Conventional thrombolytic drugs for vascular blockage such as tissue plasminogen activator (tPA) are challenged by the low bioavailability, off-target side effects and limited penetration in thrombi, leading to delayed recanalization. We hypothesize that these challenges can be addressed with the targeted and controlled delivery of thrombolytic drugs or precision drug delivery. A porous and magnetic microbubble platform is developed to formulate tPA. This system can maintain the tPA activity during circulation, be magnetically guided to the thrombi, and then remotely activated for drug release. The ultrasound stimulation also improves the drug penetration into thrombi. In a mouse model of venous thrombosis, the residual thrombus decreased by 67.5% when compared to conventional injection of tPA. The penetration of tPA by ultrasound was up to several hundred micrometers in thrombi. This strategy not only improves the therapeutic efficacy but also accelerates the lytic rate, enabling it to be promising in time-critical thrombolytic therapy.
Amplification
strategies for low-level microRNA detection in living
cells are pivotal for gene diagnosis and many cellular bioprocesses.
In this work, we develop an amplification strategy for microRNA-21
(miRNA-21) imaging in living cells with MoS2-supported
catassembly of DNA hairpins. The MoS2 nanosheet with low
cytotoxicity serves as the nanocarrier and excellent fluorescence
quencher, which can transfer fluorescent metastable hairpin DNA into
the cells easily in a nondestructive manner and significantly reduce
background signals. The three-branched catalyzed hairpin assembly
(TB-CHA) probes contain three types of designed DNA molecular beacons
with the modification of Cy3 in the terminal. In the presence of miRNA-21,
the catalyzed hairpin assembly (CHA) reaction would be triggered and
a “Y”-shaped three-branched duplex nanostructure would
be formed, which would release from the surface of the MoS2 nanosheet due to the reduced affinity between the DNA duplex and
MoS2 nanosheet. The multisite fluorescence modification
and the circular reaction of TB-CHA probes allowed a significant fluorescence
recovery in a live-cell microenvironment. The ultrasensitive detection
of miRNA-21 is achieved with a detection limit of 75.6 aM, which is
∼5 orders of magnitude lower than that of a simple strand displacement-based
strategy (detection limit: 8.5 pM). This method offers great opportunities
for the ultrasensitive live-cell detection of miRNAs and helps in
gaining a deeper understanding of the physiological functions of miRNAs
in cancer research and life processes.
Berberine
(BBR), a traditional Chinese medicine, has therapeutic
effects on a variety of inflammation-related diseases, but its direct
proteomic targets remain unknown. Using activity-based protein profiling,
we first demonstrated that BBR directly targets the NEK7 protein via the hydrogen bond between the 2,3-methylenedioxy and
121-arginine (R121) residues. The fact that R121 is located precisely
within the key domain involved in the NEK7–NLRP3 interaction
allows BBR to specifically block the NEK7–NLRP3 interaction
and successively inhibit IL-1β release, independent of the NF-κB
and TLR4 signaling pathways. Moreover, BBR displays in vivo anti-inflammatory efficacy in a NEK7-dependent manner. Therefore,
we consider NEK7 to be a key target of BBR in the treatment of NLRP3-related
inflammatory diseases, and the development of novel NEK7–NLRP3
interaction inhibitors might be easily achieved using NEK7 as a target.
Glucose is a main carbon and energy source for virus proliferation and is usually involved in the glycolysis, pentose phosphate pathway (PPP), and tricarboxylic acid cycle (TCA cycle) pathways. In this study, we investigated the roles of glucose-related metabolic pathways during the replication of infectious spleen and kidney necrosis virus (ISKNV), which has caused serious economic losses in the cultured Chinese perch (Siniperca chuatsi) industry. We found that ISKNV infection enhanced the metabolic pathways of the PPP and the TCA cycle at the early stage of the ISKNV infection cycle and enhanced the glycolysis pathway at the late stage of the ISKNV infection cycle though the comprehensive analysis of transcriptomics, proteomics, and metabolomics. The advanced results proved that ISKNV replication induced upregulation of aerobic glycolysis at the late stage of ISKNV infection cycle and aerobic glycolysis were required for ISKNV multiplication. In addition, the PPP, providing nucleotide biosynthesis, was also required for ISKNV multiplication. However, the TCA cycle involving glucose was not important and necessary for ISKNV multiplication. The results reported here provide new insights into viral pathogenesis mechanism of metabolic shift, as well as antiviral treatment strategies.
Taking palmatine (PMT) as the lead, 20 new PMT derivatives were synthesized and examined for their antibacterial activities against six tested metronidazole (MTZ)-resistant Helicobacter pylori (H. pylori) strains. The structure–activity relationship (SAR) indicated that the introduction of a suitable secondary amine substituent at the 9-position might be beneficial for potency. Among them, compound 1c exhibited the most potent activities against MTZ-resistant strains, with minimum inhibitory concentration (MIC) values of 4–16 μg/mL, better than that of the lead. It also exhibited a good safety profile with a half-lethal dose (LD50) of over 1000 mg/kg. Meanwhile, 1c might exert its antimicrobial activity through targeting H. pylori urease. These results suggested that PMT derivatives might be a new family of anti-H. pylori components.
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