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Determining the differences in flower hydraulic traits and structural resource allocation among closely related species adapted to low mean annual precipitation (MAP) can provide insight into plant adaptation to arid environments. Here, we measured the maximum flower hydraulic conductance (Kmax-flower), water potential at induction 50% loss of Kmax-flower (P50-flower), flower pressure-volume parameters, dry mass of individual flowers and structural components (vexillum, wings, keels, stamens and sepals) of six Caragana species growing in regions ranging from 110 to 1400 mm MAP. Compared with species from high-MAP environments, those from low-MAP environments presented lower Kmax-flower, more negative P50-flower, osmotic potential at full turgor (πo) and turgor loss points (πtlp), and a greater bulk modulus of elasticity (ε). Consequently, a negative correlation between Kmax-flower (hydraulic efficiency) and P50-flower (hydraulic safety) was observed across Caragana species. Furthermore, the dry masses of individual flowers and structural components (vexillum, wings, keels, stamens and sepals) were greater in the species from the low-MAP environment than in those from the high-MAP environment. These findings suggest that greater flower hydraulic safety and drought tolerance combined with greater structural resource allocation promote drought adaptation in Caragana species to low-MAP environments.
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BACKGROUND AND AIM: Hyperuricemia is associated with nonalcoholic fatty liver disease (NAFLD), whereas whether the association differed by hyperuricemia onset age remained unclear. This study sought to investigate the associations of hyperuricemia onset age with the risk of incident NAFLD across adulthood. METHODS AND RESULTS: Based on Kailuan prospective cohort, our analysis comprised 3318 new-onset hyperuricemia cases from 2006 to 2015 and 3318 age- and sex-matched controls who were randomly selected from the general population. The risk of NAFLD across the onset age groups (<45, 45-54, 55-64, and ≥65 years) were compared using multivariable-adjusted Cox regression models. During a median follow-up of 6.78 years, 744 (22.42%) hyperuricemia participants and 586 (17.66%) normouricemia participants were diagnosed with incident NAFLD. After adjusted for potential confounders, the risk of NAFLD was gradually attenuated with each decade increase in hyperuricemia onset age. The adjusted hazard ratio (95% confidence interval) was 1.62 (1.33-1.97) for hyperuricemia onset age <45 years, 1.26 (1.01-1.57) for age of 45-54 years, 1.24 (1.00-1.59) for age of 55-64 years, and 1.19 (0.90-1.71) for age ≥65 years, respectively. The trend remained robust among the multiple sensitivity analyses. CONCLUSIONS: The relative risk of incident NAFLD differed across hyperuricemia onset age-group, and the association was more evident in those with a younger age of hyperuricemia onset, highlighting the importance of performing early strategies on the prevention of NAFLD.
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Fungal keratitis (FK) is recognized as a stubborn ocular condition, caused by intense fungal invasiveness and heightened immune reaction. The glycosaminoglycan chondroitin sulfate exhibits properties of immunomodulation and tissue regeneration. In prior investigations, oxidized chondroitin sulfate (OCS) ameliorated the prognosis of FK in murine models. To further improve the curative efficacy, we used the antifungal drug natamycin to functionalize OCS and prepared oxidized chondroitin sulfate-natamycin (ON) eye drops. The structure of ON was characterized by FTIR, UV-vis, and XPS, revealing that the amino group of natamycin combined with the aldehyde group in OCS through Schiff base reaction. Antifungal experiments revealed that ON inhibited fungal growth and disrupted the mycelium structure. ON exhibited exceptional biocompatibility and promoted the proliferation of corneal epithelial cells. Pharmacokinetic analysis indicated that ON enhanced drug utilization by extending the mean residence time in tears. In murine FK, ON treatment reduced the clinical score and corneal fungal load, restored corneal stroma conformation, and facilitated epithelial repair. ON effectively inhibited neutrophil infiltration and decreased the expression of TLR-4, LOX-1, IL-1ß, and TNF-α. Our research demonstrated that ON eye drops achieved multifunctional treatment for FK, including inhibiting fungal growth, promoting corneal repair, enhancing drug bioavailability, and controlling inflammatory reactions.
