Application of 3D-PCASL combined with t-ASL and MRA in the diagnosis of patients with isolated vertigo induced by posterior circulation ischemia.

OBJECTIVES: Isolated vertigo induced by posterior circulation ischemia (PCIV) can further progress into posterior circulation infarction. This study aimed to explore the diagnostic values of three-dimensional pseudo-continuous arterial spin labeling (3D-PCASL) combined with territorial arterial spin labeling (t-ASL) and magnetic resonance angiography (MRA) in visualizing and evaluating PCIV, seeking improved diagnostic tools for clinical guidance. METHODS: 28 PCIVs (11 males, 17 females, aged from 55 to 83 years, mean age: 69.68 ± 9.01 years) and 28 healthy controls (HCs, 12 male, 16 female, aged from 56 to 87 years, mean age: 66.75 ± 9.86 years) underwent conventional magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI), MRA, 3D-PCASL, and t-ASL. We compared the incidence of anatomic variants of the posterior circle of Willis in MRA, cerebral blood flow (CBF) and anterior collateral blood flow on postprocessing maps obtained from 3D-PCASL and t-ASL sequence between PCIVs and HCs. Chi-square test and paired t-test were analyzed statistically with SPSS 24.0 software. RESULTS: 7 PCIVs (7/28, 25%) and 6 HCs (6/28, 21%) showed fetal posterior cerebral artery (FPCA) on MRA, including 1 HC, and 6 PCIVs with FPCA appeared hypoperfusion. 18 PCIVs (64%) and 2 HCs (7%) showed hypoperfusion in the posterior circulation (PC), including 1 HC and 7 PCIVs displayed anterior circulation collateral flow. Chi-square analyses demonstrated a difference in PC hypoperfusion between PCIVs and HCs, whether in the whole or FPCA-positive group assessment (P < 0.05). Paired t-test showed that the CBF values were significant difference for the bilateral PC asymmetrical perfusion in the PCIVs (P < 0.01). When compared to the bilateral PC symmetrical non-hypoperfusion area in the PCIVs and HCs, the CBF values were not significant (P > 0.05). The CBF values of the PC in PCIVs were lower than in HCs (P < 0.05). The reduction rate in the hypoperfusion side of the bilateral PC asymmetrical perfusion of the PCIVs ranged from 4% to 37%, while the HCs reduction rate was 7.7%. The average PC symmetrical perfusion average reduction rate of the PCIVs was 52.25%, while the HCs reduction rate was 42.75%. CONCLUSION: 3D-PCASL is a non-invasive and susceptible method for detecting hypoperfusion in PC, serving as a potential biomarker of PCIV. The suspected hypoperfusion in PC may be attributed to the emergence of FPCA and the manifestation of anterior collateral flow when combining t-ASL and MRA sequences. These findings demonstrated that 3D-PCASL combined with t-ASL and MRA sequences are the potential method to identify PCIV, leading to early diagnosis of PCIV and reducing the risk of progressing into infarction.

Network Meta-Analysis Indicates Superior Effects of Omega-3 Polyunsaturated Fatty Acids in Preventing the Transition to Psychosis in Individuals at Clinical High-Risk.

BACKGROUND: The efficacy of pharmacological and nutritional interventions in individuals at clinical high risk for psychosis (CHR-P) remains elusive. This study aims to investigate the efficacy of pharmacological and nutritional interventions in CHR-P and whether these interventions can enhance the efficacy of psychological treatments. METHODS: We systematically reviewed data from 5 databases until July 24, 2021: PubMed, Web of Science, EMBASE, China National Knowledge Infrastructure, and WanFang Data. The primary outcome was the transition to psychosis. Network meta-analyses were conducted at 3 time points (6, 12, and ≥24 months) considering both pharmacological/nutritional interventions alone and its combination with psychotherapy. RESULTS: Out of 11 417 identified references, 21 studies were included, comprising 1983 participants. CHR-P participants receiving omega-3 polyunsaturated fatty acids treatment were associated with a lower probability of transition compared with placebo/control at 6 months (odds ratio [OR] = 0.07, 95% confidence interval [CI] = .01 to .054), 12 months (OR = 0.14, 95% CI = .03 to .66), and ≥24 months (OR = 0.16, 95% CI = .05 to .54). Moreover, risperidone plus psychotherapy was associated with a lower likelihood of transition at 6 months compared with placebo/control plus psychotherapy, but this result was not sustained over longer durations. CONCLUSION: Omega-3 polyunsaturated fatty acids helped in preventing transitions to psychosis compared with controls. PROSPERO REGISTRATION NUMBER: CRD42021256209.

