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1.
Front Microbiol ; 15: 1373402, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38605714

RESUMO

Introduction: The risk of ketosis is assessed by monitoring changes in plasma metabolites and cow behavior during the peripartum period. However, little is known about changes in the fecal bile acid and microbiota of cows before parturition. Therefore, this study clarified the bile acid profile and screened potential warning biomarkers in heifers 7 days before calving. Methods: Ninety healthy cows were tracked in the transition period, and plasma and feces were collected 7 days before calving, on calving day, and 7 days after calving. The cows were divided into ketosis and healthy groups based on the blood ß-hydroxybutyric acid levels from day 7 after calving. The levels of serum biochemical indices were measured at three time points using commercial kits. Ten cows in the ketosis group (KET-7) and 10 healthy cows (HEA-7) were randomly selected 7 days before calving for metabolome and 16S rRNA amplicon sequencing. Results: No significant differences in serum energy-related indices were observed 7 days before calving. The major bile acids in the feces of the KET-7 group were non-conjugated secondary bile acids (UnconSBA). Differential bile acids were primarily derived from UnconSBA. The potential ketosis warning metabolite in feces for 7 days before delivery was isodeoxycholic acid. The abundance of Rikenellaaceae-RC9-gut-group in the KET-7 group increased, whereas the abundance of Oscillospiraceae UCG-010 bacteria significantly decreased. Lactobacillus and Prevotella-9 in feces were potential warning biomarkers for ketosis in dairy cows 7 days before calving. The variation in differential bile acids in the plasma, consistent with the feces, was mainly derived from UnconSBA. Lithocholic acid in the plasma was a potential ketosis warning metabolite 7 days before delivery. Conclusion: Ketotic cows experienced bile acid metabolism disorders 7 days before calving, and the gut microbiota was closely related to bile acid metabolism disorders. Future studies should investigate the relationship between secondary bile acids and the development of ketosis.

2.
Ultrason Sonochem ; 105: 106873, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38608436

RESUMO

Starting from the consideration of the structure of human milk fat globule (MFG), this study aimed to investigate the effects of ultrasonic treatment on milk fat globule membrane (MFGM) and soy lecithin (SL) complexes and their role in mimicking human MFG emulsions. Ultrasonic power significantly affected the structure of the MFGM-SL complex, further promoting the unfolding of the molecular structure of the protein, and then increased solubility and surface hydrophobicity. Furthermore, the microstructure of mimicking MFG emulsions without sonication was unevenly distributed, and the average droplet diameter was large. After ultrasonic treatment, the droplets of the emulsion were more uniformly dispersed, the particle size was smaller, and the emulsification properties and stability were improved to varying degrees. Especially when the ultrasonic power was 300 W, the mimicking MFG emulsion had the highest encapsulation rate and emulsion activity index and emulsion stability index were increased by 60.88 % and 117.74 %, respectively. From the microstructure, it was observed that the spherical droplets of the mimicking MFG emulsion after appropriate ultrasonic treatment remain well separated without obvious flocculation. This study can provide a reference for the screening of milk fat globules mimicking membrane materials and the further utilization and development of ultrasound in infant formula.

3.
Int J Antimicrob Agents ; : 107172, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38608845

RESUMO

OBJECTIVES: This study aimed to discover novel antifungals targeting Candida albicans glyceraldehyde-3-phosphate dehydrogenase (CaGAPDH), have an insight into inhibitory mode, and provide evidence supporting CaGAPDH as a target for new antifungals. METHODS: Virtual screening was utilized to discover inhibitors of CaGAPDH. The inhibitory effect on cellular GAPDH was evaluated by determining the levels of ATP, NAD, NADH, etc., as well as examining GAPDH mRNA and protein expression. The role of GAPDH inhibition in C. albicans was supported by drug affinity responsive target stability and overexpression experiments. The mechanism of CaGAPDH inhibition was elucidated by Michaelis-Menten enzyme kinetics and site-specific mutagenesis based on docking. Chemical synthesis was used to produce an improved candidate. Different sources of GAPDH were used to evaluate inhibitory selectivity across species. In vitro and in vivo antifungal tests, along with antibiofilm activity, were carried out to evaluate antifungal potential of GAPDH inhibitors. RESULTS: A natural xanthone was identified as the first competitive inhibitor of CaGAPDH. It demonstrated in vitro anti-C. albicans potential but also caused hemolysis. XP-W, a synthetic side-chain-optimized xanthone, demonstrated a better safety profile, exhibiting a 50-fold selectivity for CaGAPDH over human GAPDH. XP-W also exhibited potent antibiofilm activity and displayed broad-spectrum anti-Candida activities in vitro and in vivo, including multi-azole-resistant C. albicans. CONCLUSION: These results demonstrate for the first time that CaGAPDH is a valuable target for antifungal drug discovery, and XP-W provides a promising lead.

