Nano Self-Assembly for Apoptosis Induction and Early Therapeutic Efficacy Monitoring.

Real-time monitoring of early antitumor efficacy is one of the key issues in realizing high-efficiency and more precise tumor treatment. As a highly specific event in the early stage of apoptosis, the release of cytochrome c may act as a key biomarker for monitoring cell apoptosis. However, achieving real-time monitoring of the cytochrome c release in vivo remains a challenge. Herein, we report a novel integrated nanosystem named DFeK nanoparticle (DFeK NP) to achieve a favorable collaboration of inducing tumor cell apoptosis and monitoring early therapeutic efficacy, which combined the cytochrome c-activated DNA nanoprobe cApt-App with pro-apoptotic peptide [KLAKLAK]2 and ferrous ions. [KLAKLAK]2 can target the mitochondria to disrupt the mitochondrial membrane together with reactive oxygen species produced by ferrous ions via the Fenton reaction to promote mitochondrial damage. Then, cytochrome c is released from damaged mitochondria to trigger apoptosis, further activating the cApt-App probe from the fluorescence "off" state to the "on" state. The cytochrome c-specific "off-to-on" transition was successfully applied in fluorescence imaging of cytochrome c in vivo and thus achieved real-time early therapeutic efficacy monitoring. Collectively, this work presents a valuable integrated tool for tumor inhibition and therapeutic efficacy evaluation to realize more precise and more effective tumor treatment.

The protective effect of puerarin-loaded mesoporous silicon nanoparticles on alcoholic hepatitis through mTOR-mediated autophagy pathway.

Puerarin, a bioactive flavone compound isolated from Pueraria (Wild.), provides hepatoprotection by anti-inflammatory, anti-alcoholism, and regulating mechanistic target of rapamycin (mTOR). Building evidence suggests that the activation of mTOR reduces liver injuries associated with alcohol consumption and metabolism. However, the poor water solubility, low bioavailability, and short half-life of puerarin hinder its clinical application. The utility of mesoporous silicon nanoparticles (MSNs) can improve traditional Chinese medicine limitations. Stober methods were used to fabricate MSNs@Pue, and the size, zeta potentials and drug encapsulation efficiency were characterized by a series of analytical methods. IVIS Imaging System demonstrated liver-targeted bio-distribution, and then high-throughput sequencing, immunoproteomics and ultrastructure methods indicated autophagy related protective mechanism, followed by curative effect evaluation for the treatment efficacy. An acute-on chronic ethanol-drinking according to Gao-binge model induced alcoholic hepatitis (AH) pathology and resulted in hepatic hyper-autophagy, which was improved with MSNs@Pue administration (puerarin: 30 mM, 42 mg/kg; intravenously [i.v.]). Ethanol-fed mice were found to have increased expression of autophagy-related proteins (Atg3, Atg7, LC3 and p62). In contrast, MSNs@Pue administration significantly decreased the expression of these proteins and alleviated fatty droplets infiltration in damaged liver. Furthermore, acute-on-chronic ethanol feeding also resulted in the activiation of ERK activation and mTOR expression, which were reversed with MSNs@Pue administration and better than the usage of puerarin alone. Results point to MSNs@Pue mediated ERK/mTOR signaling pathway activation as a possible protective strategy to improve AH, which provides a strategy and evidence for treating liver disease using an MSN delivery system.

Single-nucleotide polymorphisms and activities of indoleamine 2,3-dioxygenase isoforms, IDO1 and IDO2, in tuberculosis patients.

