RESUMO
Rapid urbanization and industrialization have resulted in diverse anthropogenic activities and emissions between urban and non-urban regions, leading to varying levels of exposure to air pollutants and associated health risks. However, endeavors to mitigate air pollution and health benefits have displayed considerable heterogeneity across different regions. Therefore, comprehending the changes in air pollutant concentrations and health impacts within an urbanization context is imperative for promoting environmental equity. This paper uses gross domestic product (GDP)- and population-weighted methods to distinguish anthropogenic emissions from urban and non-urban areas in China and quantified their contributions to fine particulate matter (PM2.5) using the Community Multiscale Air Quality (CMAQ) model in 2010 and 2019. Anthropogenic emissions from urban and non-urban (outside urban) regions decreased by 26 and 44% from 2010 to 2019, respectively, resulting in 31 and 28% reductions of PM2.5 in China. PM2.5-related premature mortality attributed to non-urban and urban anthropogenic emission decreases by 8%. Non-urban anthropogenic activities are the main contributor to PM2.5 (56% in 2010 and 2019) and its associated premature mortality (59%), which also predominantly affects non-urban premature mortality (37-42% in 2010-2019). Population changes increase the proportion of premature mortality in urban populations (7-19%) from 2010 to 2019. This study emphasizes the shift of affected populations due to urbanization and population changes.
Assuntos
Poluentes Atmosféricos , Poluição do Ar , Material Particulado , Urbanização , China , Material Particulado/análise , Poluentes Atmosféricos/análise , Humanos , Monitoramento AmbientalRESUMO
Icariin, a flavonoid glycoside derived from Epimedium brevicornum Maxim, exerts bone protective effects via estrogen receptors (ERs). This study aimed to investigate the role of ER-α66, ER-α36, and GPER in bone metabolism in osteoblasts following treatment with icariin. Human osteoblastic MG-63 cells and osteoblast-specific ER-α66 knockout mice were employed. The ERs crosstalk in the estrogenic action of icariin was evaluated in ER-α66-negative human embryonic kidney HEK293 cells. Icariin, like E2, regulated ER-α36 and GPER protein expression in osteoblasts by downregulating them and upregulating ER-α66. ER-α36 and GPER suppressed the actions of icariin and E2 in bone metabolism. However, the in vivo administration of E2 (2 mg/kg/day) or icariin (300 mg/kg/day) restored bone conditions in KO osteoblasts. ER-α36 and GPER expression increased significantly and rapidly activated and translocated in KO osteoblasts after treatment with E2 or icariin. ER-α36 overexpression in KO osteoblasts further promoted the OPG/RANKL ratio induced by E2 or icariin treatment. This study showed icariin and E2 elicit rapid estrogenic responses in bone through recruiting ER-α66, ER-α36, and GPER. Notably, in osteoblasts lacking ER-α66, ER-α36, and GPER mediate the estrogenic effects of icariin and E2, while in intact osteoblasts, ER-α36 and GPER act as negative regulators of ER-α66.
Assuntos
Fitoestrógenos , Receptores de Estrogênio , Animais , Camundongos , Humanos , Fitoestrógenos/farmacologia , Receptor alfa de Estrogênio , Células HEK293 , Flavonoides/farmacologia , Osteoblastos/metabolismoRESUMO
Secoisolariciresinol (SECO) is one of the major lignans occurring in various grains, seeds, fruits, and vegetables. The gut microbiota plays an important role in the biotransformation of dietary lignans into enterolignans, which might exhibit more potent bioactivities than the precursor lignans. This study aimed to identify, synthesize, and evaluate the microbial metabolites of SECO and to develop efficient lead compounds from the metabolites for the treatment of osteoporosis. SECO was fermented with human gut microbiota in anaerobic or micro-aerobic environments at different time points. Samples derived from microbial transformation were analyzed using an untargeted metabolomics approach for metabolite identification. Nine metabolites were identified and synthesized. Their effects on cell viability, osteoblastic differentiation, and gene expression were examined. The results showed that five of the microbial metabolites exerted potential osteogenic effects similar to those of SECO or better. The results suggested that the enterolignans might account for the osteoporotic effects of SECO in vivo. Thus, the presence of the gut microbiota could offer a good way to form diverse enterolignans with bone-protective effects. The current study improves our understanding of the microbial transformation products of SECO and provides new approaches for new candidate identification in the treatment of osteoporosis.
