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1.
Front Pharmacol ; 15: 1442870, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39148546

RESUMEN

Herbal medicines (HMs) have long played a pivotal role in preventing and treating various human diseases and have been studied widely. However, the complexities present in HM metabolites and their unclear mechanisms of action have posed significant challenges in the modernization of traditional Chinese medicine (TCM). Over the past two decades, mass spectrometry imaging (MSI) has garnered increasing attention as a robust analytical technique that enables the simultaneous execution of qualitative, quantitative, and localization analyses without complex sample pretreatment. With advances in technical solutions, MSI has been extensively applied in the field of HMs. MSI, a label-free ion imaging technique can comprehensively map the spatial distribution of HM metabolites in plant native tissues, thereby facilitating the effective quality control of HMs. Furthermore, the spatial dimension information of small molecule endogenous metabolites within animal tissues provided by MSI can also serve as a supplement to uncover pharmacological and toxicological mechanisms of HMs. In the review, we provide an overview of the three most common MSI techniques. In addition, representative applications in HM are highlighted. Finally, we discuss the current challenges and propose several potential solutions. We hope that the summary of recent findings will contribute to the application of MSI in exploring metabolites and mechanisms of action of HMs.

2.
World J Gastroenterol ; 30(26): 3247-3252, 2024 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-39086634

RESUMEN

BACKGROUND: Multiple endocrine neoplasias (MENs) are a group of hereditary diseases involving multiple endocrine glands, and their prevalence is low. MEN type 1 (MEN1) has diverse clinical manifestations, mainly involving the parathyroid glands, gastrointestinal tract, pancreas and pituitary gland, making it easy to miss the clinical diagnosis. CASE SUMMARY: We present the case of a patient in whom MEN1 was detected early. A middle-aged male with recurrent abdominal pain and diarrhea was admitted to the hospital. Blood tests at admission revealed hypercalcemia and hypophosphatemia, and emission computed tomography of the parathyroid glands revealed a hyperfunctioning parathyroid lesion. Gastroscopy findings suggested a duodenal bulge and ulceration. Ultrasound endoscopy revealed a hypoechoic lesion in the duodenal bulb. Further blood tests revealed elevated levels of serum gastrin. Surgery was performed, and pathological analysis of the surgical specimens revealed a parathyroid adenoma after parathyroidectomy and a neuroendocrine tumor after duodenal bulbectomy. The time from onset to the definitive diagnosis of MEN1 was only approximately 1 year. CONCLUSION: For patients who present with gastrointestinal symptoms accompanied by hypercalcemia and hypophosphatemia, clinicians need to be alert to the possibility of MEN1.


Asunto(s)
Hipercalcemia , Neoplasia Endocrina Múltiple Tipo 1 , Neoplasias de las Paratiroides , Paratiroidectomía , Humanos , Neoplasia Endocrina Múltiple Tipo 1/cirugía , Neoplasia Endocrina Múltiple Tipo 1/diagnóstico , Neoplasia Endocrina Múltiple Tipo 1/complicaciones , Neoplasia Endocrina Múltiple Tipo 1/patología , Masculino , Neoplasias de las Paratiroides/cirugía , Neoplasias de las Paratiroides/diagnóstico , Neoplasias de las Paratiroides/patología , Neoplasias de las Paratiroides/complicaciones , Persona de Mediana Edad , Hipercalcemia/diagnóstico , Hipercalcemia/etiología , Hipercalcemia/sangre , Adenoma/cirugía , Adenoma/diagnóstico , Adenoma/patología , Adenoma/sangre , Neoplasias Duodenales/cirugía , Neoplasias Duodenales/diagnóstico , Neoplasias Duodenales/patología , Hipofosfatemia/etiología , Hipofosfatemia/diagnóstico , Dolor Abdominal/etiología , Dolor Abdominal/diagnóstico , Tumores Neuroendocrinos/cirugía , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/sangre , Tumores Neuroendocrinos/patología , Diarrea/etiología , Diarrea/diagnóstico , Detección Precoz del Cáncer/métodos , Gastroscopía , Resultado del Tratamiento
3.
Artículo en Inglés | MEDLINE | ID: mdl-39127314

