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1.
J Exp Med ; 218(1)2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-32991668

RESUMO

Immunotherapy has revolutionized the treatment of many tumors. However, most glioblastoma (GBM) patients have not, so far, benefited from such successes. With the goal of exploring ways to boost anti-GBM immunity, we developed a B cell-based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism and IFNγ stimulation. BVax migrates to key secondary lymphoid organs and is proficient at antigen cross-presentation, which promotes both the survival and the functionality of CD8+ T cells. A combination of radiation, BVax, and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. This treatment elicited immunological memory that prevented the growth of new tumors upon subsequent reinjection in cured mice. GBM patient-derived BVax was successful in activating autologous CD8+ T cells; these T cells showed a strong ability to kill autologous glioma cells. Our study provides an efficient alternative to current immunotherapeutic approaches that can be readily translated to the clinic.

2.
J Hazard Mater ; 401: 123361, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32645541

RESUMO

Contaminated sites from pesticide industry have attracted global concern due to the characteristics of organic pollution with high concentrations and complete loss of habitat conditions. Remediation of organophosphorus pesticide polluted soil using microwave-activated persulfate (MW/PS) oxidation was investigated in this study, with parathion as the representative pesticide. Approximately 90 % of parathion was degraded after 90 min of MW/PS oxidation treatment, which was superior to those by single PS or MW treatment. Relatively greater performances for parathion degradation were obtained in a relatively larger PS dosage, higher microwave temperature, and lower organic matter content. Appropriate soil moisture favored parathion degradation in soil. SO4-, OH, O2-, and 1O2 generated in the MW/PS system all contributed to parathion degradation. Multiple spectroscopy analyses indicated that PO and PS bonds in parathion were destroyed after MW/PS oxidation, accompanied by generation of hydroxylated and carbonylated byproducts. The soil safety after parathion degradation was assessed via model prediction. Furthermore, MW/PS oxidation also exhibited great performance for degradation of other organophosphorus pesticides, including ethion, phorate, and terbufos.

3.
iScience ; : 101642, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33043282

RESUMO

COVID-19 has broken out since the end of December 2019 and is still spreading rapidly, which has been listed as an international concerning public health emergency. We found the Spike protein of SARS-CoV-2 contains a furin cleavage site, which did not exist in any other betacoronavirus subtype B. Based on a series of analysis, we speculate that the presence of a redundant furin cut site in its Spike protein is responsible for SARS-CoV-2's stronger infectious than other coronaviruses, which leads to higher membrane fusion efficiency. Subsequently, a library of 4,000 compounds including approved drugs and natural products were screened against furin through structure-based virtual screening and then assayed for their inhibitory effects on furin activity. Among them, an anti-parasitic drug, Diminazene, showed the highest inhibition effects on furin with an IC50 of 5.42 ± 0.11 µM, which might be used for the treatment of COVID-19.

5.
Cancer Med ; 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33058559

RESUMO

PURPOSE: To compare the clinical characteristics and survival outcomes of patients with ascending type (type A), descending type (type D), and mixed type (type AD) of nasopharyngeal carcinoma (NPC) in non-endemic areas. MATERIALS AND METHODS: The cohort included 628 patients diagnosed with type A, type D, and type AD of NPC between January 2009 and December 2014. Type A was defined as T3-4  N0-1 , type D as T0-1  N2-3 , and type AD as T3-4  N2-3 . Propensity score matching (PSM) was performed to balance clinical factors and match patients. Kaplan-Meier methods and Cox proportional hazards models were used to evaluate the impact of different NPC types on survival outcomes. RESULTS: There were 145 patients with type A, 194 with type D, and 289 with type AD. However, after PSM, there were only 130 patients with each type. Compared with patients with type A, those with type D had lower 5-year disease-specific survival (96.9% vs 91.5%) and distant metastasis-free survival (92.3% vs 77.7%) and higher local relapse-free survival (88.5% vs 96.9%) (p < 0.05 for all). Patients with type AD may have an increased risk of disease progression (progression-free survival, 56.9% vs 74.6% and 66.2%) and death (overall survival [OS], 76.9% vs 85.4% and 85.4%) (p < 0.05 for all) compared to patients with the other two types of tumors. We further analyzed the metastasis trend. Similar metastasis patterns were observed in types AD and D, and types AD and A had similar recurrence trends. The mortality rate of patients with types AD and D in the first 3 years after metastasis was remarkably higher than that of patients with type A. CONCLUSIONS: In non-endemic areas of China, metastases and recurrence patterns differed across tumor types. Type AD has the worst OS, and the clinical process is more radical. Type D has a lower recurrence rate, higher metastasis, and disease-related mortality rates, and poorer prognosis after metastasis than type A.