Assuntos
4-Butirolactona , Lignanas , Humanos , Dieta , Lignanas/farmacologia , Lignanas/metabolismo , Butileno Glicóis/farmacologia , Butileno Glicóis/metabolismoRESUMO
BACKGROUND: Lenvatinib and lenvatinib-based combination treatments are widely used in patients with unresectable hepatocellular carcinoma (uHCC) in clinical practice, but their curative effect and safety need further study in the real world. METHODS: This was a retrospective study involving patients with uHCC receiving lenvatinib monotherapy and lenvatinib-based combination treatment between Nov, 2018 and Sep, 2020 in Nanfang Hospital. Efficacy was evaluated with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to tumor progression (TTP), and overall survival (OS). Treatment-related adverse events (TRAEs) were recorded and graded. Efficacy and safety of monotherapy and combination therapy were compared. Stratified analysis was performed according to systemic line of treatment and medication regimen for combination therapy. RESULTS: For lenvatinib monotherapy (n = 39), OS and PFS were 80 weeks and 24.3 weeks, respectively. For combination treatment (n = 72), median OS and PFS were 99 weeks and 45.6 weeks, respectively. OS, PFS, and TTP for patients in the combination treatment cohort were significantly longer compared to those of patients in the monotreatment cohort (OS: P = 0.04, PFS: P = 0.003; TTP, P = 0.005). The incidence of TRAEs could be controlled both in the monotherapy cohort and the combination treatment cohort. In the monotherapy cohort, OS and PFS were significantly decreased in the second-line treatment group compared with the first-line treatment group, while no differences were observed in the combination cohort. The efficacy of triple therapy (lenvatinib plus PD-1 antibody plus TACE or HAIF) was similar to lenvatinib plus PD-1 antibody or lenvatinib plus TACE or HAIF. CONCLUSIONS: Our real-world study showed that lenvatinib monotherapy and lenvatinib-based combination therapy were well tolerated, with encouraging efficacies in patients with uHCC. Lenvatinib-based combination therapy showed a better curative effect compared with lenvatinib single-agent therapy. In patients who have failed first-line TKI treatment, lenvatinib-based combination therapy may be a better choice than lenvatinib single-agent therapy. Lenvatinib-based triple therapy may not have an advantage over dual therapy.
RESUMO
More and more menopausal women use Danggui Buxue Tang (DBT) for relieving their symptoms. Concerns for its safety have been raised as it contains phytoestrogen and acts via estrogen receptors (ERs). Our study aimed to determine whether DBT could selectively exert estrogenic activities and interact with tamoxifen in bone, brain, uterus, and breast by using ovariectomized (OVX) rats and ER-positive cells. In OVX rats, DBT induced a 31.4% increase in bone mineral density and restored the mRNA expression of dopamine biomarker in striatum, 3.32-fold for tyrosine hydrolase (p < .001) and 0.21-fold for dopamine transporter (p < .001), which was similar to tamoxifen; tamoxifen, but not DBT, increased uterus weight and Complement component 3 expression by more than twofold (p < .001); unlike tamoxifen, DBT induced mild proliferation in mammary gland. Two-way ANOVA indicated the interactions between them in OVX rats (p < .05) but DBT did not alter the responses to tamoxifen. DBT stimulated proliferation or differentiation and estrogen response element in MCF-7, MG-63, Ishikawa, and SHSY5Y cells and altered the effects of tamoxifen. In summary, DBT exerted estrogenic effects in tissue-selective manner, which was different from tamoxifen. DBT interacted with tamoxifen but did not significantly alter its effects in OVX rats.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Estrogênios/uso terapêutico , Menopausa/efeitos dos fármacos , Tamoxifeno/uso terapêutico , Animais , Medicamentos de Ervas Chinesas/farmacologia , Estrogênios/farmacologia , Feminino , Humanos , Ratos , Ratos Sprague-Dawley , Tamoxifeno/farmacologiaRESUMO
The above article from British Journal of Clinical Pharmacology, published online on July 5, 2020 in Wiley Online Library (http://wileyonlinelibrary.com) has been withdrawn by agreement among the authors and John Wiley & Sons Ltd on behalf of the British Pharmacology Society. The withdrawal has been agreed in accordance with the authors' decision to revise their study providing the latest data.
