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In this work, a novel polyaniline-modified magnetic microporous organic network (MMON-PANI) composite was fabricated for effective magnetic solid phase extraction (MSPE) of five typical nonsteroidal anti-inflammatory drugs (NSAIDs) from animal-derived food samples before high performance liquid chromatography (HPLC) detection. The core-shell sea urchin shaped MMON-PANI integrates the merits of Fe3O4, MON, and PANI, exhibiting large specific surface area, rapid magnetic responsiveness, good stability, and multiple binding sites to NSAIDs. Convenient and effective extraction of trace NSAIDs from chicken, beef and pork samples is realized on MMON-PANI via the synergetic π-π, hydrogen bonding, hydrophobic, and electrostatic interactions. Under optimal conditions, the MMON-PANI-MSPE-HPLC-UV method exhibits wide linear ranges (0.2-1000 µg L-1), low limits of detection (0.07-1.7 µg L-1), good precisions (intraday and inter-day RSDs < 5.4 %, n = 3), large enrichment factors (98.6-99.9), and less adsorbent consumption (3 mg). The extraction mechanism and selectivity of MMON-PANI are also evaluated in detail. This work proves the incorporation of PANI onto MMON is an efficient way to promote NSAIDs enrichment and provides a new strategy to synthesize multifunctional MON-based composites in sample pretreatment.
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Compuestos de Anilina , Antiinflamatorios no Esteroideos , Extracción en Fase Sólida , Compuestos de Anilina/química , Animales , Antiinflamatorios no Esteroideos/aislamiento & purificación , Antiinflamatorios no Esteroideos/análisis , Antiinflamatorios no Esteroideos/química , Extracción en Fase Sólida/métodos , Cromatografía Líquida de Alta Presión/métodos , Límite de Detección , Porcinos , Pollos , Bovinos , Adsorción , Carne/análisis , Porosidad , Reproducibilidad de los ResultadosRESUMEN
Despite the great potential of starving therapy caused by nanoreactor based on glucose oxidase (GOX) in tumor therapy, efficiency and uncontrolled reaction rates in vivo lead to inevitable toxicity to normal tissues, which seriously hindering their clinical conversion. Herein, a cascade nanoreactor (GOX/Mn/MPDA) was constructed by coating mesoporous polydopamine nanoparticles (MPDA) with MnO2 shell and then depositing GOX into honeycomb-shaped manganese oxide nanostructures to achieve a combination of ferroptosis, photothermal therapy and starving therapy. Upon uptake of nanodrugs to cancer cells, the MnO2 shell would deplete glutathione (GSH) and produce Mn2+, while a large amount of H2O2 generated from the catalytic oxidation of glucose by GOX would accelerate the Fenton-like reaction mediated by Mn2+, producing high toxic â¢OH. More importantly, the cascade reaction between GOX and MnO2 would be further strengthened by localized hyperthermia caused by irradiated by near-infrared laser (NIR), inducing significant anti-tumor effects in vitro and in vivo. Regarding the effectiveness of tumor treatment in vivo, the tumor inhibition rate achieved an impressive 64.33%. This study provided a new strategy for anti-tumor therapeutic by designing a photothermal-enhanced cascade catalytic nanoreactor.