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Inflammatory cell infiltration is a characteristic feature of COPD and correlates directly with the severity of the disease. Interleukin-23 (IL-23) is a pro-inflammatory cytokine that regulates Th-17 inflammation, which mediates many pathophysiological events in COPD. The primary goal of this study was to determine the role of IL-23 as a mediator of key pathologic processes in cigarette smoke-induced COPD. In this study, we report an increase in IL23 gene expression in the lung biopsies of COPD patients compared to controls and identified a positive correlation between IL23 gene expression and disease severity. In a cigarette smoke-induced murine emphysema model, the suppression of IL-23 with a monoclonal blocking antibody reduced the severity of cigarette smoke-induced murine emphysema. Mechanistically, the suppression of IL-23 was associated with a reduction in immune cell infiltration, oxidative stress injury, and apoptosis, suggesting a role for IL-23 as an essential immune mediator of the inflammatory processes in the pathogenesis of CS-induced emphysema.
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Background: Previous studies on the direction of the association between arterial stiffness (AS) and chronic kidney disease (CKD) were inconsistent, leaving a knowledge gap in understanding the temporal sequence of the association. Objectives: This study sought to assess the temporal and longitudinal relationship between AS and CKD. Methods: The temporal relationship between AS measured by brachial ankle pulse wave velocity and CKD measured by estimated glomerular filtration rate (eGFR) was analyzed among 7,753 participants with repeated examinations in the Kailuan study using cross-lagged panel analysis. The longitudinal associations of AS status and vascular aging (VA) phenotype with incident CKD were analyzed among 10,535 participants. Results: The adjusted cross-lagged path coefficient (ß 1 = -0.03; 95% CI: -0.06 to -0.01; P < 0.0001) from baseline brachial ankle pulse wave velocity to follow-up eGFR was significantly greater than the path coefficient (ß 2 = -0.01; 95% CI: -0.02 to 0.01; P = 0.6202) from baseline eGFR to follow-up brachial ankle pulse wave velocity (P < 0.0001 for the difference). During a median follow-up of 8.48 years, 953 cases of incident CKD (9.05%) occurred. After adjustment for confounders, borderline (HR: 1.17; 95% CI: 1.08-1.38) and elevated AS (HR: 1.39; 95% CI: 1.12-1.72) was associated a higher risk of CKD, compared with normal AS. Consistently, supernormal VA (HR: 0.76; 95% CI: 0.66-0.86) was associated with a decreased and early VA (HR: 1.36; 95% CI: 1.29-1.43) was associated with an increased risk of CKD, compared with normal VA. Conclusions: AS appeared to precede the decrease in eGFR. Additionally, increased AS and early VA were associated with an increased risk of incident CKD.
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BACKGROUND: Calculus bovis (CB), used in traditional Chinese medicine, exhibits anti-tumor effects in various cancer models. It also constitutes an integral component of a compound formulation known as Pien Tze Huang, which is indicated for the treatment of liver cancer. However, its impact on the liver cancer tumor microenvironment, particularly on tumor-associated macrophages (TAMs), is not well understood. AIM: To elucidate the anti-liver cancer effect of CB by inhibiting M2-TAM polarization via Wnt/ß-catenin pathway modulation. METHODS: This study identified the active components of CB using UPLC-Q-TOF-MS, evaluated its anti-neoplastic effects in a nude mouse model, and elucidated the underlying mechanisms via network pharmacology, transcriptomics, and molecular docking. In vitro assays were used to investigate the effects of CB-containing serum on HepG2 cells and M2-TAMs, and Wnt pathway modulation was validated by real-time reverse transcriptase-polymerase chain reaction and Western blot analysis. RESULTS: This study identified 22 active components in CB, 11 of which were detected in the bloodstream. Preclinical investigations have demonstrated the ability of CB to effectively inhibit liver tumor growth. An integrated approach employing network pharmacology, transcriptomics, and molecular docking implicated the Wnt signaling pathway as a target of the antineoplastic activity of CB by suppressing M2-TAM polarization. In vitro and in vivo experiments further confirmed that CB significantly hinders M2-TAM polarization and suppresses Wnt/ß-catenin pathway activation. The inhibitory effect of CB on M2-TAMs was reversed when treated with the Wnt agonist SKL2001, confirming its pathway specificity. CONCLUSION: This study demonstrated that CB mediates inhibition of M2-TAM polarization through the Wnt/ß-catenin pathway, contributing to the suppression of liver cancer growth.