RESUMO
Docosahexaenoic acid (DHA) is one ω-3 fatty acid that is essential for the development and function of the brain. However, a large number of clinical trials found that the DHA supplementation showed no advantage on mental and motor skill development in term infants. A strategy based on DHA nanoencapsulation (nano FO) using an edible plant protein, zein, mimicking the milk structure is applied for enhanced maternal and fetal absorptions of DHA to improve early brain development. The nano FO achieved increased absorption in GI tract, enhanced delivery to the maternal, fetal, and offspring brains, and reduced fatty acid accumulation in the fetal liver. In the behavior assessments, the nano FO diet showed enhanced learning and memory improvement compared to the normal FO diet. It indicated that zein nanoencapsulation is with high potential for drug and nutrient deliveries to brain and through placenta to fetus with no toxicity concern.
Assuntos
Biomimética , Encéfalo/crescimento & desenvolvimento , Ácidos Docosa-Hexaenoicos/metabolismo , Feto/metabolismo , Troca Materno-Fetal , Nanocápsulas/química , Zeína/química , Animais , Encéfalo/metabolismo , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/química , Feminino , Trato Gastrointestinal/metabolismo , Absorção Intestinal , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Leite , Gravidez , SuspensõesRESUMO
The Lancang River flows through the alpine canyon region of southwest China, an area that has experienced frequent geological disasters over the years. Early monitoring of geological hazards is essential for disaster prevention and mitigation. However, traditional ground monitoring techniques are limited by the complex terrain conditions in high-altitude valley regions. In contrast, interferometric synthetic aperture radar (InSAR) technology can provide a high-precision, wide-range monitoring of slow rock-slope deformation, making it an effective tool for studying geological hazards. Within the study area, multiple synthetic aperture radar (SAR) images from the Sentinel-1A satellite were collected, and surface deformation was obtained using the small baseline subset InSAR (SBAS-InSAR). The results demonstrate that combining ascending and descending orbit images can be successfully applied to landslide monitoring in complex mountainous areas. Over 30 potential landslides were identified by combining InSAR results with optical images. The Line-Of-Sight (LOS) direction deformation features and their relationship with precipitation were analyzed based on two typical landslides, and two-dimensional/three-dimensional (2D/3D) deformation decomposition was carried out to reveal its motion characteristics. It was found that the cumulative deformation fluctuation amplitude was higher during the rainy season, and the main movement direction of the landslide was east-west. In addition, based on the spatial distribution and statistical analysis of deformation points along with meteorological data, geological elements, human activities, and topographic conditions, it is inferred that factors such as low vegetation coverage, tectonic movements, human activities, and high-altitude glacier thawing may contribute to the occurrence of disasters. And it was found that areas with high vegetation cover, high rainfall, and snow cover exhibit lower coherence coefficients. This study offers valuable insights for investigating large-scale geological in alpine canyon regions.
Assuntos
Desastres , Deslizamentos de Terra , Humanos , Radar , Chuva , TecnologiaRESUMO
Oleanolic acid (OA) is previously shown to exert bone protective effects in aged animals. However, its role in regulating osteoblastic vitamin D bioactivation, which is one of major causes of age-related bone loss, remains unclear. Our results revealed that treatment of OA significantly increased skeletal CYP27B1 expression and circulating 1,25(OH)2D3 in ovariectomized mice (p <0.01). Moreover, OA upregulated CYP27B1 protein expression and activity, as well as the vitamin D-responsive bone markers alkaline phosphatase (ALP) activity and osteopontin (OPN) protein expression, in human osteoblast-like MG-63 cells (p<0.05). CYP27B1 expression increased along with the osteoblastic differentiation of human bone marrow derived mesenchymal stem cells (hMSCs). CYP27B1 expression and cellular 1,25(OH)2D3 production were further potentiated by OA in cells at mature osteogenic stages. Notably, our study suggested that the osteogenic actions of OA were CYP27B1 dependent. In summary, the bone protective effects of OA were associated with the induction of CYP27B1 activity and expression in bone tissues and osteoblastic lineages. Hence, OA might be a potential approach for management of age-related bone loss.
