Escherichia coli is the leading cause of neonatal Gram-negative bacterial meningitis, but the pathogenesis of E. coli meningitis remains elusive. E. coli penetration of the blood-brain barrier (BBB) ...is the critical step for development of meningitis. Here, we identify Caspr1, a single-pass transmembrane protein, as a host receptor for E. coli virulence factor IbeA to facilitate BBB penetration. Genetic ablation of endothelial Caspr1 and blocking IbeA-Caspr1 interaction effectively prevent E. coli penetration into the brain during meningitis in rodents. IbeA interacts with extracellular domain of Caspr1 to activate focal adhesion kinase signaling causing E. coli internalization into the brain endothelial cells of BBB. E. coli can invade hippocampal neurons causing apoptosis dependent on IbeA-Caspr1 interaction. Our results indicate that E. coli exploits Caspr1 as a host receptor for penetration of BBB resulting in meningitis, and that Caspr1 might be a useful target for prevention or therapy of E. coli meningitis.
Species of Cirsium (Asteraceae family) have been used in folk hepatoprotective medicine in Taiwan. We collected four Cirsium species-including the aerial part of
(CAH), the aerial part of
(CKH), the ...flower part of
DC. var.
(CJF), and Cirsii Herba (CH)-and then made extractions from them with 70% methanol. We compared the antioxidant contents and activities of these four Cirsium species extracts by a spectrophotometric method and high-performance liquid chromatography⁻photodiode array detector (HPLC-DAD). We further evaluated the hepatoprotective effects of these extracts on CCl₄-induced acute liver damage in C57BL/6 mice. The present study found CAH possesses the highest antioxidant activity among the four Cirsium species, and these antioxidant activities are closely related to phenylpropanoid glycoside (PPG) contents. The extracts decreased serum ALT and AST levels elevated by injection with 0.2% CCl₄. However, only CJF and CH decreased hepatic necrosis. Silibinin decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and hepatic necrosis caused by CCl₄. CJF and CH restored the activities of hepatic antioxidant enzymes and decreased hepatic malondialdehyde (MDA) levels. CJF further restored the expression of hepatic antioxidant enzymes including Cu/Zn-superoxide dismutase (Cu/Zn-SOD), Mn-superoxide dismutase (Mn-SOD), and glutathione
-transferase (GST) proteins. HPLC chromatogram indicated that CKH, CJF, and CH contained silibinin diastereomers (α and β). Only CJF contained diosmetin. Hence, the hepatoprotective mechanism of CJF against CCl₄-induced acute liver damage might be involved in restoring the activities and protein expression of the hepatic antioxidant defense system and inhibiting hepatic inflammation, and these hepatoprotective effects are related to the contents of silibinin diastereomers and diosmetin.
In the present investigation, we compared the radical-scavenging activities and phenolic contents of seven Taiwanese Cirsium species with a spectrophotometric method. We further analyzed their ...phytochemical profiles with high-performance liquid chromatography–photodiode array detection (HPLC–DAD). We found that the flower part of Cirsium japonicum var. australe (CJF) showed the best radical-scavenging activities against 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), and the hypochlorite ion, for which the equivalents were 6.44 ± 0.17 mg catechin/g, 54.85 ± 0.66 mmol Trolox/g and 418.69 ± 10.52 mmol Trolox/g respectively. CJF also had the highest contents of total phenolics (5.23 ± 0.20 mg catechin/g) and phenylpropanoids (29.73 ± 0.72 mg verbascoside/g). According to the Pearson’s correlation coefficient, there was a positive correlation between the total phenylpropanoid content and ABTS radical-scavenging activities (r = 0.979). The radical-scavenging activities of the phenylpropanoids are closely related to their reducing power (r = 0.986). HPLC chromatograms obtained in validated HPLC conditions confirm that they have different phytochemical profiles by which they can be distinguished. Only CJF contained silicristin (0.66 ± 0.03 mg/g) and silydianin (9.13 ± 0.30 mg/g). CJF contained the highest contents of apigenin (5.56 ± 0.09 mg/g) and diosmetin (2.82 ± 0.10 mg/g). Among the major constituents, silicristin had the best radical-scavenging activities against DPPH (71.68 ± 0.66 mg catechin/g) and ABTS (3.01 ± 0.01 mmol Trolox/g). However, diosmetin had the best reducing power and radical-scavenging activity against the hypochlorite anion (41.57 ± 1.14 mg mmol Trolox/g). Finally, we found that flavonolignans (especial silicristin and silydianin) and diosmetin acted synergistically in scavenging radicals.
