Unraveling the effects and mechanisms of antibiotics on aerobic simultaneous nitrogen and phosphorus removal by Acinetobacter indicus CZH-5.

The effects of antibiotics, such as tetracycline, sulfamethoxazole, and ciprofloxacin, on functional microorganisms are of significant concern in wastewater treatment. This study observed that Acinetobacter indicus CZH-5 has a limited capacity to remove nitrogen and phosphorus using antibiotics (5 mg/L) as the sole carbon source. When sodium acetate was supplied (carbon/nitrogen ratio = 7), the average removal efficiencies of ammonia-N, total nitrogen, and orthophosphate-P increased to 52.46 %, 51.95 %, and 92.43 %, respectively. The average removal efficiencies of antibiotics were 84.85 % for tetracycline, 39.32 % for sulfamethoxazole, 18.85 % for ciprofloxacin, and 23.24 % for their mixtures. Increasing the carbon/nitrogen ratio to 20 further improved the average removal efficiencies to 72.61 % for total nitrogen and 97.62 % for orthophosphate-P (5 mg/L antibiotics). Additionally, the growth rate and pollutant removal by CZH-5 were unaffected by the presence of 0.1-1 mg/L antibiotics. Transcriptomic analysis revealed that the promoted translation of aceE, aarA, and gltA genes provided ATP and proton -motive forces. The nitrogen metabolism and polyphosphate genes were also affected. The expression of acetate kinase, dehydrogenase, flavin mononucleotide enzymes, and cytochrome P450 contributed to antibiotic degradation. Intermediate metabolites were investigated to determine the reaction pathways.

Effect of Acupoint Application of Chinese Medicine Combined with a Hot Compress on Pain of Uterine and Fallopian Tube Contrast Agent in Infertile Women.

Objective: To investigate the effects of combining traditional Chinese medicine acupoint sticking with sea salt hot compress on pain relief and promoting physical and mental comfort in infertile women undergoing Hysterosalpingo contrast sonography (HyCoSy). Methods: Infertile women admitted to Zhujiang Hospital of Southern Medical University from October 2021 to December 2022 were selected and 150 of them were selected by random number table method as the main subjects of the study and divided into three groups. The control group received psychological soothing and music therapy. The hot compress group received a sea salt package hot compress at temperatures of 50-65°C in addition to psychological and music soothing. The combined group received an acupoint application of traditional Chinese medicine along with the hot compress and psychological soothing. Pain levels, assessed using the Numeric Rating Scale (NRS), were recorded at different stages of the HyCoSy procedure: cervical dilatation (T0), balloon intubation (T1), contrast medium injection (T2), 10 minutes after examination (T3), 30 minutes after examination (T4), 24 hours after examination (T5), 48 hours after examination (T6), and 1 week after examination (T7).Stacey salpingography adverse reaction grading method: Adverse reactions were evaluated using the grading method for adverse reactions in salpingography designed by Stacey, and adverse reactions were classified into 0 to 4 levels. Stacey grading was used to evaluate pain severity, and adverse reactions of the vagus nerve, anxiety status, and test comfort were also compared among the three groups. Results: Statistically significant differences in NRS scores were observed among the three groups of patients at various stages of the HyCoSy procedure (T0-T5) (P = .001, P = .001, P = .001, P = .001, P = .012,). The combined group showed a higher proportion of grade 1-2 pain (96%) compared to the control group (83%) and the hot compress group (90%), while the proportion of grade 3 pain (4%) was lower than that in the control group (17%) and the hot compress group (10%) (P < .001). There were no significant differences in anxiety scores before and 1 week after examination (P= .273, P = 1.000, P = .779). The Kolcaba comfort scores were significantly higher in the combined group (67.54±7.58) and the hot compress group (65.02±8.12) compared to the control group (58.96±7.53) (P < .001,). No complications, scalds, or severe skin allergies were reported in any of the three groups during the one-week follow-up. Conclusions: The combination of acupoint application with hot compress during HyCoSy resulted in reduced pain levels and improved physical and mental comfort in infertile women. This simple and safe approach can be effectively utilized in clinical practice to enhance the patient experience during the procedure.

Genomics and metabolic characteristics of simultaneous heterotrophic nitrification aerobic denitrification and aerobic phosphorus removal by Acinetobacter indicus CZH-5.

