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Diabetic wounds arise great attention as they are difficult to heal and easily suffer from serious bacterial infection. However, the overuse of antibiotics increases the resistance of bacteria and makes common drugs ineffective. Here, we developed a photothermal hydrogel (TFP/NP) composed of tremella fuciformis polysaccharides (TFPs) and cuttlefish ink-derived melanin nanoparticles (NPs). The NPs can produce reliable photothermal effects under near-infrared laser (NIR) irradiation and help to remove the bacteria in the wounds, while TFPs were able to form hydrogel frameworks which possessed anti-inflammatory effects and could be applied to promote wound healing. The TFP/NP hydrogels produced stable thermal effects under NIR irradiation and could continuously kill bacteria. The experiment on a full-layer skin wound sMRSA activity and could improve the healing efficiency. The wounds of the mice could be repaired within 14 days after reasonable treatment. In addition, the hydrogels play significant roles in promoting collagen deposition, anti-inflammation, angiogenesis, and cell proliferation during the therapeutic process. This research provides a simple and effective method for the therapy of bacterial infection wounds through the synergistic effect of TFPs and NPs.
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The emergence of 16S rRNA and metagenomic sequencing has gradually revealed the close relationship between dysbiosis and colorectal cancer (CRC). Recent studies have confirmed that intestinal dysbiosis plays various roles in the occurrence, development, and therapeutic response of CRC. Perturbation of host immunity is one of the key mechanisms involved. The intestinal microbiota, or specific bacteria and their metabolites, can modulate the progression of CRC through pathogen recognition receptor signaling or via the recruitment, polarization, and activation of both innate and adaptive immune cells to reshape the protumor/antitumor microenvironment. Therefore, the administration of gut bacteria to enhance immune homeostasis represents a new strategy for the treatment of CRC. In this review, we cover recent studies that illuminate the role of gut bacteria in the progression and treatment of CRC through orchestrating the immune response, which potentially offers insights for subsequent transformative research.
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Limaprost, an orally administered analogue of prostaglandin E1, possesses potent vasodilatory, antiplatelet, and cytoprotective properties. Due to its extremely low therapeutic doses and exceedingly low plasma concentrations, the pharmacokinetic and bioequivalence studies of limaprost necessitate a highly sensitive quantitative method with a sub-pg/mL level of lower limit of quantification. Moreover, the intensity of endogenous interferences can even exceed the maximum concentration level of limaprost in human plasma, presenting further challenge to the quantification of limaprost. As a result, existing methods have not yet met the necessary level of sensitivity, selectivity, and throughput needed for the quantitative analysis of limaprost in pharmacokinetic and bioequivalence investigations. This study presents a new methodology that combines differential mobility spectrometry (DMS) with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and utilizes a distinctive strategy to achieve more accurate DMS conditions. This integration yields a method that is currently the most sensitive and features the shortest analytical time, making it the sole technique capable of meeting the requirements for limaprost pharmacokinetic and bioequivalence investigations. This method demonstrates robustness and is successfully employed in a pharmacokinetic investigation of limaprost in human subjects, underscoring that the combination of DMS with LC-MS/MS serves as an efficacious strategy for overcoming the challenges inherent in analyzing biological samples afflicted by multiple interferences.
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Alprostadil , Espectrometría de Masas en Tándem , Espectrometría de Masas en Tándem/métodos , Humanos , Alprostadil/farmacocinética , Alprostadil/análogos & derivados , Alprostadil/sangre , Alprostadil/análisis , Cromatografía Liquida/métodos , Límite de Detección , Cromatografía Líquida con Espectrometría de MasasRESUMEN
The increasing prevalence of drug-resistant Escherichia coli (E. coli) resulting from the excessive utilization of antibiotics necessitates the immediate exploration of alternative approaches to counteract pathogenic E. coli. Phages, with their unique antibacterial mechanisms, are considered promising candidates for treating bacterial infections. Herein, we isolated a lytic Escherichia phage Tequatrovirus YZ2 (phage YZ2), which belongs to the genus Tequatrovirus. The genome of phage YZ2 consists of 168,356 base pairs with a G + C content of 35.34% and 269 putative open reading frames (ORFs). Of these, 146 ORFs have been annotated as functional proteins associated with nucleotide metabolism, structure, transcription, DNA replication, translation, and lysis. In the mouse model of a skin wound infected by E. coli, phage YZ2 therapy significantly promoted the wound healing. Furthermore, histopathological analysis revealed reductions in IL-1ß and TNF-α and increased VEGF levels, indicating the potential of phages as effective antimicrobial agents against E. coli infection.
