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1.
World J Emerg Med ; 13(1): 24-26, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35003411

RESUMO

BACKGROUND: A national standardized emergency medicine (EM) curriculum for medical students, including specific competencies in procedural skills, are absent in many countries. The development of an intensive simulating training program in EM, based on a tight schedule, is anticipated to enhance the competency of medical students. METHODS: A 3-day intensive EM training program, consisting of four procedural skills and 8-hour case-based learning (CBL), was developed by experienced physicians from the EM department in Peking Union Medical College Hospital (PUMCH). Medical students from Peking Union Medical College (PUMC) and Tsinghua University (THU) participated in the training. Three written tests were cautiously designed to examine the short-term (immediately after the program) and long-term (6 months after the program) efficacy of the training. After completion of the training program, an online personal appraisal questionnaire was distributed to the students on WeChat (a mobile messaging App commonly used in China) to achieve anonymous self-evaluation. RESULTS: Ninety-seven out of 101 students completed the intensive training and took all required tests. There was a significant increase in the average score after the intensive simulating training program (pre-training 13.84 vs. 15.57 post-training, P<0.001). Compared with the pre-training test, 63 (64.9%) students made progress. There was no significant difference in scores between the tests taken immediately after the program and 6 months later (15.57±2.22 vs. 15.38±2.37, P=0.157). Students rated a higher score in all diseases and procedural skills, and felt that their learning was fruitful. CONCLUSIONS: The introduction of a standardized intensive training program in EM focusing on key competencies can improve clinical confidence, knowledge, and skills of medical students toward the specialty. In addition, having such a program can also enhance student's interest in EM as a career choice which may enhance recruitment into the specialty and workplace planning.

2.
Br J Pharmacol ; 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-34997582

RESUMO

BACKGROUND AND PURPOSE: As the only ionotropic receptor in 5-HT receptor family, 5-HT3 receptor (5-HT3R) involves in psychiatric disorders and its modulators have potential therapeutic effects for cognitive impairment in these disorders. However, it remains unclear how 5-HT3Rs shape synaptic plasticity for memory function. EXPERIMENTAL APPROACH: Extracellular as well as whole-cell recordings were used to monitor hippocampal long-term potentiation (LTP) and synaptic transmission in hippocampal slices from 5-HT3AR knock-out or 5-HT3AR-GFP mice. Immunocytochemistry, qRT-PCR and Western blot were used to measure receptor expression. We also assessed hippocampal dependent cognition and memory using the Morris water maze (MWM) and novel object recognition. KEY RESULTS: We found that 5-HT3R dysfunction impaired hippocampal LTP in Schaffer collateral (SC)-CA1 pathway in hippocampal slices by facilitating GABAergic inputs in pyramidal cells. This effect was dependent on 5-HT3Rs on axon-terminals. It resulted from reduced expression and function of cannabinoid receptor 1 (CB1R) co-localized with 5-HT3Rs on axon terminals, which led to diminishment of tonic inhibition of GABA release by CB1Rs. Inhibition of CB1Rs mimicked the facilitation of GABAergic transmission by 5-HT3R disruption. Consequently, mice with hippocampal 5-HT3R disruption exhibited impaired spatial memory in Morris water maze tasks. CONCLUSION AND IMPLICATIONS: These results suggest that 5-HT3Rs are crucial in enabling hippocampal synaptic plasticity via a novel CB1R-GABAA -dependent pathway to regulate spatial memory.