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Ferroptosis , Glucosa Oxidasa , Indoles , Compuestos de Manganeso , Nanopartículas , Óxidos , Terapia Fototérmica , Polímeros , Terapia Fototérmica/métodos , Compuestos de Manganeso/química , Animales , Humanos , Ferroptosis/efectos de los fármacos , Ferroptosis/fisiología , Indoles/química , Polímeros/química , Glucosa Oxidasa/metabolismo , Glucosa Oxidasa/administración & dosificación , Nanopartículas/química , Ratones , Óxidos/química , Línea Celular Tumoral , Peróxido de Hidrógeno/metabolismo , Ratones Endogámicos BALB C , Terapia Combinada/métodos , Femenino , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Ratones DesnudosRESUMEN
This study represents the first documentation of the coexistence of complete androgen insensitivity syndrome (CAIS) with Müllerian duct remnants (MDRs) in mainland China. Additionally, we provide a comprehensive review of the existing literature concerning CAIS with MDRs resulting from androgen receptor (AR) gene mutations. This study broadens the clinical spectrum of CAIS and offer novel insights for further exploration into Müllerian duct regression. A 14-year-old patient, initially raised as female, presented to the clinic with complaints of "primary amenorrhea." Physical examination revealed the following: armpit hair (Tanner stage 2), breast development (Tanner stage 4 with bilateral breast nodule diameter of 7â cm), sparse pubic hair (Tanner stage 3), clitoris measuring 0.8â cm × 0.4â cm, separate urethral and vaginal openings, and absence of palpable masses in the bilateral groin or labia majora. The external genital virilization score was 0 points. Serum follicle-stimulating hormone level was 13.43â IU/L, serum luteinizing hormone level was 31.24â IU/L, and serum testosterone level was 14.95â nmol/L. Pelvic magnetic resonance imaging (MRI) did not reveal a uterus or bilateral fallopian tubes, but nodules on both sides of the pelvic wall indicated cryptorchidism. The karyotype was 46,XY. Genetic testing identified a maternal-derived hemizygous variation c.2359C > T (p.Arg787*) in the AR gene. During abdominal exploration, dysplastic testicles and a dysplastic uterus were discovered. Histopathological analysis revealed the presence of fallopian tube-like structures adjacent to the testicles. The CAIS patient documented in this study exhibited concurrent MDRs, thus expanding the spectrum of clinical manifestations of AIS. A review of prior literature suggests that the incidence of CAIS combined with histologically MDRs is not uncommon. Consequently, the identification of MDRs in AIS cases may represent an integral aspect of clinical diagnosis for this condition.
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Addressing the pervasive issue of bacteria and biofilm infections is crucial in the development of advanced antifouling wound dressings. In this study, a novel wound healing treatment using sulfobetaine (SBMA) decorated electrospun fibrous membrane based on polycaprolactone (PCL)/nitric oxide (NO) donors was developed. The fabrication involved a dual strategy, first integrating NO donors into mesoporous polydopamine (MPDA) and complexed with PCL/PEI to electrospin nanofibers. The fibrous membrane exhibited a potent antibacterial response upon irradiation at 808 nm, owing to a combination of NO and photothermal effect that effectively targets bacteria and disrupts biofilms. Surface functionalization of the membrane with PEI allowed for the attachment of SBMA via Michael addition, fabricating a zwitterionic surface, which significantly hinders protein adsorption and reduces biofilm formation on the wound dressing. In vitro and in vivo assessments confirmed the rapid bactericidal capabilities and its efficacy in biofilm eradication. Combining photothermal activity, targeted NO release and antifouling surface, this multifaceted wound dressing addresses key challenges in bacterial infection management and biofilm eradication, promoting efficient wound healing.