4.
Ann Nutr Metab ; 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38631305

RESUMO

BACKGROUND: A major risk factor for neurodegenerative disorders is old age. Nutritional interventions that delay aging, such as calorie restriction (CR) and intermittent fasting (IF), as well as pharmaceuticals that affect the pathways linking nutrition and aging processes, have been developed in recent decades and have been shown to alleviate the effects of aging on the brain. SUMMARY: CR is accomplished by alternating periods of ad libitum feeding and fasting. In animal models, IF has been shown to increase lifespan and slow the progression and severity of age-related pathologies such as cardiovascular and neurodegenerative diseases and cancer. According to recent research, dietary changes can help older people with dementia retain brain function. However, the mechanisms underlying the neuroprotective effect of IF on the aging brain and related questions in this area of study (i.e., the potential of IF to treat neurodegenerative disorders) remain to be examined. KEY MESSAGES: This review addresses the hypothesis that IF may have translational potential in protecting the aged brain while summarizing the research supporting the putative neuroprotective mechanisms of IF in animal models. Additionally, given the emerging understanding of the connection between aging and dementia, our investigations may offer a fresh perspective on the use of dietary interventions for enhancing brain function and preventing dementia in elderly individuals. Finally, the absence of guidelines regarding the application of IF in patients hampers its broad utilization in clinical practice, and further studies are needed to improve our knowledge of the long-term effects of IF on dementia before it can be widely prescribed. In conclusion, IF may be an ancillary intervention for preserving memory and cognition in elderly individuals.

5.
J Vis Exp ; (205)2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38587395

RESUMO

This paper presents a novel and efficient method for certifying primary organs involved in secondary metabolite synthesis. As the most important secondary metabolite in Parispolyphylla var. yunnanensis (Franch.) Hand. -Mzt. (PPY), Paris saponin (PS) has a variety of pharmacological activities and PPY is in increasing demand. This study established leaf, rhizome, and stem-vascular-bundle 13C6-Glucose feeding and non-feeding four treatments to precisely certify the primary organs involved in Paris saponins VII (PS VII) synthesis. By combining liquid chromatography-mass spectrometry (LC-MS), the 13C/12C ratios of leaf, rhizome, stem, and root in different treatments were quickly and accurately calculated, and four types of PS isotopic ion peak(M-) ratios were found: (M+1) -/M-, (M+2) -/M-, (M+3) -/M- and (M+4) -/M-. The results showed that the ratio of 13C/12C in the rhizomes of the stem-vascular-bundle and rhizome feeding treatments was significantly higher than that in the non-feeding treatment. Compared to the non-feeding treatment, the ratio of PS VII molecules (M+2) -/M- in the leaves increased significantly under leaf and stem-vascular-bundle feeding treatments. Simultaneously, compared to the non-feeding treatment, the ratio of PS VII molecules (M+2) -/M- in the leaves under rhizome treatment showed no significant difference. Furthermore, the ratio of PS VII molecules (M+2) -/M- in the stem, root, and rhizome showed no differences among the four treatments. Compared to the non-feeding treatment, the ratio of the Paris saponin II (PS II) molecule (M+2) -/M- in leaves under leaf feeding treatment showed no significant difference, and the (M+3) -/M- ratio of PS II molecules in leaves under leaf feeding treatment were lower. The data confirmed that the primary organ for the synthesizing of PS VII is the leaves. It lays the foundation for future identification of the primary organs and pathways involved in the synthesis of secondary metabolites in medicinal plants.


