RESUMO
The cell interior is packed with macromolecules of mesoscale size, and this crowded milieu significantly influences cellular physiology. Cellular stress responses almost universally lead to inhibition of translation, resulting in polysome collapse and release of mRNA. The released mRNA molecules condense with RNA-binding proteins to form ribonucleoprotein (RNP) condensates known as processing bodies and stress granules. Here, we show that polysome collapse and condensation of RNA transiently fluidize the cytoplasm, and coarse-grained molecular dynamic simulations support this as a minimal mechanism for the observed biophysical changes. Increased mesoscale diffusivity correlates with the efficient formation of quality control bodies (Q-bodies), membraneless organelles that compartmentalize misfolded peptides during stress. Synthetic, light-induced RNA condensation also fluidizes the cytoplasm. Together, our study reveals a functional role for stress-induced translation inhibition and formation of RNP condensates in modulating the physical properties of the cytoplasm to enable efficient response of cells to stress conditions.
Assuntos
Citoplasma , Polirribossomos , Ribonucleoproteínas , Polirribossomos/metabolismo , Citoplasma/metabolismo , Humanos , Ribonucleoproteínas/metabolismo , Ribonucleoproteínas/genética , Simulação de Dinâmica Molecular , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Biossíntese de Proteínas , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Condensados Biomoleculares/metabolismo , Grânulos de Estresse/metabolismo , Grânulos de Estresse/genéticaRESUMO
Phase separation can concentrate biomolecules and accelerate reactions. However, the mechanisms and principles connecting this mesoscale organization to signaling dynamics are difficult to dissect because of the pleiotropic effects associated with disrupting endogenous condensates. To address this limitation, we engineered new phosphorylation reactions within synthetic condensates. We generally found increased activity and broadened kinase specificity. Phosphorylation dynamics within condensates were rapid and could drive cell-cycle-dependent localization changes. High client concentration within condensates was important but not the main factor for efficient phosphorylation. Rather, the availability of many excess client-binding sites together with a flexible scaffold was crucial. Phosphorylation within condensates was also modulated by changes in macromolecular crowding. Finally, the phosphorylation of the Alzheimer's-disease-associated protein Tau by cyclin-dependent kinase 2 was accelerated within condensates. Thus, condensates enable new signaling connections and can create sensors that respond to the biophysical properties of the cytoplasm.
Assuntos
Transdução de Sinais , Proteínas tau , Quinase 2 Dependente de Ciclina/metabolismo , Citoplasma/metabolismo , Humanos , Substâncias Macromoleculares/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Aberrant transcripts expression of the m6A methyltransferase complex (MTC) is widely found across human cancers, suggesting a dysregulated signaling cascade which integrates m6A epitranscriptome to drive tumorigenesis. However, the responsible transcriptional machinery directing the expression of distinct MTC subunits remains unclear. Here, we identified an unappreciated interplay between the histone acetyl-lysine reader BRD4 and the m6A writer complex across human cancers. BRD4 directly stimulates transcripts expression of seven MTC subunits, allowing the maintenance of the nuclear writer complex integrity. Upon BET inhibition, this BRD4-MTC signaling cascade accounts for global m6A reduction and the subsequent dynamic alteration of BRD4-dependent transcriptome, resulting in impaired DNA damage response that involves activation of homologous recombination (HR) repair and repression of apoptosis. We further demonstrated that the combined synergy upon BET/PARP inhibition largely relies on disrupted m6A modification of HR and apoptotic genes, counteracting PARP inhibitor (PARPi) resistance in patient-derived xenograft models. Our study revealed a widespread active cross-talk between BRD4-dependent epigenetic and MTC-mediated epitranscriptomic networks, which provides a unique therapeutic vulnerability that can be leveraged in combined DNA repair-targeted therapy.
