Inhibition of endocytic uptake of severe acute respiratory syndrome coronavirus 2 and endo-lysosomal acidification by diphenoxylate.

Cell culture-based screening of a chemical library identified diphenoxylate as an antiviral agent against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The observed 50% effective concentrations ranged between 1.4 and 4.9 µM against the original wild-type strain and its variants. Time-of-addition experiments indicated that diphenoxylate is an entry blocker targeting a host factor involved in viral infection. Fluorescence microscopic analysis visualized that diphenoxylate prevented SARS-CoV-2 particles from penetrating the cell membrane and also impaired endo-lysosomal acidification. Diphenoxylate exhibited a synergistic inhibitory effect on SARS-CoV-2 infection in human lung epithelial Calu-3 cells when combined with a transmembrane serine protease 2 (TMPRSS2) inhibitor, nafamostat. This synergy suggested that efficient antiviral activity is achieved by blocking both TMPRSS2-mediated early and endosome-mediated late SARS-CoV-2 entry pathways. The antiviral efficacy of diphenoxylate against SARS-CoV-2 was reproducible in a human tonsil organoids system. In a transgenic mouse model expressing the obligate SARS-CoV-2 receptor, human angiotensin-converting enzyme 2, intranasal administration of diphenoxylate (10 mg/kg/day) significantly reduced the viral RNA copy number in the lungs by 70% on day 3. This study underscores that diphenoxylate represents a promising core scaffold, warranting further exploration for chemical modifications aimed at developing a new class of clinically effective antiviral drugs against SARS-CoV-2.

Case report: Acquired resistance to crizotinib from a MET Y1230H mutation in a patient with non-small cell lung cancer and KIF5B-MET fusion.

Background: The c-met proto-oncogene (MET) serves as a significant primary oncogenic driver in non-small cell lung cancer (NSCLC) and has the potential to fuse with other genes, such as KIF5B, although it occurs infrequently. Only a limited number of reported cases have examined the clinical efficacy of crizotinib in patients with KIF5B-MET gene fusion, with no known data regarding acquired resistance to crizotinib and its potential mechanisms. In this report, we present the clinical progression of a female patient diagnosed with NSCLC and harboring a KIF5B-MET gene fusion. Case description: The patient initially exhibited partial response to first-line crizotinib treatment, albeit for a short duration and with limited efficacy. Subsequent disease progression revealed the emergence of a secondary MET mutation, specifically MET Y1230H, leading to acquired resistance to crizotinib. Conclusion: The reporting of this case is imperative for informing clinical practice, given the uncommon occurrence of NSCLC with MET fusion, displaying responsiveness to MET tyrosine kinase inhibitor therapy, as well as the emergence of the secondary Y1230H alteration as a potential resistance mechanism.

Sex differences in normal fetal regional brain apparent diffusion coefficient changes assessed by in utero DWI.

Objective: There are differences in the vulnerability of male and female fetal brains to adverse intrauterine exposure, preterm birth, and associated perinatal brain injury. The main objective of this study was to identify any statistically significant difference in the change of apparent diffusion coefficient (ADC) in the intracranial regions of male and female fetuses in the second and third trimesters. Methods: Diffusion-weighted imaging (DWI) was performed in 200 fetuses between 20 and 37 gestational ages (GA) with normal results or suspicious results on sonography followed by structural MRI. Pairwise ADC values of the regions of interest (ROIs) were manually delineated on either side of the cerebral white matter: frontal white matter (FWM), parietal white matter (PWM), occipital white matter (OWM), temporal white matter (TWM), basal ganglia (BG), thalamus (THA), cerebellar hemisphere (CBM), and a single measurement in the pons. The changes in these values were studied over the gestational range, along with potential sex differences and asymmetries of the cerebral hemispheres. Results: During the third trimester, ADC values in OWM, TWM, and CBM were significantly higher in male fetuses than those in female fetuses (p < 0.05). After the correction of false-discovery rates (FDR), the difference in CBM was the only statistically significant (p = 0.0032). However, the decreased rate of ADC values in male fetuses in CWM (except for FWM), BG, THA, CBM, and pons was higher than that in female fetuses during the second and third trimesters. Conclusions: We have shown some differences in the intracranial regional ADC changes between male and female fetuses using in utero DWI during the second and third trimesters.

