Weina Li

Body-protective compound (BPC) 157 demonstrates protective effects against damage to various organs and tissues. For future clinical applications, we had previously established a solid-phase synthesis process for BPC157, verified its biological activity in different wound models, and completed preclinical safety evaluations. This study aimed to investigate the pharmacokinetics, excretion, metabolism, and distribution profiles of BPC157. After a single intravenous (IV) administration, single intramuscular (IM) administrations at three doses in successive increments along with repeated IM administrations, the elimination half-life (t_1/2) of prototype BPC157 was less than 30 min, and BPC157 showed linear pharmacokinetic characteristics in rats and beagle dogs at all doses. The mean absolute bioavailability of BPC157 following IM injection was approximately 14%–19% in rats and 45%–51% in beagle dogs. Using [³H]-labeled BPC157 and radioactivity examination, we proved that the main excretory pathways of BPC157 involved urine and bile. [³H]BPC157 was rapidly metabolized into a variety of small peptide fragments in vivo, thus forming single amino acids that entered normal amino acid metabolism and excretion pathways. In conclusion, this study provides the first analysis of the pharmacokinetics of BPC157, which will be helpful for its translation in the clinic.

Idiopathic pulmonary fibrosis (IPF) is a progressive, life‐threatening lung disease with a poor prognosis. N‐acetyl‐seryl‐aspartyl‐lysyl‐proline (Ac‐SDKP) is a critical negative regulator of fibrosis development. However, it's extremely short half‐life greatly limits its applications. Previously, we reported an Ac‐SDKP analog peptide in which Asp and Lys residues were replaced with D‐amino acids (Ac‐SD_DK_DP). Ac‐SD_DK_DP exhibits better resistance to angiotensin‐1‐converting enzyme (ACE)‐mediated degradation and a longer half‐life than Ac‐SDKP in rat and human sera. The objective of this study was to explore the potential application of Ac‐SD_DK_DP for the treatment of IPF and to clarify the underlying mechanisms. We found that Ac‐SD_DK_DP exerted similar antifibrotic effects as Ac‐SDKP on human fetal lung fibroblast‐1 (HFL‐1) proliferation, α‐smooth muscle actin (α‐SMA), collagen I and collagen III expression, and Smad‐2 phosphorylation in vitro. In vivo, Ac‐SD_DK_DP exhibited significantly greater protective effects against bleomycin‐induced pulmonary fibrosis than Ac‐SDKP in mice. α‐SMA, CD45, collagen I and collagen III expression, and Smad‐2 phosphorylation were significantly decreased in the lungs of Ac‐SD_DK_DP‐treated but not Ac‐SDKP‐treated mice. Furthermore, a pull‐down experiment was used to screen for molecules that interact with Ac‐SDKP. Co‐immunoprecipitation (Co‐IP) and computer‐based molecular docking experiments demonstrated an interaction between Ac‐SDKP or Ac‐SD_DK_DP (Ac‐SDKP/Ac‐SD_DK_DP) and serine/arginine‐rich protein‐specific kinase 1 (SRPK1) that caused inhibition SRPK1‐mediated phosphatidylinositol‐3 kinase/ serine/threonine kinase (PIK3/AKT) signaling pathway activation and Smad2 phosphorylation and thereby attenuated lung fibrosis. Our data suggest that long‐acting Ac‐SD_DK_DP may potentially be an effective drug for the treatment of pulmonary fibrosis. The interacting molecule and antifibrotic mechanism of Ac‐SDKP/Ac‐SD_DK_DP were also identified, providing an experimental and theoretical foundation for the clinical application of the drug.

Estrogen receptor alpha (ERα), which has been detected in over 70% of breast cancer cases, is a driving factor for breast cancer growth. For investigating the underlying genes and networks regulated by ERα in breast cancer, RNA-seq was performed between ERα transgenic MDA-MB-231 cells and wild type MDA-MB-231 cells. A total of 267 differentially expressed genes (DEGs) were identified. Then bioinformatics analyses were performed to illustrate the mechanism of ERα. Besides, by comparison of RNA-seq data obtained from MDA-MB-231 cells and microarray dataset obtained from estrogen (E2) stimulated MCF-7 cells, an overlap of 126 DEGs was screened. The expression level of ERα was negatively associated with metastasis and EMT in breast cancer. We further verified that ERα might inhibit metastasis by regulating of VCL and TNFRSF12A, and suppress EMT by the regulating of JUNB and ID3. And the relationship between ERα and these genes were validated by RT-PCR and correlation analysis based on TCGA database. By PPI network analysis, we identified TOP5 hub genes, FOS, SP1, CDKN1A, CALCR and JUNB, which were involved in cell proliferation and invasion. Taken together, the whole-genome insights carried in this work can help fully understanding biological roles of ERα in breast cancer.

