A multifunctional nanoplatform for chemotherapy and nanocatalytic synergistic cancer therapy achieved by amplified lipid peroxidation.

Traditional cancer chemotherapy suffers from low efficacy and severe side effects, limiting its use as a first-line treatment. To address this issue, we investigated a novel way to induce lipid peroxidation (LPO), which plays an essential role in ferroptosis and may be useful against cancer cells and tumors. In this study, a pH-responsive synergistic cancer therapy nanoplatform was prepared using CaCO3 co-loaded with oleanolic acid (OA) and lipoxygenase (LOX), resulting in the formation OLCaP NP. This nanoplatform exhibited good drug release properties in an acidic tumor environment owing to the presence of CaCO3. As a result of acidic stimulation at tumor sites, the OLCaP NP released OA and LOX. OA, a chemotherapeutic drug with anticancer activity, is already known to promote the apoptosis of cancer cells, and LOX is a natural enzyme that catalyzes the oxidation of polyunsaturated fatty acids, leading to the accumulation of lipid peroxides and promoting the apoptosis of cancer cells. More importantly, OA upregulated the expression of acyl-coenzyme A synthetase long-chain family member 4 (ACSL4), which promoted enzyme-mediated LPO. Based on our combined chemotherapy and nanocatalytic therapy, the OLCaP NP not only had remarkable antitumor ability but also upregulated ACSL4 expression, allowing further amplification of LPO to inhibit tumor growth. These findings demonstrate the potential of this nanoplatform to enhance the therapeutic efficacy against tumors by inducing oxidative stress and disrupting lipid metabolism, highlighting its clinical potential for improved cancer treatment. STATEMENT OF SIGNIFICANCE: This study presents a novel nanoplatform that combines oleanolic acid (OA), a chemotherapeutic drug, and lipoxygenase (LOX), which oxidizes polyunsaturated fatty acids to trigger apoptosis, for targeted cancer therapy. Unlike traditional treatments, our nanoplatform exhibits pH-responsive drug release, specifically in acidic tumor environments. This innovation enhances the therapeutic effects of OA and LOX, upregulating acyl-CoA synthetase long-chain family member 4 expression and amplifying lipid peroxidation to promote tumor cell apoptosis. Our findings significantly advance the existing literature by demonstrating a synergistic approach that combines chemotherapy and nanocatalytic therapy. The scientific impact of this work lies in its potential to improve cancer treatment efficacy and specificity, offering a promising strategy for clinical applications and future research in cancer therapy.

Calcium-sensing receptor-mediated macrophage polarization improves myocardial remodeling in spontaneously hypertensive rats.

Chronic inflammation is a key element in the progression of essential hypertension (EH). Calcium plays a key role in inflammation, so its receptor, the calcium-sensing receptor (CaSR), is an essential mediator of the inflammatory process. Compelling evidence suggests that CaSR mediates inflammation in tissues and immune cells, where it mediates their activity and chemotaxis. Macrophages (Mφs) play a major role in the inflammatory response process. This study provided convincing evidence that R568, a positive regulator of CaSR, was effective in lowering blood pressure in spontaneously hypertensive rats (SHRs), improving cardiac function by alleviating cardiac hypertrophy and fibrosis. R568 can increase the content of CaSR and M2 macrophages (M2Mφs, exert an anti-inflammatory effect) in myocardial tissue, reduce M1 macrophages (M1Mφs), which have a pro-inflammatory effect in this process. In contrast, NPS2143, a negative state regulator of CaSR, exerted the opposite effect in all of the above experiments. Following this study, R568 increased CaSR content in SHR myocardial tissue, lowered blood pressure, promoted macrophages to M2Mφs and improved myocardial fibrosis, but interestingly, both M1Mφs and M2Mφs were increased in the peritoneal cavity of SHRs, the number of M2Mφs remained lower than M1Mφs. In vitro, R568 increased CaSR content in RAW264.7 cells (a macrophage cell line), regulating intracellular Ca2+ ([Ca2+]i) inhibited NOD-like receptor family protein 3 (NLRP3) inflammasome activation and ultimately prevented its conversion to M1Mφs. The results showed that a decrease in CaSR in hypertensive rats causes further development of hypertension and cardiac damage. EH myocardial remodeling can be improved by CaSR overexpression by suppressing NLRP3 inflammasome activation and macrophage polarization toward M1Mφs and increasing M2Mφs.