Assuntos
60705 , Espectrometria de Massas em Tandem , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida , Folhas de Planta
6.
Angew Chem Int Ed Engl ; : e202404952, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38588012

RESUMO

The vast bulk of polystyrene (PS), a major type of plastic polymers, ends up in landfills, which takes up to thousands of years to decompose in nature. Chemical recycling promises to enable lower-energy pathways and minimal environmental impacts compared with traditional incineration and mechanical recycling. Herein, we demonstrated that methanol as a hydrogen supplier assisted the depolymerization of PS (denoted as PS-MAD) into alkylbenzenes over a heterogeneous catalyst composed of Ru nanoparticles on SiO2. PS-MAD achieved a high yield of liquid products which accounted for 93.2 wt% of virgin PS at 280 oC for 6 h with the production rate of 118.1 mmolcarbon gcatal.-1 h-1. The major components were valuable alkylbenzenes (monocyclic aromatics and diphenyl alkanes), the sum of which occupied 84.3 wt% of liquid products. According to mechanistic studies, methanol decomposition dominates the hydrogen supply during PS-MAD, thereby restraining PS aromatization which generates by-products of fused polycyclic arenes and polyphenylenes.

7.
Adv Mater ; : e2400082, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38563579

RESUMO

Soft and stretchable conductors with high electrical conductivity and tissue-like mechanical properties are crucial for both on-skin and implantable electronic devices. Liquid metal-based conductors hold great promise due to their metallic conductivity and minimal stiffness. However, the surface oxidation of liquid metal particles in polymeric matrices poses a challenge in forming a continuous pathway for highly conductive elastic composites. Here, it is reported a printable composite material based on liquid metal and conducting polymer that undergoes a self-assembly process, achieving high conductivity (2089 S cm-1) in the bottom surface while maintaining an insulated top surface, high stretchability (>800%), and a modulus akin to human skin tissue. This material is further applied to fabricate skin-interfaced strain sensors and electromyogram sensors through 3D printing.

8.
J Exp Clin Cancer Res ; 43(1): 104, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38576051

RESUMO

BACKGROUND: Cholangiocarcinoma (CCA) comprises a heterogeneous group of biliary tract cancer. Our previous CCA mutation pattern study focused on genes in the post-transcription modification process, among which the alternative splicing factor RBM10 captured our attention. However, the roles of RBM10 wild type and mutations in CCA remain unclear. METHODS: RBM10 mutation spectrum in CCA was clarified using our initial data and other CCA genomic datasets from domestic and international sources. Real-time PCR and tissue microarray were used to detect RBM10 clinical association. Function assays were conducted to investigate the effects of RBM10 wild type and mutations on CCA. RNA sequencing was to investigate the changes in alternative splicing events in the mutation group compared to the wild-type group. Minigene splicing reporter and interaction assays were performed to elucidate the mechanism of mutation influence on alternative splicing events. RESULTS: RBM10 mutations were more common in Chinese CCA populations and exhibited more protein truncation variants. RBM10 exerted a tumor suppressive effect in CCA and correlated with favorable prognosis of CCA patients. The overexpression of wild-type RBM10 enhanced the ASPM exon18 exon skipping event interacting with SRSF2. The C761Y mutation in the C2H2-type zinc finger domain impaired its interaction with SRSF2, resulting in a loss-of-function mutation. Elevated ASPM203 stabilized DVL2 and enhanced ß-catenin signaling, which promoted CCA progression. CONCLUSIONS: Our results showed that RBM10C761Y-modulated ASPM203 promoted CCA progression in a Wnt/ß-catenin signaling-dependent manner. This study may enhance the understanding of the regulatory mechanisms that link mutation-altering splicing variants to CCA.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Mutação , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Via de Sinalização Wnt , Ductos Biliares Intra-Hepáticos/metabolismo , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Isoformas de Proteínas , Proteínas do Tecido Nervoso/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
9.
Materials (Basel) ; 17(7)2024 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-38612108