Assuntos
Antineoplásicos , Proteínas que Contêm Bromodomínio , Proteínas Nucleares , Humanos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Reparo do DNA , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Epigênese Genética , Proteínas que Contêm Bromodomínio/genética , Proteínas que Contêm Bromodomínio/metabolismo , AnimaisRESUMO
OBJECTIVE: Fatty acids play a critical role in the proper functioning of the brain. This study investigated the effects of a high-fat (HF) diet on brain fatty acid profiles of offspring exposed to maternal gestational diabetes mellitus (GDM). METHODS: Insulin receptor antagonist (S961) and HF diet were used to establish the GDM animal model. Brain fatty acid profiles of the offspring mice were measured by gas chromatography at weaning and adulthood. Protein expressions of the fatty acid transport pathway Wnt3/ß-catenin and the target protein major facilitator superfamily domain-containing 2a (MFSD2a) were measured in the offspring brain by Western blot. RESULTS: Maternal GDM increased the body weight of male offspring (P < 0.05). In weaning offspring, factorial analysis showed that maternal GDM increased the monounsaturated fatty acid (MUFA) percentage of the weaning offspring's brain (P < 0.05). Maternal GDM decreased offspring brain arachidonic acid (AA), but HF diet increased brain linoleic acid (LA) (P < 0.05). Maternal GDM and HF diet reduced offspring brain docosahexaenoic acid (DHA), and the male offspring had higher DHA than the female offspring (P < 0.05). In adult offspring, factorial analysis showed that HF diet increased brain MUFA in offspring, and male offspring had higher brain MUFA than female offspring (P < 0.05). The HF diet increased brain LA in the offspring. Male offspring had higher level of AA than female offspring (P < 0.05). HF diet reduced DHA in the brains of female offspring. The brain protein expression of ß-catenin and MFSD2a in both weaning and adult female offspring was lower in the HF + GDM group than in the CON group (P < 0.05). CONCLUSIONS: Maternal GDM increased the susceptibility of male offspring to HF diet-induced obesity. HF diet-induced adverse brain fatty acid profiles in both male and female offspring exposed to GDM.
Assuntos
Encéfalo , Diabetes Gestacional , Dieta Hiperlipídica , Ácidos Graxos , Efeitos Tardios da Exposição Pré-Natal , Animais , Gravidez , Feminino , Diabetes Gestacional/metabolismo , Camundongos , Dieta Hiperlipídica/efeitos adversos , Encéfalo/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Masculino , Ácidos Graxos/metabolismo , Modelos Animais de Doenças , Fenômenos Fisiológicos da Nutrição MaternaRESUMO
In severely phosphorus (P)-impoverished environments, plants have evolved to use P very efficiently. Yet, it is unclear how P allocation in leaves contributes to their photosynthetic P-use efficiency (PPUE) and position along the leaf economics spectrum (LES). We address this question in 10 species of Banksia and Hakea, two highly P-efficient Proteaceae genera. We characterised traits in leaves of Banksia and Hakea associated with the LES: leaf mass per area, light-saturated photosynthetic rates, P and nitrogen concentrations, and PPUE. We also determined leaf P partitioning to five biochemical fractions (lipid, nucleic acid, metabolite, inorganic and residual P) and their possible association with the LES. For both genera, PPUE was negatively correlated with fractional allocation of P to lipids, but positively correlated with that to metabolites. For Banksia only, PPUE was negatively correlated with residual P, highlighting a strategy contrasting to that of Hakea. Phosphorus-allocation patterns significantly explained PPUE but were not linked to the resource acquisition vs resource conservation gradient defined by the LES. We conclude that distinct P-allocation patterns enable species from different genera to achieve high PPUE and discuss the implications of different P investments. We surmise that different LES axes representing different ecological strategies coexist in extremely P-impoverished environments.
RESUMO
Gold nanoclusters (AuNCs) are a class of novel luminescent nanomaterials that exhibit unique properties of ultra-small size, featuring strong anti-photo-bleaching ability, substantial Stokes shift, good biocompatibility, and low toxicity. Various biomolecules have been developed as templates or ligands to protect AuNCs with enhanced stability and luminescent properties for biomedical applications. In this review, the synthesis of AuNCs based on biomolecules including amino acids, peptides, proteins and DNA are summarized. Owing to the advantages of biomolecule-protected AuNCs, they have been employed extensively for diverse applications. The biological applications, particularly in bioimaging, biosensing, disease therapy and biocatalysis have been described in detail herein. Finally, current challenges and future potential prospects of bio-templated AuNCs in biological research are briefly discussed.