3.
Hepatology ; 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35006626

RESUMO

BACKGROUND & AIMS: Although nonalcoholic steatohepatitis (NASH) can lead to severe clinical consequences, including cirrhosis and hepatocellular carcinoma, no effective treatment is currently available for this disease. Increasing evidence indicates that liver sinusoidal endothelial cells (LSECs) play a critical role in NASH pathogenesis; however, the mechanisms involved in LSEC-mediated NASH remain to be fully elucidated. APPROACH & RESULTS: In the current study, we found that LSEC homeostasis was disrupted and LSEC-specific gene profiles were altered in methionine-choline-deficient (MCD) diet-induced NASH mouse models. Importantly, Notch signaling was found to be activated in LSECs of NASH mice. To then investigate the role of endothelial Notch in NASH progression, we generated mouse lines with endothelial-specific NICD overexpression or RBP-J knockout to respectively activate or inhibit Notch signaling in endothelial cells. Notably, endothelial-specific overexpression of the NICD accelerated LSEC maladaptation and aggravated NASH, whereas EC-specific inhibition of Notch signaling restored LSEC homeostasis and improved NASH phenotypes. Furthermore, we demonstrated that endothelial-specific Notch activation exacerbated NASH by inhibiting eNOS transcription, while administration of the pharmacological eNOS activator YC-1 alleviated hepatic steatosis and lipid accumulation resulting from Notch activation. Finally, to explore the therapeutic potential of using Notch inhibitors in NASH treatment, we applied two gamma-secretase inhibitors-DAPT and LY3039478-in a MCD diet-induced mouse model of NASH, and found that both inhibitors effectively ameliorated hepatic steatosis, inflammation, and liver fibrosis. CONCLUSIONS: Endothelial-specific Notch activation triggered LSEC maladaptation and exacerbated NASH phenotypes in an eNOS-dependent manner. Genetic and pharmacological inhibition of Notch signaling effectively restored LSEC homeostasis and ameliorated NASH progression.

4.
Heart Lung ; 52: 130-135, 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-35016108

RESUMO

BACKGROUND: This study aimed to investigate the changes of body surface temperature of stable chronic obstructive pulmonary disease (COPD) patients and explore its clinical significance for the progression of COPD. OBJECTIVES: The aim of this study was to explore the correlation between body surface temperature and disease severity in COPD patients. METHODS: From May 2015 to May 2016, the patients who were diagnosed as COPD at stable phase (n = 148) were enrolled in this study. The subjects in control group (n = 49) were healthy people. The patients' general condition modified Medical Research Council (mMRC) dyspnea scale and the COPD assessment test (CAT) score were recorded, and pulmonary function of patients was determined. Back average temperature measurement was made using a thermal infrared imager (DT-9875, CEM, China). RESULTS: Patients in the COPD group had significantly lower mean temperatures of the back than those in the control group. The mean temperature of the back presented a decreased tendency with the aggravation of airflow limitation. Correlation analysis revealed that in the COPD group, the back temperature was negatively correlated with smoking index and mMRC score. FEV1%, FVC% and FEV1/FVC were positively correlated with pulmonary function. Smoking showed a tendency to lower the back temperature of COPD patients. CONCLUSIONS: This study preliminarily suggested that the body surface temperature of COPD patients decreased compared with that of healthy people, which may be associated with the dysfunction of autonomic nerve, increased basal metabolic rate, metabolic syndrome and peripheral nerve injury in COPD patients.

5.
Arterioscler Thromb Vasc Biol ; : ATVBAHA121317093, 2022 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-35021856

RESUMO

BACKGROUND: Endothelial cells (ECs) play a critical role in angiogenesis and vascular remodeling. The heterogeneity of ECs has been reported at adult stages, yet it has not been fully investigated. This study aims to assess the transcriptional heterogeneity of developmental ECs at spatiotemporal level and to reveal the changes of embryonic ECs clustering when endothelium-enriched microRNA-126 (miR-126) was specifically knocked out. METHODS: C57BL/6J mice embryos at day 14.5 were harvested and digested, followed by fluorescence-activated cell sorting to enrich ECs. Then, single-cell RNA sequencing was applied to enriched embryonic ECs. Tie2 (Tek receptor tyrosine kinase)-cre-mediated ECs-specific miR-126 knockout mice were constructed, and ECs from Tie2-cre-mediated ECs-specific miR-126 knockout embryos were subjected to single-cell RNA sequencing. RESULTS: Embryonic ECs were clustered into 11 groups corresponding to anatomic characteristics. The vascular bed (arteries, capillaries, veins, lymphatics) exhibited transcriptomic similarity across the developmental stage. Embryonic ECs had higher proliferative potential than adult ECs. Integrating analysis showed that 3 ECs populations (hepatic, mesenchymal transition, and pulmonary ECs) were apparently disorganized after miR-126 being knocked out. Gene ontology analysis revealed that disrupted ECs were mainly related to hypoxia, glycometabolism, and vascular calcification. Additionally, in vivo experiment showed that Tie2-cre-mediated ECs-specific miR-126 knockout mice exhibited excessive intussusceptive angiogenesis; reductive glucose and pyruvate tolerance; and excessive accumulation of calcium. Agonist miR-126-3p agomir significantly rescued the phenotype of glucose metabolic dysfunction in Tie2-cre-mediated ECs-specific miR-126 knockout mice. CONCLUSIONS: The heterogeneity of ECs is established as early as the embryonic stage. The deficiency of miR-126 disrupts the differentiation and diversification of embryonic ECs, suggesting that miR-126 plays an essential role in the maintenance of ECs heterogeneity.

