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1.
J Immunol ; 211(9): 1397-1405, 2023 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-37721419

RESUMEN

High levels of IFN-γ are produced in the lung during an adaptive immune response to Pneumocystis, but the effects of this prototypical Th1 cytokine on fungal clearance and immunopathogenesis have not been fully defined. Therefore, Pneumocystis-infected immunodeficient mice were immune reconstituted and administered control or anti-IFN-γ neutralizing Ab to determine how IFN-γ regulates the balance between host defense and immune-mediated lung injury. Mice treated with anti-IFN-γ demonstrated an initial worsening of Pneumocystis pneumonia-related immunopathogenesis, with greater weight loss, heightened lung inflammation, and more severe pulmonary function deficits than control mice. However, IFN-γ neutralization also enhanced macrophage phagocytosis of Pneumocystis and accelerated fungal clearance. When anti-IFN-γ-treated mice were also given IL-4 and IL-13 to promote a Th2-biased lung environment, the accelerated fungal clearance was preserved, but the severity of immunopathogenesis was reduced, and a more rapid recovery was observed. A direct suppressive effect of IFN-γ on macrophages was required but was not solely responsible for delayed fungal clearance, suggesting that IFN-γ acts through multiple mechanisms that likely include modulation of both macrophage and Th polarization. Enhanced Pneumocystis clearance in anti-IFN-γ-treated and IFN-γR-deficient mice was associated with significantly elevated IL-17+ CD4+ T cells and IL-17 protein in the lungs. Furthermore, neutralization of IL-17, but not IL-4, signaling blocked the accelerated fungal clearance observed in anti-IFN-γ-treated mice. Together, these data demonstrate that although IFN-γ delays fungal clearance by suppressing the lung Th17 response, it also serves an important regulatory role that limits immunopathogenesis and preserves pulmonary function.


Asunto(s)
Pneumocystis , Neumonía por Pneumocystis , Animales , Ratones , Neumonía por Pneumocystis/microbiología , Neumonía por Pneumocystis/patología , Interleucina-17 , Pulmón , Interferón gamma , Ratones Endogámicos C57BL , Ratones Noqueados
2.
Infect Immun ; 91(4): e0049022, 2023 04 18.
Artículo en Inglés | MEDLINE | ID: mdl-36916933

RESUMEN

Pneumocystis is a respiratory fungal pathogen that is among the most frequent causes of life-threatening pneumonia (PcP) in immunocompromised hosts. Alveolar macrophages play an important role in host defense against Pneumocystis, and several studies have suggested that M2 polarized macrophages have anti-Pneumocystis effector activity. Our prior work found that the immunomodulatory drug sulfasalazine (SSZ) provides a dual benefit during PcP-related immune reconstitution inflammatory syndrome (IRIS) by concurrently suppressing immunopathogenesis while also accelerating macrophage-mediated fungal clearance. The benefits of SSZ were associated with heightened Th2 cytokine production and M2 macrophage polarization. Therefore, to determine whether SSZ improves the outcome of PcP through a mechanism that requires Th2-dependent M2 polarization, RAG2-/- mice lacking interleukin 4 receptor alpha chain (IL-4Rα) on macrophage lineage cells were generated. As expected, SSZ treatment dramatically reduced the severity of PcP-related immunopathogenesis and accelerated fungal clearance in immune-reconstituted RAG2-/- mice. Similarly, SSZ treatment was also highly effective in immune-reconstituted RAG2/IL-4Rα-/- and RAG2/gamma interferon receptor (IFN-γR)-/- mice, demonstrating that neither IL-4Rα-dependent M2 nor IFN-γR-dependent M1 macrophage polarization programs were required for the beneficial effects of SSZ. Despite the fact that macrophages from RAG2/IL-4Rα-/- mice could not respond to the Th2 cytokines IL-4 and IL-13, M2-biased alveolar macrophages were identified in the lungs following SSZ treatment. These data demonstrate that not only does SSZ enhance phagocytosis and fungal clearance in the absence of macrophage IL-4Rα signaling, but also that SSZ promotes M2 macrophage polarization in an IL-4Rα-independent manner. These findings could have implications for the treatment of PcP and other diseases in which M2 polarization is beneficial.


