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1.
Mol Cell ; 83(24): 4614-4632.e6, 2023 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-37995688

RESUMO

CRISPR screens have empowered the high-throughput dissection of gene functions; however, more explicit genetic elements, such as codons of amino acids, require thorough interrogation. Here, we establish a CRISPR strategy for unbiasedly probing functional amino acid residues at the genome scale. By coupling adenine base editors and barcoded sgRNAs, we target 215,689 out of 611,267 (35%) lysine codons, involving 85% of the total protein-coding genes. We identify 1,572 lysine codons whose mutations perturb human cell fitness, with many of them implicated in cancer. These codons are then mirrored to gene knockout screen data to provide functional insights into the role of lysine residues in cellular fitness. Mining these data, we uncover a CUL3-centric regulatory network in which lysine residues of CUL3 CRL complex proteins control cell fitness by specifying protein-protein interactions. Our study offers a general strategy for interrogating genetic elements and provides functional insights into the human proteome.


Assuntos
Lisina , Proteoma , Humanos , Proteoma/genética , Lisina/genética , RNA Guia de Sistemas CRISPR-Cas , Sistemas CRISPR-Cas , Códon
2.
Cancer Sci ; 115(4): 1060-1072, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38308498

RESUMO

Liquid biopsy is emerging as a pivotal tool in precision oncology, offering a noninvasive and comprehensive approach to cancer diagnostics and management. By harnessing biofluids such as blood, urine, saliva, cerebrospinal fluid, and pleural effusions, this technique profiles key biomarkers including circulating tumor DNA, circulating tumor cells, microRNAs, and extracellular vesicles. This review discusses the extended scope of liquid biopsy, highlighting its indispensable role in enhancing patient outcomes through early detection, continuous monitoring, and tailored therapy. While the advantages are notable, we also address the challenges, emphasizing the necessity for precision, cost-effectiveness, and standardized methodologies in its broader application. The future trajectory of liquid biopsy is set to expand its reach in personalized medicine, fueled by technological advancements and collaborative research.


Assuntos
DNA Tumoral Circulante , Células Neoplásicas Circulantes , Humanos , Medicina de Precisão/métodos , Biomarcadores Tumorais/genética , Biópsia Líquida/métodos , DNA Tumoral Circulante/genética , Células Neoplásicas Circulantes/patologia
3.
Anal Chem ; 96(12): 4884-4890, 2024 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-38494753

RESUMO

The parallel double-stranded DNA (dsDNA) demonstrates potential utility in molecular biology, diagnosis, therapy, and molecular assembly. However, techniques for the characterization of parallel dsDNA are limited. Here, we demonstrate that a series of intensive characteristic Raman bands of three parallel dsDNAs, which are stabilized by reverse Hoogsteen A+·A+ base pairs or hemiprotonated C+·C, G·G minor groove edge, Hoogsteen A·A base pairs, or Hoogsteen T·A, C+·G base pairs, have been observed by surface-enhanced Raman spectroscopy (SERS) when the gold nanoparticles modified by bromine and magnesium ions (Au BMNPs) were used as substrates. The featured bands can not only accurately discriminate parallel dsDNA from antiparallel one but also identify the strand orientation within dsDNA. The proposed approach will have a significant impact on DNA analysis, especially in the detection and differentiation of various DNA conformations.


Assuntos
Ouro , Nanopartículas Metálicas , Ouro/química , Análise Espectral Raman , Brometos , Nanopartículas Metálicas/química , DNA/química
4.
Anal Chem ; 96(39): 15816-15823, 2024 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-39307967