6.
Artigo em Inglês | MEDLINE | ID: mdl-35022817

RESUMO

PURPOSE: The repeated use of doxorubicin is limited due to dose-limiting cardiac toxicity. Pegylated liposomal doxorubicin (PEG-LD, Duomeisu) has a reduced cardiac toxicity. This phase I study aimed to investigate the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of the PEG-LD and cisplatin combination in patients with metastatic and recurrent osteosarcoma. METHODS: Patients were given PEG-LD at a dose of 40, 50, or 60 mg/m2 on day 1 of each 21-day cycle, according to a 3 + 3 approach for dose escalation. Cisplatin was administered as a fixed dose of 100 mg/m2 for every cycle. Toxicities and tumor response were observed. RESULTS: A total of 15 patients were enrolled in this trial, and nine of the patients had received prior doxorubicin. The MTD of PEG-LD was reached at 50 mg/m2 in this regimen, with neutropenic fever and stomatitis as DTLs. The main adverse event (AE) was myelosuppression. The most common non-hematological AEs were vomiting, hypoproteinemia, stomatitis and transient sinus arrhythmia. Grade 3-4 toxicity was neutropenia, leukopenia, thrombocytopenia, anemia and stomatitis in the whole cohort. All the AEs were relieved after symptomatic and supportive treatment. Totally, the overall response rate was 13.3% and disease control rate was 66.7%. For the six patients who have not received prior doxorubicin, one partial response and five stable diseases were observed. CONCLUSION: We provide the data showing that PEG-LD 50 mg/m2 combined with cisplatin 100 mg/m2 demonstrated an acceptable safety profile and promising clinical activity in advanced osteosarcoma, which merits further evaluation in phase II studies. TRIAL REGISTRATION: ChiCTR1900021550.

7.
Cancer Control ; 29: 10732748211053150, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34989251

RESUMO

BACKGROUND: Breast cancer (BC), especially metastatic BC, is one of the most lethal diseases in women. CA 125 and CA 15-3 are commonly used indicators for diagnosis and prognosis of BC. Some serological indicators, such as lactate dehydrogenase (LDH) and C-reactive protein (CRP), can also be used to assess the prognosis and progression in BC. METHODS: Univariate Cox regression analysis and LASSO regression analysis were performed to identify prognostic factors and build prognostic models. We distributed the patients into 2 groups based on the median risk score, analyzed prognosis by Kaplan-Meier curve, and screened independent prognostic factors by multivariate Cox regression analysis. RESULT: We identified 4 indicators-LDH, CRP, CA 15-3, and CA 125-related to the prognosis in BC and established a prognostic model. The high LDH group showed worse overall survival (OS) than low LDH group (P = .017; hazard ratio (HR), 1.528; 95% confidence interval (CI), 1.055-2.215). The high CRP group showed worse OS than low CRP group (P = .004; HR, 1.666; 95% CI, 1.143-2.429). The high CA153 group showed worse OS than low CA 15-3 group (P=.011; HR, 1.563; 95% CI, 1.075-2.274). The high CA 125 group showed worse OS than low CA 125 group (P = .021; HR, 1.499; 95% CI, 1.031-2.181). The area under the curve for risk score was .824, Ki-67 was .628, age was .511, and grade was .545. Risk score was found to be an independent prognostic factor using multivariate Cox regression analysis. CONCLUSION: We successfully established an optimization model by combining 4 prognosis-related indicators to assess the prognosis in patients with metastatic BC.

