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MT-1207 (MT) as a new antihypertensive drug is under clinical trial. However, its hypotensive mechanism has not been experimentally explored, and it is unknown whether MT can be used for bilateral renal artery stenosis hypertension. Using two-kidney two-clip (2K2C) to mimic bilateral renal artery stenosis in rats, a stroke-prone renovascular hypertension model, the present study further verified its antihypertensive effect, cardiovascular and renal protection, mortality reduction and lifespan prolongation, as well as demonstrated its two novel pharmacological effects for uric acid-lowering and cognition-improving. Notably, MT did not aggravate renal dysfunction; instead, it had beneficial effects on reducing serum uric acid level and maintaining serum K+ at a relatively stable level in 2K2C rats. In contrast, angiotensin receptor blocker losartan aggravated renal dysfunction in 2K2C rats. Mechanistically, MT hypotensive effect was dependent on its blockade of α1 and 5-HT2 receptors, since MT pretreatment abolished these receptor agonists-induced blood pressure elevations in vivo. Further evidence showed MT bound to and interacted with these receptor subtypes including α1A, α1B, α1D, 5-HT2A, 5-HT2B, and 5-HT2C receptors known for control of blood pressure. In conclusion, MT may be used for treatment of bilateral renal artery stenosis hypertension, different from losartan that is prohibited for treatment of bilateral renal artery stenosis hypertension. Targets validation of MT hypotensive mechanism and beneficial effects of MT on uric acid and cognitive function provide new insights for this novel multitarget drug, deserving clinical trial attention.
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OBJECTIVE: Hepatolenticular degeneration (HLD) is an autosomal recessive disorder that manifests as multiorgan damage due to impaired copper (Cu) metabolism. Female patients with HLD often experience reproductive impairments. This study investigated the protective effect of berberine against ovarian damage in toxic-milk (TX) mice, a murine model for HLD. METHODS: Mice were categorized into control group, HLD TX group (HLD group), penicillamine (Cu chelator)-treated TX group and berberine-treated TX group. Body weight, ovary weight and the number of ovulated eggs were recorded. Follicular morphology and cellular ultrastructure were examined. Total iron, ferrous iron (Fe2+) and trivalent iron (Fe3+) levels, as well as malondialdehyde (MDA), glutathione (GSH) and oxidized glutathione (GSSG), were measured in the ovaries. Western blot analysis was used to analyze the expression of proteins related to ferroptosis and endoplasmic reticulum (ER) stress. RESULTS: Ovarian tissue damage was evident in the HLD group, with a significant increase in ferroptosis and ER stress compared to the control group. This damage was inhibited by treatment with penicillamine, a Cu chelator. Compared with the HLD group, berberine increased the number of ovulations, and improved ovarian morphology and ultrastructure. Further, we found that berberine reduced total iron, Fe2+, MDA and GSSG levels, elevated GSH levels, decreased the expression of the ferroptosis marker protein prostaglandin-endoperoxide synthase 2 (PTGS2), and increased glutathione peroxidase 4 (GPX4) expression. Furthermore, berberine inhibited the expression of ER stress-associated proteins mediated by the protein kinase RNA-like ER kinase (PERK) pathway. CONCLUSION: Ferroptosis and ER stress are involved in Cu-induced ovarian damage in TX mice. Berberine ameliorates ovarian damage in HLD TX mice by inhibiting ferroptosis and ER stress. Please cite this article as: Liu QZ, Han H, Fang XR, Wang LY, Zhao D, Yin MZ, Zhang N, Jiang PY, Ji ZH, Wu LM. Berberine alleviates ovarian tissue damage in mice with hepatolenticular degeneration by suppressing ferroptosis and endoplasmic reticulum stress. J Integr Med. 2024; 22(4): 494-503.