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Infecciones por Escherichia coli , Escherichia coli , Genoma Viral , Infección de Heridas , Animales , Escherichia coli/virología , Escherichia coli/genética , Ratones , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/tratamiento farmacológico , Infección de Heridas/microbiología , Infección de Heridas/virología , Infección de Heridas/tratamiento farmacológico , Sistemas de Lectura Abierta , Colifagos/genética , Colifagos/fisiología , Terapia de Fagos , Modelos Animales de Enfermedad , Cicatrización de Heridas , Composición de Base , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética , Interleucina-1beta/genética , Interleucina-1beta/metabolismoRESUMEN
Oxidative stress contributes to the pathology of cerebral ischemia/reperfusion (I/R) injury. Galectin-1 has shown an anti-oxidative stress effect. The present study investigated whether this anti-oxidative stress effect can account for the neuroprotective actions of galectin-1 induced by cerebral I/R injury. A cerebral I/R injury model was created in C57Bl/6 mice by transient occlusion of the middle cerebral artery, after which the mice were treated with galectin-1 for 3 days. Infarct volumes were measured. A rotarod test and neurological deficit score assessment was performed to evaluate the neurological deficits. Oxidative stress was evaluated by measuring the levels of reactive oxygen species (ROS) and lipid peroxidation malondialdehyde (MDA), while the anti-oxidative stress status was assessed by measuring molecules such as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidation enzyme (GSH-Px) in the ischemic cerebral hemisphere of mice. The inflammatory cytokines, including Interleukin 1 (IL-1), IL-6 and tumor necrosis factor alpha (TNF-α) were measured, and the expression of microglia was evaluated by immunohistochemistry in the ischemic cerebral hemisphere of mice. Galectin-1 treatment ameliorated neurological deficits and reduced infarct volumes in the mice model with cerebral I/R injury. Moreover, it was demonstrated that galectin-1 can significantly alleviate cerebral I/R injury in the ischemic cerebral hemisphere by decreasing the production of ROS and MDA, but increasing the production of CAT, SOD and GSH-Px. Galectin-1 treatment decreased microglia expression, and IL-1, IL-6 and TNF-α levels in the ischemic cerebral hemisphere of mice. Galectin-1 could improve the outcome of cerebral I/R injury by alleviating oxidative stress. Moreover, the neuroprotective effect of galectin-1 in cerebral ischemia could be related to its anti-oxidative stress effect.
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Ever-growing demands for zinc-air batteries (ZABs) call for the development of advanced electrocatalysts. Single-atom catalysts (SACs), particularly those for isolating non-noble metals (NBMs), are attracting great interest due to their merits of low cost, high atom utilization efficiency, structural tunability, and extraordinary activity. Rational design of advanced NBM SACs relies heavily on an in-depth understanding of reaction mechanisms. To gain a better understanding of the reaction mechanisms of oxygen electrocatalysis in ZABs and guide the design and optimization of more efficient NBM SACs, we herein organize a comprehensive review by summarizing the fundamental concepts in the field of ZABs and the recent advances in the reported NBM SACs. Moreover, the selection of NBM elements and supports of SACs and some effective strategies for enhancing the electrochemical performance of ZABs are illustrated in detail. Finally, the challenges and future direction in this field of ZABs are also discussed.
