Inhibition of cell growth and invasion by epidermal growth factor-targeted phagemid particles carrying siRNA against focal adhesion kinase in the presence of hydroxycamptothecin

<p>Abstract</p> <p>Background</p> <p>Previous studies demonstrated the EGF-targeted phagemid particles carrying siRNA against Akt could be expressed efficiently in the presence of hydroxycamptothecin (HCPT). However, no significant cell growth inhibition was obtained. This study was to further investigate whether the EGF-targeted phagemid particles carrying siRNA would be a promising tool for anti-cancer siRNA delivery.</p> <p>Results</p> <p>We found that pSi4.1-siFAK phagemid particles could significantly inhibit the expression of focal adhesion kinase in the HCPT-treated cells. Moreover, we also observed that the particles could potently suppress cell growth and cell invasion.</p> <p>Conclusion</p> <p>These results indicated that EGF-targeted phagemid particles might be a promising tool for anti-cancer siRNA delivery in the presence of HCPT.</p

3,3′-Dibromo-5,5′-bis­[(S)-l-menth­yloxy]-4,4′-(hexane-1,6-diyldiimino)difuran-2(5H)-one

The title compound, C34H54Br2N2O6, was obtained by the Michael addition–elimination reaction of (5S)-5-(l-menthyl­oxy)-3,4-dibromo­furan-2(5H)-one with 1,6-hexa­nediamine in the presence of triethyl­amine. The crystal structure contains two chiral five-membered furan­one rings, in twist and envelope conformations, and two six-membered cyclo­hexane rings in chair conformations

Antimicrobial peptaibols, novel suppressors of tumor cells, targeted calcium-mediated apoptosis and autophagy in human hepatocellular carcinoma cells

<p>Abstract</p> <p>Background</p> <p>Hepatocellular carcinoma (HCC) is one of the most common cancers in the world which is highly chemoresistant to currently available chemotherapeutic agents. Thus, novel therapeutic targets are needed to be sought for the successful treatment of HCC. Peptaibols, a family of peptides synthesized non-ribosomally by the <it>Trichoderma </it>species and other fungi, exhibit antibiotic activities against bacteria and fungi. Few studies recently showed that peptaibols exerted cytotoxicity toward human lung epithelial and breast carcinoma cells. However, the mechanism involved in peptaibol-induced cell death remains poorly understood.</p> <p>Results</p> <p>Here, we showed that Trichokonin VI (TK VI), a peptaibol from <it>Trichoderma pseudokoningii </it>SMF2, induced growth inhibition of HCC cells in a dose-dependent manner. It did not obviously impair the viability of normal liver cells at lower concentration. Moreover, the suppression of cell viability resulted from the programmed cell death (PCD) with characteristics of apoptosis and autophagy. An influx of Ca²⁺triggered the activation of μ-calpain and proceeded to the translocation of Bax to mitochondria and subsequent promotion of apoptosis. On the other hand, typically morphological characteristics consistent with autophagy were also observed by punctate distribution of MDC staining and the induction of LC3-II, including extensive autophagic vacuolization and enclosure of cell organelles by these autophagosomes. More significantly, specific depletion of Bak expression by small RNA interfering (siRNA) could partly attenuate TK VI-induced autophagy. However, siRNA against Bax led to increased autophagy.</p> <p>Conclusion</p> <p>Taken together, these findings showed for the first time that peptaibols were novel regulators involved in both apoptosis and autophagy, suggesting that the class of peptaibols might serve as potential suppressors of tumor cells.</p

3-Chloro-4-dimethyl­amino-5-[(1R,2S,5R)-2-isopropyl-5-methyl­cyclo­hex­yloxy]furan-2(5H)-one

The title compound, C16H26ClNO3 contains one almost planar furan­one ring [maximum deviation of 0.021 (2) Å for the O atom] with a stereogenic center (S) and one cyclo­hexane ring which displays a chair conformation and has three stereogenic centers [S at the C atom bearing the isopropyl group, R at the C atom attached to the O atom and R at the C atom bearing the methyl group]

Isolation, identification, and complete genome sequence of a bovine adenovirus type 3 from cattle in China