RESUMO

Methyl iodide (CH3I) gas as a toxic gas causes great harm to organisms due to its high volatility and high reactivity with biological nucleophiles. Unfortunately, the sensing and detection of CH3I gas are challenging because of the diffusive nature of the gases and its low concentrations in the environment. Herein, we have developed a fast, green, and sensitive CH3I gas visual sensing method based on the capture technology of toxic gases by natural deep eutectic solvents (NADESs) coupled to the halide rapid exchange capability of perovskite nanocrystals (PNCs). In this strategy, NADESs are used as an absorption solution to adsorb gaseous CH3I, while simultaneously exposing I- through the action of the nucleophilic reagent; then, CsPbBr3 PNCs were synthesized in NADESs and used as sensing material to achieve I- exchange. Benefiting from the capture and enrichment of CH3I gas, the sensitivity of the gas sensor was highly improved. The sensor exhibited the lowest detection limit (limits of detection) of 164.15 µmol/m3, below the minimum safe level for human inhalation, which is 200 µmol/m3. This breakthrough offers greater possibilities for the quantitative detection of CH3I gas.

5.
Plant Cell ; 33(8): 2716-2735, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34043798

RESUMO

Reactive oxygen species (ROS) are unstable reactive molecules that are toxic to cells. Regulation of ROS homeostasis is crucial to protect cells from dysfunction, senescence, and death. In plant leaves, ROS are mainly generated from chloroplasts and are tightly temporally restricted by the circadian clock. However, little is known about how ROS homeostasis is regulated in nonphotosynthetic organs, such as petals. Here, we showed that hydrogen peroxide (H2O2) levels exhibit typical circadian rhythmicity in rose (Rosa hybrida) petals, consistent with the measured respiratory rate. RNA-seq and functional screening identified a B-box gene, RhBBX28, whose expression was associated with H2O2 rhythms. Silencing RhBBX28 accelerated flower senescence and promoted H2O2 accumulation at night in petals, while overexpression of RhBBX28 had the opposite effects. RhBBX28 influenced the expression of various genes related to respiratory metabolism, including the TCA cycle and glycolysis, and directly repressed the expression of SUCCINATE DEHYDROGENASE 1, which plays a central role in mitochondrial ROS (mtROS) homeostasis. We also found that PHYTOCHROME-INTERACTING FACTOR8 (RhPIF8) could activate RhBBX28 expression to control H2O2 levels in petals and thus flower senescence. Our results indicate that the circadian-controlled RhPIF8-RhBBX28 module is a critical player that controls flower senescence by governing mtROS homeostasis in rose.


Assuntos
Flores/fisiologia , Mitocôndrias/metabolismo , Proteínas de Plantas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Rosa/fisiologia , Ritmo Circadiano/fisiologia , Regulação da Expressão Gênica de Plantas , Homeostase , Peróxido de Hidrogênio/metabolismo , Mitocôndrias/genética , Proteínas de Plantas/genética , Senescência Vegetal , Plantas Geneticamente Modificadas , Succinato Desidrogenase/genética , Succinato Desidrogenase/metabolismo
6.
Chemistry ; 30(36): e202401171, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38646836

RESUMO

Stimuli-responsive crystalline materials have received much attention for being potential candidates of smart materials. However, the occurrence of polymorphism-driven stimuli responses in crystalline materials remains interesting but rare. Herein, three polymorphs of an acylhydrazone derivative, N'-[(E)-(1-benzofuran-2-yl) methylidene] pyridine -4-carbohydrazide (BFMP) were prepared. Form-1 undergoes a photomechanical response via E→Z photoisomerization under UV irradiation, accompanied by a decrease in fluorescence intensity and a change from colorless to yellow. Two types of Z→E thermal isomerization mechanisms with significant differences in conversion rate were observed at different temperatures in form-1. The solid-melt-solid transition has a faster conversion rate compared to the solid-solid transition due to freedom from lattice confinement. The transition from form-2 to form-3 can be achieved under grinding, coupled with a significant decrease in fluorescence intensity. The similar molecular stacking pattern of form-2 and form-3 provides a structural basis for the grinding-induced crystalline transition behavior. In addition, the presence of the pyridine moiety imparts an acidochromic property. The combination of photochromism and acidochromism explores the possible applications of acylhydrazone derivatives in information encryption.

