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2.
Chemistry ; : e202402607, 2024 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-39215487

RESUMEN

Functional group interconversion is of great significance in organic synthesis. However, aerobic cleavage of C=N bonds to access carbonyl compounds still suffered from some limitations such as harsh reaction conditions, stoichiometric oxidants, poor substrate scope and use of toxic reagents. Herein, we report a catalyst-free and photo-induced aerobic cleavage of C=N bonds to afford diverse carbonyl compounds using oxygen from air as green oxidant. This mild methodology permits N-tosylhydrazones converted into the corresponding carbonyl compounds including ketones, aldehydes and carboxylic acids, showing broad functional group tolerance and compatibility. Moreover, the gram-scale reaction and post-modification of complicated molecules proved the applicability and efficiency of this strategy. Finally, a plausible mechanism was proposed based on spectroscopic investigations and detailed mechanistic studies.

3.
Zhonghua Nan Ke Xue ; 30(6): 514-518, 2024 Jun.
Artículo en Chino | MEDLINE | ID: mdl-39212360

RESUMEN

OBJECTIVE: To compare thulium laser enucleation of the prostate (ThuLEP) with plasma kinetic resection of the prostate (PKRP) in the treatment of BPH. METHODS: We retrospectively analyzed the medical records of 160 cases of BPH treated by ThuLEP (the observation group, n = 80) or PKRP (the control group, n = 80) in our hospital from January 2021 to December 2023. We recorded the operation time, bladder irrigation time, catheter retention time, hospitalization time, postoperative complications, and pre- and postoperative maximum urinary flow rate (Qmax), residual urine volume (PVR), prostate-specific antigen (PSA) and prostate volume, followed by comparison of the data obtained between the two groups of patients. RESULTS: Compared with the controls, the patients of the observation group showed significantly shorter operation time (ï¼»67.25 ± 7.24ï¼½ vs ï¼»60.10 ± 5.15ï¼½ min, P< 0.05), bladder irrigation time (ï¼»46.90 ± 10.77ï¼½ vs ï¼»43.24 ± 6.65ï¼½ h, P< 0.05), catheterization time (ï¼»5.60 ± 1.31ï¼½ vs ï¼»5.03 ± 1.24ï¼½ d, P< 0.05) and hospitalization time (ï¼»7.31 ± 2.00ï¼½ vs ï¼»6.55 ± 1.67ï¼½ d, P< 0.05), higher Qmax (ï¼»18.50 ± 1.24ï¼½ vs ï¼»20.68 ± 1.45ï¼½ ml/s, P< 0.05), lower PVR (ï¼»12.10 ± 3.53ï¼½ vs ï¼»10.82 ± 3.10ï¼½ ml, P< 0.05), PSA (ï¼»4.60 ± 0.78ï¼½ vs ï¼»3.38 ± 0.40ï¼½ µg/L, P< 0.05) and prostate volume (ï¼»25.35 ± 6.46ï¼½ vs ï¼»20.12 ± 5.13ï¼½ ml, P< 0.05) at 3 months after surgery, but no statistically significant difference in the total incidence of postoperative complications (7.50% ï¼»6/80ï¼½ vs 5.00% ï¼»4/80ï¼½, P > 0.05). CONCLUSION: ThuLEP, with its advantages of notable effect, short operation and hospitalization time, significant improvement of urinary flow dynamics and prostate function, deserves clinical promotion for the treatment of BPH.


