A Hypochlorite-Activated Theranostic Prodrug for Selective Imaging of High Myeloperoxidase Expression Acute Myeloid Leukemia Cells and Drug Release.

Acute myeloid leukemia (AML) is a fatal hematologic disease. Diagnosis and proper treatment are important for prognosis. High myeloperoxidase (MPO) expression AML cells are characterized with high levels of hypochlorite (ClO-). In this study, we report a ClO--activated theranostic agent, FNC, for AML therapy. FNC responds to ClO- specifically in high MPO expression AML cells, resulting in bright fluorescence and chlorambucil release. FNC can be used to quickly distinguish high MPO expression AML cells from other cells, including low MPO expression leukemia and activated inflammatory cells. FNC exhibits selective toxicity to highly MPO expression AML cells and can efficiently inhibit tumor growth. Meanwhile, FNC can be used to indicate differentiation through the detection of ClO-.

Single-Molecule Protein Analysis by Centrifugal Droplet Immuno-PCR with Magnetic Nanoparticles.

Detecting proteins in ultralow concentrations in complex media is important for many applications but often relies on complicated techniques. Herein, a single-molecule protein analyzer with the potential for high-throughput applications is reported. Gold-coated magnetic nanoparticles with DNA-labeled antibodies were used for target recognition and separation. The immunocomplex was loaded into microdroplets generated with centrifugation. Immuno-PCR amplification of the DNA enabled the quantification of proteins at the level of single molecules. As an example, ultrasensitive detection of α-synuclein, a biomarker for neurodegenerative diseases, is achieved. The limit of detection was determined to be ∼50 aM in buffer and ∼170 aM in serum. The method exhibited high specificity and could be used to analyze post-translational modifications such as protein phosphorylation. This study will inspire wider studies on single-molecule protein detection, especially in disease diagnostics, biomarker discovery, and drug development.

Topological Photonic Alloy.

We present the new concept of photonic alloy as a nonperiodic topological material. By mixing nonmagnetized and magnetized rods in a nonperiodic 2D photonic crystal configuration, we realized photonic alloys in the microwave regime. Our experimental findings reveal that the photonic alloy sustains nonreciprocal chiral edge states even at very low concentration of magnetized rods. The nontrivial topology and the associated edge states of these nonperiodic systems can be characterized by the winding of the reflection phase. Our results indicate that the threshold concentrations for the investigated system within the first nontrivial band gap to exhibit topological behavior approach zero in the thermodynamic limit for substitutional alloys, while the threshold remains nonzero for interstitial alloys. At low concentration, the system exhibits an inhomogeneous structure characterized by isolated patches of nonpercolating magnetic domains that are spaced far apart within a topologically trivial photonic crystal. Surprisingly, the system manifests chiral edge states despite a local breakdown of time-reversal symmetry rather than a global one. Photonic alloys represent a new category of disordered topological materials, offering exciting opportunities for exploring topological materials with adjustable gaps.

Determining the maximum tolerated dose of paclitaxel combined with fixed dose of cisplatin for hyperthermic intraperitoneal chemotherapy in ovarian cancer: A multicenter phase I trial.

OBJECTIVE: To determine the maximum tolerated dose (MTD) of paclitaxel combined with a fixed dose of cisplatin (75 mg/m2) delivered via hyperthermic intraperitoneal chemotherapy (HIPEC) to patients with ovarian cancer. METHODS: This multicenter Phase I trial employed a Bayesian Optimal Interval (BOIN) design. The MTD was determined to have a target dose-limiting toxicity (DLT) rate of 25%. The starting dose was 175 mg/m2. The Data and Safety Monitoring Board made decisions regarding dose escalation or de-escalation in increments of 25 mg/m2 for subsequent patient cohorts, up to a maximum sample size of 30 or 12 patients treated at a given dose. RESULTS: Twenty-one patients participated in this study. Among the three evaluable patients who received 150 mg/m2 paclitaxel, no DLTs were observed. Among the 12 evaluable patients who received 175 mg/m2 paclitaxel, two reported DLTs: one had grade 4 neutropenia and one had grade 4 anemia, neutropenia, and leukopenia. Four of the six evaluable patients who received 200 mg/m2 paclitaxel reported DLTs: one patient had grade 4 diarrhea, one had grade 3 kidney injury, and two had grade 4 anemia. The isotonic estimate of the DLT rate in the 175 mg/m2 dose group was 0.17 (95% confidence interval, 0.02-0.42), and this dose was selected as the MTD. CONCLUSION: Paclitaxel, when combined with a fixed dose of cisplatin (75 mg/m2), can be safely administered intraperitoneally at a dose of 175 mg/m2 in patients with ovarian cancer who received HIPEC (43 °C, 90 min) following cytoreductive surgery.

