ABSTRACT
Glucose-6-phosphate dehydrogenase (G6PD) is a promising target in cancer therapy. However, poor cellular uptake and off-target toxicity have impeded the clinical translation of a canonical G6PD inhibitor (6-aminonicotinamide/6AN). Here, we report a prodrug strategy to address this issue. The tailored 6AN prodrug contains an azo-bearing protection moiety. The hydrophobic prodrug showed increased cellular uptake than 6AN and was vulnerable to hypoxia, resulting in NAD(P)H quinone dehydrogenase 1 (NQO1)-triggered cleavage of azo bonds. Intriguingly, the prodrug showed configuration-dependent anti-cancer potency. Despite the lower thermodynamic stability, the cis isomer showed enhanced cellular uptake compared to the trans counterpart due to the increased aqueous solubility. Moreover, the boosted potency of the cis isomer compared to the trans isomer arose from the enhancement of NOQ1-catalyzed 6AN release under hypoxia, a hallmark of solid tumors. The discovery of hypoxia-responsive 6AN prodrugs in the current work opens up new avenues for G6PD-targeting cancer medicines.
Subject(s)
6-Aminonicotinamide , Antineoplastic Agents , NADP , Oxidation-Reduction , Prodrugs , Prodrugs/chemistry , Prodrugs/pharmacology , Prodrugs/chemical synthesis , Humans , 6-Aminonicotinamide/pharmacology , 6-Aminonicotinamide/chemistry , NADP/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Cell Proliferation/drug effects , Molecular Structure , Glucosephosphate Dehydrogenase/metabolism , Glucosephosphate Dehydrogenase/antagonists & inhibitors , Cell Hypoxia/drug effects , Drug Screening Assays, AntitumorABSTRACT
Diabetic kidney disease (DKD) is often featured with redox dyshomeostatis. Pyruvate dehydrogenase kinase 4 (PDK4) is the hub for DKD development. However, the mechanism by which PDK4 mediates DKD is poorly understood. The current work aimed to elucidate the relationship between PDK4 and DKD from the perspective of redox manipulation. Oxidative stress was observed in the human proximal tubular cell line (HK-2 cells) treated with a high concentration of glucose and palmitic acid (HGL). The mechanistic study showed that PDK4 could upregulate Kelch-like ECH-associated protein 1 (Keap1) in HGL-treated HK-2 cells through the suppression of autophagy, resulting in the depletion of nuclear factor erythroid 2-related factor 2 (Nrf2), the master regulator of redox homeostasis. At the cellular level, pharmacological inhibition or genetic knockdown of PDK4 could boost Nrf2, followed by the increase of a plethora of antioxidant enzymes and ferroptosis-suppression enzymes. Meanwhile, the inhibition or knockdown of PDK4 remodeled iron metabolism, further mitigating oxidative stress and lipid peroxidation. The same trend was observed in the DKD mice model. The current work highlighted the role of PDK4 in the development of DKD and suggested that PDK4 might be a promising target for the management of DKD.
Subject(s)
Diabetic Nephropathies , NF-E2-Related Factor 2 , Oxidative Stress , NF-E2-Related Factor 2/metabolism , Oxidative Stress/drug effects , Humans , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Animals , Mice , Mice, Inbred C57BL , Male , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism , Cell Line , Kelch-Like ECH-Associated Protein 1/metabolism , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/pathologyABSTRACT
Electroplated diamond wire sawing is widely used as a processing method to cut hard and brittle difficult-to-machine materials. Currently, obtaining the sawing capability of diamond wire saw through the wire bow is still difficult. In this paper, a method for calculating the sawing capability of diamond wire saw in real-time based on the wire bow is proposed. The influence of the renewed length per round trip, crystal orientation of sapphire, wire speed, and feed rate on the wire sawing capability has been revealed via slicing experiments. The results indicate that renewing the diamond wire saw, and reducing the wire speed and feed rate can delay the reduction in sawing capability. Furthermore, controlling the value of renewed length per round trip can make the diamond wire saw enter a stable cutting state, in which the capability of the wire saw no longer decreases. The sawing capability of diamond wire saw cutting in the A-plane of the sapphire is smaller than that of the C-plane, and a suitable feed rate or wire speed within the range of sawing parameters studied in this study can avoid a rapid decrease in the sawing capability of the wire saw during the cutting process. The knowledge obtained in this study provides a theoretical basis for monitoring the performance of the wire saw, and guidance for the wire cutting process in semiconductor manufacturing. In the future, it may even be possible to provide real-time performance parameters of diamond wire saw for the digital twin model of wire sawing.