Functional Activity in the Effect of Transcranial Magnetic Stimulation Therapy for Patients with Depression: A Meta-Analysis.

Depression is a long-lasting mental disorder that affects more than 264 million people worldwide. Transcranial magnetic stimulation (TMS) can be a safe and effective choice for the treatment of depression. Functional neuroimaging provides unique insights into the neuropsychiatric effects of antidepressant TMS. In this meta-analysis, we aimed to assess the functional activity of brain regions caused by TMS for depression. A literature search was conducted from inception to 5 January 2022. Studies were then selected according to predetermined inclusion and exclusion criteria. Activation likelihood estimation was applied to analyze functional activation. Five articles were ultimately included after selection. The main analysis results indicated that TMS treatment for depression can alter the activity in the right precentral gyrus, right posterior cingulate, left inferior frontal gyrus and left middle frontal gyrus. In resting-state studies, increased activation was shown in the right precentral gyrus, right posterior cingulate, left inferior frontal gyrus and left superior frontal gyrus associated with TMS treatment. In task-related studies, clusters in the right middle frontal gyrus, left sub-gyrus, left middle frontal gyrus and left posterior cingulate were hyperactivated post-treatment. Our study offers an overview of brain activity changes in patients with depression after TMS treatment.

A Supramolecular Nitric Oxide Nanodelivery System for Prevention of Tumor Metastasis by Inhibiting Platelet Activation and Aggregation.

Tumor cell-induced platelet aggregation (TCIPA) is known as a critical step in hematogenous tumor metastasis. The endogenous nitric oxide (NO) plays an important role in anticoagulation, which might have great potential to inhibit TCIPA. Herein, a glutathione-sensitive supramolecular nanocarrier is prepared via host-guest interaction for effective delivery of NO and chemotherapeutic agent gemcitabine (GEM). NO could be effectively released in tumor cells and inhibits platelet activation and aggregation. The inhibition of TCIPA by NO could effectively attenuate the migration and invasion of tumor cells in vitro. Furthermore, the in vivo experiments demonstrate that the NO and GEM co-delivered supramolecular nanocarriers can suppress the growth of primary tumor. More importantly, although NO-containing nanocarriers cannot inhibit the growth of primary tumors effectively, they can significantly inhibit tumor metastasis. This NO-based nano-delivery system not only provides new inspiration for multifunctional applications of NO in cancer therapy but also shows great potential in clinical antimetastatic applications.

A mitochondria-targeted supramolecular nanoplatform for peroxynitrite-potentiated oxidative therapy of orthotopic hepatoma.

Oxidative therapy, which generates reactive oxygen species (ROS) via intracellular enzymatic reactions to achieve tumor ablation, is considered as an emerging approach to cancer treatment. Herein, nitric oxide (NO)-combined oxidative therapy is reported by integrating glutathione (GSH)-sensitive NO donor and pH-sensitive cinnamaldehyde (CA) prodrug into a mitochondria-targeted drug nanocarrier, which is prepared by the host-guest interaction between α-cyclodextrin (α-CD) and polyethylene glycol (PEG). After internalized by cancer cells, CA can be released in acidic endo/lysosome and finally induce ROS generation in mitochondria for oxidative therapy. At the same time, NO can be targeted delivered to mitochondria by a mitochondria-targeting strategy and then realize selective release of NO in mitochondria. NO can deplete intracellular predominant antioxidant GSH, which will enhance oxidative therapy of CA. Furthermore, peroxynitrite (ONOO-) with strong peroxidation and nitration capability can be produced in mitochondria by the reaction between NO and ROS for reactive nitrogen species (RNS)-mediated oxidative therapy. The generation of ONOO- in mitochondria is very effective in facilitating mitochondrial membrane permeabilization, which can cause mitochondrial dysfunction and finally induce mitochondrial apoptosis. The antitumor ability of mitochondria-targeted ONOO--potentiated oxidative therapy is fully investigated on subcutaneous and orthotopic hepatoma model on nude mice. This innovative strategy for the selective generation of ONOO- in mitochondria may serve as an afflatus for future applications in cancer treatment.