8.
Zhongguo Zhen Jiu ; 42(1): 91-5, 2022 Jan 12.
Artigo em Chinês | MEDLINE | ID: mdl-35025164

RESUMO

Regarding the development of international standard of Guideline for Clinical Practice of Acupuncture and Moxibustion: Migraine, the existing problems of the design and methodology of randomized controlled trial (RCT) on acupuncture and moxibustion for migraine were summarized in views of participant, intervention, control, outcome and study design. Four directions need to be further explored, (1) research of adolescent migraine, special subtype of migraine and migraine in a special population; (2) research of the immediate analgesic effect of acupuncture and moxibuation at the attack stage of migraine and the therapeutic effect of migraine at each stage; (3) research on safety and health economics; (4) clinical trial registration of acupuncture and moxibustion. In study, the target population should be further determined and specialized, the diagnosis criteria of western medicine and traditional Chinese medicine be generalized and concentrated, the staging and type division of disease be accurate, the intervention procedure be integrated, the control design be rationalized, the outcomes be validated, and the description of randomization and blinding be clarified.


Assuntos
Terapia por Acupuntura , Acupuntura , Transtornos de Enxaqueca , Moxibustão , Adolescente , Humanos , Medicina Tradicional Chinesa , Transtornos de Enxaqueca/terapia
9.
Neurotox Res ; 2022 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-35038134

RESUMO

Oxidative stress is becoming increasingly implicated in the development of a variety of neurological disorders. However, the underlying mechanism remains elusive. In the present study, we investigated the function and related signal pathway which Cpg15, a neuronal-specific expressed neurotrophic factor, plays in the oxidative stress of neurons using a H2O2-treated N2a cell model. The results showed that the Cpg15 expression was decreased under oxidative stress, and overexpression of Cpg15 increased the activity of antioxidative SOD enzymes and decreased the expression level of prooxidative COX2 enzyme, and the level of oxidative products malondialdehyde (MDA), indicating its function and potential mechanism in alleviating the oxidative stress of cells. The results also indicated that the Nrf2/HO-1 antioxidative pathway was involved in the Cpg15-mediated alleviation of oxidative stress. Also, overexpression of Cpg15 activated the Nrf2 antioxidative pathway in the thalamus of the REM sleep-deprived mice. In conclusion, our results implied that supplemental expression of Cpg15 may alleviate oxidative stress in neuronal cells via regulating the redox enzymes or activating the Nrf2 antioxidant pathway.

10.
J Neurochem ; 2022 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-35038178

RESUMO

Glutamate AMPA receptors (AMPARs) lacking GluA2 subunit are calcium permeable (CP-AMPARs), which are increased in the hypothalamic paraventricular nucleus (PVN) and maintain sympathetic outflow in hypertension. Here, we determined the role of α2δ-1, an NMDA receptor-interacting protein, in regulating synaptic CP-AMPARs in the hypothalamus in spontaneously hypertensive rats (SHR). Co-immunoprecipitation showed that levels of GluA1/GluA2, but not GluA2/GluA3, protein complexes in hypothalamic synaptosomes were reduced in SHR compared with Wistar-Kyoto rats (WKY). The level of GluA1/GluA2 heteromers in endoplasmic reticulum-enriched fractions of the hypothalamus was significantly lower in SHR than in WKY, which was restored by inhibiting α2δ-1 with gabapentin. Gabapentin also switched AMPAR-mediated excitatory postsynaptic currents (AMPAR-EPSCs) from inward rectifying to linear and attenuated the inhibitory effect of IEM-1460, a selective CP-AMPAR blocker, on AMPAR-EPSCs in spinally projecting PVN neurons in SHR. Furthermore, co-immunoprecipitation revealed that α2δ-1 directly interacted with GluA1 and GluA2 in the hypothalamus of rats and humans. Levels of α2δ-1/GluA1 and α2δ-1/GluA2 protein complexes in the hypothalamus were significantly greater in SHR than in WKY. Disrupting the α2δ-1-AMPAR interaction with an α2δ-1 C terminus peptide normalized GluA1/GluA2 heteromers in the endoplasmic reticulum of the hypothalamus diminished in SHR. In addition, α2δ-1 C terminus peptide diminished inward rectification of AMPAR-EPSCs and the inhibitory effect of IEM-1460 on AMPAR-EPSCs of PVN neurons in SHR. Thus, α2δ-1 augments synaptic CP-AMPARs by inhibiting GluA1/GluA2 heteromeric assembly in the hypothalamus in hypertension. These findings extend our understanding of the molecular basis of sustained sympathetic outflow in neurogenic hypertension.