7.
Inorg Chem ; 2024 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-39303073

RESUMO

As a representative of zeolitic imidazolate framework glass, agZIF-62 has been reported to be synthesized using a melt-quenching method in which the ZIF-62 crystal is heated to a temperature above the melting point. Interestingly, we unexpectedly found that agZIF-62 can also be synthesized by simple heating at temperatures lower than the melting point, which may be assisted by the release of encapsulated solvent molecules. The structural differences between melt-quenched agZIF-62 (MQ-agZIF-62) and heat-cooled agZIF-62 (HC-agZIF-62) were investigated. The results indicated that MQ-agZIF-62 is closer to the liquid state, while HC-agZIF-62 is closer to the crystal state. Interestingly, their luminescent emissions exhibit significant differences. Compared with the ZIF-62 crystal, MQ-agZIF-62 showed a blue-shift of 14 nm, whereas HC-agZIF-62 showed a red-shift of 9 nm. The emission intensity of agZIF-62 is also significantly stronger than that of ZIF-62; thus, rapid semiquantitative detection of the content of the MOF glass in glass and crystal mixtures can be achieved. In addition, HC-agZIF-62 and MQ-agZIF-62 can transform into ZIF-62 crystals via a solvent-media mechanism. This study provides new insights into ZIF-62 glass.

8.
Int J Colorectal Dis ; 39(1): 99, 2024 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-38926205

RESUMO

PURPOSE: Achieving a pathologic complete response (pCR) after neoadjuvant chemoradiotherapy (NCRT) remains a challenge for most patients with rectal cancer. Exploring the potential of combining NCRT with immunotherapy or targeted therapy for those achieving a partial response (PR) offers a promising avenue to enhance treatment efficacy. This study investigated the impact of NCRT on the tumor microenvironment in locally advanced rectal cancer (LARC) patients who exhibited a PR. METHODS: This was a retrospective, observational study. Five patients demonstrating a PR after neoadjuvant treatment for LARC were enrolled in the study. Biopsy samples before treatment and resected specimens after treatment were stained with a panel of 26 antibodies targeting various immune and tumor-related markers, each labeled with distinct metal tags. The labeled samples were then analyzed using the Hyperion imaging system. RESULTS: Heterogeneity within the tumor microenvironment was observed both before and after NCRT. Notably, tumor-associated macrophages, CD4 + T cells, CD8 + T cells, CD56 + natural killer cells, tumor-associated neutrophils, cytokeratin, and E-cadherin exhibited slight increase in abundance within the tumor microenvironment following treatment (change ratios = 0.78, 0.2, 0.27, 0.32, 0.17, 0.46, 0.32, respectively). Conversely, the number of CD14 + monocytes, CD19 + B cells, CD45 + CD4 + T cells, collagen I, α-smooth muscle actin, vimentin, and ß-catenin proteins displayed significant decreases post-treatment (change ratios = 1.73, 1.92, 1.52, 1.25, 1.52, 1.12, 2.66, respectively). Meanwhile, Foxp3 + regulatory cells demonstrated no significant change (change ratio = 0.001). CONCLUSIONS: NCRT has diverse effects on various components of the tumor microenvironment in LARC patients who achieve a PR after treatment. Leveraging combination therapies may optimize treatment outcomes in this patient population.


Assuntos
Terapia Neoadjuvante , Neoplasias Retais , Microambiente Tumoral , Humanos , Neoplasias Retais/terapia , Neoplasias Retais/patologia , Neoplasias Retais/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Quimiorradioterapia , Resultado do Tratamento , Estudos Retrospectivos
9.
J Appl Microbiol ; 135(6)2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38849313