ABSTRACT
Objective: This study endeavors to translate and psycho-metrically validate the metacognitive awareness inventory scale (MAS) for nursing students in China. Method: A total of 592 nursing students were enlisted from four universities situated in the eastern, southern, western, and northern regions of China. Content validity and reliability were evaluated using the content validity index and item-total correlation coefficient, and Cronbach's alpha coefficients, respectively. Convergent validity examined the goodness of fit among sub-scales through the average extracted variance and composite reliability. Results: Exploratory factor analysis confirmed the first-order and second-order factor models, contributing to a cumulative variance of 89.4 and 59.5%, respectively. The Cronbach's alpha values were 0.963 and 0.801, respectively. Confirmatory factor analysis outcomes indicated an excellent overall fit index for the model, satisfying the convergent validity criteria and achieving a target coefficient of 96.0%, which is consistent with the original scale structure. Conclusion: The Chinese version of the MAS (C-MAS) is a reliable and valid instrument for assessing metacognitive awareness among Chinese nursing students. Further research should consider a broader sample of nursing students across China to reinforce the scale's applicability.
ABSTRACT
This study aimed to investigate the changing trends, level differences, and prognostic performance of the leukocyte and lymphocyte levels of patients infected with the Wild strains, Delta strains and Omicron strains to provide a reference for prognostic assessment. In the current study, we conducted a retrospective cross-sectional study to evaluate the changing trends, level differences, and prognostic performance of leukocyte and lymphocyte of different strains at admission and discharge may already exist in patients with coronavirus disease-2019 (COVID-19) infected with the Wild type, Delta, and Omicron strains. A retrospective cross-sectional study was conducted. We recruited and screened the 243 cases infected with the Wild-type strains in Wuhan, the 629 cases infected with the Delta and 116 cases infected strains with the Omicron strains in Xi'an. The leukocyte and lymphocyte levels were compared the cohort of Wild-type infection with the cohort of Delta and the Omicron. The changes in the levels of leukocytes and lymphocytes exhibit a completely opposite trend in patients with COVID-19 infected with the different strains. The lymphocyte level at admission and discharge in patients with COVID-19 infected with Omicron strains (area under curve [AUC] receiver operating characteristic curve [ROC] 72.8-90.2%, 82.8-97.2%) presented better performance compared patients with COVID-19 infected with Wild type strains (AUC ROC 60.9-80.7%, 82.3-97.2%) and Delta strains (AUC ROC 56.1-84.7%, 40.3-93.3%). Kaplan-Meier curves showed that the leukocyte levels above newly established cutoff values and the lymphocyte levels below newly established cutoff values had a significantly higher risk of in-hospital mortality in COVID-19 patients with Wild-type and Omicron strains (P < .01). The levels of leukocyte and lymphocyte at admission and discharge in patients with COVID-19 infected with the Wild type, Delta, and Omicron strains may be differences among strains, which indicates different death risks. Our research may help clinicians identify patients with a poor prognosis for severe acute respiratory syndrome coronavirus 2 infection.