Assuntos
Ouro , Nanopartículas Metálicas , Ouro/química , Nanopartículas Metálicas/química , Humanos , Técnicas Biossensoriais/métodos , Luminescência , Animais , Peptídeos/química , DNA/química , Proteínas/química , Substâncias Luminescentes/química , Aminoácidos/químicaRESUMO
BACKGROUND: Undertreatment of ovarian cancer is common among older women. We aimed to evaluate the treatment modalities offered to older patients and their impact on overall survival (OS). METHODS: The study identified 5,055 patients with high-grade serous ovarian cancer and 3584 patients with advanced stage (IIIC + IV) disease from the Surveillance, Epidemiology, and End Results (SEER) database from January 1, 2010, to December 31, 2017. We performed comparisons of OS and ovarian cancer-specific survival (OCSS) across age groups using a Cox proportional hazards model. RESULTS: Very elderly patients (≥ 75 years old) received treatment with significantly less surgical complexity, such as no lymphadenectomy (59.7% vs. 48.6%; p < 0.001) and a lower rate of optimal debulking surgery (44.0% vs. 52.7%; p < 0.001), as well as lower rates of chemotherapy (78.2% vs. 89.4%; P<0.001) and standard treatment (70.6% vs. 85%; p < 0.001). High proportions of both very elderly and elderly patients received neoadjuvant chemotherapy (NACT), with no significant difference (38.7% vs. 36.2%; P = 0.212). Patients aged ≥ 75 years had significantly worse OS and OCSS. CONCLUSION: With increasing age, the survival rate of women with ovarian cancer decreases significantly. Noticeably fewer ovarian cancer patients aged over 75 years receive standard treatments, and more very elderly patients are treated with NACT.
Assuntos
Neoplasias Ovarianas , Idoso , Humanos , Feminino , Estadiamento de Neoplasias , Quimioterapia Adjuvante , Estudos Retrospectivos , Neoplasias Ovarianas/patologia , Terapia NeoadjuvanteRESUMO
The study investigated the effect of Compound Shougong Powder(CSGP) on the biological functions of triple-negative breast cancer(TNBC) cells and whether its mechanism of action was related to the epithelial-mesenchymal transition(EMT) signaling pathway. TNBC cells(MDA-MB-231 and BT-549) were treated with different concentrations of CSGP-containing serum. MTS assay was used to detect the effect of CSGP on the proliferation of TNBC cells. The EdU staining was used to detect the effect of CSGP on the proliferation of TNBC cells. Flow cytometry was used to examine the impact of CSGP on apoptosis of TNBC cells. Wound-healing and Transwell assays were used to evaluate the effects of different concentrations of CSGP on the migration and invasion capabilities of TNBC cells. RNA sequencing technology was utilized to elucidate its mechanism. Subsequently, qRT-PCR was performed to measure the mRNA expression levels of E-cadherin, N-cadherin, Slug, Snail, Vimentin, Twist, Zinc finger E-box-Binding homeobox 1(Zeb1), and Zinc finger E-box-Binding homeobox 2(Zeb2). Western blot was used to assess the protein expression levels of Slug, Vimentin, and E-cadherin. After intervention with CSGP, the proliferation of MDA-MB-231 and BT-549 cells significantly decreased, while the apoptosis rate markedly increased. The expression levels of the epithelial marker protein E-cadherin significantly increased, while the expression levels of the EMT-related transcription factors Slug and Vimentin showed a decrease. In conclusion, CSGP inhibits the EMT, thereby suppressing the malignant progression of TNBC.
Assuntos
Apoptose , Proliferação de Células , Medicamentos de Ervas Chinesas , Transição Epitelial-Mesenquimal , Neoplasias de Mama Triplo Negativas , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Medicamentos de Ervas Chinesas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Pós/química , Caderinas/genética , Caderinas/metabolismoRESUMO
Gold nanoclusters (Au NCs) are widely used as fluorescent probes in biomedical sensing and imaging due to their versatile optical properties and low cytotoxicity. Surface engineering of gold nanoclusters (Au NCs) aims to design a surface with versatile physicochemical performances, but previous investigations have primarily focused on the acquisition of the "brightest" species. This has resulted in other types of Au NC being neglected. In the present study, our group prepared a series of Au NCs that were rich in surface Au(0), using the "aged" form of bovine serum albumin (BSA) via controlling the pH during synthesis. We found that slight increases of alkalinity during synthesis over that which produced Au NCs with the most intensive photoluminescence generated the "darkest" Au NCs, which exhibited the strongest absorption. These Au NCs included more Au atoms and had a higher Au(0) content. Furthermore, the addition of Au3+ quenched the emission of the "brightest" Au NCs, but increased that of the "darkest" Au NCs. The increased Au(I) proportion observed in the Au3+-treated "darkest" Au NCs resulted in a novel comproportionation-induced emission enhancement effect, which we utilized to construct a "turn-on" ratiometric sensor for toxic Au3+. The addition of Au3+ generated simultaneous, opposite effects on blue-emissive diTyr BSA residues and red-emissive Au NCs. After optimization, we successfully constructed ratiometric sensors for Au3+ with high sensitivity, selectivity, and accuracy. This study will inspire a new pathway to redesign the protein-framed Au NCs and analytical methodology via comproportionation chemistry.
