A peptidic network antibody inhibits both angiogenesis and inflammatory response.

Corneal neovascularization (CNV) is a global threat to human health. Traditional anti-angiogenesis agent may have therapy effect, while the inflammation in disease area remains unsolved. Herein, we reported two binding-induced fibrillogenesis (BIF) peptides as peptidic network antibodies for high-efficient and long-lasting anti-angiogenesis with reduced inflammatory response. BIF peptides could self-assemble into nanoparticles and further perform BIF behavior through binding Ca2+. In vitro, the migration of integrin αvß3 highly expressed endothelial cells was inhibited by BIF peptides. In vivo, one BIF peptide (0.012 mg/Kg) exhibited higher anti-angiogenesis effect than monoclonal antibody bevacizumab (0.96 mg/Kg) in a CNV rabbit model on day 14, despite that the dose of BIF was only 1.3% of bevacizumab. Meanwhile, the inflammatory response, such as PI3 kinase/Akt pathway in CNV was successfully inhibited as well. The peptidic network antibody could block integrin αvß3 via a long-term retention mode, which led to long-term therapeutic effect. The study provides BIF peptides as promising therapeutic agents for both anti-angiogenesis and reduced inflammatory response.

Smart Peptide Defense Web In Situ Connects for Continuous Interception of IgE against Allergic Rhinitis.

Allergic rhinitis (AR) is a chronic inflammatory reaction by immunoglobulin E (IgE) mediators after individual contact with allergens. It affects 10-40% of the world's population and reduces the quality of life. Long-term symptoms of rhinitis can cause inflammation to spread and trigger asthma, which can harm human health. Herein, we develop a Smart PeptIde defeNse (SPIN) web technique, which in situ constructs a peptide web, trapping IgE against AR. Two candidate SPINs, SPIN-1 and SPIN-2, are designed with different IgE-binding sequences. The SPIN-1 or SPIN-2 is able to bind to IgE and transform from nanoparticles into entangled nanofibers. In turn, the web of SPIN-1 or SPIN-2 acts as a long-term trap of IgE to prevent the IgE from binding to mast cells. SPIN-1 or SPIN-2 (10 mg/kg) is able to treat AR model Balb/c mice with high efficiency and reduced symptoms of rhinitis and inflammatory factors, even better than a first-line clinical drug, cetirizine (10 mg/kg). For example, the amount of IL-4 released in the AR group (185.5 ± 6.8 pg/mL) is significantly reduced after the treatment with SPIN-1 (70.4 ± 14.1 pg/mL), SPIN-2 (86.0 ± 9.3 pg/mL), or cetirizine (112.8 ± 19.3 pg/mL). More importantly, compared with the cetirizine group (1 day), the SPIN-1 or SPIN-2 group shows long-term therapeutic effects (1 week). The SPIN web technique shows the great potential for blocking IgE binding to mast cells in vivo, attenuating AR or other allergic reactions.

Ca2+ accelerates peptide fibrillogenesis via a heterogeneous secondary nucleation pathway.

A binding-induced fibrillogenesis (BIF) peptide mimics the fibrillogenesis of fibronectin, forming fibrous networks for disease theranostics. However, the mechanism of fast fibrillogenesis of the BIF peptide remains unclear. In this study, the fibrillogenesis processes of the BIF peptide in the absence and presence of receptors, i.e. Ca2+, are carefully studied. The BIF peptide, lauric acid-FFVLK-HSDVHK (LAFH) can self-assemble into nanoparticles (NPs) in solution and further transform into a fibrous structure, the fibrillogenesis of which could be accelerated by the addition of Ca2+. In detail, the fibrillogenesis of LAFH NPs without Ca2+ is achieved through a nucleation-elongation mechanism, in which homogeneous secondary nucleation is involved, followed by detachment of the newly formed fibers from pre-formed nanofibers (NFs). The fibrillogenesis of LAFH NPs in the presence of Ca2+ starts with an Ostwald ripening process, followed by a heterogeneous secondary nucleation, in which LAFH NPs bind to pre-formed LAFH NFs via Ca2+. The phenomenon of heterogeneous secondary nucleation including the attachment and shape change of LAFH NPs on pre-formed LAFH NFs is first revealed by TEM observation. These findings contribute to the understanding of the fast BIF process, supporting the mechanism study at the cellular level.