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Antibacterianos , Vendajes , Betaína , Biopelículas , Indoles , Nanofibras , Poliésteres , Cicatrización de Heridas , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/administración & dosificación , Biopelículas/efectos de los fármacos , Animales , Cicatrización de Heridas/efectos de los fármacos , Poliésteres/química , Indoles/química , Indoles/farmacología , Betaína/química , Betaína/farmacología , Betaína/análogos & derivados , Nanofibras/química , Polímeros/química , Óxido Nítrico/metabolismo , Staphylococcus aureus/efectos de los fármacos , Incrustaciones Biológicas/prevención & control , Donantes de Óxido Nítrico/farmacología , Donantes de Óxido Nítrico/química , Ratones , Propiedades de Superficie , Escherichia coli/efectos de los fármacos , Polietileneimina/químicaRESUMEN
GH11 enzyme is known to be specific and efficient for the hydrolysis of xylan. It has been isolated from many microorganisms, and its enzymatic characteristics and thermostability vary between species. In this study, a GH11 enzyme PphXyn11 from a novel xylan-degrading strain of Paenibacillus physcomitrellae XB was characterized, and five mutants were constructed to try to improve the enzyme's thermostability. The results showed that PphXyn11 was an acidophilic endo-ß-1,4-xylanase with the optimal reaction pH of 3.0-4.0, and it could deconstruct different kinds of xylan substrates efficiently, such as beechwood xylan, wheat arabinoxylan and xylo-oligosaccharides, to produce xylobiose and xylotriose as the main products at the optimal reaction temperature of 40 °C. Improvement of the thermal stability of PphXyn11 using site-directed mutagenesis revealed that three mutants, W33C/N47C, S127C/N174C and S49E, designed by adding the disulfide bonds at the N-terminal, C-terminal and increasing the charged residues on the surface of PphXyn11 respectively, could increase the enzymatic activity and thermal stablility significantly and make the optimal reaction temperature reach 50 °C. Molecular dynamics simulations as well as computed the numbers of salt bridges and hydrogen bonds indicated that the protein structures of these three mutants were more stable than the wild type, which provided theoretical support for their improved thermal stability. Certainly, further research is necessary to improve the enzymatic characteristics of PphXyn11 to achieve the bioconversion of hemicellulosic biomass on an applicable scale.
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Endo-1,4-beta Xilanasas , Estabilidad de Enzimas , Paenibacillus , Paenibacillus/enzimología , Paenibacillus/genética , Endo-1,4-beta Xilanasas/genética , Endo-1,4-beta Xilanasas/química , Endo-1,4-beta Xilanasas/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/química , Proteínas Bacterianas/metabolismo , Xilanos/metabolismo , Xilanos/química , Concentración de Iones de Hidrógeno , Mutagénesis Sitio-Dirigida , Proteínas Recombinantes/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Temperatura , Especificidad por SustratoRESUMEN
Acute lung injury (ALI) is a common clinical syndrome, which often results in pulmonary edema and respiratory distress. It has been recently reported that phosphatidylethanolamine binding protein 4 (PEBP4), a basic cytoplasmic protein, has anti-inflammatory and hepatoprotective effects, but its relationship with ALI remains undefined so far. In this study, we generated PEBP4 knockout (KO) mice to investigate the potential function of PEBP4, as well as to evaluate the capacity of alveolar fluid clearance (AFC) and the activity of phosphatidylinositide 3-kinases (PI3K)/serine-theronine protein kinase B (PKB, also known as AKT) signaling pathway in lipopolysaccharide (LPS)-induced ALI mice models. We found that PEBP4 deficiency exacerbated lung pathological damage and edema, and increased the wet/dry weight ratio and total protein concentration of bronchoalveolar lavage fluid (BALF) in LPS-treated mice. Meanwhile, PEBP4 KO promoted an LPS-induced rise in the pulmonary myeloperoxidase (MPO) activity, serum interleuin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α levels, and pulmonary cyclooxygenase-2 (COX-2) expression. Mechanically, PEBP4 deletion further reduced the protein expression of Na+ transport markers, including epithelial sodium channel (ENaC)-α, ENaC-γ, Na,K-ATPase α1, and Na,K-ATPase ß1, and strengthened the inhibition of PI3K/AKT signaling in LPS-challenged mice. Furthermore, we demonstrated that selective activation of PI3K/AKT with 740YP or SC79 partially reversed all of the above effects caused by PEBP4 KO in LPS-treated mice. Altogether, our results indicated the PEBP4 deletion has a deterioration effect on LPS-induced ALI by impairing the capacity of AFC, which may be achieved through modulating the PI3K/AKT pathway.