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Berberina , Estresse do Retículo Endoplasmático , Ferroptose , Degeneração Hepatolenticular , Ovário , Animais , Feminino , Ferroptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Camundongos , Berberina/farmacologia , Ovário/efeitos dos fármacos , Ovário/metabolismo , Degeneração Hepatolenticular/tratamento farmacológico , Degeneração Hepatolenticular/metabolismo , Degeneração Hepatolenticular/genética , Modelos Animais de Doenças , Cobre , Glutationa/metabolismo , Ferro/metabolismo , Malondialdeído/metabolismoRESUMO
This study aims to investigate whether tetramethylpyrazine(TMP) can stimulate angiogenesis in cerebral microvascular endothelial cells and alleviate cerebral ischemic stroke(CIS) and to explore the underlying mechanisms. In the animal study, adult Sprague-Dawley rats(n=15) were assigned into sham surgery(sham), middle cerebral artery occlusion/reperfusion(MCAO/R), and MCAO/R+TMP(intraperitoneal injection of 20 mg·kg~(-1)) groups. The neurological function was evaluated by the Z-Longa method. The cerebral infarction volume was detected by TTC staining. Enzyme-linked immunosorbent assay(ELISA) was employed to detect the expression of vascular endothelial growth factor(VEGF), angiopoietin(Ang), and platelet-derived growth factor(PDGF). Immunofluorescence staining was employed to detect Ki67 and the expression of vascular endothelial growth factor A(VEGFA) and slient information regulator 1(SIRT1). Western blot was employed to determine the expression levels of VEGFA, SIRT1, angiopoietin-2(Ang-2), and platelet-derived growth factor B(PDGFB). In the cell study, mouse brain-derived endothelial cells(Bend.3) were cultured, and the optimal concentration of TMP was determined. Then, VEGF, Ang, and PDGF were detected by ELISA after the addition of cabozantinib. Western blot was employed to measure the expression of VEGFA, Ang-2, and PDGFB. Immunofluorescence staining was used to detect CD31, CD34, and Ki67, and the proliferation, migration, and tube formation ability of Bend.3 cells were observed in vitro. Western blot and immunofluorescence staining were performed to measure the expression of SIRT1 and VEGFA after addition of the SIRT1-specific inhibitor selisistat(EX-527). The results showed that compared with the sham group, the MCAO/R group had severe neurological function damage, increased infarction volume, up-regulated expression of VEGF, VEGFA, Ang, Ang-2, PDGF, and PDGFB, and down-regulated expression of Ki67 and SIRT1(P<0.01). Compared with the MCAO/R group, the MCAO/R+TMP group presented alleviated neurological function damage, reduced infarction volume, and activated expression of VEGF, VEGFA, Ang, Ang-2, PDGF, PDGFB, Ki67, and SIRT1(P<0.01). The cell experiments showed that compared with the normal group, Bend.3 cells were activated by oxygen glucose deprivation/reoxygenation(OGD/R) treatment(P<0.05, P<0.01). Compared with the OGD/R group, the OGD/R+TMP group upregulated the expression levels of VEGF, VEGFA, Ang, Ang-2, PDGF, PDGFB, SIRT1, Ki67, CD31, and CD34, enhanced the angiogenic ability of Bend.3 cells without being inhibited by BMS or EX-527(P<0.05, P<0.01, P<0.001). The results suggest that TMP can activate the SIRT1/VEGFA signaling pathway to stimulate angiogenesis and alleviate CIS injury.
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Isquemia Encefálica , AVC Isquêmico , Pirazinas , Acidente Vascular Cerebral , Ratos , Animais , Camundongos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Células Endoteliais/metabolismo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Ratos Sprague-Dawley , Proteínas Proto-Oncogênicas c-sis , Sirtuína 1/genética , Sirtuína 1/metabolismo , Angiogênese , Antígeno Ki-67/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/genética , Transdução de Sinais , Infarto da Artéria Cerebral MédiaRESUMO
Metrnl is a secreted protein involved in neurite outgrowth, insulin sensitivity, immunoinflammatory responses, blood lipids and endothelial protection. In this study, we investigated the role of Metrnl in ischemic stroke. Fifty-eight ischemic stroke patients (28 inpatient patients within 2 weeks of onset and 30 emergency patients within 24 h of onset) and 20 healthy controls were enrolled. Serum Metrnl was measured by enzyme-linked immunosorbent assay. We showed that serum Metrnl levels were significantly reduced in both inpatient and emergency patient groups compared with the controls. Different pathological causes for ischemic stroke such as large artery atherosclerosis and small artery occlusion exhibited similar reduced serum Metrnl levels. Transient ischemic attack caused by large artery atherosclerosis without brain infarction also had lower serum Metrnl levels. Metrnl was correlated with some metabolic, inflammatory and clotting parameters. Reduced serum Metrnl was associated with the severity of intracranial arterial stenosis and the presence of ischemic stroke. In order to elucidate the mechanisms underlying the reduced serum Metrnl levels, we established animal models of ischemic stroke in normal mice, atherosclerotic apolipoprotein E-knockout mice and Metrnl-knockout mice by middle cerebral artery occlusion (MCAO) using intraluminal filament or electrocoagulation. We demonstrated that serum Metrnl levels were significantly lower in atherosclerosis mice than normal mice, whereas acute ischemic stroke injury in normal mice and atherosclerosis mice did not alter serum Metrnl levels. Metrnl knockout did not affect acute ischemic stroke injury and death. We conclude that reduced serum Metrnl levels are attributed to the chronic vascular pathogenesis before the onset of ischemic stroke. Metrnl is a potential target for prevention of ischemic stroke.