Asunto(s)
Terapia por Láser , Hiperplasia Prostática , Tulio , Humanos , Masculino , Hiperplasia Prostática/cirugía , Tulio/uso terapéutico , Estudios Retrospectivos , Terapia por Láser/métodos , Próstata/cirugía , Resección Transuretral de la Próstata/métodos , Resultado del Tratamiento , Complicaciones Posoperatorias , Tempo Operativo , Anciano , Antígeno Prostático Específico/sangre
4.
Adv Sci (Weinh) ; 11(29): e2305593, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38873820

RESUMEN

Centromere protein A (CENP-A), a centromere-specific histone H3 variant, is crucial for kinetochore positioning and chromosome segregation. However, its regulatory mechanism in human cells remains incompletely understood. A structure-activity relationship (SAR) study of the cell-cycle-arresting indole terpenoid mimic JP18 leads to the discovery of two more potent analogs, (+)-6-Br-JP18 and (+)-6-Cl-JP18. Tubulin is identified as a potential cellular target of these halogenated analogs by using the drug affinity responsive target stability (DARTS) based method. X-ray crystallography analysis reveals that both molecules bind to the colchicine-binding site of ß-tubulin. Treatment of human cells with microtubule-targeting agents (MTAs), including these two compounds, results in CENP-A accumulation by destabilizing Cdh1, a co-activator of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. This study establishes a link between microtubule dynamics and CENP-A accumulation using small-molecule tools and highlights the role of Cdh1 in CENP-A proteolysis.


Asunto(s)
Proteína A Centromérica , Microtúbulos , Proteolisis , Humanos , Antígenos CD , Proteínas Cdh1/metabolismo , Proteínas Cdh1/genética , Proteína A Centromérica/metabolismo , Proteína A Centromérica/genética , Cristalografía por Rayos X/métodos , Indoles/metabolismo , Indoles/farmacología , Indoles/química , Microtúbulos/metabolismo , Microtúbulos/efectos de los fármacos , Proteolisis/efectos de los fármacos , Huso Acromático/metabolismo , Huso Acromático/efectos de los fármacos , Relación Estructura-Actividad
5.
Surg Laparosc Endosc Percutan Tech ; 34(3): 301-305, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38722747

RESUMEN

BACKGROUND: Transoral endoscopic thyroidectomy vestibular approach (TOETVA) is newly applied technology. Carbon nanoparticles (CNs) are novel lymph node tracers that have been widely used in China to help remove central lymph nodes (CLNs) and protect the parathyroid glands (PGs) in open thyroid cancer surgery. This study is to evaluate the effectiveness and safety of CNs in TOETVA. MATERIALS AND METHODS: A total of 158 patients who underwent TOETVA with unilateral papillary thyroid carcinoma were enrolled in this study from March 2019 to February 2022. The participants were divided into a CNs group (n=88) and a control group (n=70), based on whether they received a intraoperative injection of CNs or not. Meanwhile, the CNs group were additionally divided into 2 subgroups, leakage subgroup (n=26) and standard subgroup (n=62). The 2 groups and subgroups were compared in terms of patient characteristics, perioperative clinical results, and postoperative outcomes. RESULTS: All common metrics had no significant differences were found between the CNs group and the control group ( P >0.05). The standard subgroup of CNs group had advantage over the control group on PGs identification (59/62 vs. 59/70 for superior PG, 56/62 vs. 52/70 for inferior PG, P <0.05). Moreover, the standard subgroup harvested more CLNs than the control group (8.97±2.96 vs. 7.47±2.93, P <0.05). More operation time was spent on the leakage subgroup of CNs group than the control group (160.00±17.61 vs. 140.00±13.32, P <0.05). Meanwhile, the leakage subgroup had disadvantage on intraoperative hemorrhage (26.15±10.80 vs. 21.21±7.09, P <0.05) and hospital durations (4.96±0.72 vs. 4.57±0.69, P <0.05). Furthermore, the leakage group identified fewer inferior PG than the control group (7/26 vs. 52/70, P <0.05). Contrary to the standard subgroup, the CLNs of the leakage subgroup was also unsatisfactory compared with the control group (4.96±1.84 vs. 7.47±2.93, P <0.05). CONCLUSIONS: The application of CNs suspension tracing technology has a definite effect in TOETVA. It can improve the thoroughness of lymph node dissection in the central region and enhance recognition of the PG. However, refined extracapsular anatomy is indispensable to prevent CN leakage. Leaked CNs will also be counterproductive to the operation.