Asunto(s)
Pneumocystis , Neumonía por Pneumocystis , Ratones , Animales , Sulfasalazina/farmacología , Neumonía por Pneumocystis/tratamiento farmacológico , Antifúngicos/farmacología , Macrófagos , Macrófagos Alveolares/microbiología
3.
Anesth Analg ; 135(3): 633-640, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-35061634

RESUMEN

BACKGROUND: Regional anesthesia such as interscalene brachial plexus block (ISBPB) with intermediate cervical plexus block (ICPB) is generally a preferred choice for clavicular surgery. However, various studies have shown that these blocks, especially ISBPB, could cause phrenic nerve paralysis and decrease diaphragmatic motion. The study aimed to evaluate the efficacy of clavipectoral fascial plane block (CPB), an alternative technique to ISBPB, with ICPB, in reducing hemidiaphragmatic paralysis during midshaft clavicular surgery. METHODS: Forty patients scheduled for right midshaft clavicular surgery were randomized (1:1) into an ultrasound-guided ISBPB with ICPB (BC) group or ultrasound-guided CPB with ICPB (CC) group. Five milliliter of 0.375% ropivacaine was used for ICPB, another 20 mL for ISBPB or CPB, and no administration of additional sedative or general anesthetic was planned. Primary outcome was measured by the incidence of hemidiaphragmatic paralysis using M-mode ultrasonography, while secondary outcomes were measured by bedside pulmonary function test, the success rate of block, the time required for the block procedure and onset of block, and motor block score in right upper extremity. RESULTS: In comparison with BC group, the incidence of hemidiaphragmatic paralysis postblock was decreased in CC group (50% vs 0%; P < .001), and measurement of bedside pulmonary function was significantly improved. There was a 100% success rate for anesthetic block in both BC and CC groups, and CC group showed lower motor block score in upper extremity and less block procedure time than BC group (7.1 ± 1.2 vs 3.2 ± 0.6 minutes; P < .001). Moreover, no significant differences were found between time of onset of block and other anesthetic complications in the 2 groups. CONCLUSIONS: Ultrasound-guided CPB with ICPB could significantly reduce hemidiaphragmatic paralysis and provide an adequate surgical anesthesia with fewer complications such as motor block in upper extremity during right midshaft clavicular surgery.


Asunto(s)
Bloqueo del Plexo Braquial , Bloqueo del Plexo Cervical , Anestésicos Locales , Bloqueo del Plexo Braquial/efectos adversos , Bloqueo del Plexo Braquial/métodos , Bloqueo del Plexo Cervical/efectos adversos , Humanos , Parálisis , Estudios Prospectivos , Ultrasonografía , Ultrasonografía Intervencional/métodos
4.
Pak J Pharm Sci ; 34(6(Special)): 2423-2427, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35039254

RESUMEN

To analyze the effect of traditional Chinese medicine Paishi decoction combined with laparoscopic ureterectomy and lithotripsy in the treatment of complex kidney stones. Totally 100 patients with complicated kidney stones admitted to our hospital from January 2019 to January 2021 were selected and randomly divided into a control group and an experimental group, with 50 cases in each group. The control group was treated with laparoscopic ureterectomy for stone removal, the experimental group was treated with traditional Chinese medicine Paishi decoction combined with laparoscopic ureterectomy for stone removal. The therapeutic effects of the two groups were compared. The total effective rate of treatment in the control group was 76% and that of the experimental group was 96%. The stone clearing time, time to pain resolution and time to hematuria disappearance time in the experimental group were significantly shorter as compared with the control group. After treatment, the levels of serum creatinine and blood urea nitrogen in the experimental group were significantly lower than those in the control group. Traditional Chinese medicine Paishi decoction combined with laparoscopic ureterectomy and lithotripsy for treatment of complex kidney stones ameliorates the treatment efficacy, shortens the time of stone removal, mitigates the clinical symptoms of patients, and helps restore renal function, which is worthy of clinical promotion and application.


