Curcumin-Encapsulated Fusion Protein-Based Nanocarrier Demonstrated Highly Efficient Epidermal Growth Factor Receptor-Targeted Treatment of Colorectal Cancer.

Curcumin, a polyphenol derived from turmeric, has multiple biological functions, such as anti-inflammatory, antioxidant, antibacterial and, above all, antitumor activity. Colorectal cancer is a common malignancy of the gastrointestinal tract with an extremely high mortality rate. However, the low bioavailability and poor targeting properties of curcumin generally limit its clinical application. In the present study, we designed a fusion protein GE11-HGFI as a nanodrug delivery system. The protein was connected by flexible linkers, inheriting the self-assembly properties of hydrophobin HGFI and the targeting ability of GE11. The data show that the encapsulation of curcumin by fusion protein GE11-HGFI can form uniform and stable nanoparticles with a size of only 80 nm. In addition, the nanocarrier had high encapsulation efficiency for curcumin and made it to release sustainably. Notably, the drug-loaded nanosystem selectively targeted colorectal cancer cells with high epidermal growth factor receptor expression, resulting in high aggregated concentrations of curcumin at tumor sites, thus showing a significant anticancer effect. These results suggest that the nanocarrier fusion protein has the potential to be a novel strategy for enhancing molecular bioactivity and drug targeting in cancer therapy.

Evaluation of efficacy and safety of aspirin combination treatment in treating patients with coronary heart disease: A protocol for systematic review and meta-analysis.

BACKGROUND: Coronary heart disease (CHD) has a high incidence rate as a cardiovascular condition, primarily affecting the elderly and middle-aged individuals. CHD has debilitating effects on the standard of life of the elderly, and affecting their physical and psychological health. Reportedly, using aspirin alone is less effective as a first line of treatment for CHD. Therefore, this systematic review and meta-analysis will synthesize evidence on the effectiveness and safeness of aspirin combination treatment in treating patients with CHD. METHODS: A comprehensive meta-analysis is to be performed to evaluate the effectiveness and safety of aspirin combination treatment for CHD patients. A search will be performed on PubMed, EMBASE, Cochrane Central, WanFang, and Chinese National Knowledge Infrastructure till December 25, 2021 to identify randomized controlled trials, assess all related studies on the aspirin combination treatment in treating patients with CHD. In this systematic review, we will adopt the second version of Cochrane risk of bias assessment tool to assess the bias risk in all studies that fulfil the eligibility conditions. Two authors will separately conduct the study selection process, risk of bias assessment, and data extraction. Moreover, a random-effects meta-analysis will be conducted to synthesize evidence for all outcomes. Provided there is sufficient homogeneity among the studies, we will perform meta-analysis. I2 test will be employed to assess the heterogeneity of the outcomes. OSF REGISTRATION NUMBER: 10.17605/OSF.IO/MDTCA.

Levels of Serum sST2, MMP-3, and Gal-3 in Patients with Essential Hypertension and Their Correlation with Left Ventricular Hypertrophy.

Essential hypertension (EH) is a clinically frequent cardiovascular disease, with insidious onset, causing increased pressure load and neuroregulation disorders in patients. Long-term EH can cause left ventricular hypertrophy (LVH), which can lead to arrhythmia and even death. The soluble suppression of tumorigenicity 2 (sST2), matrix metalloproteinase-3 (MMP-3), and galectin-3 (Gal-3) in serum plays an important role in the occurrence, development, and prognosis of cardiovascular diseases. In our study, we divided EH patients into 3 levels and groups with or without LVH, according to their condition. The levels of sST2, MMP-3, and Gal-3 in the serum were measured in different groups of patients. Our results showed that the levels of sST2, MMP-3, and Gal-3 in the serum increased progressively with the level in different EH groups. The levels of sST2, MMP-3, and Gal-3 in the serum of the LVH group were higher than those of the NLVH group, and it is positively correlated with LVH-related indexes. The risk of developing and progressing to LVH in patients with EH can be determined by the method of measuring three indicators.

Specialised metabolites as chemotaxonomic markers of Coptosapelta diffusa, supporting its delimitation as sisterhood phylogenetic relationships with Rubioideae.