RESUMEN

Mitochondrial function can be regulated by ion channels. Mitochondrial RNA splicing 2 (Mrs2) is a magnesium ion (Mg2+) channel located in the inner mitochondrial membrane, thereby mediating the Mg2+ influx into the mitochondrial matrix. However, its potential role in regulating the Mg homeostasis and mitochondrial function in aquatic species is still unclear. This study molecularly characterizes the gene encoding Mrs2 in fish M. amblycephala with its functions in maintaining the Mg homeostasis and mitochondrial function verified. The mrs2 gene is 2133 bp long incorporating a 1269 bp open reading frame, which encodes 422 amino acids. The Mrs2 protein includes two transmembrane domains and a conserved tripeptide Gly-Met-Asn, and has a high homology (65.92-97.64%) with those of most vertebrates. The transcript of mrs2 was relatively high in the white muscle, liver and kidney. The inhibition of mrs2 reduces the expressions of Mg2+ influx/efflux-related proteins, mitochondrial Mg content, and the activities of mitochondrial complex I and V in hepatocytes. However, the over-expression of mrs2 increases the expressions of Mg2+ influx/efflux-related proteins, mitochondrial Mg content, and the complex V activity, but decreases the activities of mitochondrial complex III and IV and citrate synthase in hepatocytes. Collectively, Mrs2 is highly conserved among different species, and is prerequisite for maintaining Mg homeostasis and mitochondrial function in fish.

4.
Stroke ; 2024 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-39114924

RESUMEN

BACKGROUND: Cerebral small vessel disease (CSVD) is a group of neurological disorders that affect the small blood vessels within the brain, for which no effective treatments are currently available. We conducted a Mendelian randomization (MR) study to identify candidate therapeutic genes for CSVD. METHODS: We retrieved genome-wide association study data from 6 recently conducted, extensive investigations focusing on CSVD magnetic resonance imaging markers and performed a 2-sample MR analysis to assess the potential causal effects of gene expression and protein level within druggable genes on CSVD in blood and brain tissues. Colocalization analyses and repeat studies were undertaken to verify the relationship. Additionally, mediation analysis was conducted to explore the potential mechanisms involving druggable genes and known risk factors for CSVD. Finally, phenome-wide MR analyses were applied to evaluate the potential adverse effects related to the identified druggable genes for CSVD treatment. RESULTS: Overall, 5 druggable genes consistently showed associations with CSVD in MR analyses across both the discovery and validation cohorts. Notably, the ALDH2 and KLHL24 genes were identified as associated with CSVD in both blood and brain tissues, whereas the genes ADRB1, BTN3A2, and EFEMP1 were exclusively detected in brain tissue. Moreover, mediation analysis elucidated the proportion of the total effects mediated by CSVD risk factors through candidate druggable genes, which ranged from 5.5% to 18.5%, and offered potential explanations for the observed results. A comprehensive phenome-wide MR analysis further emphasized both the therapeutic benefits and potential side effects of targeting these candidate druggable genes. CONCLUSIONS: This study provides genetic evidence supporting the potential therapeutic benefits of targeting druggable genes for treating CSVD, which will be useful for prioritizing CSVD drug development.

5.
Adv Sci (Weinh) ; : e2405880, 2024 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-39162177

RESUMEN

Hydrogel sensors are widely utilized in soft robotics and tissue engineering due to their excellent mechanical properties and biocompatibility. However, in high-water environments, traditional hydrogels can experience significant swelling, leading to decreased mechanical and electrical performance, potentially losing shape, and sensing capabilities. This study addresses these challenges by leveraging the Hofmeister effect, coupled with directional freezing and salting-out techniques, to develop a layered, high-strength, tough, and antiswelling PVA/MXene hydrogel. In particular, the salting-out process enhances the self-entanglement of PVA, resulting in an S-PM hydrogel with a tensile strength of up to 2.87 MPa. Furthermore, the S-PM hydrogel retains its structure and strength after 7 d of swelling, with only a 6% change in resistance. Importantly, its sensing performance is improved postswelling, a capability rarely achievable in traditional hydrogels. Moreover, the S-PM hydrogel demonstrates faster response times and more stable resistance change rates in underwater tests, making it crucial for long-term continuous monitoring in challenging aquatic environments, ensuring sustained operation and monitoring.