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Neoplasias Hepáticas , Ratones Desnudos , Simulación del Acoplamiento Molecular , Microambiente Tumoral , Macrófagos Asociados a Tumores , Vía de Señalización Wnt , Vía de Señalización Wnt/efectos de los fármacos , Animales , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Humanos , Ratones , Células Hep G2 , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/efectos de los fármacos , Macrófagos Asociados a Tumores/inmunología , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/metabolismo , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Proliferación Celular/efectos de los fármacos , Ratones Endogámicos BALB C , Masculino , Farmacología en Red , beta Catenina/metabolismo , Medicina Tradicional China/métodosRESUMEN
Systolic blood pressure (SBP) time in target (TTR) over months were associated with lower risk of adverse clinical outcomes in hypertensive patients, whether short-term of 24-h SBP TTR was effective in predicting heart failure (HF) risk in the general population remained unclear. This prospective study aimed to investigate the association of 24-h SBP TTR with HF in the real-world settings. Based on Kailuan study, 24-h SBP target range defined as 110-140 mmHg was calculated with linear interpolation. Among 5152 participants included in the analysis, 186 (3.61%) cases of incident HF occurred during a median follow-up of 6.96 years. Compared with participants with SBP TTR of 0 to <25%, those with TTR of 75% to 100% had 47% lower risk of HF (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.32-0.89). The restricted spline curve depicted an inverse relationship between SBP TTR and incident HF. Additionally, the addition of SBP TTR, rather than mean SBP and SBP variation, to a conventional risk model had an incremental effect on the predictive value for HF, with integrated discrimination improvement value of 0.31% (P = 0.0003) and category-free net reclassification improvement value of 19.79% (P = 0.0081). Higher SBP TTR was associated with a lower risk of incident HF. Efforts to attain SBP within 110 to 140 mmHg may be an effective strategy to prevent HF.
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BACKGROUND: Recent Mendelian randomization and meta-analysis highlight the relevance of MCP-1 (monocyte chemoattractant protein-1) in stroke. We aimed to investigate the associations between MCP-1 and clinical outcomes in patients with ischemic stroke or transient ischemic attack and test whether inflammation mediates or jointly contributes to the relationships. METHODS AND RESULTS: A total of 10 700 patients from the Third China National Stroke Registry study were included. Multivariable Cox regression was used for recurrent stroke and all-cause death, and logistic regression was used for poor functional outcome. Mediation analyses were performed to clarify whether inflammation mediates the associations. After adjusting for potential confounders, low MCP-1 level (<337.6 pg/mL) was associated with a reduced risk of all-cause death (hazard ratio [HR], 0.65 [95% CI, 0.51-0.82]) and poor functional outcome (odds ratio, 0.81 [95% CI, 0.70-0.94]) but was not associated with recurrent stroke (HR, 1.10 [95% CI, 0.95-1.27]), compared with high MCP-1 level (≥337.6 pg/mL). The association between MCP-1 and all-cause death was partially mediated by highly sensitive C-reactive protein, interleukin-6, and YKL-40 (Chitinase-3-like protein 1; mediated proportion: 7.4%, 10.5%, and 7.4%, respectively). The corresponding mediated proportion for poor functional outcome was 9.9%, 17.1%, and 7.1%, respectively. Patients with combined high levels of MCP-1 and inflammatory biomarkers had the highest risks of all-cause death and poor functional outcome. CONCLUSIONS: Low plasma MCP-1 level was associated with decreased risks of all-cause mortality and poor functional outcome after ischemic stroke or transient ischemic attack. Inflammation partially mediated and jointly contributed to the associations.