Lingonberry Anthocyanins Inhibit Hepatic Stellate Cell Activation and Liver Fibrosis via TGFß/Smad/ERK Signaling Pathway.

Phytochemicals from lingonberry have rich pharmacological value and may play an essential role in treating liver diseases. We investigated the regulatory role of lingonberry anthocyanins (LA) on HSC activation in vitro and liver fibrogenesis in vivo. The viability of HSCs treated with LA was significantly reduced in a dose-dependent manner at the concentration of 25-100 µg/mL, in which the monomers of LA also reduced the proliferation of HSCs via IC50 assay. The inducer transforming growth factor ß1 (TGFß1) and the effector α-smooth muscle actin (α-SMA) of HSC activation were all decreased both in protein and RNA levels treated by LA. Moreover, LA alleviated CCl4-induced liver fibrosis in rats, reducing collagen aggregation and production and decreasing the hydroxyproline (HYP) and malondialdehyde (MDA) levels in the liver tissue. Moreover, LA reduced the indexes of serum liver fibrosis and reversed the index of serum liver function in CCl4-induced rats. Furthermore, the antioxidant enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT), in the liver tissue and serum were significantly increased upon treatment with LA. Importantly, LA promoted hepatic parenchymal cell proliferation and inhibited the expression of TGFß/Smad/extracellular regulated protein kinase (ERK) signaling pathway-related genes. This study demonstrates the anti-liver fibrosis activity of LA and investigates its mechanism, which may provide a novel strategy for treating liver fibrosis using lingonberry.

The Effect of Suppression Taurine on Relocation and Epithelial-Mesenchymal Transition in Mankind Lung Cancer Cells.

Aim: Taurine is believed to have antioxidant properties and has been implicated in the treatment of neurodegenerative disease, atherosclerosis, coronary heart disease, and prostate cancer. This research focused on taurine inhibition effects of expression related to migration and epithelial-mesenchymal transition- (EMT-) A549 study on related genes of human being non-small-cell lung cancer. Methods: MTT assays assessed cell viability and a RadiusTM assay showed that taurine also inhibited the lung cancer cell migration. Using RT-PCR and Western blot, the migration and EMT markers were identified and evaluated. Results: We found that taurine significantly decreased the expression of migration markers matrix metallopeptidase 9 (MMP-9) and vascular endothelial growth factor (VEGF). In contrast, TIMP metallopeptidase inhibitor 1 (TIMP-1) and TIMP metallopeptidase inhibitor 2 (TIMP-2) expressions were increased with taurine treatment. In addition, we found an association between taurine treatment and the expression of EMT markers. The expression of epithelial marker E-cadherin and the mesenchymal marker N-cadherin TWIST-1 was decreased, but the expression of zinc finger protein SNAIL-1 and E-zinc finger homeobox 1 (ZEB-1) was increased. Conclusion: Taken together, our study strongly suggests the therapeutic significance of taurine, which possesses antimigration activity and induces EMT markers expression in lung cancer cells.

Tailoring Supramolecular Prodrug Nanoassemblies for Reactive Nitrogen Species-Potentiated Chemotherapy of Liver Cancer.

The development of a controllable reactive nitrogen species (RNS) generation system for cancer treatment has remained elusive. Herein, a supramolecular prodrug nanoassemblies (SPNA) strategy that co-delivers a nitric oxide (NO) donor and a superoxide anion (O2•-) inducing chemotherapeutic agent was reported for RNS-potentiated chemotherapy. The mole ratio of platinum(IV) prodrug and NO donor could be precisely tailored in SPNAPt/NO. Platinum(II) and NO would be released intracellularly to produce a highly toxic RNS, peroxynitrite anion (ONOO-). The levels of glutathione reductase (GR) and xeroderma pigmentosum group A (XPA) were down-regulated by ONOO-, thus synergistically decreasing detoxification and blocking DNA damage repair of Pt-based chemotherapy. The RNS-potentiated efficacy of SPNAPt/NO was validated on subcutaneous hepatoma xenograft models and an orthotopic cisplatin-resistant hepatoma model. This co-delivery strategy of NO donor and O2•- inducing chemotherapeutic agents for RNS-mediated therapy provides an insightful direction for cancer treatment.