11.
Traffic ; 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-34994051

RESUMO

The extremely dynamic life cycle of gap junction connections requires highly efficient intracellular trafficking system especially designed for gap junction proteins, but the underlying mechanisms are largely unknown. Here, we identified that the COPII-associated proteins ERGIC2 (ER-Golgi intermediate compartment) and ERGIC3 are specifically required for the efficient intracellular transport of gap junction proteins in both C. elegans and mice. In the absence of Ergic2 or Ergic3, gap junction proteins accumulate in the ER and Golgi apparatus and the size of endogenous gap junction plaques is reduced. Knocking out the Ergic2 or Ergic3 in mice results in heart enlargement and cardiac malfunction accompanied by reduced number and size of connexin 43 (Cx43) gap junctions. Invertebrates' gap junction protein innexins share no sequence similarity with vertebrates' connexins. However, ERGIC2 and ERGIC3 could bind to gap junction proteins in both worms and mice. Characterization of the highly specialized roles of ERGIC2 and ERGIC3 in metazoans reveals how the early secretory pathway could be adapted to facilitate the efficient transport for gap junction proteins in vivo. This article is protected by copyright. All rights reserved.

12.
Food Res Int ; 151: 110847, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34980385

RESUMO

Photodynamic inactivation (PDI) is an effective alternative to traditional antibiotics to broadly kill bacteria. This study aimed to develop a potent PDI system by coupling calcinated melamine sponges (CMSs) with the Fenton reaction. The results showed that CMS calcined at 350 ℃ was successfully carbonized with intact and porous structures, and it possessed excellent hydrophilicity and photothermal conversion performance. When Fe2+ was added and internalized, the Fenton reaction in which Fe2+ reacted with H2O2 in cells occurred to produce reactive oxygen species (ROS) (OH, OOH, etc.) and O2, and notably, the O2 molecules could serve as a raw material to absorb the photothermal energy of CMS to generate highly reactive 1O2. Under synergistic effects, CMS-350 coupled with Fe2+ potently inactivated > 6 Log CFU/mL (>99.9999%) of Salmonella under 201.6 J/cm2 blue LED illumination by destroying Na+/K+-ATPase and Ca2+/Mg2+-ATPase, DNA synthesis-related enzymes, cell membranes, etc. Meanwhile, the composite photocatalyst was proven to be nontoxic and could inactivate Salmonella in various foods, including vegetables (Brassica chinensis L), eggs and fresh cucumber juice. As a result, CMS coupled with the Fenton reaction greatly improves the inactivation potency of PDI against harmful bacteria.

13.
Food Chem ; 379: 132159, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35063848

RESUMO

New polyphenol-protein conjugates were successfully prepared by covalently crosslinking soluble Antarctic krill proteins with rutin (SAKPs-rutin). The physico-chemical and functional properties of SAKPs-rutin conjugates were systematically evaluated by measuring the changes in interfacial tension, structural conformation, and emulsifying ability, etc. The results showed that SAKPs-rutin conjugates possessed higher surface hydrophobicity, surface charge, and thermal denaturation temperature, and lower ß-sheet conformation compared to native SAKPs. On this basis, the interfacial tension of SAKPs-rutin conjugates was reduced, which greatly contributed to the formation of denser and more ordered networks at the oil-water interface. Meanwhile, the emulsifier endowed the fabricated high internal phase emulsions (HIPEs) with excellent physical performance and oxidative stability, evidenced by low peroxide values (POV) and malondialdehyde (MDA) after the treatment of long-term storage (15d), heating (65 °C) and UV light treatment. These findings suggest that SAKPs-rutin conjugates are a novel and promising food resource for preparing food-grade emulsions.