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BACKGROUND AIMS: Dendritic cell (DC)-based immunotherapy is a promising approach to treat cancer. However, key aspects governing the reproducible manufacturing of high-quality DC remain incompletely defined. Here, we show that the time window between leukapheresis and DC manufacturing is critical. METHODS: Transcriptomic profiling by RNA-seq was used to unbiasedly characterize cellular states during each step of DC manufacturing process, and functional assays were used to determine the anti-tumor activities of DC. RESULTS: During preclinical development of a DC-based cytotherapy platform, CUD-002 (NCT05270720), we found that DC quality varied among different batches, even though commonly used DC maturation markers CD80, CD83 and CD86 were indistinguishable. Multivariate analysis indicated that DC quality was negatively associated with the shipping time from the leukapheresis site to the manufacturing center. To investigate the potential effect of shipping time, we stored leukapheresis materials from three donors for 0, 1, 2 or 3 days before DC manufacturing. For each step, we carried out RNA-seq analysis to unbiasedly characterize cellular states. Integrated bioinformatic analyses indicated that longer storage time reduced the expression of several transcription factors to attenuate interferon pathways. CONCLUSIONS: Consistently, we found that 3-day storage of leukapheresis materials significantly lowered the efficiency to generate DC but also impaired DC responses to inflammatory signals, resulting in inferior antigen-presentation and cytotoxic T-cell activities. Thus, we recommend using leukapheresis materials within 48 h to manufacture therapeutic DCs.
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Leucaféresis , Neoplasias , Humanos , Leucaféresis/métodos , Neoplasias/metabolismo , Inmunoterapia/métodos , Células Dendríticas/fisiologíaRESUMEN
Binary SiO2-CaO mesoporous bioactive glass nanoparticles (MBGNs) are multifunctional biomaterials able to promote osteogenic, angiogenic, and immunomodulatory activities. MBGNs have been applied in a variety of tissue regeneration strategies. However, MBGNs lack strong antibacterial activity and current strategies (loading of antibacterial ions or antibiotics) toward enhanced antibacterial activity may cause cytotoxicity or antibiotic resistance. Here we engineered MBGNs using bacteriophages (phages) to enhance the antibacterial activity. Salmonella Typhimurium (S. T) phage PFPV25.1 that can infect Salmonella enterica serovar Typhimurium strain LT2 was used as a model phage to engineer MBGNs. MBGNs were first modified with amine groups to enhance the affinity between phages and MBGNs surfaces. Afterward, the physicochemical and antibacterial activity of phage-engineered MBGNs was evaluated. The results showed that S. T phage PFPV25.1 was successfully bound onto MBGNs surfaces without losing their bioactivity. A higher quantity of phages could be bounded onto amine-functionalized MBGNs than onto non-functionalized MBGNs. Phages on amine-functionalized MBGNs exhibited higher antibacterial activity. The stability test showed that phages could remain on amine-functionalized MBGNs for over 28 days. This work provides valuable information on developing phage-modified MBGNs as a new and effective antibacterial system for biomedical applications.
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Bacteriófagos , Nanopartículas , Dióxido de Silicio , Antibacterianos/farmacología , Aminas , VidrioRESUMEN
BACKGROUND: KRASG12C inhibitors (KRASG12Ci) AMG510 and MRTX849 have shown promising efficacy in clinical trials and been approved for the treatment of KRASG12C-mutant cancers. However, the emergence of therapy-related drug resistance limits their long-term potential. This study aimed to identify the critical mediators and develop overcoming strategies. METHODS: By using RNA sequencing, RT-qPCR and immunoblotting, we identified and validated the upregulation of c-Myc activity and the amplification of the long noncoding RNA ST8SIA6-AS1 in KRASG12Ci-resistant cells. The regulatory axis ST8SIA6-AS1/Polo-like kinase 1 (PLK1)/c-Myc was investigated by bioinformatics, RNA fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down and chromatin immunoprecipitation. Gain/loss-of-function assays, cell viability assay, xenograft models, and IHC staining were conducted to evaluate the anti-cancer effects of co-inhibition of ST8SIA6-AS1/PLK1 pathway and KRAS both in vitro and in vivo. RESULTS: KRASG12Ci sustainably decreased c-Myc levels in responsive cell lines but not in cell lines with intrinsic or acquired resistance to KRASG12Ci. PLK1 activation contributed to this ERK-independent c-Myc stability, which in turn directly induced PLK1 transcription, forming a positive feedback loop and conferring resistance to KRASG12Ci. ST8SIA6-AS1 was found significantly upregulated in resistant cells and facilitated the proliferation of KRASG12C-mutant cancers. ST8SIA6-AS1 bound to Aurora kinase A (Aurora A)/PLK1 and promoted Aurora A-mediated PLK1 phosphorylation. Concurrent targeting of KRAS and ST8SIA6-AS1/PLK1 signaling suppressed both ERK-dependent and -independent c-Myc expression, synergistically led to cell death and tumor regression and overcame KRASG12Ci resistance. CONCLUSIONS: Our study deciphers that the axis of ST8SIA6-AS1/PLK1/c-Myc confers both intrinsic and acquired resistance to KRASG12Ci and represents a promising therapeutic target for combination strategies with KRASG12Ci in the treatment of KRASG12C-mutant cancers.