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Biomarcadores , Quimiocina CCL2 , Ataque Isquémico Transitorio , Accidente Cerebrovascular Isquémico , Sistema de Registros , Humanos , Masculino , Quimiocina CCL2/sangre , Femenino , Biomarcadores/sangre , Ataque Isquémico Transitorio/sangre , Ataque Isquémico Transitorio/mortalidad , Ataque Isquémico Transitorio/diagnóstico , Accidente Cerebrovascular Isquémico/sangre , Accidente Cerebrovascular Isquémico/mortalidad , Accidente Cerebrovascular Isquémico/diagnóstico , Accidente Cerebrovascular Isquémico/epidemiología , Persona de Mediana Edad , Anciano , Pronóstico , China/epidemiología , Inflamación/sangre , Recurrencia , Medición de Riesgo , Factores de Riesgo , Causas de MuerteRESUMEN
Perioperative neurocognitive disorders (PND) are intractable, indistinct, and considerably diminish the postoperative quality of life of patients. It has been proved that Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was involved in neurodegenerative diseases by regulating mitochondrial biogenesis. The underlying mechanisms of PGC-1α and Nod-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome in PND are not well understood. In this study, we constructed a model of laparotomy in aged mice, and then examined the cognition changes with novel object recognition tests and fear condition tests. The protein levels of PGC-1α and NLRP3 in the hippocampus were detect after surgery. Our results showed that NLRP3 and downstream PI3K/AKT pathway expressions were augmented in the hippocampus after surgery, whereas, the expressions of PGC-1α/estrogen-related receptor α (ERRα)/Unc-51-like autophagy activating kinase 1 (ULK1) pathway were diminished after surgery. In addition, we found that NLRP3 was mainly co-localized with neurons in the hippocampus, and synaptic-related proteins were reduced after surgery. At the same time, transmission electron microscopy (TEM) showed that mitochondria were impaired after surgery. Pharmacological treatment of MCC950, a selective NLRP3 inhibitor, effectively alleviated PND. Activation of PGC-1α with ZLN005 significantly ameliorated PND by enhancing the PGC-1α/ERRα/ULK1 signaling pathway, and further suppressing NLRP3 activation. As a result, we conclude that suppression of the PGC-1α/ERRα/ULK1 signaling pathway is the primary mechanism of PND which caused mitochondrial dysfunction, and activated NLRP3 inflammasome and downstream PI3K/AKT pathway, eventually improved cognitive dysfunction.
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Homólogo de la Proteína 1 Relacionada con la Autofagia , Hipocampo , Inflamasomas , Ratones Endogámicos C57BL , Mitocondrias , Proteína con Dominio Pirina 3 de la Familia NLR , Trastornos Neurocognitivos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Receptores de Estrógenos , Transducción de Señal , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Inflamasomas/metabolismo , Ratones , Transducción de Señal/fisiología , Transducción de Señal/efectos de los fármacos , Hipocampo/metabolismo , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Mitocondrias/metabolismo , Masculino , Receptores de Estrógenos/metabolismo , Trastornos Neurocognitivos/metabolismo , Trastornos Neurocognitivos/etiología , Envejecimiento/metabolismo , Laparotomía/efectos adversos , Sulfonamidas/farmacología , Furanos , IndenosRESUMEN
OBJECTIVE: Fungal keratitis (FK) usually develops to a poor clinical prognosis due to the fungal invasion and excessive inflammatory reaction. In order to enhance the therapeutic effect of natamycin (NAT), we used the anti-inflammatory biological polysaccharide bletilla striata polysaccharide (BSP) combined with NAT to prepare a new eye drop -- oxidized bletilla striata polysaccharide-natamycin (OBN). METHODS: UV-vis, FT-IR, and fluorescence spectroscopy were used to identify the synthesis of OBN. Biocompatibility of OBN was determined by CCK-8, scratch assay, and corneal toxicity test. RAW264.7 cells and C57BL/6 mice were stimulated with A. fumigatus and treated with PBS, OBN, or NAT. The anti-inflammatory activity of OBN was detected by RT-PCR and ELISA. In mice with FK, the clinical scores were used to evaluate the effect of OBN; HE staining was performed to assess the corneal pathological changes; MPO assay and immunofluorescence staining were used to investigate neutrophil infiltration. RESULTS: OBN was synthesized by combining oxidized bletilla striata polysaccharide (OBSP) with NAT through Schiff base reaction. OBN did not affect cell viability at a concentration of 160 µg/mL in HCECs, RAW264.7 cells, and mouse corneas. OBN versus NAT significantly improved the prognosis of A. fumigatus keratitis by reducing disease severity, neutrophil infiltration, and expression of inflammatory factors in vivo. Additionally, OBN treatment down-regulated the mRNA and protein expression levels of inflammatory factors IL-1ß, TNF-α, and IL-6 in RAW264.7 and mouse models. CONCLUSION: OBN is a compound prepared by covalently linking OBSP to the imino group of NAT through Schiff base reaction. OBN treatment down-regulated inflammation and improved the prognosis of mice with A. fumigatus keratitis.
