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BACKGROUND: Peripheral arterial disease (PAD) has become one of the leading causes of disa-bility and death in diabetic patients. Restoring blood supply to the hindlimbs, especially by promoting arteriogenesis, is currently the most effective strategy, in which endothelial cells play an important role. Tongxinluo (TXL) has been widely used for the treatment of cardio-cerebrovascular diseases and extended for diabetes-related vascular disease. AIM: To investigate the effect of TXL on diabetic PAD and its underlying mechanisms. METHODS: An animal model of diabetic PAD was established by ligating the femoral artery of db/db mice. Laser Doppler imaging and micro-computed tomography (micro-CT) were performed to assess the recovery of blood flow and arteriogenesis. Endothelial cell function related to arteriogenesis and cellular pyroptosis was assessed using histopathology, Western blot analysis, enzyme-linked immuno-sorbent assay and real-time polymerase chain reaction assays. In vitro, human vascular endothelial cells (HUVECs) and human vascular smooth muscle cells (VSMCs) were pretreated with TXL for 4 h, followed by incubation in high glucose and hypoxia conditions to induce cell injury. Then, indicators of HUVEC pyroptosis and function, HUVEC-VSMC interactions and the migration of VSMCs were measured. RESULTS: Laser Doppler imaging and micro-CT showed that TXL restored blood flow to the hindlimbs and enhanced arteriogenesis. TXL also inhibited endothelial cell pyroptosis via the reactive oxygen species/nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3/Caspase-1/GSDMD signaling pathway. In addition, TXL restored endothelial cell functions, including maintaining the balance of vasodilation, acting as a barrier to reduce inflammation, and enhancing endothelial-smooth muscle cell interactions through the Jagged-1/Notch-1/ephrin-B2 signaling pathway. Similar results were observed in vitro. CONCLUSION: TXL has a pro-arteriogenic effect in the treatment of diabetic PAD, and the mechanism may be related to the inhibition of endothelial cell pyroptosis, restoration of endothelial cell function and promotion of endothelial cell-smooth muscle cell interactions.
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OBJECTIVE: To investigate the effects of Tongxinluo (TXL) on thromboangiitis obliterans (TAO) and the underlying mechanisms. METHODS: Ninety male C57/BL6J mice were randomly divided into 6 groups according to a random number table: the sham group, TAO model group, Compound Danshen Tablet (CDT) group, and the high-, medium-, and low-dose TXL groups. All mice except the sham group were injected with sodium laurate (0.1 mL, 5 mg/mL) in the femoral artery to establish TAO mouse model. After modeling, mice in the sham and TAO model groups were intragastrically administered 0.5% (w/v) sodium carboxymethylcellulose, mice in the CDT group were intragastrically administered 0.52 g/kg CDT, and mice in the TXL-H, TXL-M, and TXL-L groups were intragastrically administered 1.5, 0.75, and 0.38 g/kg TXL, respectively. After 4 weeks of gavage, the recovery of blood flow in the lower limbs of mice was detected by Laser Doppler Imaging. The pathological changes and thrombosis of the femoral artery were observed by morphological examination. The expressions of tumor necrosis factor α (TNF-α) and inducible nitric oxide synthase (iNOS) in the femoral artery wall were detected by HE staining. Levels of thromboxane B2 (TXB2), 6-keto-prostaglandin F1α (6-keto-PGF1α), endothelin-1 (ET-1), interleukin (IL)-1ß and IL-6 were measured using enzyme-linked immunosorbent assay (ELISA). Levels of activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT) and fibrinogen (FIB) were detected by a fully automated biochemical analyzer. RESULTS: TXL promoted the restoration of blood flow in the lower limbs, reduced the area of thrombosis in the femoral artery, and alleviated the pathological changes in the femoral artery wall. Moreover, the levels of TXB2, ET-1, IL-6, IL-1ß, TNF-α and iNOS were significantly lower in the TXL groups compared with the model group (P<0.05 or P<0.01), while the level of 6-keto-PGF1α was significantly higher (P<0.01). In addition, APTT, PT, and TT were significantly prolonged in TXL groups compared with the model group (P<0.05 or P<0.01), and FIB levels were significantly decreased compared with the model group (P<0.01). CONCLUSIONS: TXL had a protective effect on TAO mice, and the mechanism may involve inhibition of thrombosis and inflammatory responses. TXL may be a potential drug for the treatment of TAO.