With a rapidly aging population, the prevalence of hypertension in adults continues to rise, placing a substantial and escalating social and economic burden. Ilex hainanensis Merr. is commonly used as a folk remedy for treating hypertension, dyslipidemia and inflammation in China. This systematic review aims to evaluate current evidence for the therapeutic effect of Ilex hainanensis Merr. extract (EIH) on essential hypertension. Six electronic databases (Pubmed, MEDLINE, The Cochrane Central Register of Controlled Trials, Chinese Scientific Journals Database, Wanfang and CNKI) were searched to identify eligible randomized controlled trials (RCTs) relevant to EIH on essential hypertension up to Jan 2018. Six RCTs including 772 participants met eligibility criteria. Methodological quality of the trials was generally low. Meta-analysis showed that EIH demonstrated a beneficial effect for lowering systolic and diastolic blood pressure (SBP/DBP), left ventricular mass (LVM) in participants with essential hypertension. There was no significant difference between EIH and antihypertensive drugs in SBP (WMD: -0.44 [-2.30, 1.43]; P =0.65), DBP (WMD: WMD: -0.02[-1.13, 1.09]; P =0.98) and LVM (WMD: -1.36 [-4.99, 2.26]; P =0.46). Moreover, one trial showed that EIH combined with antihypertensive drugs was more effective in lowering blood pressure than those antihypertensive drugs used alone. However, the findings were limited by the small sample sizes, duration and low methodological quality of the trials. This is the first systematic review of EIH on essential hypertension. More rigorous RCTs with high quality are still needed to prove the effectiveness and safety of EIH and its preparations for essential hypertension.

The purpose of this work was to find an objective and quantitative method for epileptic foci lateralization that may aid and support the decision made by the usually chosen lateralizing criteria. A frequency-derived causal analysis method, full frequency adaptive directed transfer function, was applied to the interictal scalp EEG data collected from 2 groups of total 30 epileptic patients. Group A included 15 refractory epileptic patients who had undergone an epileptic surgery; group B consisted of 15 outpatient epileptic patients who had a seizure type of generalized tonic-clonic seizure. All patients had no abnormalities detected in their routine brain MRI examinations. The methodology that leads to the lateralization is based on several processing steps: interictal spikes selection, full frequency adaptive directed transfer function analysis, significant causal connections extraction, and then lateralization. Ninety-six of 104 spikes' sources lateralized by full frequency adaptive directed transfer function were consistent with their corresponding surgery side in group A, with the accuracy of 92.31%. Ninety-seven of 101 spikes' sources were lateralized correctly in group B, according to technicians' judgments from ictal scalp video-EEG recordings, with the accuracy of 96.04%. The results demonstrated the feasibility of correctly lateralizing the epileptic foci by using full frequency adaptive directed transfer function to scalp EEG interictal spike activity.

B cell activating factor (BAFF) is a cytokine of tumor necrosis factor family mainly produced by monocytes and dendritic cells. BAFF can regulate the proliferation, differentiation, and survival of B lymphocytes by binding with BAFF-R on B cell membrane. Accumulating evidences showed that BAFF played crucial roles and was overexpressed in various autoimmune diseases such as systemic lupus erythematous (SLE) and rheumatoid arthritis (RA). This suggests that BAFF may be a therapeutic target for these diseases. In the present study, we developed a BAFF therapeutic vaccine by coupling a T helper cell epitope AKFVAAWTLKAA (PADRE) to the N terminus of BAFF extracellular domains (PADRE-BAFF) and expressed this fusion protein in Escherichia coli. The purified vaccine can induce high titer of neutralizing BAFF antibodies and ameliorate the syndrome of complete Freunds adjuvant (CFA) induced rheumatoid arthritis in rats. Our data indicated that the BAFF autovaccine may be a useful candidate for the treatment of some autoimmune diseases associated with high level of BAFF.

Background: Tumor angiogenesis is critical for tumor growth, infiltration and metastasis. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor and targeting it is important in reducing angiogenesis. Bevacizumab (Avastin), a monoclonal antibody that reacts directly against VEGF, has been demonstrated to be an effective treatment for various cancers such as rectal cancer, colon carcinoma, and non-small cell lung cancer, etc. Results: In the current study, we used the phage display technique to generate mimotopes that complemented the screening Avastin antibody (Ab). The candidate mimotopes of VEGF were isolated from a 12-mer peptide library. The phage displaying peptide DHTLYTPYHTHP (designated as 12P) exhibited high affinity to Avastin. The chemically synthesized 12P was conjugated to keyhole limpet hemocyanin (KLH) by glutaraldehyde (GA) to form vaccine KLH-12 peptide (KLH-12P). This epitope vaccine significantly induced humoral immunity in mice. The blood serum from KLH-12P-immunized mice associated with VEGF and blocked its binding to VEGFR, thus inhibiting vascular endothelial cell proliferation and migration. Conclusions: Our data indicate that the isolated mimotope 12P reported here could potentially elicit specific antibodies against VEGF and result in the induction of anti-angiogenesis responses.

To screen Foxp3Delta2-interacting proteins by yeast two-hybria. pGBKT7-Foxp3Delta2 bait plasmid was constructed. Its toxicity and transcriptional activation in yeast cell AH109 was tested by observation of phenotypes and color. The bait plasmid pGBKT7-Foxp3Delta2 was constructed successfully and there was no self-activation or toxicity in AH109. Forty positive clones were obtained. After sequence comparison and analysis, nine candidate proteins were finally selected for further confirmation. Yeast two hybrid system could be used for screening Foxp3Delta2-interacting proteins. These results provide essential clues for further investigation of Foxp3Delta2 function.