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Our previous study has verified that activation of group â metabotropic glutamate receptors (mGluRâ ) in the red nucleus (RN) facilitate the development of neuropathological pain. Here, we further discussed the functions and possible molecular mechanisms of red nucleus mGluR â ¡ (mGluR2 and mGluR3) in the development of neuropathological pain induced by spared nerve injury (SNI). Our results showed that mGluR2 and mGluR3 both were constitutively expressed in the RN of normal rats. At 2 weeks post-SNI, the protein expression of mGluR2 rather than mGluR3 was significantly reduced in the RN contralateral to the nerve lesion. Injection of mGluR2/3 agonist LY379268 into the RN contralateral to the nerve injury at 2 weeks post-SNI significantly attenuated SNI-induced neuropathological pain, this effect was reversed by mGluR2/3 antagonist EGLU instead of selective mGluR3 antagonist ß-NAAG. Intrarubral injection of LY379268 did not alter the PWT of contralateral hindpaw in normal rats, while intrarubral injection of EGLU rather than ß-NAAG provoked a significant mechanical allodynia. Further studies indicated that the expressions of nociceptive factors TNF-α and IL-1ß in the RN were enhanced at 2 weeks post-SNI. Intrarubral injection of LY379268 at 2 weeks post-SNI significantly suppressed the overexpressions of TNF-α and IL-1ß, these effects were reversed by EGLU instead of ß-NAAG. Intrarubral injection of LY379268 did not influence the protein expressions of TNF-α and IL-1ß in normal rats, while intrarubral injection of EGLU rather than ß-NAAG significantly boosted the expressions of TNF-α and IL-1ß. These findings suggest that red nucleus mGluR2 but not mGluR3 mediates inhibitory effect in the development of SNI-induced neuropathological pain by suppressing the expressions of TNF-α and IL-1ß. mGluR â ¡ may be potential targets for drug development and clinical treatment of neuropathological pain.
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Interleucina-1beta , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico , Núcleo Rojo , Factor de Necrosis Tumoral alfa , Animales , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Receptores de Glutamato Metabotrópico/biosíntesis , Masculino , Interleucina-1beta/metabolismo , Interleucina-1beta/biosíntesis , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Ratas , Núcleo Rojo/metabolismo , Núcleo Rojo/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , AminoácidosRESUMEN
BACKGROUND AND AIMS: Risk factor modification may decrease the risk of cardiovascular disease (CVD). Whether risk factor modification can mitigate the effect of hyperuricemia on CVD is unclear. This study aimed to investigate the risk of CVD among individuals with hyperuricemia, according to risk factors on target, compared with controls without hyperuricemia. METHODS AND RESULTS: This prospective study included 91,722 participants free of CVD at baseline (2006-2007) of the Kailuan study. Individuals with hyperuricemia were categorized according to the number of seven selected risk factors within the guideline-recommended target range (nonsmoking, physical activity, healthy diet, guideline-recommended levels of body mass index, blood pressure, fasting blood glucose, and total cholesterol). During a median follow-up of 13.00 years, 671 out of 6740 individuals (9.96%) with hyperuricemia and 6301 out of 84,982 control subjects (7.41%) had incident CVD. Compared with control subjects without hyperuricemia, individuals with hyperuricemia who had 4 or 5 to 7 risk factors on target had no significant excess CVD risk, the hazard ratio (HR) (95% confidence internal [CI]) was 0.93 (0.79-1.10) and 0.88 (0.71-1.10), respectively. Among individuals with hyperuricemia, excess CVD risk decreased stepwise for a higher number of risk factors on target, the HR of CVD associated with per additional risk factor within target range was 0.82 (95% CI, 0.77-0.87). Similar results were yielded for CVD subtypes. CONCLUSIONS: Among individuals with hyperuricemia, excess CVD risk decreased stepwise for a higher number of risk factors within target.