RESUMO

Tensile-compression fatigue deformation tests were conducted on AZ31 magnesium alloy at room temperature. Electron backscatter diffraction (EBSD) scanning electron microscopy was used to scan the microstructure near the fatigue fracture surface. It was found that lamellar {10-11}-{10-12} secondary twins (STs) appeared inside primary {10-11} contraction twins (CTs), with a morphology similar to the previously discovered {10-12}-{10-12} STs. However, through detailed misorientation calibration, it was determined that this type of secondary twin is {10-11}-{10-12} ST. Through calculation and analysis, it was found that the matrix was under compressive stress in the normal direction (ND) during fatigue deformation, which was beneficial for the activation of primary {10-11} CTs. The local strain accommodation was evaluated based on the geometric compatibility parameter (m') combined with the Schmid factor (SF) of the slip system, leading us to propose and discuss the possible formation mechanism of this secondary twin. The analysis results indicate that when the local strain caused by basal slip at the twin boundaries cannot be well transmitted, {10-11}-{10-12} STs are activated to coordinate the strain, and different loading directions lead to different formation mechanisms. Moreover, from the microstructure characterization near the entire fracture surface, we surmise that the presence of such secondary twins is not common.

10.
BMC Plant Biol ; 24(1): 261, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38594606

RESUMO

BACKGROUND: Rhubarb is one of common traditional Chinese medicine with a diverse array of therapeutic efficacies. Despite its widespread use, molecular research into rhubarb remains limited, constraining our comprehension of the geoherbalism. RESULTS: We assembled the genome of Rheum palmatum L., one of the source plants of rhubarb, to elucidate its genome evolution and unpack the biosynthetic pathways of its bioactive compounds using a combination of PacBio HiFi, Oxford Nanopore, Illumina, and Hi-C scaffolding approaches. Around 2.8 Gb genome was obtained after assembly with more than 99.9% sequences anchored to 11 pseudochromosomes (scaffold N50 = 259.19 Mb). Transposable elements (TE) with a continuous expansion of long terminal repeat retrotransposons (LTRs) is predominant in genome size, contributing to the genome expansion of R. palmatum. Totally 30,480 genes were predicted to be protein-coding genes with 473 significantly expanded gene families enriched in diverse pathways associated with high-altitude adaptation for this species. Two successive rounds of whole genome duplication event (WGD) shared by Fagopyrum tataricum and R. palmatum were confirmed. We also identified 54 genes involved in anthraquinone biosynthesis and other 97 genes entangled in flavonoid biosynthesis. Notably, RpALS emerged as a compelling candidate gene for the octaketide biosynthesis after the key residual screening. CONCLUSION: Overall, our findings offer not only an enhanced understanding of this remarkable medicinal plant but also pave the way for future innovations in its genetic breeding, molecular design, and functional genomic studies.


Assuntos
Rheum , Rheum/genética , Melhoramento Vegetal , Antraquinonas , Cromossomos , Tamanho do Genoma , Evolução Molecular
11.
Cancer Discov ; 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38563585

RESUMO

Glioblastoma (GBM) exhibits profound metabolic plasticity for survival and therapeutic resistance, while the underlying mechanisms remain unclear. Here, we show that GBM stem cells (GSCs) reprogram the epigenetic landscape by producing substantial amounts of phosphocreatine (PCr). This production is attributed to the elevated transcription of brain-type creatine kinase (CKB), mediated by Zinc finger E-box binding homeobox 1 (ZEB1). PCr inhibits the poly-ubiquitination of the chromatin regulator bromodomain containing protein 2 (BRD2) by outcompeting the E3 ubiquitin ligase SPOP for BRD2 binding. Pharmacological disruption of PCr biosynthesis by cyclocreatine leads to BRD2 degradation and a decrease in its targets' transcription, which inhibits chromosome segregation and cell proliferation. Notably, cyclocreatine treatment significantly impedes tumor growth and sensitizes tumors to a BRD2 inhibitor in mouse GBM models without detectable side effects. These findings highlight that high production of PCr is a druggable metabolic feature of GBM and a promising therapeutic target for GBM treatment.

12.
Opt Express ; 32(7): 12941-12949, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38571101

RESUMO

Replacing expensive silver with inexpensive copper for the metallization of silicon wafer solar cells can lead to significant reductions in material costs associated with cell production, but the susceptibility of the Cu material to oxidation remains a challenging issue to solve. In this study, we investigate copper metallization of Indium Tin Oxide surfaces to define copper grid electrodes for heterojunction cells. We propose a novel laser-induced selective metallization (LISM) method to fabricate large-scale copper electrodes for heterojunction solar cells at low cost. This study includes a comprehensive evaluation of the morphological characteristics and electrical properties of the electrodes. The effects of laser parameters on the morphology, composition, size, and conductivity of copper electrodes are investigated. The goal of establishing the process window is to obtain the optimal laser parameters for manufacturing highly conductive copper electrodes. These optimized parameters will then be employed to fabricate high-performance electrodes for solar cells. Furthermore, a detailed analysis of the mechanism underlying laser selective metallization is provided. The resulting Cu electrodes exhibit high conductivity and low resistivity of 1.98 × 10-5Ω.cm, demonstrating the potential of this method for efficient and cost-effective solar electrode production.