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Adipocinas , AVC Isquêmico , Humanos , Animais , Masculino , AVC Isquêmico/sangue , AVC Isquêmico/genética , Feminino , Pessoa de Meia-Idade , Idoso , Camundongos Endogâmicos C57BL , Camundongos , Infarto da Artéria Cerebral Média/sangue , Camundongos Knockout para ApoERESUMO
The use of biologics in various diseases has dramatically increased in recent years. Stroke, a cerebrovascular disease, is the second most common cause of death, and the leading cause of disability with high morbidity worldwide. For biologics applied in the treatment of acute ischaemic stroke, alteplase is the only thrombolytic agent. Meanwhile, current clinical trials show that two recombinant proteins, tenecteplase and non-immunogenic staphylokinase, are most promising as new thrombolytic agents for acute ischaemic stroke therapy. In addition, stem cell-based therapy, which uses stem cells or organoids for stroke treatment, has shown promising results in preclinical and early clinical studies. These strategies for acute ischaemic stroke mainly rely on the unique properties of undifferentiated cells to facilitate tissue repair and regeneration. However, there is a still considerable journey ahead before these approaches become routine clinical use. This includes optimising cell delivery methods, determining the ideal cell type and dosage, and addressing long-term safety concerns. This review introduces the current or promising recombinant proteins for thrombolysis therapy in ischaemic stroke and highlights the promise and challenges of stem cells and cerebral organoids in stroke therapy.
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Meteorin-like (Metrnl) is a novel secreted protein with various biological activities. In this study, we investigated whether and how Metrnl regulated skin wound healing in mice. Global Metrnl gene knockout mice (Metrnl-/-) and endothelial cell-specific Metrnl gene knockout mice (EC-Metrnl-/-) were generated. Eight-mm-diameter full-thickness excisional wound was made on the dorsum of each mouse. The skin wounds were photographed and analyzed. In C57BL/6 mice, we observed that Metrnl expression levels were markedly increased in skin wound tissues. We found that both global and endothelial cell-specific Metrnl gene knockout significantly retarded mouse skin wound healing, and endothelial Metrnl was the key factor affecting wound healing and angiogenesis. The proliferation, migration and tube formation ability of primary human umbilical vein endothelial cells (HUVECs) were inhibited by Metrnl knockdown, but significantly promoted by addition of recombinant Metrnl (10 ng/mL). Metrnl knockdown abolished the proliferation of endothelial cells stimulated by recombinant VEGFA (10 ng/mL) but not by recombinant bFGF (10 ng/mL). We further revealed that Metrnl deficiency impaired VEGFA downstream AKT/eNOS activation in vitro and in vivo. The damaged angiogenetic activity in Metrnl knockdown HUVECs was partly rescued by addition of AKT activator SC79 (10 µM). In conclusion, Metrnl deficiency retards skin wound healing in mice, which is related to impaired endothelial Metrnl-mediated angiogenesis. Metrnl deficiency impairs angiogenesis by inhibiting AKT/eNOS signaling pathway.