Asunto(s)
Medicamentos Herbarios Chinos , Cálculos Renales , Laparoscopía , Procedimientos Quirúrgicos Urológicos , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios de Casos y Controles , Terapia Combinada , Medicamentos Herbarios Chinos/efectos adversos , Medicamentos Herbarios Chinos/uso terapéutico , Cálculos Renales/diagnóstico por imagen , Cálculos Renales/terapia , Laparoscopía/efectos adversos , Litotricia , Distribución Aleatoria , Factores de Tiempo , Resultado del Tratamiento , Procedimientos Quirúrgicos Urológicos/efectos adversos
5.
BMC Anesthesiol ; 18(1): 142, 2018 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-30309327

RESUMEN

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication after cardiac surgery that influences the clinical outcomes and quality of life of patients. This study aimed to evaluate the effects of Shenmai injection (SMI) on POCD of patients who underwent cardiac valve replacement under cardiopulmonary bypass (CPB). METHODS: This prospective, randomized, controlled trial was conducted from September 2014 to January 2017. Eighty-eight patients receiving cardiac valve replacement under CPB were randomized into the control (C) or the SMI (S) group. SMI (0.6 mL/kg) was administered intravenously from the time of anesthesia induction to the beginning of CPB. Cognitive function was assessed at 3 days before surgery and 3 days, 7 days, and 1 month after surgery using the Beijing version of the Montreal Cognitive Assessment (MoCA-BJ) score. The serum levels of neuroglobin (Ngb), hypoxia-inducible factor-1α (HIF-1α), and neuron-specific enolase (NSE) were measured at 30 min after induction (T0), immediately after the endonasal temperature rewarmed to 36 °C (T1), and 1 h (T2), 6 h (T3), 24 h (T4), 48 h (T5), and 72 h (T6) after CPB. RESULTS: Compared with the baseline values at T0, the serum Ngb levels in group C were significantly decreased at T1-2 and then increased at T3-6, while the levels in group S were decreased at T1-2 and increased at T4-6, compared to group C (p < 0.05). The serum HIF-1α levels at T1-4 and the serum NSE levels at T1-6 were significantly increased in both groups (p < 0.05). The serum levels of Ngb at T3, HIF-1α at T1-3, and NSE at T3-4,6 were lower in group S, compared to group C (p < 0.01). The MoCA-BJ scores were decreased at 3 and 7 days after surgery in both groups, and the MoCA-BJ scores in group S were higher than those in group C at 3 and 7 days after surgery (p < 0.01). CONCLUSION: Cognitive function is impaired postoperatively in patients who have undergone cardiac valve replacement under CPB. In addition, treatment with the traditional Chinese medicine SMI decreases the serum levels of Ngb, HIF-1α, and NSE as well as attenuates cognitive dysfunction. TRIAL REGISTRATION: This trial was registered with Clinicaltrials.gov as ChiCTR-TRC-14004373 on March 11, 2014.


Asunto(s)
Puente Cardiopulmonar/efectos adversos , Disfunción Cognitiva/prevención & control , Medicamentos Herbarios Chinos/administración & dosificación , Implantación de Prótesis de Válvulas Cardíacas/métodos , Administración Intravenosa , Anciano , Puente Cardiopulmonar/métodos , Cognición/efectos de los fármacos , Disfunción Cognitiva/etiología , Combinación de Medicamentos , Medicamentos Herbarios Chinos/farmacología , Femenino , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/sangre , Masculino , Persona de Mediana Edad , Fosfopiruvato Hidratasa/metabolismo , Complicaciones Posoperatorias/prevención & control , Estudios Prospectivos , Calidad de Vida , Factores de Tiempo
6.
Biochim Biophys Acta Proteins Proteom ; 1865(11 Pt B): 1522-1528, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28844740

RESUMEN

Global functions of nicotinic acetylcholine receptors, such as subunit cooperativity and compatibility, likely emerge from a network of amino acid residues distributed across the entire pentameric complex. Identification of such networks has stymied traditional approaches to acetylcholine receptor structure and function, likely due to the cryptic interdependency of their underlying amino acid residues. An emerging evolutionary biochemistry approach, which traces the evolutionary history of acetylcholine receptor subunits, allows for rational mapping of acetylcholine receptor sequence space, and offers new hope for uncovering the amino acid origins of these enigmatic properties.