Different prevalence trend of depression and anxiety among healthcare workers and general public before and after the peak of COVID-19 occurred in China: A meta-analysis.

OBJECTIVE: We aim to evaluate the prevalence of depression and anxiety among general public and healthcare workers during COVID-19 in China and the changes of prevalence before and after the peak of the epidemic occurred. METHODS: Studies were searched from following database: PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), WANGFANG DATA, from inception to 1 st May 2020. Random-effects model was applied to pool the prevalence. Comparative analysis was also applied to evaluate the changes of prevalence before and after the peak of the epidemic occurred. RESULTS: 34 articles were finally included. Prevalence of depression and anxiety was higher among healthcare worker than general public. Among general public, 26 % (95 %CI: 17 %-36 %) were suffering from depression and 22 % (95 %CI: 15 %-30 %) were having anxiety during COVID-19, while the prevalence of depression and anxiety among healthcare workers was 31 % (95 %CI: 25 %-37 %) and 40 % (95 %CI: 33 %-46 %) respectively. Comparative analysis showed healthcare workers (depression: 40 %, anxiety: 38 %) had higher percentage of having depression and anxiety than the general public (depression: 33 %, anxiety: 24 %) before the peak. Then a descended prevalence among healthcare workers (depression: 22 %, anxiety: 22 %) was detected compared with that before, while the prevalence among the general public raised (depression: 62 %, anxiety: 44 %) after the peak occurred. CONCLUSION: The COVID-19 epidemic had a potential psychiatric impact on general public and healthcare workers in China, which is more severer among healthcare workers. However, the psychiatric status of the general public trend to deteriorated, while healthcare workers trend to improve after the peak of epidemic.

Neuroimaging in the effect of transcranial magnetic stimulation therapy for patient with depression: a protocol for a coordinate-based meta-analysis.

INTRODUCTION: As a prevalent psychiatric disease, depression is a life-threatening mental disorder that may cause work disability and premature death. Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation procedure, which has been reported to have a significant effect on antidepressant treatment in recent years. However, the parameters of TMS for depression that can produce the best clinical benefits remain unknown. In the present study, we will evaluate the effect of TMS treatment for depression from the perspective of functional neuroimaging by performing a meta-analysis based on included studies. METHODS AND ANALYSIS: Two independent reviewers will search published studies in the following five databases: PubMed, Web of Science, Embase, China National Knowledge Infrastructure and WANGFANG DATA from inception to 1 June 2020. Then we will select studies according to predesigned inclusion and exclusion criteria. After extracting data from included studies, activation likelihood estimation will be applied to data synthesis. Any disagreement will be checked by the third reviewer who will also make the final decision. ETHICS AND DISSEMINATION: This work does not require ethics approval as it will be based on published studies. This review will be published in peer-reviewed journals.PROSPERO registration numberCRD42020165436.

3-Bromopyruvate-Conjugated Nanoplatform-Induced Pro-Death Autophagy for Enhanced Photodynamic Therapy against Hypoxic Tumor.

Autophagy triggered by reactive oxygen species (ROS) in photodynamic therapy (PDT) generally exhibits an anti-apoptotic effect to promote cell survival. Herein, an innovative supramolecular nanoplatform was fabricated for enhanced PDT by converting the role of autophagy from pro-survival to pro-death. The respiration inhibitor 3-bromopyruvate (3BP), which can act as an autophagy promoter and hypoxia ameliorator, was integrated into photosensitizer chlorin e6 (Ce6)-encapsulated nanoparticles to combat hypoxic tumor. 3BP could inhibit respiration by down-regulating HK-II and GAPDH expression to significantly reduce intracellular oxygen consumption rate, which could relieve tumor hypoxia for enhanced photodynamic cancer therapy. More importantly, the autophagy level was significantly elevated by the combination of 3BP and PDT determined by Western blot, immunofluorescent imaging, and transmission electron microscopy. It was very surprising that excessively activated autophagy promoted cell apoptosis, leading to the changeover of autophagy from pro-survival to pro-death. Therefore, PDT combined with 3BP could achieve efficient cell proliferation inhibition and tumor regression. Furthermore, hypoxia-inducible factor-1α (HIF-1α) could be down-regulated after tumor hypoxia was relieved by 3BP. Tumor metastasis could then be effectively inhibited by eliminating primary tumors and down-regulating HIF-1α expression. These results provide an inspiration for future innovative approaches of cancer therapy by triggering pro-death autophagy.