RESUMO

AIMS: Understanding the inhibitory effects of natural organic substances on soil-borne pathogenic fungi and the relevant molecular mechanisms are highly important for future development of green prevention and control technology against soil-borne diseases. Our study elucidates the inhibitory effect of the combined application of humic acids (HAs) and chitosan on Alternariasolani and the light on the corresponding mechanism. METHODS AND RESULTS: The effect on A. solani growth by HAs incorporated with chitosan was investigated by plate culture and the corresponding mechanism was revealed using transcriptomics. The colony growth of A. solani was suppressed with the highest inhibition rate 33.33% when swine manure HAs was compounded with chitosan at a ratio of 1:4. Chitosan changed the colony morphology from round to irregularly. RNA-seq in the HAs and chitosan (HC) treatment revealed 239 differentially expressed genes compared with the control. The unigenes associated with enzymes activities related to growth and biological processes closely related to mycelial growth and metabolism were downregulated. RNA-seq also revealed that chitosan altered the expression of genes related to secondary metabolism, fungal cell wall formation and polysaccharide synthesis, and metabolism. Meanwhile, weighted gene co-expression network analysis showed that, genes expression in the module positively correlated with mycelial growth was significantly reduced in the HC treatment; and the results were verified by real-time quantitative polymerase chain reaction. CONCLUSIONS: The co-inhibition effect of HAs and chitosan on A. solani is associated with downregulated genes expression correlated with mycelial growth.


Assuntos
Alternaria , Quitosana , Perfilação da Expressão Gênica , Substâncias Húmicas , Quitosana/farmacologia , Alternaria/efeitos dos fármacos , Alternaria/genética , Alternaria/crescimento & desenvolvimento , Animais , Transcriptoma , Suínos , Esterco/microbiologia , Microbiologia do Solo , Micélio/crescimento & desenvolvimento , Micélio/efeitos dos fármacos , Micélio/genética
10.
Pediatr Nephrol ; 39(8): 2403-2412, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38578470

RESUMO

BACKGROUND: Previously, several studies have indicated that pediatric IgA nephropathy (IgAN) might be different from adult IgAN, and treatment strategies might be also different between pediatric IgAN and adult IgAN. METHODS: We analyzed two prospective cohorts established by pediatric and adult nephrologists, respectively. A comprehensive analysis was performed investigating the difference in clinical and pathological characteristics, treatment, and prognosis between children and adults with IgAN. RESULTS: A total of 1015 children and 1911 adults with IgAN were eligible for analysis. More frequent gross hematuria (88% vs. 20%, p < 0.0001) and higher proteinuria (1.8 vs. 1.3 g/d, p < 0.0001) were seen in children compared to adults. In comparison, the estimated glomerular filtration rate (eGFR) was lower in adults (80.4 vs. 163 ml/min/1.73 m2, p < 0.0001). Hypertension was more prevalent in adult patients. Pathologically, a higher proportion of M1 was revealed (62% vs. 39%, p < 0.0001) in children than in adults. S1 (62% vs. 28%, p < 0.0001) and T1-2 (34% vs. 8%, p < 0.0001) were more frequent in adults. Adjusted by proteinuria, eGFR, and hypertension, children were more likely to be treated with glucocorticoids than adults (87% vs. 45%, p < 0.0001). After propensity score matching, in IgAN with proteinuria > 1 g/d, children treated with steroids were 1.87 (95% CI 1.16-3.02, p = 0.01) times more likely to reach complete remission of proteinuria compared with adults treated with steroids. CONCLUSIONS: Children present significantly differently from adults with IgAN in clinical and pathological manifestations and disease progression. Steroid response might be better in children.


Assuntos
Taxa de Filtração Glomerular , Glomerulonefrite por IGA , Proteinúria , Humanos , Glomerulonefrite por IGA/tratamento farmacológico , Glomerulonefrite por IGA/fisiopatologia , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/patologia , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/terapia , Masculino , Feminino , Criança , Adulto , Proteinúria/etiologia , Proteinúria/diagnóstico , Adolescente , Estudos Prospectivos , Adulto Jovem , Prognóstico , Pessoa de Meia-Idade , Fatores Etários , Hematúria/etiologia , Hematúria/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Hipertensão/diagnóstico , Rim/patologia , Rim/fisiopatologia , Progressão da Doença , Glucocorticoides/uso terapêutico
11.
Biochem Genet ; 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38436815