Photoilluminated Redox-Processed Rh2P Nanoparticles on Photocathodes for Stable Hydrogen Production in Acidic Environments.

While photoelectrochemical (PEC) cells show promise for solar-driven green hydrogen production, exploration of various light-absorbing multilayer coatings has yet to significantly enhance their hydrogen generation efficiency. Acidic conditions can enhance the hydrogen evolution reaction (HER) kinetics and reduce overpotential losses. However, prolonged acidic exposure deactivates noble metal electrocatalysts, hindering their long-term stability. Progress requires addressing catalyst degradation to enable stable, efficient, and acidic PEC cells. Here, we proposed a process design based on the photoilluminated redox deposition (PRoD) approach. We use this to grow crystalline Rh2P nanoparticles (NPs) with a size of 5-10 on 30 nm-thick TiO2, without annealing. Atomically precise reaction control was performed by using several cyclic voltammetry cycles coincident with light irradiation to create a system with optimal catalytic activity. The optimized photocathode, composed of Rh2P/TiO2/Al-ZnO/Cu2O/Sb-Cu2O/ITO, achieved an excellent photocurrent density of 8.2 mA cm-2 at 0 VRHE and a durable water-splitting reaction in a strong acidic solution. Specifically, the Rh2P-loaded photocathode exhibited a 5.3-fold enhancement in mass activity compared to that utilizing just a Rh catalyst. Furthermore, in situ scanning transmission electron microscopy (STEM) was performed to observe the real-time growth process of Rh2P NPs in a liquid cell.

A multifunctional biomimetic nanoplatform for image-guideded photothermal-ferroptotic synergistic osteosarcoma therapy.

Much effort has been devoted to improving treatment efficiency for osteosarcoma (OS). However, most current approaches result in poor therapeutic responses, thus indicating the need for the development of other therapeutic options. This study developed a multifunctional nanoparticle, PDA-MOF-E-M, an aggregation of OS targeting, programmed death targeting, and near-infrared (NIR)-aided targeting. At the same time, a multifunctional nanoparticle that utilises Fe-MOFs to create a cellular iron-rich environment and erastin as a ferroptosis inducer while ensuring targeted delivery to OS cells through cell membrane encapsulation is presented. The combination of PDA-MOF-E-M and PTT increased intracellular ROS and LPO levels and induced ferroptosis-related protein expression. A PDA-based PTT combined with erastin showed significant synergistic therapeutic improvement in the anti-tumour efficiency of the nanoparticle in vitro and vivo. The multifunctional nanoparticle efficiently prevents the osteoclasia progression of OS xenograft bone tumors in vivo. Finally, this study provides guidance and a point of reference for clinical approaches to treating OS.

Piezoelectric catalytic driven advanced oxidation process using two-dimensional metal dichalcogenides for wastewater pollutants remediation.

The public and society have increasingly recognized numerous grave environmental issues, including water pollution, attributed to the rapid expansion of industrialization and agriculture. Renewable energy-driven catalytic advanced oxidation processes (AOPs) represent a green, sustainable, and environmentally friendly approach to meet the demands of environmental remediation. In this context, 2D transition metal dichalcogenides (TMDCs) piezoelectric materials, with their non-centrosymmetric crystal structure, exhibit unique features. They create dipole polarization, inducing a built-in electric field that generates polarized holes and electrons and triggers redox reactions, thereby facilitating the generation of reactive oxygen species for wastewater pollutant remediation. A broad spectrum of 2D TMDCs piezoelectric materials have been explored in self-integrated Fenton-like processes and persulfate activation processes. These materials offer a more simplistic and practical method than traditional approaches. Consequently, this review highlights recent advancements in 2D TMDCs piezoelectric catalysts and their roles in wastewater pollutant remediation through piezocatalytic-driven AOPs, such as Fenton-like processes and sulfate radicals-based oxidation processes.

Enriched environment ameliorates fear memory impairments induced by sleep deprivation via inhibiting PIEZO1/calpain/autophagy signaling pathway in the basal forebrain.