Murine Cytomegalovirus Infection Induced miR-1929-3p Down-Regulation Promotes the Proliferation and Apoptosis of Vascular Smooth Muscle Cells in Mice by Targeting Endothelin A Receptor and Downstream NLRP3 Activation Pathway.

Our previous study demonstrated in vivo that mouse cytomegalovirus (MCMV) infection promoted vascular remodeling after downregulation of miR-1929-3p. This study aimed to investigate the role of miR-1929-3p/ETAR/NLRP3 pathway in mouse vascular smooth muscle cells (MOVAS) after MCMV infection. First, PCR was used to detect the success of the infection. Second, MOVAS were transfected with the miR-1929-3p mimic, inhibitor, and ETAR overexpressed adenovirus vector. Cell proliferation was detected using EdU, whereas apoptosis was detected using flow cytometry. The expression of miR-1929-3p and ETAR were detected using qRT-PCR. Western blot detected proteins of cell proliferation, apoptosis, and the NLRP3 inflammasome. Interleukin-1ß and interleukin-18 were determined using ELISA. The results revealed that after 48 h, MCMV infection promoted the proliferation of MOVAS when the MOI was 0.01. MCMV infection increased ETAR by downregulating miR-1929-3p. The miR-1929-3p mimic reversed the proliferation and apoptosis, whereas the miR-1929-3p inhibitor promoted this effect. ETAR overexpression further promoted MCMV infection by downregulating miR-1929-3p-mediated proliferation and apoptosis. MCMV infection mediates the downregulation of miR-1929-3p and the upregulation of ETAR, which activates NLRP3 inflammasome. In conclusion, MCMV infection promoted the proliferation of MOVAS, possibly by downregulating miR-1929-3p, promoting the upregulation of the target gene ETAR and activating NLRP3 inflammasome.

Low expression of miR-1929-3p mediates murine cytomegalovirus-induced fibrosis in cardiac fibroblasts via targeting endothelin a receptor/NLRP3 inflammasome pathway.

MicroRNAs are crucial in the development of myocardial remodeling in hypertension. Low miR-1929-3p expression induced by murine cytomegalovirus (MCMV) infection is closely related to hypertensive myocardial remodeling. This study investigated the molecular mechanism of miR-1929-3p-induced myocardial remodeling after MCMV infection. We modeled MCMV-infected mouse cardiac fibroblasts (MMCFs) as the primary cell model. First, MCMV infection reduced the expression of miR-1929-3p and increased the mRNA and protein expression of its target gene endothelin receptor type A (ETAR) in mouse cardiac fibroblasts (MCFs), which demonstrated an internal relationship with myocardial fibrosis (MF) based on high proliferation, phenotypic transformation (α-SMA), and collagen expression in MMCFs. The transfection of the miR-1929-3p mimic downregulated the high expression of ETAR and alleviated these adverse effects in MMCFs. Inversely, these effects were exacerbated by the miR-1929-3p inhibitor. Second, the transfection of endothelin receptor type A over-expressed adenovirus (adETAR) reversed these positive effects of the miR-1929-3p mimic on MF improvement. Third, the transfection of adETAR exhibited a strong inflammatory response in MMCFs with increased expression of NOD-like receptors pyrin domain containing 3 (NLRP3) and increased secretion of interleukin-18. However, we found that the ETAR antagonist BQ123 and the selected NLRP3 inflammasome inhibitor MCC950 effectively eliminated the inflammatory response induced by both MCMV infection and miR-1929-3p inhibitor. Moreover, the MCF supernatant was related to cardiomyocyte hypertrophy. Our findings suggest that MCMV infection promotes MF by inducing the downregulation of miR-1929-3p and the high expression of ETAR, which activates NLRP3 inflammasomes in MCFs.