Cardioprotective effect of saffron total glycoside tablets in patients with breast cancer receiving anthracycline-based chemotherapy: study protocol for a multicentre, randomised, parallel, double-blind, placebo-controlled clinical trial.

BACKGROUND: Breast cancer is the most common cancer worldwide. Anthracyclines, alone or in combination with other chemotherapeutic agents, are the most effective chemotherapy agents against breast cancer. However, the dose-dependent cardiotoxicity of anthracyclines is a serious drawback in clinical treatment. Considerable efforts have been made to establish suggestions to avoid anthracycline-induced cardiotoxicity. Crocin extracted from saffron has potential cardioprotective effects against anthracycline-induced cardiotoxicity. The aim of this study was to estimate the cardioprotective effects and safety of saffron total glycoside tablets relative to placebo in patients with breast cancer undergoing anthracycline-based chemotherapy. METHODS: This is a multicentre, randomised, double-blind, placebo-controlled clinical trial. A sample of 200 participants (100 per group) with breast cancer will be randomly assigned to receive either saffron total glycoside tablet or placebo (four tablets each time, three times each day) for 6 months. Each participant will be interviewed three times: baseline (visit 1), after 3 months (visit 2), and after 6 months (visit 3). The primary outcome is to confirm if administration of saffron total glycoside tablets reduces the rate of cardiotoxicity relative to that with placebo. Secondary outcomes include new arrhythmic events, and cardiac troponin I and N-terminal pro-B-type natriuretic peptide levels. The quantity, quality, and severity of the adverse events will be carefully documented. DISCUSSION: We look forward to obtaining high-quality evidence that can be used to formulate clinical practice guidelines. Thus, the findings of this study are expected to help fill the current gap in cardiotoxicity prevention drugs. TRIAL REGISTRATION: This trial was published in the Chinese Clinical Trial Registry (No. ChiCTR2000041134, registered on 19th December 2020).

A Monotargeting Peptidic Network Antibody Inhibits More Receptors for Anti-Angiogenesis.

The overexpression of growth factors and receptors on neovascular endothelial cells (ECs) and their binding may promote the abnormal growth of new blood vessels, leading to corneal neovascularization (CNV). Normally, monoclonal antibodies may bind and block only one growth factor or receptor, such as bevacizumab binding and blocking vascular endothelial growth factor (VEGF). Herein, we develop a monotargeting peptidic network antibody (pepnetibody) that blocks multiple receptors on the membrane of ECs through forming a fibrous network and ultimately achieves high-efficient treatment of CNV. The pepnetibody could bind to integrin αvß3 in particulate formulation and in situ fibrillogenesis on ECs, mimicking the process of fibronectin fibrillogenesis on the cell membrane. The in situ formed peptidic network could firmly block integrin and cover other angiogenesis-related receptors, such as VEGF receptor-2 and neuropilin-1, exhibiting competitive efficacy of antiangiogenesis compared with traditional monoclonal antibody bevacizumab with 97.7 times lower dose.

Effect of Pei Yuan Tong Nao capsules on neuronal function and metabolism in cerebral ischemic rats.