Unraveling the interplay between dyskinesia and overactive bladder symptoms in Parkinson's disease: a comprehensive cohort study based on the long-term follow-up database of Parkinson's disease.

OBJECTIVES: Overactive bladder (OAB) and dyskinesia are frequent complications in patients with Parkinson's disease (PD). However, the correlation between OAB and dyskinesia has been insufficiently explored. The purpose of this study was to examine the relationship between dyskinesia, OAB, and clinical characteristics among individuals with PD. METHODS: 1338 PD patients were included in the present study. Demographic features were compared between patients with or without dyskinesia and OAB symptoms. Logistic regression was conducted on dyskinesia to screen clinically relevant factors. Overactive Bladder Symptom Score (OABSS) was further used to stratify the association between the severity of OAB and the occurrence of dyskinesia. RESULTS: This study indicates that both dyskinesia and OAB are significantly related to disease severity and cognitive status. PD patients with dyskinesia and OAB having higher UPDRS scores (p < 0.001), H-Y scores (p < 0.001), NMSQ (p < 0.001) and MoCA scores (p < 0.001), and lower MMSE scores (p < 0.001) are identified. The multivariate logistic regression confirms that disease duration (p = 0.041), LEDD (p < 0.001), UPDRSII (p < 0.001), MoCA (p = 0.024), urgency (p < 0.001), frequency (p < 0.001), and nocturia (p = 0.002) are independent risk factors for dyskinesia. Trend analysis indicates that the risk of dyskinesia significantly increases when patients exhibit moderate to severe OAB symptoms (OABSS > 5) (p < 0.001). No significant interactions were found between OABSS and age, gender, disease duration, LEDD, and NMSQ scores in different subgroups, indicating that dyskinesia is more pronounced in patients with OABSS > 5. DISCUSSION: This study provides compelling evidence supporting the strong correlation between OAB and dyskinesia in PD patients, emphasizing the presence of shared pathogenic mechanisms between these two conditions. Our findings underscore the importance of considering both OAB and dyskinesia in the clinical management of PD, investigating the intricate connections between OAB and dyskinesia could unveil valuable insights into the complex pathophysiology of PD and potentially identify novel therapeutic targets for more effective PD treatment strategies.

PL-ReliefTMplus Alleviates Atopic Dermatitis and Regulates Inflammatory Responses via Inhibiting NF-κB Signaling Pathway.

BACKGROUND: Atopic dermatitis (AD) has various detrimental effects on individuals with limited drug cure rates which necessitate the development of new treatment methods. PL-ReliefTMplus (PLR) is composed of SupraOlive, Crocus Sativus extracts and Citrus reticulata extracts. The effect of PLR on AD remains to be explored. METHODS: 2,4-dinitrofluorobenzene-induced AD model mice were involved and the histopathology of the skin lesions was observed along with the levels of inflammatory chemokines levels were measured. To further validate the molecular mechanism of PLR, RNA-seq was performed in HaCaT cells. Western blotting and immunofluorescence were performed to investigate NF-κB signaling pathways response in AD. RESULTS: Due to PLR treatment, the thickening of the epidermis and dermis was inhibited and the number of eosinophils, mast cells, and CD4+ T cells in the skin lesion was decreased. In addition, the levels of inflammatory cytokines were decreased in dorsal skin tissues and LPS-stimulated HaCat cells. Furthermore, KEGG pathway analysis suggested that most identified downstream biological functions were associated with inflammatory response. PLR inhibited NF-κB signaling in AD mice and HaCaT cells. CONCLUSIONS: These results indicate that PLR is a potent therapeutic agent for attenuating symptoms of AD.