ATP Suppression by pH-Activated Mitochondria-Targeted Delivery of Nitric Oxide Nanoplatform for Drug Resistance Reversal and Metastasis Inhibition.

Mitochondria, which are important mediators for cancer initiation, growth, metastasis, and drug resistance, have been considered as a major target in cancer therapy. Herein, an acid-activated mitochondria-targeted drug nanocarrier is constructed for precise delivery of nitric oxide (NO) as an adenosine triphosphate (ATP) suppressor to amplify the therapeutic efficacy in cancer treatments. By combining α-cyclodextrin (α-CD) and acid-cleavable dimethylmaleic anhydride modified PEG conjugated mitochondria-targeting peptide, the nanocarrier shows prolonged blood circulation time and enhanced cellular uptake together with selectively restoring mitochondria-targeting capability under tumor extracellular pH (6.5). Such specific mitochondria-targeted delivery of NO proves crucial in inducing mitochondria dysfunction through facilitating mitochondrial membrane permeabilization and downregulating ATP level, which can inhibit P-glycoprotein-related bioactivities and formation of tumor-derived microvesicles to combat drug resistance and cancer metastasis. Therefore, this pioneering acid-activated mitochondria-targeted NO nanocarrier is supposed to be a malignant tumor opponent and may provide insights for diverse NO-relevant cancer treatments.

Intervertebral disc degeneration associated with vertebral marrow fat, assessed using quantitative magnetic resonance imaging.

OBJECTIVE: To investigate the potential clinical application of quantitative MRI in assessing the correlation between lumbar vertebrae bone marrow fat deposition and intervertebral disc degeneration. MATERIALS AND METHODS: A total of 104 chronic lower-back pain volunteers underwent 3.0-T MRI with T2-weighted imaging, T2 mapping, and iterative decomposition of water and fat with echo asymmetry and least squares estimation (IDEAL-IQ) between August 2018 and June 2019. Each disc was assessed with T2 value by T2 mapping, and the L1-S1 vertebral bone marrow fat fraction was assessed by IDEAL-IQ. The differences and relationship between T2 value and the adjacent vertebral bone marrow fat fraction values within the five Pfirrmann groups, five age groups, and five lumbar levels were statistically analyzed. RESULTS: The vertebral bone marrow fat fraction had a significant negative correlation with T2 values of nucleus pulposus' T2 values (p < 0.001). However, the significant negative correlation was only found between T2 values of nucleus pulposus and adjacent vertebral bone marrow fat in Pfirrmann II-III, L1/2-L5/S1 level, and 40-49 years' age groups. Pfirrmann grades of the intervertebral disc were positively correlated with adjacent vertebrae bone marrow fat fraction (p < 0.05). CONCLUSION: Lumbar bone marrow fat deposition significantly increases during the early stages of intervertebral disc degeneration. Quantitative measurements of bone marrow fat deposition and water content of intervertebral discs have a predictive value and are an important supplement to the qualitative traditional classification strategies for the early stages of intervertebral disc degeneration.

Nitric oxide-induced stromal depletion for improved nanoparticle penetration in pancreatic cancer treatment.

Abundant desmoplastic stroma, which typically exists in pancreatic ductal adenocarcinoma (PDAC), can act as a natural protective physical barrier rendering insufficient drug delivery and penetration. To address this issue, we herein report a two-step sequential delivery strategy for enhanced pancreatic cancer therapy. In this sequential strategy, the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) loaded liposomes (Lip-SNAP) were firstly delivered to pancreatic stellate cells (PSCs) in tumor tissue to inhibit the production of dense stroma, by inhibiting the expression of TGF-ß1 and its downstream profibrotic signal transduction. Therefore, the PSC-mediated desmoplastic reaction could be suppressed by inhibiting the expression of fibronectin, α-SMA and collagen. The gemcitabine (GEM) loaded liposomes (Lip-GEM) were administrated subsequently. The enhanced intratumoral penetration of Lip-GEM was then achieved due to the stromal disruption in consequence of NO treatment, thus significantly improving the drug delivery efficiency. The tumor growth inhibition of the two-step sequential delivery of Lip-SNAP and Lip-GEM was investigated on both subcutaneous and orthotopic tumor mouse models, to show the remarkably improved therapeutic efficacy of GEM. Such NO-induced stromal depletion provides a general strategy to overcome the blockage of desmoplastic stroma on other therapeutic agents.

