When antibiotic-resistant pathogenic bacteria pose a high threat to human health, bacterial multidrug efflux pumps become major contributors to the high-level antibiotic resistance in most ...microorganisms. Since traditional antibiotics are still indispensable currently, we report a dual drug delivery system to maximize the antibacterial efficacy of antibiotics by inhibiting efflux pumps in bacteria before their exposure to antibiotics. In this research, a microsphere/hydrogel composite was constructed from ciprofloxacin (Cip)-loaded poly (lactic-co-glycolic acid) (PLGA) microspheres and ginsenoside Rh2 (G-Rh2) dispersed thermo-sensitive hydrogel to treat skin infections. In vitro drug release studies indicated that while G-Rh2 in hydrogel presented a faster and short-term release manner to rapidly inhibit the NorA efflux pumps, Cip showed a sustained and long-term release behavior to provide a local high concentration gradient for facilitating drug percutaneous penetration. The combination of Cip and G-Rh2 demonstrated a high degree of synergism against both methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), hence significantly improving their in vitro antibacterial activity and efficiency. Moreover, the antibacterial performance of the microsphere/hydrogel composite with a sequential release profile is superior to that of other formulations in mouse model of MRSA skin infections, indicating its great potential to treat antibiotic-resistant skin infections.
Nanoparticles (NPs) have shown potential in cancer therapy, while a single administration conferring a satisfactory outcome is still unavailable. To address this issue, the dissolving microneedles ...(DMNs) were developed to locally deliver functionalized NPs with combined chemotherapy and photothermal therapy (PTT). α-Tocopheryl polyethylene glycol succinate (TPGS)/hyaluronic acid (HA) dual-functionalized PLGA NPs (HD10 NPs) were fabricated to co-load paclitaxel and indocyanine green. HD10 NPs significantly enhanced the cytotoxicity of low-dose paclitaxel because of active and mitochondrial targeting by HA and TPGS, respectively. PTT could further sensitize tumor cells toward chemotherapy by promoting apoptosis into the advanced period, highly activating caspase 3 enzyme, and significantly reducing the expression of survivin and MMP-9 proteins. Further, the anti-tumor effects of HD10 NPs delivered through different administration routes were conducted on the 4T1 tumor-bearing mice. After a single administration, HD10 NPs delivered with DMNs showed the best anti-tumor effect when giving chemotherapy alone. As expected, the anti-tumor effect was profoundly enhanced after combined therapy, and complete tumor ablation was achieved in the mice treated with DMNs and intra-tumor injection. Moreover, DMNs showed better safety due to moderate hyperthermia. Therefore, the DMNs along with combined chemo-photothermal therapy provide a viable treatment option for superficial tumors.
Dissolving microneedles encapsulating TPGS/HA functionalized PLGA nanoparticles provide a highly efficient local treatment for superficial tumor by integrating chemotherapy and photothermal therapy (PTT). The functionalized nanoparticles significantly enhanced the cytotoxicity, and sensitized tumor cells toward chemotherapy through multiple pathways. Display omitted
The
gene, a prominent member of the FOXO family, has been identified as a potential quantitative trait locus for muscle atrophy and lipid metabolism in livestock. It is also considered a promising ...candidate gene for meat quality traits such as Warner-Bratzler shear force (WBSF) and water holding capacity (WHC). The aim of this study was to identify sequence mutations in the
gene of yaks and to analyze the association of genotypes and haplotypes with meat traits such as WBSF and WHC. Quantitative reverse-transcriptase PCR (RT-qPCR) was applied to determine the expression levels of
in yak tissues, with the results revealing a high expression in the yak longissimus dorsi muscle. Exons of the
gene were then sequenced in 572 yaks using hybrid pool sequencing. Five single nucleotide polymorphisms were identified. Additionally, four effective haplotypes and four combined haplotypes were constructed. Two mutations of the
gene, namely C>G at exon g.636 and A>G at exon g.1296, were associated with cooked meat percentage (CMP) (
< 0.05) and WBSF (
< 0.05), respectively. Furthermore, the WBSF of the H2H3 haplotype combination was significantly lower than that of other combinations (
< 0.05). The findings of this study suggest that genetic variations in
could be a promising biomarker for improving yak meat traits.