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BACKGROUND: Caspase 6 is an essential regulator in innate immunity, inflammasome activation and host defense. We aimed to characterize the causal mechanism of Caspase 6 in liver sterile inflammatory injury. METHODS: Human liver tissues were harvested from patients undergoing ischemia-related hepatectomy to evaluate Caspase 6 expression. Subsequently, we created Caspase 6-knockout (Caspase 6KO) mice to analyze roles and molecular mechanisms of macrophage Caspase 6 in murine models of liver ischemia/reperfusion (IR) injury. RESULTS: In human liver biopsies, Caspase 6 expression was positively correlated with more severe histopathological injury and higher serum ALT/AST level at one day postoperatively. Moreover, Caspase 6 was mainly elevated in macrophages but not hepatocytes in ischemic livers. Unlike in controls, the Caspase 6-deficient livers were protected against IR injury, as evidenced by inhibition of inflammation, oxidative stress and iron overload. Disruption of macrophage NF-κB essential modulator (NEMO) in Caspase 6-deficient livers deteriorated liver inflammation and ferroptosis. Mechanistically, Caspase 6 deficiency spurred NEMO-mediated IκBα phosphorylation in macrophage. Then phosphorylated-inhibitor of NF-κBα (p-IκBα) co-localized with receptor-interacting serine/ threonine-protein kinase 1 (RIPK1) in the cytoplasm to degradate RIPK1 under inflammatory conditions. The disruption of RIPK1-IκBα interaction preserved RIPK1 degradation, triggering downstream apoptosis signal-regulating kinase 1 (ASK1) phosphorylation and inciting NIMA-related kinase 7/NOD-like receptor family pyrin domain containing 3 (NEK7/NLRP3) activation in macrophages. Moreover, ablation of macrophage RIPK1 or ASK1 diminished NEK7/NLRP3-driven inflammatory response and dampened hepatocyte ferroptosis by reducing HMGB1 release from macrophages. CONCLUSIONS: Our findings underscore a novel mechanism of Caspase 6 mediated RIPK1-IκBα interaction in regulating macrophage NEK7/NLRP3 function and hepatocytes ferroptosis, which provides therapeutic targets for clinical liver IR injury. Video Abstract.
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Caspasa 6 , Inmunidad Innata , Transducción de Señal , Animales , Humanos , Ratones , Caspasa 6/metabolismo , Inflamación/metabolismo , Isquemia/metabolismo , Hígado/metabolismo , Ratones Endogámicos C57BL , Inhibidor NF-kappaB alfa/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismoRESUMEN
The intercalation of H into Pd-based nanocatalysts plays a crucial role in optimizing the catalytic performance by tailoring the structural and electronic properties. We herein present a comprehensive review about the recent progress of interstitial hydrogen atom modified Pd-based nanocatalysts for various energy-related electrocatalytic reactions. Before systematically manifesting the great potential of Pd-based hydrides for electrocatalytic applications, we have briefly illustrated the synthesis strategies and corresponding mechanisms for the Pd-based hydrides. This is followed by a comprehensive discussion about the fundamentals and functions of H intercalation in tailoring their physicochemical and electrochemical properties. Subsequently, we focus on the widespread application of Pd-based hydrides for electrocatalytic reactions, with the emphasis on the role of H intercalation played in determining electrocatalytic performance. Finally, the future direction and perspectives regarding the development of more efficient Pd-based hydrides are also manifested.