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Lesión Pulmonar Aguda , Lipopolisacáridos , Animales , Ratones , Lesión Pulmonar Aguda/inducido químicamente , Lipopolisacáridos/farmacología , Pulmón/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/farmacología , ATPasa Intercambiadora de Sodio-Potasio/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Carbohydrate-binding module (CBM) family 91 is a novel module primarily associated with glycoside hydrolase (GH) family 43 enzymes. However, our current understanding of its function remains limited. PphXyl43B is a ß-xylosidase/α-L-arabinofuranosidase bifunctional enzyme from physcomitrellae patens XB belonging to the GH43_11 subfamily and containing CBM91 at its C terminus. To fully elucidate the contributions of the CBM91 module, the truncated proteins consisting only the GH43_11 catalytic module (rPphXyl43B-dCBM91) and only the CBM91 module (rCBM91) of PphXyl43B were constructed, respectively. The result showed that rPphXyl43B-dCBM91 completely lost hydrolysis activity against both p-nitrophenyl-ß-D-xylopyranoside and p-nitrophenyl-α-L-arabinofuranoside; it also exhibited significantly reduced activity towards xylobiose, xylotriose, oat spelt xylan and corncob xylan compared to the control. Thus, the CBM91 module is crucial for the ß-xylosidase/α-L-arabinofuranosidase activities in PphXyl43B. However, rCBM91 did not exhibit any binding capability towards corncob xylan. Structural analysis indicated that CBM91 of PphXyl43B might adopt a loop conformation (residues 496-511: ILSDDYVVQSYGGFFT) to actively contribute to the catalytic pocket formation rather than substrate binding capability. This study provides important insights into understanding the function of CBM91 and can be used as a reference for analyzing the action mechanism of GH43_11 enzymes and their application in biomass energy conversion.
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Dominio Catalítico , Glicósido Hidrolasas , Paenibacillus , Xilosidasas , Xilosidasas/química , Xilosidasas/metabolismo , Xilosidasas/genética , Glicósido Hidrolasas/química , Glicósido Hidrolasas/genética , Glicósido Hidrolasas/metabolismo , Paenibacillus/enzimología , Especificidad por Sustrato , Hidrólisis , Modelos Moleculares , Conformación Proteica , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Arabinosa/metabolismo , Arabinosa/análogos & derivadosRESUMEN
The anabolism of tumor cells can not only support their proliferation, but also endow them with a steady influx of exogenous nutrients. Therefore, consuming metabolic substrates or limiting access to energy supply can be an effective strategy to impede tumor growth. Herein, a novel treatment paradigm of starving-like therapy-triple energy-depleting therapy-is illustrated by glucose oxidase (GOx)/dc-IR825/sorafenib liposomes (termed GISLs), and such a triple energy-depleting therapy exhibits a more effective tumor-killing effect than conventional starvation therapy that only cuts off one of the energy supplies. Specifically, GOx can continuously consume glucose and generate toxic H2O2 in the tumor microenvironment (including tumor cells). After endocytosis, dc-IR825 (a near-infrared cyanine dye) can precisely target mitochondria and exert photodynamic and photothermal activities upon laser irradiation to destroy mitochondria. The anti-angiogenesis effect of sorafenib can further block energy and nutrition supply from blood. This work exemplifies a facile and safe method to exhaust the energy in a tumor from three aspects and starve the tumor to death and also highlights the importance of energy depletion in tumor treatment. It is hoped that this work will inspire the development of more advanced platforms that can combine multiple energy depletion therapies to realize more effective tumor treatment.