Subject(s)
COVID-19 , Humans , Cross-Sectional Studies , Retrospective Studies , Leukocytes , LymphocytesABSTRACT
In women, breast cancer (BC) accounts for 7%-10% of all cancer cases and is one of the most common cancers. To identify a new method for treating BC, the role of CD93 and its underlying mechanism were explored. MDA-MB-231 cells were used in this study and transfected with si-CD93, si-MMRN2, oe-CD93, si-integrin ß1, or oe-SP2 lentivirus. After MDA-MB-231 cells were transfected with si-NC or si-CD93, they were injected into nude mice by subcutaneous injection at a dose of 5 × 106/mouse to construct a BC animal model. The expression of genes and proteins and cell migration, invasion and vasculogenic mimicry were detected by RTâqPCR, western blot, immunohistochemistry, immunofluorescence, Transwell, and angiogenesis assays. In pathological samples and BC cell lines, CD93 was highly expressed. Functionally, CD93 promoted the proliferation, migration, and vasculogenic mimicry of MDA-MB-231 cells. Moreover, CD93 interacts with MMRN2 and integrin ß1. Knockdown of CD93 and MMRN2 can inhibit the activation of integrin ß1, thereby inhibiting the PI3K/AKT/SP2 signaling pathway and inhibiting BC growth and vasculogenic mimicry. In conclusion, the binding of CD93 to MMRN2 can activate integrin ß1, thereby activating the PI3K/AKT/SP2 signaling pathway and subsequently promoting BC growth and vasculogenic mimicry.
Subject(s)
Breast Neoplasms , Integrin beta1 , Membrane Glycoproteins , Receptors, Complement , Animals , Female , Humans , Mice , Breast Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation , Integrin beta1/genetics , Integrin beta1/metabolism , Mice, Nude , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , Receptors, Complement/metabolism , Membrane Glycoproteins/metabolismABSTRACT
Ferroptotic cancer therapy has been extensively investigated since the genesis of the ferroptosis concept. However, the therapeutic efficacy of ferroptosis induction in heterogeneous and plastic melanoma has been compromised, because the melanocytic and transitory cell subpopulation is resistant to iron-dependent oxidative stress. Here, we report a phenotype-altering liposomal nanomedicine to enable the ferroptosis-resistant subtypes of melanoma cells vulnerable to lipid peroxidation via senescence induction. The strategy involves the ratiometric coencapsulation of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor (palbociclib) and a ferroptosis inducer (auranofin) within cRGD peptide-modified targeted liposomes. The two drugs showed a synergistic anticancer effect in the model B16F10 melanoma cells, as evidenced by the combination index analysis (<1). The liposomes could efficiently deliver both drugs into B16F10 cells in a targeted manner. Afterward, the liposomes potently induced the intracellular redox imbalance and lipid peroxidation. Palbociclib significantly provoked cell cycle arrest at the G0/G1 phase, which sensitized auranofin-caused ferroptosis through senescence induction. Meanwhile, palbociclib depleted intracellular glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH), further boosting ferroptosis. The proof-of-concept was also demonstrated in the B16F10 tumor-bearing mice model. The current work offers a promising ferroptosis-targeting strategy for effectively treating heterogeneous melanoma by manipulating the cellular plasticity.
Subject(s)
Ferroptosis , Melanoma , Animals , Mice , Melanoma/drug therapy , Liposomes/pharmacology , Coenzymes/pharmacology , Auranofin/pharmacology , Lipid PeroxidationABSTRACT
Source characteristics and health risks of indoor organophosphate esters (OPEs) are limited by the lack of knowledge on emission processes. This study attempted to integrate the contents and emissions of OPEs from indoor building materials to assess human health effects. Thirteen OPEs were investigated in 80 pieces of six categories of building materials. OPEs are ubiquitous in the building materials and ∑13OPE contents varied significantly (p < 0.05) from 72.8 ng/g (seam agent) to 109,900 ng/g (wallpaper). Emission characteristics of OPEs from the building materials were examined based on a microchamber method. Depending on the sample category, the observed initial area-specific emission rates of ∑13OPEs varied from 154 ng/m2/h (carpet) to 2760 ng/m2/h (wooden floorboard). Moreover, the emission rate model was developed to predict the release levels of individual OPEs, quantify source contributions, and assess associated exposure risks. Source apportionments of indoor OPEs exhibited heterogeneities in multiple environmental media. The joint OPE contribution of wallpaper and wooden floorboard to indoor dust was up to 94.8%, while latex paint and wooden floorboard were the main OPE contributors to indoor air (54.2%) and surface (76.1%), respectively. Risk assessment showed that the carcinogenic risks of tris(2-chloroethyl) phosphate (3.35 × 10-7) were close to the acceptable level (1 × 10-6) and deserved special attention.
