Antioxidant and antibacterial hydrogel formed by protocatechualdehyde-ferric iron complex and aminopolysaccharide for infected wound healing.

To better treat bacteria-infected wounds and promote healing, new wound dressings must be developed. In this study, we obtained PA@Fe by chelating iron trivalent ions (Fe3+) with protocatechualdehyde (PA), which has a catechol structure. Subsequently, we reacted it with ethylene glycol chitosan (GC) via a Schiff base reaction and loaded vancomycin to obtain an antibacterial Gel@Van hydrogel with a photothermal response. The as-prepared Gel@Van hydrogel exhibited good injectability, self-healing, hemostasis, photothermal stability, biocompatibility, and antioxidant and antibacterial properties. Moreover, Gel@Van hydrogel achieved highly synergistic antibacterial efficacy through photothermal and antibiotic sterilization. In a mouse skin-damaged infection model, Gel@Van hydrogel had a strong ability to promote the healing of methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds, indicating the great potential application value of Gel@Van hydrogel in the field of treating and promoting the healing of infected wounds.

Two new glycosides from Stachys geobombycis C.Y.Wu.

Two new compounds geobomlin A (1) and geobomlin B (2) were isolated from the roots of Stachys geobombycis C. Y. Wu. Structural determinations were established principally by two-dimensional NMR and MS data analyses. Geobomlin B showed moderate inhibitory activity against α-glucosidase with IC50 = 248.77 µM. We have also determined the mechanism by which geobomlin B elicit its inhibitory effect on α-glucosidase, for which we have established a competitive inhibition mode. Docking studies confirmed our results on geobomlin B α-glucosidase inhibitory properties.

Recent Progress in Phage Therapy to Modulate Multidrug-Resistant Acinetobacter baumannii, including in Human and Poultry.

Acinetobacter baumannii is a multidrug-resistant and invasive pathogen associated with the etiopathology of both an increasing number of nosocomial infections and is of relevance to poultry production systems. Multidrug-resistant Acinetobacter baumannii has been reported in connection to severe challenges to clinical treatment, mostly due to an increased rate of resistance to carbapenems. Amid the possible strategies aiming to reduce the insurgence of antimicrobial resistance, phage therapy has gained particular importance for the treatment of bacterial infections. This review summarizes the different phage-therapy approaches currently in use for multiple-drug resistant Acinetobacter baumannii, including single phage therapy, phage cocktails, phage-antibiotic combination therapy, phage-derived enzymes active on Acinetobacter baumannii and some novel technologies based on phage interventions. Although phage therapy represents a potential treatment solution for multidrug-resistant Acinetobacter baumannii, further research is needed to unravel some unanswered questions, especially in regard to its in vivo applications, before possible routine clinical use.

The Mechanism of Wnt Pathway Regulated by Telocytes to Promote the Regeneration and Repair of Intrauterine Adhesions.

Background: Telocytes (TCs), a novel interstitial cell type in the reproductive tract, participating in pathophysiology of intrauterine adhesions (IUA). This study further investigates the hypothesis that TCs, a source of Wnt, promote the regeneration and repair of IUA. Methods: RNA sequencing datasets of IUA patient (GSE160633) and mouse intestine mesenchymal cells (GSE94072) in GEO database were analyzed for differentially expressed genes (DEGs), and quantitative real-time PCR (qRT-PCR) measured indicated gene expression in TC-educated endometrial stromal cells (ESCs) and noneducated ESCs and verified the results of data mining from GEO database. Results: The expression levels of Wnt genes were downregulated in IUA compared to the control and were upregulated in TCs. In particular, the changes of Wnt5a expression level were the most significant (logFC = 4.0314 and adjusted P value = 0.0023), and the relative Wnt5a expression level was remarkably higher in TC-educated ESCs than noneducated ESCs verified by qRT-PCR (P = 0.0027). Conclusions: TCs may enhance the regeneration and repair of IUA through the Wnt signaling pathway.