ETHNOPHARMACOLOGICAL SIGNIFICANCE: Pei Yuan Tong Nao (PYTN) capsules have been used in traditional Chinese medicine (TCM) for many centuries for the treatment of renal and vascular diseases, including cerebral ischemia. Although they are used in clinical practice, the evidence of their efficacy is lacking. MATERIALS AND METHODS: The cerebral ischemic rat model was established by bilateral carotid artery ligation and shear surgery. The laser speckle blood flow imaging apparatus was used to observe the changes in cerebral blood flow before and after surgery. The working memory of rats were analyzed using the Morris water maze (MWM) test. The 2-deoxy-2-[18F]fluoro-D-glucose (18-FDG) standard uptake values (SUVs) of rats with cerebral ischemia were evaluated by small-living animal positron emission tomography (PET) imaging. The quantity of acetylcholine in the hippocampus and the protein quantity of α7 nicotinic acetylcholine receptor in the hippocampus were detected with high-resolution fluid phase chromatography and Western blot analysis. RESULTS: There was no significant difference in the preoperative mean cerebral blood perfusion between the groups. There was a significant decrease (P < 0.01) in cerebral perfusion in the model-operation, nimodipine, and PYTN groups after bilateral common carotid artery occlusion (BCCAo) compared with presurgery. The escape latency is shortened in the PYTN group (P < 0.05) compared with the model-operation group. SUVs of the nimodipine and PYTN groups increased (P < 0.05) compared with the model-operation group. After treatment with nimodipine and PYTN, acetylcholine levels in the hippocampus of the rats in the respective groups were lower than that of the sham-operation group (P < 0.01), and acetylcholine levels in the hippocampus of the nimodipine and PYTN groups were higher than that of the model-operation group (P < 0.05). α7 nicotinic acetylcholine receptor analysis showed that the protein levels of the nimodipine and PYTN groups increased after treatment compared with the model-operation group (P < 0.05). CONCLUSION: PYTN capsules improved the performance of rats with cerebral ischemia (analyzed using the MWM test), which may be due the to improvement of glucose metabolism in the hippocampus (evaluated by estimating acetylcholine and α7 nicotinic acetylcholine receptor protein).

Yiqihuoxuejiedu formula inhibits vascular remodeling by reducing proliferation and secretion of adventitial fibroblast after balloon injury.

Vascular remodeling occurs in atherosclerosis, hypertension, and restenosis after percutaneous coronary intervention. Adventitial remodeling may be a potential therapeutic target. Yiqihuoxuejiedu formula uses therapeutic principles from Chinese medicine to supplement Qi, activate blood circulation, and resolve toxin and it has been shown to inhibit vascular stenosis. To investigate effects and mechanisms of the formula on inhibiting vascular remodeling, especially adventitial remodeling, rats with a balloon injury to their common carotid artery were used and were treated for 7 or 28 days after injury. The adventitial area and α -SMA expression increased at 7 days after injury, which indicated activation and proliferation of adventitial fibroblasts. Yiqihuoxuejiedu formula reduced the adventitial areas at 7 days, attenuated the neointima and vessel wall area, stenosis percent, and α -SMA expression in the neointima, and reduced collagen content and type I/III collagen ratio in the adventitia at 28 days. Yiqihuoxuejiedu formula had more positive effects than Captopril in reducing intimal proliferation and diminishing stenosis, although Captopril lowered neointimal α -SMA expression and reduced the collagen content at 28 days. Yiqihuoxuejiedu formula has inhibitory effects on positive and negative remodeling by reducing adventitial and neointimal proliferation, reducing content, and elevating adventitial compliance.

Yiqi Huoxue Recipe Improves Heart Function through Inhibiting Apoptosis Related to Endoplasmic Reticulum Stress in Myocardial Infarction Model of Rats.

Objective. To explore the mechanism of cardioprotective effects of Chinese medicine, Yiqi Huoxue recipe, in rats with myocardial infarction- (MI-) induced heart failure. Methods. Male Sprague-Dawley rats underwent left anterior descending artery (LAD) ligation or sham operation. The surviving MI rats were divided randomly into three groups: MI (5 mL/kg/d NS by gavage), MI + Metoprolol Tartrate (MT) (12 mg/kg/d MT by gavage), and MI + Yiqi Huoxue (5 mL/kg recipe by gavage). And the sham operation rats were given 5 mL/kg/d normal saline. Treatments were given on the day following surgery for 4 weeks. Then rats were detected for heart structure and function by transthoracic echocardiography. Apoptosis in heart tissues was detected by TUNEL staining. To determine whether the endoplasmic reticulum (ER) stress response pathway is included in the cardioprotective function of the recipe, ER stress related proteins such as GRP78 and caspase-12 were examined. Results. Yiqi Huoxue recipe attenuated heart function injury, reversed histopathological damage, alleviated myocardial apoptosis and inhibited ER stress in MI rats. Conclusion. All the results suggest that Yiqi Huoxue recipe improves the injured heart function maybe through inhibition of ER stress response pathway, which is a promising target in therapy for heart failure.