Fluorescent detection of brown spot of tobacco caused by Alternaria alternata based on lambda exonuclease-induced DNAzyme amplification.

A rapid, simple, and sensitive fluorescent detection method for brown spot of tobacco is established by lambda exonuclease-induced Mg2+-dependent DNAzyme amplification. It contains hybridization of the Alternaria alternata genome and HP1, digestion of the 5'-phosphorylated strand of the hybrid dsDNA by lambda exonuclease, acquisition of complete Mg2+-dependent DNAzyme, cleavage of the substrate modified with FAM and BHQ-1, and fluorescent detection. The proposed assay exhibits good sensitivity (10 pg L-1), selectivity and reproducibility. The method does not require pure DNA and expensive instruments, and can be performed within 2.5 hours. To the best of our knowledge, this is the first report of fluorescent detection of Alternaria alternata and its tobacco field samples. This method can be applied to the rapid and sensitive detection of Alternaria alternata in tobacco and its seedlings, and is particularly important for the green prevention and control of tobacco brown spot disease.

Detection of Tobacco Bacterial Wilt Caused by Ralstonia solanacearum by Combining Polymerase Chain Reaction with an α-Hemolysin Nanopore.

Tobacco bacterial wilt is a serious disease caused by the soil-borne bacterium Ralstonia solanacearum (R. solanacearum). Herein, a rapid and purification-free α-hemolysin (α-HL) nanopore-sensing strategy based on polymerase chain reaction (PCR) and lambda exonuclease digestion was established to detect R. solanacearum. A 198-nucleotide-long single-stranded DNA was obtained via asymmetric PCR or the lambda exonuclease-mediated digestion of the PCR product. The DNA fragment produced unique long-lived, current-blocking signals when it passed through the α-HL nanopore. This sensing approach can allow for the determination of R. solanacearum in tobacco samples and can be conveniently extended to other DNA monitoring because of the extremely wide range of PCR applications.

Carrier-Free ATP-Activated Nanoparticles for Combined Photodynamic Therapy and Chemotherapy under Near-Infrared Light.

The combination of photodynamic therapy (PDT) and chemotherapy (chemo-photodynamic therapy) for enhancing cancer therapeutic efficiency has attracted tremendous attention in the recent years. However, limitations, such as low local concentration, non-suitable treatment light source, and uncontrollable release of therapeutic agents, result in reduced combined treatment efficacy. This study considered adenosine triphosphate (ATP), which is highly upregulated in tumor cells, as a biomarker and developed ingenious ATP-activated nanoparticles (CDNPs) that are directly self-assembled from near-infrared photosensitizer (Cy-I) and amphiphilic Cd(II) complex (DPA-Cd). After selective entry into tumor cells, the positively charged CDNPs would escape from lysosomes and be disintegrated by the high ATP concentration in the cytoplasm. The released Cy-I is capable of producing single oxygen (1 O2 ) for PDT with 808 nm irradiation and DPA-Cd can concurrently function for chemotherapy. Irradiation with 808 nm light can lead to tumor ablation in tumor-bearing mice after intravenous injection of CDNPs. This carrier-free nanoparticle offers a new platform for chemo-photodynamic therapy.

Label-free Sensing of Main Protease Activity of SARS-CoV-2 with an Aerolysin Nanopore.

The main protease (Mpro ), which is highly conserved and plays a critical role in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a natural biomarker for SARS-CoV-2. Accurate assessment of the Mpro activity is crucial for the detection of SARS-CoV-2. Herein, we report a nanopore-based sensing strategy that uses an enzyme-catalyzed cleavage reaction of a peptide substrate to measure the Mpro activity. The peptide was specifically cleaved by the Mpro , thereby releasing the output products that, when translocated through aerolysin, quantitatively produced the signature current events. The proposed method exhibited high sensitivity, allowing the detection of Mpro concentrations as low as 1 nM without the use of any signal amplification techniques. This simple, convenient, and label-free nanopore assay may expand the diagnostic tools for viruses.

Strong π-π Stacking Stabilized Nanophotosensitizers: Improving Tumor Retention for Enhanced Therapy for Large Tumors in Mice.

