Multidrug
membrane transporters (efflux pumps) are responsible
for multidrug resistance (MDR) and the low efficacy of therapeutic
drugs. Noble metal nanoparticles (NPs) possess a high surface-area-to-volume
ratio and size-dependent plasmonic optical properties, enabling them
to serve both as imaging probes to study sized-dependent MDR and as
potential drug carriers to circumvent MDR and enhance therapeutic
efficacy. To this end, in this study, we synthesized three different
sizes of silver nanoparticles (Ag NPs), 2.4 ± 0.7, 13.0 ±
3.1, and 92.6 ± 4.4 nm, functionalized their surface with a monolayer
of 11-amino-1-undecanethiol (AUT), and covalently conjugated them
with antibiotics (ofloxacin, Oflx) to prepare antibiotic drug nanocarriers
with conjugation ratios of 8.6 × 102, 9.4 × 103, and 6.5 × 105 Oflx molecules per NP, respectively.
We purified and characterized the nanocarriers and developed cell
culture medium in which the cells grew normally and the nanocarriers
were stable (non-aggregated), to quantitatively study the size, dose,
and efflux pump (MexAB-OprM) dependent inhibitory effect of the nanocarriers
against two strains of Pseudomonas aeruginosa, WT (normal expression of MexAB-OprM) and ΔABM (deletion of
MexAB-OprM). We found that the inhibitory effect of these nanocarriers
highly depended on the sizes of NPs, the doses of antibiotic, and
the expression of MexAB-OprM. The same amount of Oflx on the largest
nanocarriers (92.6 ± 4.4 nm) showed the highest inhibitory effect
(the lowest minimal inhibitory concentration) against P. aeruginosa. Surprisingly, the smallest nanocarriers
(2.4 ± 0.7 nm) exhibited a lower inhibitory effect than free
Oflx. The results suggest that size-dependent multivalent effects,
the distribution and localization of Oflx (pharmacodynamics), and
the efflux of Oflx all play a role in the inhibitory effects. Control
experiments using three sizes of AgMUNH2 NPs (absence of
Oflx) showed that these NPs do not exhibit any significant inhibitory
activity toward both strains. These new findings demonstrate the need
for and possibility of designing optimal sized antibiotic nanocarriers
to achieve the highest efficacy against P. aeruginosa.
MicroRNAs (miRNAs) are small noncoding RNAs, which downregulate gene expression by repressing or degrading mRNA targets. Lung cancer (LC), together with liver and colorectal cancers are the three leading causes of cancer death worldwide, and 80% of LCs belong to non-small cell lung cancers (NSCLCs). Despite a great advancement in developing distinct and delicate tools for early diagnosis and targeted therapies over the last decade, only about 15% of the NSCLC patients eventually survived. MiRNAs are frequently dysregulated in carcinoma, including LC. Numerous lines of evidence have demonstrated various roles played by miRNAs in the development and progression of LC. In this review, we propose to summarize the current understanding of miRNAs in LC, with a particular focus on translational application of miRNAs as novel diagnostic and prognostic biomarkers and tools for treatment.
Acid–base balance plays a key role in regulating biological processes, and the cells must stabilize the pH within a certain range, and pH instability will cause a series of diseases.
The conventional method for quantitating Mycobacterium tuberculosis (Mtb) in vitro and in vivo relies on bacterial colony forming unit (CFU) enumeration on agar plates. Due to the slow growth rate of Mtb, it takes 3–6 weeks to observe visible colonies on agar plates. Imaging technologies that are capable of quickly quantitating both active and dormant tubercle bacilli in vitro and in vivo would accelerate research toward the development of anti-TB chemotherapies and vaccines. We have developed a fluorescent probe that can directly label the Mtb cell wall components. The fluorescent probe, designated as DLF-1, has a strong affinity to the D-Ala-D-Ala unit of the late peptidoglycan intermediates in the bacterial cell wall. We demonstrate that DLF-1 is capable of detecting Mtb in both the actively replicating and dormant states in vitro at 100 nM without inhibiting bacterial growth. The DLF-1 fluorescence signal correlated well with CFU of the labeled bacteria (R2 = 1 and 0.99 for actively replicating and dormant Mtb, respectively). DLF-1 can also quantitate labeled Mtb inside of cells. The utility of DLF-1 probe to quantitate Mtb was successfully applied to identify genes critical for cell invasion. In conclusion, this novel near infrared imaging probe provides a powerful new tool for enumerating Mtb with potential future use in bacterial virulence study.
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