14.
Eur J Med Chem ; 229: 114081, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34992039

RESUMO

Targeted protein degradation using small molecules is an intriguing strategy for drug development. The marine sesterterpene compound MHO7 had been reported to be a potential ERα degradation agent. In order to further improve its biological activity, two series of novel MHO7 derivatives with long side chains were designed and identified as novel selective estrogen receptor down-regulators (SERDs). The growth inhibition activity of the novel SERD compounds were significantly affected by the type and length of the side chain. Most of the derivatives were significantly more potent than MHO7 against both drug-sensitive and drug-resistant breast cancer cells. Among them, compound 16a, with IC50 values of 0.41 µM against MCF-7 cell lines and 9.6-fold stronger than MHO7, was the most potential molecule. A whole-genome transcriptomic analysis of MCF-7 cells revealed that the mechanism of 16a against MCF-7 cell was similar with that of MHO7. The estrogen signaling pathway was the most affected among the disturbed genes, but the ERα degradation activity of 16a was observed higher than that of MHO7. Other effects of 16a were confirmed similar with MHO7, which means that the basic mechanisms of the derivatives are the same with the ophiobolin backbone, i.e. the degradation of ERα is mediated via proteasome-mediated process, the induction of apoptosis and the cell cycle arrest at the G1 phase. Meanwhile, a decrease of mitochondrial membrane potential and an increase of cellular ROS were also detected. Based on these results, as a novel modified ophiobolin derived compound, 16a may warrant further exploitation as a promising SERD candidate agent for the treatment of breast cancer.

15.
Comp Biochem Physiol B Biochem Mol Biol ; 259: 110715, 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-34999220

RESUMO

Fatty acid-binding protein (Fabp)-4 is a member of the FABP family. Mammalian fabp4 has been demonstrated to involve in inflammation and immunity, whereas the related data of fish fabp4 remain limited. Therefore, we further investigated the effects of fabp4 on immunity in Ctenopharyngodon idella. The fabp4 sequence spanned 405 bp was cloned first, sharing high identity to fabp4 from other fish and mammals. Fabp4 expression was the highest in the adipose tissue, followed by the heart, muscle, and liver. In vivo, lipopolysaccharide (LPS) triggered the expression of fabp4, toll-like receptor (tlr)-22, interleukin (il)-1ß, and tumor necrosis factor (tnf)-α in the kidney and spleen. In vitro, exposing C. idella CIK cells to LPS decreased their viability, and the expression of fabp4 was also increased by LPS. However, BMS309403, an inhibitor of FABP4, mitigated these effects. Furthermore, treating the cells with LPS or fabp4 overexpression plasmids resulted in reactive oxygen species (ROS) generation and upregulation of inflammatory genes expression, including tlr22, type-I interferon (ifn-1), interferon regulatory factor (irf)-7, tnfα, il-1ß, and interferon-ß promoter stimulator 1. These effects were ameliorated by preincubation with BMS309403. Moreover, incubating the cells with glutathione reduced the production of ROS and the expression of inflammatory genes that were evoked by LPS and plasmid treatments. These results showed that fabp4 acts as a pro-inflammatory molecule via elevating ROS levels, providing a novel understanding of the molecular regulation of innate immunity in teleosts.