Size and Charge Adaptive Clustered Nanoparticles Targeting the Biofilm Microenvironment for Chronic Lung Infection Management.

Chronic lung infection caused by bacterial biofilms is an extremely serious clinical problem, which can lead to the failure of antibiotic therapy. Although nanoparticles have shown great potential in the treatment of biofilms, the efficient penetration and retention of nanoparticles in biofilms is still a big challenge. To address this issue, we herein fabricate size and charge adaptive azithromycin (AZM)-conjugated clustered nanoparticles (denoted as AZM-DA NPs) as therapeutic agents for treating biofilms. The AZM-DA NPs are prepared by electrostatic complexation between AZM conjugated amino-ended poly(amidoamine) dendrimer (PAMAM) and 2,3-dimethyl maleic anhydride (DA) modified poly(ethylene glycol)-block-polylysine (PEG-b-PLys). It is noteworthy that the AZM-DA NPs can disassemble in an acidic biofilm microenvironment (pH 6.0), leading to the release of secondary AZM-conjugated PAMAM nanoparticles (PAMAM-AZM NPs). PAMAM-AZM NPs with small size and positive charge are beneficial for improved penetration and retention inside biofilms, enhanced permeabilization of the bacterial membrane, and increased internalization of AZM, thus exhibiting excellent antibiofilm activities. AZM-DA NPs are also favorable as long-term antibacterial agents due to the reduced occurrence of drug resistance. In vivo therapeutic performance is confirmed by the reduced bacterial burden and the alleviated inflammation in the chronic lung infection model. This research not only develops an innovative strategy for antibiotic delivery in vivo but also provides an effective way for the management of biofilm-associated infections, including chronic lung infection.

Supramolecular Aggregation-Induced Emission Nanodots with Programmed Tumor Microenvironment Responsiveness for Image-Guided Orthotopic Pancreatic Cancer Therapy.

Supramolecular nanomaterials as drug carriers have recently received increasing attention due to their intrinsic merits such as high stability, strong inclusion capability, and facile modification of the parental structure; however, intelligent ones with combined capacities of long blood circulation, highly efficient tumor cell uptake, and site-oriented drug release inside tumor cells are still rather limited. Herein, we report a strategy using supramolecular aggregation-induced emission (AIE) nanodots for image-guided drug delivery, which integrate both the advantages of AIE and supramolecular nanomaterials. The supramolecular AIE dots are prepared by the host-guest coassembly of the matrix metalloproteinase-2 (MMP-2) sensitive PEG-peptide (PEG2000-RRRRRRRR (R8)-PLGLAG-EKEKEKEKEKEK (EK6)) and functional α-cyclodextrins (α-CD) derivatives that are conjugated with the anticancer drug gemcitabine (GEM) and a far-red/near-infrared fluorescent rhodanine-3-acetic acid-based AIE luminogen, respectively. The supramolecular AIE dots realize long blood circulation time by virtue of the zwitterionic stealth peptide EK6. After largely accumulating in tumor tissues by the enhanced permeability and retention effect, the supramolecular AIE dots can successively respond to the tumor-overexpressed MMP-2 and intracellular reductive microenvironment, achieving both enhanced cancer cellular uptake and selective GEM release within cancer cells, which thus exhibit excellent tumor inhibition ability in both subcutaneous and orthotopic pancreatic tumor models.

Polymyxin B-Polysaccharide Polyion Nanocomplex with Improved Biocompatibility and Unaffected Antibacterial Activity for Acute Lung Infection Management.