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Neovascularização Fisiológica , Proteínas Proto-Oncogênicas c-akt , Animais , Humanos , Camundongos , Movimento Celular , Proliferação de Células , Células Endoteliais da Veia Umbilical Humana/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , CicatrizaçãoRESUMO
Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis. Thus far, hepatic Nampt has not been extensively explored in terms of its effects on serum lipid stability and liver lipids metabolism. In this study, hepatocyte-specific Nampt knockout (HC-Nampt-/-) mice were generated by Cre/loxP system. Nampt mRNA expression was reduced in the liver, but not in other tissues, in HC-Nampt-/- mice compared with wild-type (WT) mice. Hepatic Nampt deficiency had no effect on body weight and fasting blood glucose, and it did not induce atherosclerosis in mice under both normal chow diet (NCD) and high fat diet (HFD). At baseline state under NCD, hepatic Nampt deficiency also did not affect liver weight, liver function index, including alanine aminotransferase, aspartate aminotransferase, albumin and alkaline phosphatase, and serum levels of lipids, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and non-esterified fatty acids (NEFA). However, under HFD, deficiency of hepatic Nampt resulted in increased liver weight, liver function index, and serum levels of TG, TC, HDL-C, and NEFA. Meanwhile, histopathological examination showed increased fat accumulation and fibrosis in the liver of HC-Nampt-/- mice compared with WT mice. Taken together, our results show that hepatic Nampt deficiency aggravates dyslipidemia and liver damage in HFD fed mice. Hepatocyte Nampt can be a protective target against dyslipidemia and fatty liver.
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Dislipidemias , Fígado Gorduroso , Doenças não Transmissíveis , Camundongos , Animais , Dieta Hiperlipídica , Nicotinamida Fosforribosiltransferase/metabolismo , Ácidos Graxos não Esterificados , Fígado Gorduroso/metabolismo , Triglicerídeos/metabolismo , HDL-ColesterolRESUMO
This study aims to investigate the effect of Astragali Radix-Curcumae Rhizoma(AC) combination on the proliferation, migration, and invasion of colon cancer HT-29 cells based on epithelial-mesenchymal transition(EMT). HT-29 cells were respectively treated with 0, 3, 6 and 12 g·kg~(-1) AC-containing serum for 48 h. The survival and growth of cells were measured by thiazole blue(MTT) colorimetry, and the proliferation, migration, and invasion of cells were detected by 5-ethynyl-2'-deoxyuridine(EdU) test and Transwell assay. Cell apoptosis was examined by flow cytometry. The BALB/c nude mouse model of subcutaneous colon cancer xenograft was established, and then model mice were classified into blank control group, 6 g·kg~(-1) AC group, and 12 g·kg~(-1) AC group. The tumor weight and volume of mice were recorded, and the histopathological morphology of the tumor was observed based on hematoxylin-eosin(HE) staining. The expression of apoptosis-associated proteins B-cell lymphoma-2-associated X protein(Bax), cysteine-aspartic acid protease-3(caspase-3), and cleaved caspase-3, and EMT-associated proteins E-cadherin, MMP9, MMP2 and vimentin in HT-29 cells and mouse tumor tissues after the treatment of AC was determined by Western blot. The results showed that cell survival rate and the number of cells at proliferation stage decreased compared with those in the blank control group. The number of migrating and invading cells reduced and the number of apoptotic cells increased in the administration groups compared with those in the blank control group. As for the in vivo experiment, compared with the blank control group, the administration groups had small tumors with low mass and shrinkage of cells and karyopycnosis in the tumor tissue, indicating that the AC combination may improve EMT. In addition, the expression of Bcl2 and E-cadherin increased and the expression of Bax, caspase-3, cleaved caspase-3, MMP9, MMP2, and vimentin decreased in HT-29 cells and tumor tissues in each administration group. In summary, the AC combination can significantly inhibit the proliferation, invasion, migration, and EMT of HT-29 cells in vivo and in vitro and promote the apoptosis of colon cancer cells.
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Humanos , Animais , Camundongos , Caspase 3 , Metaloproteinase 2 da Matriz , Metaloproteinase 9 da Matriz , Vimentina , Células HT29 , Proteína X Associada a bcl-2 , Neoplasias do Colo , Proliferação de CélulasRESUMO
In this study, H2O2 was introduced into thermally activated persulfate oxidation system (T-HPS), and the oxidation of pyrene (PYR) was investigated by the combined T-HPS technology. The results showed that H2O2 could significantly improve the reactivity of the thermally activated persulfate system (T-PS), with 240-min PYR degradation ratio increasing from 79.3% to 97.2% at 70 °C. In the T-HPS system, as persulfate initial concentration increased from 5 to 100 µM, the kinetic rate constant (kobs) of PYR degradation increased from 4.70 × 10-3 to 3.01 × 10-2 min-1, but the kobs did not show a positive association with H2O2 concentration with the same range, and the highest kobs was obtained at the H2O2 initial concentration of 20 µM. The optimal ratio of PS and H2O2 was set at 1:1 with the initial concentrations of the two oxidants both being 20 µM. Furthermore, PYR could be removed efficiently in a wide range of pH, and the best PYR degradation performance was obtained under neutral pH. Scavenging experiments demonstrated that OH played a more important role in PYR degradation in the T-HPS system than in the T-PS system. As suggested by the Arrhenius equation, the activation energy decreased from 124.5 to 107.4 kJ mol-1 after adding H2O2 to the T-PS system. This study provides a new oxidation approach that could prompt the T-PS activity by adding a suitable dosage of H2O2.