6.
Genome Res ; 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060173

RESUMO

Retrotransposons are populated in vertebrate genomes, and when active, are thought to cause genome instability with potential benefit to genome evolution. Retrotransposon-derived RNAs are also known to give rise to small endo-siRNAs to help maintain heterochromatin at their sites of transcription; however, as not all heterochromatic regions are equally active in transcription, it remains unclear how heterochromatin is maintained across the genome. Here, we address these problems by defining the origins of repeat-derived RNAs and their specific chromatin locations in Drosophila S2 cells. We demonstrate that repeat RNAs are predominantly derived from active gypsy elements and processed by Dcr-2 into small RNAs to help maintain pericentromeric heterochromatin. We also show in cultured S2 cells that synthetic repeat-derived endo-siRNA mimics are sufficient to rescue Dcr-2-deficiency-induced defects in heterochromatin formation in interphase and chromosome segregation during mitosis, demonstrating that active retrotransposons are required for stable genetic inheritance.

7.
Microbiome ; 8(1): 143, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33008466

RESUMO

BACKGROUND: "Western" style dietary patterns are characterized by a high proportion of highly processed foods rich in fat and low in fiber. This diet pattern is associated with a myriad of metabolic dysfunctions, including neuroinflammation and cognitive impairment. ß-glucan, the major soluble fiber in oat and barley grains, is fermented in the lower gastrointestinal tract, potentially impacting the microbial ecosystem and thus may improve elements of cognition and brain function via the gut-brain axis. The present study aimed to evaluate the effect of ß-glucan on the microbiota gut-brain axis and cognitive function in an obese mouse model induced by a high-fat and fiber-deficient diet (HFFD). RESULTS: After long-term supplementation for 15 weeks, ß-glucan prevented HFFD-induced cognitive impairment assessed behaviorally by object location, novel object recognition, and nesting building tests. In the hippocampus, ß-glucan countered the HFFD-induced microglia activation and its engulfment of synaptic puncta, and upregulation of proinflammatory cytokine (TNF-α, IL-1ß, and IL-6) mRNA expression. Also, in the hippocampus, ß-glucan significantly promoted PTP1B-IRS-pAKT-pGSK3ß-pTau signaling for synaptogenesis, improved the synaptic ultrastructure examined by transmission electron microscopy, and increased both pre- and postsynaptic protein levels compared to the HFFD-treated group. In the colon, ß-glucan reversed HFFD-induced gut barrier dysfunction increased the thickness of colonic mucus (Alcian blue and mucin-2 glycoprotein immunofluorescence staining), increased the levels of tight junction proteins occludin and zonula occludens-1, and attenuated bacterial endotoxin translocation. The HFFD resulted in microbiota alteration, effects abrogated by long-term ß-glucan supplementation, with the ß-glucan effects on Bacteroidetes and its lower taxa particularly striking. Importantly, the study of short-term ß-glucan supplementation for 7 days demonstrated pronounced, rapid differentiating microbiota changes before the cognitive improvement, suggesting the possible causality of gut microbiota profile on cognition. In support, broad-spectrum antibiotic intervention abrogated ß-glucan's effects on improving cognition, highlighting the role of gut microbiota to mediate cognitive behavior. CONCLUSION: This study provides the first evidence that ß-glucan improves indices of cognition and brain function with major beneficial effects all along the gut microbiota-brain axis. Our data suggest that elevating consumption of ß-glucan-rich foods is an easily implementable nutritional strategy to alleviate detrimental features of gut-brain dysregulation and prevent neurodegenerative diseases associated with Westernized dietary patterns. Video Abstract.