This study provides for the first time a systematic understanding of Acinetobacter indicus CZH-5 performance, metabolic pathway and genomic characteristics for aerobic nitrogen (N) and phosphorus (P) removal. Acinetobacter indicus CZH-5 showed promising performance in heterotrophic nitrification aerobic denitrification and aerobic phosphorus removal. Under optimal conditions, the maximum ammonia-N, total nitrogen and orthophosphate-P removal efficiencies were 90.17%, 86.33%, and 99.89%, respectively. The wide tolerance range suggests the strong environmental adaptability of the bacteria. The complete genome of this strain was reconstructed. Whole genome annotation was used to re-construct the N and P metabolic pathways, and related intracellular substance metabolic pathways were proposed. The transcription levels of related functional genes and enzyme activities further confirmed these metabolic mechanisms. N removal was achieved via the nitrification-denitrification pathway. Furthermore, CZH-5 exhibited significant aerobic P uptake, with phosphate diesters as the main species of intracellular P.

Performance and mechanism of simultaneous nitrification and denitrification in zeolite spheres internal loop airlift reactor.

An internal loop airlift reactor was constructed with zeolite spheres as biofilm carriers (ZS-ALR), and the performance and mechanism of nitrogen removal were investigated. The results indicated that the TN, NH4+-N and TOC removal efficiencies of ZS-ALR reached 96.12%, 100% and 94.54% under appropriate conditions (HRT of 6-8 h, aeration rates of 80-120 mL/min, C/N ratios of 4-6), and the highest TN removal rate constant was 0.01156 min-1. Further investigating the influence of ammonia-N concentrations on nitrogen removal and biofilm stability revealed that catabolism was important in TN removal, and the prominent genera for nitrogen removal included Sphaerotilus (42.20%), Flavobacterium (17.47%) and Fusibacter (6.14%). Meanwhile, the abundance of amoA, napA, narG and nosZ genes was markedly influenced by ammonia-N concentrations. The nitrogen removal of ZS-ALR was mainly through ammonia-N adsorption by zeolite spheres and simultaneous nitrification and denitrification by biofilm.

Phosphorus biorecovery from wastewater contaminated with multiple nitrogen species by a bacterial consortium.

Recovering finite and non-substitutable phosphorus from liquid waste streams through bio-mediated techniques has attracted increasing interest, but current approaches are incredibly dependent on ammonium. Herein, a process to recover phosphorus from wastewater under multiple nitrogen species conditions was developed. This study compared the effects of nitrogen species on the recovery of phosphorus resources by a bacterial consortium. It found that the consortium could not only efficiently utilize ammonium to enable phosphorus recovery but also utilize nitrate via dissimilatory nitrate reduction to ammonium (DNRA) to recover phosphorus. The characteristics of the generated phosphorus-bearing minerals, including magnesium phosphate and struvite, were evaluated. Furthermore, nitrogen loading positively influenced the stability of the bacterial community structure. The genus Acinetobacter was dominant under nitrate and ammonium conditions, with a relatively stable abundance of 89.01% and 88.54%, respectively. The finding may provide new insights into nutrient biorecovery from phosphorus-containing wastewater contaminated with multiple nitrogen species.

Rehabilitation of motor function after stroke: A bibliometric analysis of global research from 2004 to 2022.

Background and aims: The mortality rate of stroke has been increasing worldwide. Poststroke somatic dysfunctions are common. Motor function rehabilitation of patients with such somatic dysfunctions enhances the quality of life and has long been the primary practice to achieve functional recovery. In this regard, we aimed to delineate the new trends and frontiers in stroke motor function rehabilitation literature published from 2004 to 2022 using a bibliometric software. Methods: All documents related to stroke rehabilitation and published from 2004 to 2022 were retrieved from the Web of Science Core Collection. Publication output, research categories, countries/institutions, authors/cocited authors, journals/cocited journals, cocited references, and keywords were assessed using VOSviewer v.1.6.15.0 and CiteSpace version 5.8. The cocitation map was plotted according to the analysis results to intuitively observe the research hotspots. Results: Overall, 3,302 articles were retrieved from 78 countries or regions and 564 institutions. Over time, the publication outputs increased annually. In terms of national contribution, the United States published the most papers, followed by China, Japan, South Korea, and Canada. Yeungnam University had the most articles among all institutions, followed by Emory University, Fudan University, and National Taiwan University. Jang Sung Ho and Wolf S.L. were the most productive (56 published articles) and influential (cited 1,121 times) authors, respectively. "Effect of constraint-induced movement therapy on upper extremity function 3-9 months after stroke: the Extremity Constraint Induced Therapy Evaluation randomized clinical trial" was the most frequently cited reference. Analysis of keywords showed that upper limbs, Fugl-Meyer assessment, electromyography, virtual reality, telerehabilitation, exoskeleton, and brain-computer interface were the research development trends and focus areas for this topic. Conclusion: Publications regarding motor function rehabilitation following stroke are likely to continuously increase. Research on virtual reality, telemedicine, electroacupuncture, the brain-computer interface, and rehabilitation robots has attracted increasing attention, with these topics becoming the hotspots of present research and the trends of future research.