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Glucosa Oxidasa , Liposomas , Sorafenib , Liposomas/química , Humanos , Glucosa Oxidasa/metabolismo , Glucosa Oxidasa/química , Animales , Sorafenib/farmacología , Línea Celular Tumoral , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Metabolismo Energético , Peróxido de Hidrógeno/metabolismo , Peróxido de Hidrógeno/química , IndolesRESUMEN
Apolipoprotein C3 (apoC3) and angiopoietin-like protein 3 (ANGPTL3) inhibit lipolysis by lipoprotein lipase and may influence the secretion and uptake of various lipoproteins. Genetic studies show that depletion of these proteins is associated with improved lipid profiles and reduced cardiovascular events so it was anticipated that drugs which mimic the effects of loss-of-function mutations would be useful lipid treatments. ANGPTL3 inhibitors were initially developed as a treatment for severe hypertriglyceridaemia including familial chylomicronaemia syndrome (FCS), which is usually not adequately controlled with currently available drugs. However, it was found ANGPTL3 inhibitors were also effective in reducing low-density lipoprotein cholesterol (LDL-C) and they were studied in patients with homozygous familial hypercholesterolaemia (FH). Evinacumab targets ANGPTL3 and reduced LDL-C by about 50% in patients with homozygous FH and it has been approved for that indication. The antisense oligonucleotide (ASO) vupanorsen targeting ANGPTL3 was less effective in reducing LDL-C in patients with moderate hypertriglyceridaemia and its development has been discontinued but the small interfering RNA (siRNA) ARO-ANG3 is being investigated in Phase 2 studies. ApoC3 can be inhibited by the ASO volanesorsen, which reduced triglycerides by >70% in patients with FCS and it was approved for FCS in Europe but not in the United States because of concerns about thrombocytopaenia. Olezarsen is an N-acetylgalactosamine-conjugated ASO targeting apoC3 which appears as effective as volanesorsen without the risk of thrombocytopaenia and is undergoing Phase 3 trials. ARO-APOC3 is an siRNA targeting apoC3 that is currently being investigated in Phase 3 studies.
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The existence of a delicate redox balance in tumors usually leads to cancer treatment failure. Breaking redox homeostasis by amplifying oxidative stress and reducing glutathione (GSH) can accelerate cancer cell death. Herein, we construct a ferroptosis-reinforced nanocatalyst (denoted as HBGL) to amplify intracellular oxidative stress via dual H2O2 production-assisted chemodynamic therapy (CDT). Specifically, a long-circulating liposome is employed to deliver hemin (a natural iron-containing substrate for Fenton reaction and ferroptosis), ß-lapachone (a DNA topoisomerase inhibitor with H2O2 generation capacity for chemotherapy), and glucose oxidase (which can consume glucose for starvation therapy and generate H2O2). HBGL can achieve rapid, continuous, and massive H2O2 and â¢OH production and GSH depletion in cancer cells, resulting in increased intracellular oxidative stress. Additionally, hemin can reinforce the ferroptosis-inducing ability of HBGL, which is reflected in the downregulation of glutathione peroxidase-4 and the accumulation of lipid peroxide. Notably, HBGL can disrupt endo/lysosomes and impair mitochondrial function in cancer cells. HBGL exhibits effective tumor-killing ability without eliciting obvious side effects, indicating its clinical translation potential for synergistic starvation therapy, chemotherapy, ferroptosis therapy, and CDT. Overall, this nanocatalytic liposome may be a promising candidate for achieving potentiated cancer treatment.
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Ferroptosis , Neoplasias , Humanos , Peróxido de Hidrógeno , Hemina , Liposomas , Estrés Oxidativo , Glutatión , Neoplasias/tratamiento farmacológico , Línea Celular Tumoral , Microambiente TumoralRESUMEN
Hemiphragma heterophyllum Wall. is commonly used in traditional Yi herbal medicine for treating bellyache and toothache. In the current study, an unreported monoterpene glucoside, (S)-thymoquinol O-(6-O-oleuropeoyl)-ß-d-glucopyranoside (1), together with 11 known glucosides were obtained from the whole herb of H. heterophyllum. Their structures were determined based on a detailed analysis of spectroscopic data and acid hydrolysis and methanolysis reactions. Bioassay results showed that compounds 1 and 10 at 40 mg/kg exhibited significant antinociceptive activity in the acetic acid-induced writhing model, with inhibitions of 59.80% and 64.07%, respectively. Moreover, five of the isolates showed moderate anti-α-glucosidase activities with IC50 values ranging from 5.67 to 46.16 µM.