8.
Urology ; 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33045289

RESUMO

OBJECTIVE: To explore the role of TRPM8 in the occurrence and development of bladder pain in IC /BPS patients. The differences in the content and location distribution of TRPM8 in bladder were compared between IC/BPS and control group. METHODS: All enrolled patients answered questionnaire such as O'leary-Sant symptom index, VAS, QOL and PUF score, then bladder specimens were collected. Analyses such as qRT-PCR, western blot, and immunofluorescence were performed to determine the changes in TRPM8 content and expression in neurons and sensory nerves between the IC/BPS and control group, and the relationships between TRPM8 and various clinical scores were also analyzed. RESULTS: There were significant differences in the O'leary-Sant score, PUF score, VAS and QOL score between IC/BPS and the control group (P<0.05). Compared with the control group, the expression levels of TRPM8 mRNA and protein were significantly increased in the IC/BPS bladder tissues (P<0.01). Immunofluorescence examination also revealed that1 the number of neurons and sensory nerves displayed a significant upward trend in the bladder tissue of IC/BPS patients2 the expression levels of TRPM8 on neurons and sensory nerves also increased significantly in IC/BPS group. CONCLUSIONS: In IC/BPS patients, TRPM8 content increased significantly and mainly expressed on increased neurons and sensory nerves in bladder tissue. These results may indicate a mechanism by which bladder pain is more easily to spread in IC/BPS patients, and may also indicate an important mechanism for pain sensitization in such patients.

9.
Mol Cell Biochem ; 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33000352

RESUMO

Mitochondria have various cellular functions, including ATP synthesis, calcium homeostasis, cell senescence, and death. Mitochondrial dysfunction has been identified in a variety of disorders correlated with human health. Among the many underlying mechanisms of mitochondrial dysfunction, the opening up of the mitochondrial permeability transition pore (mPTP) is one that has drawn increasing interest in recent years. It plays an important role in apoptosis and necrosis; however, the molecular structure and function of the mPTP have still not been fully elucidated. In recent years, the abnormal opening up of the mPTP has been implicated in the development and pathogenesis of diverse diseases including ischemia/reperfusion injury (IRI), neurodegenerative disorders, tumors, and chronic obstructive pulmonary disease (COPD). This review provides a systematic introduction to the possible molecular makeup of the mPTP and summarizes the mitochondrial dysfunction-correlated diseases and highlights possible underlying mechanisms. Since the mPTP is an important target in mitochondrial dysfunction, this review also summarizes potential treatments, which may be used to inhibit pore opening up via the molecules composing mPTP complexes, thus suppressing the progression of mitochondrial dysfunction-related diseases.

10.
Adv Healthc Mater ; : e2001014, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33000917

RESUMO

Advances in material science have set the stage for nanoparticle-based research with potent applications for the diagnosis, bioimaging, and precise treatment of diseases. Despite the wide range of biomaterials developed, the rational design of biomaterials with predictable bioactivity and safety remains a critical challenge. In recent years, the field of cell-membrane-based therapeutics has emerged as a promising platform for addressing unmet medical needs. The utilization of natural cell membranes endows biomaterials with a remarkable ability to serve as biointerfaces that interact with the host environment. To improve the function and efficacy of cell-membrane-based therapeutics, a series of novel strategies is developed as cell-membrane-display nanotechnology, which utilizes various methods to selectively display therapeutic molecules of cell membranes on nanoparticles. Although cell-membrane-display nanotechnology remains in the early phases, considerable work is currently being conducted in the field. This review discusses details of innovative strategies for displaying cell-membrane molecules, including the following: 1) displaying molecules of cell membranes on biomaterials, 2) pretreating cell membranes to induce increased expression of inherent molecules of cell membranes and enhance their function, and 3) inserting additional functional molecules on cell membranes. For each area, the theoretical basis, application scenarios, and potential development are highlighted.