Solid slow-release carbon sources improve the simultaneous nitrification and denitrification processes in low carbon resource wastewater.

In this study, A Acinetobacter pittii sp. was isolated with high efficiency for heterotrophic nitrification and aerobic denitrification (HN-AD). The boundary conditions for total nitrogen (TN) removal were as follows: C/N ratios 8-14, temperature 25-35 °C, initial pH 7-9, and shaker speed 100-120 rpm. Addition of mixed carbon resources achieved 97.38 % ammonia-N and 91.50 % TN removal, which was higher than that of the group with sole carbon resources. The ammonia-N and TN removal profiles matched well with first-order kinetics in the rapid response period and zero-order kinetics in the slow reaction period. Meanwhile, enzyme activity related to nitrogen conversion would remarkably increase with mixed carbon resources. Furthermore, proposed a possible relationship between the solid carbon source, hydrolysis, soluble small molecule organic matter, microbial activity, and heterotrophic nitrification and aerobic denitrification (HN-AD). This study provides a new strategy for improving nitrogen removal in wastewater with low-carbon resources.

Enhanced denitrification of sewage via bio-microcapsules embedding heterotrophic nitrification-aerobic denitrification bacteria Acinetobacter pittii SY9 and corn cob.

In this work, bio-microcapsules were prepared by embedding heterotrophic nitrification and aerobic denitrification (HN-AD) bacteria (Acinetobacter Pittii SY9) and corn cob. Bio-microcapsules (20 g/L of corn cob and 30% v/v suspension of strain SY9) were porous (pore size 2579.74-3725.44 nm; porosity 53.6%-79.9%). Under the appropriate conditions (C/N > 2, temperature of 20-35 ℃, rotation speed of 100-120 rpm, pH of 7-9), TN removal efficiency of bio-microcapsules reached 94.4%, and 74.0% of nitrogen was converted into N2. The results of kinetics fitting indicated that aerobic denitrification was the limiting step during HN-AD process. Bio-microcapsules could slow the carbon release of corn cob for 120 days, which ensuring high HN-AD performance even at low C/N of 2.8. Bio-microcapsule SBR could stably run for 88 days with TN removal efficiency > 90% for synthetic sewage. Bio-microcapsules embedding strain SY9 and corn cob have prospective applications for enhancing denitrification of sewage.

Effect of tetracycline on nitrogen removal in Moving Bed Biofilm Reactor (MBBR) System.

The effect of tetracycline (TC) on nitrogen removal in wastewater treatment plants has become a new problem. This study investigated the effects of TC on nitrogen removal using a Moving Bed Biofilm Reactor system. The results showed that there was no significant effect on nitrogen removal performance when the concentration of TC was 5 mg/L, and that the total nitrogen (TN) removal efficiency could reach 75-77%. However, when the concentration of TC increased to 10 mg/L, the denitrification performance was affected and the TN removal efficiency decreased to 58%. The abundance of denitrifying bacteria such as those in the genus Thauera decreased, and TC-resistant bacteria gradually became dominant. At a TC concentration of 10 mg/L, there were also increases and decreases, respectively, in the abundance of resistance and denitrification functional genes. The inhibitory effect of TC on denitrification was achieved mainly by the inhibition of nitrite-reducing bacteria.

Effects of various antibiotics on aerobic nitrogen removal and antibiotic degradation performance: Mechanism, degradation pathways, and microbial community evolution.