PURPOSE: To explore the role and effects of the single-nucleotide polymorphisms (SNPs) of the two functionally related indoleamine 2,3-dioxygenase (IDO) isoforms on IDO activity in the Chinese Han ethnic population. METHODS: A total of 151 consecutive patients of Chinese Han ethnicity (99 men and 52 women; average age 51.92 ± 18.26 years) with pulmonary TB admitted to Beijing Chest Hospital between July 2016 and February 2017 were enrolled in the study. The serum levels of tryptophan (Trp) and its metabolites, IDO1 and IDO2 mRNA levels, and the relationship of IDO1 and IDO2 SNPs with the serum Kyn/Trp ratio in TB patients and healthy controls were examined by LC/ESI-MS/MS analysis. Genomic DNA was isolated from whole blood, and the PCR products were sequenced and analyzed. RESULTS: In Chinese Han participants, only IDO2 had SNPs R248W and Y359X that affected IDO activity, as determined by the serum Kyn/Trp ratio. IDO1 and IDO2 mRNA levels were inversely related in TB patients and healthy controls. CONCLUSIONS: IDO2 SNPs and the opposite expression pattern of IDO1 and IDO2 affected IDO activity in Chinese Han TB patients.

Integrated proteomic analysis to explore the molecular regulation mechanism of IL-33 mRNA increased by black carbon in the human endothelial cell line EA.hy926.

Black carbon (BC) correlates with the occurrence and progression of atherosclerosis and other cardiovascular diseases. Increasing evidence has demonstrated that BC could impair vascular endothelial cells, but the underlying mechanisms remain obscure. It is known that IL-33 exerts a significant biological role in cardiovascular disease, but little is known about the molecular regulation of IL-33 expression at present. We first found that BC significantly increased IL-33 mRNA in EA.hy926 cells in a concentration and time-dependent manner, and we conducted this study to explore its underlying mechanism. We identified that BC induced mitochondrial damage and suppressed autophagy function in EA.hy926 cells, as evidenced by elevation of the aspartate aminotransferase (GOT2), reactive oxygen species (ROS) and p62, and the reduction of mitochondrial membrane potential (ΔΨm). However, ROS cannot induce IL-33 mRNA-production in BC-exposed EA.hy926 cells. Further, experiments revealed that BC could promote IL-33 mRNA production through the PI3K/Akt/AP-1 and p38/AP-1 signaling pathways. It is concluded that BC could induce oxidative stress and suppress autophagy function in endothelial cells. This study also provided evidence that the pro-cardiovascular-diseases properties of BC may be due to its ability to stimulate the PI3K/AKT/AP-1 and p38/AP-1 pathway, further activate IL-33 and ultimately result in a local vascular inflammation.

Upconversion Luminescence-Controlled DNA Computation for Spatiotemporally Resolved, Multiplexed Molecular Imaging.

DNA-based molecular circuits able to perform complex information processing in biological systems are highly desirable. However, conventional DNA circuits are constitutively always in an ON state and immediately operate when they meet the biomolecular inputs, precluding precise molecular computation at a desired time and in a desired site. In this work, we report a conceptual methodology for the construction of photonic nanocircuits that enable DNA molecular computation in vitro and in vivo with high spatial precision. Upon remote activation by spatially restricted NIR-light input, two types of cancer biomarker inputs can sequentially trigger conformational changes of the DNA circuit through a structure-switching aptamer and toehold-mediated strand exchange, leading to release of a signaling output. Of note, the NIR-light-gated nanocircuit allows for intended control over the specific timing and location of DNA computation, providing spatial and temporal capabilities for multiplexed imaging. Furthermore, an OR-AND-gated nanocircuit of higher complexity was designed to illustrate the versatility of our approach. The present work illustrates the potential of the use of upconversion nanotechnology as a regulatory tool for spatial and temporal control of DNA computation in cells and animals.

A NIR Light Gated DNA Nanodevice for Spatiotemporally Controlled Imaging of MicroRNA in Cells and Animals.

Nanodevices have potential as intelligent sensing systems for detection of microRNAs (miRNAs) in living cells. However, the resolution offered by "always active" nanodevices is often insufficient to manipulate miRNA sensing with high spatiotemporal control. In this work, using DNA nanotechnology we constructed an activatable DNA nanodevice programmed to detect miRNAs in vitro and in vivo with the high spatial and temporal precision of NIR light. Our nanodevice is functionalized on the surface of upconversion nanoparticles (UCNPs) with a rationally designed DNA beacon that displays UV light-activatable miRNA sensing activity. The UCNPs absorb deep-tissue-penetrable NIR light and emit high-energy UV light locally, which serve as transducers to operate the nanodevice in the NIR window. The nanodevice can naturally enter cells and enable remote regulation of its fluorescent imaging activity for miRNAs in living cells by NIR light illumination in a chosen place and time. Furthermore, we demonstrate that the nanodevice can be expanded to activatable imaging of intratumoral miRNAs in living mice. This work illustrates the potential of DNA nanodevices for miRNA detection with high spatiotemporal resolution, which could expand the toolbox of technologies for precise biological and medical analysis.