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Peróxido de Hidrogênio , Poluentes Químicos da Água , Oxidantes , Oxirredução , Pirenos , Sulfatos , Poluentes Químicos da Água/análiseRESUMO
OBJECTIVE@#To investigate the potential inhibitory effect of interference with PD-L1 on B cell lymphoma in mice.@*METHODS@#Three shRNA vectors for mouse CD274 (PD-L1) were constructed and transiently transfected into 293T cells. RT-qPCR was used to validate the interference efficiency of CD274. The shRNA vector that interfere efficiently with CD274 expression was packaged by using lentivirus packaging system to generate shRNA lentivirus, and then transfected into A20 lymphoma cell line. The methyl thiazol terazolium (MTT) assay was used to detect proliferation after 48 h culture of CD274-sh A20 cells. Meanwhile, BALB/c mice were hypodermically infected with CD274-sh A20 cells. Infected mice were observed daily and assessed to visualize tumor by in vivo fluorescence imaging.@*RESULTS@#The proliferation rate of CD274-sh A20 cells in vitro was significantly lower than that of A20 cells (P<0.05). The tumor size detected by in vivo fluorescence imaging showed a significant reduce in tumor bearing mice with CD274-sh compared with other tumor bearing mice. And the weight and size of tumor in CD274-sh group were also significantly reduced compared with other group (P<0.05). Moreover, the survival time of tumor bearing mice in CD274-sh group was longer than that of the PD-L1 high expression group.@*CONCLUSION@#PD-L1 plays an important role in the incidence and the progression of lymphoma, and the shRNA-based PD-L1 knockdown can inhibit cell proliferation of A20 cells and partly suppress tumor growth.
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Animais , Humanos , Camundongos , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Linfoma , Linfoma de Células B , Camundongos Endogâmicos BALB C , RNA Interferente Pequeno/genéticaRESUMO
Objective: To explore the quality of life and its influencing factors of enhanced recovery after surgery (ERAS) of esophageal cancer patients. Methods: The quality of life of 134 esophageal cancer patients was assessed using the quality of life assessment scale (EORTC QLQ-C30) developed by the European Cancer Research and Treatment Organization. Student's t test, One-way ANOVA and multiple linear regression statistical methods were used to analyze the effects of sociodemographic and clinical characteristics on patients' quality of life. Results: The overall score of quality of life (74.00) was lower than that of the general population (75.30). However, the scores of emotion and cognition in function dimension (93.97 and 95.77) were better than those of the general population (82.80 and 86.50). The results of fatigue, pain, insomnia and constipation in symptom dimension (14.18, 10.94, 11.69 and 5.72) were better than those of the general population (28.80, 20.50, 20.40 and 10.70). The pathological stage, body mass index and dietary were independent influencing factors for the quality of life of patients with esophageal cancer (P<0.05). Conclusions: ERAS can partially improve the quality of life of esophageal cancer patients. More attention should be paid to the esophageal cancer patients after surgery and take targeted measures to improve their quality of life.