Little information about the selective stress of various antibiotics and how they influence different stages of aerobic nitrogen removal is available. A long-term aerobic nitrogen removal-moving bed biofilm reactor was established by the inoculation of Achromobacter sp. JL9, capable of heterotrophic nitrification and aerobic denitrification, and aerobic activated sludge. The nitrogen removal and antibiotic degradation performances of various antibiotics were then measured. High total nitrogen (91.83% and 91.51%) removal efficiencies were achieved with sulfamethoxazole or no antibiotics, and lower efficiencies were observed with other antibiotics (trimethoprim, teicoplanin, and ciprofloxacin). These results suggest that various antibiotics have different selective inhibitory effects on aerobic nitrogen removal. Additionally, all antibiotics were partly degraded; proposed degradation pathways according to the detected intermediates included ring-opening, S-N bond cleavage, amination, hydroxylation, and methylation. High-throughput sequencing indicated that aerobic denitrifying, recalcitrant pollutant degrading, and antibiotic-resistant bacteria dominate during the community evolution process.

HIF-1α/JMJD1A signaling regulates inflammation and oxidative stress following hyperglycemia and hypoxia-induced vascular cell injury.

BACKGROUND: Endothelial cell (EC) injury accelerates the progression of diabetic macrovascular complications. Hypoxia is an important cause of EC injury. Hypoxia-inducible factor-1 alpha (HIF-1α) is an important hypoxia regulatory protein. Our previous studies showed that high-glucose and hypoxic conditions could upregulate HIF-1α expression and enhance EC inflammatory injury, independently of the nuclear factor kappa-B (NF-κB) pathway. However, it is not clear whether HIF-1α plays a role in vascular disease through epigenetic-related mechanisms. METHODS: We conducted gene expression analysis and molecular mechanistic studies in human umbilical vein endothelial cells (HUVECs) induced by hyperglycemia and hypoxia using RNA sequencing (RNA-seq) and small interfering HIF-1α (si-HIF-1α). We determined HIF-1α and Jumonji domain-containing protein 1 A (JMJD1A) expression by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot, analyzed inflammatory protein secretion in the cell supernatant by enzymelinked immunosorbent assay (ELISA), and assessed protein interaction between HIF-1α and JMJD1A by chromatin immunoprecipitation (Ch-IP). We used the Cell Counting Kit8 (CCK-8) assay to analyze cell viability, and assessed oxidative stress indicators by using a detection kit and flow cytometry. RESULTS: High glucose and hypoxia up-regulated HIF-1α expression, and down-regulated HIF-1α decreased the level of inflammation and oxidative stress in HUVECs. To determine the downstream pathways, we observed histone demethylases genes and related pathway by RNA-sEq. Among these, JMJD1A was the most upregulated gene in histone demethylases. Moreover, we observed that HIF-1α bound to the promoter of JMJD1A, and the ameliorative effects of si-HIF-1α on oxidative stress and inflammatory cytokines in high-glucose and hypoxia-induced HUVECs were reversed by JMJD1A overexpression. Furthermore, knockdown of JMJD1A decreased inflammatory and oxidative stress injury. To determine the JMJD1A-related factors, we conducted gene expression analysis on JMJD1A-knockdown HUVECs. We observed that downregulation of inflammation and the oxidative stress pathway were enriched and FOS and FOSB might be important protective transcription factors. CONCLUSIONS: These findings provide novel evidence that the HIF-1α/JMJD1A signaling pathway is involved in inflammation and oxidative stress in HUVECs induced by high glucose and hypoxia. Also, this pathway might act as a novel regulator of oxidative stress and inflammatory-related events in response to diabetic vascular injury and thus contribute to the pathological progression of diabetes and vascular disease.

Bone marrow mesenchymal stem cell-derived exosomes attenuate cerebral ischemia-reperfusion injury-induced neuroinflammation and pyroptosis by modulating microglia M1/M2 phenotypes.