AIMS: To verify the hypothesis that an enriched environment (EE) alleviates sleep deprivation-induced fear memory impairment by modulating the basal forebrain (BF) PIEZO1/calpain/autophagy pathway. METHODS: Eight-week-old male mice were housed in a closed, isolated environment (CE) or an EE, before 6-h total sleep deprivation. Changes in fear memory after sleep deprivation were observed using an inhibitory avoidance test. Alterations in BF PIEZO1/calpain/autophagy signaling were detected. The PIEZO1 agonist Yoda1 or inhibitor GsMTx4, the calpain inhibitor PD151746, and the autophagy inducer rapamycin or inhibitor 3-MA were injected into the bilateral BF to investigate the pathways involved in the memory-maintaining role of EE in sleep-deprived mice. RESULTS: Mice housed in EE performed better than CE mice in short- and long-term fear memory tests after sleep deprivation. Sleep deprivation resulted in increased PIEZO1 expression, full-length tropomyosin receptor kinase B (TrkB-FL) degradation, and autophagy, as reflected by increased LC3 II/I ratio, enhanced p62 degradation, increased TFEB expression and nuclear translocation, and decreased TFEB phosphorylation. These molecular changes were partially reversed by EE treatment. Microinjection of Yoda1 or rapamycin into the bilateral basal forebrain induced excessive autophagy and eliminated the cognition-protective effects of EE. Bilateral basal forebrain microinjection of GsMTx4, PD151746, or 3-MA mimicked the cognitive protective and autophagy inhibitory effects of EE in sleep-deprived mice. CONCLUSIONS: EE combats sleep deprivation-induced fear memory impairments by inhibiting the BF PIEZO1/calpain/autophagy pathway.

Metformin protects human lens epithelial cells from high glucose-induced senescence and autophagy inhibition by upregulating SIRT1.

PURPOSE: The aim of this study is to explore whether metformin (MET) protects the human lens epithelial cells (HLECs) from high glucose-induced senescence and to identify the underlying mechanisms. METHODS: A cellular senescence model was established by treating HLE-B3 cells with D-glucose and then intervened with MET. Concentrations of high glucose (HG) and MET were detected using CCK-8 and western blot. qRT-PCR, western blot, and senescence-associated ß-galactosidase (SA-ß-gal) were performed to verify the protective effect of MET on senescent HLE-B3 cells. Additionally, western blot and qRT-PCR were conducted to detect the effects of MET on autophagy-related markers p62 and LC3, as well as SIRT1. RESULTS: In vitro, we observed apparent senescence in human lens epithelial cells (HLECs) under high glucose conditions. This was characterized by increased senescence-associated genes p21 and p53. However, the addition of MET significantly reduced the occurrence of HLECs senescence. We also observed that high glucose inhibited both autophagy and SIRT1, which could be restored by MET. Moreover, we verified that the anti-senescence effect of MET was mediated by SIRT1 using SIRT1 activators and inhibitors. CONCLUSION: We have demonstrated that autophagy and SIRT1 activity are inhibited in HLE-B3 cells using the HG induced senescence model. Furthermore, our results showed that MET can delay senescence by activating SIRT1 and autophagy. These findings suggest that MET may be a promising candidate for alleviating cataract development and provide a direction for further investigation into the underlying molecular mechanisms.

The marine Penicillium sp. GGF16-1-2 metabolite dicitrinone G inhibits pancreatic angiogenesis by regulating the activation of NLRP3 inflammasome.

Citrinin derivatives have been found to have various pharmacological activities, such as anti-inflammatory, anti-tumor, and antioxidant effects. Dicitrinone G (DG) was a new citrinin dimer isolated from marine-derived fungus Penicillium sp. GGF 16-1-2 which has potential activity. Here, we aim to investigate whether DG has anti-pancreatic cancer activity. In xenograft tumor model, 2 × 106 BXPC-3 cells were injected into the hind flank of NU/NU nude mice by subcutaneously for 2 weeks followed by treating with DG (0.25, 0.5, 1 mg/kg) and 5-FU (30 mg/kg) for 4 weeks. Tumor volume and weight were measured, and the expression of CD31, IL-18, NLRP3, and Caspase-1 in tumor tissue were detected. In vitro, HUVECs were treated with conditioned medium (CM) derived from BXPC-3 cells, the effects of DG on angiogenesis were detected by tube formation and western blot analysis. In vivo studies showed that the tumor growth and angiogenesis were greatly suppressed. The tumor weight inhibition rates of DG and 5-FU groups were about 42.36%, 38.94%, 43.80%, and 31.88%. Furthermore, the expression of CD31 and Caspase-1 were decreased. In vitro, CM derived from BXPC-3 cells which treated with DG could inhibit the tube formation and expression of pro-angiogenic NICD in HUVECs. Our study suggests that DG could suppress angiogenesis via the NLRP3/IL-18 pathway and may have the potential to inhibit tumor development.