Subject(s)
Environmental Monitoring , Flame Retardants , Humans , Esters/analysis , Flame Retardants/analysis , China , Organophosphates/analysis , Dust/analysis , Construction MaterialsABSTRACT
As an iron-dependent, non-apoptosis, regulated cell death (RCD) modality, ferroptosis has gained growing attention for cancer therapy. With the development of nanomaterials in the biomedical field, ferroptotic cancer nanomedicine is extensively investigated. Amongst various nanomaterials, metal-organic frameworks (MOFs) are hybridized porous materials consisting of metal ions or clusters bridged by organic linkers. The superior properties of MOFs, such as high porosity and cargo loading, ease of surface modification, and good biocompatibility, make them appealing in inducing or sensitizing ferroptotic cell death. There are remarkable achievements in the field of MOF-based ferroptosis cancer therapy. However, this topic is not reviewed. This review will introduce the fundamentals of MOF and ferroptosis machinery, summarize the recent progress of MOF-based ferroptotic anticancer drug delivery, discuss the benefits and problems of MOFs as vehicles and sensitizers for cancer ferroptosis, and provide the perspective on future research direction on this promising field.
Subject(s)
Ferroptosis , Metal-Organic Frameworks , Nanomedicine , Neoplasms , Metal-Organic Frameworks/chemistry , Humans , Ferroptosis/drug effects , Nanomedicine/methods , Neoplasms/drug therapy , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/administration & dosage , Animals , Drug Delivery Systems/methodsABSTRACT
Tire road wear particles (TRWPs) are a large source of microplastics in the environment, while the quantification of TRWPs is still challenging due to the complex interferences and the uncertainties and inconsistencies among different methods. This study developed a TRWPs quantification method using optimized pretreatments and bonded-sulfur as marker. Road dust samples (n = 48) were collected, pretreatments including density separation, digestion and extraction were optimized to remove interferences of the bonded-sulfur (minerals, sulfur-containing proteins, hydrosoluble/hydrophobic sulfur-containing substances). Presence of TRWPs in the samples was confirmed by microscopy and scanning electron microscopyenergy dispersive spectrometry. Bonded-sulfur in the samples were quantified by inductively coupled plasmamass spectrometry (ICPMS). Additionally, bonded-sulfur in tire wear particles (TWPs) abraded from tires of top 10 best-selling brands were measured to calculate conversion factor (1.1 ×104 µg/g) for the quantification of TRWPs in real samples. TRWPs contents were 5.40 × 104 µg/g11.02 × 104 µg/g and 2.36 × 104 µg/g5.30 × 104 µg/g in samples from heavy and light traffic roads, respectively. The method provided better recoveries (88-107%, n = 18) and repeatability (RSD=2.0-7.9%, n = 3) compared to methods using rubber, benzothiazole and organic zinc as markers. Furthermore, stability of the bonded-sulfur was validated by Raman and ICPMS. Thus, this accurate and stable quantification method could promote research on TRWPs.