16.
J Ethnopharmacol ; 288: 114973, 2022 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-34990768

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Shenlian extract (SL), extracted from Salvia miltiorrhiza Bunge and Andrographis paniculata (Burm. f.) Nees, has been proved to be effective in the prevention and treatment of atherosclerosis. Recently, we have partially elucidated the mechanisms involved in the therapeutic effects of SL on myocardial ischemia (MI). However, the underlying mechanisms remain largely unclear. AIM OF THE STUDY: This study aims to explore the potential molecular mechanism of SL on MI on the basis of network pharmacology. MATERIALS AND METHODS: First, the main active ingredients of SL were screened in the Traditional Chinese Medicine Integrated Database, and the MI-associated targets were collected from the DisGeNET database. Then, we used compound-target and target-pathway networks to uncover the therapeutic mechanisms of SL. On the basis of network pharmacology analysis results, we assessed the effects of SL in MI rat model and oxygen glucose deprivation model of H9c2 cells and validated the possible molecular mechanisms of SL on myocardial injury in vivo and in vitro. RESULTS: The network pharmacology results showed that 37 potential targets were recognized, including TNF-α, Bcl-2, STAT3, PI3K and MMP2. These results revealed that the possible targets of SL were involved in the regulation of inflammation and apoptosis signaling pathway. Then, in vivo experiments indicated that SL significantly reduced the myocardial infarction size of MI rats. Serum CK-MB, cTnT, CK, LDH, and AST levels were significantly decreased by SL (P < 0.05 or P < 0.01). In vitro, SL significantly increased H9c2 cell viability. The levels of inflammation factors including TNF-α and MMP2 were significantly decreased by SL (P < 0.05 or P < 0.01). TUNEL and Annexin V/propidium iodide assays indicated that SL could significantly decrease the cell apoptotic rate in vivo and in vitro (P < 0.05 or P < 0.01). The remarkable upregulation of anti-apoptotic Bcl-2 and downregulation of pro-apoptotic Bax protein level further confirmed this result. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the PI3K-AKT and JAK2-STAT3 pathways were significantly enriched in SL. Compared with the model group, SL treatment significantly activated the PI3K-AKT and JAK2-STAT3 pathways in vivo and in vitro according to Western blot analyses. CONCLUSION: SL could protect the myocardium from MI injury. The underlying mechanism may be related to the reduction of inflammation and apoptosis by activating the PI3K/AKT and JAK2/STAT3 pathways.

17.
Acta Trop ; 228: 106307, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35016884

RESUMO

BACKGROUND: To explore the efficacy of microwave ablation (MWA) in the treatment of hepatic alveolar echinococcosis (HAE) with a diameter of ≤5 cm. METHOD: From June 2014 to January 2020, patients diagnosed with HAE were retrospectively analyzed. After balancing the confounding factors by propensity score matching (PSM) , the patients were divided into MWA group (n = 20) and radical operation group (n = 20) by 1:1 matching. The safety and effectiveness of MWA were assessed by comparing the differences between the two groups in terms of postoperative general laboratory indices, grading of postoperative complications, length of postoperative hospitalization, the outcome of treatment, and disease recurrence. RESULT: After PSM, all confounders were not statistically different (P>0.05) . Compared with the radical surgery group, patients in the MWA group had lower postoperative ALT and WBC elevations (P<0.001) , shorter postoperative hospital stay (P<0.001) ) , lower hospital costs (P<0.001) . The effective rate of the two groups was 100%. There was no statistical difference in the incidence of postoperative complications and recurrence rate (P>0.05). CONCLUSION: MWA is a safe and effective means of treating HAE ≤ 5 cm in diameter.