RESUMO

Plants have evolved sophisticated signaling networks to adjust flowering time, ensuring successful reproduction. Two crucial flowering regulators, FLOWERING LOCUS T (FT) and CONSTANS (CO), play pivotal roles in regulating flowering across various species. Previous studies have indicated that suppressing Gossypium hirsutum CONSTANS-LIKE 2 (GhCOL2), a homolog of Arabidopsis CO, leads to delayed flowering in cultivated cotton. However, the underlying regulatory mechanisms remain unknown. In this study, a yeast one-hybrid and dual-LUC expression assays were used to elucidate the molecular mechanism through which GhCOL2 regulates the transcription of GhHD3A. RT-qPCR was used to examine the expression of GhCOL2 and GhHD3A. Our findings reveal that GhCOL2 directly binds to CCACA cis-elements and atypical CORE (TGTGTATG) cis-elements in the promoter regions of HEADING DATE 3 A (HD3A), thereby activating GhHD3A transcription. Notably, GhCOL2 and GhHD3A exhibited high expression levels in the adult stage and low levels in the juvenile stage. Interestingly, the expression of GhCOL2 and GhHD3A varied significant between the two cotton varieties (Tx2094 and Maxxa). In summary, our study enhances the understanding of the molecular mechanism by which cotton GhCOL2-GhHD3A regulates flowering at the molecular level. Furthermore, it contributes to a broader comprehension of the GhCOL2-GhHD3A model in G. hirsutum.

12.
Brain Inj ; 38(2): 68-75, 2024 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-38329075

RESUMO

OBJECTIVES: To investigate the effects of long-term repetitive transcranial direct current stimulation on patients with DOC in the subacute phase. METHODS: In a randomized, double-blind, controlled study, 33 patients were randomly assigned to the active or sham group, and 28 patients completed the study. Patients in the active group received anodal stimulation over the DLPFC, while patients in the sham group received placebo stimulation (20 min/day, 5 days/week, for 4 weeks). The level of consciousness among patients was assessed with the Coma Recovery Scale-Revised (CRS-R) at baseline and at the end of every week from the first to the fourth week. RESULTS: The CRS-R scores of both the active and sham groups showed a consistent increasing trend over time; however, the treatment effect of the active group was better than that of the sham group. In addition, there was a statistically significant difference in the total CRS-R score between the two groups at weeks 1, 2, 3 and 4. Moreover, 10 patients (71.4%) in the active group and 3 patients (21.4%) in the sham group were regarded as responders. CONCLUSION: Long-term tDCS could improve the level of consciousness of patients with DOC in the subacute stage.


Assuntos
Estimulação Transcraniana por Corrente Contínua , Humanos , Coma , Estado de Consciência/fisiologia , Transtornos da Consciência/terapia , Resultado do Tratamento , Método Duplo-Cego
13.
Ecotoxicol Environ Saf ; 281: 116563, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38878560

RESUMO

Evodiamine (EVO), the main active alkaloid in Evodia rutaecarpa, was shown to exert various pharmacological activities, especially anti-tumor. Currently, it is considered a potential anti-cancer drug due to its excellent anti-tumor activity, which unfortunately has adverse reactions, such as the risk of liver and kidney injury, when Evodia rutaecarpa containing EVO is used clinically. In the present study, we aim to clarify the potential toxic target organs and toxicity mechanism of EVO, an active monomer in Evodia rutaecarpa, and to develop mitigation strategies for its toxicity mechanism. Transcriptome analysis and related experiments showed that the PI3K/Akt pathway induced by calcium overload was an important step in EVO-induced apoptosis of renal cells. Specifically, intracellular calcium ions were increased, and mitochondrial calcium ions were decreased. In addition, EVO-induced calcium overload was associated with TRPV1 receptor activation. In vivo TRPV1 antagonist and calcium chelator effects were observed to significantly reduce body weight loss and renal damage in mice due to EVO toxicity. The potential nephrotoxicity of EVO was further confirmed by an in vivo test. In conclusion, TRPV1-mediated calcium overload-induced apoptosis is one of the mechanisms contributing to the nephrotoxicity of EVO due to its toxicity, whereas maintaining body calcium homeostasis is an effective measure to reduce toxicity. These studies suggest that the clinical use of EVO-containing herbal medicines should pay due attention to the changes in renal function of patients as well as the off-target effects of the drugs.