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Tromboangiite Obliterante , Trombose , Camundongos , Masculino , Animais , Tromboangiite Obliterante/tratamento farmacológico , Tromboangiite Obliterante/induzido quimicamente , Interleucina-6/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
CONTEXT: Jinlida (JLD) as a traditional Chinese medicine formula has been used to treat type 2 diabetes mellitus (T2DM) and studies have shown its anti-obesity effect. OBJECTIVE: To investigate the therapeutic effects of JLD in a mouse model of non-alcoholic fatty liver (NAFL). MATERIALS AND METHODS: C57BL/6J mice were divided into three groups and fed a low-diet diet (LFD), high-fat diet (HFD), or HFD + JLD (3.8 g/kg) for 16 weeks, respectively. The free fatty acids-induced lipotoxicity in HepG2 cells were used to evaluate the anti-pyroptotic effects of JLD. The pharmacological effects of JLD on NAFL were investigated by pathological examination, intraperitoneal glucose and insulin tolerance tests, western blotting, and quantitative real-time PCR. RESULTS: In vivo studies showed that JLD ameliorated HFD-induced liver injury, significantly decreased body weight and enhanced insulin sensitivity and improved glucose tolerance. Furthermore, JLD suppressed both the mRNA expression of caspase-1 (1.58 vs. 2.90), IL-1ß (0.93 vs. 3.44) and IL-18 (1.34 vs. 1.60) and protein expression of NLRP3 (2.04 vs. 5.71), pro-caspase-1 (2.68 vs. 4.92) and IL-1ß (1.61 vs. 2.60). In vitro, JLD inhibited the formation of lipid droplets induced by 2 mM FFA (IC50 = 2.727 mM), reduced the protein expression of NLRP3 (0.74 vs. 2.27), caspase-1 (0.57 vs. 2.68), p20 (1.67 vs. 3.33), and IL-1ß (1.44 vs. 2.41), and lowered the ratio of p-IKB-α/IKB-α (0.47 vs. 2.19). CONCLUSION: JLD has a protective effect against NAFLD, which may be related to its anti-pyroptosis, suggesting that JLD has the potential as a novel agent in the treatment of NAFLD.
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Medicamentos de Ervas Chinesas/farmacologia , Hepatócitos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Piroptose/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Glucose/metabolismo , Células Hep G2 , Hepatócitos/patologia , Humanos , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
OBJECTIVE: To assess whether the dietary supplement (bromelain) has the potential to reduce plasma fibrinogen and other cardiovascular disease (CVD) risk factors in patients with diabetes. METHODS: This randomized placebo controlled, double blind, parallel design, efficacy study was carried out in China and investigated the effect of 12 weeks of bromelain (1,050 mg/day) on plasma fibrinogen. This randomized controlled trial (RCT) recruited 68 Chinese diabetic patients [32 males and 36 females; Han origin, mean age of 61.26 years (standard deviation (SD), 12.62 years)] with at least one CVD risk factor. Patients were randomized into either bromelain or placebo group. While bromelain group received bromelain capsule, the placebo group received placebo capsule which consisted inert ingredient and has no treatment effect. Subjects were required to take 1,050 mg (3×350 mg) of either bromelain or starch-filled placebo capsules, two to be taken (2×350 mg) after breakfast and another (350 mg) after dinner, daily for 12 weeks. Plasma fibrinogen, CVD risk factors and anthropometric indicators were determined at baseline and at 12 weeks. RESULTS: The change in the fibrinogen level in the bromelain group at the end of the study showed a mean reduction of 0.13 g/L (standard deviation (SD) 0.86g/L) compared with the mean reduction of 0.36 g/L (SD 0.96 g/L) for the placebo group. However, there was no significant difference in the mean change in fibrinogen between the placebo and bromelain groups (mean difference=0.23g/L (SD 0.22 g/L), =0.291). Similarly, the difference in mean change in other CVD risk factors (blood lipids, blood pressure), blood glucose, C-reactive protein and anthropometric measures between the bromelain and placebo groups was also not statistically significant. Statistical differences in fibrinogen between bromelain and placebo groups before the trial despite randomization may have influenced the results of this study. CONCLUSION: This RCT failed to show a beneficial effect in reducing fibrinogen or influencing other selected CVD risk factors but suggests other avenues for subsequent research on bromelain.