From the aerial extracts of Coptosapelta diffusa (Champ. ex Benth.) Steenis, twenty-one compounds were isolated and identified by means of column chromatography and NMR and MS techniques, respectively. Amongst, ten ones were determined to be undescribed compounds including six seco-iridoid glucosides (1-6), 2-(hydroxymethyl)-1,2,3,4-tetrahydroanthracene-9,10-dione (7) and three guaiane-type sesquiterpenes (15-17). Compounds 7, 8 and 9 exhibited inhibitory activities against Staphylococcus aureus ATCC25923 with MIC of 8, 4 and 8 µg/mL. The use of 1-6 (iridoids), 7-14 (anthraquinones) and 15-17 (sesquiterpenes) as chemotaxonomic markers for this species was evidenced. Structurally, 7-14 are similar to those anthraquinones isolated from other species of the family Rubiaceae, confirming their close phylogenetic relationship. Whereas, these iridoids and sesquiterpenes with unique structures provided chemotaxonomic evidence to support the genus Coptosapelta (the tribe Coptosapelteae) as a sister of the subfamily Rubioideae. These results contrast with the general producing tendency of indole alkaloids by the species of the subfamily Cinchonoideae, and merit chemotaxonomic significance for the delimitation of Coptosapelta.

Metals in Traditional Chinese medicinal materials (TCMM): A systematic review.

Traditional Chinese medicine has become an important pillar of "Healthy China" and the national medical system in recent years. Due to the wide range of raw materials in traditional Chinese medicinal materials (TCMM), the issue of metals has attracted more and more attention. In this paper, a comprehensive review of public reports on metals in TCMM in recent decades was conducted. From a total of 1969 reported articles, a total of 296 research reports on metals in TCMM were screened. The 296 reports involved 255 species in 85 families, with a total of 274 medicinal materials. These TCMM were divided into taproot-type, leaf-type, flower and fruit-type, herba-type, stem-type and bark-type medicinal materials according to the medicinal parts. The content of five metals lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As), chromium (Cr) in these TCMM was noted, and the distribution rules for metals were analyzed. The results showed that: (1) For the distribution of metals in different medicinal parts, Pb was mainly distributed in leaves; Cd was mainly distributed in flowers and fruits, stems and leaves; Hg was mainly distributed in barks; As was mainly distributed in stems; Cr was mainly distributed in stems, flowers and fruits. (2) The areas with the highest risk of metal residues were the Qinghai-Tibet Plateau, south China, and southwest China. (3) Among all types of TCMM, herba-type medicinal materials had the highest risk of metal content. (4) Combined with the pharmacopoeia metal limit standards implemented in 2019, the exceeding rate of Pb in TCMM was the highest, with a maximum value of 37.67%; among the six major types of TCMM, the medicinal materials with the highest exceeding rate were herba-type medicinal materials, among which Hg had the highest exceeding rate of 23.08%; in terms of medicinal parts, the highest exceeding rate of metals was in leaf-type medicinal materials, among which Pb had the highest exceeding rate of 37.67%. On the whole, the situation in regard to metal residues in TCMM was acceptable, but it cannot be ignored. It needed to be paid attention to in the industrialization and management of TCMM.

Broadening and Enhancing Functions of Antibodies by Self-Assembling Multimerization at Cell Surface.

Monoclonal antibody therapy has offered treatment benefits. Nonetheless, a lack of efficacy still exists, partially because monovalent binding of antibodies to specific receptors fails to translate into an active response. Here, we report a pretargeting-postassembly approach that exploits the selective Watson-Crick base pairing properties of oligonucleotides and multivalently tethers receptor-prebound antibodies to albumin at the cell surface. We demonstrate that this two-step self-assembling strategy allows sequential actions of receptor binding and clustering that broadens and strengthens the functions of antibodies. We show that anti-CD20 obinutuzumab (OBN) modified with one morpholino oligonucleotide (OBN-MORF1) maintains the feature of naked OBN antibody upon CD20 binding, and results in actin redistribution, homotypic adhesion, and lysosome-mediated cell death. Consecutive treatment with albumin grafted with multiple copies of a complementary morpholino oligonucleotide (HSA-(MORF2)x) hybridizes with surface-attached OBN-MORF1, manipulates CD20 clustering, and engages additional signals to induce calcium influx and caspase-related apoptosis. With the two types of different mechanisms collaborating in one system, the simple design exerted a notable survival extension of mice bearing disseminated B-cell lymphomas.