Assuntos
Apoptose , Cálcio , Evodia , Homeostase , Rim , Quinazolinas , Quinazolinas/toxicidade , Quinazolinas/farmacologia , Animais , Homeostase/efeitos dos fármacos , Cálcio/metabolismo , Camundongos , Apoptose/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Evodia/química , Masculino , Canais de Cátion TRPV/metabolismo , Quelantes de Cálcio/farmacologia
14.
Drug Dev Ind Pharm ; 50(4): 363-375, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38482839

RESUMO

OBJECTIVE: The purpose of the present study was to formulate a menantine hydrochloride (MH) sustained-release suspension. METHODS: Menantine hydrochloride drug resin complex (MH-DRC) was prepared with strong acid cation exchange resin as carrier using water bath method. The MH-DRC was characterized using scanning electron microscopy, X-ray diffraction and infrared spectroscopy. The MH-coated microcapsule (MH-CM) with optimized formulation was further dispersed in a suitable medium to obtain a sustained-release suspension. The rats were given both the MH sustained-release suspension and the commercial MH sustained-release capsule by intragastric administration. The plasma concentration-time curves and related pharmacokinetic parameters were also investigated using a non-atrioventricular model. RESULTS: MH and ion-exchange resin were ionically bonded. AmberliteIRP®69 had a higher affinity for MH at the initial concentration of 5 mg·mL-1 and a reaction temperature of 25.0 ± 0.5 °C. In vitro drug release profile showed that both the drug resin complex and the coated microcapsules had a certain level of sustained-release effect. The t1/2 of MH sustained-release suspension was extended from 68.44 h to 72.79 h with the peak blood concentration being decreased to 3.56 µg·mL-1 and the Tmax extended to 12 h compared with the commercial MH sustained-release capsule. The concentration-time curve of the self-made MH sustained-release suspension was flattened and the average relative bioavailability (Fr) was 116.65% compared with the commercial MH sustained-release capsules. CONCLUSIONS: The findings showed that the MH sustained-release suspension was successfully formulated with acceptable pharmacokinetic indices for effective treatment of Alzheimer's disease.


Assuntos
Resinas de Troca Iônica , Ratos , Animais , Preparações de Ação Retardada , Cápsulas , Administração Oral , Liberação Controlada de Fármacos , Disponibilidade Biológica
15.
Int J Mol Sci ; 25(16)2024 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-39201287

RESUMO

Medicinal plants play a pivotal role in traditional medicine and modern pharmacology due to their various bioactive compounds. However, heat stress caused by climate change will seriously affect the survival and quality of medicinal plants. In this review, we update our understanding of the research progress on medicinal plants' response mechanisms and control measures under heat stress over the last decade. This includes physiological changes, molecular mechanisms, and technical means to improve the heat tolerance of medicinal plants under heat stress. It provides a reference for cultivating heat-resistant varieties of medicinal plants and the rational utilization of control measures to improve the heat resistance of medicinal plants.