18.
Cell Mol Life Sci ; 79(1): 64, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35013841

RESUMO

Nicotinic acetylcholine receptors (nAChRs) are widespread throughout the central nervous system. Signaling through nAChRs contributes to numerous higher-order functions, including memory and cognition, as well as abnormalities such as nicotine addiction and neurodegenerative disorders. Although recent studies indicate that the PDZ-containing proteins comprising PSD-95 family co-localize with nicotinic acetylcholine receptors and mediate downstream signaling in the neurons, the mechanisms by which α7nAChRs are regulated remain unclear. Here, we show that the PDZ-LIM domain family protein PDLIM5 binds to α7nAChRs and plays a role in nicotine-induced α7nAChRs upregulation and surface expression. We find that chronic exposure to 1 µM nicotine upregulated α7, ß2-contained nAChRs and PDLIM5 in cultured hippocampal neurons, and the upregulation of α7nAChRs and PDLIM5 is increased more on the cell membrane than the cytoplasm. Interestingly, in primary hippocampal neurons, α7nAChRs and ß2nAChRs display distinct patterns of expression, with α7nAChRs colocalized more with PDLIM5. Furthermore, PDLIM5 interacts with α7nAChRs, but not ß2nAChRs in native brain neurons. Knocking down of PDLIM5 in SH-SY5Y abolishes nicotine-induced upregulation of α7nAChRs. In primary hippocampal neurons, using shRNA against PDLIM5 decreased both surface clustering of α7nAChRs and α7nAChRs-mediated currents. Proteomics analysis and isothermal titration calorimetry (ITC) results show that PDLIM5 interacts with α7nAChRs through the PDZ domain, and the interaction between PDLIM5 and α7nAChRs can be promoted by nicotine. Collectively, our data suggest a novel cellular role of PDLIM5 in the regulation of α7nAChRs, which may be relevant to plastic changes in the nervous system.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Hipocampo/metabolismo , Proteínas com Domínio LIM/metabolismo , Nicotina/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Comportamento Aditivo/fisiopatologia , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Células HEK293 , Hipocampo/citologia , Humanos , Proteínas com Domínio LIM/genética , Neurônios/metabolismo , Domínios Proteicos/fisiologia , Interferência de RNA , RNA Interferente Pequeno/genética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Fumar , Regulação para Cima , Receptor Nicotínico de Acetilcolina alfa7/biossíntese
19.
J Hazard Mater ; 425: 127997, 2022 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-34986566

RESUMO

Microplastic (MP) release from household plastic products has become a global concern due to the high recorded levels of microplastic and the direct risk of human exposure. However, the most widely used MP measurement protocol, which involves the use of deionized (DI) water, fails to account for the ions and particles present in real drinking water. In this paper, the influence of typical ions (Ca2+/HCO3-, Fe3+, Cu2+) and particles (Fe2O3 particles) on MP release was systematically investigated by conducting a 100-day study using plastic kettles. Surprisingly, after 40 days, all ions resulted in a greater than 89.0% reduction in MP release while Fe2O3 particles showed no significant effect compared to the DI water control. The MP reduction efficiency ranking is Fe3+ ≈ Cu2+ > Ca2+/HCO3- > > Fe2O3 particles ≈ DI water. Physical and chemical characterization using SEM-EDX, AFM, XPS and Raman spectroscopy confirmed Ca2+/HCO3-, Cu2+ and Fe3+ ions are transformed into passivating films of CaCO3, CuO, and Fe2O3, respectively, which are barriers to MP release. In contrast, there was no film formed when the plastic was exposed to Fe2O3 particles. Studies also confirmed that films with different chemical compositions form naturally in kettles during real life due to the different ions present in local regional water supplies. All films identified in this study can substantially reduce the levels of MP release while withstanding the repeated adverse conditions associated with daily use. This study underscores the potential for regional variations in human MP exposure due to the substantial impact water constituents have on the formation of passivating film formation and the subsequent release of MPs.

20.
Drug Test Anal ; 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35060358

RESUMO

Dried blood spots (DBS) provide a valuable complementary sample matrix for routine doping analysis, and the full automation of analysis for DBS samples is achievable to avoid extensive and repetitive manual laboratory work. In the current study, a fully automated online DBS preparation and detection method for the screening and quantification analysis of 13 anabolic steroid esters by means of the DBSA-TLX-HRMS system was developed and validated, based on the purpose for the determination of endogenous anabolic steroids administered exogenously. Validation of the method yielded linear (R2 > 0.99), precise and accurate (RSD% and Re% < 20% at low, medium, high concentration levels) results. The LOD of testosterone laurate was established at 0.5 ng/mL, and at 0.2 ng/mL for other steroid esters. The extraction recovery of the target compounds from DBS ranged from 10.5% to 88.9%, and matrix effects were moderate. Furthermore, the developed and validated method was applied in the analysis of DBS samples collected after the oral administration of a single dose of 80mg testosterone undecanoate demonstrating its applicability. Evaluation of analyte stability showed that testosterone undecanoate are more stable (8 weeks) in DBS samples of administration study when stored in frozen (-20°C) condition compared to cold storage (4°C). Collectively, these findings demonstrate the applicability of DBS sampling in doping control for detection of anabolic steroid esters.

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