BACKGROUND: Pyroptosis mediated by NLRP3 inflammasome plays a critical role in the pathogenesis of cerebral ischemia-reperfusion (I/R) injury. Mounting evidences have verified the efficacy of exosomes by relieving the inflammatory response during cerebral I/R injury, but the specific mechanism has not been well elucidated. This study aimed to clarify whether the neuroprotective effects of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) are associated with the attenuation of NLPR3-mediated neuron pyroptosis by modulating microglial polarization. METHODS: Rats were initially subjected to middle cerebral artery occlusion (MCAO) followed by reperfusion. Then, BMSC-Exos were administered intravenously 2 h after MCAO. The neuroprotective effects were measured using a modified neurological severity score(mNSS), triphenyltetrazolium chloride (TTC) staining, brain water content, Morris water maze,and CatWalk system. Western blotting and immunofluorescence staining were applied to detect NLRP3 inflammasome and pyroptosis. Microglial polarization was determined by real-time polymerase chain reaction (RT-PCR) and immunofluorescence staining. To mimic cerebral I/R injury in vitro, BV2 and PC12 cells were exposed to oxygen-glucose deprivation/reoxygenation. After treatment with PBS, BMSC-Exos, IL-4, or LPS, BV2 cells were co-cultured with PC12 cells in a Transwell system. RESULTS: BMSC-Exos reduced the brain infarct area and brain water content at 24 h dose dependently and improved the neurological function up to 5 weeks after stroke. In vivo, NLRP3 inflammasome- and pyroptosis-related proteins were mainly expressed on neurons and downregulated by BMSC-Exos. Furthermore, cerebral I/R injury-induced M1-polarized microglia could be shifted toward M2 phenotype by BMSC-Exos. In vitro, BMSC-Exos alleviated the neuron pyroptosis partially by modulating microglial polarization. CONCLUSION: BMSC-Exos could ameliorate cerebral I/R injury via suppression of NLRP3 inflammasome-mediated inflammation and pyroptosis by modulating microglial polarization.

JMJD1A/NR4A1 Signaling Regulates the Procession of Renal Tubular Epithelial Interstitial Fibrosis Induced by AGEs in HK-2.

Diabetic kidney disease (DKD) is one of the most serious complications of diabetic patients. Advanced glycation end products (AGEs) induce epithelial-mesenchymal transformation (EMT) of renal tubular epithelial cells (HK-2), resulting in renal tubulointerstitial fibrosis. However, the underlying epigenetic mechanisms remain to be further investigated. In this work, we investigated the functional role of JMJD1A involved in DKD progression. The molecular mechanism study was performed in AGEs-induced HK-2 cells by gene expression analysis, RNA sequencing (RNA-seq), and JMJD1A lentiviral knockdown and overexpression particle transfection. The results showed that AGEs could upregulate JMJD1A, and the expressions of related fibrotic factor were also increased. At the same time, in the DKD animal model induced by unilateral nephrectomy plus streptozotocin (STZ), IHC immunohistochemical staining showed that compared with the control group, the expressions of JMJD1A, FN, and COL1 in the model group were all increased, masson staining results also show that the model group has typical fibrotic changes. This is consistent with the results of our in vitro experiments. In order to determine the downstream pathway, we screened out JMJD1A downstream transcription factors by RNA-seq. Further analysis showed that JMJD1A overexpression could accelerate the progression of AGEs-induced renal fibrosis by reducing the expression of NR4A1 in HK-2 cells. Meanwhile, NR4A1 inhibitor can promote the expression of fibrosis-related factors such as VIM, a-SMA in HK-2 cells, and aggravate the process of fibrosis. Taken together, JMJD1A/NR4A1 signaling can regulate the procession of renal tubular epithelial interstitial fibrosis induced by AGEs in HK-2.

Exosomes Secreted From Bone Marrow Mesenchymal Stem Cells Attenuate Oxygen-Glucose Deprivation/Reoxygenation-Induced Pyroptosis in PC12 Cells by Promoting AMPK-Dependent Autophagic Flux.