Assuntos
Resposta ao Choque Térmico , Plantas Medicinais , Plantas Medicinais/química , Mudança Climática
16.
Immunology ; 168(1): 152-169, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35986643

RESUMO

Multiple sclerosis (MS) is an autoimmune disease driven by lymphocyte activation against myelin autoantigens in the central nervous system leading to demyelination and neurodegeneration. The deoxyribonucleoside salvage pathway with the rate-limiting enzyme deoxycytidine kinase (dCK) captures extracellular deoxyribonucleosides for use in intracellular deoxyribonucleotide metabolism. Previous studies have shown that deoxyribonucleoside salvage activity is enriched in lymphocytes and required for early lymphocyte development. However, specific roles for the deoxyribonucleoside salvage pathway and dCK in autoimmune diseases such as MS are unknown. Here we demonstrate that dCK activity is necessary for the development of clinical symptoms in the MOG35-55 and MOG1-125 experimental autoimmune encephalomyelitis (EAE) mouse models of MS. During EAE disease, deoxyribonucleoside salvage activity is elevated in the spleen and lymph nodes. Targeting dCK with the small molecule dCK inhibitor TRE-515 limits disease severity when treatments are started at disease induction or when symptoms first appear. EAE mice treated with TRE-515 have significantly fewer infiltrating leukocytes in the spinal cord, and TRE-515 blocks activation-induced B and T cell proliferation and MOG35-55 -specific T cell expansion without affecting innate immune cells or naïve T and B cell populations. Our results demonstrate that targeting dCK limits symptoms in EAE mice and suggest that dCK activity is required for MOG35-55 -specific lymphocyte activation-induced proliferation.


Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Camundongos , Desoxicitidina Quinase/genética , Linfócitos/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL
17.
Small ; 19(38): e2301003, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37211708

RESUMO

Bone is one of the prone metastatic sites of patients with advanced breast cancer. The "vicious cycle" between osteoclasts and breast cancer cells plays an essential role in osteolytic bone metastasis from breast cancer. In order to inhibit bone metastasis from breast cancer, NIR-II photoresponsive bone-targeting nanosystems (CuP@PPy-ZOL NPs) are designed and synthesized. CuP@PPy-ZOL NPs can trigger the photothermal-enhanced Fenton response and photodynamic effect to enhance the photothermal treatment (PTT) effect and thus achieve synergistic anti-tumor effect. Meanwhile, they exhibit a photothermal enhanced ability to inhibit osteoclast differentiation and promote osteoblast differentiation, which reshaped the bone microenvironment. CuP@PPy-ZOL NPs effectively inhibited the proliferation of tumor cells and bone resorption in the in vitro 3D bone metastases model of breast cancer. In a mouse model of breast cancer bone metastasis, CuP@PPy-ZOL NPs combined with PTT with NIR-II significantly inhibited the tumor growth of breast cancer bone metastases and osteolysis while promoting bone repair to achieve the reversal of osteolytic breast cancer bone metastases. Furthermore, the potential biological mechanisms of synergistic treatment are identified by conditioned culture experiments and mRNA transcriptome analysis. The design of this nanosystem provides a promising strategy for treating osteolytic bone metastases.


Assuntos
Neoplasias Ósseas , Osteólise , Animais , Camundongos , Terapia Fototérmica , Microambiente Tumoral , Osso e Ossos/patologia , Neoplasias Ósseas/terapia , Neoplasias Ósseas/patologia , Osteoclastos , Osteólise/terapia , Osteólise/patologia , Linhagem Celular Tumoral
18.
World J Surg Oncol ; 21(1): 339, 2023 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-37880729