Implantable Self-Reporting Stents for Detecting In-Stent Restenosis and Cardiac Functional Dynamics.

Despite the increasing number of stents implanted each year worldwide, patients remain at high risk for developing in-stent restenosis. Various self-reporting stents have been developed to address this challenge, but their practical utility has been limited by low sensitivity and limited data collection. Herein, we propose a next-generation self-reporting stent that can monitor blood pressure and blood flow inside the blood arteries. This proposed self-reporting stent utilizes a larger inductor coil encapsulated on the entire surface of the stent strut, resulting in a 2-fold increase in the sensing resolution and coupling distance between the sensor and external antenna. The dual-pressure sensors enable the detection of blood flow in situ. The feasibility of the proposed self-reporting stent is successfully demonstrated through in vivo analysis in rats, verifying its biocompatibility and multifunctional utilities. This multifunctional self-reporting stent has the potential to greatly improve cardiovascular care by providing real-time monitoring and unprecedented insight into the functional dynamics of the heart.

Correction: Quantitative assessment of cardiomyocyte mechanobiology through high-throughput cantilever-based functional well plate systems.

Correction for 'Quantitative assessment of cardiomyocyte mechanobiology through high-throughput cantilever-based functional well plate systems' by Jongyun Kim et al., Analyst, 2023, 148, 5133-5143, https://doi.org/10.1039/D3AN01286G.

Zaluzanin C Alleviates Inflammation and Lipid Accumulation in Kupffer Cells and Hepatocytes by Regulating Mitochondrial ROS.

Zaluzanin C (ZC), a sesquiterpene lactone isolated from Laurus nobilis L., has been reported to have anti-inflammatory and antioxidant effects. However, the mechanistic role of ZC in its protective effects in Kupffer cells and hepatocytes has not been elucidated. The purpose of this study was to elucidate the efficacy and mechanism of action of ZC in Kupffer cells and hepatocytes. ZC inhibited LPS-induced mitochondrial ROS (mtROS) production and subsequent mtROS-mediated NF-κB activity in Kupffer cells (KCs). ZC reduced mRNA levels of pro-inflammatory cytokines (Il1b and Tnfa) and chemokines (Ccl2, Ccl3, Ccl4, Cxcl2 and Cxcl9). Tumor necrosis factor (TNF)-α-induced hepatocyte mtROS production was inhibited by ZC. ZC was effective in alleviating mtROS-mediated mitochondrial dysfunction. ZC enhanced mitophagy and increased mRNA levels of fatty acid oxidation genes (Pparα, Cpt1, Acadm and Hadha) and mitochondrial biosynthetic factors (Pgc1α, Tfam, Nrf1 and Nrf2) in hepatocytes. ZC has proven its anti-lipid effect by improving lipid accumulation in hepatocytes by enhancing mitochondrial function to facilitate lipid metabolism. Therefore, our study suggests that ZC may be an effective compound for hepatoprotection by suppressing inflammation and lipid accumulation through regulating mtROS.

Retraction: Progressive p-channel vertical transistors fabricated using electrodeposited copper oxide designed with grain boundary tunability.

Retraction of 'Progressive p-channel vertical transistors fabricated using electrodeposited copper oxide designed with grain boundary tunability' by Sung Hyeon Jung et al., Mater. Horiz., 2022, 9, 1010-1022, https://doi.org/10.1039/D1MH01568K.

Quantitative assessment of cardiomyocyte mechanobiology through high-throughput cantilever-based functional well plate systems.