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Biomarcadores , Enfermedades Cardiovasculares , Factores de Riesgo de Enfermedad Cardiaca , Hiperuricemia , Ácido Úrico , Humanos , Hiperuricemia/epidemiología , Hiperuricemia/sangre , Hiperuricemia/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/prevención & control , Estudios Prospectivos , Medición de Riesgo , Adulto , China/epidemiología , Incidencia , Biomarcadores/sangre , Factores de Tiempo , Ácido Úrico/sangre , Conducta de Reducción del Riesgo , Dieta Saludable , Pronóstico , Factores Protectores , Anciano , Fumar/epidemiología , Fumar/efectos adversos , Ejercicio Físico , Glucemia/metabolismo , Factores de RiesgoRESUMEN
Identification of potential bacterial players in colorectal tumorigenesis has been a focus of intense research. Herein, we find that Clostridium symbiosum (C. symbiosum) is selectively enriched in tumor tissues of patients with colorectal cancer (CRC) and associated with higher colorectal adenoma recurrence after endoscopic polypectomy. The tumorigenic effect of C. symbiosum is observed in multiple murine models. Single-cell transcriptome profiling along with functional assays demonstrates that C. symbiosum promotes the proliferation of colonic stem cells and enhances cancer stemness. Mechanistically, C. symbiosum intensifies cellular cholesterol synthesis by producing branched-chain amino acids (BCAAs), which sequentially activates Sonic hedgehog signaling. Low dietary BCAA intake or blockade of cholesterol synthesis by statins could partially abrogate the C. symbiosum-induced cell proliferation in vivo and in vitro. Collectively, we reveal C. symbiosum as a bacterial driver of colorectal tumorigenesis, thus identifying a potential target in CRC prediction, prevention, and treatment.
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Aminoácidos de Cadena Ramificada , Carcinogénesis , Proliferación Celular , Colesterol , Neoplasias Colorrectales , Neoplasias Colorrectales/microbiología , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Colesterol/metabolismo , Animales , Humanos , Ratones , Aminoácidos de Cadena Ramificada/metabolismo , Clostridium/metabolismo , Clostridium/genética , Transducción de Señal , Proteínas Hedgehog/metabolismo , Línea Celular Tumoral , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Masculino , FemeninoRESUMEN
Silyl enol ethers react with bicyclo[1.1.0]butanes (BCBs) through Yb(OTf)3-promoted formal [2π + 2σ] cycloaddition reactions to furnish bicyclo[2.1.1]hexanes (BCHs). This new reaction tolerated a wide range of enol silyl ethers and BCBs. Furthermore, the amplification experiments and synthetic transformations of the cycloaddition compounds further highlighted their practicality.