Assuntos
Anabolizantes , Ácido Oleanólico , Osteoporose , Vitamina D/análogos & derivados , Humanos , Animais , Camundongos , Idoso , 25-Hidroxivitamina D3 1-alfa-Hidroxilase/metabolismo , Ácido Oleanólico/farmacologia , Vitamina D/farmacologia , Vitamina D/metabolismo , Osso e Ossos/metabolismo , VitaminasRESUMO
This paper reports a novel highly ordered tripetaloid structure array (TPSA) which performs very well as an active surface-enhanced Raman scattering (SERS) substrate. The TPSA is easily fabricated by anisotropic etching of a self-assembly silica-nanoparticle bilayer and a subsequent metal deposition step, with notable uniformity and reproducibility. Electromagnetic simulation indicates that the narrow inter-gaps and edge protrusions in the TPSA act as hot spots. In addition, the peak electromagnetic field intensity in the inter-gaps changes slightly and periodically as the polarization of the incident light varies from 0° to 360°. SERS experiments show that the SERS enhancement factor (EF) of a Au-film-covered TPSA is 12 times higher than that of regular Au-film-over-nanoparticles, and not sensitive to the polarization of the incident light. The spatially averaged EF of the TPSA is as high as 5.7 × 10(6), and the local EF of its hot spots is much higher.
Assuntos
Cristalização/métodos , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Ressonância de Plasmônio de Superfície/métodos , Luz , Teste de Materiais , Tamanho da Partícula , Espalhamento de RadiaçãoRESUMO
The rapidly changing global conditions of the environment and climate have resulted in higher requirements for urban design. Significant annual temperature variations and large day/night temperature differences in cold-region cities leads to high energy consumption. Therefore, it is challenging to achieve low energy consumption in cold-region cities. Urban morphology focuses on the physical elements of urban areas, reflecting the relationship between the city and its environment and the city's response to natural climatic conditions. Building clusters are common in cold regions due to the extreme climate. Thus, it is crucial to study the energy performance of cities by considering urban morphology. This study focuses on four morphological patterns of building clusters: point, linear, courtyard, and mixed patterns. A case study is conducted in Harbin, a cold-region city in China. Samples of the four morphological patterns are extracted, and GIS analysis and manual labeling are used to analyze the dominant morphological patterns of building clusters in cold regions. Average nearest-neighbor analysis is used to obtain quantitative results and determine the prevalence of different morphological patterns of building clusters in cold regions. This process can be used to determine the dominant patterns of urban building clusters and provide a scientific basis for selecting the morphological patterns of new building clusters in cold regions.
Assuntos
Temperatura Baixa , Temperatura , Cidades , China/epidemiologiaRESUMO
Our previous study demonstrated that the bone protective actions of herbal medicine Rhizoma Drynariae (Gusuibu, RD) were mainly mediated by flavonoid phytoestrogens via estrogen receptors, raising concerns about the safety of using RD as it may induce estrogen-like risk-benefit profile and interact with other ER ligands, such as selective estrogen receptor modulators (SERMs), when coadministered. The present study evaluated the estrogenic activities of RD and its potential interaction with tamoxifen, a SERM, in estrogen-sensitive tissues by using mature ovariectomized (OVX) rats and ER-positive cells. Similar to but weaker than tamoxifen, RD at its clinical dose dramatically ameliorated OVX-induced changes in bone and dopamine metabolism-related markers in OVX rats. However, tamoxifen, but not RD, induced uterotrophic effects. No significant alteration in mammary gland was observed in OVX rats treated with RD, which was different from the inhibitory actions of tamoxifen. The two-way ANOVA results indicated the interactions between RD and tamoxifen in the bone, brain, and uterus of OVX rats while RD did not alter their responses to tamoxifen. Our results demonstrate that RD selectively exerts estrogenic actions in a different manner from tamoxifen. Moreover, RD interacts with tamoxifen without altering its effects in OVX rats.