13.
Small ; : e2310158, 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38573962

RESUMO

The integration of one-selector-one-resistor crossbar arrays requires the selectors featured with high nonlinearity and bipolarity to prevent leakage currents and any crosstalk among distinct cells. However, a selector with sufficient nonlinearity especially in the frame of device miniaturization remains scarce, restricting the advance of high-density storage devices. Herein, a high-performance memory selector is reported by constructing a graphene/hBN/WSe2 heterostructure. Within the temperature range of 300-80 K, the nonlinearity of this selector varies from ≈103 - ≈104 under forward bias, and increases from ≈300 - ≈105 under reverse bias, the highest reported nonlinearity among 2D selectors. This improvement is ascribed to direct tunneling at low bias and Fowler-Nordheim tunneling at high bias. The tunneling current versus voltage curves exhibit excellent bipolarity behavior because of the comparable hole and electron tunneling barriers, and the charge transport polarity can be effectively tuned from N-type or P-type to bipolar by simply changing source-drain bias. In addition, the conceptual memory selector exhibits no sign of deterioration after 70 000 switching cycles, paving the way for assembling 2D selectors into modern memory devices.

14.
J Mol Cell Biol ; 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38578631

RESUMO

The recognition of cytosolic nucleic acid triggers the DNA/RNA sensor-IRF3 axis-mediated production of type I interferons (IFNs), which are essential for antiviral immune responses. However, the inappropriate activation of these signaling pathways is implicated in autoimmune conditions. Here, we report that indomethacin, a widely used nonsteroidal anti-inflammatory drug, inhibits nucleic acid-triggered IFN production. We found that both DNA- and RNA-stimulated IFN expression can be effectively blocked by indomethacin. Interestingly, indomethacin also prohibits the nuclear translocation of IRF3 following cytosolic nucleic acid recognition. Importantly, in cell lines and a mouse model of Aicardi-Goutières syndrome, indomethacin administration blunts self-DNA-induced autoimmune responses. Thus, our study reveals a previously unknown function of indomethacin and provides a potential treatment for cytosolic nucleic acid-stimulated autoimmunity.

15.
Comput Biol Med ; 173: 108291, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38522254

RESUMO

BACKGROUND: It is very important to detect mandibular fracture region. However, the size of mandibular fracture region is different due to different anatomical positions, different sites and different degrees of force. It is difficult to locate and recognize fracture region accurately. METHODS: To solve these problems, M3YOLOv5 model is proposed in this paper. Three feature enhancement strategies are designed, which improve the ability of model to locate and recognize mandibular fracture region. Firstly, Global-Local Feature Extraction Module (GLFEM) is designed. By effectively combining Convolutional Neural Network (CNN) and Transformer, the problem of insufficient global information extraction ability of CNN is complemented, and the positioning ability of the model to the fracture region is improved. Secondly, in order to improve the interaction ability of context information, Deep-Shallow Feature Interaction Module (DSFIM) is designed. In this module, the spatial information in the shallow feature layer is embedded to the deep feature layer by the spatial attention mechanism, and the semantic information in the deep feature layer is embedded to the shallow feature layer by the channel attention mechanism. The fracture region recognition ability of the model is improved. Finally, Multi-scale Multi receptive-field Feature Mixing Module (MMFMM) is designed. Deep separate convolution chains are used in this modal, which is composed by multiple layers of different scales and different dilation coefficients. This method provides richer receptive field for the model, and the ability to detect fracture region of different scales is improved. RESULTS: The precision rate, mAP value, recall rate and F1 value of M3YOLOv5 model on mandibular fracture CT data set are 97.18%, 96.86%, 94.42% and 95.58% respectively. The experimental results show that there is better performance about M3YOLOv5 model than the mainstream detection models. CONCLUSION: The M3YOLOv5 model can effectively recognize and locate the mandibular fracture region, which is of great significance for doctors' clinical diagnosis.