Functionalized PAMAM-based Nanoformulation for Targeted Delivery of 5-Fluorouracil in Hepatocellular Carcinoma.

BACKGROUND: The efficacy of a traditional anticancer drug is challenged by adverse effects of the drug, including its nonspecific bio-distribution, short half-life, and side effects. Dendrimer-based targeted drug delivery system has been considered a promising strategy to increase targeting ability and reduce adverse effects of anti-cancer drugs. OBJECTIVE: This study analyzed the feasibility of whether the anticancer drug 5-fluorouracil (5-FU) could be delivered by functionalized fifth-poly(amidoamine) (PAMAM) with the peptide WP05 and the acetic anhydride to the liver cancer cells, reducing the toxicity of the PAMAM and improving the targeting property of 5-FU during delivery. METHODS: The functionalized PAMAM-based nanoformulation (WP05-G5.0NHAC-FUA) was fabricated through an amide condensation reaction to improve the therapeutic efficacy of 5-Fluorouracil (5-FU) in hepatocellular carcinoma (HCC). The physicochemical structure, particle size, zeta potential, stability, and in vitro release characteristics of WP05-G5.0NHAC-FUA were evaluated. In addition, the targeting, biocompatibility, anti-proliferation, and anti-migration of WP05-G5.0NHAC-FUA were investigated. The anti-tumor effect of WP05-G5.0NHAC-FUA in vivo was evaluated by constructing xenograft tumor models of human hepatoma cells (Bel-7402) implanted in nude mice. RESULTS: The resultant WP05-G5.0NHAC-FUA displayed spherical-like nanoparticles with a size of 174.20 ± 3.59 nm. Zeta potential and the drug loading of WP05-G5.0NHAC-FUA were 5.62 ± 0.41mV and 28.67 ± 1.25%, respectively. Notably, the optimized 5-FU-loaded formulation showed greater cytotoxicity with an IC50 of 30.80 ± 4.04 µg/mL than free 5-FU (114.93 ± 1.43 µg/mL) in Bel-7402 cancer liver cells, but a significantly reduced side effect relative to free 5-FU in L02 normal liver cells. In vivo animal study further confirmed efficient tumor accumulation and enhanced therapeutic efficiency. CONCLUSION: The developed nanoformulation is a promising platform for the targeting delivery of 5-FU and provides a promising solution for improving the efficacy of hepatocellular carcinoma chemotherapy.

Preventive effect of swim bladder hydrolysates on cyclophosphamide-induced ovarian injury in mice.

AIMS: This study aimed to prepare swim bladder hydrolysate (SBH) with Mn  < 4000 Da, and investigate its effects on cyclophosphamide (CTX)-mediated ovarian injury in mice. METHODS: Hydrolysates were prepared by heating extraction, enzymatic hydrolysis and ultrafiltration. Mn and distribution of SBH were analyzed via gel filtration chromatography and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Changes in the mouse oestrus cycle were determined by cytological examination. The number of follicles was examined using histopathology. Enzyme-linked immunosorbent assays (ELISAs) were used to determine the serum sex hormone levels. RESULTS: The Mn of SBH, prepared by heating extraction, enzymatic hydrolysis, ultrafiltration, and from different batches, was below 4000 Da, and the preparation process was stable. Compared with the control group, the low-, middle-, and high-dose SBH treatment groups showed different trends in oestrus duration, serum sex hormone levels, and the number of primordial and secondary follicles. The oestrus cycle duration of the high-dose SBH group was longer than that of the model group. The serum luteinizing hormone, follicle-stimulating hormone, and anti-Müllerian hormone levels in the middle-dose group were the closest to those of control group. The number of primordial and secondary follicles in the medium-dose group was significantly higher than that in the model group and closest to those of control group. CONCLUSION: After heating extraction, trypsin/Flavourzyme hydrolysis and ultrafiltration, a hydrolysate with Mn below 4000 Da could be prepared. We found that a moderate (400 mg/kg) SBH dose resulted in the greatest effect on ovarian injury remission in mice.

A newly identified polyunsaturated macamide alleviates dextran sulfate sodium-induced colitis in mice.