6.
Adv Sci (Weinh) ; : e2404913, 2024 Aug 09.
Artículo en Inglés | MEDLINE | ID: mdl-39119888

RESUMEN

Actuators based on shape memory polymers and composites incorporating nanomaterial additives have been extensively studied; achieving both high output stress and precise shape change by low-cost, scalable methods is a long-term-desired yet challenging task. Here, conventional polymers (polyurea) and carbon nanotube (CNT) fillers are combined to fabricate reinforced composite fibers with exceptional actuation performance, by a wet-spinning method amenable for continuous production. It is found that a thermal-induced shrinkage step could obtain densified strong fibers, and the presence of CNTs effectively promotes the tensile orientation of polymer molecular chains, leading to much improved mechanical properties. Consequently, the CNT/ polyurea composite fibers exhibit stresses as high as 33 MPa within 0.36 s during thermal actuation, and stresses up to 22 MPa upon electrical stimulation enabled by the built-in conductive CNT networks. Utilizing the flexible thin fibers, various shape change behavior are also demonstrated including the conversion between different structures/curvatures, and recovery of predefined simple patterns. This high-performance composite fibers, capable of both thermal and electrical actuation and produced by low-cost materials and fabrication process, may find many potential applications in wearable devices, robotics, and biomedical areas.

7.
J Phys Chem A ; 128(31): 6402-6411, 2024 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-39069663

RESUMEN

As two-photon absorption (TPA) materials, phthalocyanine molecules have promising application prospects due to their large TPA absorption cross-section, high third-order nonlinear optical susceptibility, and ultrafast response characteristics. In this work, optical properties and the ultrafast response of three modified zinc phthalocyanine molecules (P-HPcZn, Pc-P-Pc, and (DR1)4PcZn) were analyzed. No obvious side-shoulder absorption peaks in the Q-band can be observed from the steady-state absorption spectra of the three molecules, confirming the lack of aggregation products in the solutions of our measurement. Open-aperture Z-scan results show relatively large TPA cross-section values of 136.4 and 55.3 GM for Pc-P-Pc and (DR1)4PcZn, respectively. The nonlinear optical results show that the absorption process observed under the excitation of femtosecond pulses is a reverse saturable absorption (RSA) mechanism. Up-conversion fluorescence spectra of (DR1)4PcZn in THF solution indicate that the fluorescence emission mechanism is TPA. In the study of ultrafast dynamics, the transient absorption spectra were investigated and the decay lifetime of the dynamic traces corresponding to some representative probe wavelengths was obtained through data fitting with a multi-exponential function. Finally, the charge transfer and excited state properties of the modified zinc phthalocyanine molecules were discussed in depth by the DFT method. The energy gaps of P-HPcZn, Pc-P-Pc, and (DR1)4PcZn are 2.16, 1.39, and 2.13 eV, respectively. The results indicate that the Pc-P-Pc of donor-acceptor-donor (D-A-D) structure has the smallest energy gap as well as the best charge transfer properties.