Asunto(s)
Evolución Molecular , Receptores Colinérgicos/química , Animales , Humanos , Estructura Terciaria de Proteína , Receptores Colinérgicos/metabolismo , Relación Estructura-Actividad
7.
Anesth Analg ; 135(4): e25, 2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-36108197
8.
Anesth Analg ; 135(4): e26-e27, 2022 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-36108199
9.
Sensors (Basel) ; 17(12)2017 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-29206188

RESUMEN

This article proposes a lightweight biometric sensing system using ubiquitous narrowband radio frequency (RF) links for path-dependent walker classification. The fluctuated received signal strength (RSS) sequence generated by human motion is used for feature representation. To capture the most discriminative characteristics of individuals, a three-layer RF sensing network is organized for building multiple sampling links at the most common heights of upper limbs, thighs, and lower legs. The optimal parameters of sensing configuration, such as the height of link location and number of fused links, are investigated to improve sensory data distinctions among subjects, and the experimental results suggest that the synergistic sensing by using multiple links can contribute a better performance. This is the new consideration of using RF links in building a biometric sensing system. In addition, two types of classification methods involving vector quantization (VQ) and hidden Markov models (HMMs) are developed and compared for closed-set walker recognition and verification. Experimental studies in indoor line-of-sight (LOS) and non-line-of-sight (NLOS) scenarios are conducted to validate the proposed method.


Asunto(s)
Biometría , Ondas de Radio
10.
Infect Immun ; 83(12): 4594-603, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26371121

RESUMEN

Pneumocystis is a respiratory fungal pathogen that causes pneumonia (Pneumocystis pneumonia [PcP]) in immunocompromised patients. Alveolar macrophages are critical effectors for CD4(+) T cell-dependent clearance of Pneumocystis, and previous studies found that alternative macrophage activation accelerates fungal clearance during PcP-related immune reconstitution inflammatory syndrome (IRIS). However, the requirement for either classically or alternatively activated macrophages for Pneumocystis clearance has not been determined. Therefore, RAG2(-/-) mice lacking either the interferon gamma (IFN-γ) receptor (IFN-γR) or interleukin 4 receptor alpha (IL-4Rα) were infected with Pneumocystis. These mice were then immune reconstituted with wild-type lymphocytes to preserve the normal T helper response while preventing downstream effects of Th1 or Th2 effector cytokines on macrophage polarization. As expected, RAG2(-/-) mice developed severe disease but effectively cleared Pneumocystis and resolved IRIS. Neither RAG/IFN-γR(-/-) nor RAG/IL-4Rα(-/-) mice displayed impaired Pneumocystis clearance. However, RAG/IFN-γR(-/-) mice developed a dysregulated immune response, with exacerbated IRIS and greater pulmonary function deficits than those in RAG2 and RAG/IL-4Rα(-/-) mice. RAG/IFN-γR(-/-) mice had elevated numbers of lung CD4(+) T cells, neutrophils, eosinophils, and NK cells but severely depressed numbers of lung CD8(+) T suppressor cells. Impaired lung CD8(+) T cell responses in RAG/IFN-γR(-/-) mice were associated with elevated lung IFN-γ levels, and neutralization of IFN-γ restored the CD8 response. These data demonstrate that restricting the ability of macrophages to polarize in response to Th1 or Th2 cytokines does not impair Pneumocystis clearance. However, a cell type-specific IFN-γ/IFN-γR-dependent mechanism regulates CD8(+) T suppressor cell recruitment, limits immunopathogenesis, preserves lung function, and enhances the resolution of PcP-related IRIS.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Síndrome Inflamatorio de Reconstitución Inmune/inmunología , Macrófagos Alveolares/inmunología , Pneumocystis/inmunología , Neumonía por Pneumocystis/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Linfocitos T CD8-positivos/microbiología , Linfocitos T CD8-positivos/patología , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Eosinófilos/inmunología , Eosinófilos/microbiología , Eosinófilos/patología , Regulación de la Expresión Génica , Interacciones Huésped-Patógeno , Síndrome Inflamatorio de Reconstitución Inmune/genética , Síndrome Inflamatorio de Reconstitución Inmune/microbiología , Síndrome Inflamatorio de Reconstitución Inmune/patología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/microbiología , Células Asesinas Naturales/patología , Pulmón/inmunología , Pulmón/microbiología , Pulmón/patología , Activación de Macrófagos , Macrófagos Alveolares/microbiología , Macrófagos Alveolares/patología , Ratones , Ratones Noqueados , Ratones SCID , Neutrófilos/inmunología , Neutrófilos/microbiología , Neutrófilos/patología , Pneumocystis/patogenicidad , Neumonía por Pneumocystis/genética , Neumonía por Pneumocystis/microbiología , Neumonía por Pneumocystis/patología , Receptores de Superficie Celular/deficiencia , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/inmunología , Receptores de Interferón/deficiencia , Receptores de Interferón/genética , Receptores de Interferón/inmunología , Transducción de Señal , Linfocitos T Colaboradores-Inductores/microbiología , Linfocitos T Colaboradores-Inductores/patología , Balance Th1 - Th2 , Receptor de Interferón gamma
11.
Mol Biotechnol ; 2024 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-38907071