11.
Genome ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33002386

RESUMO

Cereal rye and its wild forms are important sources of genetic diversity for wheat breeding due to their resistances to biotic and abiotic stresses. Secale strictum subsp. anatolicum (Boiss.) K.Hammer (SSA) is a weedy relative of cultivated rye, S. cereale. Meiotic chromosome pairing in F1 hybrids of SSA and S. cereale reveals strong genomic affinity between the two genomes. A study of the transferability of S. cereale sequence-based markers to SSA and hexaploid triticale demonstrated their applicability for tracing SSA chromatin in wheat. The transferability of the markers was over 80% from homoeologous groups 1, 2 and 3, and greater than 70% from groups 4 to 7, respectively. This study focused on the generation and molecular and cytogenetic characterization of wheat-SSA alien derivatives. Twelve were identified using combinations of non-denaturing fluorescence in situ hybridization (ND-FISH), genomic in situ hybridization (GISH) and molecular marker analysis. All SSA chromosomes, except 3Ra and 6Ra, were transferred to wheat either in the form of monosomic (MAs), mono-telosomic (MtAs), double-mono-telosomic (dMtAs) or double-monosomic (dMAs) additions. The germplasm developed in this study will help to enhance the genetic base of wheat and facilitate molecular breeding of wheat and triticale.

12.
Anticancer Drugs ; 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33105152

RESUMO

This study was performed to investigate pneumothorax characteristics and association with clinical outcomes in patients with osteosarcoma treated with apatinib. We retrospectively reviewed the medical records of osteosarcoma patients treated with apatinib between January 2016 and April 2020 at three institutions. We evaluated the prevalence, healing time, recurrence, severity, clinical management, and prognosis of pneumothorax in these patients. A total of 54 osteosarcoma patients who received apatinib treatment were enrolled in this study. Among them, 14 patients had pneumothorax. There were significant differences between the patients with and without pneumothorax with regard to the cavitating rate of lung metastases (92.86 vs. 32.50%, respectively, P < 0.001), objective response rate (42.86 vs. 10.00%, P = 0.013), disease control rate (85.71 vs. 42.50%, P = 0.006), 4-month progression-free survival (PFS) rate (57.10 vs. 20.00%, P < 0.001), and median PFS (5.65 vs. 2.90 months, P = 0.011). Compared with pneumothorax patients treated with chest tube drainage only [non-staphylococcal enterotoxin C (SEC) group], those treated with chest tube drainage and SEC thoracic perfusion in parallel (SEC group) had a shorter pneumothorax healing time (12.00 ± 4.50 days vs. 24.00 ± 14.63 days for SEC group and non-SEC group, respectively, P = 0.103), a lower recurrence rate of pneumothorax (25.00% vs. 66.67%, P = 0.277), and a longer median PFS (5.9 months vs. 4.75 months, P = 0.964). however, these numerical differences for the SEC/non-SEC data did not reach statistical significance. Pneumothorax and cavitation in lung metastases may be effective prognostic markers for patients with osteosarcoma treated with apatinib. SEC may be effective for treatment of such pneumothorax patients, warranting further study.