8.
Exp Gerontol ; 195: 112532, 2024 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-39068693

RESUMEN

BACKGROUND: Globally, Parkinson's disease (PD) is one of the common neurodegenerative diseases in the elderly with increasing morbidity and disability, and its clinical pathogenesis is not clear. OBJECTIVE: To compare the differences in disease severity and blood biomarkers levels and their correlation between patients with early-onset Parkinson's disease (EOPD) and late-onset Parkinson's disease (LOPD). METHODS: A total of 342 patients diagnosed with PD were retrospectively collected. PD patients were categorized into EOPD (24 patients) and LOPD (318 patients) according to the age of onset of the disease. The Hoehn-Yahr (HY) staging was used to assess the severity of the disease in PD patients. Subjective rating scales such as the Mini-mental State Examination (MMSE) were used to assess the motor and non-motor functions of the patients. The differences of objective blood biomarkers such as triglyceride (TG) between the two groups were investigated. The correlation between them and PD was explored by logistic analysis. RESULTS: Percentage of EOPD group with HY staged as intermediate to late and Scales for Outcomes in Parkinson's Disease-Autonomic (SCOPA-AUT), Movement Disorder Society-Unified Parkinson's disease Rating Scale-III (MDS-UPDRS-III), Montreal Cognitive Assessment (MoCA) score and TG, non-high-density lipoprotein-cholesterol (N-HDL-C), homocysteine (HCY), apolipoprotein B (Apo-B), free triiodothyronine (FT3), free thyroxine (FT4), high-sensitivity C-reactive protein (hs-CRP) levels were lower than those in the LOPD group (P < 0.05); and the proportion of HY staged as early stage, Hamilton Anxiety Scale (HAMA) and Fatigue severity scale (FSS) scores and the levels of vitamin B12 were higher than those in the LOPD group (P < 0.05). The results of Multifactorial Logistic regression analysis showed that N-HDL-C [OR = 1.409, 95 % CI (1.063, 1.868)], Apo-B [OR = 0.797, 95 % CI (0.638, 0.997)], Vitamin B12 [OR = 0.992, 95 % CI (0.987, 0.998)] and hs-CRP [OR = 1.124, 95 % CI (1.070, 1.182)] were independent factors affecting the severity of PD, with significant differences between groups (P < 0.05). CONCLUSION: N-HDL-C, Apo-B, Vitamin B12, and hs-CRP levels play an important role in the progression of PD.

9.
Exp Gerontol ; 195: 112530, 2024 Jul 29.
Artículo en Inglés | MEDLINE | ID: mdl-39059516

RESUMEN

BACKGROUND: The gut microbiota (GM) plays an important role in the development of immune-related diseases, and the immune response is one of the pathomechanisms of depression (Dep); whether the effect of GM on Dep is mediated by immune cells (ImC) is unclear. OBJECTIVE: ImC may mediate the effect of GM on Dep. Our aim is to identify and quantify the role of immune characteristics as potential mediators. METHODS: Pooled statistics for GM (n = 7738) and ImC (n = 3757) were obtained from publicly available genome-wide association studies (GWAS), and for Dep (n = 47,696) from the Finnish database R10. We used a mediated Mendelian randomization (MR) study to investigate the causal relationship between GM and Dep and the mediating role of ImC between GM and Dep associations. RESULTS: The results showed that the genetically predicted GM was significantly correlated with both ImC as well as Dep. MR analysis identified five microbiomes that had significant causal effects on Dep (Methionine biosynthesis III, PWY-6737-Starch degradation V, Parasutterella excrementihominis, Parasutterella, and Lysine biosynthesis I). In addition, five of the 26 ImC trait significantly associated with GM were most closely associated with Dep (T cell %lymphocyte、CD28-CD127-CD25++CD8br AC、CD28-CD8br AC、CD27 receptor on peripheral blood plasma cells (CD27 on PB/PC) and CD11b receptor on mononuclear myeloid-derived suppressor cells (CD11b on Mo MDSC)). This mediated MR illustrates the causal role of methionine biosynthesis III on Dep (IVW: OR = 1.08, 95%CI [1.04,1.14], P = 0.001). And there was no strong evidence for a causal effect of depression on methionine biosynthesis III. In the B cell group, the proportion of CD27 on PB/PC mediated was 7.88 %(95%CI [-0.04,0.03]) of the total effect. This study further suggests that Dep patients should actively seek immunologic intervention therapy. CONCLUSION: This MR study found that GM may play a causal role in Dep by mediating ImC. Our findings will help to understand the pathogenic mechanism of GM in Dep and the risk of immune mediation.