Conventional photosensitizers (PSs) often show poor tumor retention and are rapidly cleared from the bloodstream, which is one of the key hindrances to guarantee precise and efficient photodynamic therapy (PDT) in vivo. In this work, a photosensitizer assembly nanosystem that sharply enhances tumor retention up to ≈10 days is present. The PSs are synthesized by meso-substituting anthracene onto a BODIPY scaffold (AN-BDP), which then self-assembles into stable nanoparticles (AN-BDP NPs) with amphiphilic block copolymers due to the strong intermolecular π-π interaction of the anthracene. Additionally, the incorporated anthracene excites the PSs, producing singlet oxygen under red-light irradiation. Although AN-BDP NPs can completely suppress regular test size tumors (≈100 mm3 ) by one-time radiation, only 12% tumor growth inhibition rate is observed in the case of large-size tumors (≈350 mm3 ) under the same conditions. Due to the long-time tumor retention, AN-BDP NPs allow single-dose injection and three-time light treatments, resulting in an inhibition rate over 90%, much more efficient than single-time radiation of conventional clinically used PSs including chlorin-e6 (Ce6) and porphyrin with poor tumor retention. The results reveal the importance of long tumor retention time of PSs for efficient PDT, which can accelerate the clinical development of nanophotosensitizers.

A Sequential Dual-Model Strategy Based on Photoactivatable Metallopolymer for On-Demand Release of Photosensitizers and Anticancer Drugs.

The synergistic combination of chemotherapy and photodynamic therapy has attracted considerable attention for its enhanced antitumoral effects; however, it remains challenging to successfully delivery photosensitizers and anticancer drugs while minimizing drug leakage at off-target sites. A red-light-activatable metallopolymer, Poly(Ru/PTX), is synthesized for combined chemo-photodynamic therapy. The polymer has a biodegradable backbone that contains a photosensitizer Ru complex and the anticancer drug paclitaxel (PTX) via a singlet oxygen (1 O2 ) cleavable linker. The polymer self-assembles into nanoparticles, which can efficiently accumulate at the tumor sites during blood circulation. The distribution of the therapeutic agents is synchronized because the Ru complex and PTX are covalently conjugate to the polymer, and off-target toxicity during circulation is also mostly avoided. Red light irradiation at the tumor directly cleaves the Ru complex and produces 1 O2 for photodynamic therapy. Sequentially, the generated 1 O2 triggers the breakage of the linker to release the PTX for chemotherapy. Therefore, this novel sequential dual-model release strategy creates a synergistic chemo-photodynamic therapy while minimizing drug leakage. This study offers a new platform to develop smart delivery systems for the on-demand release of therapeutic agents in vivo.

An Organic Nanotherapeutic Agent Self-Assembled from Cyanine and Cu (II) for Combined Photothermal and Chemodynamic Therapy.

Although the combination of photothermal/chemodynamic therapy (PTT/CDT) based on various inorganic nanomaterials has promising anticancer effects, poor biocompatibility and biodegradability of inorganic nanoplatforms pose obstacles to their use in clinic. On the contrary, nanoscale metal-organic particles are considered to be a promising platform because of their biocompatibility and efficient metabolism. Herein, HA@Cy-Cu NPs are prepared using the coordination-driven assembly of cyanine dyes with Cu2+ ions. HA@Cy-Cu NPs demonstrate excellent synergistic PTT/CDT, a high photothermal conversion efficiency (43%), and enhanced photostability. Moreover, Cu2+ in the NPs can be reduced to Cu+ by glutathione (GSH) and can transform H2 O2 to •OH, which down-regulates intracellular GSH levels and up-regulates significant oxidative damage. Therefore, promising in vivo tumor ablation is observed at a low dose of HA@Cy-Cu, suggesting that the combination of PTT/CDT greatly improved the antitumor performance. HA@Cy-Cu can further improve organic nano-systems for anti-tumor therapy by integrating PTT and CDT.

MicroRNA­1929­3p participates in murine cytomegalovirus­induced hypertensive vascular remodeling through Ednra/NLRP3 inflammasome activation.