Asunto(s)
Carbono , Nanopartículas , Cirugía Endoscópica por Orificios Naturales , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Tiroidectomía , Humanos , Masculino , Femenino , Cáncer Papilar Tiroideo/cirugía , Cáncer Papilar Tiroideo/patología , Tiroidectomía/métodos , Neoplasias de la Tiroides/cirugía , Cirugía Endoscópica por Orificios Naturales/métodos , Adulto , Persona de Mediana Edad , Escisión del Ganglio Linfático/métodos , Tempo Operativo , Estudios Retrospectivos , Resultado del Tratamiento
6.
Org Lett ; 26(15): 3130-3134, 2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-38587308

RESUMEN

Isoxazolines and isoxazoles commonly serve as core structures of many therapeutic agents and natural products. However, the metal-free and catalysis-free strategy for the synthesis of these privileged motifs at room temperature remains a challenging task. Herein, we report a three-component strategy to afford diverse isoxazolines and isoxazoles via [3 + 2] cycloadditions of in situ-formed nitronates and olefins/alkynes under visible-light irradiation.

7.
J Org Chem ; 89(9): 6180-6192, 2024 May 03.
Artículo en Inglés | MEDLINE | ID: mdl-38632865

RESUMEN

The photochemistry of noncovalent interactions to promote organic transformations is an emerging approach to providing fresh opportunities in synthetic chemistry. Generally, the external substance is necessary to add as an interaction partner, thereby sacrificing the atom economy of the reaction. Herein, we describe a catalyst-free and noncovalent interaction-mediated strategy to access the olefination of N-tosylhydrazones using acetone as a solvent and an interaction partner. This protocol also features broad substrate scope, excellent functional group compatibility, and mild reaction conditions without transition metals. Moreover, the gram-scale synthesis of olefins and the generation of pharmaceutical intermediates highlighted its practical applicability. Lastly, mechanistic studies indicate that the reaction was initiated via noncovalent interactions between acetone and N-tosylhydrazone anion, which is also supported by density functional theory calculations.

8.
Adv Healthc Mater ; 13(26): e2303445, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-38290499

RESUMEN

The application of oncolytic peptides has become a powerful approach to induce complete and long-lasting remission in multiple types of carcinomas, as affirmed by the appearance of tumor-associated antigens and adenosine triphosphate (ATP) in large quantities, which jumpstarts the cancer-immunity cycle. However, the ATP breakdown product adenosine is a significant contributor to forming the immunosuppressive tumor microenvironment, which substantially weakens peptide-driven oncolytic immunotherapy. In this study, a lipid-coated micelle (CA@TLM) loaded with a stapled oncolytic peptide (PalAno) and an adenosine 2A receptor (A2AR) inhibitor (CPI-444) is devised to enact tumor-targeted oncolytic immunotherapy and to overcome adenosine-mediated immune suppression simultaneously. The CA@TLM micelle accumulates in tumors with high efficiency, and the acidic tumor microenvironment prompts the rapid release of PalAno and CPI-444. Subsequently, PalAno induces swift membrane lysis of tumor cells and the release of antigenic materials. Meanwhile, CPI-444 blocks the activation of the immunosuppressive adenosine-A2AR signaling pathway. This combined approach exhibits pronounced synergy at stalling tumor growth and metastasis in animal models for triple-negative breast cancer and melanoma, providing a novel strategy for enhanced oncolytic immunotherapy.