10.
Biodivers Data J ; 12: e127029, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39015795

RESUMEN

Background: The genus of Polypedates Tschudi, 1838 currently comprises 25 recognised species with four of these species reported in Yunnan, China. Dubois (1987) speculated the distribution of P.teraiensis in China; however, there was no study carried out to confirm its distribution in the region. New information: We herein describe P.teraiensis as a new national record, based on a specimen collected from Yunnan border region. Phylogenetically, our sequence clustered with the sequences of recognised P.teraiensis specimens from Bangladesh, Myanmar and India. The uncorrected pairwise distances between the specimens from China and other P.teraiensis localities was small, ranging from 0.0-0.7%, based on 16S rRNA gene. Therefore, we report P.teraiensis as a new species record for China.

11.
Drug Resist Updat ; 76: 101115, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39002266

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, notably resistant to existing therapies. Current research indicates that PDAC patients deficient in homologous recombination (HR) benefit from platinum-based treatments and poly-ADP-ribose polymerase inhibitors (PARPi). However, the effectiveness of PARPi in HR-deficient (HRD) PDAC is suboptimal, and significant challenges remain in fully understanding the distinct characteristics and implications of HRD-associated PDAC. We analyzed 16 PDAC patient-derived tissues, categorized by their homologous recombination deficiency (HRD) scores, and performed high-plex immunofluorescence analysis to define 20 cell phenotypes, thereby generating an in-situ PDAC tumor-immune landscape. Spatial phenotypic-transcriptomic profiling guided by regions-of-interest (ROIs) identified a crucial regulatory mechanism through localized tumor-adjacent macrophages, potentially in an HRD-dependent manner. Cellular neighborhood (CN) analysis further demonstrated the existence of macrophage-associated high-ordered cellular functional units in spatial contexts. Using our multi-omics spatial profiling strategy, we uncovered a dynamic macrophage-mediated regulatory axis linking HRD status with SIGLEC10 and CD52. These findings demonstrate the potential of targeting CD52 in combination with PARPi as a therapeutic intervention for PDAC.


Asunto(s)
Carcinoma Ductal Pancreático , Recombinación Homóloga , Macrófagos , Neoplasias Pancreáticas , Humanos , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Microambiente Tumoral/inmunología
12.
Angew Chem Int Ed Engl ; : e202410363, 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-39043558

RESUMEN

The homolysis of chemical bonds represents one of the most fundamental reactivities of excited molecules. Historically, it has been exploited to generate radicals under ultraviolet (UV) light irradiation. However, unlike most contemporary radical-generating mechanisms, the direct excitation to homolyze chemical bonds and produce aliphatic carbon-centered radicals under visible light remains rare, especially in metallaphotoredox cross couplings. Herein, we present our design of the dihydropyrimidoquinolinone (DHPQ) reagents derived from ketones, which can undergo formal deacylation and homolytic C-C bond cleavage to release alkyl radicals without external photocatalysts. Spectroscopic and computational analysis reveal unique optical and structural features of DHPQs, rationalizing their faster kinetics in alkyl radical generation than a structurally similar but visible-light transparent radical precursor. Such a capability allows DHPQ to facilitate a wide range of Ni-metallaphotoredox cross couplings with aryl, alkynyl and acyl halides. Other catalytic and non-catalyzed alkylative transformations of DHPQs are also feasible with various radical acceptors. We believe this work would be of broad interest, aiding the synthetic planning with simplified operation and expanding the synthetic reach of photocatalyst-free approaches in cutting-edge research.

13.
Phytother Res ; 38(7): 3782-3800, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38839050

RESUMEN

Pediatric intestinal development is immature, vulnerable to external influences and produce a variety of intestinal diseases. At present, breakthroughs have been made in the treatment of pediatric intestinal diseases, but there are still many challenges, such as toxic side effects, drug resistance, and the lack of more effective treatments and specific drugs. In recent years, dietary polyphenols derived from plants have become a research hotspot in the treatment of pediatric intestinal diseases due to their outstanding pharmacological activities such, as anti-inflammatory, antibacterial, antioxidant and regulation of intestinal flora. This article reviewed the mechanism of action and clinical evidence of dietary polyphenols in the treatment of pediatric intestinal diseases, and discussed the influence of physiological characteristics of children on the efficacy of polyphenols, and finally prospected the new dosage forms of polyphenols in pediatrics.