The Combination of Sinusoidal Perfusion Enhancement and Apoptosis Inhibition by Riociguat Plus a Galactose-PEGylated Bilirubin Multiplexing Nanomedicine Ameliorates Liver Fibrosis Progression.

Chronic liver injury and continuous wound healing lead to extracellular matrix (ECM) deposition and liver fibrosis. The elevated production of reactive oxygen species (ROS) in the liver leads to the apoptosis of hepatocytes and the activation of hepatic stellate cells (HSCs). In the current study, we describe a combination strategy of sinusoidal perfusion enhancement and apoptosis inhibition enabled by riociguat together with a tailor-designed galactose-PEGylated bilirubin nanomedicine (Sel@GBRNPs). Riociguat enhanced sinusoidal perfusion and decreased the associated ROS accumulation and inflammatory state of the fibrotic liver. Concurrently, hepatocyte-targeting galactose-PEGylated bilirubin scavenged excessive ROS and released encapsulated selonsertib. The released selonsertib inhibited apoptosis signal-regulating kinase 1 (ASK1) phosphorylation to alleviate apoptosis in hepatocytes. The combined effects on ROS and hepatocyte apoptosis attenuated the stimulation of HSC activation and ECM deposition in a mouse model of liver fibrosis. This work provides a novel strategy for liver fibrosis treatment based on sinusoidal perfusion enhancement and apoptosis inhibition.

Ultrasonic Evaluation of the Asian Nasal Soft Tissue Envelope.

OBJECTIVE: The thickness of the nasal soft tissue envelope (STE) plays a crucial role in the final rhinoplasty results. The Asian nasal contour is typically characterized by a thicker STE and broader nasal tip, but objective data are lacking. The purpose of this study was to objectively measure nasal dermal thickness and overall STE thickness and to determine any demographic differences. METHODS: From July to September 2023, 110 patients presenting for consultation underwent ultrasound evaluation of their nasal STE. STE thickness was measured at predetermined subsites and compared with published data on white patients. RESULTS: The thickness of the STE in Asian patients was greater than that in white patients. The STE was thickest at the supratip (mean [SD]), (4.88 [0.74] mm) rather than at the nasion and thinnest at the rhinion (2.25 [0.51] mm). The nasal tip (4.07 [0.72] mm) showed comparable STE thickness with the nasion (4.13 [0.72] mm) but had a significantly thicker dermis than the nasion (2.35 ± 0.49 mm vs. 1.35 ± 0.35 mm, P < 0.05). Male sex and higher BMI tended to be correlated with a thicker nasal STE, but age did not show any relationship. A thicker nasal tip STE showed significantly greater nasal tip width and nasal alar thickness. CONCLUSION: STE thickness at different nasal subsites varies and affects external nasal contour and rhinoplasty outcomes. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Cognitive status and its risk factors in patients with hypertension and diabetes in a low-income rural area of China: A cross-sectional study.

OBJECTIVES: The proportion of older people with dementia in China is gradually increasing with the increase in the aging population over recent years. Hypertension and diabetes are common non-communicable diseases among rural populations in China. However, it remains unclear whether these conditions affect the occurrence and development of cognitive impairment as there is limited research on cognitive status and its risk factors among residents of rural areas. METHODS: A multi-stage stratified cluster random sampling method was used to select 5400 participants from rural permanent residents. A self-designed structured questionnaire was used to investigate demographic data of the participants. Cognitive function was assessed using the Montreal Cognitive Function Assessment Scale (MoCA). The results were analyzed using chi-square test, ANOVA and multiple linear regression analysis. RESULTS: A total of 5028 participants returned the survey, giving a response rate of 93.1%. Higher education (odds ratio (OR) = 3.2, 95% confidence interval (CI) 2.87-3.54, p < 0.001), higher income (OR = 1.61, 95% CI 1.16-2.07, p < 0.001), and dietary control (OR = 0.66, 95%CI 0.34-0.98, p < 0.001) were protective factors. A visual representation of the relationship between annual income and MoCA score showed an inverted U-curve, the group with an annual income of 6000-7999 RMB had a maximum OR of 1.93 (95%CI 0.12-2.74, p < 0.001). While difficulty in maintaining sleep were risk factors for cognitive impairment (OR = -2.28, 95% CI-4.18-0.39, p = 0.018). CONCLUSIONS: Participants with middle incomes had better cognitive status than those with the highest incomes. Higher education, proper diet control and good sleep are beneficial to the cognitive status of residents in rural areas.