Asunto(s)
Adenosina , Microambiente Tumoral , Microambiente Tumoral/efectos de los fármacos , Animales , Adenosina/química , Ratones , Humanos , Línea Celular Tumoral , Inmunoterapia/métodos , Receptor de Adenosina A2A/metabolismo , Femenino , Péptidos/química , Micelas
9.
Cell Oncol (Dordr) ; 47(1): 19-35, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37713105

RESUMEN

BACKGROUND: Ferroptosis, a newly form of regulated cell death (RCD), is characterized by iron dyshomeostasis and unrestricted lipid peroxidation. Emerging evidence depicts a pivotal role for ferroptosis in driving some pathological processes, especially in cancer. Triggering ferroptosis can suppress tumor growth and induce an anti-tumor immune response, denoting the therapeutic promises for targeting ferroptosis in the management of cancer. As an autophagic phenomenon, ferritinophagy is critical to induce ferroptosis by degradation of ferritin to release intracellular free iron. Recently, a great deal of effort has gone into designing and developing anti-cancer strategies based on targeting ferritinophagy to induce ferroptosis. CONCLUSION: This review delineates the regulatory mechanism of ferritinophagy firstly and summarizes the role of ferritinophagy-induced ferroptosis in cancer. Moreover, the strategies targeting ferritinophagy to induce ferroptosis are highlighted to unveil the therapeutic value of ferritinophagy as a target to manage cancer. Finally, the future research directions on how to cope with the challenges in developing ferritinophagy promoters into clinical therapeutics are discussed.


Asunto(s)
Ferroptosis , Neoplasias , Humanos , Hierro/metabolismo , Hierro/farmacología , Hierro/uso terapéutico , Ferritinas/metabolismo , Ferritinas/uso terapéutico , Neoplasias/metabolismo , Autofagia
10.
Biochim Biophys Acta Mol Basis Dis ; 1870(1): 166884, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37704111

RESUMEN

The ubiquitin-proteasome system (UPS) is a fundamental regulatory mechanism in cells, vital for maintaining cellular homeostasis, compiling signaling transduction, and determining cell fates. These biological processes require the coordinated signal cascades of UPS members, including ubiquitin ligases, ubiquitin-conjugating enzymes, deubiquitinases, and proteasomes, to ubiquitination and de-ubiquitination on substrates. Recent studies indicate that ubiquitination code rewriting is particularly prominent in pancreatic cancer. High frequency mutation or aberrant hyperexpression of UPS members dysregulates ferroptosis, tumor microenvironment, and metabolic rewiring processes and contribute to tumor growth, metastasis, immune evasion, and acquired drug resistance. We conduct an in-depth overview of ubiquitination process in pancreatic cancer, highlighting the role of ubiquitin code in tumor-promoting and tumor-suppressor pathways. Furthermore, we review current UPS modulators and analyze the potential of UPS modulators as cancer therapy.


Asunto(s)
Neoplasias Pancreáticas , Ubiquitina , Humanos , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación , Enzimas Ubiquitina-Conjugadoras/metabolismo , Neoplasias Pancreáticas/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Microambiente Tumoral , Neoplasias Pancreáticas
11.
J Med Virol ; 95(11): e29208, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37947293

RESUMEN

The main proteases (Mpro ) are highly conserved cysteine-rich proteins that can be covalently modified by numerous natural and synthetic compounds. Herein, we constructed an integrative approach to efficiently discover covalent inhibitors of Mpro from complex herbal matrices. This work begins with biological screening of 60 clinically used antiviral herbal medicines, among which Lonicera japonica Flos (LJF) demonstrated the strongest anti-Mpro effect (IC50 = 37.82 µg/mL). Mass spectrometry (MS)-based chemical analysis and chemoproteomic profiling revealed that LJF extract contains at least 50 constituents, of which 22 exhibited the capability to covalently modify Mpro . We subsequently verified the anti-Mpro effects of these covalent binders. Gallic acid and quercetin were found to potently inhibit severe acute respiratory syndrome coronavirus 2 Mpro in dose- and time- dependent manners, with the IC50 values below 10 µM. The inactivation kinetics, binding affinity and binding mode of gallic acid and quercetin were further characterized by fluorescence resonance energy transfer, surface plasmon resonance, and covalent docking simulations. Overall, this study established a practical approach for efficiently discovering the covalent inhibitors of Mpro from herbal medicines by integrating target-based high-throughput screening and MS-based assays, which would greatly facilitate the discovery of key antiviral constituents from medicinal plants.