MicroRNAs (miRNAs) play an important role in the development of vascular remodeling in essential hypertension (EH) by mediating the effects of human cytomegalovirus (HCMV) on the vascular system. Therefore, the aim of the present study was to investigate the effects of murine cytomegalovirus (MCMV) infection on blood pressure and vascular function in mice, in order to elucidate the role of miR­1929­3p in this process. For model development, 7­month­old C57BL/6J mice were infected with the Smith strain of MCMV, and MCMV DNA, IgG and IgM were detected. Subsequently, blood pressure was measured via the carotid artery, and the morphological changes of the aorta were evaluated by hematoxylin and eosin and Masson's trichrome staining. miR­1929­3p transfection was performed using an adeno­associated virus packaged vector and the changes in vascular structure were then observed. The levels of nitric oxide (NO) and endothelial NO synthase were also assessed with colorimetry. Vascular remodeling and expression of NLRP3 inflammasome pathway­related proteins were detected by immunohistochemistry and western blotting. Endothelin­1 (ET­1), interleukin (IL)­1ß and IL­18 were assayed by ELISA. The results revealed that MCMV infection increased the blood pressure, promoted vascular remodeling, caused endothelial cell injury, and downregulated miR­1929­3p. However, these effects were alleviated by miR­1929­3p overexpression, which downregulated endothelin A receptor (Ednra) and NLRP3 inflammasome, as well as endothelial injury­ and vascular remodeling­related genes. Taken together, the findings of the present study indicated that overexpression of miR­1929­3p may improve MCMV­induced vascular remodeling, possibly via the deactivation of the NLRP3 inflammasome by ET­1/Ednra.

Calcilytic NPS2143 promotes proliferation and inhibits apoptosis of spontaneously hypertensive rat vascular smooth muscle cells via activation of the renin-angiotensin system.

Vascular smooth muscle cell (VSMC) proliferation and apoptosis and the renin-angiotensin system (RAS) play critical roles in the development of essential hypertension. The activation of calcium-sensing receptor (CaSR), functionally expressed in VSMCs, inhibits cyclic adenosine monophosphate (cAMP) formation by elevating intracellular calcium ([Ca2+]i) and then suppressing renin release. The present study aimed to investigate the effects of NPS2143-mediated inhibition of CaSR on VSMC proliferation and apoptosis in spontaneously hypertensive rat (SHR) VSMCs and to assess whether these effects were mediated by alterations to RAS signaling. Primary VSMCs were isolated from the aortas of SHRs and Wistar-Kyoto rats. SHR VSMCs were treated with CaSR antagonist NPS2143 and cell proliferation and CaSR and RAS-related protein expression levels were measured to assess the effect. The results indicated that NPS2143 treatment promoted SHR VSMC proliferation, lower CaSR expression levels and higher RAS-related proteins levels when compared with control treatment. Additional measurement of the expression levels of proteins related to proliferation, remodeling, apoptosis and RAS related proteins, as well as cell viability, cell cycle, cell apoptosis ratio, [Ca2+]i, and the concentration of cAMP was performed after treatment with NPS2143, PLC inhibitor U73122, IP3 receptor antagonist 2-aminoethoxydiphenylborane (APB), adenylyl cyclase-V inhibitor MDL12330A, angiotensin converting enzyme inhibitor captopril, angiotensin I receptor (AT1R) inhibitor losartan, NPS2143 + U73122, NPS2143 + 2-APB, NPS2143 + MDL12330A, NPS2143 + captopril and NPS2143 + losartan. The results suggested that NPS2143 promoted cell proliferation, inhibited cell apoptosis, decreased [Ca2+]i and increased the expression of RAS compared with control treatments. NPS2143 + U73122 and NPS2143 + 2-APB enhanced the effects of NPS2143, while NPS2143 + MDL12330A, NPS2143 + captopril, NPS2143 + losartan attenuated the effected of NPS2143 in SHR VSMCs. Furthermore, the knockdown of AT1R by AT1R-short hairpin RNA also attenuated the effects of NPS2143 compared with NPS2143 alone. Collectively, these data indicated that NPS2143 promoted proliferation and inhibited apoptosis of VSMCs in SHRs, the effect of which was achieved by activation of RAS signaling.