Due to their unique afterglow ability, long-wavelength-light rechargeable persistent luminescence (PersL) nanoparticles (PLNPs) have been emerging as an important category of imaging probes. Among ...them, ZnGa2O4:0.6% Cr3+ (ZGC) PLNPs have gained widespread recognition due to the ease of synthesis and uniform morphology. Unfortunately, the limited absorption arising from the low molar extinction coefficient of Cr3+ results in relatively low afterglow intensity and rapid decay after long-wavelength LED light irradiation. Herein, we discovered a strategy that boosting dye-sensitization performance was able to effectively amplify the PersL signal under white LED light. Specifically, Dil served as a highly efficient sensitizer for Cr3+, promoting the absorption of the excitation light. By adjusting the Pr dopant concentrations, ZGCP0.5 PLNPs with optimal trap densities were obtained, which showed the highest PersL intensity and dye-sensitized performance. Strikingly, ZGCP0.5-Dil PLNPs exhibited a 24.3-fold enhancement in intensity and a 2-fold prolongation of decay time over bare ZGC PLNPs through the synergy effect of optimal electron traps and dye sensitization. Photostable ZGCP0.5-Dil PLNPs enabled imaging of the HepG2 tumor and effectively guided tumor surgical resection verified by the H&E staining analysis. This strategy could be a significant reference in other dye-sensitization PLNPs to enhance longer-wavelength rechargeable PersL.
Abstract
In this study, a novel artificial intelligence (AI) model is proposed to detect stenosis in arteriovenous fistulas (AVFs) using inexpensive and non-invasive audio recordings. The proposed ...model is a combination of two new input features based on short-time Fourier transform (STFT) and sample entropy, as well as two associated classification models (ResNet50 and ANN). The model’s hyper-parameters were optimized through the use of the design of the experiment (DOE). The proposed AI model demonstrates high performance with all essential metrics, including sensitivity, specificity, accuracy, precision, and F1-score, exceeding 0.90 at detecting stenosis greater than 50%. These promising results suggest that our approach can lead to new insights and knowledge in this field. Moreover, the robust performance of our model, combined with the affordability of the audio recording device, makes it a valuable tool for detecting AVF stenosis in home-care settings.
Display omitted
•ZP@PCM ensures PDT “off” during circulation to circumvent off-target phototoxicity.•ZP@PCM enables NIR laser triggered PTT initiation and optimized PDT switch “on”.•ZP@PCM ...facilitates 2-fold ROS yield over individual ZGGC, sustained up to 48 h.•ZP@PCM helps to visualize therapeutic outcomes and determine treatment duration.•ZP@PCM opens a novel frontier of nanophosphor for photosensitizer-free PDT.
Photodynamic therapy (PDT) has emerged as a powerful candidate for cancer intervention as for the merits of least-invasiveness, multidrug resistance-free and spatiotemporal selectivity. Whereas, clinical photosensitizers (PSs) suffer from microsecond-level reactive oxygen species (ROS) lifetime requiring 20–30 min continuous exterior light stimulation, deficient photostable nature and off-target phototoxicity in nonmalignant tissues. Persistent luminescence nanoparticles (PLNPs), are proven to exert long-lasting ROS production after the excitation cessation (hours to days), and serve as photostable imaging agent for diagnose. Herein, a traceable theranostic agent, ZP@PCM PLNPs is prepared by modifying polyaniline (PANI) onto Zn1.2Ga1.6Ge0.2O4: Cr3+ (ZGGC) to obtain ZP PLNPs and wrapping phase-change material (PCM) as outer protective shell. Solid-phase PCM isolates inner ZP PLNPs from surrounding oxygen during circulation to circumvent off-target photosensitization. Once ZP@PCM PLNPs accumulated within tumors, external laser triggered PANI assisted photothermal therapy (PTT) initiates, and thermal melting of PCM shell occurs leading to the exposure of ZP PLNPs to switch on PDT. PANI also facilitates PDT efficacy optimization, enabling ZP PLNPs of 2-fold ROS yield compared to ZGGC PLNPs, sustained up to 48 h upon 10 min of illumination. ZP@PCM PLNPs with long-term, moderate therapy modality presents ameliorated anti-tumor effect, achieving tumor inhibition rate of 92.2 % over that of ∼ 46 % with individual ZGGC PLNPs, and shows satisfactory biosafety without tissues damage or inflammatory response. Meanwhile, the autofluorescence-free visualization potency helps to self-report therapeutic outcomes and determine treatment duration. Overall, ZP@PCM PLNPs provide a promising PSs-free alternative candidate for finely controlled PDT/PTT and visualization tumor therapy.
Metastatic castration-resistant prostate cancer (CRPC), the most refractory prostate cancer, inevitably progresses and becomes unresponsive to hormone therapy, revealing a pressing unmet need for ...this disease. Novel agents targeting HDAC6 and microtubule dynamics can be a potential anti-CRPC strategy.