Assuntos
Polypodiaceae , Receptores de Estrogênio , Animais , Estrogênios/farmacologia , Estrogênios/uso terapêutico , Feminino , Ratos , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Tamoxifeno/farmacologia , ÁguaRESUMO
Background: New predictors of the efficacy of hepatocellular carcinoma (HCC) immunotherapy are needed. The ability of a single gene mutation to predict the therapeutic effect of immune checkpoint inhibitors (ICI) in HCC remains unknown. Methods: The most frequently mutated genes in HCC were analyzed using the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets. Mutant genes that correlated with the tumor mutational burden (TMB) and prognosis were obtained. The mutation pattern and immunological function of one of the most frequently mutated genes, LRP1B, were determined. A pan-tumor analysis of LRP1B expression, association with cancer prognosis, and immunological role was also explored. A retrospective clinical study was conducted using 102 HCC patients who received ICI treatment to further verify whether gene mutations can predict the effectiveness of immunotherapy and prognosis of HCC. Results: LRP1B is among the most frequently mutated genes in HCC cohorts in TCGA and ICGC datasets. TCGA data showed that the LRP1B mutation activated immune signaling pathways and promoted mast cell activation. Patients with LRP1B mutations had significantly higher TMB than those with wild-type LRP1B. LRP1B expression correlated with the cancer-immunity cycle and immune cell infiltration. High LRP1B expression was also associated with poor survival among HCC patients. Results from the clinical study showed that HCC patients in the LRP1B mutation group had a poor response to ICI and worse prognosis than the wild-type group. The LRP1B mutation group had significantly higher TMB and mast cell infiltration in tumor tissues. Conclusion: This study is the first to report that a single gene LRP1B mutation is associated with a poor clinical response to ICI treatment and negative outcomes in HCC patients. HighLRP1B expression correlated with tumor immunity and HCC prognosis.
RESUMO
Our previous study revealed that the bone anabolic effects of the lignan-rich fraction (SWCA) from Sambucus williamsii Hance was involved in modulating the metabolism of tryptophan in vivo and inhibiting serotonin (5-HT) synthesis in vitro. This study aimed to determine how SWCA modulates bone metabolism via serotonin in vivo. The effects of SWCA were evaluated by using 4-month-old Sprague-Dawley (SD) ovariectomized rats. The serum levels of 5-HT and kynurenine, the protein expressions of tryptophan hydroxylase 1 (TPH-1) and TPH-2, the genes and proteins related to the 5-HT signaling pathway as well as gut microbiota composition were determined. SWCA treatment alleviated bone loss and decreased serum levels of serotonin, which was negatively related to bone mineral density (BMD) in rats. It suppressed the protein expression of TPH-1 in the colon, and reversed the gene and protein expressions of FOXO1 and ATF4 in the femur in OVX rats, while it did not affect the TPH-2 protein expression in the cortex. SWCA treatment escalated the relative abundance of Antinobacteria and modulated several genera relating to BMD. These findings verified that the bone protective effects of lignans were mediated by serotonin, and provided evidence that lignans might be a good source of TPH-1 inhibitors.
Assuntos
Microbioma Gastrointestinal , Lignanas , Sambucus , Ratos , Animais , Serotonina , Lignanas/farmacologia , Ratos Sprague-DawleyRESUMO
Despite the great potential of the application of surface-enhanced Raman scattering (SERS), the difficulty in fabricating suitable SERS substrates is still a problem. Based on the self-assembly of silica nanoparticles, a simple method is here proposed to fabricate a highly-ordered, 3D, petal-like arrayed structure (3D PLAS) that serves as a promising SERS substrate for both its high reproducibility and enormous SERS enhancement. Such a novel structure is easily achieved by anisotropically etching a self-assembly bilayer of silica nanoparticles, followed by metal deposition. The SERS performance of the 3D PLAS and its relationship with the main parameters, including the etching time, the diameter of silica nanoparticles, and the deposited metal film, are characterized using 632.8 nm incident light. With Rhodamine 6G as a probe molecule, the spatially averaged SERS enhancement factor is on the order of 5 × 10(7) and the local enhancement factor is much higher, both of which can be improved further by optimizing the parameters.
