Comparative effects of dietary herbal mixture or guanidinoacetic acid supplementation on growth performance, cecal microbiota, blood profile, excreta gas emission, and meat quality in Hanhyup-3-ho chicken.

Phytogenic feed additives are renowned for their growth promotion, gut health enhancement, and disease prevention properties, which is important factors for sustaining prolonged poultry rearing. The study aimed to evaluate the effect of herbal mixture (mixture of ginseng and artichoke) or guanidinoacetic acid (GAA) on growth performance, cecal microbiota, excretal gas emission, blood profile, and meat quality in Hanhyup-3-ho chicken. A total of 360 one-day-old chickens (half males and half females) were allocated into one of 3 dietary treatments (12 replicate cages/treatment; 10 broilers/replicate cage) for 100 d of age. Experimental diets were CON: basal diet; TRT1: basal diet combined with 0.05% herbal mixture; and TRT2: basal diet combined with 0.06% GAA. All birds received a basal diet during the first 30 d, but from d 31 to 100, an experimental diet was supplied. The addition of 0.05% herbal mixture improved the average body weight gain and feed conversion ratio from d 31 to 100 as well as the overall experimental period. The cecal Lactobacillus, Escherichia coli, and Salmonella count remained consistent across all dietary treatments. Blood albumin and Superoxide Dismutase (SOD) levels increased in the herbal mixture supplemented diet. Additionally, there was a notable reduction in excretal NH3 and H2S emissions in the herbal mixture group. Furthermore, the herbal mixture group exhibited increased breast muscle weight, improved breast muscle color, improved water holding capacity, and a decrease in abdominal fat compared to the control group. Additionally, the supplementation of 0.06% GAA did not demonstrate any statistically significant impact on any evaluated parameter throughout the experiment. The results from the present investigation underscore the potential of ginseng together with artichoke extract supplementation as a viable feed additive, conferring improvements in growth performance, feed efficiency, excreta gas emission, meat quality parameters, and defense mechanism against oxidative stress in Hanhyup-3-ho chicken.

Correction: Suprafenacine, an Indazole-Hydrazide Agent, Targets Cancer Cells Through Microtubule Destabilization.

[This corrects the article DOI: 10.1371/journal.pone.0110955.].

Structural transition in Bcl-xL and its potential association with mitochondrial calcium ion transport.

Bcl-2 family proteins are key regulators for cellular homeostasis in response to apoptotic stimuli. Bcl-xL, an antiapoptotic Bcl-2 family member, undergoes conformational transitions, which leads to two conformational states: the cytoplasmic and membrane-bound. Here we present the crystal and small-angle X-ray scattering (SAXS) structures of Bcl-xL treated with the mild detergent n-Octyl ß-D-Maltoside (OM). The detergent-treated Bcl-xL forms a dimer through three-dimensional domain swapping (3DDS) by swapping helices α6-α8 between two monomers. Unlike Bax, a proapoptotic member of the Bcl-2 family, Bcl-xL is not converted to 3DDS homodimer upon binding BH3 peptides and ABT-737, a BH3 mimetic drug. We also designed Bcl-xL mutants which cannot dimerize and show that these mutants reduced mitochondrial calcium uptake in MEF cells. This illustrates the structural plasticity in Bcl-xL providing hints toward the probable molecular mechanism for Bcl-xL to play a regulatory role in mitochondrial calcium ion transport.

Biodegradable nanoparticle-mediated K-ras down regulation for pancreatic cancer gene therapy.

RNA interference (RNAi) targeting the K-ras oncogene mutation in pancreatic cancer mediated by small interfering RNA (siRNA) transfection is a very promising treatment. However, the rapid degradation and negative charge of naked siRNAs restrict their direct delivery into cells. In this contribution, we propose a safe and effective transmembrane transport nanocarrier formulation based on a newly developed biodegradable charged polyester-based vector (BCPV) for K-ras siRNA delivery into pancreatic cancer cells. Our results have shown that these biodegradable and biocompatible vectors are able to transfect siRNAs targeting mutant K-ras into MiaPaCa-2 cells with high transfection and knockdown efficiency. More importantly, the RNAi process initiated a cascade gene regulation of the downstream proteins of K-ras associated with cell proliferation, migration, invasion and apoptosis. We observed that after the mutant K-ras siRNA transfection, the growth, migration and invasion of the MiaPaCa-2 cells were significantly reduced; also, the apoptosis of the pancreatic cancer cells was promoted. Although in vivo testing data are limited, we propose that the BCPV based nanoparticle formulation could be a promising candidate as non-viral vectors for gene therapy in clinical settings.