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Humanos , Neoplasias Esofágicas/cirurgia , Fadiga , Qualidade de Vida , Inquéritos e QuestionáriosRESUMO
ObjectiveTo study the inhibitory effect of Celastrus orbiculatus extract (COE) on gastric cancer cells, to clarify the specific mechanism of COE promoting the apoptosis of gastric cancer cells by affecting the mitochondrial structure and function, and to provide an experimental basis for the further development and clinical application of C. orbiculatus. MethodBrdu staining combined with flow cytometry and Annexin V-fluorescein isothiocyanate (AnnexinV-FITC) staining combined with flow cytometry were employed to detect the effects of COE (20, 40, 80 mg·L-1) on the proliferation and apoptosis of gastric cancer cells, respectively. The changes in mitochondrial membrane potential were detected with JC-1 mitochondrial membrane potential assay kit. The expression of apoptosis-associated proteins including B-cell lymphoma-2 (Bcl-2), B-cell lymphoma-xL (Bcl-xL), Bcl-2-associated X (Bax), and cysteine aspartutespecific protease-3 (Caspase-3) in gastric cancer cells was determined by Western blot. Transmission electron microscopy was employed to detect changes in the mitochondrial microstructure of gastric cancer cells exposed to COE. Western blot was employed to measure the expression of mitochondrial marker proteins [superoxide dismutase 1 (SOD1), voltage-dependent anion channel (VDAC), prohibitin 1 (PHB1), and heat shock protein 60 (HSP60)] in gastric cancer cells. ResultCompared with the control group, COE (40, 80 mg·L-1) inhibited the proliferation and promoted the apoptosis of gastric cancer cells (P<0.05). Furthermore, COE reduced the mitochondrial membrane potential of gastric cancer cells. Compared with the control group, COE (20, 40, 80 mg·L-1) up-regulated the expression of Bax and Caspase-3 which promoted apoptosis of gastric cells (P<0.05, P<0.01), and COE at 40 and 80 mg·L-1 down-regulated the expression of Bcl-2 and Bcl-xL which inhibited the apoptosis of gastric cancer cells (P<0.01). The results of transmission electron microscopy showed that COE changed the microstructure of gastric cancer cells, which led to the appearance of vacuoles in the cell membrane and mitochondria and damaged the mitochondrial structure. Compared with the control group, COE (20, 40, 80 mg·L-1) changed the expression of mitochondrial marker proteins. Specifically, it up-regulated the expression of SOD1 involved in stress response (P<0.05, P<0.01) and down-regulated that of VDAC, PHB1, and HSP60 associated with mitochondrial stability and permeability (P<0.01). ConclusionCOE can significantly inhibit the proliferation and promote the apoptosis of gastric cancer cells. It may activate the mitochondrial apoptosis pathway by destroying the mitochondrial structure and function of gastric cancer cells.
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ObjectiveTo study the inhibitory effect of Celastrus orbiculatus extract (COE) on gastric cancer cells, to clarify the specific mechanism of COE promoting the apoptosis of gastric cancer cells by affecting the mitochondrial structure and function, and to provide an experimental basis for the further development and clinical application of C. orbiculatus. MethodBrdu staining combined with flow cytometry and Annexin V-fluorescein isothiocyanate (AnnexinV-FITC) staining combined with flow cytometry were employed to detect the effects of COE (20, 40, 80 mg·L-1) on the proliferation and apoptosis of gastric cancer cells, respectively. The changes in mitochondrial membrane potential were detected with JC-1 mitochondrial membrane potential assay kit. The expression of apoptosis-associated proteins including B-cell lymphoma-2 (Bcl-2), B-cell lymphoma-xL (Bcl-xL), Bcl-2-associated X (Bax), and cysteine aspartutespecific protease-3 (Caspase-3) in gastric cancer cells was determined by Western blot. Transmission electron microscopy was employed to detect changes in the mitochondrial microstructure of gastric cancer cells exposed to COE. Western blot was employed to measure the expression of mitochondrial marker proteins [superoxide dismutase 1 (SOD1), voltage-dependent anion channel (VDAC), prohibitin 1 (PHB1), and heat shock protein 60 (HSP60)] in gastric cancer cells. ResultCompared with the control group, COE (40, 80 mg·L-1) inhibited the proliferation and promoted the apoptosis of gastric cancer cells (P<0.05). Furthermore, COE reduced the mitochondrial membrane potential of gastric cancer cells. Compared with the control group, COE (20, 40, 80 mg·L-1) up-regulated the expression of Bax and Caspase-3 which promoted apoptosis of gastric cells (P<0.05, P<0.01), and COE at 40 and 80 mg·L-1 down-regulated the expression of Bcl-2 and Bcl-xL which inhibited the apoptosis of gastric cancer cells (P<0.01). The results of transmission electron microscopy showed that COE changed the microstructure of gastric cancer cells, which led to the appearance of vacuoles in the cell membrane and mitochondria and damaged the mitochondrial structure. Compared with the control group, COE (20, 40, 80 mg·L-1) changed the expression of mitochondrial marker proteins. Specifically, it up-regulated the expression of SOD1 involved in stress response (P<0.05, P<0.01) and down-regulated that of VDAC, PHB1, and HSP60 associated with mitochondrial stability and permeability (P<0.01). ConclusionCOE can significantly inhibit the proliferation and promote the apoptosis of gastric cancer cells. It may activate the mitochondrial apoptosis pathway by destroying the mitochondrial structure and function of gastric cancer cells.