Assuntos
Nanopartículas Metálicas/química , Dióxido de Silício/química , Análise Espectral Raman/métodos , Propriedades de SuperfícieRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: The increasing use of "kidney"-nourishing Traditional Chinese Medicine (TCM) like Er-xian decoction (EXD) for management of menopausal symptoms and osteoporosis has aroused concerns about their safety, and whether they interact with prescription drugs as both of them act via estrogen receptors (ERs) and regulate serum estradiol. AIM OF THE STUDY: The present study aimed to evaluate whether EXD selectively exerted estrogenic activities and interacted with Selective Estrogen Receptor Modulators (SERMs). MATERIALS AND METHODS: In vivo, mature ovariectomized (OVX) rats were administrated with EXD or combined treatment of EXD and SERMs for 12 weeks. The tissue-selective effect of EXD and its interaction of SERMs were studied in four estrogen sensitive tissues, bone, brain, breast and uterus. In vitro, the interaction of extracts of EXD-treated serum and SERMs in four ER-positive cell lines. RESULTS: In OVX rats, EXD selectively alleviated estrogen deficiency-induced changes in the bone and brain without inducing any estrogenic effects in the breast or uterus. Two-way ANOVA indicated the presence of interactions between EXD and SERMs in OVX rats but EXD did not significantly alter the tissue responses to SERMs in the bone, breast or brain. Indeed, the combined use of EXD and SERMs appeared to suppress the estrogenic effect of raloxifene and tamoxifen in the uterus. Extract of EXD-treated serum directly stimulated cell proliferation or differentiation in human osteosarcoma MG-63, neuroblastoma SHSY5Y, breast cancer MCF-7, and endometrial Ishikawa cells. Two-way ANOVA revealed that EXD-treated serum interacted with SERMs at various concentrations and altered the effects of tamoxifen in MG-63 and MCF-7 cells. CONCLUSIONS: EXD exerted estrogenic effects in a tissue-selective manner and interacted with SERMs. Combined treatment of EXD and SERMs did not hamper the beneficial effects of SERMs on the bone or brain but appeared to moderate the estrogenic effect of SERMs in the uterus.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Estrogênios/farmacologia , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Mama/efeitos dos fármacos , Mama/metabolismo , Mama/patologia , Linhagem Celular Tumoral , Sistema Nervoso Central/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Estradiol/farmacologia , Estradiol/uso terapêutico , Estrogênios/química , Estrogênios/uso terapêutico , Feminino , Interações Ervas-Drogas/fisiologia , Hormônios/sangue , Humanos , Glândulas Mamárias Humanas/efeitos dos fármacos , Medicina Tradicional Chinesa , Modelos Biológicos , Ovariectomia/efeitos adversos , Cloridrato de Raloxifeno/farmacologia , Cloridrato de Raloxifeno/uso terapêutico , Ratos Sprague-Dawley , Receptores de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Útero/efeitos dos fármacos , Útero/metabolismo , Útero/patologia , ÁguaRESUMO
Menopausal women are susceptible to have high risk of cardiovascular diseases, type II diabetes and osteoporosis due to the metabolic disorder caused by estrogen deficiency. Accumulating evidence supports that gut microbiota is a key regulator of metabolic diseases. Our previous metabolomics study interestingly demonstrated that the anti-osteoporotic effects of lignan-rich fraction (SWCA) from Sambucus wialliamsii Hance were related to the restoration of a series of lipid and glucose metabolites. This study aims to investigate how SWCA modulates lipid and glucose metabolism and the underlying mechanism. Our results show that oral administration of SWCA (140 mg/kg and 280 mg/kg) for 10 weeks alleviated dyslipidemia, improved liver functions, prevented glucose tolerance and insulin actions, attenuated system inflammation and improved intestinal barrier in OVX rats. It also induced a high abundance of Actinobacteria, and restored microbial composition. We are the first to report the protective effects of the lignan-rich fraction from S. williamsii on dyslipidemia and insulin resistance. Our findings provide strong evidence for the application of this lignan-rich fraction to treat menopausal lipid disorder and insulin resistance-related diseases.
Assuntos
Dislipidemias/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Hipolipemiantes/farmacologia , Resistência à Insulina , Lignanas/farmacologia , Sambucus/química , Administração Oral , Animais , Citocinas/metabolismo , Feminino , Glucose/metabolismo , Teste de Tolerância a Glucose , Fígado/efeitos dos fármacos , Ovariectomia , Extratos Vegetais/farmacologia , Caules de Planta/química , Ratos , Ratos Sprague-DawleyRESUMO
Oxidative stress (OS) is the common mechanism for age-related diseases. The co-occurrence of osteoporosis (OP) and cardiovascular disease (CVD) in postmenopausal women makes it warranted to find a holistic approach for treatment of multiple diseases or conditions. The rhizome of Ligusticum chuanxiong Hort. (CX), which has high anti-oxidant properties and is widely used for CVD treatment in China, might be the potential candidate. In the present study, CX ethanol extract (CXE) was applied to H2O2 induced MG63 cells to study its effects and mechanisms on osteoblastogenesis against OS. CXE was then administered to six-month-old Sprague Dawley sham or ovariectomized (OVX) rats fed either a low saturated fat-sucrose (LFS) or a high fat-sucrose (HFS) diet for 12 weeks, to confirm its anti-osteoporotic effects. The results demonstrated that CXE directly improved proliferation and differentiation in vitro in an H2O2-induced osteoblast cell model by attenuating cellular reactive oxygen species levels and inhibiting osteoblast apoptosis via PI3K/Akt signaling pathway. CXE significantly improved bone properties as revealed by the increase in trabecular bone mineral density and decrease in trabecular separation at proximal metaphysis of the tibia (PT) in HFS-fed OVX rats but not in LFS-fed OVX rats. CXE ameliorated dyslipidemia, greatly reduced lipid deposition and malondialdehyde levels, improved activities of superoxide dismutase, catalase and glutathione peroxidase in the livers of HFS-fed OVX rats. In conclusion, CXE could favor osteoblastogenesis against OS. The ability of CXE to reduce bone loss in HFS-fed OVX rats was associated with its abilities to correct dyslipidemia, and reduce lipid deposition and OS levels.
Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Hiperlipidemias/complicações , Osteoporose/etiologia , Osteoporose/prevenção & controle , Ovariectomia/efeitos adversos , Animais , Células Cultivadas , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Osteoblastos/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Fitoterapia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: The clinical significance of programmed cell death protein-1 (PD-1)-targeted immunotherapy in Chinese patients is understudied. We thus aimed to evaluate the safety and efficacy of PD-1 inhibitors with toripalimab, camrelizumab or sintilimab for Chinese hepatocellular carcinoma (HCC) patients in a real-life cohort. METHODS: We analysed hepatitis B virus (HBV)-associated HCC patients treated with toripalimab, camrelizumab, or sintilimab in a retrospective single-center cohort from November 2018 to June 2020. Efficacy was evaluated with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to tumor progression (TTP), and overall survival (OS). Safety data were also recorded. RESULTS: Seventy patients were finally included in the analysis: 23 were treated with toripalimab, 33 with camrelizumab, and 14 with sintilimab. The mean duration of follow-up was 44.7 (95% CI: 39.9-49.6) weeks and the mean cycles of PD-1 at cutoff were 8.3±8.0 for all patients. The ORR and DCR for the whole cohort were 30% and 72.9%, respectively. Overall, 25 (35.7%) patients had radiological disease progression and 10 (14.3%) patients died during follow-up. Median PFS, median TTP, and median OS had not yet been reached. Most frequent drug-related adverse events (AEs) were rash (27.1%), hypertension (18.6%), fatigue (17.1%), diarrhea (17.1%), paresthesia (15.7%), and nausea (15.7%). CONCLUSIONS: Our findings suggest that (I) PD-1 targeted immunotherapy with toripalimab, camrelizumab, or sintilimab yielded a promising outcome in Chinese HBV patients with HCC and that (II) immunotherapy was well tolerated generally and had manageable side effects. This approach thus warrants further popularization and application in clinical practice.
RESUMO
Icariin, a flavonoid phytoestrogen derived from Herba epimedii, has been reported to exert estrogenic effects in bone and activate phosphorylation of estrogen receptor (ER) α in osteoblastic cells. However, it is unclear whether icariin selectively exerts estrogenic activities in bone without inducing undesirable effects in other estrogen-sensitive tissues. The present study aimed to investigate the tissue-selective estrogenic activities of icariin in estrogen-sensitive tissues in vivo and in vitro. Long-term treatment with icariin effectively prevented bone of ovariectomized (OVX) rats from estrogen deficiency-induced osteoporotic changes in bone structure, bone mineral density, and trabecular properties. Moreover, icariin regulated the transcriptional events of estrogen-responsive genes related to bone remodeling and prevented dopaminergic neurons against OVX-induced changes by rescuing expression of estrogen-regulated tyrosine hydroxylase and dopamine transporter in the striatum. Unlike estrogen, icariin did not induce estrogenic effects in the uterus and breast in mature OVX rats or immature CD-1 mice. In vitro studies demonstrated that icariin exerted estrogen-like activities and regulated the expression of estrogen-responsive genes but did not induce estrogen response element-dependent luciferase activities in ER-positive cells. Our results support the hypothesis that icariin, through its distinct mechanism of actions in activating ER, selectively exerts estrogenic activities in different tissues and cell types.