Suprafenacine, an indazole-hydrazide agent, targets cancer cells through microtubule destabilization.

Microtubules are a highly validated target in cancer therapy. However, the clinical development of tubulin binding agents (TBA) has been hampered by toxicity and chemoresistance issues and has necessitated the search for new TBAs. Here, we report the identification of a novel cell permeable, tubulin-destabilizing molecule--4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid [1p-tolyl-meth-(E)-ylidene]-hydrazide (termed as Suprafenacine, SRF). SRF, identified by in silico screening of annotated chemical libraries, was shown to bind microtubules at the colchicine-binding site and inhibit polymerization. This led to G2/M cell cycle arrest and cell death via a mitochondria-mediated apoptotic pathway. Cell death was preceded by loss of mitochondrial membrane potential, JNK-mediated phosphorylation of Bcl-2 and Bad, and activation of caspase-3. Intriguingly, SRF was found to selectively inhibit cancer cell proliferation and was effective against drug-resistant cancer cells by virtue of its ability to bypass the multidrug resistance transporter P-glycoprotein. Taken together, our results suggest that SRF has potential as a chemotherapeutic agent for cancer treatment and provides an alternate scaffold for the development of improved anti-cancer agents.

Interleukin-8 gene silencing on pancreatic cancer cells using biodegradable polymer nanoplexes.

Pancreatic cancer is one of the deadliest cancers throughout the world with rarely efficient therapies currently available. Gene therapy on pancreatic cancer through small interfering RNA (siRNA)-based RNA interference (RNAi) has shown great potential and attracted much attention. However, due to the fragile nature of nucleic acid, the application of RNAi as a safe and efficient carrier faces great challenges. In this contribution, a self-assembly regime, which is based on well-defined cationic polylactides (CPLAs) with tertiary amine groups, has been used to encapsulate and protect siRNAs from fast degradation. CPLA is a safe and degradable formulation that allowed us to deliver siRNAs targeting the proangiogenic chemokine interleukin-8 (IL-8) to pancreatic cancer cells for gene therapy. Stable IL-8 siRNA-CPLA nanoplexes were successfully formed by electrostatic force and high gene transfection efficiencies were shown on two pancreatic cancer cell lines. We did not observe any cytotoxicity from these CPLAs over a large concentration range via cell viability evaluations. More importantly, the silencing of IL-8 gene expression significantly attenuated the proliferation of pancreatic cancer cells. Our preliminary results support the future development of gene therapy that might provide an effective and safe treatment approach towards pancreatic cancer.

Biodegradable nanocapsules as siRNA carriers for mutant K-Ras gene silencing of human pancreatic carcinoma cells.

The application of small interfering RNA (siRNA)-based RNA interference (RNAi) for cancer gene therapy has attracted great attention. Gene therapy is a promising strategy for cancer treatment because it is relatively non-invasive and has a higher therapeutic specificity than chemotherapy. However, without the use of safe and efficient carriers, siRNAs cannot effectively penetrate the cell membranes and RNAi is impeded. In this work, cationic poly(lactic acid) (CPLA)-based degradable nanocapsules (NCs) are utilized as novel carriers of siRNA for effective gene silencing of pancreatic cancer cells. These CPLA-NCs can readily form nanoplexes with K-Ras siRNA and over 90% transfection efficiency is achieved using the nanoplexes. Cell viability studies show that the nanoparticles are highly biocompatible and non-toxic, indicating that CPLA-NC is a promising potential candidate for gene therapy in a clinical setting.