Background: Cerebral ischemia-reperfusion (I/R) injury can lead to severe dysfunction, and its treatment is difficult. It is reported that nucleotide-binding domain and leucine-rich repeat family protein 3 (NLRP3) inflammasome-mediated cell pyroptosis is an important part of cerebral I/R injury and the activation of autophagy can inhibit pyroptosis in some tissue injury. Our previous study found that the protective effects of bone marrow mesenchymal stem cells (BMSCs) in cerebral I/R injury may be associated with the regulation of autophagy. Recent studies have demonstrated that exosomes secreted from BMSCs (BMSC-Exos) may play an essential role in the effective biological performance of BMSCs and the protective mechanism of BMSC-Exos is associated with the activation of autophagy and the remission of inflammation, but it has not been reported in studies of cerebral I/R injury. We aimed to investigate the effects of BMSC-Exos on cerebral I/R injury and determine if the mechanism is associated with the regulation of pyroptosis and autophagic flux. Method: PC12 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to induce cerebral I/R in vitro and were cocultured with BMSC-Exos. Cell viability was determined with CCK-8 and lactate dehydrogenase (LDH) detection kits. Scanning electron microscopy (SEM), Hoechst 33342/propidium iodide (PI) double staining, 2',7'-dichlorodihydrofluorescein diacetate assay, immunofluorescence, Western blot, and Enzyme-linked immunosorbent assay (ELISA) were used to detect cell pyroptosis. Furthermore, transmission electron microscopy (TEM), GFP-RFP-LC3 adenovirus transfection, and Western blot were used to detect autophagic flux and its influence on pyroptosis. Finally, coimmunoprecipitation was used to detect the binding interaction between NLRP3 and LC3. Results: BMSC-Exos increased cell viability in OGD/R. The inhibitory effect of BMSC-Exos on pyroptosis was comparable to the NLRP3 inhibitor MCC950 and was reversed by NLRP3 overexpression. Furthermore, BMSC-Exos promoted autophagic flux through the AMP-activated kinase (AMPK)/mammalian target of the rapamycin pathway, whereas chloroquine, AMPK silencing, and compound C blocked the inhibitory effect on pyroptosis. Conclusions: BMSC-Exos can protect PC12 cells against OGD/R injury via attenuation of NLRP3 inflammasome-mediated pyroptosis by promoting AMPK-dependent autophagic flux.

Silibinin Promotes Cell Proliferation Through Facilitating G1/S Transitions by Activating Drp1-Mediated Mitochondrial Fission in Cells.

Heart, liver, and kidney, which are known as the essential organs for metabolism, possess the unique ability to regulate the proliferation function of the body against injury. Silibinin (SB), a natural polyphenolic flavonoid extracted from traditional herb Silybum marianum L., has been used to protect hepatocytes. Whether SB can regulate mitochondrial fission in normal cells and the underlying mechanisms remain unclear. Here, we showed that SB markedly promoted cell proliferation by facilitating G1/S transition via activating dynamin-related protein 1 (Drp1), which in turn mediated mitochondrial fission in these normal cells. SB dose-dependently increased the mitochondrial mass, mtDNA copy number, cellular adenosine triphosphate production, mitochondrial membrane potential, and reactive oxygen species in normal cells. Furthermore, SB dose-dependently increased the expression of Drp1. Blocking Drp1 abolished SB-induced mitochondrial fission. In conclusion, we demonstrate that SB promotes cell proliferation through facilitating G1/S transition by activating Drp1-mediated mitochondrial fission. This study suggests that SB is a potentially useful herbal derivative for the daily prevention of various diseases caused by impaired mitochondrial fission.

Carry-On Nitric-Oxide Luggage for Enhanced Chemotherapeutic Efficacy.

In this work, we proposed a carry-on nitric-oxide (NO) luggage strategy for enhanced chemotherapeutic efficacy. A stimuli-responsive NO-releasing polypeptide was prepared as the building block to assemble into a micelle as a chemodrug-carrier. The micelle was anchored with cRGD peptide with the aim of targeting to tumors' neoangiogenesis. In situ generation of NO at the tumor site can promote the neovascularization to recruit more chemotherapeutics. Besides, the introduced exogenous NO can directly induce apoptosis, synergistically with the chemotherapeutics. A specific near-infrared-region (NIR) NO-probe was also developed to be coloaded to the micelle to report the in situ NO-release. In vitro and in vivo experiments were performed to demonstrate the targeting capability, increased accumulation, real-time NO-release reporting phenomenon, improved antitumor efficacy, and favorable biosafety. Embedding NO into drug cargo as carry-on luggage for enhanced chemotherapeutic efficacy, hopefully, can cast new lights and build a basic principle in the future clinical translation of nanomedicines.

GLUT1-mediated effective anti-miRNA21 pompon for cancer therapy.

Oncogenic microRNAs are essential components in regulating the gene expression of cancer cells. Especially miR21, which is a major player involved of tumor initiation, progression, invasion and metastasis in several cancers. The delivery of anti-miR21 sequences has significant potential for cancer treatment. Nevertheless, since anti-miR21 sequences are extremely unstable and they need to obtain certain concentration to function, it is intensely difficult to build an effective delivery system for them. The purpose of this work is to construct a self-assembled glutathione (GSH)-responsive system with tumor accumulation capacity for effective anti-miR21 delivery and cancer therapy. A novel drug delivery nanosphere carrying millions of anti-miR21 sequences was developed through the rolling circle transcription (RCT) method. GSH-responsive cationic polymer polyethyleneimine (pOEI) was synthesized to protect the nanosphere from degradation by Dicer or other RNase in normal cells and optimize the pompon-like nanoparticle to suitable size. Dehydroascorbic acid (DHA), a targeting molecule, which is a substrate of glucose transporter 1 (GLUT 1) and highly expressed on malignant tumor cells, was connected to pOEI through PEG, and then the polymer was used for contracting a RNA nanospheres into nanopompons. The anti-miR21 nanopompons showed its potential for effective cancer therapy.