Assuntos
Luminescência , Nanopartículas Metálicas , Ouro/química , Espectrometria de Fluorescência/métodos , Corantes Fluorescentes/química , Soroalbumina Bovina/química , Nanopartículas Metálicas/químicaRESUMO
OBJECTIVE: T-cell receptor (TCR) repertoire diversity is getting increasing attention as a predictive biomarker in cancer patients. However, the characteristics of the TCR together with its predictive significance for high grade serous ovarian cancer (HGSOC) patients receiving poly (ADP-ribose) polymerase inhibitor (PARPi) maintenance therapy remain unknown. METHODS: Twenty-seven patients with HGSOC were analyzed including 22 patients receiving PARPi maintenance therapy and 5 untreated patients as control. Peripheral blood samples were collected for TCR sequencing at baseline as well as one month and three months after the exposure to PARPi. To determine whether TCR diversity was related to PARPi efficacy, we compared the TCR repertoire between patients who had received PARPi and those who had not. RESULTS: For patients receiving PARPi treatment or not, we evaluated changes in clone abundance during PARPi maintenance and the similarity of the TCR repertoire before and after the treatment. The results revealed that patients receiving PARPi had TCR repertoires that were more stable than those of untreated cases. We next correlated TCR diversity with the efficacy of PARPi in the treatment group. The rising trend of TCR diversity after three months with PARPi treatment was associated with a longer PFS (21.7 vs 7.4 months, hazard ratio = 0.19, p < 0.001) and a better response to PARPi (91.7% vs 25.0%, p = 0.004). Furthermore, we discovered that the primary characteristic with predictive value for the effectiveness of PARPi is the considerable reduction of the high-frequency T cell clones. CONCLUSION: We suggested that the circulating TCR diversity could be a potential predictive biomarker for PARPi maintenance therapy in HGSOC.
Assuntos
Antineoplásicos , Neoplasias Ovarianas , Humanos , Feminino , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos/uso terapêutico , Biomarcadores , Receptores de Antígenos de Linfócitos TRESUMO
Dosing sulfide into the sulfur-packed-bed (S0PB) has great potential to enhance the denitrification efficiency by providing compensatory electron donors, however, the response of sulfur-metabolizing biofilm to various sulfide dosages has never been investigated. In this study, the S0PB reactor was carried out with increasing sulfide dosages by 3.6 kg/m3/d, presenting a decreasing effluent nitrate from 14.2 to 2.7 mg N/L with accelerated denitrification efficiency (k: 0.04 to 0.27). However, 6.5 mg N/L of nitrite accumulated when the sulfide dosage exceeded 0.9 kg/m3/d (optimum value). The increasing electron export contribution of sulfide a maximum of 85.5% illustrated its competition with the in-situ sulfur. Meanwhile, over-dosing sulfide caused serious biofilm expulsion with significant decreases in the total biomass, live cell population, and ATP by 90.2%, 86.7%, and 54.8%, respectively. This study verified the capacity of dosing sulfide to improve the denitrification efficiency in S0PB but alerted the negative effect of exceeded dosing.