Near-Infrared Light-Initiated Hybridization Chain Reaction for Spatially and Temporally Resolved Signal Amplification.

Precise control over signal amplification provides unparalleled opportunities for diverse applications. However, spatiotemporally controlled amplification has not been realized because of the lack of a design methodology. The aim of this study was thus to develop a conceptual approach for remote control over signal amplification at a chosen time and site in living cells. This system was constructed by re-engineering the functional units of the hybridization chain reaction (HCR) and combination with upconversion photochemistry, thus resulting in an activatable HCR with the high spatial and temporal precision of near-infrared (NIR) light. As a proof of concept, we demonstrate the spatially and temporally resolved amplified imaging of messenger RNA (mRNA) with ultrahigh sensitivity in vitro and in vivo. Furthermore, by using a system targeting subcellular sites we have developed a new technique for NIR-initiated amplified imaging of mRNA exclusively within a specific organelle.

Blue light filtered white light induces depression-like responses and temporary spatial learning deficits in rats.

OBJECTIVES: Ambient light has a vital impact on mood and cognitive functions. Blue light has been previously reported to play a salient role in the antidepressant effect via melanopsin. Whether blue light filtered white light (BFW) affects mood and cognitive functions remains unclear. The present study aimed to investigate whether BFW led to depression-like symptoms and cognitive deficits including spatial learning and memory abilities in rats, and whether they were associated with the light-responsive function in retinal explants. METHODS: Male Sprague-Dawley albino rats were randomly divided into 2 groups (n = 10) and treated with a white light-emitting diode (LED) light source and BFW light source, respectively, under a standard 12 : 12 h L/D condition over 30 days. The sucrose consumption test, forced swim test (FST) and the level of plasma corticosterone (CORT) were employed to evaluate depression-like symptoms in rats. Cognitive functions were assessed by the Morris water maze (MWM) test. A multi-electrode array (MEA) system was utilized to measure electro-retinogram (ERG) responses induced by white or BFW flashes. RESULTS: The effect of BFW over 30 days on depression-like responses in rats was indicated by decreased sucrose consumption in the sucrose consumption test, an increased immobility time in the FST and an elevated level of plasma CORT. BFW led to temporary spatial learning deficits in rats, which was evidenced by prolonged escape latency and swimming distances in the spatial navigation test. However, no changes were observed in the short memory ability of rats treated with BFW. The micro-ERG results showed a delayed implicit time and reduced amplitudes evoked by BFW flashes compared to the white flash group. CONCLUSIONS: BFW induces depression-like symptoms and temporary spatial learning deficits in rats, which might be closely related to the impairment of light-evoked output signals in the retina.

Ozonized carbon black induces mitochondrial dysfunction and DNA damage.