13.
Regen Med Res ; 8: 2, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33095154

RESUMO

BACKGROUND: Paclitaxel, a commonly used chemotherapeutic agent, is usually associated with peripheral neuropathy. Paclitaxel induced peripheral neuropathy (PIPN) can be dose limiting and may have detrimental influence on patients' quality of life. However, the mechanism of PIPN remains unclear. Medicinal herbs and their formulas might offer neuronal protection with their multitarget and integrated benefits in chemotherapy-induced peripheral neuropathy (CIPN). Siwei Jianbu decoction (J12) is a classic formula of traditional Chinese medicine which can promote blood circulation and treat diabetic nephropathy in clinical with the symptoms of weakness and pain. METHODS: The effects of J12 were treated in C57BL/6 mice before injected with Paclitaxel.Behaviour studies: Measurement of mechanical hyperalgesia, thermal nociception and cold allodynia. On the last day at the end of week 6, DRGs were obtained from mice for western blot and immunohistochemical analysis containing NF-κB, p-ERK1/2 and p-SAPK/JNK protein expression. Quantitative real-time polymerase chain reaction: mRNA expression of NF-κB, IL-1ß and TNF-α was analyzed. Additionally, the blood samples collected from the eye socket of the mouse were prepared to examine the levels of NF-κB, TNF-α, IL-6 and IL-1ß using ELISA assay kits. RESULTS: Hypersensitivity tests and pathology analysis have demonstrated that J12 could improve paclitaxel-induced peripheral pain. J12 acts by inhibiting the activation of (C-Jun N-terminal kinases) JNK, (extracellular signal-regulated kinase) ERK1/2 phosphorylation in (Mitogen-activated protein kinases) MAPK signaling pathway and the nuclear factor-κB (NF-κB) in C57BL/6 mice model, J12 also inhibits the production of inflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß) and IL-6. CONCLUSION: The present study showed that J12 ameliorates paclitaxel-induced peripheral neuropathic pain.

15.
Theranostics ; 10(25): 11820-11836, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33052248

RESUMO

Background: E-cigarette and other novel electronic nicotine delivery systems (ENDS) have recently entered the market at a rapid pace. The community desperately needs answers about the health effects of ENDS. The present study tested the hypothesis that perinatal nicotine exposure (PNE) causes a gender-dependent increase in vulnerability of the heart to ischemia-reperfusion (I/R) injury and cardiac dysfunction in male rat offspring via reprogramming of the miRNA-181a (miR-181a)-mediated signaling pathway and that miR-181a antisense could rescue this phenotype. Methods: Nicotine or saline was administered to pregnant rats via subcutaneous osmotic minipumps from gestational day 4 until postnatal day 10. Cardiac function and molecular biological experiments were conducted in ~3- month-old offspring. Results: PNE enhanced I/R-induced cardiac dysfunction and infarction in adult male but not in female offspring, which was associated with miR-181a over-expression in left ventricle tissues. In addition, PNE enhanced offspring cardiac angiotensin receptor (ATR) expressions via specific CpG hypomethylation of AT1R/AT2R promoter. Furthermore, PNE attenuated cardiac lncRNA H19 levels, but up-regulated cardiac TGF-ß/Smads family proteins and consequently up-regulated autophagy-related protein (Atg-5, beclin-1, LC3 II, p62) expression in the male offspring. Of importance, treatment with miR-181a antisense eliminated the PNE's effect on miR-181a expression/H19 levels and reversed PNE-mediated I/R-induced cardiac infarction and dysfunction in male offspring. Furthermore, miR-181a antisense also attenuated the effect of PNE on AT1R/AT2R/TGF-ß/Smads/autophagy-related biomarkers in the male offspring. Conclusion: Our data suggest that PNE could induce a reprogramming of cardiac miR-181a expression/DNA methylation pattern, which epigenetically modulates ATR/TGF-ß/autophagy signaling pathways, leading to gender-dependent development of ischemia-sensitive phenotype in postnatal life. Furthermore, miR-181a could severe as a potential therapeutic target for rescuing this phenotype.