Microthrombus-Targeting Micelles for Neurovascular Remodeling and Enhanced Microcirculatory Perfusion in Acute Ischemic Stroke.

Reperfusion injury exists as the major obstacle to full recovery of neuron functions after ischemic stroke onset and clinical thrombolytic therapies. Complex cellular cascades including oxidative stress, neuroinflammation, and brain vascular impairment occur within neurovascular units, leading to microthrombus formation and ultimate neuron death. In this work, a multitarget micelle system is developed to simultaneously modulate various cell types involved in these events. Briefly, rapamycin is encapsulated in self-assembled micelles that are consisted of reactive oxygen species (ROS)-responsive and fibrin-binding polymers to achieve micelle retention and controlled drug release within the ischemic lesion. Neuron survival is reinforced by the combination of micelle facilitated ROS elimination and antistress signaling pathway interference under ischemia conditions. In vivo results demonstrate an overall remodeling of neurovascular unit through micelle polarized M2 microglia repair and blood-brain barrier preservation, leading to enhanced neuroprotection and blood perfusion. This strategy gives a proof of concept that neurovascular units can serve as an integrated target for ischemic stroke treatment with nanomedicines.

Tumor Microenvironment-Triggered Aggregated Magnetic Nanoparticles for Reinforced Image-Guided Immunogenic Chemotherapy.

Anticancer therapies, which can induce cell death and elevate antitumor immune response in the meantime, are considered as effective treatments for many types of cancers. Immunogenic cell death (ICD) induced by chemodrugs is a promising and typical strategy to achieve cell cytotoxicity and immunological enhancement together. However, due to the low level of ICD induction and less tumor-targeting accumulation, application of traditional ICD inducers is limited. Here, tumor-targeting core-shell magnetic nanoparticles (ETP-PtFeNP:α-enolase targeting peptide modified Pt-prodrug loaded Fe3O4 nanoparticles) are developed to reinforce ICD induction of loaded-oxaliplatin (IV) prodrug. After tumor-targeting accumulation and endocytosis, platinum (IV) complexes are activated by intracellular reductive elimination to yield and release the Pt (II) congener, oxaliplatin, leading to DNA lesions and reactive oxygen species (ROS) generation. Simultaneously, in-progress-released ferric ions elicit highly toxic ROS (·OH or ·OOH) burst and interfere with the intracytoplasmic redox balance (like endoplasmic reticulum stress), leading to ICD-associated immunogenicity enhancement and specific antitumor immune responses to kill the tumor cells synergistically. Meanwhile, the transverse relaxation rate R 2 of ETP-PtFeNP is remarkably increased by more than three times while triggered by reductant, suggesting ETP-PtFeNP a high-sensitivity T 2 contrast agent for magnetic resonance imaging.

Endogenous albumin-mediated delivery of redox-responsive paclitaxel-loaded micelles for targeted cancer therapy.

Targeted delivery and accumulation of chemotherapeutics to tumor sites is in high demand and extremely challenging for anticancer therapy. Studies show that albumin is actively recruited into tumor tissue overexpressing albumin-binding proteins including secreted protein acidic and rich in cysteine (SPARC) and gp60. Herein, a novel redox-responsive paclitaxel-loaded micelle system with the modification of ABD035, which specifically and strongly binds to albumin, is designed to combine the strengths of albumin and micelles together for antitumor drug biomimetic delivery. The ABD035-modified micelle has a strong binding response to albumin and co-localization of BODIPY-labeled ABD035-modified micelle and SPARC is observed in tumor tissues. Furthermore, the ABD035-modified micelle significantly improves the therapeutic effect in the animal model bearing triple negative breast cancer by increasing drug accumulation in tumor tissue, enhancing cell uptake efficiency, rapidly releasing prototype drug under intracellular reductive conditions and increasing tumor cell apoptosis. These results together vote the biomimetic delivery of ABD035-modified micelle as a promising strategy for cancer therapy.