Black carbon and tropospheric ozone (O3 ), which are major air pollutants in China, are hazardous to humans following inhalation. Black carbon can be oxidized by O3 forming secondary particles of which the health effects are unknown. The present study utilized carbon black as a representative of black carbon to characterize the cytotoxicity induced by secondary particles in bronchial epithelial cells (16HBE) and C57BL/6J mice, and to investigate the implicated molecular pathways. Two types of carbon black including untreated carbon black (UCB) and ozonized carbon black (OCB) were presented. The effects of carbon black on cell viability, intracellular reactive oxygen species (ROS), oxidized/reduced glutathione ratio, mitochondrial membrane potential (MMP), intracellular ATP, and mitochondrial cytochrome c to cytoplasmic cytochrome c ratio were assessed in 16HBE. In addition, an alkaline comet assay and a cytokinesis-block micronucleus (CBMN) test with 16HBE cells in vitro and ELISA method for serum 8-hydroxy-2'-deoxyguanosine (8-OHdG) and a bone marrow micronucleus (BMN) test with C57BL/6J mice in vivo were performed to detect the genotoxicity. When compared with UCB exposed cells, OCB exposed cells had decreased cell viability, increased cell death rate, increased comet length and decreased MMP at 24 h exposure. UCB induced higher level of intracellular ROS than OCB from 4 to 23 h. No changes were observed for both OCB and UCB in serum 8-OHdG, intracellular ATP and mitochondrial cytochrome c to cytoplasmic cytochrome c ratio. The results of CBMN and BMN tests are negative. Intracellular ROS induced by OCB was lower than that of UCB. In summary, ozonization enhances the mitochondrial toxicity and genotoxicity of carbon black. Oxidative stress may not dominate in toxic effects of OCB. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 944-955, 2017.

MAP4K4 deletion inhibits proliferation and activation of CD4(+) T cell and promotes T regulatory cell generation in vitro.

CD4(+) T cells are critical for adaptive immunity. MAP4K4 is a key member of germinal center kinase group. However, the physiological function of MAP4K4 in primary CD4(+) T cells is still unclear. In this study, it was demonstrated that in vitro, MAP4K4 deletion remarkably suppressed CD4(+) T cell proliferation in response to phorbol 12-myristate 13-acetate (PMA) and ionomycin, which was not due to enhancing cell apoptosis. Additionally, MAP4K4 was required for the activation of CD4(+) T cells. MAP4K4 deletion significantly down-regulated expression of interleukin 2 (IL-2) and interferon-γ (IFN-γ), while notably up-regulating the expression of regulatory T cells (Treg) transcription factor Foxp3 in peripheral CD4(+) T cells. Furthermore, western blot analysis indicated that CD4(+) T cells lacking MAP4K4 failed to phosphorylate Jnk, Erk, p38 and PKC-θ. Thus, our results provide the evidence that MAP4K4 is essential for CD4(+) T cell proliferation, activation and cytokine production.

DNA-functionalized metal or metal-containing nanoparticles for biological applications.

The conjugation of DNA molecules with metal or metal-containing nanoparticles (M/MC NPs) has resulted in a number of new hybrid materials, enabling a diverse range of novel biological applications in nanomaterial assembly, biosensor development, and drug/gene delivery. In such materials, the molecular recognition, gene therapeutic, and structure-directing functions of DNA molecules are coupled with M/MC NPs. In turn, the M/MC NPs have optical, catalytic, pore structure, or photodynamic/photothermal properties, which are beneficial for sensing, theranostic, and drug loading applications. This review focuses on the different DNA functionalization protocols available for M/MC NPs, including gold NPs, upconversion NPs, metal-organic frameworks, metal oxide NPs and quantum dots. The biological applications of DNA-functionalized M/MC NPs in the treatment or diagnosis of cancers are discussed in detail.

A novel enzyme-linked ligand-sorbent assay (ELLSA) to screening pulmonary tuberculosis: a retrospective cross-sectional study.

BACKGROUND: Little knowledge of antigen existence in the pulmonary tuberculosis (PTB) patient serum impeded its development in antigen detection technology, despite its considerable potential. METHODS: Human ligand proteins and their adsorbent Mycobacterium tuberculosis (M.tb) proteins in the serum of PTB patients were identified using human protein chip (HuProt™) and LC-MS/MS, successively. The monoclonal antibody of ligand proteins, C5orf24, and polyclonal antibody of 9 M.tb proteins were prepared on mice and rabbits which were used to develop a novel enzyme-linked ligand-sorbent assay (ELLSA). The 412 volunteers were divided into the PTB group (n = 250) and the healthy control (n = 162). The PTB group was further divided into ATB (n = 131), LTBI (n = 18), Clinical diagnosis (n = 18), and Suspected (n = 73). All samples were tested by ELLSA to evaluate the diagnostic performance of ELLSA in PTB patients. RESULTS: Nine ligand proteins specific to PTB patients were identified on chips, with Chromosome 5 Open Reading Frame 24 (C5orf24) and kinocilin (KNCN) showing significantly higher signals. Proteomic analysis of the C5orf24-and KNCN-adsorbent protein complexes revealed 10 and 10 of the M.tb proteins, respectively. According to the composition reference of standard, the ELLSA based on C5orf24 ligand demonstrated a higher sensitivity of 69.6% and specificity of 90.18% in ATB patients and had a sensitivity of 64.22% in bacterial negative pulmonary tuberculosis, whereas the sensitivity of MGIT 960 and Xpert M.tb/RIF were 0%, respectively. CONCLUSIONS: M.tb proteins in serum can be enriched by ligand proteins and detected by ELLSA which proved to have excellent diagnostic performance for PTB.