Asunto(s)
COVID-19 , Plantas Medicinales , Humanos , SARS-CoV-2 , Ensayos Analíticos de Alto Rendimiento , Quercetina/farmacología , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/química , Extractos Vegetales/farmacología , Antivirales/farmacología , Antivirales/química , Ácido Gálico/farmacología , Simulación del Acoplamiento Molecular
12.
Pharmacol Res ; 198: 106996, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37972723

RESUMEN

Breast cancer (BC) remains the foremost cause of cancer mortality globally, with neutrophils playing a critical role in its pathogenesis. As an essential tumor microenvironment (TME) component, neutrophils are emerging as pivotal factors in BC progression. Growing evidence has proved that neutrophils play a Janus- role in BC by polarizing into the anti-tumor (N1) or pro-tumor (N2) phenotype. Clinical trials are evaluating neutrophil-targeted therapies, including Reparixin (NCT02370238) and Tigatuzumab (NCT01307891); however, their clinical efficacy remains suboptimal. This review summarizes the evidence regarding the close relationship between neutrophils and BC, emphasizing the critical roles of neutrophils in regulating metabolic and immune pathways. Additionally, we summarize the existing therapeutic approaches that target neutrophils, highlighting the challenges, and affirming the rationale for continuing to explore neutrophils as a viable therapeutic target in BC management.


Asunto(s)
Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/metabolismo , Neutrófilos/metabolismo , Resultado del Tratamiento , Microambiente Tumoral , Ensayos Clínicos como Asunto
13.
Front Cell Infect Microbiol ; 13: 1267629, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37818043

RESUMEN

Introduction: The masked palm civet (Paguma larvata) serves as a reservoir in transmitting pathogens, such as Toxoplasma gondii, to humans. However, the pathogenesis of T. gondii infection in masked palm civets has not been explored. We studied the molecular changes in the brain tissue of masked palm civets chronically infected with T. gondii ME49. Methods: The differentially expressed proteins in the brain tissue were investigated using iTRAQ and bioinformatics. Results: A total of 268 differential proteins were identified, of which 111 were upregulated and 157 were downregulated. KEGG analysis identified pathways including PI3K-Akt signaling pathway, proteoglycans in cancer, carbon metabolism, T-cell receptor signaling pathway. Combing transcriptomic and proteomics data, we identified 24 genes that were differentially expressed on both mRNA and protein levels. The top four upregulated proteins were REEP3, REEP4, TEP1, and EEPD1, which was confirmed by western blot and immunohistochemistry. KEGG analysis of these 24 genes identified signaling cascades that were associated with small cell lung cancer, breast cancer, Toll-like receptor signaling pathway, Wnt signaling pathways among others. To understand the mechanism of the observed alteration, we conducted immune infiltration analysis using TIMER databases which identified immune cells that are associated with the upregulation of these proteins. Protein network analysis identified 44 proteins that were in close relation to all four proteins. These proteins were significantly enriched in immunoregulation and cancer pathways including PI3K-Akt signaling pathway, Notch signaling pathway, chemokine signaling pathway, cell cycle, breast cancer, and prostate cancer. Bioinformatics utilizing two cancer databases (TCGA and GEPIA) revealed that the four genes were upregulated in many cancer types including glioblastoma (GBM). In addition, higher expression of REEP3 and EEPD1 was associated with better prognosis, while higher expression of REEP4 and TEP1 was associated with poor prognosis in GBM patients. Discussion: We identified the differentially expressed genes in the brain of T. gondii infected masked palm civets. These genes were associated with various cellular signaling pathways including those that are immune- and cancer-related.