Pramipexole inhibits astrocytic NLRP3 inflammasome activation via Drd3-dependent autophagy in a mouse model of Parkinson's disease.

Inflammation is one of the pathogenic processes in Parkinson's disease (PD). Dopamine receptor agonist pramipexole (PPX) is extensively used for PD treatment in clinics. A number of studies show that PPX exerts neuroprotection on dopaminergic (DA) neurons, but the molecular mechanisms underlying the protective effects of PPX on DA neurons are not fully elucidated. In the present study, we investigated whether PPX modulated PD-related neuroinflammation and underlying mechanisms. PD model was established in mice by bilateral striatum injection of lipopolyssaccharide (LPS). The mice were administered PPX (0.5 mg·kg-1·d-1, i.p.) 3 days before LPS injection, and for 3 or 21 days after surgery, respectively, for biochemical and histological analyses. We showed that PPX administration significantly alleviated the loss of DA neurons, and suppressed the astrocyte activation and levels of proinflammatory cytokine IL-1ß in the substantia nigra of LPS-injected mice. Furthermore, PPX administration significantly decreased the expression of NLRP3 inflammasome-associated proteins, i.e., cleaved forms of caspase-1, IL-1ß, and apoptosis-associated speck-like protein containing a caspase recruit domain (ASC) in the striatum. These results were validated in LPS+ATP-stimulated primary mouse astrocytes in vitro. Remarkably, we showed that PPX (100-400 µM) dose-dependently enhanced the autophagy activity in the astrocytes evidenced by the elevations in LC3-II and BECN1 protein expression, as well as the increase of GFP-LC3 puncta formation. The opposite effects of PPX on astrocytic NLRP3 inflammasome and autophagy were eliminated by Drd3 depletion. Moreover, we demonstrated that both pretreatment of astrocytes with autophagy inhibitor chloroquine (40 µM) in vitro and astrocyte-specific Atg5 knockdown in vivo blocked PPX-caused inhibition on NLRP3 inflammasome and protection against DA neuron damage. Altogether, this study demonstrates an anti-neuroinflammatory activity of PPX via a Drd3-dependent enhancement of autophagy activity in astrocytes, and reveals a new mechanism for the beneficial effect of PPX in PD therapy.

Prognostic and Predictive Utility of GPD1L in Human Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths worldwide. GPD1L, a member of the glycerol-3-phosphate dehydrogenase family, has emerged as a potential tumour suppressor gene, with high expression associated with a favourable prognosis in various cancers. Despite an intriguing inverse relationship observed with HCC, the precise role and underlying function of GPD1L in HCC remain poorly understood. Here, we aimed to investigate the prognostic significance, molecular characteristics, and predictive potential of GPD1L overexpression in HCC. Analysis of independent datasets revealed a significant correlation between high GPD1L expression and poor survival in HCC patients. Spatial and single cell transcriptome datasets confirmed elevated GDP1L expression in tumour tissue compared to adjacent normal tissue. GPD1L exhibited increased expression and promoter demethylation with advancing tumour stage, confirming positive selection during tumorigeneses. GPD1L overexpression was associated with metabolic dysregulation and enrichment of gene sets related to cell cycle control, epithelial-mesenchymal transition, and E2F targets. Moreover, we demonstrated an inverse correlation between GPD1L expression and therapeutic response for three therapeutic agents (PF-562271, Linsitinib, and BMS-754807), highlighting its potential as a predictive biomarker for HCC treatment outcomes. These data provide insights into the prognostic significance, molecular characteristics, and predictive potential of GPD1L in HCC.