Asunto(s)
Enfermedades Intestinales , Polifenoles , Humanos , Polifenoles/farmacología , Niño , Enfermedades Intestinales/tratamiento farmacológico , Enfermedades Intestinales/dietoterapia , Enfermedades Intestinales/prevención & control , Antioxidantes/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Antiinflamatorios/farmacología , Dieta
14.
J Immunother Cancer ; 12(6)2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38862251

RESUMEN

BACKGROUND: A combination of axitinib and immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in the treatment of advanced renal cell carcinoma (RCC). This study aims to prospectively evaluate the safety, efficacy, and biomarkers of neoadjuvant toripalimab plus axitinib in non-metastatic clear cell RCC. METHODS: This is a single-institution, single-arm phase II clinical trial. Patients with non-metastatic biopsy-proven clear cell RCC (T2-T3N0-1M0) are enrolled. Patients will receive axitinib 5 mg twice daily combined with toripalimab 240 mg every 3 weeks (three cycles) for up to 12 weeks. Patients then will receive partial (PN) or radical nephrectomy (RN) after neoadjuvant therapy. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease-free survival, safety, and perioperative complication rate. Predictive biomarkers are involved in exploratory analysis. RESULTS: A total of 20 patients were enrolled in the study, with 19 of them undergoing surgery. One patient declined surgery. The primary endpoint ORR was 45%. The posterior distribution of πORR had a mean of 0.44 (95% credible intervals: 0.24-0.64), meeting the predefined primary endpoint with an ORR of 32%. Tumor shrinkage was observed in 95% of patients prior to nephrectomy. Furthermore, four patients achieved a pathological complete response. Grade ≥3 adverse events occurred in 25% of patients, including hypertension, hyperglycemia, glutamic pyruvic transaminase/glutamic oxaloacetic transaminase (ALT/AST) increase, and proteinuria. Postoperatively, one grade 4a and eight grade 1-2 complications were noted. In comparison to patients with stable disease, responders exhibited significant differences in immune factors such as Arginase 1(ARG1), Melanoma antigen (MAGEs), Dendritic Cell (DC), TNF Superfamily Member 13 (TNFSF13), Apelin Receptor (APLNR), and C-C Motif Chemokine Ligand 3 Like 1 (CCL3-L1). The limitation of this trial was the small sample size. CONCLUSION: Neoadjuvant toripalimab combined with axitinib shows encouraging activity and acceptable toxicity in locally advanced clear cell RCC and warrants further study. TRIAL REGISTRATION NUMBER: clinicaltrials.gov, NCT04118855.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Axitinib , Carcinoma de Células Renales , Neoplasias Renales , Terapia Neoadyuvante , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Axitinib/uso terapéutico , Axitinib/farmacología , Masculino , Femenino , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Estudios Prospectivos , Nefrectomía/métodos
15.
Int Immunopharmacol ; 138: 112549, 2024 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-38944950

RESUMEN

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), still ranks among the leading causes of annual human death by infectious disease. Mtb has developed several strategies to survive for years at a time within the host despite the presence of a robust immune response, including manipulating the progression of the inflammatory response and forming granulomatous lesions. Here we demonstrate that IQGAP1, a highly conserved scaffolding protein, compartmentalizes and coordinates multiple signaling pathways in macrophages infected with Mycobacterium marinum (Mm or M.marinum), the closest relative of Mtb. Upregulated IQGAP1 ultimately suppresses TNF-α production by repressing the MKK3 signal and reducing NF-κBp65 translocation, deactivating the p38MAPK pathway. Accordingly, IQGAP1 silencing and overexpression significantly alter p38MAPK activity by modulating the production of phosphorylated MKK3 during mycobacterial infection. Pharmacological inhibition of IQGAP1-associated microtubule assembly not only alleviates tissue damage caused by M.marinum infection but also significantly decreases the production of VEGF-a critical player for granuloma-associated angiogenesis during pathogenic mycobacterial infection. Similarly, IQGAP1 silencing in Mm-infected macrophages diminishes VEGF production, while IQGAP1 overexpression upregulates VEGF. Our data indicate that mycobacteria induce IQGAP1 to hijack NF-κBp65 activation, preventing the expression of proinflammatory cytokines as well as promoting VEGF production during infection and granuloma formation. Thus, therapies targeting host IQGAP1 may be a promising strategy for treating tuberculosis, particularly in drug-resistant diseases.


