoparticles/chemistry , Metal-Organic Frameworks/chemistry , Nanostructures/chemistry , Spectrum Analysis, Raman/methods , Biomimetic Materials/chemistry , Catalysis , Glucose/chemistry , Glucose Oxidase/chemistry , Gold/chemistry , Humans , Hydrogen Peroxide/chemistry , Oxidation-Reduction , Oxygen/chemistry , Porphyrins/chemistry , Saliva/metabolismABSTRACT
Heart failure (HF) has been known as a global health problem, and cardiac remodeling plays an essential role in the development of HF. We hypothesized that YQWY decoction might exert a cardioprotective effect against myocardium inflammation, fibrosis, and apoptosis via activating the interleukin-10 (IL-10)/Stat3 signaling pathway. To test this hypothesis, the HF model in rats was established by pressure overload through the minimally invasive transverse aortic constriction (MTAC). Echocardiography was performed to assess the left ventricular function of rats. Myocardial fibrosis in rats was observed by Masson and Picrosirius red staining, and the degree of myocardial apoptosis was detected via TUNEL staining. In addition, expression levels of IL-10, tumor necrosis factor-α (TNF-α), Stat3 (P-Stat3), P65 (P-P65), CD68, collagen I, TGF-ß, CTGF, Bax, Bcl-2, cleaved caspase-3, and PARP in rat serum and myocardium samples were examined by ELISA, western blot, and immunohistochemistry, respectively. YQWY decoction treatment significantly improved left ventricular function in HF rats, especially in those of the high-dose group (LVEF%: 51.29 ± 5.876 vs. 66.02 ± 1.264, P < 0.01;, LVFS%: 27.75 ± 3.757 vs. 37.76 ± 1.137, P < 0.01). Furthermore, YQWY decoction markedly inhibited MTAC-induced myocardial fibrosis as evidenced by downregulated collagen I, TGF-ß, and CTGF in myocardium and alleviated apoptosis (downregulated caspase-3 and PARP and increased Bcl-2/Bax ratio in cardiomyocytes). In addition, YQWY decoction decreased the level of the proinflammatory cytokine TNF-α in both circulating blood and myocardium and attenuated infiltration of inflammatory cells in heart tissue from HF rats. Most importantly, YQWY decoction suppressed MTAC-induced NF-κB activation and phosphorylated Stat3 by upregulating IL-10 in rat heart tissues. Our study showed that YQWY decoction could attenuate MTAC-induced myocardial inflammation, fibrosis, apoptosis, and reverse the impairment of cardiac function in rats by activating the IL-10/Stat3 signaling pathway and improving myocardium remodeling. Our findings suggested a therapeutic potential of YQWY decoction in HF.