16.
Medicine (Baltimore) ; 99(42): e22472, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33080683

RESUMO

RATIONALE: Neonatal long-gap esophageal atresia (LGEA) with tracheoesophageal fistula (TEF) is an uncommon but serious congenital malformation of the esophagus in newborns, and it remains challenging for pediatric surgeons. Magnetic compress has been shown to be effective for the treatment of LGEA in children and adults. However, the implementation of this unique technique for neonatal LGEA has not been evaluated. PATIENT CONCERNS: A female infant was born at 37 weeks of gestation. Prenatal ultrasound imaging revealed signs of esophageal atresia, including the absence of the gastric bubble and polyhydramnios. DIAGNOSES: A diagnosis of LGEA with TEF was confirmed at birth by contrast X-ray. INTERVENTIONS: She was treated with magnetic compression anastomosis (MCA) following an esophago-esophagostomy. Two magnetic rings were customized, and the MCA was conducted during the same stage surgery of ligating the TEF. Under the magnetic force, the 2 magnet rings pulled along the gastric tube to achieve anastomosis. The postoperative permanent suction of these 2 pouches was instituted, and spontaneous growth was awaited. Magnet removal was performed at 36 days, and enteral nutrition was continued via a gastric tube for 4 weeks at post-operation. OUTCOMES: The upper gastrointestinal contrast confirmed the anastomotic patency perfectly after 3 months. The patient was followed up for 18 months, and exhibited durable esophageal patency without dysphagia. LESSONS: These results suggest that MCA is feasible and effective for treating LGEA in infants.

17.
Neural Plast ; 2020: 8880543, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33082779

RESUMO

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect caused by chemotherapy drugs, and its existence seriously affects the quality of life of patients. We first established an oxaliplatin-induced peripheral neuropathy (OIPN) model and then measured and evaluated mechanical hyperalgesia, thermal nociception, cold allodynia, and intraepidermal nerve fiber (IENF) density to determine Siwei Jianbu Decoction's role in preventing OIPN. Then, we conducted a systematic pharmacological study that revealed important roles for the MAPK signaling pathway and proinflammatory immune pathway and confirmed these roles by western blot, immunofluorescence, and qPCR. The data show that Siwei Jianbu Decoction can effectively prevent oxaliplatin-induced neuroinflammation by inhibiting an increase in NF-κB expression via downregulation of p-ERK1/2 and p-p38. The present study showed that SWJB may be beneficial in preventing oxaliplatin-induced peripheral neuropathy.

18.
Artigo em Inglês | MEDLINE | ID: mdl-33085470

RESUMO

Dendrimers are well-defined, highly branched macromolecules that have been widely applied in the fields of catalysis, sensing, and biomedicine. Here, we present a novel multifunctional photochromic dendrimer fabricated through grafting azobenzene units onto dendrimers, which not only enables controlled switching of adhesives and effective repair of coating scratches but also realizes high-performance solar energy storage and on-demand heat release. The switchable adhesives and healable coatings of azobenzene-containing dendrimers are attributed to the reversible solid-to-liquid transitions because trans-isomers and cis-isomers have different glass transition temperatures. The adhesion strengths increase significantly with the increase in dendrimer generations, wherein the adhesion strength of fifth-generation photochromic dendrimers (G5-Azo) can reach up to 1.62 MPa, five times higher than that of pristine azobenzenes. The solar energy storage and heat release of dendrimer solar thermal fuels, the isomers of which possess different chemical energies, can be also enhanced remarkably with the amplification of azobenzene groups on dendrimers. The storage energy density of G5-Azo can reach 59 W h kg-1, which is much higher than that of pristine azobenzenes (36 W h kg-1). The G5-Azo fuels exhibit a 5.2 °C temperature difference between cis-isomers and trans-isomers. These findings provide a new perspective and tremendously attractive avenue for the fabrication of photoswitchable adhesives and coatings and solar thermal fuels with dendrimer structures.