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Weight gain is a common harmful side effect of atypical antipsychotics used for schizophrenia treatment. Conversely, treatment with the novel phosphodiesterase-10A (PDE10A) inhibitor MK-8189 in clinical trials led to significant weight reduction, especially in patients with obesity. This study aimed to understand and describe the mechanism underlying this observation, which is essential to guide clinical decisions. We hypothesized that PDE10A inhibition causes beiging of white adipose tissue (WAT), leading to weight loss. Magnetic resonance imaging (MRI) methods were developed, validated, and applied in a diet-induced obesity mouse model treated with a PDE10A inhibitor THPP-6 or vehicle for measurement of fat content and vascularization of adipose tissue. Treated mice showed significantly lower fat fraction in white and brown adipose tissue, and increased perfusion and vascular density in WAT versus vehicle, confirming the hypothesis, and matching the effect of CL-316,243, a compound known to cause adipose tissue beiging. The in vivo findings were validated by qPCR revealing upregulation of Ucp1 and Pcg1-α genes, known markers of WAT beiging, and angiogenesis marker VegfA in the THPP-6 group. This work provides a detailed understanding of the mechanism of action of PDE10A inhibitor treatment on adipose tissue and body weight and will be valuable to guide both the use of MK-8189 in schizophrenia and the potential application of the target for weight loss indication.
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Tejido Adiposo Blanco , Inhibidores de Fosfodiesterasa , Ratones , Animales , Inhibidores de Fosfodiesterasa/farmacología , Obesidad/genética , Tejido Adiposo Pardo/patología , Pérdida de Peso , Imagen por Resonancia Magnética/efectos adversosRESUMEN
Elymus sibiricus L. is a perennial forage species that has potential to serve as a forage source in livestock grazing systems. However, E. sibiricus has been shown to have a rapid and substantial reduction of aboveground biomass and seed yield after 3 or 4 years and an accelerated aging process. To determine possible aging mechanisms, we planted E. sibiricus seeds in triplicate blocks in 2012, 2015, and 2016, respectively, and harvested samples of leaves and roots at the jointing and heading stages in 2018 and 2019 to determine oxidative indices and endogenous hormones. The fresh aboveground biomass of 4- and 5-year old plants declined by 34.2% and 52.4% respectively compared with 3-year old plants, and the seed yield declined by 12.7% and 34.1%, respectively. The water content in leaves was 51.7%, 43.3%, and 35.6%, and net photosynthesis was 7.73, 6.35, and 2.08 µmol/m2·s in 3-, 4-, and 5-year old plants, respectively. The superoxide anion radical generation rate in leaves and roots did not show any aging pattern. There was a non-significant increase in malondialdehyde concentration with plant age, particularly in leaves and roots at the heading stage in 2019. The superoxide dismutase activity showed a declining trend with age of plant roots at the jointing stage in both 2018 and 2019. The peroxidase activity declined with plant age in both leaves and roots, for example, and the catalase activity in roots 4- and 7-year old plants declined by 13.8% and 0.85%, respectively, compared to 3-year old plants at the heading stage in 2018. Therefore, the reduced capacity of the antioxidant system may lead to oxidative stress during plant aging process. Overall, the concentrations of plant hormones, auxin (IAA), gibberellin (GA), zeatin (ZT), and abscisic acid (ABA) were significantly lower in roots than in leaves. The IAA concentration in leaves and roots exhibited different patterns with plant age. The ZT concentrations in leaves of 3-year old plants was 2.39- and 2.62-fold of those in 4- and 7-year old plants, respectively at the jointing stage, and in roots, the concentration declined with plant age. The changes in the GA concentration with plant age varied between the physiological stages and between years. The ABA concentrations appeared to increase with plant age, particularly in leaves. In conclusion, the aging process of E. sibiricus was apparently associated with an increase in oxidative stress, a decrease of ZT and an increase of ABA, particularly in roots. These findings highlight the effects of plant age on the antioxidant and endogenous hormone activity of E. sibiricus. However, these plant age-related trends showed variations between plant physiological stages and between harvest years that needs to be researched in the future to develop strategies to manage this forage species.