The decade-old antibiotic, polymyxin B (PMB), is regarded as the last line defense against gram-negative "superbug." However, the serious nephrotoxicity and neurotoxicity strongly obstruct further application of this highly effective antibiotic. Herein, a charge switchable polyion nanocomplex exhibiting pH-sensitive property is proposed to deliver PMB which is expected to improve the biosafety of PMB on the premise of retaining excellent antibacterial activity. The polyion nanocomplex is prepared through electrostatic interaction of positively charged PMB and negatively charged 2,3-dimethyl maleic anhydride (DA) grafted chitoligosaccharide (CS). The negative charge of CS-DA will convert to positive due to the hydrolysis of amide bonds in acidic infectious environment, leading to the disassembly of CS-DA/PMB nanocomplex and release of PMB. CS-DA/PMB nanocomplex does not show significant toxicity to mammalian cells while retaining excellent bactericidal capability equivalent to free PMB. The nephrotoxicity and neurotoxicity of CS-DA/PMB dramatically decrease compared to free PMB. Moreover, CS-DA/PMB nanocomplex exhibits superior bactericidal activity against Pseudomonas aeruginosa in an acute lung infection mouse model. The pH-sensitive polyion nanocomplexes may provide a new way to reduce the side effects of highly toxic antibiotics without reducing their intrinsic antibacterial activity, which is the key factor to achieve extensive in vivo clinical applications.

Surface Charge Switchable Supramolecular Nanocarriers for Nitric Oxide Synergistic Photodynamic Eradication of Biofilms.

Biofilm has resulted in numerous obstinate clinical infections, posing severe threats to public health. It is urgent to develop original antibacterial strategies for eradicating biofilms. Herein, we develop a surface charge switchable supramolecular nanocarrier exhibiting pH-responsive penetration into an acidic biofilm for nitric oxide (NO) synergistic photodynamic eradication of the methicillin-resistant Staphylococcus aureus (MRSA) biofilm with negligible damage to healthy tissues under laser irradiation. Originally, by integrating the glutathione (GSH)-sensitive α-cyclodextrin (α-CD) conjugated nitric oxide (NO) prodrug (α-CD-NO) and chlorin e6 (Ce6) prodrug (α-CD-Ce6) into the pH-sensitive poly(ethylene glycol) (PEG) block polypeptide copolymer (PEG-(KLAKLAK)2-DA) via host-guest interaction, the supramolecular nanocarrier α-CD-Ce6-NO-DA was finely prepared. The supramolecular nanocarrier shows complete surface charge reversal from negative charge at physiological pH (7.4) to positive charge at acidic biofilm pH (5.5), promoting efficient penetration into the biofilm. Once infiltrated into the biofilm, the nanocarrier exhibits rapid NO release triggered by the overexpressed GSH in the biofilm, which not only produces abundant NO for killing bacteria but also reduces the biofilm GSH level to improve photodynamic therapy (PDT) efficiency. On the other hand, NO can react with reactive oxygen species (ROS) to produce reactive nitrogen species (RNS), further improving the PDT efficiency. Due to the effective penetration into the biofilm and depletion of biofilm GSH, the surface charge switchable GSH-sensitive NO nanocarrier can greatly improve the PDT efficiency at a low photosensitizer dose and laser intensity and cause negligible side effect to healthy tissues. Considering the above advantages, the strategy developed in this work may offer great possibilities to fight against biofilm infections.

Glutathione Responsive ß-Cyclodextrin Conjugated S-Nitrothiols as a Carrier for Intracellular Delivery of Nitric Oxide.

Nitric oxide (NO) exerts multiple functions in many life processes and was of great significance in a variety of biomedical scenarios. However, the mismatches between releasing locations and NO active sites seriously limited the available NO at areas of interest and greatly dampen the overall efficiency of delivery systems. Therefore, in the present study, a NO donor was developed to achieve intracellular delivery and release of NO to overcome the aforementioned challenges. Enhanced uptake and effective intracellular release of NO were realized via ß-cyclodextrin (ß-CD) mediated endocytosis and high level glutathione (GSH) inside cells, respectively. We demonstrated that intracellularly delivered NO would exert stronger bioeffects than premature release of NO outside targeted cells. Besides, ß-CD assisted cellular uptake proved indispensable in maximizing the influence of NO in modulating cellular behavior. These results demonstrated the significance of intracellular delivery and release of NO in improving its bioutilization. The carrier could efficiently inhibit proliferation of SMCs, while promoting the growth of ECs. Such cell-type-differed physiological effects were advantageous in re-endothelialization and might hold great potential in cardiovascular applications.