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ABSTRACT: The diagnosis and treatment of unexplained recurrent spontaneous abortion (URSA) is an important and hot topic in the field of obstetrics and gynecology. During our clinical investigation (observation), we have found that URSA patients usually experience recurrent vaginitis or vaginal dysbacteriosis during periods of non-pregnancy, pregnancy, and post-abortion. However, there is no research on vaginal dysbacteriosis's influence on URSA. Using women with normal induced abortion as a control group, and using 16S rRNA sequencing, which helps to screen differentially expressed flora, this study discusses the relevance between differential bacteria at the genus level and the incidence of URSA. Another aim of this study is to determine whether certain pathogenic genera can cause an imbalance in immune tolerance of the maternal and fetal interface through regulatory chemokines, which leads to recurrent spontaneous abortion. This article has explored URSA pathogenesis from the perspective of differentially expressed vaginal flora, which has great theoretical significance for the early diagnosis and treatment of URSA.
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Aborto Habitual/fisiopatologia , Quimiocinas/biossíntese , Microbiota/fisiologia , Vagina/citologia , Vagina/microbiologia , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , RNA Ribossômico 16SRESUMO
Metrnl, a secreted protein expressed in white adipose tissue, has been identified as a novel adipokine. It is also highly expressed in barrier tissues, including the skin, intestinal and respiratory tract epithelium in both mice and humans. Research shows that its expression is upregulated by inflammation, chronic high-fat diets, exercise, cold exposure, etc., and it plays important roles in promoting neurite extension, enhancing white fat browning, improving insulin sensitivity, modulating lipid metabolism and regulating inflammatory response, the latter implying Metrnl is a new cytokine. These studies suggest that Metrnl could be a promising biomarker and a potential therapeutic target for the related diseases. For proving this, clinical studies need to be performed to bridge the gap between bench and bedside. In this paper, we summarize the progress in recent clinical research on Metrnl. Most of these clinical studies are designed to confirm the relationship between circulating Metrnl and metabolic or cardiovascular disease (type 2 diabetes and coronary heart disease), or immune inflammation-related diseases, such as colitis, psoriasis and arthritis. Although blood Metrnl seems to fluctuate and are affected by many factors, such as drugs, physical exercise, and cold exposure, these clinical studies provide reliable clues that Metrnl is associated with coronary heart disease, inflammation-related diseases, etc. Nevertheless, the roles of Metrnl in some diseases such as nervous system diseases remain unclear, and its putative involvement should be further clarified. These studies could promote the application of Metrnl in clinic as a new therapeutic target.
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Adipocinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Inflamação/metabolismo , Doenças Vasculares/metabolismo , Animais , Humanos , Transdução de Sinais/fisiologiaRESUMO
The effect of rotation of the stagnation surface on the nanoparticle deposition in the flame stabilizing on a rotating surface (FSRS) configuration was numerically assessed using CFD method. The deposition properties including particle trajectories, deposition time, temperature and surrounding O2 concentration between the flame and stagnation surface were examined. The results revealed that although flame position is insensitive to the surface rotation, the temperature and velocity fields are remarkably affected, and the deposition properties become asymmetric along the burner centerline when the surface rotates at a fast speed (rotational speed ω ≥ 300 rpm). Particles moving on the windward side have similar deposition properties when the surface rotates slowly, but the off-center particles on the leeward side have remarkable longer deposition time, lower deposition temperature, and lower surrounding O2 concentration, and they even never deposit on the surface when the surface rotates at a high speed. The rotation effect of the stagnation surface can be quantitatively described by an analogous Karlovitz number (Ka'), which is defined as the ratio of characteristic residence time of moving surface to the aerodynamics time induced by flame stretch. For high quality semiconducting metal oxide (SMO) films, it is suggested that Ka' ≥ 1 should be kept.