Macamides are a class of bioactive amide alkaloids found only in maca (Lepidium meyenii). Recent studies have shown that macamide-rich extracts possess various biological activities, such as antioxidative, immune-enhancing, and reproductive health-improving activities. In the present study, N-benzyl docosahexaenamide (NB-DHA), a newly identified macamide with the highest degree of unsaturation among all identified macamides, was identified from the maca extract. Microalgae oil, a docosahexaenoic acid-rich substance, was used as the starting material for the synthesis of NB-DHA. The effects of NB-DHA in colitis-induced mice were evaluated. NB-DHA significantly alleviated weight loss, shortening of colon length, and occult blood occurrence in mice with dextran sulfate sodium-induced colitis. Histological analysis revealed that following the administration of NB-DHA in mice with colitis, the infiltration of inflammatory cells and levels of proinflammatory factors, such as tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and myeloperoxidase, decreased, whereas the level of the anti-inflammatory factor IL-10 increased. Furthermore, the decreased expression of intestinal tight junction proteins caused by colitis was upregulated by the administration of NB-DHA. These results indicate that NB-DHA could be developed as a therapeutic agent for ulcerative colitis.

Circ_0002711 knockdown suppresses cell growth and aerobic glycolysis by modulating miR-1244/ROCK1 axis in ovarian cancer.

It has been well investigated that circular RNAs (circRNAs) play important roles in various cancers. The function of circ_0002711 and its underlying mechanisms in ovarian cancer (OC) remain unknown. qRT-PCR and western blot were performed to detect the expressions of circ_0002711, microRNA-1244 (miR-1244), and Rho kinase 1 (ROCK1) in OC tissues and cells. MTT assay and colony formation assay were employed to evaluate cell proliferation. Detection of lactate production, glucose uptake, and ATP level and oxygen consumption were used to determine Warburg effect. Western blot was used to examine glycolysis or proliferationrelated genes. Dual-luciferase reporter assay and RIP pull down assay were used to address the relationship among circ_0002711, miR-1244, and ROCK1. In vivo tumor growth was evaluated in nude mice. Circ_0002711 was upregulated in OC tissues and cell lines. Circ_0002711 downregulation inhibited cell viability, colony formation ability and aerobic glycolysis. Circ_0002711 contained binding sites with miR1244. Moreover, loss of miR-1244 undermined circ_0002711 downregulation-mediated function. ROCK1 contained binding sites with miR-1244. MiR-1244 upregulation suppressed cell proliferation and aerobic glycolysis, which was rescued by enhanced expression of ROCK1. Circ_0002711 knockdown hampered ROCK1 expression by upregulating miR-1244 expression. Finally, decreased expression of circ_0002711 inhibited tumor growth in vivo. Circ_0002711/miR-1244/ROCK1 axis regulated Warburg effect and tumor growth in vivo.

miR-197-3p reduces epithelial-mesenchymal transition by targeting ABCA7 in ovarian cancer cells.

The present study was designed to explore the role of microRNA-197-3p in regulating the epithelial-mesenchymal cellular transition in ovarian cancer. The results showed that miR-197 to be significantly (P < 0.05) downregulated in human ovarian cancer tissues and cell lines. Overexpression of miR-197 significantly (P < 0.05) reduced the proliferation of OVACAR-3 cancer cells. Additionally, the colony formation of the OVACAR-3 cells was inhibited by 59% relative to control. The migration and invasion of the OVACAR-3 cells was inhibited by 64% and 72%, respectively, upon miR-197 overexpression. Western blot analysis showed miR-197 was found to upregulate the expression of E-cadherin, while the expression of N-cadherin, vimentin, and snail proteins was found to decrease significantly (P < 0.05). TargetScan analysis together with dual luciferase assay revealed that miR-197 exerts its effects by targeting ABCA7 in ovarian cancer. ABCA7 was significantly (P < 0.05) overexpressed in ovarian cancer tissues and cell lines. However, silencing of ABCA7 resulted in significant inhibition of cell proliferation, migration, and invasion. Nonetheless, overexpression of ABCA7 could abolish the tumor-suppressive effects of miR-197 on the OVACAR-3 cells. Taken together, miR-197 acts a tumor-suppressive in ovarian cancer and points towards its therapeutic implications in the treatment of ovarian cancer.