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Antioxidantes , Elymus , Elymus/fisiología , Tibet , Reguladores del Crecimiento de las Plantas , Ácido Abscísico , Zeatina , HormonasRESUMEN
The frequency of p53 mutations in colorectal cancer (CRC) is approximately 40-50%. A variety of therapies are being developed to target tumors expressing mutant p53. However, potential therapeutic targets for CRC expressing wild-type p53 are rare. In this study, we show that METTL14 is transcriptionally activated by wild-type p53 and suppresses tumor growth only in p53-wild-type (p53-WT) CRC cells. METTL14 deletion promotes both AOM/DSS and AOM-induced CRC growth in mouse models with the intestinal epithelial cell-specific knockout of METTL14. Additionally, METTL14 restrains aerobic glycolysis in p53-WT CRC, by repressing SLC2A3 and PGAM1 expression via selectively promoting m6 A-YTHDF2-dependent pri-miR-6769b/pri-miR-499a processing. Biosynthetic mature miR-6769b-3p and miR-499a-3p decrease SLC2A3 and PGAM1 levels, respectively, and suppress malignant phenotypes. Clinically, METTL14 only acts as a beneficial prognosis factor for the overall survival of p53-WT CRC patients. These results uncover a new mechanism for METTL14 inactivation in tumors and, most importantly, reveal that the activation of METTL14 is a critical mechanism for p53-dependent cancer growth inhibition, which could be targeted for therapy in p53-WT CRC.
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Neoplasias Colorrectales , MicroARNs , Animales , Ratones , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Transformación Celular Neoplásica/genética , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica , Glucólisis/genética , MicroARNs/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
TMB-5 nucleating agent (NA) treated by different solvents were used as the ß-NA of iPP. The effects of temperature on the crystalline structure of different iPP/TMB-5, as well as the crystallization and melting behaviors were investigated. It was found that strong polar solvent treated TMB-5 (TMB-5DMSO and TMB-5DMF) could induce more ß-crystal at high Tc = 140 °C than the other TMB-5 NAs, while the ß-crystal inducing efficiency of untreated TMB-5 (TMB-5UT) and non-polar solvent treated TMB-5 (TMB-5LP) is seriously reduced at high Tc = 140 °C. TMB-5DMSO can induce a high and stable content of ß-crystal with Kß = 83-94% within Tc = 90-140 °C, and TMB-5ODCB can induce a high content of ß-crystal with Kß > 91.3% within Tc = 90-130 °C. TMB-5DMF is the most temperature-sensitive one, but can induce a high fraction of ß-crystal with Kß > 92% both at low Tc = 90 °C and high Tc = 140 °C. High temperature pre-crystallization at Tpc = 150 °C tremendously reduces the ß-crystal inducing efficiency of all TMB-5 NAs. TMB-5UT and TMB-5LP exhibit higher nucleating efficiency than TMB-5DMSO, TMB-5DMF and TMB-5ODCB. During the non-isothermal crystallization process, TMB-5UT induced ß-crystal possesses higher structural perfection and stability, while TMB-5LP is more likely to induce α-crystal with considerable quantity and stability. The structural perfection and stability of TMB-5 induced ß-crystal can be enhanced with appropriate increasing of Tc.
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In order to investigate the optimization of the performance and structure of a tungsten crucible CVD reactor, the CFD simulation method was used in this paper to simulate the internal flow of the tungsten crucible CVD reactor. The velocity distribution and temperature distribution in the reactor were obtained. The simulation results show that the axial and radial heat convection will occur between the susceptor and the outer wall surface, but the axial heat convection is more intense. Moreover, it was found that the temperature distribution in the CVD reactor was more uniform and reasonable when the upper gas inlet was applied, which was beneficial to the reduction and deposition processes of tungsten. The molar ratio of H2 to WF6 has a great influence on the deposition rate of tungsten, and excess H2 is not conducive to the deposition of tungsten. Thermal radiation has a great influence on the temperature distribution of CVD reactors. It cannot be neglected.