Freeze-Driven Adsorption of Poly-A DNA on Gold Nanoparticles: From a Stable Biointerface to Plasmonic Dimers.

Increasing attention is paid to poly-adenine (poly-A) DNA-functionalized gold nanoparticles due to the high cost of thiols. Freezing is an effective approach for immobilizing poly-A DNA on gold nanoparticles, but its mechanism remains elusive. To cope with this issue, in this paper, some experimental insights are provided. It is shown that (1) the DNA loading density is independent of the length of poly-A. (2) DNA is densely packed on gold nanoparticles, and the biointerface is peculiarly stable, which is not in line with the existing "wrapping" model. (3) Using a DNA-staining dye, thiazole orange, it is shown that poly-A duplex structures are formed on the surface of gold nanoparticles, with evidence given by fluorescence and Raman measurements. An alternative model involving stable poly-A duplexes anchored by finite terminal adenines is proposed. Based on it, a strategy for constructing plasmonic dimers is developed, using freeze-driven adsorption of a DNA sequence with poly-adenine at both ends. This work provides insights into the reaction between poly-A DNA and AuNPs upon freezing and is expected to facilitate related research in biosensor development and nanotechnology.

Secondary hypogonadism following hand, foot, and mouth disease in an adult: a case report and review of literature.

BACKGROUND: Previous reports have described hypogonadism associated with virus infection such as hantavirus, human immunodeficiency virus (HIV) or severe acute respiratory syndrome coronavirus 2 (SARS-COV-2). However, to our best knowledge there has been no case report of secondary hypogonadism following hand, foot, and mouth disease (HFMD). CASE PRESENTATION: A previously healthy 28-year-old man with no history of major physical and psychological trauma, presented with bilateral gynecomastia and erectile dysfunction 2 weeks after HFMD. Laboratory testament showed the level of gonadotropin hormones declined. Imaging examination demonstrated no major abnormal change in pituitary or reproductive system. The diagnosis of hypogonadism was established. Then the patient was ordered to maintain mental health outward of hospital without drug intervention. One month after presentation, his gonadotropin hormone level and sexual desire had recovered, while bilateral gynecomastia and erectile dysfunction symptoms disappeared. CONCLUSIONS: Physicians should notice the possibility for hypogonadism in adult patients with a recent history of HFMD.

Fiber selectivity of peripheral neuropathy in patients with Parkinson's disease.

OBJECTIVE: To determine the function of each type of peripheral nerve fiber and investigate the possible role of levodopa (LD) in peripheral neuropathy (PN) in Parkinson's disease (PD) patients. METHODS: We enrolled 60 patients with idiopathic PD. All PD patients were divided into three groups: levodopa exposure >3 years (LELD), levodopa exposure ≤3 years (SELD) and de novo patients with PD (NOLD). The current perception threshold (CPT), which was measured by Neurometer at 2000, 250 and 5 Hz, the level of homocysteine, Vitamin B12 and folic acid in plasma, were compared with those of sex- and age-matched healthy controls (HCs). RESULTS: Current perception threshold was higher at 250 Hz (p < .05) and 5 Hz (p < .05) in the LELD group than the NOLD, SELD, and control group. CPT was lower at 5 Hz in the NOLD than in the HCs group (p < .05). The CPT of the more affected side of PD patients was positively correlated with H-Y stage at 5 Hz current stimulation (r = .42, p = .01). Multivariate logistic regression analysis showed that elevated homocysteine levels were the risk factor of sensory nerve injury in PD patients (p < .01). Serum homocysteine levels were positively correlated with levodopa (LD) daily dose, LD equivalent daily dose, and LD cumulative lifetime dose (p < .05). CONCLUSIONS: Peripheral neuropathy in PD patients can occur in the early stage of PD exhibiting as hyperesthesia and is fiber selectivity, especially for Aδ and C nerve fibers. PN in PD patients is related to PD itself and long-term LD exposure. Elevated plasma homocysteine is a risk factor for PN in PD patients.

Linear Spatial Misregistration Detection and Correction Based on Spectral Unmixing for FAHI Hyperspectral Imagery.