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Nervous system diseases are a global health problem, and with the increase in the elderly population around the world, their incidence will also increase. Harmful substances in the environment are closely related to the occurrence of nervous system diseases. China is a large agricultural country, and thus the insecticide cyfluthrin has been widely used. Cyfluthrin is neurotoxic, but the mechanism of this injury is not clear. Inflammation is an important mechanism for the occurrence of nervous system diseases. Mitochondria are the main regulators of the inflammatory response, and various cellular responses, including autophagy, directly affect the regulation of inflammatory processes. Mitochondrial damage is related to mitochondrial quality control (MQC) and PTEN-induced kinase 1 (PINK1). As an anti-inflammatory factor, stimulator of interferon genes (STING) participates in the regulation of inflammation. However, the relationship between STING and mitochondria in the process of cyfluthrin-induced nerve injury is unclear. This study established in vivo and in vitro models of cyfluthrin exposure to explore the role of MQC and to clarify the mechanism of action of STING and PINK1. Our results showed that cyfluthrin can increase the reactive oxygen species (ROS) level, resulting in mitochondrial damage and inflammation. In this process, an imbalance in MQC leads to the aggravation of mitochondrial damage, and high STING expression drives the occurrence of inflammation. We established a differential expression model of STING and PINK1 to further determine the underlying mechanism and found that the interaction between STING and PINK1 regulates MQC to affect the levels of mitochondrial damage and inflammation. When STING and PINK1 expression are downregulated, mitochondrial damage and STING-induced inflammation are significantly alleviated. In summary, a synergistic effect between STING and PINK1 on cyfluthrin-induced neuroinflammation may exist, which leads to an imbalance in MQC by inhibiting mitochondrial biogenesis and division/fusion, and PINK1 can reduce STING-driven inflammation.
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Mitocondrias , Nitrilos , Proteínas Quinasas , Piretrinas , Piretrinas/toxicidad , Mitocondrias/efectos de los fármacos , Animales , Nitrilos/toxicidad , Proteínas Quinasas/metabolismo , Proteínas Quinasas/genética , Enfermedades Neuroinflamatorias/inducido químicamente , Insecticidas/toxicidad , Ratones , Especies Reactivas de Oxígeno/metabolismo , Inflamación/inducido químicamente , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genéticaRESUMEN
BACKGROUND: Patients with myocardial infarction (MI) frequently experience a heightened incidence of depression, thereby increasing the risk of adverse cardiovascular events. Consequently, early detection and intervention in depressive symptoms among patients with MI are imperative. Shexiang Baoxin Pills (SBP), a Chinese patent medicine employed for the treatment of MI, exhibits diverse mechanisms targeting this condition. Nevertheless, its therapeutic efficacy on postmyocardial infarction depressive symptoms remains unclear. The aim of this study is to investigate the effectiveness and mechanism of SBP in managing depression during acute myocardial infarction (AMI). METHODS: A rat model combining MI and depression was established, and the rats were randomly divided into four groups: the model (MOD) group, SBP group, Fluoxetine (FLX) group, and Sham group. After 28 days of drug intervention, cardiac function was assessed using echocardiography while behavior was evaluated through sucrose preference test (SPT), forced swimming test (FST), and open-field test (OFT). Additionally, levels of inflammatory factors in serum and hippocampus were measured along with NLRP3 inflammasome-related protein expression via Western blotting and immunofluorescence. RESULTS: SBP can enhance cardiac function in rats with AMI and depression, while significantly ameliorating depressive-like behavior. Compared to the Sham group, levels of IL-1ß, IL-18, TNF-α, and other inflammatory factors were markedly elevated in the MOD group. However, expressions of these inflammatory factors were reduced to varying degrees following treatment with SBP or FLX. Analysis of NLRP3 inflammasome-related proteins in the hippocampus revealed a significant upregulation of IL-1ß, IL-18, NLRP3, ASC, caspase-1, and GSDMD in the MOD group; conversely, these measures were significantly attenuated after SBP intervention. CONCLUSION: We have observed a significant amelioration in depression-like behavior upon SBP administration during the treatment of AMI, suggesting that this effect may be attributed to the inhibition of NLRP3-mediated pyroptosis. (The main findings are summarized in the graphical abstract in the supplementary file.).