Asunto(s)
Macrófagos , FN-kappa B , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular , Proteínas Activadoras de ras GTPasa , Animales , Ratones , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/microbiología , MAP Quinasa Quinasa 3/metabolismo , MAP Quinasa Quinasa 3/genética , Ratones Endogámicos C57BL , Infecciones por Mycobacterium no Tuberculosas/inmunología , Infecciones por Mycobacterium no Tuberculosas/microbiología , Infecciones por Mycobacterium no Tuberculosas/metabolismo , FN-kappa B/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteínas Activadoras de ras GTPasa/metabolismo , Proteínas Activadoras de ras GTPasa/genética , Células RAW 264.7 , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/genética
16.
Nat Commun ; 15(1): 4818, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38844439

RESUMEN

Vortices in superconductors can help identify emergent phenomena but certain fundamental aspects of vortices, such as their entropy, remain poorly understood. Here, we study the vortex entropy in underdoped Bi2Sr2CaCu2O8+x by measuring both magneto-resistivity and Nernst effect on ultrathin flakes (≤2 unit-cell). We extract the London penetration depth from the magneto-transport measurements on samples with different doping levels. It reveals that the superfluid phase stiffness ρs scales linearly with the superconducting transition temperature Tc, down to the extremely underdoped case. On the same batch of ultrathin flakes, we measure the Nernst effect via on-chip thermometry. Together, we obtain the vortex entropy and find that it decays exponentially with Tc or ρs. We further analyze the Nernst signal above Tc in the framework of Gaussian superconducting fluctuations. The combination of electrical and thermoelectric measurements in the two-dimensional limit provides fresh insight into high temperature superconductivity.

17.
ACS Nano ; 18(26): 16395-16412, 2024 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-38874120

RESUMEN

Oral health is the basis of human health, and almost everyone has been affected by oral diseases. Among them, endodontic disease is one of the most common oral diseases. Limited by the characteristics of oral biomaterials, clinical methods for endodontic disease treatment still face large challenges in terms of reliability and stability. The hydrogel is a kind of good biomaterial with an adjustable 3D network structure, excellent mechanical properties, and biocompatibility and is widely used in the basic and clinical research of endodontic disease. This Review discusses the recent advances in functional hydrogels for dental hard tissue and endodontic disease treatment. The emphasis is on the working principles and therapeutic effects of treating different diseases with functional hydrogels. Finally, the challenges and opportunities of hydrogels in oral clinical applications are discussed and proposed. Some viewpoints about the possible development direction of functional hydrogels for oral health in the future are also put forward. Through systematic analysis and conclusion of the recent advances in functional hydrogels for dental hard tissue and endodontic disease treatment, this Review may provide significant guidance and inspiration for oral disease and health in the future.


Asunto(s)
Materiales Biocompatibles , Hidrogeles , Hidrogeles/química , Humanos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Animales , Enfermedades de la Pulpa Dental/terapia
18.
Plant Physiol ; 2024 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-38917205