Asunto(s)
Neoplasias de la Mama , Toxoplasma , Masculino , Animales , Humanos , Viverridae/metabolismo , Multiómica , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Encéfalo/metabolismo , Biología Computacional , Neoplasias de la Mama/metabolismo , Proteínas de Transporte de Membrana/metabolismo
14.
Zhongguo Zhong Yao Za Zhi ; 48(18): 4981-4992, 2023 Sep.
Artículo en Chino | MEDLINE | ID: mdl-37802840

RESUMEN

This study constructed a nano-drug delivery system, A3@GMH, by co-delivering the stapled anoplin peptide(Ano-3, A3) with the light-harvesting material graphene oxide(GO), and evaluated its oncolytic immunotherapy effect on triple-negative breast cancer(TNBC). A3@GMH was prepared using an emulsion template method and its physicochemical properties were characterized. The in vivo and in vitro photothermal conversion abilities of A3@GMH were investigated using an infrared thermal imager. The oncoly-tic activity of A3@GMH against TNBC 4T1 cells was evaluated through cell counting kit-8(CCK-8), lactate dehydrogenase(LDH) release, live/dead cell staining, and super-resolution microscopy. The targeting properties of A3@GMH on 4T1 cells were assessed using a high-content imaging system and flow cytometry. In vitro and in vivo studies were conducted to investigate the antitumor mechanism of A3@GMH in combination with photothermal therapy(PTT) through inducing immunogenic cell death(ICD) in 4T1 cells. The results showed that the prepared A3@GMH exhibited distinct mesoporous and coated structures with an average particle size of(308.9±7.5) nm and a surface potential of(-6.79±0.58) mV. The encapsulation efficiency and drug loading of A3 were 23.9%±0.6% and 20.5%±0.5%, respectively. A3@GMH demonstrated excellent photothermal conversion ability and biological safety. A3@GMH actively mediated oncolytic features such as 4T1 cell lysis and LDH release, as well as ICD effects, and showed enhanced in vitro antitumor activity when combined with PTT. In vivo, A3@GMH efficiently induced ICD effects with two rounds of PTT, activated the host's antitumor immune response, and effectively suppressed tumor growth in 4T1 tumor-bearing mice, achieving an 88.9% tumor inhibition rate with no apparent toxic side effects. This study suggests that the combination of stapled anoplin peptide and PTT significantly enhances the oncolytic immunotherapy for TNBC and provides a basis for the innovative application of anti-tumor peptides derived from TCM in TNBC treatment.


Asunto(s)
Nanopartículas , Neoplasias de la Mama Triple Negativas , Humanos , Animales , Ratones , Terapia Fototérmica , Neoplasias de la Mama Triple Negativas/terapia , Neoplasias de la Mama Triple Negativas/patología , Péptidos Catiónicos Antimicrobianos , Inmunoterapia/métodos , Línea Celular Tumoral , Fototerapia/métodos , Nanopartículas/química
15.
Chem Sci ; 14(38): 10411-10419, 2023 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-37799991

RESUMEN

To date, [3 + 2] cycloadditions of diazo esters with alkynes or alkenes have been a robust tool to generate pyrazoles and pyrazolines. However, methods capable of generating donor/donor diazo species from readily available N-tosylhydrazones to furnish [3 + 2] cycloadditions, remain elusive. Herein, we describe the first visible-light-induced [3 + 2] cycloadditions of donor/donor diazo precursors with alkenes to afford pyrazoles and novel (spiro)pyrazolines bearing a quaternary center. This protocol shows a tolerable substrate scope covering versatile carbonyl compounds and alkenes. Late-stage functionalization of bioactive molecules, one-pot approach, and gram-scale synthesis have also been introduced successfully to prove the practicability. At last, mechanistic experiments and DFT studies suggested the formation of non-covalent interactions enabling the activation of N-tosylhydrazones and the formation of the donor/donor diazo intermediates.