A Spatiotemporally Controlled Gene-Regulation Strategy for Combined Tumor Therapy Based on Upconversion Hybrid Nanosystem.

The lack of precise spatiotemporal gene modulation and therapy impedes progress in medical applications. Herein, a 980 nm near-infrared (NIR) light-controlled nanoplatform, namely URMT, is developed, which can allow spatiotemporally controlled photodynamic therapy and trigger the enzyme-activated gene expression regulation in tumors. URMT is constructed by engineering an enzyme-activatable antisense oligonucleotide, which combined with an upconversion nanoparticle (UCNP)-based photodynamic nanosystem, followed by the surface functionalization of triphenylphosphine (TPP), a mitochondria-targeting ligand. URMT allows for the 980 nm NIR light-activated generation of reactive oxygen species, which can induce the translocation of a DNA repair enzyme (namely apurinic/apyrimidinic endonuclease 1, APE1) from the nucleus to mitochondria. APE1 can recognize the basic apurinic/apyrimidinic (AP) sites in DNA double-strands and perform cleavage, thereby releasing the functional single-strands for gene regulation. Overall, an augmented antitumor effect is observed due to NIR light-controlled mitochondrial damage and enzyme-activated gene regulation. Altogether, the approach reported in this study offers high spatiotemporal precision and shows the potential to achieve precise and specific gene regulation for targeted tumor treatment.

Supramolecular Modulator Assisted Cryo-Engineered Porous Cu-DNA Nano-Vehicles for Versatile Theranostic Agent Delivery.

DNA nanotechnology combines structural design with therapeutic functions via programmable DNA motifs, but faces challenges in drug loading capacity. Herein a pore-engineering strategy is reported to develop a highly porous, universal DNA nano-vehicle through coordination self-assembly, cryo-engineering, and supramolecular chemistry, adapting to diverse cargo loading with desired theranostic agents. Thus, the complex synthesis and compatibility challenges typically associated with switching between different drug carriers are avoided. To this end, Cu2+ and nucleic acid therapeutic G3139 self-assemble into a prefabricated solid nanostructure, which subsequently undergoes ultrafast freezing and sublimation to introduce porosity, forming highly porous Cu-G3139 nanoparticles (CG NPs). The porous CG NPs efficiently accommodate diverse therapeutic molecules, from chemotherapeutics to non-chemotherapeutic agents, facilitated by positively-charged cyclodextrin. As a proof-of-concept, the photosensitizer indocyanine green (ICG) is loaded and coated with tannic acid (TA) to form CICG@TA, enabling remarkable photothermal and fluorescence imaging-guided synergistic tumor ablation. This work represents the first demonstration of sublimation-induced pore formation in metal-DNA hybrid nanoparticles without chemical etching, offering a scalable "plug-and-play" platform for personalized cancer therapy without redesign. This versatile pore-engineering strategy, merging supramolecular chemistry with cryo-engineered porosity, opens up new avenues for efficient, customized multidrug delivery for diverse tumor theranostic applications.

Efflux pump Rv1258c activates novel functions of the oxidative stress and via the VII secretion system ESX-3-mediated iron metabolic pathway in Mycobacterium tuberculosis.