RESUMEN

Plant virus-derived vectors are rapid and cost-effective for protein expression and gene functional studies in plants, particularly for species that are difficult to genetically transform. However, few efficient viral vectors are available for functional studies in Asteraceae plants. Here, we identified a potyvirus named zinnia mild mottle virus (ZiMMV) from common zinnia (Zinnia elegans Jacq.) through next-generation sequencing. Using a yeast homologous recombination strategy, we established a full-length infectious cDNA clone of ZiMMV under the control of the cauliflower mosaic virus 35S promoter. Furthermore, we developed an efficient expression vector based on ZiMMV for the persistent and abundant expression of foreign proteins in the leaf, stem, root, and flower tissues with mild symptoms during viral infection in common zinnia. We showed that the ZiMMV-based vector can express ZeMYB9, which encodes a transcript factor inducing dark red speckles in leaves and flowers. Additionally, the expression of a gibberellic acid (GA) biosynthesis gene from the ZiMMV vector substantially accelerated plant height growth, offering a rapid and cost-effective method. In summary, our work provides a powerful tool for gene expression, functional studies, and genetic improvement of horticultural traits in Asteraceae plant hosts.

19.
Insights Imaging ; 15(1): 150, 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38886244

RESUMEN

OBJECTIVES: Synchronous colorectal cancer peritoneal metastasis (CRPM) has a poor prognosis. This study aimed to create a radiomics-boosted deep learning model by PET/CT image for risk assessment of synchronous CRPM. METHODS: A total of 220 colorectal cancer (CRC) cases were enrolled in this study. We mapped the feature maps (Radiomic feature maps (RFMs)) of radiomic features across CT and PET image patches by a 2D sliding kernel. Based on ResNet50, a radiomics-boosted deep learning model was trained using PET/CT image patches and RFMs. Besides that, we explored whether the peritumoral region contributes to the assessment of CRPM. In this study, the performance of each model was evaluated by the area under the curves (AUC). RESULTS: The AUCs of the radiomics-boosted deep learning model in the training, internal, external, and all validation datasets were 0.926 (95% confidence interval (CI): 0.874-0.978), 0.897 (95% CI: 0.801-0.994), 0.885 (95% CI: 0.795-0.975), and 0.889 (95% CI: 0.823-0.954), respectively. This model exhibited consistency in the calibration curve, the Delong test and IDI identified it as the most predictive model. CONCLUSIONS: The radiomics-boosted deep learning model showed superior estimated performance in preoperative prediction of synchronous CRPM from pre-treatment PET/CT, offering potential assistance in the development of more personalized treatment methods and follow-up plans. CRITICAL RELEVANCE STATEMENT: The onset of synchronous colorectal CRPM is insidious, and using a radiomics-boosted deep learning model to assess the risk of CRPM before treatment can help make personalized clinical treatment decisions or choose more sensitive follow-up plans. KEY POINTS: Prognosis for patients with CRPM is bleak, and early detection poses challenges. The synergy between radiomics and deep learning proves advantageous in evaluating CRPM. The radiomics-boosted deep-learning model proves valuable in tailoring treatment approaches for CRC patients.

20.
Nat Nanotechnol ; 19(7): 932-940, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38750167

RESUMEN

Exploration of new dielectrics with a large capacitive coupling is an essential topic in modern electronics when conventional dielectrics suffer from the leakage issue near the breakdown limit. Here, to address this looming challenge, we demonstrate that rare-earth metal fluorides with extremely low ion migration barriers can generally exhibit an excellent capacitive coupling over 20 µF cm-2 (with an equivalent oxide thickness of ~0.15 nm and a large effective dielectric constant near 30) and great compatibility with scalable device manufacturing processes. Such a static dielectric capability of superionic fluorides is exemplified by MoS2 transistors exhibiting high on/off current ratios over 108, ultralow subthreshold swing of 65 mV dec-1 and ultralow leakage current density of ~10-6 A cm-2. Therefore, the fluoride-gated logic inverters can achieve notably higher static voltage gain values (surpassing ~167) compared with a conventional dielectric. Furthermore, the application of fluoride gating enables the demonstration of NAND, NOR, AND and OR logic circuits with low static energy consumption. In particular, the superconductor-insulator transition at the clean-limit Bi2Sr2CaCu2O8+δ can also be realized through fluoride gating. Our findings highlight fluoride dielectrics as a pioneering platform for advanced electronic applications and for tailoring emergent electronic states in condensed matter.

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