16.
J Cachexia Sarcopenia Muscle ; 14(5): 2098-2113, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37439183

RESUMEN

BACKGROUND: Corylifol A (CYA) is one of the main active components of Psoralea corylifolia L. CYA had been reported to have ameliorating effects on dexamethasone-induced atrophy of C2C12 mouse skeletal myotubes, but its effects on cancer cachexia were unclear. Here, we checked the influence of CYA on muscle atrophy in cancer cachexia mice and tried to clarify its mechanisms. METHODS: C26 tumour-bearing mice were applied as the animal model to examine the effects of CYA in attenuating cachexia symptoms. The in vitro cell models of TNF-α-induced C2C12 myotubes or ad-mRFP-GFP-LC3B-transfected C2C12 myotubes were used to check the influence of CYA on myotube atrophy based on both ubiquitin proteasome system (UPS) and autophagy-lysosome system. The possible direct targets of CYA were searched using the biotin-streptavidin pull-down assay and then confirmed using the Microscale thermophoresis binding assay. The levels of related signal proteins in both in vitro and in vivo experiments were examined using western blotting and immunocytochemical assay. RESULTS: The administration of CYA prevented body weight loss and muscle wasting in C26 tumour-bearing mice without affecting tumour growth. At the end of the experiment, the body weight of mice treated with 30 mg/kg of CYA (23.59 ± 0.94 g) was significantly higher than that of the C26 model group (21.66 ± 0.56 g) with P < 0.05. The values of gastrocnemius muscle weight/body weight of mice treated with 15 or 30 mg/kg CYA (0.53 ± 0.02% and 0.54 ± 0.01%, respectively) were both significantly higher than that of the C26 model group (0.45 ± 0.01%) with P < 0.01. CYA decreased both UPS-mediated protein degradation and autophagy in muscle tissues of C26 tumour-bearing mice as well as in C2C12 myotubes treated with TNF-α. The thousand-and-one amino acid kinase 1 (TAOK1) was found to be the direct binding target of CYA. CYA inhibited the activation of TAOK1 and its downstream p38-MAPK pathway thus decreased the level and nuclear location of FoxO3. siRNA knockdown of TAOK1 or regulation of the p38-MAPK pathway using activator or inhibitor could affect the ameliorating effects of CYA on myotube atrophy. CONCLUSIONS: CYA ameliorates cancer cachexia muscle atrophy by decreasing both UPS degradation and autophagy. The ameliorating effects of CYA on muscle atrophy might be based on its binding with TAOK1 and inhibiting the TAOK1/p38-MAPK/FoxO3 pathway.

17.
Am J Chin Med ; 51(5): 1153-1188, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37403214

RESUMEN

COVID-19 has posed unprecedented challenges to global public health since its outbreak. The Qing-Fei-Pai-Du decoction (QFPDD), a Chinese herbal formula, is widely used in China to treat COVID-19. It exerts an impressive therapeutic effect by inhibiting the progression from mild to critical disease in the clinic. However, the underlying mechanisms remain obscure. Both SARS-CoV-2 and influenza viruses elicit similar pathological processes. Their severe manifestations, such as acute respiratory distress syndrome (ARDS), multiple organ failure (MOF), and viral sepsis, are correlated with the cytokine storm. During flu infection, QFPDD reduced the lung indexes and downregulated the expressions of MCP-1, TNF-[Formula: see text], IL-6, and IL-1[Formula: see text] in broncho-alveolar lavage fluid (BALF), lungs, or serum samples. The infiltration of neutrophils and inflammatory monocytes in lungs was decreased dramatically, and lung injury was ameliorated in QFPDD-treated flu mice. In addition, QFPDD also inhibited the polarization of M1 macrophages and downregulated the expressions of IL-6, TNF-[Formula: see text], MIP-2, MCP-1, and IP-10, while also upregulating the IL-10 expression. The phosphorylated TAK1, IKK[Formula: see text]/[Formula: see text], and I[Formula: see text]B[Formula: see text] and the subsequent translocation of phosphorylated p65 into the nuclei were decreased by QFPDD. These findings indicated that QFPDD reduces the intensity of the cytokine storm by inhibiting the NF-[Formula: see text]B signaling pathway during severe viral infections, thereby providing theoretical and experimental support for its clinical application in respiratory viral infections.