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Purpose: Multiple myeloma, the second most common hematological tumor, is currently incurable. Multiple myeloma-related bone disease is a characteristic clinical symptom that seriously affects the survival and prognosis of patients. In recent years, gut microbiota has been shown to play an important role in the occurrence and development of multiple myeloma. However, whether and how it affects the development of myelomatous bone disease is unclear. Methods: To investigate the mechanism and influence of the microbiota on multiple myeloma and myeloma bone disease, a myeloma-gut microbiota deletion mice model was established. 16S rRNA sequencing was used to analysis of bacterial flora changes. Histochemical staining and bone micro-CT were used to assess the severity of bone disease. Bone marrow tumor load and spleen Th17 cells were detected by flow cytometry. Results: Histochemical staining revealed a reduced tumor burden after eliminating gut microbial communities in mice by administering a mixture of antibiotics. According to the 16S rRNA sequencing of intestinal contents, antibiotic treatment resulted in a significant change in the microbiota of the mice. Bone micro-CT demonstrated that antibiotic treatment could reduce bone lesions caused by myeloma while increasing mineral density, bone volume fraction, trabecular bone thickness, and trabecular number. Meanwhile, histochemical staining of the bone found that the enhanced bone resorption was weakened by the change of flora. These results were consistent with the concentration of IL17 in serum and the frequency of Th17 cells in spleen. Conclusions: Herein, the effects of the gut microbiome on myeloma bone disease are investigated for the first time, providing new insight into its pathogenesis and suggesting that gut microbiota may serve as a therapeutic target in multiple myeloma-associated bone diseases.
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INTRODUCTION: Patients with type 2 diabetes (T2D) usually show progressive deterioration in glycemic control and sequential additions of therapy are generally needed. Many new options for glucose lowering therapy have been introduced recently and it is becoming common practice to use fixed-dose combinations (FDCs) of glucose lowering agents from different classes. This article reviews the FDC of canagliflozin with metformin extended release. AREAS COVERED: A literature search was performed to identify publications describing the efficacy and safety of canagliflozin and metformin when used separately and in combinations. EXPERT OPINION: Canagliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor which has shown benefits in reducing progression of renal disease and heart failure in patients with T2D. There was an increased incidence of amputation with canagliflozin in one study, but canagliflozin results in weight loss and reduction of blood pressure which contribute to the overall benefit. Metformin has been the first line oral hypoglycemic agent for many years and is thought to have many advantages, but it should be avoided in patients with severely decreased renal function because of the risk of lactic acidosis. The combination in a single tablet given once daily should help to simplify therapy and improve medication adherence in T2D.
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Diabetes Mellitus Tipo 2 , Metformina , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Canagliflozina/efectos adversos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/efectos adversos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Glucósidos/uso terapéutico , Metformina/uso terapéutico , Glucemia , GlucosaRESUMEN
OBJECTIVE: To optimize the single centrifugation preparation protocol of rat platelet-rich plasma (PRP). METHODS: The arterial blood of rats obtained by carotid artery intubation was collected by heparin sodium anticoagulant tubes, and then the blood divided into sterile EP tubes, adjusting the red blood cell concentration with normal saline, while rat PRP was prepared by centrifugation under different conditions (the centrifugal force was 200×g-240×g, and the centrifugal time was 8-12 min). Subsequently, the blood cell count and quality evaluation of anticoagulat whole blood and PRP were performed by hematology analyzer and flow cytometry, respectively, and the differences between different groups were compared. RESULTS: The red blood cell concentration to (5.5-6.5)×1012/L after anticoagulation of rat whole blood was good for PRP extraction. When the blood samples was centrifuged at 220×g for 10 min, the platelet recovery rate was the highestï¼»(53.52±0.63)%ï¼½. The level of apoptosis and activation of plateles in PRP were not significantly different compared to whole blood(P>0.05), and the release level of growth factor was significantly increased(P<0.05). CONCLUSION: It is a key to improve the PRP extraction efficiency by reducing the amount of mixed red blood cell, and this study successfully modified the preparation method of rat PRP, with platelets high recovery rate and stable quality.