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Antidepresivos , Depresión , Medicamentos Herbarios Chinos , Inflamasomas , Infarto del Miocardio , Proteína con Dominio Pirina 3 de la Familia NLR , Ratas Sprague-Dawley , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Infarto del Miocardio/complicaciones , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/administración & dosificación , Ratas , Depresión/tratamiento farmacológico , Depresión/etiología , Antidepresivos/farmacología , Antidepresivos/administración & dosificación , Masculino , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Modelos Animales de Enfermedad , Transducción de Señal/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Conducta Animal/efectos de los fármacosRESUMEN
SHORT VEGETATIVE PHASE (SVP), a member of the MADS-box transcription factor family, has been reported to regulate bud dormancy in deciduous perennial plants. Previously, three LcSVPs (LcSVP1, LcSVP2 and LcSVP3) were identified from litchi genome, and LcSVP2 was highly expressed in the terminal buds of litchi during growth cessation or dormancy stages and down-regulated during growth stages. In this study, the role of LcSVP2 in governing litchi bud dormancy was examined. LcSVP2 was highly expressed in the shoots, especially in the terminal buds at growth cessation stage, whereas low expression was showed in roots, female flowers and seeds. LcSVP2 was found to be located in the nucleus and have transcription inhibitory activity. Overexpression of LcSVP2 in Arabidopsis thaliana resulted in a later flowering phenotype compared to the wild-type control. Silencing LcSVP2 in growing litchi terminal buds delayed re-entry of dormancy, resulting in significantly lower dormancy rate. The treatment also significantly up-regulated litchi FLOWERING LOCUS T2 (LcFT2). Further study indicates that LcSVP2 interacts with an AP2-type transcription factor, SMALL ORGAN SIZE1 (LcSMOS1). Silencing LcSMOS1 promoted budbreak and delayed bud dormancy. Abscisic acid (200 mg/L), which enforced bud dormancy, induced a short-term increase in the expression of LcSVP2 and LcSMOS1. Our study reveals that LcSVP2 may play a crucial role, likely together with LcSMOS1, in dormancy onset of the terminal bud and may also serve as a flowering repressor in evergreen perennial litchi.
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BACKGROUND: Acute graft-versus-host disease (aGVHD), which is mainly mediated by allogeneic T cells, is a decisive factor in the success of allogeneic hematopoietic stem cell transplantation (allo-HCT). Prophylaxis for aGVHD in clinical patients is unsatisfactory, and there is still a huge unmet need for novel approaches. Icariin (ICA) shows potent anti-inflammatory activity and suppresses T cell-mediated immune responses. Thus, ICA is a potential drug for the prevention of aGVHD. However, there is no data assessing the impact of ICA on aGVHD after allo-HCT. PURPOSE: This study aimed to investigate the protective effect of ICA against aGVHD and its mechanisms. Moreover, the impact of ICA on the graft-versus-leukemia (GVL) effect and engraftment of donor hematopoietic and immune cells were assessed. METHODS: Different murine models of allo-HCT were developed to study the influence of the ICA on GVHD and GVL effect. Flow cytometry was used to analyze the growth of leukemia cells, alterations in different immune cells, and apoptosis. Cell proliferation was determined using a CCK-8 assay. RNA sequencing and quantitative proteomic analysis were performed to elucidate the underlying mechanisms, which were further verified by polymerase chain reaction or functional experiments. RESULTS: Different concentrations of ICA exhibited opposite effects: low-concentration ICA promoted, while high concentrations suppressed the proliferation and function of T cells. A high dose of ICA administration during days +3 to +5 post-allo-HCT can alleviate murine aGVHD but does not affect the course of chronic GVHD (cGVHD), the GVL effect against both acute myeloid and lymphoblastic leukemia, or the recovery of donor hematological and immune cells. ICA extensively represses the expansion, function, and infiltration of donor alloreactive T cells, while preserving regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC). Quantitative proteomic analysis showed that downregulation of integrin-linked kinase (ILK) and lymphocyte cytosolic protein 2 (LCP2) expression was possibly associated with ICA-mediated aGVHD protective effects. Furthermore, an inhibitor of ILK, which can alleviate murine aGVHD administered early after allo-HCT. CONCLUSION: These findings suggest that the bioactivities of ICA are associated with its concentration and that ICA can effectively mitigate aGVHD without losing GVL activity or engraftment of donor hematopoietic and immune cells. Thus, ICA may be a promising drug for preventing aGVHD in clinical settings.