Proper regulation of the in vitro cell culture environment is essential for disease modelling and drug toxicity screening. The main limitation of well plates used for cell culture is that they cannot accurately maintain energy sources and compounds needed during cell growth. Herein, to understand the importance of perfusion in cardiomyocyte culture, changes in contractile force and heart rate during cardiomyocyte growth are systematically investigated, and the results are compared with those of a perfusion-free system. The proposed perfusion system consists of a Peltier refrigerator, a peristaltic pump, and a functional well plate. A functional well plate with 12 wells is made through injection moulding, with two tubes integrated in the cover for each well to continuously circulate the culture medium. The contractile force of cardiomyocytes growing on the cantilever surface is analysed through changes in cantilever displacement. The maturation of cardiomyocytes is evaluated through fluorescence staining and western blot; cardiomyocytes cultured in the perfusion system show greater maturity than those cultured in a manually replaced culture medium. The pH of the culture medium manually replaced at intervals of 3 days decreases to 6.8, resulting in an abnormal heartbeat, while cardiomyocytes cultured in the perfusion system maintained at pH 7.4 show improved contractility and a uniform heart rate. Two well-known ion channel blockers, verapamil and quinidine, are used to measure changes in the contractile force of cardiomyocytes from the two systems. Cardiomyocytes in the perfusion system show greater stability during drug toxicity screening, proving that the perfusion system provides a better environment for cell growth.

Discovery and Feasibility Study of Medical Fluorophore 33 as a Novel Theranostic Agent.

Fluorescent dyes have garnered significant attention as theranostic platforms owing to their inherent characteristics. In this study, we present the discovery of Medical Fluorophore 33 (MF33), a novel and potent theranostic agent with a phenaleno-isoquinolinium salt structure that can serve as a cancer therapeutic strategy. The synthesis of MF33 is readily achievable through a simple Rh(III)-catalyzed reaction. Moreover, MF33 displayed strong fluorescence signals, excellent microsomal stability, and high biocompatibility in vivo. It induces significant apoptosis in cancer cells via the p53/p21/caspase-3 signaling pathway, leading to selective cytotoxicity in various cancer cells. In vivo fluorescence imaging with MF33 enabled the visualization of sentinel lymph nodes in living mice. Notably, repeated intraperitoneal administration of MF33 resulted in antitumor activity in mice with colorectal cancer. Collectively, our findings suggest that phenaleno-isoquinolinium salt-based MF33 is a viable theranostic agent for biomedical imaging and cancer treatment.

Is epinephrine still the drug of choice during cardiac arrest in the emergency department of the hospital? A meta-analysis.

Epinephrine is the first-line emergency drug for cardiac arrest and anaphylactic reactions but is reported to be associated with many challenges resulting in its under- or improper utilization. Therefore, in this meta-analysis, the efficacy and safety of epinephrine as a first-line cardiac emergency drug for both out-of-hospital and in-hospital patients was assessed. Pertinent articles were searched in central databases like PubMed, Scopus, and Web of Science, using appropriate keywords as per the PRISMA guidelines. Retrospective and prospective studies were included according to the predefined PICOS criteria. RevMan and MedCalc software were used and statistical parameters such as odds ratio and risk ratio were calculated. Twelve clinical trials with a total of 208,690 cardiac arrest patients from 2000 to 2022 were included, in accordance with the chosen inclusion criteria. In the present meta-analysis, a high odds ratio (OR) value of 3.67 (95 % CI 2.32-5.81) with a tau2 value of 0.64, a chi2 value of 12,446.86, df value of 11, I2 value of 100 %, Z-value 5.53, and a p-value < 0.00001 were reported. Similarly, the risk ratio of 1.89 (95 % CI 1.47-2.43) with a tau2 value of 0.19, chi2 value of 11,530.67, df value of 11, I2 value of 100 %, Z-value of 4.95, and p-value < 0.000001. The present meta-analysis strongly prefers epinephrine injection as the first cardiac emergency drug for both out-of-hospital and in-hospital patients during cardiac arrest.

Tract seeding in indwelling pleural catheter placement for the drainage of malignant pleural effusions: Incidence and related clinical and imaging factors.