Meta-analysis of the effectiveness of Chinese and Western integrative medicine on medium and advanced lung cancer.

OBJECTIVE: To summarize the effectiveness of Chinese and Western integrative medicine in treating medium and advanced lung cancer, and to provide guidelines for clinical application. METHODS: For this metaanalysis, a comparative search of Chinese medicine data in Chinese National Knowledge Infrastructure (CNKI) and Chinese BioMedical Literature Database (CBM) was undertaken to identify articles related to randomized comparative research of Chinese and Western integrative medicine in treating medium and advanced lung cancer between 1996 to 2006. Quality of life (QOL) was estimated using RevMan 4.2 software for data processing, adopting the odd ratio (OR) and the 95% confidence interval (CI). RESULTS: Through meta-analysis of 10 qualified articles, the results were as follows: the merging effectiveness of QOL [OR=3.80, 95% CI (2.65, 5.47)]; the rate of survival [OR=3.44, 95% CI (2.04, 5.80)]; the tumor response rate [OR=1.88, 95% CI (1.37, 2.58)]; the tumor developing rate [OR=0.33, 95% CI (0.23, 0.48)]. Significant differences existed between the Chinese and Western integrative medicine treatment group and the Western treatment group (P<0.01). CONCLUSIONS: Chinese and Western integrative medicine treatment of medium and advanced lung cancer has shown to improve patients' QOL and survival rate; it also can control tumor development in the short term.

[Effects of Qingkailing effective components on nuclear factor-kappa B in an ischemia-reperfusion injury model of rat brain microvascular endothelial cells in vitro].

OBJECTIVE: To establish an ischemia-reperfusion injury model of rat cerebral microvascular endothelial cells (MVECs) in vitro, and to explore the relationship between nuclear factor-kappa B (NF-kappaB) and the protective effects of Qingkailing effective components (hyocholic acid, taurocholic acid, baicalin, jasminoidin, Pinctada martensii) on MVECs. METHODS: Brain MVECs of male rats were digested with trypsin and subcultured, then the content of MVECs was adjusted to 1x10 (5)/mL and the MVECs were divided into normal control group, untreated group, hyocholic acid group, taurocholic acid group, baicalin group, jasminoidin group, Pinctada martensii group and nimodipine group, with six holes in each group. Except for the normal control group, the MVECs in the other groups were exposed in oxygen and glucose deprivation (OGD) circumstance in vitro to simulate ischemia-reperfusion injury. Immunocytochemical staining and image analysis system were used to observe the expression of NF-kappaB protein. RESULTS: Under a light microscope, the nuclei of MVECs in the normal control group were blank. Staining intensity of NF-kappaB protein in the nucleus in the untreated group was much deeper than that in the endochylema, with NF-kappaB shifted to nucleus after activation; a small quantity of NF-kappaB protein were expressed in the border of nucleus next to endochylema in groups of Qingkailing effective components, and the NF-kappaB protein expression was weaker than that in the untreated group. With the image analysis, we found that transmittance of nucleus and endochylema in the untreated group was significantly lower than that in the normal control group (P<0.01). Transmittance of nucleus and endochylema in the treated groups was higher than that in the untreated group (P<0.05, P<0.01). CONCLUSION: Qingkailing effective components have significant effect in inhibiting NF-kappaB protein transferring from endochylema to nucleus in vitro.

5,11,17,23-Tetra-tert-butyl-25,27-bis-[2-(4-nitro-phen-oxy)eth-oxy]calix[4]arene-26,28-diol acetonitrile tetra-solvate.

In the crystal structure of the title compound, C(60)H(70)N(2)O(10)·4CH(3)CN, the calix[4]arene mol-ecule adopts an open-cone conformation with two intra-molecular O-H⋯O hydrogen bonds. The four benzene rings of the calix[4]arene are twisted to the mean plane defined by four methyl-ene C atoms bridging the benzene rings, with dihedral angles ranging from 57.74 (10) to 65.99 (12)°. Two pendant nitro-phenyl rings are nearly perpendicular to each other, the dihedral angle being 70.9 (3)°. The asymmetric unit of the crystal structure contains four acetonitrile solvent mol-ecules, one of which lies in the calix cavity and makes C-H⋯π inter-actions and another links with the calix[4]arene via C-H⋯O hydrogen bonding. One tert-butyl group is disordered over two sets of sites, with a 0.736 (13):0.264 (13) occupancy ratio.