Cell proliferation was examined in CRPC PC-3 and DU-145 cells using sulforhodamine B assay and anchorage-dependent colony formation assay. Flow cytometric analysis of propidium iodide staining was used to determine cell-cycle progression. Cell-based tubulin polymerization assay and confocal immunofluorescence microscopic examination determine microtubule assembly/disassembly status. Protein expressions were determined using Western blot analysis.
A total of 82 novel derivatives targeting HDAC6 were designed and synthesized, and Compound 25202 stood out, showing the highest efficacy in blocking HDAC6 (IC
, 3.5 nM in enzyme assay; IC
, 1.0 μM in antiproliferative assay in CRPC cells), superior to tubastatin A (IC
, 5.4 μM in antiproliferative assay). The selectivity and superiority of 25202 were validated by examining the acetylation of both α-tubulin and histone H3, detecting cell apoptosis and HDACs enzyme activity assessment. Notably, 25202 but not tubastatin A significantly decreased HDAC6 protein expression. 25202 prolonged mitotic arrest through the detection of cyclin B1 upregulation, Cdk1 activation, mitotic phosphoprotein levels, and Bcl-2 phosphorylation. Compound 25202 did not mimic docetaxel in inducing tubulin polymerization but disrupted microtubule organization. Compound 25202 also increased the phosphorylation of CDC20, BUB1, and BUBR1, indicating the activation of the spindle assembly checkpoint (SAC). Moreover, 25202 profoundly sensitized cisplatin-induced cell death through impairment of cisplatin-evoked DNA damage response and DNA repair in both ATR-Chk1 and ATM-Chk2 pathways.
The data suggest that 25202 is a novel selective and potent HDAC6 inhibitor. Compound 25202 blocks HDAC6 activity and interferes microtubule dynamics, leading to SAC activation and mitotic arrest prolongation that eventually cause apoptosis of CRPC cells. Furthermore, 25202 sensitizes cisplatin-induced cell apoptosis through impeding DNA damage repair pathways.
The P-type ATPase ATP7B exports cytosolic copper and plays an essential role in the regulation of cellular copper homeostasis. Mutants of ATP7B cause Wilson disease (WD), an autosomal recessive ...disorder of copper metabolism. Here, we present cryoelectron microscopy (cryo-EM) structures of human ATP7B in the E1 state in the apo, the putative copper-bound, and the putative cisplatin-bound forms. In ATP7B, the N-terminal sixth metal-binding domain (MBD6) binds at the cytosolic copper entry site of the transmembrane domain (TMD), facilitating the delivery of copper from the MBD6 to the TMD. The sulfur-containing residues in the TMD of ATP7B mark the copper transport pathway. By comparing structures of the E1 state human ATP7B and E2-Pi state frog ATP7B, we propose the ATP-driving copper transport model of ATP7B. These structures not only advance our understanding of the mechanisms of ATP7B-mediated copper export but can also guide the development of therapeutics for the treatment of WD.
Display omitted
•The cryo-EM structures of human ATP7B in the E1 state are determined•The sixth metal-binding domain (MBD6) delivers Cu+ to the transmembrane domain (TMD)•The sulfur-containing residues in the TMD mark the copper transport pathway•Comparisons with previous E2-Pi structures reveal the copper transport model of ATP7B
The Wilson disease protein ATP7B is a P-type ATPase responsible for cellular copper transport. Yang et al. report human ATP7B cryo-EM structures, proposing the copper transport pathway and model, which contributes to the understanding of the molecular mechanisms of ATP7B and the development of potential treatments.
The destruction of lipid homeostasis is associated with nervous system diseases such as Alzheimer’s disease (AD). It has been reported that dietary EPA-enriched phosphatidylcholine (EPA-PC) and ...phosphatidylethanolamine (EPA-PE) could improve brain function. However, it was unclear that whether EPA-PC and EPA-PE intervention could change the lipid composition of cerebral cortex in AD mice. All the senescence-accelerated mouse-prone 8 (SAMP8) mice were fed with a high-fat diet for 8 weeks. After another 8 weeks of intervention with EPA-PC and EPA-PE (1%, w/w), the cerebral cortex lipid levels were determined by lipidomics. Results demonstrated that dietary supplementation with EPA-PE and EPA PC for 8 weeks significantly increased the amount of choline plasmalogen (pPC) and Lyso phosphatidylethanolamine (LPE) in the cerebral cortex of SAMP8 mice fed with high fat diet. Meanwhile, administration with EPA-PE and EPA-PC could significantly decrease the level of docosapentaenoic acid (DPA)-containing phosphatidylserine (PS) as well as increase the levels of arachidonic acid (AA)-containing phosphatidylethanolamine and PS in cerebral cortex. EPA-PE and EPA-PC could restore the lipid homeostasis of dementia mice to a certain degree, which might provide a potential novel therapy strategy and direction of dietary intervention in patients with cognitive impairment.
PDF