ABSTRACT
Both ferroptotic therapy and immunotherapy have been widely employed in cancer treatment. However, ferroptotic cell death fails to induce dendritic cells maturation, which limits the therapeutic outcome of ferroptotic cancer therapy. To address this, the current work reports a tailored liposome to establish a positive loop between ferroptotic therapy and immunotherapy. As the key component of liposome, a unique phospholipid is designed to bear two arachidonic acid tails. The liposome is further surface-engineered with fucose ligand and physically encapsulates immunostimulatory CpG oligodeoxynucleotides (ODNs). The tailored liposome shows enhanced cellular uptake in a model 4T1 cell line. Meanwhile, the high level of reactive oxygen species in cancer cells can induce ferroptosis-specific peroxidation of DAPC and trigger the release CpG ODNs. The CpG ODNs further enable the maturation of dendritic cells and enhance the effector function of CD8+ T cells. IFN-γ released from CD8+ T cells promotes cancer cell ferroptosis via inhibiting SLC7A11 and suppressing the biosynthesis of glutathione. The tailored liposome can also act in synergism with PD-L1 antibody, resulting in enhanced anti-cancer efficacy in a 4T1 tumor-bearing mice model. This work provides a promising strategy for cancer treatment through orchestrating ferroptotic therapy and immunotherapy.
Subject(s)
Ferroptosis , Neoplasms , Animals , Mice , Liposomes , CD8-Positive T-Lymphocytes , Neoplasms/therapy , Immunotherapy , Cell Line, TumorABSTRACT
Ferroptotic cancer therapy is promising in many scenarios where traditional cancer therapies show a poor response. However, certain types of cancers lack the long-chain acyl-CoA synthetase 4 (ACSL4), a key modulator of ferroptosis, resulting in therapy resistance and tumor relapse. Because ACSL4 is in charge of the synthesis of ferroptotic lipids (e.g., arachidonoylphosphatidylethanolamine/PE-AA), we postulated that direct delivery of PE-AA may reverse ferroptosis resistance induced by ACSL4 deficiency. To further increase the ferroptosis sensitivity, we employed the ferrocene-bearing polymer micelles to co-load PE-AA with an FDA-approved redox modulator, auranofin (Aur), targeting the thioredoxin reductase. The presence of ferrocene enabled triggered cargo release and iron production, which can sensitize ferroptosis by boosting autoxidation-mediated PE-AA peroxidation. The micellar system could impair redox homeostasis and induce lipid peroxidation in ACSL4-deficient MCF-7 cells. Moreover, the tailored micelles potently induced ferroptosis in MCF-7 tumors in vivo, suppressed tumor growth, and increased the mice's survival rate. The current work provides a facile means for reversing the ferroptosis resistance in ACSL4-deficient tumors.
Subject(s)
Ferroptosis , Neoplasms , Animals , Mice , Cell Line, Tumor , Metallocenes , Iron , Micelles , LipidsABSTRACT
Microglial inflammation is characterized by an increase in proinflammatory cytokines and proinflammatory enzyme levels, facilitating inflammation-mediated neuronal apoptosis. Previous studies indicated that both high-mobility group protein B1 (HMGB1) and E26 transformation-specific sequence (ETS) transcription factor-1 (ESE-1) are involved in lipopolysaccharide (LPS)-mediated neuroinflammation. In the present study, we hypothesized that the ESE-1 modulates HMGB1 expression and is thus involved in LPS-mediated microglial inflammation. Moreover, we explored the potential mechanism by which ESE-1 modulates HMGB1 expression. Our study indicated that LPS increased proinflammatory cytokine and proinflammatory enzyme levels via upregulation of HMGB1 expression in BV2 cells. Moreover, LPS treatment increased ESE-1 expression while inhibiting sirt1 expression. Both sirt1 overexpression and si-ESE-1 treatment reversed LPSinduced HMGB1 expression and proinflammatory cytokine and proinflammatory enzyme levels. In addition, ESE-1 was found to be associated with sirt1. Also ESE-1 and sirt1 were found to be enriched with the HMGB1 promoter region. Sirt1 silencing increased the abundance of ESE-1 that occupied the HMGB1 promoter region. The present study indicated that ESE-1 associates with sirt1 to regulate HMGB1 expression, which participates in LPS-mediated inflammation in BV2 cells.