A photosensitizer-inhibitor conjugate for photodynamic therapy with simultaneous inhibition of treatment escape pathways.

Photodynamic therapy (PDT) has been successfully demonstrated for anticancer treatment in vivo. However, tumor metastasis during PDT are still inevitable due to the activation of the epidermal growth factor receptor (EGFR). The current work describes the synthesis of a photosensitizer (PS)-EGFR inhibitor conjugate for PDT with simultaneous tumor metastasis inhibition. The conjugate efficiently internalized into cancer cells and generated reactive oxygen species (ROS) under light, indicating strong cytotoxicity even in hypoxic tumor environment. The presence of an EGFR inhibitor significantly inhibited cell migration and invasion. Accordingly, photoactivation of the conjugate resulted in efficient tumor growth inhibition in a 4T1 tumor-bearing mouse model and suppressed angiogenesis and tumor metastasis during PDT. Therefore, combined PDT and EGFR inhibition strategy provides a new platform for future anticancer treatment with high safety.

NIR Light-Driving Barrier-Free Group Rotation in Nanoparticles with an 88.3% Photothermal Conversion Efficiency for Photothermal Therapy.

Traditional photothermal therapy requires high-intensity laser excitation for cancer treatments due to the low photothermal conversion efficiency (PCE) of photothermal agents (PTAs). PTAs with ultra-high PCEs can decrease the required excited light intensity, which allows safe and efficient therapy in deep tissues. In this work, a PTA is synthesized with high PCE of 88.3% based on a BODIPY scaffold, by introducing a CF3 "barrier-free" rotor on the meso-position (tfm-BDP). In both the ground and excited state, the CF3 moiety in tfm-BDP has no energy barrier to rotation, allowing it to efficiently dissipate absorbed (NIR) photons as heat. Importantly, the barrier-free rotation of CF3 can be maintained after encapsulating tfm-BDP into polymeric nanoparticles (NPs). Thus, laser irradiation with safe intensity (0.3 W cm-2 , 808 nm) can lead to complete tumor ablation in tumor-bearing mice after intravenous injection of tfm-BDP NPs. This strategy of "barrier-free rotation" provides a new platform for future design of PTT agents for clinical cancer treatment.

Ex vivo identification of circulating tumor cells in peripheral blood by fluorometric "turn on" aptamer nanoparticles.

The detection of the circulating tumor cells (CTCs) detached from solid tumors has emerged as a burgeoning topic for cancer diagnosis and treatment. The conventional CTC enrichment and identification mainly rely on the specific binding of the antibodies on the capture interface of the magnetic nanoparticles with the corresponding biomarkers on the cell membranes. However, these methods could easily generate false-negative results due to the extremely low concentration of CTCs and the internal heterogeneity of the tumor cells. Herein, with the aim of selectively identifying CTCs and improving the detection accuracy in peripheral blood, we designed the fluorometric "turn on" Au nanoparticles (DHANs) with the modification of a tumor-targeted moiety, dehydroascorbic acid (DHA) and a fluorometric aptamer, which could be "switched-on" by an over-expressed intracellular protein, namely hypoxia-inducible factor-1α (HIF 1α). This novel nanoformulated detection platform demonstrated the great capacity for visualizing various CTCs in peripheral blood with significantly improved detection efficiency and sensitivity. As a result, the nanoplatform has a great potential to be further applied for CTC detection in vitro or in vivo, which holds promise for extensive CTC studies.

miR-1929-3p Overexpression Alleviates Murine Cytomegalovirus-Induced Hypertensive Myocardial Remodeling by Suppressing Ednra/NLRP3 Inflammasome Activation.