RESUMEN

This study was aimed to uncover the character and potential regulatory mechanism of EPB41L3 in cervical cancer (CC). CC cells were injected into BALB/c nude mice (female) to construct a xenograft tumor model. Real-time quantitative polymerase chain reaction (qRT-PCR) and western blot were performed to evaluate the expression of EPB41L3, ERK/p38 MAPK signal markers in CC tissues and cells. Cell counting kit-8 (CCK-8) and Transwell was applied to analyze the viability, invasion, and migration of CC cell lines. EPB41L3 was substantially decreased both in CC tissues and cells. Cell viability, invasion, and migration of CC cells were reduced by overexpressing EPB41L3. Bioinformatics analysis prerdicted that EPB41L3 was strongly related to the ERK/p38 MAPK pathway. Compared with Ad-nc mice, the volume and weight of tumors and ERK/p38 MAPK signal markers were down-regulated in Ad-EPB41L3 mice. After knocking down EPB41L3 with EPB41L3 siRNA (siEPB41L3), the ERK/p38 MAPK pathway was activated. Moreover, SB203580 treatment reversed the effect of EPB41L3 silencing on the improvement in viability, migration, and invasion of CC cells. EPB41L3 suppresses the progression of CC via activating the ERK/p38 MAPK pathway. EPB41L3 may serve as an effective therapeutic target for CC.

13.
CJEM ; 25(9): 742-751, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37495927

RESUMEN

OBJECTIVES: The Children's Hospital of Eastern Ontario launched Canada's first virtual pediatric emergency department (ED) from May 2020 through November 2021 to deliver accessible care during the COVID-19 pandemic. The objective of this study was to (i) conduct a cost analysis of the virtual pediatric ED, and (ii) compare the virtual costs to in-person ED costs to inform future resource allocation decisions. METHODS: We calculated costs from a health system perspective in 2021 Canadian dollars. Using a decision tree model, we compared expected costs with and without the virtual pediatric ED, and calculated overall and per patient cost savings of implementing the virtual ED. RESULTS: The virtual ED provided care to 7394 patients. In the base case, virtual care saved $890,000 ($120 per patient). One-way sensitivity analyses suggest overall cost savings were most sensitive to the proportion of virtual care patients who would have received in-person care had the virtual option not been available (range $300,000-$1,700,000), followed by ED overhead costs (range $640,000-$1,140,000). Multivariate sensitivity analyses demonstrated robust cost savings of $920,000 (95% CI 850,000-990,000) in a scenario using billing codes to calculate costs, and savings of $1,040,000 (95% CI 960,000-1,120,000) if physician salaries were used instead. CONCLUSIONS: These findings suggest the virtual pediatric ED reduced costs per patient. Virtual care may represent a financially valuable pediatric emergency department service.


ABSTRAIT: OBJECTIFS: Le Centre hospitalier pour enfants de l'Est de l'Ontario a lancé le premier service d'urgence pédiatrique (SU) virtuel du Canada de mai 2020 à novembre 2021 pour offrir des soins accessibles pendant la pandémie de COVID-19. L'objectif de cette étude est de i) effectuer une analyse des coûts du DE pédiatrique virtuel et ii) comparer les coûts virtuels aux coûts du DE, en personne pour éclairer les décisions futures en matière d'affectation des ressources. MéTHODES: Nous avons calculé les coûts du point de vue du système de santé en dollars canadiens de 2021. À l'aide d'un modèle d'arbre décisionnel, nous avons comparé les coûts prévus avec et sans le service d'urgence pédiatrique virtuel et calculé les économies globales et par patient découlant de la mise en œuvre du service d'urgence virtuel. RéSULTATS: Le service d'urgence virtuel a fourni des soins à 7 394 patients. Dans le cas de base, les soins virtuels ont permis d'économiser 890 000 $ (120 $ par patient). Les analyses de sensibilité unidirectionnelles donnent à penser que les économies de coûts globales étaient plus sensibles à la proportion de patients en soins virtuels qui auraient reçu des soins en personne si l'option virtuelle n'avait pas été disponible (fourchette de 300 000 $ à 1 700 000 $), suivie des frais généraux du SU (fourchette de 640 000 $ à 1 140 000 $). Les analyses de sensibilité à variables multiples ont démontré de solides économies de coûts de 920 000 $ (IC à 95 %, 850 000 à 990 000) dans un scénario utilisant des codes de facturation pour calculer les coûts, et des économies de 1 040 000 $ (IC à 95 %, 960 000 à 1 120 000) si les salaires des médecins étaient utilisés à la place. CONCLUSIONS: Ces résultats suggèrent que le SU pédiatrique virtuel a réduit les coûts par patient. Les soins virtuels peuvent représenter un service d'urgence pédiatrique financièrement utile.