Acetyl-CoA carboxylase beta (ACACB) is a functional candidate gene that impacts fat deposition. In the present study, we sequenced exon 37–intron 37, exon 46–intron 46, and intron 47 of yak ACACB ...using hybrid pool sequencing to search for variants and genotyped the gene in 593 Gannan yaks via Kompetitive allele-specific polymerase chain (KASP) reaction to determine the effect of ACACB variants on carcass and meat quality traits. Seven single nucleotide polymorphisms were detected in three regions. Eight effective haplotypes and ten diplotypes were constructed. Among them, a missense variation g.50421 A > G was identified in exon 37 of ACACB, resulting in an amino acid shift from serine to glycine. Correlation analysis revealed that this variation was associated with the cooking loss rate and yak carcass weight (p = 0.024 and 0.012, respectively). The presence of haplotypes H5 and H6 decreased Warner–Bratzler shear force (p = 0.049 and 0.006, respectively), whereas that of haplotypes H3 and H4 increased cooking loss rate and eye muscle area (p = 0.004 and 0.034, respectively). Moreover, the presence of haplotype H8 decreased the drip loss rate (p = 0.019). The presence of one and two copies of haplotypes H1 and H8 decreased the drip loss rate (p = 0.028 and 0.004, respectively). However, haplotype H1 did not decrease hot carcass weight (p = 0.011), whereas H3 increased the cooking loss rate (p = 0.007). The presence of one and two copies of haplotype H6 decreased Warner–Bratzler shear force (p = 0.014). The findings of the present study suggest that genetic variations in ACACB can be a preferable biomarker for improving yak meat quality.
Instability and low transdermal permeability of protein antioxidants are major obstacles to resist oxidative stress in transdermal drug delivery system. To overcome these shortcomings, cubosomes were ...developed as an advanced transdermal delivery system to improve stability and transdermal absorption of the model antioxidant phycocyanin in this study. Glyceryl monooleate and poloxamer 407 (P407) were used to prepare cubosomes as carrier matrix and stabilizer, respectively. Phycocyanin loaded cubosomes (PC-cubosomes) were prepared by the emulsification and homogenization method. A 3 3 full factorial design was used to optimize the cubosome formulations. The final optimal PC-cubosomes possessed an average particle size of 183.2 ± 0.5 nm and a negative surface charge as well as achieved a high encapsulation efficiency of 87.2% ± 2.7%. PC-cubosomes appeared as nano-sized and well-shaped spheres with highly ordered cubical structures. The residual amount of phycocyanin in PC-cubosomes was 3-fold higher than that in the free drug solution after 10 days ultraviolet radiation exposure. In vitro release kinetics of phycocyanin from PC-cubosomes fitted to the Higuchi kinetic model, indicating that phycocyanin released from cubosomes mainly attributed to drug diffusion and dissolution. PC-cubosomes also exhibited higher permeability (39.79 μg⋅cm −2 ⋅hour −1 ) across the rat skin than phycocyanin solution (16.33 μg⋅cm −2 ⋅hour −1 ). Furthermore, PC-cubosomes were easily taken up by keratinocytes, thereby achieving a prolonged anti-oxidative stress effect. These results therefore suggested that cubosomes could be a promising transdermal delivery system to improve the stability and transdermal permeability of phycocyanin.
Amorphous solid dispersions (ASDs) are inherently unstable because of high internal energy. Evaluating physical and chemical stability during the process and storage is essential. Numerous researches ...have demonstrated how polymers influence the drug precipitation and physical stability of ASDs, while the influence of polymers on the chemical stability of ASDs is often overlooked. Therefore, this study aimed to investigate the effect of polymers on the physical and chemical stability of spray-dried ASDs using dipyridamole (DP) as a model drug. Proper polymers were selected by assessing their abilities to inhibit drug recrystallization in supersaturated solutions. HPMC E5, Soluplus®, HPMCP-55, and HPMCAS-LP were shown to be effective stabilizers. The optimized formulations were further stored at a high temperature (60 °C) and high humidity (40 °C, 75% RH) for 2 months, and their physical and chemical stability was evaluated using polarizing optical microscopy, FTIR, HPLC, and mass spectrometry (MS). In general, crystallization was observed in all samples, which indicated the physical instability under stressed storage conditions. Also, it was noted that the polymers in ASDs rather than physical mixtures, induced a dramatic drug degradation after being exposed to a high temperature (HPMCP-55 > 80% and HPMCAS-LP > 50%) and high humidity (HPMCP-55 > 40% and HPMCAS-LP > 10%). The MS analysis further confirmed the degradation products, which might be generated from the reaction between dipyridamole and phthalic anhydride decomposed from HPMCP-55 and HPMCAS-LP. Overall, the exposure of ASDs to stressed conditions resulted in recrystallization and even the chemical degradation induced by polymers.
•PLGA microspheres based on exenatide encapsulated in nanoparticles were developed.•Ex-NPs-PLGA-Ms was prepared by modified S/O/W method with a low initial burst.•Ex-NPs-PLGA-Ms achieved zero-order ...controlled release.•S/O/W method could preserve the bioactivity of exenatide without cytotoxicity.