TO901317 inhibits the development of hepatocellular carcinoma by LXRα/Glut1 decreasing glycometabolism.

This study was conducted to observe the effect and possible mechanism of TO901317 in vivo and in vitro to provide a new basis for the targeted therapy of hepatocellular carcinoma (HCC). The expressions of liver X receptor (LXR)-α, glucose transporter (Glut)-1, proliferating cell nuclear antigen (PCNA), and matrix metalloproteinase (MMP)-9 were analyzed from HCC public database (NCBI PubMed database). The result showed that LXRα was downregulated, whereas Glut1, PCNA, and MMP9 were upregulated in human HCC compared with normal liver. Furthermore, LXRα mRNA was negatively correlated with Glut1 mRNA. At the same time, HCC cells were cultivated in vitro and axillary injected in nude mice to establish the xenograft model. The xenograft in the TO901317-treated group was slower and smaller than the control group. The protein expression of LXRα, Glut1, and MMP9 could be detected by Western blot and glucose level. As a result, TO901317 could inhibit the cell proliferation of HCC in a dose-dependent manner by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. With the increase of TO901317 concentration, the cellular glucose concentration and ATP level were gradually decreased. Western blot results showed TO901317 could upregulate LXRα expression but downregulate MMP9 and Glut1 expression. Transwell and wound-healing analysis confirmed that, by increasing the concentration of TO901317, the cell invasion and migration were both decreased. LXRα small-interfering RNA (siRNA) could relieve the suppression effect of TO901317 on the cell invasion and migration and the expression of LXRα, Glut1, and MMP9. The glucose concentration was also raised. TO901317 could repress the progress of HCC cells by reducing the glucose concentration, upregulating LXRα expression, but downregulating the expression of Glut1 and MMP9. NEW & NOTEWORTHY This subject confirmed that TO901317, a specific liver X receptor agonist, could inhibit the progression of liver cancer through upregulating liver X receptor-α, downregulating the expression of glucose transporter-1 and matrix metalloproteinase-9, and decreasing the glucose content in SMMC-7721 and HepG2 cells.

Tristetraprolin: A novel target of diallyl disulfide that inhibits the progression of breast cancer.

Diallyl disulfide (DADS), a volatile component of garlic oil, has various biological properties, including antioxidant, antiangiogenic and anticancer effects. The present study aimed to explore novel targets of DADS that may slow or stop the progression of breast cancer. First, xenograft tumor models were created by subcutaneously injecting MCF-7 and MDA-MB-231 breast cancer cells into nude mice. Subsequently, western blot analysis was performed to investigate the expression of tristetraprolin (TTP), urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9) in the xenograft tumors, and cell cultures. Tablet cloning, Transwell and wound healing assays revealed that DADS treatment significantly inhibited the proliferation, invasion and migration of breast cancer cells. In addition, DADS treatment led to significant downregulation of uPA and MMP-9 protein expression, but significantly upregulated TTP expression in vivo and in vitro. Knocking down TTP expression using small interfering RNA reversed the aforementioned effects of DADS, which suggests TTP is a key target of DADS in inhibiting the progression of breast cancer.

ATP-binding cassette transporter A1: A promising therapy target for prostate cancer.

ATP-binding cassette transporter A1 (ABCA1) has been found to mediate the transfer of cellular cholesterol across the plasma membrane to apolipoprotein A-I (apoA-I), and is essential for the synthesis of high-density lipoprotein. Mutations of the ABCA1 gene may induce Tangier disease and familial hypoalphalipoproteinemia; they may also lead to loss of cellular cholesterol homeostasis in prostate cancer, and increased intracellular cholesterol levels are frequently found in prostate cancer cells. Recent studies have demonstrated that ABCA1 may exert anticancer effects through cellular cholesterol efflux, which has been attracting increasing attention in association with prostate cancer. The aim of the present review was to focus on the current views on prostate cancer progression and the various functions of ABCA1, in order to provide new therapeutic targets for prostate cancer.