Asunto(s)
COVID-19 , Pandemias , Niño , Humanos , Análisis Costo-Beneficio , Proyectos Piloto , COVID-19/epidemiología , COVID-19/terapia , Servicio de Urgencia en Hospital , Ontario
14.
Org Lett ; 25(43): 7836-7840, 2023 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-37862603

RESUMEN

Modular synthesis of novel biphen[n]arenes (n = 2-4) with customizable heterocycle blocks, functional skeletons, binding sites, and topological structures could be facilely achieved through the rational design and replacement of reaction modules (furan and thiophene), functional modules (substituted benzene, biphenyl, and naphthalene), and linking modules (methylene). These biphen[n]arenes were characterized by NMR, HRMS, and X-ray crystalline diffraction, complemented by DFT calculations. Their photophysical properties were thoroughly studied.

15.
Phytomedicine ; 117: 154912, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37295023

RESUMEN

BACKGROUND: Therapeutic approaches based on glycolysis and energy metabolism of tumor cells are new promising strategies for the treatment of cancer. Currently, researches on the inhibition of pyruvate kinase M2, a key rate limiting enzyme in glycolysis, have been corroborated as an effective cancer therapy. Alkannin is a potent pyruvate kinase M2 inhibitor. However, its non-selective cytotoxicity has affected its subsequent clinical application. Thus, it needs to be structurally modified to develop novel derivatives with high selectivity. PURPOSE: Our study aimed to ameliorate the toxicity of alkannin through structural modification and elucidate the mechanism of the superior derivative 23 in lung cancer therapy. METHODS: On the basis of the principle of collocation, different amino acids and oxygen-containing heterocycles were introduced into the hydroxyl group of the alkannin side chain. We examined the cell viability of all derivatives on three tumor cells (HepG2, A549 and HCT116) and two normal cells (L02 and MDCK) by MTT assay. Besides, the effect of derivative 23 on the morphology of A549 cells as observed by Giemsa and DAPI staining, respectively. Flow cytometry was performed to assess the effects of derivative 23 on apoptosis and cell cycle arrest. To further assess the effect of derivative 23 on the Pyruvate kinase M2 in glycolysis, an enzyme activity assay and western blot assay were performed. Finally, in vivo the antitumor activity and safety of the derivative 23 were evaluated by using Lewis mouse lung cancer xenograft model. RESULTS: Twenty-three novel alkannin derivatives were designed and synthesized to improve the cytotoxicity selectivity. Among these derivatives, derivative 23 showed the highest cytotoxicity selectivity between cancer and normal cells. The anti-proliferative activity of derivative 23 on A549 cells (IC50 = 1.67 ± 0.34 µM) was 10-fold higher than L02 cells (IC50 = 16.77 ± 1.44 µM) and 5-fold higher than MDCK cells (IC50 = 9.23 ± 0.29 µM) respectively. Subsequently, fluorescent staining and flow cytometric analysis showed that derivative 23 was able to induce apoptosis of A549 cells and arrest the cell cycle in the G0/G1 phase. In addition, the mechanistic studies suggested derivative 23 was an inhibitor of pyruvate kinase; it could regulate glycolysis by inhibiting the activation of the phosphorylation of PKM2/STAT3 signaling pathway. Furthermore, studies in vivo demonstrated derivative 23 significantly inhibited the growth of xenograft tumor. CONCLUSION: In this study, alkannin selectivity is reported to be significantly improved following structural modification, and derivative 23 is first shown to be able to inhibit lung cancer growth via the PKM2/STAT3 phosphorylation signaling pathway in vitro, indicating the potential value of derivative 23 in treating lung cancer.