19.
J Ethnopharmacol ; 266: 113453, 2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33039628

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Banxia Baizhu Tianma decoction (BBTD) is a classical representative prescription for expelling phlegm, extinguishing wind, strengthening the spleen and dissipating excessive fluid in traditional Chinese medicine (TCM). According to both TCM theory and about 300 years of clinical practice, BBTD is especially suitable for hypertensive patients of abdominal obesity and lacking physical activity. AIM OF THE STUDY: The present study tried to interpret the pharmacology of the ancient formula of BBTD. Herein, we focused on the plasma metabonomics of BBTD and evaluated the effect and targets of BBTD on endothelial protective effect. METHODS: Obesity-related hypertensive mice were induced by high-fat diet for 20 weeks. BBTD (17.8 g/kg) was administered intragastrically for 8 weeks, and telmisartan group (12.5 mg/kg) was used as positive drug. Body weight, blood pressure, triglyceride and cholesterol were recorded to evaluate the efficacy of BBTD in vivo. Lipid deposition in aortic roots was assessed by oil red O staining, while morphology of aortas was observed by HE staining. Ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was performed to study the plasma non-targeted metabonomics. According to the data of metabonomics, human aortic endothelial cells (HAECs) were treated by oxidized low-density lipoprotein (ox-LDL, 50 µg/mL) with/without BBTD (2, 1 or 0.5 mg/mL). Apoptosis rate (Annexin V-FITC/PI), migration (Transwell), cytoskeleton (Phalloidin) and density of VE-cadherin (Immunofluorescence staining) were used to investigate the effect of BBTD in vitro. Transcriptome sequencing was performed (2 mg/mL BBTD vs ox-LDL) to screen the possible targets of BBTD in endothelial protection against ox-LDL. RESULTS: BBTD effectively reduced the body weight and total cholesterol, and decreased 12.1 mmHg in SBP and 10.5 mmHg in DBP of obesity-related hypertensive mice (P < 0.05). BBTD attenuated lipid deposition in arterial roots and improved the morphology of aortas in vivo. Plasma metabolite profiles identified 94 differential metabolites and suggested BBTD mainly affected glycerophospholipids and fatty acyls. Bioinformatics analysis indicated sphingolipid metabolism and fluid shear stress and atherosclerosis were main pathways. Therefore, we focused on endothelial protective effect of BBTD against ox-LDL. In vitro, BBTD demonstrated endothelial protective effects, decreasing apoptosis rate, improving cell migration in dose-dependent manner and maintaining cell morphology. Transcriptome sequencing identified 251 downregulated and 603 upregulated mRNAs after 24h-BBTD treatment, which reversed 51.8% change in mRNAs (393 DE mRNAs) induced by ox-LDL. Bioinformatics analysis supported the potential of BBTD in hypertension and suggested that BBTD improved endothelial cells by targeting mainly on p53 and PPAR signaling pathways. CONCLUSIONS: BBTD attenuates obesity-related hypertension by regulating metabolism of glycerophospholipids and endothelial protection.

20.
Fitoterapia ; 147: 104758, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33069833

RESUMO

Three new isopimarane-type diterpenoids, botrysphins G-I (1-3), a new muurolane-type sesquiterpenoid, 11,12-dihydroxylentideusether (4), and two new triketides, 4-dechlorobotrysphone C (5) and 4,5-dihydroxy-3-methoxy-6-undecanoyloxy-2-cyclohexen-1-one (6), together with one known diterpenoid, sphaeropsidin A (7), one sesquiterpenoid, lentideusether (8), and one triketide sphaeropsidone (9), were isolated from culture of the fungus Botrysphaeria laricina associated with the moss Rhodobryum umgiganteum. The structures of the new compounds were established on the basis of extensive spectroscopic techniques including HRMS and 1D and 2D NMR data. Compounds 1 and 2 exhibited NO inhibitory activity with IC50 values of 13.9 µM and 41.9 µM, respectively. At the same time, these two compounds showed quinone reductase inducing activity with 2.7-fold of induction for 1 at 12.5 µM and 1.6-fold for 2 at 25.0 µM.

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