Assuntos
Reatores Biológicos , Desnitrificação , Sulfetos , Enxofre , BiofilmesRESUMO
OBJECTIVE: The purpose of this study was to retrospectively assess the pattern, compliance, efficacy and safety of bevacizumab in Chinese ovarian cancer patients. METHODS: We reviewed the clinicopathological data of patients with histologically confirmed epithelial ovarian cancer, fallopian tube cancer and primary peritoneal adenocarcinoma, who were diagnosed and treated at the Department of Gynecologic Oncology of Peking University Cancer Hospital between May 2012 and January 2022. RESULTS: A total of 155 patients were eventually enrolled in this study, with 77 as first-line chemotherapy (FL) and 78 as recurrence therapy (RT) among which 37 patients were platinum sensitive and 41 were platinum resistant. Among the 77 patients in the FL group, 35 received bevacizumab during neoadjuvant chemotherapy (NACT) alone (NT), 23 received bevacizumab during both neoadjuvant and first-line chemotherapy (NT + FL) and 19 received bevacizumab during first-line chemotherapy alone (FLA). Among the 43 patients of NT and NT + FL groups undergoing interval debulking surgery (IDS), 38(88.4%) patients achieved optimally debulking and 24 (55.8%) patients had no residual disease after IDS. The patients in the FL group had a median progression free survival (PFS) of 15(95%CI: 9.951-20.049) months, and the 12-month PFS was 61.7%. In the RT group, the overall response rate (ORR) was 53.8%. According to multivariate analysis, the patients' platinum sensitivity had a significant impact on the PFS in the RT group. 13(8.4%) patients discontinued bevacizumab due to toxicity. Seven patients were in the FL group while 4 patients were in the RT group. The most common adverse event associated with bevacizumab therapy was hypertension. CONCLUSION: Bevacizumab is effective and well-tolerated in the real world setting of ovarian cancer treatment. Adding bevacizumab to NACT is feasible and tolerable. Receiving the regimen containing bevacizumab in the last preoperative chemotherapy did not result in increased intraoperative bleeding of IDS. Platinum sensitivity is the most important factor affecting the effectiveness of bevacizumab in recurrent patients.
Assuntos
População do Leste Asiático , Neoplasias Ovarianas , Humanos , Feminino , Bevacizumab/uso terapêutico , Bevacizumab/efeitos adversos , Estudos Retrospectivos , Neoplasias Ovarianas/patologia , Carcinoma Epitelial do Ovário/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Munc13-1 is a large multifunctional protein essential for synaptic vesicle fusion and neurotransmitter release. Its dysfunction has been linked to many neurological disorders. Evidence suggests that the MUN domain of Munc13-1 collaborates with Munc18-1 to initiate SNARE assembly, thereby priming vesicles for fast calcium-triggered vesicle fusion. The underlying molecular mechanism, however, is poorly understood. Recently, it was found that Munc18-1 catalyzes neuronal SNARE assembly through an obligate template complex intermediate containing Munc18-1 and 2 SNARE proteins-syntaxin 1 and VAMP2. Here, using single-molecule force spectroscopy, we discovered that the MUN domain of Munc13-1 stabilizes the template complex by â¼2.1 kBT. The MUN-bound template complex enhances SNAP-25 binding to the templated SNAREs and subsequent full SNARE assembly. Mutational studies suggest that the MUN-bound template complex is functionally important for SNARE assembly and neurotransmitter release. Taken together, our observations provide a potential molecular mechanism by which Munc13-1 and Munc18-1 cooperatively chaperone SNARE folding and assembly, thereby regulating synaptic vesicle fusion.
Assuntos
Chaperonas Moleculares/metabolismo , Proteínas Munc18/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas SNARE/metabolismo , Exocitose/fisiologia , Cinética , Fusão de Membrana/fisiologia , Chaperonas Moleculares/química , Proteínas Munc18/química , Proteínas do Tecido Nervoso/química , Neurônios/metabolismo , Pinças Ópticas , Ligação Proteica , Domínios Proteicos , Proteínas Qa-SNARE/metabolismo , Proteínas SNARE/química , Transmissão Sináptica/fisiologia , Vesículas Sinápticas/metabolismo , Proteína 25 Associada a Sinaptossoma/química , Proteína 25 Associada a Sinaptossoma/metabolismo , Sintaxina 1/metabolismo , Proteína 2 Associada à Membrana da Vesícula/metabolismoRESUMO
Physical thickness of low-density polyethylene (LDPE) films might determine the release rate of phthalic acid esters (PAEs) & structural integrity and affect production efficiency. However, this critical issue is still unclear and little reported. Aging effects were evaluated in LDPE films with the thickness of 0.006, 0.008, 0.010 and 0.015 mm in a maize field of irrigation region. The Scanning electron microscope (SEM) results showed that the proportion of damaged area (Dam) to total area of LDPE films was massively lowered with increasing thickness after aging. The highest and lowest Dam was 32.2% and 3.5% in 0.006 and 0.015 mm films respectively. Also, the variations in peak intensity of asymmetric & symmetrical stretching vibrations (ASVI & SSVI) were detected using Fourier transform infrared spectrum (FTIR), indicating that the declines in peak intensity tended to be slower with thickness. Interestingly, the declines in physical integrity were tightly associated with increasing exhalation rate of PAEs. Average releasing rate of PAEs was 38.2%, 31.4%, 31.5% and 19.7% in LDPE films from 0.006 to 0.015 mm respectively. Critically, thicker film mulching can lead to greater soil water storage at plough layer (SWS-PL) and better thermal status, accordingly harvesting higher economic benefit. Therefore, LDPE film thickening may be a solution to reduce environmental risk but improve production efficiency in arid region.