Asunto(s)
COVID-19 , Interleucina-6 , Animales , Ratones , Interleucina-6/metabolismo , COVID-19/metabolismo , SARS-CoV-2 , Neutrófilos/metabolismo , Síndrome de Liberación de Citoquinas , Macrófagos/metabolismo , FN-kappa B/metabolismo
18.
Org Lett ; 25(24): 4592-4597, 2023 Jun 23.
Artículo en Inglés | MEDLINE | ID: mdl-37306653

RESUMEN

A fully catalytic nickel-photoredox process for the direct amidation of aldehydes with nitroarenes was developed. In this system, aldehydes and nitroarenes were catalytically activated by the photocatalytic cycle without the addition of an additional reductant or oxidants, which facilitated the Ni-mediated cross-coupling of the C-N bond under mild conditions. A preliminary mechanistic study indicates a reaction pathway in which nitrobenzene is directly reduced to aniline as the nitrogen source.


Asunto(s)
Aldehídos , Níquel , Aldehídos/química , Níquel/química , Catálisis , Oxidación-Reducción , Oxidantes
19.
Zhongguo Zhong Yao Za Zhi ; 48(7): 1705-1710, 2023 Apr.
Artículo en Chino | MEDLINE | ID: mdl-37282944

RESUMEN

Novel drug discovery from the active ingredients of traditional Chinese medicine is the most distinctive feature and advantageous field of China, which has provided an unprecedented opportunity. However, there are still problems such as unclear functional substance basis, action targets and mechanism, which greatly hinder the clinical transformation of active ingredients in traditional Chinese medicine. Based on the analysis of the current status and progress of innovative drug research and development in China, this paper aimed to explore the prospect and difficulties of the development of natural active ingredients from traditional Chinese medicine, and to explore the efficient discovery of trace active ingredients in traditional Chinese medicine, and obtain drug candidates with novel chemical structure, unique target/mechanism and independent intellectual property rights, in order to provide a new strategy and a new model for the development of natural medicine with Chinese characteristics.


Asunto(s)
Medicamentos Herbarios Chinos , Medicina Tradicional China , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/química , Investigación , Descubrimiento de Drogas , China
20.
Surg Laparosc Endosc Percutan Tech ; 33(4): 347-350, 2023 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-37311050

RESUMEN

BACKGROUND: Transoral endoscopic thyroidectomy vestibular approach (TOETVA) and gasless transaxillary endoscopic thyroidectomy (GTET) are 2 newly applied technologies. This study is to compare the 2 approaches from the aspects of effectiveness and safety. MATERIALS AND METHODS: A total of 339 patients who underwent TOETVA or GTET with unilateral papillary thyroid carcinoma were enrolled in this study from March 2019 to February 2022. The 2 groups were compared in terms of patient characteristics, perioperative clinical results, and postoperative outcomes. RESULTS: The operative time of the TOETVA group was significantly longer than the GTET group (141.39±16.11 vs. 98.45±12.24, P <0.05). The TOETVA group had advantages over GTET group when the reduction of parathyroid hormone was compared (19.18±17.43 vs. 23.07±15.72, P <0.05). Meanwhile, more parathyroids were detected in central neck specimens in GTET group (40/181 vs. 21/158, P <0.05). TOETVA had an advantage on total number of central lymph nodes over GTET (7.65±3.11 vs. 4.99±2.45, P <0.05), whereas the number of positive central lymph nodes was similar ( P >0.05). No differences were found between the 2 groups on other data. CONCLUSIONS: TOETVA and GTET are both safe and effective for unilateral papillary thyroid carcinomas. TOETVA has advantage on protection of inferior parathyroid glands and harvest of central lymph node dissection. Meanwhile, GTET can save more time compared with TOETVA. Surgeons and patients should freely choose the approaches based on their demands.


Asunto(s)
Neoplasias de la Tiroides , Tiroidectomía , Humanos , Tiroidectomía/métodos , Cáncer Papilar Tiroideo/cirugía , Estudios Retrospectivos , Endoscopía , Neoplasias de la Tiroides/cirugía , Neoplasias de la Tiroides/patología
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