Assuntos
Fraturas Mandibulares , Humanos , Fraturas Mandibulares/diagnóstico por imagem , Armazenamento e Recuperação da Informação , Redes Neurais de Computação , Semântica
16.
J Colloid Interface Sci ; 665: 413-421, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38537589

RESUMO

The essence of compartmentalization in cells is the inspiration behind the engineering of synthetic counterparts, which has emerged as a significant engineering theme. Here, we report the formation of ultra-stable water-in-water (W/W) emulsion droplets. These W/W droplets demonstrate previously unattained stability across a broad pH spectrum and exhibit resilience at temperatures up to 80℃, overcoming the challenge of insufficient robustness in dispersed droplets of aqueous two-phase systems (ATPS). The exceptional robustness is attributed to the strong anchoring of micelle-like casein colloidal particles at the PEO/DEX interface, which maintains stability under varying environmental conditions. The increased surface hydrophobicity of these particles at high temperatures contributes to the formation of thermally-stable droplets, enduring temperatures as high as 80℃. Furthermore, our study illustrates the adaptable affinity of micelle-like casein colloidal particles towards the PEO/DEX-rich phase, enabling the formation of stable DEX-in-PEO emulsions at lower pH levels, and PEO-in-DEX emulsions as the pH rises above the isoelectric point. The robust nature of these W/W emulsions unlocks new possibilities for exploring various biochemical reactions within synthetic subcellular modules and lays a solid foundation for the development of novel biomimetic materials.


Assuntos
Micelas , Resiliência Psicológica , Caseínas , Emulsões , Água , Concentração de Íons de Hidrogênio
17.
Int J Nanomedicine ; 19: 2057-2070, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38482522

RESUMO

Purpose: Photodynamic therapy (PDT) has been an attractive strategy for skin tumor treatment. However, the hypoxic microenvironment of solid tumors and further O2 consumption during PDT would diminish its therapeutic effect. Herein, we developed a strategy using the combination of PDT and hypoxia-activated bioreductive drug tirapazamine (TPZ). Methods: TPZ was linked to DSPE-PEG-NHS forming DSPE-PEG-TPZ to solve leakage of water-soluble TPZ and serve as an antitumor agent and monomer molecule further forming the micellar. Chlorin e6 (Ce6) was loaded in DSPE-PEG-TPZ forming DSPE-PEG-TPZ@Ce6 (DPTC). To further improve tumor infiltration and accumulation, hyaluronic acid was adopted to make DPTC-containing microneedles (DPTC-MNs). Results: Both in vitro and in vivo studies consistently demonstrated the synergistic antitumor effect of photodynamic therapy and TPZ achieved by DPTC-MNs. With laser irradiation, overexpressions of PDT tolerance factors NQO1 and HIF-1α were inhibited by this PDT process. Conclusion: The synergistic effect of PDT and TPZ significantly improved the performance of DPTC-MNs in the treatment of melanoma and cutaneous squamous cell carcinoma and has good biocompatibility.


Assuntos
Carcinoma de Células Escamosas , Nanopartículas , Compostos Organometálicos , Fenantrolinas , Fotoquimioterapia , Neoplasias Cutâneas , Humanos , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Tirapazamina/farmacologia , Hipóxia/tratamento farmacológico , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes , Microambiente Tumoral
18.
Eur J Clin Pharmacol ; 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38502358