Oxidative stress and iron metabolism are essential for Mycobacterium tuberculosis (M.tb) survival in host cells. The efflux pump Rv1258c belongs to the major facilitator superfamily (MFS) and can actively pump drugs to promote certain drug resistance in M.tb. In this study, we compared H37RvΔRv1258c with wild-type (WT) M.tb H37Rv. The qRT-PCR results suggested that Rv1258c is potentially involved in the iron metabolic pathway by regulating the expression of ESX-3, which is required for iron uptake. Protein-Protein Affinity Predictor (PPA-Pred2) and the artificial intelligence program AlphaFold 2 were used for prediction and showed that Rv1258c has direct interactions with PPE4 and EccD3 but weak interactions with EccB3. This was further determined via protein-protein interaction analysis of the yeast two-hybrid expression system. By comparing mutant H37RvΔRv1258c strains with WT strains, we discovered that the absence of Rv1258c led to elevated intracellular H+ potential and NAD+/NADH ratios in M.tb, thereby resulting in oxidative stress. We hypothesize that the efflux pump Rv1258c not only has the function of regulating drug resistance in M.tb but also has a novel function in activating oxidative stress and regulating ESX-3-associated iron metabolism in M.tb.

Recent advances in the nanoarchitectonics of metal-organic frameworks for light-activated tumor therapy.

Metal-organic frameworks (MOFs) have received extensive attention in tumor therapy because of their advantages, including large specific surface area, regular pore size, adjustable shape, and facile functionalization. MOFs are porous materials formed by the coordination bonding of metal clusters and organic ligands. This review summarized the most recent advancements in tumor treatment based on nMOFs. First, we discuss the classification of MOFs, which primarily include the series of isoreticular MOF (IRMOF), zeolitic imidazolate framework (ZIF), coordination pillared-layer (CPL), Materials of Institute Lavoisier (MIL), porous coordination network (PCN), University of Oslo (UiO) and Biological metal-organic frameworks (BioMOFs). Then, we discuss the use of nMOFs in antitumor therapy, including drug delivery strategies, photodynamic therapy (PDT), photothermal therapy (PTT), and combination therapy. Finally, the obstacles and opportunities in nMOFs are discussed.

LRRC25 Inhibits IFN-γ Secretion by Microglia to Negatively Regulate Anti-Tuberculosis Immunity in Mice.

BACKGROUND: Leucine-rich repeat-containing protein-25 (LRRC25) can degrade the ISG15 gene in virus-infected cells and prevent overactivation of the type Ⅰ IFN pathway. However, the role of LRRC25 in bacterial infection is still unclear. In this pursuit, the present study aimed to explore the regulatory role and mechanism of LRRC25 in microglia infected with Mycobacterium tuberculosis in a mouse model. METHODS: Q-PCR, WB, and cell immunofluorescence were employed to observe the change in LRRC25 in BV2 cells infected by H37Rv. Additionally, siRNA was designed to target the LRRC25 to inhibit its expression in BV2 cells. Flow cytometry and laser confocal imaging were used to observe the infection of BV2 cells after LRRC25 silencing. Q-PCR and ELISA were used to determine the changes in IFN-γ and ISG15 in the culture supernatant of each group. RESULTS: Following H37Rv infection, it was observed that the expression of LRRC25 was upregulated. Upon silencing LRRC25, the proportion of BV2 cells infected by H37Rv decreased significantly. ELISA analysis showed that IFN-γ and ISG15 levels in cell culture supernatant decreased after H37Rv infection, while they significantly increased after LRRC25 silencing. CONCLUSIONS: This study provides evidence that LRRC25 is the key negative regulator of microglial anti-Mtb immunity. It exerts its function by degrading free ISG15 and inhibiting the secretion of IFN-γ, thereby improving the anti-Mtb immunity of BV2 cells.