In push-broom hyperspectral imaging systems, the sensor rotation to the optical plane leads to linear spatial misregistration (LSM) in hyperspectral images (HSIs). To compensate for hardware defects through software, this paper develops four methods to detect LSM in HSIs. Different from traditional methods for grayscale images, the method of fitting the sum of abundance (FSAM) and the method of searching for equal abundance (SEAM) are achieved by hyperspectral unmixing for a selected rectangular transition areas containing an edge, which makes good use of spatial and spectral information. The method based on line detection for band-interleaved-by-line (BIL) images (LDBM) and the method based on the Fourier transform of BIL images (FTBM) aim to characterize the slope of line structure in BIL images and get rid of the dependence on scene and wavelength. A full strategy is detailed from aspects of data selection, LSM detection, and image correction. The full spectrum airborne hyperspectral imager (FAHI) is China's new generation push-broom scanner. The HSIs obtained by FAHI are tested and analyzed. Experiments on simulation data compare the four proposed methods with traditional methods and prove that FSAM outperforms other methods in terms of accuracy and stability. In experiments on real data, the application of the full strategy on FAHI verifies its effectiveness. This work not only provides reference for other push-broom imagers with similar problems, but also helps to reduce the requirement for hardware calibration.

Pipette-Tip-Enabled Digital Nucleic Acid Analyzer for COVID-19 Testing with Isothermal Amplification.

Herein, a pipette-tip-enabled digital nucleic acid analyzer for high-performance COVID-19 testing is demonstrated. This is achieved by digital loop-mediated isothermal amplification (digital LAMP or dLAMP) using common laboratory equipment and materials. It is shown that simply fixing a glass capillary inside conventional pipette tips enables the generation of monodisperse, water-in-oil microdroplets with benchtop centrifugation. It is shown that using LAMP, the ORF1a/b gene, a standard test region for COVID-19 screening, can be amplified without a thermal cycler. The amplification allows counting of fluorescent microdroplets so that Poisson analysis can be performed to allow quantification with a limit of detection that is 1 order of magnitude better than those of nondigital techniques and comparable to those of commercial dLAMP platforms. It is envisioned that this work will inspire studies on ultrasensitive digital nucleic acid analyzers demanding both sensitivity and accessibility, which is pivotal to their large-scale applications.

Sub-3 nm Aluminum Nanocrystals Exhibiting Cluster-Like Optical Properties.

Metal nanoclusters with distinct photophysical and photochemical properties have drawn intense research interests for their applications in optoelectronics, catalysis, and biomedicine. Herein, strong evidence is provided that light metal is capable of generating comparable optical responses of noble metal nanoclusters, but at much shorter wavelength. Air-stable, size-uniform, sub-3 nm aluminum nanocrystals are prepared with simple solution based synthetic procedures, with photoluminescence located in the ultraviolet range and short exciton lifetime. Partial modulation of the photoluminescence is achieved, indicating the key role of surface oxides. This work is envisioned to inspire new frontiers of nanocluster research with light metals.

Effects of fenofibrate therapy on renal function in primary gout patients.

OBJECTIVE: To investigate the incidence and potential risk factors for development of fenofibrate-associated nephrotoxicity in gout patients. METHODS: A total of 983 gout patients on fenofibrate treatment who visited the dedicated Gout Clinic at the Affiliated Hospital of Qingdao University between September 2016 and June 2020 were retrospectively enrolled from the electronic records system. Fenofibrate-associated nephrotoxicity was defined as an increase in serum creatinine (SCr) ≥0.3 mg/dl within 6 months of fenofibrate initiation. The change trend of SCr and uric acid levels during the treatment period were assessed by a generalised additive mixed model (GAMM). Multivariate analysis was performed for risk factors affecting elevated SCr. RESULTS: A total of 100 (10.2%) patients experienced an increase in SCr ≥0.3 mg/dl within 6 months after fenofibrate initiation. The median change of SCr in the whole cohort was 0.11 mg/dl [interquartile range (IQR) 0.03-0.20], whereas it was 0.36 (0.33-0.45) in the fenofibrate-associated nephrotoxicity group. In a multivariable regression model, chronic kidney disease (CKD) [odds ratio (OR) 2.39 (95% CI 1.48, 3.86)] and tophus [OR 2.29 (95% CI 1.39, 3.78)] were identified to be risk predictors, independent of measured covariates, of fenofibrate-associated nephrotoxicity. During the treatment period, although SCr temporarily increased, serum urate and triglyceride concentrations decreased using the interaction analysis of GAMM. Of those with fenofibrate withdrawal records, the SCr increase in 65% of patients was reversed after an average of 49 days off the drug. CONCLUSIONS: This observational study implied that fenofibrate-associated nephrotoxicity occurs frequently in gout patients, especially in patients with tophi or CKD. The potential renal risks of fenofibrate usage in gout needs additional research.