Asunto(s)
Antineoplásicos , Neoplasias Pulmonares , Naftoquinonas , Humanos , Ratones , Animales , Piruvato Quinasa/metabolismo , Línea Celular Tumoral , Naftoquinonas/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Apoptosis , Proliferación Celular , Antineoplásicos/farmacología , Antineoplásicos/química
16.
Front Microbiol ; 13: 800626, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35418970

RESUMEN

Three new sorbicillinoids, including trimer trisorbicillinone E (1), acremosorbicillinoids A and B (2 and 3), and a new alkaloid acremokaloid A (4), and a new natural product 2S,3S-acetyl-ß-methyltryptophan (5), were isolated from an endophytic fungus Acremonium citrinum SS-g13, which is found in Fructus mori plant root. In addition, eight known sorbicillinoids (6-13) were also obtained. The new compound structures were established using NMR, HRESIMS spectra, and reported spectroscopic data. The absolute configurations of compounds 1-5, were determined by spectroscopic analysis, Snatzke's method, and time-dependent density functional theory-electronic circular dichroism (TDDFT-ECD) calculations. Compound 11 exhibited significant cholesterol efflux enhancing activity. A plausible biosynthesis pathway for the sorbicillinoids is discussed.

17.
J Trauma ; 71(4): 893-7, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21336185

RESUMEN

BACKGROUND: Tourniquet has been considered as a recognized cause of lower limb ischemia-reperfusion injury in the orthopedic field. This study investigates pulmonary function after tourniquet deflation and the protective effect of Shenmai injection (SMI), a traditional Chinese medicine. METHODS: Twenty-eight patients undergoing lower extremity surgery were randomized into a control group (group C) and a SMI group (group S), 14 patients in each group. Blood gas and circulating indicators (malondialdehyde, interleukin [IL]-6, and IL-8) were measured immediately before tourniquet inflation and at 0.5 hour, 2 hours, 6 hours, and 24 hours after tourniquet deflation. RESULTS: Plasma levels of malondialdehyde, IL-6, and IL-8 in group C were significantly increased over baselines from 2 hours to 24 hours after tourniquet deflation and the levels reached their peaks at 6 hours after tourniquet deflation, when arterial partial pressures of oxygen and arterial-alveolar oxygen tension ratio were decreased, whereas alveolar-arterial oxygen difference was increased significantly. Both the changes in blood gas variables and plasma mediators were attenuated in group S. CONCLUSION: Pulmonary gas exchange is impaired after lower limb ischemia-reperfusion induced by clinical tourniquet application. Pretreatment with SMI, a traditional Chinese medicine, attenuates lipid peroxidation and systemic inflammatory response and mitigates pulmonary dysfunction.


Asunto(s)
Medicamentos Herbarios Chinos/uso terapéutico , Daño por Reperfusión/prevención & control , Adulto , Análisis de los Gases de la Sangre , Presión Sanguínea , Método Doble Ciego , Combinación de Medicamentos , Femenino , Frecuencia Cardíaca , Humanos , Interleucina-6/sangre , Interleucina-8/sangre , Pierna/irrigación sanguínea , Pierna/cirugía , Masculino , Malondialdehído/sangre , Torniquetes/efectos adversos
18.
Sci Total Environ ; 690: 900-910, 2019 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-31302554

RESUMEN

Cadmium (Cd) is a toxic metal ion in pig manure impacting on the ecosystem, and hence the immobilization of Cd by green synthesis of iron nanoparticles (G-nFe) is a potential approach. In this study, transformation of Cd (II) during the pig manure thermophilic aerobic composting process in the presence of G-nFe was investigated. The results show that the addition of G-nFe promoted the composting process and release of available phosphorus (AP). In all six experiments, obvious passivation of Cd occurred during 15 days' composting. Particularly when 500 mL kg-1 of G-nFe was added and Cd (II) was added at 0.6%(w/w%), residual Cd increased from 0.0016% to 55.70% and exchangeable Cd decreased from 98.54% to 7.21%. Batch experiments revealed that the G-nFe promoted the transformation of Cd into a larger passivation fraction. X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), SEM-Mapping and Fourier transform infrared (FTIR) analysis was used to characterize residual samples, where indicated that the passivation of Cd in compost was highly correlated with the increase of P, it can be concluded that fixing with compost resulted in the formation of Cd phosphate precipitation or co-precipitation with other phosphates.