Macrophage-targeted nanoparticles mediate synergistic photodynamic therapy and immunotherapy of tuberculosis.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that poses a serious global public health threat. Due to the high incidence of adverse reactions associated with conventional treatment regimens, there is an urgent need for better alternative therapies. CpG oligodeoxynucleotides (CpG ODNs) are synthetic oligodeoxyribonucleotide sequences. They can induce a Th1-type immune response by stimulating Toll-like receptors (TLRs) in mammalian immune cells, thus killing Mtb. However, due to the negative charge and easy degradation of CpG ODNs, it is necessary to deliver them into cells using nanomaterials. PCN-224 (hereinafter referred to as PCN), as a metal-organic framework based on zirconium ions and porphyrin ligands, not only has the advantage of high drug loading capacity, but also the porphyrin molecule in it is a type of photosensitizer, which allows these nanocomposites to play a role in photodynamic therapy (PDT) while delivering CpG ODNs. In addition, since Mtb mainly exists in macrophages, targeting anti-TB agents to macrophages is helpful to improve the anti-TB effect. Phosphatidylserine (PS) is a biological membrane phospholipid that is normally found on the inner side of cell membranes in, for example, plant and mammalian cells. When apoptosis occurs, PS can flip from the inner side of the cell membrane to the surface of the cell membrane, displaying a specific "eat-me" signal that can be recognized by specific receptors on macrophages. Therefore, we can use this macrophage-targeting property of PS to construct bio-inspired targeted drug delivery systems. In this study, we constructed PCN-CpG@PS nanocomposites. PCN-CpG@PS, combining PDT and immunotherapy, is designed to target macrophages at the site of a lesion and kill latent Mtb. We physically characterized the nanocomposites and validated their bactericidal ability in vitro and their ability to stimulate the immune system in vivo. The results demonstrated that the targeted nanocomposites have certain in vitro antituberculosis efficacy with good safety.

Rv1258c acts as a drug efflux pump and growth controlling factor in Mycobacterium tuberculosis.

The possible role of efflux pump as a survival mechanism in Mycobacterium tuberculosis (M. tb) is gaining an increasing attention. Previously, Rv1258c (Tap) and its certain mutations confer the clinically relevant drug resistance. In this study, we found new mutations of Rv1258c in G195C, T297P and I328T. Effect of modulating T297P and I328T on the drug resistance by knockout and complement in M. tb H37Rv showed that M. tb ΔRv1258c showed a slightly lower MIC for rifampin, ethambutol, ofloxacin, amikacin, capreomycin and streptomycin than M. tb H37Rv WT and the complement. Rv1258c T297P and Rv1258c I328T showed an increased drug resistance to ethambutol and capreomycin than the complement of Rv1258c WT. Most importantly, M. tb ΔRv1258c exhibited a slow growth in the normal culture medium. TMT-based quantitative proteomics analysis of M. tb ΔRv1258c and WT showed that the knockout of Rv1258c greatly down-regulated the expression of the ribosome system and one of the special five type VII secretion systems, ESX-3, which impaired the bacterial growth. These results indicate that the newly found T297P and I328T mutations of Rv1258c contributed to an increased resistance to ethambutol and capreomycin, and Rv1258c as growth controlling factor influencing the growth of M. tb.

Supramolecular-mediated dual-functional DNA nanocomposites for programmable cancer therapy.

Programmable cancer therapies may perfectly prevent mutual drug restrictions, however, developing an efficient codelivery system with such an ability remains challenging. We herein first demonstrate the use of supramolecular-mediated dual-functional DNA nanocomposites for programmable chemodynamic therapy (CDT) and chemotherapy (CT), in which a water-soluble cyclodextrin-resveratrol (CD-Res) complex can be facilely encapsulated during the coassembly of Fe2+ and DNA to form the desired spherical nanocomposites. After endocytosis, the released Fe2+ can immediately trigger an endogenous Fenton reaction, inducing ferroptosis for CDT and ˙OH depletion, followed by the sustained release of the protected Res from the CD cavity. This process improves the efficacy of CT by preventing Res from the oxidation of ˙OH. The as-prepared nano-composites can sufficiently accumulate in the tumor, demonstrating an adequate programmable therapeutic performance without serious toxicity. Thus, a facile, fresh and changeable strategy for the design of antitumor therapies is presented.