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Conductive metal-organic frameworks (cMOFs) manifest great potential in modern electrical devices due to their porous nature and the ability to conduct charges in a regular network. cMOFs applied in electrical devices normally hybridize with other materials, especially a substrate. Therefore, the precise control of the interface between cMOF and a substrate is particularly crucial. However, the unexplored interface chemistry of cMOFs makes the controlled synthesis and advanced characterization of high-quality thin films, particularly challenging. Herein, we report the development of a simplified synthesis method to grow "face-on" and "edge-on" cMOF nanofilms on substrates, and the establishment of operando characterization methodology using atomic force microscopy and X-ray, thereby demonstrating the relationship between the soft structure of surface-mounted oriented networks and their characteristic conductive functions. As a result, crystallinity of cMOF nanofilms with a thickness down to a few nanometers is obtained, the possible growth mechanisms are proposed, and the interesting anisotropic softness-dependent conducting properties (over 2 orders of magnitude change) of the cMOF are also illustrated.
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The bromodomain and extra-terminal (BET) proteins act as "readers" for lysine acetylation and facilitate the recruitment of transcriptional elongation complexes. BET protein is associated with transcriptional elongation of genes such as c-MYC and BCL-2, and is involved in the regulation of cell cycle and apoptosis. Meanwhile, BET inhibitors (BETi) have regulatory effects on immune checkpoints, immune cells, and cytokine expression. The role of BET proteins and BETi in a variety of tumors has been studied. This paper reviews the recent research progress of BET and BETi in hematologic tumors (mainly leukemia, lymphoma and multiple myeloma) from cellular level studies, animal studies, clinical trials, drug combination, etc. BETi has a promising future in hematologic tumors, and future research directions may focus on the combination with other drugs to improve the efficacy.
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Artesunate (ART) has potent anticancer activity but it suffers from poor stability and low bioavailability in vivo due to the special endoperoxide moiety in the molecules. In this work, we fabricated programmable enzyme/reactive oxygen species (ROS) responsive ART complex carriers with size and charge adaptive regulation in order to improve stability and overcome biochemical hurdles of solid tumor. The complex carries (ART/AA-PAMAM@HA) were created by electrostatic interaction between dendrimer-ART/arachidonic acid (AA) (ART/AA-PAMAM) and hyaluronic acid (HA), which can proactively penetrate deeply into tumors and selective drug release. Specifically, ART induced Fenton reaction and produced a mass of ROS and lipid peroxides (LPO), leading to the depressing of GSH level and glutathione peroxidase 4 (GPX4) activity. Meanwhile, exogenous AA further promoted the accumulation of LPO by cascade regulating ferroptosis pathway. In the anti-tumor efficacy in vivo, the tumor inhibition ratio was achieved to 46.92%. This work shows a new anti-tumor strategy triggering ferroptosis via regulating redox homeostasis.
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Ferroptosis , Neoplasias , Humanos , Artesunato/farmacología , Especies Reactivas de Oxígeno , Disponibilidad Biológica , Ácido Hialurónico , Peróxidos LipídicosRESUMEN
Herein, five undescribed oleanane-type triterpenoid saponins, namely, psammosaponins A-E, along with nine known compounds, were isolated from the roots of Psammosilene tunicoides. Moreover, part of the ethanolic extract of P. tunicoides was acid-hydrolyzed and three aglycones were isolated from the resulting hydrolysate. The structures of all compounds were established through extensive analysis involving 1D and 2D NMR experiments, HRESIMS measurements, chemical derivatization, and comparison of spectroscopic data with the values reported in the literature. In all, 10 of the isolated saponins and the three aglycones were evaluated in the acetic acid-induced writhing model for their antinociceptive activity. At a dose of 40 mg/kg, these compounds exhibited significant inhibitory effects on the mouse writhing response, with inhibitions ranging from 31.9% to 79.3%. In addition, the structure-activity relationships of the isolates were discussed. Among the isolates, quillaic acid 3-O-glucuronide and 16α-hydroxygypsogenic acid showed better antinociceptive activity with inhibitions of 79.3% and 73.7%, respectively. Both isolates also exhibited antinociceptive activities in hot plate and formalin tests on mice. Their antinociceptive mechanism was explored in lipopolysaccharide-stimulated RAW 264.7 cells. These isolates could significantly inhibit the production of nitric oxide and interleukin-6 and downregulate the expression levels of inducible NO synthase, COX-1, and COX-2.