Asunto(s)
Cadmio/química , Compostaje/métodos , Estiércol , Nanopartículas del Metal/química
19.
Cancer Manag Res ; 11: 7123-7134, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31534365

RESUMEN

Background and purpose: To evade immune defense, cancer cells can employ extracellular vesicles (EVs) to inhibit the anti-tumor activity of lymphocytes in the tumor microenvironment. However, the mechanisms and key molecules that mediate the effects of EVs on lymphocytes are unclear. Patients and methods: We used Quantibody® Human Cytokine Antibody Array 440 to determine the tumor immunity-related cytokine profile of peripheral blood lymphocytes (PBLs) stimulated with EVs derived from peritoneal washes or malignant ascites. We detected 21 upregulated and 27 downregulated proteins, including the immunosuppressive receptors Siglec-10, SLAM, PD-1, and TIM-3. Results: Flow cytometry analysis of PBLs or ovarian cancer ascites suggested that Siglec-10 expression on CD3+ T cells was higher in ovarian cancer patients than in healthy controls and in the malignant ascites of ovarian cancer patients than in their blood. Moreover, the expression of CD24, the Siglec-10 ligand, was associated with tumor stage and cancer cell metastasis. Finally, compared to the benign peritoneal wash-derived EVs, the malignant EVs significantly upregulated Siglec-10 expression on Jurkat T cells, inhibited the protein kinase C activity induced by phorbol 12-myristate 13-acetate and ionomycin, and impaired the phosphorylation of the tyrosine kinase ZAP-70 activated by crosslinking with an anti-CD3 antibody. Conclusion: The EVs secreted by malignant ovarian cells upregulated Siglec-10 expression on T cells and impaired T cell activation in the tumor microenvironment. We believe that a comprehensive understanding of the regulation of Siglec-10 and CD24 by malignant EVs has clinical importance, as it will aid in the development of better immunotherapeutic strategies for ovarian cancer.

20.
Sci Rep ; 9(1): 20128, 2019 12 27.
Artículo en Inglés | MEDLINE | ID: mdl-31882868

RESUMEN

Previous reports have suggested that many gut microbiomes were associated with the development of colorectal cancer (CRC), and could modulate response to numerous forms of cancer therapy, including checkpoint blockade immunotherapy. Here we evaluated the protective efficacy of Lactobacillus acidophilus (L. acidophilus) cell lysates combined with an anti-CTL antigen-4 blocking antibody (CTLA-4 mAb) in syngeneic BALB/c mice CRC models induce by a single intraperitoneal injection of 10 mg/kg azoxymethane (AOM), followed by three cycles of 2% dextran sulfate sodium (DSS) in drinking water. In contrast to CTLA-4 mAb monotherapy, L. acidophilus lysates could attenuate the loss of body weight and the combined administration significantly protected mice against CRC development, which suggested that the lysates enhanced antitumor activity of CTLA-4 mAb in model mice. The enhanced efficacy was associated with the increased CD8 + T cell, increased effector memory T cells (CD44 + CD8 + CD62L+), decreased Treg (CD4 + CD25 + Foxp3+) and M2 macrophages (F4/80 + CD206+) in the tumor microenvironment. In addition, our results revealed that L. acidophilus lysates had an immunomodulatory effect through inhibition the M2 polarization and the IL-10 expressed levels of LPS-activated Raw264.7 macrophages. Finally, the 16S rRNA gene sequencing of fecal microbiota demonstrated that the combined administration significantly inhibited the abnormal increase in the relative abundance of proteobacteria and partly counterbalance CRC-induced dysbiosis in model mice. Overall, these data support promising clinical possibilities of L. acidophilus lysates with CTLA-4 mAb in cancer patients and the hypothesis that probiotics help shape the anticancer immune response.


Asunto(s)
Anticuerpos Bloqueadores/farmacología , Antineoplásicos Inmunológicos/farmacología , Antígeno CTLA-4/antagonistas & inhibidores , Mezclas Complejas/farmacología , Inmunomodulación/efectos de los fármacos , Lactobacillus acidophilus , Sustancias Protectoras/farmacología , Animales , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Mezclas Complejas/química , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Microbioma Gastrointestinal , Humanos , Inmunoglobulina G/farmacología , Lactobacillus acidophilus/metabolismo , Masculino , Ratones , Sustancias Protectoras/química , Células RAW 264.7 , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Microambiente Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto
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