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To explore highly selective targeting molecules of colorectal cancer (CRC) is a challenge. We previously identified a twelve-amino acid peptide (LPKTVSSDMSLN, namely P-LPK) by phage display technique which may specifically binds to CRC cells. Here we show that P-LPK selectively bind to a panel of human CRC cell lines and CRC tissues. In vivo, Gallium-68 (68Ga) labeled P-LPK exhibits selective accumulation at tumor sites. Then, we designed a peptide-conjugated drug comprising P-LPK and camptothecin (CPT) (namely P-LPK-CPT), and found P-LPK-CPT significantly inhibits tumor growth with fewer side effects in vitro and in vivo. Furthermore, through co-immunoprecipitation and molecular docking experiment, the glutamine transporter solute carrier 1 family member 5 (SLC1A5) was identified as the possible target of P-LPK. The binding ability of P-LPK and SLC1A5 is verified by surface plasmon resonance and immunofluorescence. Taken together, P-LPK-CPT is highly effective for CRC and deserves further development as a promising anti-tumor therapeutic for CRC, especially SLC1A5-high expression type.
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Camptotecina , Neoplasias Colorrectales , Humanos , Camptotecina/farmacología , Camptotecina/química , Simulación del Acoplamiento Molecular , Péptidos/metabolismo , Glutamina/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Antígenos de Histocompatibilidad Menor/metabolismo , Sistema de Transporte de Aminoácidos ASC/metabolismoRESUMEN
Chemotherapy is one of the main treatments for colorectal cancer, but systemic toxicity severely limits its clinical use. Packaging hydrophobic chemotherapeutic drugs in targeted nanoparticles greatly improve their efficacy and reduce side effects. We previously identified a novel colorectal cancer specific binding peptide P-LPK (LPKTVSSDMSLN) from phage display peptide library. Here we designed a self-assembled paclitaxel (PTX)-loaded nanoparticle (LPK-PTX NPs). LPK-PTX NPs displayed a superior intracellular internalization and improved tumor cytotoxicity in vitro. Cy5.5-labeled LPK-PTX NPs showed much higher tumor accumulation in colorectal cancer-bearing mice. Furthermore, LPK-PTX NPs exhibit enhanced antitumor activity and decreased systemic toxicity in colorectal cancer patient-derived xenografts (PDX) model. The excellent in vitro and in vivo antitumor efficacy proves the improved targeting drug delivery, suggesting that peptide P-LPK has potential to provide a novel approach for enhanced drug delivery with negligible systemic toxicity.
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ABSTRACT Background: We aimed to investigate the clinical efficacy and safety of transurethral flexible ureteroscopic incision and drainage with holmium laser in the treatment of parapelvic renal cysts. Materials and Methods: Between October 2017 and April 2021, the clinical data of 65 patients with parapelvic renal cysts were evaluated retrospectively. Thirty-one patients with parapelvic cysts (Group 1) underwent a transurethral flexible ureteroscopic incision and drainage with a holmium laser, whereas the other 34 patients (Group 2) underwent retroperitoneal laparoscopic unroofing. The patients' clinical features were documented. The surgery time, intraoperative blood loss, hospitalization time, complications and cyst size were recorded and statistically assessed one year following the procedure. Results: All of the patients were successfully treated with flexible ureteroscopic incision and drainage or retroperitoneal laparoscopic unroofing. In terms of clinical parameters, such as age, gender, BMI, location, cyst size, and Bosniak classification of renal cysts, no statistically significant difference was detected between Groups 1 and 2. Compared to the control group (Group 2), Group 1 demonstrated a shorter surgery duration, less intraoperative blood loss, and a shorter hospital stay (p < 0.001). However, no significant differences in complications and cyst size were observed between the two groups one year after the surgery (p > 0.05). Conclusions: Transurethral flexible ureteroscopic incision and drainage with holmium laser in the treatment of parapelvic renal cysts has obvious advantages over traditional surgery, and is worthy of advancement and application, but its long-term effect needs further follow-up studies.