Subject(s)
HMGB1 Protein , Lipopolysaccharides , Humans , Cytokines/genetics , Cytokines/metabolism , HMGB1 Protein/genetics , Inflammation/chemically induced , Inflammation/genetics , Lipopolysaccharides/pharmacology , Sirtuin 1/genetics , Sirtuin 1/metabolism , Up-RegulationABSTRACT
BACKGROUND: To investigate the association between tumor mutational burden (TMB) and the therapeutic effect of Programmed Death 1/Programmed Death Ligand 1 inhibitors in non-small cell lung cancer. METHODS: Four electronic databases, PubMed, Embase, Web of Science, and Cochrane Library, were searched on May 10, 2023, and no time limitation was applied. Analyses were performed using STATA17.0. We assessed the methodological quality of each randomized controlled trial using the Newcastle-Ottawa scale. RESULTS: After exhaustive database search and rigorous screening, 10 studies were included in the meta-analysis. Our findings indicate that high TMB significantly improves progression-free survival but reduces overall response rate. The overall survival was not significantly different between the high and low TMB groups. No significant publication bias was observed. CONCLUSION: High TMB serves as a potential predictive biomarker for improved progression-free survival and reduced overall response rate in patients with non-small cell lung cancer treated with programmed death 1/programmed death ligand 1 inhibitors. However, its predictive value in overall survival requires further investigation.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Programmed Cell Death 1 Receptor/therapeutic use , Mutation , Biomarkers, Tumor , B7-H1 Antigen/therapeutic useABSTRACT
BACKGROUND: Neurogenic bowel dysfunction (NBD) is a common complication in stroke patients. OBJECTIVE: To investigate the effect of rectal balloon ice water stimulation on the rehabilitation of patients with NBD after a cerebral stroke. METHODS: Forty stroke patients with NBD were selected between March and August 2022 and randomly divided into a study group (nâ=â20) and a control group (nâ=â20). Based on routine rehabilitation training, rectal balloon ice water stimulation or finger rectal stimulation were performed on the study or control group, respectively. After two weeks, the changes in the NBD, self-rating depression scale (SDS) and self-rating anxiety scale (SAS) scores were compared between the two groups. RESULTS: Before the intervention, there were no significant differences in age, sex ratio, and NBD, SDS and SAS scores between the two groups (pâ>â0.05). The NBD, SDS and SAS scores of both groups were significantly decreased following intervention (pâ<â0.05). After 2 weeks of intervention, the NBD score of the study group was significantly lower than that of the control group (5.50±1.28 vs 6.45±1.05; pâ=â0.014). The SDS score of the study group was lower than that of the control group, and the difference was statistically significant (32.30±2.81 vs 44.05±2.19; pâ=â0.014). The study group also had significantly lower SAS scores than the control group (pâ=â0.024). In addition, the incidence of dizziness, headaches, nausea, vomiting and abdominal pain and distension in the study group was significantly lower than in the control group (pâ<â0.05). CONCLUSION: Rectal balloon ice water stimulation can significantly improve stroke patients with NBD's intestinal function and psychological status.
Subject(s)
Neurogenic Bowel , Stroke Rehabilitation , Stroke , Humans , Headache/complications , Neurogenic Bowel/etiology , Stroke/complications , Stroke Rehabilitation/adverse effectsABSTRACT
In this study, pristine kiwi peel (KP) and nitric acid modified kiwi peel (NA-KP) based adsorbents were prepared and evaluated for selective removal of cationic dye. The morphology and chemical structure of KP and NA-KP were fully characterized and compared, and results showed nitric acid modification introduced more functional groups. Moreover, the adsorption kinetics and isotherms of malachite green (MG) by KP and NA-KP were investigated and discussed. The results showed that the adsorption process of MG onto KP followed a pseudo-second-order kinetic model and the Langmuir isotherm model, while the adsorption process of MG onto NA-KP followed a pseudo-first-order kinetic model and the Freundlich isotherm model. Notably, the Langmuir maximum adsorption capacity of NA-KP was 580.61 mg g-1, which was superior to that of KP (297.15 mg g-1). Furthermore, thermodynamic studies demonstrated the feasible, spontaneous, and endothermic nature of the adsorption process of MG by NA-KP. Importantly, NA-KP showed superior selectivity to KP towards cationic dye MG against anionic dye methyl orange (MO). When the molar ratio of MG/MO was 1:1, the separation factor (αMG/MO) of NA-KP was 698.10, which was 5.93 times of KP. In addition, hydrogen bonding, π-π interactions, and electrostatic interaction played important roles during the MG adsorption process by NA-KP. This work provided a low-cost, eco-friendly, and efficient option for the selective removal of cationic dye from dyeing wastewater.