MicroRNAs (miRNAs) play crucial roles in the development of essential hypertension (EH). Previously, we found that the expression of miR-1929-3p was decreased in C57BL/6 mice with hypertension induced by murine cytomegalovirus (MCMV). In this study, we explored the role of miR-1929-3p in hypertension myocardial remodeling in MCMV-infected mice. First, we measured MCMV DNA and host IgG and IgM after infection and determined the expression of miR-1929-3p and its target gene endothelin A receptor (Ednra) mRNA in the myocardium of mice. Then, we performed invasive blood pressure (BP) monitoring. Heart-to-body weight ratio (HW/BW%), along with mRNA levels of B-type natriuretic peptide (BNP) and beta myosin heavy chain (ß-MHC), revealed myocardial remodeling. Hematoxylin/eosin and Masson's trichrome staining indicated morphological changes in the myocardium. Cardiac function was assessed via echocardiography. Moreover, MCMV-infected mice were injected with recombinant adeno-associated virus- (rAAV-) miR-1929-3p overexpression vector. Immunohistochemistry and western blotting showed the expression of Ednra and the activation of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome. And enzyme-linked immunosorbent assay (ELISA) revealed the concentrations of endothelin-1 (ET-1), interleukin-1ß (IL-1ß), and interleukin-18 (IL-18). In this study, we found that decreased expression of miR-1929-3p in MCMV-infected mice induced high BP and further development of myocardial remodeling cardiac function injury through increased expression of Ednra. Strikingly, overexpression of miR-1929-3p ameliorated these pathological changes of the heart. The positive effect was shown to be associated with inhibition of NLRP3 inflammasome activation and decreased expression of key proinflammatory cytokine IL-1ß. Collectively, these results indicate that miR-1929-3p overexpression may effectively alleviate EH myocardial remodeling by suppressing Ednra/NLRP3 inflammasome activation in MCMV-infected mice.

Unambiguous Discrimination of Multiple Protein Biomarkers by Nanopore Sensing with Double-Stranded DNA-Based Probes.

Biological research and clinical testing frequently require simultaneous quantification of multiple biomarkers for accurate disease diagnosis. In particular, the application of nanopore technology to real-sample analysis is limited in terms of discriminating multiple analytes in a mixture. In this study, we designed a series of highly specific double-stranded DNA-based probes and used them for synchronous detection of and discrimination among three protein biomarkers associated with lung cancer in a single nanopore. The probe could specifically identify and bind to the target, releasing an output DNA hybrid that generated signature current signals upon translocation through the nanopore. DNA hybrids with different hybridization stability and structure produced blockade currents clearly distinguishable in nanopore recordings, which could be unequivocally assigned to each analyte, thereby enabling accurate differentiation among multiple biomarkers. This assay based on the excellent discrimination ability of the probes facilitates unambiguous identification and quantification of multiple analytes on a natural serum background, thus presenting a powerful tool for biomedical research and clinical practice.

"Off-on" switching of intracellular singlet oxygen release under biocompatible conditions.

Precise spatiotemporal control of singlet oxygen generation is of immense importance considering its involvement in photodynamic therapy. In this work, we present a rational design for an endoperoxide which is highly stable at ambient temperatures yet, can rapidly be converted into a highly labile endoperoxide, thus releasing the "stored" singlet oxygen on demand. The "off-on" chemical switching from the stable to the labile form is accomplished by the reaction with fluoride ions. The potential utility of controlled singlet oxygen release was demonstrated in cell cultures.

Ultrasensitive Detection of Cancer Cells Combining Enzymatic Signal Amplification with an Aerolysin Nanopore.

Sensitive detection of cancer cells at extremely low concentrations would greatly facilitate the screening and early diagnosis of cancer. Herein, we present a novel nanopore-based strategy for ultrasensitive detection of Ramos cells (human Burkitt's lymphoma cells), by combining the enzymatic signal amplification with an aerolysin nanopore sensor. In this assay, an aptamer for Ramos cells was prehybridized with a short complementary DNA. The presence of target cells causes the target-aptamer complex to unwind to free the complementary DNA, which would subsequently trigger the enzymatic cycling amplification. This process eventually generated a large number of output DNA, which could quantitatively produce characteristic current events when translocated through aerolysin. The proposed method exhibits excellent sensitivity, and as few as 5 Ramos cells could be detected. With good selectivity, the approach can allow for the determination of cancer cells in human serum, offering a powerful tool for biomedical research and clinical diagnosis.