[Effect of effective components of Huanglian Jiedu decocting on NF-kappaB in cultured rat cerebral microvascular endothelial cells injury induced by hypoxia and reoxygenation].

OBJECTIVE: To investigate the protective mechanism of geniposide, baicalin and berberine on hypoxia and reoxygenation injury in cultured rat cerebral microvascular endothelial cells. METHOD: To establish a model of hypoxia four hours and reoxygenation twelve hours injury in rat cerebral microvascular endothelial cells in vitro. The injured cells were treated with geniposide (0. 128, 0.064, 0.032 micromol mL(-1), baicalin (0.028, 0.014, 0.007 micromol mL(- 1)) and berberine (0.024, 0.012, 0.006 micromol mL(-1)). The expression of p65 subunit of NF-kappaB was detected by immunocytochemical assay and techniques of image quantitative analysis. The protein expression of NF-kappaB was calculated with the mean optical density and mean area. The nuclear translocation of NF-kappaB was calculated with the percentage of positive cells and ratios of light transmittance of cytoplasm and cell nucleus. RESULT: Compared with the normal group, both the protein expression and the nuclear translocation of NF-kappaB of model group were significant increased (P <0.01). Compared with the model group, the mean optical density of all treated groups was decreased ,but these was no significant difference between them. As compared with model group, the mean area of all treated groups was significant decreased (P < 0.01). The percentage of nuclear translocation of all treated groups is not only lower than that of the model group but higher than that of the normal group (P <0.01). Compared with the model group, the ratios of light transmittance of cytoplasm and cell nucleus of all treated groups was significantly elevated (P <0.01). CONCLUSION: The results suggesed that geniposide, baicalin and berberine could protect hypoxia/reoxygenation injuried rat cerebral microvascular endothelial cells injury. One of the mechanism may lie in inhibiting both the protein expression and the nuclear translocation of NF-kappaB.

[Characteristics of coronary arteriography and traditional Chinese medicine syndrome of 1,069 patients with coronary artery disease].

OBJECTIVE: To study the characteristics of coronary arteriography and traditional Chinese medicine syndrome of 1,069 patients with coronary artery disease (CAD). METHODS: One thousand and sixty-nine patients with CAD were investigated by epidemiological method. The patients were divided into young patients (n=82, aged 45 years or younger) and middle-aged and old patients (n=987, older than 45 years). The characteristics of the two groups were analyzed, including clinical data, coronary arteriography and traditional Chinese medicine syndrome. RESULTS: Compared with middle-aged and old patients, proportion of male, triglyceride, total cholesterol, smoking patients, acute myocardial infarction and family history of CAD in young patients were significantly higher (P<0.05). Patients accompanying with hypertension and diabetes in middle-aged and old patients were more than those in young patients (P<0.05). Occurrence rates of morbidity of left circumflex coronary artery, left main coronary artery and multi-branch were higher in middle-aged and old patients (P<0.05), however, the occurrence rates of morbidity of single and double-branch were higher in young patients (P<0.05). The occurrence rates of syndromes of qi stagnation and phlegm turbidity in young patients were higher than those in middle-aged and old patients (P<0.05). But the proportions of cold coagulation, yin deficiency, yang deficiency and kidney deficiency in middle-aged and old patients were obviously higher (P<0.05). CONCLUSION: The traditional Chinese medicine syndrome and pathological changes of CAD in young patients are different from those in old patients.

[Effect of effective components of huanglian jiedu decoction on hypoxia, reoxygenation injury and the expression of VCAM in cultured rat cerebral microvascular endothelial cells].