Subject(s)
Coloring Agents , Water Pollutants, Chemical , Coloring Agents/chemistry , Adsorption , Nitric Acid , Rosaniline Dyes/chemistry , Thermodynamics , Kinetics , Water Pollutants, Chemical/chemistry , Hydrogen-Ion ConcentrationABSTRACT
Peripheral sensory organ damage leads to compensatory cortical plasticity that is associated with a remarkable recovery of cortical responses to sound. The precise mechanisms that explain how this plasticity is implemented and distributed over a diverse collection of excitatory and inhibitory cortical neurons remain unknown. After noise trauma and persistent peripheral deficits, we found recovered sound-evoked activity in mouse A1 excitatory principal neurons (PNs), parvalbumin- and vasoactive intestinal peptide-expressing neurons (PVs and VIPs), but reduced activity in somatostatin-expressing neurons (SOMs). This cell-type-specific recovery was also associated with cell-type-specific intrinsic plasticity. These findings, along with our computational modelling results, are consistent with the notion that PV plasticity contributes to PN stability, SOM plasticity allows for increased PN and PV activity, and VIP plasticity enables PN and PV recovery by inhibiting SOMs.
Subject(s)
Auditory Cortex , Mice , Animals , Auditory Cortex/physiology , Interneurons/metabolism , Neurons/metabolism , Vasoactive Intestinal Peptide/metabolism , Sound , Parvalbumins/metabolismABSTRACT
As a clinical unmet need, uncontrolled inflammation is characterized by the crosstalk between oxidative stress and an inflammatory response. Ferroptotic cell death plays an essential role in uncontrolled inflammation. Hence ferroptosis inhibition is capable of managing hyper-inflammation, but the small molecular inhibitors show poor residence in cell membranes. The plasma membrane is the major site of lipid peroxidation that is the key event of ferroptosis. To address such a challenge, chiral radical trapping polymers were engineered by mimicking the structure of the cell membrane with imbedded helical proteins. The polymers were tailored to show an α-helix conformation that enabled increased hydrophobicity, prolonged membrane retention, and enhanced lipid radical trapping. The chiral polymers are amphiphilic, and the self-assembled micelles exhibited an extended blood circulation. At the lipopolysaccharide-induced macrophage and mice models, chiral polymer micelles effectively suppressed ferroptosis and repressed inflammatory cytokines. The current work provides an innovative means for attenuating uncontrolled inflammation by anti-ferroptotic polymer micelles.