Assuntos
Luz , Polietileno , Solo , VibraçãoRESUMO
This study investigates the rheological properties of dual-network hydrogels based on acrylamide and sodium alginate under large deformations. The concentration of calcium ions affects the nonlinear behavior, and all gel samples exhibit strain hardening, shear thickening, and shear densification. The paper focuses on systematic variation of the alginate concentration-which serves as second network building blocks-and the Ca2+-concentration-which shows how strongly they are connected. The precursor solutions show a typical viscoelastic solution behavior depending on alginate content and pH. The gels are highly elastic solids with only relatively small viscoelastic components, i.e., their creep and creep recovery behavior are indicative of the solid state after only a very short time while the linear viscoelastic phase angles are very small. The onset of the nonlinear regime decreases significantly when closing the second network (alginate) upon adding Ca2+, while at the same time the nonlinearity parameters (Q0, I3/I1, S, T, e3/e1, and v3/v1) increase significantly. Further, the tensile properties are significantly improved by closing the alginate network by Ca2+ at intermediate concentrations.
RESUMO
The development of modern technologies has acclimatized biosensors to complicated applicable scenarios with integrated properties as a whole instead of the pursuit of a single-point breakthrough. Here, we targeted a few concerns in the development of enzyme-based biosensors, including stability, analyte enrichment, and signal transduction, and developed a general biosensing model utilizing enzymes, aggregation-induced emission (AIE) luminogens, and stimuli-responsive framework materials as the units. We propose such proof-of-concept of glucose biosensors by coencapsulating glucose oxidase and AIE-type gold nanoclusters into acid-sensitive zeolite imidazolate framework (ZIF)-8 nanocrystals. The acid-activated degradation of ZIF-8 bridges the molecular signals produced by the enzyme-catalytic reaction of glucose and the photon signals generated by ZIF-8-induced AIE effects of gold nanoclusters, resulting in the "turn-off" model nanoprobes for glucose detection with high selectivity. After embedding the nanoprobes into hollow-out tapes, the formed paper biosensors can conveniently detect glucose with the help of a smartphone.
Assuntos
Técnicas Biossensoriais , Zeolitas , Técnicas Biossensoriais/métodos , Glucose Oxidase/química , Ouro/química , Luminescência , Zeolitas/químicaRESUMO
Luminescent covalent organic frameworks (LCOFs) have attracted significant attention due to their tunability of structures and photophysical properties at molecular level. LCOFs are built to highly ordered and periodic 2D or 3D framework structures through covalently assembling with various luminophore building blocks. Recently, the advantages of LCOFs including predesigned properties of structure, unique photoluminescence, hypotoxicity and good biocompatibility and tumor penetration, broaden their applications in biorelated fields, such as biosensing, bioimaging, and drug delivery. A specific review that analyses the advances of LCOFs in the field of biosensing and bioimaging is thus urged to emerge. Here the construction of LCOFs is reviewed first. The synthetic chemistry of LCOFs highlights the key role of chemical linkages, which not only concrete the building blocks but also affect the optical properties and even can act as the responsive sites for potential sensing applications. How to brighten LCOFs are clarified through description of structure managements. The ability to utilize the luminescence of LCOFs for applications in biosensing and bioimaging is discussed using state-of-the-art examples of varied practical goals. A prospect finally addresses opportunities and challenges the development of LCOFs facing from chemistry, physics to the applications, according to their current progress.