This study aimed to prepare poly (D, L-lactic-co-glycolic acid) microspheres (PLGA-Ms) by a modified solid-in-oil-in-water (S/O/W) multi-emulsion technique in order to achieve sustained release with reduced initial burst and maintain efficient drug concentration for a prolonged period of time. Composite PLGA microspheres containing exenatide-encapsulated lecithin nanoparticles (Ex-NPs-PLGA-Ms) were obtained by initial fabrication of exenatide-loaded lecithin nanoparticles (Ex-NPs) via the alcohol injection method, followed by encapsulation of Ex-NPs into PLGA microspheres. Compared to Ms prepared by the conventional water-in-oil-in-water (W/O/W) technique (Ex-PLGA-Ms), Ex-NPs-PLGA-Ms showed a more uniform particle size distribution, reduced initial burst release, and sustained release for over 60 d in vitro. Cytotoxicity studies showed that Ms prepared by both techniques had superior biocompatibility without causing any detectable cytotoxicity. In pharmacokinetic studies, the effective drug concentration was maintained for over 30 d following a single subcutaneous injection of two types of Ms formulation in rats, potentially prolonging the therapeutic action of Ex. In addition, administration of Ex-NPs-PLGA-Ms resulted in a more smooth plasma concentration-time profile with a higher area under the curve (AUC) compared to that of Ex-PLGA-Ms. Overall, Ex-NPs-PLGA-Ms prepared by the novel S/O/W method could be a promising sustained drug release system with reduced initial burst release and prolonged therapeutic efficacy.
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Hormone-sensitive lipase (
) is involved in the breakdown of triacylglycerols in adipose tissue, which influences muscle tenderness and juiciness by affecting the intramuscular fat content (IMF). ...This study analyzed the association between different genotypes and haplotypes of the yak
gene and carcass and meat quality traits. We used hybridization pool sequencing to detect exon 2, exon 8, and intron 3 variants of the yak
gene and genotyped 525 Gannan yaks via KASP to analyze the effects of the
gene variants on the carcass and meat quality traits in yaks. According to the results, the
gene is highly expressed in yak adipose tissue. Three single nucleotide polymorphisms (SNPs) were identified, with 2 of them located in the coding region and one in the intron region. Variants in the 2 coding regions resulted in amino acid changes. The population had 3 genotypes of GG, AG, and AA, and individuals with the AA genotype had lower WBSF values (
< 0.05). The H3H3 haplotype combinations could improve meat tenderness by reducing the WBSF values and the cooking loss rate (CLR) (
< 0.05). H1H1 haplotype combinations were associated with the increased drip loss rate (DLR) (
< 0.05). The presence of the H1 haplotype was associated the increased CLR in yaks, while that of the H2 haplotype was associated with the decreased DLR in yaks (
< 0.05). These results demonstrated that the
gene may influence the meat quality traits in yaks by affecting the IMF content in muscle tissues. Consequently, the
gene can possibly be used as a biomarker for improving the meat quality traits in yaks in the future.
The objective of this study was to develop a novel anhydrous reverse micelle nanoparticles (ARM-NPs) system to overcome the sedimentation instability of peptide-containing pressurized metered-dose ...inhalers (pMDIs). A bottom-up method was utilized to fabricate ARM-NPs. Tertiary butyl alcohol (TBA)/water system, freeze-drying and lipid inversion method were successively used to produce the ARM-NPs for pMDI. Various characteristics of ARM-NPs were investigated including particle size, morphology, secondary structure of the peptide drug, aerosolization properties and storage stability. As revealed by the results, ARM-NPs with spherical shape possessed 147.7 ± 2.0 nm of particle size with 0.152 ± 0.021 PdI. The ARM-NPs for pMDI had satisfactory fine particle fraction (FPF) value of 46.99 ± 1.33%, while the secondary structure of the peptide drug was unchanged. Stability tests showed no pronounced sedimentation instability for over 12 weeks at 4-6 °C. Furthermore, a hypothesis was raised to explain the formation mechanism of ARM-NPs, which was verified by the differential scanning calorimetry analysis. The lecithin employed in the reverse micelle vesicles could serve as a steric barrier between peptide drugs and bulk propellant, which prevented the instability of peptide drugs in hydrophobic environment. Homogenous particle size could avoid Ostwald ripening phenomenon of particles in pMDIs. It was concluded that the ARM-NPs for pMDI could successfully overcome sedimentation instability by the steric barrier effect and homogeneous particle size.
Ethyl cellulose (EC) based microparticles (MPs) could provide sustained release for Huperzine A. The drug release mechanism of MPs was exploited to achieve an ideal drug release profile. We ...previously found that the wettability of MPs greatly contributed to facilitating drug release, which was detailed in a research article entitled “Huperzine A loaded multiparticulate disintegrating tablet: Drug release mechanism of ethyl cellulose microparticles and pharmacokinetic study” (Peng et al., 2019) 1. In this article, the influence of different polymers and drugs on the drug release behavior was investigated to broaden or compensate this finding. Besides, powder characterization of MPs was used to evaluate the further application of MPs for tablets.
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