<p>Abstract</p> <p>Background</p> <p>Bovine adenovirus type 3 (BAV-3) belongs to the <it>Mastadenovirus </it>genus of the family <it>Adenoviridae </it>and is involved in respiratory and enteric infections of calves. The isolation of BAV-3 has not been reported prior to this study in China. In 2009, there were many cases in cattle showing similar clinical signs to BAV-3 infection and a virus strain, showing cytopathic effect in Madin-Darby bovine kidney cells, was isolated from a bovine nasal swab collected from feedlot cattle in Heilongjiang Province, China. The isolate was confirmed as a bovine adenovirus type 3 by PCR and immunofluorescence assay, and named as HLJ0955. So far only the complete genome sequence of prototype of BAV-3 WBR-1 strain has been reported. In order to further characterize the Chinese isolate HLJ0955, the complete genome sequence of HLJ0955 was determined.</p> <p>Results</p> <p>The size of the genome of the Chinese isolate HLJ0955 is 34,132 nucleotides in length with a G+C content of 53.6%. The coding sequences for gene regions of HLJ0955 isolate were similar to the prototype of BAV-3 WBR-1 strain, with 80.0-98.6% nucleotide and 87.5-98.8% amino acid identities. The genome of HLJ0955 strain contains 16 regions and four deletions in inverted terminal repeats, E1B region and E4 region, respectively. The complete genome and DNA binding protein gene based phylogenetic analysis with other adenoviruses were performed and the results showed that HLJ0955 isolate belonged to BAV-3 and clustered within the <it>Mastadenovirus </it>genus of the family <it>Adenoviridae</it>.</p> <p>Conclusions</p> <p>This is the first study to report the isolation and molecular characterization of BAV-3 from cattle in China. The phylogenetic analysis performed in this study supported the use of the DNA binding protein gene of adenovirus as an appropriate subgenomic target for the classification of different genuses of the family <it>Adenoviridae </it>on the molecular basis. Meanwhile, a large-scale pathogen and serological epidemiological investigations for BVA-3 infection might be carried out in cattle in China. This report will be a good beginning for further studies on BAV-3 in China.</p

Integrated application of uniform design and least-squares support vector machines to transfection optimization

<p>Abstract</p> <p>Background</p> <p>Transfection in mammalian cells based on liposome presents great challenge for biological professionals. To protect themselves from exogenous insults, mammalian cells tend to manifest poor transfection efficiency. In order to gain high efficiency, we have to optimize several conditions of transfection, such as amount of liposome, amount of plasmid, and cell density at transfection. However, this process may be time-consuming and energy-consuming. Fortunately, several mathematical methods, developed in the past decades, may facilitate the resolution of this issue. This study investigates the possibility of optimizing transfection efficiency by using a method referred to as least-squares support vector machine, which requires only a few experiments and maintains fairly high accuracy.</p> <p>Results</p> <p>A protocol consists of 15 experiments was performed according to the principle of uniform design. In this protocol, amount of liposome, amount of plasmid, and the number of seeded cells 24 h before transfection were set as independent variables and transfection efficiency was set as dependent variable. A model was deduced from independent variables and their respective dependent variable. Another protocol made up by 10 experiments was performed to test the accuracy of the model. The model manifested a high accuracy. Compared to traditional method, the integrated application of uniform design and least-squares support vector machine greatly reduced the number of required experiments. What's more, higher transfection efficiency was achieved.</p> <p>Conclusion</p> <p>The integrated application of uniform design and least-squares support vector machine is a simple technique for obtaining high transfection efficiency. Using this novel method, the number of required experiments would be greatly cut down while higher efficiency would be gained. Least-squares support vector machine may be applicable to many other problems that need to be optimized.</p

The Changing Role of Chemotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma: A Updated Systemic Review and Network Meta-Analysis

Background and Objective: Both induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT; IC+CCRT) and CCRT plus adjuvant chemotherapy (AC; CCRT+AC) are standard treatments for advanced nasopharyngeal carcinoma (NPC). However, no prospective randomized trials comparing these two approaches have been published yet. We conducted this network meta-analysis to address this clinical question.Method: We recruited randomized clinical trials involving patients with advanced NPC randomly allocated to IC+CCRT, CCRT+AC, CCRT, or radiotherapy (RT) alone. Pairwise meta-analysis was first conducted, then network meta-analysis was performed using the frequentist approach. Effect size was expressed as hazard ratio (HR) and 95% confidence interval (CI).Results: Overall, 12 trials involving 3,248 patients were recruited for this study, with 555 receiving IC+CCRT, 840 receiving CCRT+AC, 1,039 receiving CCRT, and 814 receiving radiotherapy (RT) alone. IC+CCRT achieved significantly better overall survival ([HR], 0.69; 95% [CI], 0.51–0.92), distant metastasis-free survival (HR, 0.58; 95% CI, 0.44–0.78), and locoregional recurrence-free survival (HR, 0.67; 95% CI, 0.47–0.98) than CCRT. However, survival outcomes did not significantly differ between IC+CCRT and CCRT+AC, or between CCRT+AC and CCRT arms for all the endpoints. As expected, RT alone is the poorest treatment. In terms of P-score, IC+CCRT ranked best for overall survival (96.1%), distant metastasis-free survival (99.0%) and locoregional recurrence-free survival (87.1%).Conclusions: IC+CCRT may be a better and more promising treatment strategy for advanced NPC; however, head-to-head randomized trials comparing IC-CCRT with CCRT-AC are warranted