Assuntos
Técnicas Biossensoriais , Estruturas Metalorgânicas , Sistemas de Liberação de Medicamentos , Luminescência , Estruturas Metalorgânicas/químicaRESUMO
Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide. Emerging evidence has revealed the vital functions of microRNAs (miRNAs) in cancer malignant progressions. miR-375 has been verified to serve as an antioncogene in tumorigenesis and a potential therapeutic target in various types of cancer. In this study, we aimed to determine the role of miR-375 in the regulation of chemoresistance and metastasis of HCC. Differentially expressed miR-375 and NCAPG2 were externally validated using expression data from The Cancer Genome Atlas (TCGA) database. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression levels of miR-375 in HCC tissues and cell lines. miR-375 mimics and NCAPG2-overexpression were transfected into HepG2 and Huh7 cells to establish miR-375 overexpression models. Cell Counting Kit-8, Transwell, and flow cytometry experiments were conducted to monitor cell proliferation, migration, and apoptosis. The targeting relationship between miR-375 and non-SMC condensin II complex subunit G 2 (NCAPG2) was determined by qRT-PCR, western blot, and luciferase reporter gene assay. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted using Gene Set Enrichment Analysis (GSEA). The pathway enrichment analysis was used to predict the potential pathways for further study. miR-375 was significantly downregulated in HCC tissues and cells compared to adjacent tissue and normal hepatocyte cell line respectively while NCAPG2 was upregulated. The targeting relationship was verified by luciferase reporting assay, and miR-375 could target the 3'UTR of NCAPG2 mRNA and effectively suppress NCAPG2 protein expression. Replenishing of miR-375 significantly repressed HCC cell proliferation and migration, and induced cell apoptosis. Overexpression of NCAPG2 recovered those biological abilities in miR-375 overexpressed cells. Collective data suggested that miR-375 served as a tumor suppressor via regulating NCAPG2. Replenishing of miR-375 or knockout of NCAPG2 could be therapeutically exploited for HCC.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Apoptose/genética , Carcinoma Hepatocelular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Proteínas Cromossômicas não Histona , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , MicroRNAs/genéticaRESUMO
Fucoidan is a sulfated algal polyanionic polysaccharide that possesses many biological activities. In this paper, a fucoidan (SHF) polysaccharide was extracted from Sargassum hemiphyllum collected in the South China Sea. The SHF, with a molecular weight of 1166.48 kDa (44.06%, w/w), consisted of glucose (32.68%, w/w), galactose (24.81%, w/w), fucose (20.75%, w/w), xylose (6.98%, w/w), mannose (2.76%, w/w), other neutral monosaccharides, and three uronic acids, including glucuronic acid (5.39%, w/w), mannuronic acid (1.76%, w/w), and guronuronic acid (1.76%, w/w). The SHF exhibited excellent immunostimulatory activity. An immunostimulating assay showed that SHF could significantly increase NO secretion in macrophage RAW 264.7 cells via upregulation of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) levels based on both gene expression and protein abundance. These results suggest that SHF isolated from Sargassum hemiphyllum has great potential to act as a health-boosting ingredient in the pharmaceutical and functional-food fields.
Assuntos
Sargassum , Sargassum/química , Polissacarídeos/química , Monossacarídeos/química , MacrófagosRESUMO
Chemoresistance is a severe outcome among patients with ovarian cancer that leads to a poor prognosis. MCL1 is an antiapoptotic member of the BCL-2 family that has been found to play an essential role in advancing chemoresistance and could be a promising target for the treatment of ovarian cancer. Here, we found that deubiquitinating enzyme 3 (DUB3) interacts with and deubiquitinates MCL1 in the cytoplasm of ovarian cancer cells, which protects MCL1 from degradation. Furthermore, we identified that O6-methylguanine-DNA methyltransferase (MGMT) is a key activator of DUB3 transcription, and that the MGMT inhibitor PaTrin-2 effectively suppresses ovarian cancer cells with elevated MGMT-DUB3-MCL1 expression both in vitro and in vivo. Most interestingly, we found that histone deacetylase inhibitors (HDACis) could significantly activate MGMT/DUB3 expression; the combined administration of HDACis and PaTrin-2 led to the ideal therapeutic effect. Altogether, our results revealed the essential role of the MGMT-DUB3-MCL1 axis in the chemoresistance of ovarian cancer and identified that a combined treatment with HDACis and PaTrin-2 is an effective method for overcoming chemoresistance in ovarian cancer.