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Bromelaínas/uso terapêutico , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glicemia , Bromelaínas/farmacologia , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/sangue , Demografia , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Feminino , Fibrinogênio/metabolismo , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Placebos , Fatores de Risco , Resultado do TratamentoRESUMO
OBJECTIVE: To observe the changes of vascular endothelial functions and general neuro-endocrine-immunity (NEI) network under the state of qi-deficiency syndrome induced by excessive idleness and to approach their internal relevance and illuminate initially the pathophysiological mechanism of vascular lesion induced by excessive idleness. METHODS: A total of 100 male Wistar rats were randomly divided into the control group and the qi-deficiency syndrome model group, 50 rats in each group. The qi-deficiency syndrome model was established by feeding the animals with hyper-alimentation diet in combination with restricting movement for 10 weeks. Changes of common chemical signal molecules related to NEI and vascular endothelial functions were measured by the end of the experiment. Furthermore, their internal relevance was analyzed by the method of canonical correlation analysis. RESULTS: The vascular endothelial structure and function were obviously injured in the model group. Compared with the control group, the chemical signal molecules, such as 5-hydroxytryptamine (5-HT), corticosterone (CORT), triiodothyronine (T3), tetraiodothyronine (T4), angiotensin II (Ang II), interleukin-1 (IL-1), and tumor necrosis factor-alpha (TNF-alpha) in peripheral blood of the model group (n=43) were changed significantly (P<0.05 or P<0.01). Canonical correlation analysis showed that vascular endothelial dysfunction was correlated to the changes of these signal molecules in the NEI network. CONCLUSIONS: Comfort-based lifestyle induced not only vascular endothelial dysfunction but also an imbalance of the NEI network. Vascular endothelial dysfunction and the imbalanced NEI network interacted with each other, and an imbalance of the NEI network may be the pathophysiologic basis for the genesis and development of vascular endothelial dysfunction, even diseases of the blood vessel.
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Doenças Cardiovasculares/etiologia , Endotélio Vascular/fisiopatologia , Sistema Imunitário/fisiologia , Neuroimunomodulação/fisiologia , Sistemas Neurossecretores/fisiologia , Comportamento Sedentário , Animais , Aorta/metabolismo , Aorta/patologia , Aorta/fisiopatologia , Aorta/ultraestrutura , Biomarcadores/análise , Biomarcadores/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Modelos Animais de Doenças , Endotelinas/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Sistema Imunitário/metabolismo , Sistema Imunitário/patologia , Masculino , Sistemas Neurossecretores/metabolismo , Sistemas Neurossecretores/patologia , Óxido Nítrico/metabolismo , Qi , Ratos , Ratos Wistar , Síndrome , Deficiência da Energia Yin/etiologia , Deficiência da Energia Yin/metabolismo , Deficiência da Energia Yin/patologia , Deficiência da Energia Yin/fisiopatologiaRESUMO
OBJECTIVE: To explore the pathogenesis characteristics of variant angina pectoris (VAP) by extracting its syndrome elements and analyzing the combination and distribution regularity of the syndrome elements. METHODS: One hundred and seventy-five case files of VAP patients were collected. The extraction of syndrome elements and symptom contribution to syndrome was completed by the partition method of complex system based on entropy theory. Diagnostic threshold was established by receiver operator characteristic curve. According to the results diagnosed by diagnostic criteria for syndrome element with quantitation, the combination and distribution regularity of the syndrome elements in patients with VAP was analyzed. RESULTS: The basic syndrome elements in the patients with VAP were qi deficiency, qi stagnation, blood stasis, phlegm turbidity, phlegm-heat, stagnation-heat, yin deficiency and yang deficiency syndromes. It showed that the combination types of syndrome elements could be made up of one syndrome, two, three, four or more than four syndromes. Qi deficiency, yin deficiency, qi stagnation, blood stasis and phlegm turbidity syndromes had the higher frequency than other syndrome elements in the patients with VAP. CONCLUSION: The partition method of complex system based on entropy theory can be used in extracting the syndrome elements of the patients with VAP. It is found that VAP has complicated pathogenesis according to the combination and distribution regularity of syndrome elements. Qi deficiency, qi stagnation, blood stasis, phlegm turbidity and yin deficiency syndromes are the main syndrome elements.