Human Serum Albumin-Based Drug-Free Macromolecular Therapeutics: Apoptosis Induction by Coiled-Coil-Mediated Cross-Linking of CD20 Antigens on Lymphoma B Cell Surface.

A therapeutic platform-drug-free macromolecular therapeutics (DFMT)-that induces apoptosis in B cells by cross-linking of CD20 receptors, without the need for low molecular weight cytotoxic drug, is developed. In this report, a DFMT system is synthesized and evaluated based on human serum albumin (HSA) and two complementary coiled-coil forming peptides, CCE and CCK. Fab' fragment of anti-CD20 monoclonal antibody rituximab is attached to CCE (Fab'-CCE); multiple grafts of CCK are conjugated to HSA (HSA-(CCK)7 ). The colocalization of both nanoconjugates at the surface of non-Hodgkin's lymphoma (NHL) Raji cells is demonstrated by confocal fluorescence microscopy. The colocalization leads to coiled-coil formation, CD20 cross-linking, and apoptosis induction. The apoptotic levels are evaluated by Annexin V, Caspase 3, and terminal deoxynucleotidyl transferase dUTP nick end labeling assays. Selective surface binding of DFMT to CD20+ cells is validated in experiments on a coculture of CD20+ (Raji) and CD20-(DG-75) cells. It is found that DFMT can trigger calcium influx only in Raji cells, but not in DG-75 cells. A highly specific treatment for NHL and other B cell malignancies with considerable translational potential is presented by HSA-based DFMT system.

Shenfu Formula reduces cardiomyocyte apoptosis in heart failure rats by regulating microRNAs.

ETHNOPHARMACOLOGICAL RELEVANCE: Shenfu decoction consists of the water extract from the dried root or rootstalk of Panax ginseng C. A. Mey (Asian ginseng) and the lateral root of Aconitum carmichaeli Debx (Fuzi, Heishunpian in Chinese). Shenfu Formula has been used as a folk Chinese medicine for thousands of years. Recent studies have shown that Shenfu injection can enhance cardiac function and regulate arrhythmia. AIM OF THE STUDY: Shenfu Formula plays an important role in the treatment of heart failure. However, its microRNA-mediated mechanisms are still not fully understood. Thus, we established a heart failure model in rats to investigate the microRNA mechanism of Shenfu Formula in cardiac function and apoptosis. MATERIALS AND METHODS: The heart failure animal model was established via left-anterior descending coronary artery ligation in rats. Seven days after surgery, Shenfu Formula was given to the heart failure rats, which were selected by echocardiography with an LVEF< 45%. After Shenfu Formula was given intragastrically for 30 days, blood samples were drawn, the heart was excised after echocardiography, and echocardiographic parameters and apoptosis-related proteins were further examined. Fas/Fas-L and Bcl-2/Bax proteins were analyzed by Western blot, and microRNAs were evaluated using Affymetrix GeneChip miRNA arrays. RESULTS: Shenfu Formula increased the left ventricular ejection fraction, improved the hemodynamic index of heart failure rats, and decreased serum brain natriuretic peptide (BNP) levels. Shenfu Formula also decreased the positive rate of myocardial cells as detected by the TUNEL method and significantly suppressed caspase 3 expression. Moreover, we found that Shenfu Formula can regulate the initiative factors Fas/Fas-L in the intrinsic pathway and Bcl-2/Bax in the extrinsic apoptosis pathway to suppress apoptosis in heart failure rats. Finally, Shenfu Formula potentially alters the balance of microRNAs involved in activating and inhibiting apoptosis, ultimately suppressing apoptosis; this leads to changes in the gene expression profiles of microRNAs targets. CONCLUSION: Shenfu Granule can effectively improve cardiac function in heart failure rats, and the anti-apoptosis effects of Shenfu Formula are potential mechanisms for inhibiting heart failure.

Inhibitory effects of glycyrrhetinic Acid on the delayed rectifier potassium current in Guinea pig ventricular myocytes and HERG channel.