RESUMO

BACKGROUND: The pharmacokinetics of tacrolimus (TAC) show high intra-patient variability (IPV), which is associated with poor long-term outcomes following adult liver transplantation (LT). However, this relationship remains to be confirmed in pediatric liver transplant (PLT) recipients. The present study aimed to investigate the association between TAC IPV and grafts or patient outcomes after pediatric liver transplantion. METHODS: This retrospective study included 848 PLT recipients (including infants) between January, 2016, and June, 2021. The IPV of TAC concentrations was estimated by calculating the coefficient of variation (CV) of trough concentrations in whole blood within 1 month after transplantation. Patients were categorized into two groups, low IPV (CV < 45%) and high IPV (CV ≥ 45%), based on the third quartile of the CV distribution. RESULTS: A total of 848 patients were included in our study. The low CV group included 614 patients, with a mean TAC trough concentration of 8.59 ± 1.65 ng/ml and a median CV of 32.37%. In contrast, the high CV group included 214 patients, the mean TAC trough concentration and median CV were 8.81 ± 2.00 ng/ml and 54.88%, respectively. The median hospital duration was significantly higher in the high CV group (22 days vs. 20 days, P = 0.01). Univariate analysis was performed to evaluate the significant differences in 1-year recipient survival (P = 0.041) and 1-year graft survival (P = 0.005) between the high- and low-CV groups. Moreover, high CV (HR 2.316, 95%CI 1.026-5.231, P = 0.043) and persistent EBV viremia (HR 13.165, 95%CI 3.090-56.081, P < 0.001) were identified as independent risk factors for 1- year mortality after PLT. CONCLUSIONS: PLT recipients with high TAC trough concentration of CV in the first month were associated with poor 1-year outcomes. This CV calculation provides a valuable strategy to monitor TAC exposure.

19.
Chem Rev ; 124(5): 2553-2582, 2024 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-38476077

RESUMO

The intricate and complex features of enzymatic reaction networks (ERNs) play a key role in the emergence and sustenance of life. Constructing such networks in vitro enables stepwise build up in complexity and introduces the opportunity to control enzymatic activity using physicochemical stimuli. Rational design and modulation of network motifs enable the engineering of artificial systems with emergent functionalities. Such functional systems are useful for a variety of reasons such as creating new-to-nature dynamic materials, producing value-added chemicals, constructing metabolic modules for synthetic cells, and even enabling molecular computation. In this review, we offer insights into the chemical characteristics of ERNs while also delving into their potential applications and associated challenges.

20.
mSystems ; 9(4): e0002324, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38501812

RESUMO

Metabolic maladaptation in dairy cows after calving can lead to long-term elevation of ketones, such as ß-hydroxybutyrate (BHB), representing the condition known as hyperketonemia, which greatly influences the health and production performance of cows during the lactation period. Although the gut microbiota is known to alter in dairy cows with hyperketonemia, the association of microbial metabolites with development of hyperketonemia remains unknown. In this study, we performed a multi-omics analysis to investigate the associations between fecal microbial community, fecal/plasma metabolites, and serum markers in hyperketonemic dairy cows during the transition period. Dynamic changes in the abundance of the phyla Verrucomicrobiota and Proteobacteria were detected in the gut microbiota of dairy cows, representing an adaptation to enhanced lipolysis and abnormal glucose metabolism after calving. Random forest and univariate analyses indicated that Frisingicoccus is a key bacterial genus in the gut of cows during the development of hyperketonemia, and its abundance was positively correlated with circulating branched-chain amino acid levels and the ketogenesis pathway. Taurodeoxycholic acid, belonging to the microbial metabolite, was strongly correlated with an increase in blood BHB level, and the levels of other secondary bile acid in the feces and plasma were altered in dairy cows prior to the diagnosis of hyperketonemia, which link the gut microbiota and hyperketonemia. Our results suggest that alterations in the gut microbiota and its metabolites contribute to excessive lipolysis and insulin insensitivity during the development of hyperketonemia, providing fundamental knowledge about manipulation of gut microbiome to improve metabolic adaptability in transition dairy cows.IMPORTANCEAccumulating evidence is pointing to an important association between gut microbiota-derived metabolites and metabolic disorders in humans and animals; however, this association in dairy cows from late gestation to early lactation is poorly understood. To address this gap, we integrated longitudinal gut microbial (feces) and metabolic (feces and plasma) profiles to characterize the phenotypic differences between healthy and hyperketonemic dairy cows from late gestation to early lactation. Our results demonstrate that cows underwent excessive lipid mobilization and insulin insensitivity before hyperketonemia was evident. The bile acids are functional readouts that link gut microbiota and host phenotypes in the development of hyperketonemia. Thus, this work provides new insight into the mechanisms involved in metabolic adaptation during the transition period to adjust to the high energy and metabolic demands after calving and during lactation, which can offer new strategies for livestock management involving intervention of the gut microbiome to facilitate metabolic adaptation.


Assuntos
Microbioma Gastrointestinal , Insulinas , Feminino , Humanos , Gravidez , Bovinos , Animais , Lactação/metabolismo , Glucose/metabolismo , Lipólise , Insulinas/metabolismo
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