Experimental and Computational Study on the Intramolecular Hydrogen Atom Transfer Reactions of Maleimide-Based Enediynes After Cycloaromatization.

The follow-up reaction pathways of the diradical species formed from cycloaromatization of enediynes or enyne-allenes determine their ability of H-abstraction from DNA, significantly affecting their biological activity performance. To gain a deeper understanding of subsequent reaction pathways of the diradical intermediates formed from acyclic enediynes based on maleimide-assisted rearrangement and cycloaromatization (MARACA), a maleimide-based enediyne featuring methylene groups adjacent to the propargyl sites of the terminal alkynes was synthesized through the Sonogashira coupling reaction. Three thermal cyclization products after intramolecular hydrogen atom transfer (HAT) were obtained from the thermolysis experiment and their structures were confirmed by 1D and 2D nuclear magnetic resonance spectroscopic analysis. Density functional theory was employed to analyze the important elementary steps including rearrangement, cycloaromatization, and intramolecular HAT processes toward the formation of the cyclized products, where the low-energy barriers of HAT pathways relative to the formation of diradicals from cycloaromatization were successfully identified. Overall, the HAT processes to consume diradicals intramolecularly have become competitive with that of intermolecular H-abstraction, implying that the DNA-cleavage ability of enediynes can be further boosted once the HAT processes are halted. This study offers a promising direction for designing novel and potent acyclic enediynes for antitumor applications.

Astragaloside IV Ameliorates Cognitive Impairment and Neuroinflammation in an Oligomeric Aß Induced Alzheimer's Disease Mouse Model via Inhibition of Microglial Activation and NADPH Oxidase Expression.

Microglial activation and neuroinflammation induced by amyloid ß (Aß) play pivotal roles in Alzheimer's disease (AD) pathogenesis. Astragaloside IV (AS-IV) is one of the major active compounds of the traditional Chinese medicine Astmgali Radix. It has been reported that AS-IV could protect against Aß-induced neuroinflammation and cognitive impairment, but the underlying mechanisms need to be further clarified. In this study, the therapeutic effects of AS-IV were investigated in an oligomeric Aß (oAß) induced AD mice model. The effects of AS-IV on microglial activation, neuronal damage and reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression were further studied. Different doses of AS-IV were administered intragastrically once a day after intracerebroventricularly oAß injection. Results of behavioral experiments including novel object recognition (NOR) test and Morris water maze (MWM) test revealed that AS-IV administration could significantly ameliorate oAß-induced cognitive impairment in a dose dependent manner. Enzyme linked immunosorbent assay (ELISA) results showed that increased levels of reactive oxygen species (ROS), tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß) and IL-6 in hippocampal tissues induced by oAß injection were remarkably inhibited after AS-IV treatment. OAß induced microglial activation and neuronal damage was significantly suppressed in AS-IV-treated mice brain, observed in immunohistochemistry results. Furthermore, oAß upregulated protein expression of NADPH oxidase subunits gp91phox, p47phox, p22phox and p67phox were remarkably reduced by AS-IV in Western blotting assay. These results revealed that AS-IV could ameliorate oAß-induced cognitive impairment, neuroinflammation and neuronal damage, which were possibly mediated by inhibition of microglial activation and down-regulation of NADPH oxidase protein expression. Our findings provide new insights of AS-IV for the treatment of neuroinflammation related diseases such as AD.