Subject(s)
Micelles , Polymers , Mice , Animals , Polymers/pharmacology , Polymers/chemistry , Cell Death , Lipid Peroxidation , Inflammation/drug therapyABSTRACT
The solid tumors are characterized with oxidative stress and metabolic reprogramming, which has been independently used for targeted tumor monotherapy. However, the potential of targeting metabolism-redox circuit in tumor therapy has long been neglected. Herein, we report a hybrid nanocarrier for concurrent targeting of glycolysis and redox balance in the current work. The nanocarriers are made of pH- and ATP-responsive zeolitic imidazolate framework (ZIF-8) as the porous core that was further coated with poloxamer 407 as the steric stabilizer. Two active cargos, glucose oxidase (GOx) and 3-bromopyruvate (3-BrPA) were co-loaded in the core of nanocarrier. GOx is well-known for its ability of producing hydrogen peroxide at the expense of glucose and oxygen. 3-BrPA can reduce oxygen and glucose consumption through glycolysis, which sensitized cancer cells to GOx-induced apoptosis. At the cellular level, the hybrid nanocarrier significantly impaired the redox balance in the liver hepatocellular carcinoma cell line (HepG2), as evidenced by the depletion of glutathione and boost of reactive oxygen species. The potency of hybrid nanocarrier in terms of suppressing HepG2 cell energy metabolism was proven by the exhaustion of ATP. As a consequence, cell viability was greatly reduced. The in vivo efficacy of hybrid nanocarriers was demonstrated in HepG2 tumor-bearing mice. The current work presents an approach of targeting metabolism-redox circuit for tumor treatment, which may enrich the available anti-tumor strategies. STATEMENT OF SIGNIFICANCE: Metabolic alterations and elevated reactive oxygen species (ROS) are two characteristics of cancer. The metabolic patterns of cancer cells are elaborately reprogrammed to enable the rapid propagation of cancer cells. However, the potential of targeting the metabolism-redox circuit in anti-tumor therapy has long been neglected. As a proof-of-concept, we report an engineered stimuli-responsive nanomedicine that can eradicate cancer cells via cooperative glycolysis inhibition and redox impairment. The current work presents an approach of targeting the metabolism-redox circuit for tumor treatment, which may enrich the available anti-tumor strategies.
Subject(s)
Nanomedicine , Neoplasms , Animals , Mice , Reactive Oxygen Species/metabolism , Neoplasms/pathology , Oxidation-Reduction , Glycolysis , Oxygen , Adenosine Triphosphate/metabolism , Homeostasis , Glucose , Cell Line, TumorABSTRACT
BACKGROUND: Intravenous thrombolysis can significantly improve the neurological function of patients with acute ischemic stroke. However, the expected early dramatic recovery (EDR) of neurological function after thrombolysis is not achieved in some patients with branch atheromatous disease (BAD). Here we evaluated the factors associated with EDR after thrombolysis in BAD patients. METHODS: We conducted a retrospective study on 580 consecutive BAD patients. All patients met the diagnostic criteria of BAD and received intravenous recombinant tissue-type plasminogen activator (rt-PA). EDR was defined when the improvement of National Institutes of Health Stroke Scale (NIHSS) score was >8 points within 2 or 24 hours after rt-PA, or the total NIHSS score was 0 or 1. The factors associated with EDR were analyzed with multivariate logistic regression analysis. RESULTS: Among 580 patients, the incidence of EDR was 35.2% (204 cases). Compared with patients without EDR, patients with EDR had lower incidence of diabetes (15.7% vs 29.3%, Pâ <â .001), lower NIHSS scores at 2 and 24 hours after rt-PA (Pâ <â .001), less cerebral hemorrhage (0% vs 5.3%, Pâ =â .001), and shorter onset to treatment time (OTT) (Pâ <â .001). Multivariate logistic regression analysis in propensity score-matched cohort showed that EDR was associated with OTT (adjusted ORâ =â 0.994; 95% CI, 0.989-0.999) and NIHSS score after rt-PA (adjusted ORâ =â 0.768; 95% CI, 0.663-0.890). Notably, diabetes (adjusted ORâ =â 0.477, 95% CI, 0.234-0.972) was an independent factor related to EDR of neurological function in BAD patients. In the subgroup analysis, a lower incidence of diabetes (adjusted ORâ =â 0.205, 95% CI: 0.059-0.714, Pâ =â .013) and a lower NIHSS score after thrombolysis in patients with paramedian pontine infarction (adjusted ORâ =â 0.809, 95% CI: 0.656-0.997, Pâ =â .047) were significantly associated with EDR. CONCLUSION: Diabetes is not conducive to EDR of neurological function in patients with BAD, especially in patients with paramedian pontine infraction. Low NIHSS score and short OTT after thrombolysis may be closely related to EDR after intravenous thrombolysis.