OBJECTIVE: To investigate the protective mechanism of geniposide, baicalin and berberine on hypoxia and reoxygenation injury in cultured rat cerebral microvascular endothelial cells. METHOD: A model of four hours hypoxia and twelve hours reoxygenation injury in rat cerebral microvascular endothelial cells in vitro was established. The injured cells were treated with geniposide (0.128, 0.064, 0.032 mmol x L(-1)), baicalin (0.028, 0.014, 0.007 mmol L(-1)) and berberine (0.024, 0.012, 0.006 mmol L(-1)), respectively. The immunocytochemical method and techniques of image quantitative analysis were used to detect the mean optical density and mean area in order to match the protein expression of VCAM-1. The method of RT-PCR was adopted to observe and match the mRNA expression of VCAM-1. RESULT: As compared with the normal group, the mean optical density, the mean area and the mRNA expression of VCAM-1 of model group were significant increased (P < 0.01, P < 0.01, P < 0.01). As compared with the model group, both the mean optical density and the mean area of all treated groups were decreased, and there was significant difference between them (P < 0.01, P < 0.01). As compared with normal group, the mean optical density of baicalin (0.007 mmol x L(-1)) and berberine (0.012, 0.006 mmol x L(-1)) were significant decreased (P < 0.05, P < 0.01, P < 0.01), but there was no significant difference between the other groups and the normal group. As compared with normal group, the mean area of baicalin (0.0014 mmol x L(-1)) was significant decreased (P < 0.05), but there was significant difference between the other groups and the normal group. The mRNA expression of all treated groups was not only lower than that of the model group but also higher than that of the normal group (P < 0.05, P < 0.05). CONCLUSION: The results suggest that geniposide, baicalin and berberine, which are effective compositions of huanglian jiedu decoting, can protect hypoxia-reoxygenation injuried rat cerebral microvascular endothelial cells. One of the protected mechanisms is that they can inhibit the expression of VCAM-1.

[Protective action of effective components of Huanglian Jiedu decoction on hypoxia and reoxygenation injury in cultured rat cerebral microvascular endothelial cells].

OBJECTIVE: To investigate the protective effect of geniposide, baicalin and berberine for the rat cerebral microvascular endothelial cell. METHOD: The model of hypoxia and reoxygenation injury in rat cerebral microvascular endothelial cells in vitro was established. Both normal and model cells were treated with geniposide (1.024, 0.512, 0.256, 0.128, 0.064, 0.032, 0.016, 0.008 micromol x mL(-1)), baicalin (0.224, 0.112, 0.056, 0.028, 0.014, 0.007, 0.003 micromol x mL(-1)) and berberine (0.192, 0.096, 0.048, 0.024, 0.012, 0.006, 0.003 micromol x mL(-1)). Cell activity was measured by methyl thiazolyl tetrazolium (MTT) test. RESULT: After hypoxia/hypoglycemia cultures for 4 hour and reoxygenation for 12 hour, geniposide (0.128, 0.064, 0.032 micromol x mL(-1)), baicalin (0.028, 0.014, 0.007 micromol x mL(-1)) and berberine (0.024, 0.012, 0.006 micromol x microL(-1) could protect the injuried cerebral microvascular endothelial cells. CONCLUSION: Appropriate concentration of geniposide, baicalin and berberine, which are effective components of Huanglian Jiedu decoction, could protect the injuried cerebral microvascular endothelial cells.

[The protective effect of cholic acid on an in vitro injury model of ischemia-reperfusion in cerebral microvascular endothelial cells].

OBJECTIVE: To establish an in vitro injury model of ischemia-reperfusion in cerebral microvascular endothelial cells of rats and observe the protective effect of cholic acid. METHOD: Cultured rat microvascular endothelial cells were subjected to the oxygen-glucose deprivation (OGD) (Krebs solution) and recovery of oxygen-glucose, which simulated in vitro ischemia and reperfusion injury, and treated with cholic acid. The A value was measured with MIT chromatometry. RESULT: Cultured cells were impaired after OGD for 4 hours and recovery of oxygen-glucose for 12 hours, the A value of the cells treated with cholic acid was significantly higher than that of the cells without treatment (P < 0.01). CONCLUSION: Cholic acid could obviously protect rat cerebral microvascular endothelial cells from injury induced by an in vitro ischemia-reperfusion.