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Objective@#To understand impacts of past experiences of school bullying victimization and social supports on anxiety symptoms of college students, and to provide basic data for appropriate mental health education.@*Methods@#By using cluster random sampling method, a questionnaire survey was conducted among freshman, sophomore and junior college students majoring in clinical medicine from one medical university in Heilongjiang Province. The questionnaire included general demographic information, school bullying and self-rating anxiety scale.@*Results@#In this survey, 647 students (28.4%) were reported of anxiety symptoms, including 462 (20.3%) with mild anxiety, 162 (7.1%) with moderate anxiety, and 23(1.0%) with severe anxiety. Reported rate of mild, moderate and severe anxiety among college students with bullying victimization experiences during primary school students was 22.8%,33.9% and 59.6%, respectively (χ2=93.05, P<0.05). The figure among students with bullying victimization during junior school was 21.5%, 45.2% and 57.3%, respectively (χ2=186.79, P<0.05). Among those with bullying victimization experiences, anxiety symptoms showed no differences between students with or without social supports from peers, parents and teachers (χ2=7.95, P=0.54; χ2=11.57, P=0.24). Ordinal logistic regression showed bullying victimization during primary school and affection to primary school positively associated with anxiety symptoms among college students, while bullying victimization experiences during junior school showed no association with anxiety symptoms in college.@*Conclusion@#Bullying victimization experiences during primary school shows significant association with anxiety symptoms among college students.
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<p><b>OBJECTIVE</b>To investigate the coagulation abnormality and tumor-associated hypercoagulable state in lymphoma-bearing mice by measuring the changes in coagulation indices (D-D, vWF, TF) and platelet activation indices (P-selectin, GPIIbIIIa).</p><p><b>METHODS</b>The mouse model with lymphoma was established by the subcutaneous injection of 38B9 lymphoma cells into BALB/c mice, and the tumor formation was evaluated by using MRI and B ultrasonography. The D-D, vWF and TP levels of blood samples from inner canthal vein of tumor-bearing mice on 1 d, 14 d and 21 d were detected by using ELISA, the platelet activation indices (P-selectin, GPIIbIIIa) were detected by using flow cytometry.</p><p><b>RESULTS</b>The lymphoma-bearing mouse model was successfully established. The levels of D-D, vWF and TF as well as platelet activation indices P-selectin and GPIIbIIIa in the peripheraI blood were significantly higher than those of control group (P<0.05).</p><p><b>CONCLUSION</b>Lymphoma-bearing mice showed abnormalities of coagulation and platelet activation, which relates with the tumor hypercoagulable state in lymphoma-bearing mice.</p>
Assuntos
Animais , Camundongos , Coagulação Sanguínea , Linfoma , Camundongos Endogâmicos BALB C , Selectina-P , Ativação Plaquetária , TrombofiliaRESUMO
Objective To screen new mutations of ANGPTL8 gene in severe hypertriglyceridemia population.Meth-ods We designed a capture array encompassing all coding regions of the target genes for next -generation sequencing (NGS)in a cohort of 43 unrelated patients with severe hypertriglyceridemia.First, to exclude known TG related gene mutations,then the ANGPTL8 mutation was screened and the Sanger sequencing was performed.In combina-tion with functional prediction and conservatism analysis, the pathogenic mutation was finally screened.Results After bioinformatics analysis, a new ANGPTL8 mutation was identified in 43 patients with severe hypertriglyceri-demia.Conclusions Through ANGPTL8 mutation screening for severe hypertriglyceridemia in this study, a new rare mutation is found.
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Brain is one of the most complex organs in human. The current brain research is mainly based on the animal models and traditional cell culture. However, the inherent species differences between humans and animals as well as the gap between organ level and cell level make it difficult to study human brain development and associated disorders through traditional technologies. Recently, the brain organoids derived from pluripotent stem cells have been reported to recapitulate many key features of human brain in vivo, for example recapitulating the zone of putative outer radial glia cells. Brain organoids offer a new platform for scientists to study brain development, neurological diseases, drug discovery and personalized medicine, regenerative medicine, and so on. Here, we discuss the progress, applications, advantages, limitations, and prospects of brain organoid technology in neurosciences and related therapeutics.