BACKGROUND: The incidence of tract seeding after the placement of indwelling pleural catheter (IPC) for malignant pleural effusion drainage has been variable in the literature. RESEARCH QUESTION: To evaluate the incidence of IPC-related cancer tract seeding and find out related demographic, clinical or imaging factors to the tract seeding. STUDY DESIGN AND METHODS: This retrospective study included 124 consecutive patients seen between January 2011 and December 2021 who underwent IPC placement for malignant pleural effusion drainage. Chest radiographs before IPC placement and serial chest CT studies were obtained. One patient was diagnosed pathologically, and the other patients were diagnosed as tract seeding radiologically. The incidence of and related factors to tract seeding were assessed by reviewing medical records and imaging studies. RESULTS: The incidence of IPC tract seeding was 21.7% (27 of 124 malignant effusions). Of 27 patients, 15 had primary lung cancer and remaining 12 had extra-thoracic malignancy. Adenocarcinoma (19 of 27, 70.3%) either from the lung (N = 12) or extra-thoracic malignancy (N = 7) was the most common cell type. Mean time elapsed until tract seeding occurrence after IPC placement was 96 days (ranges; 28-306 days). The survival in seeding group after IPC placement was 185 days (ranges, 32-457 days). On odd ratio analysis, the presence of mediastinal pleural thickening (OR [95% CI]; 9.79 (2.67-35.84), p = 0.001) was significantly related to the occurrence of tract seeding. Neither tumor volume within pleural space (p = 0.168), duration of IPC indwelling (p = 0.142), days of survival after IPC placement (p = 0.26), nor pleural effusion amount (p = 0.481) was related to the tract seeding. INTERPRETATION: IPC tract seeding is seen in 27 (21.7%) of 124 malignant pleural effusion patients, particularly with adenocarcinoma cytology. CT features of mediastinal pleural thickening are related to the occurrence of tract seeding.

Intensive harmonized synapses with amorphous Cu2O-based memristors using ultrafine Cu nanoparticle sublayers formed via atomically controlled electrochemical pulse deposition.

Resistive random-access memory (RRAM) devices have significant advantages for neuromorphic computing but have fatal problems of uncontrollability and abrupt resistive switching behaviors degrading their synaptic performance. In this paper, we propose the electrochemical design of an active Cu2O layer containing a strategic sublayer of ultrafine Cu nanoparticles (U-Cu NPs) to form uniformly dispersed conducting filaments, which can effectively improve the reliability for analog switching of RRAM-based neuromorphic computing. The electrochemical pulse deposited (EPD) U-Cu NPs are linked to the bottom electrode through a semi-conductive path within the bottom Cu2O layer, since the EPD is preferentially carried out on the conductive sites. All Cu2O films with U-Cu NPs are developed in situ in the single electrolyte bath without any pause. The proposed U-Cu NPs can concentrate the external electric field and can generate conductive filament paths for analog resistive switching. The applied electric field was uniformly spread to U-Cu NPs at the center of the active layer and displays resistive switching behavior via multiple conductive filaments. This shows a strong harmony between the resistance-switching characteristics and the analog operation of the active layer. This RRAM device shows outstanding gradual analog switching, great linearity, dynamic range, endurance, precision, speed, and retention characteristics simultaneously and adequately for neuromorphic computing by realizing multiple weak filament-type operation.

NLRP3 inflammasome-mediated Pyroptosis induce Notch signal activation in endometriosis angiogenesis.

Endometriosis is characterized by the presence of endometrial tissue outside the uterus that not only causes severe pelvic pain and infertility but also increased risk for ovarian carcinogenesis in women of reproductive age. Here, we found that angiogenesis was increased and accompanied with up-regulation of Notch1 in human endometriotic tissue sample, which is associated with pyroptosis induced by activation of endothelial NLRP3 inflammasome. Further, in endometriosis model induced in wild type and NLRP3-deficient (NLRP3-KO) mice, we found that deficiency of NLRP3 suppressing the development of endometriosis. In vitro, inhibiting the activation of NLRP3 inflammasome prevents LPS/ATP-induced tube formation in endothelial cells. Meanwhile, knockdown NLRP3 expression by gRNA disrupt the interaction between Notch1 and HIF-1α under the inflammatory microenvironment. This study demonstrates that activation of NLRP3 inflammasome-mediated pyroptosis affects angiogenesis in endometriosis via Notch1-dependent manner.