Engineered endolysin of Klebsiella pneumoniae phage is a potent and broad-spectrum bactericidal agent against “ESKAPEE” pathogens

The rise of antimicrobial resistance in ESKAPEE pathogens poses significant clinical challenges, especially in polymicrobial infections. Bacteriophage-derived endolysins offer promise in combating this crisis, but face practical hurdles. Our study focuses on engineering endolysins from a Klebsiella pneumoniae phage, fusing them with ApoE23 and COG133 peptides. We assessed the resulting chimeric proteins’ bactericidal activity against ESKAPEE pathogens in vitro. ApoE23-Kp84B (CHU-1) reduced over 3 log units of CFU for A. baumannii, E. faecalis, K. pneumoniae within 1 h, while COG133-Kp84B (CHU-2) showed significant efficacy against S. aureus. COG133-L1-Kp84B, with a GS linker insertion in CHU-2, exhibited outstanding bactericidal activity against E. cloacae and P. aeruginosa. Scanning electron microscopy revealed alterations in bacterial morphology after treatment with engineered endolysins. Notably, CHU-1 demonstrated promising anti-biofilm and anti-persister cell activity against A. baumannii and E. faecalis but had limited efficacy in a bacteremia mouse model of their coinfection. Our findings advance the field of endolysin engineering, facilitating the customization of these proteins to target specific bacterial pathogens. This approach holds promise for the development of personalized therapies tailored to combat ESKAPEE infections effectively

Mesaconine alleviates doxorubicin-triggered cardiotoxicity and heart failure by activating PINK1-dependent cardiac mitophagy

Aberrant mitophagy has been identified as a driver for energy metabolism disorder in most cardiac pathological processes. However, finding effective targeted agents and uncovering their precise modulatory mechanisms remain unconquered. Fuzi, the lateral roots of Aconitum carmichaelii, shows unique efficacy in reviving Yang for resuscitation, which has been widely used in clinics. As a main cardiotonic component of Fuzi, mesaconine has been proven effective in various cardiomyopathy models. Here, we aimed to define a previously unrevealed cardioprotective mechanism of mesaconine-mediated restoration of obstructive mitophagy. The functional implications of mesaconine were evaluated in doxorubicin (DOX)-induced heart failure models. DOX-treated mice showed characteristic cardiac dysfunction, ectopic myocardial energy disorder, and impaired mitophagy in cardiomyocytes, which could be remarkably reversed by mesaconine. The cardioprotective effect of mesaconine was primarily attributed to its ability to promote the restoration of mitophagy in cardiomyocytes, as evidenced by elevated expression of PINK1, a key mediator of mitophagy induction. Silencing PINK1 or deactivating mitophagy could completely abolish the protective effects of mesaconine. Together, our findings suggest that the cardioprotective effects of mesaconine appear to be dependent on the activation of PINK1-induced mitophagy and that mesaconine may constitute a promising therapeutic agent for the treatment of heart failure

Fabrication of Chitosan/Silk Fibroin Composite Nanofibers for Wound-dressing Applications

Chitosan, a naturally occurring polysaccharide with abundant resources, has been extensively exploited for various biomedical applications, typically as wound dressings owing to its unique biocompatibility, good biodegradability and excellent antibacterial properties. In this work, composite nanofibrous membranes of chitosan (CS) and silk fibroin (SF) were successfully fabricated by electrospinning. The morphology of electrospun blend nanofibers was observed by scanning electron microscopy (SEM) and the fiber diameters decreased with the increasing percentage of chitosan. Further, the mechanical test illustrated that the addition of silk fibroin enhanced the mechanical properties of CS/SF nanofibers. The antibacterial activities against Escherichia coli (Gram negative) and Staphylococcus aureus (Gram positive) were evaluated by the turbidity measurement method; and results suggest that the antibacterial effect of composite nanofibers varied on the type of bacteria. Furthermore, the biocompatibility of murine fibroblast on as-prepared nanofibrous membranes was investigated by hematoxylin and eosin (H&E) staining and MTT assays in vitro, and the membranes were found to promote the cell attachment and proliferation. These results suggest that as-prepared chitosan/silk fibroin (CS/SF) composite nanofibrous membranes could be a promising candidate for wound healing applications