Background. Licorice has long been used to treat many ailments including cardiovascular disorders in China. Recent studies have shown that the cardiac actions of licorice can be attributed to its active component, glycyrrhetinic acid (GA). However, the mechanism of action remains poorly understood. Aim. The effects of GA on the delayed rectifier potassium current (I K), the rapidly activating (I Kr) and slowly activating (I Ks) components of I K, and the HERG K(+) channel expressed in HEK-293 cells were investigated. Materials and Methods. Single ventricular myocytes were isolated from guinea pig myocardium using enzymolysis. The wild type HERG gene was stably expressed in HEK293 cells. Whole-cell patch clamping was used to record I K (I Kr, I Ks) and the HERG K(+) current. Results. GA (1, 5, and 10 µ M) inhibited I K (I Kr, I Ks) and the HERG K(+) current in a concentration-dependent manner. Conclusion. GA significantly inhibited the potassium currents in a dose- and voltage-dependent manner, suggesting that it exerts its antiarrhythmic action through the prolongation of APD and ERP owing to the inhibition of I K (I Kr, I Ks) and HERG K(+) channel.

[Effects of glycyrrhetinic acid on sodium ion channel currents of rats' ventricular myocardial cells].

OBJECTIVE: To study the effects of glycyrrhetinic acid (GA) on the sodium ion channel currents (I(Na)) of rats' ventricular myocardial cells, and to explore its anti-arrhythmic mechanisms at the ion channel level. METHODS: Single ventricular myocardial cells was isolated from SD rats. The whole cell patch clamp was used to record the effects of GA on I(Na) of rats' ventricular myocardial cells. RESULTS: GA could inhibit I(Na) of rats' ventricular myocardial cells dose-dependently. GA at 1, 5, and 10 micromol/L decreased I(Na) of rats' ventricular myocardial cells from (-4.26 +/- 0.15) nA to (-3.54 +/- 0.10) nA, (-2.19 +/- 0.09) nA, and (-1.25 +/- 0.08) nA, respectively. GA at 1, 5, and 10 micromol/L inhibited I(Na) by 16.08% +/- 2.3%, 50.82% +/- 3.56%, and 75.98% +/- 5.12%, showing statistical difference when compared with the control group (P < 0.05). GA at 10 micromol/L shifted I(Na) current-voltage curve more positively, but the activation potential and the peak potential were not changed. CONCLUSION: GA inhibited the I(Na) of rats' ventricular myocardial cells dose-dependently, which was possibly associated with its antiarrhythmia effects.

Hybrid hydrogels self-assembled from graft copolymers containing complementary ß-sheets as hydroxyapatite nucleation scaffolds.

A biomimetic material that can assist bone tissue regeneration was proposed. A bone scaffold based on a hybrid hydrogel self-assembled from N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers grafted with complementary ß-sheet peptides was designed. Investigation of self-assembly by circular dichroism spectroscopy suggested that hydrogel formation was triggered through association of the complementary ß-sheet motifs. Congo Red and thioflavin T binding, as well as transmission electron microscopy confirmed the formation of a fibril network. Besides mimicking the natural bone extracellular matrix and maintaining preosteoblast cells viability, this hydrogel, as shown by scanning electron microscopy and Fourier transform infrared spectroscopy, provided surfaces characterized by epitaxy that favored hydroxyapatite-like crystal nucleation and growth potentially beneficial for biointegration.

Effect of matrine on human ether à go-go related gene (HERG) channels expressed in Chinese hamster ovary cells.

OBJECTIVE: To observe the effect of matrine on human ether à go-go related gene (HERG) potassium channels expressed in Chinese hamster ovary (CHO) cells and investigate whether HERG channel is a new target of the pharmacological effect of matrine on arrhythmia and tumor METHODS: HERG channel potassium current in CHO cell was recorded using whole-cell patch-clamp technique, and the influence of matrine on the current was explored. RESULTS: Matrine inhibited HERG potassium current in a dose-dependent manner, and the 50% inhibitory concentration (IC IC(50)) was 411±23 µmol/L. Matrine had no significant effect on the activation kinetics, and mainly blocked HERG channels in their closed state. CONCLUSIONS: The blocking effect of matrine on HERG channels might be one of the mechanisms against arrythmias and tumors. Unlike most other blockers exerting blocking effect at the intracellular sites by entering the cell with the opening of HERG channel, matrine blocked HERG channels at the extracellular sites.