Discovery of a small molecule targeting SET-PP2A interaction to overcome BCR-ABLT315I mutation of chronic myeloid leukemia.

Despite the great success in using tyrosine kinase inhibitors (TKIs) to treat chronic myeloid leukemia (CML), the frequent development of multi-drug resistance, particularly the T315I mutation of BCR-ABL, remains a challenging issue. Enhancement of protein phosphatase 2A (PP2A) activity by dissociating its endogenous inhibitor SET is an effective approach to combat TKI-based resistance. Here, we report the identification of a novel 2-phenyloxypyrimidine compound TGI1002 to specifically disrupt SET-PP2A interaction. By binding to SET, TGI1002 inhibits SET-PP2A interaction and increases PP2A activity. In addition, knocking-down SET expression decreases tumor cell sensitivity to TGI1002. TGI1002 treatments also markedly increase dephosphorylation of BCR-ABL. Moreover, TGI1002 significantly inhibits tumor growth and prolongs survival of xenografted mice implanted with BaF3-p210T315I cells. These findings demonstrate that TGI1002 is a novel SET inhibitor with important therapeutic potential for the treatment of drug-resistant CML.

[The expression of corticotropin-releasing factor 1 receptor in hippocampus of rats model of salicylate induced tinnitus].

OBJECTIVE: To observe the expression of corticotropin-releasing factor-1 receptor in hippocampus of rats model of salicylate induced tinnitus. METHOD: Twenty-four rats were randomly divided into three groups, eight for each group. For Group A and Group B, 10% salicylic sodium solution was intraperitoneal injected each day at the dose of 350 mg/kg for 21 days in Group A and 14 days in Group B. Group C received intraperitoneal injection with the same amount of saline solution each day for 14 days. ABR were tested 2 days before, and 2 hours after the first administration and after the last injection. Immunohistochemical test and Western Blot were utilized to detect the expression of CRF1R in hippocampus for each group. RESULT: ABR thresholds tested 2 days before the first administration of the 3 groups showed no statistically significant difference (P > 0.05). At the time point of 2 hours after the first injection, the ABR thresholds of Group A and Group B rose by 25.90 dB SPL and 25.03 dB SPL compared with that before the administration, respectively (P < 0. 01). After the last administration, the ABR thresholds of Group A and Group B rose 34.91 dB SPL and 32.62 dB SPI. compared with that before the administration, respectively (P < 0.01). The ABR thresholds of Group C showed no significant statistical difference at all the tested time points (P > 0.05). Immunohistochemical test and Western Blot revealed that the expression level of CRF1R in the hippocampus was A > B > C (P < 0.05). CONCLUSION: The expression of CRF1R in the hippocampus of salicylate induced tinnitus rat increased with the injection time, illustrating that CRF1R may participate in the mechanism of tinnitus involving the limbic system.

[Chromatography-assisted refolding of a fusion protein containing multiple disulfide bonds].

To establish a refolding process for the protein fused with 12-peptide of hirudin and reteplase (HV12p-rPA), we developed an anion-exchange chromatography assisted method to form correct disulfide bonds. After evaluating various parameters by orthogonal experiments with Q Sepharose XL as refolding medium, we found that urea gradient, sample loading size and L-Arg concentration were three major factors to affect the refolding outcomes, and urea gradient was critical to the recovery yield. Meanwhile, enzymatic activity of the refolded protein was decreased by the increase of sample loading size, and the optimal concentration of L-Arg in the eluting buffer was 1 mol/L. Thus, a dual-gradient of urea and pH on the anion-exchange chromatography resulted in remarkable increase of specific fibrinolytic and anti-coagulative activities of the refolded protein. Compared with the dilution method for refolding HV12p-rPA, the present approach was more effective and advantageous.