RESUMO

BACKGROUND: To determine the efficacy of adjuvant radiotherapy for stage II-III biliary tract carcinoma. METHODS: We retrospectively analyzed the data of 37 patients who underwent radical resection of biliary tract carcinomas at the Affiliated Hospital of Inner Mongolia Medical University between 2016 and 2020. We analyzed survival differences between patients who did (n = 17) and did not (n = 20) receive postoperative adjuvant radiotherapy by using Kaplan-Meier analysis. The log-rank test and Cox univariate analysis were used. The Cox proportional risk regression model was used for the multifactorial analysis of factors influencing prognosis. RESULTS: The median survival time (28.9 vs. 14.5 months) and the 1-year (82.40% vs. 55.0%) and 2-year survival rates (58.8% vs. 25.0%) were significantly higher among patients who received adjuvant radiotherapy than among those who did not (χ2 = 6.381, p = 0.012). Multifactorial analysis showed that pathological tumor type (p = 0.004), disease stage (p = 0.021), and adjuvant radiotherapy (p = 0.001) were independent prognostic factors in biliary tract carcinoma. Subgroup analyses showed that compared to no radiotherapy, adjuvant radiotherapy significantly improved median survival time in patients with stage III disease (21.6 vs. 12.7 months; p = 0.017), positive margins (28.9 vs. 10.5 months; p = 0.012), and T3 or T4 tumors (26.8 vs. 16.8 months; p = 0.037). CONCLUSION: Adjuvant radiotherapy significantly improved the survival of patients with biliary tract carcinoma, and is recommended especially for patients with stage III disease, positive surgical margins, or ≥ T3.


Assuntos
Sistema Biliar , Carcinoma , Neoplasias Gastrointestinais , Humanos , Radioterapia Adjuvante/efeitos adversos , Estudos Retrospectivos , Prognóstico , Estadiamento de Neoplasias
19.
Adv Neonatal Care ; 23(5): E107-E113, 2023 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-37442109

RESUMO

BACKGROUND: Biliary atresia is a rare and serious neonatal disease that affects the quality of life of both infants and parents. There is currently limited literature on the experiences of parents with infants diagnosed with biliary atresia. PURPOSE: To explore the psychological journey and coping styles of parents of infants with biliary atresia in a single center in Shanghai, China. METHODS: A qualitative study design was used. Face-to-face and semistructured interviews were conducted with 10 parents of infants with biliary atresia. Colaizzi's method of data analysis was utilized, using NVivo 11.0 software. RESULTS: The psychological journey and coping styles of parents could be divided into 4 stages. Different themes were extracted at different stages: before diagnosis, parents experienced complex emotions and actively sought treatment; at the diagnosis stage, negative emotions dominated and parents convinced themselves to accept reality; in the postoperative stage, positive emotions, accepting reality, active response, and the need to learn to take care of their infant gradually appeared; and at the discharge stage, parents accepted the coexistence of positive and negative emotions and the variety of needs that emerged. IMPLICATIONS FOR PRACTICE: The findings of the study may help healthcare professionals identify and focus on the psychological needs of parents of infants with biliary atresia, leading them to implement effective coping strategies to increase the caregiving ability of parents. IMPLICATIONS FOR RESEARCH: Future research should explore the effects of supportive interventions for parents of infants with serious chronic illnesses.


Assuntos
Atresia Biliar , Recém-Nascido , Lactente , Humanos , Atresia Biliar/cirurgia , Atresia Biliar/diagnóstico , Qualidade de Vida , China , Adaptação Psicológica , Pais/psicologia , Pesquisa Qualitativa
20.
Chem Biodivers ; 20(3): e202200940, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36721262

RESUMO

Zea mays (Z. mays) is one of the main cereal crops in the world, and it's by-products have exhibited medicinal properties to explore. This article intends to review the chemical compositions and pharmacological activities of by-products of Z. mays (corn silks, roots, bract, stems, bran, and leaves) which support the therapeutic potential in the treatment of different diseases, with emphasis on the natural occurring compounds and detailed pharmacological developments. Based on this review, 231 natural compounds are presented. Among them, flavonoids, terpenes, phenylpropanoids, and alkaloids are the most frequently reported. The by-products of Z. mays possess diuretic effects, hepatoprotective, anti-diabetic, antioxidant, neuroprotective, anti-inflammatory, anti-cancer, plant protection activity, and other activities. This article reviewed the phytochemistry and pharmacological activities of Z. mays for comprehensive quality control and the safety and effectiveness to enhance future application.


Assuntos
Alcaloides , Zea mays , Antioxidantes/farmacologia , Etnofarmacologia , Compostos Fitoquímicos/química , Fitoterapia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Folhas de Planta , Zea mays/química
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